Clinical trial NCT02173093: Activated T Cells Armed With GD2 Bispecific Antibody in Children and Young Adults With Neuroblastoma and Osteosarcoma
Official title: Treatment of Neuroblastoma and GD2-Positive Tumors With Activated T Cells Armed With OKT3 X Humanized 3F8 Bispecific Antibodies (GD2Bi): A Phase I/II Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Disseminated Neuroblastoma
Recurrent Neuroblastoma
Keywords: Neuroblastoma
Solid tumor
Immunotherapy targeting GD2
Bispecific antibodies
Activated T cells
Lead sponsor: University of Virginia
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2014-06-24
Enrollment: 40
Sex: ALL
Minimum age (years): 13
Maximum age (years): 29
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: Maximum tolerated dose (MTD) of GD2Bi-aATC
timeFrame: 35 days
Secondary outcomes:
measure: Anti-tumor activity
timeFrame: Up to 12 months
measure: Immune responses after GD2Bi-aATC infusions
timeFrame: Up to 12 months
Other outcomes:
Locations:
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Charlottesville
country: United States
facility: University of Virginia, Department of Pediatrics, Hematology/Oncology
state: Virginia
Study officials:
affiliation: Barbara Ann Karmanos Cancer Institute
name: Maxim Yankelevich
role: PRINCIPAL_INVESTIGATOR
References:
citation: Park JA, Santich BH, Xu H, Lum LG, Cheung NV. Potent ex vivo armed T cells using recombinant bispecific antibodies for adoptive immunotherapy with reduced cytokine release. J Immunother Cancer. 2021 May;9(5):e002222. doi: 10.1136/jitc-2020-002222.