gastric cancer is the fourth most common malignancy and the second leading cause of cancer death worldwide . cases of gastric cancer in eastern asia account for half of the world total , and the highest estimated mortality rates are reported in those countries . for advanced gastric cancer , first - line therapy with combination chemotherapy results in improved overall survival ( os ) compared with best supportive care or single - agent chemotherapy . treatment guidelines , therefore , recommend first - line combination regimens incorporating a platinum agent and a fluoropyrimidine . different targets contributing to the pathogenesis of gastric cancer have been explored in attempts to improve outcomes . human epidermal growth factor receptor 2 ( her2 ) is an important target in gastric cancer . the combination of trastuzumab , a her2-targeted agent , with cisplatin and a fluoropyrimidine significantly improved median os compared with chemotherapy alone as first - line therapy in patients with her2-postive advanced gastric cancer . in addition , expression of vascular endothelial growth factor ( vegf ) is more likely to occur in gastric tumors than in non - cancerous tissue , and vegf expression is associated with worse survival in patients with gastric cancer . several vegf - targeted agents ( bevacizumab , sorafenib , sunitinib [ 8 - 10 ] , and ramucirumab ) have been evaluated in patients with advanced gastric cancer . in a phase iii randomized trial , ramucirumab plus best supportive care improved os compared with best supportive care alone as second - line therapy in patients with metastatic gastric cancer . axitinib is a potent and selective second - generation inhibitor of vegf receptors 1 , 2 , and 3 . it is approved in the united states , european union , and other countries for treatment of advanced renal cell carcinoma after failure of one prior systemic therapy , based on the phase iii axis trial , which demonstrated that axitinib significantly improved progression - free survival ( pfs ) compared with sorafenib as second - line therapy . phase ii trials have evaluated the antitumor activity of axitinib as a single agent in thyroid cancer , non - small cell lung cancer , and melanoma , and in combination with chemotherapy in pancreatic , breast , colorectal cancer , and other indication . this phase i trial was designed to evaluate the tolerability of axitinib administered at the starting dose of 5 mg twice a day in combination with therapeutic doses of cisplatin / capecitabine in patients with advanced gastric cancer . this open - label phase i trial evaluating axitinib in combination with cisplatin / capecitabine in patients with previously untreated advanced gastric cancer was conducted at three sites in korea and two sites in japan . the primary objective of this trial was to assess the tolerability of axitinib administered at the standard starting dose in combination with cisplatin / capecitabine , and to determine the maximum tolerated dose ( mtd ) of the combination regimen by evaluating first - cycle dose - limiting toxicities ( dlts ) and overall safety . the secondary objectives were to evaluate the plasma pharmacokinetics ( pks ) of axitinib , cisplatin , and capecitabine and its metabolite 5-fluorouracil ( 5-fu ) when administered at the mtd , and to assess preliminary antitumor activity of the combination . the study was conducted in accordance with the declaration of helsinki , the international conference on harmonization guideline on good clinical practice , the study protocol , and applicable local regulatory requirements and laws . the study protocol , amendments , and informed consent forms were approved by an institutional review board / independent ethics committee . patients aged  20 years at japanese sites or  18 years at korean sites with stage iv gastric or gastroesophageal junction adenocarcinoma ( type ii or iii tumors ) for which curative intent was not possible , and at least one unidimensionally measureable lesion using a modified response evaluation criteria in solid tumors ( recist ) ver . patients were required to have eastern cooperative oncology group performance status of 0 or 1 ; adequate bone marrow , renal , and hepatic function ; and blood pressure ( bp )  130/80 mm hg . patients who had undergone radiation therapy or surgery within 4 weeks prior to study entry or prior treatment with a systemic anticancer agent for advanced gastric cancer were excluded . palliative radiation therapy to non - target lesions within 2 weeks prior to study entry was allowed . patients with disease progression while on prior adjuvant treatment or progression - free interval < 6 months after completion of adjuvant therapy were not permitted . because the trastuzumab trial   results were unknown when this trial was designed , her2 status was not assessed . patients in dose level ( dl ) 1 received cisplatin 80 mg / m intravenously over 2 hours on day 1 and