Primary Objectives
1. To determine the rate of induction of a Gamma-Interferon Gene Expression profile (GEP)
using a CLIA Nanostring nCounter based assay (performed in Merck's CLIA laboratory) in
patients with malignant pleural mesothelioma treated with pembrolizumab
2. To determine the safety and feasibility of neoadjuvant pembrolizumab in patients with
malignant pleural mesothelioma.
Exploratory Objectives
1. To determine 1-year progression-free survival (PFS) in patients treated with
pembrolizumab via a multimodality approach (including neoadjuvant pembrolizumab,
extended pleurectomy/decortication, adjuvant pemetrexed/cisplatin and if applicable
adjuvant pembrolizumab).
2. To determine the median overall survival (OS) for MM patients treated with
pembrolizumab via a multimodality approach (including neoadjuvant pembrolizumab,
extended pleurectomy/decortication, adjuvant pemetrexed/cisplatin and if applicable
adjuvant pembrolizumab).
3. To determine the 1-year PFS, disease free survival (DFS) and OS for PD-L1 positive or
TCIP-positive MM patients treated with a multimodality approach.
4. To determine safety of adjuvant pembrolizumab treatment after surgery and adjuvant
chemotherapy
5. To determine the objective response rate to single-agent pembrolizumab via PET/CT in
previously untreated MM patients, and to correlate this response with changes in the
immune microenvironment.
Inclusion Criteria:
1. Be willing and able to provide written informed consent for the trial.
2. Be > or = to 18 years of age on day of signing informed consent.
3. Have measurable or evaluable disease based on modified RECIST for mesothelioma
(Byrne, 2004).
4. Be willing to undergo a video assisted thoracoscopy surgery (VATS) to provide
diagnostic tissue.
5. Have a free pleural space to allow for a VATS procedure
6. Have a performance status of 0 or 1 on the ECOG Performance Scale
7. Have adequate cardiac function as assessed by echocardiogram, with an EF > 45%
8. Have adequate pulmonary function to tolerate surgery. Patients must have a diffusing
lung capacity for carbon monoxide (DLCO) >35% of predicted post-operative FEV1
(ppoFEV1)
9. Arterial blood gas predicted postoperative pCO2 < 50
10. Demonstrate adequate organ function as defined below, all screening labs should be
performed within 14 days of registration.
Adequate Organ Function Laboratory Values
HEMATOLOGICAL Absolute neutrophil count (ANC) ≥ 1,500 /mcL Platelets ≥ 100,000 / mcL
Hemoglobin ≥ 9 g/dL
RENAL Serum creatinine ≤ 1.5 X upper limit of normal (ULN) OR Measured or calculated
creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥ 60
mL/min for subject with creatinine levels > 1.5 X institutional ULN
HEPATIC Serum total bilirubin ≤ 1.5 X ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN
COAGULATION International Normalized Ratio (INR) or Prothrombin Time (PT) Activated
Partial Thromboplastin Time (aPTT) ≤ 1.5 X ULN. Patients on anticoagulation are
expected to hold anticoagulation for at least 5 days prior to surgery.
PULMONARY DLCO > 35% of ppoFEV1
CARDIAC TTE= EF > 45%
11. Have no extrathoracic disease by best surgical staging.
12. 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 serum pregnancy test
will be required.
13. Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the
course of the study through 120 days after the last dose of study medication
(Reference Section 5.8.2). Subjects of childbearing potential are those who have not
been surgically sterilized or have not been free from menses for > 1 year.
14. Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study
therapy.
Exclusion Criteria:
1. Is currently participating in a study of an investigational agent and received an
investigational agent within 4 weeks of the first dose of treatment.
2. Has received any prior anticancer therapy for mesothelioma (no prior chemotherapy,
immunotherapy, or targeted therapy).
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of
trial treatment during the neoadjuvant pembrolizumab and optional adjuvant
pembrolizumab stages.
4. Has a known history of active TB (Bacillus Tuberculosis)
5. Hypersensitivity to pembrolizumab or any of its excipients.
6. Has a known additional malignancy that is progressing or requires active treatment
within the past 3 years. Exceptions include basal cell carcinoma of the skin or
squamous cell carcinoma of the skin that has undergone potentially curative therapy
or in situ cervical cancer or other tumors that will not affect life expectancy.
7. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis.
8. Has active autoimmune disease that has required systemic treatment in the past 2
years (i.e. with use of disease modifying agents, corticosteroids (with higher than
physiologic doses) 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.
9. Has known history of, or any evidence of active, non-infectious pneumonitis.
10. Has an active infection requiring systemic therapy.
11. 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.
12. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
13. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit through 120 days
after the last dose of trial treatment.
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
16. Is on anticoagulation that cannot be discontinued in the perioperative stage.
17. 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.
