Trial of Abiraterone Acetate Plus LHRH-therapy Versus Abiraterone Acetate Sparing LHRH-therapy in Patients With Progressive Chemotherapy-naïve Castration-resistant Prostate Cancer (SPARE)

Study Overview
=================
Brief Summary
-----------------
This is an exploratory Phase 2 multicenter, randomized, open-label study with a randomization allocation ratio of 1:1 [abiraterone acetate + prednisone + LHRH-therapy (Arm A) versus abiraterone acetate + prednisone (Arm B)]. For both groups patients will receive a dose of 1000 mg abiraterone acetate and 10mg prednisone daily (QD). Study drug will be administered as 4 x 250-mg abiraterone acetate tablets and prednisone will be administered as 5 mg orally twice a day (BID). Patients randomized to the LHRH-therapy group will receive the same LHRH-therapy they received prior to entering the trial. 70 medically castrated male patients with metastatic CRPC who have shown tumor progression and are non- or mildly-symptomatic will be enrolled from approximately 12 German study sites.

Official Title
-----------------
Randomized Phase-II Trial of Abiraterone Acetate Plus LHRH-therapy Versus Abiraterone Acetate Sparing LHRH-therapy in Patients With Progressive Chemotherapy-naïve Castration-resistant Prostate Cancer (SPARE)

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

Intervention / Treatment
-----------------
* Drug: abiraterone acetate + prednisone + LHRH-therapy
* Drug: abiraterone acetate + prednisone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Willing and able to provide written informed consent Written Data Protection Consent has been obtained Male aged 18 years and above Histologically or cytologically confirmed adenocarcinoma of the prostate Metastatic disease documented by positive CT/MRI and/or bone scan (both must be performed). If lymph node metastasis is the only evidence of metastasis, it must be ≥2 cm in diameter Prostate cancer progression documented by PSA according to PCWG2 or radiographic progression according to modified RECIST criteria Asymptomatic or mildly symptomatic from prostate cancer. A score of 0-1 for the question of worst pain within last 24 hours (Appendix 8) will be considered asymptomatic, and a score of 2-3 will be considered mildly symptomatic. Medically castrated, with testosterone levels of <20-50 ng/dl (< 2.0 nM). Combined androgen blockade is permitted, but not required. If patients received combined androgen blockade with an anti-androgen they must have shown PSA progression after discontinuing the anti-androgen prior to enrollment (≥4 weeks since last flutamide, ≥6 weeks since last bicalutamide or nilutamide). Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤2 (Appendix 6) Hemoglobin ≥9.0 g/dL independent of transfusion Platelet count ≥100,000 /μl Serum albumin ≥3.0 g/dl Serum creatinine < 1.5 x ULN or a calculated creatinine clearance ≥60 ml/min (Appendix 7) Serum potassium ≥3.5 mmol/l Liver function: Serum bilirubin <1.5 x ULN (except for patients with documented Gilbert's disease) AST or ALT <2.5 x ULN Able to swallow the study drug whole as a tablet Life expectancy of at least 6 months Patients who have partners of childbearing potential must be 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 1 week after last study drug administration. Exclusion Criteria: Surgical castration (i.e. orchiectomy). Application of any LHRH-therapy (LHRH-analogue or LHRH-antagonist) within 3 months (for patients receiving a 3-months formulation) or 1 months (for patients receiving a 1-month formulation) prior to Cycle 1 day 1. Patients receiving a 6- or 12-months formulation of LHRH-therapy Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated Any chronic medical condition requiring a higher dose of corticosteroid than 5mg prednisone/prednisolone bid. Pathological finding consistent with small cell carcinoma of the prostate Liver or visceral organ metastasis Known brain metastasis Use of opiate analgesics for cancer-related pain, including codeine, tramadol, tilidin and others (see Appendix 9), currently or anytime within 4 weeks of Cycle 1 Day 1. Prior cytotoxic chemotherapy or biologic therapy for the treatment of CRPC Radiation therapy for treatment of the primary tumour within 6 weeks of Cycle 1, Day 1 Radiation or radionuclide therapy for treatment of metastatic CRPC Prior treatment with Abiraterone acetate or other CYP17 inhibitors (ketoconazole, TAK700, TOK001) ), Enzalutamide (Xtandi) or investigational agents targeting the androgen receptor for prostate cancer for more than 7 days Prior systemic treatment with an azole drug (e.g. fluconazole, itraconazole) within 4 weeks of Cycle 1, Day 1 Prior flutamide (Eulexin) treatment within 4 weeks of Cycle 1, Day 1 (patients whose PSA did not decline for three or more months in response to antiandrogen given as a second line or later intervention will require only a two week washout prior to Cycle 1, Day 1) Bicalutamide (Casodex), nilutamide (Nilandron) within 6 weeks of Cycle 1 Day 1 (patients whose PSA did not decline for three or more months in response to antiandrogen given as a second line or later intervention will require only a two week washout prior to Cycle 1, Day1) Uncontrolled hypertension (systolic BP ≥160 mmHg or diastolic BP ≥95 mmHg). Patients with a history of hypertension are allowed provided that blood pressure is controlled by anti- hypertensive treatment Active or symptomatic viral hepatitis or chronic liver disease History of pituitary or adrenal dysfunction Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of <50 % at baseline Any condition that requires treatment with Digoxin, digitoxin, and other digitalis drugs Atrial Fibrillation, or other cardiac arrhythmia requiring therapy Other malignancy with a ≥30 % probability of recurrence within 24 months, except non- melanoma skin cancer. Administration of an investigational therapy within 30 days of Cycle 1, Day 1 Any condition, which, in the opinion of the investigator, would preclude participation in this trial.

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 |
| --- | --- |
| Active Comparator: abiraterone acetate + prednisone + LHRH-therapy<br>Patients randomized to this group will continue their LHRH-therapy. | Drug: abiraterone acetate + prednisone + LHRH-therapy<br>* Hormon therapy will go on<br>|
| Active Comparator: abiraterone acetate + prednisone<br>Patients randomized to this group will stop LHRH-therapy. | Drug: abiraterone acetate + prednisone<br>* ormon therapy will be stopped<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| radiographic-progression-free survival | The primary objective of the study is to analyze the clinical benefit of abiraterone acetate plus prednisone while sparing LHRH-therapy in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (CRPC). | 12 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of radiographic-progression-free survival with early PSA-response | To establish additional clinically relevant information regarding early PSA responses to abiraterone and to correlate these with radiographic-progression free survival | 12 month | 
| Hormonal analyses | To investigate effects of both treatment arms on hormones of the pituitary gonadal axis | 12 month | 
| Adverse Events | To characterize the safety profile of abiraterone acetate while sparing LHRH-therapy in comparison to continuing LHRH-therapy | 12 month |