E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
CML in accelerated phase, blast crisis and chronic phase |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. To evaluate the safety profile of AMN107 in a large number of patients. 2. To provide patients with life threatening conditions: imatinib resistant/intolerant chronic myeloid leukemia - in blast crisis, accelerated phase and chronic phase, with expanded access to AMN107 until such time as the product is commercially available.
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
Patients under consideration for participation in this study must meet one of the following disease inclusion criteria as defined in 1, 2, or 3. Inclusion criteria number 4 applies to all three groups CML-BC, CML-AP, and CML- CP. 1. Imatinib - resistant or - intolerant Philadelphia chromosome-positive CML in blast crisis defined as at least 30% blasts in peripheral blood and/or bone marrow or extramedullary disease excluding liver and spleen 2. Imatinib - resistant or - intolerant Philadelphia chromosome-positive CML patients in accelerated phase defined with one or more of the following criteria present within 4 weeks prior to beginning treatment: • ≥ 15% but < 30% blasts in blood or bone marrow • ≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow (providing that < 30% blasts present in bone marrow) • peripheral basophils ≥ 20% • thrombocytopenia <100 X 109/L unrelated to therapy 3. Imatinib - resistant or - intolerant Philadelphia chromosome-positive CML in chronic phase defined with the following criteria: • < 15% blasts in peripheral blood and bone marrow • < 30% blasts plus promyelocytes in peripheral blood and bone marrow • < 20% basophils in the peripheral blood • ≥ 100 x 109/L (≥ 100,000/mm3) platelets • No evidence of extramedullary leukemic involvement, with the exception of liver and spleen 4. CML patients who have been treated with an investigational tyrosine kinase inhibitor who otherwise meet the definition of imatinib-resistance or intolerance are eligible The following inclusion criteria are mandatory for all patients: 5. Males or females ≥18 years of age 6. WHO Performance Status of ≤ 2 7. Patients must have the following laboratory values: • Potassium within normal limits or correctable with supplements • Total calcium (corrected for serum albumin) within normal limits or correctable with supplements • Magnesium ≥ LLN or correctable with supplements • Phosphorus ≥ LLN or correctable with supplements • ALT and AST ≤ 2.5 x ULN or ≤ 5.0 x ULN if considered due to tumor • Alkaline phosphatase ≤ 2.5 x ULN unless considered due to tumor • Serum bilirubin ≤ 1.5 x ULN • Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance 50 ml/min • Serum amylase ≤ 1.5 x ULN and serum lipase ≤ 1.5 x ULN 8. Written signed and dated informed consent prior to any study procedures being performed
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E.4 | Principal exclusion criteria |
1. Cytopathologically confirmed CNS infiltration. (in absence of suspicion of CNS involvement, lumbar puncture is not required) 2. Impaired cardiac function, including any one of the following: • LVEF < 45% as determined by MUGA scan or echocardiogram • Complete left bundle branch block • Use of a cardiac pacemaker • ST depression of > 1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads • Congenital long QT syndrome • History of or presence of significant ventricular or atrial tachyarrhythmias • Clinically significant resting bradycardia (< 50 beats per minute) • QTc > 480 msec on screening ECG (using the QTcF formula) The ICH guideline criterion of > 450 msec has been increased to > 480 msec to allow patient with this life threatening disease where no medication is currently approved, providing an acceptable benefit-risk for the patient. • Right bundle branch block plus left anterior hemiblock, bifascicular block • Myocardial infarction within 3 months prior to starting AMN107 • Uncontrolled angina pectoris • Other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen) 3. Use of therapeutic coumarin derivatives (i.e., warfarin, acenocoumarol, phenprocoumon) up to the day before study drug administration 4. Acute or chronic liver or renal disease considered unrelated to tumor 5. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol 6. Treatment with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) ≤ 1 week prior to starting study drug. 7. Patients who are currently receiving treatment with any of the medications that have the potential to prolong the QT interval (Post-text supplement 2). 8. Patients who have received chemotherapy ≤ 1 week or who are within 5 half-lives of their last dose of chemotherapy (6 weeks for nitrosurea or mitomycin-C) prior to starting study drug or who have not recovered from side effects of such therapy. Patients who have received imatinib ≤ 1 week or who have not recovered from side effects of such therapy. 9. Patients who have received immunotherapy ≤1 week prior to starting study drug or who have not recovered from side effects of such therapy 10. Patients who have received any investigational drug ≤ 4 weeks or investigational cytotoxic agent within 1 week (or who are within 5 half-lives of a previous investigational cytotoxic agent) prior to starting study drug or who have not recovered from side effects of such therapy 11. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation < 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy 12. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy 13. Known diagnosis of human deficiency virus (HIV) infection (HIV testing is not mandatory) 14. Patient with a history of another malignancy that is currently clinically significant or currently requires active intervention. 15. Patients who are pregnant or breast feeding, or adults of reproductive potential not employing an effective method of birth control. (Women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of AMN107). Post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective method of birth control throughout the study and for 3 months following discontinuation of study drug 16. Patients unwilling or unable to comply with the protocol
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E.5 End points |
E.5.1 | Primary end point(s) |
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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 | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | Yes |
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) | No |
E.8.2.2 | Placebo | No |
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.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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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Until the product is commercially available for the appropriate indication in that particular country. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
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 | 0 |