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

Alternate Title

Combination Chemotherapy With or Without Etoposide Followed By an Autologous Stem Cell Transplant in Treating Young Patients With Previously Untreated Malignant Brain Tumors

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Active Under 10 at diagnosis Other CHLA-HEAD-START-III CHLA-HSIII, CHLA-2004-020, CHLA-04.020, NCT00392886, UMN-MT2004-06

Objectives

Primary

1. Determine the 2-year event-free survival (EFS) and overall survival (OS) of pediatric patients with previously untreated nondisseminated medulloblastoma (< 4 years of age), disseminated medulloblastoma (< 10 years of age), or noncerebellar primitive neuroectodermal tumors (PNET) (disseminated or non-disseminated) treated with induction chemotherapy followed by consolidation with myeloablative chemotherapy and autologous hematopoietic stem cell rescue.
2. Determine the toxicity of this regimen in these patients.
3. Determine the mortality of patients treated with this regimen.

Secondary

1. Determine the complete and partial response rates after completion of induction chemotherapy in these patients stratified according to pathology (medulloblastoma vs noncerebellar PNET vs high-grade gliomas vs atypical teratoid/rhabdoid tumors vs choroid plexus carcinomas and atypical papillomas vs ependymomas).
2. Describe the EFS and OS of these patients stratified according to additional diagnoses (atypical teratoid/rhabdoid tumors vs choroid plexus carcinomas and atypical choroid plexus papillomas vs ependymomas vs high-grade gliomas).
3. Describe the time to progression and patterns of relapse in these patients stratified by diagnosis and radiotherapy received (< 6 years of age with evidence of no residual tumor pre-transplant and no post-transplant consolidation radiotherapy vs < 6 years of age with residual tumor present pre-transplant treated with post-transplant consolidation radiotherapy vs > 6 years of age treated with post-transplant consolidation radiotherapy).
4. Determine the neuropsychometric function, endocrinologic function, and physical growth in these patients stratified according to radiotherapy received (none vs reduced-volume craniospinal radiotherapy vs focused local-field radiotherapy).

Entry Criteria

Disease Characteristics:

• Histologically confirmed malignant brain tumor, including any of the following:
  • Posterior fossa medulloblastoma/primitive neuroectodermal tumor (PNET)*
    • All stages allowed
    • Must be < 4 years of age at diagnosis unless there is evidence of postoperative residual tumor (> 1.5 cm² tumor area) or evidence of neuraxis or extraneural dissemination (high-stage)
    • Medulloblastoma, cerebral neuroblastoma, and ependymoblastoma allowed
      • Low-stage (standard-risk) medulloblastoma not allowed in patients > 4 years of age
  • Ependymoma*
    • All stages and locations allowed
    • Cellular and anaplastic subtypes allowed (no myxopapillary ependymomas of the spinal cord)
    • Must be < 36 months of age at diagnosis for posterior fossa tumor OR < 72 months of age for supratentorial tumor
    • Evidence of neuraxis dissemination irrespective of primary site
    • No cellular (low-grade) supratentorial ependymomas at any age with complete resection of parenchymally based (i.e., not periventricular) supratentorial tumors
  • Brain stem tumor*
    • All stages allowed irrespective of extent of resection
    • No unbiopsied diffuse intrinsic pontine tumor
    • Tumor pathologically confirmed to be either malignant glioma or PNET allowed
  • High-grade glioma**
  • Primary atypical teratoid/rhabdoid tumor of the CNS*
  • Choroid plexus carcinoma or atypical choroid plexus papilloma*
    • All stages and locations allowed
  • Anaplastic astrocytoma**
  • Glioblastoma multiforme**
  • Anaplastic oligodendroglioma**
  • Anaplastic ganglioglioma**
  • Other anaplastic mixed gliomas**
  • Small-cell glioblastoma**
  • Giant-cell glioblastoma**
  • Gliosarcoma**



• The following diagnoses or subtypes are not allowed:
  • Choroid plexus papilloma
  • Pineocytoma
  • Low-grade mixed glioma
  • Primary CNS germ cell tumor
  • Primary CNS lymphoma
  • Solid leukemic lesions (i.e., chloromas, granulocytic sarcomas)
  • Pleomorphic xanthoastrocytoma, low grade
  • Desmoplastic ganglioglioma
  • Low-grade astrocytoma



• Previously untreated disease



• Has undergone definitive surgery within the past 42 days

 [Note: *Patients receive treatment according to regimen D2]

 [Note: **Patients receive treatment according to regimen C]

Prior/Concurrent Therapy:

• See Disease Characteristics
• No prior radiotherapy or chemotherapy
• Prior corticosteroids allowed
• No concurrent corticosteroids for antiemesis only
• No concurrent brachytherapy or electron radiotherapy
• No concurrent dairy products or grapefruit juice with temozolomide administration

Patient Characteristics:

• Bilirubin < 1.5 mg/dL
• ALT and AST < 2.5 times upper limit of normal
• Creatinine clearance and/or glomerular filtration rate ≥ 60 mL/min

Expected Enrollment

A total of 120 patients will be accrued for this study.

Outcomes

Time to tumor progression, disease recurrence, or death of any cause
Event-free survival at 2 years
Toxicity

Response to induction as assessed by one-time tumor measurements at baseline and after completion of induction chemotherapy
Time to death
Overall survival

Outline

This is a pilot study. Patients are stratified according to type of tumor (nonglial vs glial and diffuse pontine).

• Regimen C (patients with glial tumors):
  • Stem cell harvesting (bone marrow and/or peripheral blood): Patients undergo leukapheresis or bone marrow aspiration to collect bone marrow or peripheral blood stem cells prior to beginning induction chemotherapy or after the first course of induction chemotherapy.
  
  
  
  • Induction chemotherapy: Patients receive vincristine IV on days 1, 8, and 15 of courses 1-3, oral temozolomide once daily on days 1-5, and carboplatin IV over 4 hours on days 1 and 2. Patients also receive G-CSF SC beginning on day 6 and continuing until blood counts recover. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.

    Patients with unresectable bulky disease and corticosteroid dependence are removed from study. All other patients proceed to consolidation chemotherapy.

  
  
  
  • Consolidation chemotherapy: Patients receive carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours on days -5 to -3.
  
  
  
  • Autologous bone marrow or peripheral blood stem cell transplantation: Patients undergo reinfusion of bone marrow or peripheral blood stem cells on day 0. Patients also receive G-CSF SC beginning on day 1 and continuing until blood counts recover.
  
  
  
  • Radiotherapy: Beginning within 6 weeks after stem cell transplantation, patients > 6 years of age at diagnosis undergo radiotherapy once daily 5 days a week for 4-6 weeks in the absence of disease progression or unacceptable toxicity. Patients ≤ 6 years of age undergo radiotherapy if there is evidence of tumor remaining after completion of induction chemotherapy.
  
  
  



• Regimen D2 (patients with nonglial tumors):
  • Stem cell harvesting (bone marrow and/or peripheral blood): Patients undergo leukapheresis or bone marrow aspiration to collect bone marrow or peripheral blood stem cells prior to beginning induction chemotherapy or after the first course of induction chemotherapy.
  
  
  
  • Induction chemotherapy:
    • Courses 1, 3, and 5 (28 days per course): Patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour and etoposide IV over 2 hours on days 2 and 3, high-dose methotrexate IV over 4 hours on day 4, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. Patients also receive vincristine IV on days 1, 8, and 15 of courses 1 and 3.
    
    
    
    • Courses 2 and 4 (28 days per course): Patients receive oral temozolomide once daily on days 1-5, oral etoposide once daily on days 1-10, cyclophosphamide IV over 1 hour on days 11 and 12, and G-CSF SC beginning on day 13 and continuing until blood counts recover. Patients also receive vincristine IV on days 1, 8, and 15 of course 2.
    
    
    

    Patients with unresectable bulky disease and corticosteroid dependence are removed from study. All other patients proceed to consolidation chemotherapy.

  
  
  
  • Consolidation chemotherapy: Patients receive carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours and etoposide IV over 3 hours on days -5 to -3.
  
