A Phase I Study of PS-341 (Velcade, Bortezomib) in Pediatric Patients With Refractory/Recurrent Leukemias
A Phase I Study of PS-341 (Velcade, Bortezomib) in Pediatric Patients With Refractory/Recurrent Leukemias
This phase I trial is studying the side effects and best dose of bortezomib in treating young patients with refractory or recurrent leukemia. Bortezomib may stop the growth of cancer cells by blocking the enzymes necessary for their growth.
OBJECTIVES: Primary I. Determine the maximum tolerated dose and recommended phase II dose of bortezomib in children with refractory or recurrent leukemia.
II. Determine the toxic effects of this drug in these patients. III. Determine the pharmacokinetics of this drug in these patients.
Secondary I. Determine, preliminarily, the antitumor activity of this drug in these patients.
II. Determine, preliminarily, the biologic activity of this drug in these patients.
OUTLINE: This is a dose-escalation, open-label, multicenter study.
Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
PROJECTED ACCRUAL: A total of 3-36 patients will be accrued for this study within 1.5-36 months.
Inclusion Criteria:
Histologically confirmed leukemia of 1 of the following types:
Relapsed or refractory disease
Immunophenotypically confirmed disease, either at initial diagnosis or relapse
More than 25% blasts in the bone marrow (M3 bone marrow)
Active extramedullary disease (except leptomeningeal disease) allowed
No known curative therapy or therapy proven to prolong survival with an acceptable quality of life available
Performance status - Karnofsky 50-100% (for patients age 11 to 21)
Performance status - Lansky 50-100% (for patients age 10 and under)
Platelet count ≥ 20,000/mm^3*
Hemoglobin ≥ 8.0 g/dL*
WBC < 20,000/mm^3** (hydroxyurea for cytoreduction allowed)
No hyperleukocytosis (i.e., WBC > 100,000/mm^3)
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
ALT ≤ 5 times ULN
Albumin ≥ 2 g/dL
Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min
Creatinine based on age as follows:
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No uncontrolled infection
Recovered from prior immunotherapy
At least 7 days since prior filgrastim (G-CSF) or sargramostim (GM-CSF)
At least 7 days since prior biologic agents
At least 3 months since prior stem cell transplantation or rescue and no evidence of active graft-versus-host disease
No concurrent prophylactic G-CSF during course 1 of study
No concurrent immunotherapy
No concurrent biologic therapy
Recovered from prior chemotherapy
At least 24 hours since prior hydroxyurea for cytoreduction
At least 6 weeks since prior nitrosoureas
No concurrent chemotherapy
At least 7 days since prior steroids (except as premedication prior to blood product transfusion)
Recovered from prior radiotherapy
At least 2 weeks since prior small port local palliative radiotherapy
At least 3 months since prior total body irradiation, craniospinal irradiation, or irradiation to more than 50% of the pelvis
At least 6 weeks since other prior substantial bone marrow radiotherapy
No concurrent radiotherapy
At least 7 days since prior retinoids
No other concurrent investigational agents
No other concurrent anticancer agents
No concurrent anticonvulsant medications known to activate the cytochrome p450 system (e.g., phenytoin, carbamazepine, or phenobarbital)