Dose Escalation, Combination Chemotherapy Safety Study of Birinapant (TL32711), in Subjects With Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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This is a dose escalation safety study of birinapant (TL32711) in combination with chemotherapy in subjects with advanced or metastatic solid tumors.

Detailed Description
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The purpose of this study is to determine the safety and maximum tolerated dose of birinapant (TL32711) as a 30 minute intravenous infusion once a week, for 2 consecutive weeks, when combined with standard regimens of chemotherapy in subjects with advanced or metastatic solid tumors. Additionally the study will assess anti-tumor activity, pharmacokinetics, and exploratory biomarkers as a measurement of pharmacodynamic effects.

Official Title
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A Phase 1B/2A, Open-label, Non-randomized, Multi-arm Study of TL32711 in Combination With Chemotherapy in Subjects With Advanced or Metastatic Solid Tumors

Conditions
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Cancer

Intervention / Treatment
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* Drug: Birinapant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed advanced or metastatic malignancy for which the proposed chemotherapy regimen is appropriate in the judgment of the Investigator. Prior therapy in dose-escalation and expansion cohorts: Dose-escalation cohorts: Subjects may be naïve or may have received prior therapy with the specific chemotherapeutic agent(s) being recommended in the combination arm, provided the subject did not experience life-threatening toxicity attributed to the specific agent(s). Expansion cohorts: Subjects have advanced colorectal cancer that had been previously determined to be KRAS mutant. Subjects naïve to irinotecan may be enrolled, and the KRAS mutation status may be wild type or mutant. Subjects previously treated with an irinotecan containing regimen may be enrolled only if they have been previously determined to be KRAS wild type. The irinotecan regimen must not have been associated with life threatening adverse events. Subjects evaluated for Arm 5 (liposomal doxorubicin) may not have received >300 mg/m2 cumulative dose of anthracycline. Life expectancy >3 months. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. Adequate renal function Adequate hepatic function Adequate bone marrow function Women of childbearing potential must have a negative serum pregnancy test. Women of childbearing potential must agree to use 2 methods of adequate contraception (ie, hormonal and barrier method) prior to enrollment, during the study, and for a period of 30 days following the last dose of TL32711. Males who are sexually active must agree to use a condom during the study and for a period of 30 days following the last dose of TL32711, and if their partner is of childbearing potential, she must agree to use a secondary method of contraception (ie, hormonal, intrauterine device, barrier) during the study and for a period of 30 days following the last dose of TL32711. Exclusion Criteria: Recent anti-cancer treatment defined as: Standard or investigational anti-cancer therapy within 4 weeks prior to first dose of TL32711. Exception: continued hormonal interventions for prostate cancer. Radiation therapy within 2 weeks prior to the first dose of TL32711. Major surgery within 4 weeks prior to the first dose of TL32711. Subjects must be well recovered from acute effects of surgery prior to enrollment. Known or suspected diagnosis of human immunodeficiency virus or chronic active Hepatitis B or C. Symptomatic or uncontrolled brain metastases requiring current treatment. Impaired cardiac function or clinically significant cardiac disease QT interval corrected for heart rate (QTcB) >480 msec (including subjects on medication). Lack of recovery of prior adverse events to Grade ≤1 severity (NCI CTCAE v4) (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 TL32711. Any concurrent disease and/or medical condition that in the opinion of the Investigator that would prevent the subject's participation, render the subject at excessive risk (including excessive risks due to the toxicity profile of the planned combination chemotherapeutic regimen), or limit the subject's compliance with the protocol's required evaluations.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carboplatin/Paclitaxel + Birinapant<br>Carboplatin (AUC 6/Paclitaxel (175 mg/m2/IV) once every 3 (q3) weeks + birinapant (TL32711) once weekly (7 days +/- 2 days) for 2 consecutive weeks followed by 1 week off for each cycle (3 weeks per cycle). | Drug: Birinapant<br> <br> * Other names: TL32711;|
| Experimental: Irinotecan + Birinapant<br>Irinotecan (350 mg/m2/IV) once every 3 (q3) weeks + birinapant (TL32711) once weekly (7 days +/- 2 days) for 2 consecutive weeks followed by 1 week off for each cycle (3 weeks per cycle). | Drug: Birinapant<br> <br> * Other names: TL32711;|
| Experimental: Docetaxel + Birinapant<br>Docetaxel (75 mg/m2/IV) once every 3 (q3) weeks + birinapant (TL32711) once weekly (7 days +/- 2 days) for 2 consecutive weeks followed by 1 week off for each cycle (3 weeks per cycle). | Drug: Birinapant<br> <br> * Other names: TL32711;|
| Experimental: Gemcitabine + Birinapant<br>Gemcitabine (1000 mg/m2/IV) once weekly (7 days +/- 2 days) for 3 consecutive weeks followed by 1 week off + birinapant (TL32711) once weekly (7 days +/- 2 days) for 2 consecutive weeks followed by 2 week off for each cycle (4 weeks per cycle). | Drug: Birinapant<br> <br> * Other names: TL32711;|
| Experimental: Liposomal Doxorubicin + Birinapant<br>Liposomal doxorubicin (40 mg/m2/IV) every 4 weeks + birinapant (TL32711) once weekly (7 days +/- 2 days) for 2 consecutive weeks followed by 2 weeks off for each cycle (4 weeks per cycle). | Drug: Birinapant<br> <br> * Other names: TL32711;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Adverse Events as a Measure of Safety and Tolerability | Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms (ECGs), safety and laboratory parameters | 1 Cycle (3-4 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of Anti-tumor Efficacy | Tumor burden according to Response Evaluation Criteria in Solid Tumors (RECIST) and time to progression | Every 2 cycles | 
| Evaluation of Pharmacokinetics and Translational Biomarkers | Measurement of TL32711 pharmacokinetics: Maximum plasma concentration (Cmax), area under the curve (AUC), half-life (t1/2) and assessment of translational biomarkers in plasma, PBMC's and tumor biopsies. Gene expression profiling of tumor tissue. | Cycle 1 and Cycle 2 |