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

Conditions

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

Trial Phase

Phase 3

Trial Purpose and Description

Trial Purpose

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.


Trial Description


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.

Participation Guidelines

Age:
N/A - 30 Years
Gender:
Both

Eligibility Criteria


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
Sponsor:
National Cancer Institute (NCI)
Dates:
October 2001
Last Updated:
December 16, 2013
Study HIC#:

Clinicaltrials.gov ID: NCT00026312