BEAT-meso: Bevacizumab and Atezolizumab in Malignant Pleural Mesothelioma

A Multicentre Randomised Phase III Trial Comparing Atezolizumab Plus Bevacizumab and Standard Chemotherapy Versus Bevacizumab and Standard Chemotherapy as First-line Treatment for Advanced Malignant Pleural Mesothelioma

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.

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.

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.