The Safety and Tolerability of GT0918 in Subjects With mHSPC and mCRPC

This was a multiple-center, open-label, randomized, daily dose, two-sequence, expanded/phase II study in subjects with mHSPC or mCRPC who progressed after either abiraterone or enzalutamide treatment.

The objective of the study is to evaluate the safety and tolerability of proxalutamide and determine the RP2D for Ph III and/or other confirming studies.

Subjects will be randomized into the 2 treatment arms.

This study is an open-label, randomized, expanded/phase II study in subjects with mHSPC or mCRPC who progressed after either abiraterone or enzalutamide. All subjects will be randomized to take 400 mg or 500 mg of GT0918 by oral administration once daily on an empty stomach (2-3 hours after a meal) for initial treatment of 6 months. Randomization of subjects will be stratified by prior therapy (abiraterone or enzalutamide).

Subjects will continue treatment with GT0918 (proxalutamide) at their assigned dose on an empty stomach until disease progression, intolerable toxicities (AEs), or withdrawn consent. A post-treatment period of 4 weeks will commence that concludes with an end-of-study visit.

Disease progression will be assessed by three methods over the duration of the study. Subjects will be assessed for biochemical (PSA) progression measured monthly, as well as radiographic progression by CT scan or/and bone progression by radionuclide bone scan every 12-weeks. Progressive disease will be considered on the occurrence of the first assessed progression event. Subjects with PSA progression only may continue the study until radiographic or bone progression at the discretion of the Investigator and with agreement by the sponsor or their authorized medical monitor.

Eligibility Criteria:
Inclusion criteria:

1. Signed informed consent obtained prior to any study-related procedure being performed.
2. Subjects at least 18 years of age or older at the time of consent.
3. Subjects with histologically confirmed mHSPC or mCRPC who received abiraterone or enzalutamide for the hormonal treatment of 6 months or longer.
4. Subjects with mHSPC are required to have no prior ADT (androgen deprivation therapy) or orchiectomy. For mCRPC, ongoing androgen deprivation therapy with a luteinizing hormonereleasing hormone (LHRH) "super-agonist" or antagonist, or bilateral orchiectomy. Serum testosterone level is \< 50 ng/dL (\< 0.5 ng/mL, \< 1.7 nmol/L) at screening.
5. Metastatic disease documented by computed tomography (CT)/magnetic resonance imaging (MRI) or bone scan.
6. Progressive disease despite hormonal treatment with abiraterone or enzalutamide, but not both. However, if either of these 2 drugs was used less than 3 months due to toxicity, the patient is eligible. One line of chemotherapy is eligible. Progressive disease is defined by 1 or more of the following criteria:

   1. Subjects with a rising prostate specific antigen (PSA) value \> 2 ng/mL in at least 2 measurements, at least 1 week apart. If the confirmatory PSA value is less than the screening PSA value, then an additional test for the rising PSA is required to document progression.
   2. Subjects with measurable disease, progression defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
   3. Subjects with metastatic bone disease, progression defined by 2 or more new lesions in a radionuclide bone scan.
7. ECOG performance status of 0-1
8. Screening blood counts of the following:

   1. Absolute neutrophil count ≥ 1500/μL
   2. Platelets ≥ 100,000/μL
   3. Hemoglobin \> 9 g/dL (if asymptomatic).
9. Screening chemistry values of the following:

   1. Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 × upper limit of the normal reference range (ULN)
   2. Total bilirubin ≤ 2 × ULN
   3. Creatinine ≤ 1.5 × ULN
   4. Albumin \> 2.8 g/dL.
10. At screening, life expectancy of at least 6 months.
11. Subjects whose partners are women of childbearing potential (WOCBP) must use an adequate method of birth control while on study drug and for at least 3 months after discontinuation of study drug.
12. Subject is willing and able to comply with all protocol required visits and assessments.

Exclusion criteria:

1. Discontinuation of enzalutamide or abiraterone less than 3 weeks prior to the start of study medication.
2. Prior chemotherapy and experimental therapy (Poly (ADP-ribose) polymerase (PARP) or checkpoint inhibitor)
3. Ongoing acute treatment-related toxicity associated with a previous therapy greater than grade 1 except for grade 2 alopecia or neuropathy.
4. History of impaired adrenal gland function (e.g., Addison's disease, Cushing's syndrome).
5. Known gastrointestinal disease or condition that affects the absorption of proxalutamide.
6. History of congestive heart failure New York Heart Association (NYHA) class III or IV or uncontrolled hypertension at screening.
7. History or family history of long QT syndrome, or ECG corrected QT interval equal to and over 500 ms (CTCAE grade 2) at baseline.
8. History of other malignancy within the previous 3 years, except basal cell or squamous cell carcinoma, or non-muscle invasive bladder cancer.
9. Use of systemic glucocorticoid (e.g., prednisone, dexamethasone) within 14 days prior to the start of study medication. Inhaled or topical steroids are allowed.
10. Co-administration of CYP3A4 ligands that serve as substrates or induce or inhibit the enzyme.
11. Prior use of any herbal products known to decrease PSA levels (e.g., PC-SPES or saw palmetto) within 30 days prior to the start of study medication.
12. Major surgery within 30 days prior to the start of study medication.
13. Blood transfusion (including blood products) within 1 week of screening.
14. Serious persistent infection within 14 days prior to the start of study medication.
15. Serious concurrent medical condition including CNS disorders.
16. Previous history of difficulty swallowing capsules.
17. Known hypersensitivity to GT0918 or its excipients.
18. Any condition that, in the opinion of the investigator, would impair the subject's ability to comply with study procedures.