Patient case: 4-year-old female with neuroblastoma; genetic feature: ALK

Clinical trial: Activated T Cells Armed With GD2 Bispecific Antibody in Children and Young Adults With Neuroblastoma and Osteosarcoma

Summary: The investigators have found in the previous research that the investigators can coat (arm) T cells with a special molecule called GD2 bispecific antibody that will help T cells recognize neuroblastoma and osteosarcoma cells and kill them. This bispecific antibody recognizes GD2, a protein found on almost all neuroblastoma and osteosarcoma cells. The investigators put the GD2 bispecific antibody on T cells and give large numbers of these T cells back to patients. The investigators think that these T cells may have a better chance of killing neuroblastoma tumor cells when they are armed with GD2 bispecific antibody. This trial studies the side effects and best dose of activated T cells armed with GD2 bispecific antibody and how well they work in treating patients with neuroblastoma, osteosarcoma, and other GD2-positive solid tumors.

Detailed description: PRIMARY OBJECTIVES:
  I. To perform a phase I dose-escalation study in patients with recurrent or refractory neuroblastoma (NB) and other GD2-positive tumors to evaluate the safety and tolerability and to determine the maximum tolerated dose (MTD) for anti-CD3 x hu3F8 bispecific antibody (GD2Bi)-armed activated T cells (aATC) infused twice a week for a total of eight infusions in combination with daily IL-2 (300,000 IU/m^2/day) and GM-CSF (250 ug/m^2 twice per week) in a standard 3 + 3 dose escalation schema with 40, 80, and 160 x 10^6 cells/kg/infusion dose levels.
  II. To conduct a phase II clinical trial to explore efficacy and confirm the toxicity profile of GD2Bi-aATC combined with IL-2 and GM-CSF in a phase II expansion cohort of 22 patients with neuroblastoma (NB) using MTD determined in the phase I.
  SECONDARY OBJECTIVES:
  I. Evaluate immune responses in the phase I/II trial by sequential monitoring of anti-NB cytotoxicity of peripheral blood lymphocytes and IFN-gamma EliSpots directed at NB lines.
  II. To evaluate persistence of aATC in the blood and tumor biopsies by staining for murine IgG2a to confirm trafficking of armed T cells to tumor.
  III. To conduct exploratory study of (18F FDG) positron emission tomography (PET)/computed tomography (CT) after armed ATC infusions in selected patients with PET/CT measurable soft tissue and skeletal lesions.
  OUTLINE: This is a phase I, dose-escalation study of OKT3/humanized 3F8 bispecific antibody-aATC followed by a phase II study.
  Patients receive IL-2 subcutaneously (SC) daily on days -2 to 35, sargramostim SC twice weekly for 4 weeks, and OKT3/humanized 3F8 bispecific antibody-aATC intravenously (IV) over 30 minutes twice weekly for 4 weeks.
  After completion of study treatment, patients are followed up at 1, 3, 6, and 12 months.

Eligibility: Inclusion Criteria:
  -  The target tumor is limited to neuroblastoma, osteosarcoma, and GD2-positive solid tumors; patients must have histologic verification of neuroblastoma, osteosarcoma or other GD2-positive solid malignancy including desmoplastic small round cell tumor (DSRCT) at original diagnosis or time of recurrence
  -  Tumor GD2 status does not need to be determined for eligibility of the patients with neuroblastoma, osteosarcoma or DSRCT;
  -  Patients must have refractory or recurrent malignancy; patient's current disease state must be one for which no known curative therapy is available;
  -  Patients should not receive any other experimental or phase 1 therapy within 3 weeks prior to study enrollment and monoclonal antibody therapy within 6 weeks
  -  To be eligible for phase I study patients should have primary refractory or relapsed disease as evidenced by:
  -  Local tumor recurrence measurable on CT or magnetic resonance imaging (MRI) scans with or without metastatic lesions
  -  Refractory bone marrow involvement in patients with NB
  -  NB with MIBG-positive skeletal lesions
  -  lung lesions consistent with metastatic osteosarcoma (OST)
  -  The presence of radiographically measurable disease immediately prior to start of Phase I immunotherapy is not an eligibility requirement in the following situations:
  -  In patients with NB who have documented bone marrow (BM) involvement;
  -  In patients with NB who have MIBG-positive bony lesion(s);
  -  In patients with OST who had resection of the pulmonary lesion(s)
  -  An additional eligibility requirement for phase II study includes the presence of radiographically measurable disease with the exception of MIBG-positive NB or NB with bone marrow involvement:
  -  Patients must have a Lansky or Karnofsky performance status score of >= 70
  -  Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy
  -  Myelosuppressive chemotherapy: must not have received within 3 weeks of starting immunotherapy (IT)
  -  Hematopoietic growth factors: at least 7 days since the last dose of growth factor therapy
  -  Immunotherapy: at least 6 weeks must have elapsed since prior therapy that includes a monoclonal antibody
  -  Normal organ function
  -  All patients or their parents or legal guardians must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
  -  All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
  Exclusion Criteria:
  -  Patients who are pregnant or breast-feeding are not eligible for this study; negative pregnancy tests must be obtained in girls who are postmenarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of study therapy and for 3 months after the last dose of GD2Bi-aATC; breastfeeding women should be excluded
  -  Patients who have an uncontrolled infection are not eligible
  -  Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Relevance to patient case: not relevant