Clinical trial NCT00112242: Immunotherapy of Stage III/IV Melanoma Patients
Official title: Vaccination of Patients With Stage III or IV Malignant Melanoma With Melanoma Antigen Peptides [Melan-A/Mart-1 Analog (ELA), NY-ESO-1b(A) Analog and MAGE-A10] and Montanide Adjuvant
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Melanoma
Keywords: Immunotherapy
Vaccination
Melanoma
Melan-A/Mart-1 peptide
MAGE-A10 peptide
NY-ESO-1 peptide
Montanide
CpG
Lead sponsor: Centre Hospitalier Universitaire Vaudois
Sponsor class: OTHER
Collaborators: name: Ludwig Institute for Cancer Research
First posted: 2005-06-01
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether vaccination with melanoma antigen peptides \[Melan-A/Mart-1 (both EAA and ELA), NY-ESO-1b analog, Long NY-ESO-1 LP and MAGE-A10\] and Montanide, CpG adjuvants and low dose rIL-2 can induce an immune response in melanoma patients and to assess the safety of this vaccination.

Detailed description: Current peptide vaccines suffer from low efficiency, since they induce only weak immune activation. We have recently confirmed that in humans the immune response was readily detectable in local lymph nodes while no or only weak activation could be identified in circulating lymphocytes. Increased doses of antigen and adjuvant allow a better extension from local to systemic immune responses.

* Group 1 : vaccination with Melan-A analog (ELA) peptide + Montanide
* Group 2 : vaccination with Melan-A analog (ELA), NY-ESO-1b analog and MAGE-A10 peptides + Montanide
* Group 3: vaccination with Melan-A analog (both EAA and ELA), Mage-A10, NY-ESO-1 peptides+ Montanide + CpG adjuvant
* Group 4: vaccination with Melan-A (ELA), Mage-A10,long NY-ESO-1LP peptides + Montanide + CpG
* Group 5: vaccination with Melan-A (both EAA and ELA), Mage-A10, long NY-ESO-1 LP peptides + Montanide + CpG + low dose rIL-2

Eligibility criteria: Inclusion Criteria:

1. Histologically confirmed stage III or stage IV melanoma with at least one metastatic lymph node and/or at least one in-transit metastasis. According to the AJCC rules, this includes all patients with stage IV and stage III. Patients with or without measurable disease may be included.
2. Tumor expression of Melan-A by reverse transcriptase and polymerase chain reaction (RT-PCR) analysis for patients of group I.

   Tumor expression of Melan-A and at least one of the tumor antigens MAGE-A10, NY-ESO-1, or LAGE-1 by rt-PCR analysis for patients of group II and III and for HLA-A2+ patients of groups IV and V. HLA-A2 negative patients of groups IV and V must only have NY-ESO-1 positive tumors to be eligible, while expression of Melan-A and MAGE-A10 is unimportant.

   If no frozen tissue is available, immunohistochemistry may be performed to detect tumor expression of Melan-A and NY-ESO-1.
3. HLA-A2 positive (serological or molecular typing of Peripheral Blood Lymphocytes (PBL) for patients of groups 1 to 3. Patients of groups 4 and 5 may either be HLA-A2+ or HLA-A2-.
4. Expected survival of at least five months.
5. Full recovery from surgery.
6. Karnofsky scale performance status of 70% or more.
7. The following laboratory results:

   Neutrophil count sup or equal 2.0 x 10\^9/L Lymphocyte count sup or equal 0.5 x 10\^9/L Platelet count sup or equal 100 x 10\^9/L Creatinine ≤ 2 mg/dL (180 micromol/L) Bilirubin ≤ 2mg/dL (34 micromol/L) Granulocyte count \> 2.5x10\^9/L AST \< 2x upper limit of normal aPTT: within the normal ranges of the laboratory ± 25 %
8. Age \> 18 years.
9. Able to give written informed consent.

Exclusion Criteria:

1. Clinically significant heart disease (NYHA Class III or IV).
2. Other serious illnesses, e.g., serious infections requiring antibiotics, uncontrolled peptic ulcer, or central nervous system disorders with major dysfunction.
3. History of immunodeficiency disease or autoimmune disease.
4. Known HIV positivity.
5. Known seropositivity for hepatitis B surface antigen.
6. Chemotherapy, radiation therapy, or immunotherapy within 4 weeks before study entry (6 weeks for nitrosoureas).
7. Concomitant treatment with steroids, antihistamine drugs. Topical or inhalational steroids are permitted.
8. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to enrollment.
9. Pregnancy or lactation.
10. Women of childbearing potential not using a medically acceptable means of contraception.
11. Psychiatric or addictive disorders that may compromise the ability to give informed consent.
12. Lack of availability of the patient for immunological and clinical follow-up assessment.
13. Coagulation or bleeding disorders.
14. Metastatic disease to the central nervous system, unless treated and stable.

Primary outcomes:
measure: Change From Baseline in Mean Number of Adverse Events (Serious and Non Serious Events)
timeFrame: Change from baseline to end of Cycle 1 (3 months), end of Cycle 2 (8 months), end of Cycle 3 (13 months) and end of Boost Cycles (18 months to 23 months).
measure: Fold Change From Baseline in ex Vivo Melan-A-specific CD8+ T Cells Frequency During the Vaccination Period
timeFrame: Fold change from baseline in Melan-A-specific CD8+T-cells at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months).
measure: Fold Change From Baseline in ex Vivo Frequency of Melan-A-specific IFN-γ-secreting CD8+ T Cells During the Vaccination Period
timeFrame: Fold change from baseline in Melan-A-specific IFN-γ-secreting CD8+T-cells frequency at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months)
measure: Fold Change From Baseline in ex Vivo Frequency of NY-ESO-1-specific CD8+ T Cells During the Vaccination Period
timeFrame: Fold change from baseline in NY-ESO-1-specific CD8+T-cells at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months)
measure: Fold Change From Baseline in ex Vivo Frequency of NY-ESO-1-specific IFN-γ-secreting CD8+ T Cells During the Vaccination Period
timeFrame: Fold change from baseline in NY-ESO-1-specific IFN-γ-secreting CD8+T-cells frequency at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months)
measure: Fold Change From Baseline in ex Vivo Frequency of MAGE-A10-specific CD8+ T Cells During the Vaccination Period
timeFrame: Fold change from baseline in MAGE-A10-specific CD8+T-cells at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months)
measure: Fold Change From Baseline in ex Vivo Frequency of MAGE-A10-specific IFN-γ-secreting CD8+ T Cells During the Vaccination Period
timeFrame: Fold change from baseline in MAGE-A10-specific IFN-γ-secreting CD8+T-cells frequency at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months)
measure: Percentage of in Vitro Stimulated NY-ESO-1 Lp-specific IFN-γ/TNF-α -Secreting CD4+ T Cells During the Vaccination Period
timeFrame: Percentage of NY-ESO-1 lp-specific IFN-γ/TNF-α -secreting CD4+ T-cells at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months)
measure: Percentage of in Vitro Stimulated NY-ESO-1 Lp-specific IFN-γ/TNFα -Secreting CD8+ T Cells During the Vaccination Period
timeFrame: Percentage of NY-ESO-1 lp-specific IFN-γ/TNF-α -secreting CD8+ T cells at the end of Cycle 1 (3 months), at the end of Cycle 2 (8 months), at the end of Cycle 3 (13 months) and if applicable at the end of Boost cycles (18 to 24 months)
Secondary outcomes:
measure: Disease Status Assessment During the Vaccination Period
timeFrame: Disease status at baseline, after cycle 1 (3 months), after cycle 2 (8 months), after cycle 3 (13 months) and if applicable after boost cycles (16 months, 19 months or 22 months)
Other outcomes:
Locations:
city: Lausanne
country: Switzerland
facility: Oncology Department, Lausanne University Hospital (CHUV) and University of Lausanne
state: Vaud
city: Geneva
country: Switzerland
facility: Division of Oncology at the Geneva University Hospital
Study officials:
affiliation: Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois)
name: Olivier Michielin, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Baumgaertner P, Costa Nunes C, Cachot A, Maby-El Hajjami H, Cagnon L, Braun M, Derre L, Rivals JP, Rimoldi D, Gnjatic S, Abed Maillard S, Marcos Mondejar P, Protti MP, Romano E, Michielin O, Romero P, Speiser DE, Jandus C. Vaccination of stage III/IV melanoma patients with long NY-ESO-1 peptide and CpG-B elicits robust CD8+ and CD4+ T-cell responses with multiple specificities including a novel DR7-restricted epitope. Oncoimmunology. 2016 Sep 9;5(10):e1216290. doi: 10.1080/2162402X.2016.1216290. eCollection 2016.
citation: Hebeisen M, Schmidt J, Guillaume P, Baumgaertner P, Speiser DE, Luescher I, Rufer N. Identification of Rare High-Avidity, Tumor-Reactive CD8+ T Cells by Monomeric TCR-Ligand Off-Rates Measurements on Living Cells. Cancer Res. 2015 May 15;75(10):1983-91. doi: 10.1158/0008-5472.CAN-14-3516. Epub 2015 Mar 25.
citation: Bordry N, Costa-Nunes CM, Cagnon L, Gannon PO, Abed-Maillard S, Baumgaertner P, Murray T, Letovanec I, Lazor R, Bouchaab H, Rufer N, Romano E, Michielin O, Speiser DE. Pulmonary sarcoid-like granulomatosis after multiple vaccinations of a long-term surviving patient with metastatic melanoma. Cancer Immunol Res. 2014 Dec;2(12):1148-53. doi: 10.1158/2326-6066.CIR-14-0143. Epub 2014 Oct 2.
citation: Costa-Nunes C, Cachot A, Bobisse S, Arnaud M, Genolet R, Baumgaertner P, Speiser DE, Sousa Alves PM, Sandoval F, Adotevi O, Reith W, Protti MP, Coukos G, Harari A, Romero P, Jandus C. High-throughput Screening of Human Tumor Antigen-specific CD4 T Cells, Including Neoantigen-reactive T Cells. Clin Cancer Res. 2019 Jul 15;25(14):4320-4331. doi: 10.1158/1078-0432.CCR-18-1356. Epub 2019 Apr 23.