Everolimus MICE-regimen in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia

OBJECTIVES:

Primary

• To determine the maximum-tolerated dose of everolimus in combination with standard remission-induction therapy comprising mitoxantrone hydrochloride, cytarabine, and etoposide (MICE-regimen) followed by consolidation therapy comprising idarubicin, cytarabine, and etoposide in older patients with newly diagnosed acute myeloid leukemia.

Secondary

• To determine the safety profile of this regimen in these patients.
• To determine the anti-leukemic activity (complete remission rate [complete remission and complete remission with incomplete blood count recovery]) following one or two induction courses.

OUTLINE: This is a multicenter, dose-escalation study of everolimus.

• Standard remission-induction therapy: Patients receive mitoxantrone hydrochloride IV over 30 minutes on days 1, 3, and 5; cytarabine IV continuously on days 1-7; etoposide IV over 1 hour on days 1-3; and oral everolimus once a day on days 1-21. Patients with partial remission (PR) receive a second induction course, beginning 7-17 days after completion of induction course 1. Patients with complete remission or complete remission with incomplete blood count recovery (CR/CRi) after induction therapy proceed to consolidation therapy; patients who have failed to achieve PR after induction course 1 or a CR/CRi after induction course 2 are removed from study.
• Consolidation therapy: Beginning within 3 weeks from CR/CRi documentation, patients receive idarubicin IV over 30 minutes on days 1, 3, and 5; cytarabine IV continuously on days 1-5; etoposide IV over 1 hour on days 1-3; and oral everolimus once a day on days 1-10. Patients may receive another course of the consolidation therapy, beginning at least 4 weeks after initiation of consolidation therapy course 1.

After completion of study treatment, patients are followed up once a month for 1 year, every 3 months for 1 year, and then periodically thereafter.

DISEASE CHARACTERISTICS:

• Newly diagnosed acute myeloid leukemia (AML) (unequivocal) according to WHO diagnostic criteria (at least 20% blasts in the bone marrow), with FAB classification other than M3 (acute promyelocytic leukemia), and documented by bone marrow aspiration (or biopsy in case of dry tap)
• Previously untreated primary or secondary AML (including AML following antecedent myelodysplasia)
• No blast transformation of chronic myeloid leukemia or other myeloproliferative disorders
• No active CNS leukemia

PATIENT CHARACTERISTICS:

• WHO performance status 0-2
• Total serum bilirubin < 2 times upper limit of normal (ULN)
• Serum creatinine < 2 times ULN
• ALT/AST ≤ 3 times ULN (unless due to organ leukemic involvement)
• LVEF ≥ 50% by echocardiogram
• No other concurrent active malignancy
• No active uncontrolled infection
• No known active hepatitis B or C or HIV positivity
• No active heart disease including myocardial infarction within the past 3 months, symptomatic coronary artery disease, cardiac arrhythmias not controlled by medications, or uncontrolled congestive heart failure
• No medical condition that, in the opinion of the investigator, places the patient at an unacceptably high risk for toxicities
• No other known condition (e.g., familial, sociological, or geographical) or behavior (including drug dependence or abuse, psychological or psychiatric illness) that, in the opinion of the investigator, would make the patient a poor candidate for the trial
• No known hypersensitivity to everolimus, other rapamycins (e.g., sirolimus or temsirolimus), or to its excipients

PRIOR CONCURRENT THERAPY:

• No prior standard or investigational chemotherapy for acute myeloid leukemia or myelodysplasia (including everolimus or other mTOR inhibitors)

• Prior hydroxyurea allowed (up to a maximum of 14 days) to control peripheral blood leukemic cell counts
• No prior enrollment in this trial
• No other concurrent anti-leukemia agents, investigational agents, or biological agents