P-100 Phase IB study of sorafenib + evofosfamide in patients (pts) with advanced hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC): NCCTG N1153 (Alliance)

Abstract

Introduction: Sorafenib is a standard first line option for pts with advanced HCC not amenable to resection/transplant or loco regional therapies. Pre-clinical studies using sorafenib in the PLC/PRF/5 HCC model showed upregulation of hypoxia. Enhanced efficacy in combination with sorafenib was achieved using the hypoxia-activated prodrug (HAP) evofosfamide (Evo). The data supported conduct of a phase (ph) IB/II study of sorafenib with Evo in pts with HCC and RCC (NCT01497444). Methods: The ph IB/dose escalation component recruited pts with first/second line HCC or second line and beyond RCC. A classical 3 + 3 design investigated 3 Evo dose levels: 240, 340 and 480 mg/m2 on days 8, 15 and 22, combined with sorafenib 200 mg po bid on days 1-28 of a 28-day cycle. Primary objectives were: determination of maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of sorafenib + Evo. Secondary objectives were assessment of overall safety profile and observation for preliminary evidence of anti-tumor efficacy (RECIST response). Results: 18 eligible pts were enrolled in the ph IB portion with median age 62.5 years [range 43-86]; 17 male/1 female; 12 HCC/6 RCC. 6 received Evo at 240 mg/m2, 7 at 340 mg/m2, and 5 at 480 mg/m2. Two DLTs were reported with Evo 480 mg/m2 (grade (gr) 3 mucositis and gr 4 hepatic failure). DLT of gr 3 rash was observed in 1 pt at Evo 240 mg/m2. No DLTs were observed at Evo 340 mg/m2. Sorafenib 200 mg bid + Evo 340 mg/m2 was established as the MTD. RP2D was established at Evo 240 mg/m2 + sorafenib 200 mg bid given that dose reduction was required to this dose level for long term dosing, from patients treated at the MTD. The most common treatment-related adverse events (TRAEs) were fatigue (n = 11), hypertension (n = 7), hand-foot syndrome (n = 7), mucositis (n = 5), and rash (n = 4). There were no treatment-related deaths. 6 of 16 (37.5%) treatment discontinuations were due to AEs. For pts with HCC, the RECIST response rate was 17% (2/12). Conclusion: The RP2D was established as sorafenib 200 mg bid + Evo 240 mg/m2 (1 dose level below MTD). Preliminary activity was observed in patients with advanced HCC, supporting continuation to the ph II portion at the RP2D. Support: U10CA180821, U10CA180882.