Prostate Cancer Metastatic
Conditions
Brief summary
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
Detailed description
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.
Interventions
DRUGVeru-944
Treat hot flashes (vasomotor symptoms) in men with advanced prostate cancer on ADT
DRUGPlacebo
Placebo
Sponsors
Veru Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Frequency of Moderate to Severe Hot Flashes at 6 Weeks | 6 weeks | Percentage of change in frequency of moderate to severe hot flashes at 6 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Severity of Moderate to Severe Hot Flashes at 6 Weeks | 6 weeks | Change in severity of moderate to severe hot flashes compared to baseline at 6 weeks |
| Change of Frequency of Moderate to Severe Hot Flashes at Week 12 | Weeks 12 | Mean change in frequency of moderate to severe hot flashes compared to baseline at weeks 12 |
| Change in Severity of Moderate to Severe Hot Flashes at Week 12 | Week 12 | Mean change in severity of moderate to severe hot flashes compared to baseline at week 12 |
| Change in Bone Turnover Markers C-telopeptide (CTX) | 84 days | Change in C-telopeptide concentration at day 84 compared to baseline |
| Change in Bone Turnover Markers Alkaline Phosphatase | 84 days | Change in bone specific alkaline phosphatase at day 84 compared to baseline |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Serum Total Testosterone | 84 Days | Change in serum total testosterone concentration comparing baseline to day 30, baseline to day 60 and baseline to day 84 for each treatment group |
| Change in Serum Free Testosterone | 84 days | Change in serum free testosterone concentration comparing baseline to day 84 |
| Change in Serum SHBG | 84 days | Change in serum SHBG concentration comparing baseline to day 30, baseline to day 60 and baseline to day 84 for each treatment group |
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)Sess Safety | 114 days | Incidence of Treatment-Emergent Adverse Events will be tabulated by MedDRA terms and system organ class. The incidence of AEs and the maximum intensity and frequency of AEs will be summarized. The intensity of AE will be graded according to CTCAE version 4. Changes from baseline will be computed and tested for significant change from baseline to day 114 |
| Change in Serum PSA | 84 Days | Change in serum PSA concentration comparing baseline to day 30, baseline to day 60 and baseline to day 84 for each treatment group |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Veru-944 10 mg Veru-944 10 mg daily
Veru-944: Treat hot flashes (vasomotor symptoms) in men with advanced prostate cancer on ADT | 30 |
| Veru-944 50 mg Veru-944 50 mg daily
Veru-944: Treat hot flashes (vasomotor symptoms) in men with advanced prostate cancer on ADT | 30 |
| Placebo Placebo daily
Placebo: Placebo | 31 |
| Total | 91 |
Baseline characteristics
| Characteristic | Veru-944 10 mg | Veru-944 50 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 26 Participants | 23 Participants | 22 Participants | 71 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 7 Participants | 9 Participants | 20 Participants |
| Age, Continuous | 70.8 years STANDARD_DEVIATION 5.79 | 70.6 years STANDARD_DEVIATION 8.84 | 69.1 years STANDARD_DEVIATION 8.05 | 70.2 years STANDARD_DEVIATION 7.5 |
| Moderate to Severe Hot Flashes | 41.5 Percentage hot flashes moderate severe STANDARD_DEVIATION 36.52 | 29.7 Percentage hot flashes moderate severe STANDARD_DEVIATION 22.2 | 33.7 Percentage hot flashes moderate severe STANDARD_DEVIATION 20.23 | 34.9 Percentage hot flashes moderate severe STANDARD_DEVIATION 26.25 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 9 Participants | 10 Participants | 31 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 18 Participants | 20 Participants | 21 Participants | 59 Participants |
| Region of Enrollment United States | 30 participants | 30 participants | 31 participants | 91 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 30 Participants | 30 Participants | 31 Participants | 91 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 30 | 0 / 31 |
| other Total, other adverse events | 7 / 30 | 16 / 30 | 11 / 31 |
| serious Total, serious adverse events | 0 / 30 | 1 / 30 | 2 / 31 |
Outcome results
Primary
Change in Frequency of Moderate to Severe Hot Flashes at 6 Weeks
Percentage of change in frequency of moderate to severe hot flashes at 6 weeks
Time frame: 6 weeks
Population: Percentage of change in frequency of moderate to severe hot flashes at week 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Veru-944 10 mg | Change in Frequency of Moderate to Severe Hot Flashes at 6 Weeks | -19.72 Percentage of change in frequency | Standard Deviation 8.84 |
| Veru-944 50 mg | Change in Frequency of Moderate to Severe Hot Flashes at 6 Weeks | -42.24 Percentage of change in frequency | Standard Deviation 8.196 |
| Placebo | Change in Frequency of Moderate to Severe Hot Flashes at 6 Weeks | -46.59 Percentage of change in frequency | Standard Deviation 7.76 |
Secondary
Change in Bone Turnover Markers Alkaline Phosphatase
Change in bone specific alkaline phosphatase at day 84 compared to baseline
Time frame: 84 days
Population: Change in bone specific alkaline phosphatase at day 84 compared to baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Veru-944 10 mg | Change in Bone Turnover Markers Alkaline Phosphatase | 13.89 ug/L | Standard Deviation 4.598 |
| Veru-944 50 mg | Change in Bone Turnover Markers Alkaline Phosphatase | 15.72 ug/L | Standard Deviation 22.468 |
| Placebo | Change in Bone Turnover Markers Alkaline Phosphatase | 13.12 ug/L | Standard Deviation 6.074 |
Secondary
Change in Bone Turnover Markers C-telopeptide (CTX)
Change in C-telopeptide concentration at day 84 compared to baseline
Time frame: 84 days
Population: Change in C-telopeptide concentration at day 84 compared to baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Veru-944 10 mg | Change in Bone Turnover Markers C-telopeptide (CTX) | 419.7 ng/L | Standard Deviation 262 |
| Veru-944 50 mg | Change in Bone Turnover Markers C-telopeptide (CTX) | 362.1 ng/L | Standard Deviation 305.44 |
| Placebo | Change in Bone Turnover Markers C-telopeptide (CTX) | 466 ng/L | Standard Deviation 347.3 |
Secondary
Change in Severity of Moderate to Severe Hot Flashes at Week 12
Mean change in severity of moderate to severe hot flashes compared to baseline at week 12
Time frame: Week 12
Population: Mean percentage change from baseline to week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Veru-944 10 mg | Change in Severity of Moderate to Severe Hot Flashes at Week 12 | -12.05 percentage of change | Standard Error 5.014 |
| Veru-944 50 mg | Change in Severity of Moderate to Severe Hot Flashes at Week 12 | -16.93 percentage of change | Standard Error 5.061 |
| Placebo | Change in Severity of Moderate to Severe Hot Flashes at Week 12 | -22.48 percentage of change | Standard Error 4.674 |
Secondary
Change of Frequency of Moderate to Severe Hot Flashes at Week 12
Mean change in frequency of moderate to severe hot flashes compared to baseline at weeks 12
Time frame: Weeks 12
Population: Percentage of change from Baseline to Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Veru-944 10 mg | Change of Frequency of Moderate to Severe Hot Flashes at Week 12 | -39.94 percentage of change | Standard Error 8.458 |
| Veru-944 50 mg | Change of Frequency of Moderate to Severe Hot Flashes at Week 12 | -51.95 percentage of change | Standard Error 8.574 |
| Placebo | Change of Frequency of Moderate to Severe Hot Flashes at Week 12 | -52.70 percentage of change | Standard Error 7.881 |
Secondary
Percentage Change in Severity of Moderate to Severe Hot Flashes at 6 Weeks
Change in severity of moderate to severe hot flashes compared to baseline at 6 weeks
Time frame: 6 weeks
Population: Percentage change in severity of moderate to severe hot flashes compared to baseline at 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Veru-944 10 mg | Percentage Change in Severity of Moderate to Severe Hot Flashes at 6 Weeks | -0.21 percentage of change | Standard Deviation 0.386 |
| Veru-944 50 mg | Percentage Change in Severity of Moderate to Severe Hot Flashes at 6 Weeks | -0.31 percentage of change | Standard Deviation 0.416 |
| Placebo | Percentage Change in Severity of Moderate to Severe Hot Flashes at 6 Weeks | -0.35 percentage of change | Standard Deviation 0.508 |
Other Pre-specified
Change in Serum Free Testosterone
Change in serum free testosterone concentration comparing baseline to day 84
Time frame: 84 days
Population: Change in serum free testosterone concentration comparing baseline to day 84
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Veru-944 10 mg | Change in Serum Free Testosterone | 1.16 ng/L | Standard Deviation 0.895 |
| Veru-944 50 mg | Change in Serum Free Testosterone | 1.38 ng/L | Standard Deviation 4.873 |
| Placebo | Change in Serum Free Testosterone | 1.0 ng/L | Standard Deviation 1.635 |
Other Pre-specified
Change in Serum PSA
Change in serum PSA concentration comparing baseline to day 30, baseline to day 60 and baseline to day 84 for each treatment group
Time frame: 84 Days
Other Pre-specified
Change in Serum SHBG
Change in serum SHBG concentration comparing baseline to day 30, baseline to day 60 and baseline to day 84 for each treatment group
Time frame: 84 days
Population: Change in serum SHBG concentration comparing baseline to day 84
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Veru-944 10 mg | Change in Serum SHBG | 55.7 nmol/L | Standard Deviation 28.27 |
| Veru-944 50 mg | Change in Serum SHBG | 113.5 nmol/L | Standard Deviation 60.53 |
| Placebo | Change in Serum SHBG | 54.1 nmol/L | Standard Deviation 24.98 |
Other Pre-specified
Change in Serum Total Testosterone
Change in serum total testosterone concentration comparing baseline to day 30, baseline to day 60 and baseline to day 84 for each treatment group
Time frame: 84 Days
Other Pre-specified
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)Sess Safety
Incidence of Treatment-Emergent Adverse Events will be tabulated by MedDRA terms and system organ class. The incidence of AEs and the maximum intensity and frequency of AEs will be summarized. The intensity of AE will be graded according to CTCAE version 4. Changes from baseline will be computed and tested for significant change from baseline to day 114
Time frame: 114 days
Post Hoc
Post-hoc Analysis on the Percentage Change in Frequency of Moderate and Severe Hot Flashes From Baseline to Week 12; Exposure Response Assessment
Post-hoc exploratory MMRM analysis was conducted to explore the effect of trough plasma concentration at Week12 on the change in frequency of moderate and severe hot flashes from Baseline to Week 12 in subjects with a BMI \>25 kg/m2.
Time frame: Day 84
Population: Subjects with a BMI \>25 kg/m2 who had trough plasma concentrations ≥195 ng/mL vs \<195 ng/mL Change in moderate and severe hot flash frequency at Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Veru-944 10 mg | Post-hoc Analysis on the Percentage Change in Frequency of Moderate and Severe Hot Flashes From Baseline to Week 12; Exposure Response Assessment | -77.60 percentage of change | Standard Deviation 14.542 |
| Veru-944 50 mg | Post-hoc Analysis on the Percentage Change in Frequency of Moderate and Severe Hot Flashes From Baseline to Week 12; Exposure Response Assessment | -50.14 percentage of change | Standard Deviation 5.842 |