• Participant must be neurologically normal, defined as free of unstable neurologic and psychiatric disease as confirmed by a normal neurologic examination at screening
• Participant (GBCA-exposed or controls) agrees to undergo unenhanced magnetic resonance imaging (UE-MRI) of the brain at enrollment and at the end of the observation period (5 years)
• Participants should have at least 1 of the following indications: a) Medium to high risk for breast cancer or dense breasts undergoing breast cancer screening with MRI, b) Elevated prostate-specific antigen (PSA) and under active diagnostic surveillance for prostate cancer, c) Chronic liver disease (eg, liver cirrhosis limited to Child class A, post-hepatitis chronic hepatopathy, or primary sclerosing cholangitis) for surveillance of hepatocellular carcinoma development, d) Low-grade colorectal cancer or neuroendocrine tumor undergoing screening for liver metastases or e) Branch-duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas (maximum size ≤2 cm) undergoing imaging surveillance. In addition, for participants in the GBCA Arms only:
• Each participant should be likely to undergo ≥5 GBCA-enhanced MR examinations with the same GBCA at least annually throughout the 5-year study duration
• Prospective participants with up to 3 well documented GBCA administrations prior to study screening are acceptable, provided that the imaging was performed with the same GBCA as the one to be prospectively used in the study. If the GBCA used cannot be identified, he/she cannot be enrolled. For the Control Arm:
• Participants who never had and are not likely to receive any GBCA injection during the course of the study
• Each control participant must be willing to undergo UE-MRI of the brain at baseline and at Year 5. In Years 1 to 4, the control participants will undergo their clinically indicated UE-MRIs, computed tomography (CT), ultrasound, or X-ray procedures
• As evidenced by history or determined in the neurologic exam at screening, concurrent neurological and/or psychiatric disease (or treatments) that could influence the results of the study's motor and cognitive tests (e.g. Cerebrovascular disease, Multiple sclerosis, Neurodegenerative disease, Malignant disease other than listed in indications, Carcinoid tumors, Epilepsy, Prior neurosurgery, Psychotic disorders or any prior psychotic episode not otherwise specified
•any documented prior history of chronic schizophrenia, Remittent or current medically confirmed major depressive disorder or bipolar disorder, History of long-term major depression or bipolar affective disorder with an active episode in the past 2 to 5 years, Neurodevelopmental disorders (eg, trisomy 21), Uncontrolled severe migraine, Uncontrolled or controlled anxiety or depression within 6 months before enrollment, Screening scores of ≤24 on the MMSE and/or ≥11 on the Hospital Anxiety and Depression Scale (HADS)).
• Prior, planned, or ongoing chemotherapy or brain irradiation
• Use of concomitant medication(s) affecting neuro-cognitive or motor function
• Substance or alcohol abuse as determined by the investigator
• Alcoholic cirrhosis
• Renal disease, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2
• History of environmental/occupational/other exposure to one or more chemicals that may affect cognitive and/or motor function, including, but not limited to, heavy metals (arsenic [As], cadmium [Cd], lead [Pb], manganese [Mn], and mercury [Hg]), pesticides, solvents, or carbon monoxide.
• Clinical indications requiring >1 contrast enhanced magnetic resonance imaging (CE-MRI) every 6 months
• Pregnant or nursing (lactating) women
• Presence of any metal-containing joint implants/prostheses In addition, for participants in either of the GBCA Arms only:
•Receipt of a GBCA or generic prior to study entry other than the specific GBCA to be administered during the course of the study. For participants in the Control Arm only:
• Participants with any previous exposure to a GBCA.
• Participants with any contraindication to UE-MRI examinations.

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

General (applies to all cohorts) 1. Signed written informed consent. 2. Male or female patients aged ≥ 18 years. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at study entry and an estimated life expectancy of at least 3 months. 4. Baseline Left Ventricular Ejection Fraction (LVEF) ≥ 55% measured by echocardiography (preferred) or multigated acquisition (MUGA) scan. 5. Adequate hematological function. 6. Adequate hepatic function. 7. Adequate renal function. 8. Effective contraception for women of child bearing potential (WOCBP) patients as defined by World Health Organization (WHO) guidelines for 1 "highly effective" method or 2 "effective" methods. NSCLC (HER2 Activated) Exploratory Efficacy Cohorts
•Monotherapy and Combination with Sacituzumab Govitecan-hziy. 1. Have progression of unresectable locally advanced or metastatic NSCLC after last systemic therapy (as confirmed by investigator) or be intolerant of last systemic therapy. 2. Have HER2 overexpression status (IHC 2+ or 3+), or ERBB2 amplification, or HER2 activating mutation 3. Have recurrent or progressive disease during or after platinum doublet-based chemotherapy. 4. Have received and progressed on or after anti-PD-(L)1 therapy. Metastatic Breast Cancer (HR+/HER2-) Exploratory Efficacy Cohort - Monotherapy and Combination with Sacituzumab Govitecan-hziy. 1. Documented evidence of HR+ metastatic breast cancer 2. Documented evidence of HER2- status. 3. Disease progression or recurrence after prior therapy. Metastatic Breast Cancer (HER2+) Exploratory Efficacy Cohorts - Combination with Sacituzumab Govitecan-hziy 1. Have histologically confirmed HER2+ breast cancer. 2. Have received prior treatment with trastuzumab, pertuzumab, ado-trastuzumab emtansine (T-DM1), or trastuzumab deruxtecan (T-DXd). 3. Have progression of unresectable locally advanced metastatic breast cancer after last systemic therapy or be intolerant of last systemic therapy. Dose Escalation 1. Evidence of objective disease, but participation does not require a measurable lesion. 2. Locally advanced or metastatic solid tumors, for which no standard therapy exists, or standard therapy has failed. 3. HER2 expression by immunohistochemistry and/or erbb2 amplification and/or erbb2 activating mutations. "3+3" Nivolumab Combination Cohort 1. Eligible to receive nivolumab per its label for a malignancy of epithelial origin; or 2. Have no standard therapy available, or standard therapy has failed, and must not have received nivolumab prior to joining the study. 3. HER2 expression by immunohistochemistry and/or ebb2 amplification and/or erbb2 activating mutations must be documented on either archival tissue or fresh tumor biopsy. "3+3" Nab paclitaxel Combination Cohort 1. Patients must be eligible for treatment with nab-paclitaxel per its label, or have no standard therapy available, or standard therapy has failed. 2. HER2 expression by immunohistochemistry and/or erbb2 amplification and/or erbb2 activating mutations must be documented on either archival tissue or fresh tumor biopsy. Safety/PK/PD Expansion Cohorts (Monotherapy and Combination Therapy). 1. Fresh tumor biopsy must be obtained during the screening window. 2. HER2 expression by immunohistochemistry (IHC). 3. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1. Urothelial Bladder Cancer Expansion Cohort(s). 1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1. 2. Histologically or cytologically documented locally advanced or metastatic transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary urothelial, urethra). 3. Patients must have received a platinum containing chemotherapy and an anti PD-1 or anti PD-L1 for the treatment of urothelial bladder cancer. Breast Cancer (HER2 Low) Expansion Cohort 1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1 2. Histologically documented (metastatic or locally advanced) breast cancer. 3. Absence of erbb2 amplification by ISH and/or HER2 IHC of 0, 1+, or 2+. 4. Patient must have progressed after one line of systemic chemotherapy. Breast Cancer (HER2 High) Expansion Cohort 1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1 2. Histologically documented (metastatic or locally advanced) breast cancer. 3. Erbb2 amplification by ISH and/or HER2 IHC of 3+, or 2+. If Herceptest score is 2+, ISH results should demonstrate erbb2 amplification. Basket erbb2 amplified Expansion Cohort 1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1. 2. Documented history of erbb2 amplification. 3. Patients must have received at least one line of an approved or established therapy. Gastric Cancer (HER2 High) Expansion Cohort 1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1. 2. Advanced (unresectable/recurrent/metastatic) gastric cancer or cancer of the gastro-esophageal junction. 3. Tumor must have been declared HER2 positive. Gastric Cancer (HER2 Low) Expansion Cohort 1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1. 2. Advanced (unresectable/recurrent/metastatic) gastric cancer or cancer of the gastro-esophageal junction. 3. Tumor must have been declared HER2 low; ISH non-amplified and/or HER2 IHC of 0, 1+ or 2+. If Herceptest score is 0, HER2 must be detected by IHC on at least 1+ of the tumor cells. Esophageal Cancer (HER2 High) Expansion Cohort 1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1. 2. Advanced (unresectable/recurrent/metastatic) esophageal cancer. 3. Tumor must have been declared HER2 positive. Esophageal Cancer (HER2 Low) Expansion Cohort 1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1. 2. Advanced (unresectable/recurrent/metastatic) esophageal cancer. 3. Tumor must have been declared HER2 low; ISH non-amplified and/or HER2 IHC of 0, 1+ or 2+. If Herceptest score is 0, HER2 must be detected by IHC on at least 1+ of the tumor cells. Non-small Cell Lung Cancer (HER2 Low) Expansion Cohort 1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1. 2. Histologically confirmed NSCLC meeting stage criteria for stage IIIB, stage IV, or recurrent disease that has been confirmed to have HER2 expression (at least 1+, however, patients must not carry an erbb2 amplification) via archival or fresh biopsy tissue prior to study enrollment. 3. Patients must have recurrent or progressive disease during or after platinum doublet-based chemotherapy. Non-small Cell Lung Cancer (HER2 High) Expansion Cohort 1. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1. 2. Histologically confirmed NSCLC meeting stage criteria for stage IIIB, stage IV, or recurrent disease that has been confirmed to have amplification of erbb2 via archival or fresh biopsy tissue prior to study enrollment. 3. Patients must have recurrent or progressive disease during or after platinum doublet-based chemotherapy. 1. Concurrent anticancer treatment (eg, cytoreductive therapy, radiotherapy [with the exception of palliative bone directed radiotherapy], immune therapy, or cytokine therapy except for erythropoietin), major surgery (excluding prior diagnostic biopsy), concurrent systemic therapy with steroids or other immunosuppressive agents, or use of any investigational drug within 28 days or 5 half-lives before the start of study treatment. Note: Patients receiving bisphosphonates are eligible provided treatment was initiated at least 14 days before the first dose of DF1001. 2. Previous malignant disease other than the target malignancy to be investigated in this study within the last 3 years, with the exception of basal or squamous cell carcinoma of the skin or cervical carcinoma in situ. 3. Rapidly progressive disease. 4. Active or history of central nervous system (CNS) metastases. 5. Receipt of any organ transplantation including autologous or allogeneic stem-cell transplantation. 6. Significant acute or chronic infections (including historic positive test for human immunodeficiency virus [HIV], or active or latent hepatitis B or active hepatitis C tested during the screening window). 7. Preexisting autoimmune disease (except for patients with vitiligo) needing treatment with systemic immunosuppressive agents for more than 28 days within the last 3 years or clinically relevant immunodeficiencies (eg, dys-gammaglobulinemia or congenital immunodeficiencies), or fever within 7 days of Day 1. 8. Known severe hypersensitivity reactions to mAbs (≥ Grade 3 NCI-CTCAE v5.0), any history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of partly controlled asthma). 9. Persisting toxicity related to prior therapy > Grade 1 NCI-CTCAE v5.0, however alopecia and sensory neuropathy ≤ Grade 2 is acceptable. 10. Pregnancy or lactation in females during the study. 11. Known alcohol or drug abuse. 12. Serious cardiac illness 13. NYHA III of IV heart failure or systolic dysfunction (LVEF < 55%) 14. High-risk uncontrolled arrhythmias ie, tachycardia with a heart rate > 100/min at rest 15. Significant ventricular arrhythmia (ventricular tachycardia) or higher-grade Atrioventricular block (AV-block; second-degree AV-block Type 2 [Mobitz 2] or third-degree AV-block) 16. Angina pectoris requiring anti-anginal medication 17. Clinically significant valvular heart disease 18. Evidence of transmural infarction on ECG 19. Poorly controlled hypertension (defined by: systolic > 180 mm Hg or diastolic > 100 mm Hg) 20. Clinically relevant uncontrolled cardiac risk factors, clinically relevant pulmonary disease or any clinically relevant medical condition in the opinion of the Investigator that may limit participation in this study. 21. Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy. 22. All other significant diseases (e.g., inflammatory bowel disease), which, in the opinion of the Investigator, might impair the patient's ability to participate 23. Any psychiatric condition that would prohibit the understanding or rendering of informed consent. 24. Legal incapacity or limited legal capacity. 25. Incapable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol .

• • The patient or a legally authorized representative must provide study-specific informed consent prior to pre-entry/Step 1 and, for patients treated in the U.S., authorization permitting release of personal health information.
• The patient must have an ECOG performance status of 0 or 1.
• The patient must have undergone a lumpectomy and the margins of the resected specimen or re-excision must be histologically free of invasive tumor and DCIS 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. (Patients with margins positive for LCIS are eligible without additional resection.)
• The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
• Patient must have undergone axillary staging (sentinel node biopsy and/or axillary node dissection).
• The following staging criteria must be met postoperatively according to AJCC 8th edition criteria:
• By pathologic evaluation, primary tumor must be pT1 (less than or equal to 2 cm).
• By pathologic evaluation, ipsilateral nodes must be pN0. (Patients with pathologic staging of pN0(i+) or pN0(mol+) are NOT eligible.)
• Oncotype DX Recurrence Score of less than or equal to 18 on diagnostic core biopsy or resected specimen. ** For patients with a T1a tumor (less than or equal to 0.5 cm in size) or patients at Canadian provinces or approved international sites where Oncotype DX Recurrence Score testing would not be covered, who do not already have an Oncotype DX Recurrence Score at pre-entry/Step 1, a specimen (unstained blocks or slides) must be sent to the Genomic Health centralized laboratory. Tumor size sample must be greater than or equal to 0.2 cm for analysis. *** The Oncotype RS can be run on the biopsy core or surgical specimen. The patient cannot have initiated endocrine therapy prior to tissue collection.
• An Oncotype RS is required for eligibility, however, for a patient whose tumor has already had a MammaPrint test completed as part of usual care when being considered for enrollment and is in the binary "Low" category will meet this eligibility criteria and an Oncotype RS does not need to be performed.
• The tumor must have been determined to be ER and/or PgR positive assessed by current ASCO/CAP Guideline Recommendations for hormone receptor testing. Patients with greater than or equal to 1% ER or PgR staining by IHC are considered positive.
• The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines.
• Patients may be premenopausal or postmenopausal at the time of pre-entry/Step 1. For study purposes, postmenopausal is defined as:
• Age 56 or older with no spontaneous menses for at least 12 months prior to pre-entry/Step 1; or a documented hysterectomy; or
• Age 55 or younger with no spontaneous menses for at least 12 months prior to pre-entry/Step 1 (e.g., spontaneous or secondary to hysterectomy) and with a documented estradiol level in the postmenopausal range according to local institutional/laboratory standard; or Documented bilateral oophorectomy.
• The interval between the last surgery for breast cancer (including re-excision of margins) and pre-entry/Step 1 must be no more than 70 days.
• The patient must have recovered from surgery with the incision completely healed and no signs of infection.
• Bilateral mammogram or MRI within 6 months prior to pre-entry/Step 1. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Patients must be intending to take endocrine therapy for a minimum 5 years duration (tamoxifen or aromatase inhibitor). The specific regimen of endocrine therapy is at the treating physician's discretion.
• • Definitive clinical or radiologic evidence of metastatic disease.
• pT1 mi and pT2
•pT4 tumors including inflammatory breast cancer.
• Pathologic staging of pN0(i+) or pN0(mol+), pN1, pN2, or pN3 disease.
• Patient had a mastectomy.
• Palpable or radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary nodes, unless there is histologic confirmation that these nodes are negative for tumor.
• Suspicious microcalcifications, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign.
• Non-epithelial breast malignancies such as sarcoma or lymphoma.
• Proven multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant or separated by 4 or more centimeters. (Patients with multifocal carcinoma are eligible.)
• Paget's disease of the nipple.
• Any history, not including the index cancer, of ipsilateral invasive breast cancer or ipsilateral DCIS treated or not treated. (Patients with synchronous or previous ipsilateral LCIS are eligible.)
• Synchronous or previous contralateral invasive breast cancer or DCIS. (Patients with synchronous and/or previous contralateral LCIS are eligible.)
• 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.
• Any treatment with radiation therapy, chemotherapy, or biotherapy, administered for the currently diagnosed breast cancer prior to pre-entry/Step 1.
• History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to pre-entry/Step 1.
• Current therapy with any endocrine therapy such as raloxifene (Evista®), tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or breast cancer prevention. ** Patients are eligible for BR007 if they receive a short course of preoperative endocrine therapy of less than 6 weeks duration (prior to randomization/Step 2) for this diagnosis after the core biopsy (and can continue postoperatively if:
• the Oncotype DX Recurrence Score is assessed on the biopsy core and is less than or equal to 18, AND
• the patient had not initiated endocrine therapy prior to core biopsy tissue collection. *** This does not apply to adjuvant endocrine therapy recommended for this diagnosis which may start any time after surgery including prior to registration (Pre-entry/Step 1).
• Patients intending to continue on oral, transdermal, or subdermal estrogen replacement (including all estrogen only and estrogen-progesterone formulas) are not eligible. Patients that discontinue oral, transdermal, or subdermal estrogen replacement prior to registration are eligible.
• Prior breast or thoracic RT for any condition.
• Active collagen vascular disease, specifically dermatomyositis with a CPK level above normal or with an active skin rash, systemic lupus erythematosis, or scleroderma.
• Pregnancy or lactation at the time of pre-entry/Step 1 or intention to become pregnant during treatment. (Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to pre-entry/Step 1.)
• 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 study therapy 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.
• Use of any investigational product within 30 days prior to pre-entry/Step 1.

1. Willing to provide informed consent. 2. Willing to comply with all study procedures and be available for the duration of the study. 3. Ability to take oral medication. 4. At least 18 years of age. 5. Leukoplakia study groups: 1. Leukoplakia due to hyperkeratosis with dysplasia: biopsy-confirmed diagnosis of hyperkeratosis with dysplasia. 2. Leukoplakia due to hyperkeratosis with no dysplasia: biopsy-confirmed diagnosis of hyperkeratosis with no dysplasia. 6. Control group: Laryngoscopy showing no evidence of vocal fold mucosal disease. 1. History of malignant vocal fold mucosal pathology. 2. History of metabolic or liver disorder. 3. History of anorexia or bulimia. 4. Pregnant, lactating, or planning on becoming pregnant during the study period. 5. History of >4.5 kg weight loss in the past 90 days. 6. Medical or other inability to complete an 8 hour fast. 7. Acute respiratory or gastrointestinal illness. 8. Currently incarcerated. 9. Impaired decision-making capacity. 10. No or limited English speaking ability; illiterate or low-literacy ability. 11. Profound visual or hearing impairment that limits written or verbal communication. 12. Status relationship with a member of the study team. 13. Not suitable for study participation due to other reasons at the discretion of the investigators.

• Pathologically (histologically or cytologically) proven diagnosis of small cell lung cancer within 5 years of registration. If the original histologic proof of malignancy is greater than 5 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic or brain metastasis);
• Patients with de novo or recurrent small cell lung cancer are permitted.
• Ten or fewer brain metastases ≤ 3 cm in largest diameter and outside a 5-mm margin around either hippocampus must be visible on contrast-enhanced magnetic resonance imaging (MRI) performed ≤ 21 days prior to study entry.
• Brain metastases can be diagnosed synchronous to the initial diagnosis of small cell lung cancer or metachronous to the initial diagnosis and management of small cell lung cancer.
• The total tumor volume must be 30 cm^3 or less. Lesion volume will be approximated by measuring the lesion's three perpendicular diameters on contrast enhanced, T1-weighted MRI and the product of those diameters will be divided by 2 to estimate the lesion volume (e.g. xyz/2). Alternatively, direct volumetric measurements via slice by slice contouring on a treatment planning software package can be used to calculate the total tumor volume.
• Brain metastases 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 FLAIR (preferred) or T2 sequence is required. This can be acquired as a two dimensional (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.
• History/physical examination
• Age ≥ 18
• Karnofsky performance status of ≥ 70
• Creatinine clearance ≥ 30 ml/min
• Following the diagnosis of brain metastases, patients can initiate and treat with systemic (chemotherapy and/or immunotherapy) before enrollment only if their brain metastases are asymptomatic and not located in eloquent locations (e.g., brainstem, pre-/post-central gyrus, visual cortex). However, within 21 days prior to enrollment, brain MRI must be repeated to confirm eligibility.
• Patients with symptomatic brain metastases and/or brain metastases in eloquent locations (e.g., brainstem, pre-/post central gyrus, visual cortex) are eligible for enrollment on the trial; however, the specific treatment approach of starting with systemic therapy alone and delaying brain radiation is not recommended for these patients.
• Concurrent immunotherapy with brain radiation (SRS or HA-WBRT) is permitted.
• Negative urine or serum pregnancy test (in women of childbearing potential) within 14 days prior to registration. Women of childbearing potential and men who are sexually active must use contraception while on study.
• Patients may have had prior intracranial surgical resection. Patients must have completed prior intracranial surgical resection at least 14 days prior to registration.
• Because neurocognitive testing is the primary goal of this study, patients must be proficient in English or French Canadian.
• The patient must provide study-specific informed consent prior to study entry.
• Patients with impaired decision-making capacity are not permitted on study.
• ELIGIBILITY CRITERIA PRIOR TO STEP 2 REGISTRATION
• The following baseline neurocognitive tests must be completed within 21 days prior to Step 2 registration: HVLT-R, TMT, and COWA. The neurocognitive test will be uploaded into RAVE for evaluation by Dr. Wefel. Once the upload is complete, within 3 business days a notification will be sent via email to the RA to proceed to Step 2.
• NOTE: Completed baseline neurocognitive tests can be uploaded at the time of Step 1 registration.
• Planned infusion of cytotoxic chemotherapy on the same day as SRS or HA-WBRT treatment. Patients may have had prior chemotherapy. Concurrent immunotherapy is permitted.
• Prior allergic reaction to memantine.
• Intractable seizures while on adequate anticonvulsant therapy; more than 1 seizure per month for the past 2 months.
• Patients with definitive leptomeningeal metastases.
• Known history of demyelinating disease such as multiple sclerosis.
• Contraindication to MR imaging such as implanted metal devices that are MRI-incompatible, allergy to MRI contrast that cannot be adequately addressed with pre-contrast medications, or foreign bodies that preclude MRI imaging. (Questions regarding MRI compatibility of implanted objects should be reviewed with the Radiology Department performing the MRI).
• Current use of (other N-methyl-D-aspartate [NMDA] antagonists) amantadine, ketamine, or dextromethorphan.
• Radiographic evidence of hydrocephalus or other architectural change of the ventricular system resulting in significant anatomic distortion of the hippocampus, including placement of external ventricular drain or ventriculoperitoneal shunt.
• Mild cases of hydrocephalus not resulting in significant anatomic distortion of the hippocampus are permitted.
• Prior radiotherapy to the brain, including SRS, WBRT, or prophylactic cranial irradiation (PCI).
• 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 registration
• Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of registration
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

