A Study of Imatinib Versus Nilotinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) (ENESTnd)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00471497
First received: May 7, 2007
Last updated: October 14, 2013
Last verified: October 2013
  Purpose

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).


Condition Intervention Phase
Myelogenous Leukemia, Chronic
Drug: nilotinib
Drug: imatinib
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Molecular Response Rate (MMR) at 12 Months [ Time Frame: Baseline, 12 months ] [ Designated as safety issue: No ]
    Rate of MMR is defined as <= 0.1% BCR-ABL/ABL ratio by international scale (IS), measured by real-time quantitative polymerase chain reaction (RQ-PCR) which corresponds to a ≥ 3 log reduction of BCR-ABL transcript from standardized baseline. BCR-ABL = fusion gene from BCR (breakpoint cluster region gene/BCR gene product) and ABL (Abelson protooncogene)


Secondary Outcome Measures:
  • Rate of Durable MMR at 24 Months. [ Time Frame: Baseline, 24 months ] [ Designated as safety issue: No ]
  • Rate Reduction in BCR-ABL Transcript Levels in Nilotinib Treatment Arms With Imatinib at 12 Months [ Time Frame: Baseline, 12 months ] [ Designated as safety issue: No ]
  • Rate of Complete Cytogenetic Response (CCyR) in Nilotinib Treatment Arms With Imatinib at 12 Months [ Time Frame: Baseline, 12 months ] [ Designated as safety issue: No ]

Enrollment: 846
Study Start Date: July 2007
Estimated Study Completion Date: October 2018
Primary Completion Date: September 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Imatinib 400 mg QD
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.
Drug: imatinib
Imatinib was supplied as 100 mg and 400 mg tablets and administered orally at 400 mg QD (once a day).
Other Name: STI571
Experimental: Nilotinb 300 mg BID
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.
Drug: nilotinib
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.
Other Name: AMN107
Experimental: Nilotinib 400 mg BID
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.
Drug: nilotinib
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.
Other Name: AMN107

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00471497

  Show 219 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Additional Information:
No publications provided by Novartis

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00471497     History of Changes
Other Study ID Numbers: CAMN107A2303, 2007-000208-34
Study First Received: May 7, 2007
Results First Received: April 10, 2013
Last Updated: October 14, 2013
Health Authority: United States: Food and Drug Administration
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Austria: Ethikkommission
Belgium: Federal Agency for Medicinal Products and Health Products
Brazil: Ministry of Health
Canada: Health Canada
Colombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y Alimentos
Czech Republic: State Institute for Drug Control
Denmark: Danish Medicines Agency
Egypt: Ministry of Health and Population
Finland: Finnish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Hong Kong: Department of Health
Hungary: Research Ethics Medical Committee
Italy: Ministry of Health
Japan: Pharmaceuticals and Medical Devices Agency
Korea: Food and Drug Administration
Malaysia: Ministry of Health
Mexico: Ministry of Health
Netherlands: Medicines Evaluation Board (MEB)
Norway: Norwegian Medicines Agency
Poland: Ministry of Health
Russia: Ministry of Health of the Russian Federation
Singapore: Clinical Trials & Epidemiology Research Unit (CTERU)
Slovakia: State Institute for Drug Control
South Korea: Korea Food and Drug Administration (KFDA)
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Sweden: Medical Products Agency
Switzerland: Swissmedic
Taiwan: Department of Health
Thailand: Food and Drug Administration
Turkey: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Venezuela: Ministry of Health and Social Development

Keywords provided by Novartis:
leukemia
bone marrow
leukemia symptoms
cml
complete blood count
lymphocyte
blood cancer
leukocytes
chronic leukemia
bone marrow biopsy
leukemia research
leukemia cells
bone marrow disease
chronic myeloid leukemia
blood cancer symptoms
white blood cell diseases
chronic myelogenous leukemia
leukemia treatment
leukemia facts
leucemia
facts about leukemia
myelogenous leukemia
newly diagnosed CML
Philadelphia chromosome positive
Ph+
chronic phase
CML-CP

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Philadelphia Chromosome
Abnormal Karyotype
Chronic Disease
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Disease Attributes
Imatinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 26, 2014