Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Pemetrexed Disodium in Treating Young Patients With Solid Tumors That Have Relapsed or Not Responded to Treatment

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Treatment	Closed	6 months to 21 years	NCI	COG-ADVL0525 ADVL0525, NCT00459147

Objectives

Primary

1. Determine the response rate in young patients with relapsed or refractory solid tumors treated with pemetrexed disodium.
2. Determine the toxicity of this drug in these patients.

Secondary

1. Examine the relationship between the presence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and toxicity of patients being treated with pemetrexed.
2. Examine the relationship between the presence of a polymorphism in the TS gene and/or gene promoter and toxicity of patients being treated with pemetrexed.
3. Examine the relationship between response and tumor expression of the enzymes TS, DHFR, GARFT, RFC, FPGS and GGH as well as MTAP deletion status.

Entry Criteria

Disease Characteristics:

• Histologically confirmed solid tumor, including 1 of the following:
  • Osteosarcoma
  • Ewing's sarcoma/peripheral primitive neuroectodermal tumor (PNET)
  • Rhabdomyosarcoma
  • Neuroblastoma
  • Ependymoma
  • Medulloblastoma-supratentorial PNET
  • Non-brain stem high grade glioma
• Relapsed or refractory disease
• Disease for which no known curative therapy or therapy proven to prolong survival with an acceptable quality of life exists
• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan
  • Nonmeasurable, iodine I 131 metaiodobenzylguanidine (MIBG) evaluable neuroblastoma allowed
• No pleural effusions or ascites
• Patients with known bone marrow metastatic disease (not refractory to RBC or platelet transfusions) are eligible, though are not evaluable for hematologic toxicity

Prior/Concurrent Therapy:

• Recovered from acute toxic effects of prior chemotherapy, immunotherapy, or radiotherapy
• More than 3 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas)
• More than 1 week since prior growth factors that support platelet or WBC number or function (2 weeks for pegfilgrastim)
• At least 7 days since prior biologic anticancer agents (longer if agents have known adverse events occurring beyond 7 days after administration)
• At least 2 weeks since prior local palliative radiation therapy (i.e., small port)
• At least 6 months since prior craniospinal radiation therapy
• At least 6 months since prior radiation therapy to ≥ 50% of the pelvis
• At least 6 weeks since other prior substantial bone marrow radiation
• At least 6 months since prior allogeneic stem cell transplantation
• At least 2 weeks since prior unstablized or increasing doses of dexamethasone or other corticosteroids for patients with CNS tumors
• No prior pemetrexed disodium
• No trimethoprim-sulfamethoxazole, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs, or other drugs excreted via the renal tubules for 2 days before and after study drug administration
• No concurrent corticosteroids except for treatment of increased intracranial pressure in patients with CNS tumors
• No other concurrent investigational drugs
• No other concurrent anticancer therapies

Patient Characteristics:

• Karnofsky performance status (PS) 50-100% (for patients > 16 years of age) OR Lansky PS 50-100% (for patients ≤ 16 years of age)
• Absolute neutrophil count ≥ 1,000/mm³
• Platelet count ≥ 100,000/mm³
  • No platelet transfusions within the past 7 days
• Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)
• Creatinine normal OR creatinine clearance or radioisotope glomerular filtration rate ≥ 70mL/min
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• SGPT ≤ 110 U/L (for this study, the ULN for SGPT is 45 U/L)
• Albumin ≥ 2 g/dL
• No history of an allergic reaction to mannitol
• No concurrent uncontrolled infection
• No evidence of active graft-versus-host disease
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

Expected Enrollment

A total of 160 patients will be accrued for this study.

Outcomes

Response rate (complete and partial response) by RECIST criteria (solid tumors) or bidimensional measurements (brain tumors)
Toxicity by NCI CTCAE v 3.0

Relationship between the presence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and toxicity of patients being treated with pemetrexed
Relationship between the presence of a polymorphism in the TS gene and/or gene promoter and toxicity of patients being treated with pemetrexed
Relationship between response and tumor expression of the enzymes TS, DHFR, GARFT, RFC, FPGS and GGH as well as MTAP deletion status

Outline

This is a multicenter, open-label study. Patients are stratified according to disease type (osteosarcoma vs Ewing's sarcoma/peripheral primitive neuroectodermal tumor vs rhabdomyosarcoma vs measurable neuroblastoma vs iodine I 131 metaiodobenzylguanidine [MIBG]-positive evaluable neuroblastoma).

Patients receive pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 17 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 5 years.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Anne Warwick, MD, MPH, Protocol chair		Ph: 414-456-4170 Email: awarwick@mcw.edu

Registry Information
Official Title		A Phase II Study of Pemetrexed in Children with Recurrent Malignancies
Trial Start Date		2007-09-03
Trial Completion Date		2008-07-19 (estimated)
Registered in ClinicalTrials.gov		NCT00459147
Date Submitted to PDQ		2007-02-27
Information Last Verified		2009-10-28
NCI Grant/Contract Number		CA98543

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