We performed a sample size calculation for the study by using an alternative response rate of 60% (i

We performed a sample size calculation for the study by using an alternative response rate of 60% (i.e., response regarded as worthy of further evaluation of the new therapy), 80% power, and 5% type I error. adjusted to patient tolerance. Partial reactions (PR) or better after the first two chemoimmunotherapy programs occurred in 32 individuals [76.2%; 95% confidence interval (CI), 60.6C88.0]. This was accompanied by main tumor volume reductions (median, C76%; range, C100% to 5%). Of 35 individuals with stage 4 disease who completed induction, 31 experienced end-of-induction CSs of 2 or less. No individuals experienced progression during induction. Two-year event-free survival (EFS) was 85.7% (95% CI, 70.9C93.3). Conclusions: Adding hu14.18K322A to induction chemotherapy produced early PR or better in most individuals, reduced tumor quantities, improved CSs at the end of induction, and yielded an motivating 2-12 months EFS. These results, if validated SRT 1720 in a larger study, may switch the standard of care for children with high-risk neuroblastoma. Intro The current standard treatment for high-risk neuroblastoma includes high-dose induction chemotherapy, surgery, and consolidation with myeloablative chemotherapy, autologous hematopoietic cell transplant (AHCT), radiotherapy, and treatment of minimal residual disease (MRD) having SRT 1720 a monoclonal antibody (mAb) that focuses on the disialoganglioside GD2 SRT 1720 on neuroblasts. A chimeric anti-GD2 antibody (dinutuximab) in combination with granulocyte-macrophageCcolony-stimulating element (GM-CSF), interleukin-2 (IL-2), and isotretinoin given at the end of therapy, in the context of MRD, significantly improves 2-12 months event-free survival (EFS) (66% vs. 46%; = 0.01) (1). Despite this aggressive regimen, nearly half of all individuals still encounter relapse and succumb to disease. Dinutuximab was given at the end of therapy to avoid chemotherapy-induced immunosuppression, which is thought to adversely affect antibody-dependent cell-mediated cytotoxicity (ADCC). However, preclinical studies in neuroblastoma models and clinical studies of adult cancers shown that concurrent chemotherapy with numerous monoclonal antibodies provides additive/synergistic benefits (2C9). We postulated the addition of an anti-GD2 antibody to induction chemotherapy for neuroblastoma would further improve outcomes. We in the beginning tested the tolerability of a unique anti-GD2 antibody, hu14.18K322A, administered with chemotherapy in a small group of individuals with relapsed disease. When we observed excellent reactions (10), we immediately proceeded to evaluate this approach in children with newly diagnosed disease. Hu14.18K322A retains the binding specificity of dinutuximab, is 98% human to reduce allergic reactions, has a single point mutation to reduce complement-associated pain, and is produced in an YB2/0 rat myeloma cell collection to reduce fucosylation and enhance ADCC (11). Childrens Oncology Group (COG) investigators reported the addition of cyclophosphamide and topotecan to an intense induction regimen inside a pilot trial (12). This induction routine was utilized for children with newly diagnosed high-risk neuroblastoma in the JNKK1 recently completed ANBL0532 protocol. We used the identical induction routine as the chemotherapy backbone for any prospective nonrandomized, single-arm, two-stage, phase II medical trial in which hu14.18K322A was added to induction chemotherapy for children with newly diagnosed high-risk neuroblastoma. Primary outcomes were early reactions (after two programs of induction chemoimmunotherapy) and 2-12 months EFS. Secondary results included reduced tumor volume and semiquantitative 123I-metaiodobenzylguanidine (MIBG) rating [i.e., Curie scores (CS)] at the end of induction. Methods Patient Selection Children ( 19 years) with newly diagnosed high-risk neuroblastoma were eligible for enrollment. Individuals experienced either histologically verified neuroblastoma or clumps of tumor in bone marrow with increased urinary catecholamine metabolites. Analysis, staging, and response assessments were performed according to the International Neuroblastoma Staging System (INSS) criteria (13), and high-risk neuroblastoma was defined by the criteria used by the COG (14). Both assessments were identical to the people used by Park et al. (12), which included the historic control group for our study. This prospective pilot phase II trial () was authorized by our institutional review table in accordance with the Belmont Statement and the U.S. Common Rule. The trial opened in May 2013 and enrollment continues. Written educated consent was from all participants in accordance with institutional recommendations. All individuals were treated at St. Jude Childrens Study Hospital. Hu14.18K322A The hu14.18K322A production cell collection was provided by Merck Serono (Darmstadt, Germany) and manufactured for clinical use from the Childrens GMP, LLC (Memphis, TN). On day time 1 of each program, serum hu14.18 K322A levels were measured at 1 hour after antibody infusion by ELISA, as previously explained (10, 15). Treatment The routine and dosages of the induction chemotherapy providers cyclophosphamide, topotecan, cisplatin, etoposide, doxorubicin, and vincristine were identical to the people reported by Park et al. (12). Four daily doses of hu14.18K322A (days 2C5) were added to each course of induction chemotherapy. Each dose was planned to be given over 4 hours. This was successful in approximately half of the 256 programs of antibody/chemotherapy given. According to patient tolerance and at the discretion of the treating physician, antibody infusions were prolonged to 8 or 16 hours for some individuals SRT 1720 (Supplementary Table 1). Because hu14.18K322A may cause dose-dependent.