Recruitment status:
Recruiting
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.
Background information
Other unique IDs:
CDR0000069018
COG-ANBL0032
COG-P9842
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
Detailed description:
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.
Determine the descriptive profile of human anti-chimeric antibody (HACA) during immunotherapy.
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.
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.
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.
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. PROJECTED ACCRUAL: A total of 423 patients will be accrued for this study within 5 years.
Clinical information
Eligibility 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
PATIENT CHARACTERISTICS: Age:
30 and under at diagnosis
Performance status:
Lansky 50-100% OR
Karnofsky 50-100%
Life expectancy:
Hematopoietic:
Total absolute phagocyte count (neutrophils and monocytes) ≥ 1,000/mm^3
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
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)
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:
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)
Study design:
Treatment
Randomized
Active Control
Interventions:
aldesleukin
isotretinoin
sargramostim
monoclonal antibody Ch14.18
Study arms:
Active Comparator: 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.
Outcome measurements:
Toxic effects [ Designated as safety issue: Yes ]
Overall survival (OS) [ Designated as safety issue: No ]
Reduction of minimal residual disease (MRD) [ Designated as safety issue: No ]
Association between change from baseline MRD and EFS and OS [ Designated as safety issue: No ]
Correlation of tumor biology at diagnosis with EFS and OS [ Designated as safety issue: No ]
Correlation of antibody-dependent cellular cytotoxicity with event-free survival [ Designated as safety issue: Yes ]
Comparison of outcome of patients with persistent disease with historical data [ Designated as safety issue: No ]
Correlation of pharmacokinetic and pharmacogenomic parameters with EFS or systemic toxicity [ Designated as safety issue: Yes ]
Funding
Dates
Date the data was first received:
