Muscadine Plus (MPX) In Men With Prostate Cancer

Prostate specific antigen (PSA) is a single-chain glycoprotein produced by the epithelial
cells of the prostate. PSA has been used for early detection and monitoring of patients with
prostate cancer who receive a variety of treatments. Due to the widespread use of serum PSA
to monitor for prostate cancer recurrence following primary treatment, there exists a group
of men with a rising PSA as their only evidence of recurrence. These patients may not
demonstrate clinical or radiographic evidence of disease progression for an average 8 years
from the time of detectable PSA to detectable metastatic disease by standard imaging.
Currently there are limited treatment options for these patients that may delay disease
progression or improve survival, including salvage radiation for prior surgical patients,
hormonal therapy, and active surveillance.

Although some surgical patients are candidates for salvage radiation, not all patients will
want salvage radiation. Even the early initiation of hormonal therapy (e.g., luteinizing
hormone releasing hormone (LHRH) analogs) has not demonstrated a survival benefit, although
Schroder et al suggests an advantage for early hormone therapy in the setting of metastatic
regional lymph nodes. Furthermore, early initiation of androgen ablation is associated with
significant morbidity and impact on quality of life, including fatigue, hot flashes, loss of
libido, decreased muscle mass, and osteoporosis with long term use. This group of relatively
well men with biochemical recurrence are currently offered androgen ablation therapy or
active surveillance (regular PSA monitoring and annual scans) until there is evidence of
metastatic disease, because other options have not been available. These patients are
excellent candidates for innovative treatments hypothesized to slow the progression of
clinical prostate cancer and delay the development of metastatic disease.

As the previous section documents, preclinical studies of muscadine grape skin offer evidence
that it may extend the time between biochemical recurrence and development of metastatic
disease. While the Phase II study described above found no significant difference in PSA
doubling time between placebo and either dose of MPX, there was a signal of benefit in the
subgroup analysis of men with the Alanine/Alanine superoxide dismutase 2 (SOD2) genotype that
received high dose MPX. It is therefore proposed to test the benefits of high dose MPX in
capsule formulation in a randomized, controlled study of men who have failed primary therapy,
either radiation, surgery or cryotherapy, as primary treatment for prostate cancer. Eligible
subjects will have a rising PSA and will have 3 PSA values at least 7 days apart with a
recovered testosterone to be able to calculate a baseline PSA doubling time. The primary
endpoint of this study will be mean PSA slope during the study period.

Inclusion Criteria:

Patients meeting the following conditions are eligible for registration and participation
in the study:

1. Subject has histologically or cytologically confirmed adenocarcinoma of the prostate

2. Subject has undergone definitive treatment (surgery, surgery with radiation therapy,
cryotherapy, radiation therapy or brachytherapy) for the primary prostate tumor.

a. A subject with a rising PSA post-prostatectomy should consider radiation as a
potentially curative alternative. If subject declines radiation or is not a candidate
for radiation, he may be considered eligible in this setting.

3. Subject has a rising PSA on a minimum of 3 time points (2 rises) within the 12 months
prior to study initiation (this will include the PSA measurement taken at the
screening visit, but not at the baseline day 0 study visit).

For purposes of calculating PSADT:

1. All PSA values used in the calculation should be ≥ 0.20 ng/ml and overall should
follow a rising trend;

2. Record every available PSA drawn within the last 12 months of the most recent
local PSA;

3. The minimum requirement is 3 PSA values obtained over 3 months with a minimum of
4 weeks between measurements;

4. If there are 4 or more PSAs available, the time interval between the first and
last PSA measurements must be at least 3 months, and, there is no minimum time
interval requirement between any two PSA measurements;

5. For radiotherapy only patients, record PSA nadir value and collection date. PSADT
must be positive according to Memorial Sloan Kettering Cancer Center Prostate
Cancer Nomograms under this link:
http://www.mskcc.org/applications/nomograms/prostate/PsaDoublingTime.aspx

4. One of the following criteria must be met.

1. Absolute level of PSA >0.4 ng/mL following surgery. (surgery only)

2. Absolute level of PSA >0.4 ng/mL for subjects treated with multiple treatment
modalities (e.g., surgery + radiation, surgery + cryotherapy, etc.).

3. A rise by 2 ng/mL or more above the nadir PSA will be considered the standard
definition for biochemical failure after radiation therapy with or without
hormonal therapy. (radiation only)

5. Subject is >18 years of age.

6. Subject has life expectancy of greater than 12 months.

7. Subject has Eastern Cooperative Oncology Group performance status 0, 1 or 2

8. Subject has testosterone level of ≥1.5 ng/mL at screening.

9. Subject has normal organ and marrow function as defined below:

1. Leukocytes >3,000/microliter

2. absolute neutrophil count >1,500/microliter

3. platelets >100,000/microliter

4. total bilirubin <1.5 x upper limit of normal except for Gilberts <2.5 x upper
limit of normal

5. aspartate aminotransferase/Alanine transaminase ≤ 2.5 X upper limit of normal

6. creatinine ≤ 2.5 upper limit of normal

10. Subject agrees to abstain from other commercially available MuscadinePlus (MP)
products (Vinetra, MuscadinePlus or MP capsules) while participating in this study.

11. Subject's use of other dietary/herbal supplements (e.g. saw palmetto, selenium,
pomegranate juice or pills, acai concentrated extract, etc) has been stable for at
least 2 months prior to screening and the subject agrees not to stop or change the
dose(s) while participating in the study.

12. Subject has signed a written informed consent document and agrees to comply with
requirements of the study.

13. CT or MRI chest/abdomen/pelvis and bone scan without evidence of metastatic disease as
an inclusion.

14. Subject agrees to genotyping of manganese-dependent superoxide dismutase 2 (MnSOD2)
gene and any genetic counseling. Only those with Alanine/Alanine SOD2 genotype will be
randomized.

Exclusion Criteria:

Subjects meeting the following conditions are not eligible for participation in the study:

1. Subject has known radiographic evidence of metastatic disease, except for presence of
positive lymph nodes from the surgical pathology. Pelvic/intraperitoneal lymph nodes
less than 2.0 cm maybe considered nonspecific and the patient would be eligible. If
there is any clinical suspicion for metastatic disease, CT and Bone Scan must be
performed to rule out metastatic disease, within the last four months, per standard of
care.

2. Subject has received any therapies that modulate testosterone levels (e.g., androgen
ablative/anti-androgen therapy, 5 alpha reductase inhibitors) for a minimum of 12
months prior to study.

3. Subject has had prior or concomitant treatment with experimental drugs, high dose
steroids, or any other cancer treatment within 4 weeks prior to the first dose of the
study product.

4. Subject has consumed any Muscadine Plus over the past 2 months.

5. Subject has a known allergy to muscadine grapes, ellagic acid or rice

6. Subject has uncontrolled concurrent illness including, but not limited to, ongoing or
active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements.

7. Subject has negative PSA doubling time (negative doubling time corresponds with
decreasing PSA) Doubling time may be computed using the Sloan Kettering prediction
tools posted at
http://www.mskcc.org/applications/nomograms/prostate/PsaDoublingTime.aspx