Background: Futibatinib, an irreversible FGFR1-4 inhibitor, is indicated for the treatment of adu... more Background: Futibatinib, an irreversible FGFR1-4 inhibitor, is indicated for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions or other rearrangements. As the primary elimination pathway for futibatinib is hepatic metabolism, we conducted a phase 1 study to evaluate the effect of hepatic impairment (HI) on futibatinib pharmacokinetics (PK) and safety in healthy adults. Methods: A single oral dose of 20 mg futibatinib was administered to adult subjects with mild (Child-Pugh score, 5-6), moderate (7-9), or severe (10-15) HI. Control healthy subjects were matched to each HI cohort according to age, body mass index, and sex. Intensive PK samples were collected up to 72 hours post-dose. Exposure measures (AUC0-inf, AUC0-t, and Cmax) in subjects with HI were compared with matching control cohorts and with the overall healthy-control cohort. Relationships between plasma PK and HI were examined graphically via scatter/regression plots of PK parameters versus baseline Child-Pugh score, bilirubin, albumin, international normalized ratio, and aspartate aminotransferase. Results: Overall, 38 subjects were enrolled (mild HI, n = 8; moderate HI, n = 8; severe HI, n = 6; healthy controls, n = 16). Following the administration of futibatinib, no trend was observed between the severity of HI and the extent of futibatinib exposure increase. Compared with matched controls, AUC0-inf increased by 21%, 20% and 18%, and Cmax by 43%, 15%, and 10% in subjects with mild, moderate, and severe HI, respectively. Changes in exposure were not considered clinically relevant as geometric mean ratios were within 80-125% bioequivalence limits, except for Cmax in subjects with mild HI (43%). Futibatinib PK parameters and HI measures did not appear to be associated based on visual inspection or statistical evaluation of regression plots (p-values all > 0.05). No subjects discontinued from the study due to treatment-emergent adverse events (TEAEs). Overall, two (12.5%) subjects in the healthy-control cohort reported one Grade 1 TEAE each (dyspepsia and headache) and two (25.0 %) subjects in the mild HI cohort each reported one Grade 1 TEAE (toothache and headache). All TEAEs were considered related to treatment. No subjects with moderate/severe HI reported TEAEs. Conclusions: No clinically meaningful differences in the systemic plasma exposure of futibatinib were observed based on the severity of HI. Single oral doses of futibatinib were well tolerated among subjects with varying degrees of HI and matched healthy adult subjects in this study. The data suggest that dose adjustment may not be necessary in patients with HI receiving futibatinib 20 mg QD for its approved indication. Citation Format: Ling Gao, Ikuo Yamamiya, Mark Pinti, Juan Carlos Rondón, Thomas Marbury, Gareth Tomlinson, Lukas Makris, Nanae Hangai, Volker Wacheck. Phase 1, open-label, single-dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib in adult subjects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT192.
Background. The management of modifiable risk factors exposure, in particular dyslipidemia, is th... more Background. The management of modifiable risk factors exposure, in particular dyslipidemia, is the first line of intervention in preventing cardiovascular events. HDLs have been demonstrated to have anti-inflammatory and atheroprotective properties and, among HDLs, Apolipoprotein A-I (APOA-1), which promotes reverse cholesterol efflux, has been deeply investigated for the great therapeutic potential, particularly emphasized for the naturally occurring mutation APOA-1Milano (APOA-1M). Despite the high therapeutic potential of these molecules, their purification and delivery into the disordered organism is still limited by a very low efficiency in these processes. Aim: To develop an efficient system of production and delivery of APOA-1 muteins without need of purification. Methods and Results. Rice plants were genetically modified to express APOA-1M protein in their seeds. Protein extract from transgenic rice seeds (the 'APOA-1M rice milk') was tested for functionality in vitro on THP-1 macrophages exposed to oxLDL. Protein extract from wild type rice seeds (the 'WT rice milk') was used as control. The APOA-1M rice milk, but not the WT rice milk, significantly reduced expression of MCP-1 in oxLDL-loaded THP-1 macrophages in a dose-dependent manner and it promoted reverse cholesterol efflux in THP-1 macrophages. The lack of toxicity and the tolerability of the orally administered APOA-1M rice milk was evaluated in healthy mice. In an early-intermediate atherosclerotic mouse model (Apoe-/mice fed with Western Diet for 8 weeks), 3 weeks of APOA-1M, but not the WT, rice milk treatment (15d, 5d/week, by oral gavage) significantly reduced area of lipid deposition and lipids concentration at aortic arch (en face analysis). Moreover, the APOA-1M, but not the WT, rice milk treatment reduced the hepatic CD68-positive cells and ameliorated the lipid management gene expression profile in liver of WD-fed Apoe-/mice. Interestingly, all these findings were observed in mice still exposed to WD during the therapeutic treatment. Conclusion. The oral delivery of APOA-1M muteins, by means of genetically modified rice seeds extract, is athero-protective and anti-inflammatory even if the organism is exposed to high fat diet during the treatment, suggesting that this therapeutic approach could be effective in preventing and in counteracting atherogenic risk factors.
