hu14.18-Interleukin-2 Fusion Protein in Treating Young Patients With Recurrent or Refractory Neuroblastoma

A Phase II Study Of hu14.18-IL2 In Children With Recurrent Or Refractory Neuroblastoma

RATIONALE: Biological therapies such as hu14.18-interleukin-2 fusion protein work in different ways to stimulate the immune system and stop tumor cells from growing.

PURPOSE: This phase II trial is studying how well hu14.18-interleukin-2 fusion protein works in treating young patients with recurrent or refractory neuroblastoma.

Study Overview

• Status: Completed
• Conditions: Neuroblastoma
• Intervention / Treatment: Biological: hu14.18-Interleukin-2 fusion protein

Detailed Description

OBJECTIVES:

• Determine the response rate in children with recurrent or refractory neuroblastoma treated with hu14.18-interleukin-2 (hu14.18-IL2) fusion protein.
• Determine the adverse events of this drug in these patients.
• Determine the immunologic activation in patients treated with this drug.
• Determine the induction of anti-hu14.18-IL2 antibody in patients treated with this drug.
• Correlate antitumor response with measurements of toxicity, immune activation, and anti-hu14.18-IL2 antibody activity in patients treated with this drug.

OUTLINE: This is a multicenter study. Patients are stratified according to measurable/evaluable disease (measurable by standard radiographic criteria vs evaluable by MIBG (meta-iodobenzylguanidine) scanning and/or bone marrow histology vs disease identified and quantified by bone marrow immunohistochemistry).

For standard radiographic criteria this study will use the definitions of measurable disease from the Response Evaluation Criteria In Solid Tumors (RECIST) from the National Cancer Institute. Complete Response (CR) - Disappearance of all target lesions. No evidence of tumor at any site (chest, abdomen, liver, bone, bone marrow, nodes, etc). Very Good Partial Response (VGPR) - Greater than 90% decrease of the disease measurement for CT/MRI target lesions, taking as reference the disease measurement done to confirm measurable disease in target lesions at study entry; all pre-existing bone lesions with CR by MIBG; MIBG scan can be SD or CR in soft tissue lesions corresponding to lesions on CT/MRI. Partial Response (PR) - At least a 30% decrease in the disease measurement for CT/MRI target lesions, taking as reference the disease measurement done to confirm measurable disease in target lesions at study entry. Progressive Disease (PD) - Any one of the following: a) At least a 20% increase in the disease measurement for CT/MRI target lesions, taking as reference the smallest disease measurement recorded since the start of treatment. b) Appearance of one or more new lesions or new sites of tumor. c) PD as defined above for either bone marrow or MIBG lesions.

Stable disease (SD) - The patient will be classified as stable disease for overall response if there is stable disease by either CT/MRI lesion, bone marrow, or MIBG criteria. No new lesions; no new sites of disease.

Patients will be enrolled in 3 strata, and evaluated for antitumor response following 2 monthly courses (treatment on Days 1-3, followed by 25 days of observation,). Patients with progressive disease will be taken off protocol therapy. Patients with stabilization or regression of disease will be eligible to receive 2 more monthly courses of treatment. Additional treatment following course 4 will be allowed for patients showing a continued clinical response, up to a maximum of 10 courses of treatment.

Patients are followed for survival.

