Clinical trial NCT03762018: BEAT-meso: Bevacizumab and Atezolizumab in Malignant Pleural Mesothelioma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pleural Mesothelioma Malignant Advanced
Keywords: MPM
Lead sponsor: ETOP IBCSG Partners Foundation
Sponsor class: NETWORK
Collaborators: name: Hoffmann-La Roche
First posted: 2018-12-03
Enrollment: 401
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: From date of randomisation until death from any cause, assessed up to 58 months
Secondary outcomes:
measure: Progression-free Survival (PFS) according to the mRECIST v1.1
timeFrame: From date of randomisation until documented progression or death, if progression is not documented, assessed up to 58 months
measure: Objective Response Rate (ORR)
timeFrame: From start of protocol treatment acorss all time-points until end of protocol treatment or, as an alternative approach, until the end of follow-up, assessed up to 58 months
measure: Disease Control (DC) at 24 weeks
timeFrame: 24 weeks after protocol treatment start
measure: Time to Treatment Failure (TTF)
timeFrame: From randomisation until discontinuation of protocol treatment for any reason, assessed up to 58 months
measure: Duration of Response (DoR)
timeFrame: From date of first documentation of objective response until date of first documented progression/ relapse or death, assessed up to 58 months
measure: Number of participants with treatment related adverse events according to Common Toxicity Criteria for Adverse Events (CTCAE) v5.0
timeFrame: Assessed from the date of informed consent until 90 days after protocol treatment discontinuation. Analysed at 58 months after randomisation of the first patient
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: University Hospital Leuven
city: Liege
country: Belgium
facility: CHU Liege
city: Bordeaux
country: France
facility: Unicancer - Institut Bergonie
city: Caen
country: France
facility: Caen- CHU
city: Le Mans
country: France
facility: Le Mans - CHG
city: Lyon
country: France
facility: Lyon - Centre Léon Bérard
city: Marseille
country: France
facility: Hospital Nord
city: Paris
country: France
facility: Curie Cancer Center Paris
city: Toulouse
country: France
facility: Toulouse - CHU
city: Tours
country: France
facility: Tours - CHU
city: Alessandria
country: Italy
facility: SS Antonio e Biagio e Cesare Arrigo Hospital
city: Bari
country: Italy
facility: IRCCS Instituto Tumori Giovanni Paolo II
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Nazionale die Tumori
city: Milan
country: Italy
facility: Instituto Europeo di Oncologia (IEO)
city: Treviso
country: Italy
facility: AULSS2 Marca Trevigiana Treviso
city: Turin
country: Italy
facility: University Hospital of Turin
city: Alicante
country: Spain
facility: Alicante University Hospital ISABIAL
city: Barcelona
country: Spain
facility: ICO Hospitalet
city: Barcelona
country: Spain
facility: Vall Hebron University Hospital/Vall Hebron Institue Oncology
city: Majadahonda
country: Spain
facility: Puerta de Hierro Hospital
city: Sabadell
country: Spain
facility: Hospital Parc Tauli Sabadell
city: Seville
country: Spain
facility: Virgen del Rocio
city: Vigo
country: Spain
facility: Complexo Hospitalario Universitario de Vigo
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Bellinzona
country: Switzerland
facility: Istituto Oncologica della Svizzera Italiana
city: Bern
country: Switzerland
facility: Ferdinando Cerciello
city: Chur
country: Switzerland
facility: Kantonsspital Graubünden
city: Lausanne
country: Switzerland
facility: CHUV
city: Lucerne
country: Switzerland
facility: Luzerner Kantonsspital
city: Saint Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zürich
country: Switzerland
facility: UniversitätSpital Zürich
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Liverpool
country: United Kingdom
facility: Clatterbridge Cancer Centre
city: London
country: United Kingdom
facility: Guy's and St Thomas' Hospital
city: London
country: United Kingdom
facility: Royal Marsden Hospital (Fulham Road)
city: London
country: United Kingdom
facility: Royal Marsden Hospital (Sutton)
city: Maidstone
country: United Kingdom
facility: Kent Oncology Centre
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital
city: Plymouth
country: United Kingdom
facility: Plymouth Hospitals NHS Trust
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
Study officials:
affiliation: Vall d'Hebron University Hospital
name: Enriqueta Felip, MD-PhD
role: STUDY_CHAIR
affiliation: Royal Marsden NHS Foundation Trust
name: Sanjay Popat, PhD, MBBS
role: STUDY_CHAIR
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