Efficacy and Safety of Leuprolide Acetate 22.5 mg Depot in Treatment of Prostate Cancer
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: Leuprolide acetate 22.5 mg depot, GP-Pharm SA
Intervention description: Administered by im injection, twice during the study, three months apart
Intervention MeSH terms: Leuprolide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 163.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Prostate Cancer; androgen deprivation therapy.; Leuprolide Acetate Depot Formulation; Pharmacokinetics; testosterone; serum luteinizing hormone; follicle-stimulating hormone; prostate-specific antigen

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.
    

Eligibility 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/exclusion criteria are met concerning coagulation parameters and
             thromboembolic history. Special care to avoid hematoma at the injection site must be
             observed.

         24. Abnormal coagulation studies (prothrombin time [PT]/partial thromboplastin time [PTT])
             at Baseline.

         25. History of serious bleeding on injections, an elevated INR, concomitant medications or
             any other condition (i.e. significant thrombocytopenia) that in opinion of the
             investigator would render the subject at risk of significant bleeding with injections.

         26. Blood donations/losses within 2 months of Baseline, apart from previous prostatic
             surgery patients (see exclusion 10 [rationale: to avoid excessive blood donations]).

         27. Known hypersensitivity to GnRH, GnRH agonists, including any LHRH analogues, or any
             excipients of the study formulation (rationale: to minimize hypersensitivity reaction
             to study drug).

         28. History of Immunization (within 4 weeks of Baseline) and specifically flu shots
             (within 1 week of Baseline or 1 week before and after study drug administration)
             (Rationale: to decrease the possibility of non treatment-related AEs being attributed
             to study drug).

         29. Skin disease that would interfere with injection site evaluation.

         30. Men not willing to use appropriate birth control methods such as surgical
             sterilization or barrier contraception or men with partners of child bearing potential
             not willing to use appropriate birth control methods, such as surgical sterilization,
             hormonal birth control (partner), an intrauterine device (partner) or double-barrier
             method for the entire study period.