Interleukin-12 and Interleukin-2 in Treating Patients With Refractory or Recurrent Neuroblastoma

A Phase I Investigation of IL-12 (NSC 672423)/Pulse IL-2 (Aldesleukin) in Children With Persistent and/or Refractory Neuroblastoma (13623)

Phase I trial to compare the effectiveness of interleukin-12 with or without interleukin-2 in treating young patients who have refractory or recurrent neuroblastoma. Biological therapies use different ways to stimulate the immune system and stop cancer cells from growing. Combining interleukin-2 with interleukin-12 may kill more tumor cells.

Study Overview

• Status: Terminated
• Conditions: Recurrent Neuroblastoma
• Intervention / Treatment: Biological: aldesleukin; Biological: recombinant interleukin-12

Detailed Description

OBJECTIVES:

I. Define the maximum tolerated dose and dose-limiting toxicity of interleukin-12 with or without interleukin-2 in patients with refractory or recurrent neuroblastoma.

II. Determine, preliminarily, the antitumor effect of interleukin-12 with or without interleukin-2 in these patients.

III. Evaluate the immunoregulatory activity of interleukin-12 with or without interleukin-2 in these patients.

IV. Evaluate the antiangiogenic activity of interleukin-12 with or without interleukin-2 in these patients.

OUTLINE: This is a dose-escalation, multicenter study. Patients are assigned to 1 of 2 treatment cohorts.

COHORT A: Patients receive interleukin-12 (IL-12) IV over 5-15 seconds on days 1, 3, 5, 8, 10, and 12.

COHORT B: Patients receive interleukin-2 (IL-2) IV over 15 minutes twice daily on days 1 and 8 and IL-12 IV as in cohort A.

Treatment in both cohorts repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Some patients may receive additional courses at the discretion of the principal investigator.

Cohorts of 3-6 patients in both cohorts receive escalating doses of IL-2 and IL-12 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Once the MTD is determined, an additional cohort of 8 patients receives IL-12 and IL-2 at the MTD.

Patients are followed at 3 weeks.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Los Angeles, California, United States, 90027-6016
      • New Approaches to Neuroblastoma Treatment (NANT)
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital Stanford University
    • San Francisco, California, United States, 94143-0875
      • University of California at San Francisco - Comprehensive Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • AFLAC Cancer Center and Blood Disorders Service
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Childrens Memorial Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan University Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of neuroblastoma

  • Histologically confirmed disease AND/OR disease defined by tumor cells in the bone marrow and elevated urinary catecholamine metabolites

• Persistent and/or refractory disease, with at least 1 of the following:

  • Biopsy-proven residual disease at least 12 weeks after myeloablative therapy
  • Progressive disease after nonmyeloablative or myeloablative therapy

• Recurrent disease, evidenced by any of the following:

  • Biopsy-proven recurrent soft tissue disease
  • Metaiodobenzylguanidine (MIBG)-positive lesions visible on any other imaging modality or repeat MIBG obtained 2-4 weeks or more apart
  • Histologically confirmed bone marrow disease
  • Progressive or stable disease after at least 1 prior standard salvage regime
• No clinically significant pleural effusion
• ECOG 0-1
• Life expectancy >= 12 weeks
• Hepatitis A antibody negative

• Hepatitis B surface antigen negative

  • Positive hepatitis B titer allowed if patient has been immunized and has no history of disease
• Hepatitis C virus negative
• No history of congenital or acquired coagulation disorder
• Cardiac function normal by ECG
• No dyspnea at rest
• No exercise intolerance
• Oxygen saturation at least 94% by pulse oximetry
• DLCO greater than 60% of predicted
• FEV1 greater than 70% of predicted
• Negative pregnancy test
• Skull-based bony lesions without space-occupying intracranial extension are allowed
• No prior or concurrent intracranial metastatic disease to the brain parenchyma
• Not pregnant or nursing
• Fertile patients must use effective barrier contraception during and for at least 2 months after study
• No prior hematologic malignancy (including leukemia or lymphoma)
• No history of malignant hyperthermia
• No prior or concurrent autoimmune disease
• No positive direct Coombs testing
• No history of ongoing or intermittent bowel obstruction
• No active infection or other significant systemic illness
• More than 2 weeks since prior fenretinide
• More than 2 weeks since prior 13-cis-retinoic acid
• More than 2 weeks since prior filgrastim (G-CSF) or sargramostim (GM-CSF)
• More than 2 weeks since prior interferons or interleukins
• More than 2 weeks since prior cytokine-fusion proteins
• More than 2 weeks since prior IV immunoglobulin (IVIG)
• No prior interleukin-12
• No concurrent cytokines
• No concurrent fenretinide
• No concurrent 13-cis-retinoic acid

