Clinical trial NCT02349386: Maintaining Suppression of Testosterone With Transdermal Estradiol Gel
Official title: A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study of BHR-200 (0.36% Transdermal Estradiol Gel) for the Maintenance of Testosterone Suppression in Men With Advanced Androgen-Sensitive Prostate Cancer
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Cancer of the Prostate
Lead sponsor: BHR Pharma, LLC
Sponsor class: INDUSTRY
Collaborators: name: H2O Clinical LLC
name: Q2 Solutions
First posted: 2015-01-28
Enrollment: 34
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of this clinical study is to evaluate the safety and efficacy of three different doses of BHR-200 (0.36% transdermal estradiol gel) compared to placebo for the maintenance of testosterone (T) suppression in men with advanced androgen-sensitive prostate cancer.

Detailed description: This is a multi-center, randomized, double-blind, placebo-controlled, dose finding study in men with advanced androgen-sensitive prostate cancer. Patients who give informed consent will have screening evaluations, and if fulfilling the entry criteria, will be randomized to one of 4 treatment groups: 1mL, 2mL or 3mL of 0.36% BHR-200 (transdermal estradiol gel) or Placebo. Study drug will be initiated on the day they were scheduled to receive next depot GnRH agonist injection. Patients will be offered low-dose radiation to aid in the prevention of gynecomastia. Patients will apply the study drug once per day. The first dose of study gel will be applied under the supervision of the PI/designee. Subsequent doses will be self-administered daily by the patient until he is no longer chemically castrated (testosterone levels increase above 50 ng/dL), a rise over baseline PSA of \> 0.5 ng/mL is observed, or he has completed 52 weeks of study drug administration. At the conclusion of study participation, patients will be advised to resume standard of care treatment under the supervision of their healthcare provider. While on treatment, patients will be evaluated at Day 1 and every 2 weeks, for the first 24 weeks and every 4 weeks thereafter with a final post-treatment follow-up visit 2 weeks (+/- 1 week) post last dose administration.

Eligibility criteria: Inclusion Criteria:

1. Males, Ages 18 and older
2. Body Mass Index (BMI) between 18 and 35 kg/m2 (inclusive)
3. Not currently hospitalized
4. Clinical indication of adenocarcinoma of the prostate evidenced by a biopsy report on record
5. At present receiving ADT treatment with a GnRH agonist for at least 2 months but not longer than 36 months without interruption - Note: If the patient received GnRH agonist treatment prior to the treatment described under 5, there must be evidence of a period without GnRH agonist treatment for a minimum of 2 months prior to starting the present treatment as is seen, for example with intermittent treatment regimens.
6. Able to initiate Screening procedures 2 weeks prior to the next scheduled injection with a GnRH agonist
7. Willing to discontinue current ADT regimen for the duration of the study
8. T level less than 50 ng/dL at Screening
9. WHO/ECOG performance status of 0 or 1
10. Life expectancy of at least 1 year
11. Adequate renal function demonstrated by having normal blood urea nitrogen (BUN) and Creatinine Screening lab values

Exclusion Criteria:

1. History or presence of allergic or adverse response to estradiol
2. Presence of symptomatic metastatic disease, risk of spinal cord compression or urinary obstruction
3. History within the past 2 years of deep vein thrombosis (DVT), pulmonary embolism (PE2), a known thrombophilic disorder (eg.protein C, protein S, or antithrombin deficiency), or cerebrovascular accident (CVA)
4. History within the past 2 years of myocardial infarction or a coronary vascular procedure (e.g. percutaneous coronary intervention, coronary artery bypass graft)
5. History of congestive heart failure
6. Use of any investigational drug, biologic, or device within 28 days prior to the first dose of study gel
7. Use of any of the following known inducers or inhibitors of cytochrome P450 3A4 (CYP3A4): phenobarbital, carbamazepine, rifampin, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, St. John's Wort preparations (Hypericum perforatum), and grapefruit juice
8. Hematological parameters (Hematocrit or Hemoglobin) outside 20% of the upper or lower limits of normal at Screening
9. Active skin rash, sunburn, or other skin disorder on the upper arm(s) that requires treatment or may affect skin absorption of study gel
10. Resting uncontrolled hypertension (HTN) (160/100 mmHg) at Screening
11. Co-existent malignancy or a history of malignancy during the past 5 years, with the exception of basal and/or squamous cell carcinoma of the skin
12. Any other significant concurrent illness or disease or condition that in the opinion of the Investigator might interfere with the patient's ability to receive the treatment outlined in the protocol or might put him at additional risk

Primary outcomes:
measure: Maintenance of Testosterone Suppression at Week 12
timeFrame: Week 12
Secondary outcomes:
measure: Maintenance of Testosterone Suppression at Week 24
timeFrame: Week 24
measure: Number of Patients Reporting Thromboembolic Adverse Events
timeFrame: To Week 52/End of Study: Both 24-Week Main Study and Optional 28-Week Extension Study
Other outcomes:
measure: Luteinizing Hormone (LH)
timeFrame: Reported for Baseline, Week 12, Week 24, Week 36 and Week 48
measure: Sex Hormone Binding Globulin (SHBG)
timeFrame: Reported for Baseline, Week 12, Week 24, Week 36 and Week 48
measure: Prostate Specific Antigen (PSA)
timeFrame: To Week 52/End of Study: Both 24-Week Main Study and Optional 28-Week Extension Study
measure: Follicle-stimulating Hormone (FSH)
timeFrame: Reported for Baseline, Week 12, Week 24, Week 36 and Week 48
measure: Maintenance of Testosterone Suppression at Week 52/ End of Study
timeFrame: Double-blind 28-Week Optional Extension Study from Week 24 to Week 52/End of Study
Locations:
city: Tucson
country: United States
facility: Urological Associates of Southern Arizona
state: Arizona
city: Aventura
country: United States
facility: South Florida Medical Research
state: Florida
city: Daytona Beach
country: United States
facility: Advanced Urology Institute
state: Florida
city: Council Bluffs
country: United States
facility: Adult Pediatric Urology, PC
state: Iowa
city: Omaha
country: United States
facility: Adult Pediatric Urology, PC
state: Nebraska
city: Voorhees
country: United States
facility: Delaware Valley Urology
state: New Jersey
city: Albuquerque
country: United States
facility: AccumetRX Clinical Trials
state: New Mexico
city: Syracuse
country: United States
facility: Associated Medical Professionals of NY (AMP of NY)
state: New York
city: Greenville
country: United States
facility: Eastern Urological Associates
state: North Carolina
city: Bala-Cynwyd
country: United States
facility: Urologic Consultants of Southeastern Pennsylvania (UCSEPA)
state: Pennsylvania
city: Myrtle Beach
country: United States
facility: Carolina Urologic Research Center
state: South Carolina
city: Dallas
country: United States
facility: Urology Clinics of North Texas
state: Texas
Study officials:
affiliation: BHR Pharma, LLC
name: Roland Gerritsen van der Hoop, MD, PhD
role: STUDY_DIRECTOR
References:
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citation: Ockrim JL, Lalani el-N, Kakkar AK, Abel PD. Transdermal estradiol therapy for prostate cancer reduces thrombophilic activation and protects against thromboembolism. J Urol. 2005 Aug;174(2):527-33; discussion 532-3. doi: 10.1097/01.ju.0000165567.99142.1f.
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citation: Langley RE, Cafferty FH, Alhasso AA, Rosen SD, Sundaram SK, Freeman SC, Pollock P, Jinks RC, Godsland IF, Kockelbergh R, Clarke NW, Kynaston HG, Parmar MK, Abel PD. Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09). Lancet Oncol. 2013 Apr;14(4):306-16. doi: 10.1016/S1470-2045(13)70025-1. Epub 2013 Mar 4.
citation: Bland LB, Garzotto M, DeLoughery TG, Ryan CW, Schuff KG, Wersinger EM, Lemmon D, Beer TM. Phase II study of transdermal estradiol in androgen-independent prostate carcinoma. Cancer. 2005 Feb 15;103(4):717-23. doi: 10.1002/cncr.20857.
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citation: Lycette JL, Bland LB, Garzotto M, Beer TM. Parenteral estrogens for prostate cancer: can a new route of administration overcome old toxicities? Clin Genitourin Cancer. 2006 Dec;5(3):198-205. doi: 10.3816/CGC.2006.n.037.
citation: Sayed Y, Taxel P. The use of estrogen therapy in men. Curr Opin Pharmacol. 2003 Dec;3(6):650-4. doi: 10.1016/j.coph.2003.07.004.