Carboplatin and Vincristine Plus Radiation Therapy Followed By Adjuvant Chemotherapy in Treating Young Patients With Newly Diagnosed CNS Embryonal Tumors

An Intergroup Pilot Study of Concurrent Carboplatin, Vincristine and Radiotherapy Followed by Adjuvant Chemotherapy in Patients With Newly Diagnosed High-Risk Central Nervous System Embryonal Tumors

RATIONALE: Drugs used in chemotherapy, such as carboplatin and vincristine, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining carboplatin and vincristine with radiation therapy followed by adjuvant chemotherapy may kill more tumor cells.

PURPOSE: Randomized phase II trial to study the effectiveness of combination chemotherapy plus radiation therapy followed adjuvant chemotherapy in treating young patients who have newly diagnosed high-risk CNS embryonal tumors.

Study Overview

• Status: Completed
• Conditions: Neuroblastoma; Brain Tumors; Central Nervous System Tumors
• Intervention / Treatment: Procedure: adjuvant therapy; Drug: cyclophosphamide; Drug: vincristine sulfate; Drug: cisplatin; Drug: carboplatin; Biological: filgrastim; Radiation: radiation therapy

Detailed Description

OBJECTIVES:

• Determine the feasible dose and duration of carboplatin combined with craniospinal and local radiotherapy and adjuvant chemotherapy in children with newly diagnosed, high-risk CNS embryonal tumors (Phase I completed as of 11-25-03).
• Determine the feasibility of administering cyclophosphamide and vincristine with or without cisplatin after concurrent carboplatin, vincristine, and radiotherapy in these patients.
• Determine the overall and individual toxicity rates of this regimen in these patients.
• Determine the complete response rate in patients treated with this regimen.
• Obtain preliminary estimates of event-free survival of patients treated with this regimen.
• Determine the prognostic significance of enhancing tumor after completion of radiotherapy on event-free survival of these patients.

OUTLINE: This is a pilot, dose-escalation study of carboplatin. (Phase I completed as of 11-25-03.)

Within 31 days of definitive surgery, all patients receive vincristine IV weekly for 6 weeks and carboplatin IV over 15-20 minutes (after completion of vincristine infusion) 5 days a week for 6 weeks. Patients undergo radiotherapy (1-4 hours after carboplatin infusion) 5 days a week for 6 weeks.

Cohorts of 6-12 patients receive escalating doses of carboplatin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which no more than 3 of 12 patients experience dose-limiting toxicity. (Phase I completed as of 11-25-03.)

At 6 weeks after completion of radiotherapy, patients are assigned to arm II for adjuvant/maintenance chemotherapy. (Arm I closed to accrual as of 11-25-03.)

• Arm I (closed to accrual as of 11-25-03): Patients receive cyclophosphamide IV over 1 hour on days 0 and 1, vincristine IV on days 0 and 7, and filgrastim (G-CSF) IV or subcutaneously (SC) beginning on day 2 and continuing for at least 10 days until blood counts recover.
• Arm II: Patients receive cyclophosphamide IV over 1 hour on days 1 and 2, vincristine IV on days 0 and 7, cisplatin IV over 6 hours on day 0, and G-CSF IV or SC beginning on day 3 and continuing for at least 10 days until blood counts recover.

In both arms, adjuvant/maintenance chemotherapy repeats every 4 weeks for 6 courses.

Patients are followed every 3 months for 8 months, every 4 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 162 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 168
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Western Australia
    • Perth, Western Australia, Australia, 6001
      • Princess Margaret Hospital for Children
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • British Columbia Children's Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3J 3G9
      • IWK Grace Health Centre
• United States
  • California
    • Long Beach, California, United States, 90806
      • Long Beach Memorial Medical Center
    • Los Angeles, California, United States, 90095-1781
      • Jonsson Comprehensive Cancer Center, UCLA
    • Los Angeles, California, United States, 90027-0700
      • Children's Hospital Los Angeles
    • Orange, California, United States, 92668
      • Children's Hospital of Orange County
    • San Francisco, California, United States, 94115-0128
      • UCSF Cancer Center and Cancer Research Institute
  • Colorado
    • Denver, Colorado, United States, 80218
      • Children's Hospital of Denver
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Cancer Research Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5265
      • Indiana University Cancer Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0752
      • University of Michigan Comprehensive Cancer Center
    • Kalamazoo, Michigan, United States, 49007-3731
      • CCOP - Kalamazoo
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Cancer Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198-3330
      • University of Nebraska Medical Center
  • New Jersey
    • Paterson, New Jersey, United States, 07503
      • St. Joseph's Hospital and Medical Center
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10016
      • NYU School of Medicine's Kaplan Comprehensive Cancer Center
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center, UNC
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • CCOP - Merit Care Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Children's Hospital Medical Center - Cincinnati
    • Cleveland, Ohio, United States, 44106-5065
      • Ireland Cancer Center
    • Columbus, Ohio, United States, 43205-2696
      • Children's Hospital of Columbus
  • Oregon
    • Portland, Oregon, United States, 97201-3098
      • Doernbecher Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
  • Tennessee
    • Nashville, Tennessee, United States, 37232-6838
      • Vanderbilt Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas - MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Huntsman Cancer Institute
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Comprehensive Cancer Center

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

DISEASE CHARACTERISTICS:

• Histologically proven high-risk CNS embryonal tumors, including:

  • Primitive neuroectodermal tumors
  • Atypical teratoid/rhabdoid tumor
  • Medulloblastoma
  • Desmoplastic medulloblastoma
  • Ependymoblastoma
  • Medullomyoblastoma
  • Spongioblastoma
  • Spongioblastoma polare
  • Primitive polar spongioblastoma
  • Neuroepitheliomatous neoplasms
  • Medulloepithelioma
  • Neuroblastoma
  • Pineoblastoma
• No bone marrow involvement or bone metastases
• No M4 disease
• M3 disease must have evidence of tumor on spinal MRI

PATIENT CHARACTERISTICS:

Age:

• 3 to 21 at diagnosis

Performance status:

• Not specified

Life expectancy:

• At least 8 weeks

Hematopoietic:

• Absolute neutrophil count greater than 1,500/mm^3
• Platelet count at least 100,000/mm^3 (transfusion independent)
• Hemoglobin at least 10.0 g/dL (packed red blood cell transfusions allowed)

Hepatic:

• Bilirubin less than 1.5 mg/dL
• SGOT/SGPT less than 2.5 times normal

Renal:

• Creatinine less than 1.5 times upper limit of normal OR
• Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy

Surgery:

• Prior definitive surgery allowed

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: Newly diagnosed cerebral PNET with histologic verification; Begin therapy within 31 days of surgery. Radiation therapy will be given in standard fractions along with filgrastim. The craniospinal axis will be treated first. Patients will receive carboplatin at 35 mg/m2/day IV over 15-20 minutes Monday through Friday, 1-4 hours prior to radiation for 6 weeks (total of 30 doses). Vincristine sulfate 1.5 mg/m2 IV will be given weekly x 6. Following radiation, patients will receive Maintenance chemotherapy. Patients enrolled prior to Amendment #5 will receive six cycles of cyclophosphamide and vincristine (Regimen A). Patients enrolled after Amendment #5 will receive six cycles of cyclophosphamide, vincristine sulfate and cisplatin (Regimen B).

Procedure: adjuvant therapy; Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; NSC-26271; Drug: vincristine sulfate; Given IV; Other Names: Oncovin; NSC-67574; Drug: cisplatin; Given IV; Other Names: Platinol-AQ; NSC-119875; Drug: carboplatin; Given IV; Other Names: Paraplatin; NSC-241240; Biological: filgrastim; Given IV; Other Names: G-CSF; Neupogen; NSC-614629; Radiation: radiation therapy; 1.8 Gy/fx x 20fx=36Gy Craniospinal XRT*; Other Names: radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event Free Survival	Minimum time to disease progression or recurrence, time to death for any reason, or time to occurrence of a second malignant neoplasm (SMN).	Length of study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	Time to death from any cause	Length of study

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Regina Jakacki, MD, University of Pittsburgh

Publications and helpful links

General Publications

• Jakacki RI, Burger PC, Zhou T, Holmes EJ, Kocak M, Onar A, Goldwein J, Mehta M, Packer RJ, Tarbell N, Fitz C, Vezina G, Hilden J, Pollack IF. Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children's Oncology Group Phase I/II study. J Clin Oncol. 2012 Jul 20;30(21):2648-53. doi: 10.1200/JCO.2011.40.2792. Epub 2012 Jun 4.
• Jakacki R, Burger P, Zhou T, et al.: Outcome for metastatic (M+) medulloblastoma (MB) treated with carboplatin during craniospinal radiotherapy (CSRT) followed by cyclophosphamide (CPM) and vincristine (VCR): preliminary results of COG 99701. [Abstract] J Clin Oncol 25 (Suppl 18): A-2017, 2007.

Study record dates

Study Major Dates

• Study Start: March 1, 1998
• Primary Completion (Actual): October 1, 2007
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: May 16, 2003
• First Posted (Estimate): May 19, 2003

Study Record Updates

• Last Update Posted (Estimate): August 23, 2013
• Last Update Submitted That Met QC Criteria: August 22, 2013
• Last Verified: August 1, 2013

More Information

Terms related to this study

• Keywords: localized unresectable neuroblastoma; stage 4S neuroblastoma; regional neuroblastoma; untreated childhood medulloblastoma; untreated childhood supratentorial primitive neuroectodermal tumor
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neoplasms; Nervous System Neoplasms; Central Nervous System Neoplasms; Neuroblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Cyclophosphamide; Carboplatin; Cisplatin; Vincristine
• Other Study ID Numbers: A9971; COG-A9971 (Other Identifier: Children's Oncology Group); CCG-99701 (Other Identifier: Children's Cancer Group); CDR0000066055 (Other Identifier: Clinical Trials.gov)