Solid Tumors
Conditions
Brief summary
An ascending dose study in patients with solid tumors to evaluate the safety, tolerability, pharmacodynamics and efficacy of birinapant when given in combination with pembrolizumab. A dose expansion phase of 4 cohorts will also be included.
Detailed description
This study will be conducted in two phases. The Phase 1 portion of the study will employ a sequential group dose-escalation design to determine the dose-limiting toxicity (DLT) and recommended Phase 2 dose (RP2D) of birinapant administered in combination with 200 mg pembrolizumab, both administered as a 30-minute intravenous (IV) infusion. The following proposed doses of birinapant are to be evaluated: 5.6, 11, 17, and 22 mg/m2. The Phase 2 portion, the dose expansion phase, will compromise 4 cohorts of 26-30 patients. The 4 cohorts will include the following: * Colorectal cancer * Ovarian Cancer * Cervical cancer * Various solid tumors (30 patients, including 5 patients with each of the following 6 tumor types: Head and Neck Squamous Cell Carcinoma (HNSCC)-checkpoint-inhibitor naïve; and HNSCC checkpoint-inhibitor experienced; Gastroesophageal carcinoma; Mesothelioma; Small cell lung cancer (SCLC); Cholangiocarcinoma A Simon's 2-stage design will be used for each of the cohorts in colorectal cancer, ovarian cancer and cervical cancer. A predefined interim analysis allowing stopping each of these cohorts for futility and safety will be conducted in the first stage to limit undue exposure before further inclusion into a given cohort. The design of the various solid tumors cohort will limit undue exposure in any of the selected tumor types by limiting the number of enrolled patient to five in each tumor type.
Interventions
DRUGBirinapant
Birinapant intravenous (IV) on Days 1 and 8 of each 21-Day Cycle. The following escalating doses of birinapant to be studied: 5.6, 11, 17, and 22 mg/m2. In the expansion phase the assigned recommended phase two dose will be administered in all cohorts
DRUGPembrolizumab
200 mg pembrolizumab IV on Day 1 of each 21-Day Cycle
Sponsors
Merck Sharp & Dohme LLC
Medivir
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed solid malignancy that is metastatic or unresectable for which standard curative or palliative measures do not exist or are no longer effective (Dose Escalation phase only) * Measurable disease according to response evaluation criteria in solid tumors (RECIST) v 1.1 * Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 * Normal organ and marrow function Dose Expansion phase specific additional inclusion criteria: * Patients with metastatic colorectal cancer with no available therapy options that are known to provide clinical benefit per institutional standard of care (colorectal cancer cohort only) * Patients must have a histologically confirmed epithelial ovarian cancer, primary peritoneal cancer or fallopian tube solid tumor cancer that is locally advanced or metastatic with no available therapy options that are known to provide clinical benefit per institutional standard of care (ovarian cancer cohort only) * Patients must have histologically or cytologically confirmed cervical squamous cell carcinoma that is locally advanced or metastatic with no available therapy options that are known to provide clinical benefit per institutional standard of care (cervical cancer cohort only) * Patients must have histologically or cytologically confirmed head and neck squamous cell carcinoma that is locally advanced or metastatic with no available therapy options that are known to provide clinical benefit per institutional standard of care. (various solid tumors cohort: head and neck squamous cell carcinoma groups only). * Patients must have received prior therapy with an anti-programmed death protein (PD-1) or anti-PD-ligand 1(L1) antibody, or previously participated in Merck MK 3475 clinical trials. Patients must have experienced documented, confirmed radiographic progression of disease by immune RECIST (iRECIST), or by RECIST v1.1 (various solid tumors cohort head and neck squamous cell carcinoma, Check point inhibitor experienced group only). * Patients must have histologically or cytologically confirmed small cell lung carcinoma (SCLC) that is locally advanced or metastatic with no available therapy options that are known to provide clinical benefit per institutional standard of care (various solid tumors cohort, SCLC group only). * Patients must have histologically or cytologically confirmed cholangiocarcinoma that is locally advanced or metastatic with no available therapy options that are known to provide clinical benefit per institutional standard of care (various solid tumors cohort, cholangiocarcinoma group only). * Patients must have histologically or cytologically confirmed mesothelioma that is locally advanced or metastatic with no available therapy options that are known to provide clinical benefit per institutional standard of care (various solid tumors cohort, mesothelioma group only). * Patients must have histologically or cytologically confirmed carcinoma of the esophagus including the gastroesophageal junction that is locally advanced or metastatic with no available therapy options that are known to provide clinical benefit per institutional standard of care (various solid tumors cohort, gastroesophageal carcinoma group only).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Physical Exam (Safety and Tolerability in the Dose Escalation Phase) | Baseline and up to 2 yrs (follow-up) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through physical exam. |
