NCT00972309已完成1 期
A Pilot Study of Vaccination With Epitope-Enhanced TARP Peptide and TARP Peptide-Pulsed Dendritic Cells in the Treatment of Stage D0 Prostate Cancer
适应症
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 41
- 试验地点
- 1
- 主要终点
- Grades 1-5 Adverse Events Possibly, Probably, or Definitely Related to Drug
研究概览
简要总结
Background:
- PSA (prostate specific antigen) is a protein found on normal and cancerous prostate cells. Levels of this protein are used to identify men who are at risk for prostate cancer and to monitor responses to treatment in men who have been diagnosed with prostate cancer.
- Research has shown that men who continue to have an elevated PSA level following primary treatment for prostate cancer are at increased risk for cancer progression. Studies have shown that the change in PSA levels over time, or PSA doubling time (PSADT), can be accurate in predicting how quickly the cancer is likely to progress. Individuals with a PSADT of less than 3 months are at extremely high risk for disease progression and death from prostate cancer. Individuals with a PSADT of greater than 15 months have a very low risk of death from prostate cancer.
- T-cell receptor alternate reading frame protein (TARP) is a protein that is found in about 95% of prostate cancers and is known to stimulate the immune system. The TARP prostate cancer vaccine is made from pieces of the TARP protein called peptides and includes peptides that have been modified to make them more effective at stimulating immunity. Although these TARP peptides have been shown to stimulate the immune systems of mice, information is needed to determine if they also stimulate the immune system in humans. Since it is unclear what is the best way to give peptide vaccines, the TARP peptides will be given with substances known to stimulate the immune system or in a vaccine made with the patient s own cells.
Objectives:
- To determine the immune systems response to vaccination with TARP peptides.
- To determine the safety and toxicity of TARP peptide vaccination.
- To determine if vaccination with the TARP prostate cancer vaccine can slow down PSADT in men with an intermediate PSADT of 3 to 15 months.
Eligibility:
- Males 18 years of age and older who have completed their primary treatment for prostate cancer, have stage D0 disease, are Human leukocyte antigen (HLA) A*0201 positive and who have a PSADT greater than 3 and less than 15 months.
Design:
- Patients will be randomized to one of two treatment arms:
- Arm A will receive the TARP vaccine with other substances that stimulate the immune system.
- Arm B will receive the TARP vaccine that includes a patients own white blood cells.
- First week of study, after screening for eligibility has been completed:
- Day 1: Apheresis procedure to extract white blood cells to test the immune response to the vaccine.
- Day 3: Flu vaccine to allow researchers to determine how well a patients immune system is working.
- Clinic visits in Weeks 3, 6, 9, 12, and 15 for physical examination, blood samples, and administration of the TARP peptide vaccine.
- Physical examination and blood samples only in Weeks 18 and 36.
- Additional blood samples and apheresis procedures in Weeks 24 and 48.
- A 6th dose of TARP peptide vaccine will be administer to those patients who have a response to vaccination at week 24.
- No follow-up or long-term study is associated with this study.
详细描述
BACKGROUND:
- T-cell receptor alternate reading frame protein (TARP) is expressed by both normal and malignant prostate cancer tissue and is found in about 95% of prostate cancer specimens. TARP is immunogenic and hence is a target antigen for vaccination.
- The immunogenicity of TARP peptides can be augmented through epitope enhancement that is achieved through amino acid substitutions resulting in increased peptide binding affinity.
- Two HLA-A*0201 TARP peptide epitopes are associated with generation of catalytic T-cell responses: TARP27-35 and TARP29-37. Substitution of Val for Leu at position 9 in TARP29-37, results in a peptide with increased binding affinity (TARP29-37-9V) that induces antigen specific T cells able to recognize wild type and multiple modified TARP peptides. The affinity of the TARP 27-35 peptide, corresponding to a distinct but overlapping epitope, is high enough that no enhancement was required.
- Stage D0 prostate cancer patients have no evidence of visceral or bony metastatic disease but have persistently elevated or rising prostate-specific antigen (PSA) levels (biochemical progression) and are at increased risk for disease progression. Since they lack much of the immune dysfunction associated with the high tumor burden characteristic of end-stage metastatic disease, they are an ideal population in which to study therapeutic vaccination to slow or prevent disease recurrence and progression.
- Dendritic cells (DC) are the most potent antigen-presenting cells of the immune system and are being studied extensively for anti-tumor activity in a broad spectrum of cancer patients.
- As the optimal method for therapeutic immunization with peptide vaccines in patients with cancer is unclear, vaccination with TARP peptides in Montanide ISA 51 VG adjuvant plus Sargramostim will be studied in a randomized fashion with autologous, TARP peptide-pulsed dendritic cells (DCs) in HLA-A*0201 Stage D0 prostate cancer patients.
OBJECTIVES:
- Determine the safety and toxicity of TARP peptide and TARP peptide-pulsed dendritic cell vaccination in patients with Stage D0 prostate cancer.
- Determine the T-lymphocyte immune responses to TARP peptide vaccination with Montanide ISA 51 VG plus Sargramostim or autologous dendritic cells as measured by tetramer staining, interferon (IFN)-gamma enzyme-linked immune absorbent spot (ELISpot) and (51)Cr release cytotoxic T lymphocytes (CTL) assays.
ELIGIBILITY:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •Males greater than or equal to 18 years of age with histologically confirmed adenocarcinoma of the prostate.
- •Human leukocyte antigen-A (HLA-A)*201 positive
- •Patients must have
- •Completed and recovered from all prior definitive therapy (surgery, brachytherapy, cryotherapy or radiotherapy) for the primary tumor, or other definitive-intent local therapy.
