A Phase 2 Open-Label Study to Evaluate the Efficacy and Safety of VT-464 in Patients With Metastatic Castration Resistant Prostate Cancer Who Have Previously Been Treated With Enzalutamide

Background:

- For patients with castration-resistant prostate cancer, selective inhibition of CYP17,
a key enzyme in secondary androgen production, with abiraterone plus prednisone has
been shown to be effective. However, the anticipated survival of these patients, often
greater then 5 years, limits the utility of abiraterone, because of the associated
chronic toxicity of prednisone over an extended time.

- Alternative methods of CYP17 inhibition that do not require chronic prednisone and
could have great therapeutic potential in prostate cancer patients with both early and
late stages of disease are needed.

- VT-464 is a potent inhibitor of CYP17 lyase, with greater potency for the lyase
reaction then the hydroxylase reaction, as well as greater overall CYP selectivity
compared to other therapies available for patients with CRPC.

- Preliminary data, both clinical and pre-clinical, indicate that VT-464 can inhibit
CYP17 and will not require prednisone to off-set toxicity.

- Additional pre-clinical data suggest that VT-464 could have better efficacy then
abiraterone in enzalutamide resistant/refractory prostate cancer.

Objectives:

-Determine the PSA response as defined by a greater than or equal to 50% decrease in serum
PSA per the Prostate Cancer Clinical Trials Working Group 2 criteria after 12 weeks of
dosing with VT-464 compared to the PSA level at baseline in patients who have previously
been treated with enzalutamide.

Eligibility:

- Patients must have documented histological or cytological evidence of adenocarcinoma of
the prostate. This is the only required pathology documentation for this protocol.

- Must have progressive, metastatic castration-resistant prostate cancer (mCRPC). There
must be radiographic evidence of disease after primary treatment with surgery or
radiotherapy that has continued to progress radiographically or biochemically (rising
PSA levels on successive measurements) despite adequate androgen-deprivation therapy,
which is defined as having undergone bilateral surgical castration or continued
treatment on GnRH agonists or antagonists.

- All patients in this trial must have been treated with enzalutamide. Patients in Cohort
1 will not be allowed to have received prior chemotherapy; patients in Cohort 2 must
have received one (and not more) prior course of chemotherapy for mCRPC. Progression
must be evidenced and documented by any of the following parameters:

- PSA progression defined by a minimum of two rising PSA levels with an interval of
greater than or equal to 1 week between each determination

- Appearance of one or more new lesions on bone scan

- Progressive measurable disease by RECIST 1.1

Design:

- This is a Phase 2 open label study that will explore the potential benefit of VT-464 in
patients with mCRPC who have previously been treated with enzalutamide.

- Patients will be stratified into two cohorts; pre-docetaxel based chemotherapy (cohort
1) or post-docetaxel based chemotherapy (cohort 2).

- VT-464 will be administered twice daily, every 12 hours, in continuous 28 day cycles at
the recommended Phase 2 dose.

- For this study, it is assumed that patients will remain on VT-464 for a median of 4
8 twenty-eight day cycles, with prostate cancer in more heavily pre-treated patients
likely to progress more rapidly then in those who are less heavily pre-treated.

- The initial plan is for 18 patients for this study, 9 patients in the pre-chemotherapy
arm, 9 patients in the post-chemotherapy arm.

- If 1 of the 9 patients have a response, then accrual would continue until a total of 24
patients have enrolled in that cohort. There will be up to 48 patients accrued in
total, with an accrual ceiling of 52 patients in order to allow for a small number of
unevaluable patients.

- INCLUSION CRITERIA

1. Patients must have histologically or cytologically confirmed adenocarcinoma of
the prostate confirmed by the Laboratory of Pathology at NIH Clinical Center or
Walter Reed National Military Medical Center at Bethesda. (If every effort is
made but the original pathology cannot be retrieved, a pathology report and a
clinical course consistent with prostate cancer would sufficient.) This is the
only required pathology documentation for this protocol.

2. Must have progressive mCRPC. There must be radiographic evidence of disease
after primary treatment with surgery or radiotherapy that has continued to
progress radiographically or biochemically (rising PSA levels on successive
measurements) despite adequate androgen-deprivation therapy, which is defined as
having undergone bilateral surgical castration or continued treatment on GnRH
agonists or antagonists.

3. Progression must be evidenced and documented by any of the following parameters:

- PSA progression defined by a minimum of two rising PSA levels with an interval of
greater than or equal to 1 week between each determination

- Appearance of one or more new lesions consistent with prostate cancer on bone scan

- New or growing lesions on CT scan

4. Patients must have metastatic disease, defined as at least one lesion on bone
scan or at least one lesion that can be accurately measured in at least one dimension
(longest diameter to be recorded for non-nodal lesions and short axis for nodal
lesions) as greater than or equal to 20 mm with conventional techniques or as greater
than or equal to 10 mm with spiral CT scan. See Section

1. for the evaluation of measurable disease.

5. Patients must have discontinued enzalutamide at least 28 days prior to enrollment
and have been weaned off of systemic prednisone or other exogenous corticosteroids by
the day of enrollment. In both cohorts, patients will be stratified based on
completion of enzalutamide greater than 6 months versus greater than 6 months prior
to study enrollment.

6. Patients must have received treatment with prior enzalutamide for greater than
three 28-day cycles and must have had evidence of disease progression while on
enzalutamide.

7. Age greater than or equal to 18 years.

8. ECOG performance status less than 1 (Karnofsky greater than or equal to 70%, see
Section 13.1, Appendix A). (ECOG performance status less than or equal to 2
(Karnofsky greater than or equal to 60) will be allowed in post-chemotherapy cohort
given their advanced state of disease.)

9. Patients must have normal organ and marrow function as defined below:

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,500/mcL

- platelets greater than or equal to 100,000/mcL

- Hgb greater than 9 g/dL

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal

- creatinine within normal institutional limits

OR

- creatinine clearance greater than or equal to 60 mL/min/1.73 m2 for patients with
creatinine levels above institutional normal.

10. Patients must have castrate levels of testosterone (less than 50 ng/dl [1.74
nmol/l]).

11. Patients must have undergone bilateral surgical castration or must continue on
LHRH agonists/antagonists for the duration of the study.

12. Ability of subject to understand and the willingness to sign a written informed
consent document.

13. Patients who have completed ketoconazole, aminoglutethimide, or high-dose
estrogen must be more than 28 days prior to study entry.

14. Patients who have received antiandrogens such as flutamide (EULEXIN ),
bicalutamide (CASODEX ), or nilutamide (NILANDRON ) for greater than 3 months must
be off treatment for 6 weeks and demonstrate a continued rise in PSA after
withdrawal. Patients on antiandrogens for less than 3 months must be off medication
for 2 weeks.

15. Patients on 5 alpha reductase inhibitors such as finasteride (PROSCAR , PROPECIA
), or dutasteride (AVODART ) must stop medication at least 28 days prior to study
entry.

EXCLUSION CRITERIA

1. Patients who have received palliative radiotherapy within 2 weeks of study entry and
not recovered from associated toxicities.

2. Patients with adrenal insufficiency requiring daily hydrocortisone/prednisone.

3. Patients with a history within the last 3 years of another invasive malignancy.
(Superficial bladder cancer and localized non-melanoma skin cancers are allowed.)

4. Patients who have been treated with prior VT-464, abiraterone (Zytiga ), TAK-700
(Orteronel ), TOK-001 (Galeterone ), or any investigational product directed toward
CYP17.

5. Patients who have received more then 1 prior cytotoxic chemotherapy regimen for mCRPC
in the post-chemotherapy cohort (Cohort 2).

6. Patients who have received prior cytotoxic chemotherapy regimen for mCRPC in the
pre-chemotherapy cohort (Cohort 1).

7. Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse
events.

8. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations within 6 months that would limit
compliance with study requirements.

9. HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with VT-464. Appropriate studies will
be undertaken in patients receiving combination antiretroviral therapy when
indicated.