Talazoparib and Axitinib for People With Previously Treated Advanced Kidney Cancer

Inclusion Criteria

• •Biopsy proven metastatic or unresectable renal cell carcinoma with clear cell component
• •Prior treatment with at least 1 VEGFR TKI and 1 PD-1/PD-L1 immune checkpoint inhibitor (ICI).Combination VEGFR TKI plus ICI will be counted as 1 line of therapy. During the dose escalation portion of the study prior TKI exposure is not required.
• •Dose escalation portion: No maximum prior lines of therapy. Dose expansion portion: maximum of two prior lines of therapy
• •Adequate Hematologic Function
• •* Absolute Neutrophil Count ≥ 1.5 x 109 / 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 ≥ 60 ml/min according to the Cockcroft-Gault formula
• •° Patients with moderate renal impairment (creatinine clearance 30-59 ml/min by Cockcroft-Gault) may be eligible in the phase II dose expansion
• •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 urine or 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 women, and 4 months for men.
• •Recovery of baseline CTCAE v5.0 grade ≤1 toxicities related to prior study treatments unless adverse events are clinically non-significant per investigator's discretion 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.
• •Maximum 2 lines of prior therapy. Combination VEGFR TKI plus ICI therapy will be accepted as 1 line of therapy.
• •Adequate Renal Function ≥ 30 ml/min according to the Cockcroft-Gault formula.
• •* Patients with normal renal function (Cr clearance ≥ 60 ml/min by Cockcroft-Gault formula) will receive talazoparib at RP2D.
• •* Patients with moderate renal impairment (Cr clearance 30-59 ml/min by Cockcroft-Gault formula) will receive talazoparib at one dose level lower than RP2D.
• •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 and axitinib or its excipients, known malabsorption syndrome, or other conditions which impair intestinal absorption.