  
  
  • Autologous bone marrow or peripheral blood stem cell transplantation: Patients undergo re-infusion of bone marrow or peripheral blood stem cells on day 0. Patients also receive G-CSF SC beginning on day 1 and continuing until blood counts recover.
  
  
  
  • Radiotherapy:Patients undergo radiotherapy as in regimen C.
  
  
  

Patients in both regimens undergo neuropsychological testing after induction chemotherapy but before consolidation chemotherapy and then at 18, 36, and 54 months after completion of study treatment. Neuropsychometric and neuroendocrine testing is performed before and after radiotherapy. Quality of life is also assessed periodically.

After completion of study treatment, patients are followed periodically.

Trial Contact Information

Trial Lead Organizations

Childrens Hospital Los Angeles

Jonathan Finlay, MB, ChB, Protocol chair		Ph: 323-361-8147 Email: jfinlay@chla.usc.edu
Girish Dhall, MD, Protocol co-chair		Ph: 323-361-8589 Email: gdhall@chla.usc.edu
Kelley Haley, RN, BSN, Research coordinator		Ph: 323-361-2480 Email: khaley@chla.usc.edu

U.S.A.
Arizona
	Phoenix
	Phoenix Children's Hospital Outpatient Center
		Michael Etzl, MD	Ph:  602-546-0920
			Email: metzl@phoenixchildrens.com
California
	Loma Linda
	Loma Linda University Cancer Institute at Loma Linda University Medical Center
		Clinical Trials Office - Loma Linda University Cancer Institute	Ph:  909-558-3375
	Long Beach
	Jonathan Jaques Children's Cancer Center at Miller Children's Hospital
		Ramesh Patel, MD	Ph:  562-933-8600
	Los Angeles
	Childrens Hospital Los Angeles
		Jonathan Finlay, MB, ChB	Ph:  323-361-8147
			Email: jfinlay@chla.usc.edu
	Mattel Children's Hospital at UCLA
		Joseph Lasky, MD	Ph:  310-825-6708
			Email: jlasky@mednet.ucla.edu
	Oakland
	Children's Hospital and Research Center Oakland
		Clinical Trial Office - Children's Hospital and Research Center Oakland	Ph:  510-450-7600
	Orange
	Children's Hospital of Orange County
		Wei-Ping Shen, MD	Ph:  714-516-4348
			Email: vshen@choc.org
Delaware
	Wilmington
	Alfred I. duPont Hospital for Children
		Clinical Trials Office - Alfred I. duPont Hospital for Children	Ph:  302-651-5755
Florida
	Jacksonville
	Nemours Children's Clinic
		Michael Joyce, MD, PhD	Ph:  904-390-3793
			Email: mjoyce@nemours.org
Illinois
	Chicago
	Children's Memorial Hospital - Chicago
		Stewart Goldman, MD	Ph:  773-880-4585
	University of Chicago Comer Children's Hospital
		Charles Rubin, MD	Ph:  773-702-6808 800-289-6333
			Email: crubin@uchicago.edu
Indiana
	Indianapolis
	Riley's Children Cancer Center at Riley Hospital for Children
		Kamnesh Pradhan, MD	Ph:  317-274-8784
			Email: pkamnesh@iupui.edu
Kentucky
	Louisville
	Kosair Children's Hospital
		Clinical Trials Office - Kosair Children's Hospital	Ph:  502-629-5500
			Email: CancerResource@nortonhealthcare.org
Michigan
	Grand Rapids
	Helen DeVos Children's Hospital at Spectrum Health
		Clinical Trials Office - Helen DeVos Children's Hospital	Ph:  616-391-3050
Minnesota
	Minneapolis
	Masonic Cancer Center at University of Minnesota
		Clinical Trials Office - Masonic Cancer Center at University of Minnesota	Ph:  612-624-2620
Missouri
	Kansas City
	Children's Mercy Hospital
		Richard Shore, MD	Ph:  816-234-3265
