A Phase I Dose–Escalation Study of Regorafenib (BAY 73–4506), an Inhibitor of Oncogenic, Angiogenic, and Stromal Kinases, in Patients with Advanced Solid Tumors

Abstract

Purpose: Regorafenib is a novel oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-b, FGFR), and oncogenic kinases (KIT, RET, and RAF). This first-in-man, phase I dose-escalation study assessed the safety, pharmacokinetic, pharmacodynamic, and efficacy profiles of regorafenib in patients with advanced solid tumors.Patients and Methods: Patients aged 18 years or older with advanced solid tumors refractory to standard treatment were recruited. Regorafenib was administered orally for 21 days on/seven days off in repeating cycles, until discontinuation due to toxicity or tumor progression. Adverse events (AE) were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Pharmacokinetic profiles were measured after a single dose and on day 21. Pharmacodynamic and efficacy evaluations included tumor perfusion assessment using dynamic contrast-enhanced MRI, plasma cytokines, and tumor response using RECIST (v1.0).Results: Fifty-three patients were enrolled into eight cohorts at dose levels from 10 to 220 mg daily. The recommended dose for future studies was determined to be 160 mg daily, with a treatment schedule of 21 days on/seven days off in repeating 28-day cycles. The most common drug-related grade 3 or 4 AEs were dermatologic AEs (hand-foot skin reaction, rash), hypertension, and diarrhea. Pharmacokinetic analysis revealed a similar exposure at steady state for the parent compound and two pharmacologically active metabolites. Tumor perfusion and plasma cytokine analysis showed biologic activity of regorafenib. Three of 47 evaluable patients achieved a partial response (renal cell carcinoma, colorectal carcinoma, and osteosarcoma).Conclusion: Regorafenib showed an acceptable safety profile and preliminary evidence of antitumor activity in patients with solid tumors. Clin Cancer Res; 18(9); 2658-67. Ó2012 AACR.

Optimizing Treatment Outcomes With Regorafenib: Personalized Dosing and Other Strategies to Support Patient Care

“…To identify the most frequently reported adverse events associated with regorafenib treatment, we reviewed all of the presented and published safety and tolerability data on regorafenib reported in the clinical trials [2][3][4][5][6][7][8][9].…”

“…The study designs and patient characteristics for the regorafenib clinical trials are summarized in Table 1 [2][3][4][5][6][7][8][9]. Analysis of the most frequent drug-related adverse events reveals a consistent safety profile across all trials, regardless of patient population, ethnicity, previous treatment status, and tumor site or burden of disease ( Table 2).…”

“…More than half of the patients in each trial (range 49%-61%) experienced grade 3 or greater toxicities (based on National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 3.0 or 4.0) ( Table 2) [2][3][4][5][6][7][8][9]. The most frequently reported grade 3 or higher events were HFSR (13%-33% of patients), hypertension (0%-36%), fatigue (0%-17%), diarrhea (3%-10%), and laboratory abnormalities, such as elevated aspartate or alanine aminotransferase (13% each, but reported in the Japanese trial only [5]), hypophosphatemia (4%-27%), or hyperbilirubinemia (2%-6%).…”

Systemic treatment of hepatocellular carcinoma: why so many failures in the development of new drugs?

“…c-kit, RET and BRAF) and the tumor microenvironment (e.g. PDGFR and FGFR) [35]. Regorafenib, at the daily dose of 160 mg, was tested in a single-arm phase II study in patients with advanced HCC after failure of prior sorafenib therapy [36].…”

Genetic markers of bevacizumab-induced hypertension

“…Treatment-related hypertension has been linked with several anti-angiogenic therapies, including bevacizumab [13][14][15] Hypertension is one of the most common side effects of bevacizumab therapy. According to a metaanalysis of 12,656 patients with cancer participating in phase II/III trials of bevacizumab, the incidence of allgrade bevacizumab-induced hypertension was 23.6 % [16]; grade 3/4 hypertension occurred in 7.9 % of patients.…”