| Hemoglobin (Safety and Tolerability in the Dose Escalation Phase) | Baseline and up to 2 yrs (follow-up) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through hemoglobin. |
| Thyrotropin (Safety and Tolerability in the Dose Escalation Phase) | Baseline and up to 2 yrs (follow-up) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through Thyrotropin. |
| Overall Response (Applicable for: Dose Escalation Phase and Dose Expansion Phase in Cohorts of Colorectal Cancer, Ovarian Cancer and Cervical Cancer) | Baseline and up to 2 yrs (follow-up) | Evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. A responder was a patient who showed best overall response of complete response (CR, disappearance of all target lesions) or partial response (PR, ≥30% decrease in the sum of the longest diameter of target lesions), which was confirmed again at least 4 weeks after the initial assessment. |
| Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Baseline and up to 2 yrs (follow-up) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through blood pressure. |
| Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Escalation Phase) | Baseline and up to 2 yrs (follow-up) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through electrocardiogram. |
| Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Baseline and up to 2 yrs (follow-up) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through amylase and lipase. |
| Thyroxine Free (Safety and Tolerability in the Dose Escalation Phase) | Baseline and up to 2 yrs (follow-up) | Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through thyroxine free. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hemoglobin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Baseline and up to 2 yrs (follow-up) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through hemoglobin. |
| Tumor Response Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1: | Every 9 weeks; up to 2 yrs | Analysis of progression-free survival (PFS); time to progression, where progressive disease (PD) corresponds to ≥20% increase in the sum of the longest diameter of target lesions. |
| Blood Pressure (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Baseline and up to 2 yrs (follow-up) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through blood pressure. |
| Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Baseline and up to 2 yrs (follow-up) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through electrocardiogram. |
| Amylase and Lipase (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Baseline and up to 2 yrs (follow-up) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through amylase and lipase. |
| Thyroxine Free (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Baseline and up to 2 yrs (follow-up) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through thyroxine free. |
| Thyrotropin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Baseline and up to 2 yrs (follow-up) | Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through thyrotropin. |
| Physical Exam (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Baseline and up to 2 yrs (follow-up) | Evaluation of the safety and tolerability of the RP2D of birinapant when given in combination with pembrolizumab assessed through physical exam. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Assess Tumor Activity | Baseline and up to 2 yrs (follow-up) | To be evaluated according to immune response evaluation criteria in solid tumors (iRECIST) |
| Pharmacokinetics of Birinapant in Plasma | Day 1 through Day 8 | The plasma concentrations of birinapant was to be measured and summarized descriptively |
| Translational Biomarker Assessments of Tumor Biopsy Samples | Baseline and up to 2 yrs (follow-up) | Measured by: Programmed death ligand 1 (PD-1L), programmed cell death protein 1 receptor (PD-1) and related proteins, genome analysis, IAP gene copy number and TILs cluster of differentiation (CD)3, CD4, CD8 and CD19 |
| Translational Biomarker Assessments Obtained From Blood | Day 1 through Day 8 | Measured by inhibitor of apoptosis proteins (IAPs), cytokines, tumor infiltrating lymphocytes (TILs) cluster of differentiation (CD)3, CD4, CD8, and CD19 as well as absolute neutrophil and lymphocyte counts |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 - 5.6 mg Dose escalation (Phase 1): 5.6 mg birinapant + pembrolizumab | 3 |
| Phase 1 - 11 mg Dose escalation (Phase 1): 11 mg birinapant + pembrolizumab | 3 |
| Phase 1 - 17 mg Dose escalation (Phase 1): 17 mg birinapant + pembrolizumab | 6 |
| Phase 1 - 22 mg Dose escalation (Phase 1): 22 mg birinapant + pembrolizumab | 7 |
| Phase 2 - 22 mg Dose expansion (Phase 2): 22 mg birinapant + pembrolizumab | 15 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Clinical progression | 0 | 1 | 2 | 0 | 1 |
| Overall Study | Radiological progression | 2 | 2 | 2 | 5 | 10 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 | 4 |
Baseline characteristics
| Characteristic | Phase 1 - 5.6 mg | Phase 1 - 11 mg | Phase 1 - 17 mg | Phase 1 - 22 mg | Phase 2 - 22 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 16.09 | 71.3 years STANDARD_DEVIATION 3.21 | 60.2 years STANDARD_DEVIATION 6.15 | 59.1 years STANDARD_DEVIATION 11.61 | 53.8 years STANDARD_DEVIATION 10.43 | 60.08 years STANDARD_DEVIATION 9.5 |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants | 6 Participants | 12 Participants | 30 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment United States | 3 participants | 3 participants | 6 participants | 7 participants | 15 participants | 34 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 5 Participants | 4 Participants | 10 Participants | 23 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 5 Participants | 11 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 | 0 / 3 | 0 / 3 | 1 / 6 | 0 / 7 | 1 / 15 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 6 / 6 | 7 / 7 | 15 / 15 |
| serious Total, serious adverse events | 2 / 3 | 1 / 3 | 4 / 6 | 3 / 7 | 5 / 15 |
Outcome results
Primary
Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase)
Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through amylase and lipase.
Time frame: Baseline and up to 2 yrs (follow-up)
Population: As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - 5.6 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Amylase at baseline | 33.7 U/L | Standard Deviation 32.5 |
| Phase 1 - 5.6 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Amylase at follow-up | 27.0 U/L | — |
| Phase 1 - 5.6 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Lipase at baseline | 17.0 U/L | Standard Deviation 12.2 |
| Phase 1 - 5.6 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Lipase at follow-up | 12.0 U/L | — |
| Phase 1 - 11 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Amylase at follow-up | 49.0 U/L | Standard Deviation 41 |
| Phase 1 - 11 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Lipase at baseline | 24.0 U/L | Standard Deviation 21 |
| Phase 1 - 11 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Lipase at follow-up | 15.5 U/L | Standard Deviation 10.6 |
| Phase 1 - 11 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Amylase at baseline | 38.3 U/L | Standard Deviation 9 |
| Phase 1 - 17 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Lipase at baseline | 32.2 U/L | Standard Deviation 21.4 |
| Phase 1 - 17 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Amylase at follow-up | 56.5 U/L | Standard Deviation 38.9 |
| Phase 1 - 17 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Lipase at follow-up | 16.0 U/L | Standard Deviation 2.8 |
| Phase 1 - 17 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Amylase at baseline | 64.3 U/L | Standard Deviation 8 |
| Phase 1 - 22 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Lipase at follow-up | 18.0 U/L | — |
| Phase 1 - 22 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Amylase at follow-up | 60.0 U/L | — |
| Phase 1 - 22 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Amylase at baseline | 40.6 U/L | Standard Deviation 27.4 |
| Phase 1 - 22 mg | Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase) | Lipase at baseline | 49.9 U/L | Standard Deviation 63.3 |
Primary
Blood Pressure (Safety and Tolerability in the Dose Escalation Phase)
Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through blood pressure.
Time frame: Baseline and up to 2 yrs (follow-up)
Population: As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - 5.6 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Diastolic blood pressure at follow-up | 84.0 mmHg | — |
| Phase 1 - 5.6 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Systolic blood pressure at baseline | 137.3 mmHg | Standard Deviation 18.6 |
| Phase 1 - 5.6 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Diastolic blood pressure at baseline | 78.0 mmHg | Standard Deviation 2 |
| Phase 1 - 5.6 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Systolic blood pressure at follow-up | 120.0 mmHg | — |
| Phase 1 - 11 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Diastolic blood pressure at baseline | 77.0 mmHg | Standard Deviation 15.5 |
| Phase 1 - 11 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Diastolic blood pressure at follow-up | 66.0 mmHg | Standard Deviation 8.5 |
| Phase 1 - 11 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Systolic blood pressure at follow-up | 107.0 mmHg | Standard Deviation 1.4 |
| Phase 1 - 11 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Systolic blood pressure at baseline | 143.3 mmHg | Standard Deviation 14.5 |
| Phase 1 - 17 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Diastolic blood pressure at baseline | 74.3 mmHg | Standard Deviation 9.3 |
| Phase 1 - 17 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Systolic blood pressure at follow-up | 119.7 mmHg | Standard Deviation 30.2 |
| Phase 1 - 17 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Systolic blood pressure at baseline | 134.0 mmHg | Standard Deviation 22.1 |
| Phase 1 - 17 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Diastolic blood pressure at follow-up | 71.3 mmHg | Standard Deviation 11.4 |
| Phase 1 - 22 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Systolic blood pressure at baseline | 118.6 mmHg | Standard Deviation 11.4 |
| Phase 1 - 22 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Diastolic blood pressure at follow-up | 75.0 mmHg | — |
| Phase 1 - 22 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Systolic blood pressure at follow-up | 120.0 mmHg | — |
| Phase 1 - 22 mg | Blood Pressure (Safety and Tolerability in the Dose Escalation Phase) | Diastolic blood pressure at baseline | 66.6 mmHg | Standard Deviation 7.9 |
Primary
Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Escalation Phase)
Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through electrocardiogram.