- •Stage D0 disease with documented biochemical progression documented by a rising prostate-specific antigen (PSA).
- •No evidence of metastatic disease by physical examination, computed tomography (CT) scan or bone scan.
- •For patients following definitive radiation therapy or cryotherapy: a rise in PSA of >2ng/mL above the nadir.
- •For patients following radical prostatectomy: 2 absolute PSA values > 0.3 ng/mL
- •Non-castrate level of testosterone: greater than or equal to 50 ng/dL (prior androgen deprivation treatment (ADT) allowed; must be greater than or equal to 6 months since last dose of ADT).
- •A Pre-Enrollment/Baseline prostate-specific antigen doubling time (PSADT) > 3 months and less than or equal to 15 months
- •Patients must have greater than or equal to 3 PSA measurements over greater than or equal to 3 months
- •The interval between PSA measurements must be greater than or equal to 4 weeks
- •For patients receiving 5-alpha reductase inhibitors (5ARI) e.g. finasteride or dutasteride, only PSA values obtained after at least 3 months on therapy may be used to calculate PSADT.
- •Performance Status: Eastern Cooperative Oncology Group (ECOG) 0-2 or Karnofsky 70-100%
- •Life expectancy greater than or equal to 1 year.
- •Hemoglobin greater than or equal to 10.0 gm/dL, white blood cell (WBC) greater than or equal to 2,500/mm(3), absolute lymphocyte count (ALC) greater than or equal to 500/mm(3), absolute neutrophil count (ANC) greater than or equal to 1,000/mm(3), platelet count greater than or equal to 100,000/mm(3).
- •Prothrombin time (PT)/ partial thromboplastin time (PTT) less than or equal to 1.5 times upper limits of normal (ULN) unless receiving clinically indicated anticoagulant therapy.
- •Serum glutamic oxaloacetic transaminase (SGOT)/Serum glutamic pyruvic transaminase (SGPT) < 2.5 times ULN, total bilirubin < 1.5 times ULN, creatinine (Cr) < 1.5 times ULN, estimated glomerular filtration rate (GFR) estimated glomerular filtration rate (eGFR) > 60 ml/min.
- •Hepatitis B and C negative, unless the result is consistent with prior vaccination or prior infection with full recovery.
- •Human immunodeficiency virus (HIV) negative
- •No use of investigational agents within 4 weeks of study enrollment.
- •No use of immunosuppressive (cytotoxic chemotherapy, systemic steroids) or immunomodulating agents (including intravenous immune globulin (IVIG) within 8 weeks of study entry. Note: topical and intranasal steroid therapy is permitted.
- •No other concurrent anticancer therapy.
- •No alternative medications known to alter PSA (e.g. phytoestrogens and saw palmetto). Note: patients receiving medications for urinary symptoms such as Flomax or 5-alpha reductase inhibitors (finasteride and dutasteride) on a chronic stable dose for at least 3 months are allowed.
- •No prior prostate cancer vaccines expressing TARP or HLA A
- •Able to understand and provide Informed Consent.
排除标准
- •HLA-A*201 negative
- •Patients with an active second malignancy other than adequately treated squamous or basal cell carcinoma of the skin, or superficial bladder carcinoma.
- •Patients with active infection.
- •Patients with brain, visceral or bony metastatic disease.
- •Patients in who live attenuated intranasal influenza vaccine (FluMist) is contraindicated including individuals with asthma or reactive airways disease, cardiovascular or pulmonary disease, chronic metabolic diseases (including diabetes mellitus), renal dysfunction or hemoglobinopathies.
研究组 & 干预措施
Cohort 1: T-cell receptor alternate reading frame protein (TARP)
Experimental
TARP peptides
干预措施: T-cell receptor alternate reading frame protein (TARP) peptide vaccine (Biological)
Cohort: 2 -T-cell receptor alternate reading frame protein (TARP)
Experimental
TARP dendritic cells
干预措施: T-cell receptor alternate reading frame protein (TARP) dendritic cell vaccine (Biological)
结局指标
主要结局
Grades 1-5 Adverse Events Possibly, Probably, or Definitely Related to Drug
时间窗: From date treatment consent signed and continuously through 30 days after last vaccination, approximately 59 months and 16 days for Arm A and 58 months and 24 days for Arm B.
Adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0). Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse event.
Number of Participants With an Immunological Response of Chromium 51 (51Cr) Release Measured by Tetramer Staining OR Interferon (IFN)-Gamma Enzyme-linked Immune Absorbent Spot (ELISPOT) Assay
时间窗: Weeks 0, 12, 18 and 24
A three-fold increase over baseline in the number of positive cells by tetramer staining OR Interferon (IFN)-gamma enzyme-linked immune absorbent spot (ELISPOT) assay was considered a positive immunological response.
Number of Participants With a Positive Immune Response Following Vaccination Determined by Interferon (IFN) Gamma Enzyme-linked Immunosorbent Spot (ELISpot)
时间窗: Week 24
The number of participants in each arm with positive response determined by 3-fold increase over baseline in the number of positive cells by interferon (IFN) gamma enzyme-linked immunosorbent spot (ELISpot) at week 24. Presence of tumor antigen-specific T cells (positive response) mean the vaccine was able to generate immune response (i.e. immunogenicity) which is a good outcome.
次要结局
- PSA Doubling Time (PSADT) Response and Failure(Weeks 12, 24, 36, and 48)
- Change in Tumor Growth Rate Constant: Pre-versus Post T-cell Receptor Alternate Reading Frame Protein (TARP) Vaccination(42-651 days on treatment)
研究者
Hoyoung M. Maeng, M.D.
Principal Investigator
National Cancer Institute (NCI)
研究点 (1)
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