Safety, Tolerability, PK and Antitumor Activity of KPG-121 Plus Enzalutamide in mCRPC Patients

This Phase 1 study will comprise two parts: Part 1 will be a 3+3 dose escalation design to
characterize the MTD and a RP2D, Part 2 will be an expansion cohort at RP2D. In Part 1,
multiple escalating dose levels of KPG-121 (six cohorts: 1.5, 2.5, 5.0, 10, 20, and 30
mg/day) in combination with enzalutamide will be evaluated to determine the MTD and RP2D of
KPG-121. The MTD is the dose level prior to that which causes ≥33% of subjects to experience
a DLT. Even though an MTD may have been reached, a RP2D may still be selected which will take
into account the MTD as well as the available information on lower grade AEs that occur in
later cycles including safety, efficacy, and PSA data. There will be 6 mid-cycle Safety
Review Meetings that will be held when the first enrolled subject in each cohort reaches Day
14. All safety data collected through that timepoint for that cohort will be reviewed. An
End-of-Treatment (EOT) or Early Termination (ET) visit will be conducted within 14 days of
the last dose of KPG-121, and a Safety Follow-up/End-of-Study (EOS) visit will be conducted
approximately 28 days after the last dose of KPG-121. All subjects will be followed for AEs,
serious adverse events, and concomitant medications (including any new cancer treatments) for
28 days following the last dose of KPG-121. The Part 2, expansion cohort 7, will follow the
same Schedule of Procedures as Part 1 once the RP2D has been decided. For the expansion
cohort of part 2, 6-12 subjects will be given the RP2D once daily for 21 consecutive days
along with oral 4 x 40 mg enzalutamide capsules followed by 7 days without KPG-121 for each
28-day cycle.

Inclusion Criteria:

1. Have provided written informed consent prior to any study-related procedure being
performed;

2. Male of at least 18 years of age or older at the time of consent;

3. Histologically confirmed mCRPC who failed to achieve and/or maintain >90% reduction in
PSA after >3 months of enzalutamide (pre-enzalutamide PSA values must be available);

4. Radiographically stable or better disease while on enzalutamide (no new evidence of
metastatic disease or disease progression) and ongoing treatment on enzalutamide for
>3 months;

5. Subjects who have received a single prior regimen of either abiraterone or apalutamide
(but not both) are eligible if their duration of response (defined as radiographically
non-progressive disease) on these therapies was at least 6 months;

6. Serum testosterone level < 50 ng/dL (< 0.5 ng/mL, < 1.7 nmol/L). Patients 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;

7. ECOG performance status of 0-2;

8. If subject's partner is a woman of childbearing potential (WOCBP), then an adequate
method of birth control should be used while on the study drug and enzalutamide, and
for 3 months post last dose of study drug and enzalutamide; and

9. Willing and able to comply with all protocol required visits and assessments.

Exclusion Criteria:

1. Life expectancy less than 3 months;

2. Discontinuation of bicalutamide or nilutamide less than 6 weeks, and other
antiandrogens less than 4 weeks, prior to the start of study medication;

3. 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 abiraterone acetate and apalutamide use is
permitted);

4. Have an indication for the use of cytotoxic chemotherapy, including marked visceral
disease or substantial pain;

5. Screening blood counts with:

1. absolute neutrophil count <1500/μL

2. platelets <100,000/μL

3. hemoglobin < 9 g/dL;

6. Screening chemistry test results with:

1. alanine aminotransferase (ALT) and aspartate transaminase (AST) >2.5 × ULN

2. total bilirubin >2 × ULN

3. creatinine clearance of <70 mL/min as determined by Cockcroft and Gault formula
for entry into the dose escalation part of the study. In the cohort expansion
part of the study, 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)

4. albumin <2.8 g/dL;

7. Uncontrolled hypothyroidism, or thyroid stimulating hormone (TSH) >2.0 x ULN at
screening. Subjects who are clinically euthyroid and on stable thyroid replacement
therapy for 2 months prior to screening are allowed;

8. Ongoing acute treatment-related toxicity associated with a previous therapy greater
than grade 1 except for grade 2 alopecia or neuropathy;

9. History of impaired adrenal gland function (e.g., Addison's disease, Cushing's
syndrome);

10. History of congestive heart failure New York Heart Association (NYHA) class III or IV,
uncontrolled hypertension or evidence of coronary artery disease (including a
myocardial infarction) within the previous 6 months at screening;

11. History or family history of long QT syndrome or a screening ECG showing a QTc
interval of more than 450 msec;

12. History of other malignancy within the previous 3 years, except basal cell or squamous
cell carcinoma, or non-muscle invasive bladder cancer;

13. Anticoagulants used by subjects with a history of thromboembolic conditions. Note:
Subjects receiving anticoagulants for atrial fibrillation are eligible for the study;

14. Use of systemic glucocorticoid (e.g., prednisone, dexamethasone) within 14 days prior
to the start of study medication;

15. 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;

16. Major surgery within 30 days prior to the start of study medication;

17. Blood transfusion (including blood products) within 1 week of screening;

18. Serious persistent infection within 14 days prior to the start of study medication;

19. Serious concurrent medical condition including central nervous system (CNS) disorders;

20. Previous history of difficulty swallowing capsules;

21. Any condition that, in the opinion of the investigator, would impair the subject's
ability to comply with study procedures;

22. History of or active thromboembolism within last 6 months;

23. Allergy to aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs);

24. History of Stevens-Johnson syndrome; or

25. Baseline left ventricular ejection fraction (LVEF) <45% at Screening; or

26. Prior treatment with any inhibitors of PD-1 or PD-L1 within 3 months.