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

Alternate Title

Chemotherapy and Radiation Therapy in Treating Infants With Brain Tumors

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Treatment	Closed	Under 3 at diagnosis	NCI	PBTC-001 NCT00005063, NCT00042367

Objectives

1. Assess the feasibility of the addition of regional therapy with intrathecal (IT) mafosfamide to an intensive regimen of systemic chemotherapy in children under 3 years of age at diagnosis with medulloblastoma/primitive neuroectodermal tumor, ependymoma with metastatic disease, or other primary intracranial embryonal tumors.
2. Determine the safety and feasibility of a limited dose-escalation schedule of IT mafosfamide in this patient population.
3. Assess the feasibility, including expected disease progression, of delivering 20 weeks of systemic chemotherapy plus IT mafosfamide in this patient population.
4. Determine the subsequent progression-free survival and pattern of failure associated with the use of IT mafosfamide and conformal irradiation to the local tumor region followed by 2 further courses of systemic chemotherapy among these patients with initially local disease (M0) at diagnosis.
5. Develop preliminary estimates of the local and neuraxis response rate to intensive postoperative systemic/regional chemotherapy in these patients.
6. Determine the acute and chronic toxic effects associated with the delivery of the first 20 weeks of this chemotherapy in these patients.
7. Determine whether the first 10 weeks of systemic chemotherapy can restore normal CSF flow, thus permitting administration of IT mafosfamide during the second 10 weeks of systemic chemotherapy in patients initially ineligible to receive IT mafosfamide because of subarachnoid block by tumor.
8. Assess the pharmacokinetics of IT mafosfamide using a limited sampling strategy in these patients.
9. Determine the concentration of matrix metalloproteinases (MMPs) in the CSF of these patients.

Entry Criteria

Disease Characteristics:

• Histologically confirmed primary intracranial CNS medulloblastoma/primitive neuroectodermal tumor or other embryonal tumor (medulloepithelioma, ependymoblastoma, neuroblastoma, pineoblastoma), atypical teratoid/rhabdoid tumor, intracranial germ cell tumor, choroid plexus tumor, or metastatic ependymoma



• If positive bone scan, pre-treatment bone marrow aspirate and biopsy must be free of tumor

Prior/Concurrent Therapy:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Prior steroids allowed

Radiotherapy:

• No prior radiotherapy

Surgery:

• No more than 35 days since prior definitive surgery

Other:

• No other concurrent investigational agents

Patient Characteristics:

Age:

• Under 3 at diagnosis

Performance status:

• Karnofsky 30-100%

  OR

• Lansky 30-100%

Life expectancy:

• Not specified

Hematopoietic:

• Hemoglobin at least 10 g/dL
• Absolute neutrophil count at least 1,500/mm³
• Platelet count at least 100,000/mm³

Hepatic:

• Bilirubin less than 1.5 mg/dL
• SGPT less than 5 times upper limit of normal

Renal:

• Creatinine normal

  OR

• Creatinine clearance greater than 40 mL/min/m²

Other:

• Willing to have a central line
• Willing to have CSF flow study to determine whether or not they will receive intrathecal chemotherapy
• Willing to have Ommaya reservoir placed if needed

Expected Enrollment

A total of 113-119 patients will be accrued for this study within 5-6 years.

Outline

This is a multicenter, dose-escalation study of mafosfamide. All patients receive regimen 1 chemotherapy. Children whose tumor is limited to 1 area at the beginning of the study proceed to radiotherapy and then regimen 2 chemotherapy. Children whose tumor is found in more than 1 part of the brain or in the CSF at the beginning of the study complete treatment after regimen 1 chemotherapy.

• Regimen 1: Children with normal CSF flow at the beginning of the study receive regimen 1 chemotherapy along with intrathecal (IT) mafosfamide. Children with abnormal CSF flow receive regimen 1 without IT mafosfamide. Patients with initially abnormal CSF flow who show no evidence of obstructive hydrocephalus or compartmentalization on the repeat study receive IT mafosfamide beginning with course 2. Patients receive cyclophosphamide IV over 30 minutes twice weekly on weeks 1, 4, 11, and 14, vincristine IV once weekly on weeks 1-6 and 11-16, cisplatin IV over 6 hours once weekly on weeks 1, 4, 11, and 14, and oral etoposide once daily on weeks 7-9 and 17-19. IT mafosfamide is administered twice weekly on weeks 1-6 and then once weekly on weeks 7-9, 11, 14, and 17. Patients are evaluated at weeks 10 and 20. After completion of regimen 1, patients may undergo surgery to remove more of their tumor.

  Patients who are initially M0 with stable or responding disease begin conformal radiotherapy 2 weeks after completing regimen 1 chemotherapy or second surgery. Patients receive radiotherapy once daily 5 days a week.




• Regimen 2: After completing radiotherapy, patients receive cyclophosphamide IV over 30 minutes twice weekly on weeks 1, 4, 11, and 14, vincristine IV once weekly on weeks 1-6 and 11-16, and oral etoposide once weekly on weeks 7-9 and 17-19. Patients are evaluated at weeks 10 and 20.

Cohorts of 3-6 patients receive escalating doses of IT mafosfamide during regimen 1 chemotherapy 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.

Patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter.

Blaney SM, Boyett J, Friedman H, et al.: Phase I clinical trial of mafosfamide in infants and children aged 3 years or younger with newly diagnosed embryonal tumors: a Pediatric Brain Tumor Consortium study (PBTC-001). J Clin Oncol 23 (3): 525-31, 2005.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Pediatric Brain Tumor Consortium

Susan Blaney, MD, Protocol chair		Ph: 832-822-1482 Email: sblaney@txccc.org
Richard Heideman, MD, Protocol co-chair		Ph: 505-272-4461 Email: rheideman@salud.unm.edu

Registry Information
Official Title		Pilot Study of Systemic and Intrathecal Chemotherapy Followed by Conformal Radiation for Infants with Embryonal Intracranial Central Nervous System Tumors
Trial Start Date		2001-02-01
Registered in ClinicalTrials.gov		NCT00005063NCT00042367
Date Submitted to PDQ		2000-02-11
Information Last Verified		2006-01-05
NCI Grant/Contract Number		U01-CA81457

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