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Targeted therapy of mesothelin expressing mesotheliomas (MM), ovarian cancer (OC) and pancreatic cancer (PC): Results of phase I study of SS1(dsFv)PE38 (SS1P).

SOURCE: ASCO, 2004 Annual Meeting

R. Hassan, S. Bullock, R. J. Kreitman, H. L. Kindler, I. Pastan; National Cancer Institute, Bethesda, MD; University of Oklahoma Health Sciences Center, Oklahoma City, OK; University of Chicago, Chicago, IL

Background: Mesothelin, a cell surface glycoprotein is an attractive candidate for antibody-based therapies given its limited expression on normal mesothelial cells and overexpression in MM, OC and PC. To target mesothelin we developed the immunotoxin-SS1P, consisting of an anti-mesothelin Fv linked to a mutated Pseudomonas exotoxin that mediates cell killing. Based on the antitumor activity of SS1P in preclinical studies we initiated a multicenter phase I clinical trial of SS1P.

Methods: Eligible patients (pts) had previously treated MM, OC and PC, ECOG PS 0-2, and tumor mesothelin expression as determined by immunohistochemistry. SS1P was administered intravenously over 30 minutes every other day (QOD) for 6 or 3 doses.

Results: A total of 20 pts (7 peritoneal MM; 4 pleural MM; 8 OC; 1 PC) have been treated to date. On the QOD x 6 schedule 17 pts were treated at 4 dose levels (8, 12, 18 and 25 µg/kg/dose) and the maximum tolerated dose (MTD) of SS1P was 18 µg/kg/dose. Dose limiting toxicities (DLT's) included Grade 3 urticaria (1 pt) and vascular leak syndrome (VLS) (2 pts). Grade 2 toxicities included hypoalbuminemia, abdominal pain, pleuritic pain, asymptomatic pleural and pericardial effusion and VLS. Since the DLT's on the SS1P QOD x 6 schedule were seen in pts who had received more than 4 doses of SS1P, the protocol was amended to treat pts QOD x 3 doses to allow further dose escalation. Three pts have been treated on the QOD x 3 schedule at 25 µg/kg/dose with no DLT's and dose escalation is ongoing. Of the 17 evaluable pts treated, 10 had stable disease; 2 had minor response and 5 had progressive disease. One pt with OC had complete resolution of abdominal and pelvic ascites lasting 6 months; 1 pt with peritoneal MM has had complete resolution of abdominal ascites lasting >30 months and has required no further treatment.

Conclusions: SS1P is well tolerated and shows promising clinical activity including resolution of ascites and stable disease in some pts. SS1P could be potentially useful in pts with small volume disease and ascites who have failed standard chemotherapy. Dose escalation on the QOD x 3 schedule is ongoing.