Dose-escalation Study of Birinapant and Pembrolizumab in Solid Tumors

Solid Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02587962
• Other study ID #: BPT-201
• Secondary ID: MK3475 KEYNOTE K
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: August 4, 2017
• Est. completion date: February 17, 2020

Study information

• Verified date: December 2020
• Source: Medivir
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 34
• Est. completion date: February 17, 2020
• Est. primary completion date: February 17, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumors

Intervention

Drug:
• Birinapant
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
• Pembrolizumab
200 mg pembrolizumab IV on Day 1 of each 21-Day Cycle

Locations

Country	Name	City	State
United States	The Sidney Kimmel Comprehensive Cancer Center at John Hopkins	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Mary Crowley Cancer Research	Dallas	Texas
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	MD Anderson Cancer Center, The University of Texas	Houston	Texas
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Mid Florida Hematology and Oncology Center	Orange City	Florida
United States	Thomas Jefferson University Sidney Kimmel Cancer Center	Philadelphia	Pennsylvania
United States	UCLA Dept of Medicine-Hematology/Oncology	Santa Monica	California

Sponsors (2)

Lead Sponsor	Collaborator
Medivir	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Assess Tumor Activity	To be evaluated according to immune response evaluation criteria in solid tumors (iRECIST)	Baseline and up to 2 yrs (follow-up)
Other	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	Day 1 through Day 8
Other	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	Baseline and up to 2 yrs (follow-up)
Other	Pharmacokinetics of Birinapant in Plasma	The plasma concentrations of birinapant was to be measured and summarized descriptively	Day 1 through Day 8
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.	Baseline and up to 2 yrs (follow-up)
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.	Baseline and up to 2 yrs (follow-up)
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.	Baseline and up to 2 yrs (follow-up)
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.	Baseline and up to 2 yrs (follow-up)
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.	Baseline and up to 2 yrs (follow-up)
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.	Baseline and up to 2 yrs (follow-up)
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.	Baseline and up to 2 yrs (follow-up)
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.	Baseline and up to 2 yrs (follow-up)
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.	Every 9 weeks; up to 2 yrs
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.	Baseline and up to 2 yrs (follow-up)
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.	Baseline and up to 2 yrs (follow-up)
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.	Baseline and up to 2 yrs (follow-up)
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.	Baseline and up to 2 yrs (follow-up)
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.	Baseline and up to 2 yrs (follow-up)
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.	Baseline and up to 2 yrs (follow-up)
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.	Baseline and up to 2 yrs (follow-up)