A phase Ib/II study of onvansertib (PCM-075) in combination with FOLFIRI and bevacizumab for second-line treatment of metastatic colorectal cancer in patients with a KRAS mutation

Abstract

Background: FOLFOX (5-flourouracil, leucovorin, oxaliplatin) and FOLFIRI (fluorouracil, leucovorin, irinotecan) in combination with targeted agents are standard-ofcare options for patients for mCRC with response rates>50% in first line. In the second line setting, efficacy of chemotherapy and targeted agents are much lower with response rates of 4% for FOLFIRI+ bevacizumab (Tabernero 2014) and treatment options are limited in particular for the 50%of patients harboring a RAS mutation. Polo-like kinase 1 (PLK1) is a serine/threonine kinase, master regulator of G2/M cell-cycle progression and genome wide RNAi screens identified PLK1 to be synthetic lethal for KRAS mutated tumor cells inducing arrest and apoptosis (Luo 2009). Onvansertib is an oral, highly selective PLK1 inhibitor that demonstrates single agent and synergistic activity with irinotecan in preclinical CRC models. Additionally, KRAS mutated vs wild-type tumor cells showed higher sensitivity to onvansertib. PLK1 inhibition is a potential target in KRAS-mutated mCRC and onvansertib+ FOLFIRI may provide a new secondline treatment option. Trial design: The primary objective of this single-arm study is to assess the safety and preliminary efficacy of onvansertib in combination with FOLFIRI and bevacizumab in the second line setting for KRAS-mutated mCRC patients by determining the MTD and RP2D in the Phase 1b segment of the trial, and using the RP2D to treat patients in the Phase 2 continuation segment. For the phase 1b, a standard 3+ 3 dose-escalation design will be used with enrollment stopping when 6 patients have been treated at the highest dose level at which 1 or fewer patients experience a DLT. For the phase 2, based on a one-sided one sample log-rank test with 10% Type I error, there will be at least 90% power to detect an improvement in ORR from 5% to 20% with 26 patients. Preliminary efficacy will be determined by objective response (RECIST v1.1) and exploratory studies include quantitation of KRAS circulating tumor DNA (ctDNA) and genomic studies of circulating tumor cells and ctDNA to determine activated pathways that correlate with patient response.