A phase II, multicentre study of oral LBH589 in patients with accelerated phase or blast phase (blast crisis) chronic myeloid leukemia with resistant disease following treatment with at least two BCR-ABL tyrosine kinase inhibitors

• Conditions: 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).; MedDRA version: 8.1Level: LLTClassification code 10009015Term: Chronic myeloid leukemia

• Registration Number: EUCTR2006-002011-27-DE
• Lead Sponsor: ovartis Pharma Services AG

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2007-01-19
• Last Update Posted: 19 March 2012

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 71

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 peripheral blood or bone marrow
- =30% blasts + 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 sole therapy
Blast phase (blast crisis) - the presence of one of the following:
- = 30% blasts in the blood, bone marrow or both
- Extramedullary infiltrates of leukemic cells
• Prior treatment with at least 2 BCR-ABL tyrosine kinase inhibitors (including imatinib and another BCR-ABL TKI (such as nilotinib, dasatinib, etc) and demonstrate 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 inhibitor will be considered eligible to enter the study if they demonstrate resistance to their most recent BCR-ABL kinase inhibitor as defined above. Intolerance is defined as discontinuation of treatment due to either grade 3 or 4 adverse events related to treatment, or grade 2 adverse events related to treatment that persist for =one month or that recurs for more than 3 times despite dose reduction
• Patients must also 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

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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 for the treatment of CML
• 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 (NYHA class III or IV)
- Right bundle branch block and left anterior hemiblock (bifasicular block)
- Uncontrolled hypertension
• Concomitant use of drugs with a risk of causing QTc prolongation or torsades de pointes, see section 6.6.8
• Concomitant use of CYP3A4/5 inhibitors, see section 6.6.8
• 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 would need to receive valproic acid for any reason during the study or = 5 days prior to starting study drug
• Patients who have received chemotherapy = 3 weeks 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 = 2 weeks (or within 5 half-lives of the investigational agent or active metabolites) prior to starting study drug or who have not recovered from side effects of such therapy
• Patients who have undergone major surgery = 3 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 willing to use a double methode of contraception including a barrier method (i.e. condom) during the study and 3 months after the end of treatment. 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 willing to use a double methode of contraception including condom during the study and 3 months after the end of treatment.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified