Neoadjuvant Phase 2 Study Comparing the Effects of AR Inhibition With/Without SRC or MEK Inhibition in Prostate Cancer

Most prostate cancers respond to hormone therapy, also known as chemical castration.
Unfortunately, castration resistance may occur in certain prostate cancers. Castration
resistance or hormone refractory prostate cancer means that the cancer continues to progress
as seen by progressively rising PSA and/or or an increase in tumor mass on bone scan, X-ray,
CT scan or MRI despite previous hormonal therapy. The researchers are interested in
understanding mechanisms of castration resistance in prostate cancer by analyzing prostate
tissue before radical prostatectomy (from prostate biopsy tissue) and after radical
prostatectomy (whole prostate specimen). They will look at the "molecular signature" of
prostate cancer cells after hormone therapy to identify the key steps that the cancer cells
undergo to become resistant to hormone therapy. In addition, the researchers will use other
medications in addition to hormone therapy in order to block some of the key biochemical
steps that are thought to mediate treatment resistance. This research will provide crucial
information for the development of therapies that can improve the clinical outcome of
patients with advanced prostate cancer.

Inclusion Criteria (patients must meet all of the following inclusion criteria to
participate in this study)

1. Willing and able to give informed consent.

2. Adenocarcinoma of the prostate with planned RP with curative intent as part of
standard of care management plan.

3. Patient is a candidate for radical prostatectomy.

4. Tumor accessible to biopsy.

5. Age ≥ 18 years.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

7. Estimated life expectancy of ≥ 6 months,

8. Adequate organ function: normal renal, liver, hematologic, coagulation and cardiac
function:

1. Absolute neutrophil count > 1,500/µL, or platelet count > 100,000/µL, or
hemoglobin > 5.6 mmol/L (9 g/dL) at the Screening visit,

2. Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase
(AST) within the normal range at the Screening visit,

3. Creatinine < 1.5 mg/dL at the Screening visit,

4. INR < 1.3 (or < 3 if on warfarin or other anticoagulants) at the Screening
visit,

5. Albumin > 30 g/L (3.0 g/dL) at the Screening visit,

6. Left ventricular ejection fraction (LVEF) ≥ LLN by ECHO or MUGA,

9. Patients with clinically localized adenocarcinoma of the prostate who are scheduled
to undergo radical prostatectomy (RP) with curative intent and have the following
clinico-pathologic features: (1) Gleason score sum ≥ 4+3 or any Gleason 5, (2) PSA >
20, (3) clinical stage ≥ T3a (staging by MRI is allowed).

10. Able to swallow and retain orally administered medication and does not have any
clinically significant gastrointestinal abnormalities that may alter absorption such
as malabsorption syndrome or major resection of the stomach or bowels,

11. Willing to abstain from procreative sex or partake in appropriate form of
contraception. For the purpose of this study, condom use or abstinence will be
required.

Exclusion Criteria (all candidates meeting any of the following exclusion criteria will be
excluded from participation in the study)

1. Any prior treatment for prostate cancer,

2. Any non-adenocarcinoma histologic component,

3. Any evidence of lymphatic or hematogenous metastases,

4. Clinically significant cardiovascular disease including:

1. LVEF < LLN

2. History of acute coronary syndromes (including myocardial infarction and
unstable angina), coronary angioplasty, or stenting within 6 months,

3. Uncontrolled angina within 3 months,

4. Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or
patients with history of congestive heart failure NYHA class 3 or 4 in the past,
unless a screening echocardiogram or multi-gated acquisition scan performed
within 3 months results in a left ventricular ejection fraction that is ≥ 45%,

5. Any history of congestive heart failure of any NYHA class for patients assigned
to Group 2 (trametinib arm).

6. History of clinically significant ventricular arrhythmias (e.g., ventricular
tachycardia, ventricular fibrillation, torsades de pointes),

7. Patients with intra-cardiac defibrillators or permanent pacemakers,

8. Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury
(mmHg) at the Screening visit,

9. Bradycardia as indicated by a heart rate of < 50 beats per minute on the
Screening ECG,

10. Treatment refractory hypertension defined as a blood pressure of systolic > 140
mmHG and/or diastolic > 90 mmHG which cannot be controlled by anti-hypertensive
therapy,

11. QTC ≥ 480 milliseconds,

12. Known cardiac metastases.

5. Presence of a comorbid disease or medical condition that would impair the ability of
the patient to receive or comply with the study protocol,

6. History of interstitial lung disease or pneumonitis,

7. History or current evidence/risk of retinal vein occlusion (RVO) or central serous
retinopathy (CSR):

- History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled
glaucoma or ocular hypertension, uncontrolled systemic disease such as
hypertension, diabetes mellitus, or history of hyperviscosity or
hypercoagulability syndromes).

- Visible retinal pathology as assessed by ophthalmic exam that is considered a
risk factor for RVO or CSR such as:

- Evidence of new optic disc cupping

- Evidence of new visual field defects

- Intraocular pressure > 21 mm Hg

8. Evidence of a coagulopathy,

9. Patient receiving therapeutic anticoagulation.

10. Unwillingness to engage in adequate contraception,

11. Allergy/sensitivity to any study drug (degarelix, enzalutamide, trametinib,
dasatinib), or drugs chemically related to study drug, or excipients or to
dimethylsulfoxide.

12. Prior use of degarelix, enzalutamide, trametinib, or dasatinib in any context,

13. Known or suspected brain metastasis or active leptomeningeal disease or spinal cord
compression.

14. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C
Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV
infection will be permitted).

15. History of seizure or any condition that may predispose to seizure (e.g., prior
cortical stroke, significant brain trauma) at any time in the past,

16. History of loss of consciousness or transient ischemic attack within past 12 months,

17. Prior use of androgen deprivation therapy or radiation therapy,

18. Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic
ulcer disease within last 3 months),

19. Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity,
biologic therapy, or immunotherapy within 30 days of enrollment and/or daily or
weekly chemotherapy without the potential for delayed toxicity within 14 days of
enrollment,

20. Hospitalization within 30 days of enrollment,

21. History of another malignancy within the previous 5 years other than curatively
treated non-melanoma skin cancer,

22. Use of an investigational agent within 4 weeks of enrollment,

23. Use of herbal products that may have hormonal anti-prostate cancer activity and/or
are known to decrease PSA levels (e.g., saw palmetto) or systemic corticosteroids
greater than the equivalent of 10 mg of prednisone per day within 4 weeks of
enrollment,

24. Use of any medications known to affect the serum androgen levels or the PSA,

25. Any condition or reason that, in the opinion of the Investigator, interferes with the
ability of the patient to participate in the trial, which places the patient at undue
risk, or complicates the interpretation of safety data.