Decitabine, Vaccine Therapy, and Pegylated Liposomal Doxorubicin Hydrochloride in Treating Patients With Recurrent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Peritoneal Cancer

Study Overview
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Brief Summary
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This phase I trial is studying the side effects and best dose of decitabine when given together with pegylated liposomal doxorubicin hydrochloride and vaccine therapy in treating patients with recurrent ovarian epithelial cancer, fallopian tube cancer, or peritoneal cancer. Drugs used in chemotherapy, such as decitabine and pegylated liposomal doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vaccines made from a peptide or antigen may help the body build an effective immune response to kill tumor cells. Giving combination chemotherapy together with vaccine therapy may kill more tumor cells

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the safety of 5-aza-2'-deoxycytidine (decitabine) in combination with immunization with NYESO-I protein mixed with montanide and granulocyte-macrophage colony stimulating factor (GM-CSF) in patients scheduled to receive liposomal doxorubicin for recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma. SECONDARY OBJECTIVES: I. To evaluate NY-ESO-l specific cellular and humoral immunity by determination of NY-ESO-I specific antibody, CD8+ and CD4+ T-cells following immunization with NY-ESO-l protein mixed with montanide and GM-CSF in combination with 5-aza-2' -deoxycytidine (decitabine) in patients receiving liposomal doxorubicin for recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma. II. To determine the impact of 5-aza-2'-deoxycytidine on NY-ESO-I specific expression, NY-ESO-l promoter methylation, and global DNA methylation. III. To compare the time to progression (ttp) for the proposed therapy with the ttp for standard therapy (historical studies). OUTLINE: This is a dose escalation study of decitabine. Patients receive decitabine intravenously (IV) over 3 hours on day 1, pegylated liposomal doxorubicin hydrochloride IV on day 8, and NY-ESO-1 peptide vaccine emulsified in incomplete Freund's adjuvant and sargramostim subcutaneously on day 15. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 6 months.

Official Title
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A Phase I Clinical Trial of NY-ESO-1 Protein Immunization in Combination With 5-AZA-2'-Deoxycytidine (Decitabine) in Patients Receiving Liposomal Doxorubicin for Recurrent Epithelial Ovarian or Primary Peritoneal Carcinoma

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

Intervention / Treatment
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* Drug: decitabine
* Biological: NY-ESO-1 peptide vaccine
* Drug: pegylated liposomal doxorubicin hydrochloride
* Biological: sargramostim
* Biological: incomplete Freund's adjuvant
* Other: immunohistochemistry staining method
* Other: liquid chromatography
* Other: mass spectrometry
* Genetic: reverse transcriptase-polymerase chain reaction
* Other: laboratory biomarker analysis
* Genetic: DNA methylation analysis
* Other: enzyme-linked immunosorbent assay


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with relapsed epithelial ovarian cancer (including fallopian tube and primary peritoneal cancer) who will receive liposomal doxorubicin as salvage therapy for recurrent disease Patients may have received up to four previous lines of chemotherapy The relapse may be defined by an increase in CA125; there may or may not be either measurable or symptomatic disease Any human leukocyte antigen (HLA) type No requirement for tumor expression of NY-ESO-1 Karnofsky performance status of > 70% Not previously treated with doxorubicin Life expectancy >= 6 months Hematology and biochemistry laboratory results within the limits normally expected for the patient population, without evidence of major organ failure No immunodeficiency Have been informed of other treatment options Able and willing to give valid written informed consent Neutrophil count >= 1.5 x 10^9 Platelet count >= 100 x 10^9 Serum creatinine =< 2.1 mg/dL Serum bilirubin =< 2 mg/dL Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.6 x upper limit of normal (ULN) (normal ranges: AST 15-46 U/L; ALT 11-66 U/L) Exclusion Criteria: Metastatic disease to the central nervous system for which other therapeutic options, including radiotherapy, may be available Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders) History of autoimmune disease (e.g., thyroiditis, lupus) except vitiligo Concomitant systemic treatment with corticosteroids, anti-histamine or non-steroidal anti-inflammatory drugs; specific CQX-2 inhibitors are permitted Chemotherapy, radiation therapy, or immunotherapy within 4 weeks prior to first dosing of study agent (6 weeks for nitrosoureas) Known human immunodeficiency virus (HIV) positivity Known allergy or history of life threatening reaction to GM-CSF 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 Participation in any other clinical trial involving another investigational agent within 4 weeks prior to first dosing of study agent Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study Lack of availability of a patient for immunological and clinical follow-up assessment

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy and vaccine therapy)<br>Patients receive decitabine IV over 3 hours on day 1, pegylated liposomal doxorubicin hydrochloride IV on day 8, and NY-ESO-1 peptide vaccine emulsified in incomplete Freund's adjuvant and sargramostim subcutaneously on day 15. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. | Drug: decitabine<br>* Given IV<br>* Other names: DAC;Biological: NY-ESO-1 peptide vaccine<br>* Given SC<br>* Other names: ESO-1 Peptide Vaccine;Drug: pegylated liposomal doxorubicin hydrochloride<br>* Given IV<br>* Other names: LipoDox;Biological: sargramostim<br>* Given SC<br>* Other names: Prokine;Biological: incomplete Freund's adjuvant<br>* Given SC<br>* Other names: Montanide ISA 51;Other: immunohistochemistry staining method<br>* Correlative studies<br>* Other names: immunohistochemistry;Other: liquid chromatography<br>* Correlative studies<br>* Other names: LC;Other: mass spectrometry<br>* Correlative studies<br>Genetic: reverse transcriptase-polymerase chain reaction<br>* Correlative studies<br>* Other names: RT-PCR;Other: laboratory biomarker analysis<br>* Correlative studies<br>Genetic: DNA methylation analysis<br>* Correlative studies<br>Other: enzyme-linked immunosorbent assay<br>* Correlative studies<br>* Other names: ELISA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity as assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0 | Estimated with a one-sided, 95%, Wilson score binomial confidence interval. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NY-ESO-1 specific cellular and humoral immunity as assessed by NY-ESO-1-specific CD8+ and CD4+ T cells and antibodies and frequency of CD4+ CD25+ FOXP3+ regulatory T cells | Will be summarized by quartiles. Also, confidence intervals will be constructed for the median and the mean. | Up to 6 months | 
| NY-ESO-l expression using Q-RT-PCR and IHC |  | Days 1, 8, 15, 36, 43, 64, 71, 92, and 99 | 
| Time to progression | Summarized by a Kaplan-Meier survival curve. | Up to 6 months | 
| NY-ESO-l promoter DNA methylation using pyrosequencing |  | Days 1, 8, 15, 36, 43, 64, 71, 92, and 99 | 
| Global genomic DNA methylation using liquid chromatography-mass spectrometry (LC-MS) and LINE-l pyrosequencing |  | Days 1, 8, 15, 36, 43, 64, 71, 92, and 99 |