Pleural Mesothelioma Malignant Advanced
Conditions
Keywords
MPM
Brief summary
Trial comparing standard treatment (chemotherapy) with pembrolizumab treatment in patients with advanced pretreated malignant mesothelioma.
Detailed description
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.
Interventions
DRUGPembrolizumab
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.
DRUGGemcitabine
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").
DRUGVinorelbine
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.
Sponsors
ETOP IBCSG Partners Foundation
Merck Sharp & Dohme LLC
Frontier Science Foundation, Hellas
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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. * Adequate liver function * ALT and AST 2.5 × ULN. If the patient has liver metastases, ALT and AST must be ≤5 × ULN. * Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 35 days before randomisation (the test has to be repeated 72 hours before pembrolizumab treatment start). * Written informed consent must be signed and dated by the patient and the investigator prior to any trial-related intervention including the submission of mandatory biomaterial.
Exclusion criteria
* 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. * Patients with other serious diseases or clinical conditions, including but not limited to uncontrolled active infection and any other serious underlying medical condition that could affect the patient's capacity to participate in the trial. * Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the trial or evaluation of the trial results. * Women who are pregnant or in the period of lactation. * Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the trial and up to 120 days following cessation of trial treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) as Assessed 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). | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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). | 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. |
| Overall Survival. | Time from randomization of the first patient until database cutoff date for the OS analysis (Sep 2017 - Aug 2019; approximately 2 years). | 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 from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years). | 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. |
| 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). | 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. Adverse events are collected from study treatment initiation to 30 days after treatment is ceased for any reason. Serious adverse events and events of clinical interest are collected within 90 days after last dose of trial treatment. |
| 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). | Investigator assessed PFS, from the date of randomisation until documented progression or death, if progression is not documented. Censoring occurs at the last tumor assessment. |
Countries
Spain, Switzerland, United Kingdom
Contacts
STUDY_CHAIRSanjay Popat, MD
Royal Marsden NHS Foundation Trust
STUDY_CHAIRAlessandra Curioni-Fontecedro, MD
University Hospital, Zürich
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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: 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. | 73 |
| 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: 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).
Vinorelbine: 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. | 71 |
| Total | 144 |
Baseline characteristics
| Characteristic | Pembrolizumab Arm | Standard Chemotherapy Arm | Total |
|---|---|---|---|
| Age, Continuous | 69.0 years | 71.0 years | 70.0 years |
| Age, Customized Age category <70 years | 42 Participants | 29 Participants | 71 Participants |
| Age, Customized Age category ≥70 years | 31 Participants | 42 Participants | 73 Participants |
| ECOG performance status 0 | 21 Participants | 14 Participants | 35 Participants |
| ECOG performance status 1 | 51 Participants | 57 Participants | 108 Participants |
| ECOG performance status 2 | 1 Participants | 0 Participants | 1 Participants |
| EORTC score Good prognosis | 45 Participants | 54 Participants | 99 Participants |
| EORTC score Poor prognosis | 28 Participants | 17 Participants | 45 Participants |
| Histologic subtype Epithelioid | 66 Participants | 62 Participants | 128 Participants |
| Histologic subtype Non-epithelioid | 7 Participants | 9 Participants | 16 Participants |
| PD-L1 Tumour proportion score <1% | 36 Participants | 30 Participants | 66 Participants |
| PD-L1 Tumour proportion score 1-20% | 20 Participants | 18 Participants | 38 Participants |
| PD-L1 Tumour proportion score ≥20% | 11 Participants | 14 Participants | 25 Participants |
| PD-L1 Tumour proportion score Not evaluable | 2 Participants | 4 Participants | 6 Participants |
| PD-L1 Tumour proportion score Not scored | 4 Participants | 5 Participants | 9 Participants |
| Prior treatment Carboplatin/Pemetrexed | 27 Participants | 27 Participants | 54 Participants |
| Prior treatment Cisplatin/Pemetrexed | 24 Participants | 22 Participants | 46 Participants |
| Prior treatment Cisplatin/Pemetrexed and Carboplatin/Pemetrexed | 7 Participants | 1 Participants | 8 Participants |
| Prior treatment Missing | 2 Participants | 4 Participants | 6 Participants |
| Prior treatment Platinum+/-Pemetrexed+/-Other | 13 Participants | 17 Participants | 30 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Spain | 6 Participants | 4 Participants | 10 Participants |
| Region of Enrollment Switzerland | 13 Participants | 14 Participants | 27 Participants |
| Region of Enrollment United Kingdom | 54 Participants | 53 Participants | 107 Participants |
| Sex: Female, Male Female | 15 Participants | 11 Participants | 26 Participants |
| Sex: Female, Male Male | 58 Participants | 60 Participants | 118 Participants |
| Smoking history Current | 5 Participants | 4 Participants | 9 Participants |
| Smoking history Former (≥100 cigarettes in the past during the whole life) | 34 Participants | 28 Participants | 62 Participants |
| Smoking history Never (0-99 cigarettes during the whole life) | 33 Participants | 39 Participants | 72 Participants |
| Smoking history Unknown/Missing | 1 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 48 / 73 | 44 / 71 |
| other Total, other adverse events | 70 / 72 | 65 / 70 |
| serious Total, serious adverse events | 25 / 72 | 20 / 70 |
Outcome results
Primary
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 frame: Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).
Population: All efficacy evaluations were conducted in the intent-to-treat (ITT) population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab Arm | Progression Free Survival (PFS) as Assessed by Independent Radiological Review | 2.5 months |
| Standard Chemotherapy Arm | Progression Free Survival (PFS) as Assessed by Independent Radiological Review | 3.4 months |
p-value: 0.76Log Rank
Secondary
Objective Response Rate by Independent Radiological Review
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.
Time frame: Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab Arm | Objective Response Rate by Independent Radiological Review | 21.9 percentage of participants |
| Standard Chemotherapy Arm | Objective Response Rate by Independent Radiological Review | 5.6 percentage of participants |
Secondary
Overall Survival.
Defined as time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.
Time frame: Time from randomization of the first patient until database cutoff date for the OS analysis (Sep 2017 - Aug 2019; approximately 2 years).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab Arm | Overall Survival. | 10.7 months |
| Standard Chemotherapy Arm | Overall Survival. | 12.4 months |
Secondary
Percentage of Patients Experienced AEs/SAEs
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. Adverse events are collected from study treatment initiation to 30 days after treatment is ceased for any reason. Serious adverse events and events of clinical interest are collected within 90 days after last dose of trial treatment.
Time frame: Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).
Population: Safety evaluation was conducted in the as-treated (AT) population: all randomised patients that received at least one dose of trial treatment, with treatment assignments designed according to actual study treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pembrolizumab Arm | Percentage of Patients Experienced AEs/SAEs | Experienced treatment related adverse event | 50 Participants |
| Pembrolizumab Arm | Percentage of Patients Experienced AEs/SAEs | Experienced treatment related adverse event leading to death | 1 Participants |
| Pembrolizumab Arm | Percentage of Patients Experienced AEs/SAEs | Experienced treatment related adverse event of grade 3-5 | 14 Participants |
| Pembrolizumab Arm | Percentage of Patients Experienced AEs/SAEs | Experienced treatment related adverse event leading to treatment discontinuation | 5 Participants |
| Pembrolizumab Arm | Percentage of Patients Experienced AEs/SAEs | Experienced any adverse event | 70 Participants |
| Standard Chemotherapy Arm | Percentage of Patients Experienced AEs/SAEs | Experienced treatment related adverse event leading to treatment discontinuation | 5 Participants |
| Standard Chemotherapy Arm | Percentage of Patients Experienced AEs/SAEs | Experienced any adverse event | 65 Participants |
| Standard Chemotherapy Arm | Percentage of Patients Experienced AEs/SAEs | Experienced treatment related adverse event | 52 Participants |
| Standard Chemotherapy Arm | Percentage of Patients Experienced AEs/SAEs | Experienced treatment related adverse event of grade 3-5 | 18 Participants |
| Standard Chemotherapy Arm | Percentage of Patients Experienced AEs/SAEs | Experienced treatment related adverse event leading to death | 1 Participants |
Secondary
Progression Free Survival (PFS) Assessed by Investigator
Investigator assessed PFS, from the date of randomisation until documented progression or death, if progression is not documented. Censoring occurs at the last tumor assessment.
Time frame: Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab Arm | Progression Free Survival (PFS) Assessed by Investigator | 3.5 months |
| Standard Chemotherapy Arm | Progression Free Survival (PFS) Assessed by Investigator | 3.7 months |
Secondary
Time to Treatment Failure.
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.
Time frame: Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab Arm | Time to Treatment Failure. | 2.8 months |
| Standard Chemotherapy Arm | Time to Treatment Failure. | 2.3 months |