A phase 1 study of CPI-1205, a small molecule inhibitor of EZH2, preliminary safety in patients with B-cell lymphomas

Abstract

Background: NF-kB has been found to be constitutively activated in many lymphomas, such as diffuse large B-cell lymphomas (DLBCL), particularly the ABC subgroup. In preclinical studies, CPI-0610, a BET specific small molecule inhibitor, results in down-regulation of NF-jB signaling activity, accompanied by loss of viability of ABC-DLBCL cell lines. Here we report the results from the first-in human Phase 1 study of CPI-0610 in patients with relapsed or refractory lymphomas (NCT01949883). Methods: Eligible patients were those whose lymphoma had progressed and for whom no effective therapies are available. Doses (mg) of 6 12, 24, 48, 80, 120, 170, 230, 300 (capsules) and 125 and 225 (tablets) administered orally QD on a 14 day on, 7 days off schedule were evaluated. The primary objective was to determine the maximum tolerated dose (MTD) and key secondary objectives were to determine the pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of CPI-0610. Results: 64 patients were enrolled (56% DLBCL) with a median of 4 prior lines of therapy. MTD for this trial was 225 mg QD tablets. Ten patients were treated at MTD with only 1 DLT (thrombocytopenia). The most frequent treatment related adverse events were thrombocytopenia (45%), fatigue (34%), nausea (27%) decreased appetite (27%) and anemia (25%). Thrombocytopenia, a class effect for all BET inhibitors, was dose limiting however, is was reversible (<1 week) and not cumulative. Five patients had an objective response; 2 CRs (1 T-cell/histocyte-rich DLBCL, 1 ABC-DLBCL), 3 PRs (1 follicular lymphoma, 2 ABC-DLBCL) and 5 patients had prolonged (> 6 months) SD. Three of the responses and 1 of the prolonged SD were in patients with ABC-DLBCL. PK was dose-proportional with C max reached after 3 hours and a half-life of 16 hours. PD analysis of BET target genes demonstrated dose dependent decreases in IL8 and CCR1 mRNA between 2-8 hours post dose. Conclusions: CPI-0610 is a well-tolerated, oral BET inhibitor that has demonstrated anti-tumor activity in advanced lymphoma patients. Background: EZH2 is the catalytic subunit of the PRC2 complex, and plays an important role in transcriptional repression. EZH2 over-expression is correlated with poor prognosis. Hot spot mutations in EZH2 were first identified in GCB-DLBCL and fol-licular lymphoma (FL). CPI-1205 is a potent, selective, SAM-competitive EZH2 inhibi-tor. A Phase I study was conducted in B-cell lymphoma patients. Primary Objectives: Define maximum tolerated dose of CPI-1205 and the dose-limiting toxicities (DLTs). Methods: CPI-1205 was given orally twice daily (BID, in 28-day cycles) in 4 dose co-horts: 200 [n ¼ 4], 400 [n ¼ 5], 800 [n ¼ 10] and 1600 mg [n ¼ 13]. Eligibility criteria included adults that had progressed on standard therapy, ECOG PS of 0-2, and adequate organ function. The PK and PD profiles were evaluated. Disease responses were determined using the 2014 Lugano Response Criteria. Results: 32 pts were enrolled (22 escalation, 10 expansion): 17 DLBCL, 4 FL, 2 marginal zone lymphoma and 9 others. Median age: 63 yrs (29-80), 22 pts: male, median prior