Pharmacokinetic Analysis Of Response In Hairy Cell Leukemia Treated By Anti-CD22 Recombinant Immunotoxin Moxetumomab Pasudotox (2013)

Abstract Background Moxetumomab pasudotox, an anti-CD22 recombinant immunotoxin, contains truncated Pseudomonas exotoxin and is currently undergoing pivotal phase III testing for relapsed and refractory hairy cell leukemia (HCL). The dose-escalation portion of the phase I trial was reported to achieve an overall response rate (ORR) of 86% including 46% complete remissions (CRs) in 28 HCL patients. A completely reversible form of grade 2 hemolytic uremic syndrome (HUS), based on laboratory changes but lacking clinical signs, was observed in 2 patients, and no dose-limiting toxicity (DLT) was observed. To determine the relationship between response and CD22 antigen ‘sink’ from high CD22 density on HCL cells, plasma levels were studied. Those analyzed included the original 28 in the dose-escalation arm, an additional 20 at the highest dose level enrolled prior to 2012, and one additional patient enrolled prior to initiation of the pivotal trial. Methods Moxetumomab pasudotox was administered to 49 patients at 5, 10, 20, and 30 µg/kg every other day for 3 doses (QODx3, n=3 each dose level), and then 4 and 33 patients received 40 and 50 µg/kg QODx3, respectively. Patients received retreatment cycles at 4 week intervals, with retreatment halted after progressive disease, high levels of neutralizing antibodies, HUS, or 2 cycles after achievement of MRD-free CR. MRD was studied using bone marrow biopsy (BMBx) immunohistochemistry (IHC), and flow cytometry of blood or bone marrow aspirate (BMA). Pharmacokinetics was determined from cytotoxicity assays to quantify active moxetumomab pasudotox in the plasma. Results There were 28 (57%) CRs and 15 (31%) PRs for an ORR of 88% out of 49 patients. While CRs were insignificantly more frequent at 50 µg/kg QODx3 vs lower doses (64% of 33 vs 44% of 16, p=0.23), the difference in MRD-free CR rate was significant (39% vs 6%, p=0.02). Of the 21 CRs at 50 µg/kg QODx3, 13 (62%) remain in CR at a median relapse-free follow-up time of 32 months, and relapse occurred in 7 (88%) of 8 with MRD vs 1 (8%) of 13 without MRD (p&lt;0.001). With respect to pharmacokinetics assessed on day 5 (3rd dose) of the 1st cycle (C1D5), dose level correlated with both peak level (r=0.58, p&lt;0.0001) and area under the curve (AUC, r=0.45, p=0.003), but these varied within each dose level. Focusing on the 50 µg/kg QODx3 dose level, CR was more likely with lower volume of distribution (Vd, p=0.014) and clearance (p=0.02). With respect to PK parameters as a result of tumor burden, circulating HCL count correlated with C1D5 clearance (r=0.86, p&lt;0.0001), and spleen diameter correlated with clearance on both C1D1 (r=0.50, p=0.01) and C1D5 (r=0.78, p&lt;0.0001). An inverse correlation was observed between spleen diameter and peak level on C1D1 (p=0.027), and trends (p=0.06) were observed between spleen diameter and peak level on C1D5, and AUC on both C1D1 and C1D5. Conclusions Moxetumomab pasudotox can achieve durable CR without MRD in relapsed and refractory HCL, with a safety profile supporting its current pivotal testing, including a dose level consistent with the activity of the 50 µg/kg QODx3 phase I dose. Our results also indicate that lower HCL tumor burden minimizes the CD22 ‘sink’ effect allowing higher plasma levels, and suggest that patients treated while tumor burden is relatively low may have improved chance of durable CR. Moreover, strategies for improving the efficacy of moxetumomab pasudotox might include combination or sequential use of other therapies to decrease HCL burden. This summary contains investigator reported data. This study was sponsored by MedImmune and supported by NCI’s Intramural Research Program and the Hairy Cell Leukemia Research Foundation. Disclosures: Kreitman: NIH: Co-inventor on the patent for moxetumomab pasudotox, Co-inventor on the patent for moxetumomab pasudotox Patents &amp; Royalties, Employment, Research funding via CRADA with MedImmune Other. Arons:NIH: Employment. Stetler-Stevenson:NIH: Employment. Wilson:NIH: Employment. FitzGerald:National Cancer Institute, NIH: Employment, Moxetumomab Pasudotox, Moxetumomab Pasudotox Patents &amp; Royalties. Pastan:NIH: Employment, Inventor on immunotoxin patents, which are all assigned to NIH, Inventor on immunotoxin patents, which are all assigned to NIH Patents &amp; Royalties.