NY-ESO-1 Protein With Montanide and CpG 7909 as Cancer Vaccine in Several Tumors

Study Overview
=================
Brief Summary
-----------------
This is a Phase I, open-label, randomized study of NY-ESO-l protein with immune adjuvants CpG 7909 and Montanide ISA-51 VG in patients with tumors that often express NY-ESO-1. The vaccinations was to be administered subcutaneously every 3 weeks for 4 doses. Patients with any malignancy that is known to frequently express NY-ESO-1 were eligible, regardless of whether antigen expression in the autologous tumor could be demonstrated or not by either PCR or immunohistochemistry. The primary objective of the study was to define safety. Secondarily, the study was to evaluate whether patients developed a specific immunologic response to the NY-ESO-1 protein. Blood samples were to be obtained at baseline, prior to each vaccination, one week after each vaccination, and at the last study visit for the assessment of NY-ESO-1-specific CD4+ and CD8+ T cells. Cytokine secretion by NY-ESO-1-specific CD8+ and CD4+ T cells, as a measure of T cell activation, was to be determined by FACS analysis. In addition, humoral immunity was to be determined by the presence of NY-ESO-1-specific antibodies which were to be assessed in all patients by ELISA. Disease status was to be assessed at baseline and 2-4 weeks after the fourth vaccination in patients with evaluable (measurable and non-measurable) disease.

Detailed Description
-----------------
Subjects were to receive an investigational (research) cancer vaccine every 3 weeks for a total of 4 treatments. It was given by injection underneath the skin in an extremity (leg or arm). A vaccine is a compound designed to strengthen the immune system (the cells and substances that protect the body from infection and foreign matter) to fight an illness such as infections or cancer. This vaccine is called NY-ESO-1 protein. NY-ESO-1 protein (an antigen, which is a compound that is recognized by the immune system) is found in many cancers. Proteins such as NY-ESO-1 and their fragments are the targets the immune system needs to recognize cancer cells. If the immune system can recognize these antigens (foreign substances) it may be able to kill the cells that carry them. NY-ESO-1 can be found at different stages of cancers, and is likely to be expressed (shown) at some point in the lifecycle of these types of cancer (that are eligible for this study). Therefore this study tries to boost (strengthen) the immune system toward NY-ESO-1 protein regardless of whether it is found in your tumor or not. Since we do not know whether different doses of the NY-ESO-1 protein may result in varying degrees of immune stimulation, we will be randomizing (that is, at the flip of a coin or, in other words, by chance). You may receive either the lower dose of NY-ESO-1 protein (100 µg) or the higher dose (400 µg). The NY-ESO-1 protein vaccine was to be mixed with 2 substances, called adjuvants (the full names are: CPG 7909 and Montanide ISA-51 VG). Adjuvants are substances to increase the vaccine's ability to stimulate the immune system. By adding two adjuvants to the vaccine, it is hoped that the boosting of the immune system will be especially effective. It is important to understand, that vaccines are only experimental (investigational, research) for the treatment of cancer. They are not approved by the Food and Drug Administration (FDA) as treatment. Therefore they are only offered in clinical trials. All tests and treatments were performed as an outpatient.

Official Title
-----------------
A Phase I Study Using Vaccination With NY-ESO-1 Recombinant Protein Mixed With CpG 7909 and Montanide ISA-51 VG in Patients With Cancers That Often Express NY-ESO-1.

