Maintaining Suppression of Testosterone With Transdermal Estradiol Gel

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Cancer of the Prostate

Intervention / Treatment
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* Drug: BHR-200 (0.36% transdermal 17β-estradiol gel)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males, Ages 18 and older Body Mass Index (BMI) between 18 and 35 kg/m2 (inclusive) Not currently hospitalized Clinical indication of adenocarcinoma of the prostate evidenced by a biopsy report on record 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. Able to initiate Screening procedures 2 weeks prior to the next scheduled injection with a GnRH agonist Willing to discontinue current ADT regimen for the duration of the study T level less than 50 ng/dL at Screening WHO/ECOG performance status of 0 or 1 Life expectancy of at least 1 year Adequate renal function demonstrated by having normal blood urea nitrogen (BUN) and Creatinine Screening lab values Exclusion Criteria: History or presence of allergic or adverse response to estradiol Presence of symptomatic metastatic disease, risk of spinal cord compression or urinary obstruction 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) History within the past 2 years of myocardial infarction or a coronary vascular procedure (e.g. percutaneous coronary intervention, coronary artery bypass graft) History of congestive heart failure Use of any investigational drug, biologic, or device within 28 days prior to the first dose of study gel 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 Hematological parameters (Hematocrit or Hemoglobin) outside 20% of the upper or lower limits of normal at Screening Active skin rash, sunburn, or other skin disorder on the upper arm(s) that requires treatment or may affect skin absorption of study gel Resting uncontrolled hypertension (HTN) (160/100 mmHg) at Screening 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BHR-200 Low Dose<br>3 mg estradiol per 1 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. | Drug: BHR-200 (0.36% transdermal 17β-estradiol gel)<br>* An absorptive hydroalcoholic gel preparation containing 17β-estradiol.<br>* Other names: BHR-200;|
| Experimental: BHR-200 Mid Dose<br>6 mg estradiol per 2 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. | Drug: BHR-200 (0.36% transdermal 17β-estradiol gel)<br>* An absorptive hydroalcoholic gel preparation containing 17β-estradiol.<br>* Other names: BHR-200;|
| Experimental: BHR-200 High Dose<br>9 mg estradiol per 3 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. | Drug: BHR-200 (0.36% transdermal 17β-estradiol gel)<br>* An absorptive hydroalcoholic gel preparation containing 17β-estradiol.<br>* Other names: BHR-200;|
| Placebo Comparator: Placebo<br>1, 2 or 3 mL of Placebo gel containing 0 mg estradiol applied daily for up to 52 weeks. | Drug: Placebo<br>* An absorptive hydroalcoholic gel preparation gel of the same ingredients as BHR-200, but without 17β-estradiol.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maintenance of Testosterone Suppression at Week 12 | Primary Efficacy Endpoint was the percentage of patients failing to maintain castrate levels of T (T < 50 ng/dL). Testosterone suppression, defined as the absence of any T level measurement over 50 ng/dL during Weeks 4 to 12. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maintenance of Testosterone Suppression at Week 24 | Pproportion of patients failing to maintaincastrate levels of T (T < 50 ng/dL). Testosterone suppression, defined as the absence of any T level measurement over 50 ng/dL during Weeks 4 to 24. | Week 24 | 
| Number of Patients Reporting Thromboembolic Adverse Events | Number of patients and severity of thromboembolic adverse events | To Week 52/End of Study: Both 24-Week Main Study and Optional 28-Week Extension Study |