• Histologically or cytologically confirmed urothelial carcinoma with predominantly transitional-cell features
• Locally advanced or metastatic disease before starting ICI therapy
• Must be receiving current active treatment with SOC FDA approved PD-1/L1 ICI containing therapy
• Tumor decrease (either in target or non-target lesions) after 12-15 months on ICI.  Does not need to be formal PR/CR. Any decrease confirmed by repeat scan 4 weeks later is OK
• ECOG PS 0-2
• Adequately treated CNS disease is eligible
• No current immunosuppresive drugs

Inclusion Criteria:

• 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

Exclusion Criteria:

• Male
• Metastatic cancer (Stage IV)
• Lobular carcinoma as primary diagnosis
• Previous ipsilateral breast surgery for benign or malignant disease (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 undergoing breast conserving surgery whose resected specimen will be evaluated with intraoperative pathology, frozen section, or imprint cytology

• T1c or T2, cN0 or cN1 early breast cancer with plans for surgical resection
• ER/PR <10%, HER2 negative
• ECOG PS 0-1
• ANC >1200, Hgb >10, Plt >100,000
• Tumor determined to have abnormal HER2-driven signaling activity based on the CELx HSF test (to be conducted during screening)
• No T3 or T4 tumors
• No definitive surgical treatment performed yet
• No evidence of metastatic disease
• No prior history of ipsilateral DCIS or breast cancer
• No prior therapy with anthracyclines, taxanes, or anti-HER2 therapy
• No other malignancies within 2 years prior
• No active cardiac disease
• No uncontrolled hypertension
• No known HIV/HBV/HCV
• No neuropathy grade >=2

• HER2 positive invasive breast cancer
• Stage at disease presentation: any cT2-4, any cN1-3, M0
  • Patients with cT1-3N0-1/M0 at presentation must have pathologic evidence of residual cancer in the axilla at time of surgery
  • Patients with T4 or N2-3 disease must have pathologic evidence of residual cancer in either the breast and/or the axilla
• Completion of at least 6 cycles and 16 weeks of pre-operative systemic chemotherapy including 9 weeks of a taxane and 9 weeks of trastuzumab
• Cannot have had a best response to neoadjuvant therapy of progressive disease
• < or = 12 weeks since primary surgery and randomization
• ECOG PS 0-1
• LVEF >or = 50%
• No prior T-DM1 or immune checkpoint inhibitors
• Documentation of PD-L1 status

• Postmenopausal or pre-menopausal but treated with LHRH agonist therapy for the duration of study treatment
• Locally advanced or metastatic adenocarcinoma of the breast not curable
• Documented ER-positive and HER2-negative
• No prior systemic anti-cancer therapy for metastatic disease
• Measurable disease
• ECOG PS 0-1
• No disease recurrence within 12 months of treatment with an AI or a CDK4/6 inhibitor in adjuvant/neoadjuvant setting
• No prior SERD
• No active CNS disease

• Breast cancer with history of HER2-low expression, defined as IHC2+/ISH negative or IHC1+ with a validated assay
• May be either hormone receptor positive or negative
• ECOG PS 0-1
• If hormone receptor positive disease
  • Part 1: Must have had at least 1 prior treatment line of endocrine therapy with or without a targeted therapy (CDK4/6, mTOR, or PI3K) and at least one prior line of chemotherapy, all for metastatic disease
  • Part 2: Only 1 prior treatment line of ET with or without a targeted therapy. No prior chemothearpy for MBC
• If hormone receptor negative disease
  • Part 1: At least 1 prior line of chemotherapy for MBC
  • Part 2: For Module 2, no prior lines of thearpy for MBC. For Modules 1 and 3, only 1 prior line fo chemotherapy for MBC
• No significant cardiovascular disease
• No history of pneumonitis requiring steroids
  • No clinically active CNS metastatses or spinal cord compression

• Triple negative metastatic breast cancer
• 2nd line
• ECOG PS 0-2
• No prior treatment with any study agents
• No history of autoimmune disease
• Presence of measurable disease
• No symptomatic or untreated CNS disease

• Must have measurable disease by RECIST 1.1
• Diagnosis of TNBC
• Must have received or been intolerant to not more than 2 lines of therapy for metastatic disease
• Prior therapy should have included anthracycline and/or taxane
• LDH must be <2x ULN at screening
• May be PD-L1 treatment refractory (number capped)
• ECOG PS 0-1
• No 2nd malignancy within 2 years
• No active CNS involvement
• No history of interstitial lung disease
• No active pneumonitis or history of non-infectious pneumonitis that required steroids
• No active autoimmune disease that required systemic tx in past 2 years (other than replacement therapy)
• No known HIV, HBV, HCV
• No need for steroids at dose of greater than 10mg prednisone or equivalent daily
• No recent history of substance abuse

