Temozolomide in Treating Young Patients With Refractory or Recurrent Leukemia

A Phase I Trial Of Temozolomide In Pediatric Patients With Refractory/Recurrent Leukemias

RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop cancer cells from dividing so they stop growing or die.

PURPOSE: This phase I trial is studying the side effects and best dose of temozolomide in treating young patients with refractory or recurrent leukemia.

OBJECTIVES:

Primary

• Determine the maximum tolerated dose and recommended phase II dose of temozolomide in pediatric patients with refractory or recurrent leukemia.
• Determine the toxic effects of this drug in these patients.
• Determine the pharmacokinetics of this drug in these patients.

Secondary

• Determine the antitumor activity of this drug in these patients.
• Determine the biologic activity and mechanism(s) of resistance to this drug in these patients.

OUTLINE: This is an open-label, dose-escalation, multicenter study.

Patients receive oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of temozolomide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

PROJECTED ACCRUAL: A total of 3-36 patients will be accrued for this study within 18-24 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed leukemia of any of the following types:

  • Acute lymphoblastic leukemia
  • Acute myeloid leukemia
  • Chronic myelogenous leukemia in blast crisis

• Refractory or recurrent disease

• Immunophenotypic confirmation of disease at initial diagnosis or recurrence

• More than 25% blasts in the bone marrow (M3)

• Active extramedullary disease allowed except for leptomeningeal disease

• No known curative therapy or therapy proven to prolong survival with an acceptable quality of life

• No active CNS disease

PATIENT CHARACTERISTICS:

Age

• 1 to 21

Performance status

• Karnofsky 50-100% (for patients > 10 years of age)
• Lansky 50-100% (for patients ≤ 10 years of age)

Life expectancy

• Not specified

Hematopoietic

• WBC < 30,000/mm^3 (hydroxyurea or leukapheresis allowed at the discretion of the principal investigator)
• Platelet count ≥ 20,000/mm^3 (platelet transfusions allowed)
• Hemoglobin ≥ 8.0 g/dL (red blood cell transfusions allowed)

Hepatic

• ALT ≤ 5 times upper limit of normal (ULN)
• Albumin ≥ 2 g/dL
• Bilirubin ≤ 1.5 times ULN

Renal

• Creatinine normal for age OR
• Creatinine clearance OR radioisotope glomerular filtration rate ≥ 70 mL/min/1.73 m^2

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No uncontrolled infection

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 7 days since prior biologic therapy, including immunotherapy

• At least 3 months since prior stem cell transplantation

  • No evidence of active graft-vs-host disease

• No concurrent biologic therapy

• No concurrent immunotherapy

Chemotherapy

• Recovered from prior chemotherapy
• At least 6 weeks since prior nitrosoureas
• Prior therapy with hydroxyurea allowed for up to 24 hours before initiation of study drug
• No other concurrent chemotherapy

Endocrine therapy

• Concurrent hydrocortisone or other corticosteroids allowed as premedications prior to blood product transfusions in patients with prior severe allergic reactions

Radiotherapy

• Recovered from prior radiotherapy
• No concurrent radiotherapy

Surgery

• Not specified

Other

• No other concurrent anticancer agents
• No other concurrent investigational drugs