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

Phase 1

Completed

• Conditions: Cancer
• Interventions: Drug: Birinapant

• Registration Number: NCT01188499
• Lead Sponsor: TetraLogic Pharmaceuticals

Brief Summary

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

Detailed Description

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.

Study Timeline

• Study First Submitted: 2010-08-23
• Study First Submitted QC: 2010-08-23
• Study First Posted: 2010-08-25
• Study Start: 2010-10
• Primary Completion: 2013-10
• Study Completion: 2014-03
• Status Verified: 2016-04
• Results First Submitted: 2016-04-21
• Results First Submitted QC: 2016-04-21
• Last Update Submitted: 2016-04-21
• Results First Posted: 2016-05-30
• Last Update Posted: 2016-05-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 176

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Carboplatin/Paclitaxel + Birinapant	Birinapant	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).
Docetaxel + Birinapant	Birinapant	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).
Gemcitabine + Birinapant	Birinapant	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).
Liposomal Doxorubicin + Birinapant	Birinapant	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).
Irinotecan + Birinapant	Birinapant	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).

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Evaluation of Pharmacokinetics and Translational Biomarkers	Cycle 1 and Cycle 2	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.
Evaluation of Anti-tumor Efficacy	Every 2 cycles	Tumor burden according to Response Evaluation Criteria in Solid Tumors (RECIST) and time to progression

Trial Locations

Locations (7)

Barbara Ann Karmanos Cancer Center; 🇺🇸 Detroit, Michigan, United States

Roswell Park Cancer Institute; 🇺🇸 Buffalo, New York, United States

Holy Cross Hospital; 🇺🇸 Fort Lauderdale, Florida, United States

University of Pennsylvania Abramson Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Mary Crowley Cancer Research Center; 🇺🇸 Dallas, Texas, United States

Fox Chase Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

South Texas Accelerated Research Therapeutics (START); 🇺🇸 San Antonio, Texas, United States