Talazoparib and Avelumab for the Treatment of 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 I: Presence of VHL alteration by next-generation sequencing (NGS) with a state-approved assay
• COHORT I: 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
• COHORT I: Maximum 3 prior lines of therapy
• COHORT II: 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
• COHORT II: For renal cell carcinoma (RMC) patients: histologic confirmation of RMC (no immunohistochemistry [IHC]/NGS criteria required)
• COHORT II: At least one prior line of therapy
• COHORT II: 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)
• COHORT II: For renal cell 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)
• COHORT II: No maximum lines of therapy
• 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 Cockcroft-Gault equation * Patients with moderate renal impairment (creatinine clearance 30-59 by Cockcroft-Gault equation) will start with a reduced dose of talazoparib
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) =< 3 x upper limit of normal (ULN) without liver metastasis
• Alanine aminotransferase (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 =< 3 x ULN
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Patients must have measurable disease by RECIST version (v)1.1. 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 Common Terminology Criteria for Adverse Evens (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 procedures
• LIFESTYLE REQUIREMENTS: The teratogenic risk of combination talazoparib and avelumab remains unknown. Talazoparib has been associated with teratogenic risk. Therefore, all fertile male patients and female patients who are of childbearing potential, and who remain sexually active during this study and who are at risk for pregnancy must agree for 2 methods of contraception (one which is considered highly effective), for at least 7 months after last dose of study treatment for women, and for at least 4 months after last dose of study treatment for men. Study team personnel including investigators and clinical nursing staff should confirm that the patient and their partner have selected 2 appropriate methods of contraception from the list of contraceptive methods (as listed below). The study team will confirm that the patient has received informed consent regarding proper use. Continued confirmation of contraceptive use will be obtained during the study protocol at time points outlined, with documentation of affirmation. Highly effective contraceptive methods include, but not limited to: * Established hormonal methods of contraception associated with ovulation inhibition (i.e. oral, inserted, injected or implanted), provided that the patient or male patient’s partner remains on same treatment throughout the entire study period * Intrauterine device * Male sterilization with absence of sperm in post vasectomy ejaculate * Bilateral tubal ligation, bilateral salpingectomy or bilateral tubal occlusive procedure * Female partner of male patient who meets criteria for non-childbearing potential as defined above, including: ** Medically confirmed ovarian failure ** Hysterectomy and/or bilateral oophorectomy ** Post-menopausal state as defined as a cessation of regular menses > 12 months with no alternative pathologic or physiologic cause, with serum follicular stimulating hormone within reference range for postmenopausal women by laboratory * All sexually active male patients must agree to prevent potential transfer or exposure of study agents through ejaculate by using a condom consistently and correctly. Condom use must begin at the first dose of investigational product, and for at least 30 days after avelumab or after at least 4 months after last dose of talazoparib, whichever is later

Exclusion Criteria

• Patients < 18 years old
• Patients who are pregnant or breast-feeding. Fertile patients who are unwilling or unable to use two methods of contraception (at least one of which considered highly effective) for duration of study and after 7 months after last dose of study treatment for female, and 4 months for males
• Patients who had prior immune checkpoint blockade therapy (either anti-PD-1, anti-PD-L1 and/or anti-CTLA-4) discontinued due to development of an immune related adverse event
• Prior diagnosis of myelodysplastic syndrome (MDS) or diagnosis of other malignancy that requires anti-cancer directed therapy within the last 24 months. Exclusions include those cancers that are considered cured by local therapy (i.e. basal cell carcinoma, squamous cell carcinoma, ducal carcinoma in situ of breast, bladder of cervix) or other cancers that have low malignant potential and do not require systemic therapy (i.e. Gleason-grade < 6 prostate adenocarcinoma, borderline ovarian malignancy / low malignant potential)
• Prior treatment with talazoparib or other agents that target PARP
• Treatment with anti-cancer therapies within 21 days or five half-lives, whichever shorter, of start date, including monoclonal antibody, cytotoxic therapy, or another investigational agent. There is no specific time window between last PD-1/PD-L1 therapy and start date of new therapy on protocol
• Significant vascular disease (i.e. aortic aneurysm requiring surgical repair, recent arterial thrombosis) within 6 months prior to first dose of therapy
• Evidence of bleeding diathesis or significant unexplained coagulopathy (i.e. absent of anticoagulation)
• Clinical signs or symptoms of gastrointestinal obstruction requirement parenteral hydration, parenteral nutrition, or feeding tube
• Uncontrolled effusion management (pleural effusion, pericardial effusion, or ascites) which requires recurrent drainage procedures
• Patients treated with systemic immunosuppressants; except for * Chronic physiologic replacement of =< 10 mg prednisone (or equivalent) for treatment of adrenal insufficiency; Steroids required for pre-medication reactions * Local steroid use is permitted (e.g. intranasal, topical, inhaled, or local steroid injection, i.e. intra-articular)
• Patients with autoimmune disease that may worsen during immune checkpoint blockade therapy are excluded. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requirement immunosuppressive treatment as above are eligible
• Prior organ transplantation including allogeneic stem cell transplant
• No active infection requiring parenteral antibiotic therapy
• Prior diagnosis of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS)
• History of either positive hepatitis C virus (HCV) ribonucleic acid (RNA) viral load or anti-HCV antibody screening detectable; hepatitis B virus (HBV) infection with HBV surface antigen detection and/or positive HBV DNA viral load
• Known hypersensitivity to talazoparib or avelumab, or any component in formulations. Patients with known hypersensitivity to monoclonal antibodies (grade >= 3 by CTCAE v5.0)
• Live vaccination within 4 weeks of first dose of therapy. All vaccines except inactivated are prohibited while on study
• Severe acute or chronic medical conditions which may significantly increase the risk of study participants, per treating investigator’s discretion
• Radiation therapy to any site (including bone) < 2 weeks prior to the first dose of therapy. Patients with clinically relevant ongoing complications from prior radiation therapy, per investigators’ assessment, are not eligible
• Symptomatic brain metastasis or leptomeningeal disease requiring steroid use. Patients are eligible if they neurologically stable for 4 weeks, and have completed radiation therapy or surgery, and recovered from side effects. Patients must have discontinued steroid therapy for at least 2 weeks prior to first dose of study treatment
• Current or anticipated use of potent P-gp inhibitors within 7 days prior to randomization or anticipated use during the study
• Inability to swallow capsules, known intolerance to talazoparib or its excipients, known malabsorption syndrome, or other conditions which impair intestinal absorption
• Investigator site staff members directly involved in study conduct, including but not limited to their family members, or patients who are Pfizer members, including their family members, who are directly involved in study conduct