interleukin-12 and interleukin-2 in treating patients with refractory or recurrent neuroblastoma

Conditions: Recurrent Neuroblastoma

Summary: 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