Prostate Cancer
Conditions
Brief summary
Assess the efficacy and safety of Triptorelin pamoate 3M formulation (11.25mg) when administered by subcutaneous route.
Interventions
DRUGTriptorelin Pamoate 11.25mg
Sponsors
Ipsen
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
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Demonstrating Castration at Day 29 and Maintaining Castration at Day 183 | At Day 29 and 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Probability of Testosterone <50 ng/dL | Day 29 through Day 183 | 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 |
| Percentage of Subjects Demonstrating Castration With Testosterone Level <50 ng/dL at Day 95 | 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. |
| Time to Achieve Castration (Tcast) | Up to Day 36 | 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) |
| Plasma Triptorelin Levels (Cmin) | At Day 92 and 183 | 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. |
| Percentage Change in Prostate Specific Antigen (PSA) Levels From Baseline in All Subjects | From Day 1 (Baseline) to Day 183 (End of study) | 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. |
| Percentage of Subjects With Normal and Abnormal PSA Levels at Day 183 (End of Study Visit) | At Day 183 | 0-4 ng/mL (normal PSA value) \>4 ng/mL (abnormal PSA levels) |
| Percentage of Subjects Demonstrating Castration Before Administration of the Second Dose | At Day 92 | 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. |
| 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 | — |
| Clinically Apparent Tumor Progression | Day 92 and 183 | 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). |
Countries
Bulgaria, France, Latvia, Poland, Romania
Participant flow
Pre-assignment details
A total of 139 subjects were screened and 13 subjects were screen failures.
Participants by arm
| Arm | Count |
|---|---|
| Triptorelin Pamoate Triptorelin Pamoate corresponding to 11.25 mg of triptorelin administered subcutaneously on Day 1 and 92 | 126 |
| Total | 126 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event, fatal | 1 |
| Overall Study | Consent Withdrawn | 2 |
| Overall Study | Lack of Efficacy | 3 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Other | 1 |
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Triptorelin Pamoate |
|---|---|
| Age, Continuous | 70.4 years STANDARD_DEVIATION 7.3 |
| Body Mass Index (BMI) | 27.16 kg/m² STANDARD_DEVIATION 3.96 |
| Height | 172.2 cm STANDARD_DEVIATION 6.7 |
| Prostate Specific Antigen (PSA) | 133.53 ng/mL STANDARD_DEVIATION 385.6 |
| Race/Ethnicity, Customized Caucasian / White | 120 participants |
| Race/Ethnicity, Customized Missing | 6 participants |
| Sex/Gender, Customized Male | 126 participants |
| Weight | 80.6 kg STANDARD_DEVIATION 12.8 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 45 / 126 |
| serious Total, serious adverse events | 6 / 126 |
Outcome results
Primary
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
Time frame: At Day 29 and 183
Population: N=Number of subjects attending the visit
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Triptorelin Pamoate | Percentage of Subjects Demonstrating Castration at Day 29 and Maintaining Castration at Day 183 | Day 29 (N=126) | 97.6 Percentage of subjects |
| Triptorelin Pamoate | Percentage of Subjects Demonstrating Castration at Day 29 and Maintaining Castration at Day 183 | Day 183 (N=119) | 96.6 Percentage of subjects |
Secondary
Area Under the Concentration Versus Time Curve Between 0 and 24 Hours (AUC0-24) of Triptorelin
Time frame: At 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours after first dose on Day 1
Population: PK profile was assessed in a subset of 18 subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Triptorelin Pamoate | Area Under the Concentration Versus Time Curve Between 0 and 24 Hours (AUC0-24) of Triptorelin | 304.6 h*ng/mL | Standard Deviation 103.7 |
Secondary
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).
Time frame: Day 92 and 183
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Triptorelin Pamoate | Clinically Apparent Tumor Progression | Day 92: Non Progressive Disease | 122 participants |
| Triptorelin Pamoate | Clinically Apparent Tumor Progression | Day 92: Progressive Disease | 0 participants |
| Triptorelin Pamoate | Clinically Apparent Tumor Progression | Day 183: Non Progressive Disease | 114 participants |
| Triptorelin Pamoate | Clinically Apparent Tumor Progression | Day 183: Progressive Disease | 3 participants |
Secondary
Cmin of Triptorelin in Subset of 18 Subjects
Time frame: At Day 92 and 183
Population: Day 92: Four subjects (presenting particularly high levels of triptorelin) were excluded from 18-subject subset.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Triptorelin Pamoate | Cmin of Triptorelin in Subset of 18 Subjects | Day 92 (N=14) | 0.078 ng/mL | Standard Deviation 0.038 |
| Triptorelin Pamoate | Cmin of Triptorelin in Subset of 18 Subjects | Day 183 (N=18) | 0.062 ng/mL | Standard Deviation 0.023 |
Secondary
Peak Plasma Concentration Value (Cmax) of Triptorelin
Time frame: At 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours after first dose on Day 1
Population: PK profile was assessed in a subset of 18 subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Triptorelin Pamoate | Peak Plasma Concentration Value (Cmax) of Triptorelin | 18.58 ng/mL | Standard Deviation 7.35 |
Secondary
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.
