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A Pilot Window-Of-Opportunity Study of the Anti-PD-1 Antibody Pembrolizumab in Patients With Resectable Malignant Pleural Mesothelioma

Brief Summary

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 tissue. 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 via an extended/pleurectomy decortication 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 starting about 6-8 weeks following surgery, after a new baseline CT scan is obtained. Restaging CT scans will be obtained to assess response after every two cycles of chemotherapy. After the completion of standard chemotherapy, optional adjuvant treatment with pembrolizumab will be given to eligible patients for 1 year post-surgery.

Tracking Information
First Received DateFebruary 29, 2016
Last Changed DateDecember 28, 2016
Start DateFebruary 2016
Anticipated Primary Completion DateMarch 2018
Primary Outcome Measures

Gamma-Interferon Gene Expression profile (GEP) response rate defined as an increase beyond the median value of the sum of individual genes [Time Frame: 12 months after completion of treatment]

Number of participants with adverse events as measured by CTCAEv4.0 [Time Frame: 12 months after completion of treatment]

Descriptive Information
PhasePhase 1
Study TypeInterventional
Condition
  • Pleural Mesothelioma
Intervention
  • Drug: Pembrolizumab
  • Drug: Cisplatin and Pemetrexed
Study Arms / Comparison Groups1 / 0
Detailed Description

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.

Recruitment Information
Recruitment StatusRecruiting
Anticipated Enrollment15
GenderAll
Ages18 Years - N/A
Accepts Healthy VolunteersNo
Contact Mehwish Ahmad
Email: mahmad3@medicine.bsd.uchicago.edu
Phone: 773 834 1472
Eligibility Criteria

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.

Administrative Information
NCTIDNCT02707666
Responsible Party,
SponsorUniversity of Chicago
Verification DateDecember 2016
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