Trial Title:
Integration of the PD-L1 Inhibitor Atezolizumab and WT1/DC Vaccination Into Platinum/Pemetrexed-based First-line Treatment for Epithelioid Malignant Pleural Mesothelioma
NCT ID:
NCT05765084
Condition:
Malignant Pleural Mesothelioma
Conditions: Official terms:
Mesothelioma
Mesothelioma, Malignant
Pemetrexed
Atezolizumab
Conditions: Keywords:
Dendritic cell vaccination
Chemo-immunotherapy
Wilms' Tumor 1 (WT1)
Checkpoint inhibition
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
Dendritic cell vaccination
Description:
WT1/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).
Arm group label:
Single arm
Intervention type:
Drug
Intervention name:
Atezolizumab
Description:
Atezolizumab (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.
Arm group label:
Single arm
Intervention type:
Drug
Intervention name:
Platinum/pemetrexed based chemotherapy
Description:
On 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.
Arm group label:
Single arm
Summary:
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.
Detailed 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.
Criteria for eligibility:
Criteria:
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:
- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1500/μL) without granulocyte
colony- stimulating factor support
- Lymphocyte count ≥ 0.5 x 10^9/L (500/μL)
- Platelet count ≥ 100 x 10^9/L (100,000/μL) without transfusion
- Hemoglobin ≥ 90 g/L (9 g/dL) Patients may be transfused to meet this criterion
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline
phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN), with the following
exceptions:
- Patients with documented liver metastases: AST and ALT ≤ 5 x ULN
- Patients with documented liver or bone metastases: ALP ≤ 5 x ULN
- Total bilirubin ≤ 1.5 x ULN with the following exception:
- Patients with known Gilbert disease: total bilirubin ≤ 3 x ULN
- Creatinine ≤ 1.5 x ULN
- Albumin ≥ 25 g/L (2.5 g/dL)
- For patients not receiving therapeutic anticoagulation: prothrombin
international normalized ration (PT-INR) and activated partial thromboplastin
time (APTT) ≤ 1.5 x ULN
- 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
- The HBV DNA test will be performed only for patients who have a negative HBsAg
test and a positive total HBcAb test.
- 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:
- 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.
- The patient has no ongoing requirement for corticosteroids as therapy for CNS
disease.
- If the patient is receiving anti-convulsant therapy, the dose is considered
stable.
- Metastases are limited to the cerebellum or the supratentorial region (i.e., no
metastases to the midbrain, pons, medulla, or spinal cord).
- There is no evidence of interim progression between completion of CNS directed
therapy and initiation of study treatment.
- Asymptomatic patients with CNS metastases newly detected at screening are
eligible for the study after receiving radiotherapy and/or surgery, with no
need to repeat the screening brain scan.
- 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:
- Rash must cover < 10% of body surface area
- Disease is well controlled at baseline and requires only low-potency
topical corticosteroids
- No occurrence of acute exacerbations of the underlying condition requiring
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
agents, oral calcineurin inhibitors, or high potency or oral
corticosteroids within the previous 12 months.
- 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:
- Patients who received acute, low-dose systemic immunosuppressant medication or
a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours
of corticosteroids for a contrast allergy) may be eligible for the study after
Medical Monitor confirmation has been obtained.
- Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or
low dose corticosteroids for COPD or asthma, or low-dose corticosteroids for
orthostatic hypotension or adrenal insufficiency are eligible for the study.
- 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Antwerp University Hospital
Address:
City:
Edegem
Zip:
2650
Country:
Belgium
Status:
Recruiting
Contact:
Last name:
Zwi N Berneman, MD, PhD
Email:
zwi.berneman@uza.be
Facility:
Name:
AZ Maria Middelares
Address:
City:
Ghent
Zip:
9000
Country:
Belgium
Status:
Recruiting
Contact:
Last name:
Paul Germonpré, MD, PhD
Facility:
Name:
VITAZ
Address:
City:
Sint-Niklaas
Zip:
9100
Country:
Belgium
Status:
Recruiting
Contact:
Last name:
Koen Deschepper, MD
Start date:
February 24, 2023
Completion date:
October 2026
Lead sponsor:
Agency:
University Hospital, Antwerp
Agency class:
Other
Collaborator:
Agency:
Algemeen Ziekenhuis Maria Middelares
Agency class:
Other
Collaborator:
Agency:
Vitaz
Agency class:
Other
Collaborator:
Agency:
Kom Op Tegen Kanker
Agency class:
Other
Collaborator:
Agency:
Roche Pharma AG
Agency class:
Industry
Source:
University Hospital, Antwerp
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05765084
