This phase II trial is studying how well hu14.18-interleukin-2 (IL2) fusion protein works when given together with sargramostim and isotretinoin in treating patients with relapsed or refractory neuroblastoma. Biological therapy, such as hu14.18-IL2 fusion protein, and sargramostim work in different ways to stimulate the immune system and stop tumor cells from growing. Drugs used in chemotherapy, such as isotretinoin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving hu14.18-IL2 fusion protein together with sargramostim and isotretinoin may kill more tumor cells.
PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of sargramostim (GM-CSF) and isotretinoin given in combination with hu14.18-IL-2 (hu14.18-IL2 fusion protein), as a test of feasibility for a future Phase III study. II. To evaluate the anti-tumor activity of hu14.18-IL2 given in combination with GM-CSF and isotretinoin in patients with recurrent or refractory neuroblastoma with disease measurable by standard radiographic criteria (stratum-1). III. To evaluate the anti-tumor activity of hu14.18-IL2 given in combination with GM-CSF and isotretinoin in patients with recurrent or refractory neuroblastoma evaluable only by meta iodo benzyl guanidine I 123 (MIBG) scintigraphy and/or bone marrow histology (stratum-2). SECONDARY OBJECTIVES: I. To describe the disease burden of stratum-2 patients by semi-quantitative assessment of bone marrow and MIBG scintigraphy and determine whether there is an association between lower disease burden and response to hu14.18-IL2. II. To assess molecular parameters of response (reverse-transcriptase (RT) polymerase chain reaction (PCR)) for patients meeting complete response (CR) criteria. III. To evaluate the immunologic activation induced in vivo by hu14.18-IL2. IV. To determine the induction of anti-hu14.18-IL2 antibody by treatment with hu14.18-IL2. V. To test for associations between tumor response versus immune activation and anti-hu14.18-IL2 activity, and between measurements of toxicity versus immune activation and anti-hu14.18-IL2 activity. OUTLINE: This is a multicenter study. Patients are stratified according to measurable disease (disease measurable by standard radiographic criteria \[stratum-1\] vs disease evaluable only by meta iodo benzyl guanidine I 123 (MIBG) and/or bone marrow histology \[stratum-2\]). Patients receive sargramostim subcutaneously (SC \[preferred\]) or IV over 2 hours on days 1-2 and 8-14, hu14.18-IL2 fusion protein IV over 4 hours on days 4-6, and isotretinoin orally (PO) twice daily on days 11-24. Treatment repeats every 28 days for 4-10 courses in the absence of disease progression or unacceptable toxicity. Patients in stratum-1 who achieve stable disease (SD) after course 4 are removed from protocol therapy. Patients in stratum-2 who achieve SD after course 4 receive 2 additional courses of study treatment. Patients may undergo blood and bone marrow sample collection periodically for correlative studies. After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for 2 years, and then yearly for 2 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
52
Given IV
Given PO
Given SC
Correlative studies
University of Alabama at Birmingham
Birmingham, Alabama, United States
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Children's Oncology Group
Arcadia, California, United States
Loma Linda University Medical Center
Loma Linda, California, United States
Children's Hospital Los Angeles
Los Angeles, California, United States
Number of Patients With Unacceptable Dose Limiting Toxicities (DLTs)
Test for tolerability and monitor for the occurrence of too many unacceptable DLTs using a two-stage stopping rule: (Stage 1) Accrue 10 patients. If more than 1 experience at least one unacceptable DLT during the first treatment cycle, the regimen will be considered to have unacceptable toxicity, and accrual will be temporarily closed, to review all relevant data and consider modifying the regimen to improve safety. If 1 or no patients have an unacceptable DLT in the first treatment cycle, then continue. (Stage 2) Accrue 20 more patients. If 7 or more experience at least one unacceptable DLT in the first treatment cycle, temporarily close the study for possible dosing-safety modifications. If 6 or fewer have an unacceptable DLT in the first treatment cycle, it is reasonable to assume that the combination therapy is safe.
Time frame: Up to 10 courses
Overall Response Evaluated in This Study Using the New International Criteria Proposed by the Revised Response Evaluation Criteria in Solid Tumors (RECIST)
Number of patients where best overall response is a complete response (CR)-\[disappearance of all target lesions and disappearance of any other measureable disease\], a very Good Partial Response (VGPR)- \[\>90% decrease of the disease measurement for CT/MRI lesions, taking as reference the disease measurement done to confirm measurable disease at study entry. Non-target CT/MRI lesions stable to smaller in size\], or partial Response (PR)- \[\>= 30% decrease in the disease measurement, taking as reference the disease measurement done to confirm measurable disease at study entry. Non-target CT/MRI lesions stable to smaller in size\], and maintains the response. It is possible that a subject's response to therapy may not occur until after several months of treatment. In order to prevent bias, the maximum duration of time/treatment over which a subject's response is to be assessed for determination of the best overall response is after the completion of up to 10 courses.
Time frame: Every two cycles (each cycle lasts 28 days)
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Children's Hospital Central California
Madera, California, United States
Childrens Hospital of Orange County
Orange, California, United States
Rady Children's Hospital - San Diego
San Diego, California, United States
University of California San Francisco Medical Center-Parnassus
San Francisco, California, United States
Children's Hospital Colorado
Aurora, Colorado, United States
...and 66 more locations