External Beam Radiation Therapy and Cetuximab Followed by Irinotecan and Cetuximab for Children and Young Adults With Newly Diagnosed Diffuse Pontine Tumors and High-Grade Astrocytomas

A Phase II Trial of External Beam Radiation Therapy and Cetuximab Followed by Irinotecan and Cetuximab for Children and Young Adults With Newly Diagnosed Diffuse Pontine Tumors and High-Grade Astrocytomas (POE08-01)

Standard treatment for patients with diffuse pontine tumors is radiation therapy, but less than 10% of patients are cured. Adding standard chemotherapy has not improved the cure rate.

Standard treatment for high-grade astrocytomas is surgery and radiation. The surgeon removes as much of the tumor as she or he can. Radiation after that tries to kill any cancer cells that are left. Some patients also get chemotherapy. These are anti-cancer drugs. They can be given during or after radiation. Current standard treatments do not cure many patients.

In this study the doctors are adding a new medication called cetuximab to the treatment and will also use a chemotherapy medication (irinotecan) that has been promising for patients treated for recurrent disease.

Study Overview

• Status: Completed
• Conditions: Brain Cancer
• Intervention / Treatment: Other: cetuximab in conjunction with external beam radiation therapy, followed by cetuximab and irinotecan

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 1N4
      • Alberta Children's Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • Colorado
    • Denver, Colorado, United States
      • University of Colorado Health Sciences Center
  • Florida
    • Gainesville, Florida, United States
      • University of Florida
    • Orlando, Florida, United States, 32806
      • MD Anderson Cancer Center Orlando at Arnold Palmer Hospital for Children
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta at Egleston
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • John Hopkins Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital & Clinics
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States
      • Seattle Children's Hospital

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:

• Patients must have either (1) histologic proof of a high-grade astrocytoma reviewed by a POETIC institutional pathologist or (2) a radiological diagnosis via MRI scan of a typical diffuse pontine tumor made by a POETIC institutional neuroradiologist. Patients with a radiological diagnosis via MRI scan of a typical diffuse pontine tumor will be enrolled on the diffuse pontine tumor arm of the study regardless of histology in cases that are biopsied. Note: For collaborating non-POETIC institutions, the reviews may be done by an institutional pathologist/neuroradiologist.
• Patients must begin study prescribed therapy within 42 days of neurosurgical resection or biopsy of the tumor (high-grade astrocytoma patients) or radiological diagnosis (diffuse pontine tumor patients).
• Age ≥ 3-years and < 22-years-old.
• Brain MRI (and any other studies done according to clinical indications) must not show any definitive evidence of leptomeningeal or extra-neural metastases.
• ANC ≥ 1000/μL and platelet count ≥ 100,000/μL
• Patients must have adequate organ function as defined by:
• Hepatic: total bilirubin < 1.5 mg/dl, AST ≤ 2.5 x the upper limit of normal.
• Renal: serum creatinine ≤ 1.5 x the upper limit of normal for age, or calculated creatinine clearance or nuclear GFR ≥ 70 ml/min/1.73 m2.
• The patient, or for minors, a parent or legal guardian, must give informed written consent indicating they are aware of the investigational nature of this study.

Exclusion Criteria:

