A Study of Neoadjuvant TAK-700 and Leuprorelin Acetate Followed by Surgery Versus Surgery Alone (NEPTUNE)

Inclusion Criteria:

1. Willing and able to provide written informed consent
2. No previous treatment for prostate cancer (including surgery, any hormone therapy, radiotherapy, cryotherapy).
3. Age ≥ 18 years and male
4. Histologically or cytologically confirmed adenocarcinoma of the prostate with Gleason score. A prostate biopsy within 6 months from screening is allowed for entry requirements.

5. Intermediate or high risk prostate cancer according to National Comprehensive Cancer Network (NCCN) risk stratification criteria

   • Intermediate: PSA >10 & <20 or a Gleason score 7 or clinical stage up to and including T2c disease
   • High risk: PSA>20 or Gleason 8-10 or clinical stage >T2c
6. Serum testosterone > 200 ng/dL
7. Prostatectomy is the planned treatment option.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

9. Adequate organ function, defined as follows:

   • Hemoglobin >10.0g/dL
   • Absolute neutrophil count > 1.5 x 10.9/L
   • Platelet count >100 x 10.9/L
   • AST and /or ALT <2.5 x ULN
   • Total Bilirubin <1.5 x ULN

Exclusion Criteria:

1. Serious co-existent medical conditions such as chronic active autoimmune disease, (within the last 6 months) or infection (such as hepatitis).
2. Uncontrolled hypertension within the screening period (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg). Patients with a history of hypertension are allowed to enrol provided blood pressure is controlled by anti-hypertensive therapy.
3. Patients taking regular oral steroids for any reason.
4. Previously treated prostate cancer (including radiotherapy, hormone therapy or surgery).
5. History of pituitary or adrenal dysfunction

6. Other active malignancy over the last 5 years that has required systemic therapy excluding:

   1. Adjuvant therapy in the curative setting
   2. Non-melanoma skin cancer
   3. Superficial transitional cell carcinoma (CIS-T1).
7. History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug
8. Current enrolment in an investigational drug or device study or participation in such a study within 30 days of Day 1
9. Not willing to comply with the procedural requirements of this protocol, including repeat prostate biopsies
10. Patients who have partners of childbearing potential who are not willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the principal investigator and sponsor during the study and for 16 weeks after last study drug administration.
11. Uncontrolled diabetes mellitus, in the opinion of the treating physician
12. Known hypersensitivity to compounds related to TAK-700 or to TAK-700 excipients.
13. Hypersensitivity to any of the ingredients or to synthetic Gn-RH or Gn-RH derivatives.
14. Screening calculated ejection fraction of <50% by echocardiogram.
15. History of myocardial infarction, unstable symptomatic ischemic heart disease, ongoing arrhythmias of Grade > 2 (NCI CTCAE, version 4.02), thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (e.g., pericardial effusion restrictive cardiomyopathy) within 6 months prior to first dose of study drug. Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed.
16. New York Heart Association Class III or IV heart failure
17. ECG abnormalities of Q-wave infarction, unless identified 6 or more months prior to screening
18. QTc interval > 460 msec on ECG