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

Abstract

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.

Conflict of interest statement

Conflict-of-interest disclosure: A.S.W. has received honoraria and travel support from MedImmune. A.S.W., R.J.K., I.P., and N.N.S. have participated in research through a cooperative research and development agreement between MedImmune and the National Institutes of Health (NIH). A.S.W., R.J.K., and I.P. are co-inventors and hold patents assigned to the NIH for the investigational product. D.B. has served as a consultant and received travel support from Amgen (funds received by her affiliation). J.A.W. has received research funding from MedImmune. M.L., J.Y., and M.C.L. are employees of MedImmune. The remaining authors declare no competing financial interests.

Figures

Figure 1.

Treatment-emergent AEs (by preferred term) reported in ≥15% of patients in the DLT-evaluable population, regardless of attribution. Each AE was counted only once per patient, regardless of the number of events observed in an individual patient. Events are rank ordered by overall frequency, and maximum event grade is displayed. *AEs were coded by preferred term by the reporting investigator according to MedDRA, which includes edema and peripheral edema.

Figure 2.

Mean concentration-time profiles for cycle 1 (dose 1). Error bars represent standard error of the mean. LLOQ, lower limit of quantification. *Manufacturing process change: 32 µg/kg bioactively equivalent to 40 µg/kg of prior product.

Figure 3.

Responses: patient examples. (A) Flow cytometric CRc in patients #14 and #37. Pretreatment (left panels) bone marrow aspirates demonstrated ALL blasts expressing abnormally bright CD20 and CD10. Posttreatment (right panels) bone marrow aspirates demonstrated only pre–B cells with a normal maturation profile based on CD20 and CD10 expression. Both patients achieved CRc (#14, CR; #37, CR incomplete blood count recovery [CRi]) after cycle 1 and were MRD negative after cycle 2. The limit of detection for this assay was 0.004%. (B) Patient #2: pretreatment (left panel) and posttreatment (right panel) bone marrow biopsies revealed decreased blast infiltration with 1 cycle of therapy (original magnification ×100; hematoxylin and eosin stain). Patient achieved PR after cycle 1 and CRi after cycle 2. (C) Patient #22: pretreatment (left panel) and posttreatment (right panel) fluorodeoxyglucose positron emission tomography scans show marked reduction in areas of uptake after 2 cycles of therapy.