Bortezomib in Treating Children With Advanced Solid Tumors

• MTD defined as the dose at which fewer than 20% of patients experience DLT assessed using CTC version 2.0 [ Time Frame: 3 weeks ] [ Designated as safety issue: Yes ]
• 20S proteasome inhibition [ Time Frame: Up to 2 weeks ] [ Designated as safety issue: No ]
  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.
• Progression free survival [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]

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.

• Drug: bortezomib
  Given IV
  Other Names:

  • LDP 341
  • MLN341
  • VELCADE
• Other: laboratory biomarker analysis
  Correlative studies
• Other: pharmacological study
  Correlative studies
  Other Name: pharmacological studies

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