Phase 1 Study of NY-ESO-1 Overlapping Peptides in Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Study Overview
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Brief Summary
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This was a Phase 1, open-label study of repeated vaccination with NY-ESO-1 overlapping peptides (OLP4) with or without the immunoadjuvants Montanide and polyinosinic-polycytidylic acid - poly-L-lysine carboxymethylcellulose (poly-ICLC) administered every 3 weeks for a total of 5 vaccinations in subjects with epithelial ovarian, fallopian tube, or primary peritoneal cancer in second or third clinical remission. Study objectives included determination of the safety and immunogenicity following vaccination.

Detailed Description
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Subjects received NY-ESO-1 OLP4 by subcutaneous injection once every 3 weeks (Weeks 1, 4, 7, 10, and 13) for a total of 5 vaccinations. Subjects were assigned sequentially to 1 of 3 dosing cohorts: Cohort 1: received NY-ESO-1 OLP4 alone; Cohort 2: received NY-ESO-1 OLP4 in combination with Montanide; Cohort 3: received NY-ESO-1 OLP4 in combination with Montanide and Poly-ICLC. Enrollment into each subsequent dosing cohort was dependent on a dose-limiting toxicity (DLT) rate of <33% in the preceding cohort. No dose escalation was planned. Subjects were observed by study staff for up to 30 minutes following each vaccination. Immunologic assessments were performed prior to the first vaccination and 3 weeks after each vaccination. Toxicity assessments were performed with each vaccination and 3 weeks after the completion of therapy (ie, the final study visit was Week 16). Immunologic assessments included measurement of the anti-NY-ESO-1 antibody by enzyme-linked immunsorbent assay (ELISA), detection of CD-4 and CD-8 cellular responses by tetramer and enzyme-linked immunosorbent spot assay (ELISPOT), and delayed-type hypersensitivity (DTH).

Official Title
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A Phase 1 Study of NY-ESO-1 Overlapping Peptides With or Without Immunoadjuvants Montanide and Poly-ICLC Vaccination of Epithelial Ovarian Cancer, Fallopian Tube, or Primary Peritoneal Cancer Patients in Second or Third Remission

Conditions
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Fallopian Tube Cancer, Epithelial Ovarian Cancer, Primary Peritoneal Cancer

