OKT3 / Humanized 3F8 Bispecific Antibody-Activated T Lymphocytes, Aldesleukin, and Sargramostim in Treating Younger Patients with GD2-Positive Metastatic, Recurrent or Refractory Solid Tumors
This phase I / II trial studies the side effects and best dose of OKT3 / humanized 3F8 bispecific antibody-activated T lymphocytes with given together with aldesleukin and sargramostim and to see how well they work in treating younger patients with disialoganglioside GD2 (GD2)-positive solid tumors that have spread to other parts of the body (metastatic), have come back (recurrent), or do not respond to treatment (refractory). Biological therapies, such as OKT3 / humanized 3F8 bispecific antibody-activated T lymphocytes, use substances made from living organisms that may attack specific tumor cells and stop them from growing or kill them. Aldesleukin and sargramostim may stimulate white blood cells to kill tumor cells. Giving white blood cells that have been activated by OKT3 / humanized 3F8 bispecific antibody-activated T lymphocytes with aldesleukin and sargramostim may kill more tumor cells.
- The target tumor is limited to neuroblastoma and other GD2-positive solid tumors; diagnosis should be histologically verified at Children’s Hospital of Michigan (CHM) or Memorial Sloan Kettering Cancer Center (MSKCC)
- Assessment of GD2 status is not required for NB or for other tumors known to express GD2 in 70% or more of cases: specifically osteosarcoma (GD2 expressed in 88%), spindle cell sarcoma (93%) and desmoplastic small round cell tumor (DSRCT) (70%); all other non-NB tumors will require confirmation of GD2 expression on cell surface by immunohistochemistry on fresh frozen tissue that will be performed at MSKCC; patients with suspected GD2-positive tumors (other than osteosarcoma, spindle cell sarcoma or DSRCT) will have their tumors assessed after obtaining a separate informed consent for this purpose
- Patients must have disease refractory to standard therapy or recurrent malignancy; patient’s current disease state must be one for which no known curative therapy is available; to be eligible for phase I study patients should have primary refractory or relapsed disease as evidenced by either: * Local or/and metastatic tumor recurrence or primary refractory tumor measurable on CT or magnetic resonance imaging (MRI) scans * Refractory persistent bone marrow disease with evidence of NB involvement of bone marrow in at least one site of biopsy * NB with metaiodobenzylguanidine (MIBG)-positive skeletal lesions (at least one site) * For sarcoma patients with resected pulmonary lesions pre-surgery CT scans demonstrating disease are required
- 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 to undergo 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: * Measurable disease is defined as the presence of at least one solid lesion on MRI or CT scan that can be accurately measured with the longest diameter of at least 10 mm in at least one dimension * Patients with NB who do not have measurable soft tissue disease but have MIBG-positive evaluable skeletal disease are eligible for phase II study * Patients with NB who have evidence of tumor cells in bone marrow are eligible for phase II study
- Patients must have a Lansky or Karnofsky performance status score of >= 70; Karnofsky system will be used for patients > 16 years of age and Lansky system for patients < 16 years of age
- Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy * Myelosuppressive chemotherapy: must not have received chemotherapy within 2 weeks of enrollment and within 2 week of starting protocol therapy * Hematopoietic growth factors: at least 7 days since the last dose of growth factor therapy for both enrollment on study and for commencement of protocol therapy * Immunotherapy: patients may not have received immunotherapy within 3 weeks of enrollment and within 6 weeks of commencing protocol therapy
- Absolute neutrophil count (ANC) >= 500/mm^3 (patients should be off granulocyte colony-stimulating factor [G-CSF] for at least 7 days)
- Platelet count >= 50,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment); in NB patients with known bone marrow involvement relaxed platelet count eligibility requirement should be used: a platelet count of >= 20,000/mm that can be maintained with =< 1 platelet transfusion per week
- Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions)
- Absolute lymphocyte count >= 500/mm^3
- Serum creatinine =< 1.5 x upper limit of normal or a creatinine clearance or glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2
- Shortening fraction >= 28% by echocardiogram or ejection fraction >= 50% by echocardiogram or radionuclide study
- Total bilirubin =< 1.5 x upper limit of normal
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x upper limit of normal; for the purpose of this study, the upper limit of normal (ULN) for SGPT is 45 U/L
- 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
- 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
- Concomitant medication restrictions * Growth factor(s): growth factors that support platelet or white cell number or function must not have been administered within 7 days prior to enrollment (14 days if Neulasta) * Corticosteroids: patients requiring corticosteroids should not be on a chronic dose; patients should be off steroid for at least 14 days prior to immunotherapy (IT) and they should not receive steroids during protocol treatment * Investigational drugs: patients who are currently receiving another investigational drug are not eligible
- 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
Locations & Contacts
Contact: Julie Nucci
Contact: Maxim Yankelevich
Contact: Shakeel Modak
Contact: Daniel Warnell Lee
Trial Objectives and Outline
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-cluster of differentiation (CD)3 x human (hu3F8) bispecific antibody (GD2Bi)-armed activated T cells (aATC) (OKT3/humanized 3F8 bispecific antibody-activated T lymphocytes) infused twice a week for a total of eight infusions in combination with daily concurrent low dose aldesleukin (IL-2) (300,000 IU/m^2/day) and sargramostim (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 using MTD determined in the phase I.
I. Evaluate immune responses in the phase I/II trial by sequential monitoring of anti-NB cytotoxicity or anti-osteosarcoma (OST) of peripheral blood mononuclear cells (PBMC) and interferon (IFN)-gamma enzyme-linked immunosorbent spots (EliSpots) directed at NB or OST lines, phenotyping of the blood, type 1 helper cell (Th1)/type 2 helper cell (Th2) cytokine patterns, and antibodies to NB or OST.
II. To evaluate persistence of armed activated T cells (ATC) in the blood and to obtain tumor biopsies for staining for murine immunoglobulin G 2 alpha (IgG2a) in 6 selected patients to confirm trafficking of armed T cells to tumor.
III. To conduct exploratory study of fludeoxyglucose F 18 (18F FDG) positron emission tomography (PET)/computed tomography (CT) after armed ATC infusions in selected patients with PET/CT measurable soft tissue, lung, and skeletal lesions.
OUTLINE: This is a phase I, dose-escalation study of OKT3/humanized 3F8 bispecific antibody-activated T lymphocytes followed by a phase II study.
Patients receive aldesleukin subcutaneously (SC) daily on days -4/-2 to 35, sargramostim SC twice weekly starting on day -3 for up to 11 doses, and OKT3/humanized 3F8 bispecific antibody-activated T lymphocytes intravenously (IV) over 5-30 minutes twice weekly starting on day 1 for up to 8 doses. Patients with partial responses may remain on study and receive another course of ATC 3-6 months later if they have not received any interim treatment. Patients with complete responses may remain on the study for up to 2 years.
After completion of study treatment, patients are followed up at 1 and 2 months and then periodically for up to 1 year.
Trial Phase & Type
University of Virginia Cancer Center
Secondary IDs NCI-2014-01149, 1403012875
Clinicaltrials.gov ID NCT02173093