Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

All Drugs and Chemicals

Vaccines

Immunomodulating Agents

Monatide (IMS 3015)

Immunologic Factors

Adjuvants, Immunologic

9 patients initially planned: patients received peptides with IMP321/LAG-3Ig and Montanide in 2 injections sites at 5 cm distance from each other 2 vaccine injections in same limb (vaccine 1 : NY-ESO-1, MAGE-3.A2, NA-17 peptides + IMP321 + Montanide) (vaccine 2 : Melan-A, MAGE-A3-DP4 peptides + IMP321 + Montanide)

Groupe2: 2 vaccine injections in different limb should include 9 patients that were initially planned: patients received the same vaccine in 2 syringes injected each in a distinct limb (vaccine 1: NY-ESO-1, MAGE-3.A2, NA-17 peptides + IMP321 + Montanide) (vaccine 2: Melan-A, MAGE-A3-DP4 peptides + IMP321 + Montanide)

Groupe3: 2 vaccine injections in distinct limb should include 9 patients that were initially planned; due to premature trial termination, no patients could be enrolled. Patients of this group should have received the same vaccine but without the MHC class II peptide (MAGE-A3)

Participants receive the vaccine separated in 2 syringes with syringe 1 containing NA-17, MAGE-3.A2 and NY-ESO-1 peptides with IMP321/LAG3 ± Montanide, and syringe 2 containing Melan-A and MAGE-A3-DP4 peptides with IMP321/LAG-3 ± Montanide. The content of each syringe is injected s.c. in the same limb at about 5 cm distance from each other.

2 vaccine injections in 1 limb

Participants receive the vaccine separated in 2 syringes with syringe 1 containing NA-17, MAGE-3.A2 and NY-ESO-1 peptides with IMP321/LAG3 ± Montanide, and syringe 2 containing Melan-A and MAGE-A3-DP4 peptides with IMP321/LAG-3 ± Montanide.The content of each syringe is injected s.c. in different limbs.

2 vaccine injections in distinct limbs

2 "vaccine injections" in distinct limbs

Olivier Michielin, MD PhD

The purpose of this study is to determine whether vaccination with tumor antigenic peptides and both IMP321/LAG-3 and Montanide adjuvants can induce an immune response in melanoma patients and to assess the safety and tolerability of this vaccination. Tumor responses following this vaccination will also be documented.

The primary objective of this study is:

* to evaluate melanoma antigen specific immune response induced by this vaccination with tumor antigenic peptides derived from MAGE-A3 (Melanoma Antigen family A3) (MHCI: MAGE-A3.A2 and MHCII: MAGE-A3.DP4), NY-ESO-1 (New York Esophageal squamous cell carcinoma antigen-1), Melan A (analog ELA and native EAA) and NA-17A with IMP321 (ImmuFact)/ LAG-3Ig (Lymphocyte activation gene-3 immunoglobulin-like domains) as adjuvant/immunostimulant, formulated with Montanide ISA-51.
* to assess the safety and tolerability of this vaccination

The secondary objective is to document tumor responses in patients following this vaccination.

open label, non comparative study in patients suffering from stage II, III or IV melanoma

Immunotherapy of HLA-A2 Positive Stage II-IV Melanoma Patients

Vaccination of Melanoma Patients (Stage II-IV) With ImmuFact IMP321, Tumor Antigenic Peptides and Montanide

Cellular immunity was evaluated through the activation and the expansion of Melan-A-specific CD8+ cytotoxic T lymphocytes. Their frequency was measured in the peripheral blood mononuclear cells (PBMC) directly ex vivo (i.e. without prior in vitro expansion) by multicolor flow cytometry with Melan-A ELA tetramers.

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.

The activation of peptide-specific CD4+ T cells was analyzed in vitro before and after vaccination by Intracellular Cytokine Staining (ICS).

From each patient, total CD4+ T-cells were stimulated in the presence of peptide MAGE-A3.DP4 LP (MAGE-A3243-258 peptide presented by autologous cells).

After 10 days, cell cultures were challenged for 4h with the peptide or left unchallenged.

Specific CD4+ T cells responses were identified via detection of IFN-γ producing cells.

The activation of peptide-specific CD4+ T cells was analyzed in vitro before and after vaccination by ICS.

From each patient, total CD4+ T-cells were stimulated in the presence of peptide MAGE-A3.DP4 LP (MAGE-A3243-258 peptide presented by autologous cells).

After 10 days, cell cultures were challenged for 4h with the peptide or left unchallenged.

Specific CD4+ T cells responses were identified via detection of TNF-α producing cells.

Frequencies of specific MAGE-A3.DP4-specific CD4+ T cells were quantified by flow cytometry using class II tetramers after 10 days of in vitro stimulation.

The fold change for each time point compared to baseline was calculated as: MAGE-A3.DP4-specific CD4+ T cell frequency at the time point/ MAGE-A3.DP4-specific CD4+ T cell frequency at baseline.

After 12 days of in vitro stimulation with Melan-A peptides, CD8+ T cells were analyzed by flow cytometry using tetramer staining.

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.

After 12 days of in vitro stimulation with NY-ESO-1 peptide, CD8+ T cells were analyzed by flow cytometry using tetramer staining.

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.

The assessment of the baseline disease status was performed, using CT (Computed Tomography) scan or PET (Positron Emission Tomography)/ CT scan, at screening visit or within 8 weeks preceding the screening visit. Imagery examinations occurred after the end of each vaccination cycle. The tumor response was assessed according to the classification World Health Organization (WHO) 1979 and defined as:

* No evidence of disease (NED),
* Stable disease (SD): change in size of all measurable lesions (the sum of the products of the greatest and perpendicular parameters), of less than a 25% increase or 25% decrease from baseline for at least 4 weeks, without appearance of new lesions or progression of any lesion.
* Progressive disease (PD): appearance of new tumors, or increase in size of any measurable tumor by at least 25% of the sum of the product of the greatest and perpendicular diameter.

Immutep S.A.S.

Centre Hospitalier Universitaire Vaudois

Professor

No patients were included in the group 3. All adverse events were collected irrespective of their frequency, their severity and relationship to the study drug.

The adverse events that were expected, according to the Investigator's Brochure of the different vaccine components, were assessed systematically at each visit study.

2 vaccine injections in same limb (vaccine 1 : NY-ESO-1, MAGE-3.A2, NA-17 peptides + IMP321 + Montanide) (vaccine 2 : Melan-A, MAGE-A3-DP4 peptides + IMP321 + Montanide)

2 vaccine injections in 1 limb: All participants receive the vaccine separated in 2 syringes with syringe 1 containing NA-17, MAGE-3.A2 and NY-ESO-1 peptides with IMP321/LAG3 ± Montanide, and syringe 2 containing Melan-A and MAGE-A3-DP4 peptides with IMP321/LAG-3 ± Montanide. The content of each syringe is injected s.c. in the same limb at about 5 cm distance from each other.

Group 1

2 vaccine injections in different limbs (vaccine 1: NY-ESO-1, MAGE-3.A2, NA-17 peptides + IMP321 + Montanide) (vaccine 2: Melan-A, MAGE-A3-DP4 peptides + IMP321 + Montanide)

2 vaccine injections in different limbs: All participants receive the vaccine separated in 2 syringes with syringe 1 containing NA-17, MAGE-3.A2 and NY-ESO-1 peptides with IMP321/LAG3 ± Montanide, and syringe 2 containing Melan-A and MAGE-A3-DP4 peptides with IMP321/LAG-3 ± Montanide.The content of each syringe is injected s.c. in different limbs.

Group 2

2 vaccine injections in different limbs (vaccine 1: NY-ESO-1, MAGE-3.A2, NA-17 peptides + IMP321 + Montanide) (vaccine 2: Melan-A peptide + IMP321 + Montanide)

2 vaccine injections in different limbs, the vaccine does not contain the MHC class II peptide MAGE-A3-DP4: All participants receive the vaccine separated in 2 syringes with syringe 1 containing NA-17, MAGE-3.A2 and NY-ESO-1 peptides with IMP321/LAG3 ± Montanide, and syringe 2 containing Melan-A peptide with IMP321/LAG-3 ± Montanide. The content of each syringe is injected s.c. in different limbs.

Group 3

9 patients initially planned: patients received peptides with IMP321/LAG-3Ig and Montanide in 2 injections sites at 5 cm distance from each other 2 vaccine injections in same limb (vaccine 1 : NY-ESO-1, MAGE-3.A2, NA-17 peptides + IMP321 + Montanide)(vaccine 2 : Melan-A, MAGE-A3-DP4 peptides + IMP321 + Montanide)

2 vaccine injections in 1 limb: Participants receive the vaccine separated in 2 syringes with syringe 1 containing NA-17, MAGE-3.A2 and NY-ESO-1 peptides with IMP321/LAG3 ± Montanide, and syringe 2 containing Melan-A and MAGE-A3-DP4 peptides with IMP321/LAG-3 ± Montanide. The content of each syringe is injected s.c. in the same limb at about 5 cm distance from each other.

Group 1: 2 Vaccine Injections in 1 Limb

9 patients initially planned: patients received the same vaccine in 2 syringes injected each in a distinct limb 2 vaccine injections in different limbs (vaccine 1: NY-ESO-1, MAGE-3.A2, NA-17 peptides + IMP321 + Montanide) (vaccine 2: Melan-A, MAGE-A3-DP4 peptides + IMP321 + Montanide)

2 vaccine injections in different limbs: Participants receive the vaccine separated in 2 syringes with syringe 1 containing NA-17, MAGE-3.A2 and NY-ESO-1 peptides with IMP321/LAG3 ± Montanide, and syringe 2 containing Melan-A and MAGE-A3-DP4 peptides with IMP321/LAG-3 ± Montanide.The content of each syringe is injected s.c. in different limbs.

Group 2: 2 Injections in Different Limbs

9 patients initially planned: due to premature trial termination, no patients could be enrolled in this last group. 2 vaccine injections in different limbs; patients of this group should have received the same vaccine but without the MHC class II peptide (MAGE-A3 LP) in 2 syringes injected each in a distinct limb.

2 vaccine injections without MHC class II peptide in different limbs: Participants receive the vaccine separated in 2 syringes with syringe 1 containing NA-17, MAGE-3.A2 and NY-ESO-1 peptides with IMP321/LAG3 ± Montanide, and syringe 2 containing Melan-A peptide with IMP321/LAG-3 ± Montanide.

Group 3: 2 Injections in Different Limbs

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Switzerland

Region of Enrollment

Due to premature trial termination, no patients could be enrolled in the Group 3.

Early termination leading to small numbers of subjects analyzed

Spots Global Cancer Trial Database for 2 vaccine injections in 1 limb