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

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ClinicalTrials.gov Identifier: NCT02707666
Recruitment Status : Recruiting
First Posted : March 14, 2016
Last Update Posted : January 4, 2018
Sponsor:
Information provided by (Responsible Party):
University of Chicago

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.

Condition or disease Intervention/treatment Phase
Pleural Mesothelioma Drug: Pembrolizumab Drug: Cisplatin and Pemetrexed Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Window-of-opportunity Study of the Anti-PD-1 Antibody Pembrolizumab in Patients With Resectable Malignant Pleural Mesothelioma
Study Start Date : February 2016
Estimated Primary Completion Date : March 2018
Estimated Study Completion Date : September 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Mesothelioma

Arm Intervention/treatment
Experimental: Pembrolizumab+Surgery+Chemotherapy
Neoadjuvant pembrolizumab, followed by surgery, followed by adjuvant pemetrexed and cisplatin
Drug: Pembrolizumab
Neoadjuvant pembrolizumab every 21 days for three cycles

Drug: Cisplatin and Pemetrexed
Adjuvant chemotherapy with cisplatin and pemetrexed every 21 days for 4 cycles




Primary Outcome Measures :
  1. 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 ]
    Determined using a CLIA Nanostring nCounter based profiling assay

  2. Number of participants with adverse events as measured by CTCAEv4.0 [ Time Frame: 12 months after completion of treatment ]
    Adverse events will be summarized by type, grade, and relationship to the study drug.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02707666


Contacts
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Contact: Mehwish Ahmad 773 834 1472 mahmad3@medicine.bsd.uchicago.edu
Contact: Buerkley Rose, RN 773 834 4002 brose@medicine.bsd.uchicago.edu

Locations
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United States, Illinois
University of Chicago Recruiting
Chicago, Illinois, United States, 60637
Contact: Mehwish Ahmad    773-834-1472    mahmad3@medicine.bsd.uchicago.edu   
Contact: Buerkley Rose, RN    773 834 4002    brose@medicine.bsd.uchicago.edu   
Principal Investigator: Hedy Kindler, M.D.         
Sponsors and Collaborators
University of Chicago

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Responsible Party: University of Chicago
ClinicalTrials.gov Identifier: NCT02707666     History of Changes
Other Study ID Numbers: IRB15-1149
First Posted: March 14, 2016    Key Record Dates
Last Update Posted: January 4, 2018
Last Verified: January 2018
Keywords provided by University of Chicago:
resectable malignant pleural mesothelioma
Pembrolizumab
Additional relevant MeSH terms:
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Mesothelioma
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Mesothelial
Cisplatin
Pembrolizumab
Pemetrexed
Antibodies
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors