Trial Information

CML/021 "A Phase II Exploratory Study of IMATINIB High Dose (800mg/gg) in the Treatment of Newly Diagnosed Intermediate Risk Chronic Myeloid Leukemia in Chronic Phase"

This is a phase II multicenter, open-label study designed to investigate the efficacy
(hematological response, cytogenetic response and molecular response) and feasibility
(tolerance, compliance and safety) of the tyrosine kinase inhibitor imatinib mesylate
(formerly STI 571, GLIVECÔ, Novartis Pharma) at high dose (800 mg/daily) (serial number
protocol ICSG/CML/021) in patients with Ph+ chronic myeloid leukemia (CML) in chronic phase
(CP) previously untreated, at intermediate Sokal risk.

With aIFN, responses (HR and CgR) are significantly influenced by the disease phase and, in
CP patients, by risk. aIFN induces rare and short lived HR and CgR (any degree) in late CP
and particularly in accelerated and blastic phase.

Moreover, in CP patients Sokal's risk influences significantly the probability of obtaining
a MCgR after aIfaIFN . As far as survival, after aIFN even in CCgR patients, the long term
survival is signifcantly influenced by risk. The European investigators on Interferon in CML
(EICML) collected informations on response and survival on 317 complete cytogenetic
responders to IFN. The 10 years survival of the whole patients population was 75% but, after
stratification by risk, a significant difference in 10 years survival rates was found in
favour of low risk patients (89%) if compared with intermediate risk (70%) and high risk
patients (54%) (low vs high risk p 0.0001; intermediate vs high p 0.003, log-rank test).

Long term survival data still lacks after imatinib. However, it has been already shown that
the disease phase influences the efficacy of imatinib in CML: responses (HR and particularly
CgR) are better in CP versus accelerated and blastic phase. Results in CP are better in
patients treated early after the onset of the disease with respect to late CP . To date,
the early McR rate to imatinib is clearly higher in low and intermediate risk versus high
risk (88 and 84% versus 65%).

Two scoring systems are available for disease risk evaluation, Sokal and Euro. Sokal risk
is based on chemotherapy treated patients and Euro risk is based on aIFN trated patients:
it is not known to date if one or both of the scoring systems will apply to imatinib
treated patients. Moreover, the Sokal system has been applied to stratify the patients by
risk in all the large clinical trials of imatinib in CML in the last 3 years and
consequently, Sokal score will be employed in the present trial.

Study objectives

Primary:

To determine the rate of complete cytogenetic response at 12 months in adult patients with
previously untreated intermediate Sokal risk CML treated with imatinib 800 mg/daily

Secondary:

To determine:

1. The rate of major cytogenetic response at 6 and 12 months.

2. The kinetic of cytogenetic response at 6 and 12 months

3. The duration of complete cytogenetic response.

4. The rate and duration of hematologic response.

5. The degree and the timing of molecular response

6. The time to accelerated and blast crisis and overall survival

7. The safety and tolerability of the treatment.