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


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Fariba 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.
Fariba
F
Navid
Paul M
PM
Sondel
Raymond
R
Barfield
Barry L
BL
Shulkin
Robert A
RA
Kaufman
Jim A
JA
Allay
Jacek
J
Gan
Paul
P
Hutson
Songwon
S
Seo
Kyungmann
K
Kim
Jacob
J
Goldberg
Jacquelyn A
JA
Hank
Catherine A
CA
Billups
Jianrong
J
Wu
Wayne L
WL
Furman
Lisa M
LM
McGregor
Mario
M
Otto
Stephen D
SD
Gillies
Rupert
R
Handgretinger
Victor M
VM
Santana
D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009447:Neuroblastoma / Q000188:drug therapy*; D012008:Recurrence
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C112746:dinutuximab