| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Androgen-sensitive advanced prostate cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Serious and advanced prostate cancer in men whose cancer responds to male hormones |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060862 |
| E.1.2 | Term | Prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the ability of relugolix to achieve and maintain serum
testosterone suppression to castrate levels (≤ 50 ng/dL [1.7 nmol/L])
in men with androgen-sensitive advanced prostate cancer. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the time course and change in serum testosterone during
treatment with relugolix;
To evaluate the time course and magnitude of prostate-specific
antigen (PSA) reduction during treatment with relugolix;
To evaluate testosterone recovery following discontinuation of
relugolix;
To evaluate quality of life using validated patient-reported outcome
instruments;
To evaluate the safety of relugolix 120 mg once daily in men with androgen-sensitive advanced prostate cancer;
To evaluate the effect of relugolix and leuprolide acetate on
endocrine pharmacodynamic parameters;
To collect relugolix plasma concentration data to further evaluate
relugolix population pharmacokinetics (PK) and the relationship
between relugolix exposure and serum testosterone; and
To characterize the relugolix plasma PK parameters in a subset of
patients from China and Japan;
PLEASE REFER TO THE PROTOCOL AMENDMENT 3 FOR THE REMAINING LIST OF STUDY OBJECTIVES |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Has voluntarily signed and dated the informed consent form prior to initiation of any screening or study-specific procedures;
2. Is a male aged 18 years or older on the day of signing and dating the informed consent form;
3. Has histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate;
4. Is a candidate for, in the opinion of the investigator, at least 1 year of continuous androgen deprivation therapy for the management of androgen-sensitive advanced prostate cancer with one of the following clinical disease state presentations:
a. Evidence of biochemical (PSA) or clinical relapse following local primary intervention with curative intent, such as surgery, radiation therapy, cryotherapy, or high-frequency ultrasound and not a candidate for salvage treatment by surgery; or b. Newly diagnosed androgen-sensitive metastatic disease; or c. Advanced localized disease unlikely to be cured by - local primary intervention with either surgery or radiation with curative intent; (Note: Radiotherapy, cryotherapy, or high frequency ultrasound are allowed after 2 months of androgen deprivation therapy. Prior palliative radiation to sites other than the prostate bed is permitted.
Note: Once 915 patients are enrolled worldwide, only patients with metastatic advanced prostate cancer will be eligible for the study in all regions except China, where both metastatic and non-metastatic patients will continue to be enrolled.
5. Has a serum testosterone at the Screening visit of ≥ 150 ng/dL (1.5 ng/mL or 5.2 nmol/L);
6. Has a serum PSA concentration at the Screening visit of > 2.0 ng/mL (2.0 μg/L), or, when applicable, post radical prostatectomy of > 0.2 ng/mL (0.2 μg/L) or post radiotherapy, cryotherapy, or high frequency ultrasound > 2.0 ng/mL (2.0 μg/L) above the post interventional nadir; (Note: If patient has had a radical prostatectomy then PSA must be > 0.2 ng/mL (0.2 μg/L) irrespective of any other treatment the patient has had.
7. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at initial screening and at baseline (refer to Appendix 1 of Protocol Amendment 3);
8. Is a male patient who, even if surgically sterilized (ie, status post vasectomy): a. Agrees to use a male condom if having sex with a woman of childbearing potential or a pregnant woman, during the entire study Treatment Period and through 4 months after the last dose of study drug; or b. Agrees to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods for the female partner) and withdrawal are not acceptable
methods of contraception;
9. Must agree not to donate sperm from first dose of study drug through 4 months after the last
dose of study drug;
10. A randomization authorization form has been signed by a study medical monitor approving the patient for randomization into the trial. |
|
| E.4 | Principal exclusion criteria |
1. In investigator’s opinion, is likely to require chemotherapy or surgical therapy for symptomatic disease management within 2 months of initiating androgen deprivation therapy (ADT);
2. Previously received GnRH analog or other form of androgen deprivation therapy (estrogen or antiandrogen) for > 18 months total duration. If ADT was received for ≤ 18 months total duration, then that therapy must have been completed at least 3 months prior to baseline. If the dosing interval of the depot is longer than 3 months, then the prior ADT must been completed at least as long as the dosing interval of the depot;
3. Previous systemic cytotoxic treatment for prostate cancer(e.g. taxane-based regimen);
4. Metastases to brain per prior clinical evaluation;
5. Scheduled for major surgery after baseline;
6. History of surgical castration;
7. Active malignancy beyond prostate cancer with the exception of any of the following: adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ carcinoma of any type; adequately treated Stage I cancer from which the subject is currently in remission and has been in remission for ≥ 2 years; any other cancer from which the subject has been disease-free for ≥ 5 years;
8. Abnormal laboratory values at the Screen visit that suggest a clinically unstable underlying disease, or the following lab values:
a. Serum gamma-GT > 2.0 x upper limit of normal (ULN); b. Serum ALT and/or AST >ULN; c. Total Bil. >ULN (unless secondary to Gilbert’s syndrome or the pattern is consistent with a diagnosis of Gilbert’s syndrome) or; d. Serum creatinine > 2.0 mg/dL (176.8 μmol/L); e. Platelets < 100 x 103/μL or history of bleeding disorder; f. Hemoglobin < 10.0 g/dL (100 g/L); g. WBC < 3 x 103/μL (3 GI/L); h. Absolute neutrophil count<1.5 x 103/μL(1.5 GI/L); 9. HbA1c > 10% in patients previously diagnosed with diabetes. HbA1c > 8% in patients whose diabetes is previously undiagnosed. (Excluded patients may be rescreened after referral and evidence of improved control of their condition); 10. Has jaundice or known current active liver disease from any cause, including hep. A (hep. A virus IgM positive), hep. B (hep. B virus surface antigen [HBsAg] positive), or hep. C (hep. C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid); 11. Known human HIV infection;
12. Any of the following within 6 months before Baseline Day1: a. myocardial infarction b. unstable angina c. unstable symptomatic ischaemic heart disease d. NYHA class 3 or 4 heart failure e. Thromboembolic events (deep vein thrombosis, pulmonary embolism, symptomatic cerebrovascular events f. Any other significant cardiac condition (pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, severe congenital heart disease;
13. These ECG abnormalities are excluded: a. ECG evidence of ischaemia b. Q-wave infarction, unless identified 6 or more months before the Screen visit; c. QTc > 470 msec, measured by Fridericia's formula [QTcF = QT/(RR^0.33)]. If the QTc is prolonged in a patient with a pacemaker, the patient may be enrolled in the study if confirmed by the medical monitor. d. Congenital long QT syndrome. e. Active conduction system abnormalities, e.g.,
• Mobitz II second degree heart block without a permanent pacemaker in place;
• Third degree heart block without permanent pacemaker in place;
• Untreated supraventricular tachycardia (heart rate ≥ 120 beats per minute);
• Clinically significant ventricular arrhythmias such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes;
• Uncontrolled atrial fibrillation (patients with chronic stable atrial fibrillation on stable anticoagulant therapy or patients with stable cardiac rhythm controlled by a pacemaker are allowed);
14. Uncontrolled hypertension despite appropriate medical therapy (sitting blood pressure of greater than 160 mmHg systolic and/or 100 mmHg diastolic at 2 separate measurements no more than 45 minutes apart during the Screen visit). Patients may be re-screened after referral and further management of hypertension;
15. Hypotension indicated by systolic blood pressure< 84 mmHg on 2 repeat measures at least 15 minutes apart, or treated ongoing symptomatic orthostatic hypotension with > 20 mmHg decrease in systolic blood pressure one minute or more after assuming upright position;
16. Bradycardia indicated by a heart rate of < 45 beats per min on the ECG at the Screen or Baseline Day 1;
17. Treatment with any investigational product within 28days or 5 half lives whichever is longer;
18. Previous treatment with relugolix in a clinical study;
19. Patient is a study site employee or is primary family member (spouse, parent, child, sibling) of a site employee involved in study conduct;
PLEASE REFER TO PROTOCOL AMENDMENT 3 FOR REMAINING LIST OF EXCLUSION CRITERIA
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint will be analyzed in the initial 915 patients enrolled to the study.
The primary efficacy endpoint is the sustained castration rate, defined as the cumulative probability of testosterone suppression to ≤ 50 ng/dL (1.7 nmol/L) while on study treatment from Week 5 Day 1 (Study Day 29) through Week 49 Day 1 (Study Day 337). This probability will be estimated for each treatment group using the Kaplan-Meier method with the confidence interval calculated using the exponential Greenwood formula via log-log transformation of the survival function. Patients who discontinue treatment prior to observing a testosterone level > 50 ng/dL (1.7 nmol/L) will be censored at the last testosterone assessment prior to discontinuation.
