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

Alternate Title

Isotretinoin With or Without Monoclonal Antibody, Interleukin-2, and Sargramostim Following Stem Cell Transplantation in Treating Patients With Neuroblastoma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Active	30 and under at diagnosis	NCI	COG-ANBL0032 ANBL0032, COG-P9842, NCT00026312

Objectives

Primary

1. Compare the event-free survival of patients with neuroblastoma who have completed myeloablative therapy and autologous stem cell transplantation (ASCT) when treated with adjuvant isotretinoin with or without monoclonal antibody Ch14.18, interleukin-2, and sargramostim (GM-CSF).

Secondary

1. Compare the overall survival of patients treated with these regimens.
2. Compare the event-free survival of the subgroup of high-risk, stage IV patients treated with these regimens.
3. Compare the reduction of minimal residual disease (MRD) in patients treated with these regimens.
4. Determine whether change from baseline MRD is associated with event-free and overall survival in patients treated with these regimens.
5. Determine whether tumor biology at diagnosis correlates with event-free and overall survival in patients treated with these regimens.
6. Determine the toxic effects of this combination regimen in these patients.
7. Determine whether antibody-dependent cellular cytotoxicity correlates with event-free survival in patients treated with these regimens.
8. Determine the descriptive profile of human anti-chimeric antibody (HACA) during immunotherapy.
9. Compare outcome data of patients with persistent disease with historical data after being treated with these regimens.
10. Correlate the pharmacokinetics and pharmacogenomic parameters with event-free survival or systemic toxicity.
11. Further describe and refine the event-free survival and overall survival estimates and baseline characteristics for patients treated with isotretinoin, monoclonal antibody Ch14.18, and interleukin-2 following cessation of the randomized portion of the study.
12. Further describe the safety and toxicity of isotretinoin, monoclonal antibody Ch14.18, and interleukin-2 in these patients following cessation of the randomized portion of the study including the number of courses delivered per patient, the number of dose reductions or stoppage (CH14.18 and/or interleukin-2) and the number of toxic deaths.

Entry Criteria

Disease Characteristics:

• Diagnosis of neuroblastoma
  • Categorized as high risk at diagnosis



• Meets all of the following criteria:
  • Patients much have completed therapy including intensive induction followed by autologous stem cell transplantation (ASCT) and radiotherapy
  • Completed frontline therapies, examples of such therapy includes:
    • Following treatment per COG-A3973 protocol
    • Following treatment per POG-9340-42
    • Following treatment per CCG-3891
    • Following treatment on NANT-2001-02
    • Enrollment on or following treatment per COG-ANBL02P1 protocol
    • Enrollment on or following treatment per ANBL07P1
    • Tandem transplant patients are eligible
      • Following enrollment and treatment on or per COG-ANBL0532
      • Following treatment per POG-9640 protocol
      • Following treatment per COG-ANBL00P1 protocol
      • Following treatment per CHP 594 or DFCI 34-DAT
    • Other frontline therapy with permission from study chairs
  • Patients with biopsy confirmed residual disease after ASCT are eligible



• Must meet the International Neuroblastoma Response Criteria (INRC) for CR, VGPR, or PR for primary site, soft tissue metastases, and bone metastases AND must also meet the protocol specified criteria for bone marrow response as follows:
  • No more than 10% tumor (of total nucleated cellular content) seen on any specimen from a bilateral bone marrow aspirate/biopsy
  • Patient who have no tumor seen on the prior bone marrow, and then have ≤ 10% tumor on any of the bilateral marrow aspirate/biopsy specimens done at pre-ASCT and/or pre-enrollment evaluation will also be eligible



• No more than 9 months from starting the first induction chemotherapy after diagnosis to the date of ASCT *



• No progressive disease at time of registration except for protocol specified bone marrow response

 [Note: * For tandem ASCT patients this is the date of the first stem cell infusion]

Prior/Concurrent Therapy:

Biologic therapy:

• See Disease Characteristics
• No more than 1 prior stem cell transplantation
• No other concurrent cytokines or growth factors (e.g., filgrastim [G-CSF] or interferon)
• No IV immunoglobulin G within 2 weeks before, during, and for 1 week after monoclonal antibody Ch14.18 (arm II patients)
• No prior anti-GD2 antibody therapy

Chemotherapy:

• No more than 1 prior myeloablative consolidation regimen
• No concurrent myelosuppressive chemotherapy (arm II patients)

Endocrine therapy:

• No concurrent corticosteroids unless for life-threatening conditions (e.g., increased intracranial pressure from CNS tumors or life-threatening allergic reactions)

Radiotherapy:

• See Disease Characteristics
• At least 7 days since prior radiotherapy

Surgery:

• Not specified

Other:

• No other concurrent anticancer therapy
• No concurrent immunosuppressive drugs (e.g., cyclosporine)
• No concurrent pentoxifylline
• No radiographic contrast materials during and for at least 1 week after interleukin-2 (arm II)

Patient Characteristics:

Age:

• 30 and under at diagnosis

Performance status:

• Lansky 50-100%

  OR

• Karnofsky 50-100%

Life expectancy:

• At least 2 months

Hematopoietic:

• Total absolute phagocyte count (neutrophils and monocytes) ≥ 1,000/mm³

Hepatic:

• Bilirubin ≤ 1.5 times normal
• SGPT ≤ 5 times normal
• Veno-occlusive disease (if present) stable or improving

Renal:

• Creatinine adjusted according to age as follows:
  • No greater than 0.4 mg/dL (≤ 5 months)
  • No greater than 0.5 mg/dL (6 months -11 months)
  • No greater than 0.6 mg/dL (1 year-23 months)
  • No greater than 0.8 mg/dL (2 years-5 years)
  • No greater than 1.0 mg/dL (6 years-9 years)
  • No greater than 1.2 mg/dL (10 years-12 years)
  • No greater than 1.4 mg/dL (13 years and over [female])
  • No greater than 1.5 mg/dL (13 years to 15 years [male])
  • No greater than 1.7 mg/dL (16 years and over [male])

  OR

• Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min

Cardiovascular:

• Shortening fraction ≥ 30% by echocardiogram

  OR

• Ejection fraction ≥ 55% by MUGA

Pulmonary:

• FEV₁ and FVC > 60% predicted by pulmonary function test

  OR

• No evidence of dyspnea at rest, no exercise intolerance

Other:

• Not pregnant
• Fertile patients must use effective contraception
• Seizure disorder allowed if well-controlled and on anticonvulsants
• CNS toxicity < grade 2

Expected Enrollment

A total of 423 patients will be accrued for this study within 5 years.

Outcomes

Event-free survival (EFS)

Overall survival (OS)
Reduction of minimal residual disease (MRD)
Association between change from baseline MRD and EFS and OS
Correlation of tumor biology at diagnosis with EFS and OS
Toxic effects
Correlation of antibody-dependent cellular cytotoxicity with event-free survival
Comparison of outcome of patients with persistent disease with historical data
Correlation of pharmacokinetic and pharmacogenomic parameters with EFS or systemic toxicity

Outline

This is a randomized, multicenter study. Patients are stratified according to pre-autologous stem cell transplantation (ASCT) response (complete vs very good partial vs partial), stem cells received (purged vs unpurged), and frontline chemotherapy (COG-A3973 vs POG 9341/9342 vs COG-ANGL02P1 vs other therapy). A further stratum consists of patients with biopsy-confirmed post-ASCT persistent disease who are also enrolled on COG-A3973 or COG-ANBL0532. These patients are not randomized but assigned to treatment arm II. Patients in the first set of strata are randomized to 1 of 2 treatment arms.

• Arm I (closed to accrual as of 4/16/2009): Beginning on day 67 post-ASCT, patients receive oral isotretinoin twice daily for 14 days. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients may cross over to Arm II provided they have not experienced disease progression and have not received any further anti-neuroblastoma therapy following completion of isotretinoin therapy.



• Arm II: Beginning on day 56 post-ASCT, patients receive immunotherapy comprising sargramostim (GM-CSF) subcutaneously (SC) or IV over 2 hours on days 0-13 during courses 1, 3, and 5 and monoclonal antibody Ch14.18 IV over 10-20 hours on days 3-6 of courses 1-5. Patients also receive interleukin-2 IV continuously on days 0-3 and 7-10 during courses 2 and 4. Immunotherapy repeats every 28 days for 5 courses in the absence of disease progression or unacceptable toxicity. Patients also receive oral isotretinoin as in arm I beginning on day 11 of immunotherapy.

Patients are followed periodically for 10 years.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Alice Yu, MD, PhD, Protocol chair		Ph: 858-822-5354

U.S.A.
Kentucky
	Louisville
	Kosair Children's Hospital
		Clinical Trials Office - Kosair Children's Hospital	Ph:  502-629-5500
			Email: CancerResource@nortonhealthcare.org
Louisiana
	New Orleans
	Children's Hospital of New Orleans
		Clinical Trials Office - Children's Hospital of New Orleans	Ph:  504-894-5377
Minnesota
	Minneapolis
	Masonic Cancer Center at University of Minnesota
		Clinical Trials Office - Masonic Cancer Center at University of Minnesota	Ph:  612-624-2620
New York
	Valhalla
	New York Medical College
		Fevzi Ozkaynak	Ph:  914-493-7997
Ohio
	Cleveland
	Cleveland Clinic Taussig Cancer Center
		Clinical Trials Office - Cleveland Clinic Taussig Cancer Center	Ph:  866-223-8100
	Dayton
	Children's Medical Center - Dayton
		Emmett Broxson	Ph:  937-641-3111
Pennsylvania
	Philadelphia
	Children's Hospital of Philadelphia
		Richard Aplenc	Ph:  267-426-7252
South Carolina
	Columbia
	Palmetto Health South Carolina Cancer Center
		Clinical Trials Office - Palmetto Health South Carolina Cancer Center	Ph:  803-434-3680
Washington
	Seattle
	Children's Hospital and Regional Medical Center - Seattle
		Julie Park	Ph:  206-987-1947
	Spokane
	Providence Cancer Center at Sacred Heart Medical Center
		Judy Felgenhauer	Ph:  509-474-2777

Related Information

PDQ® clinical trial COG-A3973
PDQ® clinical trial COG-ANBL02P1
PDQ® clinical trial CCG-3891
PDQ® clinical trial NANT-2001-02
PDQ® clinical trial COG-ANBL0532
PDQ® clinical trial POG-9340-42

Registry Information
Official Title		Phase III Randomized Study Of Chimeric Antibody 14.18 (CH14.18) In High Risk Neuroblastoma Following Myeloablative Therapy And Autologous Stem Cell Rescue
Trial Start Date		2001-10-18
Trial Completion Date		2012-06-01 (estimated)
Registered in ClinicalTrials.gov		NCT00026312
Date Submitted to PDQ		2001-09-14
Information Last Verified		2009-05-13
NCI Grant/Contract Number		CA30969