Clinical trial NCT02147873: Study of Azacitidine With or Without Birinapant in Subjects With MDS or CMMoL
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Myelodysplastic Syndrome (MDS)
Chronic Myelomonocytic Leukemia (CMML)
Keywords: MDS
CMML
myelodysplastic syndrome
chronic myelomonocytic leukemia
TL32711
TL32711-0094
azacitidine
birinapant
higher risk
naive
double blind
placebo
placebo controlled
randomized
Lead sponsor: TetraLogic Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2014-05-28
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Response Rate
timeFrame: participants will be followed for until disease progression an expected average of 1 year
Secondary outcomes:
measure: Hematologic improvement
timeFrame: participants will be followed for until disease progression an expected average of 1 year
measure: Relapse free survival
timeFrame: An expected average of 2 year post last study dose
measure: Time to respond
timeFrame: participants will be followed for until disease progression an expected average of 1 year
measure: Change in transfusion requirements
timeFrame: participants will be followed for until disease progression an expected average of 1 year
measure: duration of response
timeFrame: participants will be followed for until disease progression an expected average of 1 year
measure: overall survival
timeFrame: An expected average of 2 year post last study dose
measure: Adverse events profile
timeFrame: participants will be monitored for adverse events throughout the treatment period and during follow up period
Other outcomes:
measure: exploratory translational biomarkers for antitumor effect
timeFrame: 30 days
Locations:
city: Glendale
country: United States
facility: Palo Verde Hematology Oncology
state: Arizona
city: Glendale
country: United States
facility: Arizona Center for Cancer Care
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic
state: Arizona
city: Tucson
country: United States
facility: Arizona Oncology Associates
state: Arizona
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center
state: California
city: Oceanside
country: United States
facility: North County Oncology
state: California
city: Rancho Mirage
country: United States
facility: Desert Hematology Oncology Medical Group
state: California
city: Stanford
country: United States
facility: Stanford Hospital and Clinics
state: California
city: West Hills
country: United States
facility: Wellness Oncology & Hematology
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Jacksonville
country: United States
facility: Cancer Specialists of North Florida
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Port St. Lucie
country: United States
facility: Hematology Oncology Associates of the Treasure Coast
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute
state: Florida
city: Winter Haven
country: United States
facility: Bond Clinic PA
state: Florida
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Springfield
country: United States
facility: Simmons Cancer Institute at Southern Illinois University
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Louisville
country: United States
facility: University of Louisville Hospital/James Graham Brown Cancer Center
state: Kentucky
city: New Orleans
country: United States
facility: Tulane Medical Center
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland, Greenebaum Cancer Center
state: Maryland
city: Worcester
country: United States
facility: University of Massachusetts Worcester
state: Massachusetts
city: Ann Arbor
country: United States
facility: St. Joseph Mercy Hospital
state: Michigan
city: Brick
country: United States
facility: New Jersey Hematology Oncology Associates
state: New Jersey
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: East Setauket
country: United States
facility: North Shore Hematology Oncology Associates
state: New York
city: Lake Success
country: United States
facility: Monter Cancer Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College - New York-Presbyterian Hospital
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center Research
state: Ohio
city: Cincinnati
country: United States
facility: Oncology Hematology Care, Inc.
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Sciences University
state: Oregon
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina, Hollings Cancer Center
state: South Carolina
city: Rock Hill
country: United States
facility: Carolina Blood and Cancer Care Associates, P.A.
state: South Carolina
city: Chattanooga
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Tyler
country: United States
facility: Tyler Hematology Oncology PA
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah, Huntsman Cancer Hospital
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University Massey Cancer Center
state: Virginia
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Woolloongabba
country: Australia
facility: Metro South Health, Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Malvern
country: Australia
facility: Cabrini Hospital
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred
state: Victoria
city: Wodonga
country: Australia
facility: Border Medical Oncology
state: Victoria
city: Nedlands
country: Australia
facility: Perth Blood Institute
state: Western Australia
city: Munchen
country: Germany
facility: Klinikum Rechts der Isar, Technischen Universitat Munchen
state: Bayern
city: Munich
country: Germany
facility: Klinikum der Ludwig-Maximilians-Universitat Munchen
state: Bayern
city: Dusseldorf
country: Germany
facility: Marien Hospital Dusseldorf
state: Nordrhein-Westfalen
city: Cologne
country: Germany
facility: University Hospital of Cologne
state: North Rhine Westphalia
city: Halle (Saale)
country: Germany
facility: University Hospital Halle
state: Saxony-Anhalt
city: Essen
country: Germany
facility: Universitatsklinikum Essen
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Medizinische Universitatsklinik Heidelberg
city: Wurzburg
country: Germany
facility: Universitatsklinikum Wurzburg
city: Leganes
country: Spain
facility: Hospital Universitario Severo Ochoa
state: Madrid
city: El Palmar
country: Spain
facility: Hospital Clinico Universitario Virgen de la Arrixaca
state: Murcia
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
state: Navarra
city: La Laguna
country: Spain
facility: Hospital Universitario de Canarias
state: S/C Tenerife
city: Badalona
country: Spain
facility: Hospital Germans Trias I Pujol
city: Cordoba
country: Spain
facility: Hospital University Reina Sofia
city: Madrid
country: Spain
facility: Hospital Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: MD Anderson Cancer Center
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Toledo
country: Spain
facility: Complejo Hospitalario Virgen de la Salud
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
Study officials:
References: