A Pilot Study of Vaccination With Epitope-Enhanced TARP Peptide and TARP Peptide-Pulsed Dendritic Cells in the Treatment of Stage D0 Prostate Cancer
Condition: Prostate Specific Antigens; Prostate Neoplasms
MeSH terms: Prostatic Neoplasms
Study type: Interventional
Phase: Phase 1

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.

        -  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.
    

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 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:

        -  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, computed tomography (CT) scan or
           bone scan.

        -  Prostate-specific antigen doubling time (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 Radiation Therapy Oncology Group (RTOG)-American Society for
           Radiation Oncology (ASSTRO) consensus criteria).

        -  For patients following radical prostatectomy: 2 absolute PSA values > 0.3ng/ml (per
           National Comprehensive Cancer Network (NCCN) guidelines).

        -  Non-castrate level of testosterone: greater than or equal to 50 ng/dL (prior androgen
           deprivation therapy (ADT) allowed; must be greater than or equal to 6 months since last
           dose of ADT).

        -  HLA-A*0201 positive.

        -  Performance Status: Eastern Cooperative Oncology Group (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, 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), and 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 pyruvic
           transaminase (SGPT)/Serum glutamic oxaloacetic transaminase (SGOT) less 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 glomerular filtration rate (GFR) estimated
           glomerular filtration rate (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); human immunodeficiency virus (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 human leukocyte antigen (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, interleukin 4 (IL4), 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 Sargramostim given 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.
    

Intervention name(s): T-cell receptor alternate reading frame protein (TARP) peptide vaccine; T-cell receptor alternate reading frame protein (TARP) dendritic cell vaccine
Intervention type(s): Biological; Biological
Intervention description(s): Will receive an admixture of the wildtype and epitope enhanced TARP peptides emulsified with Montanide ISA 51 VG and granulocyte-macrophage colony-stimulating factor (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; Will receive peptide pulsed 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.
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Epitope-Enhanced TARP Peptide; Prostate Cancer; TARP Peptide-Pulsed Dendritic Cells; PSADT; HLA-A*0201