E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced Prostate Carcinoma |
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E.1.1.1 | Medical condition in easily understood language |
Prostate Cancer, that has progressed over the past |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036921 |
E.1.2 | Term | Prostate carcinoma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary objectives:
1. Determine the safety and tolerability of LMIS 50 mg for up to 1 year of exposure following 2 subcutaneous doses given at 6 months apart in subjects with advanced prostate carcinoma;
2. Establish the efficacy of LMIS 50 mg for up to 1 year following 2 subcutaneous doses given at 6 months apart in subjects with advanced prostate carcinoma, as determined by the magnitude and duration of suppression of serum testosterone levels; and
3. Evaluate the pharmacokinetic behavior of serum leuprolide following 2 subcutaneous injections of LMIS 50 mg given 6 months apart. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to characterize the effects of LMIS 50 mg on the ancillary laboratory markers of serum prostate specific antigen (PSA) and luteinizing hormone (LH). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria
(1) Males aged ≥ 18 years old
(2) Males with histologically confirmed carcinoma of the prostate
(3) Subjects who are judged by the attending physician and/or Principal Investigator to be a candidate for androgen ablation therapy
(4) Baseline morning serum testosterone level >150 ng/dL
(5) ECOG Performance score ≤ 2
(6) Life expectancy of at least 18 months
(7) Laboratory values
o Absolute neutrophil count ≥ 1,500 cells/μL
o Platelets ≥ 100,000 cells/μL
o Hemoglobin ≥ 10 gm/dL
o Total bilirubin ≤ 1.5 × upper limit of normal (ULN)
o AST (SGOT) ≤ 2.5 × ULN
o ALT (SGPT) ≤ 2.5 × ULN
o Serum creatinine ≤ 1.5 mg/dL
o Lipid profile within acceptable range according to investigator´s opinion
o Serum glucose within acceptable range according to investigator´s opinion
o HgbA1c within acceptable range according to investigator´s opinion
o Clinical chemistries (K, Na, Mg, Ca and P) within acceptable range according to investigator´s opinion
o Urinalysis within normal range according to the investigator´s opinion
(8) Agree to use male contraceptive methods during study trial
(9) In the Investigator’s opinion, the ability to understand the nature of the study and any hazards of participation, and to communicate satisfactorily with the Investigator and to participate in, and to comply with, the requirements of the entire protocol
(10) All aspects of the protocol explained and written informed consent obtained |
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E.4 | Principal exclusion criteria |
Main exclusion criteria:
(1) Receipt of chemotherapy, immunotherapy, cryotherapy, radiotherapy, or anti-androgen therapy concomitantly, or within 8 weeks prior to Screening Visit, for treatment of carcinoma of the prostate. Radiation for pain control will be allowed during the study.
(2) Receipt of any vaccination (including influenza) within 4 weeks of Baseline
(3) History of blood donation within 2 months of Baseline
(4) History of anaphylaxis to any LH-RH analogues
(5) Receipt of any LHRH suppressive therapy within 6 months of Baseline
(6) Major surgery, including any prostatic surgery, within 4 weeks of Baseline
(7) History and concomitant clinical and radiographic evidence of central nervous system/spinal cord metastases. Subjects at risk for spinal cord compression will be excluded.
(8) Clinical evidence of active urinary tract obstruction and subjects at risk for urinary obstruction
(9) History of bilateral orchiectomy, adrenalectomy, or hypophysectomy
(10) History or presence of hypogonadism, or receipt of exogenous testosterone supplementation within 6 months of Baseline
(11) Clinically significant abnormal ECG and/or history of clinically significant cardiovascular disease as judged by the investigator
(12) History of drug and/or alcohol abuse within 6 months of Baseline
(13) Contraindication to leuprolide or an LHRH agonist as indicated on package labeling
(14) Use of 5-alpha reductase inhibitor within the last 6 months of Baseline
(15) History or presence of insulin-dependent diabetes mellitus (Type I). Presence of well controlled diabetes mellitus Type II will be allowed if only oral hypoglycemic are required.
(16) Use of systemic corticosteroids at a dose >10mg/d or anti-androgens
(17) Use of any investigational agent within 4 weeks of Baseline
(18) Use of any over-the-counter (OTC) medication within 4 weeks of Baseline except for those listed in the permitted Concomitant Treatment section.
(19) Uncontrolled intercurrent illness that would jeopardize the subject’s safety, interfere with the objectives of the protocol, or limit the subject’s compliance with study requirements, as determined by the Investigator in consultation with the Sponsor |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoints
1. Determine the safety and tolerability by:
• Change in bone pain measurement (by VAS scale)
• Change in urinary pain measurement (by VAS scale)
• Change in urinary signs and symptoms (by AUA Symptom Score sheet)
• Change in vital signs (BP, HR, RR)
• Change in physical examinations (including weight)
• Assessment for local skin tolerability
• Change in lab data, including liver function (AST, ALT, ALP), renal function (BUN, SCr), complete blood count with platelets, clinical chemistries (K, Na, Mg, Ca and P), urinalysis, serum glucose, lipid profile (LDL, HDL, triglycerides) and HgbA1c
• Adverse event (AE) reporting
• Clinically significant changes in 12-lead resting electrocardiograms (ECGs) per the Investigator
2. Efficacy evaluation
• The percentage of subjects with a serum testosterone concentration suppressed to castrate levels (≤ 50 ng/dL) within 28 days following the first injection of LMIS 50 mg and the percentage of subjects with serum testosterone suppression (≤ 50 ng/dL) from Day 28 through Day 336 (remaining duration of the study).
3. Evaluation of pharmacokinetics
• Pharmacokinetic behavior of leuprolide: full pharmacokinetic profiles from serum leuprolide concentrations in Part I subjects will be performed. Additional serum leuprolide concentration data will be collected during Part II. The pharmacokinetic behavior of leuprolide will be determined in subjects during in Part II on a more limited basis. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. safety and tolerability Endpoints: Visits 1-23
2. Efficacy evaluation: Visits 1-23
3. Evaluation of pharmacokinetics: Visits 2-23 |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints
1. The proportion of subjects exhibiting post-suppression excursions of serum testosterone to >50 ng/dL, either through “breakthrough” (i.e., episodes unrelated to LMIS 50 mg dosing), or through the “acute-on-chronic” phenomenon (i.e., related to the second dose of LMIS 50 mg)
2. Effect of LMIS 50 mg on serum PSA levels
3. Effect of LMIS 50 mg on serum LH levels |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. The proportion of subjects exhibiting post-suppression excursions of serum
testosterone: Visits 2-23
2. Effect of LMIS 50 mg on serum PSA levels: Visits 2-23
3. Effect of LMIS 50 mg on serum LH levels: Visits 2-23 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Czech Republic |
Germany |
Lithuania |
Poland |
Slovakia |
Taiwan |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |