Bortezomib in Treating Young Patients With Refractory or Recurrent Leukemia

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I Study of PS-341 (Velcade, Bortezomib) in Pediatric Patients With Refractory/Recurrent Leukemias

Conditions
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Blastic Phase Chronic Myelogenous Leukemia, Childhood Acute Promyelocytic Leukemia (M3), Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: bortezomib
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed leukemia of 1 of the following types: Acute lymphoblastic leukemia Acute myeloid leukemia Chronic myelogenous leukemia in blast crisis 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: ≤ 0.8 mg/dL for patients age 5 and under ≤ 1.0 mg/dL for patients age 6 to 10 ≤ 1.2 mg/dL for patients age 11 to 15 ≤ 1.5 mg/dL for patients age 16 to 21 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) Concurrent benzodiazepines and gabapentin are allowed

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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. | Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose and recommended phase II dose |  | Up to 21 days | 
| Toxicity as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 3.0 |  | Up to 2 years | 
| Pharmacokinetics as assessed by confidence intervals (CI), area under the curve (AUC), and half-life (T ½) |  | Pretreatment, days 1, 8, 18-22 of course 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antitumor activity |  | Up to 2 years | 
| Correlate apoptosis and NF-kB activation |  | Prestudy, days 8 and 18 |