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Immunotherapy of HLA-A2 Positive Stage II-IV Melanoma Patients (LAG-3/IMP321)

Primary Purpose

Melanoma

Status

Terminated

Phase

Phase 1

Locations

Switzerland

Study Type

Interventional

Intervention

2 vaccine injections in 1 limb

2 vaccine injections in distinct limbs

2 "vaccine injections" in distinct limbs

About this trial

This is an interventional treatment trial for Melanoma focused on measuring Melanoma, Stage II-IV, Immunotherapy, Vaccination, HLA class I and II tumor-specific peptides, IMP321, Montanide ISA-51

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Histologically confirmed stage II, III or IV melanoma patients.
Tumor expression of Melan-A.
Human leukocyte antigen-A2 (HLA-A2) positive.
Expected survival of at list 3 months.
Karnofsky scale performance status of 70 % or more.
Age ≥ 18 years.
Able to give a written informed consent.
The following laboratory results:

Hemoglobin ≥ 100g/L, Neutrophil count ≥ 1.5 x 109/L, Lymphocyte count ≥ 0.5 x 109/L, Platelet count ≥ 100 x 109/L, Serum creatinine ≤ 2 mg/dL (0.18mmol/L), Serum bilirubin ≤ 2mg/dL (0.034mmol/L), Granulocyte count > 2.5x109/L, Aspartate Amino Transférase (ASAT), Alanine Amino Transferase (ALAT) < 2.5 x upper limit of normal, Activated Partial Thromboplastin Time (aPTT) within the normal ranges ±25%, Thromplastin (TP) ≥ 80%

Exclusion Criteria:

Clinically significant heart disease.
Serious illness, eg. serious infections requiring antibiotics, uncontrolled peptic ulcer, or central nervous system disorders.
History of immunodeficiency disease or autoimmune disease.
Metastatic disease to the central nervous system, unless treated and stable.
Known HIV positivity.
Known seropositivity for hepatitis B surface antigen.
Concomitant treatment with steroids, antihistamine drugs. Topical or inhalation 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.
Kidney dysfunction with creatinine > 2 X the upper limit of the normal value.
Reported strong (allergic) reactions to previous vaccination.

Sites / Locations

Oncology Department, CHUV

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

2 vaccine injections in 1 limb

2 vaccine injections in distinct limbs

2 "vaccine injections" in distinct limbs

Arm Description

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)

Outcomes

Primary Outcome Measures

Ex Vivo Frequency of Melan-A Specific CD8+T Cells

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.

In Vitro Frequency of MAGE A3.DP4-specific CD4+ T Cells Producing Interferon-gamma (IFN-γ)

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.

In Vitro Frequency of MAGE A3.DP4-specific CD4+ T Cells Producing Tumor Necrosis Factor-alpha (TNF-α)

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.

In Vitro Frequency of MAGE A3.DP4-specific CD4+ T 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.

In Vitro Frequency of Melan-A-specific CD8+T Cells After Stimulation

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.

In Vitro Frequency of NY-ESO-1-specific CD8+ T Cells

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.

Secondary Outcome Measures

Tumor Response

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.

Full Information

NCT ID

NCT01308294

First Posted

March 3, 2011

Last Updated

May 26, 2020

Sponsor

Centre Hospitalier Universitaire Vaudois

Collaborators

Immutep S.A.S.

1. Study Identification

Unique Protocol Identification Number

NCT01308294

Brief Title

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

Acronym

LAG-3/IMP321

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2020

Overall Recruitment Status

Terminated

Why Stopped

Low enrollment rate

Study Start Date

June 2010 (Actual)

Primary Completion Date

April 2014 (Actual)

Study Completion Date

April 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Centre Hospitalier Universitaire Vaudois

Collaborators

Immutep S.A.S.

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Melanoma

Keywords

Melanoma, Stage II-IV, Immunotherapy, Vaccination, HLA class I and II tumor-specific peptides, IMP321, Montanide ISA-51

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Model Description

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

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

16 (Actual)

8. Arms, Groups, and Interventions

Arm Title

2 vaccine injections in 1 limb

Arm Type

Experimental

Arm Description

Arm Title

2 vaccine injections in distinct limbs

Arm Type

Experimental

Arm Description

Arm Title

2 "vaccine injections" in distinct limbs

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

2 vaccine injections in 1 limb

Other Intervention Name(s)

vaccine1: NY-ESO-1,MAGE-3.A2, NA-17, IMP321, Montanide, vaccine 2: Melan-A, MAGE-A3-DP4 , IMP321, Montanide

Intervention Description

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.

Intervention Type

Biological

Intervention Name(s)

2 vaccine injections in distinct limbs

Other Intervention Name(s)

vaccine 1: NY-ESO-1, MAGE-3.A2, NA-17,IMP321, Montanide, vaccine 2: Melan-A, MAGE-A3-DP4, IMP321, Montanide)

Intervention Description

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.

Intervention Type

Biological

Intervention Name(s)

2 "vaccine injections" in distinct limbs

Other Intervention Name(s)

vaccine 1: NY-ESO-1, NA-17, IMP321, Montanide, vaccine 2: Melan-A, NA-17, IMP321, Montanide

Primary Outcome Measure Information:

Title

Ex Vivo Frequency of Melan-A Specific CD8+T Cells

Description

Time Frame

Melan-A specific CD8+ T cells were measured in PBMC collected at the end of Cycle 1 (Week 7), end of Cycle 2 (Week 25), end of Cycle 3 (Week 40), and Follow-up (6 to 18 months after the end of Cycle 3).

Title

In Vitro Frequency of MAGE A3.DP4-specific CD4+ T Cells Producing Interferon-gamma (IFN-γ)

Description

Time Frame

MAGE A3.DP4 specific CD4+ T cells producing IFN-γ were measured in PBMC collected at the end of Cycle 1 (Week 7), end of Cycle 2 (Week 25), end of Cycle 3 (Week 40), and Follow-up (6 to 18 months after the end of Cycle 3).

Title

In Vitro Frequency of MAGE A3.DP4-specific CD4+ T Cells Producing Tumor Necrosis Factor-alpha (TNF-α)

Description

Time Frame

MAGE A3.DP4 specific CD4+ T-cells producing TNF-α were measured in PBMC collected at the end of Cycle 1 (Week 7), end of Cycle 2 (Week 25), end of Cycle 3 (Week 40), and Follow-up (6 to 18 months after the end of Cycle 3).

Title

In Vitro Frequency of MAGE A3.DP4-specific CD4+ T Cells

Description

Time Frame

MAGE A3.DP4 specific CD4+ T cells were measured in PBMC collected at the end of Cycle 1 (Week 7), end of Cycle 2 (Week 25), end of Cycle 3 (Week 40) and Follow-up (6 to 18 months after the end of Cycle 3).

Title

In Vitro Frequency of Melan-A-specific CD8+T Cells After Stimulation

Description

Time Frame

In vitro stimulated Melan-A specific CD8+ T cells were measured in PBMC collected at the end of Cycle 1 (Week 7), end of Cycle 2 (Week 25), end of Cycle 3 (Week 40) and Follow-up (6 to 18 months after the end of Cycle 3).

Title

In Vitro Frequency of NY-ESO-1-specific CD8+ T Cells

Description

Time Frame

In vitro stimulated NY-EYO-1 specific CD8+ T cells were measured in PBMC collected at the end of Cycle 1 (Week 7), end of Cycle 2 (Week 25), end of Cycle 3 (Week 40), and Follow-up (6 to 18 months after the end of Cycle 3).

Secondary Outcome Measure Information:

Title

Tumor Response

Description

Time Frame

Change from baseline in tumor response at the end of Cycle 1 (Week 7), end of Cycle 2 (Week 25) and end of Cycle 3 (Week 40)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Histologically confirmed stage II, III or IV melanoma patients. Tumor expression of Melan-A. Human leukocyte antigen-A2 (HLA-A2) positive. Expected survival of at list 3 months. Karnofsky scale performance status of 70 % or more. Age ≥ 18 years. Able to give a written informed consent. The following laboratory results: Hemoglobin ≥ 100g/L, Neutrophil count ≥ 1.5 x 109/L, Lymphocyte count ≥ 0.5 x 109/L, Platelet count ≥ 100 x 109/L, Serum creatinine ≤ 2 mg/dL (0.18mmol/L), Serum bilirubin ≤ 2mg/dL (0.034mmol/L), Granulocyte count > 2.5x109/L, Aspartate Amino Transférase (ASAT), Alanine Amino Transferase (ALAT) < 2.5 x upper limit of normal, Activated Partial Thromboplastin Time (aPTT) within the normal ranges ±25%, Thromplastin (TP) ≥ 80% Exclusion Criteria: Clinically significant heart disease. Serious illness, eg. serious infections requiring antibiotics, uncontrolled peptic ulcer, or central nervous system disorders. History of immunodeficiency disease or autoimmune disease. Metastatic disease to the central nervous system, unless treated and stable. Known HIV positivity. Known seropositivity for hepatitis B surface antigen. Concomitant treatment with steroids, antihistamine drugs. Topical or inhalation 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. Kidney dysfunction with creatinine > 2 X the upper limit of the normal value. Reported strong (allergic) reactions to previous vaccination.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Olivier Michielin, MD PhD

Organizational Affiliation

Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne

Official's Role

Principal Investigator

Facility Information:

Facility Name

Oncology Department, CHUV

City

Lausanne

State/Province

Vaud

ZIP/Postal Code

1011

Country

Switzerland

12. IPD Sharing Statement

Citations:

PubMed Identifier

21142803

Citation

Sierro S, Romero P, Speiser DE. The CD4-like molecule LAG-3, biology and therapeutic applications. Expert Opin Ther Targets. 2011 Jan;15(1):91-101. doi: 10.1517/14712598.2011.540563.

Results Reference

background

PubMed Identifier

19755389

Citation

Brignone C, Escudier B, Grygar C, Marcu M, Triebel F. A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma. Clin Cancer Res. 2009 Oct 1;15(19):6225-31. doi: 10.1158/1078-0432.CCR-09-0068. Epub 2009 Sep 15.

Results Reference

background

PubMed Identifier

20413326

Citation

Speiser DE, Romero P. Molecularly defined vaccines for cancer immunotherapy, and protective T cell immunity. Semin Immunol. 2010 Jun;22(3):144-54. doi: 10.1016/j.smim.2010.03.004. Epub 2010 Apr 21.

Results Reference

background

PubMed Identifier

26500235

Citation

Legat A, Maby-El Hajjami H, Baumgaertner P, Cagnon L, Abed Maillard S, Geldhof C, Iancu EM, Lebon L, Guillaume P, Dojcinovic D, Michielin O, Romano E, Berthod G, Rimoldi D, Triebel F, Luescher I, Rufer N, Speiser DE. Vaccination with LAG-3Ig (IMP321) and Peptides Induces Specific CD4 and CD8 T-Cell Responses in Metastatic Melanoma Patients--Report of a Phase I/IIa Clinical Trial. Clin Cancer Res. 2016 Mar 15;22(6):1330-40. doi: 10.1158/1078-0432.CCR-15-1212. Epub 2015 Oct 23.

Results Reference

result

Links:

URL

http://www.cancer-chuv.ch/ccl_home.htm

Description

Multidisciplinary Oncology Center, CHUV, Lausanne

Learn more about this trial

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

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