BET Inhibitor CPI-0610 Is Well Tolerated and Induces Responses in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma: Preliminary Analysis of an Ongoing Phase 1 Study

Abstract

Abstract BET (bromodomain and extra-terminal) proteins are chromatin modifiers that bind to acetylated lysine residues on histones. They regulate the expression of a subset of genes that includes oncogenes such as MYC. We are conducting a first-in-human Phase 1 study of CPI-0610, a potent and selective small molecule inhibitor of BET proteins, in patients with relapsed/refractory lymphoma. CPI-0610 is given orally once daily (QD) on days 1-14 of a 21-day cycle. Between September 2013 and March 2015 44 patients had been enrolled and treated at doses of 6, 12, 24, 48, 80, 120, 170, 230 mg QD. Fifty percent of the patients had received ≥ 4 lines of previous systemic therapy and 25% received 3 lines. The most common lymphoma subtypes accrued were diffuse large B-cell lymphoma (DLBCL, 55%), follicular lymphoma (FL, 18%) and Hodgkin lymphoma (HL, 9%). The study has subsequently enrolled three additional patients to a dose of 300 mg/day. CPI-0610 exhibits dose-related increases in systemic exposure through the 230 mg QD dose level. Interpatient variability in exposure at each dose level is characterized by an average coefficient of variation of 37% for Cmax and 47% for AUC0-24hr following the first dose. The overall (mean ± SD) apparent oral clearance is 15.1 ± 7.0 L/hour and the apparent biological half-life is 10.7 ± 3.5 hours. The difference in systemic exposure between days 1 and 14 of the first cycle is minor, with a mean accumulation factor of 1.21 ± 0.42. Genes sensitive to BET inhibition were identified ex vivo in peripheral blood mononuclear cells from healthy volunteers. An assay was then developed to evaluate the expression of these genes by qPCR in peripheral blood samples from patients. Expression of the BET target gene CCR1 was suppressed at the 170 mg QD and 230 mg QD dose levels. This pharmcodynamic effect was associated with plasma CPI-0610 concentrations ≥ 3 μM. CPI-0610 has been well tolerated, with the principal toxicity being dose-dependent thrombocytopenia that is reversible and non-cumulative. The maximum decline in the platelet count occurs around day 14, with recovery over the following 1-2 week break from treatment. Doses of 170 and 230 mg QD are associated with a 50% average decline in the platelet count by day 14 of cycle 1, and have required a one-week delay in the start of the second cycle of treatment in approximately one third of patients. One patient treated at 230 mg QD developed dose-limiting grade 4 thrombocytopenia. Dose-limiting grade 3 diarrhea has occurred in one patient at both the 170 and 230 mg QD doses. Anti-lymphoma activity has been observed with CPI-0610 treatment. One patient with DLBCL achieved a partial response (PR) after 4 cycles of treatment at 48 mg QD and a complete response (CR) after 2 additional cycles of treatment at 80 mg QD; he then proceeded to allogeneic stem cell transplantation. Another patient with DLBCL achieved a CR after 3 cycles of treatment at 230 mg QD and 2 subsequent cycles at 170 mg QD; he remains in CR after 7 cycles. A patient with FL achieved a PR after 4 cycles of treatment at 230 mg QD with further improvement after 6 cycles; he continues on CPI-0610 treatment after 8 cycles. Five patients experienced smaller decreases in tumor volume (33-37%), and 6 patients with stable disease completed 6 or more cycles of treatment. Seven patients remain on treatment at a median of 8 cycles (range 3-26). Although the maximum tolerated dose has not yet been determined, CPI-0610 has activity in patients with relapsed/refractory lymphoma at doses that are generally well tolerated. Future trials will aim to identify molecularly defined subsets of patients with DLBCL and FL who are most likely to respond to treatment with CPI-0610. Disclosures Flinn: Celgene Corporation: Research Funding. Goy:Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Cooper:Constellation Pharmaceuticals: Employment, Equity Ownership. O'Meara:Constellation Pharmaceuticals: Employment, Equity Ownership. Mertz:Constellation Pharmaceuticals: Employment, Equity Ownership. Sims:Constellation Pharmaceuticals: Employment, Equity Ownership.