In this multicenter phase I/II trial, the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab and dendritic cells (DCs) loaded with the mesothelioma-associated tumor antigen WT1 will be integrated into platinum/pemetrexed-based first-line chemotherapy for the treatment of epitheloid malignant pleural mesothelioma (MPM). The general objective is to provide the first-in-human experimental demonstration that the combination of platinum/pemetrexed-based chemotherapy with atezolizumab and WT1/DC vaccination is feasible and safe, has clinical activity and enables the induction of mesothelioma-specific immune responses in patients with MPM.
Signed informed consent
Diagnosis with histologically proven epithelioid unresectable MPM (stage I-IV)
Age ≥ 18 years at the time of signing informed consent
World Health Organization (WHO) performance status 0-1
History of malignancy within 3 years prior to initiation of study treatment, with the exception of the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer
Measurable disease, per RECIST v1.1, must be present outside the CNS.
The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.
The patient has not undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, whole-brain radiotherapy within 14 days prior to initiation of study treatment, or neurosurgical resection within 28 days prior to initiation of study treatment.
Single group
Dendritic cell vaccination
Biological/VaccineWT1/DC vaccines (8-10 x 10\^6 cells in 500 μL saline solution with 5% human albumin) will be administered through intradermal injection at 5 sites (100 μL/site) in the ventromedial region of the upper arm (5-10 cm from the axillary lymph nodes). Injection sites will alternate between left and right arms. WT1/DC vaccines are administered on day 14 of each 3-weekly platinum/pemetrexed-based chemotherapy cycle. Additional WT1/DC vaccinations after the study treatment schedule can be administered (optional) at 4-weekly intervals (± 1 week).
Atezolizumab
DrugAtezolizumab (1200 mg) will be administered on day 0 of each 3-weekly platinum/pemetrexed-based chemotherapy cycle. Atezolizumab should be administered before chemotherapy administration as an IV infusion over 60 (±15) minutes. If the first infusion is tolerated, all subsequent infusions may bedelivered over 30 (±10) minutes. Additional atezolizumab treatment (1680 mg) after the study treatment schedule can be administered (optional) at 4-weekly intervals (± 1 week) as an IV infusion over 30-60 minutes.
Platinum/pemetrexed based chemotherapy
DrugOn the first day of each cycle (day 0), pemetrexed 500 mg/m2 should be administered as intravenous (IV) infusion over 10 minutes, followed by cisplatin 75 mg/m2 as IV over approximately 2 hours. The actual doses of the drugs to be administered to patients will be determined by calculating the patient's body surface area at the beginning of each cycle. For ease of dose administration, the protocol allows ± 5% variance in the calculated total dose per infusion. If deemed necessary, the treating physician can decide to replace cisplatin by carboplatin. In that case, carboplatin will be delivered to an area under the concentration-time curve (AUC) of 5 as an IV infusion over 1 hour.
Proportion of patients that experienced (S)AEs possibly, probably or definitely related to pemetrexed and/or cisplatin/carboplatin and/or atezolizumab and/or WT1/DC vaccination
The relationship of an AE to the investigational agents will be determined by the Investigator as either related or non-related, based on their clinical judgment.
Number and grade of AEs and SAEs
AEs are defined and graded according to the latest version of the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) and Common Toxicity Criteria (CTC)
Proportion of patients who completed study treatment schedule
Study treatment schedule = administration of four platinum/pemetrexed-based chemotherapy cycles (CT1-4) in combination with four atezolizumab treatments (A1-4) and four WT1/DC vaccinations (V1-4).
Best overall response
Best overall response will be determined per patient as the best overall response designation. The BOR categories are complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD).
Duration of response
Duration of response will be calculated for patients with an objective response as the time between the first date of the first documented tumor response (CR or PR) and the subsequent date of the objectively documented disease progression or death, whichever occurs first, or the last tumor assessment in case of censoring.
Disease control rate
Disease control rate is defined as the proportion of patients whose BOR is either CR, PR or SD, where the dominator is the total number of evaluable patients.
Objective response rate
Objective response rate is defined as the proportion of patients whose BOR is either CR or PR, where the dominator is the total number of evaluable patients.
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University Hospital, Antwerp
Lead sponsor
Algemeen Ziekenhuis Maria Middelares
Collaborator
Vitaz
Collaborator
Kom Op Tegen Kanker
Collaborator
Roche Pharma AG
Collaborator
