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.

• Newly diagnosed histologically confirmed prostate adenocarcinoma within 6 months prior to study registration with evidence of high-volume distant metastasis on conventional imaging
• Distant metastasis is defined by non-regional lymph node(s) metastasis (M1a), bone metastasis (M1b), and/or other site(s) of metastatic disease (M1c).
• Conventional imaging consists of CT, MRI or radionuclide bone scan
• High volume of disease is defined by presence of four or more bone lesions with at least one beyond the vertebral bodies or pelvis or any site of visceral metastasis.
• Age ≥18 years
• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
• Subjects with ECOG performance status of 2 are only eligible if the performance status decline is attributed to metastatic prostate cancer
• Serum PSA > 4.0 ng/mL before initiation of ADT
• Serum testosterone > 100 ng/dL before initiation of ADT
• Subjects whose testosterone level is unknown before initiation of ADT may be allowed after discussion with Sponsor-Investigator.
• Grade ≤ 1 peripheral neuropathy, defined as asymptomatic or paresthesia and/or decreased deep tendon reflexes is allowed.
• Subjects must have adequate organ and marrow function as defined below:
• Absolute neutrophil count ≥1,500 /mcL
• Platelets ≥100,000 /mcL
• Total bilirubin ≤1.5 × institutional upper limit of normal. Exception: Subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology) may be allowed after consultation with treating physician
• AST(SGOT) and ALT(SGPT) ≤2.5 × institutional upper limit of normal. Exception: ≤5 x institutional upper limit of normal in subjects with liver metastasis
• Creatinine (Cr) and creatinine clearance (CrCl) Cr <1.6 mg/dL or CrCl ≥30 mL/min; CrCl should be calculated using the Cockcroft-Gault formula: CrCl (mL/min) = (140-Age) x Body weight (Kg)/72 x Serum creatinine (mg/dL)
• PT, INR and PTT ≤ 1.5 x institutional upper limit of normal. Exception: Subjects who are on a stable regimen of therapeutic anticoagulation for an appropriate clinical indication may be enrolled
• Availability of adequate baseline prostate biopsy tissue for integral biomarker analysis and correlative studies:
• Sources of tumor tissue allowed are (1) prostate biopsy, (2) transurethral resection of the prostate tissue (TURP) , (3) trans urethral resection of bladder tumor tissue (TURBT) with contiguous spread of prostate cancer to the bladder, and (4) metastatic biopsy tissue excluding bone and lymph node metastases (e.g. lung or liver biopsies are acceptable).
• For OncoPanel, submit at least one (1) H&E slide and ten (10) 5-micron thick serially sectioned unstained formalin-fixed paraffin-embedded (FFPE) slides. Biopsy should contain at least 20% tumor involvement with the highest Gleason score(s). If requested tissue is unavailable, a lower number of 4-micron or 5- micron slides and/or slides containing lower tumor involvement may be accepted after discussion with the Sponsor-Investigator.
• For ImmunoProfile, submit at least one (1) H&E slide and one (1) 5-micron thick serially sectioned unstained, freshly cut, FFPE slide. Biopsy should contain at least 50% tumor involvement with the highest Gleason score(s). If requested tissue is unavailable, a 5-micron slide containing lower tumor involvement may be accepted after discussion with the study Sponsor-Investigator.
• Submission of one (1) H&E slide and at least one (1) FFPE tissue core block with at least 3mm2 tumor area with the highest Gleason score is an acceptable alternative to unstained FFPE slides.
• Subjects who have insufficient baseline prostate biopsy tissue for OncoPanel analysis but have baseline metastatic biopsy tissue available may have OncoPanel analysis performed using metastatic biopsy tissue. Successful OncoPanel testing (but not ImmunoProfile) of metastatic biopsy tissue is acceptable from any source including lymph node or bone, after discussion with the study Sponsor- Investigator.
• For Exploratory Correlative Studies, at least 1 tissue core block (preferred) or one (1) H&E slide and twelve (12) 5-micron thick FFPE slides with unstained, freshly cut, serial sections from biopsy cores containing at least 20% tumor involvement with the highest Gleason score(s) will be requested, if available.
• Tissue should be submitted with redacted pathology report.
• Successful OncoPanel and ImmunoProfile biomarker analysis for allocation into a study cohort during pre-screening
• Subjects whose tumors harbor somatic or germline homozygous deletions and/or deleterious mutations in a DDR gene using OncoPanel will be assigned to Cohort 1, regardless of ImmunoProfile results
• DDR genes include and are not limited to BRCA2, ATM, CHEK2, BRCA1, PALB2, RAD51D, ATR, NBN, PMS2, GEN1, MLH1, MSH2, MSH6, RAD51C, MRE11A, BRIP1, FAM175A, and CDK12
• Deleterious mutations are defined as loss of function, splice site, nonsense, or frameshift mutations, and determination will be made between DFCI molecular pathology and study Sponsor-Investigator
• Tumors identified as mismatch repair deficient (MMR-d) or microsatellite instability high (MSI-H) will also be included in Cohort 1
• Patients with germline DDRD or MMR-d/MSI-H (Lynch Syndrome) or tumors with DDRD or MMR-d/MSI-H identified in another CLIAcertified laboratory (e.g., Foundation Medicine) using prostate or metastatic tissue may be assigned to Cohort 1 after discussion with the Sponsor-Investigator. If archival tissue is available, it will be requested for OncoPanel testing; however, results will not influence eligibility.
• Subjects whose tumors are PD-L1 positive and/or CD8+ T cell inflamed using ImmunoProfile without the presence of DDRD will be assigned to Cohort 2
• PD-L1 positivity will be defined as Combined Positive Score (CPS) ≥ 1, which is the number of PD-L1 staining cells (e.g., tumor cells, immune cells) divided by the total number of tumor cells, multiplied by 100
• CD8+ T cell inflammation will be defined as CD8+ T cell density ≥ 200, which is the number of CD8+ cells divided by the surface area of a region of interest (mm2)
• Subjects whose tumors do not harbor DDRD and are PD-L1 negative with low CD8+ T cell infiltration will be assigned to Cohort 3
• Subjects whose prescreening is unsuccessful for cohort allocation or whose biomarker status matches that of a filled cohort will not be eligible
• Subjects who underwent successful ImmunoProfile pre-screening but failed OncoPanel pre-screening may be allocated to Cohort 2 or Cohort 3 based on ImmunoProfile results and assuming DDRD negativity, at the discretion of the Sponsor-Investigator.
• Before one of the study cohorts enrolls 15 of 20 subjects (Cohort 3 is anticipated to complete accrual first), subjects may undergo main study screening when ImmunoProfile and OncoPanel analyses are ongoing, and may proceed to study treatment if they meet all eligibility criteria with the exception that OncoPanel analysis is ongoing. These patients will be allocated into their respective cohort after OncoPanel results return.
• Willingness to provide leftover metastatic biopsy tissue for correlative studies, if obtained for clinical purposes
• Based on its mechanism of action and data from animal studies, nivolumab can cause fetal harm. For this reason non-sterilized men who are sexually active with a female partner of childbearing potential treated or enrolled on this protocol must agree to use adequate contraception prior to the study, for the duration of study participation, and for 7 months after last dose of nivolumab administration
• Adequate contraception includes male condom plus spermicide
• Not engaging in sexual activity is an acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception
• Subjects in this study should refrain from sperm donation
• Ability to understand and the willingness to sign a written informed consent document, or have a legally authorized representative sign on the subject's behalf
• Subjects must not have received prior ADT (LHRH analogue +/- antiandrogen), chemotherapy, or immunotherapy for prostate cancer. The following exception is allowed:
• Subjects who have initiated ADT prior to study registration and are able to complete biomarker pre-screening, cohort allocation, and start C1D1 study chemoimmunotherapy ≤120 days from initiation of ADT are allowed
• The 120-day window commences at the start of either the antiandrogen agent or LHRH analogue, whichever is earlier
• Antiandrogens (e.g., bicalutamide or flutamide) may be used in addition to LHRH analogue ≤60 days before initiation of LHRH analogue to cover the testosterone surge associated with certain LHRH agonists but must be discontinued prior to study registration
• Second-generation hormonal agents (e.g., abiraterone acetate) are not allowed
• Subjects must not have undergone prostatectomy
• Prostate radiation is allowed before or after study enrollment and may be delivered concurrently with study chemoimmunotherapy, per provider discretion, assuming adequate prostate biopsy tissue is collected before prostatic radiation
• Metastasis-directed radiation is allowed before or after study enrollment and may be delivered concurrently with study chemoimmunotherapy, per provider discretion
• Subjects who are receiving any other investigational agents
• Any previous treatment with a PD-1 or PD-L1 inhibitor
• Subjects with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other AEs
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to docetaxel (including any drugs formulated with polysorbate 80), nivolumab, or LHRH analogue (e.g., leuprolide, goserelin acetate, degarelix)
• History of another primary malignancy, except for:
• Malignancy treated with curative intent and with no known active disease for ≥2 years before the first dose of study treatment and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Major surgical procedure as defined by the Site Investigator within 28 days prior to the first dose of chemoimmunotherapy
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. HIV-positive subjects on combination antiretroviral therapy are ineligible because of the potential for nivolumab to be less clinically active in this population. In addition, these subjects are at increased risk of lethal infections when treated with marrow-suppressive chemotherapy
• History of allogeneic bone marrow or organ transplantation
• Active or prior documented autoimmune or inflammatory disorders, including= inflammatory bowel disease (e.g., Crohn's disease), systemic lupus erythematosus, Sarcoidosis syndrome, Grave's disease, rheumatoid arthritis, hypophysitis, uveitis, with the following exceptions:
• Vitiligo or alopecia
• Hypothyroidism stable on hormone replacement
• Chronic skin condition that does not require systemic therapy
• Celiac disease controlled by diet alone
• Subjects with inactive disease in the last 5 years may be included but only after consultation with the study physician
• Active infection including tuberculosis, hepatitis B (known positive HBV surface antigen [HBsAg]), or hepatitis C (HCV)
• Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible
• Subjects with positive HCV antibody are eligible if polymerase chain reaction is negative for HCV RNA
• Concurrent or prior use of immunosuppressive medication within 14 days before the first dose of study chemoimmunotherapy, with the following exceptions:
• Premedication for docetaxel with oral dexamethasone (See Section 5.1)
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)
• Systemic corticosteroids at physiologic doses not exceeding 10mg/day of prednisone or its equivalent
• Steroids as premedication for hypersensitivity reactions (e.g., premedication for iodinated contrast allergy before CT scan) Inclusion of Minorities • Men of all races and ethnic groups are eligible for this trial.

