Evaluation of Safety and Efficacy of KPG-121 Plus Enzalutamide, Abiraterone or Apalutamide in CRPC Patients

Inclusion Criteria:

Signed informed consent provided prior to any study-related procedure being performed;
Able to swallow and retain orally administered medication;
Male aged 18 years and older (adult, older adult) at the time consent is obtained;
Histologically or cytologically confirmed diagnosis of prostate carcinoma;
Men with either non-metastatic or metastatic CRPC are eligible;
Completed at least 4 or more weeks of prior continuous therapy with fixed stable dose enzalutamide, abiraterone or apalutamide prior to initiating study treatment (for Part 1), or with fixed stable dose enzalutamide (for Part 2), with no change in dose for at least 2 weeks prior to screening;
Serum testosterone level <50 ng/dL (<0.5 ng/mL, <7.0 nmol/L). Subjects may have ongoing androgen deprivation therapy (ADT) with a luteinizing hormone-releasing hormone (LHRH) "super-agonist" or antagonist, and/or be surgically or medically castrated;
ECOG performance status of 0 or 1;
Adequate baseline organ function;
Must have a QT interval corrected for heart rate according to Fridericia's formula (QTcF) <470 milliseconds (msec) or <480 msec with bundle branch block;
Male subject with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from time of screening until 3 months after the last dose of study medication;
Willing and able to comply with all protocol required visits and assessments.

Exclusion Criteria:

Life expectancy less than 3 months;
Discontinuation of bicalutamide or nilutamide in less than 6 weeks, and other antiandrogens in less than 4 weeks, prior to the start of study medication;
Prior chemotherapy, radiation (limited radiotherapy to control bone pain is permitted), sipuleucel-T or other experimental immunotherapy less than 4 weeks prior to the start of study medication;
Prior malignancy other than CRPC. Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible;

Screening blood counts with:

absolute neutrophil count <1500/μL
platelets <100,000/μL
hemoglobin <9 g/dL;

Screening chemistry test results with:

alanine aminotransferase (ALT) and aspartate transaminase (AST) >2.5 × ULN
total bilirubin >2 × ULN
for the dose escalation cohort, creatinine clearance of <70 mL/min as determined by Cockcroft and Gault formula
for the dose expansion cohort, subjects with creatinine clearance of <50 mL/min will be excluded (if kidneys are not working properly, there is a risk that KPG-121 may stay in the blood circulation longer than expected and may increase side-effects)
albumin <2.8 g/dL;
Uncontrolled hypothyroidism, or TSH >2.0 x ULN at screening. Subjects who are clinically euthyroid and on stable thyroid replacement therapy for 2 months prior to enrollment are allowed;
Current use of or anticipated requirement during the study of prohibited medication(s), any investigational drug, other anti-cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, or hormone therapy other than for replacement), AR antagonists (e.g., bicalutamide, flutamide, nilutamide), 5-alpha reductase inhibitors (e.g., finasteride, dutasteride), androgens (e.g., testosterone, dihydroepiandrosterone), Herbal medication(s) that may affect PSA levels (e.g., saw palmetto), Other herbal medications including, but not limited to: St. John's wort, kava, ephedra (ma huang), gingko biloba, yohimbe and ginseng);
Any unresolved ≥grade 2 (per CTCAE v5.0) toxicity from previous anti-cancer therapy at the time of enrollment, except for grade 2 alopecia, anemia (if hemoglobin is >9.0 g/dL) or neuropathy;
Any ≥grade 2 hypophosphatemia (per CTCAE v5.0) at the time of enrollment;
Serum calcium ≥grade 1 (per CTCAE v5.0) at time of enrollment, unless ionized calcium is within normal range;
Presence of any clinically significant gastrointestinal (GI) abnormality or other condition(s) that may alter absorption such as malabsorption syndrome or major resection of the stomach or substantial portion of the small intestine;
Active peptic ulcer disease or history of abdominal fistula, GI perforation, or intra abdominal abscess within 28 days prior to enrollment;
Previous history of difficulty swallowing capsules;
Known active infection requiring intravenous (IV) or oral anti-infective treatment or serious persistent infection within 14 days prior to the start of study medication;
Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to the start of study medication;
Laboratory-confirmed SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) infection as determined by RT-PCR (Reverse transcription polymerase chain reaction) or other approved clinical testing;
Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal or cardiac disease);
History of seizure or any condition that may predispose subject to seizure (e.g., prior cortical stroke or significant brain trauma). History of loss of consciousness or transient ischemic attack within 12 months prior to the start of study medication;
Poorly controlled hypertension (defined as systolic BP ≥ 150 mmHg) or diastolic BP >100 mmHg based on a mean of three measurements at approximately 2-minute intervals);
Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to enzalutamide or abiraterone or apalutamide or excipients. Allergy to acetaminophen or NSAIDs;
History of impaired adrenal gland function (e.g., Addison's disease, Cushing's syndrome);
History or evidence of cardiovascular risk including any of the following: Clinically significant ECG abnormalities including second degree (Type II) or third degree atrioventricular block; history of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, stenting, or bypass grafting within 6 months prior to enrolment, Class III or IV heart failure as defined by the New York Heart Association functional classification system, left ventricular ejection fraction (LVEF) below 45% at screening; known cardiac metastases;
Anticoagulants used by subjects with a history of thromboembolic conditions within 6 months prior to enrolment. Note: Subjects receiving anticoagulants for atrial fibrillation are eligible for the study;
Use of systemic glucocorticoid (e.g., prednisone, dexamethasone) within 14 days prior to the start of study medication (except the protocol specified study treatment, such as abiraterone plus low-dose prednisone 5-mg bid);
Serious concurrent medical condition including central nervous system disorders;
Previous major surgery within 30 days prior to the start of study medication;
Blood transfusion (including blood products) within 1 week of screening;
Any condition that, in the opinion of the investigator, would impair the subject's ability to comply with study procedures.