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Testing Radiation and HER2-targeted Therapy Versus HER2-targeted Therapy Alone for Low-risk HER2-positive Breast Cancer (HERO)

This Phase III trial compares the recurrence-free interval (RFI) among patients with early-stage, low risk HER2+ breast cancer who undergo breast conserving surgery and receive HER2-directed therapy, and are randomized to not receive adjuvant breast radiotherapy versus those who are randomized to receive adjuvant radiotherapy per the standard of care.
Bethany Anderson, MD
All
40 Years and over
Phase 3
This study is NOT accepting healthy volunteers
NCT05705401
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Inclusion Criteria:

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information.
• female and male patients who have undergone breast conserving surgery and completed a minimum of 4 cycles (12 weeks) of neoadjuvant or adjuvant chemotherapy in combination with HER2-targeted therapy. -≥ 40 years of age
• ECOG performance status of 0 ,1, or 2/Karnofsky performance status above 60
• Histologically or cytologically confirmed invasive breast carcinoma.
• tumor must have been determined to be HER2-positive by current ASCO/CAP guidelines based on local testing results.
• Patient must have undergone axillary staging, either sentinel node biopsy (SNB) or axillary lymph nodal dissection (ALND). In neoadjuvant patients, SNB following neoadjuvant therapy is strongly recommended. SNB prior to neoadjuvant therapy is discouraged, but patients are permitted if node negative (pN0).
• The following staging criteria must be met according to AJCC 8th edition criteria: Adjuvant cohort : By pathologic evaluation, the patient's primary tumor must be • For the Adjuvant cohort, adjuvant therapy must have consisted of a minimum of 4 cycles (12 weeks) of chemotherapy in combination with HER2-targeted therapy.
• For the Neoadjuvant cohort, neoadjuvant therapy must have consisted of a minimum of 4 cycles (12 weeks) of chemotherapy in combination with HER2-targeted therapy.- ; Patients who did not receive chemotherapy in the neoadjuvant setting are not eligible, even if they achieved pCR with their preoperative treatment; nor would these patients become eligible by receiving chemotherapy after surgery.
• In patients assigned to radiation therapy, treatment should start ≤ 12 weeks from surgery on the Neoadjuvant cohort and ≤ 8 weeks from the completion of chemotherapy on the Adjuvant cohort. Patients should continue HER2-targeted therapy during assigned study treatment (radiation or observation).
• Bilateral mammogram or MRI within 52 weeks prior to randomization.
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial.
Exclusion Criteria:

• Definitive clinical or radiologic evidence of metastatic disease.
• On the Adjuvant cohort, patients with a primary tumor >2 cm on pathologic examination of the surgical specimen. On the Neoadjuvant cohort, patients with a primary tumor > 3 cm or with abnormal or suspicious ipsilateral axillary nodes by pretreatment imaging, unless demonstrated to be negative by cytologic or histologic examination.
• Pathologically positive axillary nodes at any time including of pN0(i+) or pN0(mol+) ypN0(i+) or ypN0(mol+) disease.
• Patient planning for or status-post mastectomy.
• Radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary lymph nodes, unless there is histological confirmation that these nodes are negative for metastatic disease.
• Suspicious microcalcifications, densities, or palpable abnormalities (in the ipsilateral or contralateral breast), or mass or non-mass enhancement on MRI (if performed) aside from the known cancer, unless biopsied and found to be benign.
• Non-epithelial breast malignancies such as sarcoma or lymphoma.
• Multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant or separated by > 4 centimeters. If multifocal, all foci should be confined to a maximum tumor bed of 3 cm determined by pathological assessment.
• Paget's disease of the nipple.
• Synchronous (unilateral or bilateral) invasive breast cancer or DCIS. (Patients with synchronous and/or previous contralateral LCIS are eligible.)
• On the Adjuvant cohort, surgical margins that cannot be microscopically assessed or are positive at pathologic evaluation. (If surgical margins are rendered free of disease by re-excision, the patient is eligible).
• Treatment plan that includes regional nodal irradiation.
• Patients treated for a prior invasive breast malignancy are excluded. Contralateral DCIS ≥ 10 years prior to enrollment is permissible.
• 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.
• Patients on oral, transdermal, or subdermal estrogen replacement (including all estrogen only and estrogen-progesterone formulas) are not eligible unless discontinued prior to randomization.
• Prior ipsilateral breast or thoracic RT for any condition (contralateral RT for DCIS ≥ 10 years prior to randomization is permitted).
• Active collagen vascular disease, specifically dermatomyositis with a CPK level above normal or with an active systemic lupus erythematosus, or scleroderma.
• Clinicians should consider whether any conditions would make this protocol unreasonably hazardous for the patient.
• Pregnancy or lactation at the time of randomization or intention to become pregnant during treatment. (Note: Pregnancy testing according to institutional standards for patients of childbearing potential must be performed within 14 days prior to randomization.)
• Use of any investigational product within 30 days prior to randomization.
Breast, HER2-positive Breast Cancer
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Selinexor in Maintenance Therapy After Systemic Therapy for Participants With p53 Wild-Type, Advanced or Recurrent Endometrial Carcinoma (XPORT-EC-042)

The purpose of this study is to evaluate the efficacy and safety of selinexor as a maintenance treatment in patients with p53 wt endometrial carcinoma (EC), who have achieved a partial response (PR) or complete response (CR) (per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST v 1.1]) after completing at least 12 weeks of platinum-based therapy. A total of 220 participants will be enrolled in the study and randomized in a 1:1 ratio to maintenance therapy with either selinexor or placebo.
Ellen Hartenbach, M.D.
All
18 Years and over
Phase 3
This study is NOT accepting healthy volunteers
NCT05611931
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Inclusion Criteria:

• At least 18 years of age at the time of signing informed consent.
• Histologically confirmed EC including: endometrioid, serous, undifferentiated, and carcinosarcoma.
• TP53 wt assessed by next generation sequencing (NGS), evaluated by a central vendor.
• Completed a single line, at least 12 weeks of platinum-based therapy (not including adjuvant or neoadjuvant therapy for Stage I-III disease) and achieved confirmed partial or complete response (PR or CR) by imaging, according to RECIST version 1.1. The participants should have received treatment for: Primary Stage IV disease, defined as:
• had a primary or later debulking surgery during first-line platinum-based therapy with R0 resection (R0 resection indicates a macroscopic complete resection of all visible tumor) and achieved CR after at least 12 weeks platinum-based therapy, OR
• had a primary or later debulking surgery during first-line platinum-based therapy with R1 resection (R1 resection indicates incomplete removal of all macroscopic disease) and achieved PR or CR after at least 12 weeks platinum-based chemotherapy, OR
• had no surgery and achieved PR or CR after at least 12 weeks platinum-based chemotherapy OR At first relapse (i.e., relapse after primary therapy including surgery and/or chemotherapy and/or immunotherapy for Stage I-IV disease), defined as:
• had Stage I
•III disease at diagnosis and received, at initial diagnosis, adjuvant chemotherapy and relapsed later. Participants should have PR or CR after at least 12 weeks of platinum-based chemotherapy compared with the start of this chemotherapy at the time of relapse,
• had Stage I-III disease at diagnosis and did not receive adjuvant chemotherapy at initial diagnosis and relapsed later. Participants should have PR or CR after at least 12 weeks of platinum-based chemotherapy compared with the start of this chemotherapy at the time of relapse, OR
• had Stage IV disease at diagnosis and received initially chemotherapy with or without surgery and relapsed later. At the time of relapse, participants should have PR or CR after at least 12 weeks of platinum-based chemotherapy compared with the start of this chemotherapy at the time of relapse.
• Previous treatment with anti-programmed cell death protein 1(PD-1) or anti-programmed death-ligand 1(PD-L1) monoclonal antibody and concomitant biologic agents (e.g., bevacizumab, trastuzumab) is allowed.
• Must be able to initiate study drug 3 to 8 weeks after completion of their final dose of chemotherapy.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Participants must have adequate bone marrow function and organ function within 2 weeks before starting study drug as defined by the following laboratory criteria:
• Hepatic function: total bilirubin up to less than (<) 3*upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to (<=) 2.5*ULN in participants without liver metastasis. For participants with known liver involvement of their tumor: AST and ALT (<=) 5*ULN
• Hematopoietic function within 1 week: Absolute neutrophil count (ANC) greater than or equal to (>=) 1.5*10^9/liter (L); platelet count >= 100*10^9/L; hemoglobin >= 9.0 gram per deciliter (g/dL) per local laboratory results
• Renal function: estimated creatinine clearance (CrCl) of >= 20 milliliter per minute (mL/min), calculated using the standard local formula, as applicable
•In the opinion of the Investigator, the participant must:
• Have a life expectancy of at least 12 weeks, and
• Be fit to receive investigational therapy
• Premenopausal females of childbearing potential must have a negative pregnancy test (serum β-human chorionic gonadotropin test) prior to the first dose of study drug. Female participants of childbearing potential must agree to use highly effective methods of contraception throughout the study and for 90 days following the last dose of study drug.
• Written informed consent signed in accordance with federal, local, and institutional guidelines prior to the first screening procedure.
Exclusion Criteria:

• Participants meeting any of the following exclusion criteria are not eligible to enroll in this study:
• Has any uterine sarcomas (carcinosarcomas
•not excluded), clear cell or small cell carcinoma with neuroendocrine differentiation
• Received a blood or platelet transfusion during the 2 weeks prior to Cycle 1 Day 1 (C1D1). Participants' hemoglobin must be assessed within 2 weeks of screening and at least 1 week post transfusion
• Concurrent systemic steroid therapy higher than physiologic dose (> 10 milligram per day [mg/day] of prednisone or equivalent). Systemic steroid therapy as pre-medication for taxane is allowed
• Insufficient time since or not recovered from procedures or anti-cancer therapy, defined as:
• Not recovered from major surgery <= 28 days prior to Day 1 dosing. Minor procedures, such as biopsies, dental work, or placement of a port or intravenous (IV) line for infusion are permitted
• Having ongoing clinically significant anti-cancer therapy-related toxicities CTCAE Grade > 1, with the exception of alopecia. In specific cases, participants whose toxicity has stabilized or with Grade 2 non-hematologic toxicities can be allowed following documented approval by the Sponsor's Medical Monitor
• Palliative radiotherapy within 14 days of the intended C1D1. Palliative radiotherapy may be permitted for symptomatic control of pain from bone metastases, provided that the radiotherapy does not involve target lesions, and the reason for the radiotherapy does not reflect evidence of disease progression.
• Any gastrointestinal dysfunctions that could interfere with the absorption of selinexor (e.g., bowel obstruction, inability to swallow tablets, malabsorption syndrome, unresolved nausea, vomiting, diarrhea CTCAE v 5.0 > grade 1).
• Participants unable to tolerate two forms of antiemetics for at least 2 cycles will not be eligible for the trial.
• Active, ongoing or uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week of screening.
• Serious psychiatric or medical condition that could interfere with participation in the study or in the opinion of the Investigator would make study involvement unreasonably hazardous.
• Previous treatment with an XPO1 inhibitor.
• Stable disease or PD on the post-chemotherapy scan or clinical evidence of progression prior to randomization.
• Participants who received any systemic anticancer therapy including investigational agents <= 3 weeks (or <= 5 half-lives of the drug [whichever is shorter]) prior to C1D1.
• Major injuries or surgery within 14 days prior to C1D1 and/or planned major surgery during the on-treatment study period.
• Other malignant disease with disease-free <= 3 years except: curatively treated carcinoma in situ of the cervix, basal cell carcinoma of the skin, or ductal carcinoma in situ (DCIS) of the breast.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to selinexor, or other agents used in the study.
• Active brain metastases (e.g., stable for < 8 weeks, no adequate previous treatment with radiotherapy and/or surgery, symptomatic, requiring treatment with anti-convulsant therapy. Corticoid therapy is allowed if administered as stable dose for at least 1 month before randomization).
• Females who are pregnant or lactating.
• Any other life-threatening illness, active medical condition, organ system dysfunction, or serious active psychiatric issue which, in the Investigator's opinion, could compromise the participant's safety or the participant's ability to remain compliant with study procedures.
Endometrial Cancer, Corpus Uteri, Uterus
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Testing the Addition of Whole Brain Radiotherapy Using a Technique That Avoids the Hippocampus to Stereotactic Radiosurgery in People With Cancer That Has Spread to the Brain and Come Back in Other Areas of the Brain After Earlier Stereotactic Radiosurgery

