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Phase III Randomized Study Of Chimeric Antibody 14.18 (CH14.18) In High Risk Neuroblastoma Following Myeloablative Therapy And Autologous Stem Cell Rescue

Phase 3
30 Years
Open (Enrolling)
Disseminated Neuroblastoma, Localized Resectable Neuroblastoma, Localized Unresectable Neuroblastoma, Regional Neuroblastoma, Stage 4S Neuroblastoma

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Trial Information

Phase III Randomized Study Of Chimeric Antibody 14.18 (CH14.18) In High Risk Neuroblastoma Following Myeloablative Therapy And Autologous Stem Cell Rescue


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-ASCT
response of CR, VGPR, or PR.


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 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,
RT-PCR for tyrosine hydroxylase, PGP 9.5, and MAGE-1 in blood and bone marrow.

IV. Determine if change from baseline of MRD as measured by above parameters 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

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

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

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 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 OS estimates and baseline characteristics for
subjects receiving Chl4.18 + 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 IL-2); 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 FcR and Kir/Kir-Ligand correlate with EFS.

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. 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 and day 11 of immunotherapy.

Patients are followed periodically for 10 years.

Inclusion Criteria:

- Diagnosis of neuroblastoma

- Categorized as high risk at 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

- Meets all of the following criteria:

- Patients must have completed therapy including intensive induction followed by
autologous stem cell transplantation (ASCT) and radiotherapy

- 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

- 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

- 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 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

- Prior to enrollment on ANBL0032, a determination of mandatory disease staging must be
performed (tumor imaging studies including CT or MRI, MIBG scan, bone marrow
aspiration & biopsy); 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; these patients will be
enrolled on Stratum 07

- Performance status - Lansky 50-100%

- Performance status - Karnofsky 50-100%

- Total absolute phagocyte count (neutrophils and monocytes) ≥ 1,000/mm^3

- Bilirubin ≤ 1.5 times normal

- SGPT ≤ 5 times normal

- Veno-occlusive disease (if present) stable or improving

- 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])

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

- Shortening fraction ≥ 30% 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

- FEV1 and FVC > 60% predicted by pulmonary function test; for children who are unable
to do PFTs, no evidence of dyspnea at rest and no exercise intolerance should be

- Note: The pulmonary function test must be performed within 4 weeks prior to

- No evidence of dyspnea at rest, no exercise intolerance

- Not pregnant

- Fertile patients must use effective contraception

- Seizure disorder allowed if well-controlled and on anticonvulsants

- CNS toxicity < grade 2

- No concurrent pentoxifylline

- No more than 1 prior stem cell transplantation

- No other concurrent cytokines or growth factors (e.g., filgrastim [G-CSF] or

- No IV immunoglobulin G within 2 weeks before, during, and for 1 week after monoclonal
antibody Ch14.18 (arm II patients)

- 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 PBSC
infusion (day from 2nd stem cell infusion for tandem transplant); patients must
be enrolled no later than Day 100 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

- All clinical and laboratory studies for organ functions to determine eligibility
must be performed within 7 days prior to enrollment unless otherwise indicated

- No prior anti-GD2 antibody therapy

- No more than 1 prior myeloablative consolidation regimen

- No concurrent myelosuppressive chemotherapy (arm II patients)

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

- No radiographic contrast materials during and for at least 1 week after interleukin-
2 (arm II)

- At least 7 days since prior radiotherapy

- No other concurrent anticancer therapy

- No concurrent immunosuppressive drugs (e.g., cyclosporine)

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Event-free survival (EFS)

Outcome Description:

An event is defined as a relapse, progressive disease, secondary malignancy, or death

Outcome Time Frame:

Time 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

Safety Issue:


Principal Investigator

Alice Yu

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

October 2001

Completion Date:

Related Keywords:

  • Disseminated Neuroblastoma
  • Localized Resectable Neuroblastoma
  • Localized Unresectable Neuroblastoma
  • Regional Neuroblastoma
  • Stage 4S Neuroblastoma
  • Neuroblastoma



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