Isotretinoin With or Without Monoclonal Antibody Ch14.18, Aldesleukin, and Sargramostim Following Stem Cell Transplant in Treating Patients With Neuroblastoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00026312
First received: November 9, 2001
Last updated: July 22, 2014
Last verified: June 2014

November 9, 2001
July 22, 2014
October 2001
December 2016   (final data collection date for primary outcome measure)
EFS [ Time Frame: From study enrollment until the first occurrence of an event or until last contact with the patient if no event occurs, assessed up to 3 years ] [ Designated as safety issue: No ]
Kaplan-Meier curves will be generated and log rank tests will be performed.
Not Provided
Complete list of historical versions of study NCT00026312 on ClinicalTrials.gov Archive Site
  • OS [ Time Frame: From study enrollment until death or until last contact with the patient if the patient dose not die, assessed up to 3 years ] [ Designated as safety issue: No ]
    Kaplan-Meier curves will be generated and log rank tests will be performed.
  • Change in MRD [ Time Frame: Baseline to up to 10 years ] [ Designated as safety issue: No ]
    A descriptive analysis of the change from baseline of MRD will be performed. Also, a Wilcoxon rank-sum test will be performed to compare the median change from baseline of MRD between the two treatment arms. A multivariate Cox proportional hazards regression model will test to see if the change in MRD burden is associated with EFS or OS.
  • Change in tumor biology [ Time Frame: Baseline to up to 10 years ] [ Designated as safety issue: No ]
    A multivariate Cox proportional hazards regression model will test to see if the Ch14.18 serum level, HACA titer, effector cell function, or serum marker for effector cell activation are associated with EFS or OS.
  • Incidence of toxicities assessed using Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 10 years ] [ Designated as safety issue: Yes ]
    Descriptive analyses of toxicity will be performed over all patients.
  • Levels of ADCC [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Will be descriptively compared.
  • Average level of HACA [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    The average level of HACA at each collection time point during immunotherapy will be calculated.
  • Historical data for the analogous patients [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    A historical comparison will be made. This comparison will be a descriptive one only.
  • 13-cis-retinoic-acid pharmacokinetic parameters [ Time Frame: At 4 hours after administration on day 14 of course 1 ] [ Designated as safety issue: No ]
    To determine if there is a relationship of the peak serum concentration level with EFS, the term for this level will be tested in a Cox proportional hazards model. To determine if there is a relationship of the peak serum concentration level with toxicity rates, Kendall's Tau statistic will be calculated.
  • Presence of naturally occurring anti-glycan antibodies [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    A Fisher's exact test will be performed to determine if the presence of naturally occurring anti-glycan antibodies correlates with allergic reactions. A Wilcoxon test will be performed to determine if the presence of naturally occurring anti-glycan antibodies correlates with blood levels of ch14.18.
  • Genotype of Kir/Kir-Ligand [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Kaplan-Meier plots of EFS will be generated for the three genotype subgroups of FcR as well as for the three genotype subgroups of Kir/Kir-Ligand. In addition, a log rank test comparison will be made in a pairwise fashion of each of the genotypes within FcR and within Kir/Kir-Ligand.
  • EFS of patients from the non-randomized portion of the trial [ Time Frame: From study enrollment until the first occurrence of an event or until last contact with the patient if no event occurs, assessed up to 3 years ] [ Designated as safety issue: No ]
    Kaplan-Meier curves of EFS and OS will be generated, including 95% confidence intervals on the curves.
  • OS of patients from the non-randomized portion of the trial [ Time Frame: From study enrollment until death or until last contact with the patient if the patient dose not die, assessed up to 3 years ] [ Designated as safety issue: No ]
    Kaplan-Meier curves of EFS and OS will be generated, including 95% confidence intervals on the curves.
  • Cardiac repolarization [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    In general, descriptive summaries will include n, mean, standard deviation, median, minimum, maximum and 90% confidence intervals for continuous variables, and n and percent for categorical variables. Summaries will present data by assessment time when appropriate.
  • Genotype of FcR [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    Kaplan-Meier plots of EFS will be generated for the three genotype subgroups of FcR as well as for the three genotype subgroups of Kir/Kir-Ligand. In addition, a log rank test comparison will be made in a pairwise fashion of each of the genotypes within FcR and within Kir/Kir-Ligand.
  • Number of courses of therapy delivered [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
    A Wilcoxon test will be used to compare the number of courses of therapy delivered.
Not Provided
Not Provided
Not Provided
 
Isotretinoin With or Without Monoclonal Antibody Ch14.18, Aldesleukin, and Sargramostim Following Stem Cell Transplant in Treating Patients With Neuroblastoma
Phase III Randomized Study of Chimeric Antibody 14.18 (Ch14.18) in High Risk Neuroblastoma Following Myeloablative Therapy and Autologous Stem Cell Rescue

This partially randomized phase III trial studies isotretinoin with monoclonal antibody Ch14.18, aldesleukin, and sargramostim to see how well it works compared to isotretinoin alone following stem cell transplant in treating patients with neuroblastoma. Drugs used in chemotherapy, such as isotretinoin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as monoclonal antibody Ch14.18, can block tumor growth in different ways. Some block the ability of tumors to grow and spread. Others find tumor cells and help kill them or deliver tumor-killing substances to them. Aldesleukin 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 Ch14.18, aldesleukin, and sargramostim following stem cell transplant in treating neuroblastoma.

PRIMARY OBJECTIVES:

I. Determine if monoclonal antibody Chl4.18 + cytokines + isotretinoin (13-cis-retinoic acid, or RA) improves event free survival after myeloablative therapy and stem cell rescue as compared to RA alone, in high risk neuroblastoma patients who have achieved a pre-autologous stem cell transplant (ASCT) response of complete response (CR), very good partial response (VGPR), or partial response (PR).

SECONDARY OBJECTIVES:

I. Determine if monoclonal antibody Chl4.18 + cytokines + isotretinoin (13-cis-retinoic acid, or RA) improves overall survival after myeloablative therapy and stem cell rescue as compared to RA alone, in high risk neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR.

II. Determine if immunotherapy + RA improves event free survival and overall survival as compared to RA alone, in the subgroup of high risk International Neuroblastoma Staging System (INSS) stage 4 neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR.

III. In the subgroup of neuroblastoma patients who have achieved a pre-ASCT response of CR, VGPR, or PR, determine if there is a difference between the two randomized regimens in reducing the minimal residual disease (MRD) burden as detected by the following parameters: meta-iodobenylguanidine (MIBG) scan, immunocytology (IC) of blood and bone marrow samples, reverse transcriptase-polymerase chain reaction (RT-PCR) for tyrosine hydroxylase, phosphoglycolate phosphatase (PGP) 9.5, and melanoma antigen family A, 1 (MAGE-1) in blood and bone marrow.

IV. Determine if change from baseline of MRD is associated with event free and overall survival V. Determine whether tumor biology at diagnosis correlates with event-free and overall survival, for either of the randomized regimens.

VI. Determine the toxicities of the combination of monoclonal antibody Ch14.18 with cytokines.

VII. To explore the relationship between antibody-dependent cellular cytoxicity (ADCC) and event free survival (EFS).

VIII. To determine a descriptive profile of human anti-chimeric antibody (HACA) during immunotherapy.

IX. To compare the outcome data of the patients with persistent disease documented by biopsy (Stratum 07) to the historical data for the analogous patients from Children's Cancer Group (CCG)-3981.

X. To determine the variability of 13-cis-retinoic-acid pharmacokinetics and relationship to pharmacogenomic parameters and determine if these levels and/or genetic variations correlate with EFS or systemic toxicity.

XI. To further describe and refine the EFS and overall survival (OS) estimates and baseline characteristics for subjects receiving Chl4.18 (monoclonal antibody Ch14.18) + cytokines + RA, following cessation of the randomized portion of the study.

XII. To further describe the safety and toxicity of Chl4.18 + cytokines + RA under the new administration guidelines implemented following cessation of the randomized portion of the study with focus on: a) number of courses delivered per subject; b) number of dose reductions or stoppage (ch14.18 and/or interleukin [IL]-2 [aldesleukin]); and c) number of toxic deaths.

XIII. To determine the potential effect of ch14.18 on cardiac repolarization and to evaluate ch14.18 plasma levels.

XIV. To determine if the presence of naturally occurring anti-glycan antibodies correlates with allergic reactions and blood levels of ch14.18.

XV. To determine if the genotype of Fc receptor (FcR) and killer cell immunoglobulin-like receptor (Kir)/Kir-Ligand correlate with EFS.

OUTLINE: Patients stratified with biopsy-confirmed post-ASCT persistent disease who are also enrolled on Children's Oncology Group (COG)-A3973 or COG-ANBL0532 are 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 isotretinoin orally (PO) twice daily (BID) 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 intravenously (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 aldesleukin 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 isotretinoin as in Arm I beginning on day 11 of immunotherapy.

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

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Disseminated Neuroblastoma
  • Localized Resectable Neuroblastoma
  • Localized Unresectable Neuroblastoma
  • Regional Neuroblastoma
  • Stage 4S Neuroblastoma
  • Drug: isotretinoin
    Given PO
    Other Names:
    • 13-CRA
    • Amnesteem
    • Cistane
    • Claravis
    • Sotret
  • Biological: sargramostim
    Given IV or SC
    Other Names:
    • GM-CSF
    • Leukine
    • Prokine
  • Biological: dinutuximab
    Given IV
    Other Names:
    • Ch14.18
    • MOAB Ch14.18
    • monoclonal antibody Ch14.18
  • Biological: aldesleukin
    Given IV
    Other Names:
    • IL-2
    • Proleukin
    • recombinant human interleukin-2
    • recombinant interleukin-2
  • Other: laboratory biomarker analysis
    Correlative studies
  • Other: quality-of-life assessment
    Ancillary studies
    Other Name: quality of life assessment
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
  • Active Comparator: Arm I (isotretinoin) (closed to accrual as of 4/16/2009)
    Beginning on day 67 post-ASCT, patients receive isotretinoin PO BID 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.
    Interventions:
    • Drug: isotretinoin
    • Other: laboratory biomarker analysis
    • Other: quality-of-life assessment
    • Other: pharmacological study
  • Experimental: Arm II (GM-CSF, Ch14.18, aldesleukin, isotretinoin)
    Beginning on day 56 post-ASCT, patients receive immunotherapy comprising GM-CSF 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 aldesleukin 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 isotretinoin as in Arm I beginning on day 11 of immunotherapy.
    Interventions:
    • Drug: isotretinoin
    • Biological: sargramostim
    • Biological: dinutuximab
    • Biological: aldesleukin
    • Other: laboratory biomarker analysis
    • Other: quality-of-life assessment
    • Other: pharmacological study
Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM; Children's Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010 Sep 30;363(14):1324-34.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
1660
Not Provided
December 2016   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • All patients must be diagnosed with neuroblastoma, and categorized as high risk at the time of diagnosis; exception: patients who are initially diagnosed as non-high-risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma are also eligible
  • All patients must have completed therapy including intensive induction followed by ASCT and radiotherapy to be eligible for ANBL0032; radiotherapy may be waived for patients who either have small adrenal masses which are completely resected up front, or who never have an identifiable primary tumor; examples of such therapies include:

    • Following treatment per A3973 protocol
    • Following treatment per POG-9341/9342 protocol
    • Following treatment per CCG3891
    • Following treatment on New Approaches to Neuroblastoma Therapy (NANT) 2001-02
    • Enrollment on or following treatment per ANBL02P1
    • Enrollment on or following treatment per ANBL07P1
    • Tandem transplant patients are eligible:

      • Following treatment on or per ANBL0532
      • Following treatment per Pediatric Oncology Group (POG) 9640
      • Following treatment per COG ANBL00P1
      • Following treatment per CHP 594/Dana-Farber Cancer Institute (DFCI) 34-DAT
  • No more than 12 months from the date of starting the first induction chemotherapy after diagnosis to the date of ASCT except for the rare occasions as noted below; for tandem ASCT patients, this will be the date of the FIRST stem cell infusion; exception: for those who are initially diagnosed as non-high risk neuroblastoma, but later converted (and/or relapsed) to high risk neuroblastoma, the 12 months restriction should start from the date of induction therapy for high risk neuroblastoma (not from the initial induction therapy for non-high risk disease), to the date of ASCT
  • At pre-ASCT evaluation patients must meet the International Neuroblastoma Response Criteria (INRC) for CR, VGPR, or PR for primary site, soft tissue metastases and bone metastases; patients who meet those criteria must also meet the protocol specified criteria for bone marrow response as outlined below:

    • =< 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 (note that per INRC this would have been defined as "overall" response of progressive disease [PD])
  • Prior to enrollment on ANBL0032, a determination of mandatory disease staging must be performed (tumor imaging studies including computed tomography [CT] or magnetic resonance imaging [MRI], MIBG scan, and vanillylmandelic acid [VMA]/homovanillic acid [HVA]; bone marrow aspirates are required but biopsy may be omitted if negative prior to ASCT); this disease assessment is required for eligibility and should be done preferably within 2 weeks, but must be done within a maximum of 4 weeks before enrollment

    • For those with residual disease before radiotherapy, re-evaluation of irradiated residual tumors is preferably performed at the earliest 5 days after completing radiotherapy; patients with residual disease are eligible; biopsy is not required; patients who have biopsy proven residual disease after ASCT will be enrolled on Stratum 07
    • Patients must not have progressive disease at the time of study enrollment except for protocol specified bone marrow response and except for elevations of catecholamines as the only sign of disease in a patient who had normal catecholamines at pre-ASCT evaluation
  • Patients must be enrolled before treatment begins; the date protocol therapy is projected to start must be no later than ten (10) calendar days after the date of study enrollment; patients should be enrolled preferably between day 56 and day 85 after peripheral blood stem cell (PBSC) infusion (day from 2nd stem cell infusion for tandem transplant); patients must be enrolled no later than day 200 after PBSC infusion; enrollment must occur after completion of radiotherapy, and after completion of tumor assessment post-ASCT and radiotherapy; informed consent should be obtained within 3 weeks pre-ASCT up to the time of registration
  • Patients must not have received prior anti-disialoganglioside (GD2) antibody therapy
  • Patients must have a Lansky or Karnofsky performance scale score of >= 50% and patients must have a life expectancy of >= 2 months
  • Total absolute phagocyte count (APC = %neutrophils + %monocytes) X white blood cell (WBC) is at least 1000/uL
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

    • No greater than 0.4 mg/dL (1 month to < 6 months)
    • No greater than 0.5 mg/dL (6 months to < 1 year)
    • No greater than 0.6 mg/dL (1 to < 2 years)
    • No greater than 0.8 mg/dL (2 to < 6 years)
    • No greater than 1.0 mg/dL (6 to < 10 years)
    • No greater than 1.2 mg/dL (10 to < 13 years)
    • No greater than 1.4 mg/dL (>= 13 years [female])
    • No greater than 1.5 mg/dL (13 to < 16 years [male])
    • No greater than 1.7 mg/dL (>= 16 years [male])
  • Total bilirubin =< 1.5 x normal
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5 x normal
  • Veno-occlusive disease, if present, should be stable or improving
  • Shortening fraction of >= 27% by echocardiogram, or if shortening fraction abnormal, ejection fraction of >= 55% by gated radionuclide study or echocardiogram; note: the echocardiogram or gated radionuclide study must be performed within 4 weeks prior to enrollment
  • Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) > 60% predicted by pulmonary function test; for children who are unable to do pulmonary function tests (PFTs), no evidence of dyspnea at rest and no exercise intolerance should be documented; note: the pulmonary function test must be performed within 4 weeks prior to enrollment
  • Patients with seizure disorder may be enrolled if on anticonvulsants and well-controlled; central nervous system (CNS) toxicity < grade 2
  • Written informed consent in accordance with institutional and Food and Drug Administration (FDA) guidelines must be obtained from parent or legal guardian
  • Females of childbearing potential must have a negative pregnancy test; patients of childbearing potential must agree to use an effective birth control method; female patients who are lactating must agree to stop breast-feeding
Both
up to 30 Years
No
United States,   Australia,   Canada,   New Zealand,   Puerto Rico
 
NCT00026312
NCI-2009-01064, NCI-2009-01064, CDR0000069018, COG-ANBL0032, ANBL0032, ANBL0032, U10CA098543
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Alice Yu Children's Oncology Group
National Cancer Institute (NCI)
June 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP