Isotretinoin with or without Dinutuximab, Aldesleukin, and Sargramostim following Stem Cell Transplant in Treating Patients with Neuroblastoma

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IIIBiomarker/Laboratory analysis, Treatment30 and under at diagnosisANBL0032
NCI-2009-01064, CDR0000069018, COG-ANBL0032, PANBL0032_A33PAMDREVW01, COG-P9842, NCT00026312

Trial Description

Summary

This partially randomized phase III trial studies isotretinoin with dinutuximab, 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, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as dinutuximab, may block tumor growth in different ways by targeting certain cells. 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 dinutuximab, aldesleukin, and sargramostim following stem cell transplant in treating neuroblastoma.

Further Study Information

PRIMARY OBJECTIVES:

I. Determine if monoclonal antibody Ch14.18 (dinutuximab) + 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 Ch14.18 + 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. Determine the toxicities of the combination of monoclonal antibody Ch14.18 with cytokines.

IV. 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.

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

VI. To further describe the safety and toxicity of Ch14.18 + 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); and c) number of toxic deaths.

TERTIARY OBJECTIVES:

I. 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.

II. Determine if change from baseline of MRD is associated with event free and overall survival.

III. Determine whether tumor biology at diagnosis correlates with event-free and overall survival, for either of the randomized regimens.

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

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

VI. 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.

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

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

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

X. To determine if natural killer cell p30-related protein (NKp30) isoform expression and single nucleotide polymorphism (SNP), and circulating ligand B7-H6 are prognostic of EFS or OS.

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

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 dinutuximab 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.

Eligibility Criteria

Inclusion Criteria:

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 Pediatric Oncology Group (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 POG 9640
  • Following treatment per COG ANBL00P1
  • Following treatment per CHP 594/Dana-Farber Cancer Institute (DFCI) 34-DAT

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

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

Patients must not have received prior anti-disialoganglioside (GD2) antibody therapy

Veno-occlusive disease, if present, should be stable or improving

Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5 x normal

Total bilirubin =< 1.5 x normal

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

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])

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

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

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])

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

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

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

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

National Cancer Institute

  • National Cancer Institute
Alice Lin-Tsing Yu, Principal Investigator

Trial Sites

U.S.A.

Alabama
Birmingham

Children's Hospital of Alabama

Alyssa Terry Reddy
Ph: 888-823-5923
Email: ctsucontact@westat.com

Alyssa Terry Reddy
Principal Investigator

California
Duarte

City of Hope Comprehensive Cancer Center

Alice Lin-Tsing Yu
Ph: 619-543-2438
Email: aliceyu@ucsd.edu

Alice Lin-Tsing Yu
Principal Investigator

Los Angeles

Children's Hospital Los Angeles

Leo Mascarenhas
Ph: 323-361-4110

Leo Mascarenhas
Principal Investigator

Madera

Children's Hospital Central California

Vonda Lee Crouse
Ph: 866-353-5437

Vonda Lee Crouse
Principal Investigator

Palo Alto

Lucile Packard Children's Hospital Stanford University

Neyssa Maria Marina
Ph: 650-498-7061
Email: clinicaltrials@med.stanford.edu

Neyssa Maria Marina
Principal Investigator

Sacramento

Sutter General Hospital

Alice Lin-Tsing Yu
Ph: 619-543-2438
Email: aliceyu@ucsd.edu

Alice Lin-Tsing Yu
Principal Investigator

Colorado
Aurora

Children's Hospital Colorado

Brian Scott Greffe
Ph: 720-777-6672

Brian Scott Greffe
Principal Investigator

Delaware
Wilmington

Alfred I duPont Hospital for Children

Christopher N. Frantz
Ph: 302-651-5755

Christopher N. Frantz
Principal Investigator

District of Columbia
Washington

Children's National Medical Center

Jeffrey Stuart Dome
Ph: 202-884-2549

Jeffrey Stuart Dome
Principal Investigator

MedStar Georgetown University Hospital

Alice Lin-Tsing Yu
Ph: 619-543-2438
Email: aliceyu@ucsd.edu

Alice Lin-Tsing Yu
Principal Investigator

Florida
Jacksonville

Nemours Children's Clinic-Jacksonville

Scott M. Bradfield
Ph: 904-697-3529

Scott M. Bradfield
Principal Investigator

Orlando

Arnold Palmer Hospital for Children

Vincent Ferdinando Giusti
Ph: 321-841-7246
Email: CancerClinicalTrials@orlandohealth.com

Vincent Ferdinando Giusti
Principal Investigator

West Palm Beach

Saint Mary's Hospital

Narayana Gowda
Ph: 888-823-5923
Email: ctsucontact@westat.com

Narayana Gowda
Principal Investigator

Georgia
Atlanta

Children's Healthcare of Atlanta - Egleston

Glen Lew
Ph: 404-785-1112

Glen Lew
Principal Investigator

Savannah

Memorial University Medical Center

J. Martin Johnston
Ph: 912-350-8568

J. Martin Johnston
Principal Investigator

Hawaii
Honolulu

Kapiolani Medical Center for Women and Children

Robert W. Wilkinson
Ph: 808-983-6090

Robert W. Wilkinson
Principal Investigator

Illinois
Chicago

University of Chicago Comprehensive Cancer Center

Navin Robert Pinto
Ph: 773-834-7424

Navin Robert Pinto
Principal Investigator

Peoria

Saint Jude Midwest Affiliate

Karen Sofia Fernandez
Ph: 309-655-3258

Karen Sofia Fernandez
Principal Investigator

Indiana
Indianapolis

Riley Hospital for Children

Robert J. Fallon
Ph: 888-823-5923
Email: ctsucontact@westat.com

Robert J. Fallon
Principal Investigator

Saint Vincent Hospital and Health Services

Bassem I. Razzouk
Ph: 317-338-2194

Bassem I. Razzouk
Principal Investigator

Iowa
Iowa City

University of Iowa/Holden Comprehensive Cancer Center

Mariko Sato
Ph: 800-237-1225

Mariko Sato
Principal Investigator

Massachusetts
Boston

Dana-Farber Cancer Institute

Carlos Rodriguez-Galindo
Ph: 877-442-3324

Carlos Rodriguez-Galindo
Principal Investigator

Massachusetts General Hospital Cancer Center

Howard Jeffrey Weinstein
Ph: 877-726-5130

Howard Jeffrey Weinstein
Principal Investigator

Minnesota
Minneapolis

Children's Hospitals and Clinics of Minnesota - Minneapolis

Bruce Charles Bostrom
Ph: 612-813-5193

Bruce Charles Bostrom
Principal Investigator

Missouri
Saint Louis

Washington University School of Medicine

David Brian Wilson
Ph: 800-600-3606
Email: info@siteman.wustl.edu

David Brian Wilson
Principal Investigator

Nevada
Las Vegas

Children's Specialty Center of Nevada II

Nik Farahana Nik Abdul Rashid
Ph: 702-384-0013

Nik Farahana Nik Abdul Rashid
Principal Investigator

Nevada Cancer Research Foundation CCOP

Jonathan Bernstein
Ph: 702-384-0013

Jonathan Bernstein
Principal Investigator

New Jersey
Summit

Overlook Hospital

Steven Lon Halpern
Ph: 973-971-5900

Steven Lon Halpern
Principal Investigator

New Mexico
Albuquerque

University of New Mexico

Alice Lin-Tsing Yu
Ph: 619-543-2438
Email: aliceyu@ucsd.edu

Alice Lin-Tsing Yu
Principal Investigator

New York
Albany

Albany Medical Center

Vikramjit Singh Kanwar
Ph: 518-262-3368

Vikramjit Singh Kanwar
Principal Investigator

Mineola

Winthrop University Hospital

Mark E. Weinblatt
Ph: 866-946-8476

Mark E. Weinblatt
Principal Investigator

New York

Laura and Issac Perlmutter Cancer Center at NYU Langone

Sharon Leigh Gardner
Ph: 212-263-4434
Email: prmc.coordinator@nyumc.org

Sharon Leigh Gardner
Principal Investigator

Syracuse

State University of New York Upstate Medical University

Karol Hicks Kerr
Ph: 315-464-5476

Karol Hicks Kerr
Principal Investigator

North Carolina
Chapel Hill

University of North Carolina at Chapel Hill

Stuart Harrison Gold
Ph: 877-668-0683
Email: cancerclinicaltrials@med.unc.edu

Stuart Harrison Gold
Principal Investigator

Ohio
Akron

Children's Hospital Medical Center of Akron

Steven J. Kuerbitz
Ph: 330-543-3193

Steven J. Kuerbitz
Principal Investigator

Cleveland

Rainbow Babies and Childrens Hospital

Yousif (Joe) H. Matloub
Ph: 216-844-5437

Yousif (Joe) H. Matloub
Principal Investigator

Columbus

Nationwide Children's Hospital

Mark Anthony Ranalli
Ph: 614-722-2708

Mark Anthony Ranalli
Principal Investigator

Oregon
Portland

Legacy Emanuel Hospital and Health Center

Janice Faye Olson
Ph: 503-413-2560

Janice Faye Olson
Principal Investigator

Pennsylvania
Danville

Geisinger Medical Center

Jagadeesh Ramdas
Ph: 570-271-5251

Jagadeesh Ramdas
Principal Investigator

Hershey

Penn State Hershey Children's Hospital

Lisa MacNabb McGregor
Ph: 717-531-6012

Lisa MacNabb McGregor
Principal Investigator

Philadelphia

Children's Hospital of Philadelphia

John M. Maris
Ph: 215-590-2810

John M. Maris
Principal Investigator

Saint Christopher's Hospital for Children

Akash Nahar
Ph: 215-427-8991

Akash Nahar
Principal Investigator

PR
San Juan

San Jorge Children's Hospital

Luis A. Clavell
Ph: 787-765-2363

Luis A. Clavell
Principal Investigator

South Carolina
Greenville

Greenville Cancer Treatment Center

Cary E. Stroud
Ph: 864-241-6251

Cary E. Stroud
Principal Investigator

Tennessee
Memphis

St. Jude Children's Research Hospital

Wayne Lee Furman
Ph: 866-278-5833
Email: info@stjude.org

Wayne Lee Furman
Principal Investigator

Texas
Dallas

UT Southwestern/Simmons Cancer Center-Dallas

Tanya Carens Watt
Ph: 214-648-7097

Tanya Carens Watt
Principal Investigator

Fort Worth

Cook Children's Medical Center

Mary Meaghan Petty Granger
Ph: 682-885-2103

Mary Meaghan Petty Granger
Principal Investigator

Houston

Baylor College of Medicine

Karen Ruth Rabin
Ph: 713-798-1354
Email: burton@bcm.edu

Karen Ruth Rabin
Principal Investigator

San Antonio

Methodist Children's Hospital of South Texas

Jaime Estrada
Ph: 210-575-7000

Jaime Estrada
Principal Investigator

Vermont
Burlington

University of Vermont College of Medicine

Alan Charles Homans
Ph: 802-656-4101

Alan Charles Homans
Principal Investigator

Virginia
Falls Church

Inova Fairfax Hospital

Marshall A. Schorin
Ph: 703-208-6650

Marshall A. Schorin
Principal Investigator

Norfolk

Childrens Hospital-King's Daughters

Eric Jeffrey Lowe
Ph: 757-668-7243

Eric Jeffrey Lowe
Principal Investigator

Richmond

Virginia Commonwealth University/Massey Cancer Center

Gita Vasers Massey
Ph: 804-628-1939

Gita Vasers Massey
Principal Investigator

Washington
Seattle

Seattle Children's Hospital

Douglas S. Hawkins
Ph: 866-987-2000

Douglas S. Hawkins
Principal Investigator

Spokane

Providence Sacred Heart Medical Center and Children's Hospital

Judy L. Felgenhauer
Ph: 800-228-6618
Email: HopeBeginsHere@providence.org

Judy L. Felgenhauer
Principal Investigator

West Virginia
Morgantown

West Virginia University Healthcare

Alice Lin-Tsing Yu
Ph: 619-543-2438
Email: aliceyu@ucsd.edu

Alice Lin-Tsing Yu
Principal Investigator

Wisconsin
Marshfield

Marshfield Clinic

Michael John McManus
Ph: 715-389-4457

Michael John McManus
Principal Investigator

Milwaukee

Midwest Children's Cancer Center

Michael Edward Kelly
Ph: 414-805-4380

Michael Edward Kelly
Principal Investigator

Australia

Herston

Royal Brisbane and Women's Hospital

Helen Irving
Ph: 888-823-5923
Email: ctsucontact@westat.com

Helen Irving
Principal Investigator

North Adelaide

Women's and Children's Hospital-Adelaide

Maria Louise Kirby
Ph: (08) 8161 7327
Email: cywhs.oncsec@health.sa.gov.au

Maria Louise Kirby
Principal Investigator

Parkville

Royal Children's Hospital

Francoise Marie Mechinaud
Email: crdo.info@mcri.edu.au

Francoise Marie Mechinaud
Principal Investigator

South Brisbane

Lady Cilento Children's Hospital

Helen Irving
Ph: 888-823-5923
Email: ctsucontact@westat.com

Helen Irving
Principal Investigator

Canada

British Columbia
Vancouver

British Columbia Children's Hospital

Caron Strahlendorf
Ph: 604-875-2345ext6477

Caron Strahlendorf
Principal Investigator

Manitoba
Winnipeg

CancerCare Manitoba

Rochelle Avis Yanofsky
Ph: 866-561-1026
Email: CIO_Web@cancercare.mb.ca

Rochelle Avis Yanofsky
Principal Investigator

Ontario
Hamilton

Chedoke Hospital at Hamilton Health Sciences

Carol Portwine
Ph: 905-521-2100ext74595

Carol Portwine
Principal Investigator

Toronto

Hospital for Sick Children

Sarah Weeks Alexander
Ph: 416-813-7654ext2027
Email: jason.mcguire@sickkids.ca

Sarah Weeks Alexander
Principal Investigator

Quebec
Quebec

Centre Hospitalier Universitaire de Quebec

Bruno Michon
Ph: 418-525-4444

Bruno Michon
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00026312

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.