A phase I study of SAR566658, an anti CA6-antibody drug conjugate (ADC), in patients (Pts) with CA6-positive advanced solid tumors (STs)(NCT01156870).

Abstract

2511 Background: SAR566658 (SAR) is a maytansinoid-loaded ADC targeting CA6, a sialoglycotope of MUC-1 over-expressed in solid tumors and rarely in normal tissues. Methods: Phase I dose escalation and expansion study to evaluate SAR intravenous administration as single agent every 3 weeks (q3w) and 2 weeks (q2w). Primary objective included dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended dose (RD). Secondary objectives were PK, PD and preliminary efficacy assessment (RECIST1.1). Results: One hundred and fourteen patients (Pts) with heavily pretreated solid tumors expressing CA6 in ≥ 30% tumor cells with an intensity 2/3+ by immunohistochemistry were enrolled. SAR was administered across 11 dose levels (DLs) (10 to 240 mg/m² q3w and 120 mg/m² q2w). DLTs [1 grade (Gr) 3 diarrhea and 2 Gr3 keratitis] were observed at 240 mg/m². Initial RD was 190 mg/m² however a high incidence of keratopathy was seen mainly at cycle 2. PK/safety simulation, preserving drug exposure and limiting keratopathy incidence, proposed two alternative schedules: 90 mg/m² D1,D8 q3w and 120 mg/m² q2w. Most common adverse event (AE) was reversible Gr2/3 keratopathy in 41/114 (36%) (Gr3 in 9 Pts). Among these 41 Pts, 15/23 (65%) received 190 mg/m², 12/33 (36%) 150 mg/m², 6/8 (75%) 240 mg/m², 6/17 (35%) 90 mg/m² D1,D8 and 2/16 (13%) 120 mg/m² q2w. Prophylaxis with vasoconstrictor and steroids eye drops implemented in 8 patients in alternative schedules prevented keratopathy. Other AEs were fatigue (32.6%), peripheral neuropathy (31.6%), GI disorders [(nausea (29%), abdominal pain (26%), diarrhea (25%)] and neutropenia (2.6%). Low grade liver and renal abnormalities were noted.Tumor regression was noted in about 60% Pts at 190 and 90 mg/m² D1,D8 and 35% Pts at 150 and 120 mg/m² q2w. One complete response (ovary), 8 partial responses (3 breast, 2 ovary, 1 NSCLC, 1 cervix and 1 bladder) and 39% stable disease were noted. Highest overall response rate (ORR) was observed in 2/15 at 90 mg/m² D1,D8 and 3/23 at 190 mg/m². Conclusions: SAR 90 mg/m² D1,D8 q3w provided a favorable safety profile and encouraging antitumor activity and is selected as the RD for further clinical development. Clinical trial information: NCT01156870.