Teverelix Evaluated in Advanced Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and efficacy of teverelix TFA in the treatment of advanced prostate cancer

Detailed Description
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After being informed about the study and potential risks, all patients giving written informed consent will undergo an up to 7 day screening period to determine eligibility for study entry. On Day 0, patients who meet the eligibility requirements will be enrolled in an open-label manner and will receive a loading dose of teverelix TFA (one subcutaneous (SC) injection in the abdomen and one intramuscular (IM) injection in the buttock). Patients will then receive maintenance doses of teverelix TFA (one SC injection in the abdomen) at 4- or 6-weekly intervals up to week 24. The patients will return for a final assessment 4 weeks after their last maintenance dose injection. The initial dosing regimen to be tested (Group 1) is: Loading Dose = 120 mg teverelix TFA SC + 120 mg teverelix TFA IM Maintenance Dose = 120 mg teverelix TFA SC every 6 weeks If this dosing regimen is unsuccessful (more than 2 (of 20) patients fail treatment) then recruitment to Group 1 will end and enrollment in Group 2 will open. The dosing regimen that may be tested (Group 2) is: Loading Dose = 180 mg teverelix TFA SC + 180 mg teverelix TFA IM Maintenance Dose = 180 mg teverelix TFA SC every 6 weeks If this dosing regimen is unsuccessful (more than 6 (of 60) patients fail treatment) then recruitment to Group 2 will end and the study will be terminated.

Official Title
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An Adaptive Phase 2, Open-Label, Multicentre Study Investigating the Pharmacokinetics, Pharmacodynamics, Efficacy and Safety of Teverelix Trifluoroacetate, a GnRH Antagonist, in Participants With Advanced Prostate Cancer

Conditions
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Prostatic Adenoma

Intervention / Treatment
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* Drug: teverelix TFA 120 mg
* Drug: teverelix TFA 180 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is male, aged ≤80 years (≥18 years) at the beginning of the treatment period (Day 0) Has histologically proven advanced adenocarcinoma of the prostate (metastatic or non metastatic hormone-sensitive non curative), suitable for ADT Is treatment naïve for any of the following: a. GnRH analogues b. Androgen receptor antagonists, or c. Androgen synthesis inhibitors (e.g. abiraterone) Agrees to practice contraception during the entire study treatment period and for 3 months after the last dose of IMP is administered: a. Either by using double barrier contraception, b. or, is truly sexually abstinent, when this is in line with the preferred and usual lifestyle of the participant Has provided written (personally signed and dated) informed consent before completing any study-related procedure, which means any assessment or evaluation that would not have formed a part of his normal medical care Exclusion Criteria: Has abnormal screening and/or baseline laboratory values that suggest a clinically significant underlying disease, or the following laboratory values: a. Liver function test (aspartate aminotransferase [ASAT/SGOT], alanine aminotransferase [ALAT/SGPT]), or total bilirubin exceeding twice the upper limit of the normal (ULN) range b. Creatinine twice the ULN range c. Uncontrolled diabetes (HbA1c >7.5%) or previously undiagnosed diabetes mellitus with HbA1c >6.5% Has any contraindication to the use of teverelix TFA Has life expectancy of less than 1 year Has T levels <2.0 ng/mL at screening Has a medical history of bilateral orchidectomy Using any of the following prohibited treatments: a. Within 25 weeks prior to screening: dutasteride b. Within 12 weeks prior to screening: finasteride c. Current use of any of the following: i. Anti-androgen therapy, including T replacement therapy and 5α-reductase inhibitor treatment etc. ii. GnRH analogues, androgen receptor antagonists iii. Androgen synthesis inhibitors (e.g. abiraterone) iv. Any other medication or herbal product that may affect hormone levels and might, therefore, confound interpretation of the study results (e.g. St. John's wort) Has neurological disease, psychiatric disease, drug or alcohol abuse, which could interfere with the participant's proper compliance Has a history of myocardial infarction, unstable symptomatic ischaemic heart disease, any ongoing cardiac arrhythmias of grade >2 (chronic stable atrial fibrillation on stable anticoagulant therapy is allowed), thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other significant cardiac condition (e.g. pericardial effusion, restrictive cardiomyopathy) within 6 months before screening Has congenital long QT syndrome or ECG abnormalities at screening of: a. Q-wave infarction, unless identified ≥6 months before screening b. Fridericia corrected QT interval (QTcF interval) >480 msec. If QTcF is prolonged in a participant with a pacemaker, the participant may be enrolled in the study upon discussion with the project clinician c. If the QTcF interval is 450-480 msec, inclusive, in a participant with current use of medications with known effects on QT interval, the participant may be enrolled in the study following discussion with the Medical Lead Has known or suspected severe renal impairment Has a medical history of diagnosis of, or treatment for, another malignancy within 2 years before the first dose of IMP, or previous diagnosis of another malignancy with evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection Is currently using Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic medications Has uncontrolled hypertension despite appropriate medical therapy (sitting BP of >180 millimetres of mercury [mmHg] systolic and >95 mmHg diastolic at 2 separate measurements taken no more than 60 minutes apart during the screening visit). Participants with isolated systolic BP measurements >180 mmHg may be rescreened. Participants with isolated systolic BP measurements 141 to 180 mmHg or isolated diastolic BP measurements ≥95 mmHg, although eligible, should be referred for further management of hypertension if indicated Has known, previously diagnosed human immunodeficiency virus (HIV) infection, active chronic hepatitis B or C, life-threatening illness unrelated to prostate cancer, or any serious medical condition that could, in the investigator's opinion, potentially interfere with participation in this study. Specific screening for chronic viral illness is at the discretion of the site and/or local Institutional Review Board (IRB) Has been exposed to another investigational drug within the 3 months prior to screening Has anticipated non-availability for study visits/procedures Plans to undergo surgery during the study period Known presence of hepatic metastases

