Dose-escalation Study of Birinapant and Pembrolizumab in Solid Tumors

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1/2 Multicenter, Single-Arm, Open-Label, Dose-Escalation Study of Birinapant in Combination With Pembrolizumab (KEYTRUDA®) in Patients With Relapsed or Refractory Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: Birinapant
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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). Exclusion Criteria: Exclusion criteria apply to all phases and cohorts in the study unless otherwise stated Prior monoclonal antibody, within 4 weeks prior to first dose of study drug. Prior chemotherapy, targeted small molecule therapy or radiotherapy within 2 weeks prior to first dose of study drug. Patients who have received any other investigational agents within 4 weeks of first dose of study drug. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-ligand 2(L2), anti-cluster of differentiation 137 (anti-CD137), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody. (Not applicable for various solid tumors cohort, head and neck squamous cell carcinoma check-point inhibitor experienced group) History of allergic reactions attributed to compounds of similar chemical or biologic composition to birinapant or pembrolizumab or their constituents. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, hypertension, unstable angina pectoris, cardiac arrhythmia, autoimmune disease or inflammatory diseases, or psychiatric illness/social situations that would limit compliance with study requirements. Evidence of active, non-infectious pneumonitis or a history of interstitial lung disease. Known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies), or Active Hepatitis B (HBsAg reactive). Patients with active Hepatitis C (HCV-RNA qualitative). Currently breast feeding, pregnant or planning to conceive or father Children from screening through 120 Days after last dose of study drug. Patients who have received anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) (Various solid tumor cohort, head and neck squamous cell carcinoma check point inhibitor experienced group only)

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Birinapant in combination with pembrolizumab<br>Birinapant in combination with pembrolizumab | Drug: Birinapant<br>* 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<br>Drug: Pembrolizumab<br>* 200 mg pembrolizumab IV on Day 1 of each 21-Day Cycle<br>* Other names: SCH 9000475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and up to 2 yrs (follow-up) | 
| 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. | Baseline and up to 2 yrs (follow-up) | 
| 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. | Baseline and up to 2 yrs (follow-up) | 
| 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. | Baseline and up to 2 yrs (follow-up) | 
| 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. | Baseline and up to 2 yrs (follow-up) | 
| 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. | Baseline and up to 2 yrs (follow-up) | 
| 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. | Baseline and up to 2 yrs (follow-up) | 
| 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. | Baseline and up to 2 yrs (follow-up) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Every 9 weeks; up to 2 yrs | 
| 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. | Baseline and up to 2 yrs (follow-up) | 
| 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. | Baseline and up to 2 yrs (follow-up) | 
| 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. | Baseline and up to 2 yrs (follow-up) | 
| 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. | Baseline and up to 2 yrs (follow-up) | 
| 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. | Baseline and up to 2 yrs (follow-up) | 
| 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. | Baseline and up to 2 yrs (follow-up) | 
| 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. | Baseline and up to 2 yrs (follow-up) |