Clinical trial NCT02867020: Study of Abiraterone Acetate Plus ADT Versus APALUTAMIDE Versus Abiraterone and APALUTAMIDE in Patients With Advanced Prostate Cancer With Non-castrate Testosterone Levels
Official title: Phase II Randomized Study of Abiraterone Acetate Plus ADT Versus APALUTAMIDE Versus Abiraterone and APALUTAMIDE in Patients With Advanced Prostate Cancer With Non-castrate Testosterone Levels
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prostate Cancer
Keywords: apalutamide
abiraterone
prostate cancer
Lead sponsor: Latin American Cooperative Oncology Group
Sponsor class: OTHER
Collaborators: name: Janssen Pharmaceuticals
First posted: 2016-08-15
Enrollment: 128
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Evaluation of the activity, safety and patients reported outcome of ADT plus abiraterone, abiraterone plus APALUTAMIDE (a second-generation antiandrogen) or APALUTAMIDE alone in hormone naïve locally advanced or metastatic prostate cancer which ADT was indicated.

Detailed description: Based on the current guidelines, ADT alone or combined with is antiandrogens are considered the appropriate active therapy for the patient population planned for this study. Recent data showed that chemotherapy also benefit patients in this setting. Even though, there is a clear unmet medical need for alternative treatment option in metastatic hormone sensitive prostate cancer (mHSPC). Treatments that can delay disease progression, and are associated with less comorbidities would be of significant clinical benefit in this patient population. The study is designed to assess the efficacy and safety of abiraterone plus APALUTAMIDE (a second-generation antiandrogen) or APALUTAMIDE alone without castration side effects and the other arm a combination of ADT and abiraterone; this last arm is to reflect an Abiraterone ongoing pivotal trial (LATITUDE), that assess the efficacy of adding abiraterone to castration in this setting of patients. Abiraterone had already showed clinical benefit in CRPC patients without prior chemotherapy.

Eligibility criteria: Inclusion Criteria:

1. Histologically confirmed prostate adenocarcinoma;
2. Hormone naïve patients with indication to ADT in the following settings:

   * Advanced loco-regional disease not amenable to curative local therapy (surgery or radiotherapy): T category T3/4 or node positive
   * Biochemical relapse after primary treatment (surgery or radiotherapy): patients in whom primary therapy is not appropriate or feasible with Previously treated with radical surgery and/or radiotherapy, now relapsing with at least one of the criteria: PSA \>= 4 ng/ml and rising with doubling time less than 10 months. or PSA \>= 20 ng/ml or N+ or M+
   * Newly diagnosed metastatic disease: Tany Nany M+
3. Patient is asymptomatic or moderately symptomatic regarding bone symptoms, i.e., no need for palliative radiation or radionuclide therapy;
4. Non-castration level of testosterone \> 230ng/dL (\> 8 nmol/L);
5. Baseline level of prostatespecific antigen (PSA) \> 2ng/dL;
6. ECOG performance status of 0 to 2;
7. Adequate hematologic, hepatic and renal function:

   1. hemoglobin \> 10 g/dL, neutrophils \> 1.5×109 / L, platelets\> 100×109 / L;
   2. total bilirubin \< 1.5x upper limit of normal (ULN); alanine (ALT) and aspartate (AST) aminotransferase \< 2.5 x ULN;
   3. serum creatinine \< 1.5x ULN; potassium \> 3.5 mM;
8. No previous cancer (except treated basal-cell skin cancer);
9. Written informed consent obtained prior to any study procedure;
10. Men age 18 years and older;
11. Agrees to use a condom 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.

Exclusion Criteria:

1. Prostate adenocarcinoma with neuroendocrine differentiation or small cell histology;
2. Biochemical recurrence without evidence of clinical or radiological disease;
3. Use of hormonal therapy or chemotherapy prior to randomization. Exception is courses of hormone therapy for localised disease must have been completed at least 12 months previously. It can have been given as adjuvant or neoadjuvant therapy.
4. Prior radiation therapy for a primary tumour within the 3 months before enrollment or for the treatment of metastases;
5. Known or suspected brain or skull metastases or leptomeningeal metastatic disease;
6. Any concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study;
7. Administration of an investigational therapeutic or invasive surgical procedure (not including surgical castration) within 28 days of Cycle 1 Day 1 or currently enrolled in an investigational study;
8. Active or symptomatic viral hepatitis or chronic liver disease; ascites or bleeding disorders secondary to hepatic dysfunction;
9. Current or prior treatment with anti-epileptic medications for the treatment of seizures;
10. Impaired cardiac function, including any of the following:

