PembROlizuMab Immunotherapy Versus Standard Chemotherapy for Advanced prE-treated Malignant Pleural Mesothelioma (PROMISE-meso)
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|ClinicalTrials.gov Identifier: NCT02991482|
Recruitment Status : Active, not recruiting
First Posted : December 13, 2016
Last Update Posted : June 26, 2018
|Condition or disease||Intervention/treatment||Phase|
|Pleural Mesothelioma Malignant Advanced||Drug: Pembrolizumab Drug: Gemcitabine Drug: Vinorelbine||Phase 3|
Mesothelioma is an aggressive malignancy usually affecting the surfaces of body coelomic cavities. It most commonly originates from the pleura with a propensity to the lower parietal pleura and costo-diaphragmatic recess, and is almost always caused by asbestos exposure, with a usual lag time of 30 years between exposure and presentation. Outcomes for most patients are invariably fatal, with median survival from presentation around 9-12 months in most series due to difficulties in achieving a complete microscopic surgical resection and tumour relative chemo-refractoriness. Whilst initially considered rare, due to the demand of asbestos of all varieties associated with industrialization following the Second World War, the background incidence of mesothelioma of 1/million has risen to 40/million in some countries. In the UK, where substantial asbestos exposure continued until the 1970s, the death rate is the highest in the world with a current epidemic of new cases, predicted to continue for another 5-10 years. Two main histological subtypes of mesothelioma are identified. The epitheliod subtype is the commonest, accounting for around 40% of cases, whilst the sarcomatoid subtype is observed in 20% of cases; the latter being typically aggressive and chemorefractory. Around 35% cases have features of both epitheliod and sarcomatoid subtypes and are termed biphasic subtype.
For patients with pleural mesothelioma, in whom surgery is not considered appropriate, systemic chemotherapy (platinum combined with pemetrexed) remains the international standard of care. Cisplatin/pemetrexed is associated with a response rate of 41% and confers an OS advantage of 3 months over cisplatin alone, and is the only licensed systemic therapy for mesothelioma in Europe. Despite this, the median survival is 9-12 months from most series in unresectable cases. At relapse, after platinum-based chemotherapy, no anti-cancer systemic therapies are licensed. Whilst several small phase II studies and retrospective series have suggested potential efficacy for chemotherapy with agents including carboplatin/gemcitabine, or vinorelbine, none thus far have demonstrated efficacy benefit in a randomised study, with median PFS rates reported of about 3 months for both gemcitabine and vinorelbine. There is therefore a huge unmet need for effective therapy for patients with relapsed pleural mesothelioma. The largest trial ever performed of systemic therapy in relapsed pleural mesothelioma in 661 patients documented the natural outcome of this group of relapsed mesothelioma patients, reporting a median OS of 27.1 weeks (6 months) and median PFS for 6.1 weeks (1.5 months) for placebo.
Programmed cell death-1 (PD-1) is a co-inhibitory molecule at the immunological synapse that acts as a major regulator of adaptive immunity, and is exploited by tumour cells to result in adaptive immune resistance (tolerance). This occurs when PD-1 binds to the ligands PD-L1 (B7H1) or PD-L2, which are expressed on many tumour types. High PD-L1 expression on tumours is associated with poorer outcomes. Mesothelioma has been shown to express PD-L1, with a small study identifying PDL1 expression in up to 40% of mesotheliomas. Moreover, immunologically-mediated inflammation is known to be a key driver for mesothelioma development via the Nalp3 imflammasome.
Pembrolizumab (MK-3475) is a potent and highly selective humanized 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.
There is a need to identify new ways for the systemic therapy of malignant mesothelioma and immune checkpoint inhibition is a promising way forward. Results from the proposed trial will contribute to overcoming tumour-specific immune suppression with immune checkpoint inhibition.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||144 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Multicentre Randomised Phase III Trial Comparing Pembrolizumab Versus Standard Chemotherapy for Advanced Pre-treated Malignant Pleural Mesothelioma|
|Actual Study Start Date :||September 12, 2017|
|Estimated Primary Completion Date :||December 2020|
|Estimated Study Completion Date :||December 2020|
Experimental: Pembrolizumab arm
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.
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.
Active Comparator: Standard chemotherapy arm
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.
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").
Other Name: Gemzar
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.
Other Name: Navelbine
- Progression Free Survival (PFS) in patients with advanced pre-treated malignant mesothelioma. [ Time Frame: Assessed from the date of randomisation until documented progression or death, if progression is not documented; assessed at 36 months after inclusion of first patient. ]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.
- Objective response. [ Time Frame: Assessed across all tumour evaluation time-points during the period from randomisation to termination of trial treatment; assessed at 36 months after inclusion of the first patient. ]Defined as the best overall response (complete or partial response) across all assessment time-points from randomisation to end of trial treatment, determined by RECIST 1.1 criteria, compared between treatment groups by the Fisher's exact test.
- Overall survival. [ Time Frame: From date of randomisation until death from any cause, assessed at 36 months from enrollment of the first patient. ]Defined as time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.
- Time to treatment failure. [ Time Frame: Assessed across all tumour evaluation time-points from time of randomisation to discontinuation of treatment; assessed at 36 months after inclusion of the first patient. ]Time from from randomisation to discontinuation of treatment for any reason, including progression of disease, treatment toxicity, refusal and death, by Kaplan Meier method. Censoring will occur at the last follow-up date.
- Toxicity/adverse events. [ Time Frame: Assessed from day 1 of every treatment cycle to within 30 days after treatment is ceased for any reason. ]The safety and tolerability of pembrolizumab treatment will be assessed through analysis of the worst grade of toxicity/adverse events according to CTCAE v4.0 criteria observed over the whole treatment period.
- Investigator assessed PFS [ Time Frame: Radiological assessments at all tumour evaluation time-points from randomisation to discontinuation of treatment for any reason; assessed at 36 months after inclusion of the first patient. ]Investigator assessed PFS, from the date of randomisation until documented progression or death, if progression is not documented; assessed at 36 months after inclusion of first patient.
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): NCT02991482
|Hospital Teresa Herrera|
|La Coruña, Spain|
|Hospital Clínico Universitario de Valladolid|
|Centre Hospitalier Universitaire Vaudois|
|University Hospital Zürich|
|Maidstone and Tunbridge Wells NHS Trust, Kent Oncology Centre|
|Maidstone, Kent, United Kingdom, ME16 9QQ|
|Cambridge, United Kingdom|
|Clatterbridge Cancer Centre|
|Liverpool, United Kingdom|
|Royal Marsden Hospital|
|London, United Kingdom, SW3 6JJ|
|Guy's and St Thomas' Hospital|
|London, United Kingdom|
|Plymouth Hospitals NHS Trust|
|Plymouth, United Kingdom, PL6 8DH|
|Weston Park Hospital|
|Sheffield, United Kingdom, UK S10 2SJ|
|Study Chair:||Sanjay Popat, MD||Royal Marsden NHS Foundation Trust|
|Study Chair:||Alessandra Curioni-Fontecedro, MD||University Hospital, Zürich|