• Metastatic, unresectable colorectal adenocarcinoma, PDL1+
• Has measurable disease per RECIST 1.1 
• Has been previously treated for the disease and radiographically progressed on or after or could not tolerate standard treatment.
• Submits an archival (≤ 5 years) or newly obtained tumor tissue sample or newly obtained tumor tissue sample that has not been previously irradiated.
• ECOG 0-1
• Life Expectancy >= 3 months
• Ability to swallow oral medications
• Has adequate organ function.
• MMR proficient
• Does not have active central nervous system (CNS) metastases and/or carcinomatous meningitis or leptomeningeal disease.
• Has not received prior therapy with an anti-programmed cell death 1 (PD-1), anti-programmed death ligand 1 (PD-L1), or anti-programmed cell death ligand 2 (PD-L2), anti-lymphocyte activation gene 3 (LAG-3) antibody, with a tyrosine kinase inhibitor (TKI; eg, lenvatinib) other than rapidly accelerated fibrosarcoma (RAF) inhibitors (binimetinib is permitted if combined with a RAF inhibitor), or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4, OX-40, cluster of differentiation [CD] 137).
• Has not previously received regorafenib or TAS-102.
• Has not received prior radiotherapy within 2 weeks of start of study intervention.

• Unresectable, locally advanced, or metastatic gastric or gastroesophageal junction adenocarcinoma
• Fibroblast growth factor receptor 2b (FGFR2b) overexpression positive by centrally performed IHC testing
• No prior therapy for metastatic or unresectable disease except for up to 1 dose FOLFOX with or withouy nivolumab. Prior adjuvant therapy allowed as long as completed longer than 6 months prior
• ECOG PS 0-1
• Measurable or non-measurable disease allowed
• No symptomatic CNS mets
• No corneal abnormalities
• No known HER2 positive status
• No peripheral sensory neuropathy grade 2 or higher

• Histologic confirmed diagnosis of GBM per WHO classification criteria
• Age >or= 22
• Recovered from maximal debulking surgery, if applicable (gross total resection, partial resection, and biopsy-only patients are all acceptable)
• Planned treatment with RT-TMZ followed by TTFields and maintenance TMZ
• KPS >or= 70%
• Must have stable or decreasing steroid use
• Concomitant RT with TMZ planned to start no later than 8 weeks post surgery
• Able to undergo MRI with contrast of brain
• No infratentorial or leptomeningeal disease
• No plts <100, ANC <1.5, AST/ALT > 3xULN, Tbili >1.5x ULN, creatinine >1.7
• No institutionalized patients
• No active implanted medical devices, bullet fragments, or other skull defects

• Squamous cell carcinoma of the oropharynx
• Measurable disease either in primary or lymph node
• P16 posotive locally
• T1-2N1M0 or T3N0-1M0
• No more than 10 pack years of smoking history
• ECOG PS 0-1
• No T4 or N2
• No recurrent disease
• No supraclavicular nodes
• No prior malignancy unless disease free for at least 3 years
• No allergy to cisplatin

• Must have one of the following
  • Disease progression after platinum based chemotherapy (with or without PD-1 therapy) for recurrent or metastatic disease
  • Refractory disease defined as progression or recurrence within six months after the last dose of platinum based chemoradiation for locally advanced disease
• No more than two prior lines of treatment
• ECOG PS 0-1
• Able to swallow and retain oral medications
• No prior taxane
• No symptomatic CNS disease
• No known HIV
• No symptomatic CHF or LVEF <50%
• No active psychiatric illness

• SCCHN
• Must have received prior PD-1 or PD-L1 inhibitor
• ECOG PS 0-1
• No known autoimmune disease
• No need for steroids or other immunsuppressive medicine
• No interstitual lung disease or pulmonary fibrosis

Major Inclusion Criteria:

• Previously untreated patients with local biopsy-proven, CD20-positive DLBCL, including one of the following diagnoses by 2016 World Health Organization (WHO) classification of lymphoid neoplasms are eligible:

  1. DLBCL, NOS including GCB type, ABC type
  2. T-cell rich large BCL
  3. Epstein-Barr virus-positive DLBCL, NOS
  4. Anaplastic lymphoma kinase (ALK)-positive large BCL
  5. Human herpes virus-8 (HHV8)-positive DLBCL, NOS
  6. High-grade BCL with MYC and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) rearrangements (double-hit or triple-hit lymphoma). Please note: Patients must be appropriate candidates for R-CHOP. If an investigator deems a patient with a known double- or triple-hit lymphoma (HGBL) should be treated more aggressively (e.g. dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab [DA-EPOCH-R] or cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) followed by methotrexate and cytarabine [Hyper CVAD]), this patient would not be considered eligible for this study
  7. DLBCL coexistent with either follicular lymphoma (FL) of any grade, gastric MALT lymphoma or non-gastric MALT lymphoma
  8. FL grade 3b
• Availability of archival or freshly collected tumor tissue sent for retrospective central pathology review
• IPI status of 3 to 5 (for patients > 60 years of age) or aaIPI 2 to 3 (for patients ≤ 60 years of age)
• Diagnosis to treatment interval, defined as the time between the date of DLBCL diagnosis (date of the first biopsy specimen containing lymphoma according to the local pathology report) and the start of treatment (C1D1) ≤ 28 days
• ECOG performance status of 0, 1, or 2
• Left ventricular ejection fraction equal to or greater than lower limit of institutional normal range, assessed by local echocardiography or cardiac multi-gated acquisition (MUGA) scan
• Adequate hematologic function
•  

Major Exclusion Criteria:

• Any other histological type of lymphoma according to WHO 2016 classification of lymphoid neoplasms, e.g., primary mediastinal (thymic) large B-cell lymphoma, Burkitt's lymphoma, BCL, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (grey-zone lymphoma); primary effusion lymphoma; primary cutaneous DLBCL, leg type; primary DLBCL of the CNS; DLBCL arising from CLL or indolent lymphoma

• History of prior non-hematologic malignancy except for the following:

  1. Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening
  2. Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer
  3. Adequately treated carcinoma in situ without current evidence of disease
• Any systemic anti-lymphoma and/or investigational therapy prior to the start of C1D1, except for permitted pre-phase treatment
• Contraindication to any of the individual components of R-CHOP, including prior receipt of anthracyclines
• Known CNS lymphoma involvement
• Known active systemic bacterial, viral, fungal, or other infection at screening, including patients with suspected active or latent tuberculosis (as confirmed by a positive interferon-gamma release assay)
• History or evidence of clinically significant cardiovascular, CNS and/or other systemic disease that in the investigator's opinion would preclude participation in the study or compromise the patient's ability to give informed consent

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Histologically or cytologically documented NSCLC with locally advanced, unresectable Stage III NSCLC of either squamous or non-squamous histology
• Whole-body Positron Emission Tomography-Computed Tomography (PET-CT) scan, performed prior and within 42 days of the first dose of concurrent chemoradiotherapy (cCRT)
• At least two prior cycles of platinum-based chemotherapy administered concurrently with radiotherapy (RT), which must be completed within 1 to 42 days prior to randomization in the study (one cycle of cCRT is defined as 21 or 28 days)
• The radiotherapy (RT) component in the cCRT must have been at a total dose of radiation of 60 (±10 percent [%]) gray (Gy) (54 Gy to 66 Gy) administered by intensity modulated RT (preferred) or 3D-conforming technique
• No progression during or following concurrent platinum-based CRT
• A known PD-L1 result
• Life expectancy >/= 12 weeks
• Adequate hematologic and end-organ function
• Female participants must be willing to avoid pregnancy for 90 days after the final dose of tiragolumab and 5 months after the final dose of atezolizumab, or for 3 months after the final dose of durvalumab
• Male participants must remain abstinent or use a condom during the treatment period and for 90 days after the final dose of tiragolumab
• Male participants must not donate sperm during the treatment period and for 90 days after the final dose of tiragolumab

Exclusion Criteria:

• Any history of prior NSCLC and/or any history of prior treatment for NSCLC (participants must be newly diagnosed with unresectable Stage III disease)
• NSCLC known to have a mutation in the epidermal growth factor receptor (EGFR) gene or an anaplastic lymphoma kinase (ALK) fusion oncogene
• Any evidence of Stage IV disease
• Treatment with sequential CRT for locally advanced NSCLC
• Participants with locally advanced NSCLC who have progressed during or after the definitive cCRT prior to randomization
• Any Grade >2 unresolved toxicity from previous CRT
• Grade >= 2 pneumonitis from prior CRT
• Active or history of autoimmune disease or immune deficiency
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis or evidence of active pneumonitis
• History of malignancy other than NSCLC within 5 years prior to screening with the exception of malignancies with a negligible risk of metastasis or death
• Prior allogeneic stem cell or solid organ transplantation
• Active Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV infection at screening
• Treatment with investigational therapy within 28 days prior to initiation of study treatment
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T lymphocyte-associated protein 4, anti-T-cell immunoreceptor with Ig and ITIM domains (anti-TIGIT), anti-PD-1 and anti-PD-L1
• Any prior Grade >/= 3 immune-mediated adverse event or any unresolved Grade > 1 immune-mediated adverse event while receiving any previous immunotherapy agent other than immune checkpoint blockade agents
• Treatment with systemic immunosuppressive medication
• Women who are pregnant, or breastfeeding

• New diagnosis of brain mets from a histologically or cytological confirmed primary or metastatic NSCLC tumor. If original histologic proof of malignancy is >5 years, new pathologic confirmation is needed
• KPS >70
• 1 inoperable brain mets or 2-10 brain lesions per screening MRI, confirmed by contrast enhanced MRI amenable to SRS according to following criteria
  • Largest tumor volume < 10cc
  • Longest tumor diameter < 3cm
  • Cumulative volume of all tumors < 15cc
• At least one measurable lesion per RANO-BM
• May continue on systemic therapy during trial. Should be receiving optimal systemic therapy.
• Patient must be able to operate NovoTTF-100M device independently or with caregiver
• No ALK/ROS-1 alterations. No BRAF, EGFR mutations
• No significant edema with risk of brain herniation
• No midline shift > 10mm
• No intractable seizures
• No infratentorial or leptomeningeal mets
• No recurrent brain mets or brain mets previously treated with surgery/XRT/radiosurgery
• No implantable electronic medical devices in the brain
• No other concurrent brain directed therapy