• 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

1. Patients must have a malignant solid tumor with a pathogenic inactivating TSC1 or TSC2 alteration. Genetic alterations should be identified using NGS in tumor tissue or liquid biopsy). • Patients will be enrolled after the central evaluation of NGS report confirms eligibility. 2. Patients must have solid tumors that are metastatic or locally advanced where surgical resection is not an option or likely to result in severe morbidity. 3. Patients must have received all standard therapies appropriate for their tumor type and stage of disease or, in the opinion of the Investigator, the patient would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy, or the patient has no satisfactory alternative treatments. 4. Patients must have 1 or more measurable target lesions by computed tomography (CT) scan or magnetic resonance imaging (MRI) (RECIST v1.1). 5. Age: 12 years or older. 6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 or Karnofsky Performance Status (KPS) ≥80 or Lansky play-performance scale for pediatric patients ≥80. 7. Adequate liver function: 1. Total bilirubin ≤1.5 × upper limit of normal (ULN) (unless due to Gilbert's syndrome, then ≤3 × ULN) 2. Aspartate aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN if attributable to liver metastases) 8. Adequate renal function: creatinine clearance ≥30 mL/min, Cockcroft-Gault CCr = ((140-age) × weight[kg]) / (72 × SCr[mL/min]) × 0.85, if female 9. Adequate hematologic parameters: 1. Absolute neutrophil count (ANC) ≥1.0 × 109/L (growth factor support allowed) 2. Platelet count ≥100,000/mm3 (100 × 109/L) (transfusion and/or growth factor support allowed) 3. Hemoglobin ≥8.0 g/dL (transfusion and/or growth factor support allowed) 10. Fasting serum triglyceride must be ≤300 mg/dL; fasting serum cholesterol must be ≤350 mg/dL. 11. Minimum of 4 weeks since any major surgery, completion of radiation, or completion of prior systemic anticancer therapy, or at least 5 half-lives if the prior therapy is a single agent small-molecule therapeutic, and adequately recovered from the acute toxicities of any prior therapy, including neuropathy, to Grade ≤1. 12. Male or non-pregnant and non-breastfeeding female: 1. Females of childbearing potential must agree to use effective contraception or abstinence without interruption from 28 days prior to starting investigational product (IP) throughout 3 months after last dose of IP and have a negative serum pregnancy test (beta human chorionic gonadotropin, β-hCG) result at screening and agree to ongoing pregnancy testing during the course of the study, and after the end of study treatment. A second form of birth control is required even if she has had a tubal ligation. 2. Male patients must agree not to donate sperm and must practice abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study and throughout 3 months after last dose of IP. A second form of birth control is required even if he has undergone a successful vasectomy. 13. The patient or the patient's parent(s) or legal guardian(s) understand(s) and sign(s) the informed consent. 14. Willingness and ability to comply with scheduled visits, laboratory tests, and other study procedures. 1. Prior treatment with an mTOR inhibitor, including nab-sirolimus. 2. Severe (Grade ≥3) ongoing infection requiring parenteral or oral anti-infective treatment, either ongoing or completed ≤7 days prior to enrollment. 3. Patients with primary brain tumors or PEComa. 4. Patients who have any severe and/or uncontrolled medical or psychiatric conditions or other conditions that could affect their participation including: 1. Patients with meningeal carcinomatosis, leptomeningeal carcinomatosis, spinal cord compression, untreated brain metastases or symptomatic or unstable brain metastases. Note: Patients with stable brain metastases (defined as asymptomatic or no requirement for high-dose [defined as dexamethasone 10 mg daily or higher] or increasing dose of systemic corticosteroids) and without imminent need of radiation therapy are eligible. If applicable, patients must have completed brain radiation therapy and recovered adequately from any associated toxicity and/or complications prior to eligibility assessment. For patients who have received prior radiation therapy, post-treatment MRI scan should show no increase in brain lesion size/volume. 2. Unstable angina pectoris, symptomatic congestive heart failure (New York Heart Association, NYHA class III or IV), myocardial infarction ≤6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease. 3. Pre-existing severely impaired lung function. If a patient has a pre-existing pulmonary condition, eligible patients should have a spirometry and diffusing capacity for carbon monoxide (DLCO) that is >50% of the normal predicted value and/or O2 saturation that is >88% at rest on room air (Note: spirometry and pulmonary function tests [PFTs] not required to be performed unless clinically indicated). 4. Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy. 5. A history of malignancies other than the one under treatment unless the patient is disease-free for more than 5 years from diagnosis. Note, controlled non-melanoma skin cancers, carcinoma in situ of the cervix, resected incidental prostate cancer, certain low grade hematologic malignancies (eg CLL, follicular lymphoma, etc), or other adequately treated carcinoma-in-situ may be eligible, after discussion with the medical monitor. 6. Uncontrolled hypertension (systolic blood pressure ≥160 mm-Hg and/or diastolic blood pressure ≥100 mm Hg). 7. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension. 8. Individuals with known human immunodeficiency virus (HIV) infection are excluded from this study as combination antiretroviral therapy could potentially result in significant pharmacokinetic interactions. In addition, these individuals are at increased risk of serious infections due to the immunosuppressive effects of mTOR inhibition. 9. Active Hepatitis B or Hepatitis C, with detectable viral load. 5. Regarding concomitant medications with significant CYP3A4 and P-gp interactions, discontinuation of strong inhibitors (eg, ketoconazole, itraconazole, voriconazole, erythromycin, clarithromycin, telithromycin, and others), strong inducers (eg, rifampin, rifabutin), and known CYP3A4 substrates with a narrow therapeutic window (eg, fentanyl, alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, or terfenadine) is required at least 5 half lives prior to receiving the first dose of nab-sirolimus, whichever is longer.

• 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

1. 1 month of age up to < 18 years of age at the time of signing the informed consent. 2. Received HSCT within the past 6 months. 3. Diagnosis of TMA that persists despite initial management of any triggering condition. 4. Body weight ≥ 5 kilograms. 5. Female participants of childbearing potential and male participants with female partners of childbearing potential must use highly effective contraception starting at Screening and continuing until at least 8 months after the last dose of ravulizumab. 6. Participants must be vaccinated against meningococcal infections if clinically feasible, according to institutional guidelines for immune reconstitution after HSCT. Participants must be re-vaccinated against Haemophilus influenzae type b and Streptococcus pneumoniae if clinically feasible, according to institutional guidelines for immune reconstitution after HSCT. All participants should be administered coverage with prophylactic antibiotics according to institutional post-transplant infection prophylaxis guidances, including coverage against Neisseria meningitidis for at least 2 weeks after meningococcal vaccination. Participants who cannot receive meningococcal vaccine should receive antibiotic prophylaxis coverage against Neisseria meningitidis the entire Treatment Period and for 8 months following the final dose of ravulizumab. 1. Known familial or acquired 'a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13' deficiency (activity < 5%). 2. Known Shiga toxin-related hemolytic uremic syndrome. 3. Positive direct Coombs test. 4. Diagnosis or suspicion of disseminated intravascular coagulation. 5. Known bone marrow/graft failure. 6. Diagnosis of veno-occlusive disease (VOD). 7. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody titer). 8. Unresolved meningococcal disease. 9. Presence of sepsis requiring vasopressor support. 10. Pregnancy or breastfeeding. 11. Hypersensitivity to murine proteins or to 1 of the excipients of Ravulizumab. 12. Previously or currently treated with a complement inhibitor.

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.

Key
• Has a Karnofsky performance scale (KPS) score ≥ 70 at screening
• Has a new diagnosis of GBM (WHO GRADE III or Grade IV GBM) based on the treating neurosurgeon's best clinical judgement
• Has a diagnostic contrast-enhanced magnetic resonance imaging (MRI) scan with fluid attenuated inversion-recovery (FLAIR) sequence of the brain at screening. Participants must have a confirmed measurable disease pre-operatively with at least 1 lesion measuring a total bi-perpendicular product of 4 centimeter square (cm^2) in 2 different planes (axial, sagittal, or coronal)
• The tumor must be located in the supratentorial compartment
• Has adequate bone marrow and organ function at screening Key
• Has bi-hemispheric disease, multicentric disease, or disease burden involving the brain stem or cerebellum based on MRI post-gadolinium enhancement
• Has received any previous surgical resection or any anticancer intervention for glioma
• Has any history of glioma, a concurrent malignancy, or malignancy within 3 years of randomization, unless definitive therapy is completed, with the exception of basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast that has completed curative therapy
• Has any severe immunocompromised condition (eg, human immunodeficiency virus (HIV) with a cluster of differentiation [CD] 4+ cell count <200*10^6/liter [L]) or any active uncontrolled autoimmune disease (eg, Crohn's disease)
• Has an active cardiac disease or a history of cardiac dysfunction
• Is receiving any other investigational agent(s) or has received an investigational agent within 30 days or 5 half-lives of investigational agent use, whichever is longer, prior to screening
• Is partaking in another interventional study. Participants who are partaking in an observational study are eligible
• Has received a live vaccine within 30 days of screening
• Has active and uncontrolled/untreated hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, or any other active infections that, in the Investigator's opinion, would impair or prohibit a participant's participation in this study.
• Is receiving treatment with Tumor Treating Fields or Optune®

• Clinical diagnosis of Graves' Disease and/or autoimmune Hashimoto's thyroiditis associated with active moderate to severe TED with a CAS ≥ 4 (on the 7- item scale) for the most severely affected eye (primary study eye) at Screening and Baseline
• Confirmed active TED (not sight-threatening but has an appreciable impact on daily life, with onset (as determined by patient records) within 12 months prior to the Baseline visit and usually associated with one or more of the following: lid retraction ≥ 2 mm, moderate or severe soft tissue involvement, exophthalmos ≥ 3 mm above normal for race and gender, and/or inconstant or constant diplopia.
• Subjects must be euthyroid with the participant's baseline disease under control or have mild hypo- or hyperthyroidism (defined as free thyroxine [FT4] and free triiodothyronine levels [FT3] < 50% above or below the normal limits) at Screening.
• Does not require immediate ophthalmic surgery, radiotherapy to orbits or other ophthalmological intervention at the time of Screening and is not planning for any such treatment during the course of the study.
• Decreased best corrected visual acuity due to optic neuropathy as defined by a decrease in vision of 2 lines on the Snellen chart, new visual field defect, or color defect secondary to optic nerve involvement within the last 6 months.
• Corneal decompensation unresponsive to medical management.
• Previous orbital irradiation or orbital surgery.
• Any glucocorticoid use (intravenous [IV] or oral) with a cumulative dose equivalent to >= 1g of methylprednisolone or equivalent for the treatment of TED within 3 months of Screening.
• Prior IGF-1R inhibitor therapy for any condition.

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. 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

• 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]

• >= 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

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
• 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 advanced or metastatic breast cancer with: 1. ≤1 line of chemotherapy, 2. ≥1 cyclin-dependent kinases (CDK) 4/6 inhibitor, and 3. ≥1 antiestrogen therapy 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 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