    1. Uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic BP ≥95 mmHg);
    2. Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events or history of cardiac failure in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease;
    3. Existing atrial fibrillation with or without pharmacotherapy. Other cardiac arrhythmia requiring pharmacotherapy;
    4. History of seizure or condition that may predispose to seizure (including, but not limited to prior stroke, transient ischemic attack or loss of consciousness ≤1 year prior to randomization; brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect);
11. Specific underlying conditions for oral agents. For example: impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of abiraterone or APALUTAMIDE (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
12. General excluded medications (e.g., relevant to cytochrome P450 interactions)

    1. Use of prescription drugs within 14 days prior to dosing or over-the-counter (OTC) medication within 7 days prior to dosing;
    2. Consumption of grapefruit product or St John's wort within 7 days prior to dosing;
    3. G-CSF, GM-CSF, erythropoietin, etc;
    4. Coumadin;
    5. Drugs which may cause QT prolongation;
    6. Known sensitivity to drugs or metabolites from similar classes;
    7. Known or suspected contraindications or hypersensitivity to APALUTAMIDE, bicalutamide or GnRH agonists or any of the components of the formulations;
13. Any condition or situation which, in the opinion of the investigator, would put the subject at risk, may confound study results, or interfere with the subject's participation in this study.

Primary outcomes:
measure: Number of patients that achieves an undetectable PSA level, defined as ≤ 0.2 ng/mL
timeFrame: Week 25
Secondary outcomes:
measure: PSA progression rate
timeFrame: Week 25
measure: Comparison of PSA progression rate
timeFrame: Week 25
measure: PSA response of 50 and 80%
timeFrame: Week 25
measure: Comparison of PSA response of 50 and 80%
timeFrame: Week 25
measure: Maximum PSA declines
timeFrame: Baseline up to week 25 to 52
measure: Overall PSA change
timeFrame: Baseline up to week 25 to 52
measure: Hormonal levels during treatment
timeFrame: Baseline up to week 25
measure: Comparison of hormonal levels during treatment
timeFrame: Baseline up to week 25
measure: Evaluation of bone mineral density according to RECIST 1.1
timeFrame: Week 25
measure: Comparison of bone mineral density according to RECIST 1.1 between three experimental groups
timeFrame: Week 25
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: Baseline to 2 years of follow-up
measure: Number of participants with pain progression assessed by BPI-SF of three experimental arms
timeFrame: Baseline up to week 25
measure: Number of participants in opioid use during treatment among three experimental arms
timeFrame: Baseline up to week 25
measure: Comparison of pain progression assessed by opioid use
timeFrame: Baseline up to week 25
measure: Comparison of pain progression assessed by BPI-SF questionnaire
timeFrame: Baseline up to week 25
measure: Quality of life assessed by FACT-P questionnaire
timeFrame: Baseline up to week 25
measure: Comparison of quality of life assessed by FACT-P questionnaire
timeFrame: Baseline up to week 25
measure: Radiographic progression-free survival (rPFS)
timeFrame: Week 25
Other outcomes:
Locations:
city: Salvador
country: Brazil
facility: Clínica AMO
state: Bahia
city: Fortaleza
country: Brazil
facility: CRIO
state: Ceará
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner
state: Paraná
city: Natal
country: Brazil
facility: Liga Norte Riograndense de Oncologia
state: Rio Grande Do Norte
city: Ijuí
country: Brazil
facility: Hospital de Caridade de Ijuí
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: CPO - Pucrs
state: Rio Grande Do Sul
city: Rio de Janeiro
country: Brazil
facility: Oncologia Rede D'Or S.A.
state: RJ
city: Barretos
country: Brazil
facility: Hospital de Câncer de Barretos
state: São Paulo
city: Santo André
country: Brazil
facility: Centro de Pesquisa Clínica em Hematologia e Oncologia - CEPHO
state: São Paulo
city: Rio de Janeiro
country: Brazil
facility: Grupo COI
city: São Paulo
country: Brazil
facility: Beneficiencia Portuguesa de São Paulo/Hospital São José
city: São Paulo
country: Brazil
facility: Hospital Israelita Albert Einstein
city: São Paulo
country: Brazil
facility: IBCC
city: São Paulo
country: Brazil
facility: ICESP
Study officials:
affiliation: Beneficiência Portuguesa de São Paulo
name: Fernando Maluf, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Latin American Cooperative Oncology Group
name: Gustavo Werutsky, MD
role: STUDY_DIRECTOR
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