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Adaptive design - enrollment will open in Group 1 (6-weekly dosing regimen). Only if Group 1 dosing regimen is unsuccessful will enrollment open in Group 2 (4-weekly dosing regimen)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Teverelix TFA 120 mg 6-weekly<br>Participants receive teverelix TFA loading dose on Day 0 (120 mg SC + 120 mg IM) and teverelix TFA maintenance doses of 120 mg SC at week 6 and 6-weekly thereafter up to week 24 | Drug: teverelix TFA 120 mg<br>* Teverelix TFA 240 mg Day 0 and 120 mg every 6 weeks from week 6 to week 24<br>|
| Experimental: Teverelix TFA 180 mg 6-weekly<br>Participants receive teverelix TFA loading dose on Day 0 (180 mg SC + 180 mg IM) and teverelix TFA maintenance doses of 180 mg SC at week 6 and 6-weekly thereafter up to week 24 | Drug: teverelix TFA 180 mg<br>* Teverelix TFA 360 mg Day 0 and 180 mg every 6 weeks from week 6 to week 24<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Testosterone (T) levels (castrate) at Week 4 | Proportion of participants achieving castration level with serum T <0.5 ng/mL at Day 28. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Testosterone (T) levels (0.2 ng/mL) at Week 4 | Proportion of participants achieving castration level with serum T <0.2 ng/mL at Day 28 | 4 weeks | 
| Testosterone (T) levels (castrate) at Week 6 | Proportion of participants achieving castration level with serum T <0.5 ng/mL at Day 42 | 6 weeks | 
| Testosterone (T) levels (0.2 ng/mL) at Week 6 | Proportion of participants achieving profound castration level (0.2 ng/mL) with serum T <0.5 ng/mL at Day 42 | 6 weeks | 
| Testosterone levels (castrate) at Week 24 | Proportion of participants achieving a T castration rate over 168 days of treatment period | 24 weeks | 
| Testosterone levels (0.2 ng/mL) at Week 24 | Proportion of participants achieving profound castration rate (<0.2 ng/mL) over 168 days of treatment period | 24 weeks | 
| Time to achieve castrate levels of testosterone (T) | Mean time to T levels falling below castration level (<0.5 ng/mL) for the first time | 4 weeks | 
| Time to escape castrate levels of testosterone (T) | Mean time to (first) overstep of T castration level after achieving castration | 24 weeks | 
| Luteinizing Hormone (LH) levels (castrate) at Week 4 | Proportion of participants achieving castration level for LH (LH <1.1 U/L) at Day 28 | 4 weeks | 
| Luteinizing Hormone (LH) levels (castrate) at Week 24 | Proportion of participants with effective LH castration rate over 168 days of treatment period | 24 weeks | 
| Time to achieve castrate levels of Luteinizing Hormone (LH) | Mean time to LH levels falling below castration level (LH <1.1 U/L) for the first time | 4 weeks | 
| Time to escape castrate levels of Luteinizing Hormone (LH) | Mean time to (first) overstep of LH castration level after achieving castration | 24 weeks | 
| Change in testosterone levels over time | Change in testosterone levels over time | 24 weeks | 
| Change in LH levels over time | Change in LH levels over time | 24 weeks | 
| Change in FSH levels over time | Change in FSH levels over time | 24 weeks | 
| Area under the concentration time-curve from time zero up to the last quantifiable concentration at time point t (AUC0-t) | Area under the concentration time-curve from time zero up to the last quantifiable concentration at time point t (Ct), calculated using the linear up/log down trapezoidal rule. | 24 weeks | 