Conditions
-----------------
Tumors

Intervention / Treatment
-----------------
* Biological: NY-ESO-1 Protein Vaccine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histological diagnosis of hepatocellular carcinoma, bladder cancer, breast cancer, non-small lung cancer (NSCLC), melanoma, sarcoma, prostate cancer, esophageal cancer, or ovarian cancer, independent of NY-ESO-1 expression in a tumor biopsy. or Histological diagnosis of other types of cancers, provided NY-ESO-1 or LAGE-1 expression can be shown in a tumor biopsy. At least 4 weeks since surgery prior to first dosing of study agent. Laboratory values within the following limits: Hemoglobin ≥ 11.0 g/dL Neutrophil count ≥ 1.5 x l0^9/L Lymphocyte count ≥ lower limit of institutional normal Platelet count ≥ 80 x l0^9/L Serum creatinine ≤ 2.0 mg/dL Serum bilirubin ≤ 2 x upper limit of institutional normal AST/ALT ≤ 2 x upper limit of institutional normal Patients must have a Karnofsky performance status of ≥70%. Life expectancy ≥ 6 months. Age ≥ 18 years. Able and willing to give witnessed, written informed consent for participation in the trial. Exclusion Criteria: 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). Other serious illnesses, eg, serious infections requiring antibiotics, bleeding disorders. Previous bone marrow or stem cell transplant. History of immunodeficiency disease or autoimmune disease except vitiligo. Metastatic disease to the central nervous system, unless treated and stable. 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. Known HIV, Hepatitis B or Hepatitis C positivity. Chemotherapy, radiation therapy or immunotherapy within 4 weeks prior to first dose of study agent (6 weeks for nitrosoureas). Concomitant treatment with steroids. Topical or inhalational steroids are permitted. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to first dose of study agent. Pregnancy or lactation. Women of childbearing potential not using a medically acceptable means of contraception. Psychiatric or addictive disorders that may compromise the ability to give informed consent. Lack of availability of the patient for immunological and clinical follow-up assessment.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A; 100 μg NY-ESO-1 protein co-mixed with CpG 7909 and Montanide ISA-51 VG<br>100 μg NY-ESO-1 protein co-mixed with 2.5 mg CpG 7909 and 1.25 mL Montanide ISA-51 VG. The vaccine was administered subcutaneously every 3 weeks for a total of 4 doses (study weeks 1, 4, 7 and 10). | Biological: NY-ESO-1 Protein Vaccine<br>* NY-ESO-1 recombinant protein mixed with CpG 7909 and Montanide ISA-51 VG<br>|
| Experimental: Arm B; 400 μg NY-ESO-1 protein co-mixed with CpG 7909 and Montanide ISA-51 VG<br>400 μg NY-ESO-1 protein co-mixed with 2.5 mg CpG 7909 and 1.25 mL Montanide ISA-51 VG. The vaccine was administered subcutaneously every 3 weeks for a total of 4 doses (study weeks 1, 4, 7 and 10). | Biological: NY-ESO-1 Protein Vaccine<br>* NY-ESO-1 recombinant protein mixed with CpG 7909 and Montanide ISA-51 VG<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reporting Adverse Events (AEs) and Dose-limiting Toxicities (DLTs) | All AEs occurring during the study were documented in the source records and on the respective AE case report form (CRF) pages, regardless of the assumption of a causal relationship. All events that occurred after the first administration of study drug were to be documented. The severity of an AE was assessed according to the NCI CTCAE scale (Version 3.0). DLT was defined as ≥ Grade 3 hematological and non-hematological toxicities or ≥ Grade 2 allergic reaction for generalized urticaria that was definitely, probably, or possibly related to the administration of the NY-ESO-1 protein vaccine. | up to 14 weeks | 
| Number of Subjects With NY-ESO-1-Specific Humoral Immunity as Determined by an Increase in Antibody Titer From Baseline. | Blood samples were taken at baseline and in weeks 2, 4, 5, 7, 8, 10, 11, and 12-14 for the assessment of NY-ESO-1-specific antibodies by an enzyme-linked immunosorbent assay (ELISA). Sera were assessed over a range of dilutions from 1/100 to 1/100,000. Titers were calculated as the serum dilution giving 50% of maximal optical density obtained by using a standard positive serum. Positive results were reciprocal serum titers greater than 100. | Up to 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Tumor Responses as Measured by the Response Evaluation Criteria in Solid Tumors (RECIST) | Computed tomography (CT) or magnetic resonance imaging (MRI) scans were performed at screening and weeks 12-14 and 16-18, and tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) according to Therasse P et al. 2000. Per RECIST, target lesions were categorized as follows: complete response (CR): disappearance of all target lesions; partial response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; progressive disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; stable disease (SD): small changes that do not meet above criteria; no evidence of disease (NED): no evidence of disease at baseline and post-baseline assessments. | up to 18 weeks | 
| Number of Subjects With NY-ESO-1 Specific Cellular Immunity as Measured by an Increase in NY-ESO-1-Specific CD4+ T Cells After in Vitro Stimulation | Blood samples were taken at baseline and in weeks 2, 4, 5, 7, 8, 10, 11, 12-14, 16-18, 20-22, 24-26, and 28-32. Subjects were consented separately for blood draws after week 14. The induction of specific T cells was assessed after in vitro stimulation of pre- and post-treatment samples with a pool of overlapping peptides spanning the protein sequence, followed by quantification of specific IFN-γ-producing cells by intracellular staining. The response was considered significant if the frequency of T cells detected in at least one post-treatment sample exceeded by 3-fold that found in the baseline sample. | up to 32 weeks | 
| Number of Subjects With NY-ESO-1-Specific Cellular Immunity as Measured by an Increase in NY-ESO--Specific CD8+ T Cells After in Vitro Stimulation | Blood samples were taken at baseline and in weeks 2, 4, 5, 7, 8, 10, 11, 12-14, 16-18, 20-22, 24-26, and 28-32. Subjects were consented separately for blood draws after week 14. The induction of specific T cells was assessed after in vitro stimulation of pre- and post-treatment samples with a pool of overlapping peptides spanning the protein sequence, followed by quantification of specific IFN-γ-producing cells by intracellular staining. The response was considered significant if the frequency of T cells detected in at least one post-treatment sample exceeded by 3-fold that found in the baseline sample. | up to 32 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NY-ESO-1, Vaccine, Adjuvant or metastatic setting, Several tumor types eligible