NY-ESO-1 Vaccine in Combination With Ipilimumab in Patients With Unresectable or Metastatic Melanoma

This was a Phase 1, open-label, non-randomized study of the combination of NY-ESO-1 plus ipilimumab in patients with unresectable or metastatic melanoma for whom treatment with ipilimumab was indicated. Patients must have had evidence of NY-ESO-1 or LAGE-1 tumor positivity and radiologically measurable disease by the immune-related Response Criteria (irRC). Primary study objectives were to determine the safety and tolerability of the combination and to evaluate humoral and cellular immune response. Secondary objectives were to evaluate tumor response and immunological changes in the tumor microenvironment.

Patients were enrolled sequentially, alternating among 3 treatment arms. Study treatment comprised ipilimumab 3 mg/kg administered intravenously (IV) over 90 minutes every 3 weeks for 4 doses followed by the NY-ESO-1 vaccine administered subcutaneously (SC). Arm A received the NY-ESO-1 recombinant protein mixed with polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose (Poly-ICLC) and Montanide; Arm B received NY-ESO-1 overlapping long peptides 4 (OLP4) mixed with Poly-ICLC and Montanide; and Arm C received NY-ESO-1 OLP4 mixed with Poly-ICLC (without Montanide). The vaccine was administered immediately following the ipilimumab infusion, and patients were observed for 1 hour following administration. No dose adjustments or delays were permitted.

Because the study treatment regimens had not been previously investigated in humans, the first patient in each treatment arm was followed for 28 days and evaluated for any regimen-limiting toxicity (RLT), defined as any dose-limiting toxicity (DLT) that could not be attributed solely to either the vaccine or ipilimumab and was therefore considered to be related to the combination. If an RLT was observed in the first patient, the second patient was to be evaluated for 28 days before the third patient was enrolled. If at any point ≥ 2 RLTs were observed in a treatment arm, accrual to that arm was to be terminated and the combination in that arm was to be declared unsafe.

Patients were monitored for safety, immune and tumor response, and immunological changes in the tumor microenvironment for the duration of study participation, which may have been up to 6 months.

Eligibility Criteria:
Inclusion Criteria:

1. Patients with unresectable or metastatic melanoma, for whom treatment with ipilimumab was indicated as per ipilimumab/Yervoy® package insert (applicable for United States \[US\] sites) or product information (applicable for Australia site).
2. Radiologically measurable disease by irRC.
3. Tumor expression of NY-ESO-1 or LAGE-1 antigen by immunohistochemistry or reverse transcriptase-polymerase chain reaction (RT-PCR), or evidence of seropositivity to NY-ESO-1 or LAGE-1.
4. Willingness to provide at least one pre-and post-vaccination tumor biopsy sample.
5. Expected survival of at least 4 months.
6. At the time of Day 1 of the study, patients must have been at least 3 weeks since surgery.
7. At the time of Day 1 of the study, patients with brain metastases must have been asymptomatic and:

   * at least 8 weeks without tumor progression after any whole brain radiotherapy;
   * at least 4 weeks since craniotomy and resection or stereotactic radiosurgery;
   * at least 3 weeks without new brain metastases as evidenced by magnetic resonance imaging (MRI).
8. Eastern Cooperative Oncology Group performance status of 0 to 2.
9. Laboratory parameters for vital functions must have been in the normal range. Laboratory abnormalities that were not clinically significant were generally permitted, except for the following laboratory parameters, which must have been within the ranges specified:

   * hemoglobin: ≥ 10 g/dL;
   * neutrophil count: ≥ 1.5 x 10\^9/L;
   * lymphocyte count: ≥ lower limit of normal (LLN);
   * platelet count: ≥ 80 x 10\^9/L;
   * serum creatinine: ≤ 2 mg/dL;
   * serum bilirubin: ≤ 2 x upper limit of normal (ULN);
   * aspartate aminotransferase (AST)/alanine aminotransferase (ALT): ≤ 2 x ULN.
10. Had been informed of other treatment options.
11. Age ≥ 18 years.
12. Able and willing to give valid written informed consent.

Exclusion Criteria:

1. Any contraindications for ipilimumab/Yervoy® as per package insert (applicable for US sites) or product information (applicable for Australia site).
2. Prior exposure to NY-ESO-1 vaccine.
3. Active autoimmune disease, symptoms or conditions except for vitiligo, type I diabetes, treated thyroiditis, asymptomatic laboratory evidence of autoimmune disease (e.g., +antinuclear antibody \[ANA\], +rheumatoid factor \[RF\], antithyroglobulin antibodies), or mild arthritis requiring no therapy or manageable with nonsteroidal anti-inflammatory drugs (NSAIDs).
4. Unresolved immune-related adverse events following prior biological therapy.
5. Systemic treatment with high-dose corticosteroids (greater than prednisone 10 mg daily or equivalent).
6. Treatment with protocol-specified non-permitted concomitant therapies.
7. Metastatic disease to the central nervous system for which other therapeutic options, including radiotherapy, may have been available.
8. Myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, chest pain or shortness of breath with activity, or other heart conditions being treated by a doctor.
9. Other malignancy within 3 years prior to entry into the study, except for treated non-melanoma skin cancer and cervical carcinoma in situ.
10. Known immunodeficiency or human immunodeficiency virus positivity, active Hepatitis B or active Hepatitis C.
11. History of severe allergic reactions to vaccines or unknown allergens.
12. Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders).
13. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to Day 1 of the study.
14. Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study.
15. Lack of availability for immunological and clinical follow-up assessments.
16. Women who were breast feeding or pregnant as evidenced by positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[HCG\]) done within 14 days prior to first dosing and urine test within 72 hours prior to first dosing.
17. Women of childbearing potential not using a medically acceptable means of contraception for the duration of the study.
18. Any condition that, in the clinical judgment of the treating physician, was likely to prevent the patient from complying with any aspect of the protocol or that may have put the patient at unacceptable risk.