• Histologically confirmed diagnosis of metastatic or unresectable NSCLC (squamous or nonsquamous) not a candidate for definitive therapy
• KRAS G12C mutation
• Known PD-L1 status (can enroll regardless of level)
• 1st line- no prior treatment for metastatic NSCLC
  • OK to have had radiosensitizing chemo >1 year prior
• ECOG PS 0-1
• Measurable disease
• No active CNS mets
• No XRT to the lungs within 6 months prior to first dose of study treatment
• No known autimmune disease

• Eligibility for induction phase (Carbo etoposide)
  • Histologically or cytologically confirmed extensive stage SCLC
  • ECOG PS 0-1
  • No prior therapy for extensive stage disease
  • At least 6 monmths since chemo or XRT for earlier stage disease
  • Measurable disease
  • Negative for HIV and no known HBV/HCV
  • No CNS mets
  • No other malignancies within 5 years
• Eligibilty for maintenance phase (atezolizumab +/- lurbinectidin)
  • Ongoing response or stable disease after 4 cycles of induction therapy
  • All toxicities attributed to prior induction therapy resolved to Grade
  • Not receiving consolidative chest radiation
  • Not receiving antibiotics at the time of randomization

• Histologically or cytologically confirmed melanoma
• Clinically detectable and resectable Stage IIIB, IIIC, or IIID melanoma
• Has been untreated for the melanoma with the exception that primary lesion may have been resected or irradiated
• No known CNS mets
• No ocular or mucosal melanoma
• No known HIV/HBV/HCV
• No active autoimmune disease requiring therapy in past 2 years
• Must not have received prior oncolytic viruses

• Must have been diagnosed with either Stage IIIA (>1mm tumor in lymph node), Stage IIIB, Stage IIIC, Stage IIID, or Stage IV melanoma and have histologically confirmed melanoma that is completely surgically resected with negative margins
• ECOG PS 0-1
• Resection must have been performed within 12 weeks prior to randomization
• Tumor tissue available
• No history of uveal melanoma
• No untreated CNS metastases

• Has unresectable Stage III or Stage IV melanoma, not amenable to local therapy
• Has been untreated for advanced disease
• No ocular or mucosal melanoma
• No known additional malignancy that is progressing or requires active treatment within the past two years
• No known CNS metastatses
• No active autoimmune disease requiring systemic treatment in the past two years
• No known HIV/HBV/HCV
• Adequate organ function

• Has unresectable Stage III or Stage IV melanoma not amenable to curative therapy
• Has progressed on treatment with an anti-PD1/L1 monoclonal antibody administered either as monotherapy or in combination with other therapies
• Hsa not received more than 3 lines of therapy
• No known additional malignancy with past 2 years
• No known CNS metastases
• No active autoimmune disease requiring systemic treatment in the last 2 years
• No known HIV/HBV/HCV

• Stage IIIB-IV melanoma, following progression on PD-1 containing regimen
• ECOG PS 0-1
• At least one injectable tumor (visceral or deep nodal lesions may be injectable)
• Measruable disease by RECIST 1.1
• No prior oncolytic virus therapy (no prior T-VEC)
• No active CNS disease
• No history of major autoimmune disease
• No known HBV, HCV, or HIV
• No need for steroids >20mg prednisone daily or equivalent
• No need for chronic use of anti-virals (e.g. acyclovir)
• No prior malignancy in past 3 years except locally curable cancers such as non-melanoma skin cancer, or carcinoma in situ.

• Histologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal carcinoma per pre-treatment biopsies (laparoscopic or percutaneous)
• Histologic documentation of the original primary tumor is required
• FIGO Stage III-IV
• Following histologic subtypes eligible: high grade serous adenocarcinoma, endometrioid adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, or adenocarcinoma NOS.
• ECOG PS 0-2
• No need for treatment with immunosuppressive medication
• No patients receiving treatment for active autoimmune disease
• No known CNS involvement
• No prior abdominal radiation or chemotherapy for abdominal or pelvic tumor

• Histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma
• Has received 1 or 2 prior lines of systemic therapy, including at least 1 prior platinum-based therapy. 
• Patients may have received prior PARPi, anti-PD-1/L1 or bevacizumab and these are not considered prior line of therapy
• Radiographic evidence of disease progression within 6 months after the lat dose of platinum-based chemo
• ECOG PS 0-1
• Radiographically evaluable disease (measurable or non-measurable)
• Cannot have primary platinum-refractory disease (defined as PD while actively receiving firstline platinum therapy)
• Cannot have uncontrolled hypertenstion, clinically relevant bowel obstruction, or rectosigmoid involvement of cancer
• Cannot have received more than 2 lines prior lines of systemic therapy
• No known active CNS metastases
• No known HIV/HBV/HCV

• Histologic confirmation of adenocarcinoma of the prostate without small cell features
• Current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft tissue lesions on CT/MRI
• ECOG PS 0-1
• Ongoing androgen deprivation therapy (ADT) with a GnRH analogue or bilateral orchiectomy
• Documented disease progression per PCWG3 criteria within 6 months prior to screening
• Only one prior 2nd generation hormonal therapy in the metastatic setting
  • Patients may have received two prior 2nd gen HT (abi + enza or apalutamide or darolutamide) if and only if the first drug had been used in the non-metastatic setting
• Chemotherapy naive for metastatic CRPC
• Must have progressed during or after 2nd gen hormonal therapy or have documented intolerance to 2nd gen HT
• No active brain mets
• No known or suspected autoimmune disease
• No condition requiring systemic corticosteroids (>10 mg prednisone or equivalent)
• No prior treatment with PD-1 or PD-L1 antibodies
•  

Inclusion Criteria:

• Has a histologically or cytologically confirmed diagnosis of RCC with clear cell component per American Joint Committee on Cancer (AJCC) (8th Edition), with or without sarcomatoid features

• Has intermediate-high risk, high risk, or M1 no evidence of disease (NED) RCC as defined by the following pathological tumor-node metastasis and tumor grading:

  1. Intermediate-high risk RCC: pT2, Grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0
  2. High risk RCC: pT4, any Grade N0, M0; pT any stage, any Grade, N+, M0
  3. M1 NED RCC participants who present not only with the primary kidney tumor but also solid, isolated, soft tissue metastases that can be completely resected at one of the following: the time of nephrectomy (synchronous) or, ≤2 years from nephrectomy (metachronous)
• Has undergone complete resection of the primary tumor (partial or radical nephrectomy) and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants
• Must have undergone a nephrectomy and/or metastasectomy ≤12 weeks prior to randomization
• ECOG PS 0-1
• Must not have a pulse oximeter reading <92% at rest, requires intermittent supplemental oxygen, or requires chronic supplemental oxygen
• No clinically significant cardiovascular disease within 6 months from first dose of study intervention
• No preexisting brain or bone metastatic lesions
• No prior systemic therapy for RCC
• No prior radiotherapy for RCC
• No diagnosis of immunodeficiency or receiving chronic systemic steroid therapy
• No known additional malignancy (other than RCC treated with nephrectomy and/or metastasectomy) that is progressing or has required active treatment within the past 3 years
• No active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs); replacement therapy is allowed
• No history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• No known HIV/HBV/HCV

• Diagnosis of locally advanced or metastatic non-melanoma skin cancer not considered treatable by surgery. Could include;
  • Basal cell carcinoma,
  • Cutaneous squamous cell carcinoma,
  • Merkel cell carcinoma
  • Angiosarcoma of the skin
  • Eccrine carcinoma
  • high grade dermatofibroma protuberans
  • CTCL is NOT allowed
• Must have exhausted or refused currently available therapy
• ECOG PS 0-1
• At least one injectable tumor (visceral or deep nodal lesions may be injectable)
• Measurable disease by RECIST 1.1
• No prior oncolytic virus therapy (no prior T-VEC)
• No active CNS disease
• No history of major autoimmune disease
• No known HBV, HCV, or HIV
• No need for steroids >20mg prednisone daily or equivalent
• No need for chronic use of anti-virals (e.g. acyclovir)
• No prior malignancy in past 3 years except locally curable cancers such as non-melanoma skin cancer, or carcinoma in situ.

• Patient planned to receive one of the following agents for Cancer with or without chemotherapy that has a risk of diarrhea in 50% of patients
  • CDK4/6 inhibitors (abemaciclib), 
  • PI3 kinase blockers (alpelisib),
  • anti-EGFR TKIs (afatinib, dacomitinib, erlotinib, gefitinib) 
  • anti VEGF-TKIs (axitinib, cabozantinib, lenvatinib, pazopanib, sorafenib, sunitinib, vendatinib)
  • anti ALK TKIs (ceritinib, crizotinib)
  • MEK inhibitor (cobimetinib) 
  • Anti HER2 TKIs (lapatinib, tucatinib)
• ECOG PS 0-2
• Not receiving immunotherapy (PD-1, CTLA-4, IL-2)
• No diarrhea before enrolling on the study (or starting TKI)
• No ongoing IBS or colitis
• Not planning on receiving an agent where anti-diarrheal prophylaxis is mandatory (e.g. neratinib, irinotecan, etc.)
• No laxative use within 7 days prior to randomization

Inclusion Criteria:

