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 | 15.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006187 |
E.1.2 | Term | Breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
Safety Run In: To assess the safety and tolerability and to determine a dose of AZD4547 in combination with a standard dose of exemestane.
Randomised Phase IIa with embedded safety assessment: To assess the relative efficacy and safety of AZD4547 in Combination with fulvestrant vs. fulvestrant alone by progression free survival.
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E.2.2 | Secondary objectives of the trial |
Safety run-in: To investigate the pharmacokinetics of AZD4547 and exemestane, when given in combination
Randomised phase IIa with embedded safety assessment: To assess the relative efficacy of AZD4547 in combination with fulvestrant compared with fulvestrant + placebo by comparison of the change in tumour size at 12 weeks, objective response rate, duration of response in all randomised patients, patients with tumours that have FGFR1 gene amplification (FISH 6), and patients with moderate to high FGFR1 gene amplification alone
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Post-menopausal women (either through bilateral oophorectomy or amenorrhoeic for 24 months)
Histological confirmation of Breast Cancer with documented ER+ receptor status
Safety run-in: Relapsing during/within 12 months of completion of a single regimen of adjuvant endocrine therapy with non-steroidal AI and/ tamoxifen or progression following 1st line endocrine therapy with non-steroidal AI
Randomised phase IIa: Received at least 1 prior endocrine therapy in the metastatic setting or have relapsed during/ within 6 months of completion of adjuvant endocrine therapy (either non-steroidal AI or tamoxifen or a combination of both). Chemotherapy administered in the adjuvant setting is permitted.
Randomised phase IIa: Mandatory provision of tumour sample to confirm FGFR1 polysomy or gene amplification
At least one measurable lesion that can be accurately assessed by CT/MRI/x-ray at baseline and follow up visits
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E.4 | Principal exclusion criteria |
Prior exposure to exemestane (safety run-in) / fulvestrant (randomised phase IIa), or any agent known to inhibit FGFRs.
More than 1 prior regimen of chemotherapy for breast cancer
ECG recordings that demonstrate significant abnormalities in cardiac rate, rhythm or conduction
History of hypersensitivity to active or inactive excipients of AZD4547 or exemestane (safety run-in ) or fulvestrant (Randomised phase), including castor oil, or drugs with a similar chemical structure or class to AZD4547 or exemestane or fulvestrant.
Randomised phase IIa: bleeding/blood clotting conditions that would prevent the administration of the fulvestrant injection into the buttocks |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety Run-in: Safety and tolerability in terms of number of patients with Adverse events (serious and non-serious)
Randomised phase IIa: To assess the relative tumour response of AZD4547 in combination with fulvestrant compared with fulvestrant + placebo by measuring Progression Free Survival via measurement of Response Evaluation Criteria in Solid Tumours (RECIST) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Adverse events recorded from patient screening to discontinuation from study plus 28 days safety follow-up
RECIST assessments at Baseline, week 12 and then every 8 weeks until objective disease progression |
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E.5.2 | Secondary end point(s) |
Safety Run-in:
To investigate the Pharmacokinetics(PK)/Pharmacodynamics(PD) of AZD4547 and exemestane when given in combination by measuring blood plasma concerntrations
Measure the effects of AZD4547 on circulating oestradiol.
Randomised phase IIa:
Measurement in the change of tumour size at week 12 across the two arms as measured by RECIST.
Measurement of Objective Response Rate (ORR) (the percentage of patients with at least one visit response). As measured by RECIST.
Duration of Response (DoR) the time taken from first response until progression or death. As measured by RECIST
Measurement of the percentage of patients without progressive disease at 12 weeks.
Measurement of the laboratory changes in clinical chemistry, haematology and urine as compared to baseline
Measurement of changes in vital signs compared to baseline.
Measurement of Health Related Quality of Life using a Cancer Quality of Life Questionnaire. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Blood sample taken on last day of exemestane monotherapy and Cycle 1 day 7 (AZD4547+exemestane), (sampling time: pre-dose to 10-12h)
Blood sample for oestradiol level taken at screening, on last day of exemestane monotherapy and day 7 of cycle 1
RECIST assessment at baseline and week 12.
RECIST assessmentat baseline, week 12 and then every 8 weeks until objective disease progression
RECIST assessment at baseline, week 12 and then every 8 weeks until progression
RECIST assessment at Baseline and week 12
Laboratory data will be collected from screening to 28 days post drug discontinuation
Vital signs will be recorded from screening to 28 days after study drug discontinuation
Questionaire collected at screening and at each visit up to 28 days post discontinuation of study drug. |
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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 | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Open label safety run-in followed by blinded parallel randomised Phase II |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 55 |
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 |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Romania |
Russian Federation |
United Kingdom |
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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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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 | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 3 |