This phase III trial compares the effect of adding whole brain radiotherapy with hippocampal avoidance and memantine to stereotactic radiosurgery versus stereotactic radiosurgery alone in treating patients with cancer that has spread to the brain and come back in other areas of the brain after earlier stereotactic radiosurgery. Hippocampus avoidance during whole-brain radiation therapy decreases the amount of radiation that is delivered to the hippocampus, which is a brain structure that is important for memory. The medicine memantine is also often given with whole brain radiation therapy because it may decrease the risk of side effects of radiation on thinking and memory. Stereotactic radiosurgery delivers a high dose of radiation only to the small areas of cancer in the brain and avoids the surrounding normal brain tissue. Adding whole brain radiotherapy with hippocampal avoidance and memantine to stereotactic radiosurgery may be effective in shrinking or stabilizing cancer that has spread to the brain and returned in other areas of the brain after receiving stereotactic radiosurgery.
Andrew Baschnagel, MD
All
18 Years and over
Phase 3
This study is NOT accepting healthy volunteers
NCT04588246
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Inclusion Criteria:

• Patients must have developed their first or second distant brain relapse(s) at least 8 weeks after upfront SRS and within 21 days prior to randomization
• Distant brain relapse lesions to be treated must measure =< 3.0 cm in maximal extent and total volume of distant brain relapses to be treated must measure < 30 mL on the contrast-enhanced diagnostic magnetic resonance imaging (MRI) brain scan obtained within 21 days prior to randomization
• Distant brain relapse lesions must be diagnosed on MRI, which will include the following elements:
• REQUIRED MRI ELEMENTS
• Post gadolinium contrast-enhanced T1-weighted three-dimensional (3D) spoiled gradient (SPGR). Acceptable 3D SPGR sequences include magnetization-prepared 3D gradient recalled echo (GRE) rapid gradient echo (MP-RAGE), turbo field echo (TFE) MRI, BRAVO (brain volume imaging) or 3D fast FE (field echo). The T1-weighted 3D scan should use the smallest possible axial slice thickness, not to exceed 1.5 mm
• Pre-contrast T1 weighted imaging (3D imaging sequence strongly encouraged)
• A minimum of one axial T2 fluid attenuated inversion recovery (FLAIR) (preferred) or T2 sequence is required. This can be acquired as a 2D or 3D image. If 2D, the images should be obtained in the axial plane
• ADDITIONAL RECOMMENDATIONS
• Recommendation is that an axial T2 FLAIR (preferred) sequence be performed instead of a T2 sequence
• Recommendation is that that pre-contrast 3D T1 be performed with the same parameters as the post-contrast 3D T1
• Recommendation is that imaging be performed on a 3 Tesla (3T) MRI
• Recommendation is that the study participants be scanned on the same MRI instrument at each time point
• Recommendation is that if additional sequences are obtained, these should meet the criteria outlined in Kaufmann et al., 2020
• If additional sequences are obtained, total imaging time should not exceed 60 minutes
• Brain metastasis velocity (BMV) since upfront SRS must be >= 4 brain metastases/year
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
• Pathologically (histologically or cytologically) proven diagnosis of non-small cell lung cancer, melanoma, breast cancer, renal cell carcinoma, or gastrointestinal cancer within 10 years prior to randomization. If the original histologic proof of malignancy is greater than 10 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic metastasis or brain metastasis)
• Other histologies are not permitted
• History and physical examination within 28 days prior to randomization
• Karnofsky performance status of >= 70 within 28 days prior to randomization
• Calculated creatinine clearance (CrCl) >= 30 ml/min (within 28 days prior to randomization)
• Blood urea nitrogen (BUN) within 1.5 times the institutional upper limit of normal (ULN) (e.g., if the ULN is 20 mg/dL, then BUN up to 30 mg/dL is permitted) (within 28 days prior to randomization)
• Negative urine or serum pregnancy test (in women of childbearing potential) within 14 days prior to randomization
Exclusion Criteria:

• Prior WBRT or prophylactic cranial irradiation
• Local relapse of metastasis previously treated with upfront SRS (i.e., relapse outside previously SRS-treated metastases is allowed)
• Brain metastases from primary germ cell tumor, small cell carcinoma, or lymphoma
• Definitive leptomeningeal metastasis
• Planned cytotoxic chemotherapy on the same day as SRS or HA-WBRT; concurrent immunotherapy is permitted
• Radiographic evidence of enlargement or other architectural distortion of the lateral ventricles, including placement of external ventricular drain or ventriculoperitoneal shunt
• Known history of demyelinating disease such as multiple sclerosis
• Inability to swallow pills
• Contraindication to MR imaging such as non-MR conditional implanted metal devices or unknown metallic foreign bodies, or contraindication to gadolinium contrast administration during MR imaging, such as anaphylactic allergy that cannot be adequately addressed with pre-contrast medications or acute kidney injury
• Contraindications to memantine, including:
• Allergy, including prior allergic reaction to memantine
• Intractable seizures on adequate anticonvulsive therapy-more than 1 seizure per month for the past 2 months
• Current use of N-methyl-D-aspartate (NMDA) agonist
• Current alcohol or drug abuse, which can exacerbate lethargy/dizziness with memantine
• Severe, active co-morbidity defined as follows:
• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
• Transmural myocardial infarction within the last 6 months
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of randomization
• Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of randomization
• Severe hepatic disease defined as a diagnosis of Child-Pugh class B or C hepatic disease
• Renal tubular acidosis or metabolic acidosis
• Human immunodeficiency virus (HIV) positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count >= 200 cells/microliter within 30 days prior to randomization. Note also that HIV testing is not required for eligibility for this protocol
• Pregnant or lactating women, or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the medication and radiation involved in this study has unknown effects on the unborn fetus
Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Breast Carcinoma, Metastatic Digestive System Carcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Malignant Neoplasm in the Brain, Metastatic Melanoma, Metastatic Renal Cell Carcinoma, Prognostic Stage IV Breast Cancer AJCC v8, Recurrent Brain Neoplasm, Stage IV Lung Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8, Brain and Nervous System, Brain/Central Nervous System
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A Study of Camizestrant in ER+/HER2- Early Breast Cancer After at Least 2 Years of Standard Adjuvant Endocrine Therapy (CAMBRIA-1)

This is a Phase III open-label study to assess if camizestrant improves outcomes compared to standard endocrine therapy in patients with ER+/HER2 - early breast cancer with intermediate or high risk for disease recurrence who completed definitive locoregional therapy (with or without chemotherapy) and standard adjuvant endocrine therapy (ET) for at least 2 years and up to 5 years. The planned duration of treatment in either arm of the study is 60 months.
Kari Wisinski, MD
All
18 Years to 130 Years old
Phase 3
This study is NOT accepting healthy volunteers
NCT05774951
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Inclusion Criteria:

• Women and Men, ≥18 years at the time of screening (or per national guidelines)
• Histologically confirmed ER+/HER2- early-stage resected invasive breast cancer with high or intermediate risk of recurrence, based on clinical-pathological risk features, as defined in the protocol.
• Completed adequate (definitive) locoregional therapy (surgery with or without radiotherapy) for the primary breast tumour(s), with or without (neo)adjuvant chemotherapy
• Completed at least 2 years but no more than 5 years (+3 months) of adjuvant ET (+/- CDK4/6 inhibitor)
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
• Adequate organ and marrow function Exclusion criteria:
• Inoperable locally advanced or metastatic breast cancer
• Pathological complete response following treatment with neoadjuvant therapy
• History of any other cancer (except non-melanoma skin cancer or carcinoma in situ of the cervix or considered at very low risk of recurrence per investigator judgement) unless in complete remission with no therapy for a minimum of 5 years from the date of randomisation
• Any evidence of severe or uncontrolled systemic diseases which, in the investigator's opinion precludes participation in the study or compliance
• Known LVEF <50% with heart failure NYHA Grade ≥2.
• Mean resting QTcF interval >480 ms at screening
• Concurrent exogenous reproductive hormone therapy or non-topical hormonal therapy for non-cancer-related conditions
• Any concurrent anti-cancer treatment not specified in the protocol with the exception of bisphosphonates (e.g. zoledronic acid) or RANKL inhibitors (eg, denosumab)
• Previous treatment with camizestrant, investigational SERDs/investigational ER targeting agents, or fulvestrant
• Currently pregnant (confirmed with positive serum pregnancy test) or breastfeeding
• Patients with known hypersensitivity to active or inactive excipients of camizestrant or drugs with a similar chemical structure or class to camizestrant. In pre-/peri-menopausal female and male patients, known hypersensitivity or intolerance to LHRH agonists, that would preclude the patient from receiving any LHRH agonist
Breast Cancer, Early Breast Cancer, Breast
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Testing the Use of the Combination of Selumetinib and Olaparib or Selumetinib Alone Targeted Treatment for RAS Pathway Mutant Recurrent or Persistent Ovarian and Endometrial Cancers, A ComboMATCH Treatment Trial

This phase II ComboMATCH treatment trial compares selumetinib plus olaparib to selumetinib alone in women with endometrial or ovarian (fallopian tube and primary peritoneal) cancer that has come back (recurrent) or that remains despite treatment (persistent) and harbors a mutation in the RAS pathway. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. The addition of olaparib to selumetinib could increase the percentage of tumors that shrink as well as lengthen the time that the tumors remain stable (without progression) as compared to selumetinib alone.
Janelle Sobecki, MD
Female
18 Years and over
Phase 2
This study is NOT accepting healthy volunteers
NCT05554328
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Inclusion Criteria:

• Patient must have enrolled onto EAY191 and must have been given a treatment assignment to ComboMATCH to EAY191-N4 based on the presence of an actionable mutation as defined in EAY191
• Patients must be enrolled on the ComboMATCH Master Registration Trial EAY191
• Patients must have RAS pathway mutations as determined by the ComboMATCH screening assessment
• Cohort 1: Patients with histologically confirmed RAS pathway mutant ovarian, primary peritoneal, or fallopian tube ("ovarian") cancer (activating mutations in KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, or inactivating mutations in NF1)
• Cohort 2: Patients with histologically confirmed RAS pathway mutant endometrial cancer (activating mutations in KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, or inactivating mutations in NF1).
• Patients must have disease that can be safely biopsied and agree to a pre-treatment biopsy, if disease cannot be safely biopsied, or have archival tissue available from within 12 months prior to registration on the ComboMATCH Registration Trial (EAY191)
• Patients must have progressed after first-line treatment for recurrent or persistent disease
• Patients with ovarian cancer should not be eligible for further platinum-based therapy
• Patients with endometrial cancer must have received or been offered an immune oncology agent (alone or in combination with lenvatinib) unless there are existing contraindications for immune oncology agents or lenvatinib
• Patients may have received unlimited prior therapy
• Patients must have measurable and biopsiable disease. Measurable disease is defined by RECIST 1.1 as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be > 10 mm when measured by CT, magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or > 20 mm when measured by chest x-ray. Lymph nodes must be > 15 mm in short axis when measured by CT or MRI
• Patients must have at least one "target lesion" separate from the lesion to be biopsied to be used to assess response on this protocol as defined by RECIST version 1.1. Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy
• Prior therapy must have been completed at least four weeks prior to registration
• Age >= 18
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2
• Hemoglobin (Hgb) >= 9.5 g/dL with no blood transfusion in the past 28 days (within 14 days prior to registration)
• Platelets >= 100,000/mcl (within 14 days prior to registration)
• Absolute neutrophil count (ANC) >= 1,500/mcl (within 14 days prior to registration)
• Patients must have creatinine clearance estimated of >= 50 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test (within 14 days prior to registration)
• Total bilirubin level =< 1.5 x institutional upper limit of normal (ULN) or =< 3 x ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) (within 14 days prior to registration)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (within 14 days prior to registration)
• Patients must be able to swallow and retain oral medications and be without gastrointestinal illnesses that would preclude absorption of selumetinib or olaparib
• 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. To be eligible for this trial, patients should be class 2B or better
• Women of childbearing potential (WOCBP) must agree to use two forms of birth control (hormonal or barrier method of birth control; abstinence) during the study and for 12 weeks after completing treatment
• Non-sterilized male partners of WOCBP (including males sterilized by a method other than bilateral orchidectomy e.g., vasectomy) who intend to be sexually active with a female partner must be using an acceptable method of contraception such as male condom plus spermicide (condom alone in countries where spermicides are not approved) from the time of screening throughout the total duration of the study and the drug washout period (at least 16 weeks after the last dose of study intervention) to prevent pregnancy in a partner. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Vasectomized (i.e., sterile) males are considered fertile and should still use a male condom plus spermicide as indicated above during the clinical study
• 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
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial
• Patients with evidence of chronic hepatitis B virus (HBV) infection must have an undetectable HBV viral load 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
• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required during the first cycle of therapy
• Patients with treated brain metastases are eligible if follow-up brain imaging after CNS-directed therapy shows no evidence of progression
• Extra caution should be taken with olaparib, as it crosses the blood brain barrier and can cause edema in brain metastases
• 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 who have received any MEK inhibitors
• Patients who have progressed while receiving a PARP inhibitor
• Patients who have received chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to registration
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
• Patients with uncontrolled intercurrent illness
• Patients with >= grade 2 neuropathy within 14 days of registration
• Patients with severe (Child-Pugh C) liver dysfunction
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib and selumetinib or any excipients thereof
• Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
• Supplementation with vitamin E greater than 100% of the daily recommended dose. Any multivitamin containing vitamin E must be stopped prior to study enrollment even if less than 100% of the daily recommended dosing for vitamin E
• Vitamin E must not be taken in the 7 days prior to initiation of treatment with selumetinib
• Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or known moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, Fluconazole, verapamil). The required washout period prior to starting olaparib is at least 14 days or 5 half-lives (whichever is longer) before the first dose of study medication
• Concomitant use of strong CYP2C19 inhibitors (e.g., ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole). The required washout period prior to starting selumetinib is at least 14 days or 5 half-lives (whichever is longer) before the first dose of study medication
• Have received or are receiving an investigational medicinal product (IMP) or other systemic anti-cancer treatment (including chemotherapy, immunotherapy, targeted therapy, biologic therapy, tumor embolization, or monoclonal antibodies) within 4 weeks prior to registration, or within a period during which the IMP or systemic target treatment has not been cleared from the body (e.g., a period of 5 'half-lives'), whichever is longer
• Known myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
• Patients who have had previous organ transplant, allogenic bone marrow transplant or double umbilical cord blood transplantation
• Patients who have had whole blood transfusion within 28 days prior to registration
• Patients with ophthalmological conditions as follows:
• Current or past history of retinal pigment epithelial detachment/central serous retinopathy or retinal vein occlusion.
• Intraocular pressure >21 mmHg (or ULN adjusted by age) or uncontrolled glaucoma (irrespective of intraocular pressure [IOP]). Subjects with known glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) and are not experiencing pain related to the glaucoma, may be eligible after discussion with the study chair
• Patients with any other significant abnormality on ophthalmic examination should be discussed with the study chair for potential eligibility
• Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or longstanding orbito-temporal plexiform neurofibroma (PN) (such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study
• Patients with severe, active co-morbidity defined as any of the following:
• History and/or confirmed pneumonitis
• Uncontrolled hypertension (blood pressure [BP] >= 150/90 mmHg despite medical therapy)
• Acute coronary syndrome within 6 months prior to registration
• Uncontrolled atrial fibrillation
• Known family history of long QT syndrome
• Women who are pregnant or unwilling to discontinue nursing
Recurrent Endometrial Carcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma, Corpus Uteri, Ovary, Uterus
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Biomarkers to Detect Endocrine Therapy Resistance

This pilot observational study is being done to identify possible biomarkers of response to endocrine therapy in patients with ER/PR+ metastatic lobular breast cancer (LBC) starting new endocrine therapy. 18F-fluorofuranylnorprogesterone Positron Emission Tomography/Computed Tomography (FFNP-PET/CT) and liquid biopsies will be performed at baseline and after 4 weeks of treatment. Baseline levels and dynamic on-treatment changes in estrogen signaling as measured by FFNP-PET/CT and circulating tumor cell (CTC) liquid biopsy will be correlated with clinical response to endocrine therapy and progression-free survival in the above cohort of patients.
Marina Sharifi, MD, PhD
All
18 Years and over
Phase 2
This study is NOT accepting healthy volunteers
NCT06067503
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Inclusion Criteria:
1. Willing to provide informed consent 2. Individuals at least 18 years of age 3. Have biopsy-proven ER/PR-positive (defined as ER ≥1 percent and PR ≥1 percent by IHC) and HER2-negative advanced or metastatic LBC starting new standard of care endocrine therapy 4. Adequate organ function as indicated by standard laboratory tests (CBC, liver function tests or CMP) allowing for systemic breast cancer treatment per treating oncologist 5. Patients with evaluable bone-only disease that is lytic or mixed lytic-sclerotic are eligible 6. Willing to comply with all study procedures and be available for the duration of the study 7. Disease may be measurable by RECIST 1.1 criteria or non-measurable. Lesion size must be at least 1cm. If only bone lesions present, they should be lytic or mixed lytic-sclerotic. If only liver lesions present, patient is not eligible.
Exclusion Criteria:
1. Patients with active brain metastases 2. Patients with liver-only disease are not eligible due to high background liver activity related to the radiopharmaceutical's hepatobiliary route of elimination 3. Unable to lie flat during or tolerate PET/CT 4. Patients with a history of allergic reaction attributable to compounds of similar chemical or biologic composition to FFNP 5. Presence of liver failure as judged by patient's treating physician 6. Individuals who are pregnant, lactating, or planning on becoming pregnant during the study 7. Not suitable for study participation due to other reasons at the discretion of the investigators 8. Patients with progesterone-receptor negative disease defined as PR <1 percent by IHC
Metastatic Cancer, Breast Cancer, Lobular Breast Carcinoma, Breast
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Study of 18F-FFNP Breast PET/MRI

This clinical trial will investigate an estrogen-regulated parameter as an early measure of endocrine therapy response: progesterone receptor (PR) protein with a progestin-based radioligand, 18F-fluorofuranylnorprogesterone (18F-FFNP). The overall purpose of this research is to test the efficacy of 18F-FFNP PET/MRI for predicting response to presurgical endocrine therapy and to determine the quantitative reliability of 18F-FFNP breast PET/MRI in patients with newly diagnosed ER+/PR+/HER2- primary breast cancer.
Amy Fowler, MD, PhD
Female
18 Years and over
Phase 2
This study is NOT accepting healthy volunteers
NCT06086704
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Inclusion Criteria:

• Postmenopausal status defined by either
• prior bilateral oophorectomy
• age greater than or equal to 60 years of age
• age less than 60 years of age and amenorrheic for 12 or more months in the absence of prior chemotherapy, tamoxifen, toremifene or ovarian suppression and FSH and estradiol in the postmenopausal range per local normal range
• Diagnosis of biopsy-proven invasive breast cancer measuring at least 1.0 cm in diameter by any imaging modality
• Biopsy-proven ER-positive, PR-positive, HER2-negative invasive breast cancer
• Breast MRI planned or performed before surgery
• Definitive surgical excision of the primary tumor planned without neoadjuvant therapy; defined as therapy (chemotherapy, targeted therapy, radiation therapy or endocrine therapy) given to decrease the size of the tumor prior to planned surgery.
Exclusion Criteria:

• Inability or unwillingness to provide informed consent to the study
• PR and Ki67 IHC slides or FFPE tissue blocks from clinical breast biopsy not available
• Patients who have completed neoadjuvant chemotherapy, endocrine therapy, targeted therapy, surgical resection, or radiation for the current biopsy-proven malignancy
• Patients who are planning to undergo anastrozole as standard of care neoadjuvant therapy
• Patients who are currently taking aromatase inhibitors or ER antagonists (tamoxifen, raloxifene)
• Patients with breast expanders
• Patients who are pregnant or lactating
• Patients whose girth exceeds the bore of the PET/MRI scanner
• Patients with a contraindication to gadolinium-based contrast agents, including allergy or impaired renal function (per UW Health Guidelines)
• Patients with a history of allergic reaction attributable to compounds of similar chemical or biologic composition to 18F-FFNP
• Patients with history of allergic reaction to anastrozole
• Patients in liver failure as judged by the patient's physician
• Patients with standard contraindications to MRI (per UW Health Guidelines)
• Patients requiring conscious sedation for imaging are not eligible; patients requiring mild, oral anxiolytics for the clinical MRI scan will be allowed to participate as long as the following criteria are met:
• The patient has their own prescription for the medication
• The informed consent process is conducted prior to the self-administration of the medication.
• The patient comes to the research visit with a driver.
• Patients unable to lie prone for 45 minutes for imaging
• Patients taking hormone replacement therapy or over-the-counter products/supplements/herbal preparation with potential estrogenic effects who are unwilling to discontinue these agents during the timeframe of the study until surgery.
Breast Cancer, Breast
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Pembrolizumab vs. Observation in People With Triple-negative Breast Cancer Who Had a Pathologic Complete Response After Chemotherapy Plus Pembrolizumab

The phase III trial compares the effect of pembrolizumab to observation for the treatment of patients with early-stage triple-negative breast cancer who achieved a pathologic complete response after preoperative chemotherapy in combination with pembrolizumab. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This trial may help researchers determine if observation will result in the same risk of cancer coming back as pembrolizumab after surgery in triple-negative breast cancer patients who achieve pathologic complete response after preoperative chemotherapy with pembrolizumab.
Malinda West, MD
All
18 Years and over
Phase 3
This study is NOT accepting healthy volunteers
NCT05812807
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Inclusion Criteria:

• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
• Triple Negative Breast Cancer:
• Patients with a history of stage T1cN1-2 or T2-4N0-2 breast cancer according to the primary tumor-regional lymph node anatomic staging criteria of the American Joint Committee on Cancer (AJCC), 8th edition as determined by the investigator in radiologic assessment, clinical assessment or both
• Patients must have no residual invasive disease in the breast or lymph nodes after the completion of neoadjuvant therapy. Residual ductal carcinoma in situ (DCIS) is allowed. Isolated tumor cells are considered node-negative
• Estrogen (ER) and progesterone (PR) =< 10%; HER2-negative by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines (immunohistochemistry [IHC] and fluorescence in situ hybridization [FISH])
• If invasive disease was present in both breasts, participation in the study is permitted as long as the eligibility criteria are met for both tumors/breasts
• Patients must have received neoadjuvant chemotherapy in combination with pembrolizumab for a minimum of 6 cycles. All systemic chemotherapy and ICI therapy should have been completed preoperatively
• An interval of no more than 12 weeks between the completion date of the final surgery and the date of randomization * Note: Adjuvant radiation can be given on study. If given, it is encouraged to be given concurrently with pembrolizumab, per investigator discretion. Treatment with adjuvant pembrolizumab is strongly discouraged prior to participation in this trial, but if administered (e.g., if patients are awaiting pathology results), pembrolizumab may be administered for up to 6 weeks post-surgery and must be completed prior to registration
• Use of investigational anti-cancer agents must be discontinued at time of registration
• Adequate excision: Surgical removal of all clinically evident disease in the breast and lymph nodes as follows:
• Breast surgery: Total mastectomy or breast-conserving surgery with histologically negative margins, including no ink on tumor for DCIS, at the time of excision ** For patients who undergo breast-conserving surgery, the margins of the resected specimen must be histologically free of ductal carcinoma in-situ (DCIS) as determined by the local pathologist. If pathologic examination demonstrates DCIS at the line of resection, additional operative procedures may be performed to obtain clear margins. If DCIS 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:
• For a patient with clinically N0 disease, a sentinel lymph node biopsy should have been performed at time of surgical evaluation, and if pathologically node positive, the patient is no longer eligible. Isolated tumor cells are considered node-negative
• For a patient with clinically N1 disease at diagnosis (with positive results from a fine-needle aspiration, core biopsy, or sentinel node biopsy performed prior to preoperative therapy) additional surgical evaluation of the axilla following preoperative therapy is required *** If they become cN0 (no palpable adenopathy), then a sentinel lymph node biopsy could have been performed at time of surgery (axillary dissection would also be permitted); if the sentinel lymph node biopsy is positive, the patient is no longer eligible
• If sentinel node biopsy performed before preoperative therapy was negative, no additional surgical evaluation of the axilla is required after preoperative therapy. If sentinel node biopsy performed before preoperative therapy was positive, an ALND is required after preoperative therapy
• If the only sentinel node identified by isotope scan is in the internal mammary chain, surgical evaluation of the axilla is still required
• If sentinel node evaluation after preoperative therapy is negative, no further additional surgical evaluation of the axilla is required
• Axillary dissection without sentinel node evaluation is permitted as the initial or sole axillary evaluation after preoperative therapy
• If breast-conserving surgery was performed but patient will not be receiving breast radiation, the patient is not eligible
• Not pregnant and not nursing, because this study involves an agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative serum or urine pregnancy test done =< 7 days prior to randomization is required
• Absolute neutrophil count (ANC) >= 1,000/mm^3
• Platelet Count >= 100,000/mm^3
• Estimated glomerular filtration rate (eGFR) >= 15 mL/min/1.73m^2
• Total Bilirubin =<1.5 x upper limit of normal (ULN) * Patients with Gilbert's disease with a total bilirubin =< 2.5 x ULN and direct bilirubin within normal limits are permitted
• Aspartate aminotransferase (AST) serum aspartate aminotransferase [SGOT] / alanine aminotransferase (ALT) serum glutamic pyruvic transaminase [SGPT] =< 3 x institutional ULN
• Patients must be willing to provide tumor tissue from the diagnostic core biopsy. If inadequate tumor tissue is available, patients are still eligible to participate in the trial
• 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
• 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. To be eligible for this trial, patients should be class 2B or better
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial
Exclusion Criteria:

• No stage IV (metastatic) breast cancer
• No history of any prior (ipsi- or contralateral) invasive breast cancer. Prior DCIS is allowed
• No evidence of recurrent disease following preoperative therapy and surgery
• No known active liver disease, e.g. due to hepatitis B virus (HBV), hepatitis C virus (HCV), autoimmune hepatic disorders, or sclerosing cholangitis
• No history of intolerance, including Grade 3 or 4 infusion reaction or hypersensitivity to pembrolizumab or murine proteins or any components of the product * Note: Prior immune-related adverse events (irAEs) are allowed if they resolved and the patient tolerated subsequent therapy without requiring chronic steroids for the irAE
• No medical conditions that require chronic systemic steroids (>10 mg prednisone daily or equivalent) or any other form of immunosuppressive medications and has required such therapy in the last two years. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic therapy
• Patients who are unable or unwilling to comply with the requirements of the protocol per investigator assessment are not eligible
Breast, Anatomic Stage I Breast Cancer AJCC v8, Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, Early Stage Triple-Negative Breast Carcinoma
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KO-2806 Monotherapy and Combination Therapies in Advanced Solid Tumors (FIT-001)

This first-in-human (FIH) dose-escalation and dose-validation/expansion study will assess KO-2806, a farnesyl transferase inhibitor (FTI), as a monotherapy and in combination, in adult patients with advanced solid tumors.
Justine Bruce, MD
All
18 Years and over
Phase 1
This study is NOT accepting healthy volunteers
NCT06026410
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Inclusion Criteria:

• At least 18 years of age.
• Histologically or cytologically confirmed advanced solid tumors
• Arm #1 (Monotherapy): HRAS-mutant and/or amplified tumors (any solid tumor type); HRAS overexpression (only for HNSCC tumors); KRAS and/or NRAS, and/or HRAS-mutant and/or amplified NSCLC or CRC; KRAS-mutant and/or amplified PDAC
• Arm #2 (Combination): Must have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic RCC with predominantly clear cell subtype
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
• Karnofsky Performance Status of 70 or higher with no clinically significant deterioration over the previous 2 weeks.
• Acceptable liver, renal, endocrine, and hematologic function.
• Other protocol-defined inclusion criteria may apply.
Exclusion Criteria:

• Ongoing treatment with certain anticancer agents.
• Prior treatment with an FTI or HRAS inhibitor.
• Major surgery, other than local procedures, within 28 days prior to Cycle 1 Day 1, without complete recovery.
• Spinal cord compression, leptomeningeal disease, or clinically active CNS metastases.
• Toxicity (excluding alopecia) from prior therapy that has not been completely resolved to baseline at the time of consent.
• Active or prior documented autoimmune or inflammatory disorders within the past 5 years prior to Cycle 1 Day 1 (with exceptions).
• Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy.
• Inability to swallow, impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the trial drugs.
• Inadequate cardiac and/or vascular function, including receipt of treatment for unstable angina, myocardial infarction, and/or cerebro-vascular attack within the prior 6 months, mean QTcF ≥470 ms, or Class II or greater congestive heart failure.
• Other invasive malignancy within 2 years.
• Other protocol-defined exclusion criteria may apply.
Solid Tumors With HRAS Alterations, Non Small Cell Lung Cancer (NSCLC), Colorectal Cancer (CRC), Pancreatic Ductal Adenocarcinoma (PDAC), Clear Cell Renal Cell Carcinoma (ccRCC), Lip, Oral Cavity and Pharynx, Esophagus, Stomach, Small Intestine, Colon, Rectum, Anus, Liver, Pancreas, Other Digestive Organ, Larynx, Lung, Other Respiratory and Intrathoracic Organs, Bones and Joints, Soft Tissue, Melanoma, Skin, Kaposi's Sarcoma, Other Skin, Breast, Cervix, Corpus Uteri, Ovary, Other Female Genital, Prostate, Other Male Genital, Urinary Bladder, Kidney, Other Urinary, Eye and Orbit, Brain and Nervous System, Thyroid, Other Endocrine System, Unknown Sites, Ill-Defined Sites, Any Site, Anal, Bladder, Brain/Central Nervous System, Colon and Rectum, Endocrine cancers, Gastrointestinal cancers, other, Genitourinary cancers, other, Head and Neck, Melanoma/Skin cancer, Sarcoma, Uterus
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A Study of NDI 1150-101 in Patients With Solid Tumors

This study is to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) and to investigate the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of NDI-101150 given as monotherapy or in combination with pembrolizumab in adult patients with advanced solid tumors.
Hamid Emamekhoo, M.D.
All
18 Years and over
Phase 1/Phase 2
This study is NOT accepting healthy volunteers
NCT05128487
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Key
Inclusion Criteria:

• Life expectancy of ≥ 12 weeks
• Measurable or non-measurable disease for Dose Escalation; measurable disease using RECIST v1.1 is required for Dose Expansion
• Recovered from prior therapy to Grade ≤ 1 or return to baseline status (except for alopecia)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Patients with adequate bone marrow, kidney and liver function
• Last dose of previous anticancer therapy ≥ 4 weeks prior to first dose of NDI-101150; includes prior anti-PD-1 or anti-PD-L1 therapy, other anticancer therapy, radiotherapy, or surgical intervention
• For Dose Escalation Phase Only (Dose Escalation, Monotherapy and Combination Therapy): Histologically or cytologically confirmed advanced or metastatic solid tumors for whom no standard therapies are available or refractory to standard therapy
• For Dose Expansion Phase (Dose Expansion, Monotherapy and Combination Therapy): Willing to consent to required tumor biopsy(ies). Histologically or cytologically confirmed advanced or metastatic G/GEJ, NSCLC or RCC for which no standard therapy is available or are refractory to standard therapy Key
Exclusion Criteria:

• Previous solid organ or hematopoietic cell transplant
• Central nervous system (CNS) malignant disease not previously treated, active leptomeningeal disease, uncontrolled symptomatic CNS involvement, or CNS malignant disease requiring steroid or other therapeutic intervention
• Prior anticancer therapy within 2-6 weeks of trial start (depending on nature of therapy).
• Clinically significant cardiovascular disease
• History of severe hypersensitivity reaction to treatment with monoclonal antibody(ies) (for combination therapy cohorts only)
• History of interstitial lung disease, idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of history of pneumonitis on chest computed tomography scan in the last 6 months
• Known additional malignancy that is active and/or in progression requiring treatment
• Unstable or severe uncontrolled medical condition (e.g., unstable cardiac function, unstable pulmonary condition, uncontrolled diabetes, thromboembolic event within the past 3 months) or any important medical or psychiatric illness or abnormal laboratory finding
• Unable to discontinue medications that are strong inducers or inhibitors of CYP3A4 and/or CYP2C8
• History of severe irAE that led to permanent discontinuation of prior immunotherapy
• History of recent Grade >/= 3 irAE or any Grade 4 life-threatening irAE, neurologic or ocular AE of any grade while receiving prior immunotherapy NOTE: Other protocol defined Inclusion and Exclusion criteria may apply.
Lip, Oral Cavity and Pharynx, Esophagus, Stomach, Small Intestine, Colon, Rectum, Anus, Liver, Pancreas, Other Digestive Organ, Larynx, Lung, Other Respiratory and Intrathoracic Organs, Bones and Joints, Soft Tissue, Melanoma, Skin, Kaposi's Sarcoma, Other Skin, Breast, Cervix, Corpus Uteri, Ovary, Other Female Genital, Prostate, Other Male Genital, Urinary Bladder, Kidney, Other Urinary, Eye and Orbit, Brain and Nervous System, Thyroid, Other Endocrine System, Unknown Sites, Ill-Defined Sites, Any Site, Anal, Bladder, Brain/Central Nervous System, Colon and Rectum, Endocrine cancers, Gastrointestinal cancers, other, Genitourinary cancers, other, Head and Neck, Melanoma/Skin cancer, Sarcoma, Uterus, Solid Tumor
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Open-Label Umbrella Study To Evaluate Safety And Efficacy Of Elacestrant In Various Combination In Patients With Metastatic Breast Cancer (ELEVATE)

