Prostate Cancer
Conditions
Keywords
Prostate Cancer, androgen deprivation therapy., Leuprolide Acetate Depot Formulation, Pharmacokinetics, testosterone, serum luteinizing hormone, follicle-stimulating hormone, prostate-specific antigen
Brief summary
Some patients with prostate cancer benefit from androgen deprivation therapy which reduces levels of testosterone. Leuprolide is a synthetic Luteinizing hormone releasing hormone (LHRH) analogue which upon administration can decrease testosterone levels to ≤0.5 ng/mL. Leuprolide Acetate 22.5 mg Depot is a microencapsulated formulation of leuprolide which is released slowly over time and effectively reduces testosterone levels in many patients to ≤0.5 ng/mL for up to three months. In this study Leuprolide acetate 22.5 mg Depot will be administered by intramuscular injection twice over a period of 6 months. The proportion of patients with testosterone ≤0.5 ng/mL evaluated over a period of 168 days.
Detailed description
This in an open-label, multicenter, multiple-dose investigation of 2 doses of leuprolide acetate 22.5 mg administered with a 3-month interval to patients with histologically proven carcinoma of prostate who might benefit from medical androgen deprivation therapy. A total of up to 160 male patients will receive their first single intramuscular injection of leuprolide acetate 22.5 mg on Day 0 (after baseline assessment) and then after 3 months (Day 84). The study duration will be 6 months. Thirty(30) patients will be screened per protocol and enrolled at selected centers to form the PK cohort. The PK/PD analysis will be performed using plasma specimens from the first 20 of 30 patients enrolled in the study (and included in the PK/PD cohort). Patients not belonging to the PK cohort will be screened and enrolled per protocol and will follow the same study schedule as those enrolled in the PK portion of the study, except they will provide only sparse PK sampling.
Interventions
DRUGLeuprolide acetate 22.5 mg depot, GP-Pharm SA
Administered by im injection, twice during the study, three months apart
Sponsors
GP-Pharm
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main selection criteria: Patients with histologically documented prostate cancer who might benefit from medical androgen deprivation therapy (i.e., reduction of androgen levels) will be considered for enrollment in the study if they meet the following criteria: Inclusion Criteria: 1. Males ≥18 years of age 2. Patients with histologically documented prostate carcinoma who might benefit from medical androgen deprivation therapy. 3. Life expectancy of at least 1 year. 4. WHO/ECOG performance status of 0, 1, or 2. 5. Adequate renal function at Screening as defined by serum creatinine ≤1.6 times the upper limit of normal (ULN) for the clinical laboratory. 6. Adequate and stable hepatic function as defined by bilirubin ≤1.5 times the ULN and transaminases (i.e., aspartate aminotransferase, alanine aminotransferase) ≤2.5 times the ULN for the clinical laboratory at Screening. 7. Ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to cooperate with the investigator and to comply with the requirements of the entire study. 8. Following receipt of verbal and written information about the study,the patient must provide signed informed consent before any study related activity is carried out.
Exclusion criteria
1. Evidence of brain metastases, in the opinion of the investigator, taking into account medical history, clinical observations, and symptoms (rationale: to minimize possibility of serious acute flare reactions that would necessitate concomitant administration of other drugs). 2. Evidence of spinal cord compression, in the opinion of the investigator, taking into account medical history, clinical observations, and symptoms (rationale: see rationale in criterion 1). 3. Evidence of severe urinary tract obstruction with threatening urinary retention, in the opinion of the investigator, taking into account medical history, clinical observations, and symptoms (rationale: see rationale in criterion 1). 4. Presence of any tumor in the immediate vicinity that could cause spinal cord compression, in the opinion of the investigator, taking into account medical history and clinical observations (rationale: see rationale in criterion 1). 5. Excruciating, severe pain from extensive osseous deposits, taking into account medical history, clinical observations, and symptoms (rationale: see rationale in criterion 1). 6. Testosterone levels \<1.5 ng/mL at Screening, This testosterone level will be locally determined at the laboratory of each clinical site (rationale: to ensure that all patients have normal baseline testosterone levels). 7. Previous androgen ablative therapy lasting more than 6 months, such as LHRH analogues (e.g., Leuprolide acetate, Goserelin, Buserelin) or antagonists (degarelix). Also, therapy must have not occurred within 12 months before the screening visit. Any prior ADT must have not exceeded 6 months of therapy. 8. Previous treatment with androgen-receptor blockers, such as Bicalutamide, Flutamide, Megestrol acetate, Ciproterone will only be allowed after a 3 month washout prior to the screening visit (rationale: these therapies alter a patient's androgenic hormonal response for a sustained period). 9. Previous orchiectomy, adrenalectomy, or hypophysectomy (no washout allowed) (rationale: these therapies could have altered a patient's androgenic hormonal response). 10. Previous prostatic surgery (e.g., radical prostatectomy, transurethral resection of the prostate) within 2 weeks before Baseline (rationale: these therapies could have altered a patient's androgenic hormonal response and/or adverse reaction profile). 11. Previous local therapy to the primary tumor with a curative attempt other than surgery (external beam radiotherapy, brachytherapy, thermotherapy, cryotherapy) within 2 weeks before Baseline (rationale: these therapies could have altered a patient's adverse reaction profile). 12. Previous cancer systemic therapy such as chemotherapy, immunotherapy (e.g., antibody therapies, tumor vaccines), biological response modifiers (e.g., cytokines). 13. Any investigational drug within 5 half-lives of its physiological action or 3 months, whichever is longer, before Baseline (rationale: to prevent adverse effects of another drug being attributed to study drug and to prevent potential interactions). 14. Administration of 5-α-reductase inhibitors (Finasteride, Dutasteride) within 3 months before Baseline (rationale: alters PSA levels and androgen metabolism of the prostate cells). Prior use of 5-α-reductase inhibitors will be allowed with a 3 month washout. 15. Over-the-counter or alternative medical therapies that have an estrogenic or antiandrogenic effect (i.e., PC-SPES, saw palmetto, Glycyrrhiza, Urinozinc, dehydroepiandrosterone) within the 3 months before Baseline. 16. Hematological parameters (red blood cells, total and differential white blood cell count, platelet count, hemoglobin, hematocrit) outside 20% of the ULN or lower limits of normal for the clinical laboratory at Screening (rationale: to render potential study drug-related laboratory abnormalities easier to observe). 17. Coexistent malignancy, in the opinion of the investigator (rationale: to decrease possibility of disease-caused or associated therapy-caused adverse effects being attributed to study drug). 18. Uncontrolled congestive heart failure, myocardial infarction or a coronary vascular procedure (e.g., balloon angioplasty, coronary artery bypass graft) or significant symptomatic cardiovascular disease(s) within 6 months before Baseline; resting uncontrolled hypertension (≥160/100 mm Hg) or symptomatic hypotension within 3 months before Baseline (rationale: to decrease possibility of disease-caused or associated therapy-caused adverse effects being attributed to study drug). 19. Venous thrombosis within 6 months of Baseline (rationale: influencing testosterone levels may be associated with increased likelihood of deep venous thrombosis). 20. Uncontrolled diabetes, in the opinion of the investigator (rationale: patients with uncontrolled diabetes need to compensate the metabolic disorder before treatment with LHRH analogues). 21. History of drug and/or alcohol abuse within 6 months of Baseline (rationale: these patients are likely to have numerous medical abnormalities and are unlikely to comply with protocol). 22. Serious concomitant illness(es) or disease(s) (e.g., hematological, renal, hepatic, respiratory, endocrine, psychiatric) that may interfere with, or put patients at additional risk for, their ability to receive the treatment outlined in the protocol (rationale: to decrease possibility of disease-caused or associated therapy-caused adverse effects being attributed to study drug). 23. Patients on anticoagulative therapy including warfarin (Coumadin®), Dabigatran Etexilate (Pradaxa®) and heparin. Those patients on low-dose, low-molecular weight heparin may be enrolled in the study (rationale: to decrease possibility of disease-caused or associated therapy-caused adverse effects being attributed to study drug). Plavix and Aspirin are allowed for cardiac prophylaxis as long as all inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Chemical Castration (Defined as Testosterone Levels ≤ 0.5 ng/mL) at Days 28, 84, and 168. | 168 days | The primary endpoint was testosterone ≤ 0.5 ng/mL assessed on Days 28, 84, and 168. Thereby, maintenance of castration was to be demonstrated through Day 168 with no missing data at these key time points, unless the missing data were due to an event unrelated to the study drug (ITT patients). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Follicle-stimulating Hormone (FSH) | 168 days | For purposes of calculating summary statistics, any concentration values Below Limit of Quantification (BLQ) were to be assigned ½ the Low Limit of Quantification (LLOQ) (LLOQ=3.66). If the calculated mean, median or minimum value at a time point was less than LLOQ, BLQ is presented. In addition, since a high proportion of BLQ values may affect the Standard Deviation (SD); if more than 50% of values were imputed, then no mean or median was to be calculated for that time point. |
| Prostate-specific Antigen (PSA) Concentrations | 168 days | For purposes of calculating summary statistics, any concentration values Below Limit Quantification (BLQ) were to be assigned ½ the Low Limit Quantification (LLOQ) (LLOQ=0.36). If the calculated mean, median or minimum value at a time point was less than LLOQ, BLQ is presented. In addition, since a high proportion of BLQ values may affect the Standard Deviation (SD); if more than 50% of values were imputed, then no mean or median was calculated for that time point. |
| Determination of Serum Luteinizing Hormone (LH) | 168 days | For purposes of calculating summary statistics, any concentration values Below Limit of Quantification (BLQ) were to be assigned ½ the Low Limit of Quantification (LLOQ) (LLOQ=2.00). If the calculated mean, median or minimum value at a time point was less than LLOQ, BLQ is presented. In addition, since a high proportion of BLQ values may affect the Standard Deviation (SD); if more than 50% of values were imputed, then no mean or median was calculated for that time point. |
| Safety Endpoints | 168 Days | The WHO/ECOG, bone pain, urinary pain and urinary symptoms data reported are the most frequent percentage at the assessment time. * The WHO/ECOG performance status was summarized using the 0 to 4 WHO/ECOG performance status scale. (0= fully active, able to carry on all pre-disease performances without restriction). * Bone pain, urinary pain and urinary symptoms were determined using a 10-point scale (1= no pain/symptoms, 10= worst pain/symptom imaginable). |
| Determination of Leuprolide Tmax | 84 days | Leuprolide Pharmacokinetic Parameters (PK Population). |
| Determination of Leuprolide Cmax | Cmax1: 0, 1 and 4 hours post-dose on Day 0 and once on Days 2, 14, 28, 56; Cmax2: 0, 1 and 4 hours post-dose on Day 84 and once on Days 86, 112 and 168. | Leuprolide Pharmacokinetic Parameters (PK Population). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Leuprolide Acetate 22.5 mg Depot Leuprolide acetate 22.5 mg depot administered twice, 3 months apart
Leuprolide acetate 22.5 mg depot, GP-Pharm SA: Administered by im injection, twice during the study, three months apart | 161 |
| Total | 161 |
Baseline characteristics
| Characteristic | Leuprolide Acetate 22.5 mg Depot |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 119 Participants |
| Age, Categorical Between 18 and 65 years | 42 Participants |
| Age, Continuous | 71 years STANDARD_DEVIATION 9.02 |
| Region of Enrollment United States | 161 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 161 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 141 / 163 |
| serious Total, serious adverse events | 12 / 163 |
Outcome results
Primary
Percentage of Participants Achieving Chemical Castration (Defined as Testosterone Levels ≤ 0.5 ng/mL) at Days 28, 84, and 168.
The primary endpoint was testosterone ≤ 0.5 ng/mL assessed on Days 28, 84, and 168. Thereby, maintenance of castration was to be demonstrated through Day 168 with no missing data at these key time points, unless the missing data were due to an event unrelated to the study drug (ITT patients).
Time frame: 168 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Leuprolide Acetate 22.5 mg Depot | Percentage of Participants Achieving Chemical Castration (Defined as Testosterone Levels ≤ 0.5 ng/mL) at Days 28, 84, and 168. | 98.1 percentage of participants |
Secondary
Determination of Leuprolide Cmax
Leuprolide Pharmacokinetic Parameters (PK Population).
Time frame: Cmax1: 0, 1 and 4 hours post-dose on Day 0 and once on Days 2, 14, 28, 56; Cmax2: 0, 1 and 4 hours post-dose on Day 84 and once on Days 86, 112 and 168.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Leuprolide Acetate 22.5 mg Depot | Determination of Leuprolide Cmax | Day 0/Dose 1 Cmax | 46.79 ng/mL | Standard Deviation 18.008 |
| Leuprolide Acetate 22.5 mg Depot | Determination of Leuprolide Cmax | Day 84/Dose 2 Cmax | 48.30 ng/mL | Standard Deviation 18.557 |
Secondary
Determination of Leuprolide Tmax
Leuprolide Pharmacokinetic Parameters (PK Population).
Time frame: 84 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Leuprolide Acetate 22.5 mg Depot | Determination of Leuprolide Tmax | Day 0/Dose 1 Tmax | 0.07 day | Standard Deviation 0.051 |
| Leuprolide Acetate 22.5 mg Depot | Determination of Leuprolide Tmax | Day 84/Dose 2 Tmax | 0.08 day | Standard Deviation 0.056 |
Secondary
Determination of Serum Luteinizing Hormone (LH)
For purposes of calculating summary statistics, any concentration values Below Limit of Quantification (BLQ) were to be assigned ½ the Low Limit of Quantification (LLOQ) (LLOQ=2.00). If the calculated mean, median or minimum value at a time point was less than LLOQ, BLQ is presented. In addition, since a high proportion of BLQ values may affect the Standard Deviation (SD); if more than 50% of values were imputed, then no mean or median was calculated for that time point.
Time frame: 168 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Leuprolide Acetate 22.5 mg Depot | Determination of Serum Luteinizing Hormone (LH) | Baseline | 7.24 mIU/mL | Standard Deviation 6.48 |
| Leuprolide Acetate 22.5 mg Depot | Determination of Serum Luteinizing Hormone (LH) | Day 28 | 1 mIU/mL | Standard Deviation 2.79 |
| Leuprolide Acetate 22.5 mg Depot | Determination of Serum Luteinizing Hormone (LH) | Day 168 | 1 mIU/mL | Standard Deviation 0.92 |
Secondary
Follicle-stimulating Hormone (FSH)
For purposes of calculating summary statistics, any concentration values Below Limit of Quantification (BLQ) were to be assigned ½ the Low Limit of Quantification (LLOQ) (LLOQ=3.66). If the calculated mean, median or minimum value at a time point was less than LLOQ, BLQ is presented. In addition, since a high proportion of BLQ values may affect the Standard Deviation (SD); if more than 50% of values were imputed, then no mean or median was to be calculated for that time point.
Time frame: 168 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Leuprolide Acetate 22.5 mg Depot | Follicle-stimulating Hormone (FSH) | Baseline | 15.14 mIU/mL | Standard Deviation 13.46 |
| Leuprolide Acetate 22.5 mg Depot | Follicle-stimulating Hormone (FSH) | Day 28 | 1 mIU/mL | Standard Deviation 1.44 |
| Leuprolide Acetate 22.5 mg Depot | Follicle-stimulating Hormone (FSH) | Day 168 | 5.80 mIU/mL | Standard Deviation 3.62 |
Secondary
Prostate-specific Antigen (PSA) Concentrations
For purposes of calculating summary statistics, any concentration values Below Limit Quantification (BLQ) were to be assigned ½ the Low Limit Quantification (LLOQ) (LLOQ=0.36). If the calculated mean, median or minimum value at a time point was less than LLOQ, BLQ is presented. In addition, since a high proportion of BLQ values may affect the Standard Deviation (SD); if more than 50% of values were imputed, then no mean or median was calculated for that time point.
Time frame: 168 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Leuprolide Acetate 22.5 mg Depot | Prostate-specific Antigen (PSA) Concentrations | Baseline | 44.36 ng/mL | Standard Deviation 165.81 |
| Leuprolide Acetate 22.5 mg Depot | Prostate-specific Antigen (PSA) Concentrations | Day 168 | 2.37 ng/mL | Standard Deviation 10.3 |
Secondary
Safety Endpoints
The WHO/ECOG, bone pain, urinary pain and urinary symptoms data reported are the most frequent percentage at the assessment time. * The WHO/ECOG performance status was summarized using the 0 to 4 WHO/ECOG performance status scale. (0= fully active, able to carry on all pre-disease performances without restriction). * Bone pain, urinary pain and urinary symptoms were determined using a 10-point scale (1= no pain/symptoms, 10= worst pain/symptom imaginable).
Time frame: 168 Days
Population: Safety endpoints adverse events (AEs), local tolerability, vital signs, performance status, bone pain, urinary pain, and urinary symptoms, occurrence of hot flushes and clinical laboratory and electrocardiogram (ECG) results.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Leuprolide Acetate 22.5 mg Depot | Safety Endpoints | Baseline WHO/ECOG Score 0 (n=161) | 83.9 percentage of participants |
| Leuprolide Acetate 22.5 mg Depot | Safety Endpoints | Day 168 WHO/ECOG Scores 0 (n=152) | 82.9 percentage of participants |
| Leuprolide Acetate 22.5 mg Depot | Safety Endpoints | Baseline Bone Pain score 1 (n=161) | 95.0 percentage of participants |
| Leuprolide Acetate 22.5 mg Depot | Safety Endpoints | Day 168 Bone Pain score 1 (n=152) | 94.1 percentage of participants |
| Leuprolide Acetate 22.5 mg Depot | Safety Endpoints | Baseline Urinary Pain score 1 (n=161) | 98.8 percentage of participants |
| Leuprolide Acetate 22.5 mg Depot | Safety Endpoints | Day 168 Urinary Pain Score 1 (n=152) | 97.4 percentage of participants |
| Leuprolide Acetate 22.5 mg Depot | Safety Endpoints | Baseline Urinary Symptoms score 1 (n=161) | 87.6 percentage of participants |
| Leuprolide Acetate 22.5 mg Depot | Safety Endpoints | Day 168 Urinary Symptoms score 1 (n=152) | 89.5 percentage of participants |