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

• ClinicalTrials.gov Identifier: NCT00392886
• Recruitment Status: Unknown
• First Posted: October 26, 2006
• Last Update Posted: December 18, 2013
• Sponsor: Children's Hospital Los Angeles
• Information provided by: National Cancer Institute (NCI)

Study Description

Brief Summary:

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. A bone marrow or peripheral stem cell transplant using stem cells from the patient may be able to replace blood-forming cells that were destroyed by chemotherapy. This may allow more chemotherapy to be given so that more tumor cells are killed.

PURPOSE: This phase III trial is studying how well giving combination chemotherapy with or without etoposide followed by an autologous stem cell transplant works in treating young patients with previously untreated malignant brain tumors.

Condition or disease	Intervention/treatment	Phase
Brain and Central Nervous System Tumors	Drug: carboplatin; Drug: cisplatin; Drug: cyclophosphamide; Drug: etoposide; Drug: methotrexate; Drug: temozolomide; Drug: thiotepa; Drug: vincristine sulfate; Procedure: autologous bone marrow transplantation; Procedure: autologous hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Radiation: radiation therapy	Phase 3

Detailed Description:

OBJECTIVES:

Primary

• 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.
• Determine the toxicity of this regimen in these patients.
• Determine the mortality of patients treated with this regimen.

Secondary

• 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).
• 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).
• 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).
• 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).

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.

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Primary Purpose: Treatment
• 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]
• Study Start Date: March 2004
• Estimated Primary Completion Date: December 2010

Arms and Interventions

Arm	Intervention/treatment
Experimental: Regimen C; Patients receive induction therapy of 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 receive consolidation therapy of carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours on days -5 to -3, undergo reinfusion of bone marrow or peripheral blood stem cells on day 0, and receive G-CSF SC beginning on day 1 and continuing until blood counts recover. Beginning within 6 weeks after transplantation, some patients undergo radiotherapy once daily 5 days a week for 4-6 weeks in the absence of disease progression or unacceptable toxicity and some patients undergo radiotherapy if there is evidence of tumor remaining after completion of induction chemotherapy.	Drug: carboplatin; Given IV; Drug: temozolomide; Given orally; Drug: thiotepa; Given IV; Drug: vincristine sulfate; Given IV; Procedure: autologous bone marrow transplantation; Given on day 0; Procedure: autologous hematopoietic stem cell transplantation; Given on day 0; Procedure: peripheral blood stem cell transplantation; Given on day 0; Radiation: radiation therapy; Some patients undergo radiation therapy once daily, 5 days a week for 4-6 weeks.
Experimental: Regimen D2; In courses 1, 3, and 5, 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, vincristine IV on days 1, 8, and 15 (in courses1 and 3), and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until blood counts recover. In courses 2 and 4, 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, vincristine IV on days 1, 8, and 15 (in course 2), and G-CSF SC beginning on day 13 and continuing until blood counts recover. Patients receive consolidation therapy as in regimen C in combination with etoposide IV over 3 hours on days -5 to -3 and undergo autologous bone marrow or peripheral blood stem cell transplantation, receive G-CSF, and undergo radiotherapy as in regimen C.	Drug: carboplatin; Given IV; Drug: cisplatin; Given IV; Drug: cyclophosphamide; Given IV; Drug: etoposide; Given IV and orally; Drug: methotrexate; Given IV; Drug: temozolomide; Given orally; Drug: thiotepa; Given IV; Drug: vincristine sulfate; Given IV; Procedure: autologous bone marrow transplantation; Given on day 0; Procedure: autologous hematopoietic stem cell transplantation; Given on day 0; Procedure: peripheral blood stem cell transplantation; Given on day 0; Radiation: radiation therapy; Some patients undergo radiation therapy once daily, 5 days a week for 4-6 weeks.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: up to 10 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