capecitabine 1,000 mg / m twice a day orally within 30 minutes after a meal on days 1 to 14 of each 21-day cycle . axitinib was taken orally with food at a starting dose of 5 mg twice a day on days 1 to 21 . on day 1 , a 5-hydroxytryptamine3-receptor antagonist and dexamethasone were administered before cisplatin , with vigorous hydration according to institutional practices . in cycle 1 , patients in the pk expansion subgroup received lead - in dosing with axitinib beginning on day 3 and continuing through day 18 , with administration of cisplatin on day 1 and capecitabine on days 1 to 14 . on day 19 of cycle 1 , axitinib was temporarily stopped for 3 days before cycle 2 . in cycle 2 , cisplatin was administered on day 1 and capecitabine on days 1 to 14 , with axitinib restarted on day 2 and continued without any planned interruptions thereafter ( fig . if more than one of the first six patients experienced a dlt ( table 1 ) during cycle 1 , patients would have been enrolled in dl 1 : axitinib 3 mg twice a day on days 1 - 21 or cisplatin 60 mg / m on day 1 or capecitabine 800 mg / m twice a day on days 1 - 14 of each 21-day cycle . investigators , in discussion with the sponsor , had the discretion to discontinue , delay , or modify the dosages of the drugs depending on the severity and timing of adverse events ( aes ) . axitinib - related hypertension ( bp > 150/100 mm hg ) was managed by increasing the dose of existing or adding new antihypertensive medication . if the patient was already on maximal antihypertensive therapy , axitinib was to be reduced to the next lower dose ( i.e. , 3 or 2 mg twice a day ) . if the patient developed recurrent bp > 150/100 mm hg , axitinib was to be reduced to the next lower dose ; reductions < 2 mg twice a day required discussion with the sponsor . if bp was > 160/105 mm hg , axitinib was to be stopped and then restarted at the next lower dose when bp returned to < 150/100 mm hg . once the dose was reduced for axitinib - related toxicity , it was not generally re - escalated . patients were treated until disease progression , intolerable toxicity , withdrawal of consent , or removal from the study by the investigator . patients requiring the use of strong cytochrome p450 ( cyp ) 3a4/5 or cyp1a2 inducers or strong cyp3a4/5 inhibitors were not eligible for enrollment ; however , if these drugs were required during the study , they were allowed and adjustment of axitinib dosage was to be considered . to determine the mtd , if no more than one dlt ( table 1 ) was observed during cycle 1 , another three patients were to be enrolled at dl1 to complete the enrollment of six patients into the cohort . if cycle 1 toxicities at dl1 exceed the mtd , patients would be enrolled in dl 1 . if no more than one of the six patients experienced a dlt during cycle 1 , another six patients were to be entered at dl1 . the mtd was the highest dose at which  30% of the 12 patients experienced a dlt during cycle 1 . if dl1 did not exceed the mtd for the combination , this would be declared the mtd as higher dose level cohorts were not planned in this study . an additional 10 patients were to be enrolled in an expansion cohort at the mtd for collection of further safety , pk , and antitumor activity data . safety was based on the incidence and severity ( graded by common terminology criteria for adverse events ver . 3.0 ) of aes , and assessment of laboratory tests , home bp monitoring , and physical examinations . pk sampling and analysis for axitinib , cisplatin , and capecitabine and its metabolite 5-fu in plasma were performed for 10 patients in the mtd expansion cohort from whom complete data were available . standard plasma pk parameters , including maximum observed plasma concentration ( cmax ) , time at which cmax was observed ( tmax ) , area under the curve ( auc ) from time 0 extrapolated to infinite time ( aucinf ) , auc from time 0 to 24 hours ( auc24 ) , terminal half - life ( t1/2 ) , clearance ( cl ) or apparent oral clearance ( cl / f ) , and volume of distribution during the elimination phase ( vz ) or apparent volume of distribution during the elimination phase ( vz / f ) , were estimated using the validated enca ver . , new york , ny ; proprietary software for non - compartmental parameter estimation ) . the study design allowed for evaluation in each patient of the pk of steady - state axitinib alone on cycle 1 , day 1 ; cisplatin / capecitabine alone on cycle 2 , day 1 ; and cisplatin / capecitabine plus steady - state axitinib on cycle 1 , day 1 ( fig . axitinib pk samples were collected prior to and 1 , 2 , 3 , 4 , 6 , and 8 hours after axitinib dosing . capecitabine pk samples were collected prior to and 0.25 , 0.5 , 1 , 2 , 3 , 4 , 6 , and 8 hours after capecitabine dosing . cisplatin pk samples were collected prior to the start of cisplatin infusion , 0.5 and 1 hours ( during infusion ) , 2 hours ( end of infusion ) , and 1 , 2 , 4 , and 6 hours after the