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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I Trial of Apalutamide Plus Abiraterone Acetate, Docetaxel, and Prednisone in Patients With Metastatic Castrate Resistant Prostate Cancer (mCRPC)

Conditions
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Prostate Cancer Metastatic

Intervention / Treatment
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* Drug: Apalutamide
* Drug: Abiraterone acetate
* Drug: Docetaxel
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All patients<br>Apalutamide, 120 mg (cohort 1), 240 mg (cohort 2), 180 mg (cohort 3) Abiraterone Acetate 1000mg Prednisone 10mg Docetaxel 75 mg/m2 | Drug: Apalutamide<br>* Orally available, small molecule, nonsteroidal potent and selective antagonist of the androgen receptor. Cohort 1 dose: 120 mg QD Cohort 2 dose: 240 mg QD Cohort 3 dose: 180 mg QD<br>* Other names: ARN-509;Drug: Abiraterone acetate<br>* Abiraterone acetate is the prodrug of the active drug abiraterone. Once absorbed after oral administration, abiraterone acetate is rapidly converted to the active form, abiraterone. Dose: 1000 mg QD<br>* Other names: Zytiga;Drug: Docetaxel<br>* Taxane cytotoxic chemotherapy with demonstrated survival benefit in those with advanced prostate cancer. Dose: 75 mg/m2 Q3W<br>* Other names: Taxotere;Drug: Prednisone<br>* Dose: 5 mg BID<br>* Other names: Deltasone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with dose limiting toxicities (DLT) | Dose limiting toxicities will be measured by using the Common Terminology Criteria for Adverse Events or CTCAE version 4.0 which uses a grading scale from 1-5. | From the time of study drug administration till PSA progression or study completion ( 36 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the number of subjects with prostate-specific antigen (PSA) response |  | Starting after 12 weeks, at the beginning of Week 4 of combination therapy with docetaxel, apalutamide, abiraterone acetate plus prednisone until PSA progression or study completion ( 36 months) | 
| Change in PSA response | PSA response will be captured through blood sample collection and radiographic scans | At the start of treatment until PSA progression or study completion ( 36 months) | 
| Change in the time to PSA progression | PSA progression will be determined by protocol-specific/modified Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria | At the start of treatment until PSA progression or study completion ( 36 months) | 
| Change is radiographic progression-free survival | Radiographic progression will be determined via scans metric of CT, MRI and Bone scans | Images will be collected at baseline, 12 weeks and at end of study, an average of 100 months | 
| Change in CellSearch circulating tumor cells (CTC) enumration | CTCs will be collected via blood sample collection | Collected at baseline, 12 weeks and at end of study, an average of 100 months |