E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic phase chronic myeloid leukemia with resistant disease following treatment with at least two BCR-ABL tyrosin kinase inhibitors. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 6.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10009013 |
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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 assess the major (complete/partial) cytogenetic response (MCyR) rate |
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E.2.2 | Secondary objectives of the trial |
1. To determine the duration of MCyR 2. To determine the complete hematologic response (CHR) rate 3. To determine the complete cytogenetic response (CCyR) rate 4. To determine the overall complete/partial/minor/minimal) cytogenetic response rate 5. To determine the major and complete molecular response rates 6. To characterize BCR-ABL mutations of patients at study entry and, in responding patients, at the time of disease progression 7. To estimate progression-free survival time 8. To characterize the population pharmacokinetics 9. To monitor the QTc interval in patients receiving oral LBH589 10. To evaluate the safety and tolerability profile of oral LBH589 when given at 20 mg p.o. Mon, Wed, Fri weekly |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
ユ Male or female patients aged >= 18 years old ユ Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed ユ Diagnosis of Ph+ chronic phase CML defined as the presenceInclusion ユ Male or female patients aged >= 18 years old ユ Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed ユ Diagnosis of Ph+ chronic phase CML defined as the presence of all of the following criteria: ユ < 15% blasts in peripheral blood and bone marrow ユ < 30% blasts plus promyelocytes in peripheral blood and bone marrow ユ < 20% basophiles in the peripheral blood ユ >= 100 x 109/L >= 100,000 /mm3) platelets ユ No evidence of extramedullary leukemic involvement, with the exception of liver or spleen Prior treatment with at least two BCR-ABL tyrosine kinase inhibitors (i.e. imitinib, nilotinib, or dasatinib) and demonstrates resistance to the most recent kinase inhibitor therapy. Resistance to a tyrosine kinase inhibitor for eligibility into this protocol is defined as one of the following while the patient was on therapy: 1. Primary hematologic resistance: ユ Patients who do not achieve a CHR within 6 months of starting therapy. ユ Patients who did not achieve a CHR at any time and whose disease progressed on therapy as defined by a doubling of the count to a value of more than 20,000 per cubic 2. Acquired hematologic resistance i.e., the loss of complete hematologic response (defined as the appearance of any of the following in two blood samples obtained at least 2 weeks apart: a white-cell count of more than 20,000 per cubic millimeter, a platelet count of at least 600,000 per cubic millimeter, the appearance of extramedullary disease, the appearance of at least 5 percent myelocytes and metamyelocytes in the peripheral blood, or the appearance of blasts or promyelocytes in the peripheral blood) 3. Acquired cytogenetic resistance defined i.e., the loss of major cytogenetic response (defined as an increase in Ph+ positive cells in metaphase by at least 30 %) Patients with a history of intolerance to one BCR-ABL kinase inhibitors (defined as discontinuation of treatment due grade 3 or 4 adverse events related to treatment) will be considered eligible to enter the study if they demonstrate resistance to their most recent BCR-ABL kinase inhibitor as defined above. Patients who are intolerant of at least 2 BCR-ABL kinase inhibitors will be considered eligible to enter this study if they also demonstrate resistance to or intolerance of interferon-alpha (IFN alpha) by the same criteria defined above. ユ Patients must meet the following laboratory criteria: ユ Serum albumin > 3g/dL ユ AST/SGOT and ALT/SGPT <= 2.5 x upper limit of normal (ULN) ) or <= 5.0 x ULN if the transaminase elevation is due to leukemic involvement ユ Serum bilirubin <= 1.5 x ULN ユ Serum creatinine <= 1.5 x ULN or 24-hour creatinine clearance >= 50 ml/min ユ Serum potassium >= LLN ユ Serum phosphorus >= LLN ユ Total calcium (corrected for serum albumin) or ionized calcium >= LLN ユ Serum magnesium >= LLN ユ TSH and free T4 WNL (patients may be on thyroid hormone replacement) ユ Baseline MUGA or ECHO must demonstrate LVEF >= the lower limit of the institutional normal ユ Patients with an ECOG Performance Status of <= 2 |
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E.4 | Principal exclusion criteria |
ユ A candidate for hematopoitic stem cell transplantation (HSCT) (i.e. patient is a candidate, has an appropriate donor, and agrees to transplantation) ユ Prior treatment with an HDAC inhibitor ユ Patients with a prior history of accelerated phase or blast crisis CML ユ Impaired cardiac function including any one of the following: ユ Screening ECG with a QTc > 450 msec ユ Patients with congenital long QT syndrome ユ History of sustained ventricular tachycardia ユ Any history of ventricular fibrillation or torsades de pointes ユ Bradycardia defined as HR < 50 beats per minute (patients with a history of bradycardia who now have a permanent pacemaker and >= 50 bpm are eligible) ユ Patients with a myocardial infarction or unstable angina within 6 months of study entry ユ Congestive heart failure (NY Heart Association class III or i.v) ユ Right bundle branch block and left anterior hemiblock (bifasicular block) ユ Uncontrolled hypertension ユ Concomitant use of drugs with a risk of possible risk of causing QTc prolongation or torsades de pointes listed in Post-text Supplement 1 ユ Concomitant use of CYP3A4 inhibitors listed in Post-text Supplement 1 ユ Concomitant use of any other anti-cancer therapy except anegrilide or hydroxyurea (see Section 6.6.7) ユ Patients with unresolved diarrhea >CTCAE grade 1 ユ Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LBH589 ユ Patients who have received chemotherapy, any investigational drugs or undergone major surgery < 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy ユ Patients who have received a BCR-ABL tyrosine-kinase inhibitor within 1 week of first treatment with LBH589 ユ Female patients who are pregnant or breast feeding or patients of reproductive potential not using an effective method of birth control. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of the first administration of oral LBH589 ユ Male patients whose sexual partners are WOCBP not using effective birth control |
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E.5 End points |
E.5.1 | Primary end point(s) |
ユ Major Cytogenetic response evaluation |
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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 | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Information not present in EudraCT |
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 | Yes |
E.8.1.7.1 | Other trial design description |
STUDIO IN APERTO - DISEGNO A 3 STADI |
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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.8.5 | 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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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 | 7 |
E.8.9.1 | In the Member State concerned days | |
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 | 7 |