• No other concurrent immunomodulators, including:

  • G-CSF and GM-CSF
  • Interferons
  • Other interleukins
  • IVIG
• More than 4 weeks since prior chemotherapy
• No other unstable medical condition or critical illness that would preclude study participation
• More than 12 weeks since prior myeloablative chemotherapy followed by autologous stem cell transplantation:

No prior myeloablative chemotherapy followed by allogeneic bone marrow transplantation

• More than 2 weeks since prior growth hormones
• More than 4 weeks since prior systemic corticosteroids
• More than 2 weeks since prior non-corticosteroid hormonal therapy (including oral birth control pills)
• No concurrent hormonal therapy (including oral birth control pills)
• No concurrent growth hormones
• No concurrent systemic corticosteroids, except for use in life-threatening complications
• More than 4 weeks since prior radiotherapy
• No prior solid organ transplantation
• More than 4 weeks since prior investigational agents
• No other concurrent investigational agents
• No prior enrollment on COG-A3973, unless disease has progressed
• No history of hemolytic anemia
• Absolute neutrophil count at least 1,500/mm^3 [Note: Independent of growth factor or transfusion support]
• Platelet count at least 75,000/mm^3 [Note: Independent of growth factor or transfusion support]
• AST and ALT less than 2.5 times upper limit of normal
• Bilirubin less than 2.0 mg/dL
• Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min OR creatinine normal
• HIV negative
• Ejection fraction at least 50% by echocardiogram or MUGA OR Fractional shortening at least 30% by echocardiogram
• No congestive heart failure
• No uncontrolled cardiac arrhythmia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (IL-12, aldesleukin); Cohort A: Patients receive interleukin-12 (IL-12) IV over 5-15 seconds on days 1, 3, 5, 8, 10, and 12. Cohort B: Patients receive interleukin-2 (IL-2) IV over 15 minutes twice daily on days 1 and 8 and IL-12 IV as in cohort A. Treatment in both cohorts repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Some patients may receive additional courses at the discretion of the principal investigator. Cohorts of 3-6 patients in both cohorts receive escalating doses of IL-2 and IL-12 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, an additional cohort of 8 patients receives IL-12 and IL-2 at the MTD.

Biological: aldesleukin; Given IV; Other Names: Proleukin; IL-2; recombinant human interleukin-2; recombinant interleukin-2; Biological: recombinant interleukin-12; Given IV; Other Names: cytotoxic lymphocyte maturation factor; IL-12; interleukin-12; natural killer cell stimulatory factor; Ro 24-7472

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose (MTD) assessed by Common Toxicity Criteria (CTC)	28 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall response assessed by Response Evaluation Criteria for Solid Tumors (RECIST)	Up to 3 weeks

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jon Wigginton, New Approaches to Neuroblastoma Treatment (NANT)

Study record dates

Study Major Dates

• Study Start: December 1, 2002
• Primary Completion (Actual): May 1, 2009

Study Registration Dates

• First Submitted: February 5, 2003
• First Submitted That Met QC Criteria: February 5, 2003
• First Posted (Estimate): February 6, 2003

Study Record Updates

• Last Update Posted (Estimate): April 9, 2013
• Last Update Submitted That Met QC Criteria: April 8, 2013
• Last Verified: April 1, 2013

More Information

Terms related to this study

• 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; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Adjuvants, Immunologic; Aldesleukin; Interleukin-12; Interleukin-2
• Other Study ID Numbers: NCI-2009-00024; P01CA081403 (U.S. NIH Grant/Contract); NANT 2001-01; CDR0000270447 (Registry Identifier: PDQ (Physician Data Query))