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315 Study Matches

A Safety, Tolerability, and Efficacy Study of VX-880 in Participants With Type 1 Diabetes

This study will evaluate the safety, tolerability and efficacy of VX-880 infusion in participants with Type 1 diabetes mellitus (T1D) and impaired awareness of hypoglycemia (IAH) and severe hypoglycemia.
Jon Odorico, MD
All
18 Years to 65 Years old
Phase 1/Phase 2
This study is NOT accepting healthy volunteers
NCT04786262
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Key
Inclusion Criteria:

• Clinical history of T1D with > 5 years of duration
• At least two episodes of documented severe hypoglycemia in the 12 months prior to enrollment
• Stable diabetic treatment
• Consistent use of continuous glucose monitor (CGM) for at least 3 months before Screening and willingness to use CGM for the duration of the study Key
Exclusion Criteria:

• Prior islet cell transplant, organ transplant, or cell therapy Other protocol defined Inclusion/Exclusion criteria may apply
Diabetes Mellitus, Type 1, Impaired Hypoglycemic Awareness, Severe Hypoglycemia, Other specified diabetes mellitus, Other, Transplant
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Study of TJ033721 in Subjects With Advanced or Metastatic Solid Tumors

This is an open label, multi-center, multiple dose Phase 1 study to evaluate the safety, tolerability, MTD PK, and PD of TJ033721 in subjects with advanced or metastatic solid tumors.
Jeremy Kratz, MD
All
18 Years and over
Phase 1
This study is NOT accepting healthy volunteers
NCT04900818
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Inclusion Criteria:

• Subjects with advanced or metastatic solid tumor in subjects whose disease has progressed despite standard therapy, or who has no further standard therapy, or who is unsuitable for available standard treatment options.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 with adequate organ function
• Have known PD-L1 status with prior testing by immunohistochemistry and a corresponding combined positive score (CPS) For dose expansion study only:
• Advanced or metastatic gastric cancer, gastroesophageal junction carcinoma, and esophageal adenocarcinoma without further standard therapy or unsuitable for available standard treatment options.
• Must have CLDN18.2-positive tumor expression as determined by the CLDN18.2 IHC assay Exclusion Criteria
• Prior exposure to CLDN18.2 -targeted therapy
• Prior exposure to 4-1BB agonists
• Second malignancy within the last 3 years with the exception of cutaneous squamous cell carcinoma or cutaneous basal cell carcinoma or cervical carcinoma in situ
• Known active or chronic Hepatitis B or Hepatitis C, other hepatitides
• Unstable/active ulcer or digestive tract bleeding within 6 weeks
• Active autoimmune disease requiring systemic treatment within the past 2 years
• Active interstitial lung disease (ILD) or pneumonitis or a history of ILD or pneumonitis requiring treatment
• Known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment;
• New York Heart Association (NYHA) Class 3 or 4 congestive heart failure, severe/unstable angina, myocardial infarction (MI), symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack (TIA), arterial embolism, pulmonary embolism, percutaneous transluminal coronary angioplasty (PTCA), deep vein thrombosis, or coronary artery bypass grafting (CABG) in the previous 6 months
• Diagnosis of immunodeficiency such as known active HIV
• Any active infection requiring parenteral treatment
Solid Tumor, Advanced Cancer, Metastatic Cancer, Gastric Cancer, Gastroesophageal Junction Carcinoma, Esophageal Adenocarcinoma, Lip, Oral Cavity and Pharynx, Esophagus, Colon, Anus, Liver, Pancreas, Other Digestive Organ, Larynx, Lung, Other Respiratory and Intrathoracic Organs, Bones and Joints, Melanoma, Skin, Kaposi's Sarcoma, Breast, Cervix, Corpus Uteri, Other Female Genital, Other Male Genital, Kidney, Eye and Orbit, Brain and Nervous System, Other Endocrine System, Ill-Defined Sites, Anal, Brain/Central Nervous System, Colon and Rectum, Endocrine cancers, Gastrointestinal cancers, other, Genitourinary cancers, other, Head and Neck, Melanoma/Skin cancer, Ovary, Sarcoma, Uterus
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Evaluation of the GORE® EXCLUDER® Thoracoabdominal Branch Endoprosthesis in the Treatment of Thoracoabdominal and Pararenal Aortic Aneurysms (TAMBE)

Prospective, non-randomized, , multicenter study with two independent arms: - Primary Study Arm - TAAA and Pararenal aneurysms requiring only TAMBE System. Hypothesis-driven analysis. - Up to 65 additional subjects may be implanted in Continued Access Phase under the Primary Study Arm only - Secondary Study Arm - TAAA requiring TAMBE System and CTAG Device(s). Non hypothesis-driven analysis. Minimum: 122 implanted subjects. Maximum: 202 implanted subjects with up to 65 additional subjects implanted in Continued Access (Primary Study arm)
Dai Yamanouchi
All
19 Years and over
N/A
This study is NOT accepting healthy volunteers
NCT03728985
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Inclusion Criteria:
1. Aortic aneurysm involving the visceral vessels requiring treatment defined as at least one of the following:
• Fusiform aneurysm diameter ≥ 5 cm
• Saccular aneurysm (no diameter requirement)
• Rapid aneurysm growth (≥ 5 mm in one year) 2. Aortic aneurysm that involves the abdominal aorta, with:
• Involvement of at least one visceral vessel and aneurysmal extension as far as 65 mm proximal to the celiac artery, and/or
• No normal aorta between the upper extent of aneurysm and renal artery(s) 3. Adequate access for TAMBE Device components (femoral, axillary, and / or brachial arteries as required) 4. Age ≥ 19 years at the time of informed consent signature 5. Male or infertile female 6. Patient assessment favors an endovascular approach when compared to open surgical repair, as deemed by the treating physician 7. Capable of complying with protocol requirements, including follow-up 8. An Informed Consent Form signed by Subject or legal representative 9. Sufficient distal landing zones in both iliac arteries, with at least one patent internal iliac artery and without planned placement of a branched iliac device, or planned coverage/occlusion/embolization of any patent internal iliac artery. 10. Appropriate aortic anatomy to receive the TAMBE Device defined as all of the following:
• For the TAMBE aortic component, proximal aortic landing zone diameters between 22-34 mm
• Proximal seal zone ≥ 20 mm in length
• Aortic neck angle ≤ 60°
• Distal landing zone (iliac arteries) 8-25 mm
• Distal seal zone in iliac arteries of at least 10 mm in length
• Renal artery landing zone diameters between 4-10 mm
• Celiac and superior mesenteric artery landing zone diameters between 5-12 mm
• ≥ 15 mm landing zone in each branch vessel
• Landing zones in the proximal and distal aorta and all branch vessels cannot be aneurysmal, heavily calcified, or heavily thrombosed
• Patent left subclavian artery Secondary Study Arm Only: 11. If aneurysm extends greater than 65 mm above celiac artery, proximal extension with a CTAG Device is required. The aortic landing zone diameter treatment range with the CTAG Device is 19.5-32 mm 12. The most proximal aspect of the aneurysm is at least 2.0 cm distal to the left subclavian artery. 13. The most proximal aortic device seal zone will be within native aorta or a previously-deployed TAG or CTAG Device • Placement inside a Dacron graft or another device manufacturer's stent graft will not be supported
Exclusion Criteria:
The patient is / has: 1. Prior open, aortic surgery of the ascending aorta or aortic arch 2. Ruptured or leaking aortic aneurysm 3. Aneurysmal dilatation due to chronic aortic dissection 4. Infected aorta 5. Mycotic aneurysm 6. Life expectancy <2 years 7. Myocardial infarction or stroke within 1 year of treatment (staged or index procedure) 8. Systemic infection which may increase risk of endovascular graft infection 9. Degenerative connective tissue disease, e.g. Marfan's or Ehler-Danlos Syndrome 10. Participation in an investigational drug study (within 30 days of last administration) or investigational medical device study (within 1 year of implant) from the time of study screening 11. History of drug abuse, e.g. cocaine or amphetamine or alcohol, within 1 year of treatment 12. Tortuous or stenotic iliac and / or femoral arteries and the inability to use a conduit for vascular access 13. A branch vessel(s) that is dissected or has significant calcification, tortuosity, thrombus formation that would interfere with device delivery or ability to exclude from blood flow 14. Known sensitivities or allergies to the device materials 15. Previous instance of Heparin Induced Thrombocytopenia type 2 (HIT-2) or known hypersensitivity to heparin 16. Patient has body habitus or other medical condition which prevents adequate fluoroscopic and CT visualization of the aorta 17. Renal Insufficiency (creatinine value > 1.8 mg/dL, GFR < 30, or patient undergoing dialysis) 18. Known concomitant aneurysm of the ascending aorta or aortic arch anticipated to require surgical intervention within one year of study treatment
Thoracoabdominal aortic aneurysm, without rupture, Other, Heart & Vascular, Thoracoabdominal Aortic Aneurysm
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Androgen Deprivation, With or Without pTVG-AR, and With or Without T-Cell Checkpoint Blockade, in Patients With Newly Diagnosed, High-Risk Prostate Cancer

The current protocol will examine the use of a plasmid DNA vaccine encoding AR, alone or with T-cell checkpoint blockade, to induce and/or augment therapeutic T-cells following androgen deprivation in patients with newly diagnosed prostate cancer scheduled to undergo prostatectomy. Patients without evidence of metastatic disease, with tissue remaining from a pre-treatment biopsy, and who are being considered for standard treatment by prostatectomy, will be invited to participate and will be on study for up to 15 months.
Christos Kyriakopoulos, MD
Male
18 Years and over
Phase 1/Phase 2
This study is NOT accepting healthy volunteers
NCT04989946
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Inclusion Criteria:

• Histologically confirmed adenocarcinoma of the prostate
• Patients must be considered candidates for prostatectomy as per standard of care
• High-risk patients for recurrent disease, with high risk defined based on one of the following criteria:
• Gleason score 7 and baseline serum prostate specific antigen (PSA) > 20 ng/mL
• Gleason score > 7
• Life expectancy of at least 12 months at screening
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate hematologic, renal and liver function as evidenced by the following within 4 weeks of day 1:
• Absolute neutrophil count (ANC) > 1000 / mm3
• HgB > 9.0 gm/dL independent of transfusion
• Platelets > 100,000 / mm3
• Creatinine < 2.0 mg/dL
• Aspartate aminotransferase (AST), Alanine transaminase (ALT) < 2.5 x institutional upper limit of normal (ULN)
• Total bilirubin < 2x institutional ULN (NOTE: in subjects with Gilbert's syndrome, if total bilirubin is >2x ULN, measure direct and indirect bilirubin and if direct bilirubin is within normal range, subject may be eligible)
• No known history of HIV 1 and 2, HTLV-1, or active Hepatitis B or Hepatitis C
• Must have adequate tissue (ten 5µm unstained formalin-fixed paraffin-embedded (FFPE) sections containing prostate cancer) remaining from pre-treatment diagnostic prostate biopsy for research purposes
• Patients must be willing to undergo large-volume blood draws (up to 200mL per time point) for the investigational component of this trial
• For those patients who are sexually active, they must be willing to use barrier contraceptive methods during the period of treatment on this trial
• Patients must be informed of the experimental nature of the study and its potential risks, and must sign an IRB-approved written informed consent form indicating such an
• Ability to comply with all study procedures and willingness to remain supine for 120 minutes during imaging
Exclusion Criteria:

• Small cell or other variant (non-adenocarcinoma) prostate cancer histology
• Prior treatment for prostate cancer, including androgen deprivation therapy (ADT), orchiectomy, antiandrogens, ketoconazole, abiraterone acetate or enzalutamide
• Prior radiation to the prostate
• Patients may not be receiving other investigational agents or be receiving concurrent anticancer therapy other than the treatment-prescribed androgen deprivation therapy
• Treatment with any of the following medications while on study is prohibited, washout period not required except as indicated:
• Systemic corticosteroids (at doses over the equivalent of 10 mg prednisone daily)
•not permitted within 3 months of registration; inhaled, intranasal or topical corticosteroids are acceptable
• PC-SPES
• Herbal supplements that have been shown to modulate testosterone or androgen signaling (e.g. Saw Palmetto) are not allowed while on study
• Megestrol
• Ketoconazole
• 5-α-reductase inhibitors
•patients already taking 5-α-reductase inhibitors prior to 28 days prior to registration may stay on these agents throughout the course of therapy, but these should not be started while patients are on study
• Diethylstilbesterol
• Any other non-study hormonal agent or supplement being used with the intent of cancer treatment
• Major surgery within 4 weeks of registration is prohibited
• Active cardiac disease defined as active angina, symptomatic congestive heart failure, or myocardial infarction within 6 months of registration
• Patients with known psychological or sociological conditions, addictive disorders or family problems, which would preclude compliance with the protocol
• Patients who have undergone splenectomy
• Patients must not have other active malignancies other than non-melanoma skin cancers or carcinoma in situ of the bladder, that have been adequately treated. Subjects with a history of other cancers who have been adequately treated and have been recurrence-free for > 3 years are eligible.
• Any other medical intervention or condition, which, in the opinion of the principle investigator (PI) or treating physician, could compromise patient safety or adherence with the study requirements over the primary 3-6 month treatment period.
• Patients who have concurrent enrollment on other phase I, II, or III investigational treatment studies cannot be actively receiving treatment and the last dose cannot be within 4 weeks.
• Patients who have received a live vaccine within 14 days prior to the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
• Patients with a history of life-threatening autoimmune disease or active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Patients with a history of non-infectious pneumonitis that required corticosteroid treatment, or has current pneumonitis
• Patients with a history of allergic reactions to the tetanus vaccine
Prostate Cancer, Prostate
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Open-label Study Comparing Iberdomide, Daratumumab and Dexamethasone (IberDd) Versus Daratumumab, Bortezomib, and Dexamethasone (DVd) in Participants With Relapsed or Refractory Multiple Myeloma (RRMM) (EXCALIBER-RRMM)

This is a multicenter, two-stage, randomized, controlled, open-label, Phase 3 study comparing the efficacy and safety of iberdomide in combination with dexamethasone and daratumumab (IberDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in participants with relapsed or refractory multiple myeloma (RRMM).
Timothy Schmidt, MD
All
18 Years and over
Phase 3
This study is NOT accepting healthy volunteers
NCT04975997
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Inclusion Criteria
• Documented diagnosis of multiple myeloma (MM) and measurable disease.
• Received 1 to 2 prior lines of anti-myeloma therapy.
• Must have documented disease progression during or after their last anti-myeloma regimen.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2. Exclusion Criteria
• Any condition that confounds the ability to interpret data from the study.
• Has plasma cell leukemia, Waldenstrom's macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or clinically significant amyloidosis.
• Known central nervous system involvement with MM.
• Prior therapy with iberdomide.
• Other protocol-defined Inclusion/Exclusion criteria apply.
Multiple Myeloma
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Botox for the Treatment of Recurrent Chronic Exertional Compartment Syndrome

10 participants with Recurrent Chronic Exertional Compartment Syndrome (R-CECS) will be enrolled in a 6 month study at the University of Wisconsin Hospitals and Clinics to test the hypothesis that injection of Botox into the affected muscle group will alleviate pain associated with R-CECS.
Michael Suer
All
18 Years and over
Phase 4
This study is NOT accepting healthy volunteers
NCT05006417
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Inclusion Criteria:

• Willing to provide written informed consent
• Willing to comply with all study procedures and be available for the duration of the study
• Documented diagnosis of R-CECS determined with elevated compartmental pressure testing following lower extremity fascia release (fasciotomy or fasciectomy)
• Females of childbearing potential must have a negative urine pregnancy test prior to enrollment and agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to randomization, for the duration of study participation, and for 7 days following completion of therapy.
• A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
Exclusion Criteria:

• History of hypersensitivity or allergy to any of the study drugs or drugs of similar chemical classes
• Known neuromuscular disease
• Known pulmonary disease including but not limited to asthma, pneumonia, or upper respiratory tract infection
• Dysphagia
• Known cardiac disease including but not limited to congestive heart failure, arrhythmia, or history of myocardial infarction
• Enrolled in another clinical trial or has used of any investigational drugs, biologics, or devices within 30 days prior to enrollment
• Currently or have taken in the past medications that affect neuromuscular function, aminoglycosides, muscle relaxants, or other botulinum neurotoxin agents. Currently taking any blood-thinning medications including, but not limited to Plavix, Coumadin, Eliquis, Xarelto
• Women who are pregnant or breast-feeding
• Vulnerable populations
• Not suitable for study participation due to other reasons at the discretion of the investigator
Certain early complications of trauma, Other, Compartment Syndrome of Leg
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T-DM1 and Tucatinib Compared With T-DM1 Alone in Preventing Relapses in People With High Risk HER2-Positive Breast Cancer, the CompassHER2 RD Trial

This phase III trial studies how well trastuzumab emtansine (T-DM1) and tucatinib work in preventing breast cancer from coming back (relapsing) in patients with high risk, HER2 positive breast cancer. T-DM1 is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called DM1. Trastuzumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors, and delivers DM1 to kill them. Tucatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving T-DM1 and tucatinib may work better in preventing breast cancer from relapsing in patients with HER2 positive breast cancer compared to T-DM1 alone.
Kari Wisinski, MD
All
18 Years and over
Phase 3
This study is NOT accepting healthy volunteers
NCT04457596
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Inclusion Criteria:

• HER2-positive status will be based on pretreatment biopsy material and defined as an immunohistochemistry (IHC) score of 3+ and/or positive by in situ hybridization (ISH) according to current American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines. Central testing is not required * Known hormone receptor (HR) status as defined by ASCO/CAP guidelines (based on pretreatment biopsy material). Hormone receptor positive status can be determined by either known positive estrogen receptor (ER) or known positive progesterone receptor (PR) status; hormone receptor negative status must be determined by both known negative ER and known negative PR
• Patients with clinical stage T1-4, N0-3 disease at presentation and residual invasive disease postoperatively as defined above are eligible. (Note: Patients with T1a/bN0 tumors are not eligible at initial breast cancer diagnosis are not eligible)
• Patients with residual HR-negative, HER2 positive (+) disease in the breast and/or lymph nodes per the surgical pathology report are eligible; however, patients with HR+ HER2+ cancers must have node-positive residual disease per the surgical pathology report in order to qualify for the study. The presence of residual invasive disease in the breast is not mandatory for these patients
• Patients with weakly ER-positive (1-10%) breast cancer (based on the pretreatment core biopsy) are eligible even if they have node-negative disease per the surgical pathology report
• The residual disease tissue (breast and/or lymph nodes) is not required to be HER2-positive, as eligibility for NCI-2020-03770 (A011801) is based on a positive HER2 status at the time of the initial breast cancer diagnosis * Note: The presence of micrometastases in lymph nodes after preoperative therapy counts as residual disease, whereas the presence of isolated tumor cells does not
• Patients with synchronous bilateral invasive disease are eligible provided both lesions were confirmed to be HER2-positive, and at least one of the lesions meets the criteria outlined above. Multifocal disease is allowed, as long as the largest biopsied breast tumor was HER2-positive
• Patients must have received neoadjuvant chemotherapy with one of the following regimens: docetaxel/trastuzumab/pertuzumab (THP), paclitaxel/methotrexate/cisplatin (TMP), doxorubicin/cyclophosphamide/paclitaxel/trastuzumab/pertuzumab (AC-TH(P)); docetaxel/carboplatin/trastuzumab/pertuzumab (TCH(P)); fluorouracil/doxorubicin/cyclophosphamide-docetaxel/trastuzumab/pertuzumab (FAC-TH(P)), or fluorouracil/epirubicin/cyclophosphamide-docetaxel/trastuzumab/pertuzumab (FEC-TH(P)). Note: apart from TCHP, where T is docetaxel, treatment with docetaxel or paclitaxel is acceptable
• Prior receipt of T-DM1 in the neoadjuvant setting is not allowed.
• Prior treatment must have consisted of >= 6 cycles of chemotherapy and HER2-directed therapy, with a total duration of >= 12 weeks, including at least 9 weeks of preoperative taxane and trastuzumab with or without pertuzumab (or Food and Drug Administration [FDA]-approved biosimilars). Patients who have received at least 9 weeks of preoperative taxane, pertuzumab and margetuximab are also eligible if they received >= 6 cycles of systemic therapy prior to enrollment. Note: Patients who complete at least nine of a planned twelve doses of weekly paclitaxel, or three of a planned four doses of docetaxel, but discontinue prematurely due to toxicity are eligible. Patients receiving dose-dense chemotherapy regimens are also eligible. Prior use of nab-paclitaxel (Abraxane) instead of paclitaxel or docetaxel is permitted. Prior use of subcutaneous trastuzumab (Hylecta) and subcutaneous trastuzumab and pertuzumab (Phesgo) is also allowed.
• Patients who received neoadjuvant systemic therapy which included experimental HER2-targeted therapy/therapies are potentially eligible, as long as the investigational agent was not a HER2-targeted antibody-drug conjugate (e.g. T-DM1, DS-8201a [trastuzumab deruxtecan]) or a HER2 targeted tyrosine kinase inhibitor (TKI) (e.g. tucatinib, lapatinib, neratinib).
• Patients may have received =< 1 cycles of T-DM1 in the adjuvant setting. Note: These patients will be randomized to receive a further 14 cycles of T-DM1 and tucatinib/placebo as tolerated. The most recent cycle of T-DM1 should have been administered =< 5 weeks prior to registration * Note: Both of the following two criteria need to be met for the patient to be eligible for this study
• An interval of no more than 12 weeks between the completion date of the last definitive treatment (e.g. postoperative chemotherapy or radiation, or if neither given, breast surgical date) and the date of registration. Concurrent radiation therapy is permitted while receiving study treatment
• Patients must be registered on study within =< 180 days of the date of the most recent definitive breast cancer surgery (not including reconstructive surgery)
• All systemic chemotherapy should have been completed preoperatively unless participating in EA1181 (CompassHER2 pathologic complete response [pCR]) or the BIG DECRESCENDO Trial (which is very similar to CompassHER2 pCR in terms of study design, drugs, and eligibility). However, patients who received 4 cycles of neoadjuvant THP off study can receive a further 2-4 cycles of chemotherapy postoperatively to meet eligibility for A011801. Patients who participated in EA1181 or MA41 and proceeded to surgery immediately after the de-escalated trial regimen must receive postoperative chemotherapy to complete a total of >= 6 cycles of systemic treatment prior to enrollment on A011801, as outlined above (e.g. 4 cycles pre-operatively, and 2 cycles post-operatively). The postoperative chemotherapy regimen prescribed is at the discretion of the treating oncologist (i.e. 2-4 cycles AC or THP, other). Continuation of trastuzumab + pertuzumab (HP) pre- or post-operatively as maintenance therapy (while awaiting a surgical date or an official pathology report) is allowed for all study participants
• Toxicities related to prior systemic treatment should have resolved or be at baseline, apart from alopecia and peripheral neuropathy =< grade 1
• Adequate excision: surgical removal of all clinically evident disease in the breast and lymph nodes as follows:
• Breast surgery: total mastectomy with no gross residual disease at the margin of resection, or breast-conserving surgery with histologically negative margins of excision
• For patients who undergo breast-conserving surgery, the margins of the resected specimen must be histologically free of invasive tumor and ductal carcinoma in situ (DCIS) as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional operative procedures may be performed to obtain clear margins. If tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible. Patients with margins positive for classic lobular carcinoma in situ (LCIS) are eligible without additional resection
• Lymph node surgery ** The axilla needs to be evaluated with either sentinel node biopsy or axillary lymph node dissection. If patients have a sentinel lymph node biopsy and sentinel nodes are negative, no further axillary treatment is necessary. If patients have isolated tumor cells (ITCs) in the setting of residual breast disease, at least one of the following is required: axillary lymph node dissection (ALND) or planned nodal irradiation. If patients have micro- or macro-metastatic nodal disease, ALND and planned nodal irradiation are required. Of note, co-enrollment on Alliance A011202 is not allowed
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Absolute neutrophil count (ANC) >= 1,000/mm^3
• Hemoglobin >= 8 g/dL (Note: packed red blood cells [PRBC] transfusion is not permitted to achieve eligibility)
• Platelet count >= 100,000/mm^3
• Creatinine =< 1.5 x upper limit of normal (ULN)
• Total bilirubin =< 1.0 x upper limit of normal (ULN) or direct bilirubin within the institutional normal range for patients with Gilbert's syndrome
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• Screening left ventricular ejection fraction (LVEF) >= 50% on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) after receiving neoadjuvant chemotherapy and no decrease in LVEF by more than 15% absolute percentage points from the pre-chemotherapy LVEF. Or, if pre-chemotherapy LVEF was not assessed, the screening LVEF must be >= 55% after completion of neoadjuvant chemotherapy. Note: LVEF assessment may be repeated once up to 3 weeks following the initial screening assessment to assess eligibility
Exclusion Criteria:

• No adjuvant treatment with any anti-cancer investigational drug within 28 days prior to registration
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative serum pregnancy test done =< 7 days prior to registration is required
• Patients with known active and/or untreated hepatitis B or hepatitis C or chronic liver disease are ineligible. Patients with a diagnosis of hepatitis B or C that has been treated and cleared and normal liver function are eligible to participate in the study if the other eligibility parameters are met
• Stage IV (metastatic) breast cancer
• History of any prior (ipsi- or contralateral) invasive breast cancer within 3 years of registration
• Patients with ER+ HER2+ residual invasive disease that is lymph node-negative per the surgical pathology report
• Evidence of recurrent disease following preoperative therapy and surgery
• Patients for whom radiotherapy would be recommended for breast cancer treatment but for whom it is contraindicated because of medical reasons (e.g., connective tissue disorder or prior ipsilateral breast radiation)
• History of exposure to the following cumulative doses of anthracyclines: doxorubicin > 240 mg/m^2; epirubicin or liposomal doxorubicin-hydrochloride (Myocet) > 480 mg/m^2. For other anthracyclines, exposure equivalent to doxorubicin > 240 mg/m^2
• Cardiopulmonary dysfunction as defined by any of the following:
• History of National Cancer Institute (NCI) CTCAE version (v) 5.0 grade >= 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) criteria class >= II
• Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality, or clinically significant valvular disease
• High-risk uncontrolled arrhythmias: i.e., atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade atrioventricular block (AV)-block (second degree AV-block type 2 [Mobitz 2] or third degree AV-block)
• Significant symptoms (grade >= 2) relating to left ventricular dysfunction, cardiac arrhythmia, or cardiac ischemia while or since receiving preoperative therapy
• History of a decrease in left ventricular ejection fraction (LVEF) to < 40% with prior trastuzumab treatment (e.g., during preoperative therapy)
• Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood pressure > 100 mmHg)
• Current severe, uncontrolled systemic disease
• Major surgical procedure unrelated to breast cancer or significant traumatic injury within 28 days prior to registration or anticipation of the need for major surgery during the course of study treatment
• History of intolerance, including grade 3 to 4 infusion reaction or hypersensitivity to trastuzumab or murine proteins or any components of the product
• Peripheral neuropathy of any etiology that exceeds grade 1
• Assessment by the investigator as being unable or unwilling to comply with the requirements of the protocol
• Use of a strong CYP3A4 or CYP2C8 inhibitor within 2 weeks, or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to registration is prohibited.
• Please note that use of sensitive CYP3A substrates should be avoided two weeks before registration and during study treatment. Additionally, CYP3A4 or CYP2C8 inducers are prohibited as concomitant medications within 5 days following discontinuation of tucatinib treatment. Patients who require medications that are known to be sensitive substrates of CYP3A4 with a narrow therapeutic window should be excluded.
Breast, Anatomic Stage IA Breast Cancer AJCC v8, Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage IIA Breast Cancer AJCC v8, Anatomic Stage IIB Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8, Anatomic Stage IIIB Breast Cancer AJCC v8, Anatomic Stage IIIC Breast Cancer AJCC v8, HER2 Positive Breast Carcinoma, Invasive Breast Carcinoma, Multifocal Breast Carcinoma, Prognostic Stage I Breast Cancer AJCC v8, Prognostic Stage IA Breast Cancer AJCC v8, Prognostic Stage IB Breast Cancer AJCC v8, Prognostic Stage II Breast Cancer AJCC v8, Prognostic Stage IIA Breast Cancer AJCC v8, Prognostic Stage IIB Breast Cancer AJCC v8, Prognostic Stage III Breast Cancer AJCC v8, Prognostic Stage IIIA Breast Cancer AJCC v8, Prognostic Stage IIIB Breast Cancer AJCC v8, Prognostic Stage IIIC Breast Cancer AJCC v8, Synchronous Bilateral Breast Carcinoma
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Sustained Humoral and Cell-Mediated Immunogenicity of COVID-19 Vaccines in Patients With Inflammatory Bowel Disease

The aim of this study is to determine the impact of systemic immunosuppression on sustained antibody COVID-19 concentrations in patients with IBD who received a COVID-19 vaccine.
Freddy Caldera
All
18 Years to 85 Years old
N/A
This study is NOT accepting healthy volunteers
NCT05014555
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A patient will be eligible for inclusion in this study if he or she meets all the following criteria:
• Patient is between the ages of 18-85 years, inclusive
• Patient has a history of ulcerative colitis (UC), or Crohn's disease diagnosed by standard clinical, radiographic, endoscopic, and histopathologic criteria
• On one of the following treatment regimens for at least three months at the time of immunization and continued same therapy at the time of recruitment. Should be on stable doses defined as: Group A should have taken a dose of medication within the past week; Group B infliximab within the previous 8 weeks, golimumab within the previous 4 weeks, adalimumab within the previous 2 weeks, or certolizumab within the previous 4 weeks; Those on combination therapy in group B will have taken azathioprine or methotrexate within the past week. Group C ustekinumab at least within the previous 4 weeks. Those on combination therapy in group C will have taken azathioprine or methotrexate within the past week; Group D vedolizumab at least within the previous 4 weeks. Those on combination therapy in group D will have taken azathioprine or methotrexate within the past week
• Group A non-biologic group: mesalamine monotherapy or thiopurine monotherapy
• Group B: Anti-TNF Therapy Group: on maintenance therapy infliximab (at least 5mg/kg every 8 weeks), golimumab (at least monthly), adalimumab (at least every 2 weeks), or certolizumab (at least monthly Combination Therapy Anti- TNF Combination Therapy Group: on anti-TNF therapy as described above along with either 15mg of methotrexate or azathioprine at least 1.0mg/kg or 6MP 0.5mg/kg at least 40% of the group; Approximately 40-50% of the group will be combination therapy
• Group C: Ustekinumab on either ustekinumab monotherapy or combination therapy with methotrexate or azathioprine
• Group D: Vedolizumab Therapy Group: Vedolizumab Therapy: on either vedolizumab monotherapy or combination therapy with methotrexate or azathioprine
• Patient received at least two doses of mRNA COVID-19 vaccine per standard of care A patient will not be eligible for inclusion in this study if he or she meets all the following criteria:
• Patient cannot or will not provide written informed consent
• Unable to provide appropriate informed consent due to being illiterate or impairment in decision-making capacity
• Received a COVID-19 booster within the previous 28 days
Inflammatory Bowel Diseases, Other
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BK With VST for Kidney Transplant Patients

This study measures the safety, feasibility, and efficacy of viral-specific T cells (VST) against BK Virus (BKV) in adult kidney transplant recipients. Participants are expected to be on study for 52 weeks.
Sandesh Parajuli
All
18 Years to 75 Years old
Phase 1
This study is also accepting healthy volunteers
NCT05042076
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Inclusion Criteria:

• Age18 ≤ 75 years
• Have BKV infection/viremia following kidney transplantation, where BKV viremia is defined as positive BKV qPCR (≥ 250 copies)
• Have evidence of invasive BKV infection (BK Nephropathy)
• Experience one of the following:
• New, persistent and/or worsening BKV-related symptoms, signs and/or markers of end organ compromise despite being on lower immunosuppressive medication
• Adverse effects of lower immunosuppressive medications (e.g., dnDSA, biopsy proven rejection)
• Eligible Donor
• Provide Written informed consent
Exclusion Criteria:

• Non-kidney organ transplant recipient
• Patient with acute rejection of the kidney allograft at time of T-cell transfer
• Patient receiving steroids (>0.5 mg/kg body weight (BW) prednisone equivalent) at the time of T-cell transfer
• Patient treated with Thymoglobulin (ATG), Alemtuzumab or T-cell immunosuppressive monoclonal antibodies within 28 days prior to T-cell transfer
• Extra renal tissue invasive BK infection
• Concomitant enrollment in another clinical trial interfering with endpoints of this study
• Any medical condition which could compromise participation in the study according to the investigator's assessment
• Known HIV infection
• Female patient who is pregnant or breast-feeding, or adult of reproductive potential not willing to use an effective method of birth control during study treatment Note: Women of childbearing potential must have a negative urine pregnancy test at study entry.
• Patients unwilling or unable to comply with the protocol or unable to give informed consent Donor Eligibility
• ≥ 18 years old
• Available and capable of undergoing a single standard 2 blood volume leukapheresis
• HLA Compatible (see Donor selection priority below):
• Original kidney transplant donor
• Fully HLA matched family member (6/6 HLA match considering HLA-A, HLA-B and HLA-DRB1 genes)
• Partially matched family member (≥ 2/6 HLA match, considering HLA-A, HLA-B and HLA-DRB1 genes)
• BK IgG seropositive
• Meets the criteria for donor eligibility defined in the UW Program for Advanced Cell Therapy Standard Operating Policies and Procedures for Donor Evaluation and Eligibility Determination for the Donation of Viral Specific T Cells, which is in compliance with FACT standards for Immune Effector Cells, and 21 CFR 1271, subpart C.
• Provide written informed consent Donor selection priority: The original kidney donor will be the first choice of donor peripheral mononuclear cells. If the original donor is not available or does not meet all donor eligibility criteria, alternative related donors will be selected, with preference for fully matched related donors (6/6 HLA match, considering HLA-A, -B, and -DRB1 genes) over related donors with partial HLA match (≥ 2/6 HLA match, considering HLA-A, -B, and -DRB1 genes). Note that if the selected donor is related, but not a biological parent or child of the recipient (i.e., at least haploidentical), then high resolution testing of HLA-A and HLA-B will be performed on donor and recipient (if high resolution HLA genotyping not already available in the medical record). If the degree of matching at high resolution reveals a less favorable match than an alternative donor, then prioritization of the alternative donor will occur.
Kidney replaced by transplant, Other, Kidney Transplant Infection, BK Virus Infection, Infections, Immune System & Allergies, Kidney Disease & Urinary
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Pivotal 1 Study of RGX-314 Gene Therapy in Participants With nAMD (ATMOSPHERE)

RGX-314 is being developed as a novel one-time gene therapy for the treatment of neovascular (wet) age-related macular degeneration (wet AMD). Wet AMD is characterized by loss of vision due to new, leaky blood vessel formation in the retina. Wet AMD is a significant cause of vision loss in the United States, Europe and Japan, with up to 2 million people living with wet AMD in these geographies alone. Current anti-VEGF therapies have significantly changed the landscape for treatment of wet AMD, becoming the standard of care due to their ability to prevent progression of vision loss in the majority of patients. These therapies, however, require life-long intraocular injections, typically repeated every four to 12 weeks in frequency, to maintain efficacy. Due to the burden of treatment, patients often experience a decline in vision with reduced frequency of treatment over time. RGX-314 is being developed as a potential one-time treatment for wet AMD.
Jonathan Chang
All
50 Years to 89 Years old
Phase 2/Phase 3
This study is NOT accepting healthy volunteers
NCT04704921
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Inclusion Criteria:
1. Age ≥ 50 years and ≤ 89 years 2. An ETDRS BCVA letter score between ≤ 78 and ≥ 40 in the study eye 3. Diagnosis of subfoveal CNV secondary to AMD in the study eye previously treated with anti-VEGF 4. Must be pseudophakic (at least 12 weeks postcataract surgery) in the study eye. 5. Willing and able to provide written, signed informed consent for this study 6. Participants must have demonstrated a meaningful response to anti-VEGF therapy at study entry
Exclusion Criteria:
1. CNV or macular edema in the study eye secondary to any causes other than AMD 2. Subfoveal fibrosis or atrophy in the study eye 3. Any condition in the investigator's opinion that could limit VA improvement in the study eye 4. Active or history of retinal detachment in the study eye 5. Uncontrolled glaucoma in the study eye 6. History of intraocular surgery in the study eye within 12 weeks prior to Screening Visit 1 7. History of intravitreal therapy in the study eye, such as intravitreal steroid injection or investigational product, other than anti-VEGF therapy, in the 6 months prior to Screening Visit 1. 8. Prior treatment with gene therapy. 9. Recent myocardial infarction, cerebrovascular accident, or transient ischemic attack within the past 6 months.
AMD, nAMD, Wet Age-related Macular Degeneration, wAMD, Wet AMD, CNV, Exudative age-related macular degeneration, Other, Eye & Vision
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APOLLO: A Randomized Phase II Double-Blind Study of Olaparib Versus Placebo Following Curative Intent Therapy in Patients With Resected Pancreatic Cancer and a Pathogenic BRCA1, BRCA2 or PALB2 Mutation

This phase II trial investigates how well the addition of olaparib following completion of surgery and chemotherapy works in treating patients with pancreatic cancer that has been surgically removed (resected) and has a pathogenic mutation in BRCA1, BRCA2, or PALB2. Olaparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep tumor cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy.
Monica Patel
All
18 Years and over
Phase 2
This study is NOT accepting healthy volunteers
NCT04858334
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Inclusion Criteria:

• STEP 0 (PRE-REGISTRATION) INCLUSION CRITERIA
• Patient must be >= 18 years of age on day of consent
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Patient must have a diagnosis of pancreatic cancer and have successfully undergone a curative intent surgical resection and must have no evidence of recurrent disease as determined by the investigator
• NOTE: This includes patients with adenocarcinoma, acinar carcinoma, squamous cell carcinoma adenosquamous and variants thereof. Patients with neuroendocrine tumors are excluded from enrolling
• Patient must (1) be planning to receive, (2) be receiving or (3) have received at least three combined months (i.e., 12 weeks) of perioperative (neoadjuvant, adjuvant or a combination of both) systemic, multi-agent chemotherapy. Patients may have had up to 6 months of perioperative systemic therapy as deemed appropriate by their primary treating medical team (patients can have received radiation or chemoradiation in addition to this 6 month course)
• Patient must be no more than 12 weeks from their most recent treatment (this may be chemotherapy, radiotherapy or surgery)
• Patient must have a known pathogenic or likely pathogenic germline or somatic mutation in BRCA1, BRCA2, or PALB2, as determined by a Clinical Laboratory Improvement Amendments (CLIA) certified or equivalently-accredited laboratory. Mutations must be considered pathogenic or likely pathogenic by a reference database such as ClinVar or OncoKb.org
• STEP 1 (RANDOMIZATION) INCLUSION CRITERIA
• Patient must have met the eligibility criteria outlined above
• Patient must have undergone at least 3 combined months (i.e., 12 weeks) of perioperative (neoadjuvant, adjuvant or a combination of both) systemic, multi-agent chemotherapy. Patients may have had up to 6 months of perioperative systemic therapy as deemed appropriate by their primary treating medical team (patients can have received radiation or chemoradiation in addition to this 6 months course)
• Central expert reviewer must have determined the patient eligible for randomization after review of local genetic testing reports
• If mutation in BRCA1, BRCA2 or PALB2 was identified in tumor tissue and the patient has not previously undergone germline testing, the patient must agree to undergo germline testing
• Patient must have no evidence of recurrent or metastatic pancreatic cancer at the time of randomization as documented by baseline scans obtained =< 4 weeks prior to Step 1 randomization
• Patient must not have previously had evidence of progressive pancreatic cancer while receiving platinum-based therapy
• Patient must be >= 21 days (three weeks) from their last treatment (including chemotherapy radiotherapy or surgery) but =< 84 days (twelve weeks) from their last treatment at the time of Step 1 randomization. Patients who have received neoadjuvant and/or adjuvant radiotherapy are eligible
• Patient must have recovered from any adverse events due to prior anti-cancer therapy (i.e., have no residual toxicities > grade 1 with the exception of alopecia and/or neuropathy)
• Patient must not be receiving any other investigational agents at the time of Step 1 randomization and while on protocol treatment
• Patient must not have any history of allergic reactions attributed to compounds of similar chemical or biological composition to olaparib
• Patient must not have any personal history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML.
• Patient must not have any uncontrolled gastrointestinal disorder that would, in the opinion of the investigator, interfere with the ingestion or absorption of olaparib
• Patient must not be pregnant or breast-feeding due the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to Step 1 randomization to rule out pregnancy. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Patients must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and for 6 months after the last dose of protocol treatment for female patients and for 3 months after the last dose of protocol treatment for male patients. Patients must also not donate sperm while on protocol treatment and for 3 months after the last dose of protocol treatment. Patients must also not breast-feed while on protocol treatment and for 1 month after the last dose of protocol treatment
• Leukocytes >= 3,000/mcL (obtained =< 28 days prior to Step 1 randomization)
• Absolute neutrophil count >= 1,500/mcL (obtained =< 28 days prior to Step 1 randomization)
• Platelets >= 100,000/mcL (obtained =< 28 days prior to Step 1 randomization)
• Hemoglobin >= 9.0 g/dL with no blood transfusion in the past 28 days (obtained =< 28 days prior to Step 1 randomization)
• Total bilirubin =< 1.5 institutional upper limit of normal (ULN) except in patients with Gilbert's syndrome. Patients with Gilbert's syndrome may enroll if direct bilirubin =< 2.5 x ULN of the direct bilirubin (obtained =< 28 days prior to Step 1 randomization)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 institutional ULN (obtained =< 28 days prior to Step 1 randomization)
• Creatinine =< 1.5 institutional ULN OR calculated Cockcroft Gault creatinine clearance > 50 mL/min/1.73 m^2 (obtained =< 28 days prior to Step 1 randomization)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patient must not have resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g. unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT [QTc] prolongation > 500 ms, electrolyte disturbances, etc.) or have congenital long QT syndrome
• Concomitant use of known potent CYP3A4/5 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir is prohibited
• Patients who are being actively treated for an ongoing concurrent malignancy are ineligible, with the exception of those receiving adjuvant hormone therapies and those receiving topical therapies for skin cancers
• Patient must not have, in the opinion of the investigator, any other concurrent medical condition that would prevent the patient from complying with the study procedures
• Patient must not be considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent
• Patient must have the ability to understand and the willingness to sign a written informed consent document, or have legally authorized representative provide authorization to participate
• Patient must not have had major surgery within 2 weeks prior to Step 1 randomization and patients must have recovered from any effects of any major surgery
Pancreas, Pancreatic Acinar Cell Carcinoma, Pancreatic Adenosquamous Carcinoma, Pancreatic Squamous Cell Carcinoma, Resectable Pancreatic Acinar Cell Carcinoma, Resectable Pancreatic Adenocarcinoma, Resectable Pancreatic Adenosquamous Carcinoma, Resectable Pancreatic Carcinoma
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A Study of ARV-766 Given by Mouth in Men With Metastatic Prostate Cancer

A Phase 1/2 study to evaluate the safety and efficacy of ARV-766 given by mouth alone or in combination with abiraterone in men with metastatic prostate cancer.
Joshua Lang, Post Grad
Male
18 Years and over
Phase 1/Phase 2
This study is NOT accepting healthy volunteers
NCT05067140
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Inclusion Criteria:
Part A,B,C and D:
• Histological, pathological, or cytological confirmed diagnosis of adenocarcinoma of the prostate.
• Ongoing androgen deprivation therapy (ADT) with a gonadotropin releasing hormone analog or inhibitor, or orchiectomy (surgical or medical castration).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Part A:
• Progression on at least 2 prior approved systemic therapies for metastatic prostate cancer (at least one must be a second-generation androgen inhibitor, e.g., abiraterone, enzalutamide, darolutamide, apalutamide).
• Progressive mCRPC Part B:
• Participants must have received at least one but no more than three prior second generation anti-androgen agents (e.g., enzalutamide or abiraterone).
• Participants must have received no more than two prior chemotherapy regimens.
• Progressive mCRPC Part C & D: • Metastatic castration resistant or sensitive prostate cancer with radiographic evidence of metastatic disease
Exclusion Criteria:
Part A and B:
• Known symptomatic brain metastases requiring steroids (above physiologic replacement doses).
• Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease, or previous gastric resection or lap band surgery.
• Radiation therapy within 4 weeks of first dose of study drug or prior irradiation to >25% of the bone marrow.
• Receipt of an investigational drug(s) within 4 weeks prior to anticipated first dose
• Systemic anti-cancer therapy within 2 weeks of first dose of study drug (except agents to maintain castrate status). For bicalutamide, mitomycin C, or nitrosoureas the exclusion period must be 6 weeks and for abiraterone 4 weeks. Part C and D • Prior treatment with a second generation NHA
Prostate Cancer Metastatic, Prostate
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CardiAMP Cell Therapy Chronic Myocardial Ischemia Trial (CardiAMP CMI)

Prospective, multi-center, 2:1 randomized (Treatment : Sham Control), sham-controlled, double-blinded trial to compare treatment using the CardiAMP cell therapy system to sham treatment Treatment Group: Subjects treated with aBMC using the CardiAMP cell therapy system Sham Control Group: Subjects treated with a Sham Treatment (no introduction of the Helix transendocardial delivery catheter, no administration of aBMC)
Amish Raval, MD
All
21 Years to 80 Years old
N/A
This study is NOT accepting healthy volunteers
NCT03455725
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Inclusion Criteria:
1. Male or female 21 to 80 years of age 2. Canadian Cardiovascular Society (CCS) class III or IV chronic refractory angina. 3. Lack of control of angina symptoms despite maximum tolerated doses of anti-angina drugs. 4. Evidence of inducible myocardial ischemia on baseline stress testing 5. Obstructive coronary disease unsuitable for conventional revascularization 6. Experience angina episodes at a minimum of 7 angina episodes per week (during a 4-week screening period). 7. Able to complete an exercise tolerance test on the treadmill 8. Left ventricular ejection fraction of greater than or equal to 40% as measured by echocardiography. 9. Qualification of a pre-procedure screening of bone-marrow aspiration Exclusion Criteria Other cardiac or vascular system or other health-related criteria which may be seen in a patient's history and physical examination.
Refractory Angina, Chronic Myocardial Ischemia, Chronic ischemic heart disease, Other, Heart & Vascular
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Assessment of Safety and Effectiveness of NovoSorb® BTM in Severe Burns

This is a multi-center, pivotal study to assess the safety and effectiveness of a new method of treating severe burns using NovoSorb® Biodegradable Temporizing Matrix (BTM).
Angela Gibson
All
18 Years to 75 Years old
N/A
This study is NOT accepting healthy volunteers
NCT04090424
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Inclusion Criteria:
1. Provide written informed consent directly or via legal representative prior to any clinical study procedures being performed 2. Willing to comply with all study procedures and expects to be available for the duration of the study 3. Male and females ≥ 18 years of age and ≤ 75 years of age 4. Patients with deep dermal or full thickness burns between 3% and 60%, inclusive, of their total body surface area (TBSA). Types of burns include the following:
• Scalding including from hot water, cooking oil, grease
• Flame
• Flash
• Contact 5. Subjects who have staged surgical procedures planned e.g., one procedure to excise the burn injury and a later procedure to prepare the wound bed and apply an autologous skin graft. 6. The minimum total area across all lesions to have NovoSorb® BTM applied is 3% TBSA 7. Females, who are non-pregnant, naturally postmenopausal, or who agree to use effective contraceptive methods throughout the course of the study.
Exclusion Criteria:
1. Has a known hypersensitivity to polyurethane 2. Only a non-burn injury has been experienced by the subject including soft-tissue degloving and friction burn/crush, i.e., road rash 3. Multiple traumas, i.e., significant traumatic injury to a solid organ in addition to skin 4. Presence of a medical condition with a life expectancy of less than 12 months, such as advanced malignancy 5. Presence of a medical condition that might interfere with treatment evaluation; or require a change in therapy including but not limited to, significant immune deficiency, or skin or vascular diseases in the area of the wound 6. For females
•has known or suspected pregnancy, planned pregnancy, or during lactation 7. Has exposure to any other investigational agent within the last 6 months 8. Has exposure to any other treatment/device that will interfere with NovoSorb® BTM integration 9. Anticipated inability to perform wound care and follow-up procedures 10. Anticipates of a level of non-compliance 11. The use of off-label treatments for full-thickness / deep-dermal burns is not permitted 12. Clinical signs of wound infection at areas to be potentially treated using NovoSorb® BTM that in the opinion of the investigator may compromise safety and study objectives 13. The use of NovoSorb® BTM on the face and in the perineum area is not permitted
Burns, Burns and corrosions of external body surface, Other, Injury, Trauma & Emergency Medicine
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Ultrasound-facilitated, Catheter-directed, Thrombolysis in Intermediate-high Risk Pulmonary Embolism (HI-PEITHO)

There are many available treatments for pulmonary embolism (PE), but the best treatment for this condition is not known. The HI-PEITHO study will compare two treatment options that are both available on the market for the treatment of PE. Patients will be randomized 1:1 to receive either blood thinners (anticoagulation) or blood thinners (anticoagulation) in combination with a device called the EkoSonicTM Endovascular device to dissolve blood clots. Patients will be followed for 12 months after randomization and have assessments while in the hospital as well as at 7 days, 30 days, 6 months and 12 months after randomization. The study will try to find out if one of these treatments is better than the other at reducing the risk of death and other serious problems.
Kurt Jacobson, MD, MHSA
All
18 Years to 80 Years old
Phase 4
This study is NOT accepting healthy volunteers
NCT04790370
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Inclusion Criteria:

• Age 18-80 years, inclusive
• Objectively confirmed acute PE, based on computed tomography pulmonary angiography (CTPA) showing a filling defect in at least one main or proximal lobar pulmonary artery
• Elevated risk of early death/hemodynamic collapse, indicated by at least two of the following new-onset clinical criteria: 1. ECG-documented tachycardia with heart rate ≥100 beats per minute, not due to hypovolemia, arrhythmia, or sepsis; 2. SBP ≤ 110 mm Hg for at least 15 minutes; 3. respiratory rate > 20 x min-1 or oxygen saturation on pulse oximetry (SpO2) < 90% (or partial arterial oxygen pressure < 60 mmHg) at rest while breathing room air;
• Right-to-left ventricular (RV/LV) diameter ratio ≥ 1.0 on CTPA
• Serum troponin I or T levels above the upper limit of normal
• Signed informed consent
Exclusion Criteria:

• Hemodynamic instability*, i.e. at least one of the following present: 1. cardiac arrest or need for cardiopulmonary resuscitation; 2. need for ECMO, or ECMO initiated before randomization 3. PE-related shock, defined as: (i) SBP < 90 mmHg, or vasopressors required to achieve SBP ≥ 90 mmHg, despite an adequate volume status; and (ii) end-organ hypoperfusion (altered mental status; oliguria/anuria; increased serum lactate); 4. isolated persistent hypotension (SBP < 90 mmHg, or a systolic pressure drop by at least 40 mmHg for at least 15 minutes), not caused by new-onset arrhythmia, hypovolemia, or sepsis * Patients who presented with temporary need for fluid resuscitation and/or low-dose catecholamines may be included, provided that they could be stabilized within 2 hours of admission and maintain SBP of ≥ 90 mmHg and adequate organ perfusion without catecholamine infusion.
• Need for admission to an intensive care unit for a reason other than the index PE episode. NB: Patients who test positive for SARS-CoV-2 can be enrolled where the investigator believes that the pulmonary embolism is the dominant pathology in the patient's clinical presentation and qualifying cardiorespiratory parameters.
• Temperature above 39 degrees C / 102.2 degrees F
• Logistical reasons limiting the rapid availability of interventional procedures to treat acute PE (e.g., during the outbreak of an epidemic)
• Index PE symptom duration > 14 days
• Active bleeding
• History of intracranial or intraocular bleeding at any time
• Stroke or transient ischemic attack within the past 6 months, or previous stroke at any time if associated with permanent disability
• Central nervous system neoplasm, or metastatic cancer
• Major neurologic, ophthalmologic, abdominal, cardiac, thoracic, vascular or orthopedic surgery or trauma (including syncope-associated with head strike or skeletal fracture) within the past 3 weeks
• Platelet count < 100 x 109 x L-1
• Patients who have received a once-daily therapeutic dose of LMWH or a therapeutic dose of fondaparinux within 24 hours prior to randomization
• Patients who have received one of the direct oral anticoagulants apixaban or rivaroxaban within 12 hours prior to randomization
• Patients who have received one of the direct oral anticoagulants dabigatran or edoxaban for the index PE episode, as these drugs are not approved for patients who have not received heparin for at least 5 days
• Administration of a thrombolytic agent or a glycoprotein IIb/IIIa receptor antagonist during the current hospital stay and/or within 30 days, for any reason
• Chronic treatment with antiplatelet agents other than low-dose acetylsalicylic acid or clopidogrel 75 mg once daily (but not both). Dual antiplatelet therapy is excluded.
• Chronic treatment with a direct oral anticoagulant (apixaban, dabigatran, edoxaban or rivaroxaban)
• Chronic treatment with a vitamin K antagonist, or known coagulopathy including severe hepatic dysfunction, with an International Normalized Ratio (INR) > 1.5
• Pregnancy or lactation
• Previous inclusion in the study
• Known hypersensitivity to alteplase, LMWH or UFH, or to any of the excipients
• Life expectancy less than 6 months
Pulmonary Embolism, Pulmonary embolism, Other, Heart & Vascular
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Hypofractionated vs Conventional Fractionated RT in Soft Tissue Sarcomas

This research study is designed to find out if radiation therapy treatment prior to surgery is safe and effective to treat soft tissue sarcomas. 30 participants with soft tissue sarcoma will be enrolled and can expect to be on study for up to 5 years.
Zachary Morris, MD
All
18 Years and over
Phase 2
This study is NOT accepting healthy volunteers
NCT05109494
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Inclusion Criteria:

• Biopsy proven soft tissue sarcoma of the extremity, trunk, or head and neck
• No prior sarcoma-directed therapy
• Age ≥ 18 years
• Karnofsky performance status ≥ 60
• Able to understand and sign an informed consent
• Life expectancy of greater than 12 weeks
• Hypofractionated or conventionally fractionated radiotherapy using Intensity Modulated Radiation Therapy (IMRT) are both deemed feasible and safe neoadjuvant treatments, at the treating physician's discretion
• Operable disease and medically fit for surgery, based on the opinion of the consulting surgeon; surgery within 5-14 days of completion of radiation therapy (RT)
• Adequate bone marrow function as defined by absolute neutrophil count > 500/mcL, hemoglobin > 8 g/dL, platelets > 50,000/mcL; adequate renal function as defined by creatinine clearance > 30 mL/min
Exclusion Criteria:

• Pregnant
• Unable to undergo imaging or positioning necessary for radiotherapy planning
Soft Tissue Sarcoma, Soft Tissue, Sarcoma
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PROACTIVE-HF IDE Trial Heart Failure NYHA Class III (PROACTIVE-HF)

This is a prospective, open- label, single arm, multicenter clinical trial to evaluate the safety and effectiveness of the Cordella PA Sensor System in NYHA Class III Heart Failure Patients compared to a Performance Goal (PG).
Farhan Raza
All
18 Years and over
N/A
This study is NOT accepting healthy volunteers
NCT04089059
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Inclusion Criteria 1. Subject has given written informed consent 2. Male or female, at least 18 years of age 3. Diagnosis and treatment of HF (regardless of left ventricular ejection fraction (LVEF)) for ≥ 3 months and NYHA Class III HF at time of Screening 4. Subjects should be on stable, optimally titrated medical therapy for at least 30 days, as recommended according to current American Heart Association (AHA)/American College of Cardiology (ACC) guidelines as standard-of-care for HF therapy in the United States, or current European Society of Cardiology (ESC) guidelines for HF treatment in Europe, with any intolerance documented. 5. HF related hospitalization, HF treatment in a hospital day-care setting, or urgent outpatient clinic HF visit for IV diuretics within 12 month (last hospitalization should be 30 days before Screening/Enrollment) and/or N-terminal pro B-type Natriuretic Peptide (NT proBNP) at time of Screening/ Enrollment defined as: 1. Subjects with LVEF ≤ 50%: NT-proBNP ≥ 1500 pg/mL. 2. Subjects with LVEF > 50%: NT-proBNP ≥ 800 pg/mL . Thresholds for NT-proBNP (for both LVEF ≤ 50% and LVEF > 50%) will be corrected for body mass index (BMI) using a 4% reduction per BMI unit over 25 kg/m2 6. Subjects should be on diuretic therapy 7. Subjects who are physically able to hold the myCordella™ Patient Reader unit (approximate weight 1.3lb) against the ventral thoracic surface for up to 2 minutes per day while in a seated position, as well as dock and undock the myCordella™ Patient Reader 8. Subjects with sufficient eyesight, hearing, and mental capacity to respond to the myCordella™ Patient Reader's audio/visual cues and operate the myCordella™ Patient Reader 9. Subject has sufficient Cellular and/ or Wi- Fi Internet coverage at home 10. Subject agrees to return to the treating Investigator for all scheduled follow up visits and can return to the hospital for follow up Exclusion Criteria 1. Intolerance to all neuro-hormonal antagonists (i.e., intolerance to ACE-I, ARB, ARNI, and beta-blockers) due to hypotension or renal dysfunction 2. ACC/AHA Stage D refractory HF (including having received or currently receiving pharmacologic circulatory support with inotropes) 3. Subjects with history of recurrent pulmonary embolism ( ≥2 episodes within 5 years prior to Screening Visit) and/or deep vein thrombosis (< 3 month prior to Screening Visit) 4. Subjects who have had a major cardiovascular (CV) event (e.g. myocardial infarction, stroke) within 3 months of the Screening Visit 5. Unrepaired severe valvular disease 6. Subjects with significant congenital heart disease that has not been repaired and would prevent implantation of the Cordella PA sensor or mechanical/tissue right heart valve(s) 7. Subjects with known coagulation disorders 8. Subjects with a hypersensitivity or allergy to platelet aggregation inhibitors including aspirin, clopidogrel, prasugrel, and ticagrelor; or patients unable to take dual antiplatelet or anticoagulants for one-month post implant 9. Known history of life threatening allergy to contrast dye 10. Subjects whereby RHC is contraindicated 11. Subjects with an active infection at the Sensor Implant Visit 12. Subjects with a Glomerular Filtration Rate (GFR) <25 ml/min or who are on chronic renal dialysis 13. Implanted with Cardiac Resynchronization Therapy (CRT)-Pacemaker (CRT-P) or CRT-Defibrillator (CRT-D) for less than 90 days prior to screening visit 14. Received or are likely to receive an advanced therapy (e.g. mechanical circulatory support or lung or heart transplant) in the next 12 months 15. Subjects who are pregnant or breastfeeding 16. Subjects who are unwilling or deemed by the Investigator to be unwilling to comply with the study protocol, or subjects with a history of non-compliance 17. Severe illness, other than heart disease, which would limit survival to <1 year 18. Subjects whose clinical condition, in the opinion of the Investigator, makes them an unsuitable candidate for the study 19. Subjects enrolled in another investigational trial with an active treatment arm 20. Subject who is in custody by order of an authority or a court of law
Heart Failure NYHA Class III, Other, Heart & Vascular, Aging & Geriatrics
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EPI-7386 in Combination With Enzalutamide Compared With Enzalutamide Alone in Subjects With mCRPC

This is a Phase 1/2 study of EPI-7386 orally administered in combination with enzalutamide in subjects with mCRPC. Phase 1 of the study will be a single-arm dose escalation study of EPI-7386 in combination with a fixed dose of enzalutamide. This portion of the study will primarily evaluate the safety and tolerability of the drug combination and establish the RP2CDs for EPI-7386 and enzalutamide when dosed in combination. In addition, blood sampling will be conducted for PK evaluation to assess the potential DDI between the two drugs. Once the RP2CD for each drug has been established, Phase 2 of the study will commence. Phase 2 is a two-arm, randomized (2:1), open-label study. Approximately 120 subjects will be randomized 2:1 to: - Group 1: EPI-7386 at the RP2CD + enzalutamide(depending on the results of the Phase 1) (n=80) - Group 2: Enzalutamide single agent (n=40) The planned dose of enzalutamide and EPI-7386 for the combination arm will be those determined in the Phase 1 of this study based on safety and exposure data. Subjects may remain on study treatment as long as they are tolerating treatment without disease progression based on RECIST v1.1 and/or PCWG3.
Christos Kyriakopoulos, MD
Male
18 Years and over
Phase 1/Phase 2
This study is NOT accepting healthy volunteers
NCT05075577
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Inclusion Criteria:

