E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Estrogen Receptor Positive HER2 Negative Advanced Breast Cancer |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10072737 |
E.1.2 | Term | Advanced 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 |
To determine the clinical efficacy (as assessed by PFS) of AZD9833 when compared to fulvestrant in women with advanced ER-positive HER2-negative breast cancer. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of AZD9833 when compared to fulvestrant in women with advanced ER positive HER2 negative breast cancer.
To determine anti-tumour effect of AZD9833 when compared to fulvestrant in women with advanced ER positive HER2 negative breast cancer.
To determine the effect of AZD9833 on survival and clinical benefit when compared to fulvestrant in women with advanced ER positive HER2 negative breast cancer
To evaluate the PK of AZD9833 in this patient population at steady state.
To evaluate the pharmacodynamics of AZD9833 and fulvestrant in a subgroup of patients with advanced ER positive HER2-negative breast cancer.
To evaluate the effect of AZD9833 and fulvestrant on the patients’ HRQoL, as assessed by patient completed HRQoL questionnaires. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Provision of signed and dated, written informed consent prior to any mandatory study specific procedures, sampling, and analyses. Patients are also required to consent to the provision of archival tumour biopsies. • For patients who consent, provision of signed and dated written genetic informed consent prior to collection of sample for genetic analysis. • Female patients aged at least 18 years. • Post-menopausal as per the defined criteria. • Histologically or cytological confirmation of adenocarcinoma of the breast. • ER-positive status of primary or metastatic tumour tissue. • HER2-negative. • Metastatic disease or loco-regionally recurrent disease suitable for treatment with fulvestrant. • Radiological or other objective evidence of progression on or after the last systemic therapy prior to starting study treatment. • Patients must have at least 1 lesion, not previously irradiated, that can be measured accurately at baseline as ≥10 mm in the longest diameter or in absence of measurable disease as defined above, at least 1 lytic or mixed (lytic+sclerotic) bone lesion. • Eastern Cooperative Oncology Group (ECOG)/World Health Organisation (WHO) performance status 0 to 1. Inclusion criteriion for the paired tumour biopsy research subgroup • Washout from prior tamoxifen: 4 months to elapse from last tamoxifen dose to pre-dose on-study biopsy. |
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E.4 | Principal exclusion criteria |
• Intervention with any of the following: o Any cytotoxic chemotherapy, investigational agents or other anti-cancer drugs for the treatment of breast cancer from a previous treatment regimen or clinical study within 14 days of the first dose of study treatment. o Use of systemic oestrogen-containing hormone replacement therapy within 6 months prior to the first dose of study treatment. o Medications or herbal supplements known to be strong inhibitors/inducers of cytochrome P450 (CYP) 3A4/5 and sensitive CYP2B6 substrates and drugs which are substrates of CYP2C9 and/or CYP2C19 which have a narrow therapeutic index ie, warfarin (and other coumarin-derived vitamin K antagonist anticoagulants) and phenytoin. o Drugs that are known to prolong QT and have a known risk of torsades de pointes. o The following cardiovascular criteria: QTcF >470 ms, resting heart rate <45 bpm, clinically significant abnormalities of resting ECG, uncontrolled hypertension, symptomatic hypotension, factors that increase the risk for QTc prolongation, LVEF <50% o Radiotherapy with a limited field of radiation for palliation. o Major surgical procedure or significant traumatic injury. • Presence of life-threatening metastatic visceral disease or uncontrolled central nervous system (CNS) metastatic disease. • Inadequate bone marrow reserve or organ function. • Refractory nausea and vomiting, uncontrolled chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of AZD9833. • History of hypersensitivity to active or inactive excipients of AZD9833 or fulvestrant. • Previous randomisation in the present study. • Women of childbearing potential. • Immunocompromised patients, eg, patients who are known to be serologically positive for human immunodeficiency virus (HIV). • Patients with known active hepatitis (ie, heapatitis B or C) |
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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 |
Primary analysis will be conducted when sufficient events have accrued for the treatment comparison of interest |
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E.5.2 | Secondary end point(s) |
- Objective response rate - Duration of response - Percentage change in tumour size in tumour size at 16 weeks - Overall survival - Clinical benefit rate at 24 weeks - Plasma concentrations of AZD9833 and, if appropriate, metabolite(s) - Percent change from baseline in ER and progesterone receptor (PgR) expression assessed by the manual H-score method - Percent change from baseline in Ki67 labelling index - Changes from baseline in total/subscale scores of the HrQoL questionnaires |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will be evaluated at the end of the trial. Survival analysis will be conducted at 50% overall survival maturity and may be conducted at 75% overall survival maturity or other maturities as may be appropriate. |
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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 | Yes |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 85 |
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 |
Peru |
Ukraine |
Belgium |
Canada |
France |
Georgia |
Germany |
Hungary |
Israel |
Italy |
Korea, Republic of |
Mexico |
Poland |
Portugal |
Russian Federation |
Spain |
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 end of the study is defined as the last visit of the last patient for any protocol related activity. A patient is considered to have completed the study if they have completed all phases of the study including the last visit or the last scheduled procedure shown in the Schedule of Activities (including Overall Survival determination). |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 25 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 25 |