4038 Background: The incidence of GEJC is increasing in North America and Europe, especially amon... more 4038 Background: The incidence of GEJC is increasing in North America and Europe, especially among white men. Many pts present with metastatic disease or relapse locally or systemically after resection of early-stage disease. The global phase 3 study TAGS (NCT02500043) demonstrated the efficacy and safety of FTD/TPI in previously treated pts with metastatic gastric cancer (mGC)/mGEJC. Here we report results in the mGEJC subgroup from TAGS. Methods: Pts with mGC/mGEJC treated with ≥2 prior chemotherapy regimens were randomized (2:1) to receive FTD/TPI (35 mg/m2 BID on days 1–5 and 8–12 of each 28-day cycle) or placebo, plus best supportive care. A preplanned efficacy and safety analysis was performed in pts with mGEJC. Results: Of 507 randomized pts, 145 (29%) had GEJC as the sole primary disease site (FTD/TPI, 98/337; placebo, 47/170). Of pts with mGEJC, 85% were male and 83% were white (overall population, 73% and 70%). Baseline characteristics were generally balanced for pts with mGEJC across treatment groups, except for fewer pts having prior gastrectomy (40% vs 55%) and more pts having received ≥3 prior regimens (74% vs 66%) in the FTD/TPI group than in the placebo group. FTD/TPI had an efficacy benefit in pts with mGEJC, and the FTD/TPI safety profile was similar in this subgroup and the overall population (table). Conclusions: FTD/TPI showed a manageable safety profile and efficacy benefit in pts with mGEJC in the TAGS trial, despite heavier pretreatment of the FTD/TPI than the placebo group. Clinical trial information: NCT02500043. [Table: see text]
Purpose: This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combinat... more Purpose: This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan in patients with advanced gastrointestinal tumors, and evaluated the safety, pharmacokinetics, and antitumor activity of the FTD/TPI, irinotecan, and bevacizumab triplet combination in previously treated metastatic colorectal cancer (mCRC). Patients and Methods: Dose escalation (3þ3 design) in advanced gastrointestinal tumors was followed by expansion in mCRC. During dose escalation, patients received FTD/TPI (20-35 mg/m 2 twice daily; days 1-5 of a 14-day cycle) and irinotecan (120-180 mg/m 2 ; day 1). During expansion, the MTD of FTD/TPI and irinotecan plus bevacizumab (5 mg/kg; day 1) was administered. Results: Fifty patients (26 across six dose-escalation cohorts and 24 in the expansion phase) were enrolled. Two dose-limiting toxicities (fatigue and neutropenia) were observed in the doseescalation phase, and MTD was defined as FTD/TPI 25 mg/m 2 twice daily plus irinotecan 180 mg/m 2. In the expansion phase, 83% (20/24) experienced any-cause grade !3 adverse events (AEs) with the triplet combination, most frequently neutropenia (42%), leukopenia (25%), and diarrhea (12%). AEs of any-cause led to dosing interruptions, modifications, and discontinuations in 29%, 17%, and 4% of patients, respectively. No treatmentrelated deaths occurred. Three patients (12%) experienced partial responses and 16 (67%) patients had stable disease lasting >4 months. The median progression-free survival was 7.9 months (95% confidence interval, 5.1-13.4 months). Conclusions: Tolerability and activity observed in this phase I trial support further investigation of the FTD/TPI-irinotecanbevacizumab combination in previously treated mCRC.
greater compared to normal arteries (p,0.019; Figure 1). There was a 311% increase of colony coun... more greater compared to normal arteries (p,0.019; Figure 1). There was a 311% increase of colony count in the atherosclerotic compared to control. In addition, by SEM there was extensive numbers of bacteria attached to cholesterol crystals on the atherosclerotic plaques (Figure 2). Crystals appeared to be degrading. Only few bacteria were found attached to the intimal surface of normal arteries. Conclusions: Bacteria appear to preferentially adhere to cholesterol crystals in human atherosclerotic arteries similar to previous findings reported in rabbit atherosclerotic arteries. Studies to evaluate the mechanism of this process are currently underway. However, the current findings suggest that bacteria may be utilizing cholesterol crystals as a source of nutrition.
Page 1. Antihypertensive efficacy and tolerability of once daily losartan potassium compared with... more Page 1. Antihypertensive efficacy and tolerability of once daily losartan potassium compared with Captopril in patients with mild to moderate essential hypertension Jean-Michel Mallion*, Deborah C. Bradstreet, Lukas Makrís ...
greater compared to normal arteries (p,0.019; Figure 1). There was a 311% increase of colony coun... more greater compared to normal arteries (p,0.019; Figure 1). There was a 311% increase of colony count in the atherosclerotic compared to control. In addition, by SEM there was extensive numbers of bacteria attached to cholesterol crystals on the atherosclerotic plaques (Figure 2). Crystals appeared to be degrading. Only few bacteria were found attached to the intimal surface of normal arteries. Conclusions: Bacteria appear to preferentially adhere to cholesterol crystals in human atherosclerotic arteries similar to previous findings reported in rabbit atherosclerotic arteries. Studies to evaluate the mechanism of this process are currently underway. However, the current findings suggest that bacteria may be utilizing cholesterol crystals as a source of nutrition.
Futibatinib is a covalently binding FGFR1–4 inhibitor that received US Food and Drug Administrati... more Futibatinib is a covalently binding FGFR1–4 inhibitor that received US Food and Drug Administration approval for the treatment of patients with previously treated, advanced intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions/rearrangements. This phase I trial evaluated the pharmacokinetics (PKs), safety, and tolerability of futibatinib in subjects with impaired hepatic function and matched healthy volunteers. Twenty‐two subjects with hepatic impairment (8 mild [Child‐Pugh 5–6], 8 moderate [7–9], and 6 severe [10–15]) and 16 matched healthy control subjects received a single oral dose of futibatinib 20 mg. Futibatinib PKs were compared between subjects with mild/moderate/severe hepatic impairment and each corresponding control cohort and the overall control cohort. Relationships between futibatinib PKs and Child‐Pugh scores and liver function tests were examined via scatter/regression plots. Compared with matched controls, the area under the plasma concentration–time curve f...
Objective: The objective of this Phase 2, open-label, multicenter study is to investigate the ant... more Objective: The objective of this Phase 2, open-label, multicenter study is to investigate the antitumor activity of navicixizumab monotherapy or in combination with chemotherapy in patients with advanced solid tumors. Cohort C will enroll triple-negative breast cancer (TNBC) patients. Background: Navicixizumab is a bispecific humanized monoclonal immunoglobulin G2 kappa antibody directed against human delta-like ligand 4, a critical ligand of the NOTCH pathway, and human vascular endothelial growth factor (VEGF). Aberrant NOTCH signaling is associated with chemotherapy resistance, tumor plasticity, enhanced metastatic potential, promotion of a cancer stem cell phenotype, and immune evasion. In TNBC, aberrant NOTCH expression is associated with poor prognosis, making targeting of this pathway an attractive therapeutic strategy. Additionally, NOTCH may mediate resistance to angiogenesis inhibition. While VEGF inhibitors are approved for the treatment of multiple solid tumors, observed...
634 Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trif... more 634 Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Efficacy and safety of TAS-102 in patients with metastatic colorectal cancer refractory/intolerant to standard therapies were evaluated in the RECOURSE trial. Original results of RECOURSE based on the cut-off date of January 24, 2014, in which 72% of mortality events had occurred, demonstrated a significant improvement in overall survival (OS) with TAS-102 vs placebo. Here we report results of an updated survival analysis from RECOURSE and a retrospective analysis of OS outcomes based on a clinical prognostic risk index. Methods: Patients were randomized 2:1 to receive TAS-102 or placebo. Study treatment continued until disease progression, death, or unacceptable toxicity. The primary endpoint was OS; final survival data were collected on October 8, 2014. A clinical OS prognostic risk score was assessed to evalua...
