Combination Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Children With Newly Diagnosed Neuroblastoma

NCT ID: NCT00017368

Last Updated: 2014-02-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2001-04-30
• Study Completion Date: 2012-01-31

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy followed by peripheral stem cell transplantation in treating children who have newly diagnosed neuroblastoma.

Detailed Description

OBJECTIVES:

• Determine the toxicity and feasibility of high-dose thiotepa and cyclophosphamide with autologous peripheral blood stem cell (PBSC) transplantation and sargramostim (GM-CSF) followed by high-dose carboplatin, etoposide, and melphalan with second PBSC transplantation, GM-CSF, and isotretinoin after induction in children with newly diagnosed high-risk neuroblastoma.
• Determine the role of the meta-iodobenzylguanidine (MIBG) scan in assessing response to tandem transplantation and minimal residual disease therapy in these patients.
• Determine the feasibility of quantitative polymerase chain reaction for neuroblastoma-specific ribonucleic acids at specific stages of treatment as a prognostic indicator of outcome in these patients.
• Determine the immune recovery by quantitation of lymphocyte subsets in these patients and limited functional analysis after completion of this regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to peripheral blood stem cell (PBSC) selection (selected PBSCs vs unselected PBSCs). (Selected PBSC stratum closed to accrual as of 7/17/02.)

• Induction/harvest:

• Course 1: Patients receive etoposide (VP-16) IV over 1 hour on days 2-4, cisplatin IV over 6 hours (beginning after VP-16 infusion) on days 1-5, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 6 and continuing until blood counts recover.
• Course 2: Patients receive vincristine IV and doxorubicin IV over 15 minutes on day 1, cyclophosphamide IV over 6 hours on days 1 and 2, and sargramostim (GM-CSF) SC beginning on day 3 and continuing until PBSC are harvested. Beginning after completion of course 2 and when blood counts recover, autologous PBSC are harvested.
• Course 3: Patients receive VP-16 IV over 1 hour and ifosfamide IV over 1 hour on days 1-5 and G-CSF SC beginning on day 6 and continuing until blood counts recover.
• Course 4: Patients receive VP-16 IV over 1 hour on days 1-3, carboplatin IV over 2 hours (beginning after VP-16 infusion) on days 1 and 2, and G-CSF SC beginning on day 4 and continuing until blood counts recover.
• Course 5: Patients receive treatment as in course 2 but supported by G-CSF. Courses 1-5 each last 3-4 weeks. Patients undergo resection of the primary tumor after course 4 or 5 unless primary resection was completed at diagnosis (which is not recommended), no primary site is found, or the primary site is unresectable. Patients complete courses 1-5 and then proceed to the first conditioning/PBSC transplantation (PBSCT) in the absence of disease progression or unacceptable toxicity.
• First conditioning/PBSCT: Patients receive high-dose thiotepa IV on days -7 to -5 and cyclophosphamide IV over 1 hour on days -5 to -2. CD34+ PBSC are reinfused on day 0. GM-CSF is administered SC beginning on day 5 and continuing until blood counts recover. If blood counts have not recovered by day 28, unselected PBSC are reinfused. In the absence of disease progression or unacceptable toxicity, patients proceed to the second conditioning/PBSCT.
• Second conditioning/PBSCT: Beginning within 6-8 weeks after initiating the first conditioning, patients receive high-dose carboplatin IV continuously and etoposide phosphate IV continuously on days -7 to -4 and melphalan IV on days -7 to -5. PBSC and GM-CSF are administered as in the first PBSCT.

Beginning no earlier than day 28 after the second PBSCT, patients undergo local radiotherapy to the primary site and sites that are positive by meta-iodobenzylguanidine scan after induction twice a day for 7 days (or once a day for 12 days if twice daily dosing is not possible). Beginning on day 90 after the second PBSCT, patients receive oral isotretinoin twice a day for 2 weeks. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity.

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

PROJECTED ACCRUAL: A total of 31-39 patients will be accrued for this study within 22 months.

Conditions

Neuroblastoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

All Patients

Group Type: EXPERIMENTAL

filgrastim

Intervention Type: BIOLOGICAL

sargramostim

Intervention Type: BIOLOGICAL

carboplatin

Intervention Type: DRUG

cisplatin

Intervention Type: DRUG

cyclophosphamide

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

etoposide

Intervention Type: DRUG

etoposide phosphate

Intervention Type: DRUG

ifosfamide

Intervention Type: DRUG

isotretinoin

Intervention Type: DRUG

melphalan

Intervention Type: DRUG

thiotepa

Intervention Type: DRUG

vincristine sulfate

Intervention Type: DRUG

conventional surgery

Intervention Type: PROCEDURE

peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

radiation therapy

Intervention Type: RADIATION

Interventions

filgrastim

Intervention Type: BIOLOGICAL

sargramostim

Intervention Type: BIOLOGICAL

carboplatin

Intervention Type: DRUG

cisplatin

Intervention Type: DRUG

cyclophosphamide

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

etoposide

Intervention Type: DRUG

etoposide phosphate

Intervention Type: DRUG

ifosfamide

Intervention Type: DRUG

isotretinoin

Intervention Type: DRUG

melphalan

Intervention Type: DRUG

thiotepa

Intervention Type: DRUG

vincristine sulfate

Intervention Type: DRUG

conventional surgery

Intervention Type: PROCEDURE

peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

radiation therapy

Intervention Type: RADIATION

Eligibility Criteria

Inclusion Criteria

DISEASE CHARACTERISTICS:

• Newly diagnosed high-risk neuroblastoma

• Histologically proven AND/OR
• Bone marrow specimen showing clumps of tumor cells accompanied by elevated urinary catecholamines
• Age 1-30:

• Must meet one of the following INSS staging criteria:

• Stage IV regardless of biologic factors
• Stage IIa/IIb with MYCN oncogene amplification (greater than 10) and unfavorable pathology
• Stage III with MYCN oncogene amplification (greater than 10) or unfavorable pathology
• Initially stage I, II, or IVS, that has progressed without interval chemotherapy
• Under age 1:

• INSS stage III, IV, or IVS with MYCN amplification (greater than 10)
• Must enter neuroblastoma biology study COG-ANBL00B1 within 2 weeks of diagnosis and before entry on this study

PATIENT CHARACTERISTICS:

Age:

• 30 and under at original diagnosis

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• Not specified

Other:

• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• See Disease Characteristics
• No more than 1 prior course of chemotherapy on the intergroup low- or intermediate-risk neuroblastoma studies prior to determination of MYCN status and Shimada histology

Endocrine therapy:

• Not specified

Radiotherapy:

• Prior emergent radiotherapy to sites of function- or life-threatening neuroblastoma allowed

Surgery:

• Not specified

Other:

• No other prior systemic therapy for neuroblastoma

• Maximum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Children's Oncology Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stephan A. Grupp, MD, PhD

Role: STUDY_CHAIR

Children's Hospital of Philadelphia

Locations

AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Scottish RiteCampus

Atlanta, Georgia, United States

Floating Hospital for Children

Boston, Massachusetts, United States

Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute

Boston, Massachusetts, United States

CCOP - Columbia River Oncology Program

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Baylor College of Medicine

Houston, Texas, United States

CCOP - Scott and White Hospital

Temple, Texas, United States

CCOP - Marshfield Clinic Research Foundation

Marshfield, Wisconsin, United States

Princess Margaret Hospital for Children

Perth, Western Australia, Australia

Countries

United States; Australia

References

Marcus KJ, Shamberger R, Litman H, von Allmen D, Grupp SA, Nancarrow CM, Goldwein J, Grier HE, Diller L. Primary tumor control in patients with stage 3/4 unfavorable neuroblastoma treated with tandem double autologous stem cell transplants. J Pediatr Hematol Oncol. 2003 Dec;25(12):934-40. doi: 10.1097/00043426-200312000-00005.

Reference Type: BACKGROUND

PMID: 14663275 (View on PubMed)

Kletzel M, Katzenstein HM, Haut PR, Yu AL, Morgan E, Reynolds M, Geissler G, Marymount MH, Liu D, Kalapurakal JA, Shore RM, Bardo DM, Schmoldt J, Rademaker AW, Cohn SL. Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chicago Pilot II Study. J Clin Oncol. 2002 May 1;20(9):2284-92. doi: 10.1200/JCO.2002.06.060.

Reference Type: BACKGROUND

PMID: 11980999 (View on PubMed)

Donovan J, Temel J, Zuckerman A, Gribben J, Fang J, Pierson G, Ross A, Diller L, Grupp SA. CD34 selection as a stem cell purging strategy for neuroblastoma: preclinical and clinical studies. Med Pediatr Oncol. 2000 Dec;35(6):677-82. doi: 10.1002/1096-911x(20001201)35:63.0.co;2-h.

Reference Type: BACKGROUND

PMID: 11107145 (View on PubMed)

Grupp SA, Stern JW, Bunin N, Nancarrow C, Adams R, Gorlin JB, Griffin G, Diller L. Rapid-sequence tandem transplant for children with high-risk neuroblastoma. Med Pediatr Oncol. 2000 Dec;35(6):696-700. doi: 10.1002/1096-911x(20001201)35:63.0.co;2-0.

Reference Type: BACKGROUND

PMID: 11107149 (View on PubMed)

Grupp SA, Stern JW, Bunin N, Nancarrow C, Ross AA, Mogul M, Adams R, Grier HE, Gorlin JB, Shamberger R, Marcus K, Neuberg D, Weinstein HJ, Diller L. Tandem high-dose therapy in rapid sequence for children with high-risk neuroblastoma. J Clin Oncol. 2000 Jul;18(13):2567-75. doi: 10.1200/JCO.2000.18.13.2567.

Reference Type: BACKGROUND

PMID: 10893288 (View on PubMed)

Other Identifiers

COG-ANBL00P1

Identifier Type: OTHER

Identifier Source: secondary_id

CDR0000068681

Identifier Type: OTHER

Identifier Source: secondary_id

ANBL00P1

Identifier Type: -

Identifier Source: org_study_id