PROJECTED ACCRUAL: A total of 40-60 patients (20 for strata 1 and 2 and 0-20 for stratum 3) will be accrued for this study within 2 years.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G1V 4G2
    • Centre Hospitalier Universitaire de Quebec
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Children's Hospital
    • Edmonton, Alberta, Canada, T6G 1Z2
      • University of Alberta Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • Children's & Women's Hospital of British Columbia
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • IWK Health Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster Children's Hospital at Hamilton Health Sciences
    • London, Ontario, Canada, N6A 4G5
      • Children's Hospital of Western Ontario
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • Montreal Children's Hospital at McGill University Health Center
    • Montreal, Quebec, Canada, H3T 1C5
      • Hôpital Sainte Justine
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
  • California
    • Los Angeles, California, United States, 90027
      • Childrens Hospital Los Angeles
    • Madera, California, United States, 93638-8762
      • Children's Hospital Central California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Sacramento, California, United States, 95816
      • Sutter Cancer Center
    • San Francisco, California, United States, 94115
      • UCSF Comprehensive Cancer Center
    • Stanford, California, United States, 94305
      • Stanford Comprehensive Cancer Center - Stanford
  • Colorado
    • Denver, Colorado, United States, 80218-1088
      • Children's Hospital Cancer Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610-0232
      • University of Florida Shands Cancer Center
    • Pensacola, Florida, United States, 32504
      • Sacred Heart Cancer Center at Sacred Heart Hospital
    • Tampa, Florida, United States, 33607
      • St. Joseph's Cancer Institute at St. Joseph's Hospital
    • West Palm Beach, Florida, United States, 33407
      • Kaplan Cancer Center at St. Mary's Medical Center
  • Georgia
    • Augusta, Georgia, United States, 30912-3730
      • MBCCOP - Medical College of Georgia Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital - Chicago
    • Springfield, Illinois, United States, 62794-9620
      • Southern Illinois University School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Melvin and Bren Simon Cancer Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0293
      • Markey Cancer Center at University of Kentucky Chandler Medical Center
    • Louisville, Kentucky, United States, 40232
      • Kosair Children's Hospital
  • Louisiana
    • Alexandria, Louisiana, United States, 71315-3198
      • Tulane Cancer Center Office of Clinical Research
  • Maine
    • Bangor, Maine, United States, 04401
      • CancerCare of Maine at Eastern Maine Medial Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
    • Boston, Massachusetts, United States, 02111
      • Floating Hospital for Children at Tufts - New England Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201-1379
      • Barbara Ann Karmanos Cancer Institute
    • Grand Rapids, Michigan, United States, 49503-2560
      • Spectrum Health Hospital - Butterworth Campus
    • Lansing, Michigan, United States, 48910
      • Breslin Cancer Center at Ingham Regional Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota - Minneapolis
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Cancer Center at University of Minnesota
  • Mississippi
    • Jackson, Mississippi, United States, 39216-4505
      • University of Mississippi Cancer Clinic
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
    • St. Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital
  • Nevada
    • Las Vegas, Nevada, United States, 89109-2306
      • Sunrise Hospital and Medical Center
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756-0002
      • Norris Cotton Cancer Center at Dartmouth - Hitchcock Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center Cancer Center
    • Morristown, New Jersey, United States, 07962
      • Overlook Hospital
    • New Brunswick, New Jersey, United States, 08903
      • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131-5636
      • University of New Mexico Cancer Research and Treatment Center
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
    • Charlotte, North Carolina, United States, 28232-2861
      • Blumenthal Cancer Center at Carolinas Medical Center
    • Charlotte, North Carolina, United States, 28233-3549
      • Presbyterian Cancer Center at Presbyterian Hospital
  • Ohio
    • Akron, Ohio, United States, 44308-1062
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
    • Columbus, Ohio, United States, 43205-2696
      • Columbus Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Cancer Institute
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822-0001
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Cancer Institute at Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104-9786
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
  • South Carolina
    • Columbia, South Carolina, United States, 29203
      • Palmetto Health South Carolina Cancer Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • T.C. Thompson Children's Hospital
    • Knoxville, Tennessee, United States, 37901
      • East Tennessee Children's Hospital
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
    • Nashville, Tennessee, United States, 37232-6838
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Amarillo, Texas, United States, 79106
      • Texas Tech University Health Sciences Center School of Medicine - Amarillo
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • Dallas, Texas, United States, 75390
      • Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center - Fort Worth
    • San Antonio, Texas, United States, 78207
      • University of Texas Health Science Center at San Antonio
  • Utah
    • Salt Lake City, Utah, United States, 84113-1100
      • Primary Children's Medical Center
  • Virginia
    • Richmond, Virginia, United States, 23298-0037
      • Virginia Commonwealth University Massey Cancer Center
    • Roanoke, Virginia, United States, 24029
      • Carilion Cancer Center of Western Virginia
  • Washington
    • Spokane, Washington, United States, 99220-2555
      • Providence Cancer Center at Sacred Heart Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
    • Milwaukee, Wisconsin, United States, 53226
      • Midwest Children's Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed neuroblastoma
• Relapsed or refractory to conventional therapy

• Measurable or evaluable disease documented by 1 of the following criteria:

  • Clinical
  • Radiographic
  • Histologic
  • MIBG (meta-iodobenzylguanidine) scanning
  • Immunocytochemistry
• No symptomatic pleural effusions or ascites requiring constant or intermittent drainage
• No clinical or radiological evidence of central nervous system (CNS) disease

PATIENT CHARACTERISTICS:

Age

• 21 and under

Performance status

• Karnofsky 50-100% (> 16 years of age)
• Lansky 50-100% (≤ 16 years of age)

Life expectancy

• At least 8 weeks

Hematopoietic

• Absolute neutrophil count > 1,000/mm^3

• Platelet count ≥ 75,000/mm^3*

  • Must not be refractory to platelet transfusions
• Hemoglobin ≥ 9.0 g/dL* NOTE: *Transfusion allowed if patient is known to have a history of bone marrow involvement with tumor

Hepatic

• Alanine transaminase (ALT) < 2.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN
• Hepatitis B surface antigen negative

Renal

• 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]) OR
• Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min

Cardiovascular

• Shortening fraction ≥ 27% by echocardiogram OR
• Ejection fraction ≥ 50% by Multi Gated Acquisition Scan (MUGA)
• No symptomatic congestive heart failure
• No uncontrolled cardiac rhythm disturbance

Pulmonary

• Pulse oximetry > 94% on room air
• Forced vital capacity (FVC) > 80%
• Forced expiratory volume (FEV_1) > 80%
• No abnormal respiratory function
• No dyspnea at rest
• No exercise intolerance
• No prior history of ventilator support related to lung injury (e.g., pneumonia, hemorrhagic pneumonitis, or capillary leakage)

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• No active uncontrolled infection
• No active uncontrolled peptic ulcer
• No objective peripheral neuropathy ≥ grade 2
• No significant psychiatric disabilities
• No seizure disorders requiring antiseizure medications
• No other concurrent significant illness

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Recovered from prior immunotherapy
• Prior in vivo monoclonal antibodies for biologic therapy or tumor imaging allowed provided there is documented absence of detectable antibody to hu14.18 by serology

• More than 28 days since prior autologous stem cell transplantation

  • Prior autologous marrow or stem cell infusion using monoclonal antibody-purged specimens allowed
• More than 1 week since prior growth factors
• At least 7 days since prior nonmyelosuppressive biologic agents
• No prior allogeneic bone marrow or stem cell transplantation
• No concurrent immunomodulating agents
• No concurrent growth factors

Chemotherapy

• More than 3 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas) and recovered
• No concurrent anticancer chemotherapy

Endocrine therapy

• No concurrent corticosteroids except 100 mg or less of hydrocortisone (or equivalent) as premedication for blood transfusion or treatment for transfusion reaction

  • No other use of systemic steroids

Radiotherapy

• Recovered from prior radiotherapy
• At least 2 weeks since prior local palliative radiotherapy (small port)
• At least 6 months since prior craniospinal radiotherapy
• At least 6 months since prior total body irradiation
• At least 6 months since prior radiotherapy to ≥ 50% of the pelvis
• At least 6 weeks since other prior substantial bone marrow radiotherapy
• Concurrent radiotherapy to localized painful lesions allowed provided at least 1 measurable or evaluable lesion is not irradiated

Surgery

• More than 2 weeks since prior major surgery (e.g., laparotomy or thoracotomy)
• No prior organ allografts

