Birinapant Plus Azacitidine Not Superior to Azacitidine Alone in Myelodysplastic Syndrome

CHICAGO–Adding the investigational agent birinapant to azacitidine did not improve outcomes, compared with azacitidine alone, in patients with myelodysplastic syndrome (MDS), according to results of a randomized, double-blind, placebo-controlled, phase II study presented at the 2016 American Society of Clinical Oncology Annual Meeting.

Birinapant is a second mitochondrial activator of caspase (SMAC) mimetic and antagonist of inhibitor of apoptosis proteins (IAPs). In an earlier phase Ib trial of patients with MDS, birinapant demonstrated an acceptable safety profile and showed early signs of clinical activity, prompting researchers to evaluate its efficacy when combined with the hypomethylating agent azacitidine, one of the standard therapies for MDS.

William Bruce Donnellan, MD, from the Sarah Cannon Research Institute in Nashville, Tennessee, presented the results of the study, which included 118 patients with hypomethylating agent–naïve MDS and chronic myelomonocytic leukemia. Patients had de novo International Prognostic Scoring System intermediate (INT)-2/high-risk MDS or INT-1 risk with ≥5 percent bone marrow blasts. The study protocol was later amended to include patients with secondary MDS, low blast counts but high-risk cytogenetics, and acute myeloid leukemia with low blast counts (20-30%).

Dr. Donnellan and authors compared overall response rates (ORR; including complete and partial responses) between patients who were randomized to receive either:

  • azacitidine 75 mg/m2/day administered intravenously (IV) on days 1-7 or 1-5, 8, and 9 in a 28-day cycle plus placebo
  • azacitidine 75 mg/m2/day IV on days 1-7 or 1-5, 8, and 9 in a 28-day cycle plus birinapant 13 mg/m2/day IV administered twice weekly for 3 of 4 weeks (on days 1, 4, 8, 11, 15, and 18)

The study was terminated earlier than planned when an interim analysis found no difference in ORR between the two groups. At the time the study was terminated, the best ORR was 31.8 percent for those receiving azacitidine plus placebo, compared with 29.4 percent for the cohort receiving azacitidine and birinapant (p=0.96).

Rates of serious, grade ≥3 treatment-related adverse events (AEs the study’s secondary endpoint) were higher in patients in the birinapant group, compared with the placebo group (61.4% vs. 40.8%; p value not provided). Treatment-related fatal AEs were higher with birinapant (8.8% vs. 0%; p value not provided). The most common serious AEs occurred more frequently in the birinapant than in the placebo group, including:

  • febrile neutropenia (34.4% vs. 10.3%)
  • infections (28.1% vs. 13.8%)
  • thrombocytopenia (25% vs. 20.7%)

“In this [study], the response rate of birinapant plus azacitidine was not superior to azacitidine alone,” Dr. Donnellan and authors concluded. Also, given the higher rates of AEs – and serious AEs in particular – with the combination of azacitidine and birinapant, adding the investigational agent did not provide any benefit over azacitidine alone.


Donnellan WB, Diez-Campelo M, Heuser M, et al. A phase 2 study of azacitidine (5-AZA) with or without birinapant in subjects with higher risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML). Abstract #7060. Presented at the 2016 American Society of Clinical Oncology Annual Meeting, Chicago, IL, June 6, 2016.