Safety, Tolerability, and PK of GT0918 (Proxalutamide) in Subjects With Metastatic Castrate Prostate Cancer

GT0918 treatment was initiated with the first dose of 50 mg/day in a cohort of 3 patients, and 6- patients per cohort for the subsequent escalated dose levels at 100 mg, 200 mg, 300 mg, 400 mg, 500 mg and 600 mg/day. Patients received orally administered GT0918 once daily at the indicated doses for 28 consecutive days (4 weeks), followed by a 7-day off-treatment period for PK analysis. This concluded the Cycle 1 treatment. Patients who could not complete the first cycle of 28 days for DLT evaluation were to be considered as early termination and replaced. Upon completion of the Cycle 1 treatment, if no DLT occurred in the cohort of 3 patients, or no more than 1 patient had DLT in cohorts with at least 6 patients, dose escalation was allowed for the subsequent higher dose.

Patients were to receive up to 6 cycles of GT0918 treatments at their assigned dose levels if they were evaluated by the investigator to have no unacceptable toxicity and show evidence of clinical benefit (stable disease or a response) per RECIST v1.1 criteria and PSA assessments. No off-treatment periods were scheduled for the additional cycles from Cycle 2 beyond. Patients had to be evaluated bi-monthly for their eligibility to continue the treatment of additional cycles. Patient evaluations included CT and/or MRI scans performed every 2 cycles (8 weeks), as well as physical examinations, ECOG performance status, PSA measurements, which were performed every 4 weeks. Cycles beyond the 6th cycle were optional for eligible subjects that did not exhibit progressive disease (PD). Eligible patients could be treated for a total of 6 months at their assigned dose level at the investigator's discretion.

Patients would have an End-of-Study (EOS) visit if treatment were discontinued due to intolerable toxicities, disease progression, withdrawal of consent. Safety follow-up for possible delayed drug-related AE or side effects can be performed by phone call or office visit if needed.

Inclusion criteria

• Written informed consent obtained prior to any study-related procedure being performed.
• Subjects at least 18 years of age or older at the time of consent.
• Histologically confirmed metastatic castrate resistant cancer (mCRPC) who progressed after both hormonal therapy (abiraterone or enzalutamide) and chemotherapy (docetaxel, for example); or cannot tolerate either or both of these classes of therapies.
• Ongoing androgen deprivation therapy with a luteinizing hormone-releasing hormone (LHRH) "super-agonist" or antagonist, or bilateral orchiectomy and serum testosterone level < 50 ng/dL (< 0.5 ng/mL, < 1.7 nmol/L) at screening.
• Metastatic disease documented by computed tomography (CT)/magnetic resonance imaging (MRI) or bone scan.
• Progressive disease despite ongoing androgen deprivation or chemotherapy. Progressive disease is defined by 1 or more of the following criteria:

• Subjects with a rising 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.
• Subjects with measurable disease, progression defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
• Subjects with metastatic bone disease, progression defined by 2 or more new lesions in a radionuclide bone scan.
• ECOG performance status of 0-2 (dose escalation phase); ECOG performance status of 0-1 (expansion phase).
• Screening blood counts of the following:

• Absolute neutrophil count ≥ 1500/μL
• Platelets ≥ 100,000/μL
• Hemoglobin > 9 g/dL
• Screening chemistry values of the following:

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

Exclusion criteria

• Subjects with life expectancy less than 3 months.
• Discontinuation of bicalutamide or nilutamide less than 6 weeks, and other antiandrogens less than 4 weeks, abiraterone less than 3 weeks, prior to the start of study medication.
• Prior chemotherapy, radiation, sipuleucel-T or other experimental immunotherapy less than 4 weeks prior to the start of study medication.
• Prior chemotherapies more than 2 lines (Phase II part only) .
• Ongoing acute treatment-related toxicity associated with a previous therapy greater than grade 1 except for grade 2 alopecia or neuropathy.
• History of impaired adrenal gland function (eg, Addison's disease, Cushing's syndrome).
• Known gastrointestinal disease or condition that affects the absorption of GT0918.
• History of congestive heart failure New York Heart Association (NYHA) class III or IV or uncontrolled hypertension at screening.
• History or family history of long QT syndrome.
• History of other malignancy within the previous 3 years, except basal cell or squamous cell carcinoma, or non-muscle invasive bladder cancer.
• Use of systemic glucocorticoid (eg, prednisone, dexamethasone) within 14 days prior to the start of study medication.
• Co-administration of CYP3A4 ligands that serve as substrates or induce or inhibit the enzyme.
• Prior use of any herbal products known to decrease PSA levels (eg, PC-SPES or saw palmetto) within 30 days prior to the start of study medication.
• Major surgery within 30 days prior to the start of study medication.
• Blood transfusion (including blood products) within 1 week of screening.
• Serious persistent infection within 14 days prior to the start of study medication.
• Serious concurrent medical condition including CNS disorders.
• Previous history of difficulty swallowing capsules.
• Known hypersensitivity to GT0918 or its excipients.
• Any condition that, in the opinion of the investigator, would impair the subject's ability to comply with study procedures.