Induction and Maintenance of Castration After Subcutaneous Injections of Triptorelin Pamoate in Patients With Prostate Cancer

Study Overview
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Brief Summary
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Assess the efficacy and safety of Triptorelin pamoate 3M formulation (11.25mg) when administered by subcutaneous route.

Official Title
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A Phase III Single Arm Study to Evaluate the Efficacy, Safety and Local Tolerability of a Subcutaneous 3-month Formulation of Triptorelin Pamoate (11.25 mg) in Patients With Locally Advanced or Metastatic Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Triptorelin Pamoate 11.25mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven locally advanced or metastatic prostate cancer who are suitable for androgen deprivation therapy Male aged ≥18 years old Screening testosterone level of >125 ng/dL Life expectancy of greater than 12 months in the judgement of the Investigator Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Willing to give signed informed consent freely Able to adhere to the study visit schedule and other protocol requirements. Exclusion Criteria: Prior hormonal therapy for prostate cancer Prior surgery or radiotherapy of prostate cancer with curative intent unless disease is verified by a rising prostate specific antigen (PSA) concentration on follow up (elevated PSA values on last two tests conducted at least a month apart) and the patient is eligible for androgen deprivation therapy Presence or history of any other malignancy except for non melanoma skin cancer adequately treated at least 2 years before study entry Painful local bone lesions or spinal lesions which may lead to compression History of myocardial infarction, percutaneous coronary intervention, acute coronary syndrome, coronary artery bypass graft, Class III/IV congestive heart failure, cerebrovascular accident, transient ischaemic attack, or limb claudication at rest, within six months prior to start of study treatment and ongoing symptomatic dysrhythmias, unstable angina, uncontrolled hypertension, and untreated atrial or uncontrolled ventricular arrhythmias Any condition in opinion of the Investigator, including other active or latent infections, medical or psychiatric conditions, or the presence of laboratory abnormalities, which could confound the ability to interpret data from the study, compromises the objective of the study or places the patient at unacceptable risk if he participates in the study Abnormal haematological, hepatic or renal functions: Haemoglobin <9 g/dL, absolute neutrophil count ≤1.5 x 10^9/L or platelets ≤100 x 10^9/L Serum creatinine ≥1.5 times the upper limit of normal (ULN) Aspartate aminotransferase or alanine aminotransferase >2.5 times the ULN Known hypersensitivity to the study treatment, to any of its excipients Known active use of recreational drug or alcohol dependence in the opinion of the Investigator Any current use or use within six months prior to start of treatment, of medications which are known to affect the metabolism and/or secretion of androgenic hormones: e.g. ketoconazole, aminoglutethimide, oestrogens, and progesterone Use of systemic corticosteroids (inhaled corticosteroids and topical application of corticosteroids are permitted) Aged ≥90 years for the main study and ≥80 years for those included in the pharmacokinetic (PK) patient population Participation in any other study or receipt of any investigational compound in the 30 days (or five times the elimination half life if this is longer) prior to study entry Any skin or other condition that may preclude s.c. injection administration Known brain or epidural metastases.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 11.25mg<br>11.25mg, SC on Day 1 and Day 92 | Drug: Triptorelin Pamoate 11.25mg<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Demonstrating Castration at Day 29 and Maintaining Castration at Day 183 | Percentage of subjects castrated (i.e. with serum testosterone <50 ng/dL or 1.735 nmol/L, using the LC-MS/MS method and missing data imputed by immunoassay method (at time points when LC-MS/MS data was planned to be available only) and the proportion with castration maintained at Day 183 (after receiving 2 S.C. administrations of triptorelin pamoate, three months apart); they were calculated along with their respective 95% confidence intervals (CI) using exact methods on the ITT population at Day 29 and on the initially castrated (IC) population at Day 183 | At Day 29 and 183 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Demonstrating Castration Before Administration of the Second Dose | Percentage of subjects demonstrating castration at Day 92 (before administration of the second dose) were also assessed using the LC-MS/MS method and missing data imputed by immunoassay method (at time points when LC-MS/MS data was planned to be available only) and summarised using descriptive statistics on the ITT and IC populations. | At Day 92 | 
| Probability of Testosterone <50 ng/dL | Probability of testosterone <50 ng/dL from Day 29 to Day 183 was assessed as a secondary endpoint using the time to event from first administration date to first observed (and subsequently confirmed if assessment not performed at end of study or early withdrawal visits) serum testosterone level ≥50 ng/dL or ≥1.735 nmol/L at or after Day 29, assessed using the LC-MS/MS Method and Missing Data imputed by immunoassay method Kaplan-Meier Analysis. LC-MS/MS: Liquid Chromatography-Tandem Mass Spectrometry | Day 29 through Day 183 | 
| Percentage of Subjects Demonstrating Castration With Testosterone Level <50 ng/dL at Day 95 | Percentage of subjects demonstrating castration at Day 95 (3-4 days after administration of the second dose to assess the suppression of acute-on-chronic effect following the second administration) were also assessed using the LC-MS/MS method and missing data imputed by immunoassay method (at time points when LC-MS/MS data was planned to be available only) and summarised using descriptive statistics on the ITT and IC populations. | Day 95 | 
| Time to Achieve Castration (Tcast) | Time to castration (Tcast) from first administration date until first observed serum testosterone level <50 ng/dL or <1.735 nmol/L evaluated using the immunoassay method only (i.e. defined as the number of days between the injection time at Day 1 and castration achievement) | Up to Day 36 | 
| Plasma Triptorelin Levels (Cmin) | Minimal triptorelin plasma concentration at the end of each dosage interval just before the next dose injection (Cmin) for Days 92 and 183 were assessed. | At Day 92 and 183 | 
| Percentage Change in Prostate Specific Antigen (PSA) Levels From Baseline in All Subjects | Serum PSA level was presented throughout the study using descriptive statistics displaying raw values, change from Baseline and percentage change from Baseline at each visit in all subjects from the ITT population only. Additionally, the PSA level was described in subjects with elevated PSA levels (i.e. >4 ng/mL) at study entry, and the proportion of subjects with normal PSA levels (i.e. [0-4] ng/mL) at Day 183 compared to Baseline was presented. | From Day 1 (Baseline) to Day 183 (End of study) | 
| Percentage of Subjects With Normal and Abnormal PSA Levels at Day 183 (End of Study Visit) | 0-4 ng/mL (normal PSA value) >4 ng/mL (abnormal PSA levels) | At Day 183 | 
| Clinically Apparent Tumor Progression | Tumour progression was recorded according to the Investigator's clinical judgement, considering the PSA levels and any other indications of disease; the clinical confirmation might be supplemented by radiological or other investigations or scans if required. The lack of clinically apparent tumour progression was assessed at Day 92 (prior to administration of the second dose) and Day 183 (end of study visit). | Day 92 and 183 | 
| Percentage of Subjects With Adverse Events |  | Up to Day 183 | 
| Time to Cmax (Tmax) of Triptorelin |  | At 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours after first dose on Day 1 | 
| Peak Plasma Concentration Value (Cmax) of Triptorelin |  | At 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours after first dose on Day 1 | 
| Area Under the Concentration Versus Time Curve Between 0 and 24 Hours (AUC0-24) of Triptorelin |  | At 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours after first dose on Day 1 | 
| Cmin of Triptorelin in Subset of 18 Subjects |  | At Day 92 and 183 |