Pembrolizumab Plus Lenvatinib In Second Line and Third Line Malignant Pleural mesotheLioma Patients (PEMMELA)

Primary Outcome Measures

1.  Objective response rate defined by Modified (i)RECIST criteria for pleural mesothelioma [ Time Frame: Through study completion, an average of 1 year ]

Secondary Outcome Measures

1. Safety of pembrolizumab- lenvatinib [ Time Frame: Up to 90 days after last study drug intake ]
   Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
2. Describe the disease control rate (DCR) at 3 and 6 months [ Time Frame: From date of registration until 6 months ]
   a percentage of the total number of patients in the study who are evaluable for the primary endpoint who have best overall response of CR or PR or SD.
3. Objective response rate (ORR) [ Time Frame: Assessed up to 60 months ]
   Number of patients with a partial or complete response
4. Progression-free survival [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months ]
   To describe PFS by independent radiological review

Other Outcome Measures

1. Immunological status [ Time Frame: before study and after 6 weeks of treatment ]
   The immunological status in the tumors before study and after 6 weeks of treatment with pembrolizumab +lenvatinib. This research will include PD-L1 status, mutational load and other potential biomarkers (e.g. micro vessel density count).

Inclusion Criteria

1. Histologically or cytologically diagnosed malignant pleural mesothelioma, age at least 18 years
2. Progressive disease after at least 1 and maximal 2 prior systemic treatment lines, in which one of the lines contains a platinum-based doublet (both cisplatin and carboplatin are allowed) for unresectable MPM
3. Measurable disease. At least one measurable lesion according to Modified (i)RECIST for pleural mesothelioma. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
4. WHO-ECOG performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to date of allocation
5. Adequate organ function
6. Ability to understand the study and give signed informed consent (or legally acceptable representative if applicable) prior to beginning of protocol specific procedures including the approval of the thoracoscopy or transthoracic pleural biopsy before the first treatment cycle and an optional biopsy before the third treatment cycle
7. No presence of clinically relevant treatment-related toxicity from previous chemotherapy, targeted therapy and/or radiotherapy. Note: Participates must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤2 neuropathy may be eligible
8. No active uncontrolled infection, severe cardiac dysfunction (i.e. unstable angina, history of myocardial infarction within the past 12 months prior to screening, congestive heart failure > NYHA II, serious cardiac arrhythmia), unstable peptic ulcer, unstable diabetes mellitus or other seriously disabling condition
9. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mmHg at screening ad no change in hypertensive medication within 1 week before the cycle 1/day1.
10. No prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with another agent agents direct to another stimulatory or co-inhibitory T-cell receptor (eg CTLA-4, OC-40, CD137) or TKI or antibody targeting angiogenesis. Patients who have been treated with autologous tumor cell vaccination (eg. Dendritic cell-based immunotherapy) will be eligible
11. No concomitant administration to any other experimental drugs under investigation ≤ 4 weeks prior to first admission of pembrolizumab- lenvatinib
12. No prior radiotherapy within 2 weeks before start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids as therapy for radiation induced toxicities. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
13. No major injuries and/or surgery within the past 4 weeks prior to first study dose with incomplete wound healing

Exclusion Criteria

1. presence of clinically relevant treatment-related toxicity from previous chemotherapy, targeted therapy and/or radiotherapy. Note: Participates must have recovered from all AEs due to previous therapies to 5Grade 1 or baseline. Participants with 52 neuropathy may be eligible
2. active uncontrolled infection, severe cardiac dysfunction (i.e. unstable angina, history of myocardial infarction within the past 12 months prior to screening, congestive heart failure > NYHA II, serious cardiac arrhythmia), unstable peptic ulcer, unstable diabetes mellitus or other seriously disabling condition
3. prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with another agent agents direct to another stimulatory or co-inhibitory T-cell receptor (eg CTLA-4, OC-40, CD137) or TKI or antibody targeting angiogenesis. Patients who have been treated with autologous tumor cell vaccination (eg. Dendritic cell-based imnnunotherapy) will be eligible
4. concomitant administration to any other experimental drugs under investigation 5 4 weeks prior to first admission of pembrolizumab- lenvatinib