Bromodomain Inhibitor OTX015 May Be Active in Lymphoma

The first-in-class small molecule bromodomain inhibitor OTX105 may be particularly active in patients with diffuse large B-cell lymphoma (DLBCL) and treatment results in infrequent grade 3-4 adverse events with the exception of thrombocytopenia, a study published in the journal The Lancet Haematology has shown.¹

OTX015 specifically binds to BRD2, BRD3, and BRD4 of bromodomain and extraterminal (BET) proteins. Preclinical studies have demonstrated that OTX015 is active in hematologic malignancies, including leukemia, lymphoma, and myeloma. Therefore, researchers conducted a phase 1 trial to establish the recommended dose of OTX015 in these patients.

For the non-leukemia cohort of this open-label study, researchers enrolled 33 patients with lymphoma and 12 with multiple myeloma who had experienced disease progression on standard therapies. Patients received OTX015 orally once daily continuously at a dose of 10, 20, 40, 80, or 120 mg. The study design allowed for alternative administration schedules to be evaluated.

Results showed that 3 patients with DLBCL achieved durable objective responses. Two complete responses occurred with 120 mg once daily dose and the 1 partial response was with the 80 mg daily dose. Six additional patients demonstrated evidence of clinical activity but did not meet objective response criteria.

In terms of safety, the most frequently reported treatment-related adverse events were thrombocytopenia (96%), anemia (91%), neutropenia (51%), diarrhea (47%), fatigue (27%), and nausea (24%). Grade 3-4 thrombocytopenia occurred in 58% of patients.

Researchers determined that the once-daily recommended dose for OTX015 in patients with lymphoma is 80 mg for 14 days on and 7 days off for phase 2 studies. This intermittent administration of 14 days every 3 weeks allows for recovery from toxic effects.

Reference

1. Amorim S, Stathis A, Gleeson M, et al. Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study [published online ahead of print March 18, 2016]. Lancet Haematol. doi: 10.1016/S2352-3026(16)00021-1.