Long-Term TARP Vaccination Using a Multi-Epitope TARP Peptide Autologous Dendritic Cell Vaccination in Previously Vaccinated Men on NCI 09-C-0139

Study Overview
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Brief Summary
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Background: - Few studies or literature are available about the long-term safety of repeated peptide vaccinations in people over a period of time. Long-term vaccination may be needed to control tumors. Researchers gave a group of men a series of vaccine injections over 2 years. Now they want to give those same men the new version of the vaccine. They want to see if it produces different types of immune responses and also ensure that repeated vaccinations are safe. Objectives: - To find out the long-term safety of repeated T-cell receptor alternate reading frame protein (TARP) peptide vaccinations. Eligibility: - Men who took part in National Cancer Institute (NCI) protocol 09-C-0139. Design: Participants will be screened with blood tests, scans, physical exam, medical history, and an evaluation of how well they perform everyday activities. Participants will have apheresis. Blood will be removed with a needle from one arm. A machine will separate the white blood cells. The blood, minus the white cells, will be returned through a needle in the other arm. Participants will have 14 visits. At each visit, they will have a physical exam and blood tests. They will discuss any side effects. Participants will get vaccine injections at weeks 3, 6, 9, 12, 15, and 24. The vaccine will be made from the participants own cells. Participants will get a Vaccine Report Card to complete after receiving vaccine. The study lasts 96 weeks.

Detailed Description
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TARP T-cell receptor gamma alternate reading frame protein (TARP) is an amino acid protein expressed by both normal and malignant prostate cancer tissue; 95% of prostate cancer specimens are positive for TARP expression. TARP is highly expressed in prostate cancers of all Gleason types, in primary as well as metastatic disease, and in hormone sensitive and castrate resistant prostate cancer. Therefore, TARP is an ideal tumor antigen target for a vaccine. A prospective, randomized pilot study of 1st generation TARP Peptide vaccination National Cancer Institute (NCI 09-C- 0139) utilizing TARP WT 27-35 and EE29-37-9V peptides was conducted in HLAA* 0201positive men with stage D0 prostate cancer prostate specific-antigen (PSA) biochemical recurrence) and a PSA doubling time (PSADT) of greater than or equal to 3 months and less than or equal to 15 months. TARP vaccination was found to be immunogenic, safe and well tolerated, with adverse events limited to injection site reactions less than or equal to Grade 2. TARP vaccination was also associated with a decreased slope log PSA compared to pre-vaccination baseline in 72% of subjects reaching 24 weeks and 74% reaching 48 weeks (p=0.0012 and p=0.0004 for overall changes in slope log PSA, respectively); TARP vaccination also resulted in a 50% decrease in calculated tumor growth rate constant: prevaccine g = 0.0042/day, post-vaccine g = 0.0021/day (p=0.003); TARP-specific IFN- >= enzyme-linked immunosorbent spot (ELISPOT) responses were detected in the majority of subjects but did not correlate with decreases in slope log (PSA). Multi-Epitope (ME) TARP Vaccine The vaccine platform includes the original two 9-mer HLA-A*0201 binding TARP peptide epitopes (WT27-35 and EE29-37-9V) utilized in NCI 09-C-0139 as well as an additional five 20-mer TARP peptides overlapping by 10 amino acids for a total of 7 peptides that span the amino acid sequence of the entire TARP protein. The advantage of this multi-epitope TARP peptide vaccine platform is that the overlapping epitopes cover the entire TARP protein, resulting in potential for induction of a multi-valent anti-TARP response. In addition, these longer synthetic peptides include TARP-specific MHC class II CD4 T lymphocytes (CD4+ T) cell helper epitopes that will allow generation of better cyctotoxic T cells (CD8+ T) cell responses with improved functional avidity and longevity as well as humoral anti-TARP antibody responses. Study Objectives Primary Objective: -To assess the long-term safety of repeated TARP peptide vaccination following the use of a 1st generation bivalent (09-C-0139) and a 2nd generation ME TARP peptide vaccine. Specifically, to document if less than 10% of enrolled patients experience a vaccine-related Grade 3 adverse event (local injection site reactions or systemic reactions). Eligibility Criteria All Patients Males greater than or equal to 18 years of age with histologically confirmed adenocarcinoma of the prostate. Prior enrollment in NCI protocol 09-C-0139 with receipt of at least 5 doses of TARP peptide vaccine (i.e. completion of primary vaccination series). Performance Status: Eastern Cooperative Oncology Group (ECOG) 0-1 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, 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 1.5X upper limit of normal (ULN) unless receiving clinically indicated anticoagulant therapy; serum glutamate-pyruvate transaminase (SGPT)/serum glutamic oxaloacetic transaminase (SGOT) less than or equal to 2.5X ULN, total bilirubin less than or equal to 1.5X ULN; creatinine less than or equal to 1.5X ULN and 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. Standard of care medical management of current prostate cancer disease status by the patients local oncologist e.g., androgen deprivation therapy is allowed. Must be able/willing to adhere to protocol requirements and vaccination timeline. Exclusion Criteria All Patients Patients with active infection or other significant or uncontrolled medical illness. Patients with a remote history of asthma or active mild asthma may participate. Patients on immunosuppressive therapy including systemic corticosteroid therapy for any reason. Patients receiving inhaled or topical corticosteroids may participate. Patients who, in the opinion of the Principal Investigator, have significant medical or psychosocial problems that warrant exclusion. Study Design Open label, prospective, non-randomized, long-term follow-up pilot study of 96 weeks to assess the long-term safety of repeated TARP vaccination in patients that have already received the first generation TARP vaccine. Sample size: N equals 40 maximum. All patients will undergo an 18L apheresis for mononuclear cell collection at Week 0. All patients will receive a total of 6 doses of autologous ME TARP peptide dendritic cell (DC) vaccine: 20x10^6 viable cells/dose) delivered intradermally at Weeks 3, 6, 9, 12, 15, and 24.

Official Title
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A Pilot Study of Long Term TARP Vaccination Using A Multi-Epitope TARP Peptide Autologous Dendritic Cell Vaccine in Previously Vaccinated Men on NCI 09-C-0139.

Conditions
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Prostatic Neoplasms, Neoplasms of Prostate, Prostate Cancer, Cancer Of Prostate, Stage D0 Prostate Cancer

Intervention / Treatment
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* Biological: Multi-epitope (ME) T-cell Receptor Alternate Reading Frame Protein (TARP) vaccine


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Males greater than or equal to 18 years of age with histologically confirmed adenocarcinoma of the prostate. Prior enrollment in National Cancer Institute (NCI) protocol 09-C-0139 with receipt of at least 5 doses of T cell receptor gamma alternate reading frame protein (TARP) peptide vaccine (i.e. completion of primary vaccination series). Performance Status: Eastern Cooperative Oncology Group (ECOG) 0-1, life expectancy of 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 1.5X upper limit of normal (ULN) unless receiving clinically indicated anticoagulant therapy. Serum glutamic-oxaloacetic transaminase (SGOT)/serum glutamic-pyruvic transaminase (SGPT) less than or equal to 2.5X ULN, total bilirubin less than or equal to 1.5X ULN, creatinine (Cr) less than or equal to 1.5X ULN, 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 (including Intravenous immune globulin (IVIG) within 8 weeks of study entry. Note: Use of topical, inhaled and intranasal steroid therapy is permitted. Greater than or equal to 6 weeks since the receipt of chemotherapy or radiation therapy. Standard of care medical management of current prostate cancer disease status by the patients local oncologist, e.g., androgen deprivation therapy is allowed. Able to understand and provide Informed Consent. Must be able and willing to adhere to protocol requirements, visits and vaccination timeline. EXCLUSION CRITERIA: Patients with a second malignancy requiring active treatment. Patients with an active infection. Patients on immunosuppressive therapy including: --Systemic corticosteroid therapy for any reason. Patients receiving inhaled, intranasal or topical corticosteroids may participate. Other significant or uncontrolled medical illness. Patients with a remote history of or active mild asthma may participate. Patients who, in the opinion of the Principal Investigator, have significant medical or psychosocial problems that warrant exclusion including: Other serious non-malignancy-associated medical conditions that may be expected to limit life expectancy to less than 2 years. Any condition- medical, psychiatric or otherwise, that would preclude informed consent, consistent follow-up or compliance with any aspect of the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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: Long Term T-cell Receptor Alternate Reading Frame Protein (TARP) Peptide Vaccinations<br>Intradermally given vaccine given at weeks 3, 6, 9, 12, 15 and 24. | Biological: Multi-epitope (ME) T-cell Receptor Alternate Reading Frame Protein (TARP) vaccine<br>* dose of 20 x 10^6 viable cells multiepitope TARP dendritic cell vaccine given intradermally at weeks 3, 6, 9, 12, 15 and 24.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Grade 3 Adverse Events (AEs) Probably Related to the Vaccine Treatment | The number of Grade 3 adverse events probably related to the vaccine treatment. Adverse events were measured using the Common Terminology Criteria for Adverse Events (CTCAE v.4.0). Grade 3 is severe. | Up to 30 days after week 24 vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Slope Log PSA From Pre-study Baseline (-12 Months to Entry on the Current Study) to the Change in Slope Log PSA at Weeks 3-24 and 3-48 Post Multi-Epitope (ME) T-cell Receptor Alternate Reading Frame Protein (TARP) Vaccination | PSA slope log was calculated using Memorial Sloan Kettering Cancer Center Prostate Cancer Nomograms (http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx) Slope log represents the speed of change of a series of values. Thus, it is reported without any units as it is with a concept of ratio. The clinical meaning of PSA slope change would be decrease or increase of the speed (velocity) of changes in PSA, not the changes in PSA values. Decreasing PSA slope after the investigational treatment would mean the PSA rise is slower than pre-treatment baseline. Lowered PSA slope has been reported to show a relationship with was reported as related to improved outcomes. | Weeks 3-24 minus baseline, and Weeks 3-48 minus baseline | 
| Change in Slope Log Prostate Specific-antigen (PSA) Versus the Same Change in Slope Log PSA Parameters Following 1st Generation T-cell Receptor Alternate Reading Frame Protein (TARP) Vaccination on Protocol 09-C-0139 | Participants slope log on study 09C0139 are compared with the slope log values for the same participants after receiving the updated ME-TARP vaccines on the current protocol 15C0076 in participants who were not treated with androgen deprivation. PSA slope log was calculated using Memorial Sloan Kettering Cancer Center Prostate Cancer Nomograms (http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx) Slope log represents the speed of change of a series of values. Thus, it is reported without any units as it is with a concept of ratio. The clinical meaning of PSA slope change would be decrease or increase of the speed (velocity) of changes in PSA, not the changes in PSA values. Decreasing PSA slope after the investigational treatment would mean the PSA rise is slower than pre-treatment baseline. Lowered PSA slope has been reported to show a relationship with was reported as related to improved outcomes. | Weeks 3-24 minus baseline, and Weeks 3-48 minus baseline | 
| Assess Reactivity to WT27-35 and EE29-37-9V T-cell Receptor Alternate Reading Frame Protein (TARP) Peptides | Measure of reactivity to WT27-35 and EE29-37-9V TARP peptides. | Week 24 and Week 48 following immunization with the 2nd generation Multi-Epitope (ME) TARP | 
| TARP WT27-35 and EE29-37-9V T-cell Receptor Alternate Reading Frame Protein (TARP) Peptide Interferon (IFN)-Gamma Enzyme-linked Immunosorbent Spot (ELISpot) Reactivity | WT27-35 and EE29-37-9V TARP peptide IFN-gamma ELISPOT reactivity. | Week 24 and 48 following Multi-Epitope (ME) TARP vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multi-epitope, Tarp Peptide, Dendritic Cell Vaccine, D0 Prostate Cancer