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

Alternate Title

Combination Chemotherapy and Surgery With or Without Isotretinoin in Treating Young Patients With Neuroblastoma

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Active 12 and under NCI COG-ANBL0531 ANBL0531, NCT00499616

Objectives

Primary

1. Reduce therapy for patients with intermediate-risk neuroblastoma while maintaining a 3-year overall survival (OS) rate of ≥ 95% by using a response-based duration of therapy algorithm.
2. Maintain an overall 3-year OS rate of ≥ 90% for patients within each group.
3. Utilize loss of heterozygosity, prospectively, at 1p36 and 11q23 to refine risk-stratification and treatment assignment, allowing patients whose tumors lack these chromosomal abnormalities to receive a reduction in therapy, and compare the outcome with patients treated on COG-A3961.
4. Reduce intensity of therapy for patients 365 to < 547 days (12-18 months) of age with stage 4 neuroblastoma and favorable biological features and maintain a 3-year event-free survival (EFS) rate consistent with that for patients < 1 year of age with stage 4 neuroblastoma treated on COG-A3961.
5. Reduce intensity of therapy for patients 365 to < 547 days (12-18 months) of age with stage 3 MYCN-nonamplified but unfavorable histology neuroblastoma and maintain a 3-year EFS rate consistent with that for patients < 1 year of age with stage 3, MYCN-nonamplified, unfavorable histology neuroblastoma treated on COG-A3961.
6. Reduce surgical morbidity for patients with stage 4S neuroblastoma by allowing for biopsy only, rather than complete surgical resection, of the primary tumor.
7. Systematically study the outcome of patients with stage 4S neuroblastoma who are unable to undergo biopsy for biology-based risk assignment.

Secondary

1. Determine the results of a standard retrieval approach for patients with residual disease after 8 courses of initial therapy.
2. Determine the results of a standard retrieval approach for patients with progressive, nonmetastatic disease.
3. Identify additional biological surrogate markers for disease relapse and/or metastatic progression.
4. Describe the neurologic outcome of patients with paraspinal neuroblastoma primary tumors.

Entry Criteria

Disease Characteristics:

• Histologically confirmed neuroblastoma or ganglioneuroblastoma
  • Newly diagnosed disease
  • Intermediate-risk disease



• Meets 1 of the following criteria:
  • Group 1
    • International Neuroblastoma Staging System (INSS) stage 2A/2B < 50% resected or biopsy only, age 0 to 12 years, MYCN-not amplified (NA), any histology, any ploidy, normal 1p and 11q
    • INSS stage 3, age < 365 days, MYCN-NA, favorable histology (FH), hyperdyploid (DI) > 1, normal 1p and 11q
    • INSS stage 3, age ≥ 365 days to 12 years, MYCN-NA, FH, normal 1p and 11q
    • INSS stage 4S, age < 365 days, MYCN-NA, FH, DI > 1, normal 1p and 11q, but clinically symptomatic
  • Group 2
    • INSS stage 2A/2B < 50% resected or biopsy only, age 0 to ≤ 12 years, MYCN-NA, any histology and ploidy, 1p loss of heterozygosity (LOH) and/or unb11q LOH (or data missing for either)
    • INSS stage 3, < 365 days old, MYCN-NA, FH, DI > 1, 1p LOH and/or unb11q LOH (or data missing for either)
    • INSS stage 3, < 365 days old, MYCN-na, either DI = 1 and/or unfavorable histology (UH), normal 1p and 11q
    • INSS stage 3, ≥ 365 days to 12 years old, MYCN-NA, FH, 1p LOH and/or unb11q LOH (or data missing for either)
    • INSS stage 4, < 365 days old, MYCN-NA, FH, DI > 1, normal 1p and 11q
    • INSS stage 4S, < 365 days old, MYCN-NA, either UH and any ploidy, or FH and DI = 1, normal 1p and 11q
    • INSS stage 4S, < 365 days old, MYCN-NA, FH, DI > 1, 1p LOH and/or unb11q LOH (or data missing for either) and clinically symptomatic
    • INSS stage 4S, < 365 days old, unknown MYCN, histology, and/or ploidy
  • Group 3
    • INSS stage 3, < 365 days old, MYCN-NA, either DI = 1 and/or UH, 1p LOH and/or unb11q LOH (or data missing for either)
    • INSS stage 3, 365 to < 547 days old, MYCN-NA, UH, any ploidy, any 1p and 11q
    • INSS stage 4, < 365 days old, MYCN-NA, either DI = 1 and/or UH, any 1p and 11q
    • INSS Stage 4, age < 365 days, MYCN-NA, FH, DI > 1, 1p LOH and/or unb11q LOH (or data missing for either)
    • INSS stage 4, 365 to < 547 days old, MYCN-NA, FH, DI > 1, any 1p and 11q
    • INSS stage 4S, < 365 days old, MYCN-NA, either UH and any ploidy or FH and DI = 1 and 1p LOH and/or unb11q LOH (or data missing for either)



• Must be enrolled on protocol COG-ANBL00B1

Prior/Concurrent Therapy:

• No prior chemotherapy with the exception of the following:
  • Patients with intradural tumor extension and emergent paresis can be given chemotherapy according to COG-ANBL0531 prior to biopsy provided the biopsy is subsequently performed within 96 hours
  • Patients without symptoms may be enrolled and treated immediately with chemotherapy at the discretion of the investigator if it is considered to be in the best interest of the patient (e.g., a patient with intradural tumor extension who is at risk of developing neurologic deficits)
  • Prior dexamethasone allowed at the discretion of the investigator

Patient Characteristics:

• See Disease Characteristics

Expected Enrollment

Outcomes

Overall survival
Event-free survival

Outline

This is a multicenter study. Patients are assigned to 1 of 3 treatment groups by risk-stratification based on age, stage (INSS stage 2, 3, 4, or 4S), MYCN status (amplified vs not amplified), histopathologic classification, and tumor DNA index.

• Initial chemotherapy: Courses of chemotherapy are administered every 21 days according to group assignment as outlined below:
  • Course 1: Patients receive carboplatin IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3.
  • Course 2: Patients receive carboplatin IV over 1 hour, cyclophosphamide IV over 1 hour, and doxorubicin hydrochloride IV over 15 minutes on day 1.
  • Course 3: Patients receive cyclophosphamide IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3.
  • Course 4: Patients receive carboplatin IV over 1 hour and doxorubicin hydrochloride IV over 15 minutes on day 1 and etoposide IV over 1 hour on days 1-3.
  • Course 5: Patients receive cyclophosphamide IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3.
  • Course 6: Patients receive carboplatin IV over 1 hour, cyclophosphamide IV over 1 hour, and doxorubicin hydrochloride IV over 15 minutes on day 1.
  • Course 7: Patients receive carboplatin IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3.
  • Course 8: Patients receive cyclophosphamide IV over 1 hour and doxorubicin hydrochloride IV over 15 minutes on day 1.
    • Group 1: Patients receive courses 1-2 of initial chemotherapy. Patients with a partial response (PR) to chemotherapy and surgery proceed to observation. Patients without a PR continue to receive 2-6 additional courses of chemotherapy (beginning with course 3) until PR is achieved. Patients who do not achieve a PR after additional chemotherapy and surgery proceed to retrieval chemotherapy.
    • Group 2: Patients receive courses 1-4 of initial chemotherapy. Patients with a PR after chemotherapy and surgery proceed to observation. Patients without a PR continue to receive 2-4 additional courses of chemotherapy (beginning with course 3) until PR is achieved. Patients who do not achieve a PR after additional chemotherapy and surgery proceed to retrieval chemotherapy.
    • Group 3: Patients receive courses 1-8 of initial chemotherapy. Patients under 12 months of age with stage 4 disease who achieve a very good PR (VGPR) to chemotherapy and surgery proceed to observation. Patients 12-18 months of age with stage 3 or 4 disease who achieve a VGPR proceed to isotretinoin therapy. Patients who do not achieve a VGPR proceed to retrieval chemotherapy.



• Observation: Patients do not receive any more treatment but are followed to monitor for the possibility of tumor recurrence.



• Isotretinoin therapy: Beginning 3-4 weeks after completion of chemotherapy or 2 weeks post-operatively (for patients who undergo surgical resection), patients receive oral isotretinoin twice daily on days 1-14. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.



• Retrieval chemotherapy: Patients receive cyclophosphamide IV over 30 minutes and topotecan IV over 30 minutes on days 1-5. Treatment repeats every 21 days for up to 6 courses.
  • Groups 1 and 2: Patients with a PR after 2-6 courses of retrieval chemotherapy proceed to observation. Patients without a PR after 2-6 courses of retrieval chemotherapy are removed from protocol therapy.
  • Group 3: Patients under 12 months of age with stage 4 disease with a VGPR after retrieval chemotherapy proceed to observation. Patients 12-18 months of age with stage 3 or 4 disease who achieve a VGPR after retrieval chemotherapy proceed to isotretinoin therapy. Patients who do not achieve a VGPR after retrieval chemotherapy are removed from protocol therapy.
  • Surgery: With the exception of patients with INSS 4S disease, patients will undergo surgery to remove as much of the primary tumor and involved lymph nodes as can safely be accomplished. Reassessment for definitive surgery (for patients who undergo biopsy only or partial resection at diagnosis) is made at the completion of scheduled chemotherapy (after course 2 for group 1 patients, after course 4 for group 2 patients, and after course 4 or 8 for group 3 patients).

After completion of study therapy, patients are followed periodically for up to 10 years.

Data from patients with low risk disease who are observed following surgical resection only and are not enrolled on ANBL0531, will be collected for study objectives.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Clare Twist, MD, Protocol chair		Ph: 650-723-5535
Mary Lou Schmidt, MD, Protocol co-chair		Ph: 312-996-6143 Email: mls3@uic.edu

U.S.A.
Alabama
	Birmingham
	Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
		Clinical Trials Office - Lurleen Wallace Comprehensive Cancer	Ph:  205-934-0309
Arizona
	Phoenix
	Phoenix Children's Hospital
		Jessica Boklan	Ph:  602-546-0920
	Tucson
	Arizona Cancer Center at University of Arizona Health Sciences Center
		Clinical Trials Office - Arizona Cancer Center at University of Arizona Health Sciences Center	Ph:  520-626-9008
Arkansas
	Little Rock
	Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
		Clinical Trial Office - Arkansas Cancer Research Center at University of Arkansas for Medical Sciences	Ph:  501-686-8274
California
	Downey
	Southern California Permanente Medical Group
		Robert Cooper	Ph:  323-783-5307
	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
	Los Angeles
	Childrens Hospital Los Angeles
		Leo Mascarenhas	Ph:  323-361-2529
	Madera
	Children's Hospital Central California
		Vonda Crouse	Ph:  559-353-5480
	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
		Violet Shen	Ph:  714-532-8636
	Sacramento
	Kaiser Permanente Medical Center - Oakland
		Vincent Kiley	Ph:  916-973-7331
	San Diego
	Rady Children's Hospital - San Diego
		Clinical Trials Office - Rady Children's Hospital - San Diego	Ph:  858-966-5934
	San Francisco
	UCSF Helen Diller Family Comprehensive Cancer Center
		Clinical Trials Office - UCSF Helen Diller Family Comprehensive Cancer Center	Ph:  877-827-3222
Colorado
	Aurora
	Children's Hospital Center for Cancer and Blood Disorders
		Kelly Maloney	Ph:  720-777-6673
Connecticut
	Farmington
	Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center
		Clinical Trials Office - Carole and Ray Neag Comprehensive Cancer Center	Ph:  800-579-7822
	New Haven
	Yale Cancer Center
		Clinical Trials Office - Yale Cancer Center	Ph:  203-785-5702
Delaware
	Wilmington
	Alfred I. duPont Hospital for Children
		Clinical Trials Office - Alfred I. duPont Hospital for Children	Ph:  302-651-5755
District of Columbia
	Washington
	Children's National Medical Center
		Clinical Trials Office - Children's National Medical Center	Ph:  202-884-2549
	Walter Reed Army Medical Center
		Clinical Trials Office - Walter Reed Army Medical Center	Ph:  202-782-7840
Florida
	Fort Myers
	Lee Cancer Care of Lee Memorial Health System
		Clinical Trials Office - Lee Cancer Care of Lee Memorial Health System	Ph:  877-680-0008
	Hollywood
	Memorial Cancer Institute at Memorial Regional Hospital
		Clinical Trials Office - Memorial Cancer Institute	Ph:  954-985-3443
	Jacksonville
	Nemours Children's Clinic
		Eric Sandler	Ph:  904-390-3793
	Orlando
	Florida Hospital Cancer Institute at Florida Hospital Orlando
		Clinical Trials Office - Florida Hospital Cancer Institute	Ph:  407-303-5623
	M.D. Anderson Cancer Center at Orlando
		Contact Person	Ph:  407-648-3800 800-648-3818
	Pensacola
	Sacred Heart Cancer Center at Sacred Heart Hospital
		Clinical Trials Office - Sacred Heart Cancer Center	Ph:  850-416-4611
	St. Petersburg
	All Children's Hospital
		Jerry Barbosa	Ph:  727-767-4176
	Tampa
	St. Joseph's Cancer Institute at St. Joseph's Hospital
		Clinical Trials Office - St. Joseph's Cancer Institute	Ph:  800-882-4123
	West Palm Beach
	Kaplan Cancer Center at St. Mary's Medical Center
		Narayana Gowda	Ph:  561-844-6363
Georgia
	Atlanta
	Winship Cancer Institute of Emory University
		Howard Katzenstein	Ph:  404-785-0853
	Augusta
	MBCCOP - Medical College of Georgia Cancer Center
		Colleen McDonough	Ph:  706-721-3626
	Savannah
	Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center
		Clinical Trials Office - Curtis and Elizabeth Anderson Cancer Institute	Ph:  912-350-8568
Hawaii
	Honolulu
	Cancer Research Center of Hawaii
		Clinical Trials Office - Cancer Research Center of Hawaii	Ph:  808-586-2979
Idaho
	Boise
	Mountain States Tumor Institute at St. Luke's Regional Medical Center
		Eugenia Chang	Ph:  208-381-2731
Illinois
	Chicago
	Children's Memorial Hospital - Chicago
		David Walterhouse	Ph:  773-755-6514
	University of Chicago Cancer Research Center
		Clinical Trials Office - University of Chicago Cancer Research Center	Ph:  773-834-7424
	University of Illinois Cancer Center
		Clinical Trial Office - University of Illinois Cancer Center	Ph:  312-355-3046
	Maywood
	Cardinal Bernardin Cancer Center at Loyola University Medical Center
		Clinical Trials Office - Cardinal Bernardin Cancer Center	Ph:  708-226-4357
	Oak Lawn
	Advocate Christ Medical Center
		Sharad Salvi	Ph:  708-684-4094
	Park Ridge
	Advocate Lutheran General Cancer Care Center
		Clinical Trials Office - Advocate Lutheran General Cancer Care Center	Ph:  847-384-3621
	Peoria
	Saint Jude Midwest Affiliate
		Stephen Smith	Ph:  309-624-4945
	Springfield
	Simmons Cooper Cancer Institute
		Clinical Trials Office - Simmons Cooper Cancer Institute	Ph:  217-545-7929
Indiana
	Indianapolis
	Indiana University Melvin and Bren Simon Cancer Center
		Clinical Trials Office - Indiana University Cancer Center	Ph:  317-274-2552
Iowa
	Des Moines
	Blank Children's Hospital
		Clinical Trials Office - Blank Children's Hospital	Ph:  515-241-6729
	Iowa City
	Holden Comprehensive Cancer Center at University of Iowa
		Cancer Information Service	Ph:  800-237-1225
Kentucky
	Lexington
	Lucille P. Markey Cancer Center at University of Kentucky
		Clinical Trials Office - Markey Cancer Center at University of Kentucky Chandler Medical Center	Ph:  859-257-3379
	Louisville
	Kosair Children's Hospital
		Clinical Trials Office - Kosair Children's Hospital	Ph:  502-629-5500
			Email: CancerResource@nortonhealthcare.org
Louisiana
	Alexandria
	Tulane Cancer Center Office of Clinical Research
		Clinical Trials Office - Tulane Cancer Center	Ph:  504-988-6121
Maine
	Scarborough
	Maine Children's Cancer Program at Barbara Bush Children's Hospital
		Eric Larsen	Ph:  207-885-7565
Maryland
	Baltimore
	Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
		Joseph Wiley	Ph:  410-601-5864
	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
		Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Center at John Hopkins	Ph:  410-955-8804
			Email: jhcccro@jhmi.edu
Massachusetts
	Boston
	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
		Clinical Trials Office - Dana-Farber/Harvard Cancer Center	Ph:  617-582-8480
	Floating Hospital for Children at Tufts - New England Medical Center
		Cynthia Kretschmar	Ph:  617-636-5535
	Massachusetts General Hospital
		Clinical Trials Office - Massachusetts General Hospital	Ph:  877-726-5130
Michigan
	Ann Arbor
	C.S. Mott Children's Hospital at University of Michigan Medical Center
		Clinical Trials Office - C.S. Mott Children's Hospital	Ph:  1-800-865-1125
	Flint
	Hurley Medical Center
		Clinical Trials Office - Hurley Medical Center	Ph:  810-762-8057
	Grand Rapids
	Butterworth Hospital at Spectrum Health
		David Dickens	Ph:  616-391-2086
	Grosse Pointe Woods
	Van Elslander Cancer Center at St. John Hospital and Medical Center
		Clincial Trials Office - Van Elslander Cancer Center at St. John Hospital and Medical Center	Ph:  313-343-3166
	Kalamazoo
	CCOP - Kalamazoo
		Leonard Mattano, Jr.	Ph:  269-341-6350
Minnesota
	Minneapolis
	Children's Hospitals and Clinics of Minnesota - Minneapolis
		Clinical Trials Office - Children's Hospitals and Clinics of Minnesota	Ph:  612-813-5193
	Masonic Cancer Center at University of Minnesota
		Clinical Trials Office - Masonic Cancer Center at University of Minnesota	Ph:  612-624-2620
	Rochester
	Mayo Clinic Cancer Center
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623
Mississippi
	Jackson
	University of Mississippi Cancer Clinic
		Gail Megason	Ph:  601-984-5220
Missouri
	Kansas City
	Children's Mercy Hospital
		Maxine Hetherington	Ph:  816-234-3265
	St. Louis
	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
		Robert Hayashi	Ph:  314-454-4118
Nebraska
	Omaha
	Children's Hospital
		Minnie Abromowitch	Ph:  402-955-3950
Nevada
	Las Vegas
	CCOP - Nevada Cancer Research Foundation
		Jonathan Bernstein	Ph:  702-732-1493
New Hampshire
	Lebanon
	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
		Clinical Trials Office - Norris Cotton Cancer Center	Ph:  603-650-7609
			Email: cancerhelp@dartmouth.edu
New Jersey
	Hackensack
	Hackensack University Medical Center Cancer Center
		Clinical Trials Office - Hackensack University Medical Center Cancer Center	Ph:  201-996-2879
	Morristown
	Overlook Hospital
		Hazem Mahmoud	Ph:  973-971-6720
	New Brunswick
	Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
		Clinical Trials Office - Cancer Institute of New Jersey	Ph:  732-235-8675
	Saint Peter's University Hospital
		Doug Cipkala	Ph:  732-745-6674
	Newark
	Newark Beth Israel Medical Center
		Clinical Trials Office - Newark Beth Israel Medical Center	Ph:  973-926-3136
	Paterson
	St. Joseph's Hospital and Medical Center
		Mary Ann Bonilla	Ph:  973-754-3349
New Mexico
	Albuquerque
	University of New Mexico Cancer Center
		Clinical Trials Office - University of New Mexico Cancer Center