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

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2006-000881-35-DE
• Date of registration: 28/03/2007
• Prospective Registration: No
• Primary sponsor: Novartis Pharma Services AG
• Public title: A phase II, multicentre study of oral LBH589 in patients with chronic phase chronic myeloid leukemia with resistant disease following treatment with at least two BCR-ABL tyrosine kinase inhibitors
• Scientific title: A phase II, multicentre study of oral LBH589 in patients with chronic phase chronic myeloid leukemia with resistant disease following treatment with at least two BCR-ABL tyrosine kinase inhibitors
• Date of first enrolment: 16/03/2007
• Target sample size: 120
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-000881-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no

Countries of recruitment

Belgium, Denmark, France, Germany, Italy, Netherlands, United Kingdom

Key inclusion & exclusion criteria

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+ chronic phase CML (details see study protocol)
• No evidence of extramedullary leukemic involvement, with the exception of liver or spleen
• Prior treatment with at least two BCR-ABL tyrosine kinase inhibitors (including imitinib and another BCR-ABL TKI (such as nilotinib, dasatinib etc) and demonstration of resistance to the kinase inhibitor therapy.
• Resistance for eligibility into this protocol is defined as:
1. Primary hematologic resistance:
• Patients who do not achieve a CHR within 6 months of starting therapy.
• Patients who did not achieve a CHR at any time and whose disease progressed on therapy as defined by a doubling of the WBC to a value of more than 20,000 per cubic millimeter despite receiving maximally tolerated doses of therapy. Doubling of WBC should be confirmed on two blood samples obtained at least one week apart and within two weeks, not attributable to other causes (e.g. infection)
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 not attributed to other causes (eg infection), 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 i.e., the loss of cytogenetic response
• Defined as an increase in the absolute percentage points of Ph+ positive cells in metaphase from the best response (ie, lowest percent Ph+ cells) by =30 %(eg a rise from 10 to 40%)
• Patients whose best most recent cytogenetic result was > 70% and = 80% Ph+ metaphases, will also be eligible to enter the study if they were stable for =3 month at that level, before they progressed to 100% Ph+ metaphases
• Patients with a history of intolerance to one BCR-ABL kinase inhibitors (will be considered eliginle to enter the study if they demonstrate resistance to their most recent BCR-ABL TKIas 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 recures for 3 times despite dose reduction.
• Patients who are intolerant of at least 2 BCR-ABL kinase inhibitors will be considered eligible to enter this study if they also have history of resistance to or intolerance of interferon-alpha (IFN-a) at any time by the same criteria defined above.
• Patients must also meet special laboratory criteria (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 with a prior history of accelerated phase or blast crisis 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 i.v)
- 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, 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 investigationsl 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 barrietr methode (i.e condom) during the study and 3 months after the end of tratment. 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 tratment.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Adult patients with chronic phase Ph+ CML whose disease is resistant following treatment with at least two BCR-ABL tyrosine kinase inhibitors (i.e. imitinib, nilotinib, or dasatinib).
MedDRA version: 8.1 Level: LLT Classification code 10009015 Term: Chronic myeloid leukemia

Intervention(s)

Product Name: LBH589
Product Code: LBH589
Pharmaceutical Form: Capsule, hard
Current Sponsor code: LBH589
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Product Name: LBH589
Product Code: LBH589
Pharmaceutical Form: Capsule, hard
Current Sponsor code: LBH589
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-

Primary Outcome(s)

Secondary Objective: 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 on p.o. Mon, Wed, Fri weekly

Primary end point(s): Efficacy:
• Cytogenetic response (complete, partial, minor, minimal)
• Complete hematologic response
• Molecular response (major and complete)
• Duration of major cytogenetic response
• Progression free survival time

Safety:
• AEs as determined by CTCAE version 3, SAEs

Main Objective: To assess the major (complete/partial) cytogenetic response (MCyR) rate

Secondary ID(s)

2006-000881-35-DK

CLBH589B2202