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

NCT02707666

Description:

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.

Related Conditions:
  • Malignant Pleural Mesothelioma
Recruiting Status:

Unknown status

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Pilot Window-Of-Opportunity Study of the Anti-PD-1 Antibody Pembrolizumab in Patients With Resectable Malignant Pleural Mesothelioma
  • Official Title: A Pilot Window-of-opportunity Study of the Anti-PD-1 Antibody Pembrolizumab in Patients With Resectable Malignant Pleural Mesothelioma

Clinical Trial IDs

  • ORG STUDY ID: IRB15-1149
  • NCT ID: NCT02707666

Conditions

  • Pleural Mesothelioma

Interventions

DrugSynonymsArms
PembrolizumabPembrolizumab+Surgery+Chemotherapy
Cisplatin and PemetrexedPembrolizumab+Surgery+Chemotherapy

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab+Surgery+ChemotherapyExperimentalNeoadjuvant pembrolizumab, followed by surgery, followed by adjuvant pemetrexed and cisplatin
  • Pembrolizumab
  • Cisplatin and Pemetrexed

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Determined using a CLIA Nanostring nCounter based profiling assay

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Chicago

Trial Keywords

  • resectable malignant pleural mesothelioma
  • Pembrolizumab

Last Updated

December 28, 2016