Pembrolizumab in Patients With Advanced Malignant Pleural Mesothelioma

A Phase II/III Randomized Study of Pembrolizumab in Patients With Advanced Malignant Pleural Mesothelioma

Pembrolizumab is a new type of drug for mesothelioma (immunotherapy). Laboratory tests show that this drug works by helping improve the body's immune response to help fight cancer. Pembrolizumab may help the immune system to recognize cancer cells and slow down the growth and/or spreading of cancer.

Study Overview

• Status: Completed
• Conditions: Mesothelioma
• Intervention / Treatment: Drug: Cisplatin; Drug: Pemetrexed; Drug: Pembrolizumab

Detailed Description

The purpose of this study is to find out what effects a new drug, pembrolizumab has on this type of cancer and if it can offer better results than standard pemetrexed and platinum-based chemotherapy alone. This study will also look at side effects and how the treatments impact quality of life

• Study Type: Interventional
• Enrollment (Actual): 520
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 5L3
      • BCCA - Cancer Centre for the Southern Interior
    • Surrey, British Columbia, Canada, V3V 1Z2
      • BCCA - Fraser Valley Cancer Centre
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Centre at Hamilton Health Sciences
    • London, Ontario, Canada, N6A 5W9
      • London Regional Cancer Program
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Hospital Research Institute
    • Toronto, Ontario, Canada, M5G 2M9
      • University Health Network
  • Quebec
    • Montreal, Quebec, Canada, H2X 3E4
      • CHUM-Centre Hospitalier de l'Universite de Montreal
    • Montreal, Quebec, Canada, H4A 3J1
      • The Research Institute of the McGill University
    • Quebec City, Quebec, Canada, G1V 4G5
      • University Institute of Cardiology and
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Allan Blair Cancer Centre
• France
  • Angers, France, 49033
    • CHU - Angers
  • Besancon Cedex, France, 25030
    • Hôpital Jean Minjoz
  • Bordeaux, France, 33076
    • Institut Bergonie
  • Boulogne, France, 92104
    • Boulogne - Ambroise Paré
  • Caen, France, 14000
    • Caen - CHU
  • Clermont-Ferrand, France, 63003
    • Clermont-Ferrand - CHU
  • Creteil, France, 94000
    • Centre Hospitalier Intercommunal de Créteil
  • Le Mans, France, 72037
    • Centre Hospitalier du Mans
  • Lille, France, 59037
    • Lille - Hopital Calmette
  • Marseille, France, 13915
    • Marseille - Hopital Nord
  • Montpellier 34298, France, CEDEX 5
  • Mulhouse, France, 68070
    • Centre Hospitalier de Mulhouse
  • Nantes, France, 44805
    • Centre René Gauducheau
  • Paris, France, 75877
    • Hôpital Bichat
  • Strasbourg, France, 67091
    • Nouvel Hopital Civil Hopitaux
  • Toulon, France, 83056
    • CHITS Toulon Sainte Musse
  • Toulouse, France, 31059
    • Hôpital Larrey
  • Cedex
    • Vandoeuvre les Nancy, Cedex, France, 54500
      • Centre Alexis Vautrin
  • Cedex 20
    • Paris, Cedex 20, France, 75970
      • AP-HP Hopital Tenon
  • FR
    • Limoges, FR, France, 87042
      • CHU Dupuytren
    • Lorient, FR, France, 56100
      • Hôpital du Scorff
    • Pierre-benite, FR, France, 69310
      • Lyon URCOT
    • Rennes, FR, France, 35033
      • CHU Rennes - Hôpital Pontchaillou
    • Villejuif, FR, France, 94805
      • Institut Gustave-Roussy
  • Tours Cedex 9
    • Tours Cedex, Tours Cedex 9, France, 37044
      • CHRU de Tours - Hôpital Bretonneau
• Italy
  • Brindisi, Italy, 72100
    • PO A Perrino ASL Brindisi - UOC Oncologia Medica
  • Catania, Italy, 95125
    • AOU Policlinico Vittorio Emanuele UOC di Oncologia
  • Genova, Italy, 16149
    • U.O. di Oncologia Ospedale Villa Scassi
  • Meldola, Italy, 47014
    • Intstituto Scientifico Romangnolo
  • Milano, Italy, 20133
    • Fondazione IRCCS Istituto Nazionale dei Tumori
  • Mirano, Italy, 30035
    • U.O.C. di Oncologia U.L.S.S. 13
  • Napoli, Italy, 80131
    • Azienda Ospedaliera di Rilievo Nazionale
  • Napoli, Italy, 80131
    • Dott. Fortunato Ciardiello,Cattedra Oncologia Medica
  • Napoli, Italy, 80131
    • U.O.S.D. Day Hospital Oncologico-Pneumologico
  • Napoli, Italy, 80131
    • Unita Sperimentazioni Cliniche Istituto per lo
  • Piacenza, Italy, 29100
    • Azienda USL di Piacenza, Ospedale Gugliemimo Salieto
  • AL
    • Alessandria, AL, Italy, 15121
      • Oncologia SS Antonio e Biagio Alessandria
  • AV
    • Avellino, AV, Italy, 83100
      • Azienda Ospedaliera San Giuseppe Moscati
  • BA
    • Bari, BA, Italy, 70124
      • IRCCS Ospedale Oncologico Giovanni Paolo II
  • BG
    • Bergamo, BG, Italy, 24125
      • Oncologia Medica Humanitas Gavazzeni Bergamo
  • CT
    • Catania, CT, Italy, 95123
      • Azienda Ospedaliera Garibaldi Nesima
  • Lombardia
    • Rozzano (MI), Lombardia, Italy, 20089
      • Instituto Clinico Humanitas
  • RE
    • Reggio Emilia, RE, Italy, 42123
      • Oncologia Medica IRCCS Arcispedale Maria
  • RM
    • Rome, RM, Italy, 00144
      • Istituti Fisioterapici Ospitalieri IFO Istituto

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have histologically confirmed malignant pleural mesothelioma. Patients must be eligible to receive standard chemotherapy with pemetrexed and cisplatin and have no contraindications to standard chemotherapy.
• Patients must have unresectable advanced and/or metastatic disease, incurable by standard therapies.
• All patients must have a cellular tumour block from their primary or metastatic tumour available and consent to release the block/recently cut slides for correlative analyses (See Section 11.0) and the centre/pathologist must have agreed to the submission of the specimen(s).

• Presence of radiologically documented disease. At least one site of disease must be unidimensionally measurable as follows:

  • CT scan (with slice thickness of ≤ 5 mm): ≥ 10 mm --> longest diameter
  • Physical exam (using calipers): ≥ 10 mm
  • Lymph nodes by CT scan ≥ 15 mm --> measured in short axis
• All radiology studies must be performed within 21 days prior to registration (exception: within 28 days if negative).
• Age ≥ 18 years.
• ECOG performance status 0 or 1.

Previous Therapy

Cytotoxic Chemotherapy:

• Patients must not have received prior chemotherapy for any stage of advanced/metastatic disease.
• Patients who received previous (neo)adjuvant cisplatin-based systemic chemotherapy must have received the last dose of chemotherapy at least 12 months before registration. Please contact CCTG PRIOR to randomization for such patients.

Other Anti-Cancer Therapy:

• Patients may not have received targeted small molecule therapy, immunotherapies and viral therapies, biologic therapies and angiogenesis inhibitors for advanced/metastatic disease, or any prior immunotherapy for any stage of disease.

Radiation:

• Patients may have had prior radiation therapy, but NOT to the thorax unless clear disease progression has been demonstrated and confirmed with CCTG. A minimum of 28 days must have elapsed between the end of radiotherapy and registration onto the study. Radiation must have involved < 30% of functioning bone marrow and there must be measurable disease outside the previously irradiated area (patients whose sole site of disease (for example pleural rind) is in a previously irradiated area are ineligible UNLESS there is evidence of progression, or new lesions have been documented, in the irradiated field). Please contact CCTG PRIOR to randomization if the patient has received prior thoracic radiation. Patients must have recovered from any acute toxic effects from radiation prior to registration.