• Evidence of leptomeningeal or extra-neural metastatic disease.
• Prior radiation therapy or chemotherapy
• Pregnancy, mothers unwilling to refrain from breast-feeding, and sexually mature patients unwilling to practice an effective form of birth control.
• Other significant concomitant medical illnesses that would compromise the patient's ability to receive all prescribed study therapy.
• Prior therapy which specifically and directly targets the EGFR pathway.
• Prior severe infusion reaction to a monoclonal antibody.
• Significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, recent myocardial infarction (within prior 6 months), uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction.
• Patients with known Gilbert's Syndrome.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: pts with high-grade astrocytoma; This is a 2-group parallel (high-grade astrocytoma, diffuse pontine tumor), single stage study investigating cetuximab in conjunction with external beam radiation therapy, followed by cetuximab and irinotecan in pediatric and young adult patients. Optional exploratory components of the study include (1) correlation of tumor molecular markers with outcome, (2) CSF proteomics, and (3) assay of serum cytokine levels in patients who develop a cetuximab-associated rash.	Other: cetuximab in conjunction with external beam radiation therapy, followed by cetuximab and irinotecan; External beam radiation therapy (5940 cGy in 180 cGy fractions) with weekly cetuximab (250 mg/m2/dose).4-8 weeks rest, 10 cycles of irinotecan (16 mg/m2/day x 5 consecutive days x 2 weeks) with weekly cetuximab (250 mg/m2/dose) at about 21 day intervals. Research biological evaluations will be performed in consenting patients as an optional portion of the study. Cetuximab is to be given every 7 days (+/- 2 days). Cetuximab does not need to be given on Day 1 of each week.
Experimental: pts with diffuse pontine tumor; This is a 2-group parallel (high-grade astrocytoma, diffuse pontine tumor), single stage study investigating cetuximab in conjunction with external beam radiation therapy, followed by cetuximab and irinotecan in pediatric and young adult patients. Optional exploratory components of the study include (1) correlation of tumor molecular markers with outcome, (2) CSF proteomics, and (3) assay of serum cytokine levels in patients who develop a cetuximab-associated rash.	Other: cetuximab in conjunction with external beam radiation therapy, followed by cetuximab and irinotecan; External beam radiation therapy (5940 cGy in 180 cGy fractions) with weekly cetuximab (250 mg/m2/dose).4-8 weeks rest, 10 cycles of irinotecan (16 mg/m2/day x 5 consecutive days x 2 weeks) with weekly cetuximab (250 mg/m2/dose) at about 21 day intervals. Research biological evaluations will be performed in consenting patients as an optional portion of the study. Cetuximab is to be given every 7 days (+/- 2 days). Cetuximab does not need to be given on Day 1 of each week.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With High-grade Astrocytoma and Diffuse Pontine Tumors Achieving One Year Progression Free Survival.		1 year
Number of Participants Experiencing Toxicity	To determine the safety of cetuximab administered weekly in conjunction with involved field external beam radiation therapy for diffuse pontine tumors and high-grade astrocytomas, toxicities will be assessed via the NCI Common Terminology Criteria for Adverse Events (CTCAE, version 3.0)	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Progression		2 years
Number of Participants Who Have Undergone Tumor Analysis	Participant tumor analysis for potential associations between primary tumor tissue molecular markers and tumor response.	2 years
Number of Samples Demonstrating EGFR Copy Number Gain	Identify gene transcripts for putative cetuximab	2 years
Number of Participant Tumors Analyzed for Potential Association Between Histology (Grade) With Protein and ELISA Measurements of Those Proteins.		2 years
Percentage of Participants With Development of Rash, Either Acneiform and/or Desquamation	The purpose is to investigate whether the rash associated with cetuximab is secondary to an inflammatory pathway initiated and mediated by the action of cetuximab on host cells.	2 years
Event Free Survival		up to 12 months
Overall Survival		Up to 43 months

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: Johns Hopkins University; M.D. Anderson Cancer Center; University of Colorado, Denver; Dana-Farber Cancer Institute; University of Florida; Seattle Children's Hospital; Children's Mercy Hospital Kansas City; Children's Healthcare of Atlanta; Alberta Children's Hospital; Phoenix Children's Hospital

Publications and helpful links

Helpful Links

• Memorial Sloan-Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2009
• Primary Completion (Actual): January 15, 2018
• Study Completion (Actual): January 15, 2018

Study Registration Dates

• First Submitted: November 11, 2009
• First Submitted That Met QC Criteria: November 12, 2009
• First Posted (Estimate): November 13, 2009

Study Record Updates

• Last Update Posted (Actual): March 14, 2022
• Last Update Submitted That Met QC Criteria: March 2, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: irinotecan; cetuximab; External beam radiation therapy; high-grade astrocytomas; newly diagnosed diffuse pontine tumors; POETIC
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Astrocytoma; Brain Stem Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Topoisomerase I Inhibitors; Irinotecan; Cetuximab
• Other Study ID Numbers: 09-014