Phase I trial of recombinant immunotoxin CAT-8015 (HA22) in multiply relapsed hairy cell leukemia.

Abstract

6523 Background: CAT-8015 (HA22) contains the Fv domains of the anti-CD22 Mab RFB4 and truncated pseudomonas exotoxin, inducing cell death after binding, internalization, and ADP-ribosylation of elongation factor 2. CAT-8015 is a high-affinity mutant of BL22 (CAT-3888), with increased cytotoxicity toward chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL) cells ex vivo. Methods: To determine the clinical activity of CAT-8015, separate phase I trials were initiated in CLL, HCL, and non-Hodgkin lymphoma, and the HCL trial completed accrual. Eligible patients had several prior therapies including purine analogs and needed treatment for cytopenias or symptoms. CAT-8015 was administered over 30 min iv days 1, 3 and 5 (QODx3) at 28-day intervals for up to 10 cycles. Results: 28 HCL patients received CAT-8015: 3 each at 5, 10, 20, and 30 ug/kg QODx3, 4 at 40 and 12 at 50 ug/kg QODx3. Patients had 2-7 (median 3) prior therapies. Patients received 1-9 (median 4) cycles of CAT-8015 each. Dose-limiting toxicity (DLT) was not observed. Two patients, with cycle 3 of 30 and cycle 5 of 50 ug/Kg QOD x3, had a grade 2 reversible hemolytic uremic syndrome (HUS) with peak creatinine of 1.53-1.66 mg/dL and platelet nadir of 111,000-120,000/mm3. Drug-related toxicities in 25-60% of the 28 patients included (in decreasing frequency) grade 1-2 hypoalbuminemia, edema, fever, ALT and AST elevations, headaches, and nausea. Of 25 evaluable patients, 44% made antibodies neutralizing > 75% of the cytotoxicity of 1,000 ng/mL of CAT-8015. Responses were achieved at all dose levels. The overall response rate was 79% including 12 (43%) of 28 HCL patients achieving complete remission (CR). Of the 12 CRs, 11 (92%) are ongoing 7-29 (median 21) months after enrollment. Conclusions: CAT-8015 is active in relapsed/refractory HCL and is without DLT after completion of expansion at the highest dose level (50 ug/Kg x3) to 12 patients. These results justify further treatment of patients at this dose level to further explore efficacy and safety. Dose-escalation will continue in a separate trial to determine if the increased cytotoxic activity of CAT-8015 compared to CAT-3888 will be associated with significant efficacy in CLL and non-Hodgkin lymphoma. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MedImmune