Clinical trial NCT00054405: Interleukin-12 and Interleukin-2 in Treating Patients With Refractory or Recurrent Neuroblastoma
Official title: A Phase I Investigation of IL-12 (NSC 672423)/Pulse IL-2 (Aldesleukin) in Children With Persistent and/or Refractory Neuroblastoma (13623)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Recurrent Neuroblastoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-02-06
Enrollment: 40
Sex: ALL
Minimum age (years): 3
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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.

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

Primary outcomes:
measure: Maximum tolerated dose (MTD) assessed by Common Toxicity Criteria (CTC)
timeFrame: 28 days
Secondary outcomes:
measure: Overall response assessed by Response Evaluation Criteria for Solid Tumors (RECIST)
timeFrame: Up to 3 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: New Approaches to Neuroblastoma Treatment (NANT)
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford University
state: California
city: San Francisco
country: United States
facility: University of California at San Francisco - Comprehensive Cancer Center
state: California
city: Atlanta
country: United States
facility: AFLAC Cancer Center and Blood Disorders Service
state: Georgia
city: Chicago
country: United States
facility: Childrens Memorial Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan University Hospital
state: Michigan
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: New Approaches to Neuroblastoma Treatment (NANT)
name: Jon Wigginton
role: PRINCIPAL_INVESTIGATOR
References: