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

This is a multi-center, Phase I study of apalutamide in combination with abiraterone acetate, docetaxel and prednisone in patients with metastatic mastrate resistant prostate cancer (mCRPC).

This study is designed to determine the dose that apalutamide can be administered safely in combination with abiraterone acetate, docetaxel and prednisone.

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.

Eligibility Criteria:
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:

   1. Absolute neutrophil count \>1,500/cells/mm3
   2. Hemoglobin ≥ 9 g/dL
   3. Platelet count \>100,000 x 109/microliter
   4. Serum creatinine \<1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min/1.73 m2 by Cockcroft-Gault
   5. Serum albumin ≥3.2 g/dL
   6. 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
10. Patients on stable dose of bisphosphonates or RANK-L inhibitor, Denosumab, which have been started no less than 4 weeks prior to treatment start, may continue on this medication

Exclusion Criteria

1. Liver Function

   1. 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
   2. 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
   3. 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 or \<5 half-lives 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:

    1. Uncontrolled hypertension (defined as blood pressure of \>150 mmHg systolic and/or \>100 mmHg diastolic on medication)
    2. Gastrointestinal disorder affecting absorption
    3. Active infection (e.g., human immunodeficiency virus \[HIV\] or viral hepatitis) or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated
    4. Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone/prednisolone once daily
    5. Any condition that in the opinion of the investigator, would preclude participation in this study
    6. 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