Time frame: From Day 1 (Baseline) to Day 183 (End of study)
Population: ITT population at End of Study (Day 183). One subject had no data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Triptorelin Pamoate | Percentage Change in Prostate Specific Antigen (PSA) Levels From Baseline in All Subjects | -85.503 Percentage Change | Standard Deviation 42.41 |
Secondary
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.
Time frame: At Day 92
Population: Initially Castrated (IC1) population: All treated subjects with testosterone levels \<50 ng/dL at Day 29 or at Day 36, assessed with the LC-MS/MS method and missing data imputed by immunoassay method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Triptorelin Pamoate | Percentage of Subjects Demonstrating Castration Before Administration of the Second Dose | 99.2 Percentage of subjects |
Secondary
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.
Time frame: Day 95
Population: IC1 population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Triptorelin Pamoate | Percentage of Subjects Demonstrating Castration With Testosterone Level <50 ng/dL at Day 95 | 98.3 Percentage of subjects |
Secondary
Percentage of Subjects With Adverse Events
Time frame: Up to Day 183
Population: All subjects who received at least one dose of study treatment were included in safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Triptorelin Pamoate | Percentage of Subjects With Adverse Events | Any Adverse Events | 35.7 Percentage of subjects |
| Triptorelin Pamoate | Percentage of Subjects With Adverse Events | Any Serious Adverse Events (SAEs) | 4.8 Percentage of subjects |
| Triptorelin Pamoate | Percentage of Subjects With Adverse Events | Any Treatment Emergent Adverse Events (TEAEs) | 35.7 Percentage of subjects |
| Triptorelin Pamoate | Percentage of Subjects With Adverse Events | TEAEs Leading to Withdrawal | 0.8 Percentage of subjects |
| Triptorelin Pamoate | Percentage of Subjects With Adverse Events | TEAEs Leading to Death | 0.8 Percentage of subjects |
| Triptorelin Pamoate | Percentage of Subjects With Adverse Events | Maximum Grade NCI-CTC of TEAEs: Grade 5 | 0.8 Percentage of subjects |
| Triptorelin Pamoate | Percentage of Subjects With Adverse Events | Maximum Grade NCI-CTC of TEAEs: Grade 4 | 0 Percentage of subjects |
| Triptorelin Pamoate | Percentage of Subjects With Adverse Events | Maximum Grade NCI-CTC of TEAEs: Grade 3 | 4.0 Percentage of subjects |
| Triptorelin Pamoate | Percentage of Subjects With Adverse Events | Maximum Grade NCI-CTC of TEAEs: Grade 2 | 13.5 Percentage of subjects |
| Triptorelin Pamoate | Percentage of Subjects With Adverse Events | Maximum Grade NCI-CTC of TEAEs: Grade 1 | 27.8 Percentage of subjects |
| Triptorelin Pamoate | Percentage of Subjects With Adverse Events | Most serious causality of TEAEs: Related | 21.4 Percentage of subjects |
| Triptorelin Pamoate | Percentage of Subjects With Adverse Events | Most serious causality of TEAEs: Not related | 26.2 Percentage of subjects |
Secondary
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)
Time frame: At Day 183
Population: Subjects completed Day 183 visit (End of Study)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Triptorelin Pamoate | Percentage of Subjects With Normal and Abnormal PSA Levels at Day 183 (End of Study Visit) | End of Study (0-4 ng/mL) | 84.6 Percentage of subjects |
| Triptorelin Pamoate | Percentage of Subjects With Normal and Abnormal PSA Levels at Day 183 (End of Study Visit) | End of Study (>4 ng/mL) | 15.4 Percentage of subjects |
Secondary
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.
Time frame: At Day 92 and 183
Population: ITT population. No samples were collected from 4 subjects at Day 92 and 9 subjects at Day 183
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Triptorelin Pamoate | Plasma Triptorelin Levels (Cmin) | Day 92 | 0.062 ng/mL | Standard Deviation 0.031 |
| Triptorelin Pamoate | Plasma Triptorelin Levels (Cmin) | Day 183 (N=117) | 0.049 ng/mL | Standard Deviation 0.027 |
Secondary
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
Time frame: Day 29 through Day 183
Population: Intention-to-treat (ITT) population: All treated subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Triptorelin Pamoate | Probability of Testosterone <50 ng/dL | 0.96 Proportion of subjects |
Secondary
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)
Time frame: Up to Day 36
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Triptorelin Pamoate | Time to Achieve Castration (Tcast) | 22 Day |
Secondary
Time to Cmax (Tmax) of Triptorelin
Time frame: At 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours after first dose on Day 1
Population: Pharmacokinetic (PK) profile was assessed in a subset of 18 subjects.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Triptorelin Pamoate | Time to Cmax (Tmax) of Triptorelin | 4.5 Hours |