PembROlizuMab Immunotherapy Versus Standard Chemotherapy for Advanced prE-treated Malignant Pleural Mesothelioma

NCT02991482 | Completed Phase 3 Results DMC

• 3 other identifiers: ETOP 9-152016-002062-313475-594
• Study Type: interventional
• Target: 144
• Locations: 3 countries
• Sites: 15

Brief Summary

Trial comparing standard treatment (chemotherapy) with pembrolizumab treatment in patients with advanced pretreated malignant mesothelioma.

Conditions

Pleural Mesothelioma Malignant Advanced

Keywords

MPM

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival (PFS) as Assessed by Independent Radiological Review

  To investigate whether treatment with pembrolizumab improves PFS, compared to standard, institutional choice chemotherapy, assessed according to RECIST 1.1 criteria based on independent radiological review; using Kaplan-Meier method and compared between the two treatment arms by a stratified log rank test.

  Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).

Secondary Outcomes (5)

• Objective Response Rate by Independent Radiological Review

  Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).

• Overall Survival.

  Time from randomization of the first patient until database cutoff date for the OS analysis (Sep 2017 - Aug 2019; approximately 2 years).

• Time to Treatment Failure.

  Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).

• Percentage of Patients Experienced AEs/SAEs

  Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).

• Progression Free Survival (PFS) Assessed by Investigator

  Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).

Study Arms (2)

Pembrolizumab arm

EXPERIMENTAL

Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment.

Drug: Pembrolizumab

Standard chemotherapy arm

ACTIVE COMPARATOR

Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated. Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination.

Drug: Gemcitabine; Drug: Vinorelbine

Interventions

Pembrolizumab DRUG

Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.

Also known as: KEYTRUDA, MK-3475, SCH 900475

Pembrolizumab arm

Gemcitabine DRUG

Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the "faulty" nucleoside, resulting in apoptosis (cellular "suicide").

Also known as: Gemzar

Standard chemotherapy arm

Vinorelbine DRUG

Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.

Also known as: Navelbine

Standard chemotherapy arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed malignant pleural mesothelioma (all subtypes are eligible)
• Progressing after or on previous platinum based chemotherapy.
• Availability of tumour tissue for translational research.
• Female and male patients aged 18 years or over.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Life expectancy of at least 3 months.
• Measurable or evaluable disease according to RECIST 1.1 criteria.
• Adequate renal function
• Creatinine 1.5 × Upper Limit of Normal (ULN) OR Calculated creatinine clearance 40 mL/min (using the Cockroft-Gault formula).
• Adequate haematological function
• Haemoglobin 90 g/L or 5.6 mmol/L
• White Blood Cell (WBC) 1.0 × 109/L
• Lymphocytes 0.5 g/L
• Absolute neutrophils count (ANC) 1.5 × 109/L
• Platelet count 100 × 109/L.

You may not qualify if:

• Prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), anti-programmed cell death ligand 2 (anti-PD-L2), anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
• Prior therapy with gemcitabine or vinorelbine.
• Known active central nervous system metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to randomisation 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 randomisation. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
• Known or suspected hypersensitivity to pembrolizumab or any of its excipients.
• Known unstable or unresolved surgical or chemotherapy-related toxicity that would compromise the patient's capacity to participate in the trial.
• Previous allogeneic tissue/solid organ transplant.
• Live vaccines within 30 days prior to first dose of pembrolizumab.
• Regular intake of immune-modulating drugs (such as interferon, methotrexate).
• History of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis.
• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) or topical therapy (e.g., steroids) for psoriasis or eczema is not considered a form of systemic treatment.
• Ongoing clinically serious infections requiring systemic antibiotic or antiviral, antimicrobial, or antifungal therapy.
• Human immunodeficiency virus (HIV) infection.
• Known active hepatitis B or hepatitis C.
• Known history of active tuberculosis.
• Patients with diagnosed immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomisation.

