Integration of the PD-L1 Inhibitor Atezolizumab and WT1/DC Vaccination Into Platinum/Pemetrexed-based First-line Treatment for Epithelioid Malignant Pleural Mesothelioma

NCT05765084 | Recruiting Phase 1

• 1 other identifier: CCRG21-001
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Malignant Pleural Mesothelioma

Keywords

Dendritic cell vaccination; Chemo-immunotherapy; Wilms' Tumor 1 (WT1); Checkpoint inhibition

Outcome Measures

Primary Outcomes (3)

• 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.

  through study completion, an average of 2 years

• 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)

  through study completion, an average of 2 years

• 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).

  After the chemoimmunotherapy treatment (+/- 18 weeks after entry to trial)

Secondary Outcomes (7)

• Best overall response

  through study completion, an average of 2 years

• Duration of response

  through study completion, an average of 2 years

• Disease control rate

  through study completion, an average of 2 years

• Objective response rate

  through study completion, an average of 2 years

• Progression-free survival

  through study completion, an average of 2 years

Study Arms (1)

Single arm

EXPERIMENTAL

Standard of care chemotherapy, complemented with atezolizumab and WT1/DC vaccination

Biological: Dendritic cell vaccination; Drug: Atezolizumab; Drug: Platinum/pemetrexed based chemotherapy

Interventions

Dendritic cell vaccination BIOLOGICAL

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).

Single arm

Atezolizumab DRUG

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.

Single arm

Platinum/pemetrexed based chemotherapy DRUG

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.

Single arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Hospital, Antwerp: lead
• Algemeen Ziekenhuis Maria Middelares: collaborator
• Vitaz: collaborator
• Kom Op Tegen Kanker: collaborator
• Roche Pharma AG: collaborator

Study Sites (3)

Antwerp University Hospital

Edegem, Antwerp, 2650, Belgium

RECRUITING

AZ Maria Middelares

Ghent, 9000, Belgium

RECRUITING

VITAZ

Sint-Niklaas, 9100, Belgium

RECRUITING

Related Publications (11)

• Van Tendeloo VF, Van de Velde A, Van Driessche A, Cools N, Anguille S, Ladell K, Gostick E, Vermeulen K, Pieters K, Nijs G, Stein B, Smits EL, Schroyens WA, Gadisseur AP, Vrelust I, Jorens PG, Goossens H, de Vries IJ, Price DA, Oji Y, Oka Y, Sugiyama H, Berneman ZN. Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination. Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13824-9. doi: 10.1073/pnas.1008051107. Epub 2010 Jul 14.

  PMID: 20631300 BACKGROUND

• Anguille S, Van de Velde AL, Smits EL, Van Tendeloo VF, Juliusson G, Cools N, Nijs G, Stein B, Lion E, Van Driessche A, Vandenbosch I, Verlinden A, Gadisseur AP, Schroyens WA, Muylle L, Vermeulen K, Maes MB, Deiteren K, Malfait R, Gostick E, Lammens M, Couttenye MM, Jorens P, Goossens H, Price DA, Ladell K, Oka Y, Fujiki F, Oji Y, Sugiyama H, Berneman ZN. Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia. Blood. 2017 Oct 12;130(15):1713-1721. doi: 10.1182/blood-2017-04-780155. Epub 2017 Aug 22.

  PMID: 28830889 BACKGROUND

• Van Tendeloo VF, Ponsaerts P, Lardon F, Nijs G, Lenjou M, Van Broeckhoven C, Van Bockstaele DR, Berneman ZN. Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells. Blood. 2001 Jul 1;98(1):49-56. doi: 10.1182/blood.v98.1.49.

  PMID: 11418462 BACKGROUND

• Smits EL, Anguille S, Cools N, Berneman ZN, Van Tendeloo VF. Dendritic cell-based cancer gene therapy. Hum Gene Ther. 2009 Oct;20(10):1106-18. doi: 10.1089/hum.2009.145.

  PMID: 19656053 BACKGROUND

• Benteyn D, Anguille S, Van Lint S, Heirman C, Van Nuffel AM, Corthals J, Ochsenreither S, Waelput W, Van Beneden K, Breckpot K, Van Tendeloo V, Thielemans K, Bonehill A. Design of an Optimized Wilms' Tumor 1 (WT1) mRNA Construct for Enhanced WT1 Expression and Improved Immunogenicity In Vitro and In Vivo. Mol Ther Nucleic Acids. 2013 Nov 19;2(11):e134. doi: 10.1038/mtna.2013.54.

  PMID: 24253259 BACKGROUND

• Versteven M, Van den Bergh JMJ, Marcq E, Smits ELJ, Van Tendeloo VFI, Hobo W, Lion E. Dendritic Cells and Programmed Death-1 Blockade: A Joint Venture to Combat Cancer. Front Immunol. 2018 Mar 1;9:394. doi: 10.3389/fimmu.2018.00394. eCollection 2018.

  PMID: 29599770 BACKGROUND

• Van den Bergh JMJ, Smits ELJM, Berneman ZN, Hutten TJA, De Reu H, Van Tendeloo VFI, Dolstra H, Lion E, Hobo W. Monocyte-Derived Dendritic Cells with Silenced PD-1 Ligands and Transpresenting Interleukin-15 Stimulate Strong Tumor-Reactive T-cell Expansion. Cancer Immunol Res. 2017 Aug;5(8):710-715. doi: 10.1158/2326-6066.CIR-16-0336. Epub 2017 Jun 21.

  PMID: 28637876 BACKGROUND

• Versteven M, Van den Bergh JMJ, Broos K, Fujiki F, Campillo-Davo D, De Reu H, Morimoto S, Lecocq Q, Keyaerts M, Berneman Z, Sugiyama H, Van Tendeloo VFI, Breckpot K, Lion E. A versatile T cell-based assay to assess therapeutic antigen-specific PD-1-targeted approaches. Oncotarget. 2018 Jun 12;9(45):27797-27808. doi: 10.18632/oncotarget.25591. eCollection 2018 Jun 12.

  PMID: 29963238 BACKGROUND

• Van Driessche A, Berneman ZN, Van Tendeloo VF. Active specific immunotherapy targeting the Wilms' tumor protein 1 (WT1) for patients with hematological malignancies and solid tumors: lessons from early clinical trials. Oncologist. 2012;17(2):250-9. doi: 10.1634/theoncologist.2011-0240. Epub 2012 Jan 30.

  PMID: 22291091 BACKGROUND

• Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 2014 Jun;15(7):e257-67. doi: 10.1016/S1470-2045(13)70585-0.

  PMID: 24872109 BACKGROUND

• Van den Bossche J, De Laere M, Deschepper K, Germonpre P, Valcke Y, Lamont J, Stein B, Van Camp K, Germonpre C, Nijs G, Roelant E, Anguille S, Lion E, Berneman Z. Integration of the PD-L1 inhibitor atezolizumab and WT1/DC vaccination into standard-of-care first-line treatment for patients with epithelioid malignant pleural mesothelioma-Protocol of the Immuno-MESODEC study. PLoS One. 2024 Jul 15;19(7):e0307204. doi: 10.1371/journal.pone.0307204. eCollection 2024.

  PMID: 39008481 DERIVED

MeSH Terms

Conditions

Mesothelioma, Malignant; Wilms Tumor

Interventions

atezolizumab; Platinum

Condition Hierarchy (Ancestors)

Mesothelioma; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neoplasms, Complex and Mixed; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplastic Syndromes, Hereditary; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Metals, Heavy; Elements; Inorganic Chemicals; Transition Elements; Metals

Study Officials

• Zwi N Berneman, MD, PhD

  Antwerp University Hospital, Division of Hematology and Center for Cell Therapy and Regenerative Medicine

  STUDY DIRECTOR

• Paul Germonpré, MD, PhD

  AZ Maria Middelares, Respiratory Oncology & Integrated Cancer Center Ghent

  PRINCIPAL INVESTIGATOR

• Koen Deschepper, MD

  VITAZ, Division of Pulmonary and Infectious Diseases

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Zwi N Berneman, MD, PhD

CONTACT

0032 3 821 39 15; zwi.berneman@uza.be

Barbara Stein, MSc

CONTACT

0032 3 821 31 22; Barbara.Stein@uza.be

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 13, 2023
• First Posted: March 13, 2023
• Study Start: February 24, 2023
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026
• Last Updated: May 16, 2024

Record last verified: 2024-05

Locations

BE (3)