Background: Futibatinib, an irreversible FGFR1-4 inhibitor, is indicated for the treatment of adu... more Background: Futibatinib, an irreversible FGFR1-4 inhibitor, is indicated for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions or other rearrangements. As the primary elimination pathway for futibatinib is hepatic metabolism, we conducted a phase 1 study to evaluate the effect of hepatic impairment (HI) on futibatinib pharmacokinetics (PK) and safety in healthy adults. Methods: A single oral dose of 20 mg futibatinib was administered to adult subjects with mild (Child-Pugh score, 5-6), moderate (7-9), or severe (10-15) HI. Control healthy subjects were matched to each HI cohort according to age, body mass index, and sex. Intensive PK samples were collected up to 72 hours post-dose. Exposure measures (AUC0-inf, AUC0-t, and Cmax) in subjects with HI were compared with matching control cohorts and with the overall healthy-control cohort. Relationships between plasma PK and HI were examined graphically via scatter/regression plots of PK parameters versus baseline Child-Pugh score, bilirubin, albumin, international normalized ratio, and aspartate aminotransferase. Results: Overall, 38 subjects were enrolled (mild HI, n = 8; moderate HI, n = 8; severe HI, n = 6; healthy controls, n = 16). Following the administration of futibatinib, no trend was observed between the severity of HI and the extent of futibatinib exposure increase. Compared with matched controls, AUC0-inf increased by 21%, 20% and 18%, and Cmax by 43%, 15%, and 10% in subjects with mild, moderate, and severe HI, respectively. Changes in exposure were not considered clinically relevant as geometric mean ratios were within 80-125% bioequivalence limits, except for Cmax in subjects with mild HI (43%). Futibatinib PK parameters and HI measures did not appear to be associated based on visual inspection or statistical evaluation of regression plots (p-values all > 0.05). No subjects discontinued from the study due to treatment-emergent adverse events (TEAEs). Overall, two (12.5%) subjects in the healthy-control cohort reported one Grade 1 TEAE each (dyspepsia and headache) and two (25.0 %) subjects in the mild HI cohort each reported one Grade 1 TEAE (toothache and headache). All TEAEs were considered related to treatment. No subjects with moderate/severe HI reported TEAEs. Conclusions: No clinically meaningful differences in the systemic plasma exposure of futibatinib were observed based on the severity of HI. Single oral doses of futibatinib were well tolerated among subjects with varying degrees of HI and matched healthy adult subjects in this study. The data suggest that dose adjustment may not be necessary in patients with HI receiving futibatinib 20 mg QD for its approved indication. Citation Format: Ling Gao, Ikuo Yamamiya, Mark Pinti, Juan Carlos Rondón, Thomas Marbury, Gareth Tomlinson, Lukas Makris, Nanae Hangai, Volker Wacheck. Phase 1, open-label, single-dose study to evaluate the effect of hepatic impairment on the pharmacokinetics and safety of futibatinib in adult subjects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT192.
Background. The management of modifiable risk factors exposure, in particular dyslipidemia, is th... more Background. The management of modifiable risk factors exposure, in particular dyslipidemia, is the first line of intervention in preventing cardiovascular events. HDLs have been demonstrated to have anti-inflammatory and atheroprotective properties and, among HDLs, Apolipoprotein A-I (APOA-1), which promotes reverse cholesterol efflux, has been deeply investigated for the great therapeutic potential, particularly emphasized for the naturally occurring mutation APOA-1Milano (APOA-1M). Despite the high therapeutic potential of these molecules, their purification and delivery into the disordered organism is still limited by a very low efficiency in these processes. Aim: To develop an efficient system of production and delivery of APOA-1 muteins without need of purification. Methods and Results. Rice plants were genetically modified to express APOA-1M protein in their seeds. Protein extract from transgenic rice seeds (the 'APOA-1M rice milk') was tested for functionality in vitro on THP-1 macrophages exposed to oxLDL. Protein extract from wild type rice seeds (the 'WT rice milk') was used as control. The APOA-1M rice milk, but not the WT rice milk, significantly reduced expression of MCP-1 in oxLDL-loaded THP-1 macrophages in a dose-dependent manner and it promoted reverse cholesterol efflux in THP-1 macrophages. The lack of toxicity and the tolerability of the orally administered APOA-1M rice milk was evaluated in healthy mice. In an early-intermediate atherosclerotic mouse model (Apoe-/mice fed with Western Diet for 8 weeks), 3 weeks of APOA-1M, but not the WT, rice milk treatment (15d, 5d/week, by oral gavage) significantly reduced area of lipid deposition and lipids concentration at aortic arch (en face analysis). Moreover, the APOA-1M, but not the WT, rice milk treatment reduced the hepatic CD68-positive cells and ameliorated the lipid management gene expression profile in liver of WD-fed Apoe-/mice. Interestingly, all these findings were observed in mice still exposed to WD during the therapeutic treatment. Conclusion. The oral delivery of APOA-1M muteins, by means of genetically modified rice seeds extract, is athero-protective and anti-inflammatory even if the organism is exposed to high fat diet during the treatment, suggesting that this therapeutic approach could be effective in preventing and in counteracting atherogenic risk factors.
