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Birinapant With 5-azacitidine in MDS Subjects Who Are Naïve, Have Relapsed or Are Refractory to 5-azacitidine Therapy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01828346
Recruitment Status : Completed
First Posted : April 10, 2013
Last Update Posted : April 21, 2016
Information provided by (Responsible Party):
TetraLogic Pharmaceuticals

Brief Summary:
This is a dose escalation followed by dose expansion study of TL32711 in combination with 5-Azacitidine in subjects with Myelodysplastic syndrome who are naïve, have relapsed or have failed prior 5-azacitidine therapy. Pre-clinical and mechanistic studies support that 5-Azacitidine may modulate pathways that enable birinapant-mediated anti-tumor activity.

Condition or disease Intervention/treatment Phase
Myelodysplastic Syndrome Drug: Birinapant Drug: 5-Azacitidine Phase 1 Phase 2

Detailed Description:

This is a Phase 1b/2a, open-label, non-randomized study in male and female subjects with MDS who are naïve, refractory or have relapsed to 5-Azacitidine therapy.

Primary Objective is to determine the maximum tolerated dose (MTD), recommended Phase 2 dose, and pharmacodynamics (PD) of birinapant (TL32711) when administered in combination with 5-azacitidine (5 AZA) in subjects with myelodysplastic syndrome (MDS) who are naïve, refractory or have relapsed to 5-AZA therapy.

Secondary Objectives are to determine the clinical activity using the International Working Group (IWG) (Cheson, 2006) Response Criteria for MDS during the Phase 1b dose escalation stage of the study and in the Phase 2a expansion cohort, to determine the pharmacokinetics (PK) of birinapant when administered with 5-AZA in plasma and to assess exploratory translational biomarkers of anti-tumor activity of birinapant in combination therapy.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2a, Open-label, Non-randomized Study of Birinapant in Combination With 5-azacitidine in Subjects With Myelodysplastic Syndrome Who Are Naïve, Refractory or Have Relapsed to 5-azacitidine Therapy
Study Start Date : June 2013
Actual Primary Completion Date : June 2015
Actual Study Completion Date : November 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Azacitidine

Arm Intervention/treatment
Experimental: Treatment
5-Azacitidine plus birinapant
Drug: Birinapant

Dose escalation part: (Drug escalation dose levels)

  • Dose Level (1) - 13mg/m2 (twice a week for 3 of 4 weeks)
  • Dose Level (-1) - 11 mg/m2 (twice a week for 3 of 4 weeks)
  • Dose Level (2) - 13mg/m2 (twice weekly x 4 weeks)
  • Dose Level (3a) - 17mg/m2 (twice weekly × 4 weeks)OR
  • Dose Level (3b) - 17mg/m2 (twice a week for 3 of 4 weeks)
Other Name: TL32711

Drug: 5-Azacitidine
Dose Level (0) - 75mg/m2 daily
Other Name: 5-AZA

Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) [ Time Frame: 6 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Men or women more than 18 years of age.
  • Patients with high-risk Myelodysplastic Syndrome
  • Performance status of greater or equal to 2 by the Eastern Cooperative Oncology Group (ECOG) scale.
  • Subjects with high-risk MDS who are naïve to 5-Azacitidine or have previously received 5-AZA or decitabine as first-line cytotoxic therapy. Subjects with prior 5-Azacitidine therapy were evaluated to be either refractory or relapsed as determined by the Investigator, according to IWG response criteria.Subjects with relapsed or refractory disease may have only received prior 5-Azacitidine or decitabine.
  • Hydroxyurea for patients with rapidly proliferative disease can be used up to 24 hours prior to therapy but not concomitantly with 5-Azacitidine.
  • Adequate liver, pancreatic and renal function.
  • Women of childbearing potential must have a negative serum pregnancy test at screening within 48 hours prior to the first dose
  • Women of childbearing potential must agree to use 2 methods of adequate contraception

Exclusion Criteria:

  • Subjects with life-threatening toxicity or non tolerability to prior 5-Azacitidine therapy.
  • Subjects with hypoplastic Myelodysplastic syndrome.
  • Subjects with >30% bone marrow blast cells.
  • Subjects with malignant hepatic tumors or secondary malignancy within 2 years
  • Known diagnosis of human immunodeficiency virus or chronic active Hepatitis B or C.
  • Uncontrolled hypertension
  • Impaired cardiac function, uncontrolled cardiac arrhythmias despite medications,
  • QT interval corrected for heart rate (QTcB) more than 480 msec
  • 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 women.
  • Known allergy to any of the formulation components of birinapant.
  • Known or suspected hypersensitivity to 5-Azacitidine or mannitol.
  • Any concurrent disease and/or medical condition that, in the opinion of the Investigator, would prevent the subject's participation.
  • History of Bell's Palsy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01828346

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United States, Arizona
Palo Verde Hematology Oncology
Glendale, Arizona, United States, 85304
Mayo Clinic Scottsdale
Scottsdale, Arizona, United States, 85259
United States, California
California Cancer Associates for Research and Excellence
Fresno, California, United States, 93720
United States, Florida
Mayo Clinic Jacksonville
Jacksonville, Florida, United States, 32224
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
United States, Pennsylvania
University of Pennsylvania, Abramson Cancer Center
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
The University of Texas M.D. Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
TetraLogic Pharmaceuticals
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Principal Investigator: Gautam Borthakur, MD M.D. Anderson Cancer Center
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Responsible Party: TetraLogic Pharmaceuticals Identifier: NCT01828346    
Other Study ID Numbers: TL32711-0087
First Posted: April 10, 2013    Key Record Dates
Last Update Posted: April 21, 2016
Last Verified: April 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by TetraLogic Pharmaceuticals:
Myelodysplastic syndrome
Additional relevant MeSH terms:
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Myelodysplastic Syndromes
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors