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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
N/A
30 Years
Open (Enrolling)
Both
Disseminated Neuroblastoma, Localized Resectable Neuroblastoma, Localized Unresectable Neuroblastoma, Regional Neuroblastoma, Stage 4S Neuroblastoma

Thank you

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


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-ASCT
response of CR, VGPR, or 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 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
cytokines.

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

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

- 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
interferon)

- 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:

Interventional

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:

No

Principal Investigator

Alice Yu

Investigator Role:

Principal Investigator

Investigator Affiliation:

Children's Oncology Group

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-01064

NCT ID:

NCT00026312

Start Date:

October 2001

Completion Date:

Related Keywords:

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

Name

Location

Baylor College of MedicineHouston, Texas  77030
Johns Hopkins UniversityBaltimore, Maryland  21205
Cleveland Clinic FoundationCleveland, Ohio  44195
Roswell Park Cancer InstituteBuffalo, New York  14263
Mayo ClinicRochester, Minnesota  55905
Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
University of Iowa Hospitals and ClinicsIowa City, Iowa  52242
University of Mississippi Medical CenterJackson, Mississippi  39216-4505
Washington University School of MedicineSaint Louis, Missouri  63110
Medical University of South CarolinaCharleston, South Carolina  29425-0721
Hurley Medical CenterFlint, Michigan  48503
Rhode Island HospitalProvidence, Rhode Island  02903
Medical City Dallas HospitalDallas, Texas  75230
University of Texas Health Science Center at San AntonioSan Antonio, Texas  78284-7811
Midwest Children's Cancer CenterMilwaukee, Wisconsin  53226
Sinai Hospital of BaltimoreBaltimore, Maryland  21225
Geisinger Medical CenterDanville, Pennsylvania  17822-0001
Massachusetts General Hospital Cancer CenterBoston, Massachusetts  02114
Morristown Memorial HospitalMorristown, New Jersey  07962-1956
Marshfield ClinicMarshfield, Wisconsin  54449
Loma Linda University Medical CenterLoma Linda, California  92354
Baptist Hospital of MiamiMiami, Florida  33176-2197
Newark Beth Israel Medical CenterNewark, New Jersey  07112
New York Medical CollegeValhalla, New York  10595
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
University of Arkansas for Medical SciencesLittle Rock, Arkansas  72205
University of Nebraska Medical CenterOmaha, Nebraska  68198-3330
Hackensack University Medical CenterHackensack, New Jersey  07601
Children's Hospital Los AngelesLos Angeles, California  90027-0700
Children's National Medical CenterWashington, District of Columbia  20010-2970
Broward General Medical CenterFort Lauderdale, Florida  33316
Miami Children's HospitalMiami, Florida  33155-4069
All Children's HospitalSt. Petersburg, Florida  33701
Advocate Hope Children's HospitalOak Lawn, Illinois  60453
Saint Jude Midwest AffiliatePeoria, Illinois  61637
Maine Children's Cancer ProgramScarborough, Maine  04074-9308
Carolinas Medical CenterCharlotte, North Carolina  28232-2861
University of Oklahoma Health Sciences CenterOklahoma City, Oklahoma  73104
Legacy Emanuel Hospital and Health CenterPortland, Oregon  97227
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Driscoll Children's HospitalCorpus Christi, Texas  78466
Inova Fairfax HospitalFalls Church, Virginia  22042-3300
Southern California Permanente Medical GroupDowney, California  90242
Children's Hospital Central CaliforniaMadera, California  93638-8762
Kosair Children's HospitalLouisville, Kentucky  40202-3830
Children's Hospital Medical Center of AkronAkron, Ohio  44308
University of Wisconsin Hospital and ClinicsMadison, Wisconsin  53792-0001
Overlook HospitalSummit, New Jersey  07902-0220
Winthrop University HospitalMineola, New York  11501
Mount Sinai Medical CenterNew York, New York  10029
Cincinnati Children's Hospital Medical CenterCincinnati, Ohio  45229-3039
Methodist Children's Hospital of South TexasSan Antonio, Texas  78229-3993
Primary Children's Medical CenterSalt Lake City, Utah  84113-1100
Naval Medical Center - PortsmouthPortsmouth, Virginia  23708-2197
Montefiore Medical CenterBronx, New York  10467-2490
Saint Peter's University HospitalNew Brunswick, New Jersey  08901-1780
Rady Children's Hospital - San DiegoSan Diego, California  92123-4282
Children's Hospitals and Clinics of Minnesota - MinneapolisMinneapolis, Minnesota  55404
University of New Mexico Cancer CenterAlbuquerque, New Mexico  87131-5636
Nationwide Children's HospitalColumbus, Ohio  43205-2696
Children's Hospital of Pittsburgh of UPMCPittsburgh, Pennsylvania  15213
Dell Children's Medical Center of Central TexasAustin, Texas  78723
Children's Hospital and Research Center at OaklandOakland, California  94609-1809
City of Hope Medical CenterDuarte, California  91010
Lehigh Valley Hospital - MuhlenbergBethlehem, Pennsylvania  18017
Presbyterian HospitalCharlotte, North Carolina  28233-3549
Lee Memorial Health SystemFort Myers, Florida  33902
University of VirginiaCharlottesville, Virginia  22908
University of Alabama at BirminghamBirmingham, Alabama  35294-3300
Children's Hospital of AlabamaBirmingham, Alabama  35233
Connecticut Children's Medical CenterHartford, Connecticut  06106
Vanderbilt UniversityNashville, Tennessee  37232-6305
University of North CarolinaChapel Hill, North Carolina  27599
Duke University Medical CenterDurham, North Carolina  27710
University of FloridaGainesville, Florida  32610-0277
Nemours Children's Clinic - PensacolaPensacola, Florida  32504
Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, Michigan  49503
Yale UniversityNew Haven, Connecticut  06520
Wayne State UniversityDetroit, Michigan  48202
Legacy Emanuel Children's HospitalPortland, Oregon  97227
BI-LO Charities Children's Cancer CenterGreenville, South Carolina  29605
University of Arizona Health Sciences CenterTucson, Arizona  85724
Dartmouth Hitchcock Medical CenterLebanon, New Hampshire  03756
University Of VermontBurlington,, Vermont  05403
Albany Medical CenterAlbany, New York  12208
University of Texas Southwestern Medical CenterDallas, Texas  
University of KentuckyLexington, Kentucky  40536-0098
UC Davis Comprehensive Cancer CenterSacramento, California  95817
Oregon Health and Science UniversityPortland, Oregon  97201
Virginia Commonwealth UniversityRichmond, Virginia  
Florida HospitalOrlando, Florida  32803
Memorial Health University Medical CenterSavannah, Georgia  31404
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470
Seattle Children's HospitalSeattle, Washington  98105
Wake Forest University Health SciencesWinston-Salem, North Carolina  27157
Childrens Memorial HospitalChicago, Illinois  60614
Kaiser Permanente-OaklandOakland, California  94611
M D Anderson Cancer Center- OrlandoOrlando, Florida  32806
Saint Vincent Hospital and Health ServicesIndianapolis, Indiana  46260
Saint John Hospital and Medical CenterDetroit, Michigan  48236
Michigan State University - Breslin Cancer CenterEast Lansing, Michigan  48824-1313
Saint John's Mercy Medical CenterSaint Louis, Missouri  63141
Nevada Cancer Research Foundation CCOPLas Vegas, Nevada  89106
Columbia University Medical CenterNew York, New York  10032
State University of New York Upstate Medical UniversitySyracuse, New York  13210
Mission Hospitals IncAsheville, North Carolina  28801
Saint Vincent HospitalGreen Bay, Wisconsin  54301
University of Maryland Greenebaum Cancer CenterBaltimore, Maryland  21201
University of IllinoisChicago, Illinois  60612
Cook Children's Medical CenterFort Worth, Texas  76104
Memorial Healthcare System - Joe DiMaggio Children's HospitalHollywood, Florida  33021
The Children's Medical Center of DaytonDayton, Ohio  45404
University of Minnesota Medical Center-FairviewMinneapolis, Minnesota  55455
Children's Oncology GroupArcadia, California  91006-3776
C S Mott Children's HospitalAnn Arbor, Michigan  48109
Southern Illinois UniversitySpringfield, Illinois  62702
University Of Missouri-ColumbiaColumbia, Missouri  65212
Walter Reed National Military Medical CenterBethesda, Maryland  20889
Riley Hospital for ChildrenIndianapolis, Indiana  46202
Cardinal Glennon Children's Medical CenterSt. Louis, Missouri  63104
UMDNJ - Robert Wood Johnson University HospitalNew Brunswick, New Jersey  08903
Phoenix Childrens HospitalPhoenix, Arizona  85016
Childrens Hospital of Orange CountyOrange, California  92868-3874
Alfred I duPont Hospital for ChildrenWilmington, Delaware  19803
Nemours Children's Clinic - JacksonvilleJacksonville, Florida  32207-8426
Nemours Childrens Clinic - OrlandoOrlando, Florida  32806
Saint Joseph Children's Hospital of TampaTampa, Florida  33607
Children's Healthcare of Atlanta - EglestonAtlanta, Georgia  30322
The Childrens Mercy HospitalKansas City, Missouri  64108
Rainbow Babies and Childrens HospitalCleveland, Ohio  44106
Penn State Hershey Children's HospitalHershey, Pennsylvania  17033
Palmetto Health RichlandColumbia, South Carolina  29203
East Tennessee Childrens HospitalKnoxville, Tennessee  37916
Children's Hospital and Medical Center of OmahaOmaha, Nebraska  68114
Childrens Hospital-King's DaughtersNorfolk, Virginia  23507
Sanford Medical Center-FargoFargo, North Dakota  58122
Children's Hospital ColoradoAurora, Colorado  80045
Lucile Packard Children's Hospital Stanford UniversityPalo Alto, California  94304
University of California San Francisco Medical Center-ParnassusSan Francisco, California  94143
Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical CenterDenver, Colorado  80218
Raymond Blank Children's HospitalDes Moines, Iowa  50309
Children's Hospital-Main CampusNew Orleans, Louisiana  70118
The Toledo Hospital/Toledo Children's HospitalToledo, Ohio  43606
Saint Christopher's Hospital for ChildrenPhiladelphia, Pennsylvania  19134
Greenville Cancer Treatment CenterGreenville, South Carolina  29605
Sanford USD Medical Center - Sioux FallsSioux Falls, South Dakota  57117-5134
T C Thompson Children's HospitalChattanooga, Tennessee  37403
Carilion Clinic Children's HospitalRoanoke, Virginia  24014
Providence Sacred Heart Medical Center and Children's HospitalSpokane, Washington  99204