Bortezomib in Treating Children With Advanced Solid Tumors

Study Overview
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Brief Summary
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Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Phase I trial to study the effectiveness of bortezomib in treating children who have advanced solid tumors that have not responded to previous treatment.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of bortezomib in pediatric patients with refractory solid tumors. II. Determine the dose-limiting toxicity and other toxic effects of this regimen in these patients. III. Preliminarily determine the antitumor activity of this regimen in these patients. OUTLINE: This is a dose-escalation study. Patients receive bortezomib IV 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. If dose-limiting toxicity in the form of myelosuppression occurs in stratum I, dose escalation continues with patients meeting the qualifications for stratum II. PROJECTED ACCRUAL: Approximately 24-36 patients will be accrued for this study.

Official Title
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A Phase I Study Of PS-341 In Pediatric Patients With Refractory Solid Tumors

Conditions
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Unspecified Childhood Solid Tumor, Protocol Specific

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed solid tumor that is refractory to standard therapy or for which no standard therapy exists Histologic confirmation not required for brainstem glioma or optic pathway tumor Ineligible for therapies of higher priority Stratum II only: No bone marrow involvement Performance status - Karnofsky 50-100% (over 10 years of age) Performance status - Lansky 50-100% (10 years of age and under) At least 8 weeks Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 75,000/mm^3 (transfusion independent) Hemoglobin at least 8 g/dL (RBC transfusions allowed) Bilirubin less than 1.5 mg/dL ALT less than 5 times normal for age Albumin at least 2 g/dL Creatinine no greater than upper limit of normal for age Creatinine clearance or radioisotope glomerular filtration rate greater than 70 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Neurologic deficits related to CNS tumors allowed if relatively stable for at least 2 weeks No uncontrolled infection At least 7 days since prior biologic therapy and recovered At least 3 months since prior allogeneic stem cell transplantation At least 1 week since prior growth factors Stratum II only: No prior stem cell transplantation with or without total body irradiation At least 2 weeks since prior chemotherapy (4 weeks for nitrosoureas) and recovered Stratum II only: No more than 2 prior multi-agent chemotherapy regimens More than 2 single-agent regimens allowed Concurrent dexamethasone allowed for CNS tumors if stable dose for at least 2 weeks See Biologic therapy At least 2 weeks since prior palliative local radiotherapy At least 6 months since prior craniospinal radiotherapy or radiotherapy to at least 50% of pelvis At least 6 weeks since prior substantial bone marrow radiotherapy Recovered from prior radiotherapy Stratum II only: No prior radiotherapy to more than 20% of bone marrow No prior bortezomib No concurrent anticonvulsants No other concurrent investigational agents

Ages Eligible for Study
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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: Treatment (bortezomib)<br>Patients receive bortezomib IV 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: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD defined as the dose at which fewer than 20% of patients experience DLT assessed using CTC version 2.0 |  | 3 weeks | 
| 20S proteasome inhibition | The 95% confidence interval for the percent of patients who exhibit inhibition at a recommended dose level determined according to the table above is 61%-100%, if six patients are evaluated or 55%-100% if five patients are evaluated. | Up to 2 weeks | 
| Progression free survival |  | Up to 24 months |