Immunization With the MAGE-3.A1 Peptide Mixed With the Adjuvant CpG 7909 in Patients With Metastatic Melanoma

Phase I/II Study of Immunization With the MAGE-3.A1 Peptide Mixed With the Immunological Adjuvant CpG 7909 in Patients With Metastatic Melanoma

The purposes of this study are to determine whether immunization with the MAGE-3.A1 peptide mixed with CpG 7909 results in a detectable immune response; to determine the safety of this vaccine and to document the tumor response to the vaccine.

Patients will be vaccinated every two weeks on six occasions. On each vaccination day, the MAGE-3.A1 peptide (300 µg) mixed with CpG 7909 (5 mg) will be administered twice intradermally (10% of the dose each) and twice subcutaneously (40% of the dose each) in the arms and thighs.

Tumor staging will be performed before inclusion and at week 13. PBL collections will be performed before starting the treatment, and at weeks 3, 7 and 13. They will provide the T lymphocytes for the immunological analysis.

Additional cycles of immunization 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 with the same vaccine, 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 study withdrawal.

Inclusion Criteria:

1. Histologically proven cutaneous melanoma, or clear cell sarcoma, which is considered as a subtype of melanoma.

2. Melanoma must be at one of the following AJCC 2002 stages:

   • Regional metastatic disease (any T; N2b, N2c or N3; M0).
   • Distant metastatic disease (any T; any N; M1a, M1b or M1c), except brain or leptomeningeal localizations, and except elevated LDH.

3. Patients must be HLA-A1.

4. Melanoma must express the MAGE-3 gene, as determined by RT-PCR.

5. Presence of at least one measurable or non-measurable tumor lesion, excluding leptomeningeal metastasis.

6. Expected survival of at least 3 months.

7. Karnofsky performance scale ≥70 or WHO performance status of 0 or 1.

8. Within the last 4 weeks prior to study day 1, vital laboratory parameters should be within normal range, except for the following laboratory parameters, which must be within the ranges specified:

   Lab Parameter Range

   • Hemoglobin ≥ 10 g/dl or ≥ 6,25 mmol/l
   • Granulocytes ≥ 1,500/µl
   • Lymphocytes ≥ 700/µl
   • Platelets ≥ 100,000/µl
   • Serum creatinine ≤ 2.0 mg/dl or ≤ 177 µmol/l
   • Serum bilirubin ≤ 2.0 mg/dl or ≤ 34.2 µmol/l
   • ASAT and ALAT ≤ 2 x the normal upper limits
   • LDH ≤ the normal upper limit.

9. Viral tests:

   • HIV (human immunodeficiency virus): negative antibodies.
   • HBV (hepatitis B virus): negative antigens; antibodies may be positive.
   • HCV (hepatitis C virus): negative antibodies.

10. Age ≥ 18 years.

11. Able and willing to give valid written informed consent.

Exclusion Criteria:

1. Previous treatment with more than one regimen of systemic chemotherapy, combined or not with non-specific immunotherapy such as interferon alpha or interleukins. Chemoimmunotherapy or radiotherapy must be stopped within the preceding 4 weeks (6 weeks for nitrosoureas and mitomycin C).
2. Previous treatment with a vaccine known or likely to contain the MAGE-3.A1 antigen, unless there is evidence that no CTL response against this antigen was induced by the vaccine.
3. Clinically significant heart disease i.e. NYHA class 3 congestive heart failure; myocardial infarction within the past six months; unstable angina; coronary angioplasty within the past 6 months; uncontrolled atrial or ventricular cardiac arrhythmias).
4. Active immunodeficiency or autoimmune disease. Vitiligo is not an exclusion criterion.
5. Other serious acute or chronic illnesses, e.g. active infections requiring antibiotics, bleeding disorders, or other conditions requiring concurrent medications not allowed during this study.
6. Other malignancy within 3 years prior to entry into the study, except for treated non-melanoma skin cancer and cervical carcinoma in situ.
7. Lack of availability for immunological and clinical follow-up assessments.
8. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to enrollment.
9. Pregnancy or breastfeeding.
10. Women of childbearing potential: Refusal or inability to use effective means of contraception.