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Dynamics of ABL Mutations in Imatinib Failed Ph Positive or Bcr-Abl Positive CML CP or AP Patients Who Treated With Nilotinib as Second-line TKI Therapy (AMICAN-Prospective)in Asia

Phase 2
18 Years
Open (Enrolling)
Chronic Myeloid Leukemia

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Trial Information

Dynamics of ABL Mutations in Imatinib Failed Ph Positive or Bcr-Abl Positive CML CP or AP Patients Who Treated With Nilotinib as Second-line TKI Therapy (AMICAN-Prospective)in Asia

Recently the treatment strategy of Philadelphia chromosome-positive leukemia has undergone
groundbreaking changes due to the development of new second-generation cancer-targeting
drugs. After 2001, a seven-year survival for leukemia stands at as much as 86 percent due to
the oral therapy of cancer-targeting imatinib as a standard treatment, but drug resistance
occurs in some patients in the early stage of the treatment. It is known that weakened
binding ability of imatinib to BCR-ABL is due to a point mutation in the ATP-binding site of
BCR-ABL. This accounts for 70 percent of causes of imatinib resistance. According to the
studies so far, there are approximately more than 60 types of BCR-ABL point mutation, which
causes imatinib resistance.

The international phase II clinical study of dasatinib and nilotinib, second-generation
cancer-targeting therapies, in imatinib failed patients which began in 2005 showed that more
than 70 percent of the patients achieved a complete hematological response (CHR) again, and
about 50 percent of the patients, a major hematological response (MHR). In the study, it was
also observed that kinase activation was inhibited by a second-generation cancer-targeting
therapy for most of the major imatinib-resistant point mutations. With regard to peculiar
point mutations, V299L, F317L, and E25K/V show relative resistance to dasatinib, and p-loop
mutations including G250E, Q252H, Y253F/H and E255K/V and F359C/V show relative resistance
to nilotinib. T315I mutation exhibits strong resistance to both of these cancer-targeting
therapies. Therefore, it is considered that the second-generation cancer-targeting therapies
show therapeutic effects in different domains.

According to the results of the recent studies including the one conducted by our center, it
is assumed that imatinib resistance caused by point mutations in patients induces more point
mutations and causes selective increase in T315I point mutations during treatment of the
second-generation cancer-targeting therapy.

However, in the studies so far, the subjects were selectively chosen in advance for the
pharmaceutical company to receive an approval from the health authorities and ABL point
mutations were followed up during the limited study period, which indicates that there have
been limits to accurately observe and evaluate dynamics of point mutations throughout
treatment with the second-generation cancer-targeting drug.

For this reason, this study is designed to examine ABL point mutations in patients with
Philadelphia chromosome-positive or BCR-ABL-positive chronic leukemia who are treated with
imatinib, to observe dynamics of existing point mutations during treatment with nilotinib,
and to confirm the mechanism of resistance including expression of new point mutations and
their expression patterns through a long-term follow-up. In addition, this study will
confirm whether expression pattern of ABL point mutations associated with nilotinib in Asian
is different from that in Western patients.

Inclusion Criteria:

- Patients with Philadelphia chromosome-positive or BCR-ABL positive CML

- Chronic, Accelerated phase CML patients who show an inappropriate response to the
imatinib treatment or failed the treatment according to ELN 2009 RECOMMENDATION

- Patients with ECOG performance status of 0-3

- Patients who consent to the use of study information and study specimen

Exclusion Criteria:

- Patients with diseases other than CML

- Patients treated with myelosuppressive anticancer therapy other than Hydroxyurea and

- Patients who have been treated with second-generation cancer-targeting drug

- Patients who do not consent to the use of study information and study specimen

- Previously documented T315I mutation

- Impaired cardiac function including any of the following: LVEF by echocardiography <
45% or below the institutional lower range (whichever is greater); complete left
bundle branch block; long QT syndrome or family history of; history or presence of
significant ventricular or atrial tachyarrhythmias; clinically significant
brachycardia (< 50 bpm); QTcF > 450 msec at baseline; right bundle branch block plus
left anterior hemiblock; bifascicular block; myocardial infarction ≤ 12 months;
uncontrolled angina; other clinically significant heart disease (e.g., congestive
heart failure)

- Treatment with strong inhibitors of CYP3A4 or medication that are well documented to
prolong the QT interval are contraindicated

- Impaired gastrointestinal(GI)function or GI disease that may significantly alter the
absorption of the study drug (e.g., ulcerative diseases, uncontrolled nausea,
vomitting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass

- History of acute pancreatitis within 1 year of study entry or past medical history of
chronic pancreatitis

- Know cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS
involvement, lumbar puncture not required)

- Patients who previously had a bone marrow or stem cell transplantation

- Pregnant or breast-feeding patients

- Hypersensitivity to nilotinib or any of the excipients

- The capsules contain lactose, and nilotinib is therefore not recommended for patients
with rare hereditary problem of galactose intolerance, severe lactase deficiency or
glucose-galactose malabsorption

Type of Study:


Study Design:

Observational Model: Case Control, Time Perspective: Prospective

Outcome Measure:

To confirm the patterns of resistance including point mutations which are newly expressed during the nilotinib treatment

Outcome Time Frame:

5 years

Safety Issue:


Principal Investigator

Dong-Wook Kim, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Seoul St. Mary's Hospital


Korea: Food and Drug Administration

Study ID:




Start Date:

July 2011

Completion Date:

June 2015

Related Keywords:

  • Chronic Myeloid Leukemia
  • Leukemia
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive