Randomized, double-blind, placebo controlled, dose finding Phase 2 study comparing oral daily dosing of VERU-944 after a week of loading (daily dosing) with placebo to ameliorate the vasomotor symptoms resulting from androgen deprivation therapy in men with advanced prostate cancer

This study is a multicenter, randomized, double-blind, placebo controlled, dose finding study of VERU-944 to treat hot flashes (vasomotor symptoms) in men with advanced prostate cancer on ADT. The study will have four arms with 30 subjects per arm. The subjects participating in the study will have advanced prostate cancer and will be undergoing androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone (LHRH) therapy (agonist or antagonist) for at least the three months prior to randomization and be experiencing regular moderate to severe hot flashes while on ADT. Subjects will all continue to receive ADT and will be randomized to receive, for the first four days, a loading dose followed by daily doses of placebo or VERU-944 (10 mg, 50 mg or 100 mg) orally for a total period of 12 weeks.

Inclusion Criteria

1. Be over 18 years of age;

2. Be able to communicate effectively with the study personnel;

3. Have histologically confirmed prostate cancer;

4. Have been treated with an LHRH agonist or LHRH antagonist for at least the 3 months prior to randomization;

5. Be continued on an LHRH agonist or LHRH antagonist throughout this study;

6. Have experienced hot flashes for at least one month prior to study entry;

7. Have moderate or severe vasomotor symptoms (hot flashes) (defined as a minimum of 4 moderate to severe hot flashes per day or 12 per week at baseline);

8. ECOG performance status of 0 to 2

9. Be willing to uses electronic data capture for the relevant medical events

   • Must be at least 80% compliant during the screening period

10. Subjects must agree to use acceptable methods of contraception:

    • If their female partners are pregnant or lactating, acceptable methods of contraception from the time of the first administration of study medication until 6 months following administration of the last dose of study medication must be used. Acceptable methods are: Condom used with spermicidal foam/gel/film/cream/suppository. If the subject has undergone surgical sterilization (vasectomy with documentation of azospermia), a condom with spermicidal foam/gel/film/cream/suppository should be used.
    • If the male subject's partner could become pregnant, use acceptable methods of contraception from the time of the first administration of study medication until 6 months following administration of the last dose of study medication. Acceptable methods of contraception are as follows: Condom with spermicidal foam/gel/film/cream/suppository [i.e., barrier method of contraception], surgical sterilization (vasectomy with documentation of azospermia) and a barrier method {condom used with spermicidal foam/gel/film/cream/suppository}, the female partner uses oral contraceptives (combination estrogen/progesterone pills), injectable progesterone or subdermal implants and a barrier method (condom used with spermicidal foam/gel/film/cream/suppository).
    • If the female partner has undergone documented tubal ligation (female sterilization), a barrier method (condom used with spermicidal foam/gel/film/cream/suppository) should also be used.
    • If the female partner has undergone documented placement of an intrauterine device (IUD) or intrauterine system (IUS), a barrier method (condom with spermicidal foam/gel/film/cream/suppository) should also be used.

11. Subject is willing to comply with the requirements of the protocol through the end of the study.

Exclusion Criteria

1. Have a serum total testosterone concentration > 50 ng/dL at screening;

2. Known hypersensitivity or allergy to estrogen or estrogen like drugs;

3. Any disease or condition (medical or surgical) which might compromise the hematologic, cardiovascular, endocrine, pulmonary, renal, gastrointestinal, hepatic, or central nervous system; or other conditions that may interfere with the absorption, distribution, metabolism or excretion of study drug, or would place the subject at increased risk;

4. Subjects with a personal history of abnormal blood clotting or thrombotic disease, including venous or arterial thrombotic events such as a history of stroke, deep vein thrombosis (DVT), and/or pulmonary embolus (PE);

5. Any subjects, as determined by a central laboratory, that have a:

   • Factor V Leiden gene mutation
   • Prothrombin gene mutation

6. Uncontrolled symptomatic congestive heart failure (NYHA Class III - IV), unstable angina pectoris, cardiac arrhythmia, or uncontrolled atrial fibrillation;

7. History of MI

8. The presence of consistently abnormal laboratory values which are considered clinically significant. In addition, any subject with liver enzymes (ALT or AST) above 2 times the upper limit of normal, total bilirubin above 2 times the upper limit of normal, or serum creatinine above 1.5 times the upper limit of normal will NOT be admitted to the study;

9. Received an investigational drug within a period of 90 days prior to enrollment in the study;

10. Received the study medication (VERU-944) previously;

11. Have previously taken within 6 months prior to screening or are currently taking diethylstilbestrol, other estrogens;

12. Currently taking gabapentin, estrogen, diethylstilbestrol, medroxyprogesterone acetate, clomiphene, selective serotonin reuptake inhibitors (SSRIs), other treatments for hot flashes

13. Recent hospitalization for more than 24 hours (within 30 days of screening);

14. Recent surgery (within 30 days of screening);

15. Have been previously diagnosed or treated for active cancer (other than prostate cancer or non-melanoma skin cancer) within the previous five years;

16. Have a BMI >40.

Males