Study of Azacitidine With or Without Birinapant in Subjects With MDS or CMMoL

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Azacitidine With or Without Birinapant With a Single Arm Open-Label Run-In Phase in Subjects With Higher Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia

This is a randomized double blind placebo controlled study of azacitidine with or without birinapant in subjects with higher risk Myelodysplastic syndrome, secondary MDS or myelomonocytic leukemia (CMMoL) who are naïve, to azacitidine therapy. Pre-clinical and mechanistic studies support that azacitidine may modulate pathways that enable birinapant-mediated anti-tumor activity.

This is a randomized double blind placebo controlled study of azacitidine with or without birinapant in subjects with higher risk Myelodysplastic syndrome, secondary MDS or myelomonocytic leukemia (CMMoL)

The primary purpose of this study is :

-To compare the relative effect of azacitidine plus birinapant versus azacitidine plus placebo on response rate in patients with higher-risk MDS, secondary MDS or CMMoL.

The secondary purpose of this study is to compare effect of azacitidine plus birinapant relative to azacitidine with placebo on:

• Hematologic improvement
• Relapse free survival
• Time to respond
• Change in transfusion requirements
• Duration of response
• Overall survival
• Adverse events

The exploratory objective of this study is to assess exploratory translational biomarkers for antitumor effects.

key Inclusion Criteria:

• Morphologically confirmed diagnosis of MDS/CMMoL according to FAB or WHO classification, including RAEB-t and MDS/MPN
• International prognostic score-revised (IPSS-R) of >3.5 (Intermediate, High or Very High)
• Previously untreated with hypomethylating agents for MDS/CMMoL
• Performance status of 0, 1 or 2 by the ECOG scale
• Adequate renal and liver function
• Female subjects of childbearing potential must have a negative serum pregnancy test at screening within 96 hours prior to the first study dose.
• Female subjects of childbearing potential and male subjects with partners of childbearing potential should ensure use of a highly effective method of birth control as defined by the investigator, for example, those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly during the study and for a period of 3 months following the last dose of any drug administered during the study.

Key Exclusion Criteria:

• Relapsed or refractory to hypomethylating agents
• Acute myeloid leukemia (AML), except those patients with RAEB-t who are not candidates for intensive AML therapy.
• Participated in any interventional study within 4 weeks of randomization or 5 half lives (whichever is longer).
• Received any hematopoietic growth factors within 14 days prior to screening.
• Prior malignancy or secondary malignancy within the prior 2 years (except in situ cervical cancer, squamous cell carcinoma or basal cell carcinoma of the skin).
• known diagnosis of human immunodeficiency virus or chronic active Hep B or C.
• Uncontrolled hypertension
• Impaired cardiac function, uncontrolled cardiac arrhythmias despite medications, or clinically significant cardiac disease
• Lack of recovery of prior adverse events to Grade ≤1 severity (National Cancer Institute Common Terminology Criteria for Adverse Events version 4) (except alopecia) due to therapy administered prior to the initiation of study drug dosing.
• Nursing or pregnant.
• Known allergy or hypersensitivity to any of the formulation components
• Any concurrent disease and/or medical condition that, in the opinion of the Investigator, would prevent the subject's participation.
• History of cranial nerve palsy.
• Being treated with anti-TNF therapies or has been treated with an anti-TNF therapy within 5 half-lives of randomization.