Clinical trial NCT01828346: Birinapant With 5-azacitidine in MDS Subjects Who Are Naïve, Have Relapsed or Are Refractory to 5-azacitidine Therapy
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Myelodysplastic Syndrome
Keywords: TL32711
Birinapant
5-Azacitidine
Myelodysplastic syndrome
MDS
Relapsed
Refractory
Failed
open-label
non-Randomized
dose-escalation
dose-expansion
Lead sponsor: TetraLogic Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2013-04-10
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Maximum tolerated dose (MTD)
timeFrame: 6 months
Secondary outcomes:
Other outcomes:
Locations:
city: Glendale
country: United States
facility: Palo Verde Hematology Oncology
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic Scottsdale
state: Arizona
city: Fresno
country: United States
facility: California Cancer Associates for Research and Excellence
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania, Abramson Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: The University of Texas M.D. Anderson Cancer Center
state: Texas
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Gautam Borthakur, MD
role: PRINCIPAL_INVESTIGATOR
References: