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

• 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