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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT00109707
Registration number
NCT00109707
Ethics application status
Date submitted
2/05/2005
Date registered
3/05/2005
Date last updated
29/06/2021
Titles & IDs
Public title
A Study of Oral AMN107 in Adults With Chronic Myelogenous Leukemia (CML) or Other Hematologic Malignancies
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Scientific title
A Phase IA/II Multicenter, Dose-escalation Study of Oral AMN107 on a Continuous Daily Dosing Schedule in Adult Patients With Imatinib-resistant/Intolerant CML in Chronic or Accelerated Phase or Blast Crisis, Relapsed/Refractory Ph+ ALL, and Other Hematologic Malignancies.
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Secondary ID [1]
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CAMN107A2101
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Chronic Myelogenous Leukemia
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Acute Lymphoblastic Leukemia (Philadelphia Chromosome Positive)
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Hypereosinophilic Syndrome
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Systemic Mastocytosis
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
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0
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Leukaemia - Chronic leukaemia
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Cancer
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0
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Children's - Leukaemia & Lymphoma
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Cancer
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0
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Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
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Cancer
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Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
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Skin
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Other skin conditions
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Blood
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Other blood disorders
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Blood
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Haematological diseases
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Other
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Research that is not of generic health relevance and not applicable to specific health categories listed above
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Human Genetics and Inherited Disorders
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0
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Other human genetics and inherited disorders
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Experimental: CML-CP With Prior Imatinib Only - Imatinib-resistant / intolerant PH+ CML-CP patients
Experimental: CML-AP With Prior Imatinib Onl - Imatinib-resistant / intolerant PH+ CML-AP patients
Experimental: CML-CP - Imatinib-resistant / intolerant PH+ CML-CP patients
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of Participants With Major Cytogenetic Response (MCyR)
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Assessment method [1]
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Major Cytogenetic Response (MCyR) is defined as Complete Cytogenetic Response (CCyR: 0% Ph-chromosome-positive cells in metaphase in bone marrow) or Partial Cytogenetic Response (PCyR: 1-35% Ph-chromosome-positive cells in metaphase in bone marrow).
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Timepoint [1]
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Up to End of the Treatment (Approximately 7.5 years)
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Primary outcome [2]
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Number of Participants Confirmed Overall Hematological Response (Phase II)
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Assessment method [2]
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Hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count \<10 x 109/L, Platelet count \<450 x 109/L, Basophils \<5%, No blasts and promyelocytes in peripheral blood, Myelocytes + metamyelocytes \< 5% in peripheral blood, No evidence of extramedullary disease, including spleen and liver).
Hematological response was a primary outcome measure for Arm CML-AP with prior imatinib only.
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Timepoint [2]
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Up to End of the Treatment (Approximately 7.5 years)
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Secondary outcome [1]
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Number of Participants With Overall Major Cytogenetic Responses (Phase II)
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Assessment method [1]
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Cytogenetic responses (CyRs) in CML are based on the percentage of Ph+ metaphases in bone marrow; a value of 0% Ph+ metaphases defines a complete cytogenetic response (CCyR) and \>0% to 35% defines a major cytogenetic response (MCyR). Achievement of CCyR is associated with a significant survival advantage in participants with CML-CP. MCyR was categorized as either CCyR or partial cytogenetic response (PCyR).
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Timepoint [1]
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Up to End of the Treatment (Approximately 7.5 years)
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Secondary outcome [2]
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Number of Participants With Complete Hematologic Response (Phase II)
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Assessment method [2]
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A Complete Hematologic Response (CHR) is obtained when all the following criteria are met: WBC = institutional ULN; platelets = 450,000/mm3; =20% basophils in peripheral blood; no blasts or promyelocytes in PB cells; \< 5% myelocytes plus metamyelocytes in PB cells; no extra-medullary involvement including no hepatomegaly or splenomegaly.
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Timepoint [2]
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Up to End of the Treatment (Approximately 7.5 years)
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Secondary outcome [3]
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Participants With (MMR) Major Molecular Response (Phase II)
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Assessment method [3]
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MMR was defined for participants who demonstrated a reduction in BCR-ABL/control gene % transcripts to =0.1% based on international scale. The control gene used may have been either BCR or ABL.
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Timepoint [3]
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Up to End of the Treatment (Approximately 7.5 years)
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Secondary outcome [4]
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Time to Progression (TTP) (Phase II)
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Assessment method [4]
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Time to Progression was defined as the time from the start of nilotinib to the earliest date of Disease Progression (PD), discontinuation due to PD or death.
Disease progression was defined as an increase in the number of circulating leukemic cells via cytogenetic assessment using real-time quantitative reverse transcriptase polymerase chain reaction (PCR).
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Timepoint [4]
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Up to End of the Treatment (Approximately 7.5 years)
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Secondary outcome [5]
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Overall Survival (OS) (Phase II)
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Assessment method [5]
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OS was calculated for all participants as the time between the start of nilotinib and death. Participants were followed for survival after discontinuation, every 3 months, and were included in the analysis of OS. Censoring was at the date of the last contact for discontinued participants and followed up for survival.
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Timepoint [5]
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Up to End of the Treatment (Approximately 7.5 years)
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Secondary outcome [6]
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Number of Participants With Adverse Events and Serious Adverse Events to Evaluate Long Term Safety
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Assessment method [6]
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Adverse events (AEs) were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards.
