Phase 1 study of the anti-CD22 immunotoxin moxetumomab pasudotox for childhood acute lymphoblastic leukemia

• Published in: Blood 2017-10, Vol.130 (14), p.1620-1627
• Main Authors: Wayne, Alan S., Shah, Nirali N., Bhojwani, Deepa, Silverman, Lewis B., Whitlock, James A., Stetler-Stevenson, Maryalice, Sun, Weili, Liang, Meina, Yang, Jie, Kreitman, Robert J., Lanasa, Mark C., Pastan, Ira
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Bacterial Toxins - adverse effects; Bacterial Toxins - immunology; Bacterial Toxins - pharmacokinetics; Bacterial Toxins - therapeutic use; Capillary Leak Syndrome - prevention & control; Child; Child, Preschool; Clinical Trials and Observations; Dexamethasone - therapeutic use; Exotoxins - adverse effects; Exotoxins - immunology; Exotoxins - pharmacokinetics; Exotoxins - therapeutic use; Female; Glucocorticoids - therapeutic use; Hemolytic-Uremic Syndrome - chemically induced; Humans; Hypoalbuminemia - chemically induced; Immunotoxins - adverse effects; Immunotoxins - immunology; Immunotoxins - pharmacokinetics; Immunotoxins - therapeutic use; Infant; Male; Maximum Tolerated Dose; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - immunology; Neoplasm Recurrence, Local - pathology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Sialic Acid Binding Ig-like Lectin 2 - immunology; Thrombotic Microangiopathies - chemically induced; Weight Gain - drug effects; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2017-02-749101

Novel therapies are needed to overcome chemotherapy resistance for children with relapsed/refractory acute lymphoblastic leukemia (ALL). Moxetumomab pasudotox is a recombinant anti-CD22 immunotoxin. A multicenter phase 1 study was conducted to determine the maximum-tolerated cumulative dose (MTCD) and evaluate safety, activity, pharmacokinetics, and immunogenicity of moxetumomab pasudotox in children, adolescents, and young adults with ALL (N = 55). Moxetumomab pasudotox was administered as a 30-minute IV infusion at doses of 5 to 50 µg/kg every other day for 6 (cohorts A and B) or 10 (cohort C) doses in 21-day cycles. Cohorts B and C received dexamethasone prophylaxis against capillary leak syndrome (CLS). The most common treatment-related adverse events were reversible weight gain, hepatic transaminase elevation, and hypoalbuminemia. Dose-limiting CLS occurred in 2 of 4 patients receiving 30 µg/kg of moxetumomab pasudotox every other day for 6 doses. Incorporation of dexamethasone prevented further dose-limiting CLS. Six of 14 patients receiving 50 µg/kg of moxetumomab pasudotox for 10 doses developed hemolytic uremic syndrome (HUS), thrombotic microangiopathy (TMA), or HUS-like events, exceeding the MTCD. Treatment expansion at 40 µg/kg for 10 doses (n = 11) exceeded the MTCD because of 2 HUS/TMA/HUS-like events. Dose level 6B (ie, 50 µg/kg × 6 doses) was the MTCD, selected as the recommended phase 2 dose. Among 47 evaluable patients, an objective response rate of 32% was observed, including 11 (23%) composite complete responses, 5 of which were minimal residual disease negative by flow cytometry. Moxetumomab pasudotox showed a manageable safety profile and evidence of activity in relapsed or refractory childhood ALL. This trial was registered at www.clinicaltrials.gov as #NCT00659425. •A phase 1 trial of the anti-CD22 immunotoxin moxetumomab pasudotox was conducted in children with ALL.•A 32% objective response rate was observed, including 11 composite complete responses (23%), 5 of which were minimal residual disease negative.