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

NCT01308294 | Terminated Phase 1 Results DMC

• 1 other identifier: P009-2010DR1082
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Melanoma

Keywords

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

Outcome Measures

Primary Outcomes (6)

• 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.

  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).

• 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.

  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).

• 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.

  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).

• 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.

  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).

• 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 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).

• 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.

  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 Outcomes (1)

• Tumor Response

  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)

Study Arms (3)

2 vaccine injections in 1 limb

EXPERIMENTAL

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)

Biological: 2 vaccine injections in 1 limb

2 vaccine injections in distinct limbs

EXPERIMENTAL

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)

Biological: 2 vaccine injections in distinct limbs

2 "vaccine injections" in distinct limbs

EXPERIMENTAL

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)

Biological: 2 "vaccine injections" in distinct limbs

Interventions

2 vaccine injections in 1 limb BIOLOGICAL

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.

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

2 vaccine injections in 1 limb

2 "vaccine injections" in distinct limbs BIOLOGICAL

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

2 "vaccine injections" in distinct limbs

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 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%

You may not qualify if:

• 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.

Sponsors & Collaborators

• Centre Hospitalier Universitaire Vaudois: lead
• Immutep S.A.S.: collaborator

Study Sites (1)

Oncology Department, CHUV

Lausanne, Canton of Vaud, 1011, Switzerland

Location

Related Publications (4)

• 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.

  PMID: 21142803 BACKGROUND

• 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.

  PMID: 19755389 BACKGROUND

• 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.

  PMID: 20413326 BACKGROUND

• 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.

  PMID: 26500235 RESULT

Related Links

• Multidisciplinary Oncology Center, CHUV, Lausanne

MeSH Terms

Conditions

Melanoma

Interventions

soluble LAG-3 protein, human; Monatide (IMS 3015)

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

Limitations and Caveats

Early termination leading to small numbers of subjects analyzed

Results Point of Contact

• Title: Prof. Olivier Michielin, MD PhD
• 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

  Oncology Department, Centre Hospitalier Universitaire Vaudois, Lausanne

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

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

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

Study Record Dates

• First Submitted: March 3, 2011
• First Posted: March 4, 2011
• Study Start: June 1, 2010
• Primary Completion: April 1, 2014
• Study Completion: April 1, 2014
• Last Updated: June 11, 2020
• Results First Posted: March 20, 2020

Record last verified: 2020-05

Locations

CH (1)