Epigenetic Therapy Beneficial in Blood Cancers

In recent years, researchers have begun to investigate proteins that govern epigenetic mechanisms as possible therapeutic targets for cancer. OTX015 inhibits a subset of bromodomain (BRD) proteins important to the epigenetic control and regulation of certain cancer “driver genes.” In preliminary results from an ongoing phase I trial, the drug shows tolerability and promising clinical responses in some patients with acute leukemia and other hematologic malignancies.

Esteban Cvitkovic, MD, co-founder and CEO of OncoEthix SA, the Swiss drug development company that has been studying OTX015, presented the preliminary results from the trial on April 7 at the American Association for Cancer Research Annual Meeting 2014 in San Diego, CA.

OTX015 targets three of the four members of the bromodomain and extraterminal (BET) subfamily of BRD proteins—BRD2, 3, and 4. Studies suggest that blocking these proteins can suppress MYC. With this trial, OTX015 becomes the first BET–bromodomain inhibitor, a new family of anticancer agents, to show clinical activity in patients, noted Patrice Herait, MD, chief medical officer of OncoEthix SA and a co-founder of the company.

The study was open to patients with acute leukemia or another hematologic malignancy who have failed standard therapies. Participants were given 10, 20, 40, or 80 milligrams of the drug daily, or a twice-daily dose of 40 mg. The optimal dose and schedule has not been determined.

Of the 38 patients evaluable to date, one with acute myeloid leukemia (AML) had a complete remission. A second AML patient had a complete remission with incomplete recovery of platelet levels. A patient with diffuse large B-cell lymphoma had a partial response to the drug.

The researchers reported finding no dose-limiting toxicity among leukemia patients, even at the highest doses. Most adverse events, which included aggravation of diabetes and digestive symptoms, were relatively minor. Higher-grade events, namely reversible low platelet counts, occurred in three patients with hematologic malignancies other than leukemia, and Cvitkovic noted that this could be a dose-limiting toxicity for those patients. Other higher-grade events, which were reported in one patient each, included neutropenia, diarrhea, and elevated transaminases, a sign of possible liver damage.

The researchers are currently planning single-agent expansion cohort studies in acute leukemias and other hematologic malignancies.

Although he declined to offer specifics, Cvitkovic said he suspects OTX015 could be useful in the treatment of other types of cancer. He noted that preclinical findings suggest that some pediatric and solid tumors could also be sensitive to the drug, and that it could be particularly effective when combined with existing therapies, including targeted drugs.

“It combines synergistically with almost everything we've tried,” Cvitkovic said.