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Dieter Zopf - One of the best experts on this subject based on the ideXlab platform.
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Antitumor effects of Regorafenib and sorafenib in preclinical models of hepatocellular carcinoma
Oncotarget, 2017Co-Authors: Maria Kissel, Frank-thorsten Hafner, Sandra Berndt, Lukas Fiebig, Simon Kling, Tina Lang, Michael Teufel, Dieter ZopfAbstract:The purpose of this study was to investigate the antitumor activity of Regorafenib and sorafenib in preclinical models of HCC and to assess their mechanism of action by associated changes in protein expression in a HCC-PDX mouse model. Both drugs were administered orally once daily at 10 mg/kg (Regorafenib) or 30 mg/kg (sorafenib), which recapitulate the human exposure at the maximally tolerated dose in mice. In a H129 hepatoma model, survival times differed significantly between Regorafenib versus vehicle (p=0.0269; median survival times 36 vs 27 days), but not between sorafenib versus vehicle (p=0.1961; 33 vs 28 days). Effects on tumor growth were assessed in 10 patient-derived HCC xenograft (HCC-PDX) models. Significant tumor growth inhibition was observed in 8/10 models with Regorafenib and 7/10 with sorafenib; in four models, superior response was observed with Regorafenib versus sorafenib which was deemed not to be due to lower sorafenib exposure. Bead-based multiplex western blot analysis was performed with total protein lysates from drug- and vehicle-treated HCC-PDX xenografts. Protein expression was substantially different in Regorafenib- and sorafenib-treated samples compared with vehicle. The pattern of upregulated proteins was similar with both drugs and indicates an activated RAF/MEK/ERK pathway, but more proteins were downregulated with sorafenib versus Regorafenib. Overall, both Regorafenib and sorafenib were effective in mouse models of HCC, although several cases showed better Regorafenib activity which may explain the observed efficacy of Regorafenib in sorafenib-refractory patients.
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Pharmacologic activity and pharmacokinetics of metabolites of Regorafenib in preclinical models
Cancer medicine, 2016Co-Authors: Dieter Zopf, Iduna Fichtner, Ajay Bhargava, Wolfram Steinke, Karl-heinz Thierauch, Konstanze Diefenbach, Scott Wilhelm, Frank-thorsten Hafner, Michael GerischAbstract:Regorafenib is an orally administered inhibitor of protein kinases involved in tumor angiogenesis, oncogenesis, and maintenance of the tumor microenvironment. Phase III studies showed that Regorafenib has efficacy in patients with advanced gastrointestinal stromal tumors or treatment-refractory metastatic colorectal cancer. In clinical studies, steady-state exposure to the M-2 and M-5 metabolites of Regorafenib was similar to that of the parent drug; however, the contribution of these metabolites to the overall observed clinical activity of Regorafenib cannot be investigated in clinical trials. Therefore, we assessed the pharmacokinetics and pharmacodynamics of Regorafenib, M-2, and M-5 in vitro and in murine xenograft models. M-2 and M-5 showed similar kinase inhibition profiles and comparable potency to Regorafenib in a competitive binding assay. Inhibition of key target kinases by all three compounds was confirmed in cell-based assays. In murine xenograft models, oral Regorafenib, M-2, and M-5 significantly inhibited tumor growth versus controls. Total peak plasma drug concentrations and exposure to M-2 and M-5 in mice after repeated oral dosing with Regorafenib 10 mg/kg/day were comparable to those in humans. In vitro studies showed high binding of Regorafenib, M-2, and M-5 to plasma proteins, with unbound fractions of ~0.6%, ~0.9%, and ~0.4%, respectively, in murine plasma and ~0.5%, ~0.2%, and ~0.05%, respectively, in human plasma. Estimated free plasma concentrations of Regorafenib and M-2, but not M-5, exceeded the IC50 at human and murine VEGFR2, suggesting that Regorafenib and M-2 are the primary contributors to the pharmacologic activity of Regorafenib in vivo.
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Regorafenib inhibits growth angiogenesis and metastasis in a highly aggressive orthotopic colon cancer model
Molecular Cancer Therapeutics, 2013Co-Authors: Lotfi Abouelkacem, Dieter Zopf, Susanne Arns, G Brix, Felix Gremse, Fabian Kiessling, Wiltrud LederleAbstract:The combination of target-specific drugs like bevacizumab with chemotherapeutics has improved treatment efficacy in advanced colorectal cancer (CRC). However, the clinical prognosis of metastatic CRCs is still poor, and novel drugs are currently assessed with respect to their efficacies in patients with CRCs. In a phase III study, the multikinase inhibitor Regorafenib (BAY 73-4506) has recently been shown to prolong survival of patients with CRCs after standard therapies failed. In the present study, the activity of Regorafenib was investigated in comparison with the angiogenesis inhibitor DC101 in the highly aggressive, murine CT26 metastatic colon cancer model. While a treatment for 10 days with DC101 given at a dose of 34 mg/kg every third day significantly delayed tumor growth compared with vehicle-treated animals, Regorafenib completely suppressed tumor growth at a daily oral dose of 30 mg/kg. Regorafenib also induced a stronger reduction in tumor vascularization, as longitudinally assessed in vivo by dynamic contrast-enhanced MRI (DCE-MRI) and confirmed by immunohistochemistry. In addition, Regorafenib inhibited the angiogenic activity more strongly and induced a three times higher apoptosis rate than DC101. Even more important, Regorafenib completely prevented the formation of liver metastases, whereas in DC101-treated animals, the metastatic rate was only reduced by 33% compared with the vehicle group. In addition, Regorafenib significantly reduced the amount of infiltrating macrophages. These data show that the multikinase inhibitor Regorafenib exerts strong antiangiogenic, antitumorigenic, and even antimetastatic effects on highly aggressive colon carcinomas indicative for its high potential in the treatment of advanced CRCs. Mol Cancer Ther; 12(7); 1322–31. ©2013 AACR .
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abstract 4262 Regorafenib bay 73 4506 a broad spectrum tumor deactivator with high combinability potential and antimetastasis activity
Cancer Research, 2011Co-Authors: Dieter Zopf, Iduna Fichtner, Michael Becker, Tina Muller, Arne Scholz, Maria KisselAbstract:Regorafenib is an oral multi-kinase inhibitor which is in clinical development for the treatment of patients with metastatic and/or unresectable gastrointestinal stromal tumors who have failed imatinib and sunitinib therapy and patients with advanced colorectal tumors who have failed standard therapies. Regorafenib is a tumor deactivation agent that addresses all three mechanisms of tumor growth and progression (angiogenesis, oncogenesis, and stromal interactions) by potently blocking multiple RTKs. Inhibition of angiogenic RTKs (e.g., VEGFR1-3, TIE2) by Regorafenib results in breakdown of tumor vascular structure, which disrupts the tumor9s oxygen and nutrient supply. Furthermore, Regorafenib targets oncogenic RTKs (e.g., KIT, Ret), which control tumor growth, and stromal RTKs (e.g., PDGFR, FGFR), which are implicated not only in the establishment of tumor infrastructure but also in tumor progression. Regorafenib was evaluated for additional tumor indications in several human cancer xenograft and syngeneic tumor preclinical models as single agent or in combination with standards of care or targeted agents in early clinical development. Regorafenib effectively inhibited tumor growth in a broad spectrum (e.g. liver, stomach, ovarian, breast and colon) of subcutaneous and orthotopic models of human xenograft and murine syngeneic tumors at an oral daily dose of 10mg/kg. Regorafenib inhibited various patient-derived oxaliplatin insensitive colorectal xenografts as single agent and in combination with concomitant irinotecan dosing. Finally, Regorafenib was shown to exert potent antimetastasis activity in orthotopic syngeneic 4T1 and triple-negative MDA-MB 231 human xenograft breast cancer models by prevention of the formation of lung or lymph node metastasis, respectively. In summary, by blocking multiple abnormal angiogenic and oncogenic signalling pathways, Regorafenib deactivates tumors and prevents their continued growth and metastatic potential. In preclinical models Regorafenib has shown a high potential as a combination partner with other therapeutic agents such as irinotecan, which may make it suitable as a future backbone for treatment of multiple cancer types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4262. doi:10.1158/1538-7445.AM2011-4262
Alfred H Schinkel - One of the best experts on this subject based on the ideXlab platform.
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Brain and Testis Accumulation of Regorafenib is Restricted by Breast Cancer Resistance Protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1)
Pharmaceutical Research, 2015Co-Authors: Anita Kort, Selvi Durmus, Els Wagenaar, Rolf W Sparidans, Jos H. Beijnen, Alfred H SchinkelAbstract:Purpose Regorafenib is a novel multikinase inhibitor, currently approved for the treatment of metastasized colorectal cancer and advanced gastrointestinal stromal tumors. We investigated whether Regorafenib is a substrate for the multidrug efflux transporters ABCG2 and ABCB1 and whether oral availability, brain and testis accumulation of Regorafenib and its active metabolites are influenced by these transporters. Methods We used in vitro transport assays to assess human (h)ABCB1- or hABCG2- or murine (m)Abcg2-mediated active transport at high and low concentrations of Regorafenib. To study the single and combined roles of Abcg2 and Abcb1a/1b in oral Regorafenib disposition and the impact of Cyp3a-mediated metabolism, we used appropriate knockout mouse strains. Results Regorafenib was transported well by mAbcg2 and hABCG2 and modestly by hABCB1 in vitro . Abcg2 and to a lesser extent Abcb1a/1b limited brain and testis accumulation of Regorafenib and metabolite M2 (brain only) in mice. Regorafenib oral availability was not increased in Abcg2 ^ -/- ;Abcb1a/1b ^ -/- mice. Up till 2 h, metabolite M5 was undetectable in plasma and organs. Conclusions Brain and testis accumulation of Regorafenib and brain accumulation of metabolite M2 are restricted by Abcg2 and Abcb1a/1b. Inhibition of these transporters may be of clinical relevance for patients with brain (micro)metastases positioned behind an intact blood–brain barrier.
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brain and testis accumulation of Regorafenib is restricted by breast cancer resistance protein bcrp abcg2 and p glycoprotein p gp abcb1
Pharmaceutical Research, 2015Co-Authors: Anita Kort, Selvi Durmus, Els Wagenaar, Rolf W Sparidans, Jos H. Beijnen, Alfred H SchinkelAbstract:Purpose Regorafenib is a novel multikinase inhibitor, currently approved for the treatment of metastasized colorectal cancer and advanced gastrointestinal stromal tumors. We investigated whether Regorafenib is a substrate for the multidrug efflux transporters ABCG2 and ABCB1 and whether oral availability, brain and testis accumulation of Regorafenib and its active metabolites are influenced by these transporters.
Kelvin K W Chan - One of the best experts on this subject based on the ideXlab platform.
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a comparison of Regorafenib and tas 102 for metastatic colorectal cancer a systematic review and network meta analysis
Clinical Colorectal Cancer, 2017Co-Authors: Ana Beatriz Kinupe Abrahao, Scott R Berry, Kelvin K W ChanAbstract:Abstract Background Regorafenib and TAS-102 have shown to be superior to placebo in refractory metastatic colorectal cancer. However, no studies have directly compared both drugs. Giving the lack of standard options in this scenario, a systematic review to compare the efficacy and safety of Regorafenib and TAS-102 was performed. Materials and Methods A systematic review using the PubMed, Medline, Embase, Scopus, and Cochrane databases to identify published and unpublished studies up to November 2015 for randomized controlled trials for patients with metastatic colorectal cancer, involving Regorafenib or TAS-102, was performed. Data including overall survival, progression-free survival, and toxicity were extracted. Pairwise direct meta-analyses (Regorafenib vs. placebo and TAS-102 vs. placebo) and indirect comparison (Regorafenib vs. TAS-102) using network meta-analyses methods to preserve randomization were performed using random effects. Results Three randomized controlled trials fulfilled eligibility criteria (Regorafenib monotherapy for previously treated metastatic colorectal cancer [CORRECT]: an international, multicentre, randomised, pacebo-controlled, phase 3 trial, Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer [CONCUR]: a randomised, double-blind, placebo-controlled, phase 3 trial, and randomized trial of TAS-102 for refractory metastatic colorectal cancer [RECOURSE] trials) involving 1764 patients (Regorafenib, 641; TAS-102, 534; placebo, 589). Subgroups of patients (1659) who had not received prior Regorafenib or TAS-102 were used to perform meta-analyses for efficacy. In the indirect comparison, no statistically significant differences were observed between Regorafenib and TAS-102 in overall survival (hazard ratio, 0.96; 95% confidence interval [CI], 0.57-1.66; P = .91) or progression-free survival (hazard ratio, 0.85; 95% CI, 0.40-1.81; P = .67). However, Regorafenib has statistically more all grade any toxicity (risk difference, 0.31; 95% CI, 0.25-0.38; P = .001) compared with TAS-102. Subgroup analysis of adverse events showed a different toxicity profile between both drugs. Conclusion In this indirect comparison, Regorafenib and TAS-102 appeared to have similar efficacy. However, Regorafenib was associated with more toxicity compared with TAS-102.
Toshiki Masuishi - One of the best experts on this subject based on the ideXlab platform.
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A Phase II Study of Regorafenib With a Lower Starting Dose in Patients With Metastatic Colorectal Cancer: Exposure-Toxicity Analysis of Unbound Regorafenib and Its Active Metabolites (RESET Trial).
Clinical colorectal cancer, 2019Co-Authors: Takeshi Suzuki, Hironaga Satake, Yasutaka Sukawa, Chiyo K. Imamura, Toshiki Masuishi, Yosuke Kumekawa, Shinsuke Funakoshi, Masahito Kotaka, Yoshiki Horie, Sadayuki KawaiAbstract:Abstract Background Regorafenib demonstrated survival benefits as salvage therapy for patients with metastatic colorectal cancer. However, severe toxicities frequently occurred early in the treatment with the standard dose (160 mg/day), resulting in a dose reduction or interruption. To improve the tolerability and maintain sufficient efficacy, we conducted a phase II study of Regorafenib with a lower starting dose (120 mg/day). Patients and Methods Regorafenib was initiated at 120 mg/day, and the dosage was increased to 160 mg/day on day 15 of the first cycle for patients who had met the dose escalation criteria. The primary endpoint was the disease control rate (DCR). The pharmacokinetics of the total and unbound Regorafenib and its active metabolites (M2, M5) were assessed. Results A total of 70 patients were enrolled from September 2016 to December 2017. Only 6 patients achieved dose escalation to 160 mg on day 15 as planned. For the 68 evaluable patients, the DCR was 32.4% (95% confidence interval, 21.5%-44.8%), which was less than the threshold (30%) of our statistical hypothesis. The serum concentrations of total Regorafenib for patients whose dose was escalated to 160 mg/day were significantly lower than those of the patients whose dose was not escalated (median, 3978 vs. 7244 nM; P = .027). The serum unbound concentrations of the sum of Regorafenib and the active metabolites correlated significantly with the maximum grade of Regorafenib-related symptomatic adverse events in the first cycle (11,138 vs. 19,096 pM; P = .035). Conclusion Regorafenib with a low starting dose of 120 mg/day did not achieve the expected DCR. A relationship of unbound exposure with toxicity was found.
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Regorafenib versus trifluridine tipiracil for refractory metastatic colorectal cancer a retrospective comparison
Clinical Colorectal Cancer, 2017Co-Authors: Toshiki Masuishi, Hiroya Taniguchi, Satoshi Hamauchi, Azusa Komori, Yosuke Kito, Yukiya Narita, Takahiro Tsushima, Makoto Ishihara, Akiko Todaka, Tsutomu TanakaAbstract:Abstract Background Regorafenib and trifluridine/tipiracil (TAS-102) both prolong survival for patients with refractory metastatic colorectal cancer. However, it is unclear which drug should be administered first. Materials and Methods We retrospectively evaluated the data from patients who had received Regorafenib or TAS-102 at 2 institutions from May 2013 to March 2015. The inclusion criteria were disease refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, anti-vascular endothelial growth factor antibodies, and anti-epidermal growth factor receptor (EGFR) antibodies (if KRAS exon 2 wild-type), and no previous treatment with Regorafenib or TAS-102. Results A total of 146 and 54 patients received Regorafenib and TAS-102, respectively. The baseline characteristics were similar between the 2 groups, except for a history of irinotecan and anti-EGFR therapy and high alkaline phosphatase levels. The median progression-free survival and overall survival were 2.1 months and 6.7 months, respectively, with Regorafenib and 2.1 months and 6.5 months, respectively, with TAS-102 (progression-free survival hazard ratio 1.20, P = .27; overall survival hazard ratio, 1.01, P = .97). The analysis of overall survival for patients after the approval of TAS-102 in Japan was similar to the overall survival for the entire population. The frequency of hand–foot syndrome and increased aspartate aminotransferase, alanine aminotransferase, and bilirubin levels was higher and the frequency of neutropenia, leukopenia, anemia, nausea, and febrile neutropenia was lower with Regorafenib than with TAS-102. No remarkable differences were found in the efficacy and safety of TAS-102 between patients with and without previous Regorafenib and vice versa. Conclusion Regorafenib and TAS-102 had similar efficacy but resulted in different toxicities, which could guide the agent choice.
Tsutomu Tanaka - One of the best experts on this subject based on the ideXlab platform.
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Regorafenib versus trifluridine tipiracil for refractory metastatic colorectal cancer a retrospective comparison
Clinical Colorectal Cancer, 2017Co-Authors: Toshiki Masuishi, Hiroya Taniguchi, Satoshi Hamauchi, Azusa Komori, Yosuke Kito, Yukiya Narita, Takahiro Tsushima, Makoto Ishihara, Akiko Todaka, Tsutomu TanakaAbstract:Abstract Background Regorafenib and trifluridine/tipiracil (TAS-102) both prolong survival for patients with refractory metastatic colorectal cancer. However, it is unclear which drug should be administered first. Materials and Methods We retrospectively evaluated the data from patients who had received Regorafenib or TAS-102 at 2 institutions from May 2013 to March 2015. The inclusion criteria were disease refractory or intolerant to fluoropyrimidines, oxaliplatin, irinotecan, anti-vascular endothelial growth factor antibodies, and anti-epidermal growth factor receptor (EGFR) antibodies (if KRAS exon 2 wild-type), and no previous treatment with Regorafenib or TAS-102. Results A total of 146 and 54 patients received Regorafenib and TAS-102, respectively. The baseline characteristics were similar between the 2 groups, except for a history of irinotecan and anti-EGFR therapy and high alkaline phosphatase levels. The median progression-free survival and overall survival were 2.1 months and 6.7 months, respectively, with Regorafenib and 2.1 months and 6.5 months, respectively, with TAS-102 (progression-free survival hazard ratio 1.20, P = .27; overall survival hazard ratio, 1.01, P = .97). The analysis of overall survival for patients after the approval of TAS-102 in Japan was similar to the overall survival for the entire population. The frequency of hand–foot syndrome and increased aspartate aminotransferase, alanine aminotransferase, and bilirubin levels was higher and the frequency of neutropenia, leukopenia, anemia, nausea, and febrile neutropenia was lower with Regorafenib than with TAS-102. No remarkable differences were found in the efficacy and safety of TAS-102 between patients with and without previous Regorafenib and vice versa. Conclusion Regorafenib and TAS-102 had similar efficacy but resulted in different toxicities, which could guide the agent choice.