• willing to provide informed consent
• greater than or equal to 18 years of age
• Diagnosis of biopsy-confirmed HGAIN
• Human immunodeficiency virus (HIV)-positive with CD4 count greater than 200 cells/mm^3 at screening and virologically suppressed on HIV-1 antiretroviral therapy (ART) within last 12 months
• willing to comply with all study procedures
• Diagnosis of low-grade anal dysplasia (AIN, low-grade squamous intraepithelial lesion (LSIL)) by HRA.
• CD4 count less than 200 cells/mm^3 at the time of consideration for entry into the study
• unable to provide informed consent
• Pregnant or breastfeeding female
• Currently receiving systemic chemotherapy or radiation therapy for another cancer.
• Lipid profile abnormalities
• total cholesterol greater than 240 mg/dL
• low density lipoproteins (LDL) greater than 160 mg/dL
• high density lipoproteins (HDL) less than 40 mg/dL
• triglycerides greater than 500 mg/dL
• Have received topical therapy for anal dysplasia previously
• Participants who need to take drugs that are contraindicated with lopinavir/ritonavir

• Must have histologically confirmed neuroblastoma or osteosarcoma that is recurrent or refractory and for which standard curative measures do not exist or are no longer effective. Must have histologic verification of their disease at diagnosis or at relapse
• Patients with osteosarcoma must have progressive, recurrent or refractory disease after all curative measures, including first line chemotherapy
• Patients with osteosarcoma in the dose escalation cohort, must have evaluable or measurable disease at enrollment
• Patients with osteosarcoma in the expansion cohort must have measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) at enrollment
• Patients with neuroblastoma in the dose escalation or dose the expansion cohort must have:
• Prior progressive disease OR refractory disease present since diagnosis AND at least one of the following:
• Any amount of tumor in bone marrow (BM)
• At least one MIBG-avid soft tissue or skeletal site
• For metaiodobenzylguanidine (MIBG)-nonavid disease, at least one FDG-PET- positive soft tissue or skeletal site plus past histologic confirmation
• Progressive disease is defined as any disease progression occurring at any time after the diagnosis of high-risk neuroblastoma. Refractory disease is defined as an incomplete response of high-risk neuroblastoma to all treatments but without disease progression
• Must be <40 years of age
• There is no limit to the number of prior treatment regimens. The following washout periods prior to leukapheresis apply to patients undergoing leukapheresis on this study. If a patient has cryopreserved peripheral blood mononuclear cells (PBMCs) stored, the following washout periods are strongly recommended but not required and the product is useable if it meets the criteria established in this Investigational New Drug (IND)
• Myelosuppressive chemotherapy: Patients must not have received myelosuppressive chemotherapy within 3 weeks of leukapheresis (6 weeks if prior nitrosourea).
• Hematopoietic growth factors: At least 7 days must have elapsed since the completion of therapy with a growth factor. At least 14 days must have elapsed after receiving pegfilgrastim.
• Biological agent, tyrosine kinase inhibitor, targeted agent, metronomic chemotherapy: At least 7 days must have elapsed since the completion of therapy with a biologic agent, tyrosine kinase inhibitor, targeted agent, or metronomic non-myelosuppressive regimen.
• 131I-MIBG or other radioisotope therapy: At least 6 weeks must have elapsed since prior therapy with 131I-MIBG. At least 6 weeks or 10 half-lives (whichever is shorter) must have elapsed since prior therapy with any other radioisotope.
• Monoclonal antibodies and checkpoint inhibitors: At least 3 weeks or 5 half-lives (whichever is shorter) must have elapsed since prior therapy that included a monoclonal antibody or checkpoint inhibitor.
• Radiotherapy (XRT): 3 weeks must have elapsed since XRT, but at least 6 weeks if central nervous system (CNS) or lung fields, with the exception that there is no time restriction for palliative radiation with minimal bone marrow involvement and the patient has measurable/evaluable disease outside the radiation port or the site of radiation has documented progression.
• Vaccine therapy, anti-GD2 mAb therapy, or therapy with any genetically engineered T cells: Patients may have received previous vaccine therapy, anti-GD2 monoclonal antibody (mAb) therapy, or therapy with any genetically engineered T cells except prior GD2 CAR T cell therapy. At least 3 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior vaccine or monoclonal antibody therapy. At least 42 days must have elapsed since prior modified T cell, natural killer (NK) cell, or dendritic cell therapy.
• Allogeneic stem cell transplant/infusion: At least 12 weeks must have elapsed since allogeneic stem cell transplant and without evidence of active graft versus host disease (GVHD). Patients who received an autologous stem cell infusion following myeloablative therapy should be at least 6 weeks from their infusion. Patients who received an autologous stem cell infusion following non-myeloablative therapy do not have a wash-out period; they are eligible once they meet all other eligibility requirements, including recovery from acute side effects. This criterion does not apply to patients with apheresis product or usable T cell product available for use.
• Must meet parameters for apheresis per institutional guidelines. (This criterion does not apply to patients with apheresis product or usable T cell product available for use. Cryopreserved PBMCs stored from participation in other institutional cell therapy or cell collection studies or standard of care may be used to generate the cellular product on this study if they meet the criteria established in this IND
• Patients > 16 years of age must have Karnofsky ≥ 50%. Patients ≤ 16 years of age must have Lansky scale ≥ 50%; or Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Leukocytes >= 750/mcL
• Cytopenias deemed to be disease-related and not therapy-related are exempt from this exclusion. Patients must not be refractory to transfusions
• Platelets >= 75,000/mcL
• Cytopenias deemed to be disease-related and not therapy-related are exempt from this exclusion. Patients must not be refractory to transfusions
• Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) (For the purpose of this study, the upper limit of normal [ULN] for SGOT is 50 U/L and the ULN for SGPT is 45 U/L) =< 5 x ULN
• Total bilirubin =< 2 x institutional upper limit of normal (ULN) for age. Patients with Gilbert's syndrome are excluded from the requirement of a normal bilirubin and patients will not be excluded if bilirubin elevation is due to tumor involvement. (Gilbert's syndrome is found in 3-10% of the general population, and is characterized by mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis). Note: Adult values will be used for calculating hepatic toxicity and determining eligibility
• Age, maximum serum creatinine (mg/dL):
• 1 month to < 6 months: 0.4 (male), 0.4 (female)
• 6 months to < 1 year: 0.5 (male), 0.5 (female)
• 1 to < 2 years: 0.6 (male), 0.6 (female)
• 2 to < 6 years: 0.8 (male), 0.8 (female)
• 6 to < 10 years: 1 (male), 1 (female)
• 10 to < 13 years: 1.2 (male), 1.2 (female)
• 13 to < 16 years: 1.5 (male), 1.2 (female)
• >= 16 years: 1.7 (male), 1.4 (female) OR Creatinine clearance or glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 for patients with levels above institutional normal
• Cardiac ejection fraction >= 45% or shortening fraction >= 28%, no evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO). No clinically significant electrocardiogram (ECG) findings
• Pulmonary status: No clinically significant pleural effusion. Baseline oxygen saturation > 92% on room air at rest
• No acute neurotoxicity greater than grade 2 with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible
• Females of child-bearing potential and males of reproductive potential who are sexually active must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 4 months after completion of chemotherapy preparative administration or until CAR is no longer detectable, whichever is later. Should a female become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
• Note: Females of childbearing potential are defined as those who are past the onset of menarche and are not surgically sterile (i.e., bilateral salpingectomy, bilateral oophorectomy, complete hysterectomy) or post menopausal
• All patients >= 18 years of age must be able to give informed consent or if unable to give consent have a legal authorized representative (LAR) who can give consent for the patient. For patients < 18 years old their LAR (i.e., parent or legal guardian) must give informed consent. Pediatric patients will be included in age appropriate discussion and verbal assent will be obtained for those > 7 years of age, when appropriate, according to local policy
• Receiving any other current investigational agents
• History of anaphylactic reactions attributed to anti-GD2 antibodies or to compounds of similar chemical or biologic composition to GD2CART, cyclophosphamide, fludarabine, or other agents used in this study. History of hypersensitivity to dornase alfa, Chinese hamster ovary cell products, or any of the components of pulmozyme
• Patients who require systemic corticosteroid or other immunosuppressive therapy. (A one-week washout from systemic corticosteroid or other immunosuppressive therapy is permitted.) Use of physiologic doses of corticosteroids (up to 3 mg/m^2/day prednisone equivalent) are permitted. Use of topical, ocular, intra-articular, intra-nasal, or inhaled corticosteroids are permitted
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• History of additional malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, breast) unless untreated and stable or disease free for at least 3 years
• Untreated central nervous system (CNS) metastasis. Patients with previous CNS tumor involvement that has been treated and is stable for at least 6 weeks following completion of therapy are permitted. Patients who are clinically stable as evidenced by no requirements for corticosteroids, no evolving neurologic deficits, and no progression of residual brain abnormalities without specific therapy, are permitted. Patients with asymptomatic subcentemeric CNS lesions are permitted if no immediate radiation or surgery is indicated
• CNS disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or autoimmune disease with CNS involvement that in the judgement of the investigator may impair the ability to evaluate neurotoxicity
• Presence of fungal, bacterial, viral, or other infection that is uncontrolled.
• Ongoing infection with human immunodeficiency virus (HIV), hepatitis B (hepatitis B surface antigen [HBsAg] positive), or hepatitis C virus (anti-HCV positive) as the immunosuppression contained in this study will pose unacceptable risk. A history of HIV, hepatitis B, or hepatitis C is permitted if the viral load is undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid testing
• Primary immunodeficiency or history of systemic autoimmune disease (e.g., Crohns, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years
• Females of childbearing potential must have a negative serum or urine pregnancy test. Pregnant females are excluded from this study because the effects of autologous GD2CART on the developing human fetus are unknown and because the chemotherapy agents used in this trial (cyclophosphamide and fludarabine) are category D agents with the potential for teratogenic or abortifacient effects. Additionally, because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with cyclophosphamide/fludarabine, breastfeeding should be discontinued if the mother is treated with cyclophosphamide/fludarabine. These potential risks may also apply to other agents used in this study.
• Patients with known GD2 negative tumors by validated immunohistochemistry (IHC) will be excluded from enrollment given the change in risk profile
• In the investigator's judgment, unlikely to complete protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation. Or in the investigator's judgment, if the patient is likely to develop significant toxicity and morbidity from CAR-T cell expansion mediated inflammation based on location of tumor site.

