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

ABSTRACT: 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 ? (initial phase) and ? (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.

SUBMITTER: Navid F

PROVIDER: S-EPMC4017710 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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

Navid Fariba F Sondel Paul M PM Barfield Raymond R Shulkin Barry L BL Kaufman Robert A RA Allay Jim A JA Gan Jacek J Hutson Paul P Seo Songwon S Kim Kyungmann K Goldberg Jacob J Hank Jacquelyn A JA Billups Catherine A CA Wu Jianrong J Furman Wayne L WL McGregor Lisa M LM Otto Mario M Gillies Stephen D SD Handgretinger Rupert R Santana Victor M VM

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20140407 14

<h4>Purpose</h4>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 ...[more]

PMID: 24711551

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Project description:Purpose: Anti-GD2 mAbs, acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines, and haploidentical natural killer (NK) cells.Experimental Design: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40 mg/m2/dose, days 2-5), GM-CSF, and IL2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4), and ifosfamide/carboplatin/etoposide (courses 5,6). Parentally derived NK cells were administered with courses 2, 4, and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL2 receptor alpha (sIL2Rα) levels, and human antihuman antibodies (HAHA) were obtained.Results: Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK-cell infusions. The response rate was 61.5% (4 complete responses, 1 very good partial response, 3 partial responses) and five had stable disease. The median time to progression was 274 days (range, 239-568 days); 10 of 13 patients (77%) survived 1 year. Hu14.18K322A pharmacokinetics was not affected by chemotherapy or HAHA. All patients had increased sIL2Rα levels, indicating immune activation.Conclusions: Chemotherapy plus hu14.18K322A, cytokines, and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly diagnosed neuroblastoma. Clin Cancer Res; 23(21); 6441-9. ©2017 AACR.

Project description:PurposeIn patients with neuroblastoma (NB), treatment with anti-GD2 monoclonal antibody (mAb) directs natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against tumor cells. However, tumor cytotoxicity is attenuated by ligation of inhibitory killer immunoglobulin-like receptors (KIRs) by HLA class I molecules. KIR3DL1 polymorphism influences its ability to engage HLA-Bw4 ligands. We tested the hypothesis that poorly interacting combinations of KIR3DL1 and HLA ligands are more permissive of mAb-mediated antitumor effect.MethodsKIR3DL1 and HLA-B subtyping were performed with a multiplex intermediate-resolution polymerase chain reaction assay for a cohort of 245 patients who were treated with antibody 3F8 for high-risk NB. Patient outcomes were analyzed according to expected degree of interaction between KIR3DL1 and HLA-B subtypes and grouped as strong, weak, or noninteractors. A comparison of NK response to 3F8 mAb opsonized NB cells between strong- and noninteracting donors was performed by flow cytometry.ResultsKIR3DL1 and HLA-B subtype combinations associated with noninteraction as a result of lack of receptor expression [KIR3DL1(-)], failure of interaction with inhibitory ligands [KIR3DS1(+)], or absence of KIR ligands resulted in significantly improved overall and progression-free survival. Patients with KIR3DL1 and HLA-B subtype combinations that were predictive of weak interaction had superior outcomes compared with those that were predictive of strong interaction; however, both groups were inferior to those with noninteracting subtype combinations. In vitro analysis of 3F8-mediated ADCC showed that KIR3DL1(-) and 3DS1(+) NK cells were insensitive to inhibition by HLA-Bw4-expressing NB targets.ConclusionWe conclude that KIR3LD1 and HLA-B allele combinations can have a prognostic impact on patient survival after treatment with anti-GD2 mAb that relies on NK-ADCC. The survival advantage seen in noninteracting combinations supports the therapeutic disinhibition of individuals with strongly interacting KIR and ligand pairs.

Project description:Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma.Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis.A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses).Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)

Project description:Importance:Chimeric and murine anti-GD2 antibodies are active against neuroblastoma, but the development of neutralizing antibodies can compromise efficacy. To decrease immunogenicity, hu3F8, a humanized anti-GD2 antibody, was constructed. Objective:To find the maximum-tolerated dose of hu3F8 with granulocyte-macrophage colony-stimulating factor. Design, Setting, and Participants:This phase 1 clinical trial used a 3?+?3 dose-escalation design in a single referral center (Memorial Sloan Kettering Cancer Center, New York, New York). Participants were enrolled from December 24, 2012, through May 3, 2016, with follow-up and analyses through February 28, 2018. Eligibility criteria included older than 1 year and resistant or recurrent neuroblastoma regardless of the number or kinds of prior treatments. All 57 participants met the eligibility criteria, received treatment according to the protocol, and were included in all analyses. Interventions:Treatment cycles were monthly, if human antihuman antibody remained negative. Each cycle comprised hu3F8 infused intravenously for 30 minutes on Monday, Wednesday, and Friday as well as granulocyte-macrophage colony-stimulating factor administered subcutaneously daily from 5 days before infusion through the last day of infusion. After cycle 2, hu3F8 was increased to the highest dose level that had been confirmed as safe. Main Outcomes and Measures:Toxicity, pharmacokinetics, immunogenicity, and disease response. Results:Of the 57 participants, 34 (60%) were male and 23 (40%) were female (male-to-female ratio of 1.5), with a median (range) age of 6.8 (2.4-31.3) years at enrollment and a median (range) time of 3.1 (0.6-9.0) years since initial chemotherapy. Participants received a median (range) of 4 (1-15) cycles. Treatment was outpatient with reversible neuropathic pain and without unexpected toxic effects. No maximum-tolerated dose was identified. Dose escalation was associated with increased serum levels and proceeded through dosage of 9.6 mg/kg/cycle (approximately 288 mg/m2), which is more than 2.5?times?higher than the standard dosage of 75 mg/m2/cycle or 100 mg/m2/cycle of dinutuximab and m3F8. Human antihuman antibody positivity developed in 5 of 57 patients (9%) after cycle 1, including in 1 of 10 patients (10%) not previously treated with anti-GD2 antibody and in 4 of 47 patients (9%) previously exposed to 1 or 2 anti-GD2 antibodies. Antineuroblastoma activity included major responses associated with higher dosing and prolonged progression-free survival despite a history of relapses. Conclusions and Relevance:This phase 1 clinical trial found hu3F8 to be associated with modest toxic effects, low immunogenicity, and substantial antineuroblastoma activity; phase 2 trials are in progress. Trial Registration:ClinicalTrials.gov identifier: NCT01757626.

Dataset Information

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

Publications

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

Similar Datasets

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