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

National Cancer Institute (NCI)

Status and phase: Terminated; Phase 1

Conditions: Recurrent Neuroblastoma

Treatments: Biological: aldesleukin; Biological: recombinant interleukin-12

Study type: Interventional

Funder types: NIH

Identifiers

NCT00054405

P01CA081403 (U.S. NIH Grant/Contract)

NCI-2009-00024

CDR0000270447

NANT 2001-01

Details and patient eligibility

About

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.

Full 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.

Enrollment: 40 patients

Sex: All

Ages: 3 to 21 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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40 participants in 1 patient group

Treatment (IL-12, aldesleukin)

Experimental group

Description:

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.

Treatment:

Biological: aldesleukin

Biological: recombinant interleukin-12