Study of NY-ESO-1 ISCOMATRIX® in Patients With Measurable Stage III or IV Melanoma

This was a Phase 2, open-label study of the NY-ESO-1 ISCOMATRIX® (ISCOM) vaccine administered as an intramuscular injection given every 4 weeks to subjects with measurable advanced malignant melanoma. Study objectives included determination of the anticancer activity, cellular and humoral immunogenicity, and safety and tolerability of the NY-ESO-1 ISCOM vaccine administered alone or preceded by a single administration of low-dose cyclophosphamide.

In Cohort 1, 6 subjects were initially vaccinated with the NY-ESO-1 ISCOM vaccine at a dose of 100 µg of the NY-ESO-1 protein + 120 µg of the ISCOM adjuvant. These 6 subjects were monitored for dose-limiting toxicity (DLT) for 7 days after the first vaccination. Upon observation of tolerability (ie, \< 2/6 subjects with DLT), enrollment proceeded to a total accrual of approximately 25 subjects. Subjects received 3 vaccinations administered every 4 weeks (ie, weeks 1, 5, and 9) followed by immunological and clinical response evaluations, with clinical responses categorized according to the Response Evaluation Criteria in Solid Tumors (RECIST). In the absence of disease progression, subjects may have received 3 additional vaccinations administered every 4 weeks, followed by additional vaccinations administered every 12 weeks thereafter until development of disease progression or other criteria for discontinuation.

In Cohort 2, subjects received the NY-ESO-1 ISCOM vaccine on the same schedule as described for Cohort 1, but Cohort 2 subjects also received a single intravenous infusion of low-dose cyclophosphamide 1 day prior to each NY-ESO-1 ISCOM vaccination. If responses were observed in 2 of 16 subjects initially treated in Cohort 2, then 9 additional subjects were to be accrued to Cohort 2, for a total potential accrual of 25 subjects.

Eligibility Criteria:
Inclusion Criteria:

1. Stage IV (metastatic) or unresectable stage III malignant melanoma.
2. Measurable disease using RECIST.
3. No other effective therapy available or appropriate.
4. Expression of NY-ESO-1 or LAGE-1 by immunohistochemistry (IHC) or reverse transcription-polymerase chain reaction (RT-PCR).
5. Expected survival of at least 4 months.
6. Karnofsky performance status of ≥ 70%.
7. Within 3 weeks prior to first administration of study drug, the following laboratory parameters were required to be within the ranges specified:

   * Hemoglobin ≥ 100 g/L
   * Platelets ≥ 100 x 10\^9/L
   * International normalized ratio ≤ 2.0
   * Creatinine ≤ 0.2 mmol/L
   * Bilirubin ≤ 30 mmol/L
8. Age ≥ 18 years.
9. Able and willing to give written informed consent.

Exclusion Criteria:

1. Other serious illnesses, eg, serious infections requiring antibiotics, bleeding disorders, or any condition that in the opinion of the Investigator would have interfered with the ability of the patient to complete all study requirements.
2. Other malignancy within last 3 years, except for treated melanoma or non-melanoma skin cancer or cervical cancer in situ.
3. Known immunodeficiency.
4. Known human immunodeficiency virus positivity.
5. Concomitant systemic treatment with corticosteroids, anti-histaminic drugs, or nonsteroidal anti-inflammatory drugs. Specific cyclooxygenase-2 (COX-2) inhibitors, low-dose aspirin for the prevention of an acute cardiovascular event, and topical or inhaled steroids were permitted.
6. Chemotherapy and/or radiotherapy within 4 weeks prior to study week 1.
7. Other immunotherapy within 4 weeks prior to study week 1.
8. Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study.
9. Lack of availability for immunological and clinical follow-up assessment.
10. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to enrollment.
11. Pregnancy or breastfeeding.
12. Women of childbearing potential: refusal or inability to use effective means of contraception.