A phase I study of etirinotecan pegol in combination with 5-fluorouracil and leucovorin in patients with advanced cancer

550 Background: Etirinotecan pegol (EP; NKTR-102) is the first long-acting topoisomerase I inhibitor designed to concentrate and provide continuous tumor exposure. This study was designed to identify the recommended dose of EP in combination with 5-fluorouracil (5FU; 400/2400 mg/m2 by bolus, then 46-hour infusion) and leucovorin (LV; 400 mg/m2). Methods: Patients (pts) were enrolled in a standard 3+3 design. Initially, pts received all 3 agents every 2 weeks (schedule A). Due to higher SN38 exposure with the triplet compared to single-agent EP in the 25 mg/m2dose cohort, the schedule was modified to deliver all 3 agents for the first 4 doses at 2-week intervals; 5FU/LV continued at 2-week and EP at 4-week intervals thereafter (Schedule B). The protocol enrolled adults with an advanced malignancy; pts had ECOG 0 or 1 with adequate organ function. Results: 26 pts were enrolled in 5 cohorts: median age 63 (44-80); male:female 12:14; median prior regimens 3.5 (1-9). Schedule A: 25 mg/m2 (n=8, 6 evaluable for toxicity) and 50 mg/m2 (n=3). Schedule B: 50 mg/m2 (n=3), 75 mg/m2 (n=6) and 100 mg/m2 (n=6). DLTs: Grade (G) 3 abdominal pain following the infusion (1 pt; 25 mg/m2); G3 nausea/dehydration and G4 neutropenia (NTP) >3 days (2 pts; 100 mg/m2). 5 pts at a dose of 75 mg/m2 had a dose delay due to NTP or diarrhea in the first 2 months. Common G3+ toxicity at 75 mg/m2: NTP (50%), diarrhea and lymphopenia (both 33%). At >50 mg/m2EP, SN38 exposure was comparable to that previously observed after single-agent EP. 5-FU exposure: comparable to prior reports. Two pts (ovarian, gall bladder) had a PR; 11 additional pts had stable disease >6months (3 NSCL 6M-9M; 3 CRC 6-8M; esophageal 7M, desmoplastic round cell sarcoma and pheochromocytoma 6M) or tumor marker response (pancreatic pt who had received prior irinotecan 93%, 9M; breast 82%, 5M). ORR or SD>6M was observed in 8 of the 12 patients in the two highest dose levels. Conclusions: 75 mg/m2 EP with 5FU/LV (Schedule B) shows promising clinical activity with an acceptable safety profile. The combination warrants further clinical testing. Single-agent EP is currently being studied in a phase 3 trial in breast cancer compared to physician’s choice (n=852).