This is a multicenter, Phase 1b/2 trial. The phase 1b part of the trial aims to determine the RP2D of elacestrant when administered in combination with alpelisib, everolimus, palbociclib, abemaciclib, and ribociclib. The Phase 2 part of the trial will evaluate the efficacy and safety of the various combinations in patients with ER+/HER2- advanced/metastatic breast cancer.
Marina Sharifi, MD, PhD
All
18 Years and over
Phase 1/Phase 2
This study is NOT accepting healthy volunteers
NCT05563220
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Inclusion Criteria:
1. Patient has signed the informed consent before all study specific activities are conducted. 2. Women or men aged ≥18 years (or the minimum age of consent in accordance with the local law), at the time of informed consent signature. Female patients may be of any menopausal status.
• Postmenopausal status is defined by: 1. Age ≥60 years 2. Age <60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) or a follicle-stimulating hormone (FSH) value >40 mIU/mL and an estradiol value<40 pg/mL (140 pmol/L) or in postmenopausal ranges per local reference ranges 3. Documentation of prior surgical sterilization (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, at least 1 month before first dose of trial therapy).
• Premenopausal and perimenopausal women (who do not fit postmenopausal criteria) and men must be concurrently receiving a luteinizing hormone-releasing hormone (LHRH) agonist initiated at least 4 weeks before the start of trial therapy and are planning to continue LHRH agonist treatment during the study treatment.
• For perimenopausal women to be considered of non-childbearing potential, FSH levels must be >40 mIU/ml. 3. Histopathological or cytological confirmed ER+, HER2-, breast cancer, per local laboratory, as per the American Society of Clinical Oncology (ASCO)/College of American Pathologists(CAP) guidelines (Allison et al, 2020, Wolff et al, 2018). Note: In the context of this trial, ER status will be considered positive if ≥10% of tumor cells demonstrate positive nuclear staining by immunohistochemistry, with or without PGR positivity. . 4. At least 1 not previously irradiated measurable lesion as per RECIST version 1.1 and/or at least 1 lytic or mixed (lytic +sclerotic) bone lesion with identifiable soft tissue components meeting the definition of measurability by RECIST version 1.1 that can be evaluated by CT or MRI; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible. 5. ECOG performance status of 0 or 1. 6. Patient has adequate bone marrow and organ function, as defined by the following laboratory values: 1. Absolute neutrophil count (ANC) ≥1.5 × 10^9/L 2. Platelets ≥100 × 10^9/L 3. Hemoglobin ≥9.0 g/dL 4. Potassium, sodium, calcium (corrected for serum albumin) and magnesium CTCAE grade ≤1 5. Creatinine is ≤ 1.5 x ULN or if creatinine is > 1.5 x ULN, then creatinine clearance must be ≥50 mL/min based on the Cockcroft-Gault formula. Note: C-G formula:
• Creatinine clearance (male) = ([140-age in years] × weight in kg)/ ([serum creatinine in mg/dL] × 72)
• Creatinine clearance (female) = (0.85 × [140-age in years] × weight in kg)/ ([serum creatinine in mg/dL] × 72) 6. Serum albumin ≥3.0 g/dL (≥30 g/L) 7. In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × ULN. If the patient has liver metastases, ALT and AST ≤ 5 × ULN 8. Total serum bilirubin <1.5 × ULN except for patients with Gilbert's syndrome who may be included if the total serum bilirubin is ≤3.0 × ULN or direct bilirubin ≤ 1.5 × ULN.
Exclusion Criteria:
1. Active or newly diagnosed CNS metastases, including meningeal carcinomatosis. Note: Patients with stable brain or subdural metastases are allowed if the patient has completed local therapy and was on a stable or decreasing dose of corticosteroids at baseline for management of brain metastasis for at least 4 weeks before starting treatment in this study. The dose must be ≤2.0 mg/day of dexamethasone or equivalent. Any signs (e.g., radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment. 2. Patients with advanced, symptomatic visceral spread, that are at risk of life-threatening complications in the short term, including massive uncontrolled effusions (peritoneal, pleural, pericardial), pulmonary lymphangitis, or liver involvement >50%. 3. Prior chemotherapy or elacestrant in the advanced/metastatic setting. 4. Patients with known germline BRCA mutation without prior treatment with a PARP inhibitor before study entry. 5. Prior therapy with elacestrant or other investigational selective estrogen receptor degraders (SERDs), or investigational alike agents such as selective estrogen receptor modulators (SERM), selective estrogen receptor covalent antagonists (SERCANs), complete estrogen receptor antagonists (CERANs), and proteolysis-targeting chimeras (PROTACs), in the metastatic setting. Prior treatment with fulvestrant is not exclusionary as it is an approved medication. 6. Patient has a concurrent malignancy or history of invasive malignancy within 3 years of enrollment, except basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix that has completed curative therapy. Other malignancies with low risk of recurrence may be considered eligible with Sponsor approval. 7. Uncontrolled significant active infections. • Patients with HBV and/or HCV infection must have undetectable viral load during screening. • Patients known to be HIV+ are allowed if they have undetectable viral load at baseline. 8. Documented pneumonitis/ILD prior to Cycle 1 Day 1. 9. Major surgery within 28 days before starting trial therapy. 10. Inability to take oral medications, refractory or chronic nausea, gastrointestinal conditions (including significant gastric or bowel resection), history of malabsorption syndrome, or any other uncontrolled gastrointestinal condition that impact the absorption of the study drug. 11. Known intolerance to elacestrant or any of its excipients. 12. Pregnant and breast-feeding women are excluded from the study. In addition, women of childbearing potential are excluded who: • Within 28 days before starting trial therapy, did not use a highly effective method of contraception. • Do not agree to use a highly effective method of contraception (Appendix F) or abstain from heterosexual intercourse throughout the entire study period and for 120 days after trial therapy discontinuation. 13. Men or women who do not agree to abstain from donating sperm or ova, or to use a highly effective method of contraception, during the course of the treatment period and for 120 days after the last dose of study treatment. 14. Patient is currently receiving or received any of the following medications prior to first dose of trial therapy: • Anti-cancer therapy within 14 days (28 days for anticancer antibody based treatment) or 5 half-lives, whichever is shorter. Please note: Toxicity from prior therapy must be resolved to NCI CTCAE version 5.0 Grade ≤1, except alopecia and peripheral sensory neuropathy (Grade ≤2). • Known strong or moderate inducers or inhibitors of cytochrome P450 (CYP) 3A4 within 14 days or 5 half-lives, whichever is shorter, (refer to http://medicine.iupui.edu/clinpharm/ddis/ or https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interac tions-table-substrates-inhibitors-and-inducers). • Herbal preparations/medications within 7 days. These include, but are not limited to, St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. • Vaccination, including but not limited to vaccination against COVID-19, during the 7 days prior to randomization. 15. Evidence of ongoing alcohol or drug abuse as assessed by the investigator. 16. Any severe medical or psychiatric condition that, in the Investigator's opinion, would preclude the patient's participation in a clinical study. Additional Eligibility for the Alpelisib Combination (Phase 1b and Arm A) Inclusion: In general, the SmPC of the respective combination drug should be consulted for instructions/restrictions with respect to interactions with concomitant medications. 1. PIK3CA mutation by local laboratory assessment. 2. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor. Exclusion: 1. Prior therapy with alpelisib or any other PI3K inhibitor. 2. Type 1 diabetes or uncontrolled type 2 diabetes (fasting plasma glucose level of >140 mg/dL [7.7 mmol/L], or glycosylated hemoglobin [HbA1c] level of >6.4%). 3. Known intolerance to alpelisib or any of its excipients. 4. Patient is currently receiving or received drugs known to be a BCRP inhibitor within 14 days or 5 half-lives, whichever is shorter, prior to first dose of trial therapy 5. Patient has ongoing osteonecrosis of the jaw from previous or concurrent treatment with bisphosphonates or denosumab Additional Eligibility for the Everolimus Combination (Phase 1b and Arm B) Inclusion: 1. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor. Exclusion: 1. Prior therapy with everolimus. 2. Known intolerance to everolimus or any of its excipients. Additional Eligibility for the Abemaciclib Combination (Arm C) Inclusion: 1. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor. Exclusion: 1. Prior therapy with abemaciclib in the advanced or metastatic setting. Adjuvant therapy with abemaciclib is exclusionary if the patient relapsed within the past 12 months. 2. Known intolerance to abemaciclib or any of its excipients. Additional Eligibility for the Ribociclib Combination (Phase 1b and Arm C) Inclusion: 1. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor. Exclusion: 1. Prior therapy with ribociclib in the metastatic setting. Prior adjuvant therapy with ribociclib is also exclusionary if the patient relapsed within the past 12 months. 2. Known intolerance to ribociclib or any of its excipients. 3. QTcF values ≥450 msec. 4. Patients who already have or who are at significant risk of developing QTc prolongation, including patients with:
• Long QT syndrome
• Uncontrolled or significant cardiac disease including recent (6 months) myocardial infarction, congestive heart failure, unstable angina, and brady-arrhythmias
• Electrolyte abnormalities 5. Patient is currently receiving or received drugs known to prolong QT interval within 14 days or 5 half-lives, whichever is shorter, before the first dose of trial therapy. Additional Eligibility for the Palbociclib Combination (Phase 1b) Inclusion: 1. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor. Exclusion: 1. Prior therapy with palbociclib in the metastatic setting. 2. Known intolerance to palbociclib or any of its excipients Additional Eligibility for the Palbociclib Combination (Arm D) Inclusion: 1. One or up to two prior hormonal therapies in the advanced or metastatic setting. Exclusion: 1. Prior therapy with a CDK4/6i in the metastatic setting. 2. Known intolerance to palbociclib or any of its excipients. Additional Eligibility for the Abemaciclib Combination (Arm D) Inclusion: 1. One or up to two prior hormonal therapies in the advanced or metastatic setting. Exclusion: 1. Prior therapy with any CDK4/6i in the metastatic setting. 2. Known intolerance to abemaciclib or any of its excipients. Additional Eligibility for Ribociclib Combination (Arm D) Inclusion: 1. One or up to two prior hormonal therapies in the advanced or metastatic setting. Exclusion: 1. Prior therapy with a CDK4/6i in the advanced or metastatic setting. 2. Known intolerance to ribociclib or any of its excipients. 3. QTcF values ≥450 msec. 4. Patients who already have or who are at significant risk of developing QTc prolongation, including patients with:
• Long QT syndrome
• Uncontrolled or significant cardiac disease including recent (6 months) myocardial infarction, congestive heart failure, unstable angina, and brady-arrhythmias
• Electrolyte abnormalities 5. Patient is currently receiving or received drugs known to prolong QT interval within 14 days or 5 half-lives, whichever is shorter, before the first dose of trial therapy.
Breast Cancer, Metastatic Breast Cancer, Breast
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Testing the Use of Fulvestrant and Binimetinib Targeted Treatment for NF1 Mutation in Hormone Receptor-Positive Metastatic Breast Cancer, A ComboMATCH Treatment Trial

This ComboMATCH phase II trial compares the usual treatment alone (fulvestrant) to using binimetinib plus the usual treatment in patients with hormone receptor positive breast cancer that has spread from where it first started to other places in the body (metastatic) and has an NF1 genetic change. Fulvestrant is a hormonal therapy that binds to estrogen receptors in tumor cells, resulting in estrogen receptor destruction and decreased estrogen binding, which may inhibit the growth of estrogen-sensitive tumor cells. Binimetinib is a targeted therapy that may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. The addition of binimetinib to fulvestrant in breast cancers with an NF1 genetic change could increase the percentage of tumors that shrink as well as lengthen the time that the tumors remain stable (without progression) as compared to fulvestrant alone.
Mark Burkard, MD, PhD
All
18 Years and over
Phase 2
This study is NOT accepting healthy volunteers
NCT05554354
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Inclusion Criteria:

• A COMBOMATCH TREATMENT TRIAL EAY191 ELIGIBILITY CRITERIA:
• The patient must be enrolled on the ComboMATCH Master Registration Trial EAY191
• Note: Patients must fulfill all eligibility criteria outlined in the ComboMATCH Registration Trial EAY191 at the time of registration to EAY191-N2. This includes submission of next-generation sequencing (NGS) data from one of the National Cancer Institute (NCI) credentialed designated laboratories for all potential patients prior to treatment trial assignment. Copy number and allele frequency cutoff as per the Registration protocol
• Patients must have disease that can be safely biopsied and agree to a pre-treatment biopsy or, if disease cannot be safely biopsied, have archival tissue available from within 12 months prior to the date of registration on the ComboMATCH registration trial (EAY191)
• Please note the current actionable marker of interest (aMOI)/actionable alteration list for this treatment trial can be found on the Cancer Trial Support Unit (CTSU) ComboMATCH Registration protocol page
• Please note novel/Dynamic aMOI can be submitted for review per the process described in the ComboMATCH Registration protocol
• A COMBOMATCH TREATMENT TRIAL EAY191-N2 ELIGIBILITY CRITERIA:
• 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
• Age >= 18
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 within 14 days prior to registration
• Histologically or cytologically confirmed invasive breast carcinoma
• Confirmed metastatic disease by either imaging or tissue diagnosis
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and one additional lesion that can be biopsied (primary, metastatic both allowed)
• Patients must have NF1 nonsense or frameshift mutation, or NF1 whole gene deletion detected in tumor as determined by the ComboMATCH screening assessment
• The tumor must have been determined to be estrogen receptor (ER) and/or progesterone receptor (PgR) positive assessed by current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for hormone receptor testing. Patients with >= 1% ER or PgR staining by immunohistochemistry (IHC) are considered positive
• The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines
• Prior use of CDK4/6 inhibitor(i) is required
• Prior use of fulvestrant regardless of duration is allowed and will determine treatment assignment
• Up to one line of chemotherapy in metastatic setting is allowed
• Absolute neutrophil count >= 1,500/mm^3 (within 14 days prior to registration)
• Platelet count >= 100,000/ mm^3 (within 14 days prior to registration)
• Hemoglobin level >= 10 g/dL (within 14 days prior to registration)
• Measured or calculated creatinine clearance > 30 mL/min (within 14 days prior to registration)
• Total bilirubin level =< institutional upper limit of normal (within 14 days prior to registration)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be =< 5.0 x ULN
• Left ventricular ejection fraction (LVEF) assessment must be performed within 6 weeks prior to registration (LVEF assessment performed by echocardiogram is preferred; however, multi-gated acquisition scan [MUGA] scan may be substituted based on institutional/situational preferences). The LVEF must be >= 50% regardless of the cardiac imaging facility's lower limit of normal
• 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
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial
• ELIGIBILITY CRITERIA FOR COHORT 1, TREATMENT REGIMEN 2 PATIENTS WHO TRANSITION TO COHORT 2:
• Patient's willingness to transition to Cohort 2 affirmed
• The patient must have an ECOG performance status of 0-2
• Absolute neutrophil count >= 1,500/mm^3 (within 14 days prior to second registration)
• Platelet count >= 100,000/ mm^3 (within 14 days prior to second registration)
• Hemoglobin level >= 10 g/dL (within 14 days prior to second registration)
• Total bilirubin level =< institutional upper limit of normal (ULN) (within 14 days prior to second registration)
• AST and ALT must be =< 5.0 x ULN
• Measured or calculated creatinine clearance > 30 mL/min (within 14 days prior to second registration)
• The LVEF performed within the last 3 months must be >= 50% regardless of the cardiac imaging facility's lower limit of normal (LVEF assessment performed by echocardiogram is preferred; however, MUGA scan may be substituted based on institutional/situational preferences)
• Pregnancy test according to institutional standards done within 14 days before second registration must be negative (for patients of childbearing potential only)
Exclusion Criteria:

• Concurrent anticancer therapy
• Active autoimmune disease requiring systemic treatment within the past 3 months, documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents
• Active brain metastasis. Brain metastases that have been stable for at least 1 month after completion of treatment are not an exclusion criterion
• History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous, chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration
• Patients will be excluded if they currently have the following risk factors for RVO that are documented prior to the enrollment:
• Uncontrolled glaucoma with intra-ocular pressures >= 21 mmHg
• Serum cholesterol >= grade 2.
• Hypertriglyceridemia >= grade 2
• Hyperglycemia (fasting) >= grade 2
• Patients with baseline QT corrected for heart rate (QTc) > 500 ms, either induced by medication or congenital long QT syndrome will be excluded due to known side effects of binimetinib
• Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) >= grade 2 within 14 days prior to registration. Patients with nervous system disorders that resolve to =< Grade 1 prior to registration are eligible
• 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. To be eligible for this trial, patients should be class 2B or better
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
• Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results
• Pregnancy or lactation at the time of registration or intention to become pregnant during the study (Note: Pregnancy testing according to institutional standards for patients of childbearing potential must be performed within 14 days prior to registration)
• For binimetinib, highly effective contraception should be used for at least 30 days after the last dose, and patients should not breastfeed for 3 days after the last dose
• For fulvestrant, highly effective contraception should be used for 1 year after the last dose, and patients should not breastfeed for 1 year after the last dose
• Use of any investigational product within 30 days prior to study entry
• INELIGIBILITY CRITERIA FOR COHORT 1, TREATMENT REGIMEN 2 PATIENTS WHO TRANSITION TO COHORT 2
• Not a candidate for binimetinib in the opinion of the treating investigator
Breast, Anatomic Stage IV Breast Cancer AJCC v8, Metastatic HER2-Negative Breast Carcinoma, Metastatic Hormone Receptor-Positive Breast Carcinoma
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Study of EO-3021 in Adult Patients With Solid Tumors Likely to Express CLDN18.2

This study is an open-label, international, multi-center, Phase 1 study in adult patients with solid tumors likely to express CLDN18.2.
Nataliya Uboha, MD
All
18 Years and over
Phase 1
This study is NOT accepting healthy volunteers
NCT05980416
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Key
Inclusion Criteria:

• Availability of tumor tissue (archived and fresh tumor biopsy, if medically feasible)
• Select advanced or metastatic solid tumor that is likely to express CLDN18.2 such as gastric/GEJ, pancreatic and esophageal cancer
• ≥ 18 years of age
• ECOG performance status (PS) 0 or 1 at Screening
• Progressed on or after standard therapy, or are intolerable for available standard therapy, or there is no available standard therapy
• Have at least one measurable extra-cranial lesion as defined by RECIST v1.1
• Adequate organ function
• Life expectancy > 12 weeks
• Ability to understand the nature of this study, comply with protocol requirements, and give written informed consent
• Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following study completion Key
Exclusion Criteria:

• Pregnant or breastfeeding
• Symptomatic or untreated brain metastases
• Have previously received CLDN18.2 antibody drug conjugates (ADCs) or any ADC containing an auristatin payload (prior monoclonal antibody against CLDN18.2 may be eligible)
• Have peripheral neuropathy Grade ≥2
• Have history of non-infectious pneumonitis/interstitial lung disease
• Have diagnosis of another malignancy, or history of systemic treatment for invasive cancer within last 3 years. Note: Patients with Stage I cancer who have received definitive local treatment and are considered unlikely to recur are eligible. Diagnosis of non-melanoma skin cancer, carcinoma in situ of the cervix or breast, or noninvasive tumor does not affect eligibility
• Have active ocular surface disease at baseline (based on screening ophthalmic examination)
• Have serious concurrent illness or clinically relevant active bacterial, fungal or viral infection
• Have previous hypersensitivity to any known components of EO-3021 or history of severe infusion reaction or hypersensitivity (CTCAE Grade 3 or higher) with monoclonal antibody treatment
• Clinically significant cardiac disease, including but not limited to symptomatic congestive heart failure, unstable angina, acute myocardial infarction within 6 months of planned first dose, or unstable cardiac arrhythmia requiring therapy (including torsades de pointes)
• Have history of allogenic hematopoietic stem cell transplantation or solid organ transplantation with ongoing systemic immunosuppressive therapy
• Patients who are not appropriate candidates for participation in this clinical study for any other reason as deemed by the Investigator
Pancreas Neoplasm, Stomach Neoplasm, Gastrointestinal Neoplasms, Digestive System Neoplasm, Neoplasms by Site, Neoplasms, 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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Transversus Abdominis Plane Block Compared to Local Anesthetic Wound Infiltration in Gynecologic Oncology Surgery

This study is being done to see if preoperative transversus abdominis plane (TAP) analgesia will provide similar postoperative pain control, hospital length of stay, and postoperative outcomes compared to surgeon-initiated wound infiltration with local anesthetic in participants undergoing laparotomy for gynecologic indications.
Sumer Wallace, M.D.
Female
18 Years and over
Phase 4
This study is NOT accepting healthy volunteers
NCT06213454
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Inclusion Criteria:

• Ability to understand and the willingness to sign a written informed consent document
• Patients undergoing exploratory laparotomy via midline vertical skin incision for gynecologic indications at UW Hospital and Clinics
• Patients must be >18 years old
• English speaking (able to provide consent and complete questionnaires)
• Patients must have the ability to understand visual and verbal pain scales
• Patients must be eligible for TAP block placement. This will be confirmed during preoperative visit with the primary surgeon. Patient's are not eligible if they have allergies to the anesthetic medications or have had prior abdominal reconstructive surgery that would alter their abdominal wall anatomy in a way where the block would not be expected to be effective.
Exclusion Criteria:

• Known allergy to local anesthetics.
• Known history of chronic pain disorders and/or chronic opioid use defined as greater than 10mg of PO morphine or equivalent used daily for at least 30 days prior to enrollment.
• Patient has a history of opioid dependence requiring rehabilitation or the use of opioid antagonists.
• Patients with a planned exploration with biopsies (no organs removed) will be excluded from the study.
• Individuals who are pregnant, lactating or planning on becoming pregnant during the study.
• Significant liver disease that would inhibit prescription of opioids.
• Significant kidney disease that would inhibit administration of gabapentin.
• Not suitable for study participation due to other reasons at the discretion of the investigators.
Analgesia, Surgery, Cervix, Corpus Uteri, Ovary, Other Female Genital, Uterus
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Tobacco Treatment Comparison for Cancer Care

This pilot comparative effectiveness trial will compare two active smoking cessation treatments in terms of effectiveness, equity across patient subpopulations, and efficiency among adult patients diagnosed with cancer within the past 3 years. An enhanced treatment comprising 12 weeks of varenicline treatment and 7 smoking cessation coaching calls with a cancer focus will be compared against an active comparator modeled after standard quitline treatments (2 weeks of nicotine patch therapy with 3 phone coaching calls). Approximately 50 participants will be recruited to generate estimates of the effects, acceptability, costs, and equity of enhanced treatment (vs. standard treatment), with the primary outcome being abstinence from smoking 26 weeks after trying to quit.
Danielle Mccarthy
All
18 Years and over
Phase 4
This study is NOT accepting healthy volunteers
NCT06218823
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Inclusion Criteria:

• Alive (per medical record)
• Diagnosed with cancer in the past 3 years
• Received care from a participating oncology clinic in the past year
• Has a current tobacco use status
• Does not have a preferred language other than English (missing language preference will be included).
• Valid address that is not a correctional facility or residential treatment/care facility.
• No flag for patient cognitive impairment, activated health care power of attorney, or other health care agent (e.g., legally authorized representative) in the EHR. The following additional inclusion criteria must be met for inclusion in the CET
• Smoked combustible cigarettes in the past month.
• Able to speak and understand English.
• Willing to set a date to quit smoking in the next 60 days.
• Willing to receive smoking treatment information.
• Willing to complete study activities.
Exclusion Criteria:

• No current suicidal ideation.
• Suicide attempt in the past year.
• Currently receiving treatment for bipolar disorder, schizophrenia, schizoaffective disorder, or psychotic disorder.
• Incarceration.
• Unable to provide informed consent to treatment (i.e., cannot answer questions about study procedures or risks after hearing about the study).
Smoking Cessation, Cancer, Lip, Oral Cavity and Pharynx, Esophagus, Stomach, Small Intestine, Colon, Rectum, Anus, Liver, Pancreas, Other Digestive Organ, Larynx, Lung, Other Respiratory and Intrathoracic Organs, Bones and Joints, Soft Tissue, Melanoma, Skin, Kaposi's Sarcoma, Mycosis Fungoides, Other Skin, Breast, Cervix, Corpus Uteri, Ovary, Other Female Genital, Prostate, Other Male Genital, Urinary Bladder, Kidney, Other Urinary, Eye and Orbit, Brain and Nervous System, Thyroid, Other Endocrine System, Non-Hodgkin's Lymphoma, Hodgkin's Lymphoma, Multiple Myeloma, Lymphoid Leukemia, Myeloid and Monocytic Leukemia, Leukemia, other, Other Hematopoietic, Unknown Sites, Ill-Defined Sites, Any Site, Anal, Bladder, Brain/Central Nervous System, Colon and Rectum, Endocrine cancers, Gastrointestinal cancers, other, Genitourinary cancers, other, Head and Neck, Hematologic cancers, other, Leukemia, Lymphoma, Melanoma/Skin cancer, Sarcoma, Uterus
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A Phase 1/2 Study of DCC-3116 in Patients With MAPK Pathway Mutant Solid Tumors

This is a Phase 1/2, multicenter, open label, first in human (FIH) study of DCC-3116 as monotherapy, and in combination with trametinib, binimetinib, or sotorasib in patients with advanced or metastatic solid tumors with RAS/MAPK pathway mutation. The study consists of 2 parts, a dose-escalation phase, and an expansion phase.
Nataliya Uboha, MD
All
18 Years and over
Phase 1/Phase 2
This study is NOT accepting healthy volunteers
NCT04892017
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Inclusion Criteria:
1. Male or female participants ≥18 years of age 2. Dose Escalation Phase (Part 1): 1. Participants must have a pathologically confirmed diagnosis of an advanced or metastatic solid tumor with a documented RAS, NF1, or RAF mutations. A molecular pathology report documenting mutational status of RAS, NF1, or RAF must be available. 2. Progressed despite standard therapies, and received at least 1 prior line of anticancer therapy.
• Participants with a documented mutation in BRAF V600E or V600K must have received approved treatments known to provide clinical benefit prior to study entry. 3. Participants enrolled in the DCC-3116 and sotorasib cohort (Cohort D) must have a KRAS G12C mutation. 3. Dose Expansion Phase (Part 2): 1. Cohort 1: Patients with Pancreatic Ductal Adenocarcinoma (PDAC).
• Pathologically confirmed PDAC with a documented mutation in KRAS.
• Received only 1 prior line of systemic therapy in the advanced or metastatic setting. 2. Cohort 2: Patients with Non-Small Cell Lung Cancer (NSCLC)
• Pathologically confirmed NSCLC with a documented mutation in KRAS, NRAS, NF1, or BRAF.
• Received at least 2 prior lines but no more than 4 prior lines of systemic therapy in the advanced or metastatic setting. 3. Cohort 3: Patients with Colorectal Cancer (CRC)
• Pathologically confirmed CRC with a documented mutation in KRAS, NRAS, NF1, or BRAF.
• Received at least 2 prior lines of systemic therapy in the advanced or metastatic setting. 4. Cohort 4: Patients with Melanoma
• Pathologically confirmed melanoma with a documented mutation in NRAS.
• Received at least 1 but not more than 2 prior lines of systemic therapy in the advanced or metastatic setting that included T-cell checkpoint inhibitor-based therapy.
• Have not received prior MEK inhibitor therapy. 5. Cohort 5: Patients with KRAS G12C mutant NSCLC
• Pathologically confirmed NSCLC with a documented mutation in KRAS G12C.
• Received at least 1 prior line but no more than 3 prior lines of systemic therapy in the advanced or metastatic setting.
• Have not received prior sotorasib or other KRAS G12C inhibitor therapy. 4. Must provide a fresh tumor biopsy from a primary or metastatic cancer lesion that can be biopsied with acceptable risk as determined by the Investigator, and an archival tumor tissue sample, if available. If a fresh tumor biopsy is not possible, then an archival tumor tissue sample must be provided. 5. Eastern Cooperative Oncology Group (ECOG) score of 0 to 2 (Dose Escalation) or 0 to 1 (Dose Expansion) at Screening 6. Adequate organ function and bone marrow function. 7. If a female of childbearing potential must have a negative pregnancy test prior to enrollment and agree to follow the contraception requirements. 8. Male participants must agree to follow contraception requirements. 9. Must provide signed consent to participate in the study and is willing to comply with study-specific procedures.
Exclusion Criteria:
1. Must not have received the following within the specified time periods prior to the first dose of study drug: 1. Prior therapies (anticancer or therapies given for other reasons) that are known strong or moderate inhibitors or inducers of CYP3A4 or P-gp including certain herbal medications (eg, St. John's Wort): 14 days or 5× the half-life of the medication (whichever is longer) 2. All other prior anticancer therapies or any therapy that is investigational for the participant's condition with a known safety and PK profile: 14 days or 5× the half-life of the medication (whichever is shorter) 3. Investigational therapies with unknown safety and PK profile: 28 days. If there is enough data on the investigational therapy to assess the risk for drug.-drug interactions and late toxicities of prior therapy as low, the Sponsor's Medical Monitor may approve a shorter washout of 14 days 4. Grapefruit or grapefruit juice: 14 days 2. Have not recovered from all toxicities from prior therapy according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). 3. Presence or history of central nervous system (CNS) metastases or leptomeningeal disease, with some exceptions 4. New York Heart Association Class III or IV heart disease, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension, congestive heart failure, or myocardial infarction within 6 months prior to the first dose of study drug. 5. Prolongation of the QT interval corrected by Fridericia's formula (QTcF) based on repeated demonstration of QTcF >450 ms in males or >470 ms in females at screening, or history of long QT syndrome. 6. Left ventricular ejection fraction (LVEF) <50% at Screening 7. Systemic arterial thrombotic or embolic events 8. Systemic venous thrombotic events 9. Malabsorption syndrome 10. Bone disease that requires ongoing treatment or has required treatment. 11. Major surgery within 4 weeks of the first dose of study drug. All surgical wounds must be healed and free of infection or dehiscence before the first dose of the study drug. 12. Any other clinically significant comorbidities. 13. For participants receiving DCC-3116 and trametinib combination or DCC-3116 and binimetinib combination: previous treatment with trametinib or binimetinib that resulted in treatment discontinuation due to intolerability as a result of an adverse event (AE) that was considered related to trametinib or binimetinib. 14. For participants receiving DCC-3116 and sotorasib combination in Dose Escalation Part 1: previous treatment with sotorasib that resulted in treatment discontinuation due to intolerability as a result of an adverse event (AE) that was considered related to sotorasib. 15. For participants receiving DCC-3116 and sotorasib combination: Use of proton pump inhibitors (PPIs) and H2 receptor antagonists that cannot be discontinued 3 days prior to the start of study drug administration. 16. Known allergy or hypersensitivity to any component of the investigational drug products. 17. Known human immunodeficiency virus unless the following requirements are met: 1. CD4 count >350/µL 2. No AIDS-defining opportunistic infection in the last 12 months 3. Stable anti-retroviral regimen with medications that are not prohibited by the protocol for at least 4 weeks with HIV viral load less than 400 copies/mL prior to enrollment. 18. Known active hepatitis B, active hepatitis C infection or if the participant is taking medications that are prohibited per protocol. 19. If female, the participant is pregnant or lactating. 20. Ongoing participation in an interventional study. 21. For participants receiving DCC-3116 and binimetinib combination: Known Gilbert's syndrome
Pancreatic Ductal Adenocarcinoma, Non-Small Cell Lung Cancer, Colorectal Cancer, Melanoma, Advanced Solid Tumor, Metastatic Solid Tumor, Lip, Oral Cavity and Pharynx, Esophagus, Stomach, Small Intestine, Colon, Rectum, Anus, Liver, Pancreas, Other Digestive Organ, Larynx, Lung, Other Respiratory and Intrathoracic Organs, Bones and Joints, Soft Tissue, Melanoma, Skin, Kaposi's Sarcoma, Other Skin, Breast, Cervix, Corpus Uteri, Ovary, Other Female Genital, Prostate, Other Male Genital, Urinary Bladder, Kidney, Other Urinary, Eye and Orbit, Brain and Nervous System, Thyroid, Other Endocrine System, Other Hematopoietic, Unknown Sites, Ill-Defined Sites, Anal, Bladder, Brain/Central Nervous System, Colon and Rectum, Endocrine cancers, Gastrointestinal cancers, other, Genitourinary cancers, other, Head and Neck, Hematologic cancers, other, Melanoma/Skin cancer, Sarcoma, Uterus
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Evaluating the Addition of Adjuvant Chemotherapy to Ovarian Function Suppression Plus Endocrine Therapy in Premenopausal Patients With pN0-1, ER-Positive/HER2-Negative Breast Cancer and an Oncotype Recurrence Score Less Than or Equal to 25 (OFSET)

This Phase III Trial will determine whether adjuvant chemotherapy (ACT) added to ovarian function suppression (OFS) plus endocrine therapy (ET) is superior to OFS plus ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early- stage breast cancer (EBC) patients with estrogen receptor (ER)-positive, HER2-negative tumors and 21-gene recurrence score (RS) between 16-25 (for pN0 patients) and 0-25 (for pN1 patients).
Malinda West, MD
Female
18 Years to 60 Years old
Phase 3
This study is NOT accepting healthy volunteers
NCT05879926
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Inclusion Criteria:

• A patient cannot be considered eligible for this study unless ALL of the following conditions are met.
• The patient or a legally authorized representative must provide study-specific informed consent prior to pre-entry and, for patients treated in the U.S., authorization permitting release of personal health information.
• Female patients must be greater than or equal to 18 years of age.
• Patients must be premenopausal (evidence of functioning ovaries) at the time of pre-entry. For study purposes, premenopausal is defined as:
• Age 50 years or under with spontaneous menses within 12 months; or
• Age greater than 50-60 years with spontaneous menses within 12 months plus follicle-stimulating hormone (FSH) and estradiol levels in the premenopausal range; or
• Patients with amenorrhea due to IUD or prior uterine ablation must have FSH and estradiol levels in the premenopausal range; or
• Patients with prior hysterectomy must have FSH and estradiol levels in the premenopausal range.
• The patient must have an ECOG performance status of less than or equal to 2 (or Karnofsky greater than or equal to 60%).
• Patients may have ipsilateral or contralateral synchronous breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy.
• Patients may have multicentric or multifocal breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy.
• Patient may have undergone a total mastectomy, skin-sparing mastectomy, nipple-sparing mastectomy, or a lumpectomy.
• For patients who undergo a lumpectomy, the margins of the resected specimen or re-excision must be histologically free of invasive tumor and DCIS (ductal carcinoma in situ) with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. Positive posterior margin is allowed if surgeon deems no further resection possible. (Patients with margins positive for LCIS (lobular carcinoma in situ) are eligible without additional resection.)
• For patients who undergo mastectomy, the margins must be free of residual gross tumor. (Patients with microscopic positive margins are eligible if post-mastectomy RT (radiation therapy) of the chest wall will be administered.)
• Patient must have undergone axillary staging with sentinel node biopsy (SNB), targeted axillary dissection (TAD), or axillary lymph node dissection (ALND).
• The following staging criteria must be met postoperatively according to AJCC 8th edition criteria:
• By pathologic evaluation, primary tumor must be pT1-3. (If N0, must be T1c or higher.)
• By pathologic evaluation, ipsilateral nodes must be pN0 or pN1 (pN1mi, pN1a, pN1b, pN1c).
• Patients with positive isolated tumor cells (ITCs) in axillary nodes will be considered N0 for eligibility purposes.
• Patients with micrometastatic nodal involvement (0.2-2 mm) will be considered N1.
• Oncotype DX RS (recurrence score) requirements*:
• If node-negative:
• Oncotype DX RS must be RS 21-25, or
• Oncotype DX RS must be 16-20 and disease must be high clinical risk, defined as: low histologic grade with primary tumor size greater than 3 cm, intermediate histologic grade with primary tumor size greater than 2 cm, or high histologic grade with primary tumor size greater than 1 cm.
• If 1-3 nodes involved:
• Oncotype DX RS must be less than 26. * Patients with a "Low Risk" or "MP1" MammaPrint (a genomic test that analyzes the activity of certain genes in early-stage breast cancer) result must have eligibility assessed with an Oncotype DX RS at pre-entry (see Section 3.1). Blocks or unstained slides must be sent to the Genomic Health centralized laboratory for testing at no cost to these patients. If MammaPrint High Risk or MP2, these patients are not eligible.
• The tumor must be ER and/or PgR-positive (progesterone receptor) by current ASCO/CAP guidelines based on local testing results. Patients with greater than or equal to 1% ER and/or PgR staining by IHC will be classified as positive.
• The tumor must be HER2-negative by current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines based on local testing results.
• The interval between the last surgery for breast cancer (including re-excision of margins) and pre-entry must be no more than 16 weeks.
• Short course of endocrine therapy of less than 6 weeks duration before pre-entry is acceptable either as neoadjuvant or adjuvant therapy. An Oncotype DX RS must be performed on core biopsy specimen obtained prior to initiation of neoadjuvant endocrine therapy if received.
• Patients with a prior or concurrent non-breast 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. This would include prior cancers treated with curative intent.
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• Radiation therapy should be used according to standard guidelines; the intended radiation therapy should be declared prior to pre-entry.
Exclusion Criteria:

