Multi-Epitope TARP Peptide Autologous Dendritic Cell Vaccination in Men With Stage D0 Prostate Cancer

TARP

- T-cell receptor g alternate reading frame protein (TARP) is a 58 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 (NCI
09-C-0139) utilizing TARP WT 27-35 and EE29-37-9V peptides was conducted in HLA-A
0201positive men with stage D0 prostate cancer (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:
pre-vaccine g = 0.0042/day, post-vaccine g = 0.0021/day (p=0.003); TARP-specific IFN-g
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 cell helper epitopes that will allow
generation of better CD8+ T cell responses with improved functional avidity and
longevity as well as humoral anti-TARP antibody responses.

Study Objectives:

Primary:

-To assess the difference in the slope log (PSA) for Weeks3-24 minus that formed for the 12
months prior to enrollment on study (referred to as slope324 pre-slope) as well as the slope
log (PSA) for weeks 3-48 versus the same pre-treatment slope log (PSA) (referred to as slope
348 preslope) in patients na(SqrRoot) ve to TARP vaccination receiving active, multi-epitope
TARP vaccination vs. placebo.

Eligibility:

- Males greater than or equal to 18 years of age with histologically confirmed
adenocarcinoma of the prostate.

- 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 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.

- Performance Status: ECOG 0-1 and life expectancy greater than or equal to 1 year.

- No other concurrent anticancer therapy or prior prostate cancer vaccines expressing
TARP.

Study Design:

- Phase II, prospective, single-blinded, randomized, placebo controlled study of 96 weeks
duration in men with Stage D0 prostate cancer. Men with a PSADT greater than or equal to
3 months and less than or equal to 15 months will be randomized 2:1 to receive ME TARP
autologous DC vaccination or a control eleutriated monocyte vaccine placebo.

- An initial lead-in of 6 patientswill be enrolled to allow preliminary assessment of the
safety of the ME TARP vaccine platform through 12 weeks before enrollment of
prospectively randomized subjects blinded to treatment assignment begins.

- All patients will receive a total of 6 doses of vaccine (20 x10(6) viable cells/dose)
delivered intradermally at Weeks 3, 6, 9, 12, 15, and 24. All patients will undergo a
15-18L apheresis at Week 0 and restaging at Weeks 48 and 96 to confirm maintenance of
Stage D0 disease.

Sample size: N = 72 (6 lead-in patients for safety assessment, 2:1 randomization: TARP N =
44; placebo N =22).

-INCLUSION CRITERIA:

1. Males greater than or equal to 18 years of age with histologically confirmed
adenocarcinoma of the prostate.

2. Must have completed and recovered from all prior definitive therapy (surgery,
brachytherapy, cryotherapy or radiotherapy) for the primary tumor, or other
definitiveintent local therapy.

3. 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.

4. PSADT greater than or equal to 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.

5. For patients following definitive radiation therapy or cryotherapy: a rise in PSA of >
2ng/mL above the nadir (per RTOG-ASSTRO consensus criteria).

6. For patients following radical prostatectomy: 2 absolute PSA values > 0.2ng/ml.

7. 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).

8. Performance Status: ECOG 0-1 and life expectancy greater than or equal to 1 year.

9. Hemoglobin greater than or equal to 9.0 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 75,000/mm(3), and PT/PTT less than
or equal to 1.5 times ULN unless receiving clinically indicated anticoagulant therapy;
SGPT/SGOT less than or equal to 3 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.

10. Hepatitis B and C negative (unless the result is consistent with prior vaccination or
prior infection with full recovery); HIV negative.

11. No use of investigational agents within 4 weeks of study enrollment or use of
immunosuppressive or immunomodulating agents within 8 weeks of study entry.

12. No other concurrent anticancer therapy or prior prostate cancer vaccines expressing
TARP.

13. No alternative medications or nutriceuticals 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 prior to study enrollment are allowed.

EXCLUSION CRITERIA:

1. Patients with an active second malignancy other than adequately treated squamous or
basal cell carcinoma of the skin.

2. Patients with active infection.

3. Patients on immunosuppressive therapy including:

- Systemic corticosteroid therapy for any reason. Patients receiving inhaled or
topical corticosteroids may participate.

4. Other significant or uncontrolled medical illness. Patients with a remote history of
asthma or active mild asthma may participate.

5. 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.