Patients with a variety of hematologic cancers benefited from treatment with OTX015, a member of a new class of investigational epigenetic therapies that block the activity of bromodomain and extraterminal (BET)-bromodomain proteins. These phase I clinical trial results were presented at the American Association for Cancer Research 2014 Annual Meeting, in San Diego, California.
BET-bromodomain proteins have an important role in controlling whether a gene is turned on or off. They work by attaching to special epigenetic flags on the genome. The positioning of many epigenetic flags is abnormal in many different types of cancer, and this can inappropriately turn genes on or off, helping drive these cancers.
“OTX015 is a potent, small-molecule inhibitor of the BET-bromodomain proteins BRD2, 3, and 4,” said Esteban Cvitkovic, MD, founder and CEO of OncoEthix, the sponsor of this trial. “Preclinical data showed that it may be effective against a wide range of hematologic malignancies. This ongoing study is designed to determine the recommended dose and schedule of OTX015 to be given orally as a single agent to patients with hematologic malignancies.
“We have been excited to see that several leukemia and lymphoma patients, having failed all available standard therapies, have durable, objective responses to monotherapy with oral OTX015 at doses that have little or no toxicity,” added Cvitkovic. “As far as we know, this is the first clinical evidence that BET-bromodomain inhibitors, a new family of anticancer agents, may have a role in the treatment of human malignancies.”
So far, Cvitkovic and colleagues have enrolled 42 patients in their clinical trial, 21 with acute leukemia—mainly acute myelogenous leukemia (AML)—and 21 with other hematologic malignancies, including diffuse large B-cell lymphoma and multiple myeloma. These patients were assigned to a single dose of 10 mg, 20 mg, 40 mg, or 80 mg of OTX015 daily, or to two 40-mg doses of OTX015 daily. Three to 6 patients with acute leukemia and 3 to 6 patients with another hematologic malignancy were assigned to each dosing regimen.
The researchers saw clinically meaningful activity in 7 of the 38 currently evaluable patients. Of these seven patients, four received a single 80-mg dose of OTX015 daily, one received 10 mg daily, and two received 40 mg daily. Treatment is ongoing for three of the patients, who are 2 to 6 months out from the start of treatment.
Four of the patients who benefited clinically have AML. One is experiencing an ongoing complete response, meaning the patient’s bone marrow and blood returned to normal entirely. A second patient is experiencing a complete response with incomplete recovery, meaning there are no leukemia cells detectable in the bone marrow and blood but only a partial recovery of normal blood cells is achieved.
No dose-limiting toxicities have been observed so far in patients with leukemia, Cvitkovic stated; but thrombocytopenia is emerging as a dose-limiting toxicity for patients with other hematologic malignancies.