• ROS1 fusion positive solid malignancies (except for NSCLC)
• Histologically or cytologically confirmed diagnosis of advanced and unresectable or metastatic solid malignancy
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), Response Assessment in Neuro-Oncology (RANO) criteria, or International Neuroblastoma Response Criteria (INRC)
• Performance status as follows: Participantss aged >= 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2; Participantss aged 16 to < 18 years: Karnofsky score >= 50%; Participants aged < 16 years: Lansky score >= 50%
• For participants aged >= 18 and <18 years: adequate hematologic and end-organ function
• Disease progression on prior treatment, or previously untreated disease with no available acceptable treatment
• Adequate recovery from most recent systemic or local treatment for cancer
• Life expectancy >= 8 weeks
• Ability to comply with the study protocol, in the investigator's judgment
• For female participants of childbearing potential: Negative serum pregnancy test <= 14 days prior to initiating study treatment; agreement to remain abstinent or use single or combined contraception methods that result in a failure rate of < 1% per year for the period defined in the cohort-specific inclusion criteria; and agreement to refrain from donating eggs during the same period
• For male participants: Willingness to remain abstinent or use acceptable methods of contraception as defined in the cohort-specific inclusion criteria
• In addition to the general inclusion criteria above, participants must meet all of the cohort-specific inclusion criteria for the respective cohort

Inclusion Criteria:

• Any Solid Malignancy with NTRK1/2/3 Fusion Positivity
• Histologically or cytologically confirmed diagnosis of advanced and unresectable or metastatic solid malignancy
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), Response Assessment in Neuro-Oncology (RANO) criteria, or International Neuroblastoma Response Criteria (INRC)
• Performance status as follows: Participantss aged >= 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2; Participantss aged 16 to < 18 years: Karnofsky score >= 50%; Participants aged < 16 years: Lansky score >= 50%
• For participants aged >= 18 and <18 years: adequate hematologic and end-organ function
• Disease progression on prior treatment, or previously untreated disease with no available acceptable treatment
• Adequate recovery from most recent systemic or local treatment for cancer
• Life expectancy >= 8 weeks
• Ability to comply with the study protocol, in the investigator's judgment
• For female participants of childbearing potential: Negative serum pregnancy test <= 14 days prior to initiating study treatment; agreement to remain abstinent or use single or combined contraception methods that result in a failure rate of < 1% per year for the period defined in the cohort-specific inclusion criteria; and agreement to refrain from donating eggs during the same period
• For male participants: Willingness to remain abstinent or use acceptable methods of contraception as defined in the cohort-specific inclusion criteria
• In addition to the general inclusion criteria above, participants must meet all of the cohort-specific inclusion criteria for the respective cohort

Inclusion Criteria:

• Patients with any ALK fusion positive solid malignancy except NSCLC
• Histologically or cytologically confirmed diagnosis of advanced and unresectable or metastatic solid malignancy
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), Response Assessment in Neuro-Oncology (RANO) criteria, or International Neuroblastoma Response Criteria (INRC)
• Performance status as follows: Participantss aged >= 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2; Participantss aged 16 to < 18 years: Karnofsky score >= 50%; Participants aged < 16 years: Lansky score >= 50%
• For participants aged >= 18 and <18 years: adequate hematologic and end-organ function
• Disease progression on prior treatment, or previously untreated disease with no available acceptable treatment
• Adequate recovery from most recent systemic or local treatment for cancer
• Life expectancy >= 8 weeks
• Ability to comply with the study protocol, in the investigator's judgment
• For female participants of childbearing potential: Negative serum pregnancy test <= 14 days prior to initiating study treatment; agreement to remain abstinent or use single or combined contraception methods that result in a failure rate of < 1% per year for the period defined in the cohort-specific inclusion criteria; and agreement to refrain from donating eggs during the same period
• For male participants: Willingness to remain abstinent or use acceptable methods of contraception as defined in the cohort-specific inclusion criteria
• In addition to the general inclusion criteria above, participants must meet all of the cohort-specific inclusion criteria for the respective cohort

Inclusion Criteria:

• Patients with at metastatic or advanced solid tumors with at least 2 PIK3CA mutations
• Histologically or cytologically confirmed diagnosis of advanced and unresectable or metastatic solid malignancy
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), Response Assessment in Neuro-Oncology (RANO) criteria, or International Neuroblastoma Response Criteria (INRC)
• Performance status as follows: Participantss aged >= 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2; Participantss aged 16 to < 18 years: Karnofsky score >= 50%; Participants aged < 16 years: Lansky score >= 50%
• For participants aged >= 18 and <18 years: adequate hematologic and end-organ function
• Disease progression on prior treatment, or previously untreated disease with no available acceptable treatment
• Adequate recovery from most recent systemic or local treatment for cancer
• Life expectancy >= 8 weeks
• Ability to comply with the study protocol, in the investigator's judgment
• For female participants of childbearing potential: Negative serum pregnancy test <= 14 days prior to initiating study treatment; agreement to remain abstinent or use single or combined contraception methods that result in a failure rate of < 1% per year for the period defined in the cohort-specific inclusion criteria; and agreement to refrain from donating eggs during the same period
• For male participants: Willingness to remain abstinent or use acceptable methods of contraception as defined in the cohort-specific inclusion criteria
• In addition to the general inclusion criteria above, participants must meet all of the cohort-specific inclusion criteria for the respective cohort

