Phase I Trial of Apalutamide Plus Abiraterone Acetate, Docetaxel, and Prednisone in Patients With mCRPC

Subjects are enrolled in up to three 3-6-subject cohorts and are administered combination
(apalutamide, abiraterone acetate and docetaxel plus prednisone) according to a
dose-escalation schedule. The first dose of docetaxel infusion begins on Day 1 Cycle 1. Daily
oral apalutamide, abiraterone acetate plus twice-daily oral prednisone begins on Day 1 Cycle
1. Docetaxel 1-hour infusions are administered intravenously every 3 weeks (Q3W), preceded by
oral dexamethasone. While a subject is receiving chemotherapy, a treatment cycle is defined
as 21 days. Dose limiting toxicity (DLT) determination is based on toxicities observed within
the initial 2 cycles defined as 6 weeks. DLT will be assessed before the start of the third
docetaxel infusion. Once a combination dose is determined to be safe (i.e. no more than 2 of
6 subjects experience DLT), the next cohort will enroll. Subjects remain at their allocated
combination dose until the maximum tolerated dose (MTD) is determined.

The primary objective is to determine a safe dose combination of apalutamide plus abiraterone
acetate, docetaxel, prednisone in subjects with mCRPC.

Inclusion Criteria:

1. Histologically or cytologically confirmed adenocarcinoma of prostate

2. Documented progressive metastatic CRPC based on at least one of the following
criteria:

1. PSA progression according to Prostate Cancer Working Group 3 (PCWG3) criteria

2. Objective radiographic progression in soft tissue, according to modified Response
Evaluation Criteria In Solid Tumors (RECIST) or bone scans

3. ECOG performance status of 0-2

4. Have serum testosterone < 50 ng/dL. Subjects must continue primary androgen
deprivation with an LHRH/GnRH analogue (agonist/antagonist) if they have not undergone
orchiectomy.

5. Age >18 years.

6. Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count >1,500/cells/mm3

- Hemoglobin ≥10.0 g/dL (independent of transfusion and/or growth factors within 3
months prior to randomization)

- Platelet count >100,000 x 109/uL (independent of transfusion and/or growth
factors within 3 months prior to randomization)

- Serum creatinine <1.5 x upper limit of normal (ULN) or calculated creatinine
clearance ≥ 60 mL/min/1.73 m2 by Cockcroft-Gault

- Serum albumin ≥3.5 g/dL

- Serum potassium ≥3.5 mmol/L

7. Patients must be able to take oral medication without crushing, dissolving or chewing
tablets

8. Ability to understand and the willingness to sign a written informed consent document.

9. Medications known to lower the seizure threshold (see list under prohibited
medications) must be discontinued or substituted at least 4 weeks prior to study drug
initiation.

Exclusion Criteria:

1. Liver Function

- If total bilirubin is >1.5 x ULN (NOTE: in subjects with Gilbert's syndrome, if
total bilirubin is >1.5 x ULN, measure direct and indirect bilirubin and if
direct bilirubin is within normal range, subject may be eligible) or

- Alanine (ALT) or aspartate (AST) aminotransferase >1.5xULN (or >5xULN for subject
with liver metastasis) concomitant with alkaline phosphatase >2.5xULN (or >5xULN
for subjects with bone or liver metastases) or

- Alanine (ALT or aspartate (AST) aminotransferase >2.5xULN (or >5xULN for subjects
with liver metastasis

2. Use of investigational drugs (including vaccines) or implantation of invasive medical
device ≤4 weeks of Cycle 1, Day 1 or current enrollment in investigational drug or
device study

3. Prior exposure to apalutamide. Prior exposure to abiraterone acetate and/or other
CYP17 inhibitors, enzalutamide is allowed (but not preferred) only during the dose
escalation period.

4. Prior chemotherapy for advanced prostate cancer. Prior chemotherapy for any other
disease within 3 years.

5. Prior systemic beta-emitting bone-seeking radioisotopes (i.e. strontium-90).

6. Pre-existing neuropathy ≥Grade 2

7. Systemic azole treatment (e.g. Fluconazole, itracanozole) ≤2 weeks of Cycle 1 Day 1

8. Use of potent inducers or inhibitors of CYP3A4 activity ≤2 weeks prior to Day 1 Cycle
1

9. History of adrenal insufficiency or hyperaldosteronism

10. Active or symptomatic viral hepatitis

11. Chronic liver disease.

12. Brain metastases or leptomeningeal disease

13. Known allergies, hypersensitivity or intolerance to abiraterone acetate, apalutamide,
docetaxel, dexamethasone, prednisone, or their excipients

14. Use of herbal, alternative and food supplements (i.e. PC-Spes, Saw Palmetto, St John
Wort, etc) must be discontinued before treatment start. Daily Multi-vitamin, calcium
and Vitamin D is allowed

15. Surgery or local prostatic intervention within 30 days of first dose. [Note: Any
clinically relevant sequelae from surgery must have resolved prior to Day 1 Cycle 1]

16. Radiation therapy for treatment of prostate cancer ≤4 weeks of Day 1 Cycle 1

17. Current evidence of any of the following:

- Uncontrolled hypertension (defined as blood pressure of >150 mmHg systolic and/or
>100 mmHg diastolic on medication)

- Gastrointestinal disorder affecting absorption

- Active infection (e.g., human immunodeficiency virus [HIV] or viral hepatitis) or
other medical condition that would make prednisone/prednisolone (corticosteroid)
use contraindicated

- Any chronic medical condition requiring a higher dose of corticosteroid than 10
mg prednisone/prednisolone once daily

- Any condition that in the opinion of the investigator, would preclude
participation in this study.

- Patients with baseline severe hepatic impairment (Child Pugh Class C)

18. Severe or unstable angina, myocardial infarction, symptomatic congestive heart
failure, arterial or venous thromboembolic events (e.g., pulmonary embolism,
cerebrovascular accident including transient ischemic attacks), or clinically
significant ventricular arrhythmias within 6 months prior to treatment start or New
York Heart Association (NYHA) Class II to IV heart disease

19. Seizure or known condition that may pre-dispose to seizure (including but not limited
to prior stroke, transient ischemic attack, loss of consciousness within 1 year prior
to randomization, brain arteriovenous malformation; or intracranial masses such as
schwannomas and meningiomas that are causing edema or mass effect).

20. Having partners of childbearing potential and not willing to use a method of birth
control deemed acceptable by the principle investigator and chairperson during the
study and for 1 week after last study drug administration