Time frame: Baseline and up to 2 yrs (follow-up)
Population: As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - 5.6 mg | Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Escalation Phase) | Electrocardiogram QT interval at baseline | 368.7 ms | Standard Deviation 30.6 |
| Phase 1 - 5.6 mg | Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Escalation Phase) | Electrocardiogram QT interval at follow-up | 392.0 ms | — |
| Phase 1 - 11 mg | Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Escalation Phase) | Electrocardiogram QT interval at baseline | 388.3 ms | Standard Deviation 11.2 |
| Phase 1 - 17 mg | Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Escalation Phase) | Electrocardiogram QT interval at follow-up | 380.0 ms | — |
| Phase 1 - 17 mg | Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Escalation Phase) | Electrocardiogram QT interval at baseline | 386.3 ms | Standard Deviation 32.9 |
| Phase 1 - 22 mg | Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Escalation Phase) | Electrocardiogram QT interval at baseline | 365.9 ms | Standard Deviation 32.7 |
| Phase 1 - 22 mg | Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Escalation Phase) | Electrocardiogram QT interval at follow-up | 364.0 ms | — |
Primary
Hemoglobin (Safety and Tolerability in the Dose Escalation Phase)
Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through hemoglobin.
Time frame: Baseline and up to 2 yrs (follow-up)
Population: As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - 5.6 mg | Hemoglobin (Safety and Tolerability in the Dose Escalation Phase) | Hemoglobin at baseline | 110.3 g/L | Standard Deviation 20.2 |
| Phase 1 - 5.6 mg | Hemoglobin (Safety and Tolerability in the Dose Escalation Phase) | Hemoglobin at follow-up | 89.0 g/L | — |
| Phase 1 - 11 mg | Hemoglobin (Safety and Tolerability in the Dose Escalation Phase) | Hemoglobin at baseline | 107.3 g/L | Standard Deviation 8.6 |
| Phase 1 - 11 mg | Hemoglobin (Safety and Tolerability in the Dose Escalation Phase) | Hemoglobin at follow-up | 107.0 g/L | Standard Deviation 14.1 |
| Phase 1 - 17 mg | Hemoglobin (Safety and Tolerability in the Dose Escalation Phase) | Hemoglobin at baseline | 112.0 g/L | Standard Deviation 11.8 |
| Phase 1 - 17 mg | Hemoglobin (Safety and Tolerability in the Dose Escalation Phase) | Hemoglobin at follow-up | 116.0 g/L | Standard Deviation 19.8 |
| Phase 1 - 22 mg | Hemoglobin (Safety and Tolerability in the Dose Escalation Phase) | Hemoglobin at baseline | 102.0 g/L | Standard Deviation 16 |
| Phase 1 - 22 mg | Hemoglobin (Safety and Tolerability in the Dose Escalation Phase) | Hemoglobin at follow-up | 99.0 g/L | — |
Primary
Overall Response (Applicable for: Dose Escalation Phase and Dose Expansion Phase in Cohorts of Colorectal Cancer, Ovarian Cancer and Cervical Cancer)
Evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. A responder was a patient who showed best overall response of complete response (CR, disappearance of all target lesions) or partial response (PR, ≥30% decrease in the sum of the longest diameter of target lesions), which was confirmed again at least 4 weeks after the initial assessment.
Time frame: Baseline and up to 2 yrs (follow-up)
Population: For phase 2, only the colorectal cancer (CRC) cohort was analyzed for overall response rate. Patients were not recruited to the ovarian cancer or cervical cancer cohorts due to early termination of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 - 5.6 mg | Overall Response (Applicable for: Dose Escalation Phase and Dose Expansion Phase in Cohorts of Colorectal Cancer, Ovarian Cancer and Cervical Cancer) | 1 Participants |
| Phase 1 - 11 mg | Overall Response (Applicable for: Dose Escalation Phase and Dose Expansion Phase in Cohorts of Colorectal Cancer, Ovarian Cancer and Cervical Cancer) | 0 Participants |
| Phase 1 - 17 mg | Overall Response (Applicable for: Dose Escalation Phase and Dose Expansion Phase in Cohorts of Colorectal Cancer, Ovarian Cancer and Cervical Cancer) | 0 Participants |
| Phase 1 - 22 mg | Overall Response (Applicable for: Dose Escalation Phase and Dose Expansion Phase in Cohorts of Colorectal Cancer, Ovarian Cancer and Cervical Cancer) | 0 Participants |
| Phase 2 CRC - 22 mg | Overall Response (Applicable for: Dose Escalation Phase and Dose Expansion Phase in Cohorts of Colorectal Cancer, Ovarian Cancer and Cervical Cancer) | 0 Participants |
Primary
Physical Exam (Safety and Tolerability in the Dose Escalation Phase)
Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through physical exam.
Time frame: Baseline and up to 2 yrs (follow-up)
Population: As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1 - 5.6 mg | Physical Exam (Safety and Tolerability in the Dose Escalation Phase) | Clinically significant physical exam abnormalities - baseline | 0 Participants |
| Phase 1 - 5.6 mg | Physical Exam (Safety and Tolerability in the Dose Escalation Phase) | Clinically significant physical exam abnormalities - last assessment | 0 Participants |
| Phase 1 - 11 mg | Physical Exam (Safety and Tolerability in the Dose Escalation Phase) | Clinically significant physical exam abnormalities - last assessment | 1 Participants |
| Phase 1 - 11 mg | Physical Exam (Safety and Tolerability in the Dose Escalation Phase) | Clinically significant physical exam abnormalities - baseline | 0 Participants |
| Phase 1 - 17 mg | Physical Exam (Safety and Tolerability in the Dose Escalation Phase) | Clinically significant physical exam abnormalities - baseline | 3 Participants |
| Phase 1 - 17 mg | Physical Exam (Safety and Tolerability in the Dose Escalation Phase) | Clinically significant physical exam abnormalities - last assessment | 3 Participants |
| Phase 1 - 22 mg | Physical Exam (Safety and Tolerability in the Dose Escalation Phase) | Clinically significant physical exam abnormalities - baseline | 0 Participants |
| Phase 1 - 22 mg | Physical Exam (Safety and Tolerability in the Dose Escalation Phase) | Clinically significant physical exam abnormalities - last assessment | 0 Participants |
Primary
Thyrotropin (Safety and Tolerability in the Dose Escalation Phase)
Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through Thyrotropin.
Time frame: Baseline and up to 2 yrs (follow-up)
Population: As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - 5.6 mg | Thyrotropin (Safety and Tolerability in the Dose Escalation Phase) | Thyrotropin at baseline | 3.8 mU/L | Standard Deviation 3.2 |
| Phase 1 - 5.6 mg | Thyrotropin (Safety and Tolerability in the Dose Escalation Phase) | Thyrotropin at last assessment | 14.2 mU/L | Standard Deviation 18.7 |
| Phase 1 - 11 mg | Thyrotropin (Safety and Tolerability in the Dose Escalation Phase) | Thyrotropin at last assessment | 7.7 mU/L | Standard Deviation 4 |
| Phase 1 - 11 mg | Thyrotropin (Safety and Tolerability in the Dose Escalation Phase) | Thyrotropin at baseline | 2.4 mU/L | Standard Deviation 0.9 |
| Phase 1 - 17 mg | Thyrotropin (Safety and Tolerability in the Dose Escalation Phase) | Thyrotropin at baseline | 1.7 mU/L | Standard Deviation 0.8 |
| Phase 1 - 17 mg | Thyrotropin (Safety and Tolerability in the Dose Escalation Phase) | Thyrotropin at last assessment | 2.3 mU/L | Standard Deviation 1.3 |
| Phase 1 - 22 mg | Thyrotropin (Safety and Tolerability in the Dose Escalation Phase) | Thyrotropin at baseline | 1.4 mU/L | Standard Deviation 0.9 |
| Phase 1 - 22 mg | Thyrotropin (Safety and Tolerability in the Dose Escalation Phase) | Thyrotropin at last assessment | 2.6 mU/L | Standard Deviation 2.1 |
Primary
Thyroxine Free (Safety and Tolerability in the Dose Escalation Phase)
Evaluation of the safety and tolerability of birinapant when given in combination with pembrolizumab assessed through thyroxine free.
Time frame: Baseline and up to 2 yrs (follow-up)
Population: As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - 5.6 mg | Thyroxine Free (Safety and Tolerability in the Dose Escalation Phase) | Thyroxine free at last assessment | 25.2 nmol/L | Standard Deviation 8 |
| Phase 1 - 5.6 mg | Thyroxine Free (Safety and Tolerability in the Dose Escalation Phase) | Thyroxine free at baseline | 16.8 nmol/L | Standard Deviation 5 |
| Phase 1 - 11 mg | Thyroxine Free (Safety and Tolerability in the Dose Escalation Phase) | Thyroxine free at baseline | 15.0 nmol/L | Standard Deviation 3 |
| Phase 1 - 11 mg | Thyroxine Free (Safety and Tolerability in the Dose Escalation Phase) | Thyroxine free at last assessment | 16.7 nmol/L | Standard Deviation 5.4 |
| Phase 1 - 17 mg | Thyroxine Free (Safety and Tolerability in the Dose Escalation Phase) | Thyroxine free at last assessment | 16.9 nmol/L | Standard Deviation 4.1 |
| Phase 1 - 17 mg | Thyroxine Free (Safety and Tolerability in the Dose Escalation Phase) | Thyroxine free at baseline | 15.0 nmol/L | Standard Deviation 3.3 |
| Phase 1 - 22 mg | Thyroxine Free (Safety and Tolerability in the Dose Escalation Phase) | Thyroxine free at last assessment | 16.5 nmol/L | Standard Deviation 3.6 |
| Phase 1 - 22 mg | Thyroxine Free (Safety and Tolerability in the Dose Escalation Phase) | Thyroxine free at baseline | 18.7 nmol/L | Standard Deviation 1.6 |
Secondary
Amylase and Lipase (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)
Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through amylase and lipase.
Time frame: Baseline and up to 2 yrs (follow-up)
Population: As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - 5.6 mg | Amylase and Lipase (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Amylase at baseline | 68.9 U/L | Standard Deviation 22.5 |
| Phase 1 - 5.6 mg | Amylase and Lipase (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Amylase at follow-up | 93.0 U/L | Standard Deviation 35.4 |
| Phase 1 - 5.6 mg | Amylase and Lipase (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Lipase at follow-up | 29.7 U/L | Standard Deviation 16.6 |
| Phase 1 - 5.6 mg | Amylase and Lipase (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Lipase at baseline | 44.3 U/L | Standard Deviation 41.1 |
Secondary
Blood Pressure (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)
Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through blood pressure.
Time frame: Baseline and up to 2 yrs (follow-up)
Population: As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - 5.6 mg | Blood Pressure (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Systolic blood pressure at baseline | 130.9 mmHg | Standard Deviation 20.3 |
| Phase 1 - 5.6 mg | Blood Pressure (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Systolic blood pressure at follow-up | 129.3 mmHg | Standard Deviation 16.6 |
| Phase 1 - 5.6 mg | Blood Pressure (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Diastolic blood pressure at baseline | 80.0 mmHg | Standard Deviation 8 |
| Phase 1 - 5.6 mg | Blood Pressure (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Diastolic blood pressure at follow-up | 74.4 mmHg | Standard Deviation 12.2 |
Secondary
Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)
Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through electrocardiogram.
