A Phase I-II Open Label Non-Randomized Study Using TL32711 for Patients With Acute Myelogenous Leukemia, Myelodysplastic Syndrome and Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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This was initially a phase I/II, open-label non-randomized study using an investigational new drug, TL32711, in patients with AML, MDS and ALL, however, the phase II portion was never initiated. This study initially targeted subjects 60 years of age and older (with non-M3 AML who have relapsed or refractory disease after standard therapy or who are newly diagnosed and subjects 18-59 (relapsed or refractory after failing 3 prior lines of therapy), and then targeted subjects 18 years of age and older with MDS and ALL.

Detailed Description
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This was initially a phase I/II, open-label, non-randomized study using an investigational new drug, TL 32711, in patients with acute myelogenous leukemia. This study targeted subjects 60 years of age and older (with non-M3 AML who have relapsed or refractory disease after standard therapy or who are newly diagnosed and not candidates for standard induction therapy) and subjects 18-59 (relapsed or refractory after failing 3 prior lines of therapy). Subjects would receive the study drug in 4 weeks dosing periods via one of three different treatment schedules (once weekly, twice weekly or three times weekly dosing). They would receive treatment for up to 6 cycles, however treatment may have been extended at the discretion of the study doctor if felt to be in the best interest of the subject. Up to 46 subjects were to be enrolled on this study at the University of Pennsylvania, depending on the number of subjects needed in the Phase I component in order to determine the MTD. The primary objective of the Phase 1 component was to determine the safety and tolerability of TL32711, and the MTD in this patient population. The primary objective of the Phase 2 portion of this study was to further define the safety and tolerability, and provide preliminary efficacy data, however, the Phase II portion was never initiated.

Official Title
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A Phase I-II Open Label Non-Randomized Study Using TL32711 for Patients With Acute Myelogenous Leukemia, Myelodysplastic Syndrome and Acute Lymphoblastic Leukemia

Conditions
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Acute Myelogenous Leukemia

Intervention / Treatment
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* Drug: Birinapant


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Subjects with a diagnosis of non-M3 AML, Relapsed or refractory ALL or Intermediate Risk 2 or High Risk disease MDS as follows: Subjects with a diagnosis of non-M3 AML which meets one of the following criteria: Ages 60 or older: Relapsed or refractory after at least one prior therapy for AML Ages 60 or older: Newly diagnosed in a patient with a preceding history of myelodysplastic syndrome which has been treated with azacitidine or decitabine and who are not appropriate candidates for aggressive therapy including induction followed by allogeneic stem cell transplantation Ages 18-59: Relapsed or refractory disease after failing three prior lines of therapy Subjects with a diagnosis of relapsed or refractory ALL: must have failed three prior lines of therapy and be 18 years of age or older. Subjects with a diagnosis of Intermediate Risk 2 or High Risk disease (as defined by IPSS score): Must have failed to respond/intolerant to, or progressed after a hypomethylating agent, and must not be candidates for allogeneic stem cell transplantation Life expectancy of at least 4 weeks Must have recovered from toxic effects of prior chemotherapy Patients must be able to sign consent and be willing and able to comply with scheduled visits, treatment plan and laboratory testing. Exclusion criteria Cytotoxic chemotherapy (including azacitidine or decitabine) within the past 28 days other than hydroxyurea Active participation in any other investigational treatment study for AML. ECOG performance status greater than 2 Uncontrolled intercurrent illness including, but not limited to: uncontrolled ongoing infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. QT interval corrected for heart rate (QTcB) greater than 480 msec (including subjects on medication). Subjects with a ventricular pacemaker for whom QT interval is not measurable may be eligible for enrollment after consultation with the drug manufacturer and study Medical Monitor, and written documentation of this approval. Female subjects who are pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 DL1<br>26mg/m2/dose IV once per week x 3 weeks of 4 week cycle | Drug: Birinapant<br>* IV formulation to be given weekly 3 weeks out of 4 week cycle or 4 weeks our of a 4 week cycle as a 30 minute infusion<br>* Other names: TL37211;|
| Experimental: Phase 1 DL-1<br>17mg/m2 IV/dose once per week x 3 weeks of 4 week cycle | Drug: Birinapant<br>* IV formulation to be given weekly 3 weeks out of 4 week cycle or 4 weeks our of a 4 week cycle as a 30 minute infusion<br>* Other names: TL37211;|
| Experimental: Phase 1 DL-1a<br>17mg/m2/dose IV twice per week x 3 weeks of 4 week cycle | Drug: Birinapant<br>* IV formulation to be given weekly 3 weeks out of 4 week cycle or 4 weeks our of a 4 week cycle as a 30 minute infusion<br>* Other names: TL37211;|
| Experimental: Phase 1 DL-1b<br>17mg/m2/dose IV three times per week x 3 weeks of 4 week cycle | Drug: Birinapant<br>* IV formulation to be given weekly 3 weeks out of 4 week cycle or 4 weeks our of a 4 week cycle as a 30 minute infusion<br>* Other names: TL37211;|
| Experimental: Phase 1 DL-1c<br>22mg/m2/dose IV twice per week x 3 weeks of 4 week cycle | Drug: Birinapant<br>* IV formulation to be given weekly 3 weeks out of 4 week cycle or 4 weeks our of a 4 week cycle as a 30 minute infusion<br>* Other names: TL37211;|
| Experimental: Phase 1 DL-1d<br>17mg/m2/dose IV twice per week x 3 weeks of 4 week cycle | Drug: Birinapant<br>* IV formulation to be given weekly 3 weeks out of 4 week cycle or 4 weeks our of a 4 week cycle as a 30 minute infusion<br>* Other names: TL37211;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Safety of Birinapant (TL32711) in Subjects With Acute Myeloid Leukemia, Myelodysplastic Syndromes and Acute Lymphoblastic Leukemia. Acute Lymphocytic Leukemia. | Safety of birinapant will be measured as the number of adverse events per dosing level occurring with greater than 5% frequency in the total evaluable subject population. Adverse events are any untoward medical occurrences experienced by research study participants. These events are documented and assessed for severity and relation to the study drug by the treating investigator, using the Common Terminology for Criteria for Adverse Events for severity, and information on known side effects of the study drug for relation. | First day of study treatment to 30 days after last study treatment. The average length of time for adverse event monitoring was 14 weeks. | 
| Number of Dose Limiting Toxicities Per Dosing Level. | This outcome measure will be defined as the number of dose limiting toxicities per dosing level. Dose limiting toxicities are pre-defined medical events that may be related to the dosing of the study drug. These toxicities are documented and assessed for severity based on pre-defined thresholds, and may result in modification of the study drug dosing. | First day of study treatment to 30 days after last study treatment. The average length of time for adverse event monitoring was 14 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, equal to or greater than age 60 years, non-M3 AML, relapsed disease, primary refractory disease, not appropriate or willing candidates for aggressive therapy