• Metastatic or locally advanced breast cancer not amenable to treatment with curative intent
• ER+, HER2-
• Prior endocrine therapy in combination with CDK 4/6 in either metastatic setting with disease progression after 6 months or in the adjuvant setting with relapsed disease within 12 months of exposure. (patients must have taken at least 12 months of adjuvant endocrine therapy, of which 6 months were in combination with a CDK4/6 inhibitor)
• Measurable disease or evaluable bone mets
• ECOG PS 0-1
• For premenopausal or perimenopausal women or men must have treatment with LHRH agonist therapy for duration of study
• No prior treatment with oral SERD, SERM, or everolimus. Fulvestrant is allowed if tx stopped at least 28 days prior to randomization
• No more than 2 prior lines of systemic endocrine therapy in metastatic setting
• No prior chemotherapy in metasatic setting
• No other malignancy within 5 years except nonmelanoma skin cancer, papillary thyroid cancer, or very low risk of recurrence cancers
• No known active CNS mets

Inclusion Criteria:

1. Patient must have histologically confirmed adenocarcinoma (usual/classic/NOS), squamous cell carcinoma, adenosquamous carcinoma (Including glassy cell)
2. Patient must be FIGO Stage IA2, IBI, IB2 (2018 staging) without evidence of definitive parametrial, vaginal, nodal or distant metastases on exam or imaging. Patients with tumor size less than or equal to 4 cm confirmed on MRI prior to randomization are eligible.
3. Patient must have uterine size <12 cm AND felt to be appropriate for vaginal delivery of the specimen per investigator.
4. Patient must be suitable surgical candidate with preoperative assessments such as labs and EKG performed per institutional standard.
5. Patient must be age 18 years or older.
6. Patient must have ECOG performance status 0-1.
7. Patient must have a negative urine pregnancy test within 30 days of surgery in pre-menopausal women.
8. Patient must have signed an approved informed consent and authorization permitting the release of personal health information.

Exclusion Criteria:

1. Patients with any tumor histology other than those listed above, specifically excluding the following histologies: neuroendocrine, other adenocarcinoma (gastric type, endometrioid, clear cell, serous, signet ring, minimal deviation)
2. Patients with FIGO stage 1A1, IB3, II-IV (2018 staging).
3. Patient with inability to receive an MRI.
4. Patients with a tumor size greater than 4cm or on MRI confirmed prior to randomization are excluded. Patients with definite evidence of vaginal/parametrial involvement on MRI are excluded; if MRI findings are not definitive, then clinical examination must also not reveal parametrial or vaginal extension).
5. Patients with evidence of metastatic disease (imaging or histologically positive lymph nodes).
6. Patients with a history of prior pelvic or abdominal radiotherapy.
7. Patients with a prior malignancy < 5 years from enrollment with the exception of non-melanoma skin cancer.
8. Patients who are unable to withstand prolonged lithotomy or steep trendelenberg.
9. Patient compliance and geographic proximity that do not allow adequate follow-up.
10. Patients with poorly controlled HIV with CD4 counts <500.

• 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.

1. Histologically documented locally advanced or metastatic, unresectable (i.e. surgery morbidity would outweigh potential benefits), progressive or recurrent Dedifferentiated liposarcoma (DDLPS), meeting the criteria for an open study cohort:

   • Cohort A: patient has not received prior systemic therapy for DDLPS in any setting (including adjuvant, neoadjuvant, maintenance, palliative)
   • Cohort B: patient has received any prior systemic therapy for DDLPS in any setting (including adjuvant, neoadjuvant, maintenance, palliative)
2. Written pathology report indicating the diagnosis of DDLPS with positive MDM2 immunohistochemistry or MDM2 amplification as demonstrated by fluorescence in situ hybridisation (FISH) or next-generation sequencing (NGS)
3. Measureable disease
4. ECOG PS 0-1
5. No known mutation in TP53
6. No prior MDM2 inhibitor
7. No prior or concomittant cancers within 2 years except non-melanoma skin cancers, or other treatment curative by local therapy only

• 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.

• Malignant solid tumor with pathogenic inactivating TSC1 or TSC2 alterations. GEnetic alterations should be identified using NGS in tumor tissue or liquid biopsy
• Metastatic or locally advanced solid tumors
• 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 b e unlikely to tolerate or derive clinically meaningful benefit from appropriate SOC therapy
• Measurable disease
• ECOG PS 0-1
• Fasting tryglecerid must be < or = 300; fast serus cholesterol must be < or = to 350
• No prior treatment with MTOR inhibitor
• No primary brain tumors
• No known HIV

CURRENTLY ONLY THE MELANOMA COHORT IS ENROLLING

Inclusion Criteria:

1. Histologically or cytologically-documented solid tumors.
2. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
3. Demonstrate adequate organ function.

