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

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.

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.

• Biological: recombinant interleukin-12
  Given IV
  Other Names:

  • cytotoxic lymphocyte maturation factor
  • IL-12
  • interleukin-12
  • natural killer cell stimulatory factor
  • Ro 24-7472
• Biological: aldesleukin
  Given IV
  Other Names:

  • IL-2
  • Proleukin
  • recombinant human interleukin-2
  • recombinant interleukin-2

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