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A Pilot Study of Vaccination With Epitope-Enhanced TARP Peptide and TARP Peptide-Pulsed Dendritic Cells in the Treatment of Stage D0 Prostate Cancer

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ClinicalTrials.gov Identifier: NCT00972309
Recruitment Status : Completed
First Posted : September 4, 2009
Last Update Posted : August 13, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE September 3, 2009
First Posted Date  ICMJE September 4, 2009
Last Update Posted Date August 13, 2021
Actual Study Start Date  ICMJE May 11, 2009
Actual Primary Completion Date February 4, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 14, 2018)
  • Immunologic response rate to vaccination [ Time Frame: Every 12 weeks through wk 60, additional assessment at wk 18 and wk 96 ]
    Presence of T-lymphocyte cells in patients' specimen using tetramer staining, IFNELISPOT and 51Cr release CTL assays.
  • Determine the safety and toxicity od TARP vaccines [ Time Frame: continuously through 30 days after last vaccination ]
    The quantity of AEs each subject experiences.
Original Primary Outcome Measures  ICMJE
 (submitted: September 3, 2009)
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 Sargramos.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: September 3, 2009)
Determine the effect of TARP peptide vaccination on serum prostate specific antigen doubling time (PSADT).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Pilot Study of Vaccination With Epitope-Enhanced TARP Peptide and TARP Peptide-Pulsed Dendritic Cells in the Treatment of Stage D0 Prostate Cancer
Official Title  ICMJE A Pilot Study of Vaccination With Epitope-Enhanced TARP Peptide and TARP Peptide-Pulsed Dendritic Cells in the Treatment of Stage D0 Prostate Cancer
Brief Summary

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.
  • 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 system s 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 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 patient s 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 patient s 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.
Detailed Description

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 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 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, IFN-gamma ELISPOT and (51)Cr release CTL assays.

ELIGIBILITY:

  • Males greater than or equal to 18 years of age with histologically confirmed adenocarcinoma of the prostate.
  • 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 rising PSA and no evidence of metastatic disease by physical examination, CT scan or bone scan.
  • PSADT greater than or equal to 3 months and less than or equal to 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 following definitive radiation therapy or cryotherapy: a rise in PSA of > 2ng/mL above the nadir (per RTOG-ASSTRO consensus criteria).
  • For patients following radical prostatectomy: 2 absolute PSA values > 0.3ng/ml (per NCCN guidelines).
  • Non-castrate level of testosterone: greater than or equal to 50 ng/dL (prior ADT allowed; must be greater than or equal to 6 months since last dose of ADT).
  • HLA-A*0201 positive.
  • Performance Status: ECOG 0-2 or Karnofsky 70-100% and life expectancy greater than or equal to 1 year.
  • Hemoglobin greater than or equal to 10.0 gm/dL, WBC greater than or equal to 2,500/mm(3), ALC greater than or equal to 500/ mm(3), ANC greater than or equal to 1,000/mm(3), platelet count greater than or equal to 100,000/mm(3), and PT/PTT less than or equal to 1.5 times ULN unless receiving clinically indicated anticoagulant therapy; SGPT/SGOTless than or equal to 2.5 times ULN, total bilirubin less than or equal to 1.5 times ULN; creatinine less than or equal to 1.5 times ULN and estimated GFR (eGFR) greater than or equal to 60 ml/min.
  • Hepatitis B and C negative (unless the result is consistent with prior vaccination or prior infection with full recovery); HIV negative.
  • No use of investigational agents within 4 weeks of study enrollment or use of immunosuppressive or immunomodulating agents within 8 weeks of study entry.
  • No other concurrent anticancer therapy or prior prostate cancer vaccines expressing TARP or HLA A2.
  • 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.

STUDY DESIGN:

  • This is a randomized, prospective, pilot study of vaccination with a mixture of wild type (TARP27-35) and epitope-enhanced (TARP29-37-9V) TARP peptides in HLA-A*0201 patients with stage D0 prostate cancer.
  • Vaccination with TARP peptides admixed with Montanide ISA 51 VG plus Sargramostim administered by deep subcutaneous injection will be compared with vaccination with TARP peptide-pulsed autologous dendritic cells (DCs) administered intradermally.
  • Autologous dendritic cells will be matured from peripheral blood monocytes with Sargramostim, IL-4, IFN-gamma and LPS and pulsed with wild type and epitope-enhanced TARP peptides.
  • Apheresis will be performed on all patients at weeks 0, 24, 48 and 96.
  • Randomization and assignment to received TARP peptide vaccine with Montanide ISA 51 VG plus Sargramostimgiven by deep subcutaneous injection or TARP peptide-pulsed autologous DCs given ID will be performed at week 0.
  • All patients will receive live, attenuated influenza vaccine (FluMist ) when seasonally available at the very end of their week 0 visit as a control vaccine to assess cytotoxic T lymphocyte responses.
  • TARP Peptide vaccines will be administered every three weeks at weeks 3, 6, 9, 12, and 15, with a sixth and seventh booster dose of vaccine at Week 48 and 96. Follow-up will be through 144 weeks on study.
  • The trial uses an optimal 2-stage design targeting an immunologic response between 10 and 40%. We will initially accrue 9 patients in each arm. If 0-1 patients develop an immunologic response, then no further patients will be enrolled. If 2 or more of these patients develop an immunologic response, we will accrue 11 additional patients for a maximum total of up to 20 patients in each arm. A stopping rule for excessive toxicity will be incorporated.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Prostate Specific Antigens
  • Prostate Neoplasms
Intervention  ICMJE
  • Biological: TARP peptide vaccine
    Will receive an admixture of the wildtype and epitopeenhanced TARP peptides emulsified with Montanide ISA 51 VG and GM-CSF. TARP peptide will be administered subcutaneously at weeks 3, 6, 9, 12 and 15 for a total of five vaccinations with a booster dose of vaccine at Weeks 48 and 96
  • Biological: TARP dendritic cell vaccine
    Will receive peptidepulsed dendritic cells administered intradermally in two vaccination sites. TARP pulsed dendritic cells will be administered at weeks 3, 6, 9, 12 and 15 for a total of five vaccinations with a booster dose of vaccine at Weeks 48 and 96.
Study Arms  ICMJE
  • Experimental: 1
    TARP pepties
    Intervention: Biological: TARP peptide vaccine
  • Experimental: 2
    TARP dendritic cells
    Intervention: Biological: TARP dendritic cell vaccine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 7, 2012)
41
Original Enrollment  ICMJE
 (submitted: September 3, 2009)
40
Actual Study Completion Date  ICMJE February 4, 2015
Actual Primary Completion Date February 4, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:
  • Males greater than or equal to 18 years of age with histologically confirmed adenocarcinoma of the prostate.
  • 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 PSA.
  • No evidence of metastatic disease by physical examination, 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 ADT allowed; must be greater than or equal to 6 months since last dose of ADT).
  • A Pre-Enrollment/Baseline 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: 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, WBC greater than or equal to 2,500/mm(3), ALC greater than or equal to 500/mm3, ANC greater than or equal to 1,000/mm(3), platelet count greater than or equal to 100,000/mm(3).
  • PT/PTT less than or equal to 1.5 times ULN unless receiving clinically indicated anticoagulant therapy.
  • SGOT/SGPT < 2.5 times ULN, total bilirubin < 1.5 times ULN, Cr < 1.5 times ULN, estimated GFR (eGFR) > 60 ml/min.
  • Hepatitis B and C negative, unless the result is consistent with prior vaccination or prior infection with full recovery.
  • 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 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 A2.
  • Able to understand and provide Informed Consent.

EXCLUSION CRITERIA:

  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00972309
Other Study ID Numbers  ICMJE 090139
09-C-0139
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Hoyoung M Maeng, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date June 9, 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP