Cancer
Conditions
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.
Interventions
DRUGBirinapant
Sponsors
TetraLogic Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Anti-tumor Efficacy | Every 2 cycles | Tumor burden according to Response Evaluation Criteria in Solid Tumors (RECIST) and time to progression |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Carboplatin/Paclitaxel + Birinapant Carboplatin (AUC 6/Paclitaxel (175 mg/m2/IV) once every 3 (q3) weeks + TL32711 once weekly (7 days +/- 2 days) for 2 consecutive weeks followed by 1 week off for each cycle (3 weeks per cycle).
TL32711: 30 minute intravenous (IV) infusion of TL32711 administered once weekly for two consecutive weeks followed by one week off repeated every 3 weeks as tolerated in combination with chemotherapy | 24 |
| Arm 2: Irinotecan + Birinapant Irinotecan (350 mg/m2/IV) once every 3 (q3) weeks + TL32711 once weekly (7 days +/- 2 days) for 2 consecutive weeks followed by 1 week off for each cycle (3 weeks per cycle).
TL32711: 30 minute intravenous (IV) infusion of TL32711 administered once weekly for two consecutive weeks followed by one week off repeated every 3 weeks as tolerated in combination with chemotherapy | 83 |
| Arm 3: Docetaxel + Birinapant Docetaxel (75 mg/m2/IV) once every 3 (q3) weeks + TL32711 once weekly (7 days +/- 2 days) for 2 consecutive weeks followed by 1 week off for each cycle (3 weeks per cycle).
TL32711: 30 minute intravenous (IV) infusion of TL32711 administered once weekly for two consecutive weeks followed by one week off repeated every 3 weeks as tolerated in combination with chemotherapy | 33 |
| Arm 4: Gemcitabine + Birinapant Gemcitabine (1000 mg/m2/IV) once weekly (7 days +/- 2 days) for 3 consecutive weeks followed by 1 week off + TL32711 once weekly (7 days +/- 2 days) for 2 consecutive weeks followed by 2 week off for each cycle (4 weeks per cycle).
TL32711: 30 minute intravenous (IV) infusion of TL32711 administered once weekly for two consecutive weeks followed by two weeks off repeated every 4 weeks as tolerated in combination with chemotherapy. | 18 |
| Arm 5: Liposomal Doxorubicin + Birinapant Liposomal doxorubicin (40 mg/m2/IV) every 4 weeks + TL32711 once weekly (7 days +/- 2 days) for 2 consecutive weeks followed by 2 weeks off for each cycle (4 weeks per cycle).
TL32711: 30 minute intravenous (IV) infusion of TL32711 administered once weekly for two consecutive weeks followed by two weeks off repeated every 4 weeks as tolerated in combination with chemotherapy. | 18 |
| Total | 176 |
Baseline characteristics
| Characteristic | Arm 1: Carboplatin/Paclitaxel + Birinapant | Total | Arm 5: Liposomal Doxorubicin + Birinapant | Arm 4: Gemcitabine + Birinapant | Arm 3: Docetaxel + Birinapant | Arm 2: Irinotecan + Birinapant |
|---|---|---|---|---|---|---|
| Age, Continuous | 63 years STANDARD_DEVIATION 8.77 | 59.7 years STANDARD_DEVIATION 10.82 | 56.5 years STANDARD_DEVIATION 10.44 | 56.7 years STANDARD_DEVIATION 8.55 | 60.7 years STANDARD_DEVIATION 11.16 | 59.6 years STANDARD_DEVIATION 11.58 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 8 Participants | 2 Participants | 2 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 168 Participants | 16 Participants | 16 Participants | 32 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 23 Participants | 3 Participants | 3 Participants | 3 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 22 Participants | 151 Participants | 13 Participants | 15 Participants | 30 Participants | 71 Participants |
| Region of Enrollment United States | 24 participants | 176 participants | 18 participants | 18 participants | 33 participants | 83 participants |
| Sex: Female, Male Female | 13 Participants | 91 Participants | 13 Participants | 11 Participants | 15 Participants | 39 Participants |
| Sex: Female, Male Male | 11 Participants | 85 Participants | 5 Participants | 7 Participants | 18 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 24 / 24 | 83 / 83 | 33 / 33 | 18 / 18 | 18 / 18 |
| serious Total, serious adverse events | 9 / 24 | 41 / 83 | 16 / 33 | 13 / 18 | 9 / 18 |
Outcome results
Primary
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
Time frame: 1 Cycle (3-4 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Carboplatin/Paclitaxel + TL32711 | Number of Subjects With Adverse Events as a Measure of Safety and Tolerability | 24 participants |
| Arm 2: Irinotecan + TL32711 | Number of Subjects With Adverse Events as a Measure of Safety and Tolerability | 83 participants |
| Arm 3: Docetaxel + TL32711 | Number of Subjects With Adverse Events as a Measure of Safety and Tolerability | 33 participants |
| Arm 4: Gemcitabine + TL32711 | Number of Subjects With Adverse Events as a Measure of Safety and Tolerability | 18 participants |
| Arm 5: Liposomal Doxorubicin | Number of Subjects With Adverse Events as a Measure of Safety and Tolerability | 18 participants |
Secondary
Evaluation of Anti-tumor Efficacy
Tumor burden according to Response Evaluation Criteria in Solid Tumors (RECIST) and time to progression
Time frame: Every 2 cycles
Population: Intent-to-treat (ITT)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Carboplatin/Paclitaxel + TL32711 | Evaluation of Anti-tumor Efficacy | 5 participants |
| Arm 2: Irinotecan + TL32711 | Evaluation of Anti-tumor Efficacy | 8 participants |
| Arm 3: Docetaxel + TL32711 | Evaluation of Anti-tumor Efficacy | 3 participants |
| Arm 4: Gemcitabine + TL32711 | Evaluation of Anti-tumor Efficacy | 2 participants |
| Arm 5: Liposomal Doxorubicin | Evaluation of Anti-tumor Efficacy | 0 participants |
Secondary
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.
Time frame: Cycle 1 and Cycle 2