Pemetrexed Disodium in Treating Young Patients With Recurrent Solid Tumors

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of pemetrexed disodium in children and adolescents with refractory solid tumors.
• Determine the dose-limiting toxic effects of this drug in these patients.
• Determine the pharmacokinetics of this drug in these patients.

Secondary

• Determine, preliminarily, the antitumor activity of this drug in these patients.
• Correlate the presence of the C677T polymorphism of the methylenetetrahydrolate reductase gene, the presence of a polymorphism in the enhancer region of the thymidylate synthase (TS) gene promoter (2R and 3R tandem repeats), the presence of a polymorphism within one of those repeats, and the presence of a functional polymorphism in the 3'-untranslated region with toxicity in patients treated with this drug.
• Correlate homocysteine and methylmalonic acid levels at study entry with toxicity in patients treated with this drug.
• Correlate various gene expression profiles with response in patients treated with this drug.

OUTLINE: This is a dose-escalation study.

Patients receive pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of pemetrexed disodium 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 year.

DISEASE CHARACTERISTICS:

• Histologically confirmed solid tumor for which there is no known curative therapy or therapy that is known to prolong survival with acceptable quality of life

• Histologic requirement waived for intrinsic brain stem tumors
• No pleural effusion or ascites
• Neurological deficits from CNS tumors must have been relatively stable for at least 1 week prior to study entry

PATIENT CHARACTERISTICS:

Age

• 1 to 21

Performance status

• Karnofsky 50-100% (over 10 years of age)
• Lansky 50-100% (10 years of age and under)

Life expectancy

• At least 8 weeks

Hematopoietic

• Absolute neutrophil count at least 1,000/mm^3
• Platelet count at least 100,000/mm^3 (transfusion independent)
• Hemoglobin at least 8.0 g/dL (transfusion allowed)

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• ALT no greater than 2.5 times ULN
• Albumin at least 2 g/dL

Renal

• Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min OR
• Creatinine based on age as follows:

• No greater than 0.8 mg/dL (age 5 and under)
• No greater than 1.0 mg/dL (age 6 to 10)
• No greater than 1.2 mg/dL (age 11 to 15)
• No greater than 1.5 mg/dL (age 16 and over)

Pulmonary

• No evidence of dyspnea at rest
• No exercise intolerance

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No evidence of Approved-not yet active graft-versus-host disease
• No uncontrolled infection
• Seizure disorder allowed provided it is well-controlled with anticonvulsants
• CNS toxicity no greater than grade 1

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Recovered from prior immunotherapy
• At least 7 days since prior antineoplastic biologic therapy
• At least 6 months since prior allogeneic stem cell transplantation
• More than 1 week since prior growth factors
• No concurrent biologic therapy
• No concurrent immunotherapy
• No concurrent prophylactic growth factor support during course 1

Chemotherapy

• No prior pemetrexed disodium
• More than 3 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas) and recovered
• No other concurrent chemotherapy

Endocrine therapy

• Concurrent dexamethasone for CNS tumors allowed provided dose has been stable or decreasing for at least 1 week prior to study entry

Radiotherapy

• Recovered from all prior radiotherapy
• At least 2 weeks since prior local palliative radiotherapy
• At least 6 months since prior craniospinal radiotherapy
• At least 6 months since prior radiotherapy to 50% or more of the pelvis
• At least 6 weeks since prior substantial bone marrow radiotherapy
• No concurrent radiotherapy

Surgery

• Not specified

Other

• No trimethoprim or sulfa within 2 days before and after study drug administration
• No concurrent nonsteroidal anti-inflammatory agents (e.g., ibuprofen and aspirin)
• No other concurrent anticancer or investigational agents