Status and phase
Conditions
Treatments
About
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.
Full description
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 patients diagnosed with MPM remains dismal with a median overall survival from diagnosis of only 9-16 months.
In this single arm phase I/II trial the investigators want to demonstrate the feasibility and safety of integrating the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab and WT1-targeted dendritic cell vaccination in epitheloid MPM patients in conjunction with first line platinum/pemetrexed-based chemotherapy. In addition, chemo-immunotherapy-induced immunogenicity will be studied and patient's clinical outcome will be documented for comparison with current patient's outcome allowing indication of the added value.
Fifteen patients diagnosed with histologically proven epithelial MPM (stage I-IV) will be included. Patients should be able to undergo leukapheresis, chemotherapy and immunotherapy. Patients who underwent prior treatment for MPM or with a history of another malignancy within the last three years will be excluded.
The intention of this study is to administer four 3-weekly (±3 days) platinum/pemetrexed-based chemotherapy cycles (CT1-4) combined with atezolizumab treatments (A1-4) and autologous WT1 messenger (m)RNA-loaded dendritic cells (V1-4) at day 0 and day 14 (±3 days) of each chemotherapy cycle, respectively.
Additional atezolizumab doses and/or WT1/DC vaccines after the chemo-immunotherapy study scheme can be administered to the patient if consent for continuation of atezolizumab treatment and/or WT1/DC vaccination was obtained and residual WT1/DC vaccine aliquots are available. In that case, atezolizumab and/or WT1/DC vaccines will be administered on a 4-weekly basis (±1 week). The WT1/DC vaccines will be administered within 1 week after atezolizumab administration.
After the final WT1/DC vaccination and/or atezolizumab administration, patients will enter a follow-up phase that lasts for up to 90 days after final WT1/DC vaccination and/or atezolizumab administration or 24 months after diagnosis, whichever occurs later.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Subjects must meet all the following criteria to be eligible to participate in the study:
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
Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained at the time of screening:
Negative Human Immunodeficiency Virus (HIV) test at screening
Negative hepatitis B surface antigen (HBsAg) test at screening
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening. The HCV RNA test must be performed for patients who have a positive HCV antibody test.
Willing and able to comply with the study protocol, as judged by the treating physician
Women of childbearing potential must have a negative serum or urine pregnancy test at the time of screening and agree to use effective contraception (<1% failure rate per year) before, during and for at least five months after the last atezolizumab administration or at least hundred days after the last WT1/DC vaccine administration (whichever takes longer). Men must agree to use effective contraception before, during and for at least hundred days after the last study treatment administration.
Exclusion criteria
Subjects who fulfill any of the following criteria will not be eligible for admission into the study:
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
Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. Asymptomatic patients with treated CNS lesions are eligible, provided that all of the following criteria are met:
History of leptomeningeal disease
Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study.
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could impact patient safety
Prior treatment for MPM
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease (COPD) exacerbation) are eligible for the study.
Prior allogeneic stem cell or solid organ transplantation
Use of any investigational agent within 28 days before study enrollment
Pregnant or breastfeeding. Female subjects who are breastfeeding should discontinue nursing prior to the first dose of study treatment and until at least hundred days after the last study treatment administration.
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab.
Current treatment with anti-viral therapy for HBV
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-α [TNF-α] agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:
Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 4 weeks or 5 drug-elimination half-lives of the drug, whichever is longer, prior to initiation of study treatment
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
Any other condition, either physical or psychological, or reasonable suspicion thereof on clinical or special investigation, which contraindicates the use of atezolizumab, pemetrexed, cisplatin/carboplatin and/or WT1/DC vaccination, or may negatively affect patient compliance, or may place the patient at higher risk of potential treatment complications.
Primary purpose
Allocation
Interventional model
Masking
15 participants in 1 patient group
Loading...
Central trial contact
Barbara Stein, MSc; Zwi N Berneman, MD, PhD
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal