Clinical trial NCT04693507: Teverelix Evaluated in Advanced Prostate Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prostatic Adenoma
Lead sponsor: Antev Ltd.
Sponsor class: INDUSTRY
First posted: 2021-01-05
Enrollment: 50
Sex: MALE
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention 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)
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Testosterone (T) Levels (Castrate) at Week 4
timeFrame: 4 weeks
Secondary outcomes:
measure: Testosterone (T) Levels (0.2 ng/mL) at Week 4
timeFrame: 4 weeks
measure: Testosterone (T) Levels (Castrate) at Week 6
timeFrame: 6 weeks
measure: Testosterone (T) Levels (0.2 ng/mL) at Week 6
timeFrame: 6 weeks
measure: Testosterone Levels (Castrate) at Week 24
timeFrame: 24 weeks
measure: Testosterone Levels (0.2 ng/mL) at Week 24
timeFrame: 24 weeks
measure: Time to Achieve Castrate Levels of Testosterone (T)
timeFrame: 4 weeks
measure: Time to Escape Castrate Levels of Testosterone (T)
timeFrame: Approximately 30 weeks
measure: Luteinizing Hormone (LH) Levels (Castrate) at Week 4
timeFrame: 4 weeks
measure: Luteinizing Hormone (LH) Levels (Castrate) at Week 24
timeFrame: 24 weeks
measure: Time to Achieve Castrate Levels of Luteinizing Hormone (LH)
timeFrame: 4 weeks
measure: Time to Escape Castrate Levels of Luteinizing Hormone (LH)
timeFrame: 24 weeks
measure: Change in Testosterone Levels Over Time (Change From Baseline at Day 168)
timeFrame: 24 weeks
measure: Change in LH Levels Over Time
timeFrame: 24 weeks
measure: Change in FSH Levels Over Time
timeFrame: 24 weeks
measure: Area Under the Concentration Time-curve From Time Zero up to the Last Quantifiable Concentration at Time Point t (AUC0-t)
timeFrame: 24 weeks
measure: 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)
timeFrame: 24 weeks
measure: Maximum Observed Plasma Teverelix Concentration After Administration (Cmax)
timeFrame: 24 weeks
measure: Maximum Observed Concentration After Administration From Zero up to Time Point t1 (Cmax,0-t1)
timeFrame: 24 weeks
measure: Maximum Observed Concentration After Administration From Time Point t1 up to Time Point t (Cmax,t1-t)
timeFrame: 24 weeks
measure: Time to Reach Cmax After Dosing (Tmax)
timeFrame: 24 weeks
measure: Time to Reach Cmax,0-t1 After Dosing (Tmax,0-t1)
timeFrame: 24 weeks
measure: Time to Reach Cmax,t1-t After Dosing (Tmax,t1-t)
timeFrame: 24 weeks
measure: Apparent Terminal Elimination Rate Constant (Lambda-z)
timeFrame: 24 weeks
measure: Apparent Terminal Plasma Half-life (t½)
timeFrame: 24 weeks
measure: Area Under the Concentration Time-curve From Time Zero up to Infinity (∞)(AUC0-∞)
timeFrame: 24 weeks
measure: Prostate Specific Antigen (PSA) Reduction (≥50 Percent)
timeFrame: 24 weeks
measure: PSA Response Rate at Day 28
timeFrame: 24 weeks
measure: PSA Response ≥50% at Day 168
timeFrame: 24 weeks
measure: Luteinizing Hormone (LH) Mean % Reduction at Day 168
timeFrame: 24 weeks
measure: Testosterone (T) Mean % Reduction at Day 168
timeFrame: 24 weeks
measure: Follicle Stimulating Hormone (FSH) Mean % Reduction at Day 168
timeFrame: 24 weeks
measure: Treatment-emergent Adverse Events (AEs)
timeFrame: 24 weeks
measure: ECG QTcF Interval Prolongation >450 Msec at Day 28
timeFrame: 24 weeks
measure: Injection Site Reactions (ISRs)
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Kaunas
country: Lithuania
facility: Hospital of Lithuanian University of Health Sciences Kaunas Clinics
city: Klaipeda
country: Lithuania
facility: Klaipeda University Hospital
city: Vilnius
country: Lithuania
facility: National Cancer Institute
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital Santaros Clinic
Study officials:
affiliation: National Cancer Institute, Vilnius, Lithuania
name: Albertas Ulys, MD
role: PRINCIPAL_INVESTIGATOR
References: