Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study

Abstract

BackgroundMetastatic colorectal cancer (mCRC) is commonly treated with 5-fluorouracil, folinic acid, and oxaliplatin or irinotecan. The multitargeted kinase inhibitor, regorafenib, was combined with chemotherapy as first- or second-line treatment of mCRC to assess safety and pharmacokinetics (primary objectives) and tumor response (secondary objective).Patients and methodsForty-five patients were treated every 2 weeks with 5-fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h, folinic acid 400 mg/m2, and either oxaliplatin 85 mg/m2 or irinotecan 180 mg/m2. On days 4–10, patients received regorafenib 160 mg orally once daily.ResultsThe median duration of treatment was 108 (range 2–345 days). Treatment was stopped for adverse events or death (17 patients), disease progression (11 patients), and consent withdrawal or investigator decision (11 patients). Six patients remained on regorafenib at data cutoff (two without chemotherapy). Drug-related adverse events occurred in 44 patients [grade ≥3 in 32 patients: mostly neutropenia (17 patients) and leukopenia, hand–foot skin reaction, and hypophosphatemia (four patients each)]. Thirty-three patients achieved disease control (partial response or stable disease) for a median of 126 (range 42–281 days).ConclusionRegorafenib had acceptable tolerability in combination with chemotherapy, with increased exposure of irinotecan and SN-38 but no significant effect on 5-fluorouracil or oxaliplatin pharmacokinetics.

The preclinical development of regorafenib for the treatment of colorectal cancer

“…Currently, the clinical use of regorafenib is further examined in clinical studies. In a Phase Ib study (ID: 11656) ( Table 4), the efficacy, safety and pharmacokinetics of regorafenib in combination with FOLFOX or FOLFIRI as the first-or second-line treatment of mCRC were tested, and increased effects of irinotecan but no significant effect on FU or oxaliplatin pharmacokinetics were reported in 2013 [49]. In February 2014, enrollment of CRC patients in a Phase III study (ID: 15983; 'COAST') ( Table 4) was announced.…”

Gastrointestinal Adverse Effects in Advanced Colorectal Carcinoma Patients Treated with Different Schedules of FOLFOX

“…nausea, vomiting, stomatitis or diarrhea, it is limited to the report of severity of the symptoms (Carlotto et al, 2013). Oral and gastrointestinal mucositis/stomatitis are frequently reported in myelosuppressive chemotherapy of solid cancer (Schultheis et al, 2013). Colorectal cancer (CRC) is the third most frequent and top commonly diagnosed solid cancer in the world (Halit et al, 2012;Joanne et.…”

Anti-angiogenic agents in metastatic colorectal cancer

“…More than half of the patients (66%) required dose reduction or treatment interruption due to AEs with HFS being the most common AE requiring dose reduction [61] . [62] . The CORRECT trial was a randomized multinational phase Ⅲ trial evaluating the benefit and tolerability of regorafenib in previously treated mCRC patients after failure of standard licensed therapy.…”