E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
FGFR1 amplified and non-amplified metastatic HER2 negative breast cancer |
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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 |
To determine the Overall Response Rate (ORR) in 4 groups of patients with (FGFR1+, HR+),(FGFR1+, HR-),(FGFR1-, HR+) or (FGFR1-, HR-) breast tumors treated with TKI258. |
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E.2.2 | Secondary objectives of the trial |
To determine Disease Control Rate (DCR), defined according to RECIST, (CR, PR and Stable Disease (SD) ≥ 24 weeks after start of TKI258 treatment) in the 4 groups of patients Progression Free Survival (PFS), defined according to RECIST, in the 4 groups of patients. To characterize the safety and tolerability of TKI258 treatment. To characterize the single- and repeated-dose pharmacokinetic (PK) profile of TKI258. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Female patients with histological confirmation of adenocarinoma of the breast, presenting with metastatic disease. 2. The primary tumor, metastatic axillary lymph nodes or biopsy of metastatic tumor must have been locally tested by FISH/CISH for FGFR1 amplification. Tumor material must be available for central testing. 3. Human epidermal growth factor receptor 2 (HER2) and hormone receptors (HR) (ER/PgR) status of breast cancer must have been previously determined. 4. Patients must have HER2 negative breast cancer. 5. Patients must have a documented disease progression as defined by RECIST at baseline. 6. Patients with HR+ disease must have received Adjuvant endocrine therapy: postmenopausal patients must have received aromatase inhibitor premenopausal patients must have received Tamoxifen unless ovarian ablation/suppression or aromatase inhibitor in case of ovarian ablation/suppression. and at least one line and no more than three lines of chemotherapy in the metastatic setting. Patients with newly diagnosed metastatic disease must have received at least one line of endocrine therapy and chemotherapy for metastatic disease. 7. Patients with HR- disease must have received: Adjuvant chemotherapy and at least one line and no more than three lines of chemotherapy in metastatic setting Patients who did not receive adjuvant chemotherapy must have received two lines of chemotherapy in the metastatic setting. 8. Patient must be ≥ 18 years old. 9. Patients WHO performance status equal to 0, 1 or 2. Required baseline laboratory values: 10. Electrolytes (calcium, sodium, magnesium, potassium, phosphorous) level within normal limit (WNL) 11. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L 12. Hemoglobin ≥ 9 g/dl 13. Platelets ≥ 100 x 109/L 14. Serum creatinine ≤ 1.5 x ULN. 15. AST/SGOT and ALT/SGPT ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5.0 x ULN if liver metastases are present 16. Serum bilirubin ≤ 1.5 x ULN 17. All patients must have signed and dated an informed consent form. |
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E.4 | Principal exclusion criteria |
1.Patients with known brain metastases or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases.2.Patients with history of another malignancy within the last 5 years prior to study entry, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix.3.Patients who have received the last administration of chemotherapy or immunotherapy &#8804; the timeframe defined below after the end of the cycle of the last treatment, prior to starting study drug, or who have not recovered from the side effects of such therapy: patients who have received the last administration of chemotherapy/immunotherapy in a daily schedule &#8804; 7 days prior to starting study drug; patients who have received the last administration of chemotherapy/immunotherapy in a weekly schedule &#8804; 2 weeks prior to starting study drug; patients who have received the last administration of chemotherapy/immunotherapy in a 2-weekly schedule &#8804; 3 weeks prior to starting study drug; patients who have received the last administration of chemotherapy/immunotherapy in a 3-weekly schedule &#8804; 4 weeks prior to starting study drug; patients who have received the last administration of chemotherapy/ immunotherapy in a 4-weekly schedule &#8804; 5 weeks prior to starting study drug.Patients who have received the last administration of nitrosourea, mitomycin-C &#8804; 6 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy.4.Patients who received a continuous dosing small molecule therapeutic &#8804; 7 days prior to starting study drug or who have not recovered from the side effects of such therapy.5.Patients who received the last administration of biologic therapy &#8804; 6 weeks prior to starting study drug or who have not recovered from the side effects of such therapy.6.Patients who have received any other investigational agents &#8804; 4 weeks prior to starting study drug or who have not recovered from the side effects of such therapy.7.Patients who have received wide field radiotherapy &#8804; 4 weeks or limited field radiation for palliation &#8804; 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.8.Patients who have undergone major surgery &#8804; 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy.Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study : 9.Impaired cardiac function or clinically significant cardiac diseases, including any of the following: Congenital long QT syndrome History or presence of ventricular arrhythmias or presence of atrial fibrilation Clinically significant resting bradycardia (< 50 beats per minute) QTc > 480 msec on screening ECG. LVEF assessed by 2-D echocardiogram (ECHO) or Multiple gated acquisition scanning (MUGA), < 45 %.10.Any of the following within 6 months prior to study entry: myocardial infarction, severe/unstable angina, CABG, Congestive Heart Failure, Cerebrovascular Accident, Transient Ischemic Attack, Pulmonary Embolism11.Uncontrolled hypertension defined by a SBP > 150 mm Hg and/or DBP > 100 mm Hg, with or without anti-hypertensive medication.12.Previous pericarditis; clinically significant pleural effusion in the previous 12 months or current ascites requiring two or more interventions/month.13.Impairment of gastrointestinal function or GI disease that may significantly alter the absorption of TKI258.14.Known diagnosis of HIV infection (HIV testing is not mandatory).15.History of alcoholism, drug addiction, or any psychiatric or psychological condition which, in the opinion of the investigator, would impair study compliance.(See the protocol for the last four criteria) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall Response (Complete responses (CR) or partial response (PR)) Rate. CR and PR will be defined according to RECIST. |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
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 | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 1 |