A Phase 2 Study to Evaluate the Safety and Efficacy of TAK-385, Together With a Leuprorelin Observational Cohort, in Participants With Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy of TAK 385 for achieving and maintaining testosterone suppression (<50 ng/dL).

Detailed Description
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The drug being tested in this study is called relugolix (TAK-385). Relugolix is being tested to treat people who have prostate cancer. This study will look at achieving and maintaining testosterone suppression (<50 ng/dL). The study enrolled 136 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which remained undisclosed to the patient and study doctor during the study (unless there was an urgent medical need): Relugolix 80 mg Relugolix 120 mg Leuprorelin 22.5 mg Relugolix was administered starting with a 320 mg (loading dose), followed by relugolix 80 mg or 120 mg tablets, for 48 weeks plus an optional 48-week extension at the investigator's discretion. Patients randomized to leuprorelin were administered 22.5 mg subcutaneously on Day 1 and every 12 weeks for 4 injections. This multicenter trial was conducted in the United States and Canada. The overall time to participate in this study was 114.4 weeks. Participants made multiple visits to the clinic and at 12 weeks after last dose of study drug for a follow-up assessment.

Official Title
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A Phase 2, Randomized, Open-label, Parallel Group Study to Evaluate the Safety and Efficacy of the Oral GnRH Antagonist TAK-385, Together With a Leuprorelin Observational Cohort, in Patients With Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Relugolix
* Drug: Leuprorelin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Each participant must meet all of the following inclusion criteria to be enrolled in the study: Male participant 18 years or older. Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma. Candidate for androgen deprivation therapy (ADT) for the management of hormone-sensitive prostate cancer with 1 of the following clinical disease states: 1) advanced localized disease not suitable for primary therapy, 2) evidence of prostate-specific antigen (PSA) biochemical or clinical relapse following primary surgery or radiation therapy of curative intent, or 3) newly diagnosed metastatic disease that is asymptomatic or not threatening to vital organs. Appropriate serum testosterone and serum PSA concentration at screening as specified in the protocol. A body mass index (BMI) ≥ 18.0 at screening and/or baseline. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening and/or baseline. Male participants, even if surgically sterilized, who agree to practice effective barrier contraception or agree to practice true abstinence. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care. Suitable venous access for the study-required blood sampling, including pharmacokinetic (PK) and pharmacodynamic (PD) Sampling. Exclusion Criteria Participants meeting any of the following exclusion criteria are not to be enrolled in the study: In participants with advanced, localized M0N1 or M1 disease, the presence of clinically significant symptoms or threat to vital organs requiring immediate gonadotropin-releasing hormone (GnRH) /combined or complete androgen blockade (CAB) therapy, chemotherapy, or radiotherapy. Previously received androgen deprivation therapy (ADT) for more than 8 months total duration (if ADT was received for 8 months or less, then that ADT must have been completed at least 2 years prior to screening). Visceral metastases (liver or lung). Features of the participant's medical condition that may make ADT unnecessary or not indicated. Scheduled for additional surgical or (salvage) radiation therapy within 6 months after baseline evaluations. History of surgical castration. Diagnosis of or treatment for another malignancy within the 2 years before the first dose of study drug, or previously diagnosed with another malignancy and have any 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. Abnormal screening and/or baseline laboratory values as specified in the protocol. History of any significant cardiac condition within 6 months before receiving the first dose of study drug. Electrocardiogram (ECG) abnormalities as specified in the protocol Congenital long QT syndrome. Current use of Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications. Uncontrolled hypertension despite appropriate medical therapy. Participants may be re-screened after referral and further management of hypertension. 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 or psychiatric illness 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). Treatment with any investigational products within 3 months before the first dose of study drug. A primary family member (spouse, parent, child, or sibling of the participant) is involved in the conduct of the study or is a study site employee. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of TAK-385, including difficulty swallowing tablets. Use of any medication, or food products listed in the excluded medications and dietary products table within 2 weeks before the first dose of study drug. Participant must have no history of amiodarone use in the 6 months before the first dose of TAK-385. Admission or evidence of alcohol or drug abuse or use of illicit drugs.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Relugolix 80 mg<br>Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 80 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. | Drug: Relugolix<br>* Relugolix tablets<br>* Other names: TAK-835;|
| Experimental: Relugolix 120 mg<br>Relugolix 320 mg (loading dose), tablets, orally, on Day 1 followed by relugolix 120 mg, tablets, orally, once daily for 48 weeks plus an optional 48 week extension at the investigator's discretion. | Drug: Relugolix<br>* Relugolix tablets<br>* Other names: TAK-835;|