Intervention / Treatment
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* Biological: NY-ESO-1 OLP4
* Biological: NY-ESO-1 OLP4 + Montanide
* Biological: NY-ESO-1 OLP4 + Montanide + Poly-ICLC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically documented epithelial carcinoma arising in the ovary, fallopian tube, or peritoneum, stage II to IV at diagnosis, and post-initial cytoreductive surgery and chemotherapy with at least one platinum-based chemotherapy regimen. In second or third stable complete clinical remission, defined as a) stable cancer antigen (CA)-125 < 35 U/ml (defined as CA-125 that had not doubled from the post chemotherapy nadir), b) unremarkable physical examination, and c) no definite evidence of disease by computed tomography (CT) of the abdomen and pelvis. Lymph nodes and/or soft tissue abnormalities ≤ 1.0 cm that are often present in the pelvis were not considered definite evidence of disease. Expected survival of at least 4 months. Karnofsky performance scale ≥ 70%. Laboratory values within the following limits: Hemoglobin ≥ 10.0 g/dL Neutrophil count ≥ 1.5 x 10^9/L Platelet count ≥ 80 x 10^9/L Serum creatinine ≤ 2.0 mg/dL Serum bilirubin ≤ 2.5 x institutional upper limit of normal (ULN) aspartate aminotransferase/alanine aminotransferase ≤ 2.5 x institutional ULN Age ≥ 18 years. ≥ 4 weeks since completion of prior cytotoxic chemotherapy. Able and willing to give valid written informed consent Exclusion Criteria: Clinically significant heart disease (New York Heart Association Class III or IV). Serious intercurrent illness, eg, serious infections requiring prolonged parenteral antibiotics or bleeding disorders requiring hospitalization. Positive stool guaiac excluding hemorrhoids. Known autoimmune disease (ie, rheumatoid arthritis, ulcerative colitis, etc); or immune deficiency (human immunodeficiency virus, hypogammaglobulinemia); or known active infections with Hepatitis B or Hepatitis C; or receipt of immunosuppressive drugs such as systemic corticosteroids or cyclosporin, etc. Other malignancy within 3 years prior to entry into the study, except for treated non-melanoma skin cancer and cervical carcinoma in situ. History of previous severe allergic reactions to vaccines or unknown allergens. Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study. Lack of availability for immunological and clinical follow-up assessments. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to first dose of study agent. Pregnancy or breast-feeding. Women of childbearing potential: Refusal or inability to use effective means of contraception.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Subjects received 4 synthetic peptides coded by the NY-ESO-1 gene (ie, NY-ESO-1 OLP4) once every 3 weeks for a total of 5 vaccinations. | Biological: NY-ESO-1 OLP4<br>* 1.0 mg of NY-ESO-1 OLP4 (0.25 mg of each overlapping peptide) was diluted in 0.5 mL of 5% dextrose in water (D5W) and administered subcutaneously as a single injection.<br>|
| Experimental: Cohort 2<br>Subjects received 4 synthetic peptides coded by the NY-ESO-1 gene (ie, NY-ESO-1 OLP4) in combination with Montanide ISA-51 vegetable grade (VG) once every 3 weeks for a total of 5 vaccinations. | Biological: NY-ESO-1 OLP4 + Montanide<br>* 1.0 mg of NY-ESO-1 OLP4 (0.25 mg of each overlapping peptide) was diluted in 0.5 mL of D5W, mixed with 0.5 mL of Montanide, and administered subcutaneously as a single injection.<br>|
| Experimental: Cohort 3<br>Subjects received 4 synthetic peptides coded by the NY-ESO-1 gene (ie, NY-ESO-1 OLP4) in combination with Montanide ISA-51 VG and poly-ICLC once every 3 weeks for a total of 5 vaccinations. | Biological: NY-ESO-1 OLP4 + Montanide + Poly-ICLC<br>* 1.0 mg of NY-ESO-1 OLP4 (0.25 mg of each overlapping peptide) and 1.4 mg of poly-ICLC were emulsified in 1.0 mL of Montanide and administered subcutaneously as two injections.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overview of Treatment-emergent Adverse Events (TEAEs) | Analysis of TEAEs reported from clinical laboratory tests, physical examinations, and vital signs from pre-treatment through 3 weeks after the last dose of study treatment. | Continuously for up to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Detectable Serum Immunoglobulin G (IgG) Antibody Titers Against NY-ESO-1 Up to 16 Weeks Post-Baseline | Blood samples were drawn to measure immunologic response at Screening and Weeks 4, 7, 10, 13, and 16. Specific antibodies against NY-ESO-1 were measured by enzyme-linked immunosorbent assay (ELISA). | Screening and Weeks 4, 7, 10, 13, and 16 | 
| Number of Patients With Detectable CD8+ and CD4+ T-cell Responses Up to 16 Weeks Post-Baseline | Blood samples were drawn to measure immunologic response at Screening and Weeks 4, 7, 10, 13, and 16. NY-ESO-1-specific CD8+ and CD4+ T-cell reactivity was measured by tetramer analysis (in human leukocyte antigen [HLA] 0201* patients). Interferon gamma (IFN-γ) release by T cells was measured by the enzyme-linked immunospot (ELISPOT) assay. A subject was considered to have experienced a T-cell response if IFN-γ spots were detectable (>50 spots) by ELISPOT of 50,000 CD8+ and CD4+ T cells following pre-sensitization with a pool of 20-mer OLP covering all of NY-ESO-1 and tested against Epstein-Barr virus-transformed B cells pulsed with 3 subpools of these peptides. | Screening and Weeks 4, 7, 10, 13, and 16 | 
| Number of Patients With Delayed-type Hypersensitivity (DTH) Reactions (Induration and Redness) to NY-ESO-1 OLP4 at Screening and Week 16 | NY-ESO-1-specific DTH was measured by skin tests at Screening and again at Week 16. NY-ESO-1 OLP4 (40 µg in 0.1 mL D5W) was injected intradermally, with DTH reactions read 48 hours after injection. | Screening and Week 16 | 
| Cancer Antigen (CA)-125 Levels Up to 16 Weeks Post-Baseline | Serum CA-125 was measured at Screening, Week 7, and Week 16. Stable CA-125 at baseline was < 35 U/mL (defined as CA-125 that had not doubled from the post chemotherapy nadir). | Screening, Week 7, and Week 16 | 
| Tumor Measurement Results According to the Response Evaluation Criteria for Solid Tumors (RECIST) Up to 16 Weeks Post-Baseline | Radiographic imaging (computed tomography of the abdomen and pelvis) was obtained at Screening and every 2 months during the study, and at unscheduled time points if any clinical symptoms/examination findings warranted further evaluation or if serum CA-125 rose to > 70 U/mL (confirmed by repeat value). Subjects may have had more than 1 location of disease. | Screening and every 2 months up to Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NY-ESO-1 OLP4, Ovarian Cancer, Cancer Vaccine