• Males ≥18 years.
• Histologically, pathologically, or cytologically confirmed prostate adenocarcinoma.
• Evidence of castration-resistant prostate cancer (CRPC).
• Presence of metastatic disease at study entry documented by 1 or more bone lesions on bone scan or by soft tissue disease observed by CT/MRI.
• Naïve to second generation anti-androgens.
• Evidence of progressive disease defined as 1 or more Prostate Cancer Working Group 3 (PCWG3) criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Ongoing ADT with luteinizing hormone-releasing hormone (LHRH) agonist/antagonist therapy or history of bilateral orchiectomy, with castrate level testosterone.
• Serum testosterone ≤1.73 nmol/L (50 ng/dL).
• Subjects receiving bisphosphonates or other approved bone-targeting therapy (e.g., denosumab) must be on a stable dose for at least 28 days prior to the start of study treatment.
• Demonstrate adequate organ function.
Exclusion Criteria:

• Biologic anti-cancer therapy within 28 days prior to the start of study treatment.
• Use of hormonal agents with anti-tumor activity against prostate cancer within 28 days prior to the start of study treatment.
• Use of herbal products or alternative therapies that may decrease PSA levels or that may have hormonal anti-prostate cancer activity within 28 days prior to the start of study treatment or plans to initiate during the study.
• Intervention with any chemotherapy, investigational agents, or other anti-cancer drugs within 28 days of the first dose of study treatment.
• Use of radium-223 dichloride or other radioligand/radiopharmaceutical within 28 days prior to the start of study treatment.
• Received limited-field palliative bone radiotherapy >5 fractions and/or any radiotherapy within 2 weeks prior to the start of study treatment.
• Received a blood transfusion within 28 days of hematologic screening labs.
• Known intra-cerebral disease or brain metastasis unless adequately treated and stable for the last 28 days before signing of informed consent.
• Spinal cord compression.
• Diagnosis of another clinically significant malignancy within the previous 3 years other than curatively treated non-melanomatous skin cancer or superficial urothelial carcinoma and other in situ or non-invasive malignancies.
• Gastrointestinal issues affecting absorption.
• Significant cardiovascular disease.
• Known history of seizure or conditions that may pre-dispose them to seizure, including brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformation.
• Concurrent disease or any clinically significant abnormality.
• Known or suspected hypersensitivity to any components of the formulation used for EPI-7386 or enzalutamide.
• Use of strong inhibitors of CYP2C8.
• Use of strong inducers of CYP3A.
• Use of narrow therapeutic index sensitive CYP2C8 or sensitive substrates for CYP3A and CYP2B6.
• Use of granulocyte colony stimulating factor within 7 days prior to screening laboratories.
• Not a candidate for enzalutamide treatment.
• Patients with rare hereditary problems of fructose intolerance.
Prostate Cancer, Prostate
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Testing the Addition of the Anti-cancer Drug, Tazemetostat, to the Usual Treatment (Dabrafenib and Trametinib) for Metastatic Melanoma That Has Progressed on the Usual Treatment

This phase I/II trial investigates the best dose, possible benefits and/or side effects of tazemetostat in combination with dabrafenib and trametinib in treating patients with melanoma that has a specific mutation in the BRAF gene (BRAFV600) and that has spread to other places in the body (metastatic). Tazemetostat, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving tazemetostat in combination with dabrafenib and trametinib may stabilize BRAFV600 mutated melanoma.
Mark Albertini, M.D.
All
18 Years and over
Phase 1/Phase 2
This study is NOT accepting healthy volunteers
NCT04557956
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Inclusion Criteria:

• Patient must have a diagnosis of BRAF^V600E/K-mutated metastatic melanoma
• Patient must have had documented radiographic or clinical evidence of progressive disease while on combination BRAF/MEK inhibitor therapy. For Phase 2 only, no more than one intervening therapy since progression on BRAF/MEK inhibitor therapy is allowed. Subjects who have evidence of progression while on, or within 4 weeks of completing, combination BRAF/MEK inhibitor therapy in the adjuvant setting will be eligible
• PHASE 2 ONLY: Patient must have EZH2 alteration (somatic mutation or copy number alteration). Can be performed on either archival or fresh specimen. EZH2 alterations need to be documented by a Clinical Laboratory Improvement Act (CLIA)/Clinical Laboratory Improvement Program (CLIP)-certified next generation sequencing platform (Foundation One, Tempus, Guardant360, etc.)
• PHASE 2 ONLY: Patient must have measurable disease
• PHASE 2 ONLY: Patient must have at least one tumor lesion amenable to biopsy. If possible, this lesion should be different from the lesion used for following tumor measurements but is not required
• PHASE 2 ONLY: Patient must agree to planned pre-treatment and planned on-treatment biopsy. A pre-treatment biopsy will be optional if patient has an archival tissue block or 5 formalin-fixed paraffin-embedded (FFPE) slides available from specimen used to document presence of eligible EZH2 alteration that is deemed adequate for evaluation
• Patient must be >=18 years
• Because no dosing or adverse event data are currently available on the use of tazemetostat in combination with dabrafenib and trametinib in patients < 18 years of age, children are excluded from this study
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)
• Patients with symptomatic central nervous system (CNS) metastases are eligible if previously treated with surgery and/or radiation with no evidence of radiologic CNS recurrence or progression for 4 weeks and on a stable/tapering dose of steroid for at least one week prior to start of study drug. Patients with new or progressive asymptomatic CNS metastases are eligible
• Hemoglobin >= 9 g/dL
• Albumin >= 2.5 g/dL
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN
• Creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min
• Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2
• Patients with a prior (or concurrent, if enrolling in Phase 1) malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patient must be able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
• Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN. Prophylactic low dose warfarin may be given to maintain central catheter patency
• The effects of tazemetostat, and the combination of tazemetostat, dabrafenib and trametinib on the developing human fetus are unknown. Women of childbearing potential and all male patients must agree to the following:
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period, for 6 months after tazemetostat discontinuation, or for 6 months after discontinuation of the combination of tazemetostat, dabrafenib and trametinib. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
• A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus)
• Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices
• Due to the potential of enzyme induction with tazemetostat, female subjects who use hormonal contraceptives should use an additional barrier method of birth control while on study treatment and for 6 months after discontinuation of tazemetostat or the combination of tazemetostat, dabrafenib and trametinib
• The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not acceptable methods of contraception
• Women of childbearing potential must have a negative urine or serum pregnancy test at screening
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm, as defined below:
• With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 4 months after the last dose of study drug. Men must refrain from donating sperm during this same period. In addition, female partners of male subjects should adhere to the following:
• Intrauterine device (IUD) (must provide medical documentation of IUD)
• Hormonal contraceptive (partner must be on a stable dose of the same hormonal contraceptive product for at least 4 weeks before receiving study drug) AND a condom (hormonal contraceptives must be supplemented with condoms)
• The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence and withdrawal are not acceptable methods of contraception
• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible
• Have progressed on, been intolerant to is, ineligible for, or has refused prior standard of care anti-PD-1 based immunotherapy
Exclusion Criteria:

• Previous therapy with a demethylating agent (i.e. decitabine) or previous therapy with an EZH2 inhibitor
• History of second malignancy not treated with curative intent
• History of life-threatening toxicity, including hypersensitivity, related to BRAF or MEK inhibitor therapy, or known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO)
• Active infection requiring intravenous therapy
• Presence of untreated or progressive symptomatic CNS melanoma metastases. Diffuse leptomeningeal carcinomatosis or metastases causing spinal cord compression are exclusionary. Previously treated lesions should be stable for >= 4 weeks (must be documented by imaging). Subjects on a stable dose of corticosteroids for > 1 week can be enrolled. Subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks
• Radiation therapy in the last 14 days. Palliative radiation to a localized area without residual toxicity requires a washout of at least 7 days
• Prior systemic anti-cancer therapy (chemotherapy, targeted therapy, immunotherapy, biologic therapy, or vaccine therapy) within the 3 weeks preceding the first dose of study treatment. For Phase 2 only, prior chemotherapy regimens are not permitted
• Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study
• Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0) grade 2 or higher from previous anti-cancer therapy, except alopecia, at the time of randomization
• Current use of a prohibited medication. Patients must not be treated with any medications or substances that are strong or moderate inhibitors or inducers of of CYP3A or strong inhibitors or inducers of CYP2C8 within 14 days prior to the first treatment through the end of the study. Current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with dabrafenib
• A history of hepatitis B Virus (HBV) or hepatitis C Virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed)
• History of interstitial lung disease or pneumonitis
• Clinically significant bleeding diathesis or coagulopathy, including known platelet function disorders. Patients on anticoagulation with low molecular weight heparin or low dose warfarin are allowed
• History of myeloid malignancies, including myelodysplastic syndrome (MDS)
• Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and multiple primary neoplasms (MPN) (e.g. JAK2 V617F) observed in cytogenetic testing and deoxyribonucleic acid (DNA) sequencing
• History of T-lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL)
• Patients with history of RAS mutation-positive tumors are not eligible regardless of interval from the current study. Note: Prospective RAS testing is not required. However, if the results of previous RAS testing are known, they must be used in assessing eligibility
• History or evidence of cardiovascular risks including any of the following:
• QT interval corrected for heart rate using Fridericia's formula (QT corrected by Fridericia [QTcF]) >= 450 msec
• History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization
• History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
• Intra-cardiac defibrillators
• Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (ECHO); (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study
• History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: Subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible
• Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy
• Left ventricular ejection fraction (LVEF) < institutional lower limit of normal (LLN) by ECHO or multigated acquisition scan (MUGA)
• Known cardiac metastases
• Patients with uncontrolled intercurrent illness
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with tazemetostat / dabrafenib / trametinib, breastfeeding should be discontinued prior to treatment
• Patients with uncontrolled diabetes
• Patients with a history of retinal vein occlusion (RVO), retinal pigment epithelial detachment (RPED) or other ophthalmologic toxicity
Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Melanoma, Melanoma, Skin, Melanoma/Skin cancer
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Frailty and Dysphagia in Older Adults

The purpose of this research study is to figure out if there are physical factors such as cognition level, nutrition status, walking speed, and handgrip strength that are associated with the development of swallowing problems. Investigators want to better understand how swallowing problems develop in older adults with and without frailty. Identifying factors that contribute to swallowing problems, can develop therapies in the future to improve swallowing outcomes for older adults. This study will be done at the University of Wisconsin-Madison (UW-Madison). A total of about 69 people will participate in this study.
Raele Robison
All
65 Years and over
NA
This study is also accepting healthy volunteers
NCT04975815
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Inclusion Criteria:

• 65 years of age or older
• Ability to provide informed consent or the presence of a legally authorized representative (LAR) who can consent on behalf of the patient
• Post-menopausal (female participants)
• Not pregnant
Exclusion Criteria:

• Allergy to barium
• Prior surgery to the head and neck region affecting swallowing-related structures
• Prior chemotherapy or radiation treatment to the head and neck region
• Prior cerebral vascular accident with resulting persistent dysphagia
• Non-English speaking
Dysphagia, Frailty, Other
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Study to Assess Change in Disease Activity and Adverse Events of Oral Venetoclax With Intravenous (IV) Obinutuzumab in Adult Participants With Recurring Chronic Lymphocytic Leukemia (CLL) (ReVenG)

Chronic lymphocytic leukemia (CLL) is the most common leukemia (cancer of blood cells). The purpose of this study is to assess retreatment with venetoclax-obinutuzumab (VenG) in participants previously treated with fixed duration first-line (IL) therapy of venetoclax in combination with an anti-CD20 antibody +/- X (where X is any additional drug). Adverse events and change in disease activity will be assessed. Venetoclax is an approved drug for the treatment of CLL. Study doctors put the participants in 1 of 2 groups, called cohorts, based on when symptoms of CLL came back after previous treatment in first-line. Approximately 75 adult participants with CLL who have been treated with venetoclax in combination with an anti-CD20 antibody +/- X will be enrolled in the study in approximately 60 sites worldwide. Participants will receive intravenous (IV) obinutuzumab + oral venetoclax (VenG) in 28-day cycles for a total of 6 cycles per cohort, followed by 6 to 18 cycles of venetoclax alone, for a total treatment of 12 to 24 cycles, depending on the cohort. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.
Christopher Fletcher, MD
All
18 Years and over
Phase 2
This study is NOT accepting healthy volunteers
NCT04895436
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Inclusion Criteria:

• Documented diagnosis of chronic lymphocytic leukemia (CLL) that requires treatment for CLL according to International Workshop for Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria.
• Previously completed venetoclax + anti-CD20 antibody +/- X regimen as a fixed duration first-line (1L) therapy and achieved documented response, defined as complete remission, complete remission with incomplete marrow recovery, partial remission, or nodular partial remission.
• More than 24 months (Cohort 1) or 12-24 months (Cohort 2) have elapsed between last dose of venetoclax and disease progression after completion of 1L treatment.
Exclusion Criteria:

•Received intervening treatment for CLL after completing previous treatment with a venetoclax + anti-CD20 antibody +/- X regimen.
Chronic Lymphocytic Leukemia (CLL), Lymphoid Leukemia, Leukemia
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Study of LY3537982 in Cancer Patients With a Specific Genetic Mutation (KRAS G12C)

The purpose of this study is to find out whether the study drug, LY3537982, is safe and effective in cancer patients who have a specific genetic mutation (KRAS G12C). Patients must have already received or were not able to tolerate the standard of care, except for specific groups who have not had cancer treatment. The study will last up to approximately 4 years.
Dustin Deming, MD
All
18 Years and over
Phase 1/Phase 2
This study is NOT accepting healthy volunteers
NCT04956640
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Inclusion Criteria:

• Patients have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
• Patients must have disease with evidence of KRAS G12C mutation in tumor tissue or circulating tumor deoxyribonucleic acid (DNA).
• Participants must have a histological or a cytologically proven diagnosis of locally advanced, unresectable, and/or metastatic cancer and meet cohort-specific criteria.
• Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Have adequate organ function.
• Have discontinued all previous treatments for cancer with resolution of any significant ongoing adverse events (AEs), (except in certain scenarios).
• Must be able to swallow capsule/tablet.
• Agree and adhere to contraceptive use, if applicable.
• For some parts of the study, (i.e., one of the two arms with LY3537982 in combination with pembrolizumab and the arm of LY3537982 in combination with pembrolizumab, pemetrexed, and platinum therapy) histologically or cytologically confirmed Stage IIIB-IIIC or Stage IV NSCLC that is previously untreated in the advanced/metastatic setting and not suitable for curative intent radical surgery or radiation therapy. Previously untreated patients who received adjuvant and neoadjuvant therapy are eligible if the last dose of the systemic treatment was completed at least 6 months prior to enrollment. For untreated patients in the arm with LY3537982 in combination with pembrolizumab noted above, a single cycle of pembrolizumab may be initiated within 21 days prior to enrollment. For untreated patients in the arm of LY3537982 in combination with pembrolizumab, pemetrexed, and platinum therapy, a single cycle of any or all of the drugs other than LY3537982 may be initiated within 21 days prior to enrollment. Start of study treatment may be delayed to allow sufficient time for recovery from treatment-related toxicity.
• For one part of the study, participants must have received at least one prior oxaliplatin- or irinotecan-containing regimen for advanced or metastatic CRC.
Exclusion Criteria:

