Biological Therapy in Treating Children With Refractory or Recurrent Neuroblastoma or Other Tumors

Children's Oncology Group

Status and phase: Completed; Phase 1

Conditions: Sarcoma; Neuroblastoma; Melanoma (Skin); Unspecified Childhood Solid Tumor, Protocol Specific

Treatments: Biological: hu14.18-IL2 fusion protein

Study type: Interventional

Funder types: NETWORK; NIH

Identifiers

NCT00003750

COG-ADVL0018 (Other Identifier)

CDR0000066870 (Other Identifier)

ADVL0018

Details and patient eligibility

About

RATIONALE: Biological therapies such as hu14.18-interleukin-2 fusion protein use different ways to stimulate the immune system and stop cancer cells from growing.

PURPOSE: Phase I trial to study the effectiveness of hu14.18-interleukin-2 fusion protein in treating children who have refractory or recurrent neuroblastoma or other tumors.

Full description

OBJECTIVES:

• Determine the maximum tolerated dose of hu14.18-interleukin-2 fusion protein in children with refractory or recurrent neuroblastoma or other GD2-positive tumors.
• Determine the toxicity and pharmacokinetics of the fusion protein in these patients.
• Determine the effect of the fusion protein on systemic immune modulation in these patients.
• Quantitate the antifusion protein antibodies in patients treated with fusion protein.
• Evaluate antitumor responses resulting from this fusion protein regimen in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive hu14.18-interleukin-2 (hu14.18-IL2) fusion protein IV over 4 hours once daily on days 1-3. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of hu14.18-IL2 fusion protein until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients are followed every 2 months for 1 year, every 6 months for 3 years, and then annually for 5 years.

PROJECTED ACCRUAL: A total of 18-24 patients will be accrued for this study within 1 year.

Enrollment: 28 patients

Sex: All

Ages: Under 21 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed neuroblastoma or melanoma at original diagnosis

  • Refractory to chemotherapy or recurrence after prior multiagent chemotherapy
  • Measurable or evaluable (detectable by bone scan) metastatic disease OR
  • No evidence of disease if complete response to prior surgical resection, radiotherapy, and/or chemotherapy OR

• Histologically confirmed tumor expressing GD2 antigen at original diagnosis or relapse

  • Refractory to standard treatment
  • Measurable or evaluable disease by clinical assessments or laboratory markers OR
  • No evidence of disease after prior surgical resection of metastatic, recurrent disease
  • Histologically confirmed recurrent osteogenic sarcoma after prior chemotherapy allowed
  • Soft tissue sarcoma allowed

• No primary CNS tumors

• Prior CNS metastases allowed, provided:

  • Disease previously treated
  • Disease clinically stable for 4 weeks before study
  • At least 4 weeks since prior steroids for CNS metastases

• No clinically detectable pleural effusions or ascites

PATIENT CHARACTERISTICS:

Age:

• 21 and under

Performance status:

• Karnofsky 60-100% for children over age 10
• Lansky 60-100% for children age 10 and under

Life expectancy:

• At least 12 weeks

Hematopoietic:

• Absolute neutrophil count greater than 1,000/mm^3
• Platelet count at least 75,000/mm^3 (transfusion allowed)
• Hemoglobin at least 9.0 g/dL (transfusion allowed)

Hepatic:

• Bilirubin less than 1.5 mg/dL
• ALT or AST no greater than 2.5 times normal
• Hepatitis B surface antigen negative

Renal:

• Creatinine no greater than 1.5 mg/dL OR
• Creatinine clearance or radioisotope glomerular filtration rate at least 60 mL/min

Cardiovascular:

• Shortening fraction at least 27% by echocardiogram OR
• Ejection fraction more than 50% by MUGA scan
• No congestive heart failure
• No uncontrolled cardiac rhythm disturbance

Pulmonary:

• FEV_1 and FVC more than 60% of predicted OR
• No dyspnea at rest
• No exercise intolerance
• Oxygen saturation more than 94% by pulse oximetry on room air

Neurologic:

• No seizure disorders requiring antiseizure medications
• No significant neurologic deficit or grade 2 or greater objective peripheral neuropathy

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• No significant concurrent illnesses unrelated to cancer or its treatment
• No significant psychiatric disabilities
• No uncontrolled active infections
• No uncontrolled active peptic ulcer

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• At least 1 week since prior growth factors
• At least 1 week since prior immunomodulatory therapy
• Prior monoclonal antibodies allowed if no detectable antibody to hu14.18
• Prior autologous bone marrow transplantation (BMT) or stem cell transplantation (SCT) allowed
• Prior autologous BMT or SCT with monoclonal antibody-purged specimens allowed
• No concurrent growth factors
• No concurrent interferon

Chemotherapy:

• See Disease Characteristics
• At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas, mitomycin, or melphalan)
• No concurrent palliative chemotherapy

Endocrine therapy:

• See Disease Characteristics
• At least 2 weeks since prior glucocorticoids, except for life-threatening symptoms
• No concurrent corticosteroids
• No concurrent glucocorticoids, except for life-threatening symptoms

Radiotherapy:

• See Disease Characteristics
• At least 3 weeks since prior radiotherapy
• No concurrent palliative radiotherapy

Surgery:

• See Disease Characteristics
• At least 2 weeks since prior major surgery (e.g., laparotomy or thoracotomy)
• No prior organ allografts
• No concurrent palliative surgery

Other:

• Recovered from prior therapy
• At least 1 week since prior tretinoin
• At least 3 weeks since prior immunosuppressive therapy
• No other concurrent immunosuppressive drugs

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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28 participants in 1 patient group

DG2 positive relapsed or refractory solid tumors

Experimental group

Description:

The initial hu14.18-IL2 fusion protein (FP) dose will be 2 mg/m2 given intravenously over 4 hours, daily for 3 days. Five separate dose levels are scheduled: 2 mg/m²/dose (IV over 4 hours) x 3 days, 4 mg/m²/dose (IV over 4 hours) x 3 days, 6 mg/m²/dose (IV over 4 hours) x 3 days, 8 mg/m²/dose (IV over 4 hours) x 3 days, 10 mg/m²/dose (IV over 4 hours) x 3 days.

Treatment:

Biological: hu14.18-IL2 fusion protein