Synthetic Lethality Beyond BRCA: A Phase I Study of Rucaparib and Irinotecan in Metastatic Solid Tumors With Homologous Recombination-Deficiency Mutations Beyond BRCA1/2.

Abstract

Combining poly ADP-ribose polymerase (PARP) and topoisomerase I inhibitors has demonstrated synergistic effects in in vivo models. This phase I trial evaluated rucaparib and irinotecan in metastatic solid tumors with homologous recombination deficiency. This study enrolled patients in three cohorts to determine the tolerability and preliminary efficacy of (1) rucaparib 400 mg PO twice a day (days 1-7, 15-21) and irinotecan 65 mg/m² intravenously once every 2 weeks; (2) rucaparib 400 mg PO twice a day (D1-7, 15-21) and irinotecan 100 mg/m² once every 2 weeks; and (3) rucaparib 400 mg per os twice a day (D1-7) and irinotecan 100 mg/m² once every 3 weeks. Twenty patients were enrolled: 95% with previous platinum, 40% with previous irinotecan, and 20% with previous PARP inhibitor. The maximally tolerated was determined as rucaparib 400 mg twice a day days 1-7 and irinotecan 100 mg/m² once every 3 weeks. Four dose-limiting toxicities (all grade 3-4 neutropenia) occurred during dose escalation with only neutropenia as other grade 3-4 toxicities (25%; grade 3 [n = 3], grade 4 [n = 2]). Treatment-related grade 1-2 adverse events included neutropenia (45%), diarrhea (45%), nausea (40%), and fatigue (30%). Of 17 patients with evaluable disease, six patients (35%) derived clinical benefit (n = 2 with PR, n = 4 with stable disease for over 6 months). Three patients remained on study >1 year: two with <i>ATM</i> mutations (small bowel carcinoma and pancreatic neuroendocrine tumor) and one patient with a <i>PALB2</i> mutation (primary peritoneal cancer). Pulse dosing of rucaparib and once every 3 weeks irinotecan was well tolerated for up to 18 months with durable responses in <i>BRCA-</i>, <i>PALB2-</i>, and <i>ATM</i>-mutated cancers despite progression on previous platinum.