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.

Eligibility Criteria:
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