Overview

This trial is active, not recruiting.

Condition myelogenous leukemia, chronic
Treatments nilotinib, imatinib
Phase phase 3
Target BCR-ABL
Sponsor Novartis Pharmaceuticals
Start date July 2007
End date September 2009
Trial size 846 participants
Trial identifier NCT00471497, 2007-000208-34, CAMN107A2303

Summary

In this study, the efficacy and safety of two nilotinib doses, 300 mg twice daily and 400 mg twice daily, will be compared with imatinib 400 mg once daily in newly diagnosed patients with Philadelphia chromosome-positive (Ph+) Chronic Myelogenous Leukemia in the chronic phase (CML-CP).

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Patients randomized to this arm were to receive 400 mg imatinib once a day (QD). If the patient required a dose escalation from 400 mg/day, the patient was to receive 400 mg imatinib twice daily orally. Imatinib was taken with food and a large glass of water. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits during the study. In cases of vomiting doses were not to be repeated.
imatinib STI571
Imatinib was supplied as 100 mg and 400 mg tablets and administered orally at 400 mg QD (once a day).
(Experimental)
Patients who were randomized to this arm were to receive nilotinib 300 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
nilotinib AMN107
Nilotinib was supplied as 50 mg, 150 mg and 200 mg hard gelatin capsules and administered orally at 300 mg BID (twice a day) or 400 mg BID (twice a day)depending on the randomized dose.
(Experimental)
Patients who were randomized to this arm were to receive nilotinib 400 mg twice a day (BID) by mouth each morning and evening approximately 12 hours apart. If the morning or evening dose was delayed for more than 4 hours, the patient was to skip this dose and resume dosing with the next dose as per the original schedule in order to prevent overdosing. No imatinib washout period was necessary prior to administration of nilotinib. Nilotinib was not to be taken with food. No food was to be consumed for at least 2 hours before the dose was taken and no additional oral intake other than water was to be consumed for at least one hour after the dose was taken. Patients were instructed to swallow capsules whole with a full 8 ounce glass of water, and not to chew them. All patients were to avoid grapefruit, star fruit, pomegranate and Seville oranges or juices and products containing these fruits. Vomited doses were not to be repeated.
nilotinib AMN107
Nilotinib was supplied as 50 mg, 150 mg and 200 mg hard gelatin capsules and administered orally at 300 mg BID (twice a day) or 400 mg BID (twice a day)depending on the randomized dose.

Primary Outcomes

Measure
Molecular Response Rate (MMR) at 12 Months
time frame: Baseline, 12 months

Secondary Outcomes

Measure
Rate of Durable MMR at 24 Months.
time frame: Baseline, 24 months
Rate Reduction in BCR-ABL Transcript Levels in Nilotinib Treatment Arms With Imatinib at 12 Months
time frame: Baseline, 12 months
Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months
time frame: Baseline, 12 months

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion criteria: - ECOG 0, 1, or 2. - Patients with CML-CP within 6 months of diagnosis (date of initial diagnosis is the date of first cytogenetic analysis). Standard conventional cytogenetic analysis must be done on bone marrow. (FISH cannot be used) - Diagnosis of chronic myelogenous leukemia in chronic phase with cytogenetic confirmation of Philadelphia chromosome of (9;22) translocations (presence of BCR-ABL: a review of a minimum 20 metaphases is required.). - Documented chronic phase CML will meet all the criteria defined by: - < 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 - Adequate end organ function as defined by: - Total bilirubin < 1.5 x ULN - SGOT and SGPT < 2.5 x ULN - Creatinine < 1.5 x ULN - Serum amylase and lipase ≤ 1.5 x ULN - Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related. - Female patients of childbearing potential must have a negative serum pregnancy test within 7 days before initiation of study drug. - Patients must have the following laboratory values (≥ LLN (lower limit of normal) or corrected to within normal limits with supplements prior to the first dose of study medication.): - Potassium ≥ LLN - Magnesium ≥ LLN - Phosphorus ≥ LLN - Total calcium (corrected for serum albumin) ≥ LLN. - Ability to provide written informed consent prior to any study related screening procedures being performed. Exclusion criteria: - Patients who are considered to be Philadelphia chromosome negative because they do not have a confirmed cytogenetic diagnosis of Philadelphia chromosome (9,22 translocation) positive CML. - Previously documented T315I mutations. - Treatment with tyrosine kinase inhibitor(s) prior to study entry is not allowed, except in the following situation: in emergent cases where the patient requires disease management while awaiting study start, commercial supplies of Gleevec/Glivec at any dose may be prescribed to the patient but for no longer than 2 weeks in duration. - Any medical treatment for CML prior to study entry for longer than 2 weeks with the exception of hydroxyurea and/or anagrelide - Impaired cardiac function including any one of the following: - LVEF < 45% or below the institutional lower limit of the normal range (whichever is higher) as determined by locally read echocardiogram - Inability to determine the QT interval on ECG - Complete left bundle branch block - Use of a ventricular-paced pacemaker - Congenital long QT syndrome or a known family history of long QT syndrome. - History of or presence of clinically significant ventricular or atrial tachyarrhythmias - Clinically significant resting bradycardia (<50 beats per minute) - QTc > 450 msec on the average of three serial baseline ECG (using the QTcF formula) as determined by central reading. If QTcF >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc - History of clinically documented myocardial infarction - History of unstable angina (during the last 12 months) - Other clinically significant heart disease (e.g., congestive heart failure or uncontrolled hypertension). - Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required). - Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection). - History of significant congenital or acquired bleeding disorder unrelated to cancer. - Previous radiotherapy to ≥ 25% of the bone marrow. - Major surgery within 4 weeks prior to Day 1 of study or who have not recovered from prior surgery. - Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 30 days of Day 1. - History of non-compliance to medical regimens or inability to grant consent. - Use of therapeutic coumarin derivatives (i.e., warfarin, acenocoumarol, phenprocoumon) - Patients with another primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention - Patients actively receiving therapy with strong CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. See link for complete list of these medications: http://medicine.iupui.edu/flockhart/table.htm. Novartis must be contacted if a patient needs to be started on any of these drugs during study treatment. - Patients actively receiving therapy with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbitol, St. John's Wort) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. See link for complete list of these medications: http://medicine.iupui.edu/flockhart/table.htm. Novartis must be contacted if a patient needs to be started on any of these drugs during study treatment. - Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery) - History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis. - Acute or chronic liver, pancreatic or severe renal disease considered unrelated to disease. - Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug (Please see http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm for a comprehensive list of agents that prolong the QT interval) - Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior to baseline and (d) female of childbearing potential unwilling to use contraceptive precautions throughout the trial (post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential) Other protocol-defined inclusion/exclusion criteria may apply

Additional Information

Official title A Phase III Multi-center, Open-label, Randomized Study of Imatinib Versus Nilotinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)
Trial information was received from ClinicalTrials.gov and was last updated in October 2013.
Information provided to ClinicalTrials.gov by Novartis.