Clinical trial NCT00082758: hu14.18-Interleukin-2 Fusion Protein in Treating Young Patients With Recurrent or Refractory Neuroblastoma
Official title: A Phase II Study Of hu14.18-IL2 In Children With Recurrent Or Refractory Neuroblastoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Neuroblastoma
Keywords: recurrent neuroblastoma
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2004-05-19
Enrollment: 39
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Responders (Response Rate)
timeFrame: Up to 30 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
state: Alabama
city: Little Rock
country: United States
facility: Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
state: Arkansas
city: Los Angeles
country: United States
facility: Childrens Hospital Los Angeles
state: California
city: Madera
country: United States
facility: Children's Hospital Central California
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Sacramento
country: United States
facility: Sutter Cancer Center
state: California
city: San Francisco
country: United States
facility: UCSF Comprehensive Cancer Center
state: California
city: Stanford
country: United States
facility: Stanford Comprehensive Cancer Center - Stanford
state: California
city: Denver
country: United States
facility: Children's Hospital Cancer Center
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Shands Cancer Center
state: Florida
city: Pensacola
country: United States
facility: Sacred Heart Cancer Center at Sacred Heart Hospital
state: Florida
city: Tampa
country: United States
facility: St. Joseph's Cancer Institute at St. Joseph's Hospital
state: Florida
city: West Palm Beach
country: United States
facility: Kaplan Cancer Center at St. Mary's Medical Center
state: Florida
city: Augusta
country: United States
facility: MBCCOP - Medical College of Georgia Cancer Center
state: Georgia
city: Chicago
country: United States
facility: Children's Memorial Hospital - Chicago
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Cancer Research Center
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University School of Medicine
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center
state: Indiana
city: Lexington
country: United States
facility: Markey Cancer Center at University of Kentucky Chandler Medical Center
state: Kentucky
city: Louisville
country: United States
facility: Kosair Children's Hospital
state: Kentucky
city: Alexandria
country: United States
facility: Tulane Cancer Center Office of Clinical Research
state: Louisiana
city: Bangor
country: United States
facility: CancerCare of Maine at Eastern Maine Medial Center
state: Maine
city: Boston
country: United States
facility: Floating Hospital for Children at Tufts - New England Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health Hospital - Butterworth Campus
state: Michigan
city: Lansing
country: United States
facility: Breslin Cancer Center at Ingham Regional Medical Center
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics of Minnesota - Minneapolis
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Cancer Center at University of Minnesota
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Cancer Clinic
state: Mississippi
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: St. Louis
country: United States
facility: Siteman Cancer Center at Barnes-Jewish Hospital
state: Missouri
city: Las Vegas
country: United States
facility: Sunrise Hospital and Medical Center
state: Nevada
city: Lebanon
country: United States
facility: Norris Cotton Cancer Center at Dartmouth - Hitchcock Medical Center
state: New Hampshire
city: Hackensack
country: United States
facility: Hackensack University Medical Center Cancer Center
state: New Jersey
city: Morristown
country: United States
facility: Overlook Hospital
state: New Jersey
city: New Brunswick
country: United States
facility: Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Research and Treatment Center
state: New Mexico
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
state: North Carolina
city: Charlotte
country: United States
facility: Blumenthal Cancer Center at Carolinas Medical Center
state: North Carolina
city: Charlotte
country: United States
facility: Presbyterian Cancer Center at Presbyterian Hospital
state: North Carolina
city: Akron
country: United States
facility: Children's Hospital Medical Center of Akron
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Columbus
country: United States
facility: Columbus Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma University Cancer Institute
state: Oklahoma
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Cancer Institute at Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Columbia
country: United States
facility: Palmetto Health South Carolina Cancer Center
state: South Carolina
city: Chattanooga
country: United States
facility: T.C. Thompson Children's Hospital
state: Tennessee
city: Knoxville
country: United States
facility: East Tennessee Children's Hospital
state: Tennessee
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Amarillo
country: United States
facility: Texas Tech University Health Sciences Center School of Medicine - Amarillo
state: Texas
city: Dallas
country: United States
facility: Medical City Dallas Hospital
state: Texas
city: Dallas
country: United States
facility: Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center - Fort Worth
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University Massey Cancer Center
state: Virginia
city: Roanoke
country: United States
facility: Carilion Cancer Center of Western Virginia
state: Virginia
city: Spokane
country: United States
facility: Providence Cancer Center at Sacred Heart Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Midwest Children's Cancer Center
state: Wisconsin
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Children's & Women's Hospital of British Columbia
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Halifax
country: Canada
facility: IWK Health Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: McMaster Children's Hospital at Hamilton Health Sciences
state: Ontario
city: London
country: Canada
facility: Children's Hospital of Western Ontario
state: Ontario
city: Ottawa
country: Canada
facility: Children's Hospital of Eastern Ontario
state: Ontario
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Montreal Children's Hospital at McGill University Health Center
state: Quebec
city: Montreal
country: Canada
facility: Hopital Sainte Justine
state: Quebec
city: Quebec
country: Canada
facility: Centre Hospitalier Universitaire de Quebec
Study officials:
affiliation: University of Wisconsin, Madison
name: Paul M Sondel, MD, PhD
role: STUDY_CHAIR
affiliation: Dana-Farber Cancer Institute
name: Suzanne Shusterman, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: Shusterman S, London WB, Gillies SD, et al.: Anti-neuroblastoma activity of hu14.18-IL2 against minimal residual disease in a Children's Oncology Group (COG) phase II study. [Abstract] J Clin Oncol 26 (Suppl 15): A-3002, 2008.