Radiation Therapy, Temozolomide, and Lomustine in Treating Young Patients With Newly Diagnosed Gliomas

A Phase II Study of Concurrent Radiation and Temozolomide Followed By Temozolomide and CCNU in the Treatment of Children With High-Grade Glioma

This phase II trial is studying how well giving radiation therapy together with temozolomide and lomustine works in treating young patients with newly diagnosed gliomas. Radiation therapy uses high energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide and lomustine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy together with temozolomide and lomustine after surgery may kill any remaining tumor cells.

Study Overview

• Status: Completed
• Conditions: Glioblastoma; Gliosarcoma; Anaplastic Astrocytoma; Central Nervous System Neoplasm; Spinal Cord Neoplasm
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Radiation: Radiation Therapy; Drug: Temozolomide; Drug: Lomustine

Detailed Description

PRIMARY OBJECTIVES:

I. Compare event-free survival of pediatric patients with newly diagnosed high-grade gliomas treated with adjuvant radiotherapy and temozolomide followed by temozolomide and lomustine with historical controls.

II. Determine the toxicity of this regimen in these patients. III. Correlate MGMT and p53 expression in tumor tissue with outcome in patients treated with this regimen.

IV. Correlate polymorphisms in GSTP1, GSTM1 and GSTT1 genes and GSTP1 protein expression in tumors with survival in patients treated with this regimen.

OUTLINE: This is a pilot, multicenter study.

CHEMORADIOTHERAPY: Patients receive oral temozolomide once daily on days 1-42. Patients also undergo concurrent radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33 and 36-40. Patients who did not undergo prior gross total resection also undergo boost radiotherapy once daily on days 43-47.

MAINTENANCE CHEMOTHERAPY: Four weeks after completion of chemoradiotherapy, patients receive oral temozolomide once daily on days 1-5 and oral lomustine on day 1. Treatment repeats every 42 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

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

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Oncology Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically confirmed, newly diagnosed high-grade glioma of 1 of the following histologies:

  • Anaplastic astrocytoma
  • Glioblastoma multiforme
  • Gliosarcoma
• Primary spinal cord malignant gliomas allowed
• No primary brainstem tumors

• Has undergone surgical resection or biopsy of the tumor within the past 31 days

  • Pre-operative and post-operative brain MRI with and without gadolinium-contrast OR pre-operative and post-operative spine MRI for spinal cord primaries

    • Post-operative MRI not required for patients who undergo biopsy only

• No evidence of neuraxis dissemination

  • Spine MRI and cerebrospinal fluid cytology required only if clinically indicated
• Performance status - Karnofsky 50-100% (for patients > 16 years of age)
• Performance status - Lansky 50-100% (for patients ≤ 16 years of age)
• At least 8 weeks
• Absolute neutrophil count ≥ 1,000/mm^3
• Platelet count ≥ 100,000/mm^3 (transfusion independent)
• Hemoglobin ≥ 8 g/dL (transfusions allowed)
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT ≤ 2.5 times ULN
• Albumin ≥ 2 g/dL
• Creatinine ≤ 1.5 times ULN
• Creatinine clearance or radioisotope glomerular filtration rate ≥ lower limit of normal
• No evidence of dyspnea at rest
• No exercise intolerance
• Pulse oximetry ≥ 94% (if determination is clinically indicated)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 2 months after study participation
• Able to swallow oral medication
• Seizures allowed provided they are well controlled with anticonvulsants
• No hypersensitivity to temozolomide
• No prior biologic agents
• No prior chemotherapy
• Prior corticosteroids allowed
• No concurrent corticosteroids as an antiemetic
• Concurrent corticosteroids allowed only for treatment of increased intracranial pressure
• No concurrent radiotherapy using cobalt-60
• See Disease Characteristics
• No other prior treatment
• No concurrent phenobarbital or cimetidine
• No concurrent co-trimoxazole for Pneumocystis carinii pneumonia prophylaxis during study chemoradiotherapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (lomustine, temozolomide, radiation therapy); Patients receive oral temozolomide once daily on days 1-42. Patients also undergo concurrent radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, 29-33 and 36-40. Patients who did not undergo prior gross total resection also undergo boost radiotherapy once daily on days 43-47. Four weeks after completion of chemoradiotherapy, patients receive oral temozolomide once daily on days 1-5 and oral lomustine on day 1. Treatment repeats every 42 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Other: Laboratory Biomarker Analysis; Correlative studies; Radiation: Radiation Therapy; Undergo radiation therapy; Other Names: Cancer Radiotherapy; ENERGY_TYPE; Irradiate; Irradiated; Irradiation; Radiation; Radiation Therapy, NOS; Radiotherapeutics; Radiotherapy; RT; Therapy, Radiation; Drug: Temozolomide; Given PO; Other Names: Temodar; SCH 52365; Temodal; Temcad; Methazolastone; RP-46161; Temomedac; TMZ; CCRG-81045; Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; M & B 39831; M and B 39831; Drug: Lomustine; Given PO; Other Names: CCNU; CeeNU; Gleostine; 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea; 1-Nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-; Belustin; Belustine; Cecenu; Chloroethylcyclohexylnitrosourea; Citostal; Lomeblastin; Lomustinum; Lucostin; Lucostine; N-(2-Chloroethyl)-N'-cyclohexyl-N-nitrosourea; Prava; RB-1509; WR-139017

