E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006187 |
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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 |
Randomised phase IIa: To assess the relative efficacy of AZD4547 in combination with exemestane compared with exemestane + placebo by comparison of the change in tumour size at 12 weeks in all randomised patients and also in the FGFR1 amplified (FISH score 6) patients alone. |
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E.2.2 | Secondary objectives of the trial |
Randomised phase IIa: In all randomised patients and also in the FGFR1 amplified (FISH score 6) patients alone to assess the relative efficacy of AZD4547 in combination with exemestane compared with exemestane + placebo by assessment of 1)progression-free survival 2) objective response rate 3 )percentage of patients without progressive disease at 12 weeks 4) safety and tolerability and 5) PK of AZD4547 and exemestane when given in combination. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses If a patient declines to participate in any voluntary exploratory research component of the study, there will be no penalty or loss of benefit to the patient and they will not be excluded from other aspects of the study 2. Post -menopausal women. Women will be considered post-menopausal if they have had a bilateral oophorectomy or the following specific requirements apply: a. Women under 50 years old would be consider post-menopausal if they have been amenorrhoeic for 24 months and have follicle-stimulating hormone (FSH) and oestradiol levels in the post-menopausal range. Patients with prior exposure to depot LHRH analogues must be 24 months or more following the last administration b. Women aged 50 years and older would be consider post-menopausal if they have been amenorrhoeic for 12 months and patients with prior exposure to depot LHRH analogues must be 12 months or more following the last administration c. Women rendered amenorrhoeic by adjuvant chemotherapy, who were premenopausal or perimenopausal prior to chemotherapy, must have been amenorrhoeic for at least 24 months 3. World Health Organisation performance status 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks 4. Histological confirmation of breast cancer, with documented positive oestrogen receptor status (ER+) of primary or metastatic tumour tissue, according to the local laboratory parameters Randomised phase IIa: Mandatory provision of tumour biopsy for AZ approved laboratory confirmation of FGFR1 polysomy or gene amplification (FISH score ≥ 4) 5. Fulfils specific criteria for previous treatment of breast cancer: a. Relapsing during, or within 12 months of completion of, a single regimen of adjuvant endocrine therapy with non-steroidal AI and/or tamoxifen or b. Progression following first line endocrine therapy with a non-steroidal AI and/or tamoxifen for advanced breast cancer*. Co-administration of a targeted agent with the non-steroidal AI is permitted providing all toxicities have recovered to CTCAE Grade 1 or below Randomised phase IIa: Chemotherapy administered in the adjuvant setting is permitted *Advanced breast cancer: metastatic disease or locally advanced disease which is not amenable to treatment with curative intent. 6. Randomised phase IIa: At least one lesion, not previously irradiated, that can be accurately measured at baseline as = 10 mm in the longest diameter (except lymph nodes which must have short axis = 15 mm) with CT or MRI and which is suitable for accurate repeated measurements |
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E.4 | Principal exclusion criteria |
Patients must not enter the study if any of the following exclusion criteria are fulfilled 1. Treatment with any of the following: a. More than one regimen of endocrine therapy for advanced breast cancer (oophorectomy, ovarian ablation and LH-RH analogue therapy do not count as endocrine therapy for this study) b. Previous exposure to exemestane or any agent known to inhibit FGFRs c. Safety run-in: More than 1 prior regimen of chemotherapy for advanced breast cancer d. Randomised phase IIa: Any prior chemotherapy for advanced breast cancer e. Potent inhibitors or inducers of CYP3A4 or CYP2D6 or substrates of CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St John’s Wort) f. Major surgery (excluding placement of vascular access) within 4 weeks before the first dose of study treatment g. Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks before the first dose of study treatment 2. With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment 3. Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment 4. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required 5. Any of the following cardiac criteria: h. Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 electrocardiograms (ECGs) i. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block j. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval 6. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: k. Absolute neutrophil count < 1.5 x 109/L l. Platelet count < 100 x 109/L m. Haemoglobin < 90 g/L n. Alanine aminotransferase > 2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases o. Aspartate aminotransferase > 2.5 times ULN if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases p. Total bilirubin > 1.5 times ULN if no liver metastases or > 3 times ULN in the presence of liver metastases q. Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN r. Corrected calcium > ULN s. Phosphate > ULN 7. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD4547 / exemestane |
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E.5 End points |
E.5.1 | Primary end point(s) |
Tumour response as assessed by RECIST 1.1 (PHASE IIa) |
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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 | No |
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 | No |
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.8.3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 | Information not present in EudraCT |
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 |
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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 | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |