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

Sponsor:	Children's Oncology Group
Collaborator:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00026312

Purpose

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.

Condition	Intervention	Phase
Neuroblastoma	Biological: aldesleukin Biological: monoclonal antibody Ch14.18 Biological: sargramostim Drug: isotretinoin	Phase III

Study Type:	Interventional
Study Design:	Treatment, Randomized, Active Control
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

Resource links provided by NLM:

MedlinePlus related topics: Cancer Neuroblastoma

Drug Information available for: Granulocyte-macrophage colony-stimulating factor Aldesleukin Sargramostim Immunoglobulins Isotretinoin Globulin, Immune

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Event-free survival (EFS) [ Designated as safety issue: No ]

Secondary Outcome Measures:

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 ]
Toxic effects [ Designated as safety issue: Yes ]
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 ]

Estimated Enrollment:	423
Study Start Date:	October 2001
Estimated Primary Completion Date:	June 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Arm I (closed to accrual as of 4/16/2009): 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.	Drug: isotretinoin Given orally
Arm II: Experimental 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.	Biological: aldesleukin Given IV Biological: monoclonal antibody Ch14.18 Given IV Biological: sargramostim Given subcutaneously or IV Drug: isotretinoin Given orally

Arms

Assigned Interventions

Arm I (closed to accrual as of 4/16/2009): 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.

Drug: isotretinoin

Given orally

Arm II: Experimental

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.

Biological: aldesleukin

Given IV

Biological: monoclonal antibody Ch14.18

Given IV

Biological: sargramostim

Given subcutaneously or IV

Drug: isotretinoin

Given orally

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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.

Eligibility

Ages Eligible for Study:	up to 30 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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:

At least 2 months

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:

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)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00026312

Show 157 Study Locations

Sponsors and Collaborators

Children's Oncology Group

National Cancer Institute (NCI)

Investigators

Study Chair:

Alice L. Yu, MD, PhD

University of California, San Diego

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Children's Oncology Group - Group Chair Office ( Gregory H. Reaman )
Study ID Numbers:	CDR0000069018, COG-ANBL0032, COG-P9842
Study First Received:	November 9, 2001
Last Updated:	November 25, 2009
ClinicalTrials.gov Identifier:	NCT00026312 History of Changes
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

regional neuroblastoma
disseminated neuroblastoma
stage 4S neuroblastoma
localized resectable neuroblastoma
localized unresectable neuroblastoma

Additional relevant MeSH terms:

Anti-Infective Agents
Neuroectodermal Tumors, Primitive
Immunologic Factors
Antineoplastic Agents
Neoplasms, Nerve Tissue
Physiological Effects of Drugs
Neuroblastoma
Antibodies, Monoclonal
Anti-Retroviral Agents
Neoplasms, Germ Cell and Embryonal
Therapeutic Uses
Isotretinoin
Dermatologic Agents

Immunoglobulins
Neoplasms by Histologic Type
Anti-HIV Agents
Antiviral Agents
Pharmacologic Actions
Neuroectodermal Tumors
Antibodies
Neoplasms
Aldesleukin
Neoplasms, Neuroepithelial
Neuroectodermal Tumors, Primitive, Peripheral
Neoplasms, Glandular and Epithelial

ClinicalTrials.gov processed this record on November 27, 2009