Safety Study of Adjuvant Vaccine to Treat Melanoma Patients

This is a Phase I open label dose escalation study of the TLR3 agonist Poly-ICLC as an adjuvant for NY-ESO-1 protein vaccination in patients with high risk melanoma in clinical complete remission (cCr), followed by a randomized Phase II component in which patients will be randomized to subcutaneous vaccination of NY-ESO-1 protein with Poly-ICLC alone dose TBD (Arm A) or with NY-ESO-1 protein, Poly-ICLC dose TBD and Montanide® ISA-51 VG (Montanide) (Arm B).

Patients with histological confirmed malignant melanoma, AJCC Stages: IIB, IIC, III or IV, who are in complete clinical remission (cCr) but at high risk of disease recurrence, will be eligible for enrollment, regardless of whether antigen expression in the autologous tumor can be demonstrated by either PCR or immunohistochemistry.

Primary Objectives:

* Phase I: To define the safety of subcutaneous vaccination with NY-ESO-1 protein, Montanide and escalating doses of Poly-ICLC.
* Phase II: To evaluate the induction of humoral and T cell (CD4+ and CD8+) immunity to subcutaneous vaccination with NY-ESO-1 protein in combination with Poly-ICLC when given with or without Montanide.

Exploratory analyses:

* Evaluation of primary tumor expression of NY-ESO-1 by IHC or RT-PCR.
* Histologic quantitation of original tumor TILs (tumor infiltrating lymphocytes), CD3+ cells, evaluation of mitotic index and correlation of this data with immunologic response.
* Correlation of NY-ESO-1 specific T cell responses with HLA type
* Investigation of polymorphisms for TLR3 through germline SNP analysis.
* Clinical Outcome (Time to Progression) reported descriptively.
* Skin section analysis of protein/adjuvant treated sites for immune cell infiltration and gene expression analysis

• NY-ESO-1 protein; Poly-ICLC; Montanide (Biological), also known as Cancer-Testis (CT) antigen expression: NY-ESO-1, Poly ICLC: carboxymethylcellulose, polyinosinic-polycytidylic acid & poly-L-lysine double-stranded RNA, Montanide® ISA-51 VG: mineral oil-based adjuvant; also called (IFA)incomplete Freund's adjuvant.: Phase I represents the dose-escalation component with Poly-ICLC given in combination with NY-ESO-1 and Montanide in an open-label fashion. The dose of Poly-ICLC will be increased stepwise from 0.35mg to 1.4mg while the dose of NY-ESO-1 antigen (100µg) and Montanide (1.1mL) will be held constant. Phase II: The doses of NY-ESO-1 and Montanide will remain the same as in Phase I; the highest tolerated Phase I dose of Poly-ICLC will become the Phase II Poly-ICLC dose. In Phase II, patients will be randomized to a subcutaneous vaccination of NY-ESO-1 protein with Poly-ICLC alone dose TBD (Arm A) or with NY-ESO-1 protein, Poly-ICLC dose TBD and Montanide (Arm B).

Primary outcomes

• Phase I, Number of Participants With SAE and DLT [52 weeks]: Safety measured by number of Serious Adverse Events per the CTEP v4.0 of the NCI Common Terminology Criteria for Adverse Events (CTCAE) and Dose Limiting Toxicity (DLT).

Secondary outcomes

• CD4+ and CD8+ Response [Up to 52 weeks]: Cellular response evaluated for the induction of cellular T cell (CD4+ and CD8+) immunity to subcutaneous vaccination with NY-ESO-1 protein in combination with Poly-ICLC when given with or without Montanide. Number of participants with increase CD4+ and CD8+ levels.
• NY-ESO-1 Expression by IHC [up to 52 weeks]: Analysis of immune cell infiltration at the injection site by IHC. IHC analysis of immune cell infiltration was performed for each arm using a scoring system. 0: No expression of the marker of interest, 1: single cells or small clusters (<5 cells together) expressing marker of interest, 2: medium size clusters of cells expressing marker of interest, and 3: huge and homogeneously positive clusters of cells expressing marker of interest.

Sex: All, ages: 18 Years to any

Inclusion Criteria

1. Histological diagnosis of malignant melanoma, stages IIB-IV in radiologically confirmed cCr without clinical evidence of disease.
2. At least 4 weeks since surgery prior to first dosing of study agent.
3. Laboratory values within the following limits:

   1. Hemoglobin > 10.0 g/dL
   2. Neutrophil count > 1.5 x l09/L
   3. Lymphocyte count > Lower limit of institutional normal
   4. Platelet count > 80 x l09/L
   5. Serum creatinine < 2.0 mg/dL
   6. Serum bilirubin < 2 x upper limit of institutional normal
   7. AST/ALT < 2 x upper limit of institutional normal
4. Patients must have an ECOG performance status of <2 (ECOG criteria published in \[67\].
5. Life expectancy > 6 months.
6. Age > 18 years.
7. Able and willing to give written informed consent for participation in the trial (see Section 12.2).

Exclusion Criteria

1. Serious illnesses, e.g., serious infections requiring antibiotics.
2. Previous bone marrow or stem cell transplant.
3. History of immunodeficiency disease (such as HIV) or autoimmune disease except vitiligo.
4. Metastatic disease to the central nervous system.
5. Other malignancy within 3 years prior to entry into the study, except for treated early-stage melanoma or non-melanoma skin cancer, or cervical carcinoma in situ.
6. Prior chemotherapy or vaccine therapy.
7. Radiation therapy, biological therapy or surgery within 4 weeks prior to first dose of study agent.
8. Concomitant treatment with systemic corticosteroids greater than physiologic doses. Topical (but not at the proposed vaccination sites) or inhalational steroids are permitted.
9. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to first dose of study agent.
10. Pregnancy or lactation.
11. Women of childbearing potential not using a medically acceptable means of contraception.
12. Psychiatric or addictive disorders that may compromise the ability to give informed consent.
13. Lack of availability of the patient for immunological and clinical follow-up assessment.
14. Children <18 years of age who cannot undergo the leukapheresis procedure, do not meet the disease staging and/or the size criteria for frequent blood donations

Participant flow

Outcome results

• Phase I, Number of Participants With SAE and DLT (Primary), Count of participants, Participants: Poly-ICLC 0.35 mg 0; Poly-ICLC 0.70 mg 0; Poly-ICLC 1.4mg 1
• CD4+ and CD8+ Response (Secondary), Count of participants, Participants: NY-ESO-1 Protein and Poly-ICLC 10; NY-ESO-1 Protein, Poly-ICLC and Montanide 9
• NY-ESO-1 Expression by IHC (Secondary), Mean, units on a scale: NY-ESO-1 Protein and Poly-ICLC 1.500 +/- 0.707; NY-ESO-1 Protein, Poly-ICLC and Montanide 1.944 +/- 0.682

Adverse events

Serious adverse events by term

Other adverse events by term

16 more terms not shown.

• Nina Bhardwaj, MD, PhD, Principal investigator, NYU Langone Health
• Anna Pavlick, D.O., Principal investigator, NYU Langone Health