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Dose-escalation Study of Birinapant and Pembrolizumab in Solid Tumors

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ClinicalTrials.gov Identifier: NCT02587962
Recruitment Status : Recruiting
First Posted : October 27, 2015
Last Update Posted : August 20, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Medivir

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.

Condition or disease Intervention/treatment Phase
Solid Tumors Drug: Birinapant Drug: Pembrolizumab Phase 1 Phase 2

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 135 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 4, 2017
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Birinapant in combination with pembrolizumab
Birinapant in combination with pembrolizumab
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




Primary Outcome Measures :
  1. 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

  2. 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


Secondary Outcome Measures :
  1. Tumor response evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: Every 9 weeks; up to 2 yrs ]
  2. 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


Other Outcome Measures:
  1. Assess tumor activity [ Time Frame: Every 9 weeks; up to 2 yrs ]
    Evaluated according to iRECIST

  2. 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

  3. 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

  4. Pharmacokinetics of birinapant in plasma [ Time Frame: Day 1 through Day 8 ]
    The plasma concentrations of birinapant will be measured and summarized descriptively



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02587962


Contacts
Contact: John Öhd +46854683100 Clinicaloperations@medivir.com
Contact: Cecilia Wadell +46854683100 cecilia.wadell@medivir.com

Locations
United States, California
Cedars-Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Contact: Monica Mita, MD         
United States, Florida
Mid Florida Hematology and Oncology Center Recruiting
Orange City, Florida, United States, 32763
Contact: Santosh Nair, MD         
United States, Maryland
The Sidney Kimmel Comprehensive Cancer Center at John Hopkins Recruiting
Baltimore, Maryland, United States, 21287
Contact: Dung Le, MD         
United States, Pennsylvania
Thomas Jefferson University Sidney Kimmel Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Schilder Russel, MD         
United States, Texas
Mary Crowley Cancer Research Recruiting
Dallas, Texas, United States, 75251
Contact: James Strauss, MD         
MD Anderson Cancer Center, The University of Texas Recruiting
Houston, Texas, United States, 77030
Contact: Siqing Fu, MD         
Sponsors and Collaborators
Medivir
Merck Sharp & Dohme Corp.

Responsible Party: Medivir
ClinicalTrials.gov Identifier: NCT02587962     History of Changes
Other Study ID Numbers: BPT-201
MK3475 KEYNOTE KN163 ( Other Identifier: Merck Sharp & Dohme Corp. )
First Posted: October 27, 2015    Key Record Dates
Last Update Posted: August 20, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Pembrolizumab
Antineoplastic Agents