• Patients must be less than 22 years of age at the time of study enrollment
• Patient must have one of the following:
• Patient has known or suspected relapsed/refractory (including primary refractory) AML
• This includes isolated myeloid sarcoma
• Patient has known or suspected relapsed/refractory (including primary refractory) myeloid leukemia of Down syndrome
• Patient has known or suspected relapsed ALL that meets one of the following criteria:
• Second or greater B-ALL medullary relapse, excluding KMT2Ar.
• Any first or greater B-ALL medullary relapse involving KMT2Ar.
• Any first or greater T-ALL medullary relapse with or without KMT2Ar.
• Patient has known or suspected relapsed/refractory (including primary refractory) mixed phenotype acute leukemia (MPAL)
• Patient has known or suspected de novo or relapsed/refractory (including primary refractory) treatment-related AML (t-AML) or treatment-related myelodysplastic syndrome (t-MDS)
• Patient has known or suspected de novo or relapsed/refractory (including primary refractory) myelodysplastic syndrome (MDS)
• Patient has known or suspected de novo or relapsed/refractory (including primary refractory) juvenile myelomonocytic leukemia (JMML)
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Group A
• Adult (18 years of age or older)
• No previous history of cancer
• Routine history of normal blood counts and vital signs
• Documented Informed Consent Group B
• Adult (18 years of age or older)
• Diagnosis of CLL with low disease burden defined as Rai stage 0 ((Lymphocytosis; no enlargement of the lymph nodes, spleen, or liver; red blood cell and platelet counts are near normal.)
• Treatment naïve
• Documented Informed Consent Group C
• Adult (18 years of age or older)
• Diagnosis of CLL with high systemic disease burden defined as infiltration of bone marrow causing cytopenia
• Treatment naïve
• Able/willing to have bone marrow aspiration
• Documented Informed Consent For all participants
• Prisoners
• Psychiatric inpatients or people who are institutionalized
• Minor (Less than 18 years of age)
• History of diabetes
• Cannot be on antihyperglycemic therapy
• Carbohydrate restricting diets: Atkins, Vegan, Ketogenic, etc.
• Females of child bearing potential
• Persons without decision-making capacity
• Person who cannot read/write English
• Not meeting inclusion criteria defined above

• Diagnosis of one of the following advanced (unresectable and/or metastatic) solid tumors, documented by histopathology or cytopathology:
• Hepatocellular carcinoma (HCC)
• Colorectal cancer (CRC) (non-microsatellite instability-high [non-MSI-H]/deficient mismatch repair [dMMR])
• Pancreatic ductal adenocarcinoma (PDAC).
• Biliary tract cancer (BTC) (includes intrahepatic, extrahepatic cholangiocarcinoma [CCA] and gall bladder cancer)
• Endometrial cancer (EC)
• Esophageal squamous cell carcinoma (ESCC)
• Disease progression on or since the most recent treatment (does not apply to newly diagnosed unresectable or metastatic HCC or EC).
• Measurable disease per RECIST v1.1 as assessed locally (by investigator) and verified by BICR
• Submission of an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
• Male participants are abstinent from heterosexual intercourse or agree to follow contraceptive guidance during and for at least 7 days after last dose of study intervention with belzutifan and lenvatinib
• Female participants are not pregnant or breastfeeding, not a woman of child-bearing potential (WOCBP), or is a WOCBP and agrees to follow contraceptive guidance during the intervention period and and for at least 120 days after the last dose of pembrolizumab or for at least 30 days after last dose of lenvatinib or belzutifan, whichever occurs last
• Adequate organ function
• Adequately controlled blood pressure with or without antihypertensive medications
• HCC Specific No prior systemic chemotherapy, including anti-VEGF therapy, anti-programmed cell-death (PD-1)/PD-L1 or any systemic investigational anticancer agents for advanced/unresectable HCC (1L)
• CRC ([non-MSI-H/dMMR) Specific Received at least 2 prior lines of systemic therapy for unresectable or metastatic disease which includes fluoropyrimidine, irinotecan and oxaliplatin
• PDAC Specific Prior therapy with at least 1 (platinum or gemcitabine containing regimen) but no more than 2 prior systemic therapies for unresectable or metastatic pancreatic cancer
• BTC Specific Received at least 1 prior line of systemic therapy (containing gemcitabine or fluoropyrimidine) for unresectable or metastatic disease
• EC Specific Study treatment is for 1L therapy of EC and participants should not have received prior systemic chemotherapy. Exception: May have received 1 prior line of line of systemic platinum-based adjuvant and/or neoadjuvant chemotherapy in the setting of a curative-intent resection, if the recurrence occurred ≥6 months after the last dose of chemotherapy or may have received prior radiation with or without chemotherapy
• ESCC Specific Have experienced radiographic or clinical progression on one prior line of standard systemic therapy (immune oncology (IO) naïve participants) or an anti-PD-1/PD-L1 (IO resistant participants)
• Unable to swallow orally administered medication or presence of a gastrointestinal (GI) disorder that may affect study intervention absorption
• History of a second malignancy that is progressing or has required active treatment within 3 years
• A pulse oximeter reading <92% at rest, or requirement of intermittent supplemental oxygen/ chronic supplemental oxygen
• Presence of central nervous system (CNS) metastases and/or carcinomatous meningitis
• Clinically significant cardiovascular disease within 6 months of first dose of study intervention
• Symptomatic pleural effusion, unless clinically stable after treatment
• Preexisting ≥ Grade 3 gastrointestinal (GI) or non-GI fistula
• Moderate to severe hepatic impairment
• Clinically significant history of bleeding within 3 months before screening
• Presence of serious active nonhealing wound/ulcer/bone fracture
• Requirement for hemodialysis or peritoneal dialysis
• History of human immunodeficiency virus (HIV) infection
• History of Hepatitis B or active Hepatis C virus infections. with exceptions for HCC and BTC
• Prior therapy with a PD-1, anti-PD-L1, anti-PD-L2 agent, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) or hypoxia-inducible factor 2α (HIF-2α)
• Radiographic evidence of intratumoral cavitation, or invasion/infiltration of a major blood vessel
• EC specific exclusion criteria: History of carcinosarcoma, endometrial leiomyosarcoma or other high-grade sarcomas, or endometrial stromal sarcomas
• ESCC specific exclusion criteria: Has clinically apparent ascites or pleural effusion or experienced weight loss >20% over approximately 3 months before first dose of study therapy

1. Age >18 years with no upper age limit 2. Confirmation of newly diagnosed multiple myeloma (MM) with 1-2 prior regimens utilized in induction that included an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI) combined or in different regimens 3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 4. Prior AHCT 100-180 days prior to initiation of protocol-directed therapy 5. MRD ≥ 10^-5 by clonoSEQ® NGS platform, determined 60-120 days after AHCT as part of the usual care. 6. No prior disease progression (either before or since AHCT) 7. Overall response (i.e post-AHCT compared to historical baseline prior to initiation of any therapy for MM) ≥ PR. 8. Measurable disease at the time of the initial diagnosis (i.e. prior to starting any therapy for MM) meeting at least one of the following criteria:
• Serum monoclonal (M) protein ≥1.0 g/dl
• 200 mg of M protein/24h in the urine
• Difference between involved and uninvolved free light chain ≥10 mg/dL and abnormal kappa to lambda ratio. 9. Adequate hepatic function evidenced by AST and ALT ≤ 3 x ULN and bilirubin ≤ 1.5 ULN. 10. Adequate bone marrow function evidenced by platelets ≥ 75,000 /mm3 (without transfusion of platelets in the prior 7 days) and absolute neutrophil count ≥ 1,000/mm3. 11. Creatinine clearance (CrCl) ≥ 40 mL/minute within 28 days prior to start of therapy either measured or calculated using standard Cockcroft and Gault formula (available in https://www.kidney.org/professionals/KDOQI/gfr_calculatorCoc ). 12. Females of childbearing potential (FCBP) must have two negative pregnancy tests as verified by the investigator and agree to ongoing pregnancy testing and to practice contraception during treatment. Male subjects must agree to practice contraception and refrain from donating sperm during treatment. 13. In line with the higher incidence of MM in Blacks, and to address the historical underrepresentation of ethnical minorities in MM trials, at least 25% of the enrolled patients will be of ethnical minorities. 14. Written informed consent in accordance with federal, local, and institutional guidelines. 1. Diagnosis of amyloidosis, POEMS, Waldenstrom's macroglobulinemia, plasma cell leukemia or smoldering multiple myeloma (i.e. never evolved to active myeloma). 2. Major surgery or radiotherapy within 28 days of starting protocol-directed treatment. 3. Acute active infection requiring treatment within 14 days of starting protocol-directed treatment. 4. Current or prior involvement of central nervous system by multiple myeloma. 5. MM refractory to prior CD38 monoclonal antibody therapy and/or to carfilzomib (prior exposure allowed). Refractoriness here is defined as not achieving at least a PR in a regimen containing the agent or disease progression < 60 days from last dose of the agent. 6. Pregnant or lactating females. 7. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR. 8. Seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy). 9. Unstable angina or myocardial infarction within 4 months prior to starting protocol-directed treatment, NYHA Class II, III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker. 10. A prolongation of QT interval on screening electrocardiogram (ECG) as defined by corrected QT interval (QTc) > 480 ms using Fridericia's QT correction formula. 11. Cerebrovascular disease manifested as prior stroke at any time or TIA in the 12 months prior to initiation of therapy. 12. Uncontrolled hypertension (per investigator assessment, despite optimal medical management) 13. Diagnosis of interstitial lung disease 14. Nonhematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or localized thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas. 15. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 28 days prior to starting protocol-directed treatment. 16. For regimen B
•Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib). 17. Contra indication or intolerance to required supportive care medications (Aspirin and Acyclovir) 18. Concomitant use of strong inhibitors or inducers of CYP3A4, P-gp, or BCRP, or BCRP substrate with a narrow therapeutic index, for at least 14 days or 5 half-lives (whichever is shorter). (consult https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interac tions-table-substrates-inhibitors-and-inducers ) 19. Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent Diagnosis of amyloidosis, POEMS, Waldenstrom's macroglobulinemia.

1. At least 18 years of age. 2. Histologically confirmed head and neck cancer of squamous histology not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy). 3. Documented treatment failure from at least 1 prior systemic therapy in the R/M setting, unless determined not appropriate. 4. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. 5. Has a tumor that is dependent upon HRAS and/or PIK3CA. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 7. Acceptable liver, renal, endocrine, and hematologic function. 8. Must be able to swallow alpelisib whole tablet or oral suspension containing crushed tablets. Feeding tube may not be used for alpelisib administration. 9. Other protocol defined inclusion criteria may apply. 1. Histologically confirmed salivary gland, thyroid, (primary) cutaneous squamous or nonsquamous histologies (eg, mucosal melanoma). 2. Ongoing treatment with certain anticancer agents. 3. Prior treatment (at least 1 full treatment cycle) with an FTI or PI3K, mTOR, or AKT inhibitor. 4. Received treatment for unstable angina, myocardial infarction, and/or cerebro-vascular attack within the prior 6 months. 5. Non-tolerable Grade 2, or ≥ Grade 3 neuropathy or evidence of unstable neurological symptoms within 4 weeks of Cycle 1 Day 1. 6. Major surgery, other than diagnostic surgery, within 2 weeks prior to Cycle 1 Day 1, without complete recovery. 7. Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy. 8. Participant with an established diagnosis of diabetes mellitus Type 1 or not controlled Type 2. 9. Participant has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the trial drugs based on Investigator discretion. 10. Participant has currently documented pneumonitis/interstitial lung disease. 11. Participant has a history of severe cutaneous reaction, such as Stevens-Johnson Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necrolysis (TEN), or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). 12. Other protocol defined exclusion criteria may apply.

• Female
• Age 18 years or older
• Patients undergoing elective breast conservation surgery for the treatment of Stage 0-III invasive ductal and/or ductal carcinoma in situ
• May include subjects treated with neo-adjuvant therapy (endocrine and/or chemotherapeutic), but not required for study inclusion
• Ability to understand and the willingness to sign a written informed consent document
• Male
• Metastatic cancer (Stage IV)
• Lobular carcinoma as primary diagnosis
• Previous ipsilateral breast surgery for benign or malignant disease within two years (this includes implants and breast augmentation)
• Subjects with multi-centric disease (histologically diagnosed cancer in two different quadrants of the breast), unless resected in a single specimen
• Subjects with bilateral disease (diagnosed cancer in both breasts)
• Participating in any other investigational margin assessment study which can influence collection of valid data under this study
• Use of cryo-assisted localization
• Currently lactating
• Current pregnancy
• Subjects for whom the specimen margins have been destroyed, damaged, or are otherwise not intact prior to imaging (device arm only) imaging

1. Age 18 or older and in good health 2. Each eye with one of the following qualifying diagnoses (diagnoses may differ between eyes): 1. High-risk ocular hypertension (OHT): IOP > 21 mmHg without glaucomatous optic neuropathy (excavation, diffuse or focal thinning or notching of the neuroretinal rim, visible nerve fiber layer defects, or asymmetry of the vertical cup-to-disc ratio of >0.2 between eyes) [enrollment of trial participants with High-risk OHT will be capped at 25% of total enrollment] 2. Mild primary open-angle glaucoma: glaucomatous optic neuropathy, visual field mean deviation better than -6.0 dB with no points in the central 5° <15 dB (see figure on next page) 3. Moderate primary open-angle glaucoma: glaucomatous optic neuropathy, visual field mean deviation equal to or worse than -6.0 dB but no worse than -12.0 dB and no central 5° points <15 dB or mean deviation -12.0 dB or better with 1 central 5° points <15 dB (see figure on next page). 3. Each eye with BCVA 20/200 (UK 6/60) or better 1. Use of topical IOP-lowering medications for more than 6 cumulative months at any time in the past 5 years 2. Any history of IOP-lowering laser (prophylactic iridotomy not included) or surgical procedure 3. Advanced POAG in either eye (worse than moderate POAG as defined above) 4. Glaucoma other than POAG (including pigmentary and pseudoexfoliation glaucoma) in either eye 5. Mean IOP > 35 mmHg at either the screening or baseline visit in either eye 6. Narrow or closed angle (Shaffer Grade 0, 1, or 2) in either eye 7. Contraindications to SLT or any other study intervention 8. Any corneal pathology that would preclude accurate assessment of IOP by Goldmann tonometry in either eye 9. Any intraocular surgical procedure within the past 6 months in either eye 10. Inability to attend all scheduled study visits 11. Pregnant or planning to become pregnant in the next 4 years

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 2. A confirmed diagnosis of multiple myeloma (must have an M-component in serum and/or urine) 3. Measurable disease defined as: i. M-spike ≥ 500mg/dL, or ii. Urine protein M-spike of ≥ 200 mg/day, or iii. Serum free light chains ≥ 10 mg/dL, and an abnormal κ:λ ratio 4. Participant has documented relapsed or progressive MM on or after any regimen or who are refractory to the most recent line of therapy. i. Relapsed MM is defined as previously treated MM that progresses and requires initiation of salvage therapy but does not meet the criteria for refractory MM. ii. Refractory MM is defined as disease that is nonresponsive (failure to achieve minimal response or development of progressive disease) while on primary or salvage therapy or progresses within 60 days of last therapy. 1. Participants in Part 1 should have failed all other available options including having had ≥ 3 prior lines of therapy including a proteasome inhibitor, IMiD agent, and an anti-CD38 monoclonal antibody. 2. Participants in Part 2 should have had and failed ≥ 1 but ≤ 7 prior lines of therapy and will have had prior treatment with both a proteasome inhibitor and an IMiD agent. Note: A line of therapy consists of greater ≥ 1 complete cycle of a single agent, a regimen consisting of combination of several drugs, or a planned sequential therapy of various regimens. Induction therapy with consolidation and maintenance following stem cell transplant is considered a single line of therapy. 3. Prior treatment with carfilzomib is allowed but the patient must not be considered carfilzomib refractory and not have had carfilzomib within the past 6 months 5. Positivity for t(11;14) by validated fluorescence in situ hybridization (FISH) testing assay in a pre-defined laboratory a. fresh bone marrow aspirate sample must be collected at screening and sent to central laboratory for t(11;14) FISH testing. 6. Adequate organ function defined as: 1. Hemoglobin ≥ 8.0 g/dL, within 7 days before first dose of study treatment, independent of growth factor support and transfusions 2. Platelet count ≥ 75,000/μL, within 7 days before first dose of study treatment, independent of growth factor support and transfusions 3. Absolute neutrophil count (ANC) ≥ 1000/mm3 [ANC = (% of segmented neutrophils + % of segmented bands) x total WBC count within 7 days before first dose of study treatment 4. ALT and AST ≤ 3 x upper limit of normal (ULN) and total bilirubin ≤ 2.0 x ULN Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 45 mL/min/1.73 m2 calculated by the MDRD-6 formula. 1. Participant has any of the following conditions: 1. Non secretory MM (Serum free light chains < 10 mg/dL) 2. Solitary plasmacytoma 3. Active plasma cell leukemia (ie, either 20% of peripheral white blood cells or > 2.0 x 109/L circulating plasma cells by standard differential) 4. Waldenström macroglobulinemia 5. Amyloidosis. 6. Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome 7. Uncontrolled diabetes (HbA1c > 7% or 53 mmol/mol or requiring insulin at study entry 8. Chronic respiratory disease that requires continuous oxygen 2. Significant cardiovascular disease, including but not limited to: 1. Myocardial infarction ≤ 6 months before screening 2. Ejection fraction ≤ 50% 3. Unstable angina≤ 3 months before screening 4. New York Heart Association Class III or IV congestive heart failure 5. History of clinically significant arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes) 6. Heart rate-corrected QT interval > 480 milliseconds based on Fridericia's formula 7. History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place 8. Uncontrolled hypertension at screening, defined as systolic blood pressure > 170 mmHg and diastolic blood pressure > 105 mmHg by ≥ 2 consecutive measurements 3. Known infection with human immunodeficiency virus (HIV) 4. Serologic status reflecting active viral hepatitis B (HBV) or viral hepatitis C (HCV) infection as follows: 1. Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Participants with presence of HBcAb, but absence of HBsAg, are eligible if HBV DNA is undetectable (limitation of sensitivity < 20 IU/mL) ,), and if they are willing to undergo monthly monitoring for HBV reactivation. 2. Presence of HCV antibody. Participants with presence of HCV antibody are eligible if HCV RNA is undetectable (limitation of sensitivity < 15 IU/mL). Note: Other protocol defined Inclusion/Exclusion criteria may apply.

• Patients must be < 50 years at the time of enrollment.
• Patients must have =< 4 nodules per lung consistent with or suspicious for metastases, with at least one of which being >= 3 mm and all of which must be =< 3 cm size.
• Note: Patient must have eligibility confirmed by rapid central imaging review.
• Lung nodules must be considered resectable by either open thoracotomy or thoracoscopic surgery. Determination of resectability is made by the institutional surgeon.
• Patients must have a histological diagnosis of osteosarcoma.
• Patients must have evidence of metastatic lung disease at the time of initial diagnosis, or at time of 1st recurrence following completion of therapy for initially localized disease.
• Patients with newly diagnosed disease must have completed successful gross tumor resection for their primary tumor or surgical local control of primary tumor must be planned to be performed simultaneously with thoracic surgery.
• Newly diagnosed patients must be receiving or recently completed (within 60 days) systemic therapy considered by the treating physician to be standard treatment for newly diagnosed osteosarcoma (eg, cisplatin-doxorubicin or ifosfamide-based drug regimens) at the time of enrollment on this study. Dose and drug modifications for toxicity do not exclude patients from participation.
• Patients at time of 1st recurrence must have completed systemic therapy for their initial primary tumor, considered by the treating physician to be standard treatment for newly diagnosed osteosarcoma (eg, cisplatin-doxorubicin or ifosfamide-based drug regimens) at the time of enrollment on this study. Dose and drug modifications for toxicity do not exclude patients from participation.
• Patients with unresectable primary tumor.
• Patients with pulmonary metastatic lesions that would require anatomic resection (lobectomy or pneumonectomy) or lesions that are defined as "central" (i.e., central lesion involves or is proximal to segmental bronchi and peripheral is lesion distal to segmental bronchi).
• Patients with chest wall or mediastinal based metastatic lesions, or with significant pleural effusion.
• Patients with disease progression at either the primary or pulmonary metastatic site while on initial therapy. Note: Once the patient has been enrolled on the study, additional computed tomography (CT) scans are not anticipated prior to thoracic surgery. Note: Some variation in nodule size measurements over the course of pre-operative therapy is anticipated and does not qualify for exclusion unless deemed true disease progression by the primary treatment team.
• Patients with evidence of extrapulmonary metastatic disease.
• Patients who received therapeutic pulmonary surgery for lung metastasis prior to enrollment.
• All patients and/or their parents or legal guardians must sign a written informed consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

• Age ≥ 18
• Histologically confirmed adenocarcinoma of the prostate
• Cancer classified as high-risk or very high-risk by National Comprehensive Cancer Network (NCCN) criteria: Grade group ≥4, PSA >20, or primary tumor stage ≥T3a
• ECOG performance status 0-1
• Agreed to undergo EBRT, high dose rate (HDR) brachytherapy boost, and 6-36 months of ADT as part of standard of care therapy prior to study enrollment
• Able to undergo a HDR brachytherapy implant: Pre-radiation IPSS score ≤20 with or without medical management; prostate ≤60 cc as measured by MRI or ultrasound; no prior trans-urethral resection of prostate (TURP); and, median lobe extending into the bladder <1 cm
• No prior or concurrent malignancy unless disease-free for at least 5 years
• Evidence of regional or distant metastatic disease on pre-treatment bone scan, pelvic MRI, and/or CT of the abdomen/pelvis
• Prior pelvic radiation therapy

• Age ≥ 18 years
• Total burn size (second and third degree) is ≥ 25% of the TBSA
• Burn center admission within 12 hours of injury.
• There is a plan for formal fluid resuscitation.
• Significant associated trauma
• High voltage (≥ 1000 volts) electrical burns
• Burn wound excision surgery within 48 hours from injury
• Fresh frozen plasma (FFP) given at any time ≤ 48 hours from injury
• Hypertonic saline (HTS) given at any time ≤ 48 hours from injury
• Hydroxyethyl starch (HES) given at any time ≤ 48 hours from injury
• High dose Vitamin C infusion given at any time ≤ 48 hours from injury
• Administration of human albumin prior to randomization
• Palliative comfort measures are instituted ≤ 48 hours from injury
• Pregnancy
• Pre-injury chronic renal insufficiency equal to or greater than stage 3
• Pre-injury chronic hepatic disease (Child-Pugh B or C)
• Pre-injury left ventricular (LV) dysfunction (echocardiography LV grade II-IV or ejection fraction ≤ 35%)

• Pathologically (histologically or cytologically) proven diagnosis of adenocarcinoma of the prostate within 270 days prior to registration
• Unfavorable intermediate risk prostate cancer, defined as having ALL the following bulleted criteria:
• Has at least one intermediate risk factor (IRF):
• PSA 10-20 ng/mL
• Clinical stage T2b-c (digital rectal examination [DRE] and/or imaging) by American Joint Committee on Cancer (AJCC) 8th edition
• Gleason score 7 (Gleason 3+4 or 4+3 [ International Society of Urological Pathology (ISUP) Grade Group 2-3])
• Has ONE or more of the following 'unfavorable' intermediate-risk designators:
• > 1 immature reticulocyte fraction (IRF)
• Gleason 4+3=7 (ISUP Grade Group 3)
• >= 50% of biopsy cores positive
• Biopsies may include 'sextant' sampling of right/left regions of the prostate, often labeled base, mid-gland and apex. All such 'sextant' biopsy cores should be counted. Men may also undergo 'targeted' sampling of prostate lesions (guided by MRI, ultrasound or other approaches). A targeted lesion that is biopsied more than once and demonstrates cancer (regardless of number of targeted cores involved) should count as a single additional positive core sampled and positive. In cases of uncertainty, count the biopsy sampling as sextant core(s)
• Absence of high-risk features
• Appropriate stage for study entry based on the following diagnostic workup:
• History/physical examination within 120 days prior to registration;
• Negative bone imaging (M0) within 120 days prior to registration; Note: Tc-99m bone scan or sodium fluoride (NaF) positron emission tomography (PET) are allowed. Equivocal bone scan findings are allowed if plain films X-ray, computed tomography (CT) or magnetic resonance imaging (MRI) are negative for metastasis at the concerned site(s). While a negative fluciclovine, choline, or prostate specific membrane antigen (PSMA) PET may be counted as acceptable substitute for bone imaging, any suspicious findings must be confirmed and correlated with conventional imaging (Tc-99m bone scan, NaF PET, CT, X-ray, or MRI) to determine eligibility based on the latter modalities (e.g. M0 based on conventional imaging modalities)
• Clinically negative lymph nodes (N0) as established by conventional imaging (pelvic +/- abdominal CT or MR), within 120 days prior to registration. Patients with lymph nodes equivocal or questionable by imaging are eligible if the nodes are =< 1.0 cm in short axis and/or if biopsy is negative. Note: While a negative fluciclovine, choline, or prostate specific membrane antigen (PSMA) PET may be counted as acceptable substitute for pelvic imaging, any suspicious findings must be confirmed by conventional imaging (CT, MRI or biopsy). If the findings do not meet pathological criteria based on the latter modalities (e.g. node =< 10 mm in short axis, negative biopsy), the patient will still be eligible
• Age >= 18
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 120 days prior to registration
• Non-castrate testosterone level (> 50 ng/dL) within 120 days prior to registration
• Absolute neutrophil >= 1,000 cells/mm^3 (within 120 days prior to registration)
• Hemoglobin >= 8.0 g/dL, independent of transfusion and/or growth factors (within 120 days prior to registration)
• Platelet count >= 100,000 cells/mm^3 independent of transfusion and/or growth factors (within 120 days prior to registration)
• Creatinine clearance (CrCl) >= 30 mL/min estimated by Cockcroft-Gault equation (within 120 days prior to registration)
• For African American patients specifically whose renal function is not considered adequate by the formula above, an alternative formula that takes race into account (Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula) should be used for calculating the related estimated glomerular filtration rate (GFR) with a correction factor for African American race creatinine clearance for trial eligibility, where GFR >= 30 mL/min/1.73m^2 will be considered adequate
• Total bilirubin: 1.5 =< institutional upper limit of normal (ULN) (within 120 days prior to registration) (Note: In subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin. If direct bilirubin is less than or equal to 1.5 x ULN, subject is eligible)
• Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]): =< 2.5 x institutional ULN (within 120 days prior to registration)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial; Note: HIV testing is not required for eligibility for this protocol
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• Note: Known positive test for hepatitis B virus surface antigen (HBV sAg) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-Hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B)
• For 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
• Note: Known positive test for hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy
• 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
• Previous radical surgery (prostatectomy) or any form of curative-intent ablation whether focal or whole-gland (e.g., cryosurgery, high intensity focused ultrasound [HIFU], laser thermal ablation, etc.) for prostate cancer
• Definitive clinical or radiologic evidence of metastatic disease (M1)
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years. History of or current diagnosis of hematologic malignancy is not allowed
• Prior radiotherapy to the prostate/pelvis region that would result in overlap of radiation therapy fields
• Previous bilateral orchiectomy
• Previous hormonal therapy, such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., leuprolide, goserelin, buserelin, triptorelin) or LHRH antagonist (e.g. degarelix), anti-androgens (e.g., flutamide, bicalutamide, cyproterone acetate). ADT started prior to study registration is not allowed
• Prior use of 5-alpha-reductase inhibitors is allowed, however, it must be stopped prior to enrollment on the study with at least a 30 day washout period before baseline study PSA measure and registration
• Active testosterone replacement therapy; any replacement therapy must be stopped at least 30 days prior to registration
• Severe, active co-morbidity defined as follows:
• Current severe or unstable angina;
• New York Heart Association Functional Classification III/IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification)
• History of any condition that in the opinion of the investigator, would preclude participation in this study
• Inability to swallow oral pills
• High risk features, which includes any of the following:
• Gleason 8-10 [ISUP Grade Group 4-5]
• PSA > 20
• cT3-4 by digital exam OR gross extra-prostatic extension on imaging [indeterminate MRI evidence will not count and the patient will be eligible]

• PRE ENROLLMENT: Patients must be =< 25 years of age at the time of enrollment on APEC14B1 part A cnetral nervous system (CNS)/high grade glioma (HGG) pre-enrollment eligibility screening
• Please note:
• This required age range applies to pre-enrollment eligibility for all HGG patients. Individual treatment protocols may have different age criteria.
• Non-DIPG patients with tumors that do not harbor an H3K27M-mutation and are >= 18 years of age will not be eligible to enroll on ACNS1821 (Step 1).
• PRE ENROLLMENT: Patient is suspected of having localized, newly diagnosed HGG, excluding metastatic disease, OR patient has an institutional diagnosis of DIPG
• Please note: there are specific radiographic criteria for DIPG patient enrollment on ACNS1821 (Step 1)
• PRE ENROLLMENT:
• For patients with non-pontine tumors: Patients and/or their parents or legal guardians must have signed informed consent for eligibility screening on APEC14B1 Part A.
• For patients with DIPG: Patients and/or their parents or legal guardians must have signed informed consent for ACNS1821.
• PRE ENROLLMENT:
• For patients with non-pontine tumors only, the specimens obtained at the time of diagnostic biopsy or surgery must be submitted through APEC14B1 ASAP, preferably within 5 calendar days of definitive surgery
• STEP 1: Patients must be >= 12 months and =< 21 years of age at the time of enrollment
• STEP 1: Patients must have newly-diagnosed DIPG or HGG (including DMG).
• STEP 1: Stratum DIPG
• Patients with newly-diagnosed typical DIPG, defined as tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons on at least 1 axial T2 weighted image, are eligible. No histologic confirmation is required.
• Patients with pontine tumors that do not meet radiographic criteria for typical DIPG (e.g., focal tumors or those involving less than 2/3 of the pontine cross-sectional area with or without extrapontine extension) are eligible if the tumors are biopsied and proven to be high-grade gliomas (such as anaplastic astrocytoma, glioblastoma, high-grade glioma not otherwise specified [NOS], and/or H3 K27M-mutant) by institutional diagnosis.
• STEP 1: Stratum DMG (with H3 K27M mutation)
• Patients must have newly-diagnosed non-pontine H3 K27M-mutant HGG without BRAF V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1
• Note: Patients need not have either measurable or evaluable disease, i.e., DMG patients may have complete resection of their tumor prior to enrollment. Primary spinal tumors are eligible for enrollment. For rare H3 K27M-mutant HGG in non-midline structures (e.g., cerebral hemispheres), these patients will be considered part of Stratum DMG.
• STEP 1: Stratum HGG (without H3 K27M mutation)
• Patients must have newly-diagnosed non-pontine H3 K27M-wild type HGG without BRAF V600 or IDH1 mutations as confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1
• Please note:
• Patients who fall in this category and who are >= 18 years of age are not eligible due to another standard-of-care regimen (radiation/temozolomide) that is available
• Patients need not have either measurable or evaluable disease, i.e., HGG patients may have complete resection of their tumor prior to enrollment. Primary spinal tumors are eligible for enrollment
• STEP 1: Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =<16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• STEP 1: Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to step 1 enrollment)
• STEP 1: Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to step 1 enrollment)
• STEP 1: Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to step 1 enrollment)
• STEP 1: Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 (within 7 days prior to step 1 enrollment) or A serum creatinine based on age/gender as follows (within 7 days prior to step 1 enrollment):
• Age / Maximum Serum Creatinine (mg/dL)
• 1 to < 2 years / male: 0.6; female: 0.6
• 2 to < 6 years / male: 0.8; female: 0.8
• 6 to < 10 years / male: 1; female: 1
• 10 to < 13 years / male: 1.2; female: 1.2
• 13 to < 16 years / male: 1.5; female: 1.4
• >= 16 years / male: 1.7; female: 1.4
• STEP 1: Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• STEP 1: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.
• STEP 1: Serum amylase =< 1.5 x ULN
• STEP 1: Serum lipase =< 1.5 x ULN
• STEP 1: No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination.
• STEP 1: Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled.
• STEP 1: Patients must be enrolled and protocol therapy must begin no later than 31 days after the date of radiographic diagnosis (in the case of non-biopsied DIPG patients only) or definitive surgery, whichever is the later date (Day 0). For patients who have a biopsy followed by resection, the date of resection will be considered the date of definitive diagnostic surgery. If a biopsy only was performed, the biopsy date will be considered the date of definitive diagnostic surgery.
• STEP 1: Patients must not have received any prior therapy for their central nervous system (CNS) malignancy except for surgery and steroid medications.
• STEP 1: Patients who are currently receiving another investigational drug are not eligible.
• STEP 1: Patients who are currently receiving other anti-cancer agents are not eligible.
• STEP 1: Patients >=18 years of age who have H3 K27M-wild type HGG.
• STEP 1: Patients who have an uncontrolled infection.
• STEP 1: Patients who have received a prior solid organ transplantation.
• STEP 1: Patients with grade > 1 extrapyramidal movement disorder.
• STEP 1: Patients with known macular degeneration, uncontrolled glaucoma, or cataracts.
• STEP 1: Patients with metastatic disease are not eligible; MRI of spine with and without contrast must be performed if metastatic disease is suspected by the treating physician.
• STEP 1: Patients with gliomatosis cerebri type 1 or 2 are not eligible, with the exception of H3 K27M-mutant bithalamic tumors.
• STEP 1: Patients who are not able to receive protocol specified radiation therapy.
• STEP 1:
• Female patients who are pregnant are ineligible since there is yet no available information regarding human fetal or teratogenic toxicities.
• Lactating females are not eligible unless they have agreed not to breastfeed their infants. It is not known whether selinexor is excreted in human milk.
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
• Sexually active patients of reproductive potential are not eligible unless they have agreed to use two effective methods of birth control (including a medically accepted barrier method of contraception, e.g., male or female condom) for the duration of their study participation and for 90 days after the last dose of selinexor. Abstinence is an acceptable method of birth control.

• >= 4 and < 18 years at time of study entry
• Patients must weigh 15 kg or greater at time of study entry
• Primary central nervous system tumors that have not received prior cranial radiotherapy
• Planned focal, cranial or craniospinal radiation treatment for a primary central nervous system tumor
• The patient must have receptive and expressive language skills in English, French or Spanish since the neurocognitive function and quality of life (QOL) assessment instruments are available in these languages only
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• Age: 4 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 male; 0.8 female
• Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 male; 1 female
• Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 male; 1.2 female
• Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 male; 1.4 female
• Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 male; 1.4 female
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
• The patient must be able to undergo magnetic resonance imaging
• All patients and/or their parents or legal guardians must sign a written informed consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
• Life expectancy of less than 18 months
• Pre-existing conditions:
• Any contraindication or allergy to study drug (memantine or placebo)
• Intractable seizures while on adequate anticonvulsant therapy, defined as more than one seizure per month for the past 2 months or since initiating anticonvulsant therapy
• History of neurodevelopmental disorder such as Down syndrome, Fragile X, William's Syndrome, intellectual disability (presumed intelligence quotient [IQ] < 70), etc
• Co-morbid systemic illnesses, psychiatric conditions, social situations, or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens or would limit compliance with the study requirements
• Patients with a motor, visual, or auditory condition that precludes participation in computerized neurocognitive assessments
• Patients with any medical condition or taking medications that lead to alterations of urine pH towards the alkaline condition (e.g., renal tubular acidosis, carbonic anhydrase inhibitors, sodium bicarbonate)
• Personal history of prior cranial or craniospinal radiotherapy is not allowed
• Note: Prior anti-cancer therapy including surgery, chemotherapy, targeted agents are allowed as per standard of care clinical treatment guidelines
• Female patients who are pregnant are excluded since fetal toxicities and teratogenic effects have been noted for the study drug. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who do not agree to use an effective contraceptive method for the duration of their study participation

• Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information
• NOTE: HIPAA authorization may be included in the informed consent or obtained separately
• Age >= 18 years at the time of consent
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 28 days prior to registration
• Have histologically or cytologically-documented diagnosis of extensive stage (i.e. metastatic and/or recurrent) small cell lung cancer and have progressed or recurred after platinum-based chemotherapy with immunotherapy. Eligible patients will be defined as follows:
• "Sensitive" Disease: Patients who had one previous line of chemotherapy and relapsed after > 90 days of completion of treatment
• "Resistant" Disease: Patients with no response to first-line chemo-immunotherapy or progression < 90 days after completing treatment
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 within 28 days prior to registration
• Maximum of 2 prior lines of systemic therapy is allowed in the setting of metastatic disease. Patients who recur after treatment for limited state disease, and who receive first line metastatic treatment with chemo-immunotherapy would be considered eligible upon progression on chemo-IO in the metastatic setting
• Absolute neutrophil count (ANC) >= 1.5 K/mm^3 (obtained within 28 days prior to registration)
• Platelets >= 100,000 / mcL (obtained within 28 days prior to registration)
• Serum creatinine =< 2.0 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 50 mL/min as estimated by Cockcroft and Gault formula for subject with creatinine levels > 2 x institutional ULN (obtained within 28 days prior to registration)
• Bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
• Patients with known Gilbert disease: serum bilirubin =< 3 x ULN) (obtained within 28 days prior to registration)
• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) =< 3 X ULN OR =< 5 X ULN for subjects with liver metastases (obtained within 28 days prior to registration)
• Albumin > 2.5 g/dL (obtained within 28 days prior to registration)
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN for patients not receiving therapeutic anticoagulation (obtained within 28 days prior to registration)
• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN for patients not receiving therapeutic anticoagulation (obtained within 28 days prior to registration)
• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
• Females of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to registration
• For women of childbearing potential: agreement to remain abstinent (refrain from vaginal intercourse) or use contraceptive methods and agreement to refrain from donating eggs, as defined below:
• Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the final dose of atezolizumab or temozolomide. Women must refrain from donating eggs during this same period
• Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone releasing intrauterine devices, and copper intrauterine devices
• The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, or post ovulation methods) and withdrawal are not adequate methods of contraception
• For men able to father a child: agreement to remain abstinent (refrain from vaginal intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below:
• With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 3 months after the final dose of temozolomide to avoid exposing the embryo. Men must refrain from donating sperm during this same period
• The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study
• Availability of archival tissue, preferably a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block. A recently obtained archival FFPE tumor tissue block from a primary or metastatic tumor resection or biopsy can be provided if it was obtained within 1 year of trial screening. Patients with tumor specimens older than 1 year may still be eligible if deemed so by study sponsor. For eligibility, only confirmation of archival tissue is needed. Verification of tumor burden in the biopsy is encouraged. For optimal biomarker results, tumor content should be > 30% of total tissue area
• Be willing to provide peripheral blood samples at specified time-points during the study
• Life expectancy greater than 3 months as determined by the enrolling physician or protocol designee
• Ability to swallow and retain oral medication
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
• Has received prior temozolomide therapy
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are not eligible for this trial
• Symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with asymptomatic lesions will be eligible if considered appropriate by the treating physician
• NOTE: Subjects who are symptomatic and have not undergone prior brain imaging must undergo a head computed tomography (CT) scan or brain MRI within 28 days prior to registration to exclude brain metastases
• NOTE: A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 2 weeks prior to study registration, have been off corticosteroids for ≥ 2 weeks, and are asymptomatic
• Clinically significant acute infection requiring systemic antibacterial, antifungal, or antiviral therapy including:
• Tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and TB testing in line with local practice)
• Hepatitis B (known positive HBV surface antigen [HBsAg] result)
• Hepatitis C, or
• Human immunodeficiency virus (positive HIV 1/2 antibodies)
• NOTES: Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. In patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA). Subjects with HIV/acquired immunodeficiency syndrome (AIDS) with adequate antiviral therapy to control viral load (i.e undetectable) would be allowed if they are stable and have been on treatment for >= 4 weeks prior to first dose of study drug(s). Subjects with viral hepatitis with controlled viral load would be allowed while on suppressive antiviral therapy. Testing not required
• Has had prior chemotherapy, immunotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent
• Note: Subjects with =< grade 2 neuropathy or alopecia due to chemotherapy are an exception to this criterion and may qualify for the study
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Note: Subjects with irreversible toxicity that in the opinion of the treating physician is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, hormone deficiency requiring replacement therapy)
• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions:
• Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Patients with controlled type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
• Rash must cover =< 10% of body surface area
• Disease is well controlled at baseline and requires only low-potency topical corticosteroids
• No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (more than once monthly). Patients with indwelling catheters (e.g., PleurX) are allowed.
• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium >12 mg/dL or corrected serum calcium > ULN)
• History of leptomeningeal disease

General
• Ability and willingness to provide informed consent
• Age ≥ 18 and ≤65 years at time of signing Informed Consent Form
• Ability and willingness to comply with the study protocol and to participate in all study visits and assessments in the investigator's judgement
• For candidates of childbearing potential: willingness to use a method of contraception
• Agreement not to take supplements other than vitamin A Ocular Inclusion Criteria
• Both eyes must exhibit the RP phenotype with evidence of loss of night vision, gradual constriction of visual fields, and maintenance of visual acuity;
• In addition, an eye must meet the following criteria to be included in the study:
• Gradable EZ on a horizontal SD-OCT scan through the fovea center with width ≤ 8000 µm and ≥1500 µm and with well-defined truncation at both the nasal and temporal sides;
• BCVA ≥ ETDRS letter score of 61 (20/60 Snellen equivalent);
• Sufficiently clear ocular media and adequate pupillary dilation to allow good quality images sufficient for analysis and grading by central reading center. General Exclusion Criteria
• Active cancer within the past 12 months, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or prostate cancer with Gleason score ≤ 6 and stable prostate specific antigen for > 12 months
• Renal failure requiring renal transplant, hemodialysis, peritoneal dialysis, or anticipated to require hemodialysis or peritoneal dialysis during the study
• Liver disease, cystic fibrosis, asthma, or chronic obstructive pulmonary disease (COPD), history of thrombocytopenia not due to a reversible cause or other blood dyscrasia
• Uncontrolled blood pressure (defined as systolic > 180 and/or diastolic > 100 mmHg while at rest) at screening. If a patient's initial measurement exceeds these values, a second reading may be taken 30 or more minutes later. If the patient's blood pressure must be controlled by antihypertensive medication, the patient may become eligible if medication is taken continuously for at least 30 days.
• History of other disease, physical examination finding, or clinical laboratory finding giving reasonable suspicion that oral NAC may be contraindicated or that follow up may be jeopardized
• Cerebrovascular accident or myocardial infarction within 6 months of screening
• Participation in an investigational study that involves treatment with any drug or device within 6 months of screening
• Three relatives already enrolled in study
• Pregnant, breast feeding, or intending to become pregnant during the study treatment period. Women of childbearing potential who have not had tubal ligation must have a urine pregnancy test at screening.
• Known history of allergy to NAC
• Having taken NAC in any form in the past 4 months
• Phenylketonuria
• Fructose intolerance
• Glucose-galactose malabsorption
• Sucrase-isomaltase insufficiency
• Abnormal laboratory value including the value of alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin being greater than 1.5 x the upper limit of normal
• Any major abnormal findings on blood chemistry, hematology, and renal function lab tests that in the opinion of the Site Investigator and/or the Study Chair makes the candidate not suitable to participate in the trial
• HIV or hepatitis B infection Ocular Exclusion Criteria
• Evidence of cone-rod dystrophy or pattern dystrophy including focal areas of atrophy or pigmentary changes in the central macula
• Cystoid spaces involving the fovea substantially reducing vision
• Glaucoma or other optic nerve disease causing visual field loss or reduced visual acuity
• Intra ocular pressure >27 mm Hg from two measurements. If a patient's initial measurement exceeds 27 mm Hg, a second reading must be taken.
• Any retinal disease other than RP causing reduction in visual field or visual acuity
• Any prior macular laser photocoagulation
• Intraocular surgery within 3 months prior to screening
• High myopia with spherical equivalent refractive error > 8 diopters. If an eye has had cataract surgery or refractive surgery, a pre-operative refractive error spherical equivalent > 8 diopters is an exclusion
• Any concurrent ocular condition that might affect interpretation of results
• History of uveitis in either eye

Key Inclusion Criteria Patient has ECOG performance status of 0-1 One or more documented primary oncogenic PIK3CA mutation(s) in blood and/or tumor per local assessment
•Other potentially oncogenic PIK3CA mutations may be considered but must be approved by the Sponsor prior to enrollment. Part 1
•Ability to provide archived tumor tissue or be willing to undergo pretreatment tumor biopsy to assess PIK3CA status retrospectively Part 2
•Submit tumor tissue prior to study drug initiation for determination of PIK3CA mutation retrospectively. Key Inclusion for RLY-2608 Single Agent Arm
• [For Part 1]: Evaluable disease per RECIST v1.1
• [For Part 2]: Measurable disease per RECIST v1.1
• Disease that is refractory to standard therapy, intolerant to standard therapy, or has declined standard therapy.
• Part 1- histologically or cytologically confirmed diagnosis of unresectable or metastatic solid tumor
• Part 2
•Unresectable or metastatic solid tumor with PIK3CA mutation(s) and one of the following tumor types: Group 1: clear cell ovarian cancer Group 2: head and neck squamous cell carcinoma Group 3: cervical cancer Group 4: other solid tumors, excluding colorectal, clear cell ovarian, head and neck squamous cell, and cervical cancers Group 5: unresectable or metastatic solid tumors with PIK3CA double mutations Key Inclusion for Combination Arms
• [For Part 1 and Part 2]: Evaluable disease per RECIST v1.1
• [For Part 1 and Part 2]: Male or female with histologically or cytologically confirmed diagnosis of HR+, HER2- unresectable or metastatic breast cancer that is not amenable to curative therapy. Females may be postmenopausal, premenopausal, or perimenopausal. Premenopausal or perimenopausal females must have a histologically or cytologically confirmed diagnosis of HR+ HER2- advanced or metastatic breast cancer that is not amenable to curative therapy and must have been previously treated with GnRH agonist at least 4 weeks prior to start of study drug
• [For Part 1 and Part 2]: Had previous treatment for breast cancer with: 1. ≤1 line of chemotherapy in the metastatic setting 2. ≥1 cyclin-dependent kinases (CDK) 4/6 inhibitor, in either the adjuvant and/or metastatic setting 3. ≥1 antiestrogen therapy in either adjuvant and/or metastatic setting, including, but not limited to, selective estrogen-receptor degraders (eg, fulvestrant), selective estrogen receptor modulators (eg, tamoxifen), and aromatase inhibitors (AI) (letrozole, anastrozole, exemestane), and 4. ≥1 PARP inhibitor, if appropriate, if documented germline BRCA1/2 mutation Note: Systemic local, loco-regional, or adjuvant treatment with chemotherapy and PARP inhibitors is not to be included in enumeration or previous treatment [For RLY-2608 + fulvestrant arm; Part 2, Group 2]: Received prior treatment with a PI3Kα inhibitor and discontinued the inhibitor due to intolerance and not disease progression, where intolerance is defined as treatment discontinuation due to treatment related AE (eg. hyperglycemia, rash, diarrhea, stomatitis) other than severe hypersensitivity reaction and/or life-threatening reactions, such as anaphylaxis and Stevens-Johnson syndrome. Key Exclusion Criteria Prior treatment with PI3Kα, AKT, or mTOR inhibitors (except for RLY-2608 + fulvestrant arm, Part 2, Group 2). Type 1 or Type 2 diabetes requiring antihyperglycemic medication, or fasting plasma glucose ≥140 mg/dL and glycosylated hemoglobin (HbA1c) ≥7.0%. History of hypersensitivity to PI3K inhibitors. For combination arms only: hypersensitivity to fulvestrant, palbociclib, and/or ribociclib, as appropriate for the combination. For triple combination arms only: history of pneumonitis or interstitial lung disease. For the single agent and combination arms other than with ribociclib: mean QT interval corrected using Fridericia's formula (QTcF) >480 msec. For the combination arms with ribociclib: mean QTcF ≥450 msec. Patient has a history of prolonged QT syndrome or torsades de pointes. Patient has a familial history of prolonged QT syndrome. Clinically significant, uncontrolled cardiovascular disease CNS metastases or primary CNS tumor that is associated with progressive neurologic symptoms

