the Safety and Tolerability of Proxalutamide (GT0918) in Subjects With Metastatic Castrate Resistant Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
This study is an open-label, randomized, expanded/phase II study in subjects with metastatic castrate resistant prostate cancer (mCRPC) who progressed after either abiraterone or enzalutamide. 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.

Detailed Description
-----------------
This study is an open-label, randomized, expanded/phase II study in subjects with metastatic castrate resistant prostate cancer (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(proxalutamide) at their assigned dose on an empty stomach until disease progression, intolerable toxicities (AEs), or withdrawn consent.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.

Official Title
-----------------
An Extended/Phase 2, Multi-Center, Randomized, Open-Label Study to Evaluate the Safety and Tolerability of GT0918 in Subjects With Metastatic Castrate Resistant Prostate Cancer (mCRPC) Who Failed Either Abiraterone or Enzalutamide

Conditions
-----------------
Metastatic Castrate Resistant Prostate Cancer (mCRPC)

Intervention / Treatment
-----------------
* Drug: GT0918


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Signed 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. Subjects with histologically confirmed metastatic castrate resistant prostate cancer (mCRPC) who progressed after abiraterone or enzalutamide. 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 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: 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. 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 0-1 Screening blood counts of the following: Absolute neutrophil count ≥ 1500/μL Platelets ≥ 100,000/μL Hemoglobin > 9 g/dL (if asymptomatic). 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 6 months. 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. Subject is willing and able to comply with all protocol required visits and assessments. Exclusion criteria: Discontinuation of enzalutamide or abiraterone less than 3 weeks prior to the start of study medication. Prior chemotherapy, radiation, sipuleucel-T or other experimental immunotherapy less than 3 weeks prior to the start of study medication Prior chemotherapies more than 1 line. 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 (e.g., Addison's disease, Cushing's syndrome). Known gastrointestinal disease or condition that affects the absorption of proxalutamide. 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, or ECG corrected QT interval equal to and over 500 ms (CTCAE grade 2) at baseline. 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 (e.g., prednisone, dexamethasone) within 14 days prior to the start of study medication. Inhaled or topical steroids are allowed. Co-administration of CYP3A4 ligands that serve as substrates or induce or inhibit the enzyme (See Appendix 4 for the list of medications). 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. 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 (See Appendix 5 for drug details). Any condition that, in the opinion of the investigator, would impair the subject's ability to comply with study procedures.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: biological dose group<br>400mg/day of proxalutamide Group 1: Post enzalutamide failure Group 2: Post abiraterone failure | Drug: GT0918<br>* anti-tumor activity<br>* Other names: androgen receptor antagonist;|
| Experimental: Arm 2: MTD dose group<br>500mg/day of proxalutamide Group 1: Post enzalutamide failure Group 2: Post abiraterone failure | Drug: GT0918<br>* anti-tumor activity<br>* Other names: androgen receptor antagonist;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| recommended Phase 2 dose (RP2D) | determine the RP2D for Ph III and/or other confirming studies | 6 month | 
| Number of Patients With Toxicity of proxalutamide | Only adverse events that are possibly, probably or definitely related to study drug are reported | 6 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| >50% PSA suppression | To evaluate proportion of subjects with a > 50% PSA suppression at 12 weeks | 12 weeks | 
| percentage of radiographic disease progression | To evaluate percentage of radiographic disease progression at 6 and 12 months | 6 and 12 months | 
| radiographic and bone progression time | To evaluate time to radiographic and bone progression | 6 month | 
| the time to PSA progression | To evaluate the time to PSA progression | 6 month | 
| exploratory biomarkers: cell free circulating tumor DNA (ct-DNA)/RNA (ct-RNA) | To identify exploratory biomarkers to characterize androgen receptor (AR) inhibition and/or down-regulation by proxalutamide | 6 month | 
| exploratory biomarkers: Circulating tumor cells (CTC) | anti-tumor activities | 6 months |