An investigational combination therapy showed positive results in patients with newly-diagnosed acute myeloid leukemia (AML) who have the retinoic acid receptor alpha (RARA) biomarker, according to an ongoing phase 2 trial.

SY-1425, a novel selective RARA agonist, used in combination with azacitadine is being evaluated in this genomically defined subset of newly-diagnosed patients with AML who are not suitable candidates for standard intensive chemotherapy. The study included patients with either the RARA or IRF8 biomarker, as well those without biomarkers.

For the study, all patients were treated with azacitadine administered at a standard daily dose of 75 mg/m2 intravenously or subcutaneously for 7 days, followed by SY-1425 administered at 6mg/m2 per day orally, divided into 2 doses, for the remainder of each 28-day cycle.

Forty newly diagnosed unfit patients with AML were enrolled in the trial and eligible for safety analysis, as of August 22, 2019, according to Syros.

According to the findings, SY-1425 plus azacitadine demonstrated:
 
  • Sixty-two percent complete response (CR) and CR with incomplete blood count recovery (CRi) rate, as defined by Revised International Working Group criteria, in patients who are RARA-positive.
  • Fifty-four percent CR rate in patients who are RARA positive, consisting of 7 CRs, including 3 molecular CRs and 3 cytogenetic CRs.
  • Duration of response in patients who are RARA-positive of up to 344 days, with 3 of the 8 responding patients having responses lasting beyond 7 months at the time of the data cutoff.
  • Responses in patients who are RARA-positive across all AML risk groups, including patients with mutations that are typically associated with poor outcomes.
  • CR/CRi rate of 27% in the 22 response-eligible patients who are RARA-negative.

Additionally, 82% of patients who are RARA-positive achieved or maintained transfusion independence.

According to the study, the CR/CRi rate was 0% in patients with only the IRF8 biomarker.

The combination therapy was generally tolerable with no evidence of increased toxicities beyond the established safety profile of either SY-1425 or azacitadine alone. The most commonly reported adverse effects were nausea, decreased appetite, constipation, fatigue, and peripheral edema.

“I am very encouraged by these data. AML patients continue to need new treatment options, despite recent advances in the field, that are well-tolerated and can be used in combination to extend survival and improve quality of life,” clinical investigator Stéphane de Botton, MD, Head of Acute Myeloid Malignancies at Institut Gustave Roussy, said in a statement. “These data show that SY-1425, a targeted therapy, in combination with azacitidine is highly active in a subset of patients that can be readily identified and that the combination is generally well-tolerated even in very sick AML patients. I believe SY-1425 is a promising combination agent with the potential to provide a meaningful benefit for a subset of AML patients, and I look forward to its continued development.”

Reference

Syros Announces New Data from Phase 2 Trial of SY-1425 in Combination with Azacitidine Demonstrating High Response Rates, Rapid Onset of Action and Favorable Tolerability Profile in RARA-Positive Newly Diagnosed Unfit AML Patients [news release]. Syros. https://ir.syros.com/press-releases/detail/171/syros-announces-new-data-from-phase-2-trial-of-sy-1425-in. Accessed October 24, 2019.