Official Title: “Phase III Randomized Study Of Chimeric Anti-GD2 In High Risk Neuroblastoma Following Myeloablative Therapy And Autologous Stem Cell Rescue”

RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells.

Interleukin-2 and sargramostim may stimulate a person's white blood cells to kill cancer cells. It is not yet known if chemotherapy is more effective with or without monoclonal antibody therapy, interleukin-2, and sargramostim following stem cell transplantation in treating neuroblastoma.

PURPOSE: Randomized phase III trial to compare the effectiveness of chemotherapy with or without monoclonal antibody, interleukin-2, and sargramostim following stem cell transplantation in treating patients who have neuroblastoma.

Study Type: Interventional

Study Design: Treatment, Randomized, Active Control

Study Primary Completion Date: October 2006

OBJECTIVES:

Primary - 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 - Compare the overall survival of patients treated with these regimens. - Compare the event-free survival of the subgroup of high-risk, stage IV patients treated with these regimens. - Compare the reduction of minimal residual disease (MRD) in patients treated with these regimens. - Determine whether change from baseline MRD is associated with event-free and overall survival in patients treated with these regimens. - Determine whether tumor biology at diagnosis correlates with event-free and overall survival in patients treated with these regimens. - Determine the toxic effects of this combination regimen in these patients. - Determine whether antibody-dependent cellular cytotoxicity correlates with event-free survival in patients treated with these regimens. - Compare outcome data of patients with persistent disease with historical data after being treated with these regimens. - Correlate the pharmacokinetics and pharmacogenomic parameters with event-free survival 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: 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. - 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 5.75 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.

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

Intervention(s) in this Clinical Trial

• Drug: aldesleukin
  • Given IV
• Drug: isotretinoin
  • Given orally
• Drug: monoclonal antibody Ch14.18
  • Given IV
• Drug: sargramostim
  • Given subcutaneously or IV

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: Arm I
  • 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.
• Experimental: Arm II
  • 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 5.75 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.

Primary Measures

• Event-free survival (EFS)
  • Safety Issue?: No

Secondary Measures

• Overall survival (OS)
  • Safety Issue?: No
• Reduction of minimal residual disease (MRD)
  • Safety Issue?: No
• Association between change from baseline MRD and EFS and OS
  • Safety Issue?: No
• Correlation of tumor biology at diagnosis with EFS and OS
  • Safety Issue?: No
• Toxic effects
  • Safety Issue?: Yes
• Correlation of antibody-dependent cellular cytotoxicity with event-free survival
  • Safety Issue?: Yes
• Comparison of outcome of patients with persistent disease with historical data
  • Safety Issue?: No
• Correlation of pharmacokinetic and pharmacogenomic parameters with EFS or systemic toxicity
  • Safety Issue?: Yes

DISEASE CHARACTERISTICS:

• Diagnosis of neuroblastoma
• Categorized as high risk at diagnosis
• For patients concurrently enrolled on COG-A3973, the following must be true:
• Completed frontline therapy followed by autologous stem cell transplantation (ASCT) and radiotherapy
• Achieved complete, very good partial, or partial response pre-ASCT
• For patients not concurrently enrolled on COG-A3973 but eligible for COG-ANBL0032, the following must be true:
• Completed one of the following frontline therapies:
• Following treatment per COG-A3973 protocol
• Following treatment per POG-9341 or POG-9342 protocol
• Following treatment per CCG-3891
• Following treatment on NANT-2001-02
• Enrollment on or following treatment per COG-ANBL02P1 protocol
• Tandem transplant patients are eligible
• Following enrollment and treatment on 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
• Completed ASCT and radiotherapy after completion of frontline therapy
• Achieved complete, very good partial, or partial response pre-ASCT and after treatment
• Patients with biopsy confirmed residual disease after ASCT and not enrolled in COG-A3973 are NOT eligible for COG-ANBL0032.
• 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 NOTE: * For tandem ASCT patients this is the date of the first stem cell infusion

PATIENT CHARACTERISTICS:

Age:

• 30 and under at diagnosis

Performance status:

• Lansky 50-100% OR
• Karnofsky 50-100%

Life expectancy:

• At least 2 months

Hematopoietic:

• Absolute phagocyte count (neutrophils and monocytes) ≥ 1,000/mm^3 (cytokine support allowed)

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:

• FEV_1 and FVC > 60% predicted by pulmonary function test OR
• No evidence of dyspnea at rest, no exercise intolerance, and pulse oximetry > 94% on room air

Other:

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

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)

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)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: 30 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Children's Oncology Group

Overall Clinical Trial Officials and Contacts

Alice L. Yu, MD, PhD Study Chair University of California, San Diego  

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00026312

Study ID Number: CDR0000069018

ClinicalTrials.gov Identifier: NCT00026312

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database