• Disease suitable for local therapy administered with curative intent.
• Have an active, ongoing, or untreated infection.
• Have a serious pre-existing medical condition(s) that, in the judgment of the investigator, would preclude participation in this study.
• Have a serious cardiac condition.
• Have a second active primary malignancy or have been diagnosed and/or treated for an additional malignancy within 3 years prior to enrollment.
• Have symptomatic central nervous system (CNS) malignancy or metastasis and/or carcinomatous meningitis. Patients with treated CNS metastases are eligible for this study if their disease is asymptomatic, radiographically stable for at least 30 days, and they do not require treatment with steroids in the two-week period prior to study treatment. This only applies to some parts of the study.
• Have received prior treatment with any KRAS G12C small molecule inhibitor, except in certain scenarios where such prior therapy is allowed as per protocol.
• The following patients will be excluded from some parts of the study:
• Experienced certain serious side effects with prior immunotherapy.
• Have an active autoimmune disease that has required systemic anti-autoimmune treatment in the past 2 years.
• Have received a live vaccine within 30 days prior to the first dose of study drug.
• Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial through 180 days after the last dose of study medication.
• Known allergic reaction against any of the components of the study treatments.
Carcinoma, Non-Small-Cell Lung, Colorectal Neoplasms, Endometrial Neoplasms, Ovarian Neoplasms, Pancreatic Neoplasms, Biliary Tract Neoplasms, Lip, Oral Cavity and Pharynx, Esophagus, Colon, Anus, Liver, Other Digestive Organ, Larynx, Lung, Other Respiratory and Intrathoracic Organs, Bones and Joints, Melanoma, Skin, Kaposi's Sarcoma, Breast, Cervix, Corpus Uteri, Other Female Genital, Other Male Genital, Kidney, Eye and Orbit, Brain and Nervous System, Other Endocrine System, Ill-Defined Sites, Anal, Brain/Central Nervous System, Colon and Rectum, Endocrine cancers, Gastrointestinal cancers, other, Genitourinary cancers, other, Head and Neck, Melanoma/Skin cancer, Ovary, Sarcoma, Uterus
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Comparing High-Dose Cisplatin Every Three Weeks to Low-Dose Cisplatin Weekly When Combined With Radiation for Patients With Advanced Head and Neck Cancer

This phase II/III trial compares the effect of the combination of high-dose cisplatin every three weeks and radiation therapy versus low-dose cisplatin weekly and radiation therapy for the treatment of patients with locoregionally advanced head and neck cancer. Chemotherapy drugs, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. This study is being done to find out if low-dose cisplatin given weekly together with radiation therapy is the same or better than high-dose cisplatin given every 3 weeks together with radiation therapy in treating patients with head and neck cancer.
Paul Harari, MD
All
18 Years and over
Phase 2/Phase 3
This study is NOT accepting healthy volunteers
NCT05050162
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Inclusion Criteria:

• Pathologically (histologically or cytologically) proven diagnosis of SCCHN of the oropharynx, larynx, hypopharynx, or p16-positive unknown primary prior to registration; specimen from cervical lymph nodes with a well-defined primary site documented clinically or radiologically is acceptable; in patients with carcinoma of unknown primary this will be sufficient for pathologic confirmation without a clinically or radiographically defined primary site
• For patients with oropharyngeal cancer (OPC)/cancer of unknown primary (CUP): P16 status based on local site immunohistochemical tissue staining is required. A cell block obtained from a fine needle aspiration (FNA) biopsy specimen may be used as the sole diagnostic tissue. Centers are encouraged to contact the pathology chair for clarification
• Note: Institutions must screen patients for p16 status by immunohistochemistry (IHC) in order to be eligible for the trial using a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. A rigorous laboratory accreditation process similar to the United States (U.S.) CLIA certification, such as the provincial accreditation status offered by the Ontario Laboratory Accreditation (OLA) Program in Canada, the College of American Pathologists (CAP), or an equivalent accreditation in other countries, is acceptable.
• The p16 results must be reported on the pathology report being submitted. The p16 positivity is defined as > 70% of tumor cells showing strong nuclear and/or cytoplasmic immunostaining with p16 antibody.
• For patients with laryngeal and hypopharyngeal primaries: Analysis of p16 status is NOT required
• Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations. Simple tonsillectomy or local excision of the primary without removal of nodal disease is permitted, as is excision removing gross nodal disease but with intact primary site. Limited neck dissections retrieving =< 4 nodes are permitted and considered as non-therapeutic nodal excisions
• Clinical stage (American Joint Committee on Cancer [AJCC], 8th ed.), including no distant metastases based on the following diagnostic workup:
• History/physical examination within 60 days prior to registration
• One of the following imaging studies is required within 60 days prior to registration:
• Computed tomography (CT) scan of neck (diagnostic quality with contrast, unless contraindicated) OR
• Magnetic resonance imaging (MRI) of the neck (diagnostic quality with contrast, unless contraindicated) OR
• Fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/CT of the neck; the CT component must be of diagnostic quality with contrast, unless contraindicated.
• Note: A diagnostic quality CT or MRI with contrast or FDG-PET/CT scan of neck performed for the purposes of radiation planning may serve as both staging and planning tools
• One of the following imaging studies is required within 60 days prior to registration:
• FDG-PET/CT of the chest; FDG-PET/CT scan is strongly preferred and highly recommended to be used for eligibility OR
• Chest CT
• Exam with laryngopharyngoscopy (mirror or in office direct procedure acceptable) within 70 days prior to registration;
• Eligibility by patient cohort;
• Non-OPC/p16-negative OPC Cohort; Tumor Site: Larynx/Hypopharynx; Clinical Staging (AJCC, 8th ed.): T3-4 N0 or T1-4 N1-3 T2 N0 (hypopharynx only)
• Tumor Site: p16-negative OPC; Clinical Staging (AJCC, 8th ed.): T2N1, T1-4 N2-3, or T3-4 N0-1
• p16-positive OPC/CUP Cohort;
• Tumor Site: OPC; Smoking Status: =< 10 pack-years; Clinical Staging (AJCC, 8th ed.): T1-3 N2-3 or T4 N0-3
• Tumor Site: OPC; Smoking Status: > 10 pack-years; Clinical Staging (AJCC, 8th ed.): T1N2-3, T2N1-3 or T3-4 N0-3
• Tumor Site: CUP; Smoking Status: Any; Clinical Staging (AJCC, 8th ed.): T0 N2-3 Note: Cigar and pipe tobacco consumption is not included in calculating the lifetime pack-years. Marijuana consumption is likewise not considered in this calculation. There is also no clear scientific evidence regarding the role of chewing tobacco-containing products in oropharyngeal cancer, although this is possibly more concerning given the proximity of the oral cavity and oropharynx. In any case, investigators should not count use of non-cigarette tobacco products in the pack-years calculation.
• Age >= 18
• Zubrod (Eastern Cooperative Oncology Group [ECOG]) performance status of 0-1 within 14 days prior to registration
• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (within 30 days prior to registration)
• Platelets >= 75,000 cells/mm^3 (within 30 days prior to registration)
• Hemoglobin >= 8.0 g/dL (within 30 days prior to registration)
• Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dL is acceptable)
• Calculated creatinine clearance (CrCl) >= 50 mL/min by the Cockcroft-Gault formula (within 30 days prior to registration)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 30 days prior to registration) (not applicable to patients with known Gilbert's syndrome)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x institutional ULN (within 30 days prior to registration)
• Known human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months and CD4 T Cell count > 200 cells/mm^3 are eligible for this trial. Testing is not required for entry into protocol
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes
• Willing to use highly effective contraceptives for participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) during therapy and for 14 months (females); for 11 months (males) following last dose of cisplatin; this inclusion is necessary because the treatment in this study may be significantly teratogenic
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
Exclusion Criteria:

• Patients with oral cavity cancer, nasopharynx cancer, or p16-negative cancer of unknown primary (CUP)
• Recurrence of the study cancer
• Definitive clinical or radiologic evidence of distant metastatic disease
• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable, however, any prior exposure to cisplatin is excluded
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
• Severe, active co-morbidity defined as follows:
• Unstable angina requiring hospitalization in the last 6 months
• Myocardial infarction within the last 6 months
• New York Heart Association Functional Classification III/IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.)
• Persistent grade 3-4 (CTCAE version 5.0) electrolyte abnormalities that cannot be reversed despite replacement as indicated by repeat testing
• Patient must not have an active infection requiring IV antibiotics prior to registration;
• Other chronic renal disease like nephrotic syndrome, that could be worsened by cisplatin therapy
• History of allogenic organ transplantation
• Any symptomatic peripheral sensory neuropathy grade >= 2 (CTCAE version 5.0);
• Pregnancy and individuals unwilling to discontinue nursing
• History of hypersensitivity to cisplatin or platinum-containing compounds
Lip, Oral Cavity and Pharynx, Larynx, Unknown Sites, Head and Neck, Advanced Head and Neck Squamous Cell Carcinoma, Advanced Hypopharyngeal Squamous Cell Carcinoma, Advanced Laryngeal Squamous Cell Carcinoma, Advanced Oropharyngeal Squamous Cell Carcinoma, Squamous Cell Carcinoma of Unknown Primary
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MSC in Patients With Xerostomia Post XRT in Head and Neck Cancer

This is a single center pilot study designed to determine the safety and tolerability of autologous bone marrow-derived Mesenchymal Stromal Cells (MSCs) in patients with xerostomia (dry mouth) after undergoing radiation therapy (XRT) for head and neck cancer (HNC). Up to 12 participants will be enrolled and can expect to be on study for up to 2 years.
Randall Kimple, MD, PhD
All
18 Years to 90 Years old
Phase 1
This study is NOT accepting healthy volunteers
NCT04489732
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Inclusion Criteria:

• Willing to provide informed consent
• Willing to comply with all study procedures and be available for the duration of the study
• Histological diagnosis of Head and Neck Cancer (HNC) and ≥ 2 years from completion of treatment for HNC, either clinically or radiologically No Evidence of Disease (NED), as assessed by ENT or Radiation Oncologist within 28 days of study registration
• Individuals at least 18 years of age and no older than 90 years of age
• Xerostomia defined as less than or equal to 80 percent of baseline (pre-radiation) salivary function per patient estimate
• Karnofsky performance status ≥ 70, patient eligible for bone marrow aspirate with wakeful anesthesia
• Radiographically confirmed bilateral submandibular glands
• Females of childbearing potential must agree to have a negative urine or serum pregnancy test within 7 days prior to bone marrow biopsy. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
• has not undergone a hysterectomy or bilateral oophorectomy; or
• has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
• Women of childbearing potential in sexual relationships with men must have used an acceptable method of contraception for 30 days prior to study registration and agree to use an acceptable method of contraception until 4 weeks after completing study treatment. Males must agree to avoid impregnation of women during and for four weeks after completing study treatment through use of an acceptable method of contraception. Note: Acceptable method of contraception includes, but is not limited to, barrier with additional spermicidal foam or jelly, intrauterine device, hormonal contraception (started at least 30 days prior to study enrollment), intercourse with men who underwent vasectomy)
Exclusion Criteria:

• History of sialolithiasis
• Patients with one submandibular gland
• History of autoimmune diseases affecting salivary glands, including Sjögren's syndrome, lupus, scleroderma, type I diabetes, sarcoidosis, and amyloidosis
• Chronic graft vs host disease
• Untreated oral candidiasis
• Use of anti-cholinergic medications (e.g. atropine, ipratropium, oxybutynin, scopolamine, solifenacin, tiotropium, etc…) while enrolled on study
• Malignancy within the past 2 years, except adequately treated stage I lung cancer, low risk prostate cancer that has been treated or is undergoing active surveillance, adequately treated non-melanoma skin cancer, adequately treated ductal carcinoma in situ (DCIS), or adequately treated stage I cervical cancer
• Expected life expectancy ≤ 6 months
• Lidocaine allergy
• Use of investigational drugs, biologics, or devices within 30 days prior to enrollment
• Women who are pregnant, lactating or planning on becoming pregnant during the study
• Not suitable for study participation due to other reasons at the discretion of the investigators
Xerostomia Following Radiotherapy, Lip, Oral Cavity and Pharynx, Head and Neck
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Study to Assess Dose, Efficacy and Safety of Setrusumab in Participants With Osteogenesis Imperfecta (Orbit)

The primary objectives of the study are to identify a setrusumab dosing strategy in participants with OI and to evaluate the effect of setrusumab vs placebo on reduction in fracture rate.
Neil Paloian
All
5 Years to 25 Years old
Phase 2/Phase 3
This study is NOT accepting healthy volunteers
NCT05125809
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Inclusion Criteria:

• Diagnosis of OI Type I, III, or IV as confirmed by identification of pathogenic or likely pathogenic genetic variants in COL1A1 or COL1A2. If a variant of uncertain significance is identified, then clinical presence of the expected phenotype can be used to confirm the diagnosis
• ≥ 1 fracture in the past 12 months, ≥ 2 fractures in the past 24 months or ≥ 1 tibia, femur or humerus fracture in the past 24 months
• Serum 25-hydroxyvitamin D ≥ 20 ng/mL at the Screening Visit. If 25-hydroxyvitamin D levels are below 20 ng/mL, 25-hydroxyvitamin D testing can repeated after a minimum of 14 days of vitamin D supplementation as directed by the treating physician
• Willing to not receive bisphosphonate therapy during the study
• From the period following informed consent to 60 days after the last dose of the study drug, females of childbearing potential and fertile males must consent to use highly effective contraception. If female, agree not to become pregnant. If male, agree not to father a child or donate sperm
• Willing and able to provide informed consent for subjects greater than or equal to 18 years of age, or provide assent (if possible) and have a legally authorized representative provide informed consent, after the nature of the study has been explained and prior to any research-related procedures
• Willing to provide access to medical records for the collection of radiographic data, fracture data, growth data, and disease history
• Must, in the opinion of the Investigator, be willing and able to complete all aspects of the study, adhere to the study visit schedule, and comply with the assessments
Exclusion Criteria:

• History of skeletal malignancies or bone metastases at any time
• History of neural foraminal stenosis (except if due to scoliosis)
• Clinical manifestations of Chiari malformation or basilar invagination. Presence of any other neurologic disease that has been unstable within past 2 years requires review by the Medical Monitor
• History of or uncontrolled concomitant diseases such as hypo/hyperparathyroidism, Paget's disease, abnormal thyroid function, thyroid disease or other endocrine disorders or conditions that could affect bone metabolism such as Stage IV/V renal disease
• Rickets or any skeletal condition (other than OI) leading to long-bone deformities and/or increased risk of fractures
• History of stroke, myocardial infarction, transient ischemic attack or angina.
• Hypocalcemia, defined as serum calcium levels below the age-adjusted normal limits after a ≥ 4 hour fast
• Estimated glomerular filtration rate ≤ 29 mL/min/1.73 m2
• Prior treatment with the following: 1. Teriparatide, growth hormone, or other bone anabolic or anti-resorptive medications within 6 months of Screening 2. Denosumab within 24 months of Screening 3. Romosozumab at any time
• Documented alcohol and/or drug abuse within 12 months prior to dosing or evidence of such abuse as indicated by the laboratory results during the Screening assessments
• Presence or history of any condition that, in the view of the Investigator, would interfere with participation, pose undue risk, or would confound interpretation of results
• Known hypersensitivity to setrusumab or excipients that, in the judgment of the Investigator, places the subject at increased risk for adverse effects
• History of external radiation therapy
• Pregnant or breastfeeding or planning to become pregnant (self or partner) at any time during the study
• Use of any investigational product or investigational medical device within 4 weeks or 5 half-lives of investigational drug (whichever is longer) prior to Screening, or during the study (per discretion of the Investigator in consultation with the Medical Monitor)
• Concurrent participation in another clinical study without prior approval from the Investigator in consultation with the Medical Monitor
• For Phase 2 Only: A history of bone surgery within the previous 6 months prior to Screening or planned bone surgery for the first 3 months of the study
Osteogenesis Imperfecta, Other, Children's & Adolescent Health, Kidney Disease & Urinary
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Study Assessing the Efficacy, Safety and PK of Alpelisib (BYL719) in Pediatric and Adult Patients With PIK3CA-related Overgrowth Spectrum (EPIK-P2)

