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

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.