Clinical trial NCT02587962: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Solid Tumors
Lead sponsor: Medivir
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2015-10-27
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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 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)

Primary outcomes:
measure: Blood Pressure (Safety and Tolerability in the Dose Escalation Phase)
timeFrame: Baseline and up to 2 yrs (follow-up)
measure: Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Escalation Phase)
timeFrame: Baseline and up to 2 yrs (follow-up)
measure: Amylase and Lipase (Safety and Tolerability in the Dose Escalation Phase)
timeFrame: Baseline and up to 2 yrs (follow-up)
measure: Thyroxine Free (Safety and Tolerability in the Dose Escalation Phase)
timeFrame: Baseline and up to 2 yrs (follow-up)
measure: Thyrotropin (Safety and Tolerability in the Dose Escalation Phase)
timeFrame: Baseline and up to 2 yrs (follow-up)
measure: Hemoglobin (Safety and Tolerability in the Dose Escalation Phase)
timeFrame: Baseline and up to 2 yrs (follow-up)
measure: Physical Exam (Safety and Tolerability in the Dose Escalation Phase)
timeFrame: Baseline and up to 2 yrs (follow-up)
measure: Overall Response (Applicable for: Dose Escalation Phase and Dose Expansion Phase in Cohorts of Colorectal Cancer, Ovarian Cancer and Cervical Cancer)
timeFrame: Baseline and up to 2 yrs (follow-up)
Secondary outcomes:
measure: Tumor Response Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1:
timeFrame: Every 9 weeks; up to 2 yrs
measure: Blood Pressure (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)
timeFrame: Baseline and up to 2 yrs (follow-up)
measure: Electrocardiogram: QT Interval (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)
timeFrame: Baseline and up to 2 yrs (follow-up)
measure: Amylase and Lipase (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)
timeFrame: Baseline and up to 2 yrs (follow-up)
measure: Thyroxine Free (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)
timeFrame: Baseline and up to 2 yrs (follow-up)
measure: Thyrotropin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)
timeFrame: Baseline and up to 2 yrs (follow-up)
measure: Hemoglobin (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)
timeFrame: Baseline and up to 2 yrs (follow-up)
measure: Physical Exam (Safety and Tolerability in the Dose Expansion Phase - Colorectal Cancer Cohort)
timeFrame: Baseline and up to 2 yrs (follow-up)
Other outcomes:
measure: Assess Tumor Activity
timeFrame: Baseline and up to 2 yrs (follow-up)
measure: Translational Biomarker Assessments Obtained From Blood
timeFrame: Day 1 through Day 8
measure: Translational Biomarker Assessments of Tumor Biopsy Samples
timeFrame: Baseline and up to 2 yrs (follow-up)
measure: Pharmacokinetics of Birinapant in Plasma
timeFrame: Day 1 through Day 8
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Santa Monica
country: United States
facility: UCLA Dept of Medicine-Hematology/Oncology
state: California
city: Orange City
country: United States
facility: Mid Florida Hematology and Oncology Center
state: Florida
city: Baltimore
country: United States
facility: The Sidney Kimmel Comprehensive Cancer Center at John Hopkins
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Philadelphia
country: United States
facility: Thomas Jefferson University Sidney Kimmel Cancer Center
state: Pennsylvania
city: Dallas
country: United States
facility: Mary Crowley Cancer Research
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center, The University of Texas
state: Texas
Study officials:
References: