Pleural Mesothelioma Malignant Advanced
Conditions
Keywords
MPM
Brief summary
The aim of this clinical trial is to assess the effect of treatment with a monoclonal antibody called atezolizumab in patients diagnosed with a type of lung cancer called malignant pleural mesothelioma. The efficacy (whether the treatment works), safety and tolerability (side effects of treatment) of atezolizumab plus bevacizumab in combination with standard chemotherapy versus bevacizumab in combination with standard chemotherapy will be investigated.
Detailed description
Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer arising from the mesothelial surface of the pleura. In Europe, the incidence is about 20 per million and is almost always caused by asbestos exposure, with a usual lag time of 30 years between exposure and presentation. Patients diagnosed with advanced MPM have limited treatment options, representing a strict unmet need. Despite decades of clinical research, cytotoxic chemotherapy remains one of the few therapeutic options that has been proven to improve survival in advanced MPM in a randomised controlled trial. The combination of cisplatin and pemetrexed has become standard first-line therapy worldwide for patients who are not suitable for aggressive surgery or in whom chemotherapy is recommended as part of a multimodality regimen. Carboplatin is often substituted for cisplatin, due to simpler and shorter administration and assumption of a more favourable toxicity profile based on experience in other diseases. Patients with MPM have limited treatment options, representing a strict unmet need. An antibody is a common type of protein usually made in the body in response to a foreign substance. Antibodies attack foreign substances and protect against infection. The two monoclonal antibodies (atezolizumab and bevacizumab) used in this trial are laboratory-produced antibodies. Atezolizumab is engineered to attach to immune cells to stimulate their activity against cancer cells. Atezolizumab and bevacizumab are both approved by the European Medicines Agency for the treatment of lung and other cancers. The addition of atezolizumab to bevacizumab plus standard chemotherapy for the treatment of MPM is being investigated in this trial. All participants will receive 4-6 cycles of standard chemotherapy consisting of carboplatin AUC 5 (area under the plasma concentration versus time curve) plus pemetrexed 500mg/m\^2 given intravenously, on day 1 of every 3 week cycle for about 12 to 18 weeks. Participants will be randomly assigned to one of two treatment groups: Treatment 1 * Bevacizumab 15 mg/kg intravenously on day 1 of every 3-week cycle, plus * 4-6 cycles of chemotherapy OR Treatment 2 * Atezolizumab 1200 mg fixed dose intravenously on day 1 of every 3-week cycle, plus * Bevacizumab 15 mg/kg, intravenously on day 1 of every 3-week cycle, plus * 4-6 cycles of chemotherapy Participants will continue to receive treatment until disease progression, or until treatment is stopped at the request of the participant or treating doctor, or the participant withdraws consent. A total of 400 participants from approximately 45 centres in Europe are expected to be included in this trial which will take approximately 6 years to be completed after the first participant is enrolled.
Interventions
DRUGCarboplatin
Carboplatin belongs to the group of medicines known as alkylating agents. Carboplatin interferes with the growth of cancer cells, which eventually are destroyed.
DRUGPemetrexed
Pemetrexed is a type of drug known as an anti metabolite. It stops cells making and repairing DNA so they can't grow and multiply.
DRUGBevacizumab
Bevacizumab is an angiogenesis inhibitor. It works by targeting a protein called vascular endothelial growth factor (VEGF) that helps cancers form new blood vessels. By stopping this process, bevacizumab 'suffocates' the blood supply to the cancer, shrinking it and stopping it from growing.
DRUGAtezolizumab
Atezolizumab is in a class of medications called monoclonal antibodies. It works by blocking the action of a certain protein in cancer cells. This helps the immune system to fight against the cancer cells, and helps to slow tumor growth.
Sponsors
ETOP IBCSG Partners Foundation
Hoffmann-La Roche
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 advanced malignant pleural mesothelioma (all histological subtypes are eligible) * Not amenable for radical surgery based on local standards * Evaluable disease or measurable disease as assessed according to the modified response evaluation criteria for solid tumours for mesothelioma (mRECIST) v1.1 * Availability of tumour tissue for translational research * Age \>18 years * Performance Status 0-1 * Life expectancy \>3 months * Adequate haematological, renal and liver function * Completed baseline quality of life (QoL) questionnaire * Women of childbearing potential and sexually active men must agree to use highly effective contraception * Able to understand and give written informed consent and comply with trial procedures
Exclusion criteria
* Prior treatment for malignant pleural mesothelioma. Prior radiotherapy for symptom control is allowed, but the irradiated lesion cannot be used as target lesion. If the patient has another target lesion, the patient is eligible. * Treatment with systemic immune-stimulatory agents within 4 weeks or five half-lives of the drug prior to randomisation and during protocol treatment. * Treatment with systemic immunosuppressive medications within 2 weeks prior to randomisation and during protocol treatment. * Previous allogeneic tissue/solid organ transplant * Live vaccines within 4 weeks prior to first dose of protocol treatment * Inadequately controlled hypertension * Prior history of hypertensive crisis or hypertensive encephalopathy * Significant vascular disease within 6 months prior to randomisation * History of haemoptysis * Evidence of bleeding diathesis or coagulopathy * Active autoimmune disease that has required systemic treatment in past 2 years * History of active diverticulitis * Previous treatment with atezolizumab and/or bevacizumab or parallel participation in other interventional clinical trial with atezolizumab and/or bevacizumab.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization until death from any cause, up to 52 months. | Overall survival is defined as the time from the date of randomisation until death from any cause. Data for patients who are not reported as having died at the date of analysis will be censored at the date when they were last known to be alive. Data for patients without post-baseline information will be censored at the date of randomization (plus 1 day). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) According to the mRECIST v1.1 | From randomization until documented progression (PD) according to mRECIST v1.1 or death from any cause (whichever occurred first), up to 52 months. | PFS is defined as the time from the date of randomisation until documented progression (according to the mRECIST v1.1) or death, if progression is not documented. Censoring (for participants without a PFS/death event) will occur at the date of last tumour assessment. Patients without a post-baseline tumour assessment will be censored at the date of randomization (plus 1 day). |
| Objective Response Rate (ORR) | From randomization to termination of trial treatment, up to 52 months. | Objective Response Rate (ORR) is defined as the percentage of patients that achieve a best overall response \[complete response (CR) or partial response (PR)\] evaluated according to the mRECIST v1.1 across all post-randomization time-points until the end of protocol treatment. Confirmation of response will not be required. |
| Disease Control (DC) at 24 Weeks | From randomization to 24 weeks; participants assessed for treatment response status at 24 weeks. | Disease Control (DC) is defined as complete or partial response, or disease stabilisation at 24 weeks (+/- 10 days). Patients with no available scan at this time period, but with scan performed before 24 weeks - 10 days and scan performed after 24 weeks + 10 days showing disease control, will be considered as disease control. |
| Time to Treatment Failure (TTF) | From randomization until discontinuation of protocol treatment for any reason, up to 52 months. | Time to Treatment Failure (TTF) is defined as the time from the date of randomisation to discontinuation of protocol treatment for any reason (including progression of disease, death, discontinuation of at least one of the drugs consisting the treatment combination due to any reason, such as toxicity or refusal). Censoring will occur at the last follow-up date. |
| Duration of Response (DoR) | From documentation of objective response until the date of first documented progression/relapse or death, up to 52 months. | Duration of Response (DoR) is defined as the interval from the date of first documentation of objective response (complete response or partial response, according to the mRECIST v1.1) to the date of first documented progression/relapse or death. |
| Quality of Life (QoL) | From randomization until 12 weeks after treatment start, up to 52 months. | QoL is assessed by the Lung Cancer Symptom Scale-Mesothelioma (LCSS-Meso) an 8-item questionnaire including five symptoms associated with mesothelioma (i.e., appetite loss, fatigue, cough, dyspnoea, and pain) and three items addressing symptomatic distress, normal activity, and global QoL. All items are measured by visual analogue scales (VAS) using 100-mm lines to assess the intensity of each item based on patient responses within the time frame of the past day. Each item is assigned an individual score corresponding to the length of the line representing intensity as marked by the patient on a 0-100 scale, with 0 as the best rating (i.e., no symptom distress, no interference with activity level, or best possible health-related quality of life) and 100-mm as the worst rating. The primary QoL endpoint is the change in the LCSS total score (average of all 8 items) from baseline to 12 weeks after treatment start. |
| Adverse Events | From randomization to 90 days after the last dose of protocol treatment, up to 52 months. | Adverse events, according to CTCAE v5.0. |
Countries
Belgium, France, Italy, Spain, Switzerland, United Kingdom
Contacts
STUDY_CHAIREnriqueta Felip, MD-PhD
Vall d'Hebron University Hospital
STUDY_CHAIRSanjay Popat, PhD, MBBS
Royal Marsden NHS Foundation Trust
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 70.1 years |
| Asbestos exposure No | 33 Participants |
| Asbestos exposure Possible | 51 Participants |
| Asbestos exposure Unknown/Missing | 17 Participants |
| Asbestos exposure Yes | 89 Participants |
| ECOG Performance Status 0 | 80 Participants |
| ECOG Performance Status 1 | 139 Participants |
| ECOG Performance Status Unknown/Missing | 0 Participants |
| EORTC prognostic score Good prognosis | 280 Participants |
| EORTC prognostic score Poor prognosis | 120 Participants |
| Histology Epithelioid | 311 Participants |
| Histology Non pure epithelioid | 89 Participants |
| Medical history No | 24 Participants |
| Medical history Yes | 187 Participants |
| Mesothelioma risk score (MRS) 0-Favorable | 136 Participants |
| Mesothelioma risk score (MRS) 1-Intermediate | 129 Participants |
| Mesothelioma risk score (MRS) 2-Poor | 62 Participants |
| PD-L1 TPS% <1 | 215 Participants |
| PD-L1 TPS% 1-49 | 56 Participants |
| PD-L1 TPS% ≥50 | 26 Participants |
| PD-L1 TPS% Unknown/Missing | 16 Participants |
| Race/Ethnicity, Customized Black | 1 Participants |
| Race/Ethnicity, Customized White | 199 Participants |
| Sex: Female, Male Female | 84 Participants |
| Sex: Female, Male Male | 160 Participants |
| Smoking status Current smoker | 11 Participants |
| Smoking status Former smoker | 99 Participants |
| Smoking status Never smoked | 90 Participants |
| Stage IV | 41 Participants |
| Stage Other | 159 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 145 / 200 | 150 / 200 |
| other Total, other adverse events | 197 / 199 | 197 / 199 |
| serious Total, serious adverse events | 92 / 199 | 67 / 199 |
Outcome results
None listed