e22061 Background: BRCA-associated protein-1 (BAP1) is a ubiquitin ligase associated with regulating cell cycle, cell proliferation, DNA damage pathway, and cell death. It also acts as a tumor suppressor gene as seen in hereditary cancer syndrome associated with germline mutations in BAP1. Preclinical studies have shown that PARP-inhibitor treatment of BAP1 mutant cell lines demonstrated significant synthetic lethality, independent of underlying BRCA status suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of several solid tumors including cholangiocarcinoma, mesothelioma, uveal melanoma, and clear cell renal cell carcinoma. Methods: This phase 2, open-label, single arm study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in two biologically distinct cohorts. Eligible patients (pts) with measurable metastatic and incurable solid tumors are assigned to one of the two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via Next Generation Sequencing (NGS); or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Key inclusion criteria also include age ≥18 years, adequate cardiac, renal, hepatic function and ECOG PS of 0 to 1. Key exclusion criteria include known BRCA1 or BRCA2 mutations or prior PARPi exposure. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate (ORR), and secondary endpoints are progression free survival (PFS), overall survival (OS), toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks while on treatment. Cohort B enrollment is closed. Enrollment in Cohort A continues. A maximum of 47 evaluable subjects is planned with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. Clinical trial information: NCT03207347. [Table: see text]
Chemotherapy-mediated p53-dependent DNA damage response in clear cell renal cell carcinoma: role of the mTORC1/2 and hypoxia-inducible factor pathways
