Dose-escalation Study of Birinapant and Pembrolizumab in Solid Tumors

NCT02587962 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: BPT-201MK3475 KEYNOTE KN163
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 9

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.

Conditions

Solid Tumors

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (8)

• Tumor Response Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1:

  Every 9 weeks; up to 2 yrs

• Blood Pressure (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)

  Baseline and up to 2 yrs (follow-up)

• Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)

  Baseline and up to 2 yrs (follow-up)

• Amylase and Lipase (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)

  Baseline and up to 2 yrs (follow-up)

• Thyroxine Free (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)

  Baseline and up to 2 yrs (follow-up)

Other Outcomes (4)

• Assess Tumor Activity

  Baseline and up to 2 yrs (follow-up)

• Translational Biomarker Assessments Obtained From Blood

  Day 1 through Day 8

• Translational Biomarker Assessments of Tumor Biopsy Samples

  Baseline and up to 2 yrs (follow-up)

Study Arms (1)

Birinapant in combination with pembrolizumab

EXPERIMENTAL

Birinapant in combination with pembrolizumab

Drug: Birinapant; Drug: Pembrolizumab

Interventions

Birinapant DRUG

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

Birinapant in combination with pembrolizumab

Pembrolizumab DRUG

200 mg pembrolizumab IV on Day 1 of each 21-Day Cycle

Also known as: KEYTRUDA, lambrolizumab, MK-3475, SCH 9000475

Birinapant in combination with pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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).

You may not qualify if:

• 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)

Sponsors & Collaborators

• Medivir: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (9)

Banner MD Anderson Cancer Center

Gilbert, Arizona, 85234, United States

Location

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

UCLA Dept of Medicine-Hematology/Oncology

Santa Monica, California, 90404, United States

Location

Mid Florida Hematology and Oncology Center

Orange City, Florida, 32763, United States

Location

The Sidney Kimmel Comprehensive Cancer Center at John Hopkins

Baltimore, Maryland, 21287, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Thomas Jefferson University Sidney Kimmel Cancer Center

Philadelphia, Pennsylvania, 19107, United States

Location

Mary Crowley Cancer Research

Dallas, Texas, 75251, United States

Location

MD Anderson Cancer Center, The University of Texas

Houston, Texas, 77030, United States

Location

MeSH Terms

Interventions

birinapant; pembrolizumab

Limitations and Caveats

The dose escalation (Phase 1) part was analyzed per the protocol. Based on data from the interim analysis of the colorectal cancer cohort (dose expansion \[Phase 2\] part), the study was closed early due to futility on recommendation by the data monitoring committee (DMC).

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Medivir AB

info@medivir.com

+46854683100

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 21, 2015
• First Posted: October 27, 2015
• Study Start: August 4, 2017
• Primary Completion: February 17, 2020
• Study Completion: February 17, 2020
• Last Updated: January 14, 2021
• Results First Posted: January 14, 2021

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)