Study of Relugolix in Men With Metastatic Castration-Sensitive Prostate Cancer or Non-Metastatic or Metastatic Castration-Resistant Prostate Cancer

A Phase 1, Three-Part, Open-Label, Parallel-Cohort Safety and Tolerability Study of Relugolix in Combination With Abiraterone Acetate Plus a Corticosteroid, Apalutamide, or Docetaxel With or Without Prednisone in Men With Metastatic Castration-Sensitive Prostate Cancer or Non-Metastatic or Metastatic Castration-Resistant Prostate Cancer

This study is being conducted to assess the safety and tolerability of relugolix with other agents approved for use in combination with androgen deprivation therapy (ADT) for a 12-week treatment period and an additional 40-week safety extension period in men with prostate cancer, either metastatic castration-sensitive prostate cancer (mCSPC) or non-metastatic or metastatic castration-resistant prostate cancer (nmCRPC or mCRPC).

This is a three-part, open-label, parallel-cohort study to assess the safety and tolerability of relugolix as the ADT component in combination treatment with abiraterone acetate plus a corticosteroid in patients with mCSPC or mCRPC (Part 1), apalutamide in patients with mCSPC or nmCRPC (Part 2), or docetaxel with or without prednisone in patients with mCSPC or mCRPC (Part 3).

The study will consist of a 45-day screening period followed by a 12-week treatment period with one of the three combination treatments (Parts 1, 2, or 3). All participants are required to be currently or previously treated with a GnRH receptor antagonist (analog), leuprolide acetate or triptorelin, or a GnRH receptor antagonist, degarelix or relugolix, in combination with either abiraterone plus prednisone (Part 1), apalutamide (Part 2), or docetaxel (Part 3). The study consists of a 12-week primary study treatment period in which safety and tolerability, including assessment of vital sign measurements, ECGs, clinical laboratory tests and reporting of adverse events every 2 to 4 weeks, followed by a 40-week safety extension treatment period during which adverse events and changes to concomitant medications will be reported. The total treatment duration is 52 weeks.

Key Inclusion Criteria:

1. A previous diagnosis of adenocarcinoma of the prostate confirmed by histologic or cytologic evidence and with a documented medical history of either:

   • mCSPC (Parts 1, 2, and 3) defined as having at least two of three risk factors at the baseline (Day 1) visit:

     • Total Gleason score of ≥ 6; and
     • Presence of ≥ 2 metastatic lesions on bone scan; OR
     • Radiologic evidence of measurable visceral metastases with exception of hepatic metastases.

   • nmCRPC (Part 2 only) defined as disease progression despite maintaining castration levels of testosterone with androgen deprivation therapy (ADT), as evidenced by an increase in consecutive prostate-specific antigen (PSA) concentrations (2 measurements, at least one week apart).

   • mCRPC (Parts 1 and 3) defined as disease progression despite maintaining castration levels of testosterone with ADT:

     • An increase in consecutive PSA (2 measurements at least 1 week apart); or
     • Worsening clinical symptoms; or
     • Radiologic evidence demonstrating enlarged metastatic lesions or the development of new metastases.

2. Initiating treatment or currently receiving treatment of leuprolide acetate (3-, 4-, or 6-month injections [intramuscular Lupron or subcutaneous Eligard]) or another GnRH receptor agonist (triptorelin) or a GnRH receptor antagonist (degarelix or relugolix [maximum duration of 3 months]) in combination with:

   • Part 1: abiraterone acetate 1000 mg or fine-particle abiraterone acetate 500 mg once daily plus prednisone 5 mg once daily for participants with mCSPC or twice daily for participants with mCRPC or methylprednisolone 4 mg once daily and in whom abiraterone has been well tolerated (that is, without evidence of hepatotoxicity requiring dose adjustment for abiraterone).
   • Part 2: apalutamide 240 mg once daily and in whom apalutamide has been well tolerated (that is, without a fracture, fall, or seizure episode or need to dose adjust due to any adverse events).
   • Part 3: docetaxel 75 mg/m2 and in whom docetaxel has been well tolerated (that is, no evidence of hypersensitivity reaction, febrile neutropenia or neutrophils < 500 cells/mm3 for more than 1 week, severe or cumulative cutaneous reactions, or moderate neurosensory signs and/or symptoms despite dose reduction). Note: Patients receiving treatment with another agent in addition to docetaxel, such as a steroid synthesis inhibitor or androgen receptor antagonist, may be enrolled.

Key Exclusion Criteria:

A patient will not be eligible for inclusion in the study if any of the following criteria apply:

1. A medical history of brain or hepatic metastases based on radiologic evidence or a medical history of surgical castration;

2. Received combination treatment with a GnRH analog or GnRH receptor antagonist with either abiraterone acetate plus a corticosteroid (Part 1) or apalutamide (Part 2) in patients with mCSPC (Part 1 and Part 2) or nmCRPC (Part 2) for a total duration > 24 months or in patients with mCRPC (Part 1) for a total duration > 6 months;

3. Is scheduled or anticipates being scheduled for major surgery during the study treatment period;

4. A current diagnosis of a malignancy other than prostate cancer, with the exception of any of the following:

   • Adequately treated basal cell carcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of any type;
   • Adequately treated Stage I cancer that is currently in remission and has been in remission for ≥ 2 years;
   • Any other cancer from which the patient has been disease-free for ≥ 3 years;

5. Abnormal clinical laboratory test value(s) at the screening visit or prior to the baseline (Day 1) visit including:

   • Serum creatinine > 2.0 mg/dL;
   • Platelets < 100 × 103/μL;
   • Hemoglobin < 10.0 g/dL;
   • Leukocytes (WBC) < 3 × 103/μL;
   • Absolute neutrophil count < 1.5 × 103/μL;
   • Hemoglobin A1c (HbA1c) > 8%; Note (Part 3 only): Transfusions and/or administration of growth factors are permitted as indicated for the clinical management of docetaxel-related hematologic effects and in accordance with the investigator's judgement.

6. Known hepatic disease, including alcoholic liver disease or viral hepatitis such as hepatitis A (hepatitis A virus IgM positive), chronic hepatitis B (HbsAg positive), or chronic hepatitis C (HCV antibody positive, confirmed by HCV RNA) or clinical signs of hepatic disease such as jaundice;

7. A medical history within 6 months prior to the screening visit or a current diagnosis of any of the following:

   • Myocardial infarction;
   • Unstable angina;
   • Unstable symptomatic ischemic heart disease;
   • Congestive heart failure classified as NYHA class III or IV heart failure;
   • Thromboembolic event(s) (eg, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular event[s]);
   • Any other significant cardiac condition (eg, pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, or severe congenital heart disease);

8. An abnormal ECG;

9. Uncontrolled hypertension;

10. Hypotension;

11. Bradycardia;

12. Positive HIV;

13. Medical history of a bleeding disorder or current clinical evidence of gastrointestinal bleeding or active bleeding from another anatomical location;

14. A medical history within 1 year of the screening visit of drug or alcohol abuse disorder according to Diagnostic and Statistical Manual of Mental Disorders V;

15. Received an investigational drug within 28 days or 5 half-lives, whichever is longer, prior to the baseline (Day 1) visit;

16. Prior use of any prohibited medication(s) and restrictive medication(s) without the appropriate washout period or use of a prohibited medication during the study treatment period is planned;

17. A contraindication or known history of hypersensitivity to any of the study treatments or components thereof, or has a history of drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates study participation;

18. Any other medical or psychiatric condition that, in the opinion of the investigator, would interfere with accomplishing the study objectives or the patient completing the study;

19. Is a study site employee or is a primary family member (spouse, parent, child, or sibling) of a site employee involved in the conduct of the study.