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

University of Virginia

Status and phase: Unknown; Phase 2; Phase 1

Conditions: Recurrent Neuroblastoma; Disseminated Neuroblastoma

Treatments: Biological: GD2Bi-aATC; Biological: GM-CSF; Biological: IL-2; Other: laboratory evaluations of immune responses

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT02173093

P30CA022453 (U.S. NIH Grant/Contract)

19031

2013-171

NCI-2014-01149 (Registry Identifier)

Details and patient eligibility

About

Previous research has demonstrated that 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 GD2 expressing 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.

Full 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.

Enrollment: 40 estimated patients

Sex: All

Ages: 13 months to 29 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

The study is now in the phase II expansion phase.

Inclusion Criteria for phase II:

• The target tumor is limited to neuroblastoma and the diagnosis should be histologically verified.

• 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

• 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);

• 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

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-2, GM-CSF, GD2Bi-aATC)

Experimental group

Description:

Patients receive IL-2 SC daily on days -2 to 35, GM-CSF SC twice weekly x 5 weeks, and GD2Bi-aATC IV over 30 minutes twice weekly x 4 weeks for a total of 8 infusions. Laboratory evaluations of immune responses are obtained prior and after immunotherapy.

Treatment:

Other: laboratory evaluations of immune responses

Biological: GM-CSF

Biological: IL-2

Biological: GD2Bi-aATC