Previous Surgery:

• Previous major surgery is permitted provided that it has been at least 28 days prior to patient registration and that wound healing has occurred.

• Lab Requirements:

  • Absolute neutrophils ≥ 1.5 x 10^9/L
  • Platelets ≥ 100 x 10^9/L
  • Hemoglobin ≥ 90 g/L
  • Bilirubin ≤ 1.5 x ULN (upper limit of normal)
  • AST and ALT ≤ 2.5 x ULN
  • Serum creatinine < 1.25 x ULN or Creatinine clearance ≥ 50 mL/min
• Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements.
• Patients must be accessible for treatment, response assessment and follow-up. Patients registered on this trial must be treated and followed at the participating centre.
• In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient randomization.
• Women/men of childbearing potential must have agreed to use two highly effective contraceptive methods during the study and for six months after discontinuation.
• Patient must be able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires.

Exclusion Criteria:

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (at doses more than 10 mg prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first and any dose of trial treatment.
• Has active autoimmune disease that has required systemic treatment in the past 3 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) or history of allogeneic transplantation. 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.
• Must not have received a live vaccine within 30 days of planned start of study therapy.
• Patients with known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic cardiac dysfunction including cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects) or who have had unstable angina congestive heart failure or myocardial infarction within the previous year. Patients with a significant cardiac history, this includes hypertension, even if controlled, should have a LVEF ≥ 50%.
• Patients with a history of other malignancies unless having undergone curative therapy (i.e. resection, radiation, etc) and do not require concurrent anticancer therapy.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to pembrolizumab or any of the other chemotherapy agents.
• Concurrent treatment with other investigational drugs or anti0cancer therapy.

• Patients with serious illness or medical condition that would not permit the patient to be managed according to the protocol including, but not limited to:

  • History of significant neurologic or psychiatric disorder which would impair the ability to obtain consent or limit compliance with study requirements.
  • Active infection requiring systemic therapy; (including any patient known to have active hepatitis B, hepatitis C or human immunodeficiency virus (HIV) [note: testing in asymptomatic patients is not required] or tuberculosis).
  • Known history of, or any evidence of active, non-infectious pneumonitis.
  • Any other medical conditions that might be aggravated by treatment.
  • Serious or non-healing wound, ulcer, or bone fracture.
• Patients with evidence of interstitial lung disease.
• Patients with severe/uncontrollable tumor pain that requires radiation prior to starting on systemic therapy.
• Pregnant or lactating women. (N.B.: All women of childbearing potential must have a negative pregnancy test within 72 hours prior to registration).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A - Cisplatin/Pemetrexed; Pemetrexed 500 mg/m2 IV Day 1 every 21 days for 6 cycles Cisplatin 75 mg/m2 IV Day 1 every 21 days for 6 cycles	Drug: Cisplatin; Drug: Pemetrexed
Active Comparator: Arm B - Cisplatin/Pemetrexed/Pembrolizumab; Pembrolizumab 200 mg* IV Day 1 over 30 min every 21 days for a total of 2 years Pemetrexed 500 mg/m2 IV Day 1 every 21 days for 6 cycles Cisplatin 75 mg/m2 IV Day 1 every 21 days for 6 cycles	Drug: Cisplatin; Drug: Pemetrexed; Drug: Pembrolizumab
Active Comparator: Arm C - Pembrolizumab (Phase II only); Pembrolizumab 200 mg* IV 30 min Day 1 every 21 days for a total of 2 years	Drug: Pembrolizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase II: Progression Free Survival Measured as Time From Randomization to First Observation of Objective Disease Relapse or Progression	PFS was calculated for all randomized patients from the day of randomization until the first observation of disease progression (date of objective relapse or progression of Relapse/Progression Report) or death due to any cause (recorded in Date/Cause of Death Section of Death Report).	PFS was monitored continuously, with assessments every 6 weeks for 3 visits, then every 12 weeks, 4 weeks post-discontinuation, every 12 weeks until progression, and every 24 weeks until death, over an average of 16.2 months.
Phase III: Overall Survival Defined as Time From Randomization to the Date of Death From Any Cause	Overall survival was defined as time from the day of randomization to death for patients died. For patients still alive at time of data-cutoff for analysis, it was censored at the last day the patients were known alive as the last of all dates .	Survival was monitored continuously throughout the study and during follow-up. Patients were evaluated for each cycle, 4 weeks after discontinuation, every 12 weeks until progression, and then every 24 weeks until death, an average of 16.2 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase III: Progression Free Survival Measured as Time From Randomization to First Observation of Objective Disease Relapse or Progression	PFS was calculated for all randomized patients from the day of randomization until the first observation of disease progression (date of objective relapse or progression of Relapse/Progression Report) or death due to any cause (recorded in Date/Cause of Death Section of Death Report). The primary analysis for PFS was based on the progression evaluated in this study using mesothelioma-modified RECIST (mRECIST) conducted by blinded independent review (BICR).	PFS was monitored continuously, with assessments every 6 weeks for 3 visits, then every 12 weeks, 4 weeks post-discontinuation, every 12 weeks until progression, and every 24 weeks until death, over an average of 16.2 months.
Phase III: Objective Response Rate	Objective response rate was defined as the proportion of patients with best objective response being complete response (CR) or partial response (PR).	Response was monitored continuously, with assessments every 6 weeks for 3 visits, then every 12 weeks, 4 weeks post-discontinuation, every 12 weeks until progression, and every 24 weeks until death, over an average of 16.2 months.

Collaborators and Investigators

• Sponsor: Canadian Cancer Trials Group
• Collaborators: Merck Sharp & Dohme LLC; Intergroupe Francophone de Cancerologie Thoracique; National Cancer Institute, Naples
• Investigators: Study Chair: Quincy Chu, Cross Cancer Institute, Edmonton Alberta Canada; Study Chair: Francesco Perrone, National Cancer Institute of Naples, Italy; Study Chair: Laurent Greillier Marseille, Hopital Nord, France

Publications and helpful links

General Publications

• Uprety D. CheckMate 743: A Glimmer of Hope for Malignant Pleural Mesothelioma. Clin Lung Cancer. 2021 Mar;22(2):71-73. doi: 10.1016/j.cllc.2020.11.009. Epub 2020 Dec 2. No abstract available.
• Chu Q, Perrone F, Greillier L, Tu W, Piccirillo MC, Grosso F, Lo Russo G, Florescu M, Mencoboni M, Morabito A, Cecere FL, Ceresoli GL, Dawe DE, Zucali PA, Pagano M, Goffin JR, Sanchez ML, Gridelli C, Zalcman G, Quantin X, Westeel V, Gargiulo P, Delfanti S, Tu D, Lee CW, Leighl N, Sederias J, Brown-Walker P, Luo Y, Lantuejoul S, Tsao MS, Scherpereel A, Bradbury P, Laurie SA, Seymour L. Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial. Lancet. 2023 Dec 16;402(10419):2295-2306. doi: 10.1016/S0140-6736(23)01613-6. Epub 2023 Nov 3.

Study record dates

Study Major Dates

• Study Start (Actual): November 11, 2016
• Primary Completion (Actual): October 11, 2024
• Study Completion (Actual): October 11, 2024

Study Registration Dates

• First Submitted: May 24, 2016
• First Submitted That Met QC Criteria: May 25, 2016
• First Posted (Estimated): May 26, 2016

Study Record Updates

• Last Update Posted (Actual): December 10, 2024
• Last Update Submitted That Met QC Criteria: December 5, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Neoplasms by Histologic Type; Lung Diseases; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Mesothelioma, Malignant; Mesothelioma; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors; Pemetrexed; Pembrolizumab
• Other Study ID Numbers: I227; 2016-002286-60 (EudraCT Number); IFCT-1901 (Other Identifier: Intergroupe Francophone de Cancerologie Thoracique)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No