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.

Study Overview

• Status: Terminated
• Conditions: Chronic Myelomonocytic Leukemia (CMML); Myelodysplastic Syndrome (MDS)
• Intervention / Treatment: Drug: Placebo; Drug: Azacitidine; Drug: birinapant

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Metro South Health, Princess Alexandra Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Royal Hobart Hospital
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health
    • Malvern, Victoria, Australia, 3144
      • Cabrini Hospital
    • Melbourne, Victoria, Australia, 3004
      • The Alfred
    • Wodonga, Victoria, Australia, 3690
      • Border Medical Oncology
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Perth Blood Institute
• Germany
  • Essen, Germany, 45147
    • Universitätsklinikum Essen
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Heidelberg, Germany, 69120
    • Medizinische Universitatsklinik Heidelberg
  • Wurzburg, Germany, 97080
    • Universitätsklinikum Würzburg
  • Bayern
    • Munchen, Bayern, Germany, 81675
      • Klinikum rechts der Isar, Technischen Universität München
    • Munich, Bayern, Germany, 81377
      • Klinikum der Ludwig-Maximilians-Universität München
  • Nordrhein-Westfalen
    • Dusseldorf, Nordrhein-Westfalen, Germany, 40479
      • Marien Hospital Dusseldorf
  • North Rhine Westphalia
    • Cologne, North Rhine Westphalia, Germany, 50937
      • University Hospital of Cologne
  • Saxony-Anhalt
    • Halle (Saale), Saxony-Anhalt, Germany, 06120
      • University Hospital Halle
• Spain
  • Badalona, Spain, 08916
    • Hospital Germans Trias i Pujol
  • Cordoba, Spain, 14004
    • Hospital University Reina Sofia
  • Madrid, Spain, 28007
    • Hospital Universitario Gregorio Marañon
  • Madrid, Spain, 28033
    • MD Anderson Cancer Center
  • Salamanca, Spain, 37007
    • Hospital Universitario de Salamanca
  • Toledo, Spain, 45004
    • Complejo Hospitalario Virgen de la Salud
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
  • Madrid
    • Leganes, Madrid, Spain, 28911
      • Hospital Universitario Severo Ochoa
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Hospital Clinico Universitario Virgen de la Arrixaca
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Clinica Universidad de Navarra
  • S/C Tenerife
    • La Laguna, S/C Tenerife, Spain, 38320
      • Hospital Universitario de Canarias
• United States
  • Arizona
    • Glendale, Arizona, United States, 85306
      • Arizona Center for Cancer Care
    • Glendale, Arizona, United States, 85304
      • Palo Verde Hematology Oncology
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic
    • Tucson, Arizona, United States, 85704
      • Arizona Oncology Associates
  • California
    • Los Angeles, California, United States, 90095
      • Ronald Reagan UCLA Medical Center
    • Oceanside, California, United States, 92056
      • North County Oncology
    • Rancho Mirage, California, United States, 92270
      • Desert Hematology Oncology Medical Group
    • Stanford, California, United States, 94305
      • Stanford Hospital and Clinics
    • West Hills, California, United States, 91307
      • Wellness Oncology & Hematology
  • Colorado
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
    • Jacksonville, Florida, United States, 32207
      • Cancer Specialists of North Florida
    • Port St. Lucie, Florida, United States, 34952
      • Hematology Oncology Associates of the Treasure Coast
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center & Research Institute
    • Winter Haven, Florida, United States, 33880
      • Bond Clinic PA
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Springfield, Illinois, United States, 62794
      • Simmons Cancer Institute at Southern Illinois University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville Hospital/James Graham Brown Cancer Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland, Greenebaum Cancer Center
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Worcester
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • St. Joseph Mercy Hospital
  • New Jersey
    • Brick, New Jersey, United States, 08724
      • New Jersey Hematology Oncology Associates
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Cancer Center
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
    • East Setauket, New York, United States, 11733
      • North Shore Hematology Oncology Associates
    • Lake Success, New York, United States, 11042
      • Monter Cancer Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10065
      • Weill Cornell Medical College - New York-Presbyterian Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center Research
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care, Inc.
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Sciences University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina, Hollings Cancer Center
    • Rock Hill, South Carolina, United States, 29732
      • Carolina Blood and Cancer Care Associates, P.A.
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Tennessee Oncology
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
    • Tyler, Texas, United States, 75701
      • Tyler Hematology Oncology PA
  • Utah
    • Salt Lake City, Utah, United States, 84106
      • Utah Cancer Specialists
    • Salt Lake City, Utah, United States, 84112
      • University of Utah, Huntsman Cancer Hospital
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Massey Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: azacitidine with birinapant; Azacitidine 75 mg/m2 IV on days 1-5, 8 & 9 OR days 1-7 and birinapant 13 mg/m2 IV twice a week (days 1 & 4) for 3 out of 4 weeks	Drug: Azacitidine; Drug: birinapant; Other Names: TL32711
Placebo Comparator: Azacitidine and placebo; Azacitidine 75mg/m2 IV days 1-5, 8 & 9 OR days 1-7 and placebo IV twice a week (days 1 & 4) for 3 out of 4 weeks	Drug: Placebo; Drug: Azacitidine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Response Rate	participants will be followed for until disease progression an expected average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hematologic improvement		participants will be followed for until disease progression an expected average of 1 year
Relapse free survival	According to modified IWG 2006 criteria	An expected average of 2 year post last study dose
Time to respond		participants will be followed for until disease progression an expected average of 1 year
Change in transfusion requirements		participants will be followed for until disease progression an expected average of 1 year
duration of response	According to modified IWG 2006 criteria	participants will be followed for until disease progression an expected average of 1 year
overall survival		An expected average of 2 year post last study dose
Adverse events profile		participants will be monitored for adverse events throughout the treatment period and during follow up period

Other Outcome Measures

Outcome Measure	Time Frame
exploratory translational biomarkers for antitumor effect	30 days

Collaborators and Investigators

• Sponsor: TetraLogic Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: May 13, 2014
• First Submitted That Met QC Criteria: May 22, 2014
• First Posted (Estimate): May 28, 2014

Study Record Updates

• Last Update Posted (Estimate): October 20, 2016
• Last Update Submitted That Met QC Criteria: October 18, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: placebo; chronic myelomonocytic leukemia; MDS; randomized; myelodysplastic syndrome; placebo controlled; double blind; CMML; azacitidine; naive; TL32711; TL32711-0094; birinapant; higher risk
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Myeloid; Syndrome; Myelodysplastic Syndromes; Leukemia; Preleukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine
• Other Study ID Numbers: TL32711-RAN-0094-PTL; 2014-001719-37 (EudraCT Number)