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J Clin Oncol. 2014 May 10;32(14):1445-52. doi: 10.1200/JCO.2013.50.4423. Epub 2014 Apr 7.

Phase I trial of a novel anti-GD2 monoclonal antibody, Hu14.18K322A, designed to decrease toxicity in children with refractory or recurrent neuroblastoma.

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  • 1Fariba Navid, Barry L. Shulkin, Robert A. Kaufman, Catherine A. Billups, Jianrong Wu, Wayne L. Furman, Lisa M. McGregor, and Victor M. Santana, St Jude Children's Research Hospital; Fariba Navid, Robert A. Kaufman, Wayne L. Furman, Lisa M. McGregor, and Victor M. Santana, College of Medicine, University of Tennessee Health Science Center; Jim A. Allay, Children's GMP, Memphis, TN; Paul M. Sondel, Jacek Gan, Paul Hutson, Songwon Seo, KyungMann Kim, Jacob Goldberg, Jacquelyn A. Hank, and Mario Otto, University of Wisconsin, Madison, WI; Raymond Barfield, Duke University Medical Center, Durham, NC; Stephen D. Gillies, Provenance Biopharmaceuticals, Carlisle, MA; and Rupert Handgretinger, University Children's Hospital, Tübingen, Germany.



The addition of immunotherapy, including a combination of anti-GD2 monoclonal antibody (mAb), ch14.18, and cytokines, improves outcome for patients with high-risk neuroblastoma. However, this therapy is limited by ch14.18-related toxicities that may be partially mediated by complement activation. We report the results of a phase I trial to determine the maximum-tolerated dose (MTD), safety profile, and pharmacokinetics of hu14.18K322A, a humanized anti-GD2 mAb with a single point mutation (K322A) that reduces complement-dependent lysis.


Eligible patients with refractory or recurrent neuroblastoma received escalating doses of hu14.18K322A ranging from 2 to 70 mg/m(2) per day for 4 consecutive days every 28 days (one course).


Thirty-eight patients (23 males; median age, 7.2 years) received a median of two courses (range, one to 15). Dose-limiting grade 3 or 4 toxicities occurred in four of 36 evaluable patients and were characterized by cough, asthenia, sensory neuropathy, anorexia, serum sickness, and hypertensive encephalopathy. The most common non-dose-limiting grade 3 or 4 toxicities during course one were pain (68%) and fever (21%). Six of 31 patients evaluable for response by iodine-123 metaiodobenzylguanidine score had objective responses (four complete responses; two partial responses). The first-course pharmacokinetics of hu14.18K322A were best described by a two-compartment linear model. Median hu14.18K322A α (initial phase) and β (terminal phase) half-lives were 1.74 and 21.1 days, respectively.


The MTD, and recommended phase II dose, of hu14.18K322A is 60 mg/m(2) per day for 4 days. Adverse effects, predominately pain, were manageable and improved with subsequent courses.

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[Available on 2015/5/10]
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