Donor Natural Killer Cells and Hu3F8 in Treating Patients with High-Risk Neuroblastoma

This phase I trial studies the side effects and best dose of donor natural killer cells when given together with humanized monoclonal antibody 3F8 (hu3F8) in treating patients with neuroblastoma that has not responded to standard treatment or has returned after treatment. Natural killer cells are a type of white blood cell that can recognize and kill abnormal cells in the body, and can work together with antibodies to kill target cells. Monoclonal antibodies, such as humanized monoclonal antibody 3F8, can recognize a specific protein present on the target cancer cells. Giving donor natural killer cells together with humanized monoclonal antibody 3F8 may kill more cancer cells.

Inclusion Criteria

• Diagnosis of NB as defined by international criteria, i.e., histopathology (confirmed by the Memorial Sloan Kettering Cancer Center [MSKCC] Department of Pathology) or bone marrow metastases plus high urine catecholamine levels
• High-risk NB as defined by risk-related treatment guidelines' and the International NB Staging System, i.e., stage 4 with (any age) or without (> 18 months of age) MYCN amplification, MYCN-amplified stage 3 (unresectable; any age), or MYCN-amplified stage 4S
• Patients must have a history of tumor progression or persistent disease or failure to achieve complete response following standard therapy
• Patients must have evaluable (microscopic marrow metastasis, elevated tumor markers, positive metaiodobenzylguanidine [MIBG] or positron emission tomography [PET] scans) or measurable (computed tomography [CT], magnetic resonance imaging MRI]) disease documented after completion of prior systemic therapy
• Disease staging approximately within one month of treatment
• Prior treatment with murine and hu3F8 is allowed; patients with prior humanizing murine IgG3 anti-GD2 antibody m3F8 (m3F8), hu3F8, ch14.18 or hu14.18 treatment must have human anti-human antibody (HAHA) antibody titer =< 1300 enzyme-linked immunosorbent assay (ELISA) units/ml; human anti-mouse antibody positivity is allowed
• Eligible NK donor
• Signed informed consent indicating awareness of the investigational nature of this program
• DONOR: Donor is blood-related and HLA-haploidentical to the recipient
• DONOR: Donor has undergone serologic testing for transmissible diseases as per blood banking guidelines for organ and tissue donors; tests include but are not limited to: hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, hepatitis C antibody, Epstein-Barr virus antibody, human immunodeficiency virus (HIV), human T-cell leukemia virus (HTLV) I and II, varicella zoster (herpes zoster), herpes simplex antibody, cytomegalovirus antibodies, syphilis (rapid plasma reagin [RPR] profile) for adolescents and adults, measles for pediatric patients, West Nile virus, Chagas screen, and toxoplasma antibodies; donor must have normal negative test results for HIV, HTLV I and II, and West Nile virus; donor exposure to other viral pathogens will be discussed on a case-by-case basis by investigators
• DONOR: Donor must be able to undergo leukapheresis for total volume of 10-15 liters
• DONOR: There is no age restriction for the donor

Exclusion Criteria

• Patients with complete response (CR)/very good partial response (VGPR) disease
• Existing severe major organ dysfunction, i.e., renal, cardiac, hepatic, neurologic, pulmonary, or gastrointestinal toxicity >= grade 3 except for hearing loss, alopecia, anorexia, nausea, hyperbilirubinemia and hypomagnesemia from total parenteral nutrition (TPN), which may be grade 3
• Absolute neutrophil count (ANC) should be > 500/uL
• Platelet count > 75 K/uL
• History of allergy to mouse proteins
• Active life-threatening infection
• Inability to comply with protocol requirements
• Women who are pregnant or breast-feeding
• DONOR: Cardiac risk factors precluding ability to undergo leukapheresis
• DONOR: Concurrent malignancy or autoimmune disease
• DONOR: Donor is pregnant

PRIMARY OBJECTIVES:

I. Find the maximum tolerated dose (MTD) of allogeneic haploidentical natural killer (NK) cell infusions with hu3F8 in patients with high-risk neuroblastoma (NB).

SECONDARY OBJECTIVES:

I. Estimate the anti-NB effect of allogeneic NK infusions plus hu3F8.

II. Assess the impact of killer immunoglobulin (Ig)-like receptors (KIR)/human leukocyte antigen (HLA) immunogenetics on disease response to NK/hu3F8.

III. Assess the relationship between cluster of differentiation (CD)16 polymorphism and antibody-dependent cellular cytotoxicity (ADCC) in vitro.

IV. Estimate hu3F8 pharmacokinetics.

V. Apply real-time quantitative reverse-transcript-polymerase chain reaction (qRT-PCR) to test the hypothesis that minimal residual disease (MRD) findings in cell free deoxyribonucleic acid (DNA) (cfDNA) and cell free ribonucleic acid (RNA) (cfRNA) after the first 2 cycles of hu3F8 has significant prognostic impact on outcome.

OUTLINE: This is a dose-escalation study of allogeneic NK cells.

CHEMOTHERAPY: Patients receive cyclophosphamide intravenously (IV) over 6 hours on days -6 and -5.

Hu3F8 INFUSION: Patients receive humanized monoclonal antibody 3F8 IV over 30-90 minutes on days -1, 1, 5, 7, and 9.

NK INFUSION: Patients receive allogeneic NK cells IV on day 0.

ALDESLEUKIN: Patients receive aldesleukin subcutaneously (SC) on days 0, 2-4, 6, and 8.

Treatment may repeat for up to 2 additional cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 2, 3, 6, and 12 months.

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Shakeel Modak

Primary ID 15-272
Secondary IDs NCI-2016-00064, 5415
Clinicaltrials.gov ID NCT02650648