Sponsors & Collaborators

• ETOP IBCSG Partners Foundation: lead
• Merck Sharp & Dohme LLC: collaborator
• Frontier Science Foundation, Hellas: collaborator

Study Sites (15)

Hospital Teresa Herrera

A Coruña, Spain

Location

ICO Hospitalet

Barcelona, Spain

Location

Hospital Clínico Universitario de Valladolid

Valladolid, Spain

Location

Kantonsspital Aarau

Aarau, Switzerland

Location

Centre Hospitalier Universitaire Vaudois

Lausanne, Switzerland

Location

Kantonsspital Luzern

Lucerne, Switzerland

Location

Kantonsspital Winterthur

Winterthur, Switzerland

Location

University Hospital Zürich

Zurich, Switzerland

Location

Maidstone and Tunbridge Wells NHS Trust, Kent Oncology Centre

Maidstone, Kent, ME16 9QQ, United Kingdom

Location

Addenbrooke's Hospital

Cambridge, United Kingdom

Location

Clatterbridge Cancer Centre

Liverpool, United Kingdom

Location

Royal Marsden Hospital

London, SW3 6JJ, United Kingdom

Location

Guy's and St Thomas' Hospital

London, United Kingdom

Location

Plymouth Hospitals NHS Trust

Plymouth, PL6 8DH, United Kingdom

Location

Weston Park Hospital

Sheffield, UK S10 2SJ, United Kingdom

Location

Related Publications (7)

• Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-1550. doi: 10.1016/S0140-6736(15)01281-7. Epub 2015 Dec 19.

  PMID: 26712084 BACKGROUND

• Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet. 2005 Jul 30-Aug 5;366(9483):397-408. doi: 10.1016/S0140-6736(05)67025-0.

  PMID: 16054941 BACKGROUND

• Fennell DA, Gaudino G, O'Byrne KJ, Mutti L, van Meerbeeck J. Advances in the systemic therapy of malignant pleural mesothelioma. Nat Clin Pract Oncol. 2008 Mar;5(3):136-47. doi: 10.1038/ncponc1039.

  PMID: 18227828 BACKGROUND

• Rake C, Gilham C, Hatch J, Darnton A, Hodgson J, Peto J. Occupational, domestic and environmental mesothelioma risks in the British population: a case-control study. Br J Cancer. 2009 Apr 7;100(7):1175-83. doi: 10.1038/sj.bjc.6604879. Epub 2009 Mar 3.

  PMID: 19259084 BACKGROUND

• Tsiouris A, Walesby RK. Malignant pleural mesothelioma: current concepts in treatment. Nat Clin Pract Oncol. 2007 Jun;4(6):344-52. doi: 10.1038/ncponc0839.

  PMID: 17534390 BACKGROUND

• Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003 Jul 15;21(14):2636-44. doi: 10.1200/JCO.2003.11.136.

  PMID: 12860938 BACKGROUND

• Krug LM, Kindler HL, Calvert H, Manegold C, Tsao AS, Fennell D, Ohman R, Plummer R, Eberhardt WE, Fukuoka K, Gaafar RM, Lafitte JJ, Hillerdal G, Chu Q, Buikhuisen WA, Lubiniecki GM, Sun X, Smith M, Baas P. Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Oncol. 2015 Apr;16(4):447-56. doi: 10.1016/S1470-2045(15)70056-2. Epub 2015 Mar 20.

  PMID: 25800891 BACKGROUND

MeSH Terms

Interventions

pembrolizumab; Gemcitabine; Vinorelbine

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Results Point of Contact

• Title: Heidi Roschitzki
• Organization: European Thoracic Oncology Platform (ETOP)

Heidi.Roschitzki@etop-eu.org

+41 31 511 94 00

Study Officials

• Sanjay Popat, MD

  Royal Marsden NHS Foundation Trust

  STUDY CHAIR

• Alessandra Curioni-Fontecedro, MD

  University Hospital, Zürich

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 9, 2016
• First Posted: December 13, 2016
• Study Start: September 12, 2017
• Primary Completion: February 20, 2019
• Study Completion: November 30, 2021
• Last Updated: August 24, 2022
• Results First Posted: February 7, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

CH (5); GB (7); ES (3)