Other

• No concurrent immunosuppressive drugs
• No other concurrent myelosuppressive antineoplastic drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Disease Measurable by Standard Criteria(hu14.18-interleukin-2); Patients with residual/refractory neuroblastoma and readily measurable residual/refractory disease using standard radiographic criteria. Standard radiographic criteria for CT/MRI Lesions will use the definitions of measurable disease from the Response Evaluation Criteria In Solid Tumors (RECIST) from the National Cancer Institute. hu14.18-Interleukin-2 fusion protein : Given IV	Biological: hu14.18-Interleukin-2 fusion protein; Given IV; Other Names: IMMUNOCYTOKINE HU14.18-IL2 FUSION PROTEIN; humanized anti GD2 antibody fused with human IL-2; BB-IND-9798
Experimental: Disease Eval by MIBG or BM Histology (hu14.18-interleukin-2); Patients with residual/refractory neuroblastoma with disease that is not measurable by standard radiographic criteria, but is evaluable by meta-iodobenzylguanidine (MIBG) scanning and/or by bone marrow (BM) histology. hu14.18-Interleukin-2 fusion protein : Given IV	Biological: hu14.18-Interleukin-2 fusion protein; Given IV; Other Names: IMMUNOCYTOKINE HU14.18-IL2 FUSION PROTEIN; humanized anti GD2 antibody fused with human IL-2; BB-IND-9798
Experimental: Disease Identified by BM Immunohistochemistry Only; Patients with residual/refractory neuroblastoma that do not have disease that is measurable by standard radiographic techniques or evaluable by meta-iodobenzylguanidine (MIBG) scanning or bone marrow (BM) histology, however, disease is identified and quantified by BM immunohistochemistry (>5 neuroblastoma cells per 1,000,000 nucleated marrow cells). hu14.18-Interleukin-2 fusion protein : Given IV	Biological: hu14.18-Interleukin-2 fusion protein; Given IV; Other Names: IMMUNOCYTOKINE HU14.18-IL2 FUSION PROTEIN; humanized anti GD2 antibody fused with human IL-2; BB-IND-9798

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Responders (Response Rate)	Response rate to hu14.18-Interleukin-2 in 3 separate strata of patients with recurrent or refractory neuroblastoma. Patients will have radiologic (CT/MRI) tumor and urine homovanillic acid (HVA)/vanillylmandelic acid (VMA) measurements. Patients with prior marrow involvement will have marrow assessments. Patients with MIBG+ (iodine-131-meta-iodobenzylguanidine) prior disease will have MIBG scans performed. For CT/MRI lesions, measureable disease is measured by the Response Evaluation Criteria In Solid Tumors (RECIST) from the National Cancer Institute. RECIST (v1.0) for target lesions: Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions.	Up to 30 weeks

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Paul M Sondel, MD, PhD, University of Wisconsin, Madison; Study Chair: Suzanne Shusterman, MD, Dana-Farber Cancer Institute

Publications and helpful links

General Publications

• Delgado DC, Hank JA, Kolesar J, Lorentzen D, Gan J, Seo S, Kim K, Shusterman S, Gillies SD, Reisfeld RA, Yang R, Gadbaw B, DeSantes KB, London WB, Seeger RC, Maris JM, Sondel PM. Genotypes of NK cell KIR receptors, their ligands, and Fcgamma receptors in the response of neuroblastoma patients to Hu14.18-IL2 immunotherapy. Cancer Res. 2010 Dec 1;70(23):9554-61. doi: 10.1158/0008-5472.CAN-10-2211. Epub 2010 Oct 8.
• Shusterman S, London WB, Gillies SD, Hank JA, Voss SD, Seeger RC, Reynolds CP, Kimball J, Albertini MR, Wagner B, Gan J, Eickhoff J, DeSantes KB, Cohn SL, Hecht T, Gadbaw B, Reisfeld RA, Maris JM, Sondel PM. Antitumor activity of hu14.18-IL2 in patients with relapsed/refractory neuroblastoma: a Children's Oncology Group (COG) phase II study. J Clin Oncol. 2010 Nov 20;28(33):4969-75. doi: 10.1200/JCO.2009.27.8861. Epub 2010 Oct 4.

Study record dates

Study Major Dates

• Study Start: August 1, 2005
• Primary Completion (Actual): February 1, 2008
• Study Completion (Actual): May 1, 2012

Study Registration Dates

• First Submitted: May 14, 2004
• First Submitted That Met QC Criteria: May 18, 2004
• First Posted (Estimate): May 19, 2004

Study Record Updates

• Last Update Posted (Estimate): February 12, 2015
• Last Update Submitted That Met QC Criteria: January 27, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: recurrent neuroblastoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Interleukin-2; Denileukin diftitox
• Other Study ID Numbers: ANBL0322; CDR0000360723 (Other Identifier: Clinical Trials.gov); COG-ANBL0322 (Other Identifier: Children's Oncology Group); NCI-2012-02583 (Other Identifier: NCI)