• Female between the inclusive ages of 22 and 70 at the time of initial expander surgery
• Scheduled to undergo either unilateral or bilateral mastectomy with immediate 2-stage breast reconstruction
• Is able to understand the study requirements and is willing to provide written informed consent
• Is willing and able to return for all scheduled study visits
• Is pregnant or planning to become pregnant during study participation
• Has a history of failed tissue expansion or breast implantation at the intended reconstruction site
• has a residual gross tumor at the intended reconstruction site
• has been treated for a systemic infection or a local infection at the surgical site that the investigator determines will affect the safety of the subject during breast reconstruction and/or mesh use
• has, as determined by the investigator, unsuitable tissue integrity for immediate 2-stage breast reconstruction
• has undergone previous radiation therapy to the reconstruction site or chest wall
• is scheduled to undergo post-operative radiation therapy at the reconstruction site
• has a Body Mass Index (BMI) < 14 or > 44
• has used nicotine products within 90 days of screening
• is currently taking medications including non-NSAID anti-coagulants, immunosuppressants (including systemic steroids), or other medications determined by the investigator to place the subject at an increased risk of local complications of breast reconstruction
• has been diagnosed with a comorbid condition determined by the investigator to place the subject at an increased risk of complications
• has participated in any other clinical study that the investigator feels may interfere with this clinical study

Key
• Male and female, ≥ 18 years
• Documented advanced or metastatic malignancy
• Eastern Cooperative Oncology Group performance status of 0 or 1 with no deterioration over the 2 weeks prior to baseline or day of first dosing
• All participants must provide a tumour sample for tissue-based analysis
• At least 1 measurable lesion not previously irradiated, except Substudy 3 (Prostate Cancer) which allows participants with non measurable bone metastatic disease
• Adequate bone marrow reserve and organ function
• Minimum life expectancy of 12 weeks
• At the time of screening, contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
• All women of childbearing potential must have a negative serum pregnancy test documented during screening
• Female participants must be 1 year post-menopausal, surgically sterile, or using 1 highly effective form of birth control. Female participants must not donate, or retrieve for their own use, ova at any time during this study
• Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile, avoid intercourse, or use a highly effective method of contraception. Male participants must not freeze or donate sperm at any time during this study.
• Capable of giving signed informed consent
• Provision of signed and dated written optional genetic research informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative Key
• Any evidence of diseases which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol
• History of another primary malignancy except for adequately resected basal cell carcinoma or in situ squamous cell carcinoma of the skin, or other solid malignancy treated with curative intent
• Persistent toxicities caused by previous anticancer therapy, excluding alopecia, not yet improved
• Spinal cord compression or brain metastases unless treated
• Leptomeningeal carcinomatosis
• Clinically significant corneal disease
• Active hepatitis or uncontrolled hepatitis B or C virus infection
• Uncontrolled infection requiring IV antibiotics, antivirals or antifungals, for example prodromal symptoms
• Known HIV infection that is not well controlled
• Active TB infection
• Significant cardiac diseases
• History of non-infectious Interstitial lung disease (ILD)/pneumonitis that required steroids
• Has severe pulmonary function compromise
• Prior exposure to chloroquine/hydroxychloroquine without an adequate treatment washout period
• Receipt of live, attenuated vaccine within 30 days prior to the first dose of study intervention
• Prior exposure to anticancer therapies without an adequate treatment washout period prior to enrolment or any concurrent anticancer treatment
• Major surgical procedure or significant traumatic injury within ≤ 3 weeks of the first dose of study intervention or an anticipated need for major surgery during the study
• Prior treatment with TROP2-directed Anti-drug antibody, ADC Antibody-drug conjugate (ADCs), other ADCs with deruxtecan payload
• Severe hypersensitivity to monoclonal antibodies
• Pregnant, breastfeeding, planning to become pregnant

1. endotracheal tube or tracheostomy in place and mechanically ventilated for ≤7 days; 2. admitted to a participating ICU 3. radiologic evidence of bilateral pulmonary infiltrates not fully explained by pleural effusions, atelectasis, or hydrostatic pulmonary edema 4. P/F ratio ≤200 with PEEP ≥8 cm H2O; If ABG values are not available, the P/F ratio may be inferred from SpO2 values based on Table 3 from Brown et al as long as following conditions are met: 1. SpO2 values are 80-96% 2. SpO2 is measured ≥10 min after any change in FIO2 3. PEEP is ≥ 8 cm H2O 4. the pulse oximeter waveform tracing is adequate 5. the qualifying inferred P/F ratio is confirmed 1-6h after initial determination. 5. access to an LAR to provide consent. 6. Criteria 3 AND 4 must be met within 72h of enrollment and randomization, not be fully explained by hydrostatic pulmonary edema, and must have occurred within 7 days of exposure to an ARDS-risk factor (including continuous exposure to persistent processes (e.g. sepsis, pneumonia, COVID-19).
• Patients may be enrolled and decision about randomization delayed if all criteria other than P/F ratio ≤ 200 are met and then randomized if and when the P/F ratio ≤200 (as long as this occurs within 72h of randomization). Patients on high flow nasal oxygen or non-invasive pressure ventilation may be consented if they meet criteria for starting the 72h ARDS window but may not be enrolled and randomized until they are intubated. 1. Missed moderate-severe ARDS window (>72hrs)
•Window starts when patient is intubated with a qualifying P/F ratio of ≤ 200 with PEEP ≥ 8 cm H2O or on high flow nasal oxygen with well-fitting nasal cannula with flow ≥ 40 LPM and FiO2 ≥ 0.65 or on non-invasive pressure ventilation with PEEP ≥ 8 cm H2O and FiO2 ≥ 0.6. 2. Missed NMB window: (>48 hrs) 3. Missed mechanical ventilation window (>7 days) 4. Refractory hypotension (continuous infusion of >0.3 mcg/kg/min of norepinephrine or equivalent dose of other vasopressors within 2 hours prior to randomization) 5. Core temperature <35.5°C for ≥6 hours while not receiving CRRT on day of randomization 6. Significant, active bleeding (>3u blood products and/or surgical/IR intervention) on day of randomization 7. Platelets <10K/mm3 (uncorrected) on day of randomization 8. Active hematologic malignancy 9. Skin process that precludes cooling device 10. Moribund, not likely to survive 72h 11. Pre-morbid condition makes it unlikely that patient will survive 28 days 12. Do Not Resuscitate status at time of randomization (excluding patients receiving full support EXCEPT CPR for cardiac arrest) 13. Not likely to remain intubated for ≥48h 14. Physician of record unwilling to participate 15. Severe underlying lung disease 1. Needs > 2 LPM or >28% continuous home O2 (adjusted for altitude) 2. On BIPAP (except for OSA) 3. Prior lung transplantation 16. Pregnant at time of randomization 17. BMI consistently >50 kg/m2 18. Known NYHA class IV heart disease 19. Acute Coronary Syndrome (MI, unstable angina) within 30 days of randomization 20. Cardiac arrest within 30 days of randomization 21. Burns over >20% of the body surface 22. Severe chronic liver disease (Child-Pugh score 12-15) 23. Previously randomized in CHILL study 24. Simultaneous enrollment in another inpatient interventional trial started during the current hospitalization. 25. On ECMO during the current hospitalization.

• A diagnosis of ulcerative colitis (UC), with signs and symptoms consistent with UC for at least 3 months prior to the first study intervention administration
• Moderate to severely active UC disease activity, defined as a modified Mayo score of 4 through 9, inclusive, with the following minimum subscores: i) An SF subscore ≥ 1, AND ii) An RB subscore ≥ 1, AND iii) An ES ≥ 2 (endoscopy performed within 60 days of the first study intervention administration).
• Report of a previous colonoscopy that documents extent of disease
• Current or recent (within 3 months of screening) evidence of fulminant colitis, toxic megacolon, or bowel perforation
• Extensive colonic resection or current stoma
• Colonic dysplasia that has not been removed Other protocol-defined inclusion/exclusion criteria apply

Part A Main 1. Capable of giving signed informed consent. 2. Subject who has a signed and dated Informed Consent Form (ICF). 3. Subject must be 18 to 50 years inclusive, at the time of signing the ICF. 4. Male or female. 5. Female subjects who are not of childbearing potential (or females of childbearing potential who agree to comply with the contraceptive requirements of the clinical trial protocol). 6. Good general health, as determined by the Investigator. 7. A positive SPT to histamine. The following additional inclusion criteria are only applicable to the healthy subjects in Group A1: 8. Healthy subjects (non-atopic) with no clinically significant co-morbidity (including broncho-reactive airway disease like asthma, current allergic rhinitis, etc.). 9. Subjects with no history of allergy or intolerance to peanut or any other food and who consume peanuts with no effect. 10. Subjects with lack of sensitivity to peanut allergen confirmed by SPT using whole peanut extract. 11. Peanut specific immunoglobulin E (IgE) <0.1 kU/L. 12. Ara h 2 specific IgE <0.1 kU/L. 13. Subjects with negative basophil activation test (BAT). The following additional inclusion criteria are only applicable to the subjects with PA in Group A2: 14. Clinical history of physician diagnosed PA. 15. Peanut allergen sensitivity confirmed by SPT and IgE. 16. Subjects who currently adhere to a strict peanut-free diet and who agree to continue this for the duration of the clinical trial. 17. Subjects who are able to handle and correctly use an adrenaline auto-injector. Part B Main 1. Capable of giving signed informed consent. 2. Subject who has a signed and dated ICF. 3. Subjects aged 18 to 50 years of age inclusive, at the time of signing the ICF. 4. Male or female. 5. Female subjects who are not of childbearing potential (or females of childbearing potential who agree to comply with the contraceptive requirements of the clinical trial protocol). 6. Clinical history of physician diagnosed PA. 7. Peanut allergen sensitivity confirmed by SPT and IgE (Peanut specific IgE ≥5.0 kU/L and Ara h 2 specific IgE ≥2.0 kU/L) 8. Subjects with positive BAT. 9. Subjects who currently adhere to a strict peanut-free diet and who agree to continue this for the duration of the clinical trial. 10. Good general health, as determined by the Investigator. 11. Subjects who are able to handle and correctly use an adrenaline auto-injector. Main Exclusion Criteria Part A and B: 1. Pregnant or lactating subject. 2. Presence of any medical condition that may reduce the ability to survive a serious allergic reaction. 3. Subjects with atopic dermatitis with >25% skin surface involvement. 4. For subjects with PA, presence of severe, poorly controlled or uncontrolled asthma. 5. History of severe or life-threatening anaphylactic reactions to peanut resulting in neurological compromise or requiring mechanical ventilation. 6. Clinical history of severe systemic or life-threatening anaphylactic reactions to other foods (apart from peanut), insect venom, exercise, drugs, etc. or idiopathic anaphylaxis. 7. Unable to receive epinephrine therapy or at greater risk of developing adverse reactions after epinephrine administration as assessed by the site Investigator. 8. Clinical history of drug or alcohol abuse, which, in the Investigator's opinion, could interfere with the subject's ability to participate in the clinical trial. 9. Participation in a clinical research trial with any investigational drug/placebo within 3 months of screening (Visit 1) or concomitantly with this clinical trial. 10. Personal, financial or other dependent relationship (e.g., employee or immediate relative) with the clinical trial site, Sponsor, Sponsor's representative, or another individual who has access to the clinical trial protocol. 11. Vulnerable subjects or those in judicial or governmental detention, detainment or imprisonment in a public institution.