Detailed censoring rules will be described in the statistical analysis plan. There are 2 separate evaluation criteria for the primary efficacy endpoint to support different regulatory requirements for assessing benefit: Evaluation Criterion 1: to determine whether the sustained castration rate for relugolix is greater than or equal to 90%. The lower bound of the 95% confidence interval for the cumulative probability of sustained testosterone suppression in the relugolix treatment
group will be calculated and must be greater than or equal to 90% to meet this criterion. Evaluation Criterion 2: to establish the non-inferiority of relugolix compared to leuprolide acetate 3-M depot as assessed by the cumulative probability of sustained testosterone suppression. The lower bound of the 95% confidence interval for the
difference in the cumulative probability of sustained testosterone suppression between the 2 treatment groups will be calculated and must be greater than or equal to the noninferiority margin of -10% to meet this criterion. The confidence interval of the treatment difference will be calculated using the formula (please see the study protocol).
The evaluation criteria used for the primary efficacy endpoint assessment will be determined by regional regulatory requirements and will be prespecified in separate regional statistical analysis
plans. The 2-sided type I error rates for the final analyses will be controlled at 0.05 separately for each regional analysis. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
If the result of the primary endpoint is statistically significant, the secondary endpoints will be analyzed. The methods and procedures necessary to maintain a study-wide 2-sided type I error rate of 0.05 across primary and secondary endpoint testing will be described in the statistical analysis plan.
• Castration rate defined as the cumulative probability of testosterone suppression to ≤ 50 ng/dL (1.7 nmol/L) prior to dosing at Week 1 Day 4, and prior to dosing on Week 3 Day 1 will be summarized by treatment group using the Kaplan-Meier method;
• Profound castration rate defined as the cumulative probability of testosterone suppression of ≤ 20 ng/dL (0.7 nmol/L) while on treatment from Week 25 Day 1 through Week 49 Day 1 will be estimated for each treatment group using the Kaplan-Meier method. The difference in the cumulative probabilities between the relugolix group and the leuprolide acetate group will be provided, along with the 95% confidence interval calculated in the same manner as in the primary analysis of the primary endpoint;
• PSA response and percent change from baseline in PSA at Week 3 and Week 5 will be summarized and compared between the relugolix group and the leuprolide acetate group;
• Proportions of patients who have a PSA concentration < 0.2 ng/mL (0.2 μg/L) at Week 25 will be summarized by treatment group. The proportions will be compared between the relugolix group and the leuprolide acetate group by constructing a 95% confidence interval for the difference in proportions;
• Time to testosterone recovery in approximately 100 patients randomized to relugolix and approximately 50 patients randomized to leuprolide acetate who complete 48 weeks of treatment and who do not start alternative androgen deprivation therapy within the following 12 weeks (or within 24 weeks following the last received leuprolide acetate 3-M depot injection) will be compared between the relugolix group and the leuprolide acetate group; Absolute values and changes from baseline in the scores of the EORTC-QLQ-C30 global
health domain and the EORTC-QLQ-PR25 sexual activity and hormonal-treatmentrelated symptom subdomains will be summarized by treatment group. The least square means at Week 49 will be compared between the relugolix group and the leuprolide
acetate group by constructing a 95% confidence interval for the difference in the least square means using a mixed model for repeated measures; and
• Absolute values and changes from baseline of the remaining domains in the EORTC QLQ-C30 and EORTC QLQ-PR25, as well as EQ-5D-5L will be summarized by
treatment group. The least square means at Week 49 will be compared between the relugolix group and the leuprolide acetate group by constructing a 95% confidence interval for the difference in the least square means using a mixed model for repeated measures;
•Time to PSA progression;
FOR REMAINDER OF SECONDARY AND EXPLORATORY ENDPOINTS, PLEASE REFER TO THE PROTOCOL AMENDMENT 3 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Leuprolide acetate (Eligard) |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Canada |
| China |
| Denmark |
| Finland |
| France |
| Germany |
| Italy |
| Japan |
| Korea, Democratic People's Republic of |
| Netherlands |
| New Zealand |
| Poland |
| Slovakia |
| Spain |
| Sweden |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The End of the Treatment is defined as last dose of relugolix. The end of the trial is defined as 12 weeks after the last leuprolide acetate injection. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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