Talazoparib and Avelumab in Participants With Metastatic Renal Cell Carcinoma

Inclusion Criteria

• Biopsy proven, histological confirmed renal cell carcinoma (RCC) or renal medullary carcinoma (RMC).. Patients with surgery and biopsy at outside institutions will be eligible for this protocol once archival material is reviewed and the above diagnosis confirmed by genitourinary pathology review at Memorial Sloan Kettering Cancer Center (MSKCC).

Cohort 1: (Closed to Accrual)

• Presence of VHLalteration by next-generation sequencing (NGS) with a stateapproved assay
• Patients must have radiographic evidence of disease progression after treatment with at least one prior PD-1 or PD-L1 agent, and one prior VEGF inhibitor
• Maximum 3 prior lines of therapy

Cohort 2:

• For FH/SDH patients FH- or SDH- expression-loss by immunohistochemistry (IHC) or alteration (somatic or germline) in FH or SDH per NGS with a state-approved assay
• For Renal Medullary Carcinoma (RMC) patients: histologic confirmation of RMC (no IHC/NGS criteria required)
• At least one prior line of therapy:
• For FH/SDH patients Patients must have radiographic evidence of disease progression after treatment with at least one prior line of therapy (one prior PD-1/PD-L1 and/or VEGF inhibitor).
• For Renal Medullary Carcinoma (RMC) patients prior radiographic evidence of disease progression on/after at least one line of chemotherapy (e.g. carboplatin / paclitaxel, carboplatin / paclitaxel / bevacizumab, carboplatin / gemcitabine, and gemcitabine / doxorubicin).
• No maximum lines of therapy

Both Cohorts 1 & 2

• Adequate Hematologic Function
• Absolute Neutrophil Count ≥ 1.5 x 10^9 / L
• Platelet Count ≥ 100 x 10^9 / L
• Hemoglobin ≥ 9 g/dL
• No transfusion of packed red blood cells or platelets within 21 days of Cycle 1 Day 1
• Adequate Renal Function ≥ 30 ml/min according to the Cockcroft-Gault Equation
• Patients with moderate renal impairment (creatinine clearance 30-59 by Cockcroft-Gault EquationI) will start with a reduced dose of talazoparib.
• Adequate Hepatic Function including:
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
• AST ≤ 3 x upper limit of normal (ULN) without liver metastasis
• ALT ≤ 3 x upper limit of normal (ULN) without liver metastasis
• AST or ALT ≤ 5 x upper limit of normal (ULN) for patients with liver metastasis
• Patients with known Gilbert's syndrome may be included if total bilirubin ≤ x 3 ULN
• Eastern Cooperative Group (ECOG) Performance Status 0-2.
• Patients must have measurable disease by RECIST v1.1. At least one measurable lesion should not have been previously irradiated.
• Women of childbearing potential must have negative serum pregnancy testing at screening. All women will be considered childbearing potential unless meeting criteria including:
• Achieved post-menopausal status as defined by cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause and have follicular stimulation hormone showing postmenopausal state. Women who have been amenorrhoeic for ≥12 months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anorexia, low body weight, ovarian suppression, anti-estrogen therapy or other medically inducible reasons.
• Documented hysterectomy or bilateral oophorectomy surgery
• Medically confirmed ovarian failure
• Sexually active participants and their partners must agree to use medically accepted methods of contraception (i.e. barrier methods including condoms, female condom, or diaphragm with spermicidal gel) during the study and for 7 months after the last dose of the study treatment for females, and 4 months for males.
• Recovery of baseline CTCAE v5.0 grade ≤1 toxicities related to prior study treatments unless adverse events are clinically non-significant and/or stable on supportive therapy if needed.
• Patients must be willing and able to comply with trial protocol. This includes adhering to the treatment plan, scheduled visits, laboratory and other study procedur