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

Inclusion Criteria

Histologically or cytologically confirmed adenocarcinoma of prostate

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

PSA progression according to Prostate Cancer Working Group 3 (PCWG3) criteria
Objective radiographic progression in soft tissue, according to modified Response Evaluation Criteria In Solid Tumors (RECIST) or bone scans
ECOG performance status of 0-2
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
Age >18 years

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

Absolute neutrophil count >1,500/cells/mm3
Hemoglobin ≥ 9 g/dL
Platelet count >100,000 x 109/microliter
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 ≥3.2 g/dL
Serum potassium ≥3.5 mmol/L
Patients must be able to take oral medication without crushing, dissolving or chewing tablets
Ability to understand and the willingness to sign a written informed consent document
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
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

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
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
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
Prior chemotherapy for advanced prostate cancer. Prior chemotherapy for any other disease within 3 years
Prior systemic beta-emitting bone-seeking radioisotopes (i.e. strontium-90)
Pre-existing neuropathy ≥Grade 2
Systemic azole treatment (e.g. Fluconazole, itracanozole) ≤2 weeks of Cycle 1 Day 1
Use of potent inducers or inhibitors of CYP3A4 activity ≤2 weeks prior to Day 1 Cycle 1
History of adrenal insufficiency or hyperaldosteronism
Active or symptomatic viral hepatitis
Chronic liver disease
Brain metastases or leptomeningeal disease
Known allergies, hypersensitivity or intolerance to abiraterone acetate, apalutamide, docetaxel, dexamethasone, prednisone, or their excipients
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
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]
Radiation therapy for treatment of prostate cancer ≤4 weeks of Day 1 Cycle 1

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)
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
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)
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