S1216, Phase III ADT+TAK-700 vs. ADT+Bicalutamide for Metastatic Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to compare overall survival in newly diagnosed metastatic prostate cancer patients randomly assigned to androgen deprivation therapy (ADT) + TAK-700 versus ADT + bicalutamide.

Official Title
-----------------
A Phase III Randomized Trial Comparing Androgen Deprivation Therapy + TAK-700 With Androgen Deprivation Therapy + Bicalutamide in Patients With Newly Diagnosed Metastatic Sensitive Prostate Cancer

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Drug: TAK-700
* Drug: Bicalutamide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Clinical diagnosis of metastatic prostate cancer. Serum testosterone within institutional limits of normal. PSA ≥ 2 ng/mL within 90 days prior to initiation of androgen deprivation. therapy (for early induction) or prior to registration (for late induction). DEXA scan within 2 years prior to registration. ECG within 42 days prior to registration and QTc interval ≤ 460 msec. LVEF within 42 days prior to registration and within institutional limits of normal. Adequate hepatic function as evidenced by bilirubin ≤ 2 x institutional upper limit of normal (ULN), SGOT (AST) and SGPT (ALT) ≤ 3 x institutional ULN, or ≤ 5 x institutional ULN if liver metastases are present. Adequate renal function as evidenced by calculated creatinine clearance ≥ 40 mL/min. Adequate hematologic function as evidenced by leukocytes ≥ 3,000/mcL, absolute neutrophil count (ANC) ≥ 1,500/mcL, hemoglobin ≥ 9 g/dL, and platelets ≥ 100,000/mcL. Zubrod performance status of 0 - 2. Zubrod performance status 3 will be allowed if from bone pain only. ≥ 18 years of age. Men of reproduction potential and those who are surgically sterilized (i.e., postvasectomy) must agree to practice effective barrier contraception or agree to abstain from intercourse while receiving treatment on this study and for at least 4 months after protocol treatment ends. Exclusion Criteria: Known brain metastases. No more than 36 months of prior neoadjuvant and/or adjuvant hormonal therapy. ≥ 6 months since completion of androgen deprivation therapy. Prior or concurrent therapy with ketoconazole, aminoglutethimide or abiraterone acetate, or enzalutamide (MDV3100). Concurrent megestrol for hot flashes is allowed. Prior chemotherapy for treatment of metastatic prostate cancer. Prior chemotherapy in the neoadjuvant or adjuvant setting is allowed. ≥ 2 years since completion of chemotherapy in the neoadjuvant or adjuvant setting. Concurrent use of experimental therapy is not allowed. ≥ 30 days since prior medical castration for metastatic prostate cancer. If method of castration is a LHRH agonist, the patient must be willing to continue the use of LHRH and add bicalutamide or TAK-700 during protocol treatment. If the patient was on an antiandrogen (e.g. bicalutamide, flutamide), the patient must be willing to switch over to bicalutamide or TAK-700 (according to randomization). Prior bilateral orchiectomy. Concurrent use of LHRH antagonists (e.g. Degarelix) Grade III/IV cardiac disease (as defined by the NYHA Criteria), thromboembolic event, unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia. Uncontrolled hypertension (defined as blood pressure > 160 mmHg systolic and > 90 mmHg diastolic at 2 separate measurements no more than 60 minutes apart during the Screening visit) despite appropriate medical therapy. Known human immunodeficiency virus (HIV)infection, active chronic hepatitis B or C, life-threatening illness unrelated to cancer, or any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with participation in this study. History of primary and secondary adrenal insufficiency. Hypersensitivity to TAK-700, to TAK-700 metabolites, to bicalutamide, or to LHRH agonists. Gastrointestinal (GI) disease or GI procedure that could interfere with the GI absorption or tolerance of TAK-700, including difficulty swallowing oral medications. No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ADT + TAK-700<br>LHRH agonist - given as approved for androgen deprivation at a dose necessary to maintain castrate levels and equivalent to 22.5 mg of Leuprolide IM every 3 months. TAK-700, 300 mg, PO, twice daily | Drug: TAK-700<br>* 300 mg, PO, twice daily<br>* Other names: Orteronel;|
| Active Comparator: ADT + Bicalutamide<br>LHRH agonist - given as approved for androgen deprivation at a dose necessary to maintain castrate levels and equivalent to 22.5 mg of Leuprolide IM every 3 months. Bicalutamide, 50 mg, PO, q daily | Drug: Bicalutamide<br>* 50 mg, PO, q daily<br>* Other names: Casodex;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as the time from random assignment to the date of death from any cause | From study start to the data cutoff date, May 18, 2021, approximately 8 years, 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression Free Survival (PFS) is defined as the time from random assignment to first documentation of PSA progression, radiologic progression, clinical progression, or death, whichever occurred first. PSA progression is defined as a ≥25% increase AND and absolute increase of at last 2 ng/mL from the nadir PSA (or from baseline PSA if there was no drop in PSA after starting treatment). Radiologic progression is defined as two or more new lesions on radionuclide bone scans. Clinical progression is defined using the Response Evaluation Criteria in Solid Tumors (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | From study start to the data cutoff date, May 18, 2021, approximately 8 years, 2 months | 
| PSA Response Rates | Prostate-specific antigen (PSA) response rates were divided into complete response (CR: PSA < 0.2 ng/mL), partial response (PR: PSA between 0.2 and 4.0 ng/mL), and no response (NR: PSA > 4.0 ng/mL) at a 7-month landmark after random assignment. | 7 months after randomization | 
| Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Only adverse events that are possibly, probably or definitely related to study drug are reported. Adverse events are graded using the Common Terminology Criteria for Adverse Events (CTCAE v4.0) where grade refers to the severity of the AE. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE. | From study start to the data cutoff date, May 18, 2021 | 
| Long-term Survival | Long-term survival is defined as the time from random assignment to the date of death from any cause | After 10 years of follow-up | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Prostate cancer, TAK-700, Bicalutamide, S1216, androgen therapy, Phase III