Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in previously untreated intermediate- to high-risk DLBCL

Abstract

Martin and colleagues report the results of a phase 1b trial of adding oral azacitidine (CC-486) to R-CHOP. “Priming” with CC-486 is shown to cause extensive genomewide hypomethylation in paired tumor biopsies, and the combination demonstrates promising clinical activity in patients with previously untreated intermediate- to high-risk aggressive B-cell lymphomas. This concept is being further explored in a phase 2/3 randomized study of R-miniCHOP with or without CC-486 in older patients.

Key Points

• Epigenetic priming with oral azacitidine (CC-486) before R-CHOP demonstrated an acceptable safety profile.

• CC-486 plus R-CHOP showed clinical activity in previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed FL.

Visual Abstract

Abstract

Resistance to standard immunochemotherapy remains an unmet challenge in diffuse large B-cell lymphoma (DLBCL), and aberrant DNA methylation may contribute to chemoresistance. Promising early-phase results were reported with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus subcutaneous azacitidine, a hypomethylating agent. In this phase 1 study, we evaluated CC-486 (oral azacitidine) plus 6 cycles of R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. CC-486 doses of 100, 150, 200, or 300 mg given 7 days before cycle 1 and on days 8-21 of cycles 1-5 were evaluated; additional patients were enrolled in the expansion phase to examine preliminary efficacy. The primary objectives were to determine the safety and the maximum tolerated dose (MTD) of CC-486 in combination with R-CHOP. The most common grade 3/4 toxicities were hematologic, including neutropenia (62.7%) and febrile neutropenia (25.4%); grade 3/4 nonhematologic toxicities were uncommon (<7%). The MTD was not established; 2 patients had dose-limiting toxicities (1 with grade 4 febrile neutropenia; 1 with grade 4 prolonged neutropenia). The recommended phase 2 dose was established as 300 mg. The overall response rate was 94.9%, with 52 patients (88.1%) achieving complete responses. With a median follow-up of 28.9 months, estimated 1- and 2-year progression-free survival rates were 84.1% and 78.6%, respectively. Overall, epigenetic priming with CC-486 before R-CHOP can be delivered with acceptable safety to patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. ClinicalTrials.gov: NCT02343536.