Comparing Imatinib Standard Dose With Imatinib High Dose Induction in Pretreated Chronic Myeloid Leukemia (CML) Patients in Chronic Phase

Multicenter, Phase III Study Comparing Imatinib (STI571, Glivec®) Standard Dose (400 Mg/Day) With Imatinib High Dose Induction (800 Mg/Day) Followed by Standard Dose Maintenance (400 Mg/Day) in Pretreated CML Patients in Chronic Phase

This study will investigate the efficacy and tolerability of a short (6 months) high dose therapy followed by a standard dose compared to a continuous treatment with a standard dose of imatinib (Glivec®) in pretreated Philadelphia chromosome- positive (Ph+)/BCR-ABL+ CML patients in chronic phase.

Patients with CML not achieving or losing a major cytogenetic response on whatever palliative treatment for CML, are at high risk to progress to accelerated phase and blast crisis. A new promising treatment with Imatinib (Glivec®), a tyrosine-kinase inhibitor, has been introduced recently. High rates of hematologic and cytogenetic responses can be achieved with Imatinib (Glivec®) at > = 300 mg/day in chronic phase CML patients that are refractory, resistant or intolerant to interferon-alpha. However, about 10 - 20% of these high risk patients will lose their response to Imatinib (Glivec®) within 1-2 years. Therefore, improvement of the treatment is warranted.

Since cytogenetic response rate is correlated to survival and the resistance to Imatinib (Glivec®) might be caused by mutations in the receptor, a more rapid decrease could lead to longer survival and/or less resistance development. In the initial 6 months of treatment, monotherapy with Imatinib (Glivec®) with a dose of 800 mg/day (high dose) should be more effective in the reduction of a high leukemic tumor burden, thereby allowing the residual normal progenitor and stem cells to expand. In addition, high dose Imatinib (Glivec®) should further improve the induction of a molecular response, as determined by quantitative reverse transcription polymerase chain reaction (RT-PCR), reducing the risk of relapse from residual malignant BCR-ABL positive cells.

This study will investigate the efficacy and tolerability of a short (6 months) high dose therapy followed by a standard dose compared to a continuous treatment with a standard dose of Imatinib (Glivec®).

In addition, the dynamics of the molecular and cytogenetic response will be investigated. Finally, the study will investigate the effect of this induction-maintenance concept on time-to-progression (TTP).

Inclusion Criteria:

1. Patients > 18 years of age

2. BCR-ABL positive CML patients in chronic phase, confirmed by karyotype (Ph+) or RT-PCR.

3. Patients pretreated with any drug that is known to control the disease of CML in chronic phase except imatinib (Glivec®).

4. Patients without a major cytogenetic response at study entry (> 35% Ph+ metaphases in bone marrow cytogenetic analysis performed < 3 months before study entry).

5. Patients either intolerant to interferon-alpha (non-hematologic toxicity grade 3-4 for more than 2 weeks) or having received pretreatment for CML at least 12 months before study entry.

6. World Health Organization (WHO) status 0-2

7. Adequate end organ function, defined as the following:

   • total bilirubin < 1.5 x upper limit of normal (ULN)
   • SGOT and SGPT < 2.5 x ULN
   • creatinine < 1.5 x ULN
   • absolute neutrophil count (ANC) > 1.5 x 10 ^ 9/L
   • platelets > 100 x 10 ^ 9/L

8. Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.

9. Written voluntary informed consent.

Exclusion Criteria:

1. Patients eligible for allogeneic bone marrow transplantation.
2. Patients in accelerated phase or blast crisis.
3. Known tuberculosis or other uncontrolled infection.
4. Other primary tumor of a different histological origin than the study indication (unless the relapse-free interval is > 5 years, and with the exception of cervical carcinoma in situ [CIS], basal cell epithelioma, or squamous cell carcinoma of the skin).
5. Major surgery within the last 14 days.
6. Known to be HIV positive.
7. Unstable medical disorder (except for indication) that excludes the patient in the opinion of the investigator.
8. Patient has received any other investigational agents within 28 days of first day of study drug dosing.
9. Patients with a WHO performance status score > 3
10. Patients with Grade III/IV cardiac problems as defined by the New York Heart Association criteria (i.e., congestive heart failure, myocardial infarction within 6 months of study).
11. Female patients who are pregnant or breast-feeding.
12. Refusal by female patients of childbearing age to use a safe contraceptive.
13. Patients with known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis).
14. Patients with any significant history of non-compliance to medical regimens or an inability to grant reliable informed consent.