E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
CML in chronic or accelerated phase or blast crisis, relapsed/refractory Ph+ ALL, and other hematologic malignancies |
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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 |
•Determine the maximum tolerated dose (MTD) and dose-limiting toxicity DLT of AMN107 as a single agent when administered as an oral once-daily dose to adult patients with Gleevec-resistant CML in accelerated phase or blast crisis, or relapsed/refractory Ph+ ALL. •To characterize the PK profile in plasma and, where samples are available, in tumor cells and normal hematopoietic cells
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E.2.2 | Secondary objectives of the trial |
•At the MTD, to characterize the safety and tolerability of AMN107, including acute and chronic toxicities in patients with Gleevec-resistant CML in accelerated phase or blast crisis, relapsed/refractory Ph+ ALL, systemic mastocytosis, or hypereosinophilic syndrome •To characterize the pharmacodynamic profile of AMN107 by assessing changes in the following parameters pre- and post-therapy: - the mutational status of Abl - the Bcr-Abl phosphorylation status - Stat 5 analysis/Stat 1 analysis - Crk-L analysis - QRT PCR analysis •To investigate tumor-specific mutations and compare gene expression change in tumor cells with blood cell and plasma •To investigate the effects of genetic variation in drug metabolism genes, hematologic malignancy genes and drug target genes on patient response •To obtain blood samples from patients at the MTD dose level to perform pharmacogenetic analyses. •At the MTD, to evaluate safety and preliminary anticancer activity |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
•Patients with a cytopathologically confirmed diagnosis of Ph+ ALL who are either relapsed after or refractory to standard therapy, or patients with CML in blast crisis, or CML patients in accelerated phase who are resistant to Gleevec®. Patients with Ph+ ALL who have minimal residual disease following stem cell transplantation may only be enrolled during the dose escalation portion of the study. •Following MTD determination, patients with a cytopathologically confirmed diagnosis of either CML in chronic phase who are Gleevec® resistant (Post text supplement 6), systemic mastocytosis or hypereosinophilic syndrome/ chronic eosinophilic leukemia. Patients with systemic mastocytosis or hypereosinophilia must have a clinical indication for treatment. HES/CEL patients should meet standard disease-definition criteria (Coutre and Gotlib 2004). Systemic mastocytosis patients should meet standard disease-definition criteria (Tefferi and Pardanani 2004) •Following MTD determination, patients with any of the eligible diseases who are Gleevec® intolerant (defined as patients who have discontinued Gleevec® therapy due to a grade 3 or 4 adverse event and have not had a major response to Gleevec®). •Age ≥ 18 years old •WHO Performance Status of ≤ 2 (Post-text suppl. 3) •Patients must have the following laboratory values: •Cytoreductive therapy with vincristine or cyclophosphamide is permitted up to 7 days prior to first administration of AMN107. Corticosteroids can be administered up to 48 hours prior to first administration of AMN107. Hydroxyurea is permitted as clinically indicated during the dose escalation phase •Potassium ≥ LLN (lower limit of normal) or corrected to within normal limits with supplements prior to the first dose of study medication •Total calcium (corrected for serum albumin) ≥ LLN or correctable with supplements •Magnesium ≥ LLN or corrected to within normal limits with supplements prior to the first dose of study medication •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 •Serum bilirubin ≤ 1.5 x ULN •Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥50 ml/min •Written informed consent
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E.4 | Principal exclusion criteria |
•Cytopathologically confirmed CNS infiltration NB: in absence of suspicion of CNS involvement, lumbar puncture is not required •Impaired cardiac function, including any one of the following •LVEF < 45% or below institutional lower limit of the normal range (which ever is higher) 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 > 450 msec on screening ECG (using the QTcF formula) •Right bundle branch block plus left anterior hemiblock, bifascicular block •Myocardial infarction within 12 months prior to starting AMN107 •Unstable angina diagnosed or treated during the past 12 months •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) •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of AMN107 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) •Use of therapeutic warfarin. •Acute or chronic liver or renal disease considered unrelated to tumor •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 •Treatment with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) ≤ 1 week prior to starting study drug. Erythropoietin is allowed. •Patients who are currently receiving treatment with any of the medications listed in Post-text supplement 4 (Amendment 8) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. The medications listed in Post-text supplement 4 (Amendment 8) have the potential to prolong the QT interval or are CYP3A4 inhibitors. •Patients who have received chemotherapy ≤ 1 week (6 weeks for nitrosurea or mitomycin-C) or who are within 5 half-lives of their last dose chemotherapy dose prior to starting study drug or who have not recovered from side effects of such therapy. •Patients who have received Gleevec® ≤ 1 week or who have not recovered from side effects of such therapy. •Patients who have received immunotherapy ≤1 week prior to starting study drug or who have not recovered from side effects of such therapy •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 •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 •Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy •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 barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug •Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) •Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention. •Patients unwilling or unable to comply with the protocol
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E.5 End points |
E.5.1 | Primary end point(s) |
Dose escalation phase (phase I):
1. Safety parameters, particulary dose limiting toxicity (DLT) during Cycle 1 2. Pharmacokinetic parameters (Tmax, Cmax, AUC0-24hours)
Dose expansion phase (phase II)
Response rates as follows:
Arm 1(Ph+ ALL) Hematological Response (Complete response + Partial response [CR + PR]) Arm 2 (CML-BC) Complete Hematologic Response and Major (Complete or Partial) Cytogenetic Response Arm 3 (CML-AP) Complete Hematologic Response and Major (Complete or Partial) Cytogenetic Response Arm 4 (CML-CP) Major Cytogenetic Response Arm 5 (HES/CEL) Complete response + Partial response [CR + PR] Arm 6 (SM) All categories of response better than stable disease, ie, complete remission, incomplete remission, pure clinical response, good partial response and minor response |
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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 | 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) | 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 | 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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Last visit of last subject |
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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 |