E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with accelerated phase (AP) or blast crisis (BC) CML who have disease-resistance following treatment with at least two BCR-ABL tyrosine kinase inhibitors (i.e., imatinib, nilotinib, or dasatinib). |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009015 |
E.1.2 | Term | Chronic myeloid leukemia |
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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 |
To assess the hematologic response (complete hematologic response (CHR) / no evidence of leukemia (NEL) / return to chronic phase (RTC)) rate |
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E.2.2 | Secondary objectives of the trial |
1. To determine the duration of the hematologic response 2. To determine the complete cytogenetic response (CCyR) rate 3. To determine the major (complete/partial) cytogenetic response rate 4. To determine the overall (complete/partial/minor/minimal) cytogenetic response rate 5. To determine the duration of complete cytogenetic response 6. To determine the duration of major cytogenetic response 7. To determine the major and complete molecular response rates 8. To characterize BCR-ABL mutations of patients at study entry and, in responding patients, at the time of disease progression 9. To estimate progression-free survival time 10. To estimate overall survival time 11. To characterize the population pharmacokinetics 12. To monitor the QTc interval in patients receiving oral LBH589 13. To evaluate the safety and tolerability profile of oral LBH589 when given at 20 mg p.o. on Mon, Wed, Fri weekly
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male or female patients aged ≥ 18 years old • Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed • Diagnosis of Ph+ accelerated or blast phase CML defined as: Accelerated phase - the presence of at least one of the following: - ≥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) - ≥ 20% basophiles in the peripheral blood - Thrombocytopenia <100 X 109 /L unrelated to therapy Blast phase (blast crisis) - the presence of one of the following: - ≥ 30% blasts in the blood, marrow or both - Extramedullary infiltrates of leukemic cells • Prior treatment with at least two BCR-ABL tyrosine kinase inhibitors (i.e., imatinib, nilotinib, or dasatinib) and demonstrated 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: - A patient who was in chronic phase CML who had disease progression to either accelerate phase or blast crisis - A patient who was in accelerated phase had disease progression to blast crisis - Patients in AP or BC who did not achieve a hematologic response (defined as not achieving CHR, NEL or RTC) within 3 months of starting therapy - Patients in AP or BC who had increasing blast counts in peripheral blood or increasing marrow leukemic infiltrate (MLI, the percent marrow blasts multiplied by marrow cellularity) • 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 must meet special laboratory criteria (details see protocol) • Baseline MUGA or ECHO must demonstrate LVEF ≥ the lower limit of the institutional normal • Patients with an ECOG Performance Status of ≤ 2
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E.4 | Principal exclusion criteria |
• A candidate for hematopoitic stem cell transplantation (HSCT) (i.e. patient is a candidate has an appropriate donor, and agrees to transplantation) • Prior treatment with an HDAC inhibitor • Patients who are in chronic phase (CP) CML • Impaired cardiac function including any one of the following: - Screening ECG with a QTc > 450 msec - Patients with congenital long QT syndrome - History of sustained ventricular tachycardia - Any history of ventricular fibrillation or torsades de pointes - Bradycardia defined as HR < 50 beats per minute (patients with a history of bradycardia who now have a permanent pacemaker and HR ≥ 50 bpm are eligible) - Patients with a myocardial infarction or unstable angina within 6 months of study entry - Congestive heart failure (NY Heart Association class III or IV) - Right bundle branch block and left anterior hemiblock (bifasicular block) - Uncontrolled hypertension • Concomitant use of drugs with a risk of possible risk of causing QTc prolongation or torsades de pointes listed in [Post-text Supplement 1 ] • Concomitant use of CYP3A4 inhibitors listed in [Post-text Supplement 1] • Concomitant use of any other anti-cancer therapy except anegrilide or hydroxyurea (see Section 6.6.7) • Patients with unresolved diarrhea CTCAE grade 1 • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LBH589 • Patients who have received chemotherapy, any investigational drugs (other than BCR-ABL tyrosine kinase inhibitors) or undergone major surgery < 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy • Patients who have received a BCR-ABL tyrosine kinase inhibitor within 1 week of first treatment with LBH589 • 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 • 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) |
Efficacy: • Hematologic response (CHR, NEL, RTC) • Cytogenetic response (complete, partial, minor, minimal) • Molecular response (major and complete) • Duration of hematologic response • Duration of complete cytogenetic response • Duration of major cytogenetic response • Progression free survival time • Overall survival time Safety: • AEs as determined by CTCAE version 3, SAEs
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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 | 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 | 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) | 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.8.5.1 | Number of sites anticipated in the EEA | 38 |
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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Patients may continue treatment with oral LBH589 until they experience e.g. unacceptable toxicity that precludes further treatment, disease progression, and/or at the discretion of the investigator (for details see study protocol).
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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 | 6 |
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 | 6 |