A phase III randomized, open-label, multi-center study of nilotinib versus imatinib in adult patients with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP) who have suboptimal cytogenetic response (CyR) on imatinib.

• Register: EUCTR
• Last refreshed on: 19 March 2012
• Main ID: EUCTR2005-005047-26-DE
• Date of registration: 27/09/2007
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: A phase III randomized, open-label, multi-center study of nilotinib versus imatinib in adult patients with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP) who have suboptimal cytogenetic response (CyR) on imatinib.
• Scientific title: A phase III randomized, open-label, multi-center study of nilotinib versus imatinib in adult patients with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP) who have suboptimal cytogenetic response (CyR) on imatinib.
• Date of first enrolment: 06/11/2007
• Target sample size: 608
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2005-005047-26
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no

Countries of recruitment

Belgium, Czech Republic, France, Germany, Greece, Hungary, Italy, Netherlands, Spain

Key inclusion & exclusion criteria

Inclusion criteria:
Male and female patients = 18 years of age.
ECOG performance status of 0,1, or 2.
Diagnosis of Ph+ CML-CP defined as:
<15% blasts in peripheral blood and bone marrow,
< 30% blasts plus promyelocytes in peripheral blood and bone marrow
< 20% basophils in the peripheral blood
=100 x 109 /L (>/ 100,000 /mm3) platelets
No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly
Patients with suboptimal cytogenetic response to a dose of 400 mg imatinib (1st line therapy) defined as = 6 to < 12 months of treatment and have 36 - 95% Ph+ metaphases, or = 12 to < 18 months of treatment and have 1 - 35% Ph+ metaphases. Bone marrow karyotyping is rquired on a min. of 20 metaphases. FISh analysis is not allowed.
The following laboratory results must be present:
Total bilirubin <1.5XULN; SGOT and SGPT <2.5XULN; Creatinine < 1.5XULN, Serum potassium, phosphorus, magnesium and calcium = LLN or correctable with supplements prior to the first doese of study drug. Serum amylase and lipase = 1.5xULN, alkaline phosphatase = 2.5XULN unless considered tumor related.

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:
Prior accelerated phase or blast phase CML.
Previously documented T315I mutation.
Achieved prior PCyR or CCyR on imatinib and lost that response prior to entering the study.
• Prior treatment with > 400 mg/day of imatinib.
• Patients who have received more than 18 months of imatinib therapy.
• Intolerance to imatinib = 400 mg/day defined as the inability to maintain dosing of 400 mg daily for the previous 3 months.
• Previous treatment with any other tyrosine kinase inhibitor except imatinib.
• Patients who had any other treatment for CML (e.g. interferon, transplant) except
hydroxyurea and/or anagrelide.
•Impaired cardiac function including any one of the following:
• LVEF < 45% by echocardiography
• Complete left bundle branch block
• Congenital long QT syndrome or family history of long QT syndrome
• History of or presence of significant ventricular or atrial tachyarrhythmias
• Clinically significant resting brachycardia (<50 bpm)
• QTcF > 450 msec on screening ECG (using the QTcF formula). If QTc > 450 and
electrolytes are not with normal ranges, electrolytes should be corrected and then the patient rescreened for QTc
• Use of a ventricular-paced pacemaker
• Myocardial infarction within one year of the first dose of study drug
• Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled
hypertension, unstable angina).
• Treatment with strong inducers (e.g., dexamethasone, phenytoin, carbamazepine,
rifampin, rifabutin, rifapentin, phenobarbitol, St John’s Wort), and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. See link in Section 6.6.4 for complete list of these medications.
• Treatment with strong CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. See link in Section 6.6.4 for complete list of these medications.
• Treatment with medications that have been well documented to prolong the QT interval is contraindicated. See Section 6.6.4 for further guidance.
• Impaired gastrointestinal (GI) function or GI disease that may significantly alter the
absorption of study drug (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery).
• History of acute pancreatitis within one year of study entry or medical history of chronic pancreatitis.
• Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS
involvement, lumbar puncture not required).
• Any other malignancy that is clinically significant or requires active intervention.
• Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or chronic liver disease, pancreatic, or severe renal disease unrelated to tumor, active or uncontrolled infection).
• History of significant congenital or acquired bleeding disorder unrelated to cancer.
• Previous radiotherapy to = 25% of the bone marrow.
• Patients who have had major surgery within 4 weeks prior to the first dose of study drug or who have not recovered from prior surgery.
• Use of therapeutic coumarin derivatives (i.e. warfarin, acenocoumarol, phenprocoumon).
• Treatment with other investigational agents within 28 days of Day 0 (first dose of
study drug).
• History of non-compliance to medical regimens or inability to grant consent.
• Wo

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

Health Condition(s) or Problem(s) studied

Nilotinib will be evaluated in patients having showed a suboptimal cytogenetic response to imatinib

Intervention(s)

Product Name: nilotinib
Product Code: AMN107
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: nilotinib
CAS Number: 641571-10-0
Other descriptive name: 4-Methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Trade Name: Glivec 100 mg Filmtabletten
Product Name: Glivec
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: imatinib
CAS Number: 220127-57-1
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Trade Name: Glivec 400 mg Filmtabletten
Product Name: Glivec
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: imatinib
CAS Number: 220127-57-1
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 400-

Primary Outcome(s)

Main Objective: To evaluate the complete cytogenetic response (CCyR ) rate at 12 months of nilotinib compared to imatinib in adult patients with Ph+ CML in CP who have a suboptimal cytogenetic response to imatinib.

Secondary Objective: •To evaluate the rate of durable CCyR at 24 mts (patients who have achieved CCyR by 12 mts, and maintain continuous CCyR until the 24 mts timepoint).

•To evaluate the rate of major molecular response (MMR) of nilotinib vs. Imatinib*.
•To evaluate the rate of durable CCyR over the initial 24 mts of this study*.
•To evaluate the CCyR rate of nilotinib vs. imatinib* at 24 mts.
•To evaluate the time to and duration of CCyR of nilotinib vs. imatinib*.
•To evaluate the time to, rate of, and duration of a = 4 log reduction in BCR-ABL transcript levels a from the standardized baseline (as established in the IRIS study), or = 0.01% BCR-ABL/control gene% by international scale of nilotinib vs. imatinib*.
•To evaluate the time to and duration of MMR of nilotinib vs. imatinib*.
•To describe overall survival, progression free survival and event-free survival up to 5 years*.
•To evaluate the safety profile of nilotinib and vs. imatinib*.

*in adult patients with Ph+ CML in CP

Primary end point(s): Primary efficacy
Complete cytogenetic Response (CCyR) rate at 12 months (CCyR is defined as 0% Ph+ metaphases)

Secondary ID(s)

2005-005047-26-BE

CAMN107A2302