An Open Label, Dose-Finding and Proof of Concept Study of the PD-L1 Probody* Therapeutic, CX-072, as Monotherapy and in Combination with Yervoy® (Ipilimumab) or with Zelboraf® (Vemurafenib) in Subjects with Advanced or Recurrent Solid Tumors or Lymphomas

All pts must have histologically confirmed diagnosis of metastatic or locally advanced unresectable tumors that progressed or are intolerant to standard therapy.
Inclusion criteria for subjects in each specific Part: ;• Part A: any metastatic or advanced unresectable solid tumor or lymphoma, measurable or nonmeasurable disease allowed, no further SOC therapy available;
o Immunotherapy naive, including PD-1/PD-L1 and CTLA-4 inhibitor therapy naive (where there is no immunotherapy or PD-1/PD-L1 and CTLA-4 inhibitor therapy available for their specific disease in the country where they are being treated); and
o Subjects participating in the imaging substudy must meet both main study and substudy entry criteria to be enrolled in the study; ;• Part A2: any metastatic or advanced unresectable solid tumor or lymphoma (at least 2 subjects in each cohort with thymic epithelial tumor, thymoma, or thymic carcinoma), measurable disease allowed, no further SOC therapy available;
o TPS >= 1% membranous staining based on the DAKO PD-L1 IHC 22C3 pharmDx;
o Immunotherapy naive, including PD-1/PD-L1 and CTLA-4 inhibitor therapy naive (where there is no immunotherapy or PD-1/PD-L1 and CTLA-4 inhibitor therapy
available for their specific disease in the country where they are being treated); and
o Agreement to participate in biomarker analysis and have a tumor site that is safe to biopsy; ;• Part B1: any metastatic or advanced unresectable solid tumor or lymphoma (excluding thymic epithelial tumor, thymoma, or thymic carcinoma), measurable or nonmeasurable disease allowed, no further SOC therapy available;
o Immunotherapy naive, including PD-1/PD-L1 and CTLA-4 inhibitor therapy naive (where there is no immunotherapy or PD-1/PD-L1 and CTLA-4 inhibitor therapy available for their specific disease in the country where they are being treated); ;• Part B2: any metastatic or advanced unresectable solid tumor or lymphoma (excluding thymic epithelial tumor, thymoma, or thymic carcinoma) with measurable disease allowed, no further SOC therapy available;
o Previous treatment with a PD-1/PD-L1 inhibitor;
o Discontinued treatment with PD-1/PD-L1 inhibitor for reasons other than toxicity;
o Naive to treatment with a CTLA-4 inhibitor; and
o Agreement to participate in biomarker analysis and have a tumor site that is safe to biopsy (only in cohorts receiving CX-072 + 3 mg/kg ipilimumab [but not 6 or
10 mg/kg ipilimumab]); ;• Part C: metastatic or advanced unresectable melanoma with BRAF V600E mutation-positive as detected by a diagnostic approved test (in the region where the
pt is treated), measurable or nonmeasurable disease allowed;
o Naive to treatment with BRAF-inhibitor; and
o Immunotherapy naive, including PD-1/PD-L1 and CTLA-4 inhibitor therapy naive ;• Part D: measurable disease is required;
* Must be willing to provide a blood sample at Screening for hTMB testing; and
* Immunotherapy naive, including PD-1/PD-L1 and CTLA-4 inhibitor therapy naive (where there is no available life-prolonging immunotherapy or PD-1/PD-L1 and CTLA-4 inhibitor therapy to the pt available for their specific disease in the country where they are being treated) of the following tumor types:
o UPS;
* Metastatic or advanced unresectable UPS;
* TPS >= 1% membranous staining or unknown PD-L1 status; and
* Subjects must have had SOC surgery and/or radiation for their UPS; subjects with metastatic disease should have received at least 1 prior systemic therapy according to local guidelines;
o Small bowel adenocarcinoma;
* Have metastatic or advanced unresectable small bowel adenocarcinoma of the duodenum, jejunum, ileum; and
* Subjects must have had at least 1 prior line of systemic chemotherapy for metastatic or advanced unresectable disease; adjuvant therapy does not count as first-line therapy unless cancer recurs < 6 months after last administration of that regimen;
o cSCC;
* Has primary cSCC that has metastasized to a distant site;
o MCC;
* Metastatic or advanced unresectable MCC;
* Prior surgical resection was performed if resectable or potentially of benefit; and
* Radiation therapy administered if of potential benefit with documented progression following completion of radiation therapy;
o Thymic carcinoma;
* Histologically confirmed diagnosis of thymic carcinoma (classified in accordance with 2004 World Health Organization criteria) with stage III or IV disease per Masaoka 1981; details provided in APPENDIX 2; and
* Received at least 1 prior chemotherapy regimen for thymic carcinoma;
o Anal SCC;
* Metastatic or advanced unresectable anal SCC; and
* Must have had prior radiation therapy plus chemotherapy treatment;
o TNBC;
* Must have histologically confirmed ER, progesterone receptor, and HER2 negative breast cancer; defined as ER < 1%, progesterone receptor < 1%, and HER2 negative according to ASCO/College of American Pathologists guidelines by local testing according to institutional standards. Subjects with weakly ER or progesterone receptor positive disease, defined as ER and/or progesterone receptor < 5% by IHC, are eligible, if the treating physician considers the subject not eligible for endocrine therapy;
* Have locally advanced and locally recurrent skin or subcutaneous metastases not suitable for definitive (or curative) surgical resection or radiotherapy;
* Received at least 1 and no more than 3 systemic chemotherapy regimens for metastatic breast cancer and have documented disease progression on most recent therapy; and
* Willing to provide fresh tumor biopsy or archival tissue at Screening; and
o hTMB;
* Metastatic or advanced unresectable cancer with hTMB as determined using a Clinical Laboratory Improvement Amendments validated assay (at least 16/Mb) from the subject*s archival or fresh tumor tissue or blood after the last line of treatment;
* No evidence of microsatellite instability high; and
* Subject has failed or refused available SOC therapy specific for their tumor type. ;• Part E: measurable disease is required;
o Must be willing to provide a blood sample at screening for hTMB testing
o Immunotherapy naive, including PD-1/PD-L1 and CTLA-4 inhibitor therapy naive(where there is no available life-prolonging immunotherapy or PD-1/PD-L1 and CTLA-4 inhibitor therapy available to the pt) of the following tumor: UPS,small bowel adenocarcinoma,cSCC,MCC,TET,Anal SCC,TNBC,TNBC with skin lesions;Inclusion criteria for all subjects in all Parts:
1. Agreement to provide mandatory archival/baseline biopsy. A tumor biopsy is required at baseline if there is no other record of histological diagnosis of tumor; ;2. For pts in Part A2 or Part B2 (for Part B2, only those subjects receiving 3 mg/kg of ipilimumab), and those who agree to participate in the biomarker analysis and who have a tumor site that is safe to biopsy, subjects must have a biopsy within 90 days of study entry and be willing to undergo at least 1 on-treatment tumor biopsy; ;3. Patients with treated brain metastases are eligible if the brain metastases are stable and the patient does not require radiation therapy or steroids. Active screening for brain metastases (e.g., brain computed tomography [CT] or magnetic resonance imaging [MRI]) is not required; ;4. At least 18 years of age;;5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;;6. Anticipated life expectancy of at least 3 months;;7. Screening laboratory values must meet the following criteria:
• White blood cells > 2000/µL or

1. Prior therapy with a chimeric antigen receptor (CAR) T-cell containing regimen;;2. Baseline QTc is > 470 ms or taking any medication known to prolong the QT interval; ;3. Prior history of myocarditis irrespective of the cause;;4. Treatment with strong cytochrome P450 (CYP) 3A4 inhibitors or inducers, as well as use of CYP1A2 substrates with a narrow therapeutic window assigned to the vemurafenib treatment arm. http://medicine.iupui.edu/clinpharm/ddis/main-table/; ;5. History of severe allergic or anaphylactic reactions to human mAb therapy or known hypersensitivity to any Probody therapeutic; ;6. Active or history of uveal, mucosal, or ocular melanoma is excluded in Parts B2 and C;;7. History of interstitial lung disease for patients with TET are excluded in Part B1 and B2.;8. Human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS)-related illness, acute or chronic hepatitis B or C; patients with HIV that have an undetectable viral load and a CD4 cell count > 400/mL and who remain on antiretroviral regimen will be eligible for enrollment into anal SCC cohorts in Parts D and E and hTMB cohorts cohorts in Part D; ;9. History of or current active autoimmune diseases, including but not limited to inflammatory bowel diseases, rheumatoid arthritis, autoimmune thyroiditis, autoimmune hepatitis, systemic sclerosis, systemic lupus erythematosus, autoimmune vasculitis, autoimmune neuropathies, type 1 insulin dependent diabetes mellitus or myasthenia gravis. ;10. History of syndrome or medical condition(s) that requires systemic steroids (> 10 mg daily prednisone equivalents) or immunosuppressive medications; ;11. History of allogeneic tissue/solid organ transplant, prior stem cell or bone marrow transplant; ;12. Chemotherapy, biochemotherapy, radiation or immunotherapy within 14 days prior to receiving study drug; radiation therapy within 3 months prior to receiving study medication (except for radiotherapy for the purposes of palliation confined to a single field that is not the target lesion). ;13. Patients in Part C cannot have a glomerular filtration rate < 60mL/min/1.73 m2;;14. Major surgery (requiring general anesthesia) within 3 months or minor surgery (excluding biopsies conducted with local/topical anesthesia) or gamma knife treatment within 14 days (with adequate healing) of administration of any study drug; 15. Unresolved acute toxicity of the NCI CTCAE v4.03 Grade > 1 (or baseline, whichever is greater) from prior anti-cancer therapy. Alopecia and other nonacute toxicities are acceptable; ;16. History of malignancy that is active within the previous 2 years except for localized cancers that are not related to the current cancer being treated and considered to have been cured and, in the opinion of the Investigator, present a low risk for recurrence. These exceptions include, but are not limited to, basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix or breast; ;17. Received a live vaccine within 30 days prior to first dose of study drug;;18. Known pre-existing condition of age-related macular degeneration;;19. Intercurrent illness, including, but not limited to, symptomatic congestive heart failure (i.e., New York Heart Association Class III or IV), unstable angina pectoris, clinically significant and uncontrolled cardiac arrhythmia, nonhealing wound or ulcer, or psychiatric illness/social situations that would limit compliance with study requirements; ;20. Pleural effusion, pericardial effusion, or recurrent ascites drainage.;21. Ongoing or active infection (including fever within 48 hours of Screening);;22. Participating in an ongoing clinical study involving treatment with medications, radiation, or surgery; or;23. Women who are pregnant or breastfeeding.