Phase II dose titration study of regorafenib in progressive unresectable metastatic colorectal cancer

Abstract

Regorafenib has shown significant survival benefit as a salvage therapy for colorectal cancer; however, its starting dose has been controversial in recent studies. Therefore, we conducted a prospective study on the efficacy and safety of the dose reduction of regorafenib to 120 mg. Patients received 120 mg regorafenib once per day for 3 weeks, followed by a 1-week off-treatment period. The primary endpoint was the investigator-assessed disease control rate (DCR). Sixty patients were registered, and the DCR was 38.3% with a median progression-free survival of 2.5 months (95% confidence interval [CI] 1.9–3.7) and median overall survival of 10.0 months (95% CI 6.9–15.2). Common grade 3–4 adverse events were hand-foot skin reaction and hypertension (20.0% each). The results of administration of 120 mg regorafenib as the starting dose are consistent with reports from prior phase III trials, which used starting doses of 160 mg. This lower initiating dose of regorafenib may be beneficial to certain patient populations. This clinical trial was registered in the UMIN Clinical Trials Registry (UMIN-CTR number UMIN000018968, registration date: 10/09/2015).

Phase I trial of apatinib and paclitaxel+oxaliplatin+5‐FU/levoleucovorin for treatment‐naïve advanced gastric cancer

“…Real‐world studies of anti‐angiogenic TKIs have explored doses lower than the standard dose for drug approval, suggesting decreased toxicity without compromising efficacy. 23 , 24 , 25 In our study, improvements in PFS, OS, and ORR were observed in the high‐dose apatinib cohort compared with the low‐dose cohort, consistent with outcomes from a phase I study. 26 Furthermore, a retrospective cohort study revealed that the presence of grade 3–4 apatinib‐specific TEAEs was accompanied by higher efficacy.…”

“…There is ongoing debate within the oncology community regarding the optimal dose of anti‐angiogenic TKIs such as apatinib and regorafenib, due to challenges in managing toxicity at the labeled dose. Real‐world studies of anti‐angiogenic TKIs have explored doses lower than the standard dose for drug approval, suggesting decreased toxicity without compromising efficacy 23–25 . In our study, improvements in PFS, OS, and ORR were observed in the high‐dose apatinib cohort compared with the low‐dose cohort, consistent with outcomes from a phase I study 26 .…”

“…efficacy. [23][24][25] In our study, improvements in PFS, OS, and ORR were observed in the high-dose apatinib cohort compared with the low-dose cohort, consistent with outcomes from a phase I study. 26 Furthermore, a retrospective cohort study revealed that the presence of grade 3-4 apatinib-specific TEAEs was accompanied by higher efficacy.…”

Combination of dual JAK/HDAC inhibitor with regorafenib synergistically reduces tumor growth, metastasis, and regorafenib-induced toxicity in colorectal cancer

“…Further, to optimize regorafenib treatment and to increase tolerability, a randomized phase II, ReDOS trial was conducted in previously treated mCRC. Fewer adverse effects were evident in the dose-escalation group [ 19 , 20 ]. JAK and HDAC inhibitors have been explored individually as potential therapeutic agents for various solid tumors with limited efficacy [ 21 , 22 ].…”