Clinical Trials /

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

NCT02913196

Description:

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.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 1509016578
  • NCT ID: NCT02913196

Conditions

  • Prostate Cancer Metastatic

Interventions

DrugSynonymsArms
ApalutamideARN-509All patients
Abiraterone acetateZytigaAll patients
DocetaxelTaxotereAll patients
PrednisoneDeltasoneAll patients

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
All patientsExperimentalApalutamide, 120 mg (cohort 1), 240 mg (cohort 2), 180 mg (cohort 3) Abiraterone Acetate 1000mg Prednisone 10mg Docetaxel 75 mg/m2
  • Apalutamide
  • Abiraterone acetate
  • Docetaxel
  • Prednisone

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:

               -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v4.0.
Time Frame:Until PSA progression or study completion (~36 months)
Safety Issue:
Description:Determining a safe dose combination and related toxicities of apalutamide plus abiraterone acetate, docetaxel, prednisone in subjects with mCRPC.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Weill Medical College of Cornell University

Last Updated

January 11, 2019