Immunotherapy of Stage III/IV Melanoma Patients

NCT00112242 | Completed Phase 1 Results DMC

• 1 other identifier: LUD 2001-003
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 2

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.

Conditions

Melanoma

Keywords

Immunotherapy; Vaccination; Melanoma; Melan-A/Mart-1 peptide; MAGE-A10 peptide; NY-ESO-1 peptide; Montanide; CpG

Outcome Measures

Primary Outcomes (9)

• Change From Baseline in Mean Number of Adverse Events (Serious and Non Serious Events)

  Safety of the vaccination was assessed according to the National Cancer Institute Common Toxicity Criteria (NCI CTC) scale. The adverse events (AE) and serious adverse events (SAE) were registered at each study visit during the 3 vaccination cycles and boost cycles.

  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).

• Fold Change From Baseline in ex Vivo Melan-A-specific CD8+ T Cells Frequency During the Vaccination Period

  Ex vivo frequency of Melan-A-specific CD8+ T cells was measured by multimer technique (tetramer assay) in a multicolor flow cytometry analysis. The fold change for each time point compared to baseline was calculated as: Melan-A-specific CD8+ T cell frequency at the time point/ Melan-A-specific CD8+ T cell frequency at baseline. Significant T cell response is defined by at least 2-fold change of Melan-A-specific CD8+ T cell frequency as compared to pre-immunotherapy.

  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).

• Fold Change From Baseline in ex Vivo Frequency of Melan-A-specific IFN-γ-secreting CD8+ T Cells During the Vaccination Period

  Ex vivo frequency of Melan-A-specific CD8+ T cells producing IFN-γ (Interferon-gamma) was measured through the Enzyme-Linked Immunosorbent Spot (ELISpot) assay. The fold change for each time point compared to baseline was calculated as: Melan-A-specific IFN-γ-secreting CD8+ T cell frequency at the time point/ Melan-A-specific IFN-γ-secreting CD8+ T cell frequency at baseline.

  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)

• Fold Change From Baseline in ex Vivo Frequency of NY-ESO-1-specific CD8+ T Cells During the Vaccination Period

  Ex vivo frequency of NY-ESO-1-specific CD8+ T cells was measured by multimer technique (tetramer assay) in a multicolor flow cytometry analysis. The fold change for each time point compared to baseline was calculated as: NY-ESO-1-specific CD8+ T cell frequency at the time point/ NY-ESO-1-specific CD8+ T cell frequency at baseline.

  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)

• Fold Change From Baseline in ex Vivo Frequency of NY-ESO-1-specific IFN-γ-secreting CD8+ T Cells During the Vaccination Period

  Ex vivo frequency of NY-ESO-1-specific CD8+ T cells producing IFN-γ (Interferon-gamma) was measured through the Enzyme-Linked Immunosorbent Spot (ELISpot) assay. The fold change for each time point compared to baseline was calculated as: NY-ESO-1-specific IFN-γ-secreting CD8+ T cell frequency at the time point/ NY-ESO-1-specific IFN-γ-secreting CD8+ T cell frequency at baseline.

  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)

• Fold Change From Baseline in ex Vivo Frequency of MAGE-A10-specific CD8+ T Cells During the Vaccination Period

  Ex vivo frequency of MAGE-A10-specific CD8+ T cells was measured by multimer technique (tetramer assay) in a multicolor flow cytometry analysis. The fold change for each time point compared to baseline was calculated as: MAGE-A10-specific CD8+ T cell frequency at the time point/ MAGE-A10-specific CD8+ T cell frequency at baseline.

  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)

• Fold Change From Baseline in ex Vivo Frequency of MAGE-A10-specific IFN-γ-secreting CD8+ T Cells During the Vaccination Period

  Ex vivo frequency of MAGE-A10-specific CD8+ T cells producing IFN-γ (Interferon-gamma) was measured through the Enzyme-Linked Immunosorbent Spot (ELISpot) assay. The fold change for each time point compared to baseline was calculated as: MAGE-A10-specific IFN-γ-secreting CD8+ T cell frequency at the time point/ MAGE-A10-specific IFN-γ-secreting CD8+ T cell frequency at baseline.