4038 Background: The incidence of GEJC is increasing in North America and Europe, especially amon... more 4038 Background: The incidence of GEJC is increasing in North America and Europe, especially among white men. Many pts present with metastatic disease or relapse locally or systemically after resection of early-stage disease. The global phase 3 study TAGS (NCT02500043) demonstrated the efficacy and safety of FTD/TPI in previously treated pts with metastatic gastric cancer (mGC)/mGEJC. Here we report results in the mGEJC subgroup from TAGS. Methods: Pts with mGC/mGEJC treated with ≥2 prior chemotherapy regimens were randomized (2:1) to receive FTD/TPI (35 mg/m2 BID on days 1–5 and 8–12 of each 28-day cycle) or placebo, plus best supportive care. A preplanned efficacy and safety analysis was performed in pts with mGEJC. Results: Of 507 randomized pts, 145 (29%) had GEJC as the sole primary disease site (FTD/TPI, 98/337; placebo, 47/170). Of pts with mGEJC, 85% were male and 83% were white (overall population, 73% and 70%). Baseline characteristics were generally balanced for pts with mGEJC across treatment groups, except for fewer pts having prior gastrectomy (40% vs 55%) and more pts having received ≥3 prior regimens (74% vs 66%) in the FTD/TPI group than in the placebo group. FTD/TPI had an efficacy benefit in pts with mGEJC, and the FTD/TPI safety profile was similar in this subgroup and the overall population (table). Conclusions: FTD/TPI showed a manageable safety profile and efficacy benefit in pts with mGEJC in the TAGS trial, despite heavier pretreatment of the FTD/TPI than the placebo group. Clinical trial information: NCT02500043. [Table: see text]
Purpose: This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combinat... more Purpose: This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan in patients with advanced gastrointestinal tumors, and evaluated the safety, pharmacokinetics, and antitumor activity of the FTD/TPI, irinotecan, and bevacizumab triplet combination in previously treated metastatic colorectal cancer (mCRC). Patients and Methods: Dose escalation (3þ3 design) in advanced gastrointestinal tumors was followed by expansion in mCRC. During dose escalation, patients received FTD/TPI (20-35 mg/m 2 twice daily; days 1-5 of a 14-day cycle) and irinotecan (120-180 mg/m 2 ; day 1). During expansion, the MTD of FTD/TPI and irinotecan plus bevacizumab (5 mg/kg; day 1) was administered. Results: Fifty patients (26 across six dose-escalation cohorts and 24 in the expansion phase) were enrolled. Two dose-limiting toxicities (fatigue and neutropenia) were observed in the doseescalation phase, and MTD was defined as FTD/TPI 25 mg/m 2 twice daily plus irinotecan 180 mg/m 2. In the expansion phase, 83% (20/24) experienced any-cause grade !3 adverse events (AEs) with the triplet combination, most frequently neutropenia (42%), leukopenia (25%), and diarrhea (12%). AEs of any-cause led to dosing interruptions, modifications, and discontinuations in 29%, 17%, and 4% of patients, respectively. No treatmentrelated deaths occurred. Three patients (12%) experienced partial responses and 16 (67%) patients had stable disease lasting >4 months. The median progression-free survival was 7.9 months (95% confidence interval, 5.1-13.4 months). Conclusions: Tolerability and activity observed in this phase I trial support further investigation of the FTD/TPI-irinotecanbevacizumab combination in previously treated mCRC.
greater compared to normal arteries (p,0.019; Figure 1). There was a 311% increase of colony coun... more greater compared to normal arteries (p,0.019; Figure 1). There was a 311% increase of colony count in the atherosclerotic compared to control. In addition, by SEM there was extensive numbers of bacteria attached to cholesterol crystals on the atherosclerotic plaques (Figure 2). Crystals appeared to be degrading. Only few bacteria were found attached to the intimal surface of normal arteries. Conclusions: Bacteria appear to preferentially adhere to cholesterol crystals in human atherosclerotic arteries similar to previous findings reported in rabbit atherosclerotic arteries. Studies to evaluate the mechanism of this process are currently underway. However, the current findings suggest that bacteria may be utilizing cholesterol crystals as a source of nutrition.
Page 1. Antihypertensive efficacy and tolerability of once daily losartan potassium compared with... more Page 1. Antihypertensive efficacy and tolerability of once daily losartan potassium compared with Captopril in patients with mild to moderate essential hypertension Jean-Michel Mallion*, Deborah C. Bradstreet, Lukas Makrís ...
greater compared to normal arteries (p,0.019; Figure 1). There was a 311% increase of colony coun... more greater compared to normal arteries (p,0.019; Figure 1). There was a 311% increase of colony count in the atherosclerotic compared to control. In addition, by SEM there was extensive numbers of bacteria attached to cholesterol crystals on the atherosclerotic plaques (Figure 2). Crystals appeared to be degrading. Only few bacteria were found attached to the intimal surface of normal arteries. Conclusions: Bacteria appear to preferentially adhere to cholesterol crystals in human atherosclerotic arteries similar to previous findings reported in rabbit atherosclerotic arteries. Studies to evaluate the mechanism of this process are currently underway. However, the current findings suggest that bacteria may be utilizing cholesterol crystals as a source of nutrition.
Futibatinib is a covalently binding FGFR1–4 inhibitor that received US Food and Drug Administrati... more Futibatinib is a covalently binding FGFR1–4 inhibitor that received US Food and Drug Administration approval for the treatment of patients with previously treated, advanced intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions/rearrangements. This phase I trial evaluated the pharmacokinetics (PKs), safety, and tolerability of futibatinib in subjects with impaired hepatic function and matched healthy volunteers. Twenty‐two subjects with hepatic impairment (8 mild [Child‐Pugh 5–6], 8 moderate [7–9], and 6 severe [10–15]) and 16 matched healthy control subjects received a single oral dose of futibatinib 20 mg. Futibatinib PKs were compared between subjects with mild/moderate/severe hepatic impairment and each corresponding control cohort and the overall control cohort. Relationships between futibatinib PKs and Child‐Pugh scores and liver function tests were examined via scatter/regression plots. Compared with matched controls, the area under the plasma concentration–time curve f...
Objective: The objective of this Phase 2, open-label, multicenter study is to investigate the ant... more Objective: The objective of this Phase 2, open-label, multicenter study is to investigate the antitumor activity of navicixizumab monotherapy or in combination with chemotherapy in patients with advanced solid tumors. Cohort C will enroll triple-negative breast cancer (TNBC) patients. Background: Navicixizumab is a bispecific humanized monoclonal immunoglobulin G2 kappa antibody directed against human delta-like ligand 4, a critical ligand of the NOTCH pathway, and human vascular endothelial growth factor (VEGF). Aberrant NOTCH signaling is associated with chemotherapy resistance, tumor plasticity, enhanced metastatic potential, promotion of a cancer stem cell phenotype, and immune evasion. In TNBC, aberrant NOTCH expression is associated with poor prognosis, making targeting of this pathway an attractive therapeutic strategy. Additionally, NOTCH may mediate resistance to angiogenesis inhibition. While VEGF inhibitors are approved for the treatment of multiple solid tumors, observed...
634 Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trif... more 634 Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine, and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Efficacy and safety of TAS-102 in patients with metastatic colorectal cancer refractory/intolerant to standard therapies were evaluated in the RECOURSE trial. Original results of RECOURSE based on the cut-off date of January 24, 2014, in which 72% of mortality events had occurred, demonstrated a significant improvement in overall survival (OS) with TAS-102 vs placebo. Here we report results of an updated survival analysis from RECOURSE and a retrospective analysis of OS outcomes based on a clinical prognostic risk index. Methods: Patients were randomized 2:1 to receive TAS-102 or placebo. Study treatment continued until disease progression, death, or unacceptable toxicity. The primary endpoint was OS; final survival data were collected on October 8, 2014. A clinical OS prognostic risk score was assessed to evalua...
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