Vaccine Therapy in Treating Patients With Transitional Cell Carcinomas

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Vaccines made from peptides may make the body build an immune response to kill tumor cells. Biological therapies, such as Bacille Calmette Guerin (BCG) and sargramostim (GM-CSF), use different ways to stimulate the immune system and stop tumor cells from growing. Combining vaccine therapy with biological therapy may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects of giving vaccine therapy together with BCG and sargramostim in treating patients who have undergone cystectomy for transitional cell carcinomas.

Detailed Description
-----------------
OBJECTIVES: Determine the safety and tolerability of NY-ESO-1 peptide vaccine, Bacille Calmette Guerin (BCG), and sargramostim (GM-CSF) in post-cystectomy patients with transitional cell carcinoma of the bladder expressing NY-ESO-1 or LAGE-1 antigen. Determine the immunological profile (NY-ESO-1 antibody, CD8+ cells, and delayed-type hypersensitivity) induced by this regimen in these patients. OUTLINE: This is an open-label, pilot study. Patients receive NY-ESO-1 protein vaccine mixed with BCG intradermally (ID) once weekly on weeks 1 and 2. Patients then receive NY-ESO-1 protein mixed with sargramostim (GM-CSF) ID once weekly on day 2 of weeks 3-6. Patients also receive GM-CSF subcutaneously alone on days 1, 3, 4, and 5 of weeks 3-6.

Official Title
-----------------
NY-ESO-1 Protein Immunization of Post-Cystectomy or Post-Nephroureterectomy Patients With Transitional Cell Carcinomas

Conditions
-----------------
Transitional Cell Carcinoma

Intervention / Treatment
-----------------
* Biological: TICE®-strain BCG
* Biological: NY-ESO-1 protein
* Biological: sargramostim


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Post-cystectomy or post-nephroureterectomy patients with histological confirmation of transitional cell carcinoma. Patients must have had a cystectomy or nephroureterectomy within 16 weeks of first vaccination. At least 4 weeks since surgery prior to receiving the first vaccination. Radiological imaging to document no evidence of disease within one month prior to receiving the first vaccination. Laboratory values within the following limits: Hemoglobin ≥ 10.0 g/dL Neutrophil count ≥ 1.5 x 10E9/L Lymphocyte count ≥ 0.5 x 10E9/L Platelet count ≥ 100 x 10E9/L Serum creatinine ≤ 1.8 mg/dL Serum bilirubin ≤ 2mg/dL Serum aspartate aminotransferase (AST) (SGOT) <2.5 X ULN Serum alanine aminotransaminase (ALT) (SGPT) <2.5 X ULN 6. Performance status ≤ 2 (ECOG Scale) and life expectancy ≥ 3 months. 7. Age ≥ 18 years. 8. Fertile patients must have a negative urine or serum pregnancy test and use barrier method contraception before, during and for 6 months after protocol therapy. Patients are encouraged to continue barrier method contraception for two years or longer after treatment. 9. Able and willing to give valid written informed consent. Exclusion Criteria Clinically significant heart disease (NYHA Class III or IV). Presence of severe reaction to PPD (purified protein derivative) (>40 mm induration). Prior malignancy within 5 years that has been treated with extensive chemotherapy / radiation therapy and have the potential for immune dysfunction or who have evidence of metastasis at the time of registration. Other serious illnesses, e.g., serious infections requiring antibiotics, bleeding disorders, antibiotic use within 5 days of treatment. Previous bone marrow or stem cell transplant. History of immunodeficiency disease or autoimmune disease. Known positive HIV test. Chemotherapy, radiation therapy, or immunotherapy within 4 weeks before study entry (6 weeks for nitrosoureas). Concomitant treatment with corticosteroids (within 30 days of enrollment and during treatment), antihistaminic drugs, or nonsteroidal anti-inflammatory drugs (unless chronically used in low doses for prevention of an acute cardiovascular event or pain control). Topical or inhalational steroids are permitted. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to enrollment. Mental disorders that may compromise the ability to give informed consent and comply with the requirements of the study. Lack of availability of the patient for immunological and clinical follow-up assessment. Positive urine or serum pregnancy test.

