Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Dose-escalation Study of Birinapant and Pembrolizumab in Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02587962
Recruitment Status : Terminated (Based on the outcome of a futility analysis on the MSS CRC cohort, the DMC recommended to suspend enrollment in the study based on the absence of responders.)
First Posted : October 27, 2015
Last Update Posted : March 4, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Medivir

Tracking Information
First Submitted Date  ICMJE October 21, 2015
First Posted Date  ICMJE October 27, 2015
Last Update Posted Date March 4, 2020
Actual Study Start Date  ICMJE August 4, 2017
Actual Primary Completion Date February 17, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 5, 2018)
  • Incidence of Treatment-Emergent Adverse Events (safety and tolerability) (Applicable for: Dose Escalation phase and cohort of various solid tumor types in the Dose Expansion phase) [ Time Frame: Participants monitored throughout treatment period and during follow-up; up to 2 yrs ]
    Evaluation of the safety and tolerability of the RP2D of birinapant when given in combination with pembrolizumab will be assessed through adverse events (AEs), vital signs, electrocardiograms (ECG), physical exam and changes in clinical laboratory parameters
  • Overall Response (Applicable for: Dose Expansion phase in cohorts of Colorectal Cancer, Ovarian Cancer and Cervical Cancer) [ Time Frame: Every 9 weeks; up to 2 yrs ]
    Evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Original Primary Outcome Measures  ICMJE
 (submitted: October 23, 2015)
Incidence of Treatment-Emergent Adverse Events (safety and tolerability) [ Time Frame: Participants monitored throughout treatment period and during follow-up; up to 2 yrs ]
Evaluation of the safety and tolerability of the RP2D of birinapant when given in combination with pembrolizumab will be assessed through adverse events (AEs), vital signs, electrocardiograms (ECG), physical exam and changes in clinical laboratory parameters
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 5, 2018)
  • Tumor response evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: Every 9 weeks; up to 2 yrs ]
  • Incidence of Treatment-Emergent Adverse Events (safety and tolerability) (Applicable for: Dose Expansion phase in cohorts of Colorectal Cancer, Ovarian Cancer and Cervical Cancer) [ Time Frame: Participants monitored throughout treatment period and during follow-up; up to 2 yrs ]
    Evaluation of the safety and tolerability of the RP2D of birinapant when given in combination with pembrolizumab will be assessed through adverse events (AEs), vital signs, electrocardiograms (ECG), physical exam and changes in clinical laboratory parameters
Original Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2015)
  • Tumor response evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: Every 9 weeks; up to 2 yrs ]
  • Translational biomarker assessments obtained from blood [ Time Frame: Day 1 through Day 8 ]
    Measured by inhibitor of apoptosis proteins [IAPs], cytokines, tumor infiltrating lymphocytes (TILs) CD3, CD4, CD8, and CD19 as well as absolute neutrophil and lymphocyte counts
  • Translational biomarker assessments of tumor biopsy samples [ Time Frame: Up to 2 yrs ]
    Measured by: PD-L1, PD-1 and related proteins, genome analysis, IAP gene copy number and TILs CD3, CD4, CD8 and CD19
Current Other Pre-specified Outcome Measures
 (submitted: August 29, 2017)
  • Assess tumor activity [ Time Frame: Every 9 weeks; up to 2 yrs ]
    Evaluated according to iRECIST
  • Translational biomarker assessments obtained from blood [ Time Frame: Day 1 through Day 8 ]
    Measured by inhibitor of apoptosis proteins [IAPs], cytokines, tumor infiltrating lymphocytes (TILs) CD3, CD4, CD8, and CD19 as well as absolute neutrophil and lymphocyte counts
  • Translational biomarker assessments of tumor biopsy samples [ Time Frame: Up to 2 yrs ]
    Measured by: PD-L1, PD-1 and related proteins, genome analysis, IAP gene copy number and TILs CD3, CD4, CD8 and CD19
  • Pharmacokinetics of birinapant in plasma [ Time Frame: Day 1 through Day 8 ]
    The plasma concentrations of birinapant will be measured and summarized descriptively
Original Other Pre-specified Outcome Measures
 (submitted: October 23, 2015)
Assess tumor activity [ Time Frame: Every 9 weeks; up to 2 yrs ]
Evaluated according to Immune-related RECIST (irRECIST)
 
Descriptive Information
Brief Title  ICMJE Dose-escalation Study of Birinapant and Pembrolizumab in Solid Tumors
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Solid Tumors
Intervention  ICMJE
  • Drug: Birinapant
    Birinapant 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
  • Drug: Pembrolizumab
    200 mg pembrolizumab IV on Day 1 of each 21-Day Cycle
    Other Names:
    • KEYTRUDA
    • lambrolizumab
    • MK-3475
    • SCH 9000475
Study Arms  ICMJE Experimental: Birinapant in combination with pembrolizumab
Birinapant in combination with pembrolizumab
Interventions:
  • Drug: Birinapant
  • Drug: Pembrolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: March 2, 2020)
42
Original Estimated Enrollment  ICMJE
 (submitted: October 23, 2015)
104
Actual Study Completion Date  ICMJE February 17, 2020
Actual Primary Completion Date February 17, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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-PD-1 or anti-PD-L1 antibody, or previously participated in Merck MK 3475 clinical trials. Patients must have experienced documented, confirmed radiographic progression of disease by 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 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-L2, 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. 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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02587962
Other Study ID Numbers  ICMJE BPT-201
MK3475 KEYNOTE KN163 ( Other Identifier: Merck Sharp & Dohme Corp. )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Medivir
Study Sponsor  ICMJE Medivir
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE Not Provided
PRS Account Medivir
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP