Efficacy and Safety of Leuprolide Acetate 22.5 mg Depot in Treatment of Prostate Cancer

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.

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.