Clinical Trials /

Study of Apalutamide and Abiraterone Acetate in Castration-Resistant Bone Metastatic Prostate Cancer Patients

NCT03360721

Description:

The goal of this clinical research study is to learn if apalutamide in combination with abiraterone acetate and prednisone can help to control metastatic (has spread) castration-resistant prostate cancer (mCRPC) that has a certain type of biomarker in the tumor. Biomarkers are found in the blood/tissue and may be related to your reaction to the study drug(s). This is an investigational study. Apalutamide is not FDA approved or commercially available. It is currently being used for research purposes. The combination of abiraterone acetate and prednisone is FDA approved and commercially available for the treatment of mCRPC. The study doctor can explain how the study drugs are designed to work. Up to 60 participants will be enrolled in this study. All will take part at MD Anderson.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Apalutamide and Abiraterone Acetate in Castration-Resistant Bone Metastatic Prostate Cancer Patients
  • Official Title: A Phase 2, Study of Apalutamide and Abiraterone Acetate in Castration-Resistant Bone Metastatic Prostate Cancer Patients Evaluating a Predetermined Biomarker Signature

Clinical Trial IDs

  • ORG STUDY ID: 2017-0060
  • SECONDARY ID: NCI-2018-01054
  • NCT ID: NCT03360721

Conditions

  • Castration-resistant Prostate Cancer
  • Metastatic Castration Resistant Prostate Cancer

Interventions

DrugSynonymsArms
Abiraterone Acetate 250 MG Oral Tablet [Zytiga]ZytigaAbiraterone Acetate + Apalutamide
ApalutamideARN-509Abiraterone Acetate + Apalutamide
PrednisoneAbiraterone Acetate + Apalutamide

Purpose

The goal of this clinical research study is to learn if apalutamide in combination with abiraterone acetate and prednisone can help to control metastatic (has spread) castration-resistant prostate cancer (mCRPC) that has a certain type of biomarker in the tumor. Biomarkers are found in the blood/tissue and may be related to your reaction to the study drug(s). This is an investigational study. Apalutamide is not FDA approved or commercially available. It is currently being used for research purposes. The combination of abiraterone acetate and prednisone is FDA approved and commercially available for the treatment of mCRPC. The study doctor can explain how the study drugs are designed to work. Up to 60 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed Description

      Study Drug Administration:

      Each study cycle is 28 days.

      If you are found to be eligible to take part in this study, you will take 4 apalutamide
      tablets by mouth 1 time at about the same time each day with or without food.

      You will take 4 abiraterone acetate tablets by mouth 1 time at about the same time every day.
      Do not eat for at least 2 hours before your dose and for at least 1 hour after the dose of
      abiraterone acetate.

      You will take prednisone by mouth 1 time every day. You can take the dose with or without
      food, but it is recommended that you take prednisone with a meal.

      You may take these tablets together, when possible. All tablets should be swallowed whole and
      not crushed or chewed.

      If you overdose (take 2 days of study drugs or more in 24 hours), contact the study doctor
      right away.

      Length of Study:

      You may continue taking the study drugs for as long for as long as the doctor thinks it is in
      your best interest. You will no longer be able to take the study drug if the disease gets
      worse, if intolerable side effects occur, or if you are unable to follow study directions.

      Your participation on the study will be over after the follow-up visit.

      Study Visits:

      On Day 1 of Week 1:

        -  You will have a physical exam.

        -  You will have an EKG.

        -  Blood (about 3-4 teaspoons) will be drawn for routine testing and to check for genetic
           mutations (changes).

      On Day 1 of Week 4 and then every 4 weeks starting at Week 9 (Weeks 13, 17, 21, and so on):

        -  You will have a physical exam

        -  You will have an EKG (Weeks 5 and 9).

        -  Blood (about 3-4 teaspoons) will be drawn for routine testing and to check your PSA
           levels. During Week 9, this sample will also be used to check your testosterone levels.

      On Day 1 of Week 13 and every 12 weeks after that (Weeks 25, 37, 49, and so):

        -  You will have an EKG.

        -  Blood (about 3 teaspoons) will be drawn for routine testing.

        -  At Week 13 only, you will have a chest x-ray, MRI, and a bone scan to check the status
           of the disease. If the chest x-ray shows signs of disease, you will also have a chest CT
           scan.

      End-of-Treatment Visit:

      As soon as possible after your last dose of study drugs:

        -  You will have a physical exam.

        -  You will have an EKG.

        -  Blood (about 3-4 teaspoons) will be drawn for routine testing and to check your PSA and
           testosterone levels.

        -  You will have a CT scan or MRI.

      Follow-Up Visit:

      Within 30 days after your last dose of study drug:

        -  You will have a physical exam.

