Clinical Trials /

Dose-escalation Study of Birinapant and Pembrolizumab in Solid Tumors

NCT02587962

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Terminated

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dose-escalation Study of Birinapant and Pembrolizumab in Solid Tumors
  • 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 IDs

  • ORG STUDY ID: BPT-201
  • SECONDARY ID: MK3475 KEYNOTE KN163
  • NCT ID: NCT02587962

Conditions

  • Solid Tumors

Interventions

DrugSynonymsArms
BirinapantBirinapant in combination with pembrolizumab
PembrolizumabKEYTRUDA, lambrolizumab, MK-3475, SCH 9000475Birinapant in combination with pembrolizumab

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Birinapant in combination with pembrolizumabExperimentalBirinapant in combination with pembrolizumab
  • Birinapant
  • Pembrolizumab

Eligibility 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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Secondary Outcome Measures

Measure:Tumor response evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Time Frame:Every 9 weeks; up to 2 yrs
Safety Issue:
Description:
Measure: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
Safety Issue:
Description: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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Medivir

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