Imatinib Mesylate and Interferon Alfa in Treating Patients With Chronic Myelogenous Leukemia

Study Overview
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Brief Summary
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RATIONALE: Imatinib mesylate and interferon alfa may interfere with the growth of the cancer cells. Combining imatinib mesylate with interferon alfa may kill more cancer cells. PURPOSE: Phase II trial to study the effectiveness of combining imatinib mesylate with interferon alfa in treating patients who have chronic myelogenous leukemia.

Detailed Description
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OBJECTIVES: Determine the maximum tolerated dose of interferon alfa administered with imatinib mesylate in patients with chronic phase chronic myelogenous leukemia. (Phase I closed to accrual as of 7/9/03.) Determine the safety and tolerability of this regimen in this patient population. Determine the complete, major, and minor cytogenetic response rates and complete hematologic response rate in patients after 6 and 12 months of treatment with this regimen. Determine the molecular response (reverse transcriptase-polymerase chain reaction for bcr-abl) rate in patients who have a complete cytogenetic response after 6 and 12 months of treatment with this regimen. Determine the pharmacokinetics of this regimen in these patients. OUTLINE: This is a dose-escalation, multicenter study. Phase I (closed to accrual as of 7/9/03): Patients receive oral imatinib mesylate once daily beginning on day 1 and interferon alfa (IFN-A) subcutaneously once daily or 3 times weekly beginning on day 14. Courses repeat every 35 days for up to 1 year in the absence of disease progression or unacceptable toxicity. After completion of 1 year of therapy, patients may receive additional therapy, provided that the patient is benefiting from imatinib mesylate. IFN-A is discontinued in patients who achieve a molecular remission that is confirmed on 2 successive bone marrow samples. Imatinib mesylate is discontinued in patients who achieve and maintain a molecular remission for 2 years. Sequential dose escalation of IFN-A is followed by sequential dose escalation of imatinib mesylate. Cohorts of 3-6 patients receive escalating doses of IFN-A and then imatinib mesylate until the maximum tolerated dose (MTD) of the combination is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Phase II: Patients receive imatinib mesylate and IFN-A as in phase I at the established MTD. Patients are followed for 30 days. PROJECTED ACCRUAL: Approximately 3-15 patients will be accrued for the phase I portion of this study. (Phase I closed to accrual as of 7/9/03.) A total of 40 patients will be accrued for the phase II portion of the study within 3-4 months.

Official Title
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A Phase I/II Dose-Finding Study to Determine the Safety, Tolerability, and Anti-Leukemic Effects of STI571 (NSC 716051) in Combination With Interferon-alpha in Patients With Chronic Myelogenous Leukemia in Chronic Phase

Conditions
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Leukemia

Intervention / Treatment
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* Biological: recombinant interferon alfa
* Drug: imatinib mesylate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Cytogenetically confirmed chronic myelogenous leukemia (CML) Less than 15% blasts in peripheral blood or bone marrow Less than 30% blasts and promyelocytes in peripheral blood or bone marrow Less than 20% basophils in blood or bone marrow Platelet count at least 100,000/mm^3 No leukemia beyond bone marrow, blood, liver, or spleen No chloroma Phase I (closed to accrual as of 7/9/03): Philadelphia (Ph) chromosome-positive CML in chronic phase Phase II: Newly diagnosed Ph chromosome-positive CML in chronic phase Initial diagnosis within 6 months of study No prior therapy for CML except hydroxyurea and/or anagrelide hydrochloride Phase I (closed to accrual as of 7/9/03) and II: No identified sibling donors where allogeneic stem cell transplantation is elected as first-line therapy PATIENT CHARACTERISTICS: Age: 18 and over Performance status: ECOG 0-2 Life expectancy: Not specified Hematopoietic: See Disease Characteristics Hepatic: Bilirubin no greater than 1.5 times upper limit of normal (ULN) AST or ALT no greater than 2 times ULN Renal: Creatinine no greater than 1.5 times ULN Cardiovascular: No New York Heart Association class III or IV heart disease Other: Not pregnant or nursing Negative pregnancy test Fertile patients must use 2 methods of effective barrier contraception during and for at least 3 months after study participation No other serious uncontrolled medical condition No autoimmune disease No prior noncompliance to medical regimens or potential unreliability No prior grade 3 or greater non-hematologic toxicity due to prior interferon (phase I [closed to accrual as of 7/9/03]) PRIOR CONCURRENT THERAPY: Biologic therapy: See Disease Characteristics No prior bone marrow or peripheral blood stem cell transplantation At least 2 weeks since prior interferon alfa (phase I [closed to accrual as of 7/9/03]) Chemotherapy: See Disease Characteristics At least 6 weeks since prior busulfan (phase I [closed to accrual as of 7/9/03] ) At least 2 weeks since prior cytarabine (phase I [closed to accrual as of 7/9/03]) No concurrent chemotherapy Concurrent hydroxyurea allowed during the first 3 months of study Endocrine therapy: Not specified Radiotherapy: Not specified Surgery: Not specified Other: At least 4 weeks since prior investigational agents other than imatinib mesylate (phase I [closed to accrual as of 7/9/03]) No concurrent grapefruit juice Concurrent anagrelide hydrochloride allowed during the first 3 months of study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: recombinant interferon alfa|IFN-α will be given at a dose ranging up to 5 MIU daily via subcutaneous injection.|
|Drug: imatinib mesylate|Once daily oral administration of STI571 (imatinib mesylate) at a dose of 400 mg or 600mg for 12 months.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Cytogenetic Response at 6 and 12 Months (Phase II) | Cytogenetic response in terms of the percentage of Ph chromosome positive metaphases in bone marrow is defined as follows: Complete* (0% Ph-positive cells) Partial* (1-34%) Minor (35-95%) None (96-100%). | At 6 and 12 months during phase II | 
| Minor Cytogenetic Response at 6 and 12 Months (Phase II) |  | At 6 and 12 months during phase II | 
| Complete Hematologic Response at 6 and 12 Months (Phase II) |  | At 6 and 12 months during phase II | 
| Molecular Response in Patients With Complete Cytogenetic Response at 6 and 12 Months (Phase II) |  | At 6 and 12 months during phase II | 
| Treatment-related Toxicity (i.e., Grade 3 or 4 Nonhematologic Toxicity) as Measured by NCI CTCAE v3.0 (Phase I) | 1=mild, 2=moderate, 3=severe, 4=life threatening/disabling, 5=death | 12 Months | 
| Major Cytogenetic Response After 6 and 12 Months of Treatment. | Cytogenetic response in terms of the percentage of Ph chromosome positive metaphases in bone marrow is defined as follows: Complete* (0% Ph-positive cells) Partial* (1-34%) Minor (35-95%) None (96-100%). *Major cytogenetic response includes complete and partial cytogenetic response. | 6 and 12 months after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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relapsing chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, Philadelphia chromosome positive chronic myelogenous leukemia