Bortezomib in Treating Children With Advanced Solid Tumors

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

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.

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.

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