Phase I Dose-Escalation Study of CAT-8015 (HA22), A CD22-Specific Targeted Immunotoxin, in Relapsed or Refractory Hairy Cell Leukemia.
Authors: Kreitman Robert J , Tallman Martin S. , Coutre Steven , Robak Tadeusz , Wilson Wyndham H , Stetler-Stevenson Maryalice , Noel Pierre , FitzGerald David J. , Buzoianu Manuela , Lechleider Robert , Kaucic Karen , Pastan Ira 
Published: October 2019

Abstract
Abstract 888
Novel therapies are needed for patients with relapsed or refractory hairy cell leukemia (HCL), particularly those who have failed purine analogs. CD22 is expressed in the majority of B-cell malignancies and universally in HCL, making it an ideal therapeutic target. CAT-8015 is a targeted immunotoxin composed of an anti-CD22 antibody fused to a modified form of Pseudomonas exotoxin A. It has a novel mechanism of action compared with other CD22 targeted antibodies, as CAT-8015 is internalized upon binding to CD22, inhibiting protein translation and prompting apoptosis. CAT-8015 has shown significant antitumor activity in B-cell tumor cell lines and malignant cells isolated from patients with HCL. CAT-8015 (HA22) is a high-affinity derivative of CAT-3888 (BL22) that displays higher CD22-binding and inhibitory activity due to mutation of 3 amino acids.
A multicenter, dose-escalation, phase I study is being conducted to estimate the maximum tolerated dose (MTD) of CAT-8015, and evaluate its safety, efficacy and immunogenicity profiles in HCL. Adult HCL patients who previously received at least 2 systemic therapies (including purine analogs) and had cytopenias or symptomatic splenomegaly requiring treatment are eligible to participate. A standard 3+3 dose-escalation design is being employed at doses of 5, 10, 20, 30, 40, and 50 ug/kg. CAT-8015 is administered as a 30-min IV infusion on days 1, 3, and 5 (QODx3) of each 28-day cycle for up to a total of 10 cycles until disease progression, intervening toxicity [e.g. dose-limiting toxicity (DLT)], completion of two cycles of treatment beyond documentation of complete response (CR), or other reason for which the patient might become ineligible. Patients receive premedication with hydroxyzine, ranitidine, and acetaminophen to prevent infusion reactions; and low-dose aspirin and IV hydration to prevent hemolytic uremic syndrome (HUS), which has been observed in association with CAT-3888. Data are electronically archived by each investigator and were pooled for analysis. The study is ongoing with 2 more patients expected to be treated at 50 ug/kg.
A total of 26 patients have received CAT-8015 to date. Three patients enrolled at each of the 5, 10, 20, and 30 ug/kg dose levels; 4 patients at the 40 ug/kg dose level; and 10 patients at 50 ug/kg dose level. The median age is 59 years (range 40-77), and the majority (84.6%) are male. Patients were heavily pretreated (median number of prior therapies: 3, range 2-7). Among the 26 patients in total, 14 received prior rituximab (53.8%); among 10 patients in cohort 50 ug/kg, 7 received prior rituximab (70.0%). Patients have received a median of 3 treatment cycles (range 1-8). No DLTs have been observed and an MTD has not been reached. Expanded enrollment at 50 ug/kg has been undertaken to better characterize the safety profile and antitumor activity. The most common drug-related toxicities have been of grade 2 or lower severity: hypoalbuminemia (57.7%), peripheral edema (42.3%), pyrexia (38.5%), elevated ALT (34.6%) and AST (30.8%), headaches (26.9%), and nausea (26.9%). Four patients (15.4%) developed grade 2 vascular leak syndrome (VLS). One treatment-related serious adverse event occurred, a reversible grade 2 HUS that was reported in the 30 ug/kg dose cohort. Anti-drug antibodies developed in 10 patients (38.5%).
CAT-8015 was highly active in HCL. Among the 26 patients treated, the objective response (OR) rate was 73.1% (19/26), with a CR rate of 34.6% (9 patients) and a partial response (PR) rate of 38.5% (10 patients). Responses were observed at all dose levels. Specific OR rates at the 5,10, 20, 30, 40, and 50 ug/kg/dose cohorts were 100%, 100%, 33%, 33%, 75% and 80%, respectively. At the time of this report, none of the patients achieving a CR has relapsed. Four of 9 (44.4%) patients with CR have a duration of response of >12 months.
CAT-8015 exhibited an acceptable safety profile when administered up to 50 ug/kg QOD × 3, and demonstrated substantial antitumor activity in patients with relapsed/refractory HCL. These data demonstrate that CAT-8015 is a promising new product candidate for patients with advanced HCL. These data support further investigation in newly diagnosed patients with HCL and suggest that CAT-8015 may have clinical activity in other B-cell malignancies

Disclosures:
Kreitman: NIH: Patents & Royalties. Off Label Use: Recombinant immunotoxin HA22 for targeting CD22+ cells. Robak:MedImmune, LLC: Research Funding. FitzGerald:NIH: Patents & Royalties. Pastan:NIH: Patents & Royalties.