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Timepoint [6]
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From First Participant First Visit to Last Participant Last Visit (Approximately 7.5 years)
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Eligibility
Key inclusion criteria
Main inclusion criteria include:
* Patients with CML in blast crisis, CML in accelerated phase defined as never in blast crisis phase, or CML in chronic phase defined as never been in blast crisis phase or accelerated phase who have: *developed progressive disease during therapy with at least 600 mg of imatinib per day, -OR- *patients with CML on imatinib therapy, at any dose, developing progressive disease and the presence of a genetic mutation likely to result in imatinib resistance -OR- *have developed an intolerance to imatinib
* Relapsed or refractory Ph+ ALL
* Hypereosinophilic syndrome/chronic eosinophilic leukemia.
* Systemic mastocytosis who have a clinical indication for treatment.
* Prior imatinib therapy for patients with Ph+ ALL, HES/CEL and SM is permitted but is not required
* CML patients who have been treated with an investigational tyrosine kinase inhibitor who otherwise meet the definition of imatinib-resistance or intolerance are eligible
* Written informed consent prior to any study procedures being performed
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
* Impaired cardiac function
* Patients with severe/chronic or uncontrolled medical conditions (including but not limited to diabetes, infections, GI impairment, CNS infiltration, liver and kidney disease)
* Prior and concomitant use of certain medications (including but not limited to warfarin, chemotherapy, hematopoietic colony-stimulating growth factors, medications that can affect electrocardiogram test results, other investigational drugs )
* Women who are pregnant or breastfeeding
* Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.
* Patients unwilling to comply with the protocol.
* Known diagnosis of human immunodeficiency virus (HIV) infection
Other protocol-defined inclusion/exclusion criteria may apply
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/04/2005
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/09/2012
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Sample size
Target
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Accrual to date
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Final
507
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Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
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Recruitment hospital [1]
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Novartis Investigative Site - St. Leonards
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Recruitment hospital [2]
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Novartis Investigative Site - Adelaide
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Recruitment hospital [3]
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Novartis Investigative Site - Prahran
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Recruitment postcode(s) [1]
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2065 - St. Leonards
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Recruitment postcode(s) [2]
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5000 - Adelaide
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Recruitment postcode(s) [3]
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3181 - Prahran
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Recruitment outside Australia
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California
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Colorado
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Louisiana
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Newcastle upon Tyne
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
Novartis Pharmaceuticals
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Address
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Ethics approval
Ethics application status
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Summary
Brief summary
The purpose of this trial is to assess the efficacy, safety, tolerability, biologic activity, and pharmacokinetics of AMN107 in six groups of patients with one of the following conditions: Relapsed/refractory Ph+ Acute lymphoblastic leukemia (ALL) (arm 1) Group A - Imatinib failure only (arms 2, 3 and 4) * imatinib-resistant or intolerant CML - Chronic Phase (CP) * imatinib-resistant or intolerant CML - Accelerated Phase (AP) * imatinib-resistant or intolerant CML - Blast Crisis (BC) Group B - Imatinib and other TKI failure (arms 2, 3 and 4) * imatinib-resistant or intolerant CML - Chronic Phase (CP) * imatinib-resistant or intolerant CML - Accelerated Phase (AP) * imatinib-resistant or intolerant CML - Blast Crisis (BC) Hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL) (arm 5) Systemic mastocytosis (Sm) (arm 6)
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Trial website
https://clinicaltrials.gov/study/NCT00109707
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Trial related presentations / publications
Hochhaus A, Baccarani M, Giles FJ, le Coutre PD, Muller MC, Reiter A, Santanastasio H, Leung M, Novick S, Kantarjian HM. Nilotinib in patients with systemic mastocytosis: analysis of the phase 2, open-label, single-arm nilotinib registration study. J Cancer Res Clin Oncol. 2015 Nov;141(11):2047-60. doi: 10.1007/s00432-015-1988-0. Epub 2015 May 23. Hochhaus A, le Coutre PD, Kantarjian HM, Baccarani M, Erben P, Reiter A, McCulloch T, Fan X, Novick S, Giles FJ. Effect of the tyrosine kinase inhibitor nilotinib in patients with hypereosinophilic syndrome/chronic eosinophilic leukemia: analysis of the phase 2, open-label, single-arm A2101 study. J Cancer Res Clin Oncol. 2013 Dec;139(12):1985-93. doi: 10.1007/s00432-013-1529-7. Epub 2013 Sep 22. Stein AM, Martinelli G, Hughes TP, Muller MC, Beppu L, Gottardi E, Branford S, Soverini S, Woodman RC, Hochhaus A, Kim DW, Saglio G, Radich JP. Rapid initial decline in BCR-ABL1 is associated with superior responses to second-line nilotinib in patients with chronic-phase chronic myeloid leukemia. BMC Cancer. 2013 Apr 2;13:173. doi: 10.1186/1471-2407-13-173. Kantarjian HM, Giles FJ, Bhalla KN, Pinilla-Ibarz J, Larson RA, Gattermann N, Ottmann OG, Hochhaus A, Radich JP, Saglio G, Hughes TP, Martinelli G, Kim DW, Shou Y, Gallagher NJ, Blakesley R, Baccarani M, Cortes J, le Coutre PD. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011 Jan 27;117(4):1141-5. doi: 10.1182/blood-2010-03-277152. Epub 2010 Nov 22. Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, Ossenkoppele GJ, Nicolini FE, O'Brien SG, Litzow M, Bhatia R, Cervantes F, Haque A, Shou Y, Resta DJ, Weitzman A, Hochhaus A, le Coutre P. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007 Nov 15;110(10):3540-6. doi: 10.1182/blood-2007-03-080689. Epub 2007 Aug 22. Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006 Jun 15;354(24):2542-51. doi: 10.1056/NEJMoa055104.
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Results are available at
https://clinicaltrials.gov/study/NCT00109707
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