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

• STEP 0 INCLUSION CRITERIA
• Histologically proven mucosal melanoma by local pathology
• Central PD-L1 tumor tissue submission
• STEP 1 INCLUSION CRITERIA
• Receipt of the central PD-L1 testing results available
• Disease status-Resected R0 or R1 disease patients. Patients eligible for randomization have resected R0 or R1 disease (with negative margins or positive microscopic margins) that must meet one of the following 4 criteria as defined below:
• Regional lymph node (LN) involvement; OR
• In-transit metastases/satellite primary disease; OR
• Single localized, primary disease meeting one of the following site-specific requirements:
• Head/neck
•Sinonasal (including nasopharynx): any primary lesion; Nasal or oral cavity; pT4a or above, given slightly improved OS
• NOTE: Conjunctival: does not meet the qualification for eligibility
• Anorectal
•any primary lesion
• Vaginal/cervical
•any primary, as they have 5 year OS rates of 5-25
• Urinary tract
•any primary urethral or bladder tumor
• Penile
• Vulvar- AJCC cutaneous stage IIB or higher
• Esophageal/gallbladder
•any primary
• Locoregionally recurrent following prior resection, meeting at least one of the above criteria
• In addition, patients must have undergone cross-sectional imaging of the brain, chest, abdomen and pelvis with no evidence of distant metastatic disease
• Disease status-Non-resected R2 or metastatic disease patients
• Non-resected R2 or metastatic disease that is assessable and measurable radiographically or by physical examination
• Prior Treatment:
• No prior systemic checkpoint inhibitor therapy of mucosal melanoma, including in the adjuvant setting, is allowed. Prior adjuvant chemotherapy or interferon is allowed.
• No other active, concurrent malignancy that requires ongoing systemic treatment or interferes with radiographic assessment of melanoma response as determined by the investigator. Exceptions may allow for adjuvant no evidence of disease (NED) cancers undergoing hormone based therapy may be eligible pending the other eligibility criteria are met and the principal investigator (PI) affirms the hormonal agent would not change the melanoma response.
• Any radiation must have completed 28 days prior to randomization and the patient must have adequately recovered from its effects.
• For resectable patients only: Surgery must have completed 28 days prior to randomization.
• For resectable patients only: Surgery must have completed no more than 84 days prior to randomization.
• Not pregnant and not nursing, because this study has an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl) >= 50mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Albumin >= 2.8 g/dL
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• No cardiovascular disease, including:
• No history of acute coronary syndromes (including myocardial infarction and unstable angina), coronary artery bypass graft (CABG) coronary angioplasty, or stenting within 6 months prior to study entry.
• No history of current class II or higher congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system.
• No refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg despite adequate attempts at anti-hypertensive therapy.
• No history of myocarditis.
• No history of syncope of cardiovascular etiology, uncontrolled cardiac arrhythmia, history of Mobitz II second degree or third degree heart block without a permanent pacemaker in Association (NYHA) class II to IV heart failure, or stroke/transient ischemic attack (TIA) within the past 3 months.
• No corrected QT interval by Fridericia's formula (QTcF) > 500 msec. Note: if initial QTcF is found to be > 500 ms, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is =< 500 ms, the subject meets eligibility in this regard.
• No underlying hematologic issues, including:
• Congenital bleeding diathesis
• Gastrointestinal (GI) bleeding requiring intervention within the past 6 months, unless directly related to mucosal melanoma
• Active hemoptysis within 42 days prior to study enrollment.
• Active tumor lesions with cavitations or tumor lesions which invade, encase, or abut major blood vessels. The anatomic location and characteristics of primary tumors or metastases as well as the medical history should be carefully reviewed in the selection of subjects for treatment with cabozantinib/placebo.
• Pulmonary emboli or deep vein thromboses (DVT) that require an active anticoagulation regimen.
• No known or suspected history of cytopenia (low white blood cell [WBC], hemoglobin or platelet count) of greater than 3 months duration with an unknown cause, myelodysplastic syndrome, or hematologic malignancies.
• No clinical, laboratory or radiographic evidence of an active bacterial, fungal, or viral infection requiring treatment at the time of pre-registration (e.g., active symptoms of COVID-19 infection or a post-infectious symptomatic autoimmune syndrome, serious bacterial infections requiring antibiotics).
• No known or suspected gastrointestinal disorder affecting absorption of oral medications.
• Comorbid conditions:
• No active autoimmune disease or any condition requiring systemic treatment with either corticosteroids (> 10 mg daily of prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• No history of autoimmune motor neuropathy (e.g., Guillain-Barre syndrome, myasthenia gravis) or non-infectious pneumonitis.
• No history of severe allergic reactions to an unknown allergen or any components of the study drugs or its excipients.
• No history of gastrointestinal perforation or abdominal fistula.
• No clinically suspected central nervous system (CNS) (leptomeningeal or parenchymal) metastases. Patients with a history of CNS metastasis(s) will be allowed as long as
• The metastatic site(s) were adequately treated as demonstrated by clinical and radiographic improvement, AND
• The patient has recovered from the intervention (no residual adverse events > Common Terminology Criteria for Adverse Events [CTCAE] grade 1), AND
• The patient has remained without occurrence of new or worsening CNS symptoms for a period of 28 days prior to enrollment.
• No history of seizure or any condition that may increase the patient's seizure risk (e.g., prior cortical stroke, significant brain trauma) within 2 years.
• No clinically active or chronic liver disease resulting in moderate/severe hepatic impairment (Child-Pugh class B or C), ascites, coagulopathy or bleeding due to liver dysfunction.
• No untreated spinal cord compression or evidence of spinal metastases with a risk of impending fracture or spinal cord compression. Spinal metastases must have completed planned radiation or surgical therapy prior to registration.
• Concomitant medications:
• Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 5 days prior to the start of study treatment.
• Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 5 days prior to the start of study treatment.

Patients must meet all the following criteria to participate in the study: 1. Males and females ≥ 18 years of age 2. Dose-escalation phase: Histologically or cytologically confirmed metastatic and/or unresectable solid tumor, relapsed or refractory to standard therapy, or for which no standard therapy is available that is expected to improve survival by at least 3 months 3. At least 3 weeks beyond the last chemotherapy (or 3 half-lives, whichever is shorter), radiotherapy, major surgery, or experimental treatment, and recovered from all acute toxicities (≤ Grade 1), prior to the first dose of FF-10850 4. Adequate performance status: Eastern Cooperative Oncology Group (ECOG) ≤ 1 5. Life expectancy of ≥ 3 months 6. Adequate hematologic parameters without ongoing transfusion support:
• Hemoglobin (Hb) ≥ 9 g/dL
• Absolute neutrophil count (ANC) ≥ 1.0 × 109 cells/L
• Platelets ≥ 100 × 109 cells/L 7. Creatinine ≤ 1.5 × ULN, or calculated creatinine clearance ≥ 50 mL/minute by either the Cockcroft-Gault formula or as measured by a 24-hour urine collection 8. Total bilirubin ≤ 2 × ULN unless due to Gilbert's disease; patients with Gilbert's disease who have a total bilirubin > 6 mg/dL are to be excluded 9. ALT and AST ≤ 2.5 times ULN, or < 5 × ULN for patients with liver metastases 10. QT interval corrected for rate (QT interval corrected for rate using Fridericia's Correction Formula, QTcF) ≤ 470 msec for women and ≤ 450 msec for men on the ECG obtained at Screening and confirmed pre-treatment on Cycle 1 Day 1. 11. Patient must be willing to undergo a tumor biopsy, if the patient has a biopsy-accessible tumor 1. Patients who have not received standard/approved therapies expected to improve survival by at least 3 months 2. History of severe hypersensitivity reactions to topotecan 3. Serious cardiac condition within the last 6 months, such as uncontrolled arrhythmia, myocardial infarction, unstable angina or heart disease defined by the New York Heart Association (NYHA) Class III or Class IV or hereditary long QT syndrome 4. Concomitant medication(s) that may cause QTc prolongation or induce Torsades de Pointes, except for antimicrobials that are used as standard of care to prevent or treat infections and other such drugs that are considered by the Investigator to be essential for patient care 5. Active central nervous system (CNS) malignant disease in patients with a history of CNS malignancy. Patients with previously treated stable brain metastases are allowed if they have been stable off steroid therapy for at least 4 weeks. 6. Known positive for human immunodeficiency virus (HIV), hepatitis B virus surface antigen (HBsAg) or hepatitis C virus (HCV) 7. Active infection requiring intravenous (IV) antibiotic usage within the last week prior to study treatment 8. Any other medical intervention or other condition which, in the opinion of the Principal Investigator, could compromise adherence to study requirements or confound the interpretation of study results 9. Pregnant or breast-feeding

• Patients must have histologically or cytologically confirmed recurrent or metastatic HNSCC that is considered incurable.
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as >=10 mm (>= 1 cm) with CT scan, magnetic resonance imaging (MRI), or calipers by clinical exam.
• Primary tumor locations of oral cavity, oropharynx, hypopharynx, and larynx are allowed. Participants may not have a primary tumor site of nasopharynx.
• Patients with oropharyngeal cancer must have known human papillomavirus (HPV) status defined by human papillomavirus type 16 (p16) testing.
• Patients should not have had prior systemic therapy administered in the recurrent or metastatic setting. Systemic therapy which was given as part of multimodal treatment for locally advanced disease is allowed.
• Patients must be able to provide an archival tissue specimen.
• Patients must be willing to undergo a mandatory tumor biopsy on treatment
• Tumor tissue must have a documented combined positive score (CPS) of >= 1 for PD-L1.
• Age >= 18 years. Because no dosing or adverse event data are currently available on the use of ipatasertib in combination with pembrolizumab in patients < 18 years of age, children are excluded from this study.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Karnofsky >= 60%).
• Absolute neutrophil count >= 1,000/mcL.
• Platelets >= 100,000/mcL.
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN).
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN.
• Creatinine =< 1.5 x institutional ULN.
• Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 (using the Cockcroft-Gault formula).
• Human immunodeficiency virus (HIV) infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
• Patients must be able to swallow orally administered medication whole.
• For women of childbearing potential (WOCBP): agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period, for 5 months after the last dose of pembrolizumab and 28 days after the last dose of ipatasertib, and agreement to refrain from donating eggs during this same period.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, agreement to refrain from donating sperm during the treatment period, and for 5 months after the last dose of pembrolizumab and 28 days after the last dose of ipatasertib.
• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible.
• Prior treatment with a checkpoint inhibitor given for relapsed or metastatic disease. Prior treatment with a checkpoint inhibitor for locally advanced disease as part multidisciplinary treatment is allowed.
• History of malabsorption syndrome or other condition that would interfere with enteral absorption or result in the inability or unwillingness to swallow pills.
• Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the study principal investigator (PI).
• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine or physiologic corticosteroid replacement for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Type 1 or Type 2 diabetes mellitus requiring insulin at study entry are ineligible.
• Patients who are on a stable dose of oral diabetes medication >= 4 weeks prior to initiation of study treatment may be eligible for enrollment. Patients must meet the laboratory eligibility criteria for fasting blood glucose and hemoglobin A1c.
• Fasting glucose =< 150 mg/dL (8.3 mmol/L) and hemoglobin A1c =< 7.5% (58 mmol/mol).
• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1). Note: Patients with grade =< 2 neuropathy or grade =< 2 alopecia are an exception to this criterion and may qualify for the study. Note: If patients received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Patients who are receiving any other investigational agents.
• Patients with known active CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ipatasertib or hypersensitivity (grade >= 3) to pembrolizumab and/or any of the components of the solution for injection.
• Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug is prohibited. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Patients with uncontrolled intercurrent illness (including but not limited to interstitial lung disease or active, non-infectious pneumonitis) or a history of (non-infectious) pneumonitis that required steroids.
• Patients with psychiatric illness/social situations that would limit compliance with study requirements.
• Patients who are pregnant or breastfeeding, or are expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 5 months after the last dose of study treatment. A WOCBP who has a positive urine pregnancy test (e.g., within 72 hours) prior to treatment will be excluded from the study. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Pregnant women are excluded from this study because pembrolizumab is a monoclonal antibody agent and ipatasertib is an oral AKT inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pembrolizumab and ipatasertib, breastfeeding should be discontinued if the mother is treated with pembrolizumab or ipatasertib. Due to the potential risks, WOCBPs and men 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 for 5 months after the last dose of pembrolizumab and 28 days after the last dose of ipatasertib. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Patients with grade >= 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia are excluded.
• Patient has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer) that has undergone potentially curative therapy.
• History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) or active bowel inflammation (e.g., diverticulitis).
• Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, aspergillosis, active tuberculosis, or history of opportunistic infections (pneumocystis pneumonia or cytomegalovirus pneumonia).
• Known clinically significant history of liver disease consistent with Child Pugh Class B or C, including active viral or other hepatitis (e.g., positive for hepatitis B surface antigen [HbsAg] or hepatitis C virus [HCV] antibody at screening), current drug or alcohol abuse, or cirrhosis.

