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)

Tracking Information

• First Submitted Date: October 25, 2006
• First Posted Date: October 26, 2006
• Last Update Posted Date: December 18, 2013
• Study Start Date: March 2004
• Estimated Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 9, 2006)

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

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: November 9, 2006)

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

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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.

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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Primary Purpose: Treatment
• Condition: Brain and Central Nervous System Tumors

Intervention

• 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.

Study Arms

• 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.
  Interventions:

  • Drug: carboplatin
  • 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
• 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.
  Interventions:

  • 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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: November 16, 2006): 120
• Original Enrollment: Not Provided
• Study Completion Date: Not Provided
• Estimated Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 10 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States, Australia, Canada, New Zealand, Switzerland

Administrative Information

• NCT Number: NCT00392886
• Other Study ID Numbers: CDR0000503990; CHLA-HEAD-START-III; CHLA-HSIII; CHLA-2004-020; CHLA-04.020; UMN-MT2004-06
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Jonathan L. Finlay, Childrens Hospital Los Angeles
• Study Sponsor: Children's Hospital Los Angeles
• Collaborators: Not Provided

Investigators

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

• PRS Account: National Cancer Institute (NCI)
• Verification Date: October 2010