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.
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.
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)
