Mesotheliomas Pleural
Conditions
Keywords
dendritic cell therapy, malignant pleural mesothelioma, mesopher, pleurectomy/decortication
Brief summary
The ENSURE trial is an open label, single center, phase 1, feasibility study. Sixteen adult patients diagnosed with resectable epithelioid malignant pleural mesothelioma (MPM) will be enrolled following first-line chemotherapy. Before standard-of-care chemotherapy, a leukapheresis will be performed and monocytes will be used for differentiation to dendritic cells (DCs) using specific cytokines. Allogeneic tumor lysate (Pheralys) loaded autologous DCs (MesoPher) will be re-injected 3 weeks after completing chemotherapy, 2 times every other week. Four weeks after the first injection with dendritic cell therapy (DCT), patients will undergo extrapleural pleurectomy/decortication (eP/D) surgery and receive three bi-weekly injections with DCT (starting 4 weeks after surgery). In total, five DC vaccinations will be administered. A tumor biopsy will be collected before starting neo-adjuvant DCT.
Interventions
BIOLOGICALMesopher
autologous monocyte-derived DCs loaded with PheraLys (tumor cell lysate)
Sponsors
Erasmus Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with a histologically confirmed diagnosis of epithelioid MPM who are eligible for 2 to 4 cycles of platinum-based chemotherapy. Patients who progressed after chemotherapy will not be discontinued from the trial if they are still eligible for eP/D and none of the
Exclusion criteria
is present (e.g. local progression with only focal chest invasion). * Patients must be at least 18 years old and must be able to give written informed con-sent. * Resectable disease defined by stage cT1-3, N0-1, M0 (I to IIIA) according to UICC TNM classification (8th edition). A fluorodeoxyglucose (FDG)-positron emission tomography (PET)-computerized tomography (CT) scan with fusion images showing absence of M1, N2 involvement is required. Focal chest wall lesions are acceptable. * Tumor tissue available after completing chemotherapy and before starting treatment with DCT. Tumor tissue can be obtained by either a CT-guided needle biopsy or a Video-assisted thoracoscopic surgery (VATS) biopsy. * Fit to receive platinum-based chemotherapy (as per standard of care of the treating physician/Institution) and undergo a P/D with optional removal of hemidiaphragm and pericardium. The responsible surgeon and chest physician should judge the required fitness prior to registration, taking into account the results of all the relevant (i.e. pulmonary, cardiac) examinations. * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Appendix 2). * Ability to return to the study center for adequate follow-up and vaccinations. * Positive delayed-type hypersensitivity (DTH) skin test (induration \> 2mm after 48 hrs) against at least one positive control antigen tetanus toxoid. * Written informed consent according to ICH-GCP. * Subjects must have adequate organ function and adequate bone marrow reserve at screening: * creatinine ≤ 1.5 × upper limit of normal \[ULN\] or glomerular filtration rate ≥ 50 mL/min * alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin ≤ 1.5 × ULN * Absolute neutrophil count ≥1.5 x 109/L, platelet count ≥100 x 109/L, and Hb ≥9.0 g/dL. Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks. * Women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test just prior to the first study drug administration on Day 1, and must be willing to use an effective contraceptive method (intrauterine devices, hormonal contraceptives, contraceptive pill, implants, transdermal patches, hormonal vaginal devices, infusions with prolonged release) or true abstinence (when this is in line with the preferred and usual lifestyle)\* during the study and for at least 12 months after the last study drug administration. \*True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (such as calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. * Men must be willing to use an effective contraceptive method (e.g. condom, vasectomy) during the study and for at least 12 months after the last study drug administration. * Written informed consent according to the International Conference on Harmonisation (ICH)/Good Clinical Practice (GCP) guidelines.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participant who are alive and have completed (neo)adjuvant DCT (5 administrations) and surgery at week 15 (+4 weeks) without extended treatment-related delay, persisting grade 3-4 treatment side-effects or evidence of progression [Feasibility] | 2 years | To determine the feasibility of DCT with Mesopher performed before and after eP/D in patients with resectable epithelioid MPM who received first line chemotherapy. Feasibility is measured by the number of patient who are alive and have completed neo-adjuvant plus adjuvant DCT (5 administrations in total or less in case of production shortage) and surgery at week 15 (+4 weeks) without extended treatment-related delay, persisting grade 3- 4 treatment side-effects or evidence of progression/relapse. Patients who markedly progressed after chemotherapy will be discontinued from the trial and will be considered as failures for assessment of the primary end-point. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [Safety and Tolerability] | 2 years | To assess the safety of DCT with Mesopher performed before and after eP/D in patients with resectable epithelioid MPM. |
| Median progression free and median overall survival since start of treatment [Efficacy] | 2 years | To evaluate the efficacy of combining DCT and eP/D after chemotherapy in patients with resectable epithelioid MPM. Efficacy is measured by median progression free and median overall survival since start of treatment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with increased immune cell infiltration in tumor tissue induced by (neo)adjuvant DCT [Anti-tumor immune response] | 2 years | To determine the anti-tumor immune response induced by (neo)adjuvant DCT. In order to analyze if DC-therapy induced a (tumor-specific) immune response, the following analyses will be performed: 1. Evaluate immune cell infiltration in tumor tissue prior and post DCT. 2. Characterize T-cell receptor (TCR) repertoire analysis of tumor-infiltrating T cells. 3. Characterize tumor-specific and lysate specific IFNy production by IFNy ELISPOT assay. 4. Characterize the phenotype of immune cell populations in the tumor and peripheral blood prior and post DCT. |
Countries
Netherlands
Contacts
Primary ContactJoachim Aerts, Prof
Backup ContactLuca Cantini
Outcome results
None listed