BET Inhibitors Active in DLBCL and Other Lymphomas, Two Early Trials Show

Two small-molecule inhibitors have recently shown encouraging activity in patients with lymphoma, according to the results of two phase I trials presented at the TAT International Congress 2018 in Paris.

CPI-1205 is a potent, highly selective, first-generation small-molecule inhibitor of EZH2, which is known to prevent the production of proteins that act to prevent cancer progression. CPI-0610 is a novel small-molecule bromodomain and extra terminal protein (BET) inhibitor used in patients with relapsed or refractory disease. BET proteins are known to promote cancer growth.

The first study (poster #420) enrolled 32 patients with B-cell lymphoma and assigned them to oral CPI-1205 twice daily in 28-day cycles. The study had four dose cohorts (200 mg, 400 mg, 800 mg, and 1,600 mg). All enrolled patients had progressed on standard therapy, and the majority had diffuse large B-cell lymphoma (DLBCL).

According to the abstract, one patient had a complete response after 6 cycles of treatment and five patients had stable disease.

The majority of treatment-related adverse events were grade 2 or lower. The most common treatment-related adverse events were nausea, diarrhea, anemia, and fatigue. Seven patients had grade 3 or worse adverse events, including nausea, lymphocyte count decrease, anemia, hypertension, and toxic epidermal necrolysis. No dose-limiting toxicities occurred.

Based on these results, an expansion phase in patients with germinal center B-cell DLBCL or follicular lymphoma with or without EZH2 mutation was initiated at a dose of 800 mg twice daily.

“If approved by health authorities, EZH2 inhibition may become a new treatment paradigm in relapsed or refractory EZH2 mutant follicular lymphoma patients,” study author Adrian Senderowicz, Constellation Pharmaceuticals, said in a press release.

The second phase I study (poster #410) reported results from the first-in-human study of BET inhibitor CPI-0610. The 64 enrolled patients had relapsed or refractory lymphoma with no effective available therapies. Patients had received a median of four prior lines of therapy. More than half (56%) of the patients had DLBCL.

Patients were assigned to capsules with doses ranging from 6-mg daily to 300-mg daily or to 125-mg or 225-mg tablets. Doses were administered on a 14 days on, 7 days off schedule.

Objective responses occurred in 5 patients, including two complete responses, three partial responses, and 5 patients with prolonged stable disease. Three of the patients with response and one with stable disease had activated B-cell-like subtype of DLBCL.

Ten patients were treated at the maximum tolerated dose and only one dose-limiting toxicity occurred. The most common treatment-related adverse events were thrombocytopenia, fatigue, nausea, decreased appetite, and anemia.

Thrombocytopenia, which is a class effect for all BET inhibitors, was dose limiting; however, it was reversible.

Both of these compounds are in development by Constellation Pharmaceuticals.