Background Sorafenib (Sor) remains a first-line option for hepatocellular carcinoma (HCC) or refractory renal cell carcinomas (RCC). PLC/PRF/5 HCC model showed upregulation of hypoxia with enhanced efficacy when Sor is combined with hypoxia-activated prodrug evofosfamide (Evo). Methods This phase IB 3 + 3 design investigated 3 Evo dose levels (240, 340, 480 mg/m2 on days 8, 15, 22), combined with Sor 200 mg orally twice daily (po bid) on days 1-28 of a 28-day cycle. Primary objectives included determining maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Sor + Evo. Results Eighteen patients were enrolled (median age 62.5 years; 17 male /1 female; 12 HCC/6 RCC) across three dose levels (DL0: Sor 200 mg bid/Evo 240 mg/m2 [n = 6], DL1:Sor 200 mg bid/Evo 480 mg/m2 [n = 5], DL1a: Sor 200 mg bid/Evo 340 mg/m2 [n = 7]). Two dose-limiting toxicities (DLTs) were reported with Evo 480 mg/m2 (grade 3 mucositis, grade 4 hepatic failure). Grade 3 rash DLT was observed in one patient at Evo 240 mg/m2. No DLTs were observed at Evo 340 mg/m2. MTD and RP2D were established as Sor 200 mg/Evo 340 mg/m2 and Sor 200/Evo 240 mg/m2, respectively. The most common treatment-related adverse events included fatigue, hand-foot syndrome, hypertension, and nausea/vomiting. Two partial responses were observed, one each at DL0 and DL1a.; disease control rate was 55%. Conclusions RP2D was established as sorafenib 200 mg bid + Evo 240 mg/m2. While preliminary anti-tumor activity was observed, future development must account for advances in immunotherapy in HCC/RCC.
Investigational new drugs. 2021 Mar 01 [Epub ahead of print]
Nguyen H Tran, Nathan R Foster, Amit Mahipal, Thomas Byrne, Joleen Hubbard, Alvin Silva, Kabir Mody, Steven Alberts, Mitesh J Borad
Division of Oncology, Department of Medicine, Mayo Clinic, Rochester, MN, USA., Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA., Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA., Department of Radiology, Mayo Clinic, AZ, Scottsdale, USA., Division of Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA., Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, AZ, USA. .