• Diagnosis of stage I, ER and/or PR positive, her2neu negative breast cancer within the last 6-24 monoths
• Willing to complete study procedures using email
• Receipt of chemotherapy for the stage I ER and/or PR positive, her2neu negative breast cancer diagnosed within the last 6-24 months
• Participants will be excluded if they are unable to read and write in English or if, in the opinion of a treating clinician, have cognitive impairment that would prevent completion of study procedures
• Pregnancy, based on patient self-report. If a patient becomes pregnant during the study period, they will be removed from the study at that time.
• Diagnosis of a ER and PR negative, her2neu negative breast cancer or a her2neu positive breast cancer within the last 5 years

• Participants must have histologically and pathologically confirmed melanoma that has metastasized to the brain
• Any primary (cutaneous, acral/mucosal, etc) or unknown origin are permitted, except that participants with uveal primary are not eligible
• Participants must have BRAF-V600 mutant melanoma documented by a Clinical Laboratory Improvement Act (CLIA)-certified laboratory
• All participants must have an magnetic resonance imaging (MRI) of the brain within 28 days prior to registration and must have central nervous system metastases with at least one measurable brain metastasis >= 0.5 cm in size (per modified RECIST 1.1) that has not been irradiated, or progressed (in the opinion of the treating physician) after prior radiation therapy. Participating sites MUST use MRI slice thickness of =< 1.5 mm and are recommended to adhere to the 'minimum' Brain Tumor Imaging Protocol for Clinical Trials in Brain Metastases (BTIP-BM) compliant MRI acquisition protocol. Computed tomography (CT) of the head cannot substitute for brain MRI. (NOTE: All central nervous system [CNS] disease must be documented on BOTH the Brain Metastases Baseline Tumor Assessment Form, using modified RECIST, and the Baseline Tumor Assessment Form [RECIST 1.1] using RECIST 1.1.)
• Participants may have measurable or non-measurable extracranial disease. All measurable disease must be assessed within 28 days prior to randomization; all non-measurable disease must be assessed within 42 days prior to randomization. Please note, while any extracranial disease will also be assessed and followed, participants are NOT required to have extracranial disease for randomization. NOTE: All disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1). CNS disease must be documented on BOTH the Brain Metastases Baseline Tumor Assessment Form, using modified RECIST, and the Baseline Tumor Assessment Form (RECIST 1.1) using RECIST 1.1
• Participants may have leptomeningeal disease
• Participants may be receiving corticosteroids for brain metastases at a dose of up to 8 mg of dexamethasone per day. The dose must not have exceeded 8 mg per day for at least 7 days prior to randomization
• Participants must have Zubrod performance status =< 2
• Participants must have complete history and physical examination within 28 days prior to randomization
• Participants must be able to swallow and retain pills
• Hemoglobin >= 8.0 g/dL (within 28 days prior to randomization)
• Absolute neutrophil count >= 1,500/mcL (within 28 days prior to randomization)
• Platelets >= 75,000/mcL (within 28 days prior to randomization)
• Total bilirubin =< 1.5 institutional upper limit of normal (ULN) (within 28 days prior to randomization)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN (in participants with liver metastases =< 5 x ULN) (within 28 days prior to randomization)
• Creatinine =< 2.0 institutional ULN (within 28 days prior to randomization)
• Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2B or better
• Participants with a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Participants with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 90 days prior to randomization
• Participants with a known history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment must have an undetectable HCV viral load prior to randomization
• Participants must agree to participate in image banking. Images must be submitted via the Triad System
• Participants must be offered the opportunity to participate in specimen and blood collections
• Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines
• As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
• Participants must not have received prior systemic therapy for metastatic disease. Prior systemic therapy received only in the neoadjuvant and/or adjuvant setting (e.g., BRAF/MEK inhibitor therapy, anti-PD-1 therapy or anti-CTLA4 therapy, alfa-interferon, etc.) is permitted. If patients received prior neoadjuvant/adjuvant therapy, they must have had eventual disease relapse prior to randomization
• Participants must not have had prior radiation therapy within 7 days prior to randomization
• Participants must not be planning to require any additional form of systemic anti-tumor therapy for melanoma while on protocol treatment
• Participants must not be planning to use hormonal contraceptives
• Participants must not have a serious active infection requiring systemic therapy at time of randomization in the opinion of the treating physician
• Participants must not have active autoimmune disease that has required treatment in the past 6 months with use of biologic disease modifying agents (.e.g. infliximab, adalimumab). Patients on non-biologic disease modifying agents (e.g. methotrexate) or patients on corticosteroids =< 10 mg prednisone daily or equivalent (to treat auto-immune disease), or on replacement therapy (e.g., thyroxine, insulin) are eligible if deemed in the best interest of the patient by treating physician
• Participants must not have had grade 3 or 4 immune-related adverse events on ipilimumab or nivolumab that required more than 12 weeks of immune suppression with corticosteroids
• Participants must not have had adverse events related to encorafenib and/or binimetinib specifically, that required discontinuation of one or both drugs. (Please note this does not apply to other BRAF/MEK inhibitor drugs.)
• Participants must not be pregnant or nursing. Women/men of reproductive potential must have agreed to use an effective method of contraception. (NOTE: Patients must agree to not use hormonal contraceptives, as encorafenib can result in decreased concentration and loss of efficacy.) A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate participant chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures

• Signed informed consent from patient, legal guardian(s) and/or adolescents obtained in accordance with local regulations. Pediatric patients must provide assent as required by local regulations.
• Age ≥18 years at the time of informed consent, for sarcoma age ≥16 years of age at time of informed consent/assent
• Measurable disease according to RECIST 1.1
• ECOG performance status 0-1
• Expected survival >3 months
• Platelet counts ≥100,000 cells/mm3
• Hemoglobin ≥9 g/dL
• Adequate renal function with serum creatinine ≤1.5 mg/dL or creatinine clearance ≥60mL/min as calculated using the Cockcroft-Gault equation
• Patient willing and able to comply with the trial protocol
• Systemic chemotherapy, radiotherapy, immunotherapy, or major surgery administered within 3 weeks prior to the first planned dosing of the IMP per protocol
• Patients receiving any other investigational therapy for their cancer within 3 weeks prior to the first planned dosing of the IMP per protocol
• Ongoing radiation toxicities from prior RT therapy
• Patients with a diagnosis of autoimmune diseases or immunodeficiencies or documented infection with human immunodeficiency virus (HIV) or hepatitis B or C virus (active)
• Prior treatment with anti-GD2 antibody

• All patients must be enrolled on APEC14B1 (NCT02402244) and consented to the Molecular Characterization Initiative (Part A) prior to enrollment and treatment on ARST2032 (this trial).
• Patients must be =< 21 years at the time of enrollment.
• Patients must have newly diagnosed embryonal rhabdomyosarcoma (ERMS), spindle cell/sclerosing RMS, or FOXO1 fusion negative alveolar rhabdomyosarcoma (ARMS) (institutional FOXO1 fusion results are acceptable). RMS types included under ERMS include those classified in the 1995 International Classification of Rhabdomyosarcoma (ICR) as ERMS (classic, spindle cell, and botryoid variants), which are reclassified in the 2020 World Health Organization (WHO) classification as ERMS (classic, dense and botryoid variants) and spindle cell/sclerosing RMS (encompassing the historical spindle cell ERMS variant and the newly recognized sclerosing RMS variant). Enrollment in APEC14B1 is required for all patients.
• All patients will be evaluated for stage and clinical group. Note that clinical group designation assigned at the time of enrollment on study remains unchanged regardless of any second-look operation that may be performed.
• Patients will be eligible for the very low-risk stratum (Regimen VA) if they have Stage 1, CG I disease.
• Patients will be eligible for the low-risk stratum (Regimen VAC/VA) if they have Stage 1, CG II disease, Stage 2, CG I or II disease, or Stage 1, CG III (orbit only) disease.
• Paratesticular Tumors: Staging ipsilateral retroperitoneal lymph node sampling (SIRLNS) is required for all patients >= 10 years of age with paratesticular tumors who do not have gross nodal involvement on imaging.
• Extremity Tumors: Regional lymph node sampling is required for histologic evaluation in patients with extremity tumors.
• Clinically or radiographically enlarged nodes must be sampled for histologic evaluation.
• Patients must have a Lansky (for patients =< 16 years of age) or Karnofsky (for patients > 16 years of age) performance status score of >= 50. 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 performance score.
• Peripheral absolute neutrophil count (ANC) >= 750/uL (within 7 days prior to enrollment).
• Platelet count >= 75,000/uL (transfusion independent) (within 7 days prior to enrollment).
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine (within 7 days prior to enrollment) based on age/gender as follows:
• Age: 1 month to < 6 months; Maximum serum creatinine (mg/dL): 0.4 (male) : 0.4 (female)
• Age: 6 months to < 1 year; Maximum serum creatinine (mg/dL): 0.5 (male) : 0.5 (female)
• Age: 1 to < 2 years; Maximum serum creatinine (mg/dL): 0.6 (male) : 0.6 (female)
• Age: 2 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 (within 7 days prior to enrollment), and
• If there is evidence of biliary obstruction by the tumor, then the total bilirubin must be < 3 x ULN for age.
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L.
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days 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.
• Patients who have received prior chemotherapy and/or radiation therapy for cancer prior to enrollment. Surgical resection alone of previous cancer(s) is permitted.
• Patients who have received chemotherapy or radiation for non-malignant conditions (e.g., autoimmune diseases) are eligible. Patients must discontinue chemotherapy for non-malignant conditions prior to starting protocol therapy.
• Vincristine is sensitive substrate of the CYP450 3A4 isozyme. Patients must not have received drugs that are moderate to strong CYP3A4 inhibitors and inducers within 7 days prior to study enrollment.
• Patients unable to undergo radiation therapy, if necessary, as specified in the protocol.
• Evidence of uncontrolled infection.
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
• Lactating females who plan to breastfeed their infants.
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.