A Phase 2 Study of Birinapant in Combination with 5-Azacitadine in Patients with Myelodysplastic Syndrome Who Are Naïve to 5-Azacitadine: A Preliminary Analysis of Phase 2a

Background: The Inhibitors of Apoptosis (IAP) proteins are a family of molecules that suppress apoptotic cell death. Expression of IAPs is dysregulated in Myelodysplastic Syndrome (MDS) and is a potential path for therapeutic intervention. SMAC (second mitochondrial-derived activator of caspases) is an IAP antagonist, resulting in caspase activation, inhibition of NF-k B and increased apoptosis. Birinapant is a potent bivalent SMAC mimetic under clinical investigation for several cancer types. Pre-clinical data support its investigation in myeloid malignancies, including MDS, and a previous phase 1b study demonstrated promising clinical activity in patients with higher-risk MDS who were naïve or had relapsed or were refractory to prior therapy. In this trial birinapant is combined with 5-azacitidine (5-AZA) in high-risk MDS patients who have not yet been treated with a hypomethylating agent.

Methods: This phase 2 ongoing study of birinapant plus 5-AZA in patients with MDS or CMMoL recently completed enrollment to the unblinded portion, in which 9 patients were dosed with birinapant 13 mg/m² IV twice weekly for 3 weeks of a 28-day cycle plus 5-AZA 75 mg/m² by IV infusion daily for 7 days of a 28-day cycle. The primary objective of this study is to determine the objective response rate by International Working Group criteria of birinapant plus 5-AZA in patients with high-risk MDS or CMMoL who are naïve to hypomethylating agents. Secondary objectives include assessing the tolerability of this regimen, and determining the pharmacokinetics and exploratory pharmacodynamics of the combination.

Results: Of the 9 patients enrolled, 6 patients had high or very high risk MDS; no patients had CMMoL. 8 patients were age ≥60 years. All patients were naïve to 5-AZA. Of the 9 patients enrolled, 6 completed up to four cycles of chemotherapy and were considered evaluable for response; three discontinued therapy prior to Cycle 4 (patient or investigator decision, or occurrence of adverse events (AEs)). Of the 6 evaluable patients, 3 had a complete response (CR), one had a marrow CR, and one had a partial response (PR). A sixth patient had a best response of stable disease at Cycle 4. Of these six patients evaluable, one (PR) was able to proceed to stem cell transplantation. The median duration of response (range) in these patients has not yet been assessed. Adverse events were consistent with the disease under investigation or the known profile of birinapant or 5-AZA. The most common ≥Grade 3 AEs seen in ≥2 patients were neutropenia and thrombocytopenia (5 patients each); fatigue, anemia, increased lipase and syncope (2 patients each). One patient developed a Grade 1 VIth cranial nerve palsy. No serious adverse events were reported in more than one patient, and one fatal event (sepsis) was reported. No patients developed infusion site reaction. Data showing inhibition of NF-k B, a downstream pro-survival molecule activated by IAPs, in circulating blast cells, demonstrated evidence of a potential biomarker in this population.

Conclusion: This ongoing phase 2 study provide data for an acceptable safety profile of the combination of birinapant administered with IV 5-AZA. Preliminary evidence of promising clinical activity in this non-randomized, open-label phase was observed. These results provide rationale for the continuation to the next phase of this global randomized, blinded phase 2 study comparing birinapant in combination with 5-AZA vs. 5-AZA alone in patients with high-risk MDS or CMMoL in the front-line setting.