        -  You will have an EKG.

        -  Blood (about 3 teaspoons) will be drawn for routine tests.
    

Trial Arms

NameTypeDescriptionInterventions
Abiraterone Acetate + ApalutamideExperimentalAbiraterone acetate 1,000 mg (4 x 250 mg tablets each) orally, Apalutamide 240 mg (4 x 60 mg tablets) orally and Prednisone 5 mg orally, all daily for four week course.
  • Abiraterone Acetate 250 MG Oral Tablet [Zytiga]
  • Apalutamide
  • Prednisone

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically or cytologically confirmed adenocarcinoma of the prostate without
             neuroendocrine differentiation or small cell features;

          2. Presence of metastatic disease that can be biopsied by any methodology applicable

          3. Ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH)
             analogue or orchiectomy (i.e., surgical or medical castration);

          4. Serum testosterone level </= 50 ng/dL at the Screening visit;

          5. Patients receiving bisphosphonate or denosumab therapy must have been on stable doses
             for at least 4 weeks prior to screening

          6. Progressive disease defined as one or more of the following three criteria (NOTE:
             Patients who received an antiandrogen must demonstrate disease progression following
             discontinuation of antiandrogen): - PSA progression defined by a minimum of two rising
             PSA levels with an interval of >/= 1 weeks between each determination. The PSA value
             at the Screening visit should be >/= 2 ng/mL - Soft tissue disease progression as
             defined by the Response Evaluation Criteria in Solid Tumors (RECIST) - Bone disease
             progression defined by two or more new lesions on bone scan.

          7. Patients previously treated with chemotherapy must have no more than two prior
             chemotherapy regimens for the treatment of metastatic prostate cancer;

          8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;

          9. Serum Albumin >/= 3.0 g/dL

         10. Serum potassium >/= 3.5 mmol/L

         11. Estimated life expectancy of >/= 6 months;

         12. Able to swallow the study drug and comply with study requirements;

         13. Willing and able to give informed consent.

         14. Tumor specimen obtained prior to treatment initiation by interventional radiology
             guided biopsy will be interrogated per IHC and features should be as follows for a
             patient to be eligible. - overexpression of AR-C terminal and AR-N terminal and PTEN
             with lack of ARV7 expression along with and ki67 <=10%, no RB loss or p53 mutation and
             no expression of neuroendocrine markers CD56 and chromogranin (all markers assessed by
             standardized IHC protocols)

         15. Agrees to use a condom (even men with vasectomies) and another effective method of
             birth control if he is having sex with a woman of childbearing potential or agrees to
             use a condom if he is having sex with a woman who is pregnant while on study drug and
             for 3 months following the last dose of study drug. Must also agree not to donate
             sperm during the study and for 3 months after receiving the last dose of study drug.

        Exclusion Criteria:

          1. Known allergy to the study drugs or any of its components.

          2. Severe, concurrent disease, infection, or co-morbidity that, in the judgment of the
             investigator, would make the patient inappropriate for enrollment or other medical
             condition that would make prednisone/prednisolone (corticosteroid) use
             contraindicated.

          3. Metastases in the brain;

          4. Absolute neutrophil count < 1000/µL, platelet count </= 100,000 x 10^9/µL, and
             hemoglobin < 9 g/dL at the Screening visit; (NOTE: patients may not have received any
             growth factors or blood transfusions within seven days of the hematologic laboratory
             values obtained at the Screening visit);

          5. Total bilirubin (Tbili), >1.5 times the upper limit of normal alanine aminotransferase
             (ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal at the
             Screening visit;

          6. Creatinine (Cr) > 2 mg/dL at the Screening visit;

          7. History of another malignancy within the previous 2 years with >30 % probability of
             relapse other than curatively treated non-melanomatous skin cancer;

          8. Treatment with androgen receptor antagonists (bicalutamide, flutamide, nilutamide),
             5-alpha reductase inhibitors (finasteride, dutasteride), estrogens, chemotherapy, or
             biologic therapy within 4 weeks of enrollment (Day 1 visit)

          9. Radiation therapy within 3 weeks (if single fraction of radiotherapy within 2 weeks)
             of enrollment (Day 1 visit);

         10. Planned palliative procedures for alleviation of bone pain such as radiation therapy
             or surgery;

         11. Structurally unstable bone lesions suggesting impending fracture;

         12. History of seizure or any condition that may increase the patient's seizure risk.
             Also, history of loss of consciousness or transient ischemic attack within 12 months
             of Day 1;

         13. Clinically significant cardiovascular disease including: - Myocardial infarction
             within 6 months - Uncontrolled angina within 6 months; - Congestive heart failure New
             York Heart Association (NYHA) class 3 or 4 in the past, or history of anthracycline or
             anthracenedione (mitoxantrone) treatment, unless a screening echocardiogram or
             multi-gated acquisition scan (MUGA) performed within three months results in a left
             ventricular ejection fraction that is >/= 45%; - History of clinically significant
             ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation,
             torsades de pointes);

         14. Continued from 13) Prolonged corrected QT interval by the Fridericia correction
             formula (QTcF) on the screening Electrocardiogram (ECG) > 470 msec; - History of
             Mobitz II second degree or third degree heart block without a permanent pacemaker in
             place; - Hypotension (systolic blood pressure <86 millimeters of mercury or
             bradycardia with a heart rate of <50 beats per minute on any ECG taken at the
             Screening visit; - Bradycardia with a heat rate of <50 beats per minutes in the
             Screening ECG, unless pharmaceutically induced and reversible; - Uncontrolled
             hypertension as indicated by a resting systolic blood pressure >170 mmHg or diastolic
             blood pressure >105 mmHg at the Screening visit.

         15. Have used or plan to use from 30 days prior to enrollment (Day 1 visit) through the
             end of the study the following medications known to lower the seizure threshold: -
             Aminophylline/theophylline; - Atypical antipsychotics (e.g., clozapine, olanzapine,
             risperidone, ziprasidone); - Bupropion; - Insulin; - Lithium; - Pethidine; -
             Phenothiazine antipsychotics (e.g., prochlorperazine (compazine), chlorpromazine, -
             mesoridazine, thioridazine); - Tricyclic and tetracyclic antidepressants (e.g.,
             amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine).

         16. Prior use of ketoconazole, enzalutamide, abiraterone or apalutamide or participation
             in a previous clinical trial of ketoconazole, enzalutamide, abiraterone or
             apalutamide.

         17. Use of an investigational agent within 4 weeks of enrollment (Day 1)

         18. Gastrointestinal disorder affecting absorption (e.g., gastrectomy)

         19. Major surgery within 4 weeks prior to enrollment (Day 1);

         20. History of significant bleeding disorder unrelated to cancer, including: - Diagnosed
             congenital bleeding disorders (e.g., von Willebrand's' disease) - Diagnosed acquired
             bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) -
             History of GI bleeding within one year.

         21. Active or symptomatic viral hepatitis or chronic liver disease

         22. Known history of pituitary or adrenal dysfunction

         23. Baseline moderate and severe hepatic impairment (Child Pugh Class B & C)

         24. Avoid concomitant strong CYP3A4 inducers during abiraterone acetate treatment. If a
             strong CYP3A4 inducer must be co-administered, increase the abiraterone acetate dosing
             frequency.

         25. Avoid co-administration of abiraterone acetate with CYP2D6 substrates that have a
             narrow therapeutic index. If an alternative treatment cannot be used, exercise caution
             and consider a dose reduction of the concomitant CYP2D6 substrate.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:Up to 3 years
Safety Issue:
Description:PFS is defined as the time from enrollment until radiographic progression (event), death from any cause (event), start of other therapy (censor) or last follow-up without progression (censor), whichever comes first.

Secondary Outcome Measures

Measure:Summary of Most Common Adverse Events
Time Frame:Up to 3 years
Safety Issue:
Description:Adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) v4.03 with grade and attribution to study drug
Measure:Composite progression free survival (PFSc)
Time Frame:Up to 3 years
Safety Issue:
Description:Composite progression free survival (PFSc) is defined as the time from protocol treatment start until PCWG2 progression (radiographic progression, PSA Progression, or clinical deterioration - event), death (event), starting new treatment (censor) or last follow-up without PCWG2 progression (censor), whichever comes first.
Measure:Overall Survival (OS)
Time Frame:Up to 3 years
Safety Issue:
Description:Overall Survival is the time from protocol treatment start until death (event) or last contact (censor)
Measure:Biomarkers: androgen expression signaling and survival escape pathway signaling
Time Frame:Up to 3 years
Safety Issue:
Description:Marker Evaluable Set (MES) where the MES will consist of all patients with baseline and Week 9 laboratory results derived from bone marrow samples. The number of patients with evaluable results may differ for each laboratory parameter. The MES will be used to assess the effect of treatment with apalutamide on androgen signaling and expression of survival/escape pathways in the bone marrow.
Measure:Primary Analysis Set (PAS)
Time Frame:Up to 3 years
Safety Issue:
Description:The PAS will consist of all patients who received at least one dose of any drug of the study combination treatment. This set will be used for all survival endpoints as well as safety. PSA will be measured at each time point according to the assessment schedule.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • mCRPC
  • metastatic castration resistant prostate cancer
  • nonsteroidal antiandrogen
  • androgen signaling

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