| Active Comparator: Leuprorelin 22.5 mg<br>Leuprorelin 22.5 mg, subcutaneous, injection on Day 1 and every 12 Weeks for up to 4 injections (48 weeks). | Drug: Leuprorelin<br>* Leuprorelin subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Effective Castration Rate Over 24 Weeks | Effective Castration rate is defined as the observed percentage of participants who have testosterone concentrations less than (<) 50 nanogram per deciliter (ng/dL) (1.73 nanomole per liter [nmol/L]) at all scheduled visits beginning after 4 weeks of treatment. | Day 1 of Week 5 to Day 1 of Week 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Related to Vital Signs | Vital signs included oral temperature, pulse rate, supine systolic and diastolic blood pressure, standing systolic and diastolic blood pressure, and weight. Any TEAEs that were associated with vital signs were reported. | From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks | 
| Number of Participants With TEAEs Related to Physical Examination | Physical examination consists of examinations of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) physical examinations other than body systems described in (1) to (10) including slit lamp examination of the anterior eye. Any TEAEs Related to physical examination were reported. | From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks | 
| Number of Participants With TEAEs Related to 12-lead Electrocardiogram (ECG) Findings | A single 12-lead ECG was performed. ECGs were read and interpreted locally and reviewed if indicated by the study monitor. ECG abnormalities were reported as AEs. | From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks | 
| Number of Participants With TEAES Related to Clinical Laboratory Test Results | Abnormal clinical laboratory values (serum chemistry and hematology) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention. | From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks | 
| Number of Participants Reporting One or More Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A SAE is any AE that results in death, is life threatening, requires hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. | From first dose of study drug to 30 days after last dose of study drug up to 106.7 weeks | 
| Percentage of Participants With Prostate-Specific Antigen (PSA) Response of ≥ 50% and ≥ 90% Reduction at 4 Weeks | PSA Response is defined as a reduction in PSA from Baseline and is reported for 2 categories: ≥ 50% reduction and ≥ 90% reduction. | Week 5, Day 1 | 
| Prostate-Specific Antigen Nadir | PSA nadir is the lowest PSA achieved after treatment. | During Weeks 1 to 24 | 
| Serum Prostate-Specific Antigen Concentration at the End of Weeks 12 and 24 | Blood was collected and serum concentrations of PSA were obtained using a validated laboratory test at a central laboratory facility. | Day 1 of Weeks 13 and 25 | 
| Time to Achieve Testosterone Concentrations < 50 ng/dL and < 20 ng/dL |  | During Weeks 1 to 24 | 
| TAK-385 Plasma Concentrations |  | Day 1 of Weeks 1, 2, 3, 5, 9, 13, 17, 25, 37, 49 pre-dose; Day 4 of Week 1 pre-dose; Day 1 of Weeks 5, 13, 2 hrs post-dose | 
| Serum Luteinizing Hormone (LH) Concentrations | Blood was collected and serum concentrations of LH in milli international units per milliliters (mIU/mL) were obtained using a validated laboratory test at a central laboratory facility. | Baseline and Day 4 of Week 1, Day 1 of Weeks 2, 3, 5,13, 25 and 49, End of Treatment (EOT - 106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks) | 
| Serum Follicle Stimulating Hormone (FSH) Concentrations | Blood was collected and serum concentrations of FSH were obtained using a validated laboratory test at a central laboratory facility. | Day 1 of Weeks 2, 5, 13, 25, 49, EOT (106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks) | 
| Serum Sex Hormone-binding Globulin (SHBG) Concentrations | Blood was collected and serum concentrations of SHBG were obtained using a validated laboratory test at a central laboratory facility. | Day 1 of Weeks 2, 5, 13, 25, 49, EOT (106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks) | 
| Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-P25 Score | EORTC QLQ-PR25 is an EORTC module designed to supplement the QLQ-C30 for any application in prostate cancer consisting of 25 questions distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Questions use are answered using a 4-point scale: 1=Not at all to 4 =Very much. All raw domain scores are linearly transformed to a 0 to 100 scale, with higher scores reflecting either more symptoms (urinary, bowel, hormonal treatment-related symptoms) or higher levels of activity or functioning (sexual). A positive change from Baseline in activity or functioning scales and negative change from Baseline in symptom scales indicates improvement. | Baseline and Day 1 of Weeks 5,13, 25, 37 and 49, EOT (106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks) | 
| Percent Change From Baseline of Aging Male Survey (AMS) Total Score | AMS scale is a self-administered questionnaire used to: 1) assess symptoms of aging (independent from those that are disease related) between groups of males under different conditions; 2) evaluate the severity of symptoms over time; and 3) measure changes before and after androgen therapy. Each question was answered between 1=none to 5=extremely severe for 17 items from psychological (5 items), somatic (7 items), and sexual (5 items) categories. Total score is sum of all the item scores and range from 17 (minimum) to 85 (maximum), where high score indicated high level of symptoms. | Baseline and Day 1 of Weeks 5,13, 25, 37 and 49, EOT (106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks) | 
| Change From Baseline in EORTC QLQ-C30 | The EORTC QLQ-C30 included 30 questions comprising 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, nausea/vomiting), single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties) and a global health and QOL scale. Most questions used a 4-point scale (1=Not at all to 4=Very much); 2 questions used a 7-point scale (1= Very poor to 7=Excellent). All domain scores were calculated as an average of item scores and transformed to 0 to 100 score range. A high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status/quality of life (QoL) represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problem. A positive change from Baseline in quality og life or functioning scales and negative change from Baseline in symptom or difficulties scales indicates improvement. | Day 1 of Weeks 5, 13, 25, 37, 49, 73, 97, EOT (106.4 Weeks), Follow-up (110.4 Weeks) and End of Study (114.4 Weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy