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

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

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.

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.

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