Bromodomain Inhibitor Shows Activity in Hematologic Malignancies

The bromodomain inhibitor, OTX015, may have use in the treatment of hematologic malignancies, including acute leukemia (AL) and other hematologic malignancies (OHMs) that include lymphomas and multiple myeloma, according to phase I study results presented at the 2014 Annual Meeting of the American Association for Cancer Research (AACR).

“So far, results have been encouraging. The drug has a good safety profile and significant activity in patients with AL and OHM. We have been excited to see that several of these patients who failed all standard therapy have durable objective responses to monotherapy with oral OTX015 at doses with little or no toxicity. As far as we know, this is the first clinical evidence that BET-bromodomain inhibitors may have a role in the treatment of human malignancies,” stated Esteban Cvitkovic, MD, founder and chief scientific officer of Oncoethix, the Swiss company that is producing and testing OTX015.

Bromodomain and extraterminal (BET) proteins partly determine whether a gene is turned on or off. These proteins attach to special epigenetic flags on the genome. The epigenetic flags have an abnormal position in different cancer types, turning genes on or off and driving the cancer process. OTX015 is an oral, small-molecule inhibitor of the BET-bromodomain proteins BRD2, 3, and 4. Preclinical studies suggest that this agent may be effective against a wide variety of cell lines, including leukemia, lymphoma, and myeloma. The drug appears to be additive with most conventional cytotoxic chemotherapies.

The phase I study reported at the AACR meeting enrolled 42 patients (21 with AL and 21 with OHM, including diffuse large B-cell lymphoma and multiple myeloma). Patients were assigned to single-dose OTX015 daily (10 mg, 20 mg, 40 mg, or 80 mg) or to 40 mg twice daily. For each dosing regimen there were 3 to 6 patients with AL and 3 to 6 patients with OHMs.

Significant activity was observed in 7 of 38 evaluable patients (4 with AL and 3 with OHMs); 4 were treated at the 80-mg/day dose, 1 at the 10-mg/day dose, and 2 at the 40-mg/day dose. Treatment of these 7 patients is ongoing. According to Cvitkovic these 7 patients met response criteria, but there was additional evidence of clinical activity in 4 other patients who did not fulfill standard response criteria.

“You need at least 3 months to be sure the patient is responding,” he said.

No dose-limiting toxicity was observed for patients with AL. The maximum tolerated dose was not reached at the 80- mg/day or the 40-mg/twice-daily dose. Thrombocytopenia was the dose-limiting toxicity for patients with OHM. The maximum tolerated dose was not reached at the 80-mg/day dose but is exceeded at the 40-mg twice-daily dose, suggesting schedule-dependent toxicity. Dose escalation with 120 mg/day is being explored.

Planned studies include a phase II trial of single-agent OTX015 in adult and pediatric solid tumors and a phase I-II study of combination therapy in selected hematologic malignancies.