Primary Outcome Measures
- Progression-free Survival (PFS) according to the mRECIST v1.1 [ Time Frame: From date of randomisation until documented progression or death, if progression is not documented, assessed up to 67 months ]
A co-primary endpoint, 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 last tumour assessment if the patient is lost to follow-up or refuses further documentation of follow-
up. - Overall Survival (OS) [ Time Frame: From date of randomisation until death from any cause, assessed up to 67 months ]
The second co-primary endpoint, overall survival, is defined as the time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.
Secondary Outcome Measures
- Overall Response (OR) [ Time Frame: From start of protocol treatment accorss all time-points until end of protocol treatment, assessed up to 67 months ]
Defined as the best overall response [complete response (CR) or partial response (PR)] evaluated according to the mRECIST v1.1 - Disease Control (DC) at 24 weeks [ Time Frame: 24 weeks after protocol treatment start ]
Defined as complete or partial response, or disease stabilisation at 24 weeks. - Time to Treatment Failure (TTF) [ Time Frame: From randomisation until discontinuation of protocol treatment for any reason, assessed up to 67 months ]
Defined as the time from the date of randomisation to discontinuation of protocol treatment for any reason (including progression of disease, treatment toxicity, refusal and death). Censoring will occur at the last follow-up date. - Duration of Response (DoR) [ Time Frame: From date of first documentation of objective response until date of first documented progression or relapse, assessed up to 67 months ]
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 or relapse. - Number of participants with treatment related adverse events according to Common Toxicity Criteria for Adverse Events (CTCAE) v5.0 [ Time Frame: Assessed from the date of informed consent until 90 days after protocol treatment discontinuation. Analysed at 67 months after randomisation of the first patient ]
Assessed through analysis of the worst grade of toxicity/adverse events and will include all participants who received at least one dose of protocol treatment. Adverse events leading to dose interruption, withdrawal of protocol treatment and deaths, laboratory parameters and abnormalities and vital signs over the whole treatment period will be assessed and graded according to CTCAE v5.0 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
- Treatment with systemic immune-stimulatory agents within 4 weeks or five half-lives of the drug 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
