Immunization With 8 Peptides Mixed With CpG 7909 or Montanide ISA51 in Patients With Metastatic Cutaneous Melanoma

Phase 1

Terminated

Conditions: Malignant Melanoma

Interventions: Biological: 8 HLA-A2-restricted peptides and CpG 7909
Biological: 8 HLA-A2-restricted peptides and Montanide ISA51

Registration Number: NCT00145158

Lead Sponsor: Ludwig Institute for Cancer Research

Brief Summary: The purposes of this study are to describe the immune response to individual peptides after immunization with a combination of 8 peptides and CpG 7909 or Montanide ISA51; to determine the safety of the vaccines and; to document the tumor response in patients receiving the vaccines.

Detailed Description: Patients received six sequential immunizations with 8 peptides presented by HLA-A2 and mixed with either CpG 7909 or Montanide ISA51, at 2-week intervals. The 8 peptides were injected at 8 distinct injection sites. These peptides are the following: MAGE-1.A2, MAGE-3.A2, MAGE-4.A2, MAGE-10.A2, MAGE-C2.A2 (ALKD), and NA17.A2 (20% intradermally and 80% subcutaneously); NY-ESO-1.A2 and Tyrosinase.A2 (100% subcutaneously).

300 µg of each peptide (except MAGE-10.A2 150 µg) was mixed with 4 mg CpG 7909 (Cohort 1) or 0.5ml of Montanide ISA51 (Cohort 2). In Cohort 2, the Tyrosinase.A2 was administered without Montanide ISA51.

Tumor staging was performed before inclusion and at week 13. Peripheral Blood Lymphocytes (PBL) collections were performed before starting the treatment, and at weeks 3, 7 and 13. They provided the T lymphocytes for the immunological analysis.

At week 13, the PCR results of the pre-immune tumor biopsy must be available. Additional cycles of immunization, ONLY with the peptides expressed by the tumor, mixed with Montanide ISA51, will be proposed to patients without tumor progression requiring another treatment. A second cycle of 3 injections at 6-week intervals will be started at week 17, followed by a third cycle of 12 injections at 3-month intervals, starting at month 11. At any time, progression of the disease necessitating any treatment not allowed during the study will result in withdrawal.

The immune response may well be a limiting factor to the therapeutic efficacy of the vaccine. If this is the case, it then becomes crucial to understand why some patients develop a cytotoxic t-lymphocyte (CTL) response against the vaccine, while the majority of them do not. One possible explanation for the low frequency of clinical responses is that each injection of a single peptide has a low probability to provide the adequate stimulus to activate very rare CTL precursors. This probability should be increased if several peptides known to be undoubtedly associated with tumor regressions were used together to immunize patients.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 23

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Cohort 1: 8 HLA-A2-restricted peptides and CpG 7909	8 HLA-A2-restricted peptides and CpG 7909	Patients were immunized with a combination of 8 peptides corresponding to defined tumor antigens (MAGE-1.A2, MAGE-3.A2, MAGE-4.A2, MAGE-10.A2, MAGE-C2.A2, NY-ESO-1.A2, NA17.A2 and Tyrosinase.A2), mixed with CpG 7909. Patients received six sequential injections at 2-week intervals.
Cohort 2: 8 HLA-A2-Restricted Peptides and Montanide ISA51	8 HLA-A2-restricted peptides and Montanide ISA51	Patients were immunized with a combination of 8 peptides corresponding to defined tumor antigens (MAGE-1.A2, MAGE-3.A2, MAGE-4.A2, MAGE-10.A2, MAGE-C2.A2, NY-ESO-1.A2, and NA17.A2), mixed with Montanide ISA 51. Tyrosinase.A2 was administered without Montanide ISA51. Patients received six sequential injections at 2-week intervals.

Primary Outcome Measures

Name	Time	Method
Number of Patients With Cytotoxic T-lymphocyte (CTL) Response to Individual Peptides After Immunization With a Combination of 8 Peptides and CpG 7909 or Montanide ISA51.	Week 13	Peripheral blood lymphocytes (PBL) were collected prior to the first dose of vaccine and after the completion of the six vaccinations in Week 13. Specific CTL directed against the 8 vaccine antigens ( NA17.A2, MAGE-1.A2, MAGE-3.A2, MAGE-4.A2, MAGE-10.A2, MAGE-C2.A2 and Tyrosinase.A2) was assessed by using re-stimulation in vitro, followed by staining with the corresponding tetramer (MLPC/tetramer). A patient was considered to have a positive CTL response when the post-vaccine CTL response against at least one of the vaccine antigens was ten times higher than the corresponding pre-treatment value.

Secondary Outcome Measures

Name	Time	Method
Number of Patients With Cytotoxic T-lymphocyte (CTL) Responses and Tumor Expression of the Corresponding Genes.	Week 13	Gene expression was determined by RT-PCR on a pre-treatment tumor sample. The correlation of the induction of a CTL response against a defined antigen to the prior expression of the gene coding for this antigen by the tumor removed before vaccination was assessed.
Number of Patients With Tumor Responses After Immunization With a Combination of 8 Peptides and CpG 7909 or Montanide ISA51 as Measured by RECIST.	Week 13	Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). Tumor measurements were taken at screening and at the end of Cycle 1 in Week 13. Per RECIST, target lesions are categorized as follows: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria.
Number of Patients With Dose Limiting Toxicities (DLT).	up to Week 13	Toxicity was evaluated according to the National Cancer Institute (CTC Scale Version 3.0, published December 12, 2003). Dose limiting toxicity (DLT) is defined as: * Any Grade 3 hematological or non-hematological toxicity other than skin or flu-like symptoms * Any Grade 4 toxicity To be dose-limiting, an adverse event must be definitely, probably, or possibly related to the administration of the investigational agent.