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
One Year Overall Survival	Estimated one year survival using the Kaplan-Meier methodology.	One year
Occurrence of Death Attributable to Complications of Protocol Therapy	Number of deaths due to complications of protocol therapy.	While receiving protocol therapy (up to 301 days excluding delays) or within 30 days of Termination of Protocol Therapy

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Pollack IF, Hamilton RL, Burger PC, Brat DJ, Rosenblum MK, Murdoch GH, Nikiforova MN, Holmes EJ, Zhou T, Cohen KJ, Jakacki RI; Children's Oncology Group. Akt activation is a common event in pediatric malignant gliomas and a potential adverse prognostic marker: a report from the Children's Oncology Group. J Neurooncol. 2010 Sep;99(2):155-63. doi: 10.1007/s11060-010-0297-3. Epub 2010 Jul 4.
• Pollack IF, Hamilton RL, Sobol RW, Nikiforova MN, Nikiforov YE, Lyons-Weiler MA, LaFramboise WA, Burger PC, Brat DJ, Rosenblum MK, Gilles FH, Yates AJ, Zhou T, Cohen KJ, Finlay JL, Jakacki RI; Children's Oncology Group. Mismatch repair deficiency is an uncommon mechanism of alkylator resistance in pediatric malignant gliomas: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2010 Dec 1;55(6):1066-71. doi: 10.1002/pbc.22634.
• Pollack IF, Hamilton RL, Sobol RW, Nikiforova MN, Lyons-Weiler MA, LaFramboise WA, Burger PC, Brat DJ, Rosenblum MK, Holmes EJ, Zhou T, Jakacki RI; Children's Oncology Group. IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children's Oncology Group. Childs Nerv Syst. 2011 Jan;27(1):87-94. doi: 10.1007/s00381-010-1264-1. Epub 2010 Aug 20.

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2005
• Primary Completion (Actual): September 1, 2012
• Study Completion (Actual): June 30, 2017

Study Registration Dates

• First Submitted: January 6, 2005
• First Submitted That Met QC Criteria: January 6, 2005
• First Posted (Estimate): January 7, 2005

Study Record Updates

• Last Update Posted (Actual): February 15, 2023
• Last Update Submitted That Met QC Criteria: January 18, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: childhood high-grade cerebral astrocytoma; childhood spinal cord neoplasm
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Spinal Cord Diseases; Neoplasms; Glioblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Astrocytoma; Gliosarcoma; Spinal Cord Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide; Lomustine
• Other Study ID Numbers: ACNS0423 (Other Identifier: CTEP); U10CA098543 (U.S. NIH Grant/Contract); CDR0000407744 (Clinical Trials.gov); COG-ACNS0423 (Children's Oncology Group); NCI-2012-02645 (Registry Identifier: CTRP (Clinical Trial Reporting Program))