  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)

• Percentage of in Vitro Stimulated NY-ESO-1 Lp-specific IFN-γ/TNF-α -Secreting CD4+ T Cells During the Vaccination Period

  For each patient, total CD4+ T-cells were stimulated in the presence of peptide NY-ESO-1 long peptide (lp). After 10 days, cell cultures were challenged for 4h with the peptide or left unchallenged. The activation of NY-ESO-1 long peptide (lp)-specific CD4+ T cells were analyzed in vitro by Intracellular Cytokine Staining (ICS) via detection of IFN-γ (Interferon-gamma) and TNF-α (Tumor Necrosis Factor-alpha) producing cells.

  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)

• Percentage of in Vitro Stimulated NY-ESO-1 Lp-specific IFN-γ/TNFα -Secreting CD8+ T Cells During the Vaccination Period

  For each patient, total CD8+ T cells were stimulated in the presence of peptide NY-ESO-1 long peptide (lp). After 10 days, cell cultures were challenged for 4h with the peptide or left unchallenged. The activation of NY-ESO-1 long peptide (lp)-specific CD8+ T cells were analyzed in vitro by Intracellular Cytokine Staining (ICS) via detection of IFN-γ (Interferon-gamma) and TNF-α (Tumor Necrosis Factor-alpha) producing cells.

  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 (1)

• Disease Status Assessment During the Vaccination Period

  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)

Study Arms (5)

1. Melan-A ELA

EXPERIMENTAL

500 mcg Melan-A ELA analog peptide + 1 ml Montanide ISA-51

Biological: Melan-A ELA + Montanide

2. Melan-A ELA + NY-ESO-1b + MAGE-A10

EXPERIMENTAL

500 mcg Melan-A ELA analog peptide + 500 mcg NY-ESO-1b(A) analog peptide + 500 mcg MAGE-A10 peptide + 1 ml Montanide ISA-51

Biological: Melan-A ELA + NY-ESO-1b + MAGE-A10 + Montanide

3. Melan-A ELA + NY-ESO-1b + MAGE-A10 + CpG

EXPERIMENTAL

500 mcg Melan-A ELA analog peptide + 500 mcg NY-ESO-1b(A) analog peptide + 500 mcg MAGE-A10 peptide + 1 ml Montanide ISA-51 + 2.5 mg CpG-7909/PF-3512676

Biological: Melan-A -ELA + NY-ESO-1b + MAGE-A10 peptide + Montanide + CpG

4. Melan-A EAA/ELA + NY-ESO-1lp + MAGE-A10+ CpG

EXPERIMENTAL

* If patient is HLA-A2 positive: 100 mcg Melan-A EAA native peptide (during first cycle) or 100 mcg ELA analog peptide (during other cycles) + 500 mcg NY-ESO-1lp long peptide + 100 mcg MAGE-A10 peptide + 1 ml Montanide ISA-51 (no Montanide during cycle 3) + 2.5 mg CpG-7909/PF-3512676 * If patient is HLA-A2 negative: 500 mcg NY-ESO-1lp long peptide+ 1 ml Montanide ISA-51 (no Montanide during cycle 3) + 2.5 mg CpG-7909/PF-3512676

Biological: Melan-A-EAA/ELA + NY-ESO-1 lp + MAGE-A10 + Montanide + CpG

5. Melan-A EAA/ELA + NY-ESO-1lp + MAGE-A10+ CpG+ IL-2

EXPERIMENTAL

* If patient is HLA-A2 positive: 100 mcg Melan-A EAA native peptide (during first cycle) or 100 mcg ELA analog peptide (during other cycles) + 500 mcg NY-ESO-1lp long peptide + 100 mcg MAGE-A10 peptide + 1 ml Montanide ISA-51 (no Montanide during cycle 3) + 2.5 mg CpG-7909/PF-3512676 + low dose IL-2 * If patient is HLA-A2 negative: 500 mcg NY-ESO-1lp long peptide+ 1 ml Montanide ISA-51 (no Montanide during cycle 3) + 2.5 mg CpG-7909/PF-3512676 + low dose IL-2

Biological: Melan-A-EAA/ELA + NY-ESO-1 lp + MAGE-A10 + Montanide + CpG+ IL-2

Interventions

Melan-A ELA + Montanide BIOLOGICAL

A maximum of 3 vaccination cycles (cycles 1-3) has been given, each cycle consisting of 4 vaccines in 4 week intervals. The intervals between cycles were 8 weeks. After 3 cycles, patients without major tumor progression requiring other treatment who showed an immunological response received "booster vaccinations" every 3 months.

1. Melan-A ELA

Melan-A ELA + NY-ESO-1b + MAGE-A10 + Montanide BIOLOGICAL

A maximum of 3 vaccination cycles (cycles 1-3) has been given, each cycle consisting of 4 vaccines in 4 week intervals. The intervals between cycles were 8 weeks. After 3 cycles, patients without major tumor progression requiring other treatment who showed an immunological response received "booster vaccinations" every 3 months.

2. Melan-A ELA + NY-ESO-1b + MAGE-A10

Melan-A -ELA + NY-ESO-1b + MAGE-A10 peptide + Montanide + CpG BIOLOGICAL

A maximum of 3 vaccination cycles (cycles 1-3) has been given, each cycle consisting of 4 vaccines in 4 week intervals. The intervals between cycles were 8 weeks. After 3 cycles, patients without major tumor progression requiring other treatment who showed an immunological response received "booster vaccinations" every 3 months.

3. Melan-A ELA + NY-ESO-1b + MAGE-A10 + CpG

Melan-A-EAA/ELA + NY-ESO-1 lp + MAGE-A10 + Montanide + CpG BIOLOGICAL

A maximum of 3 vaccination cycles (cycles 1-3) has been given, each cycle consisting of 4 vaccines in 4 week intervals. The intervals between cycles were 8 weeks. After 3 cycles, patients without major tumor progression requiring other treatment who showed an immunological response received "booster vaccinations" every 3 months.

4. Melan-A EAA/ELA + NY-ESO-1lp + MAGE-A10+ CpG

Melan-A-EAA/ELA + NY-ESO-1 lp + MAGE-A10 + Montanide + CpG+ IL-2 BIOLOGICAL

A maximum of 3 vaccination cycles (cycles 1-3) has been given, each cycle consisting of 4 vaccines in 4 week intervals. The intervals between cycles were 8 weeks. After 3 cycles, patients without major tumor progression requiring other treatment who showed an immunological response received "booster vaccinations" every 3 months.

5. Melan-A EAA/ELA + NY-ESO-1lp + MAGE-A10+ CpG+ IL-2

Eligibility Criteria

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

You may qualify if:

• 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.
• 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.
• 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-.
• Expected survival of at least five months.
• Full recovery from surgery.
• Karnofsky scale performance status of 70% or more.
• 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 %
• Age \> 18 years.
• Able to give written informed consent.

You may not qualify if:

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

Sponsors & Collaborators

• Centre Hospitalier Universitaire Vaudois: lead
• Ludwig Institute for Cancer Research: collaborator

Study Sites (2)

Oncology Department, Lausanne University Hospital (CHUV) and University of Lausanne

Lausanne, Canton of Vaud, 1011, Switzerland

Location

Division of Oncology at the Geneva University Hospital

Geneva, 1211, Switzerland

Location

Related Publications (4)

• 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.

  PMID: 27853637 RESULT

• 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.

  PMID: 25808864 RESULT

• 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.

  PMID: 25277238 RESULT

• 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.

  PMID: 31015344 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

MART-1 Antigen; Monatide (IMS 3015); MAGE-A10 antigen; cytidylyl-3'-5'-guanosine

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Melanoma-Specific Antigens; Neoplasm Proteins; Proteins; Amino Acids, Peptides, and Proteins; Antigens, Neoplasm; Antigens; Biological Factors

Results Point of Contact

• Title: Prof Olivier Michielin
• Organization: Department of Oncology, Division of Medical Oncology University Hospital Lausanne

Olivier.Michielin@chuv.ch

+41 21 314 01 85

Study Officials

• Olivier Michielin, MD PhD

  Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: May 31, 2005
• First Posted: June 1, 2005
• Study Start: February 1, 2004
• Primary Completion: March 1, 2013
• Study Completion: March 1, 2013
• Last Updated: June 18, 2020
• Results First Posted: June 18, 2020

Record last verified: 2020-06

Locations

CH (2)