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

Sponsor

TetraLogic Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT01828346

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Study Design

Study Type:

Interventional

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 :

Jun 1, 2013

Actual Primary Completion Date :

Jun 1, 2015

Actual Study Completion Date :

Nov 1, 2015

Arms and Interventions

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 Names: TL32711 Drug: 5-Azacitidine Dose Level (0) - 75mg/m2 daily Other Names: 5-AZA

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 Names:

TL32711

Drug: 5-Azacitidine

Dose Level (0) - 75mg/m2 daily

Other Names:

5-AZA

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose (MTD) [6 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Palo Verde Hematology Oncology	Glendale	Arizona	United States	85304
2	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259
3	California Cancer Associates for Research and Excellence	Fresno	California	United States	93720
4	Mayo Clinic Jacksonville	Jacksonville	Florida	United States	32224
5	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
6	University of Pennsylvania, Abramson Cancer Center	Philadelphia	Pennsylvania	United States	19104
7	The University of Texas M.D. Anderson Cancer Center	Houston	Texas	United States	77030