Phase I study of regorafenib (BAY 73-4506), an inhibitor of oncogenic and angiogenic kinases, administered continuously in patients (pts) with advanced refractory non-small cell lung cancer (NSCLC).

Kies, M. S.; Blumenschein, G. R.; Christensen, Olaf; Lin, Tung-Yi; Tolcher, Anthony W.

doi:10.1200/jco.2010.28.15_suppl.7585

Cited by 16 publications

(19 citation statements)

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“…Regorafenib (160mg/day for 21 of 28 days) was recently approved for monotherapy use in patients with refractory, advanced colorectal cancers (5) and gastrointestinal stromal tumors (6). In patients with advanced nsNSCLCs, regorafenib was previously evaluated as a single-agent in a continuous dose regimen in the expansion cohort of a dose-escalation phase I study (7). Of 23 patients were treated, seven (30.4%) experienced a treatment-related adverse event requiring reduction, interruption, or discontinuation of treatment; no Grade 4 or 5 toxicities were observed.…”

Section: Introductionmentioning

confidence: 99%

Preliminary Safety, Pharmacokinetics, and Efficacy of Regorafenib, Cisplatin, and Pemetrexed in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancers

Hellmann¹,

Sturm²,

Trnková³

et al. 2015

Clinical Lung Cancer

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Structured Abstract Purpose The addition of bevacizumab, an anti-angiogenesis agent, to cytotoxic chemotherapy improves survival in patients with advanced non-squamous non-small cell lung cancers (nsNSCLCs). Regorafenib is an oral multi-targeted kinase inhibitor with potent anti-angiogenic activity that is approved for patients with advanced colorectal cancer and gastrointestinal stromal tumors. This phase I trial evaluated the safety, pharmacokinetics, and efficacy of regorafenib with cisplatin and pemetrexed for patients with advanced nsNSCLCs. Methods Chemotherapy-naïve patients with advanced nsNSCLCs were treated with regorafenib 60mg/day continuously and cisplatin 75mg/m2 plus pemetrexed 500mg/m2 once every three weeks for up to six cycles. Thereafter, regorafenib with or without pemetrexed could be continued as maintenance. Results Nine patients enrolled prior to premature termination of the study due to slow recruitment and a change in the development strategy of regorafenib by the study sponsor, partially due to slow enrollment. Five patients experienced at least one treatment-related Grade 3 adverse event. No grade 4–5 toxicity occurred. 5 of 9 (56%) patients had a partial response and the median progression-free survival was 7 months (range 1.5–15.1). Minor pharmacokinetic (PK) interactions between regorafenib and chemotherapy were observed. Conclusions Regorafenib had acceptable tolerability and minor PK interactions in combination with standard doses of cisplatin and pemetrexed in patients with advanced nsNSCLCs. Encouraging activity was appreciated in chemotherapy-naïve patients with advanced nsNSCLCs. However, the small number of patients treated limits conclusions that can be drawn from these results.

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Section: Introductionmentioning

confidence: 99%

Preliminary Safety, Pharmacokinetics, and Efficacy of Regorafenib, Cisplatin, and Pemetrexed in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancers

Hellmann¹,

Sturm²,

Trnková³

et al. 2015

Clinical Lung Cancer

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“…An oral multikinase inhibitor, regorafenib, with activity against selected tyrosine kinases (VEGF-R2, VEGF-R3, TIE-2 (tyrosine kinase endothelial receptor 2), PDGFR, fibroblast growth factor receptor, RET and c-KIT) as well as a signal transduction inhibitor of the RAF/ MEK/ERK pathway has demonstrated preclinical and clinical activity in mCRC [Kies et al 2010]. Based on these findings, regorafenib was investigated in a phase III trial, designated CORRECT (patients with mCRC treated with regorafenib or placebo after failure of standard therapy), for single-agent activity in refractory CRC [Grothey et al 2012].…”

Section: Antiangiogenesis Agentsmentioning

confidence: 99%

Targeted approach to metastatic colorectal cancer: what comes beyond epidermal growth factor receptor antibodies and bevacizumab?

et al. 2012

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Abstract:The prognosis of patients with cancer remains poor in spite of the advances obtained in recent years with new therapeutic agents, new approaches in surgical procedures and new diagnostic methods. The discovery of a plethora of cellular targets and the rational generation of selective targeting agents has opened an era of new opportunities and extraordinary challenges. The specificity of these agents renders them capable of specifically targeting the inherent abnormalities of cancer cells, potentially resulting in less toxicity than traditional nonselective cytotoxics. Among the many new types of rationally designed agents are therapeutics targeting various strategic facets of growth signal transduction, malignant angiogenesis, survival, metastasis and cell-cycle regulation. The evaluation of these agents is likely to require some changes from the traditional drug development paradigms to realize their full potential. Inhibition of the epidermal growth factor receptor and the vascular endothelial growth factor have provided proof of principle that disruption of signal cascades in patients with colorectal cancer has therapeutic potential. This experience has also taught us that resistance to such rationally developed targeted therapeutic strategies is common. In this article, we review the role of signal transduction in colorectal cancer, introduce promising molecular targets, and outline therapeutic approaches under development.

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“…HFSR was the commonest cause of treatment interruption and the 100 mg daily dose continuously was declared to be the RPTD [10]. In lung cancer patients, the AUC and C max of regorafenib at steady state were 35.04 mg.h/l and 2.52 mg/l, respectively --these figures were lower than those reported following a single dose of regorafenib at 160 mg at steady state [7].…”

Section: Phase I Clinical Developmentmentioning

confidence: 87%

“…In the Phase I study by Mross et al, partial responses (PR) were observed in patients with RCC, osteosarcoma and CRC [7]. Based on these data, dose-expansion studies in other cancers have been conducted and will be discussed below [9][10][11].…”

Section: Phase I Clinical Developmentmentioning

confidence: 99%

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An update on the safety and efficacy of regorafenib in the treatment of solid cancers

Chan

B.Y.

2014

Expert Opinion on Drug Metabolism & Toxicology

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Regorafenib has expanded the treatment options of patients with treatment-refractory gastrointestinal stromal tumor (GIST) and metastatic colorectal cancer (CRC). Ongoing studies are now investigating the activity of regorafenib as earlier line of therapy in CRC as monotherapy or in combination with chemotherapy. In the next 5 years, the activity of regorafenib will be further defined in other cancers such as renal cell cancer (RCC), hepato-biliary and upper GI cancers. In terms of safety, clinical trials suggest that the incidence and severity of toxicities may be higher in certain populations such as those with RCC or GIST. However, most of the common toxicities of regorafenib could be managed with dose modification without resorting to permanent drug discontinuation. Education of both patients and clinicians is thus important in minimizing treatment-related toxicities and improving drug compliance.

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Phase I study of regorafenib (BAY 73-4506), an inhibitor of oncogenic and angiogenic kinases, administered continuously in patients (pts) with advanced refractory non-small cell lung cancer (NSCLC).

Cited by 16 publications

References 0 publications

Preliminary Safety, Pharmacokinetics, and Efficacy of Regorafenib, Cisplatin, and Pemetrexed in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancers

Preliminary Safety, Pharmacokinetics, and Efficacy of Regorafenib, Cisplatin, and Pemetrexed in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancers

Targeted approach to metastatic colorectal cancer: what comes beyond epidermal growth factor receptor antibodies and bevacizumab?

An update on the safety and efficacy of regorafenib in the treatment of solid cancers

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