| Area under the concentration time-curve from time zero up to the concentration at time point t1 after which the concentrations start to rise again towards a second peak (AUC0-t1) | Area under the concentration time-curve from time zero up to the concentration at time point t1 after which the concentrations start to rise again towards a second peak, calculated using the linear up/log down trapezoidal rule. t1 will be determined after review of the concentration-time profiles (immediate release component of total observed AUC). | 24 weeks | 
| Maximum observed plasma teverelix concentration after administration (Cmax) | Maximum observed concentration after administration | 24 weeks | 
| Maximum observed concentration after administration from zero up to time point t1 (Cmax,0-t1) | Maximum observed concentration after administration from zero up to time point t1 | 24 weeks | 
| Maximum observed concentration after administration from time point t1 up to time point t (Cmax,t1-t) | Maximum observed concentration after administration from time point t1 up to time point t | 24 weeks | 
| Time to reach Cmax after dosing (tmax) | Time to reach Cmax after dosing | 24 weeks | 
| Time to reach Cmax,0-t1 after dosing (tmax,0-t1) | Time to reach Cmax,0-t1 after dosing | 24 weeks | 
| Time to reach Cmax,t1-t after dosing (tmax,t1-t) | Time to reach Cmax,t1-t after dosing | 24 weeks | 
| Time of the last quantifiable plasma concentration of teverelix (tlast) | Time of the last quantifiable concentration | 24 weeks | 
| Apparent terminal elimination rate constant (lambda-z) | Apparent terminal elimination rate constant | 24 weeks | 
| Apparent terminal plasma half-life (t½) | Apparent terminal plasma half-life, calculated as: ln 2 / lambda-z | 24 weeks | 
| Area under the concentration time-curve from time zero up to infinity (∞)(AUC0-∞) | Area under the concentration time-curve from time zero up to infinity (∞),calculated using the linear up/log down trapezoidal rule. | 24 weeks | 
| Prostate Specific Antigen (PSA) reduction (≥50 percent) | Number of participants with a PSA response of ≥50 percent reduction at the Day 168 visit | 24 weeks | 
| Prostate Specific Antigen (PSA) reduction (≥120 percent) | Number of participants with a PSA response of ≥120 percent reduction at the Day 168 visit | 24 weeks | 
| Prostate Specific Antigen (PSA) percent reduction over time | Percent change from baseline in serum PSA concentration at each visit | 24 weeks | 
| Prostate Specific Antigen (PSA) reduction over time | Mean serum PSA concentration at each visit | 24 weeks | 
| Luteinizing Hormone (LH) reduction over time | Mean serum LH concentration at each visit | 24 weeks | 
| Testosterone (T) reduction over time | Mean serum T concentration at each visit | 24 weeks | 
| Follicle Stimulating Hormone (FSH) reduction over time | Mean serum FSH concentration at each visit | 24 weeks | 
| Treatment-emergent adverse events (AEs) | Number of participants with treatment-emergent AEs | 24 weeks | 
| Vital signs changes | Mean changes in vital signs at each visit during the 168-day treatment period, compared to baseline | 24 weeks | 
| ECG Conduction Times | ECG Conduction Times | 24 weeks | 
| ECG PR Interval (msec) | ECG PR Interval (msec) | 24 weeks | 
| ECG RR Interval (msec) | ECG RR Interval (msec) | 24 weeks | 
| ECG Ventricular Rate (msec) | ECG Ventricular Rate (msec) | 24 weeks | 
| ECG QRS Duration (bpm) | ECG QRS Duration (bpm) | 24 weeks | 
| ECG QT Interval (msec) | ECG QT Interval (msec) | 24 weeks | 
| ECG QTcF Interval (msec) | ECG QTcF Interval (msec) | 24 weeks | 
| ECG Morphology | ECG Morphology | 24 weeks | 
| Incidence of abnormal laboratory tests results | Incidence of abnormal laboratory tests results | 24 weeks | 
| Injection Site Reactions (ISRs) | Percentage of participants with ISRs at each visit during the 168 days treatment period | 24 weeks |