This is a single institution, single-arm, window of opportunity pilot trial of pembrolizumab
in patients with resectable malignant pleural mesothelioma. All patients will undergo a
pretreatment PET/CT scan for clinical staging and a VATS procedure to acquire pretreatment
Three cycles of pembrolizumab will then be administered (200 mg IV every 21 days). A PET/CT
scan will then be repeated to assess response to pembrolizumab and then surgical resection
will be performed at least 4 weeks after the third dose of pembrolizumab. Standard adjuvant
chemotherapy consisting of cisplatin and pemetrexed for 4 cycles (every 21 days) will be
given following surgery. After the completion of standard chemotherapy, optional adjuvant
treatment with pembrolizumab will be given to eligible patients for 1 year post-surgery.
- Histologically or cytologically confirmed pleural malignant mesothelioma, epithelial
or biphasic subtypes.
- Disease amenable to maximal surgical debulking via extended pleurectomy/decortication
as determined by a surgeon specializing in mesothelioma.
- No prior chemotherapy, targeted therapy, or immunotherapy for mesothelioma.
- Be willing and able to provide written informed consent for the trial.
- Be > or = to 18 years of age on day of signing informed consent.
- Have measurable or evaluable disease based on modified RECIST for mesothelioma (Byrne,
- Be willing to undergo a video assisted thoracoscopy surgery (VATS) to provide
diagnostic tissue (if not previously done and patient has adequate free pleural space
to allow for procedures).
- If VATS procedures has been previously done or patient does not have a free pleural
space to allow for a VATS procedure, then they must be able to undergo a CT or
ultrasound guided needle biopsy to obtain baseline tissue if it is feasible. If this
is not anatomically feasible, then they must be able to provide at least 15 unstained
slides or a tumor block from their prior biopsy.
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
- Have adequate cardiac function as assessed by echocardiogram, with an ejection
fraction > 45%
- Have adequate pulmonary function to tolerate surgery.Patients must have a predicted
postoperative diffusing capacity of the lung for carbon monoxide (ppoDLCO) > 35% of
predicted, and a predicted postoperative FEV1 (ppoFEV1) > 35% of predicted.
- Arterial blood gas predicted postoperative pCO2 < 50 mmHg
- Demonstrate adequate organ function as defined below.
- Absolute neutrophil count (ANC) ≥ 1,500 /mcL
- Platelets ≥ 100,000 / mcL
- Hemoglobin ≥ 9 g/dL
- 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
- Serum total bilirubin ≤ 1.5 X ULN
- AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN
- 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.
- Have no extrathoracic disease by best surgical staging.
- 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.
- 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. Subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year.
- 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.
- Is currently participating in a study of an investigational agent and received an
investigational agent within 4 weeks of the first dose of treatment.
- Has received any prior anticancer therapy for mesothelioma (no prior chemotherapy,
immunotherapy, or targeted therapy).
- 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
- Has a known history of active TB (Bacillus Tuberculosis)
- Hypersensitivity to pembrolizumab or any of its excipients.
- 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.
- Has known active central nervous system (CNS) metastases and/or carcinomatous
- 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.
- Has known history of, or any evidence of active, non-infectious pneumonitis that
required steroids or active pneumonitis
- Has evidence of interstitial lung disease
- Has an active infection requiring systemic therapy.
- 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 screening visit through 120 days
after the last dose of trial treatment.
- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
- Is on anticoagulation that cannot be discontinued in the perioperative stage.
- 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.