Inclusion Criteria:

• Patients with advanced or solid malignancy with BRAF class II mutation or fusion (ARM I)
• Patients with advanced or solid malignancy with BRAF class III mutation (ARM J)
• Histologically or cytologically confirmed diagnosis of advanced and unresectable or metastatic solid malignancy
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), Response Assessment in Neuro-Oncology (RANO) criteria, or International Neuroblastoma Response Criteria (INRC)
• Performance status as follows: Participantss aged >= 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2; Participantss aged 16 to < 18 years: Karnofsky score >= 50%; Participants aged < 16 years: Lansky score >= 50%
• For participants aged >= 18 and <18 years: adequate hematologic and end-organ function
• Disease progression on prior treatment, or previously untreated disease with no available acceptable treatment
• Adequate recovery from most recent systemic or local treatment for cancer
• Life expectancy >= 8 weeks
• Ability to comply with the study protocol, in the investigator's judgment
• For female participants of childbearing potential: Negative serum pregnancy test <= 14 days prior to initiating study treatment; agreement to remain abstinent or use single or combined contraception methods that result in a failure rate of < 1% per year for the period defined in the cohort-specific inclusion criteria; and agreement to refrain from donating eggs during the same period
• For male participants: Willingness to remain abstinent or use acceptable methods of contraception as defined in the cohort-specific inclusion criteria
• In addition to the general inclusion criteria above, participants must meet all of the cohort-specific inclusion criteria for the respective cohort

Inclusion Criteria:

• Patients with advanced or malignant solid cancers with RET-fusion positive tumors.
• Histologically or cytologically confirmed diagnosis of advanced and unresectable or metastatic solid malignancy
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), Response Assessment in Neuro-Oncology (RANO) criteria, or International Neuroblastoma Response Criteria (INRC)
• Performance status as follows: Participantss aged >= 18 years: Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2; Participantss aged 16 to < 18 years: Karnofsky score >= 50%; Participants aged < 16 years: Lansky score >= 50%
• For participants aged >= 18 and <18 years: adequate hematologic and end-organ function
• Disease progression on prior treatment, or previously untreated disease with no available acceptable treatment
• Adequate recovery from most recent systemic or local treatment for cancer
• Life expectancy >= 8 weeks
• Ability to comply with the study protocol, in the investigator's judgment
• For female participants of childbearing potential: Negative serum pregnancy test <= 14 days prior to initiating study treatment; agreement to remain abstinent or use single or combined contraception methods that result in a failure rate of < 1% per year for the period defined in the cohort-specific inclusion criteria; and agreement to refrain from donating eggs during the same period
• For male participants: Willingness to remain abstinent or use acceptable methods of contraception as defined in the cohort-specific inclusion criteria
• In addition to the general inclusion criteria above, participants must meet all of the cohort-specific inclusion criteria for the respective cohort

1. Metastatic, recurrent, or unresectable solid tumor with a pathogenic, or presumed pathogenic, somatic mutation of one of the following homologous recombination deficiency (HRD) gene mutations:  BRCA1, BRCA2, ATM, RAD51B, RAD51C, RAD54L, RAD51D, FANC/BRIP1, FANCI, FANCL, FANCN(PALB2), BARD1, CHEK1, CHEK2, CDK12, or PPP2R2A.

2. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
3. Participant must be ≥ 18 years of age

4. Participant must have adequate organ function, defined as follows:

   • Absolute neutrophil count ≥ 1,500/µL
   • Platelets ≥ 100,000/µL
   • Hemoglobin ≥ 9 g/dL
   • Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60mL/min using the Cockcroft-Gault equation
   • Total bilirubin ≤ 1.5 x ULN (≤2.0 in patients with known Gilberts syndrome) OR direct bilirubin ≤ 1 x ULN
   • Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN unless liver metastases are present, in which case they must be ≤ 5 x ULN
   • International normalized ratio (INR) or prothrombin time (PT) ≤1.5× ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin (PTT) is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin time (aPTT) ≤1.5× ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
5. Female participant has a negative serum pregnancy test within 72 hours prior to taking study treatment if of childbearing potential and agrees to use a highly effective method of contraception from screening through 180 days after the last dose of study treatment, or is of non-childbearing potential. Non-childbearing potential is defined as follows (by other than medical reasons):
   • ≥45 years of age and has not had menses for >1 year
   • Patients who have been amenorrhoeic for <2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation
   • Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use an adequate barrier method throughout the study, starting with the screening visit through 180 days after the last dose of study treatment. See Section 5.4 for a list of acceptable birth control methods. Information must be captured appropriately within the site's source documents. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.

h. Male participant agrees to use a highly effective method of contraception (see Section 5.4 for a list of acceptable birth control methods) starting with the first dose of study treatment through 180 days after the last dose of study treatment. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.

j. If an appropriate archival tumor tissue sample is not available, patient is willing to undergo a pre-treatment tumor biopsy.

Exclusion Criteria:

1. Patients with the following malignancies will be excluded:

   • Prostate cancer
   • Ovarian, breast, and pancreatic patients with known germline BRCA1 or BRCA2 mutation
   • Platinum sensitive ovarian cancer (defined as recurrence > 6 months from last platinum agent), unless platinum intolerant.

• Expansion Cohort A (ccRCC): Subjects with previously treated advanced RCC with clear cell histology (including those with a sarcomatoid component) who have radiographically progressed following treatment with at least one prior systemic anticancer regimen for inoperable locally advanced or metastatic disease.
• Expansion Cohorts B and E (nccRCC): Subjects with previously treated advanced RCC with non-clear cell histology who have radiographically progressed following treatment with at least one prior systemic anticancer regimen for inoperable locally advanced or metastatic disease.
• Expansion Cohorts C and F (HR+ BC): Subjects with breast cancer that is hormone receptor positive (ER+ and/or PR+) and negative for human epidermal growth factor receptor 2 (HER-2) and who have radiographically progressed during or following treatment with at least one prior systemic anticancer regimen for inoperable locally advanced or metastatic disease.
• Expansion Cohorts D and G (mCRPC): Subjects with metastatic CRPC (adenocarcinoma of the prostate). Neuroendocrine differentiation and other features permitted if adenocarcinoma is the primary histology.
• Expansion Cohort H (CRC): Subjects with histologically confirmed unresectable, locally advanced, or metastatic adenocarcinoma of the colon or rectum who received prior fluoropyrimidine-containing chemotherapy with oxaliplatin and irinotecan.
  • KRAS/NRAS wild type
  • Must have received all of the following: fluropyridmidine, irinotecan,  oxaliplatin,  EGFR monoclonal antibody, and, for those with BRAF mutation, BRAF inhibitor in combination with cetuximab
  • Must have progression during or within 3 months following the last dose of the most recent regimen
  • Prior therapy with regorafenib or TAS-102 are NOT allowed
• Expansion Cohort I (UC, Maintenance Therapy): Subjects with histologically confirmed, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra) who received first-line chemotherapy of gemcitabine + cisplatin and/or gemcitabine + carboplatin.
• Expansion Cohort J (UC, ICI-refractory): Subjects with histologically confirmed, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra) who progressed on or after PD-1/PD-L1 targeting ICI therapy.
• Expansion Cohort K (UC, platinum-refractory): Subjects with histologically confirmed, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra) who progressed on or after first-line platinum-based combination therapy.
•  Locally advanced, recurrent, or metastatic
• No known untreated CNS mets
• ECOG PS 0-1

Part 1:

• Locally advanced or metastatic NSCLC, or SCCHN
  • NSCLC and SCCHN must have received prior platinum-based therapy
  • Patients with targetable mutations (e.g. ALK, ROS, EGFR, etc.) must have had prior treatment with approved targeted therapy
• 1st line- no prior therapy for metastatic disease
• ECOG PS 0-1
• LVEF 50% or higher
• No known CNS mets
• No history of pneumonitis
• No prior cancer within 3 years (except locally curable cancers)
• No history of life-threatening toxicity to immunotherapy
• No known HBV/HCV/HIV

• Histologically or cytologicall confirmed patients with advanced solid tumors
• Must have documented Globo H score of at least 100 from a qualified laboratory IHC assay
• Must have been treated with established standard-f-care therapy or physicians have determined that such established therapy is not sufficiently efficacious or patients have declined to received standard-of-care therapy
• ECOG PS 0-1
• Measurable disease
• Adequate organ function
• No known untreated CNS mets
• No significant clinical cardiac abnormality

• Histologically confirmed metastatic cancer that is approved to be treated with nivolumab or pembrolizumab
• Must not be eligible for curative resection
• Must be positive for at least 1 of the following human leukocyte antigens:
  • HLA-A*02:01
  • HLA-A*02:06
  • HLA-A*24:02
  • HLA-A*03:01
  • HLA-B*15:01
• ECOG PS 0-1
• No known CNS mets
• No known HIV/HBV/HCV

• Renal cell, NSCLC, or SCCHN
• Must have received prior PD-1 or PD-L1 inhibitor
• ECOG PS 0-1
• No known autoimmune disease
• No need for steroids or other immunsuppressive medicine
• No interstitual lung disease or pulmonary fibrosis

• Histologically or cytologically confirmed, metastatic solid malignancy
• Has exhausted all available standard therapy or not a candidate for standard therapy
• ECOG PS 0-1
• Prior PD-1/PD-L1 allowed
• No other malignancy within 2 years prior
• No active autoimmune disease requiring systemic therapy within last 2 years
• No chronic steroids or immunosuppressants.