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

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

Contacts and Locations

Locations

United States, Arizona

Phoenix Children's Hospital Outpatient Center

Phoenix, Arizona, United States, 85016

United States, California

Loma Linda University Cancer Institute at Loma Linda University Medical Center

Loma Linda, California, United States, 92354

Jonathan Jaques Children's Cancer Center at Miller Children's Hospital

Long Beach, California, United States, 90806

Childrens Hospital Los Angeles

Los Angeles, California, United States, 90027

Mattel Children's Hospital at UCLA

Los Angeles, California, United States, 90095

Children's Hospital and Research Center Oakland

Oakland, California, United States, 94609

Children's Hospital of Orange County

Orange, California, United States, 92868

United States, Delaware

Alfred I. duPont Hospital for Children

Wilmington, Delaware, United States, 19803

United States, Florida

Nemours Children's Clinic

Jacksonville, Florida, United States, 32207-8482

United States, Illinois

Children's Memorial Hospital - Chicago

Chicago, Illinois, United States, 60614

University of Chicago Comer Children's Hospital

Chicago, Illinois, United States, 60637

United States, Indiana

Riley's Children Cancer Center at Riley Hospital for Children

Indianapolis, Indiana, United States, 46202-5225

United States, Kentucky

Kosair Children's Hospital

Louisville, Kentucky, United States, 40232

United States, Michigan

Helen DeVos Children's Hospital at Spectrum Health

Grand Rapids, Michigan, United States, 49503

United States, Minnesota

Masonic Cancer Center at University of Minnesota

Minneapolis, Minnesota, United States, 55455

United States, Missouri

Children's Mercy Hospital

Kansas City, Missouri, United States, 64108

United States, New Jersey

Tomorrows Children's Institute at Hackensack University Medical Center

Hackensack, New Jersey, United States, 07601

United States, New York

Albert Einstein Cancer Center at Albert Einstein College of Medicine

Bronx, New York, United States, 10461

Schneider Children's Hospital

New Hyde Park, New York, United States, 11040

NYU Cancer Institute at New York University Medical Center

New York, New York, United States, 10016

Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center

New York, New York, United States, 10032

SUNY Upstate Medical University Hospital

Syracuse, New York, United States, 13210

United States, Ohio

Rainbow Babies and Children's Hospital

Cleveland, Ohio, United States, 44106

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, United States, 44195

Nationwide Children's Hospital

Columbus, Ohio, United States, 43205-2696

Toledo Children's Hospital

Toledo, Ohio, United States, 43601

St. Vincent Mercy Medical Center

Toledo, Ohio, United States, 43608

United States, Pennsylvania

Penn State Children's Hospital

Hershey, Pennsylvania, United States, 17033

United States, Texas

M. D. Anderson Cancer Center at University of Texas

Houston, Texas, United States, 77030-4009

Australia, Western Australia

Princess Margaret Hospital for Children

Perth, Western Australia, Australia, 6001

Canada, British Columbia

Children's & Women's Hospital of British Columbia

Vancouver, British Columbia, Canada, V6H 3V4

Canada, Manitoba

CancerCare Manitoba

Winnipeg, Manitoba, Canada, R3E 0V9

Canada, Ontario

Hospital for Sick Children

Toronto, Ontario, Canada, M5G 1X8

New Zealand

Christchurch Hospital

Christchurch, New Zealand, 1

Wellington Children's Hospital

Wellington, New Zealand, 6002

Switzerland

Swiss Pediatric Oncology Group Bern

Bern, Switzerland, CH 3010

Universitaets Kinderklinik

Bern, Switzerland, CH-3010

Sponsors and Collaborators

Children's Hospital Los Angeles

Investigators

• Study Chair: Jonathan L. Finlay, MB, ChB; Children's Hospital Los Angeles
• OverallOfficial: Girish Dhall, MD; Children's Hospital Los Angeles
• OverallOfficial: Kelley Haley, RN, BSN; Children's Hospital Los Angeles

More Information

• Responsible Party: Jonathan L. Finlay, Childrens Hospital Los Angeles
• ClinicalTrials.gov Identifier: NCT00392886
• Other Study ID Numbers: CDR0000503990; CHLA-HEAD-START-III; CHLA-HSIII; CHLA-2004-020; CHLA-04.020; UMN-MT2004-06
• First Posted: October 26, 2006
• Last Update Posted: December 18, 2013
• Last Verified: October 2010

Keywords provided by National Cancer Institute (NCI):

untreated childhood medulloblastoma; untreated childhood supratentorial primitive neuroectodermal tumor; childhood infratentorial ependymoma; childhood supratentorial ependymoma; newly diagnosed childhood ependymoma; childhood high-grade cerebral astrocytoma; childhood oligodendroglioma; childhood atypical teratoid/rhabdoid tumor; childhood choroid plexus tumor; untreated childhood cerebellar astrocytoma; untreated childhood visual pathway and hypothalamic glioma; untreated childhood pineoblastoma

Additional relevant MeSH terms:

Brain Neoplasms; Nervous System Neoplasms; Central Nervous System Neoplasms; Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cyclophosphamide; Temozolomide; Thiotepa; Carboplatin; Methotrexate; Etoposide; Vincristine; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Antimetabolites, Antineoplastic; Antimetabolites; Dermatologic Agents