Clinical trial NCT02784171: Pembrolizumab in Patients With Advanced Malignant Pleural Mesothelioma
Official title: A Phase II/III Randomized Study of Pembrolizumab in Patients With Advanced Malignant Pleural Mesothelioma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Mesothelioma
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute, Naples
name: Merck Sharp & Dohme LLC
name: Intergroupe Francophone de Cancerologie Thoracique
First posted: 2016-05-26
Enrollment: 520
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

Eligibility criteria: 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).

Primary outcomes:
measure: Phase II: Progression Free Survival Measured as Time From Randomization to First Observation of Objective Disease Relapse or Progression
timeFrame: 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.
measure: Phase III: Overall Survival Defined as Time From Randomization to the Date of Death From Any Cause
timeFrame: 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 outcomes:
measure: Phase III: Progression Free Survival Measured as Time From Randomization to First Observation of Objective Disease Relapse or Progression
timeFrame: 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.
measure: Phase III: Objective Response Rate
timeFrame: 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.
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Kelowna
country: Canada
facility: BCCA - Cancer Centre for the Southern Interior
state: British Columbia
city: Surrey
country: Canada
facility: BCCA - Fraser Valley Cancer Centre
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Montreal
country: Canada
facility: CHUM-Centre Hospitalier de l'Universite de Montreal
state: Quebec
city: Montreal
country: Canada
facility: The Research Institute of the McGill University
state: Quebec
city: Quebec City
country: Canada
facility: University Institute of Cardiology and
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
state: Saskatchewan
city: Paris
country: France
facility: AP-HP Hopital Tenon
state: Cedex 20
city: Vandoeuvre les Nancy
country: France
facility: Centre Alexis Vautrin
state: Cedex
city: Limoges
country: France
facility: CHU Dupuytren
state: FR
city: Lorient
country: France
facility: Hopital du Scorff
state: FR
city: Pierre-benite
country: France
facility: Lyon URCOT
state: FR
city: Rennes
country: France
facility: CHU Rennes - Hopital Pontchaillou
state: FR
city: Villejuif
country: France
facility: Institut Gustave-Roussy
state: FR
city: Tours Cedex
country: France
facility: CHRU de Tours - Hopital Bretonneau
state: Tours Cedex 9
city: Angers
country: France
facility: CHU - Angers
city: Besancon Cedex
country: France
facility: Hopital Jean Minjoz
city: Bordeaux
country: France
facility: Institut Bergonie
city: Boulogne
country: France
facility: Boulogne - Ambroise Pare
city: Caen
country: France
facility: Caen - CHU
city: Clermont-Ferrand
country: France
facility: Clermont-Ferrand - CHU
city: Creteil
country: France
facility: Centre Hospitalier Intercommunal de Creteil
city: Le Mans
country: France
facility: Centre Hospitalier du Mans
city: Lille
country: France
facility: Lille - Hopital Calmette
city: Marseille
country: France
facility: Marseille - Hopital Nord
city: Montpellier 34298
country: France
city: Mulhouse
country: France
facility: Centre Hospitalier de Mulhouse
city: Nantes
country: France
facility: Centre Rene Gauducheau
city: Paris
country: France
facility: Hopital Bichat
city: Strasbourg
country: France
facility: Nouvel Hopital Civil Hopitaux
city: Toulon
country: France
facility: CHITS Toulon Sainte Musse
city: Toulouse
country: France
facility: Hopital Larrey
city: Alessandria
country: Italy
facility: Oncologia SS Antonio e Biagio Alessandria
state: AL
city: Avellino
country: Italy
facility: Azienda Ospedaliera San Giuseppe Moscati
state: AV
city: Bari
country: Italy
facility: IRCCS Ospedale Oncologico Giovanni Paolo II
state: BA
city: Bergamo
country: Italy
facility: Oncologia Medica Humanitas Gavazzeni Bergamo
state: BG
city: Catania
country: Italy
facility: Azienda Ospedaliera Garibaldi Nesima
state: CT
city: Rozzano (MI)
country: Italy
facility: Instituto Clinico Humanitas
state: Lombardia
city: Reggio Emilia
country: Italy
facility: Oncologia Medica IRCCS Arcispedale Maria
state: RE
city: Rome
country: Italy
facility: Istituti Fisioterapici Ospitalieri IFO Istituto
state: RM
city: Brindisi
country: Italy
facility: PO A Perrino ASL Brindisi - UOC Oncologia Medica
city: Catania
country: Italy
facility: AOU Policlinico Vittorio Emanuele UOC di Oncologia
city: Genova
country: Italy
facility: U.O. di Oncologia Ospedale Villa Scassi
city: Meldola
country: Italy
facility: Intstituto Scientifico Romangnolo
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Mirano
country: Italy
facility: U.O.C. di Oncologia U.L.S.S. 13
city: Napoli
country: Italy
facility: Azienda Ospedaliera di Rilievo Nazionale
city: Napoli
country: Italy
facility: Dott. Fortunato Ciardiello,Cattedra Oncologia Medica
city: Napoli
country: Italy
facility: U.O.S.D. Day Hospital Oncologico-Pneumologico
city: Napoli
country: Italy
facility: Unita Sperimentazioni Cliniche Istituto per lo
city: Piacenza
country: Italy
facility: Azienda USL di Piacenza, Ospedale Gugliemimo Salieto
Study officials:
affiliation: Cross Cancer Institute, Edmonton Alberta Canada
name: Quincy Chu
role: STUDY_CHAIR
affiliation: National Cancer Institute of Naples, Italy
name: Francesco Perrone
role: STUDY_CHAIR
affiliation: Hopital Nord, France
name: Laurent Greillier Marseille
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.