Teverelix Evaluated in Advanced Prostate Cancer

Phase 2

Completed

Conditions: Prostatic Adenoma

Interventions: Drug: teverelix TFA 180 mg
Drug: teverelix TFA 120 mg

Registration Number: NCT04693507

Lead Sponsor: Antev Ltd.

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

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 50

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Teverelix TFA 180 mg 6-weekly	teverelix TFA 180 mg	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
Teverelix TFA 120 mg 6-weekly	teverelix TFA 120 mg	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

Primary Outcome Measures

Name	Time	Method
Testosterone (T) Levels (Castrate) at Week 4	4 weeks	Proportion of participants achieving castration level with serum T \<0.5 ng/mL at Day 28.

Secondary Outcome Measures

Name	Time	Method
PSA Response ≥50% at Day 168	24 weeks	The number of subjects with a PSA response ≥50% at Day 168
Testosterone (T) Levels (0.2 ng/mL) at Week 4	4 weeks	Proportion of participants achieving castration level with serum T \<0.2 ng/mL at Day 28
Testosterone (T) Levels (Castrate) at Week 6	6 weeks	Proportion of participants achieving castration level with serum T \<0.5 ng/mL at Day 42
Testosterone Levels (0.2 ng/mL) at Week 24	24 weeks	Proportion of participants achieving profound castration rate (\<0.2 ng/mL) over 168 days of treatment period
Time to Achieve Castrate Levels of Testosterone (T)	4 weeks	Mean time to T levels falling below castration level (\<0.5 ng/mL) for the first time
Testosterone (T) Levels (0.2 ng/mL) at Week 6	6 weeks	Proportion of participants achieving profound castration level (0.2 ng/mL) with serum T \<0.5 ng/mL at Day 42
Testosterone Levels (Castrate) at Week 24	24 weeks	Proportion of participants achieving a T castration rate over 168 days of treatment period
Time to Escape Castrate Levels of Luteinizing Hormone (LH)	24 weeks	Mean time to (first) overstep of LH castration level after achieving castration
Time to Escape Castrate Levels of Testosterone (T)	Approximately 30 weeks	Mean time to (first) overstep of T castration level after achieving castration
Luteinizing Hormone (LH) Levels (Castrate) at Week 4	4 weeks	Proportion of participants achieving castration level for LH (LH \<1.1 U/L) at Day 28
Luteinizing Hormone (LH) Levels (Castrate) at Week 24	24 weeks	Proportion of participants with effective LH castration rate over 168 days of treatment period
Time to Achieve Castrate Levels of Luteinizing Hormone (LH)	4 weeks	Mean time to LH levels falling below castration level (LH \<1.1 U/L) for the first time
Change in Testosterone Levels Over Time (Change From Baseline at Day 168)	24 weeks	The change in testosterone levels over time (Change from Baseline at Day 168)
Change in LH Levels Over Time	24 weeks	The change in LH levels over time
Change in FSH Levels Over Time	24 weeks	The change in FSH levels over time
Maximum Observed Plasma Teverelix Concentration After Administration (Cmax)	24 weeks	The maximum observed plasma teverelix concentration after administration (Cmax)
Time to Reach Cmax,0-t1 After Dosing (Tmax,0-t1)	24 weeks	The time to reach Cmax,0-t1 after dosing (tmax,0-t1)
Area Under the Concentration Time-curve From Time Zero up to the Last Quantifiable Concentration at Time Point t (AUC0-t)	24 weeks	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.
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)	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, 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).
Maximum Observed Concentration After Administration From Zero up to Time Point t1 (Cmax,0-t1)	24 weeks	The maximum observed concentration after administration from zero up to time point t1 (Cmax,0-t1)
Time to Reach Cmax After Dosing (Tmax)	24 weeks	The time to reach Cmax after dosing (tmax)
Prostate Specific Antigen (PSA) Reduction (≥50 Percent)	24 weeks	Number of participants with a PSA response of ≥50 percent reduction at the Day 168 visit
Maximum Observed Concentration After Administration From Time Point t1 up to Time Point t (Cmax,t1-t)	24 weeks	The maximum observed concentration after administration from time point t1 up to time point t (Cmax,t1-t)
Time to Reach Cmax,t1-t After Dosing (Tmax,t1-t)	24 weeks	The time to reach Cmax,t1-t after dosing (tmax,t1-t)
Apparent Terminal Elimination Rate Constant (Lambda-z)	24 weeks	The apparent terminal elimination rate constant (lambda-z)
Apparent Terminal Plasma Half-life (t½)	24 weeks	Apparent terminal plasma half-life, calculated as: ln 2 / lambda-z
Area Under the Concentration Time-curve From Time Zero up to Infinity (∞)(AUC0-∞)	24 weeks	Area under the concentration time-curve from time zero up to infinity (∞),calculated using the linear up/log down trapezoidal rule.
PSA Response Rate at Day 28	24 weeks	PSA response is defined as \>50% decline in PSA at Day 28. PSA response rate is the number of subjects with a PSA response.
Luteinizing Hormone (LH) Mean % Reduction at Day 168	24 weeks	Luteinizing Hormone (LH) - the mean % reduction at Day 168
Injection Site Reactions (ISRs)	24 weeks	Number of participants with ISRs at each visit during the 168 days treatment period
Testosterone (T) Mean % Reduction at Day 168	24 weeks	Testosterone (T) - the mean % reduction at Day 168
Follicle Stimulating Hormone (FSH) Mean % Reduction at Day 168	24 weeks	Follicle Stimulating Hormone (FSH) - the mean % reduction at Day 168
Treatment-emergent Adverse Events (AEs)	24 weeks	Number of participants with treatment-emergent AEs
ECG QTcF Interval Prolongation >450 Msec at Day 28	24 weeks	ECG QTcF Interval prolongation \>450 msec at Day 28 study visit

Trial Locations

Locations (4): Klaipeda University Hospital
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Klaipeda, Lithuania
National Cancer Institute
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Vilnius, Lithuania
Vilnius University Hospital Santaros Clinic
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Vilnius, Lithuania
Hospital of Lithuanian University of Health Sciences Kaunas Clinics
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Kaunas, Lithuania