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

Phase 1

Completed

Conditions: Prostate Specific Antigens
Prostate Neoplasms

Interventions: Biological: T-cell receptor alternate reading frame protein (TARP) dendritic cell vaccine
Biological: T-cell receptor alternate reading frame protein (TARP) peptide vaccine

Registration Number: NCT00972309

Lead Sponsor: National Cancer Institute (NCI)

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.

* 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 41

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort: 2 -T-cell receptor alternate reading frame protein (TARP)	T-cell receptor alternate reading frame protein (TARP) dendritic cell vaccine	TARP dendritic cells
Cohort 1: T-cell receptor alternate reading frame protein (TARP)	T-cell receptor alternate reading frame protein (TARP) peptide vaccine	TARP peptides

Primary Outcome Measures

Name	Time	Method
Grades 1-5 Adverse Events Possibly, Probably, or Definitely Related to Drug	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	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)	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.

Secondary Outcome Measures

Name	Time	Method
PSA Doubling Time (PSADT) Response and Failure	Weeks 12, 24, 36, and 48	PSADT response is defined as: a \> 50% increase in calculated PSADT OR a PSADT \> 15 months. Participant's whose PSADT is decreased by \> 50% will be considered PSADT failures. Week 24 PSADT responders will be allowed to receive an additional dose of T-cell receptor alternate reading frame protein (TARP) peptide vaccine at Week 36.
Change in Tumor Growth Rate Constant: Pre-versus Post T-cell Receptor Alternate Reading Frame Protein (TARP) Vaccination	42-651 days on treatment	Changes in tumor growth rate constants (g) was calculated from fitting the prostate-specific antigen (PSA) curves to an exponential tumor growth model. Comparison of the median growth rate constant to 75th percentile \[upper quartile\]) of the estimated g of individual subjects pre- and post-TARP vaccination. The Tumor Growth Rate Constant was calculated using a regression-growth equation: f(t) = exp(-d x t) + exp(g x t) - 1, where exp is the base of the natural logarithm, e = 2.7182..., and f(t) is the PSA measurement at time t in days, normalized to (divided by) the PSA measurement at day 0, the time at which treatment is commenced. Rate constant d (decay, in days-1) represents the exponential decrease/regression rate constant of the PSA signal during therapy. Rate constant g (growth, also in days-1) represents the exponential growth/re-growth rate constant of the tumor during treatment.