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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This study was open-label, and eligible patients were sequentially entered at the time they presented in clinic. Patients were sequentially assigned to one of four groups according to HLA-A2 characteristic and previous Bacille Calmette Guerin (BCG) therapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>HLA-A2 Status Positive, Previous BCG Therapy; All patients underwent skin testing with the purified protein derivative (PPD) test. NY-ESO-1 protein, 75 mcg, was administered by intradermal injection every week for 6 weeks. TICE®-strain BCG, 1 x 10E6 viable units in Purified Protein Derivative (PPD) negative patients and 1 x 10E5 viable units in PPD positive (induration greater than or equal to 10 mm) patients, were mixed with each protein vaccination for the first 2 weeks only. For the last 4 weeks GM-CSF, 100 mcg, was mixed with NY-ESO-1 protein given once a week for 4 weeks, intradermally. GM-CSF alone was given subcutaneously on the day prior to the administration of the co-mixture (NY-ESO-1 Protein/GM-CSF) and for 3 days after. | Biological: TICE®-strain BCG<br> <br> * Other names: BCG Vaccine;Biological: NY-ESO-1 protein<br> <br> Biological: sargramostim<br> <br> * Other names: GM-CSF;|
| Experimental: Cohort 2<br>HLA-A2 Status Positive, No Previous BCG Therapy; All patients underwent skin testing with the purified protein derivative (PPD) test. NY-ESO-1 protein, 75 mcg, was administered by intradermal injection every week for 6 weeks. TICE®-strain BCG, 1 x 10E6 viable units in Purified Protein Derivative (PPD) negative patients and 1 x 10E5 viable units in PPD positive (induration greater than or equal to 10 mm) patients, were mixed with each protein vaccination for the first 2 weeks only. For the last 4 weeks GM-CSF, 100 mcg, was mixed with NY-ESO-1 protein given once a week for 4 weeks, intradermally. GM-CSF alone was given subcutaneously on the day prior to the administration of the co-mixture (NY-ESO-1 Protein/GM-CSF) and for 3 days after. | Biological: TICE®-strain BCG<br> <br> * Other names: BCG Vaccine;Biological: NY-ESO-1 protein<br> <br> Biological: sargramostim<br> <br> * Other names: GM-CSF;|
| Experimental: Cohort 3<br>HLA-A2 Status Negative, Previous BCG Therapy; All patients underwent skin testing with the purified protein derivative (PPD) test. NY-ESO-1 protein, 75 mcg, was administered by intradermal injection every week for 6 weeks. TICE®-strain BCG, 1 x 10E6 viable units in Purified Protein Derivative (PPD) negative patients and 1 x 10E5 viable units in PPD positive (induration greater than or equal to 10 mm) patients, were mixed with each protein vaccination for the first 2 weeks only. For the last 4 weeks GM-CSF, 100 mcg, was mixed with NY-ESO-1 protein given once a week for 4 weeks, intradermally. GM-CSF alone was given subcutaneously on the day prior to the administration of the co-mixture (NY-ESO-1 Protein/GM-CSF) and for 3 days after. | Biological: TICE®-strain BCG<br> <br> * Other names: BCG Vaccine;Biological: NY-ESO-1 protein<br> <br> Biological: sargramostim<br> <br> * Other names: GM-CSF;|
| Experimental: Cohort 4<br>HLA-A2 Status Negative, No Previous BCG Therapy; All patients underwent skin testing with the purified protein derivative (PPD) test. NY-ESO-1 protein, 75 mcg, was administered by intradermal injection every week for 6 weeks. TICE®-strain BCG, 1 x 106 viable units in Purified Protein Derivative (PPD) negative patients and 1 x 105 viable units in PPD positive (induration greater than or equal to 10 mm) patients, were mixed with each protein vaccination for the first 2 weeks only. For the last 4 weeks GM-CSF, 100 mcg, was mixed with NY-ESO-1 protein given once a week for 4 weeks, intradermally. GM-CSF alone was given subcutaneously on the day prior to the administration of the co-mixture (NY-ESO-1 Protein/GM-CSF) and for 3 days after. | Biological: TICE®-strain BCG<br> <br> * Other names: BCG Vaccine;Biological: NY-ESO-1 protein<br> <br> Biological: sargramostim<br> <br> * Other names: GM-CSF;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities | All adverse events were graded according to the National Cancer Institute Common Toxicity Criteria (CTCAE) (Version 3.0). A Dose limiting toxicity (DLT) was defined as: ≥ Grade 2 autoimmune phenomena Asymptomatic bronchospasm or generalized urticaria ≥ Grade 3 hematological and non hematological toxicities. To be dose limiting, an adverse event must have been definitely, probably, or possibly related to the administration of the study treatment. Patients who experienced a DLT were removed from study. | up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Developing NY-ESO-1 Antibodies After Treatment | Blood samples were obtained at baseline, and at weeks 2, 4, 6, 8 and 12 for the assessment of NY-ESO-1 and LAGE-1 specific antibodies by enzyme-linked immunosorbent assay (ELISA). | up to 12 weeks | 
| Number of Patients With CD4+ and CD8+ T-cell Responses. | Blood samples were obtained at baseline, and at weeks 2, 4, 6, 8 and 12 for the assessment of NY-ESO-1 specific T-cell responses by ELISPOT. T-cell responses were monitored after in vitro sensitization with either overlapping peptides from NY-ESO-1 or recombinant adenovirus encoding NY-ESO-1 (adeno-NY-ESO-1), and with control peptides or recombinant vectors encoding Influenza-derived proteins. | up to 12 weeks | 
| Delayed-type Hypersensitivity (DTH) as Measured by the Number of Participants With Induration and/or Redness at Each Timepoint | NY-ESO-1-specific DTH skin reaction was measured at baseline and weeks 3 and 8.The peptide solution (10 μg peptide in 0.1ml normal saline) was injected intradermally at a separate site from the vaccination to give a visible and palpable skin depot. Assessment of DTH reactions was performed 48 h after injection. The extent and intensity of DTH reactions was documented by measuring visible redness, palpable induration and other signs of local skin irritation or necrosis. | up to 8 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Bladder cancer, Renal pelvis cancer