Time frame: Baseline and up to 2 yrs (follow-up)
Population: As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - 5.6 mg | Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Electrocardiogram QT interval at baseline | 383.5 ms | Standard Deviation 25.6 |
| Phase 1 - 5.6 mg | Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Electrocardiogram QT interval at follow-up | 392.6 ms | Standard Deviation 38.7 |
Secondary
Hemoglobin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)
Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through hemoglobin.
Time frame: Baseline and up to 2 yrs (follow-up)
Population: As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - 5.6 mg | Hemoglobin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Hemoglobin at baseline | 126.4 g/L | Standard Deviation 15.4 |
| Phase 1 - 5.6 mg | Hemoglobin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Hemoglobin at follow-up | 130.2 g/L | Standard Deviation 13.2 |
Secondary
Physical Exam (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)
Evaluation of the safety and tolerability of the RP2D of birinapant when given in combination with pembrolizumab assessed through physical exam.
Time frame: Baseline and up to 2 yrs (follow-up)
Population: As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1 - 5.6 mg | Physical Exam (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Clinically significant physical exam abnormalities - last assessment | 2 Participants |
| Phase 1 - 5.6 mg | Physical Exam (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Clinically significant physical exam abnormalities - baseline | 0 Participants |
Secondary
Thyrotropin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)
Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through thyrotropin.
Time frame: Baseline and up to 2 yrs (follow-up)
Population: As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - 5.6 mg | Thyrotropin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Thyrotropin at baseline | 2.3 mU/L | Standard Deviation 1.3 |
| Phase 1 - 5.6 mg | Thyrotropin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Thyrotropin at last assessment | 9.8 mU/L | Standard Deviation 23.5 |
Secondary
Thyroxine Free (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)
Evaluation of the safety and tolerability of birinapant at the recommended phase 2 dose (RP2D) when given in combination with pembrolizumab assessed through thyroxine free.
Time frame: Baseline and up to 2 yrs (follow-up)
Population: As the population of participants were very ill, assessments outside clinical praxis were sometimes not performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1 - 5.6 mg | Thyroxine Free (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Thyroxine free at baseline | 14.7 nmol/L | Standard Deviation 3.1 |
| Phase 1 - 5.6 mg | Thyroxine Free (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort) | Thyroxine free at last assessment | 16.4 nmol/L | Standard Deviation 4.4 |
Secondary
Tumor Response Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1:
Analysis of progression-free survival (PFS); time to progression, where progressive disease (PD) corresponds to ≥20% increase in the sum of the longest diameter of target lesions.
Time frame: Every 9 weeks; up to 2 yrs
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1 - 5.6 mg | Tumor Response Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1: | 15.4 Weeks |
| Phase 1 - 11 mg | Tumor Response Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1: | 7.7 Weeks |
| Phase 1 - 17 mg | Tumor Response Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1: | 8.6 Weeks |
| Phase 1 - 22 mg | Tumor Response Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1: | 8.0 Weeks |
| Phase 2 CRC - 22 mg | Tumor Response Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1: | 9.0 Weeks |
Other Pre-specified
Assess Tumor Activity
To be evaluated according to immune response evaluation criteria in solid tumors (iRECIST)
Time frame: Baseline and up to 2 yrs (follow-up)
Population: Tumor activity according to iRECIST was not analyzed due to early termination of the study.
Other Pre-specified
Pharmacokinetics of Birinapant in Plasma
The plasma concentrations of birinapant was to be measured and summarized descriptively
Time frame: Day 1 through Day 8
Population: Birinapant pharmacokinetics was not analyzed due to early termination of the study.
Other Pre-specified
Translational Biomarker Assessments Obtained From Blood
Measured by inhibitor of apoptosis proteins (IAPs), cytokines, tumor infiltrating lymphocytes (TILs) cluster of differentiation (CD)3, CD4, CD8, and CD19 as well as absolute neutrophil and lymphocyte counts
Time frame: Day 1 through Day 8
Population: Biomarkers in blood were not analyzed due to early termination of the study.
Other Pre-specified
Translational Biomarker Assessments of Tumor Biopsy Samples
Measured by: Programmed death ligand 1 (PD-1L), programmed cell death protein 1 receptor (PD-1) and related proteins, genome analysis, IAP gene copy number and TILs cluster of differentiation (CD)3, CD4, CD8 and CD19
Time frame: Baseline and up to 2 yrs (follow-up)
Population: Biomarkers in tumor biopsy samples were not analyzed due to early termination of the study.