			Email: rwshore@cmh.edu
New Jersey
	Hackensack
	Tomorrows Children's Institute at Hackensack University Medical Center
		Steven Halpern, MD	Ph:  201-996-5437
			Email: bdhalpern@aol.com
New York
	Bronx
	Albert Einstein Cancer Center at Albert Einstein College of Medicine
		Clinical Trials Office - Albert Einstein Cancer Center at Albert Einstein College of Medicine	Ph:  718-904-2730
			Email: aecc@aecom.yu.edu
	New Hyde Park
	Schneider Children's Hospital
		Mark Atlas, MD	Ph:  718-470-3460
			Email: matlas@lij.edu
	New York
	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
		Clinical Trials Office - Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	Ph:  212-305-8615
	NYU Cancer Institute at New York University Medical Center
		Sharon Gardner, MD	Ph:  212-263-8520
			Email: sharon.gardner@med.nyu.edu
	Syracuse
	SUNY Upstate Medical University Hospital
		Clinical Trials Office - SUNY Upstate Medical University Hospital	Ph:  315-464-5476
Ohio
	Cleveland
	Cleveland Clinic Taussig Cancer Center
		Clinical Trials Office - Cleveland Clinic Taussig Cancer Center	Ph:  866-223-8100
	Rainbow Babies and Children's Hospital
		Susan Wiersma, MD	Ph:  216-844-3345
	Columbus
	Nationwide Children's Hospital
		Amanda Termuhlen, MD	Ph:  614-722-3552
	Toledo
	St. Vincent Mercy Medical Center
		Rama Jasty, MD	Ph:  419-251-8215
			Email: rjasty@med.umich.edu
	Toledo Children's Hospital
		Dagmar Stein, MD, PhD	Ph:  419-291-7815
			Email: dagmar.stein@promedica.org
Pennsylvania
	Hershey
	Penn State Children's Hospital
		Melanie Comito, MD	Ph:  717-531-6012 800-243-1455
			Email: mac36@psu.edu
Texas
	Houston
	M. D. Anderson Cancer Center at University of Texas
		Clinical Trials Office - M. D. Anderson Cancer Center at the University of Texas	Ph:  713-792-3245
Australia
Western Australia
	Perth
	Princess Margaret Hospital for Children
		David Baker, MD, MBBS, FRACP, FRCPA	Ph:  61-8-9340-8234
Canada
British Columbia
	Vancouver
	Children's & Women's Hospital of British Columbia
		Paul Rogers, MB, ChB, FRCPC, MBA, FRCP	Ph:  604-875-2322
			Email: progers@cw.bc.ca
Manitoba
	Winnipeg
	CancerCare Manitoba
		David Eisenstat, MD	Ph:  204-787-1169
			Email: eisensta@cc.umanitoba.ca
Ontario
	Toronto
	Hospital for Sick Children
		Annie Huang, MD	Ph:  416-813-7360
New Zealand
	Christchurch
	Christchurch Hospital
		Michael Sullivan, MD, PhD, FRACP	Ph:  64-3-364-0744
			Email: micke.sullivan@otago..ac.nz
	Wellington
	Wellington Children's Hospital
		Elizabeth Hesketh, MD	Ph:  64-4-918-5091
			Email: liz.hesketh@ccdhb.org.nz
Switzerland
	Bern
	Swiss Pediatric Oncology Group Bern
		Andreas Hirt, MD	Ph:  41-31-632-9495
			Email: andreas.hirt@insel.ch
	Universitaets Kinderklinik
		Andreas Hirt, MD	Ph:  41-31-632-9495

Registry Information
Official Title		Dose Intensive Chemotherapy for Children Less Than Ten Years of Age Newly-Diagnosed with Malignant Brain Tumors: A Pilot Study of Two Alternative Intensive Induction Chemotherapy Regimens, Followed by Consolidation with Myeloablative Chemotherapy (Thiotepa and Carboplatin, With or Without Etoposide) and Autologous Stem Cell Rescue [HEAD START III]
Trial Start Date		2004-03-22
Registered in ClinicalTrials.gov		NCT00392886
Date Submitted to PDQ		2006-10-17
Information Last Verified		2008-08-12