41OA phase I study of CPI-0610, a bromodomain and extra terminal protein (BET) inhibitor in patients with relapsed or refractory lymphoma

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 downregulation of NF-κB 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 Cmax 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. Clinical trial identification: NCT01949883 Legal entity responsible for the study: Constellation Pharmaceuticals Funding: Constellation Pharmaceuticals Disclosure: J. Mertz, R. Sims: Constellation Pharma employee. F. Garner: Radius stock, Constellation Pharma employee. A. Senderowicz: Constellation Pharma employee, on the BOD of Puma Pharmaceuticals. All other authors have declared no conflicts of interest.