Exclusion Criteria:

1. Prior history of or active malignant disease other than that being treated in this study.
2. Known brain metastases or cranial epidural disease.
3. A known hypersensitivity to the components of the study therapy or its' analogs.

• Histologically confirmed locally advanced, recurrent, or metastatic incurable solid tumors
• Must have tumor specimen available
• Measurable disease
• ECOG PS 0-1
• Life expectancy at least 12 weeks
• Phase 1a- must have exhausted all standard therapies for their disease
• Phase 1b- must have disease that has progressed after at least one available standard therapy
• Some cohorts are tumor-type specific- please contact study team to see if tumor type is eligible at any time during the study
• No active HBV/HCV or chronic or acute EBV
• No history of autoimmune disease
• No symptomatic or actively progressing CNS mets

• Unresected Stage IIIB, IIIC, or IV melanoma
• No prior therapy for metastatic disease
• At least 6 months from adjuvant therapy
• No clinically active CNS disease
• ECOG PS 0-1
• Measurable (at least 1 lesion >1cm)
• Injectable (total cutaneous/subcut/nodal lesions >1cm in aggregate)
• No prior ipilimumab, PD-1 inhibitors, T-VEC or tumor vaccines
• Previous BRAF or MEK inhibitors allowed if BRAF mutated
• No primary uveal or mucosal melanoma
• No prior intrathoracic XRT

-Histologically confirmed diagnosis of stage IIB, IIIC, or IVM1a melanoma elgible for complete surgical resection

- Measurable disease

- Injectable disease (cutaneous, subcutanous, or nodal lesions) measuring in aggregate > 10mm in diameter

- ECOG PS 0-1

- No ocular or mucosal melanoma

- No history of autoimmune disease

- No known HBV/HCV/HIV

• Histologically documented HER2-positive early breast cancer (EBC) participants, including clinical stage at presentation (based on mammogram or breast MRI assessment): T0-4 (inclusive of inflammatory breast cancer), N1-3, M0 or ≥ T3, N0, M0 as determined by the AJCC staging system, 8th edition

• ECOG PS 0-1
• Adequate organ and bone marrow function
• LVEF ≥ 50% within 28 days before randomization
• FFPE tissue block (2 cores) or 20 freshly-cut, serial tumor slides for HER2 assessment by central lab. If blocks are incomplete or fewer than 20 slides are available, participants may be eligible following discussion with the AstraZeneca Study Physician
• No prior history of invasive breast cancer
• No stage IV breast cancer (determined by AJCC staging system)
• No primary malignancy within 3 years (except resected non-melanoma skin cancer, curatively treated in situ disease) Note: This includes a second current breast primary malignancy (ie, bilateral breast cancer)
• No history of DCIS (except those treated with mastectomy >5 years prior to current diagnosis)
• No history of, or current, ILD/pneumonitis
• No prior systemic therapy for the treatment of breast cancer
• No previous treatment with anthracyclines, cyclophosphamide or taxanes for any malignancy

• Measurable disease

• NSCLC

  • If EGFR mut or ALK positive must have received targeted therapy

  • Must have progressed on both platinum doublet and PD-1 therapy

• Cervical Cancer

  • Persistent, recurrent, or metastatic disease

  • Squamous, adenosquamous or adenocarcinoma histology

  • At least one prior platinum based regimen

  • Confirmation of HPV status

• Bladder cancer

  • Transitional cell carcinoma involving bladder, urethra, ureter, or renal pelvis

  • Minor histologic variants are acceptable

  • Must have progression or recurrence with platinum-containing regimen (in metastatic setting or within 12 months of peri-operative setting)

• SCCHN

  • Must have documented HPV status and subtype

  • Prior treatment with platinum containing regimen with progression or recurrence within 6 months of last dose

  • Cannot be amenable to local therapy with curative intent

• Ovarian

  • Can include epithelial ovarian, primary [peritoneal, or fallopian tube cancer

  • Must have received at least 1 standard systemic therapy for metastatic disease

• HCC

  • Progressive disease to at least one line of therapy or refuse treatment with sorafenib

  • Child-Pugh score of 6 or less. No encephalopathy and Tbili must be <1.5x ULN

  • HBV and HCV must be tested. HBV viral load <100 IU/mL and must be on anti-viral therapy

  • No clinical ascites or variceal bleeding

• No more than 5 prior lines of treatment

• Acceptable lab parameters

• No active CNS metastatases (treated brain mets may be allowed)

• No prior malignancy within 2 years (except for in-situ or non-melanoma skin)

• No autoimmune disease, interstitial lung disease, or requiring immunosuppressive meds

• Resected Stage IIB or IIC cutaneous melanoma (>4 mm deep, or >2mm deep with ulceration)
• Negative sentinel lymph node biopsy
• No prior systemic therapy for melanoma
• ECOG PS 0-1
• No ocular or mucosal melanoma
• No known or suspected autoimmune disease

• Measurable disease required
• ECOG PS <1
• Brain mets allowed but must not be active, cannot require steroids, have at least one measurable lesion outside of brain
• Excluded tumors:
  • No Pancreatic
  • No endometrial with ER>10%
  • No ovarian
  • No breast
  • No esophageal
  • No gastric
  • No glioma
  • No hepatocellular carcinoma
  • No lymphoma (except primary CNS lymphoma)
  • No leukemia
  • No melanoma
  • No MDS
  • No lung cancer
  • No renal cell
  • No bladder
• Must not have had other cancer within 2 years
• No prior PD-1/L-1 or CTLA-4 therapy
• No autoimmune disease
• No active steroids
• No known HIV, HBV, or HCV
• See "malignancy" list for accepted tumor types

• Females >18 years old

• TNBC defined as ER/PR <1%, HER2 negative

• ECOG PS 0-1

• Labs within standard limits

• No known CNS disease unless adequately treated with XRT or surgery and stable by symptoms for at least 2 months prior

• No other malignancy within 3 years (except non-melanoma skin cancer or in situ cancers)

• No unstable cardiac disease

• No known sensitivity Cremaphor

• Cohort 1- 3rd+ line in African ancestry

  • Must have received prior taxane for metastatic disease but not in most recent treatment

  • Adjuvant therapy counts as therapy if time to recurrence <12 months

• Cohort 2- 1st line in African ancestry- no prior systemic tx for advanced disease

  • Adjuvant therapy only allowd if time to recurrence >12 mo

• Cohort 3- 3rd+ line in non-African ancestry

  • Similar to Cohort 1

• Cohort 4- 1st line in non-African ancestry

  • Similar to cohort 2

• Histologically or cytologically confirmed, locally advanced or metastatic solid malignancy and has exhausted all available standard therapy or not a candidate for standard therapy
• ECOG PS 0-1
• Prior therapy with immune therapy are eligible (except in ovarian cohort)
• In Expansion cohorts patients must either have
  • Advanced epithelial cancer of the ovary, fallopian tube, or peritoneum
  • Advanced MSS endometrial cancer
  • A different malignancy that has high expression of PVRL2
• No active autoimmune disease
• No interstitial lung disease
• No active CNS metastases
• In ovaran cohort, no prior immunotherapy
• No prior therapy with PVRIG inhibitor or anti-TIGIT antibody

• Metastatic or unresectable colorectal cancer.
• KRAS, NRAS, and BRAF wt
• Must have at least 1+ on HER2 testing by central vendor
• Able to provide archival tumor sample
• ECOG PS 0-1
• LVEF > or = 50%
• No surgery or radiation within 4 weeks prior to enrollment
• No MI within 6 months
• No symptomatic CHF or elevated troponins within 4 weeks
• No corneal disease
• No active CNS mets
• No other malignancy within 3 years (except solid tumors curatively treated, in situ dz, or non-melanoma skin cancer)
• No known HIV/HBV/HC

• Intrahepatic cholangiocarcinoma diagnosed by histology
• Unresectable disease
• Less than 50% of liver involved
• No clinically significant extra-hepatic disease (regional nodes 2cm or less are acceptable)
• ECOG PS 0-1
• No history of liver transplantation
• Hepatic vasculature must be compatible with perfusion (prior Whipple is allowed only if anatomy is compatible)
• No prior radiation therapy to the liver (including Y-90, I-131, etc.)
• No prior treatment with percutanous trans-arterial treatment to liver (such as TAE or TACE)
• No Class II or higher CHF
• No prior malignancy within 5 years except in-situ disease or non-melanoma skin cancer
• No active HBV or HCV
• No CNS disease
• Plts >100, Hgb >10 (independent of transfusions), ANC >1500
• Bili <1.5x normal, ALT/AST <5x normal 

• Histologically or cytologically proven ocular melanoma to the liver
• No more than 50% liver parenchema involvement
• Evidence of limited extrahepatic disease allowed as long as life threatening component of disease is in liver
• ECOG PS 0-1
• No Child Class B or C cirrhosis
• No active HBV or HCV
• No active CNS mets

• Metastatic solid tumor
• ALK alterations as follows
  • ALK gene rearrangements by NGS or FISH using Vysis ALK Break Apart FISH Probe Kit
  • Activating non-synonymous mutations in and around the ALK kinase domain by NGS
  • ALK copy number gains by NGS
  • Patients with melanoma and high ALK expression by IHC
• ECOG PS 0-2
• No prior treatment with any ALK inhibitor
• Following tumor types are not eligible
  • Non-small cell lung cancer (NSCLC)
  • Neuroblastoma
  • Childhood tumors

Metastatic solid tumor_
No known RAS mutation
No melanoma, papillary thyroid, colorectal, or hematologic malignancies2nd line or greater
ECOG PS 0-2
No prior treatment with any BRAF inhibitor (sorafenib is allowed)
No prior treatment with a MEK inhibitor
No active or untreated CNS metastastasis

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• ROS1 gene fusion positivity
• No non-small lung cancer (NSCLC)
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• No primary CNS malignancy
• One of the following PIK3CA mutations:
  • R88Q
  • ​G106A/D/R/S/V
  • K111N/R/E
  • G118D
  • N345D/H/I/K/S/T/Y
  • C420R
  • E453A/D/G/K/Q/R/V
  • E542A/D/G/K/Q/R/V
  • E545A/D/G/K/L/Q/R/V
  • Q546E/H/L/P/R
  • M1043I/T/V
  • H1047D/I/L/M/P/Q/R/T/Y
  • G1049A/C/D/R/S
  • Others only with study medical monitor approval
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No anti-hyperglycemic medication (no treated T2DM or T1DM)

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• No breast cancer (breast cancer is excluded)
• Either ERBB2 (HER2) amplification defined as a copy number of 6 or higher via FISH, CISH or DNA NGS assay OR
• Any of the following ERBB2 mutations:
  • 222C; R226S; E265K; D277H; G292R; G309A/E; S310F/Y; C311R/S; E321G; C334S; S418T; A440T; P551L; R552S; S653C; V659E; G660D; R678Q; T733I; L755P/S_T759del; I767M; L768S; D769H/N/Y; Y772_A775dup; A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); G776delins(VC/VV/LC); V777L; G778_P780dup; V779A/L; T798M; L841V; V842I; N857S; T862A; L869R; H878Y; R896C​​G
• ​TMB must be <10 mutations/megabase
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib
• No active autoimmune disease

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• No breast cancer (breast cancer is excluded)
• Either ERBB2 (HER2) amplification defined as a copy number of 6 or higher via FISH, CISH or DNA NGS assay OR
• Any of the following ERBB2 mutations:
  • 222C; R226S; E265K; D277H; G292R; G309A/E; S310F/Y; C311R/S; E321G; C334S; S418T; A440T; P551L; R552S; S653C; V659E; G660D; R678Q; T733I; L755P/S_T759del; I767M; L768S; D769H/N/Y; Y772_A775dup; A775_G776ins(SVMA/VVMA/YAMA/YVMA/YVMD); G776delins(VC/VV/LC); V777L; G778_P780dup; V779A/L; T798M; L841V; V842I; N857S; T862A; L869R; H878Y; R896C​​G
• Must ALSO have one of the following alterations
  • ​TMB > or =10 mutations/megabase
  • MSI-h
  • dMMR (negative IHC for MLH1, MSH2, MSH6, or PMS2_
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib
• No active autoimmune disease

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• Not Non-small cell lung cancer (NO NSCLC)
• ALK gene fusion positivety defined as a 3' AALK fusion with a protein coding 5' gene fusion partner, predicted to be in frame with an intact kinase domain
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• Either PTEN protein loss as determined by a CLIA or equivalently certified immunohistochemistry assay OR
• PTEN loss of function defined as PTEN dominant negative missense mutations or deleterious in-frame and missense mutations affecting protein function
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib
• No insuline dependent diabetes

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• One of the following mutations in AKT:
  • ​AKT 1 : E17K, L52R, or Q79K
  • AKT 2 : E17K
  • AKT 3: E17K, L51R, or Q78K
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib
• No insulin dependent diabetes

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• Tumor mutational burden-high (TMB-H) determined by CLIA opr quivalently certified assay, via tissue or blood
• No prior treatment with anti-PD1 or anti-PD-L1 agents
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib
• No active autoimmune disease

• Histologically or cytologically confirmed advanced unresectable or metastatic solid malignancy
• Positive biomarker results from a CLIA certified lab, either tissue or blood sample
• Microsatellite instability high (MSI-h) or deficient mismatch repair dMMR
• No prior treatment with anti-PD1 or anti-PD-L1 agents
• ECOG PS 0-2
• No symptomatic CNS metastases
• No known HIV/HBV/HCV
• No other malignancy within 3 years of study
• No prior treatment with crizotinib
• No active autoimmune disease

• Triple-negative adenocarcinoma of the breast either unresectable with curative intent and either locally advanced or metastatic 
  • Most recent biopsy shows ER and PR levels <1%, HER2 <3+
• No prior systemic therapy for metastatic disease
  • No chemotherapy for early disease in last 12 months
• Appropriate candidate for paclitaxel monotherapy if PD-L1 negative (or unknown)
• Appropriate candidate for paclitaxel and atezolizumab if PD-L1 status is positive
• Appropriate lab values
  • CBC: ANC >/= 1500, Hgb >/= 9, plts >/= 100
  • Chem: CrCl >/=50, Alb >/=3, Gluc
  • PT/PTT
• No known HIV/HBV/HCV
• No LVEF <50%
• No requirement for steroids >10mg prednisone or equivalent
• No known CNS disease or spinal cord mets
• No other malignancies in last 5 years except in-situ cervical, non-melanoma skin, or stage I endometrial
• No history of diabetes
• No Grade 2 or higher neuropathy
• No active or history of autoimmune disease

• Histologically or cytologically confirmed TNBC based on the most recent analyzed biopsy or other pathology specimen. TNBC determination as per local institution as per standard guidelines.
• Refractory to or relapsed after at least two prior standard therapeutic regimens for advanced/metastatic TNBC. Prior use of cisplatin (or carboplatin) is permitted.
• Prior exposure to a taxane (paclitaxel or docetaxel)-based regimen in localized or advanced/metastatic setting.
• Eligible for one of the chemotherapy options listed as TPC (Eribulin, capecitabine, gemcitabine, or vinorelbine) as per investigator assessment.
• ECOG performance score of 0 or 1 .
• Measurable disease by CT or MRI as per RECIST 1.1. Bone-only disease is not permitted.
• Patients with treated, non-progressive brain metastases, off high-dose steroids (>20 mg prednisone or equivalent) for at least 4 weeks can be enrolled in the trial.
• No Presence of bulky disease (defined as any single mass > 7 cm in its greatest dimension). Patients with a mass over 7 cm, but otherwise eligible, may be considered for enrollment after discussion and approval with the medical monitor.
• No Patients with active ≥ grade 2 anorexia, nausea or vomiting, and/or signs of intestinal obstruction.
• Patients with non-melanoma skin cancer or carcinoma in situ of the cervix are eligible, while patients with other prior malignancies must have had at least a 3-year disease-free interval.
• No patients known to be HIV positive, hepatitis B positive, or hepatitis C positive.

• ECOG PS 0-1
• Fresh baseline tumor biopsies are required unless med monitor approval
• No active ILD or pneumonitis
• No active receipt of steroids within 7 days or known immunodeficiency
• No prior anti-PD-1 or CTLA-4 treatment
• No known or active CNS mets
• No history of autoimmune disease
• For MSI-high CRC
  • MMR or MSI status is, respectively, determined by examining either CRC tumor: protein expression by IHC of 4 MMR enzymes (MLH1/MSH2/MSH6/PMS2) or 3 to 5 tumor microsatellite loci using PCR-based assay. Tumors are classified as MSI high when at least 2 allelic shifts among the 3 to 5 analyzed microsatellite markers are detected by PCR or absence of at least 1 of 4 MMR protein expression is detected by IHC
• For Gastric cancer (COHORT CLOSED)
  • Must have documentation of HER2 status. IF HER2+ must have progressed or been intolerant of HER2 directed therapy
  • No more than 2 prior lines of therapy
• For Hepatocellular carcinoma
  • Must be Child-Pugh Class A
  • Must be Barcelona Clinic Liver Cancer Stage C disease (or Stage B disease and either refractory to or not amenable to locoregional therapy
  • No more than 2 lines of prior therapy
  • Must have progressed on or intolerant to sorafenib
  • No history of liver transplant, clear invasion of bile duct or main portal branch, hepatorenal syndrome, or required esophageal variceal ablation within 28 days of study start
  • HBV/HCV only allowed if meet certain criteria
• For melanoma- (COHORT CLOSED)
  • Known BRAF status
  • No ocular melanoma
• For bladder/transitional cell (COHORT CLOSED)
  • TCC of bladder, ureter, or renal pelvis
  • 2nd line after progression on platinum (if no platinum received must have documented why unable to tolerate)
• For RCC (COHORT CLOSED)
  • Clear cell histology
  • Following progression on therapies with established clinical benefit
• For NSCLC (COHORT CLOSED)
  • 2nd line or later after platinum based therapy for metastatic disease
  • If EGFR or ALK positive, must have received targeted therapy
  • If progressed within 6 months of adjuvant therapy, OK to enroll 1st line
• For SCCHN (COHORT CLOSED)
  • No nasopharyngeal, salivary gland, or non-squamous histology
  • 2nd line or later after failure of platinum-based therapy
  • If progressed within 6 months of adjuvant therapy, OK to enroll 1st line
• For DLBCL
  • No prior allo transplants
  • 2nd line or later
  • Not a candidate for curative tx or SCT
•  

• Has histologically confirmed cutaneous squamous cell carcinoma (cSCC) as the primary site of malignancy (metastatic skin involvement from another primary cancer or from an unknown primary cancer is not permitted)
• Has histologically confirmed LA cSCC with ≥1 high-risk feature(s) as the primary site of malignancy
• Has undergone complete macroscopic resection of all known cSCC disease with or without microscopic positive margins
• Has completed adjuvant radiotherapy (RT) for LA cSCC with last dose of RT ≥4 weeks and ≤16 weeks from randomization
• Has completed at least 50 Gray (Gy) 25 fractions of adjuvant RT for LA cSCC prior to study entry
• Is disease free as assessed by the investigator with complete radiographic staging assessment ≤28 days from randomization
• Has provided an archival or newly-obtained tumor tissue sample adequate for Programmed Cell Death Ligand 1 (PD-L1) testing as determined by central laboratory testing
• ECOG PS 0-1
• No other histologic type of skin cancer other than invasive cSCC (eg, basal cell carcinoma) that has not been definitively treated with surgery or radiation, Merkel cell carcinoma; or melanoma
• No prior immunotherapy
• Must have recovered from all radiation-related toxicities; must have not required corticosteroids; and has not had radiation pneumonitis
• No active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
• No known HIV/HBV/HCV

• Previously untreated locally advanced non-metastatic TNBC definedn as one of the following TNM classifications:
  • T1c, N1-N2
  • T2, N0-N2
  • T3, N0-N2
  • T4a-d, N0-N2
• ECOG Performance Status 0-1
• No history of other malignancy within 5 years except cervical CIS, or non-melanoma skin cancer
• No prior therapy with anti-PD-1
• No active autoimmune disease that required systemic treatment in past 2 years

• Stage IIB or IIC Melanoma  (T3b, T4a, T4b). Must be node-negative
• No prior treatment for melanoma beyond complete surgical resection of current primary lesion
• Must have received sentinel lymph node biopsy which was negative
• 12 weeks or less from surgical resection and first study treatment
• No evidence of metastatic disease on imaging
• ECOG PS 0-1
• No known additional malignancy within the past 5 years
• Must have recovered adequately from surgery
• No active autoimmune disease requiring systemic treatment in the past 2 years
• No history of non-infectious pneumonitis
• No known HIV/HBV/HCV
•  

• Surgically resected and histologically or pathologically confirmed melanoma
• Must be Stage IIB, IIC, III, or IV cutaneous melanoma
• No prior systemic therapy for melanoma
• No more than 12 weeks between final surgical resection and randomization
• HBV/HCV/HIV are allowed if well controlled
• No ocular, conjunctival, or mucosal melanoma
• No diagnosis of immunodeficiency or receiving chronic systemic steroids >10mg prednisone or equivalent
• No active autoimmune disease
• No active CNS disease
• No other malignancy that required active treatment in last 3 years

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

• 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

Must have FGFR gene alteration as measured in CLIA-certified lab
None of the following malignancies:
Bladder cancer (urothelial)
Cholangiocarcinoma
Endometrial cancer
Glioblastoma multiforme (GBM)
Received at least 1 prior line of therapy
No standard therapy expected to result in durable remission
ECOG PS 0-1
No CNS disease
No acute/chronic pancreatitis
No impared cardiac function
No corneal or retinal disorder
No other cancer within 3 years
_

