E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective is to assess safety and efficacy of abiraterone acetate plus prednisone and abiraterone acetate plus prednisone plus exemestane, each compared with exemestane alone, in postmenopausal women with ER+ metastatic breast cancer progressing after letrozole or anastrozole therapy. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are to assess abiraterone acetate plus prednisone and abiraterone acetate plus prednisone combined with exemestane, each compared with exemestane alone, in postmenopausal women with ER+ metastatic breast cancer progressing after letrozole or anastrozole therapy, with respect to the following:
•Overall survival
•Overall response rate
•Patient-reported outcomes (PROs) EORTC-C30, EQ-5D-5L, and BPI-SF pain intensity scale
•Endocrine markers estradiol, testosterone, estrone, and other biomarkers
•PK characterization of abiraterone and exemestane |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Woman >=18 years of age and postmenopausal determined by one of the following:
•bilateral, surgical oophorectomy
•age >=60 years
•age <60 years, with amenorrhea >=24 months and follicle-stimulating hormone and luteinizing hormone concentrations within postmenopausal range
2. Subjects with ER+, Her2- metastatic breast cancer, confirmed within 7 days before randomization with FFPE tissue from either primary or metastatic breast cancer site. In a subject with multiple biopsies of metastatic sites, the most recent biopsy prior to study entry should be submitted for evaluation of hormone receptor status.
3. Subjects with disease confined only to bone may be included but subjects with purely sclerotic lesions may not participate in the study.
4. Disease must have been sensitive to anastrozole or letrozole therapy prior to disease progression. Sensitivity to anastrozole or letrozole is defined as either stable disease or better for >=6 months in the metastatic setting or relapse free for >=2 years in the adjuvant setting.
5. No more than two prior lines of therapy in the metastatic setting, of which no more than one was chemotherapy [Note: Simultaneous combination treatment is considered one line of therapy.]
6. Eastern Cooperative Oncology Group (ECOG) performance status score of <=1
7. Clinical laboratory values during Screening:
•hemoglobin >=10.0 g/dL
•neutrophils >=1.5 x 10^9/L
•platelets >=100 x 10^9/L
Note: Subjects need to meet the above 3 criteria independent of growth factors and transfusions
•total bilirubin <=1.5 x upper limit of normal (ULN)
•alanine (ALT) and aspartate (AST) aminotransferase <=2.5xULN
•alkaline phosphatase <=6xULN unless bone metastases with no liver disorder
•serum creatinine <1.5xULN or creatinine clearance >=50 mL/min
•serum potassium >=3.5 mM
•serum albumin >=3.0 g/dL
•clinically normal prothrombin time (PT) or international normalized ratio (INR) and partial thromboplastin time (PTT) per investigator assessment
8. Systolic blood pressure <160 mm Hg and diastolic blood pressure <95 mm Hg [Note: Hypertension controlled by antihypertensive therapy is permitted].
9. Cardiac ejection fraction >=50% measured by MUGA or ECHO done within 4 weeks before randomization
10. A bisphosphonate or denosumab may be initiated on the same day as the assigned study.
11 Willing and able to adhere to prohibitions and restrictions specified in this protocol
12 Signs an informed consent document within 4 weeks before randomization indicating she understands the purpose of and procedures required for the study and is willing to participate in the study
13 Signs the informed consent document within 4 weeks before randomization for pharmacogenomics research indicating willingness to participate in the pharmacogenomic component of the study, where local regulations permit. [Note: Refusal to give consent for this component does not exclude a subject from participation in this clinical study.] |
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E.4 | Principal exclusion criteria |
1. Prior treatment with exemestane, ketoconazole, aminoglutethimide, or a CYP17 inhibitor [Note: Prior treatment with ketoconazole for <= 7 days is permitted and topical formulations of ketoconazole are permitted]
2. Anticancer immunotherapy or investigational agent within 4 weeks before randomization, or anticancer radiotherapy (except palliative) or anticancer endocrine therapy within 2 weeks before randomization [Note: Potential subjects must not have taken anastrozole, letrozole, fulvestrant, or any chemotherapy for at least 2 weeks (bevacizumab for at least 3 weeks) before randomization.]
3. Serious or uncontrolled nonmalignant disease, including active or uncontrolled infection
4. Clinical or biochemical evidence of hyperaldosteronism or hypopituitarism
5. Any condition that, in the opinion of the investigator, would compromise the well-being of the patient or that could prevent, limit, or confound the protocol-specified assessments
6. Major thoracic or abdominal surgery or significant traumatic injury with 4 weeks before randomization or plans surgery during study participation or within 4 weeks after the last dose of study drug [Note: Patients with planned surgical procedures to be conducted under local anesthesia are not excluded from the study.]
7. Persistent >=Grade 2 toxicity from any cause [Note: Chemotherapy-induced alopecia and Grade 2 peripheral neuropathy are allowed.]
8. Symptomatic central nervous system disease or leptomeningeal disease
9. Gastrointestinal disorder interfering with study drug absorption
10. Active or uncontrolled disease that may require oral corticosteroid therapy
11. Active or symptomatic viral hepatitis or chronic liver disease
12. History of clinically significant heart disease, ie, myocardial infarction or arterial thrombotic event within 6 months, severe or unstable angina, or New York Heart Association Class III or IV heart disease
13. Known allergies, hypersensitivity, or intolerance to abiraterone acetate, exemestane, prednisone, or their excipients
14. Contraindications to the use of exemestane or prednisone per local prescribing information
15. Received an investigational drug (including investigational vaccines) or used an invasive investigational medical device within 4 weeks before the planned first dose of study drug or is currently enrolled in an investigational study |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression free survival |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to approximately 1.5 years |
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E.5.2 | Secondary end point(s) |
1. Overall survival
2. Overall response rate to treatment
3. Patient-reported outcomes
4. Pharmacodynamics
5. Pharmacokinetics |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 3.5 years
2. Up to 1.5 years
3. Up to approximately 3.5 years
4. Up to approximately 1.5 years
5. Approximately 4 months |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 51 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
France |
Italy |
Korea, Republic of |
Luxembourg |
Netherlands |
Poland |
Russian Federation |
Spain |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The last follow-up of the last subject participating in the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |