The Experts below are selected from a list of 5991 Experts worldwide ranked by ideXlab platform
Brian I. Rini - One of the best experts on this subject based on the ideXlab platform.
-
Axitinib plus immune checkpoint inhibitor: evidence- and expert-based consensus recommendation for treatment optimisation and management of related adverse events.
British journal of cancer, 2020Co-Authors: Viktor Grunwald, Brian I. Rini, Martin H. Voss, Thomas Powles, Laurence Albiges, Rachel H. Giles, Eric JonaschAbstract:With the recent approval of the combinations of Axitinib with the immune checkpoint inhibitor (ICI) pembrolizumab or avelumab for first-line treatment of advanced renal cell carcinoma, guidance on how to distinguish between immune-related adverse events (AEs) caused by ICI versus Axitinib-related AEs is necessary to optimise therapy with Axitinib-ICI combinations. The recommendations here are based on (1) systematic review of published evidence, (2) discussion among experts in the field and (3) a survey to obtain expert consensus on specific measures for therapy management with the combinations Axitinib/avelumab and Axitinib/pembrolizumab. The experts identified areas of AEs requiring unique management during treatment with Axitinib-ICI combinations that were not covered by current recommendations. Diarrhoea, hepatic toxicity, fatigue and cardiovascular AEs were found to be applicable to such specialised management. Triage between immune-suppressive and supportive measures is a key component in therapy management. Clinical monitoring and experience with both classes of agents are necessary to manage this novel therapeutic approach. We focused on AEs with an overlap between Axitinib and ICI therapy. Our recommendations address AE management of Axitinib-ICI combinations with the aim to improve the safety of these therapies.
-
a phase 2 randomized trial evaluating the combination of dalantercept plus Axitinib in patients with advanced clear cell renal cell carcinoma
Cancer, 2019Co-Authors: Martin H. Voss, Brian I. Rini, Mayer Fishman, Rupal S Bhatt, Nicholas J Vogelzang, Robert S Alter, Thaddeus J Beck, Monika Joshi, Ralph J Hauke, Michael B AtkinsAbstract:BACKGROUND In a prior open-label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor-like kinase 1 (ALK1), plus Axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC). METHODS In the current phase 2, randomized, double-blind, placebo-controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive Axitinib plus dalantercept versus Axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate. RESULTS Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive Axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8 months vs 5.6 months; hazard ratio, 1.11 [95% CI, 0.71-1.73; P = .670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70-2.77; P = .349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%-31.4%) in the dalantercept plus Axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%-37.3%) in the placebo plus Axitinib group. At least 1 treatment-emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment-related death occurred in the placebo plus Axitinib group. CONCLUSIONS Although well tolerated, the addition of dalantercept to Axitinib did not appear to improve treatment-related outcomes in previously treated patients with advanced RCC.
-
Patients with metastatic renal cell carcinoma who benefit from Axitinib dose titration: analysis from a randomised, double-blind phase II study
BMC, 2019Co-Authors: Yoshihiko Tomita, Hirotsugu Uemura, Mototsugu Oya, Nobuo Shinohara, Tomonori Habuchi, Yosuke Fujii, Yoichi Kamei, Yoshiko Umeyama, Angel H. Bair, Brian I. RiniAbstract:Abstract Background A prospective, randomised phase II study demonstrated clinical benefit of Axitinib dose titration in a subset of treatment-naïve patients treated with Axitinib for metastatic renal cell carcinoma. This analysis evaluated patient baseline characteristics that may impact overall survival (OS) with Axitinib dose titration. Methods Following a 4-week lead-in period during which all patients received Axitinib 5 mg twice-daily (bid); patients meeting the predefined randomisation criteria were randomly assigned to receive Axitinib 5 mg bid plus either Axitinib or placebo titration. In exploratory analyses, patients were grouped into those who achieved OS ≥24 versus
-
Patients with metastatic renal cell carcinoma who have benefit from Axitinib dose titration: Analysis from a randomized, double-blind, Axitinib dose titration phase II study.
Journal of Clinical Oncology, 2017Co-Authors: Yoshihiko Tomita, Hirotsugu Uemura, Mototsugu Oya, Nobuo Shinohara, Tomonori Habuchi, Yosuke Fujii, Yoichi Kamei, Yoshiko Umeyama, Angel H. Bair, Brian I. RiniAbstract:438Background: Axitinib is a potent, selective inhibitor of VEGF receptors. In a randomized, double-blind, phase II study in patients with metastatic renal cell carcinoma, median overall survival (OS) was 42.7 months who underwent Axitinib titration versus (vs.) 30.4 months in placebo titration (hazard ratio [HR]: 0.785; 95% confidence interval: 0.485, 1.272). OS Kaplan-Meier curves for two arms appeared to cross over at approximately 24 months and thus we investigated baseline characteristics associated with OS benefit from Axitinib titration. Methods: Patients received Axitinib 5 mg twice daily (BID) for 28 days. Patients who met the dose titration criteria were randomized 1:1 to Axitinib titration or placebo titration. Patients who did not meet the dose titration criteria continued Axitinib 5 mg BID. Baseline characteristics were compared between patients with OS ≥ 24 and < 24 months who were randomized to Axitinib titration and subsequently, multivariate analysis for baseline characteristics was condu...
-
key predictive factors for efficacy of Axitinib in first line metastatic renal cell carcinoma subgroup analysis in japanese patients from a randomized double blind phase ii study
Japanese Journal of Clinical Oncology, 2016Co-Authors: Yoshihiko Tomita, Hirotsugu Uemura, Mototsugu Oya, Nobuo Shinohara, Tomonori Habuchi, Angel H. Bair, Brian I. Rini, Ying Chen, Satoshi Fukasawa, Seiichiro OzonoAbstract:Objectives To conduct Japanese subgroup analyses of a randomized, global Phase II study of Axitinib with and without dose titration in first-line metastatic renal cell carcinoma and to explore predictive factors for Axitinib efficacy in first-line metastatic renal cell carcinoma. Methods The data included 44 Japanese and 169 non-Japanese treatment-naive patients with metastatic renal cell carcinoma. Patients received twice-daily Axitinib 5 mg during a 4-week lead-in period. Patients who met the pre-defined randomization criteria were stratified by Eastern Cooperative Oncology Group performance status and randomly assigned (1:1) to Axitinib or placebo titration. The primary endpoint was objective response rate; secondary endpoints included progression-free survival and safety. Predictive factors were analyzed using data from all patients. Results The objective response rate (95% confidence interval) was 66% (50-80%) vs. 44% (36-52%) in Japanese and non-Japanese patients, respectively. At the primary analysis, median progression-free survival could not be estimated for Japanese patients, and was 27.6 months (95% confidence interval: 16.6-33.2) in an updated analysis. Hypertension, diarrhea, hand-foot syndrome, dysphonia, hypothyroidism and proteinuria were common adverse events in Japanese patients. Due to a small number of randomized patients, effects of Axitinib dose titration could not sufficiently be confirmed among Japanese patients. The multivariate analysis identified time from histopathological diagnosis to treatment and sum of the longest diameter for target lesion at baseline as independent predictive factors for progression-free survival. Conclusions Axitinib is effective and well tolerated as first-line metastatic renal cell carcinoma therapy in Japanese patients. Predictive factors for Axitinib efficacy endpoints identified in this setting warrant further investigation.
Angel H. Bair - One of the best experts on this subject based on the ideXlab platform.
-
Patients with metastatic renal cell carcinoma who benefit from Axitinib dose titration: analysis from a randomised, double-blind phase II study
BMC, 2019Co-Authors: Yoshihiko Tomita, Hirotsugu Uemura, Mototsugu Oya, Nobuo Shinohara, Tomonori Habuchi, Yosuke Fujii, Yoichi Kamei, Yoshiko Umeyama, Angel H. Bair, Brian I. RiniAbstract:Abstract Background A prospective, randomised phase II study demonstrated clinical benefit of Axitinib dose titration in a subset of treatment-naïve patients treated with Axitinib for metastatic renal cell carcinoma. This analysis evaluated patient baseline characteristics that may impact overall survival (OS) with Axitinib dose titration. Methods Following a 4-week lead-in period during which all patients received Axitinib 5 mg twice-daily (bid); patients meeting the predefined randomisation criteria were randomly assigned to receive Axitinib 5 mg bid plus either Axitinib or placebo titration. In exploratory analyses, patients were grouped into those who achieved OS ≥24 versus
-
Patients with metastatic renal cell carcinoma who have benefit from Axitinib dose titration: Analysis from a randomized, double-blind, Axitinib dose titration phase II study.
Journal of Clinical Oncology, 2017Co-Authors: Yoshihiko Tomita, Hirotsugu Uemura, Mototsugu Oya, Nobuo Shinohara, Tomonori Habuchi, Yosuke Fujii, Yoichi Kamei, Yoshiko Umeyama, Angel H. Bair, Brian I. RiniAbstract:438Background: Axitinib is a potent, selective inhibitor of VEGF receptors. In a randomized, double-blind, phase II study in patients with metastatic renal cell carcinoma, median overall survival (OS) was 42.7 months who underwent Axitinib titration versus (vs.) 30.4 months in placebo titration (hazard ratio [HR]: 0.785; 95% confidence interval: 0.485, 1.272). OS Kaplan-Meier curves for two arms appeared to cross over at approximately 24 months and thus we investigated baseline characteristics associated with OS benefit from Axitinib titration. Methods: Patients received Axitinib 5 mg twice daily (BID) for 28 days. Patients who met the dose titration criteria were randomized 1:1 to Axitinib titration or placebo titration. Patients who did not meet the dose titration criteria continued Axitinib 5 mg BID. Baseline characteristics were compared between patients with OS ≥ 24 and < 24 months who were randomized to Axitinib titration and subsequently, multivariate analysis for baseline characteristics was condu...
-
Axitinib versus sorafenib in first line metastatic renal cell carcinoma overall survival from a randomized phase iii trial
Clinical Genitourinary Cancer, 2017Co-Authors: Thomas E. Hutson, Angel H. Bair, Glen Ian Andrews, Brad Rosbrook, Salman Alshukri, Viktor Stus, O Lipatov, Yaroslav Shparyk, Nicholas J VogelzangAbstract:Abstract Background In a randomized phase III trial in treatment-naive patients with metastatic renal cell carcinoma (RCC), Axitinib versus sorafenib yielded numerically longer progression-free survival (median, 10.1 vs. 6.5 months; hazard ratio [HR], 0.77; 1-sided P = .038) and significantly higher objective response rate (32% vs. 15%; 1-sided P = .0006). In this article, we report overall survival (OS) and updated safety results. Patients and Methods Previously untreated patients with metastatic RCC (n = 288), stratified according to Eastern Cooperative Oncology Group performance status (ECOG PS; 0 vs. 1), were randomized 2:1 to receive Axitinib 5 mg twice per day (b.i.d.; n = 192) or sorafenib 400 mg b.i.d. (n = 96). Results Median OS (95% confidence interval [CI]) was 21.7 months (18.0-31.7) with Axitinib versus 23.3 months (18.1-33.2) with sorafenib (stratified HR, 0.995; 95% CI, 0.731-1.356; 1-sided P = .4883). Among patients with ECOG PS of 0, median OS was numerically longer with Axitinib than with sorafenib (41.2 vs. 31.9 months; HR, 0.811, 1-sided P = .1748), whereas among patients with ECOG PS 1, median OS was shorter with Axitinib than with sorafenib (14.2 vs. 19.8 months; HR, 1.203; 1-sided; P = .7973). Incidence and severity of common adverse events were consistent with previous reports. Conclusion OS was similar between Axitinib and sorafenib in treatment-naive patients with metastatic RCC, and no new safety signals emerged.
-
key predictive factors for efficacy of Axitinib in first line metastatic renal cell carcinoma subgroup analysis in japanese patients from a randomized double blind phase ii study
Japanese Journal of Clinical Oncology, 2016Co-Authors: Yoshihiko Tomita, Hirotsugu Uemura, Mototsugu Oya, Nobuo Shinohara, Tomonori Habuchi, Angel H. Bair, Brian I. Rini, Ying Chen, Satoshi Fukasawa, Seiichiro OzonoAbstract:Objectives To conduct Japanese subgroup analyses of a randomized, global Phase II study of Axitinib with and without dose titration in first-line metastatic renal cell carcinoma and to explore predictive factors for Axitinib efficacy in first-line metastatic renal cell carcinoma. Methods The data included 44 Japanese and 169 non-Japanese treatment-naive patients with metastatic renal cell carcinoma. Patients received twice-daily Axitinib 5 mg during a 4-week lead-in period. Patients who met the pre-defined randomization criteria were stratified by Eastern Cooperative Oncology Group performance status and randomly assigned (1:1) to Axitinib or placebo titration. The primary endpoint was objective response rate; secondary endpoints included progression-free survival and safety. Predictive factors were analyzed using data from all patients. Results The objective response rate (95% confidence interval) was 66% (50-80%) vs. 44% (36-52%) in Japanese and non-Japanese patients, respectively. At the primary analysis, median progression-free survival could not be estimated for Japanese patients, and was 27.6 months (95% confidence interval: 16.6-33.2) in an updated analysis. Hypertension, diarrhea, hand-foot syndrome, dysphonia, hypothyroidism and proteinuria were common adverse events in Japanese patients. Due to a small number of randomized patients, effects of Axitinib dose titration could not sufficiently be confirmed among Japanese patients. The multivariate analysis identified time from histopathological diagnosis to treatment and sum of the longest diameter for target lesion at baseline as independent predictive factors for progression-free survival. Conclusions Axitinib is effective and well tolerated as first-line metastatic renal cell carcinoma therapy in Japanese patients. Predictive factors for Axitinib efficacy endpoints identified in this setting warrant further investigation.
-
Axitinib dose titration analyses of exposure blood pressure and clinical response from a randomized phase ii study in metastatic renal cell carcinoma
Annals of Oncology, 2015Co-Authors: Brian I. Rini, Mototsugu Oya, Angel H. Bair, Ying Chen, Yazdi K. Pithavala, Bohuslav Melichar, Mayer Fishman, Viktor GrunwaldAbstract:ABSTRACT Background In a randomized, double-blind phase II trial in patients with metastatic renal cell carcinoma (mRCC), Axitinib versus placebo titration yielded a significantly higher objective response rate. We evaluated pharmacokinetic and blood pressure (BP) data from this study to elucidate relationships among Axitinib exposure, BP change, and efficacy. Patients and methods Patients received Axitinib 5 mg twice daily during a lead-in period. Patients who met dose-titration criteria were randomized 1:1 to stepwise dose increases with Axitinib or placebo. Patients ineligible for randomization continued without dose increases. Serial 6-h and sparse pharmacokinetic sampling were carried out; BP was measured at clinic visits and at home in all patients, and by 24-h ambulatory BP monitoring (ABPM) in a subset of patients. Results Area under the plasma concentration–time curve from 0 to 24 h throughout the course of treatment (AUCstudy) was higher in patients with complete or partial responses than those with stable or progressive disease in the Axitinib-titration arm, but comparable between these groups in the placebo-titration and nonrandomized arms. In the overall population, AUCstudy and efficacy outcomes were not strongly correlated. Mean BP across the population was similar when measured in clinic, at home, or by 24-h ABPM. Weak correlations were observed between Axitinib steady-state exposure and diastolic BP. When grouped by change in diastolic BP from baseline, patients in the ≥10 and ≥15 mmHg groups had longer progression-free survival. Conclusions Optimal Axitinib exposure may differ among patients with mRCC. Pharmacokinetic or BP measurements cannot be used exclusively to guide Axitinib dosing. Individualization of treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors, including Axitinib, is thus more complex than anticipated and cannot be limited to a single clinical factor.
Yoshihiko Tomita - One of the best experts on this subject based on the ideXlab platform.
-
Patients with metastatic renal cell carcinoma who benefit from Axitinib dose titration: analysis from a randomised, double-blind phase II study
BMC, 2019Co-Authors: Yoshihiko Tomita, Hirotsugu Uemura, Mototsugu Oya, Nobuo Shinohara, Tomonori Habuchi, Yosuke Fujii, Yoichi Kamei, Yoshiko Umeyama, Angel H. Bair, Brian I. RiniAbstract:Abstract Background A prospective, randomised phase II study demonstrated clinical benefit of Axitinib dose titration in a subset of treatment-naïve patients treated with Axitinib for metastatic renal cell carcinoma. This analysis evaluated patient baseline characteristics that may impact overall survival (OS) with Axitinib dose titration. Methods Following a 4-week lead-in period during which all patients received Axitinib 5 mg twice-daily (bid); patients meeting the predefined randomisation criteria were randomly assigned to receive Axitinib 5 mg bid plus either Axitinib or placebo titration. In exploratory analyses, patients were grouped into those who achieved OS ≥24 versus
-
Patients with metastatic renal cell carcinoma who have benefit from Axitinib dose titration: Analysis from a randomized, double-blind, Axitinib dose titration phase II study.
Journal of Clinical Oncology, 2017Co-Authors: Yoshihiko Tomita, Hirotsugu Uemura, Mototsugu Oya, Nobuo Shinohara, Tomonori Habuchi, Yosuke Fujii, Yoichi Kamei, Yoshiko Umeyama, Angel H. Bair, Brian I. RiniAbstract:438Background: Axitinib is a potent, selective inhibitor of VEGF receptors. In a randomized, double-blind, phase II study in patients with metastatic renal cell carcinoma, median overall survival (OS) was 42.7 months who underwent Axitinib titration versus (vs.) 30.4 months in placebo titration (hazard ratio [HR]: 0.785; 95% confidence interval: 0.485, 1.272). OS Kaplan-Meier curves for two arms appeared to cross over at approximately 24 months and thus we investigated baseline characteristics associated with OS benefit from Axitinib titration. Methods: Patients received Axitinib 5 mg twice daily (BID) for 28 days. Patients who met the dose titration criteria were randomized 1:1 to Axitinib titration or placebo titration. Patients who did not meet the dose titration criteria continued Axitinib 5 mg BID. Baseline characteristics were compared between patients with OS ≥ 24 and < 24 months who were randomized to Axitinib titration and subsequently, multivariate analysis for baseline characteristics was condu...
-
key predictive factors for efficacy of Axitinib in first line metastatic renal cell carcinoma subgroup analysis in japanese patients from a randomized double blind phase ii study
Japanese Journal of Clinical Oncology, 2016Co-Authors: Yoshihiko Tomita, Hirotsugu Uemura, Mototsugu Oya, Nobuo Shinohara, Tomonori Habuchi, Angel H. Bair, Brian I. Rini, Ying Chen, Satoshi Fukasawa, Seiichiro OzonoAbstract:Objectives To conduct Japanese subgroup analyses of a randomized, global Phase II study of Axitinib with and without dose titration in first-line metastatic renal cell carcinoma and to explore predictive factors for Axitinib efficacy in first-line metastatic renal cell carcinoma. Methods The data included 44 Japanese and 169 non-Japanese treatment-naive patients with metastatic renal cell carcinoma. Patients received twice-daily Axitinib 5 mg during a 4-week lead-in period. Patients who met the pre-defined randomization criteria were stratified by Eastern Cooperative Oncology Group performance status and randomly assigned (1:1) to Axitinib or placebo titration. The primary endpoint was objective response rate; secondary endpoints included progression-free survival and safety. Predictive factors were analyzed using data from all patients. Results The objective response rate (95% confidence interval) was 66% (50-80%) vs. 44% (36-52%) in Japanese and non-Japanese patients, respectively. At the primary analysis, median progression-free survival could not be estimated for Japanese patients, and was 27.6 months (95% confidence interval: 16.6-33.2) in an updated analysis. Hypertension, diarrhea, hand-foot syndrome, dysphonia, hypothyroidism and proteinuria were common adverse events in Japanese patients. Due to a small number of randomized patients, effects of Axitinib dose titration could not sufficiently be confirmed among Japanese patients. The multivariate analysis identified time from histopathological diagnosis to treatment and sum of the longest diameter for target lesion at baseline as independent predictive factors for progression-free survival. Conclusions Axitinib is effective and well tolerated as first-line metastatic renal cell carcinoma therapy in Japanese patients. Predictive factors for Axitinib efficacy endpoints identified in this setting warrant further investigation.
-
overall survival analysis from a randomized phase ii study of Axitinib with or without dose titration in first line metastatic renal cell carcinoma
Clinical Genitourinary Cancer, 2015Co-Authors: Brian I. Rini, Yoshihiko Tomita, Hirotsugu Uemura, Mototsugu Oya, Angel H. Bair, Bohuslav Melichar, Takeshi Ueda, Viktor Grunwald, Mayer Fishman, Glen Ian AndrewsAbstract:Abstract Background In a randomized phase II trial in metastatic renal cell carcinoma (mRCC), objective response rate was significantly higher with Axitinib versus placebo titration (54% vs. 34%; 1-sided P = .019). Patients and Methods Treatment-naive patients with mRCC (n = 213) received Axitinib 5 mg twice per day (b.i.d.) for 4 weeks. Patients meeting dose titration criteria were randomized to receive Axitinib 5 mg b.i.d. with Axitinib or placebo titration (n = 56 each); 91 patients ineligible for randomization continued Axitinib 5 mg b.i.d.; 10 discontinued before randomization. Results Median overall survival (95% confidence interval [CI]) was 42.7 months (24.7-not estimable) with Axitinib titration versus 30.4 months (23.7-45.0) with placebo titration (stratified hazard ratio, 0.785; 95% CI, 0.485-1.272; 1-sided P = .162), and 41.6 months (95% CI, 33.0-not estimable) in nonrandomized patients. Safety data were consistent with previous reports. Conclusion Median overall survival was numerically longer in patients with first-line mRCC who received Axitinib versus placebo titration. No new safety signal was observed after long-term Axitinib treatment in first-line mRCC.
-
efficacy and safety of Axitinib versus sorafenib in metastatic renal cell carcinoma subgroup analysis of japanese patients from the global randomized phase 3 axis trial
Japanese Journal of Clinical Oncology, 2013Co-Authors: Takeshi Ueda, Yoshihiko Tomita, Hirotsugu Uemura, Nobuo Shinohara, Jamal Tarazi, Sinil Kim, Taiji Tsukamoto, Hiroomi Kanayama, Connie Chen, Seiichiro OzonoAbstract:Objective Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. The efficacy and safety of Axitinib in Japanese patients with metastatic renal cell carcinoma were evaluated.
Yazdi K. Pithavala - One of the best experts on this subject based on the ideXlab platform.
-
Axitinib dose titration analyses of exposure blood pressure and clinical response from a randomized phase ii study in metastatic renal cell carcinoma
Annals of Oncology, 2015Co-Authors: Brian I. Rini, Mototsugu Oya, Angel H. Bair, Ying Chen, Yazdi K. Pithavala, Bohuslav Melichar, Mayer Fishman, Viktor GrunwaldAbstract:ABSTRACT Background In a randomized, double-blind phase II trial in patients with metastatic renal cell carcinoma (mRCC), Axitinib versus placebo titration yielded a significantly higher objective response rate. We evaluated pharmacokinetic and blood pressure (BP) data from this study to elucidate relationships among Axitinib exposure, BP change, and efficacy. Patients and methods Patients received Axitinib 5 mg twice daily during a lead-in period. Patients who met dose-titration criteria were randomized 1:1 to stepwise dose increases with Axitinib or placebo. Patients ineligible for randomization continued without dose increases. Serial 6-h and sparse pharmacokinetic sampling were carried out; BP was measured at clinic visits and at home in all patients, and by 24-h ambulatory BP monitoring (ABPM) in a subset of patients. Results Area under the plasma concentration–time curve from 0 to 24 h throughout the course of treatment (AUCstudy) was higher in patients with complete or partial responses than those with stable or progressive disease in the Axitinib-titration arm, but comparable between these groups in the placebo-titration and nonrandomized arms. In the overall population, AUCstudy and efficacy outcomes were not strongly correlated. Mean BP across the population was similar when measured in clinic, at home, or by 24-h ABPM. Weak correlations were observed between Axitinib steady-state exposure and diastolic BP. When grouped by change in diastolic BP from baseline, patients in the ≥10 and ≥15 mmHg groups had longer progression-free survival. Conclusions Optimal Axitinib exposure may differ among patients with mRCC. Pharmacokinetic or BP measurements cannot be used exclusively to guide Axitinib dosing. Individualization of treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors, including Axitinib, is thus more complex than anticipated and cannot be limited to a single clinical factor.
-
Axitinib plasma pharmacokinetics and ethnic differences
Investigational new drugs, 2015Co-Authors: Ying Chen, Michael A. Tortorici, Robert R. Labadie, Yoshiko Umeyama, Akiyuki Suzuki, May Garrett, Yazdi K. PithavalaAbstract:Axitinib, a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, showed improved progression-free survival over sorafenib in patients previously treated for advanced renal cell carcinoma in the AXIS trial. Although a few studies had established the efficacy and safety of Axitinib in Asian patients, additional evaluation was necessary to obtain regulatory approval in several Asian countries, especially in light of ethnic differences that are known to exist in genetic polymorphisms for metabolizing enzymes such as cytochrome P450 (CYP) 3A5, CYP2C19 and uridine diphosphate glucuronosyltransferase (UGT) 1A1, which are involved in Axitinib metabolism. Axitinib plasma pharmacokinetics following single or multiple administration of oral Axitinib in Asian (Japanese or Chinese) healthy subjects as well as Asian patients with advanced solid tumors was compared with that obtained in Caucasians. Upon review, the data demonstrated that Axitinib can be characterized as not sensitive to ethnic factors based on its pharmacokinetic and pharmacodynamic properties. Axitinib exhibited similar pharmacokinetics in Asian and non-Asian subjects. A pooled population pharmacokinetic analysis indicated lack of a clinically meaningful effect of ethnicity on Axitinib disposition. Therefore, dose adjustment for Axitinib on the basis of ethnicity is not currently warranted.
-
Effect of Axitinib on the QT interval in healthy volunteers
Cancer chemotherapy and pharmacology, 2015Co-Authors: Ana Ruiz-garcia, Melvin Toh, Yazdi K. Pithavala, Nenad Sarapa, Brett E. Houk, Michael A. TortoriciAbstract:Purpose Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1–3, approved for second-line treatment of advanced renal cell carcinoma (RCC). Preclinical studies did not indicate potential for Axitinib-induced delayed cardiac repolarization.
-
Common questions regarding clinical use of Axitinib in advanced renal cell carcinoma
American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 2014Co-Authors: Diane Lorraine Borst, Yazdi K. Pithavala, Lillian Shahied Arruda, Elizabeth A. Maclean, James E. MorgadoAbstract:Purpose An overview of the responses to some of the most frequently asked questions regarding Axitinib administration and dosage modifications used in clinical practice are presented. Summary Axitinib was approved for second-line treatment of advanced renal cell carcinoma by the Food and Drug Administration on January 27, 2012. Inquiries received over the first six months after the approval date were reviewed. A large number of questions were related to administration of Axitinib in different patient populations or in patients with various comorbidities, such as its (1) use in patients unable to swallow oral medication or administration of Axitinib via a nasogastric tube, (2) use in patients with renal or hepatic impairment, (3) central nervous system penetration and use in patients with brain metastases, (4) drug interactions, particularly with anticoagulants, and (5) dosage modifications. Responses to these inquiries were provided based on the published literature or from data on file from the manufacturer. The dosage of Axitinib can be adjusted for use in patients with hepatic impairment or in patients who cannot otherwise tolerate the usual regimen. Patients taking concomitant warfarin can also take Axitinib, and patients who cannot swallow oral medications can receive a liquid formulation of the drug, though its efficacy and comparability to the tablet formulation has not been tested. Conclusion Based on the published literature and company data on file, the Axitinib dosage may be modified to accommodate patients with renal or hepatic impairment, who cannot swallow oral medication, are receiving concomitant warfarin, or who cannot otherwise tolerate the standard dosage regimen. For patients who cannot swallow, an oral suspension can be prepared because crushing Axitinib is not recommended.
-
Axitinib with or without dose titration for first line metastatic renal cell carcinoma a randomised double blind phase 2 trial
Lancet Oncology, 2013Co-Authors: Brian I. Rini, Angel H. Bair, Yazdi K. Pithavala, Bohuslav Melichar, Takeshi Ueda, Viktor Grunwald, Mayer Fishman, Glen Ian Andrews, Jose Angel Arranz, Dmitri PavlovAbstract:Summary Background Population pharmacokinetic data suggest Axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of Axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. Methods In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received Axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with Axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of Axitinib. This ongoing trial is registered with ClinicalTrials.gov, number NCT00835978. Findings Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the Axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40–67) in the Axitinib titration group had an objective response, as did 19 patients (34%, 22–48]) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49–70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients were hypertension (ten [18%] of 56 in the Axitinib titration group vs five [9%] of 56 in the placebo titration group vs 45 [49%] of 91 in the non-randomised group), diarrhoea (seven [13%] vs two [4%] vs eight [9%]), and decreased weight (four [7%] vs three [5%] vs six [7%]). One or more all-causality serious adverse events were reported in 15 (27%) patients in the Axitinib titration group, 13 (23%) patients in the placebo titration group, and 35 (38%) non-randomised patients. The most common serious adverse events in all 213 patients were disease progression and dehydration (eight each [4%]), and diarrhoea, vomiting, pneumonia, and decreased appetite (four each [2%]). Interpretation The greater proportion of patients in the Axitinib titration group achieving an objective response supports the concept of individual Axitinib dose titration in selected patients with metastatic renal-cell carcinoma. Axitinib shows clinical activity with a manageable safety profile in treatment-naive patients with this disease. Funding Pfizer Inc.
Sinil Kim - One of the best experts on this subject based on the ideXlab platform.
-
hypertension among patients with renal cell carcinoma receiving Axitinib or sorafenib analysis from the randomized phase iii axis trial
Targeted Oncology, 2015Co-Authors: Brian I. Rini, David I Quinn, Michael S Baum, Laura S Wood, Jamal Tarazi, Brad Rosbrook, Lillian Shahied Arruda, Laura Cisar, Gregory W Roberts, Sinil KimAbstract:Inhibitors of the vascular endothelial growth factor (VEGF) pathway frequently induce hypertension when used to treat patients with advanced renal cell carcinoma (RCC). This analysis characterizes hypertension and hypertension-related events in patients treated with the VEGF pathway inhibitors Axitinib or sorafenib in the AXIS trial. AXIS was a randomized phase III study of Axitinib versus sorafenib in patients with metastatic RCC following failure of one prior systemic regimen. Patients with uncontrolled hypertension were excluded, but patients with hypertension controlled with antihypertensive medication were allowed to participate. Guidelines for hypertension management included adjustment or addition of antihypertensive medications and/or Axitinib or sorafenib dose reductions, interruptions, or discontinuations. Treatment-emergent all-causality hypertension occurred in 145 (40.4 %) Axitinib-treated patients (N = 359) and 103 (29.0 %) sorafenib-treated patients (N = 355), with grade 3 hypertension reported in 55 (15.3 %) and 38 (10.7 %) patients, respectively, and grade 4 hypertension reported in one (0.3 %) patient in each arm. Hypertension-related events led to Axitinib dose interruptions (n = 46; 12.8 %), dose reductions (n = 16; 4.5 %), or discontinuations (n = 1; 0.3 %). Approximately 50 % of Axitinib-treated patients with grade 3 or 4 hypertension continued treatment for ≥ 9 months. Hypertension-related sequelae occurred in <1 % of Axitinib-treated patients. Hypertension was more frequently observed during treatment with Axitinib than sorafenib in patients with RCC, but Axitinib-induced hypertension rarely led to treatment discontinuation or cardiovascular sequelae. Recommendations for monitoring blood pressure and managing hypertension during Axitinib therapy are presented.
-
efficacy and safety of Axitinib versus sorafenib in metastatic renal cell carcinoma subgroup analysis of japanese patients from the global randomized phase 3 axis trial
Japanese Journal of Clinical Oncology, 2013Co-Authors: Takeshi Ueda, Yoshihiko Tomita, Hirotsugu Uemura, Nobuo Shinohara, Jamal Tarazi, Sinil Kim, Taiji Tsukamoto, Hiroomi Kanayama, Connie Chen, Seiichiro OzonoAbstract:Objective Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. The efficacy and safety of Axitinib in Japanese patients with metastatic renal cell carcinoma were evaluated.
-
Axitinib for first line metastatic renal cell carcinoma mrcc overall efficacy and pharmacokinetic pk analyses from a randomized phase ii study
Journal of Clinical Oncology, 2012Co-Authors: Brian I. Rini, Angel H. Bair, Ying Chen, Bohuslav Melichar, Takeshi Ueda, Viktor Grunwald, Mayer Fishman, Sinil Kim, Petr A Karlov, Eric JonaschAbstract:4503 Background: Axitinib is a potent, selective, second-generation inhibitor of vascular endothelial growth factor receptors with efficacy in mRCC. Due to PK and pharmacodynamic variability, some patients have sub-optimal drug exposures at the standard 5-mg twice daily (BID) dose. Prior analyses indicated higher drug exposure enhanced efficacy; thus, dose titration based on individual tolerability may optimize exposure and improve outcomes. A randomized phase II trial evaluated the efficacy and safety of Axitinib dose titration from 5 mg BID to a maximum of 10 mg BID in first-line mRCC. Methods: Patients with treatment-naive mRCC received Axitinib 5 mg BID for a 4-week lead-in period (cycle 1). Then, patients with 2 consecutive weeks of blood pressure (BP) ≤150/90 mmHg, no Axitinib-related toxicities >grade 2, no dose reductions, and ≤2 antihypertensive medications were randomized in a double-blind fashion to Axitinib 5 mg BID + dose titration with either Axitinib (arm A) or placebo (arm B); those inelig...
-
Phase III AXIS trial for second-line metastatic renal cell carcinoma (mRCC): Effect of prior first-line treatment duration and Axitinib dose titration on Axitinib efficacy.
Journal of Clinical Oncology, 2012Co-Authors: Brian I. Rini, Jamal Tarazi, Brad Rosbrook, Bernard Escudier, M. Dror Michaelson, Sylvie Negrier, Martin Gore, Stéphane Oudard, Joseph I. Clark, Sinil KimAbstract:354 Background: Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. In the phase 3 AXIS trial of Axitinib vs sorafenib for second-line mRCC, Axitinib significantly prolonged median progression-free survival (mPFS) (6.7 vs 4.7 months; hazard ratio 0.665; P grade 2 and BP 2 weeks were eligible to increase Axitinib dose to 7 mg BID and then to 10 mg BID. Result...
-
Phase I study of Axitinib (AG-013736) in combination with gemcitabine in patients with advanced pancreatic cancer.
Investigational new drugs, 2011Co-Authors: Jean-philippe Spano, Yazdi K. Pithavala, Sinil Kim, Malcolm J. Moore, Alejandro D. Ricart, Olivier RixeAbstract:Purpose Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, is under investigation for treatment of various solid tumors. The safety and pharmacokinetics of Axitinib in combination with gemcitabine in patients with advanced pancreatic cancer was evaluated in the phase I portion of this trial. The randomized phase II portion was reported separately. Patients and methods Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Pharmacokinetic profiles of the drugs were obtained on cycle (C) 1 day (D) 1 (gemcitabine alone 1,000 mg/m2), C1D14 (steady state, Axitinib alone 5 mg twice daily [BID]), and C1D15 (gemcitabine plus steady-state Axitinib). Adverse events were monitored weekly at the clinic. Results Eight patients participated in the phase IB portion of the trial. Patients received gemcitabine on D1, D8, and D15 and continuous Axitinib in a 28 day-cycle beginning C1D3. There was no dose-limiting toxicity. Common treatment-related adverse events included fatigue, diarrhea, dysphonia, and hypertension. Myelosuppression was similar to gemcitabine monotherapy. No apparent major pharmacokinetic interactions between gemcitabine and Axitinib were observed. Of six patients evaluable for efficacy, three had confirmed partial responses. Conclusions Axitinib (5 mg BID) and gemcitabine (1,000 mg/m2) were well tolerated when administered together, without any pharmacokinetic interactions, and showed encouraging antitumor activity.