ALK or ROS1 mutation, trnaslocation, rearrangement, or amplification by CLIA-certified laboratory (IHC or FISH allowed)

May not have ALK+ lung cancer (butROS1 positive lung CA allowed)
Relapsed or progressive disease
ECOG PS 0-1
2nd line or higher
No standard therapy withdurable remission expected
No CNS disease

• Prostate adenocarcinoma
• Post-prostatectomy (within last 10 years)
• Detectable serum PSA (between 0.1 and 1.0 ng/mL) at study entry
• Any of following
  • Gleason score 7-10
  • >= T3a disease
  • PSA never became undetectable following prostatectomy
• No nodal involvement
• KPS 70-100
• Availability of tissue
• Prior ADT allowed if previously given for <90 days
• GFR >35
• No prior invasive malignancy except in-situ disease, stage I resected melanoma, or disease free for at least 2 years
• No prior chemotherapy for prostate cancer
• No prior radiation that would result in overlap
• No history or predisposition to seizures
• No IBD
• No severe CAD

• 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

• Histological diagnosis of squamous cell carcinoma of hte oral cavity, oropharynx, hypopharynx, or larynx
• Eligible for the following stages:
  • For HPV negative disease
    • Stage III, IVA, or IVB
  • For HPV positive disease that is not oropharyngeal
    • Stage III, IVA, or IVB
  • For oropharyngeal HPV positive disease
    • T4 or N2c or N3
• No prior therapy for advanced stage SCCHN, must be eligible for CRT with curative intent
• ECOG PS 0-1
• No prior immunotherapy
• No other malignancy within 5 years except CIS or non-melanoma skin cancer
• No active autoimmune disease
• No severe cardiac issues with preiouvs 6 months
• No known HBV/HCV/HIV

Stage IIB, IIC, or III Melanoma
Last definitive resection within 90 days of first dose
Complete resection of all known disease
ECOG PS 0-1
Either known BRAF status or 10 unstained slides for BRAF testing
No adjuvant therapy except surgery/radiation, except-
May have had interferon if no longer than 7 days
No use of chronic steroids

• One of the following malignancies:
  • Cervical cancer
  • HR+/HER2- Breast cancer with prior CDK4/6 inhibitor
  • HR+/HER2 - Breast cancer without prior CDK4/6 inhibitor
  • TNBC
  • Salivary Gland tumor
  • NSCLC with EGFR exon-18 mutation
• Documented HER2 (ERBB2) mutation (or EGFR exon 18 mutation in NSCLC).
• At least one measurable or evaluable lesion
• LVEF >/=50%
• ECOG PS 0-2
• No prior treatment with ERBB2 (HER2) directed TKIs (eg lapatinib, afatinib, neratinib)
• No symptomatic or unstable brain mets (stable are allowed)
• No cumulative prior anthracycline dose >450mg/m2 doxorubicin or equivalent
• No uncontrolled cardiac disease
• No chronic diarrheal disorder

• Postmenopausal women with locally advanced or metastatic breast cancer
• Progression on an aromatase inhibitor (AI) in combination with a CDK4/6 inhibitor
• Demonstrated prior sensitivity to endocrine therapy (recurrence or progression after at least 12 months of treatment in metastatic setting)
• Measurable or non-measurable disease allowed
• One of the following ESR point mutations in cell-free DNA:
  • Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N
• May have received up to one chemothearpy regimen in adjuvant or neoadjuvant setting
• ECOG PS 0-1
• No prior use of any SERM with following exception
  • OK if tamoxifen previously used in adjuvant setting with relapse at least 1 year after stopping tamoxifen
• No prior everolimus or PI3K inhibitors
• No presence of CNS disease
• No immediate need for chemotherapy
• No HIV, HBV, HCV
• No prior malignancy in last 5 years except non-melanoma skin cancer or early stage cervical cancer
• No uncontrolled HTN
•  

• 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

• Completely resected cutaneous or mucosal melanoma (or unknown primary)

• Stage IIIB, IIIC, or IV (M1a, M1b, or M1c allowed). IIIA allowed only if N2a

• May be eligible either at initial presentation or following resection of recurrence

• Must have undergone wide excision of primary lesion (if present)

• Full lymphadenectomy required for all patients with positive sentinel nodes

• Must be registered within 98 days of final surgery for melanoma

• Must have 5 unstained slides available from original or current tumor

• Must be disease free on scans within 42 days of therapy

• ECOG PS 0-1

• No prior systemic therapy for melanoma

• Prior radiation is allowed

• No brain mets (or history of brain mets)

• No autoimmune disease

• No HBV or HCV

• HIV allowed if CD4 counts >350, viral load <25,000

• Stage 4 or unresectable Stage III melanoma
• Must have had prior treatment with PD-1 or PD-L1 antibody
  • Must have had best response of SD (no PR or CR) on PD-1 or PD-L1 antibody
  • Must have documented disease progression either while on PD-1 or PD-L1 agents or since stopping therapy with these agents with no intervening treatment
• No prior therapy with ipilimumab or other anti-CTLA-4 agents
• No systemic therapy between progression on the PD(L)-1 therapy and registration
• ECOG PS 0-2
• No active CNS disease
  • Patients with history of CNS disease must have been treated with XRT or surgery and have no evidence of CNS progression, and been off steroids for at least 14 days
• No history of autoimmune pneumonitis or colitis that required interruption fo therapy or steroid treatment
• No known HBV or HCV. HIV is allowed if CD4 count is normal.
• No ocular melanoma

• High-grade serous ovarian, fallopian tube, or primary peritoneal cancer who have recurrent disease and have been previously treated with chemotherapy for advanced/metastatic disease and who experience a response lasting at least 6 months to first-line platinum based-therapy but currently considered platinum-resistant
• Up to 4 lines of prior therapy allowed in Phase 1 portion, Up to 3 lines allowed in Phase 2 portion
• May not have progressed while on platinum treatment or within 1 month from completion of platinum-containing regimen in any line
• Measurable disease by RECIST 1.1
• ECOG PS 0-1
• No active CNS mets (stable for at least 4 weeks and resolution of symptoms are allowed)
• No additional malignancy within 5 years (except non-melanoma skin, in situ of  cervix)
• No chronic systemic steroid use
• No active autoimmune disease that has required treatment in last 2 years
• No history of interstitial lung disease
• No history of platelet transfusion for chemo-induced thrombocytopenia
• No prior anti-PD1 or PARP therapy

• TNBC who have been treated with at least 1 prior regimen for advanced/metastatic disease or who relapsed/progressed while on or within 1 month from completion of adjuvant chemotherapy
• Up to 3 lines of prior therapy allowed in Phase 1 portion, Up to 2 lines allowed in Phase 2 portion
• May not have progressed while on platinum treatment or within 1 month from completion of platinum-containing regimen in any line
• Measurable disease by RECIST 1.1
• ECOG PS 0-1
• No active CNS mets (stable for at least 4 weeks and resolution of symptoms are allowed)
• No additional malignancy within 5 years (except non-melanoma skin, in situ of  cervix)
• No chronic systemic steroid use
• No active autoimmune disease that has required treatment in last 2 years
• No history of interstitial lung disease
• No history of platelet transfusion for chemo-induced thrombocytopenia
• No prior anti-PD1 or PARP therapy

• Advanced solid tumor or relapsed/refractory lymphoma OR
  • eligible to receive single agent pembrolizumab as standard-of-care OR
  • eligible to receive single-agent docetaxel as standard of care OR
    ​advanced pancreatic adenocarcinoma and eligible to receive gemcitabine plus nab-paclitaxel as standard of care
• Measurable disease
• ECOG PS 0-1
• No history of severe autoimmune disease
• Not receiving high-dose systemic steorid therapy or any other form of immunosuppressive therapy

• Age >18 years at the time of informed consent
• Histologically confirmed diagnosis of melanoma
• Primary or recurrent Stage IIIB to IV M1c disease for whom surgery is not recommended
• Must have an activating BRAF mutation (limited to V600E or V600K mutations if subject is being treated first line, but can include any well-defined BRAF mutation after failure of prior immunotherapy)
• Measurable disease per RECIST 1.1
• Injectable disease defined as either of the following:
  • At least one injectable cutaneous, subcutaneous, or nodal melanoma lesion >10mm in longest diameter
  • Multiple injectable melanoma lesions that in aggregate have a longest diameter of >10mm
• ECOG Performance Status 0-1
• Any number of prior treatment regimens, provided that subject has not previously received T-VEC or combination of dabrafenib/trametinib
• No clinically active CNS mets
• No active herpes infection or prior complications of herpetic infections
• No known HIV, HBV, HCV
• No known severe autoimmune disease

Unresectable IIIB, IIIC, or IV�disease._
Cutaneous, subcutaneous, or nodal disease amenable to intralesional therapy
ECOG PS 0-1
No primary ocular or mucosal melanoma
No symptomatic autoimmune disease
At least one injectable lesion below the waist