Autologous Dendritic Cell Vaccination in Mesothelioma

Study Overview
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Brief Summary
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In this multicenter phase I/II trial, dendritic cells (DCs) loaded with the mesothelioma-associated tumor antigen WT1 will be used in conjunction with conventional chemotherapy for the frontline treatment of 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 WT1-targeted DC vaccination is feasible and safe and enables the induction of both systemic and in situ mesothelioma-specific immune responses in patients with MPM.

Detailed Description
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Malignant pleural mesothelioma (MPM) is a highly aggressive and in virtually all cases fatal cancer that is tightly associated with prior asbestos exposure. Despite some improvement over time, the prognosis of patient diagnosed with MPM remains dismal with a median overall survival from diagnosis of only 12 months. In this single arm phase I/II trial the investigators want to demonstrate the feasibility and safety of WT1-targeted dendritic cell vaccination in MPM patients as frontline treatment in conjunction with first line platinum/pemetrexed-based chemotherapy and the induction of both systemic and in situ mesothelioma-specific immune responses. During three years of recruitment the investigators aim at including 20 patients diagnosed with histologically proven epithelial MPM (WHO grade 0-1) who are able to undergo leukapheresis, chemotherapy, immunotherapy and pleurectomy/decortication (P/D; in case of resectable disease). Patients who underwent prior treatment for MPM or with a history of another malignancy within the last five years will be excluded. The intention of this study is to administer four vaccine doses in combination with standard of care of four 3-weekly cytoreductive platinum/pemetrexed-based chemotherapy cycles to each participant and prior to surgery (P/D) in the case of resectable MPM. Patients will receive four 3-weekly intradermal vaccinations with autologous WT1 messenger (m)RNA-loaded dendritic cells (V1-4), at day 14 after the start of each chemotherapy cycle (CT1-4). The dendritic cell therapy product will be generated and administered in the Antwerp University Hospital, more specifically the Center for Cell Therapy and Regenerative Medicine (CCRG) and the Division of Hematology, both headed by Prof. Zwi Berneman. The DC vaccines will be under embargo from release until the safety and quality control test results have become available and all release criteria have been met. A detailed overview of all applicable release criteria is provided in the investigational medicinal product dossier. The embargo period generally lasts 3 weeks counting from the day of cryopreservation (i.e. 8 days after leukapheresis). Recruitment started in August 2017. Study-related follow-up of the included patients is intended to be until 90 days after final DC vaccine administration or 22 months after diagnosis, whichever occurs later. In addition to feasibility and safety of the chemoimmunotherapy schedule, the investigators will look for the time to progression (TTP), progression-free survival (PFS), overall survival (OS), systemic immunogenicity and local immunogenicity.

Official Title
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First-line Immunotherapy Using Wilms' Tumor Protein 1 (WT1)-Targeted Dendritic Cell Vaccinations for Malignant Pleural Mesothelioma

Conditions
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Malignant Pleural Mesothelioma

Intervention / Treatment
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* Biological: dendritic cell vaccination plus chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis with histologically proven epithelial Aged ≥ 18 years at the time of enrollment WHO performance status 0-1 at the time of enrollment Fit to undergo general anesthesia, a thoracoscopy, leukapheresis, chemotherapy, immunotherapy and P/D (in case of resectable disease) No history of receiving any investigational treatment within 28 days of study enrollment No history of intolerance to pemetrexed and/or cisplatin Women of child bearing potential must have negative serum or urine pregnancy test at the time of screening. They should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least hundred days after the last study treatment. If pregnancy does occur within this time period, the Principal investigator must be informed as soon as possible. Female subjects who are breastfeeding should discontinue nursing prior to the first dose of study treatment and until hundred days after the last study treatment Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discusses with the patient before registration in the trial. Absence of any other inability or unwillingness to comply with the requirements of the protocol as assessed by the investigator Before patient registration written informed consent must be given according to ICH/GCP, and national/local regulations Exclusion Criteria: Unwilling or unable to comply with the study requirements Prior treatment for MPM History of another malignancy within the last five years (except for carcinoma in situ of the cervix, basal cell or spinocellular carcinoma of the skin or unless the investigator rationalizes otherwise) Known proven metastases Known concomitant presence of any immunosuppressive disease (e.g. HIV) or any active autoimmune condition, except for vitiligo Pregnant or breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>dendritic cell vaccination plus chemotherapy | Biological: dendritic cell vaccination plus chemotherapy<br>* A. Chemoimmunotherapy: four 3-weekly cycles of platinum/pemetrexed; on day 1 of each cycle, pemetrexed 500 mg/m2 should be administered as intravenous (IV) infusion over 10 minutes followed 30 minutes later by cisplatin 75 mg/m2 as IV over approximately 2 hours. four intradermal vaccinations with 8-10 x 10e6 autologous WT1 mRNA-loaded DCs; at day 14+/- 3 days after the start of each chemotherapy cycle. B. Surgery: pleurectomy/decortication; in case of resectable disease, 4-6 weeks after start of the last chemotherapy cycle.<br>* Other names: chemoimmunotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of MPM patients with feasible and safe DC vaccine production | Production of autologous DC vaccines from newly diagnosed MPM patients will be evaluated for: Feasibility, assessed by success of leukapheresis and production of sufficient (i.e. at least 4 vaccines) and qualified (phenotypic and functional requirements) vaccines. Safety, assessed by microbiological testing (bacteria, yeast, fungi, mycoplasma, endotoxin) of the DC vaccines. | Vaccine production and quality testing (i.e. 4 weeks after leukapheresis) | 
| Number of patients receiving investigational DC vaccine administration combined with standard of care chemotherapy within the proposed time frame | Administration of 4 autologous DC vaccines combined with four 3-weekly platinum/pemetrexed-based chemotherapy cycles will be evaluated for: Feasibility, assessed by successful administration of DC vaccines and prior to surgery in case of resectable disease. Safety, assessed by local (e.g. skin reactions at injection site) and systemic (toxicity grading according to the latest version of the CTCAE and CTC ) tolerability to the treatment. | After the chemoimmunotherapy treatment (+/- 15 weeks after entry to trial) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective clinical responses by tumor evaluation (clinical efficacy) | Objective clinical responses to the chemoimmunotherapy and, in case of resectable disease, after surgery as compared to baseline tumor evaluation prior to treatment (i.e. at diagnosis), will be evaluated with: radiographic assessments (CT imaging) of the tumor response using the modified RECIST criteria. FDG-PET assessments of the tumor response using the PERCIST criteria. Patients will be followed for disease progression; time to progression (TTP) and progression-free survival (PFS). | Through study completion, at least after 4 DC vaccinations, prior to surgery (in case of resectable disease) + three months after the last intervention and within every 12 months during follow-up | 
| Overall survival (clinical efficacy) | Patients will be followed for survival, from diagnosis and from start of treatment, for which the accurate date and reason of death (cancer-related or non-related) will be recorded for every patient. | Through study completion, an average of 1 year | 
| Systemic immunogenicity | Systemic immunogenicity will be evaluated by: Detection of WT1-specific T cell immunity and innate immunity in peripheral blood. Response to delayed-type hypersensitivity (DTH) skin testing to the DC vaccine. | After the fourth DC vaccine (i.e. post chemoimmunotherapy, prior to surgery in case of resectable disease) | 
| Local immunogenicity | Local immunogenicity will be evaluated by detection of immune profile in tumor biopsies and/or pleurectomy specimens (in case of resectable disease). | Upon surgery (P/D) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dendritic cell vaccination, chemo-immunotherapy, Wilms' tumor 1 (WT1)