This is a prospective Phase II multi-center study with an upfront 16-week, randomized, double-blind, placebo-controlled period, and extension periods, to assess the efficacy, safety and pharmacokinetics of alpelisib in pediatric and adult participants with PIK3CA-related overgrowth spectrum (PROS).
Beth Drolet, MD
All
2 Years and over
Phase 2
This study is NOT accepting healthy volunteers
NCT04589650
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Inclusion Criteria:
1. Signed informed consent and assent (when applicable) from the patient, parent, legal authorized representative or guardian prior to any study related screening procedures are performed 2. Patients with diagnosis of PROS with symptomatic and /or progressive overgrowth and at least one measurable PROS-related lesion confirmed by blinded independent review committee (BIRC) assessment 3. Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in local laboratories 4. A tissue sample (fresh or archival) is be sent to a Novartis-designated central laboratory. If archival tissue is not available, collection of a fresh tissue biopsy is required for participants in Groups 1, 2 and 5, if it is not clinically contraindicated. For participants in Groups 3 and 4, a fresh tissue biopsy is not mandatory. For China only: Tissue sample collection and biomarker assessments are not applicable. For Germany only: If archival tissue is available, it must be sent to a Novartis designated central laboratory. If no archival tissue is available, obtaining a fresh tissue biopsy is recommended, if it is not clinically contraindicated, but is not mandatory. 5. Karnofsky (in patients > 16 years old at study entry)/Lansky (≤16 yrs of age at study entry) performance status index ≥50 6. Adequate bone marrow and organ function including Fasting plasma glucose (FPG) ≤ 140 mg/dL (7.7 mmol/L) and Glycosylated hemoglobin (HbA1c) ≤ 6.5% (both criteria have to be met) (as assessed by central laboratory for eligibility) 7. Presence of at least one PROS-related measurable lesion defined as a lesion with longest diameter ≥2 cm, when the volume can be accurately and reproducibly measured by MRI (Magnetic resonance imaging), and associated with complaints, clinical symptoms or functional limitations affecting the patient's everyday life. Measurability must be confirmed by BIRC before randomization.
Exclusion Criteria:
1. Participant with only isolated macrodactyly, skin nevus/nevi and macroencephaly (the only clinical feature or a combination of any of three of them), in absence of other PROS-related lesions at the time of informed consent 2. Previous treatment with alpelisib and/or any other PI3K inhibitor(s) (except treatment attempt, defined as the attempt to treat PROS with any of PI3K inhibitors, with treatment duration less than 2 weeks and stopped at least 4 weeks prior to the first dose of study medication with alpelisib) 3. Radiation exposure for PROS treatment purpose within the previous 12 months on those PROS areas which are expected to qualify for target lesions (except lesion(s) progressing after completion of radiotherapy) at time of informed consent. 4. Debulking or other major surgery performed within 3 months at time of informed consent 5. Clinically meaningful PROS-related thrombotic event (Grade 2 and more as per CTCAE v.4.03) within 30 days before informed consent, and/or sclerotherapy/embolization for vascular complications performed within 6 weeks before informed consent. Note: Participants receiving anticoagulants for PROS-related coagulopathy, primary or secondary prophylaxis of thrombosis may be included in the study 6. Participants in Groups 1, 2 ad 5 with documented pneumonitis or interstitial lung disease at time of informed consent and with impaired lung function (e.g., FEV1 or DLCO ≤ 70% of predicted) that is not related to PROS. Participants in Groups 3 and 4 with documented or suspicious pneumonitis or interstitial lung disease based on MRI images at time of informed consent 7. History of acute pancreatitis within 1 year before informed consent or past medical history of chronic pancreatitis at time of informed consent 8. Participants with an established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus at time of informed consent 9. Known history of seizure, or epilepsy, regardless of relatedness to PROS spectrum at time of informed consent, when epilepsy is not controlled and/or the patient may not be switched to non-enzyme inducing antiepileptic drug(s) at time of informed consent. 10. Participants with clinically significant worsening of PROS-related laboratory anomalies, physical signs and symptoms (such as, but not limited to increase of D-dimers, worsening of underlying pain, newly occurring swelling or redness) indicating an uncontrolled condition during the screening phase, particularly if systemic treatment with any other inhibitor of the PI3K/AKT/mTOR pathway was stopped prior to the start of study treatment. This includes but is not limited to hypercoagulability state in participants not receiving prophylactic treatment. Other inclusion/exclusion criteria may apply
Congenital malformation of peripheral vascular system, Other, PIK3CA-related Overgrowth Spectrum (PROS)
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Effect on Body Movement and Mental Skills in Patients Who Received Gadolinium-based Contrast Media for Magnetic Resonance Examination Multiple Times Within 5 Years (ODYSSEY)

This study is a postmarketing requirement jointly carried out by four NDA holders (Bayer AG, Bracco, GE Healthcare and Guerbet) and the CRO IQVIA. The study aims to create detailed images of the organs and tissue of the human body during x-ray, CT-scan or MRI investigations, doctors are using contrast media (a kind of dye) which can be given to patients by injection into a blood vessel or by mouth. In this study researchers want to find out whether so called gadolinium-based contrast agents (GBCAs) have an effect on body movement and mental skills when given to participants multiple times within 5 years. The study plans to enroll about 2076 participants suffering from a condition for which they are likely to have at least annually a MRI or another imaging examinations. Only adults up to 65 years will be considered to join this study. During the study duration of 5 years participants will receive annually a MRI or other imaging tests (such as CT-scan, x-ray) and will visit the study doctor at least 7 times for physical examinations, laboratory investigations and tests on body movement and mental skills.
Richard Bruce, MD
All
18 Years to 64 Years old
Phase 4
This study is NOT accepting healthy volunteers
NCT04373564
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Inclusion Criteria:

• Participant must be neurologically normal, defined as free of unstable neurologic and psychiatric disease as confirmed by a normal neurologic examination at screening
• Participant (GBCA-exposed or controls) agrees to undergo unenhanced magnetic resonance imaging (UE-MRI) of the brain at enrollment and at the end of the observation period (5 years)
• Participants should have at least 1 of the following indications: a) Medium to high risk for breast cancer or dense breasts undergoing breast cancer screening with MRI, b) Elevated prostate-specific antigen (PSA) and under active diagnostic surveillance for prostate cancer, c) Chronic liver disease (eg, liver cirrhosis limited to Child class A, post-hepatitis chronic hepatopathy, or primary sclerosing cholangitis) for surveillance of hepatocellular carcinoma development, d) Low-grade colorectal cancer or neuroendocrine tumor undergoing screening for liver metastases or e) Branch-duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas (maximum size ≤2 cm) undergoing imaging surveillance. In addition, for participants in the GBCA Arms only:
• Each participant should be likely to undergo ≥5 GBCA-enhanced MR examinations with the same GBCA at least annually throughout the 5-year study duration
• Prospective participants with up to 3 well documented GBCA administrations prior to study screening are acceptable, provided that the imaging was performed with the same GBCA as the one to be prospectively used in the study. If the GBCA used cannot be identified, he/she cannot be enrolled. For the Control Arm:
• Participants who never had and are not likely to receive any GBCA injection during the course of the study
• Each control participant must be willing to undergo UE-MRI of the brain at baseline and at Year 5. In Years 1 to 4, the control participants will undergo their clinically indicated UE-MRIs, computed tomography (CT), ultrasound, or X-ray procedures
Exclusion Criteria:

• As evidenced by history or determined in the neurologic exam at screening, concurrent neurological and/or psychiatric disease (or treatments) that could influence the results of the study's motor and cognitive tests (e.g. Cerebrovascular disease, Multiple sclerosis, Neurodegenerative disease, Malignant disease other than listed in indications, Carcinoid tumors, Epilepsy, Prior neurosurgery, Psychotic disorders or any prior psychotic episode not otherwise specified
•any documented prior history of chronic schizophrenia, Remittent or current medically confirmed major depressive disorder or bipolar disorder, History of long-term major depression or bipolar affective disorder with an active episode in the past 2 to 5 years, Neurodevelopmental disorders (eg, trisomy 21), Uncontrolled severe migraine, Uncontrolled or controlled anxiety or depression within 6 months before enrollment, Screening scores of ≤24 on the MMSE and/or ≥11 on the Hospital Anxiety and Depression Scale (HADS)).
• Prior, planned, or ongoing chemotherapy or brain irradiation
• Use of concomitant medication(s) affecting neuro-cognitive or motor function
• Substance or alcohol abuse as determined by the investigator
• Alcoholic cirrhosis
• Renal disease, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2
• History of environmental/occupational/other exposure to one or more chemicals that may affect cognitive and/or motor function, including, but not limited to, heavy metals (arsenic [As], cadmium [Cd], lead [Pb], manganese [Mn], and mercury [Hg]), pesticides, solvents, or carbon monoxide.
• Clinical indications requiring >1 contrast enhanced magnetic resonance imaging (CE-MRI) every 6 months
• Pregnant or nursing (lactating) women
• Presence of any metal-containing joint implants/prostheses In addition, for participants in either of the GBCA Arms only:
•Receipt of a GBCA or generic prior to study entry other than the specific GBCA to be administered during the course of the study. For participants in the Control Arm only:
• Participants with any previous exposure to a GBCA.
• Participants with any contraindication to UE-MRI examinations.
Motor Function, Cognitive Function, Contrast Media, Breast
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A Study to Compare Early Use of Vinorelbine and Maintenance Therapy for Patients With High Risk Rhabdomyosarcoma

This phase III trial compares the safety and effect of adding vinorelbine to vincristine, dactinomycin, and cyclophosphamide (VAC) for the treatment of patients with high risk rhabdomyosarcoma (RMS). High risk refers to cancer that is likely to recur (come back) after treatment or spread to other parts of the body. This study will also examine if adding maintenance therapy after VAC therapy, with or without vinorelbine, will help get rid of the cancer and/or lower the chance that the cancer comes back. Vinorelbine and vincristine are in a class of medications called vinca alkaloids. They work by stopping cancer cells from growing and dividing and may kill them. Dactinomycin is a type of antibiotic that is only used in cancer chemotherapy. It works by damaging the cell's deoxyribonucleic acid (DNA) and may kill cancer cells. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill cancer cells. It may also lower the body's immune response. Vinorelbine, vincristine, dactinomycin and cyclophosphamide are chemotherapy medications that work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This trial may have the potential to eliminate rhabdomyosarcoma for a long time or for the rest of patient's life.
Kenneth Desantes, M.D.
All
up to 50 Years old
Phase 3
This study is NOT accepting healthy volunteers
NCT04994132
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Inclusion Criteria:

• Patients must be =< 50 years of age at the time of enrollment
• Patients with newly diagnosed RMS of any subtype, except adult-type pleomorphic, based upon institutional histopathologic classification are eligible to enroll on the study based upon stage, group, and age, as below. FOXO1 fusion status must be determined by week 4 (day 28) of therapy. RMS types included under embryonal RMS (ERMS) include those classified in the 1995 International Classification of Rhabdomyosarcoma (ICR) as ERMS (classic, spindle cell, and botryoid variants), which are reclassified in the 2020 World Health Organization (WHO) Classification as ERMS (classic, dense and botryoid variants) and spindle cell/sclerosing RMS (encompassing the historical spindle cell ERMS variant and the newly recognized sclerosing RMS variant). Classification of alveolar RMS (ARMS) in the 2020 WHO Classification is the same as in the ICR and includes classic and solid variants
• ERMS
• Stage 4, group IV, >= 10 years of age
• ARMS
• Stage 4, group IV Patients will be eligible to remain on protocol therapy based upon stage, group, and age
• Bone marrow metastatic disease is based on morphologic evidence of RMS based on hematoxylin and eosin (H&E) stains. In the absence of morphologic evidence of marrow involvement on H&E, patients with bone marrow involvement detected ONLY by flow cytometry, reverse transcriptase (RT)-polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), or immunohistochemistry will NOT be considered to have clinical bone marrow involvement for the purposes of this study
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (must be performed within 7 days prior to enrollment):
• Age; Maximum serum creatinine (mg/dL)
• 1 month to < 6 months; 0.4 mg/dL (male); 0.4 mg/dL (female)
• 6 months to < 1 year; 0.5 mg/dL (male); 0.5 mg/dL (female)
• 1 to < 2 years; 0.6 mg/dL (male); 0.6 mg/dL (female)
• 2 to < 6 years; 0.8 mg/dL (male); 0.8 mg/dL (female)
• 6 to < 10 years; 1 mg/dL (male); 1 mg/dL (female)
• 10 to < 13 years; 1.2 mg/dL (male); 1.2 mg/dL (female)
• 13 to < 16 years; 1.5 mg/dL (male); 1.4 mg/dL (female)
• >= 16 years; 1.7 mg/dL (male); 1.4 mg/dL (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (must be performed within 7 days prior to enrollment)
• If there is evidence of biliary obstruction by tumor, then total bilirubin must be < 3 x ULN for age
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Exclusion Criteria:

• Patients with evidence of uncontrolled infection are not eligible
• RMS that is considered a second malignancy and previous cancer(s) that were treated with chemotherapy and/or radiation. Surgical resection alone of previous cancer(s) is allowed
• Patients with central nervous system involvement of RMS as defined below:
• Malignant cells detected in cerebrospinal fluid
• Intra-parenchymal brain metastasis separate and distinct from primary tumor (i.e., direct extension from parameningeal primary tumors is allowed).
• Diffuse leptomeningeal disease
• Patients who have received any chemotherapy (excluding steroids) and/or radiation therapy for RMS prior to enrollment.
• Note: the following exception:
• Patients requiring emergency radiation therapy for RMS. These patients are eligible, provided they are consented to ARST2031 prior to administration of radiation
• Note: Patients who have received or are receiving chemotherapy or radiation for non-malignant conditions (e.g. autoimmune diseases) are eligible. Patients must discontinue chemotherapy for non-malignant conditions prior to starting protocol therapy
• Vincristine and vinorelbine are sensitive substrates of CYP450 3A4 isozyme. Patients must not have received drugs that are moderate to strong CYP3A4 inhibitors and inducers within 7 days prior to study enrollment
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
Alveolar Rhabdomyosarcoma, Botryoid-Type Embryonal Rhabdomyosarcoma, Embryonal Rhabdomyosarcoma, Metastatic Embryonal Rhabdomyosarcoma, Metastatic Rhabdomyosarcoma, Solid Alveolar Rhabdomyosarcoma, Spindle Cell Rhabdomyosarcoma, Spindle Cell/Sclerosing Rhabdomyosarcoma, Lip, Oral Cavity and Pharynx, Esophagus, Stomach, Small Intestine, Colon, Rectum, Liver, Pancreas, Other Digestive Organ, Larynx, Lung, Other Respiratory and Intrathoracic Organs, Soft Tissue, Ovary, Other Female Genital, Prostate, Other Male Genital, Urinary Bladder, Kidney, Other Urinary, Eye and Orbit, Thyroid, Other Endocrine System, Bladder, Colon and Rectum, Endocrine cancers, Gastrointestinal cancers, other, Genitourinary cancers, other, Head and Neck, Melanoma/Skin cancer, Sarcoma
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Testing the Addition of the Drug Atezolizumab to the Usual Radiation Treatment for Patients With Early Non-small Cell Lung Cancer

This phase III trial studies how well atezolizumab added to the usual radiation therapy works in treating patients with stage I-IIA non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy, such as stereotactic body radiation therapy, uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving atezolizumab and radiation therapy may work better than radiation therapy alone in treating patients with early non-small cell lung cancer.
Andrew Baschnagel, MD
All
18 Years and over
Phase 3
This study is NOT accepting healthy volunteers
NCT04214262
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Inclusion Criteria:

• Patient must have histologically or cytologically proven stage I-IIA or limited T3N0M0 non-small cell lung cancer (NSCLC), without radiographic evidence of nodal or distant involvement (N0M0). Patient may have T3 disease with the exclusion of pericardial involvement. Patients with multifocal tumors with no more than two lesions confirmed or suspected to be synchronous early stage NSCLCs are eligible provided at least one lesion is histologically or cytologically proven to be NSCLC and meets one or more high-risk features
• Disease must have one or more of the following high-risk features:
• Tumor diameter >= 2 cm (inclusive of any non-solid, ground glass component) as assessed by diagnostic CT
• Tumor standard uptake value (SUV) max >= 6.2 as assessed by FDG PET/CT
• Moderately differentiated, poorly differentiated, or undifferentiated histology
• Patient must have undergone diagnostic chest CT with or without contrast (IV contrast preferred) within 42 days prior to randomization. PET-CT may be used if the CT portion is of comparable diagnostic quality to a stand-alone CT. All disease must be assessed within 42 days prior to randomization
• Patient must have undergone FDG PET/CT of chest within 90 days prior to randomization
• Patient must not have evidence of hilar or mediastinal nodal involvement. Any patient with radiographically suspicious hilar or mediastinal nodes (including features such as non-calcified nodes with a short axis diameter > 1 cm, abnormal morphology, and/or elevated FDG avidity) must undergo cytologic sampling of suspicious nodes to rule out involvement prior to randomization. Mediastinal nodal sampling for other patients is optional. For cases in which the treating physician/multidisciplinary opinion is used to define nodes as "non-suspicious" (such as long-standing, stable enlarged nodes from other medical causes), the rationale must be clearly documented within the medical record
• Patient must have undergone history and physical examination within 28 days prior to randomization
• Patient must be medically or surgically inoperable as documented by a board certified thoracic surgeon or multi-disciplinary tumor board consensus OR patient's unwillingness to undergo surgical resection must be clearly documented
• Patient must not have received any prior treatment for the current NSCLC diagnosis
• Patient must not have undergone prior radiation to overlapping regions of the chest that, in the opinion of the treatment physician, will interfere with protocol treatment
• Patient must not have received treatment with systemic immunostimulatory or immunosuppressive agents, including corticosteroids, within 14 days prior to randomization
• Patient must be >= 18 years old
• Patient must have Zubrod performance status of 0-2
• Patient must have adequate liver function defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x institutional upper level of normal (IULN) within 28 days prior to randomization
• Patient must have adequate renal function defined as calculated creatinine clearance >= 30 mL/min using the following formula. The serum creatinine value used in the calculation must have been collected within 28 days prior to randomization
• Patient must have absolute neutrophil count (ANC), platelets, and hemoglobin measured within 28 days prior to randomization. The purpose of these tests is to collect baseline values to compare with on-treatment values
• Patient must have thyroid-stimulating hormone (TSH) measured within 28 days prior to randomization. The purpose of this test is to collect baseline values to compare with on-treatment values
• Patient must not have significant cardiovascular disease (New York Heart Association [NYHA] class II or greater)
• Patient must not have myocardial infarction within 90 days prior to randomization
• Patient must not have unstable arrhythmias or unstable angina
• Patient must not have known left ventricular ejection fraction (LVEF) < 40% within 28 days prior to randomization
• NOTE: Assessment of LVEF by echocardiogram or multigated acquisition (MUGA) is not an eligibility requirement, but if a standard of care echocardiogram or MUGA was clinically indicated, the LVEF must not be < 40% within 28 days prior to randomization
• Patient must not have had an infection >= grade 3 (Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) within 28 days prior to randomization
• Patient must not have an active autoimmune disease that has required systemic treatment in past two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
• Patient must be tested for hepatitis B within 28 days prior to randomization. Patient must not have active (chronic or acute) hepatitis B virus (HBV) infection. Patients may have past or resolved HBV infection
• Active HBV is defined as having a positive hepatitis B surface antigen (HBsAg) test
• Past or resolved HBV is defined as having a negative HBsAG test and a positive total hepatitis B core antibody (HBcAb) test
• Patient must be tested for hepatitis C within 28 days prior to randomization. Patient must not have active hepatitis C virus (HCV) infection
• Active HCV is defined as having a positive HCV antibody test followed by a positive HCV ribonucleic acid (RNA) test
• Patient must have pulmonary function testing to include, at a minimum, forced expiratory volume in 1 second (FEV1) and Diffusing capability of carbon monoxide (DLCO) documented within 90 days prior to randomization
• Patients with known human immunodeficiency virus (HIV) infection must be receiving anti-retroviral therapy and have an undetectable viral load at their most recent viral load test within 6 months prior to randomization
• Patient must not have a history of clinically significant interstitial lung disease or evidence of active pneumonitis on the screening chest CT
• Patients must not have a prior or concurrent malignancy whose natural history or treatment has the potential (in the opinion of the treating physician) to interfere with the safety or efficacy assessment of the investigational regimen
• Patients must not be pregnant due to the potential teratogenic side effects of the protocol treatment. Women of reproductive potential and men must have agreed to use an effective contraception method for the duration of protocol treatment, and for 5 months (150 days) after the last dose of atezolizumab. A woman is considered to be of "reproductive potential" if she has had a menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with atezolizumab, breastfeeding must be discontinued prior to randomization
• Patients of reproductive potential must have a negative serum pregnancy test within 14 days prior to randomization
• Patients must not have known active tuberculosis
• Patients must not have received a live, attenuated vaccine within 28 days prior to randomization
• NOTE: All coronavirus disease 2019 (COVID-19) vaccines that have received Food and Drug Administration (FDA) approval or FDA emergency use authorization are acceptable
• Patients must not have a known history of allergic reactions attributed to compounds of similar chemical or biologic composition to atezolizumab
• Patients must not have a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric antibodies, fusion proteins, or Chinese hamster ovary cell products or to any component of the atezolizumab formulation
• Patient must agree to have specimens submitted for translational medicine and banking
• Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
• As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
• Patients who can complete quality of life instruments in English, French, or Spanish must agree to complete the questionnaires at the protocol-specified time points
Lung Non-Small Cell Carcinoma, Stage I Lung Cancer AJCC v8, Stage II Lung Cancer AJCC v8, Lung
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Clinical Trial of Alpelisb and Tucatinib in Patients With PIK3CA-Mutant HER2+ Metastatic Breast Cancer.

Phase IB/II clinical trial of Alpelisb and Tucatinib in patients with PIK3CA-Mutant HER2-positive metastatic breast cancer.
Marina Sharifi, MD, PhD
All
18 Years and over
Phase 1/Phase 2
This study is NOT accepting healthy volunteers
NCT05230810
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Criteria: Inclusion criteria: 1. Women and men ≥ 18 years old are eligible to enroll 2. ECOG performance status 0-1 3. Life expectancy of more than 6 months, in the opinion of the investigator 4. Histologically confirmed diagnosis of HER2+ locally advanced unresectable or metastatic breast cancer. HER2 positivity is defined by fluorescence in situ hybridization (FISH) and/or 3+ staining by IHC according to the latest ASCO/CAP guidelines. 5. Documented presence of activating mutation in PIK3CA in the tumor, based on the analysis of solid or liquid biopsy by an assay approved for clinical decision makingby an FDA-approved test (examples include FoundationOne Liquid®; Guardant360®, Therrascreen® PIK3CA). 6. Known ER and PR status of the tumor defined by IHC according to the latest ASCO/CAP guidelines 7. Patients with HR-/HER2+ or HR+/HER2+ breast cancer may enroll 8. HR+/HER2+ patients should be men or post-menopausal women; premenopausal women with HR+/HER2+ breast cancer are eligible if on ovarian suppression, or agreeable to mandatory ovarian suppression 9. HR+/HER2+ patients should be agreeable to concomitant treatment with fulvestrant per study protocol. Prior therapy with fulvestrant is allowed. 10. Patients should have received at least two FDA-approved HER2-targeted agents at any time in the course of their disease. Note: 1 line of therapy containing EGFR or HER2-tyrosine kinase inhibitors (for example, neratinib, tucatinib, lapatinib, afatinib, pyrotinib, etc.) in the metastatic setting is allowed 11. Measurable and/or evaluable disease per RECIST 1.1 criteria and/or RANO-BM criteria (appendix C). Bone only disease is allowed. 12. CNS inclusion criteria: Based on screening contrast brain MRI, patients must have one of the following: 1. No evidence of brain metastases 2. Untreated brain metastases not needing immediate local therapy. For patients with untreated CNS lesions > 2.0 cm on screening contrast brain MRI, discussion with and approval from the medical monitor is required prior to enrollment 3. Previously treated brain metastases a. Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy, provided that there is no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator b. Patients treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study may be eligible to enroll if all of the following criteria are met: i. Time since WBRT is ≥ 21 days prior to first dose of treatment, time since surgical resection of CNS metastases is ≥ 14 days prior to the first dose of study treatment, or time since SRS is ≥ 7 days prior to first dose of treatment. ii. Other sites of disease evaluable by RECIST 1.1 or RANO-BM are present c. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions. 13. Adequate organ and marrow function as defined below:
• Absolute neutrophil count ≥ 1,500/mm3
• Platelets ≥ 75,000/mm3
• Hemoglobin ≥ 9.0 mg/dL without red blood cell transfusion ≤ 7 days prior to Cycle 1 Day 1 of therapy
• Total serum bilirubin ≤ 1.5 X upper limit of normal (ULN) except for subjects with known Gilbert's disease, who may enroll if the conjugated bilirubin is ≤ 1.5 ULN
• AST (SGOT)/ALT (SGPT) ≤2.5 X ULN;
• Serum creatinine Estimated creatinine clearance ≥50 mL/min as calculated by Cockroft-Gault formula; actual body weight must be used for creatinine clearance calculations unless BMI > 30 kg/m2 then lean body weight must be used;≤ 1.5 mg/dL
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN unless on medication known to alter INR and aPTT
• Fasting blood glucose ≤140 mg/dL
• HbA1C≤6.4%
• Left ventricular ejection fraction (LVEF) ≥ 50% (as assessed by ECHO or MUGA) documented within 4 weeks prior to first dose of study treatment
• Serum or urine pregnancy test (for women of childbearing potential, defined as premenopausal women who are not permanently sterile due to hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or bilateral tubal occlusion) negative ≤ 7 days of starting treatment 14. Patients with body mass index >25, or FBG 110-140mg/dL, or HbA1C 5.7
•6.4% should be agreeable for low glycemic diet and lifestyle modifications, and consulted by nutritionist prior to initiation of the study drugs. Ability to understand and the willingness to sign a written informed consent and comply with the study scheduled visits, treatment plans, laboratory tests and other procedures. Exclusion criteria: 1. Patients with contraindications to undergo contrast MRI imaging of the brain are excluded from the study 2. Pregnancy or breast feeding 3. Any systemic anti-cancer therapy (including hormonal therapy or investigational agents) or surgery in <14 days prior to the first dose of study treatment WBRT in <21 days, SBRT for CNS disease in <7 days, or palliative radiation to extracranial sites in <14 days prior to the first dose of study treatment5. 4. Based on screening brain MRI, patients must not have any of the following: 1. Any untreated brain lesions > 2.0 cm in size, unless discussed with medical monitor and approval for enrollment is given 2. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent). However, patients on a chronic stable dose of ≤ 2 mg total daily of dexamethasone (or equivalent) may be eligible with discussion and approval by the medical monitor 3. Any brain lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where increase in size or possible treatment-related edema may pose risk to patient (e.g. brain stem lesions). Patients who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study based on criteria described under CNS inclusion criteria 3b 4. Known or suspected leptomeningeal disease as documented by the investigator 5. Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy 5. Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the exception of peripheral neuropathy, which must have resolved to ≤ Grade 2, and alopecia 6. More than 1 line of therapy containing tucatinib, lapatinib, neratinib, afatinib, pyrotinib, or other EGFR or HER2 tyrosine kinase inhibitor in the metastatic setting. Note: receiving the above medications for <30 days is not considered to be a "line of therapy". Adjuvant treatment with EGFR or HER2 tyrosine kinase inhibitors does not count. 7. Previous treatment with alpelisib or other PI3K, mTOR or AKT inhibitor of more than 30 days duration. 8. An established diagnosis of diabetes mellitus type I, or uncontrolled diabetes mellitus type II 9. History of acute pancreatitis within 1 year of screening, or a past medical history of chronic pancreatitis 10. History of severe cutaneous hypersensitivity reactions (Steven Johnson syndrome, erythema multiforme or toxic epidermal necrolysis) 11. Active bacterial, fungal or viral infections requiring treatment with IV antibiotic, IV anti-fungal, or IV anti-viral drugs 12. Known active hepatitis B (HBV) or, active hepatitis C (HCV) or human immunodeficiency virus (HIV) infections. Note: pretesting is not required. Patients with history of treated and cured HCV infection may enroll if they have documented undetectable viral load. 13. Known HIV infection with CD4+ T-cell (CD4+) counts < 350 cells/μL. Note: pretesting is not required. Patients with known HIV infection and CD4+ T-cell (CD4+) counts ≥ 350 cells/μL may enroll. 14. Inability to swallow pills or any significant gastrointestinal disease which would preclude the adequate oral absorption of medications 15. Use of prohibited medications listed in the Appendix D (strong CYP3A4 inducers or inhibitors, and strong CYP2C8 inducers or inhibitors) within 3 elimination half-lives prior to initiation of study treatments 16. Myocardial infarction, severe/unstable angina, percutaneous transluminal coronary angioplasty/stenting (PTCA), or coronary artery bypass graft (CABG) within 6 month of the first dose of the study treatment 17. Clinically significant cardio-vascular disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension (defined as persistent systolic blood pressure > 160 mm Hg and/or diastolic blood pressure > 100 mm Hg on antihypertensive medications), or any history of symptomatic congestive heart failure (CHF) 18. Other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, or in the judgment of the investigator would make the subject inappropriate for entry into the study.
HER2-positive Metastatic Breast Cancer, Breast
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