• • Definitive clinical or radiologic evidence of metastatic disease.
• pT4 (pathological state) tumors, including inflammatory breast cancer.
• History of ipsilateral or contralateral invasive breast cancer. (Patients with synchronous and/or previous DCIS or LCIS are eligible.)
• If prior ipsilateral DCIS was treated with lumpectomy and XRT (ionizing radiation therapy), a mastectomy must have been performed for the current cancer.
• Life expectancy of less than 10 years due to co-morbid conditions in the opinion of the investigator. Known results from most recent lab studies obtained as part of routine care prior to study entry showing ANY of the following values:
• ANC (absolute neutrophil count) less than 1200/mm3;
• Platelet count less than 100,000/mm3;
• Hemoglobin less than 10 g/dL;
• Total bilirubin greater than ULN (upper limit of normal) for the lab or greater than 1.5 x ULN for patients who have a bilirubin elevation due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin;
• AST(aspartate aminotransferase)(SGOT)/ALT (alanine transminase)(SGPT): greater than 3 × institutional ULN;
• Renal function of GFR (glomular filtration rate) less than 30 mL/min/1.73m2.
• 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. To be eligible for this trial, patients should be class 2B or better.
• Non-epithelial breast malignancies such as sarcoma or lymphoma.
• Any treatment with radiation therapy, chemotherapy, or biotherapy administered for the currently diagnosed breast cancer prior to pre-entry. (Patients with prior ET of more than 6 weeks duration for treatment of this cancer are not eligible.) Prior tamoxifen given for breast cancer prevention is allowed. Prior AI or GnRH for fertility preservation is allowed.
• Hormonally based contraceptive measures must be discontinued prior to pre-entry (including progestin/progesterone IUDs).
• Patients with evidence of chronic hepatitis B virus (HBV) infection are ineligible unless the HBV viral load is undetectable on suppressive therapy. Patients with a history of hepatitis C virus (HCV) infection are ineligible unless they have been treated and cured or have an undetectable HCV viral load if still on active therapy.
• Pregnancy or lactation at the time of pre-entry. (Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to pre-entry.)
• Other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.
Breast, Breast Cancer
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A Study of Alpelisib and Fulvestrant to Treat Endometrial Cancer

This is a 2 stage multi-center study designed to evaluate the efficacy of the combination of alpelisib and fulvestrant in patients with PIK3CA-mutated ER-positive endometrioid endometrial cancers by estimating the objective response rate (ORR). Treatment will continue until either unacceptable toxicity, progression of disease, or investigator/patient request for withdrawal.
Janelle Sobecki, MD
Female
18 Years and over
Phase 2
This study is NOT accepting healthy volunteers
NCT05154487
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Inclusion Criteria:
1. Patient must have advanced (FIGO 2014 Stage III or IV), persistent, or recurrent endometrial carcinoma, which is not likely to be curable by surgery or radiotherapy. Histologic confirmation of recurrent disease is required. For cases of persistent disease, histologic confirmation of the primary disease with radiologic evidence of progression is required. 2. Patients must have endometrioid histology (all grades allowed) based on hysterectomy or biopsy specimen and have positive expression of ER and oncogenic PIK3CA mutation per criteria below. a. PIK3CA mutations considered oncogenic include R88Q, N345K, C420R, E542K, E545X, Q546X, M1043I, H1047X, or G1049R. The list of oncogenic mutations acceptable for enrollment may be expanded as further information becomes available. i. Oncogenic PIK3CA mutations identified on tests performed by the labs listed on https://ecog-acrin.org/nci-match-eay131-designated-labs will be considered confirmed for the purposes of this study ii. Oncogenic PIK3CA mutations identified by other tests will need to be confirmed by the study prior to enrollment b. Estrogen receptor (ER) status will be considered positive if ≥1% of tumor cells demonstrate positive nuclear staining by immunohistochemistry. Pathology report documenting ER status must be provided at enrollment. Sites are required to report results of previous MMR and/or MSI status testing in Medidata Rave if available. 3. All patients must have measurable disease. Measurable disease is defined by RECIST version 1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be greater than or equal to 10mm when measured by CT, MRI or caliper measurement by clinical exam; or greater than or equal to 20mm when measured by chest x-ray. Lymph nodes must be greater than or equal to 15mm in short axis when measured by CT or MRI. Patients must have at least one "target lesion" to be used to assess response on this protocol as defined by RECIST 1.1. Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy. 4. Prior chemotherapy in the adjuvant setting for Stage I, II, or III is permitted. Prior chemoradiotherapy for a pelvic recurrence is permitted. Note: No prior chemotherapy in the setting of Stage IV disease is permitted unless the patient was without evidence of disease at the completion of chemotherapy and had a least six months of progression-free survival since the completion of chemotherapy. Regardless of circumstances, no more than one prior chemotherapy regimen (including chemo-radiotherapy) is permitted. Patients who received prior chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to enrollment. A washout period of at least 21 days is required between last chemotherapy dose and initiation of therapy. Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and initiation of therapy. 5. Patient must be able to swallow oral medications. 6. Patient must have an ECOG performance status of 0 to 1. 7. Patients must have adequate glucose control as defined by the following (both criteria must be met):
• Fasting blood glucose (FBG) ≤140/dL (7.7mmol/L) AND
• Hemoglobin A1c (HbA1c) ≤6.4% 8. Patients must have adequate organ and marrow function as defined below NOTE: Institutional/laboratory upper limit of normal = ULN Institutional/laboratory lower limit of normal = LLN Bone marrow function:
• Absolute neutrophil count (ANC) greater than or equal to 1500/mcl
• Platelets greater than or equal to 100,000 cells/mcl
• Hemoglobin greater than or equal to 8 g/dL (Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after erythrocyte transfusion). Renal function: • Creatinine Clearance ≥ 35 mL/min using Cockcroft-Gault formula Pancreatic function:
• Fasting Serum amylase ≤ 2 × ULN
• Fasting Serum lipase ≤ ULN Hepatic function:
• Bilirubin less than or equal to 1.5 x ULN (Patients with Gilbert's syndrome with a total bilirubin ≤2 times ULN and direct bilirubin within normal limits are permitted).
• ALT (alanine aminotransferase) and AST (aspartate aminotransferase) less than or equal to 3 x ULN
• Alkaline phosphatase less than or equal to 2.5 x ULN
• Albumin greater than or equal to 2.8 g/dL 9. Patients must have signed an approved informed consent and authorization permitting release of personal health information. 10. Patients must be at least 18 years of age. 11. Patients of childbearing potential must have a negative serum pregnancy test prior to the study entry and be practicing a highly effective form of contraception during the study treatment and for 8 weeks after stopping the treatment. Highly effective contraception methods include combination of any of the following (oral, injected, or implanted hormonal contraceptives are prohibited:
• Placement of an intrauterine device (IUD) or intrauterine system (IUS);
• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository;
• Total abstinence or;
• Male/female sterilization. Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to randomization. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential.
Exclusion Criteria:
1. Patients who have previously received any PIK3CA, PI3K, mTOR, or AKT inhibitor. 2. Patients with clear cell, serous, carcinosarcoma, mixed histology endometrial cancers, or uterine sarcomas. 3. Known intolerance or hypersensitivity to alpelisib or fulvestrant, or any of their excipients. 4. Patients who have previously received hormonal therapy for endometrial cancer. 5. Participant has had major surgery within 14 days prior to study treatment start and/or has not recovered from major side effects. 6. Participant with an established diagnosis of diabetes mellitus type I or uncontrolled type II (based on fasting blood glucose [FBG] and HemoglobinA1c [HbA1c], see INCLUSION CRITERION 7) 7. Patients with concomitant invasive malignancy or a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the past five years. Patients are also excluded if their previous cancer treatment contraindicates this protocol. 8. Patients with active bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment, fungal infection, or detectable viral infection (such as known human immunodeficiency virus (HIV) positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]). Screening is not required for enrollment. 9. Patients with a serious pre-existing medical condition(s) that would preclude participation in this study (for example: interstitial lung disease or pneumonitis, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment (i.e. estimated creatinine clearance <30ml/min), history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or pre-existing chronic condition resulting in baseline grade 2 or higher diarrhea). 10. Patients with a known history of cardiac disease. This includes:
• Uncontrolled hypertension, defined as systolic greater than 150mm Hg or diastolic greater than 90mm Hg despite antihypertensive medications
• Myocardial infarction, unstable angina, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to registration.
• New York Heart Association (NYHA) Class II or greater congestive heart failure.
• History of clinically significant cardiac arrhythmias (i.e. ventricular tachycardia or ventricular fibrillation, complete left bundle branch block, high grade AV block (e.g. bifascicular block, Mobitz type II and third degree AV block without pacemaker in place) or serious cardiac arrhythmia requiring medication. This does not include asymptomatic atrial fibrillation with controlled ventricular rate.
• Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or Fridericia QT correction formula (QTcF) > 470 msec at screening.
• Cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) within 6 months prior to the first date of study therapy.
• Syncope of cardiovascular etiology,
• Sudden cardiac arrest. 11. Participant is currently receiving any of the following medications and cannot be discontinued 7 days prior to the start of the treatment:
• Strong CYP3A4 inducers
• Inhibitors of BCRP. 12. Patients who are pregnant or breast-feeding. 13. Patients with known central nervous system metastases which was not previously treated and not fulfilling the following 3 criteria to be eligible for the study:
• Completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 28 days prior to the start of study entry and
• CNS tumor is clinically stable at the time of screening and
• Participant is not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases. 14. Patients with an impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study drugs (i.e. ulcerative disease; uncontrolled nausea, vomiting and/or diarrhea; malabsorption syndrome; clinical signs and symptoms of gastrointestinal obstruction; and/or patients who require parenteral hydration and/or nutrition). 15. Patients who plan to receive live attenuated vaccines within 1 week of start of alpelisib and during the study. Patients should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG< yellow fever, varicella, and TY21a typhoid vaccines. 16. Patients with active bleeding or pathologic conditions that carry high risk of bleeding such as known bleeding disorder or coagulopathy. 17. Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 30 days prior to dosing, or within 5 half-lives of the investigational product, whichever is longer. 18. Patient is not able to understand and to comply with study instructions and requirements, including oral administration of study treatment.
Endometroid Endometrial Cancer, Corpus Uteri, Uterus
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