The research study procedures include screening for eligibility and study treatment including
evaluations and follow up visits.
The names of the study drugs involved in this study are:
The Investigators are looking for the highest dose of the study drug that can be administered
safely without severe or unmanageable side effects in participants that have Malignant
Pleural Mesothelioma (MPM), not everyone who participates in this research study will receive
the same dose of the study drug. The dose given will depend on the number of participants who
have been enrolled prior and how well the dose was tolerated.
The dose of the study drug, pembrolizumab, will not change no matter when the participant is
enrolled into the study.
The order in which the participant is enrolled to the study will determine the cohort
- Run-In Cohort: Pembrolizumab only followed by surgery
- Cohort 1: Pembrolizumab and defactinib followed by surgery
- Cohort 2: Pembrolizumab and defactinib followed by surgery
- Expansion Cohort: Pembrolizumab and defactinib at the maximum dose as determined from
the previous cohorts (Cohorts 1 and 2)
- The U.S. Food and Drug Administration (FDA) has not approved defactinib as a treatment
for any disease.
- The U.S. Food and Drug Administration (FDA) has not approved pembrolizumab for this
specific disease but it has been approved for other uses.
- Participant must have histologically confirmed malignant pleural mesothelioma that is
not metastatic or unresectable
- Be willing and able to provide written informed consent/assent to the trial.
- Be ≥ 18 years of age on day of signing informed consent.
- Have measurable disease based on modified RECIST 1.1.
- Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days)
prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples
cannot be provided (e.g. inaccessible or subject safety concern) may submit an
archived specimen only upon agreement from the Investigator Sponsor.
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Evaluation of ECOG is to be performed within 7 days prior to the date of
- Demonstrate adequate organ function as defined. If screening hematology and clinical
chemistry tests are performed within 10 days of Day 1, they need not be repeated at
- Adequate Organ Function Laboratory Values
- Absolute neutrophil count (ANC) ≥1,500 /mcL
- Platelets ≥100,000 / mcL
- Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (>2 days
- Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be
used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
- Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with
total bilirubin levels > 1.5 ULN
- AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver
- International Normalized Ratio (INR) or Prothrombin Time (PT)-Activated Partial
Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant
therapy as long as PT or PTT is within therapeutic range of intended use of
≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT
is within therapeutic range of intended use of anticoagulants
- Creatinine clearance should be calculated per institutional standard.
- Female subjects of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a negative serum
pregnancy test will be required.
- Female and male subjects of childbearing potential must be willing to use an adequate
method of contraception
- Contraception, for the course of the study through 120 days after the last dose
of study medication.
- Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
- The subject must be excluded from participating in the trial if the subject:
- Is currently participating or has participated in a study of an investigational agent
and received study therapy or used an investigational device within 4 weeks of the
first dose of treatment.
- Has a diagnosis of immunodeficiency including diagnosis of infection with Human
Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) or is receiving systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to the
first dose of trial treatment.
- Hypersensitivity to pembrolizumab or any of its excipients.
- Hypersensitivity to defactinib.
- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
due to monoclonal antibody administered more than 4 weeks earlier.
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to a previously administered treatment.
- Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
may qualify for the study.
- Note: If subject underwent major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include in situ cervical cancer and basal cell carcinoma of the skin or
squamous cell carcinoma of the skin that has undergone potentially curative therapy.
- History of upper gastrointestinal bleeding, ulceration, or perforation within 12
months prior to the first dose of study drug.
- Known history of Gilbert's Syndrome or any current hyperbilirubinemia of any cause.
- Known history of stroke or cerebrovascular accident within 6 months prior to the first
dose of study drug.
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis, or has previously treated brain metastases.
- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
- Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis. Has an active infection requiring systemic therapy.
- Has a known history of active TB (Bacillus Tuberculosis)
- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
- Has received a live vaccine within 30 days of planned start of study therapy.
-- Note: Seasonal influenza vaccines for injection are generally inactivated flu
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are
live attenuated vaccines, and are not allowed.
- Has a known history of myocarditis