end of infusion . plasma concentrations of axitinib were measured using a validated , sensitive , and specific high - performance liquid chromatography with tandem mass spectrometric ( hplc / ms / ms ) detection method ( charles river laboratories preclinical services , shrewsbury , ma ) . the lower limit of quantification ( lloq ) for axitinib was 0.500 ng / ml . platinum ( derived from cisplatin ) concentrations in plasma and plasma ultrafiltrate ( puf ) were analyzed ( covance laboratories , madison , wi ) using validated , sensitive , and specific inductively coupled plasma mass spectrometric methods . the lloq for platinum was 2.00 ng / ml in plasma and 1.00 ng / ml in puf . analysis of plasma samples ( wuxi apptec , shanghai , china ) for concentrations of capecitabine and its metabolite 5-fu was performed using a validated , sensitive , and specific hplc / ms / ms method . the lloq was 20.0 ng / ml for capecitabine and 5.00 ng / ml for 5-fu . the study sample size was dependent on the observed safety profile of axitinib plus chemotherapy , which determined the number of patients per dl . analysis of efficacy and safety was performed for all patients who received at least one dose of study medication . descriptive statistics ( mean , median , standard deviation , and range for continuous data ; percentage for categorical data ; and 95% confidence interval [ ci ] , if applicable ) were used to summarize patient characteristics , treatment administration / compliance , antitumor activity , safety , and pk parameters . the kaplan - meier method was used to estimate the duration of response ( time from first demonstration of partial or complete response to documented disease progression ) and pfs ( time from start date to date of first documentation of progression or death due to any cause ) . the study was not powered for detection of differences in pk parameters for capecitabine , cisplatin , or axitinib alone or in combination . all analyses were performed based on final data following database closure , with a data cutoff date of october 17 , 2012 . this open - label phase i trial evaluating axitinib in combination with cisplatin / capecitabine in patients with previously untreated advanced gastric cancer was conducted at three sites in korea and two sites in japan . the primary objective of this trial was to assess the tolerability of axitinib administered at the standard starting dose in combination with cisplatin / capecitabine , and to determine the maximum tolerated dose ( mtd ) of the combination regimen by evaluating first - cycle dose - limiting toxicities ( dlts ) and overall safety . the secondary objectives were to evaluate the plasma pharmacokinetics ( pks ) of axitinib , cisplatin , and capecitabine and its metabolite 5-fluorouracil ( 5-fu ) when administered at the mtd , and to assess preliminary antitumor activity of the combination . the study was conducted in accordance with the declaration of helsinki , the international conference on harmonization guideline on good clinical practice , the study protocol , and applicable local regulatory requirements and laws . the study protocol , amendments , and informed consent forms were approved by an institutional review board / independent ethics committee . patients aged  20 years at japanese sites or  18 years at korean sites with stage iv gastric or gastroesophageal junction adenocarcinoma ( type ii or iii tumors ) for which curative intent was not possible , and at least one unidimensionally measureable lesion using a modified response evaluation criteria in solid tumors ( recist ) ver . patients were required to have eastern cooperative oncology group performance status of 0 or 1 ; adequate bone marrow , renal , and hepatic function ; and blood pressure ( bp )  130/80 mm hg . patients who had undergone radiation therapy or surgery within 4 weeks prior to study entry or prior treatment with a systemic anticancer agent for advanced gastric cancer were excluded . palliative radiation therapy to non - target lesions within 2 weeks prior to study entry was allowed . patients with disease progression while on prior adjuvant treatment or progression - free interval < 6 months after completion of adjuvant therapy were not permitted . because the trastuzumab trial   results were unknown when this trial was designed , her2 status was not assessed . patients in dose level ( dl ) 1 received cisplatin 80 mg / m intravenously over 2 hours on day 1 and capecitabine 1,000 mg / m twice a day orally within 30 minutes after a meal on days 1 to 14 of each 21-day cycle . axitinib was taken orally with food at a starting dose of 5 mg twice a day on days 1 to 21 . on day 1 , a 5-hydroxytryptamine3-receptor antagonist and dexamethasone were administered before cisplatin , with vigorous hydration according to institutional practices . in cycle 1 , patients in the pk expansion subgroup received lead - in dosing with axitinib beginning on day 3 and continuing through day 18 , with administration of cisplatin on day 1 and capecitabine on days 1 to 14 . on day 19 of cycle 1 , axitinib was temporarily stopped for 3 days before cycle 2 . in cycle 2 , cisplatin was administered on day 1 and capecitabine on days 1 to 14 , with axitinib restarted on day 2 and continued without any planned interruptions thereafter ( fig . if more than one of the first six patients experienced a dlt ( table 1 ) during cycle 1 , patients would have been enrolled in dl 1 : axitinib 3 mg twice a day on days 1 - 21 or cisplatin 60 mg / m on day 1 or capecitabine 800 mg / m twice a day on days 1 - 14 of each 21-day cycle . the actual drug dose reductions were to be determined by the toxicity profile observed . investigators , in discussion with the sponsor , had the discretion to discontinue , delay , or modify the dosages of the drugs depending on the severity and timing of adverse events ( aes ) . axitinib - related hypertension ( bp > 150/100 mm hg ) was managed by increasing the dose of existing or adding new antihypertensive medication . if the patient was already on maximal antihypertensive therapy , axitinib was to be reduced to the next lower dose ( i.e. , 3 or 2 mg twice a day ) . if the patient developed recurrent bp > 150/100 mm hg , axitinib was to be reduced to the next lower dose ; reductions < 2 mg twice a day required discussion with the sponsor . if bp was > 160/105 mm hg , axitinib was to be stopped and then restarted at the next lower dose when bp returned to < 150/100 mm hg . once the dose was reduced for axitinib - related toxicity , it was not generally re - escalated . patients were treated until disease progression , intolerable toxicity , withdrawal of consent , or removal from the study by the investigator . patients requiring the use of strong cytochrome p450 ( cyp ) 3a4/5 or cyp1a2 inducers or strong cyp3a4/5 inhibitors were not eligible for enrollment ; however , if these drugs were required during the study , they were allowed and adjustment of axitinib dosage was to be considered . if no more than one dlt ( table 1 ) was observed during cycle 1 , another three patients were to be enrolled at dl1 to complete the enrollment of six patients into the cohort . if cycle 1 toxicities at dl1 exceed the mtd , patients would be enrolled in dl 1 . if no more than one of the six patients experienced a dlt during cycle 1 , another six patients were to be entered at dl1 . the mtd was the highest dose at which  30% of the 12 patients experienced a dlt during cycle 1 . if dl1 did not exceed the mtd for the combination , this would be declared the mtd as higher dose level cohorts were not planned in this study . an additional 10 patients were to be enrolled in an expansion cohort at the mtd for collection of further safety , pk , and antitumor activity data . safety was based on the incidence and severity ( graded by common terminology criteria for adverse events ver . 3.0 ) of aes , and assessment of laboratory tests , home bp monitoring , and physical examinations . pk sampling and analysis for axitinib , cisplatin , and capecitabine and its metabolite 5-fu in plasma were performed for 10 patients in the mtd expansion cohort from whom complete data were available . standard plasma pk parameters , including maximum observed plasma concentration ( cmax ) , time at which cmax was observed ( tmax ) , area under the curve ( auc ) from time 0 extrapolated to infinite time ( aucinf ) , auc from time 0 to 24 hours ( auc24 ) , terminal half - life ( t1/2 ) , clearance ( cl ) or apparent oral clearance ( cl / f ) , and volume of distribution during the elimination phase ( vz ) or apparent volume of distribution during the elimination phase ( vz / f ) , were estimated using the validated enca ver . , new york , ny ; proprietary software for non - compartmental parameter estimation ) . the study design allowed for evaluation in each patient of the pk of steady - state axitinib alone on cycle 1 , day 1 ; cisplatin / capecitabine alone on cycle 2 , day 1 ; and cisplatin / capecitabine plus steady - state axitinib on cycle 1 , day 1 ( fig . axitinib pk samples were collected prior to and 1 , 2 , 3 , 4 , 6 , and 8 hours after axitinib dosing . capecitabine pk samples were collected prior to and 0.25 , 0.5 , 1 , 2 , 3 , 4 , 6 , and 8 hours after capecitabine dosing . cisplatin pk samples were collected prior to the start of cisplatin infusion , 0.5 and 1 hours ( during infusion ) , 2 hours ( end of infusion ) , and 1 , 2 , 4 , and 6 hours after the end of infusion . plasma concentrations of axitinib were measured using a validated , sensitive , and specific high - performance liquid chromatography with tandem mass spectrometric ( hplc / ms / ms ) detection method ( charles river laboratories preclinical services , shrewsbury , ma ) . the lower limit of quantification ( lloq ) for axitinib was 0.500 ng / ml . platinum ( derived from cisplatin ) concentrations in plasma and plasma ultrafiltrate ( puf ) were analyzed ( covance laboratories , madison , wi ) using validated , sensitive , and specific inductively coupled plasma mass spectrometric methods . the lloq for platinum was 2.00 ng / ml in plasma and 1.00 ng / ml in puf . analysis of plasma samples ( wuxi apptec , shanghai , china ) for concentrations of capecitabine and its metabolite 5-fu was performed using a validated , sensitive , and specific hplc / ms / ms method . the lloq was 20.0 ng / ml for capecitabine and 5.00 ng / ml for 5-fu . the study sample size was dependent on the observed safety profile of axitinib plus chemotherapy , which determined the number of patients per dl . analysis of efficacy and safety was performed for all patients who received at least one dose of study medication . descriptive statistics ( mean , median , standard deviation , and range for continuous data ; percentage for categorical data ; and 95% confidence interval [ ci ] , if applicable ) were used to summarize patient characteristics , treatment administration / compliance , antitumor activity , safety , and pk parameters . the kaplan - meier method was used to estimate the duration of response ( time from first demonstration of partial or complete response to documented disease progression ) and pfs ( time from start date to date of first documentation of progression or death due to any cause ) . the study was not powered for detection of differences in pk parameters for capecitabine , cisplatin , or axitinib alone or in combination . all analyses were performed based on final data following database closure , with a data cutoff date of october 17 , 2012 . a total of 22 patients were enrolled in dl1 between april 2009 and april 2010 . all patients discontinued the study because of either disease progression ( n=16 ; leading to death in two patients during the study period ) , death ( n=1 ; due to ruptured abdominal aortic aneurysm ) , aes ( n=2 ) , refusal of further follow - up or treatment ( n=1 each ) , or enrollment in an ongoing extension study ( n=1 ; nct00828919 ) . patients started a median of four cycles of combination therapy ( range , 1 to 31 for axitinib , 1 to 10 for cisplatin , and 1 to 31 for capecitabine ) . dose delays for axitinib , cisplatin , or capecitabine occurred in 15 patients ( 68.2% ) . dose reductions for axitinib , cisplatin , and capecitabine were required in 19 patients ( 86.4% ) , 10 ( 45.5% ) , and 17 ( 77.3% ) , respectively . median ( range ) relative dose intensity ( percent of actual / intended dose intensity ) was 70.1% ( 33.3% to 95.2 % ) for axitinib , 76.5% ( 42.1% to 103.1% ) for cisplatin , and 67.5% ( 38.7% to 93.9% ) for capecitabine . three dlts occurred during cycle 1 in three ( 25% ) of the first 12 patients treated at dl1 . in the first cohort of six patients , one patient had a dlt of ruptured abdominal aortic aneurysm ( grade 5 ) , which was considered to be related to all three study drugs . in the second cohort of six patients , one patient experienced a dlt of acute renal failure ( grade 3 ) lasting 21 days , which was considered to be related to axitinib and cisplatin , and another patient missed > 5 consecutive days of axitinib doses due to thrombocytopenia ( grade 3 ) , which was considered to be related to all three study drugs . per the definition of mtd in this study , axitinib 5 mg twice a day on days 1 - 21 in combination with cisplatin 80 mg / m on day 1 and capecitabine 1,000 mg / m twice a day on days 1 - 14 of each 21-day cycle was established as the mtd . in addition , gastrointestinal perforation ( grade 3 ) , which was considered to be related to all three study drugs , was reported as a dlt in one of the 10 patients in the mtd expansion cohort . the most frequently reported all - causality , all - grade , non - hematologic aes ( table 3 ) included decreased appetite ( n=20 , 90.9% ) , nausea and fatigue ( n=17 , 77.3% each ) , and hypertension and stomatitis ( n=16 , 72.7% each ) . the most common all - causality , grade 3/4 , non - hematologic aes were hypertension ( n=8 , 36.4% ) and decreased appetite and stomatitis ( n=4 , 18.2% each ) . during the study , a total of 12 patients experienced 18 serious aes : thrombosis , headache , hypoesthesia , enterocolitis , diarrhea , pneumonia , acute prerenal failure , ruptured abdominal aortic aneurysm , bradycardia , hypertension , nausea , vomiting , gastrointestinal hemorrhage , acute renal failure , decreased appetite , and gastrointestinal perforation ( n=1 each ) , and disease progression leading to death ( n=2 ) . the most common grade 3/4 laboratory abnormalities included neutropenia ( n=8 , 36.4% ) and thrombocytopenia ( n=4 , 18.2% ) . pk parameters for axitinib at steady - state , cisplatin , and capecitabine and its metabolite 5-fu in the absence and presence of each other are summarized in table 4 , and the respective plasma concentration - time profiles are shown in fig . 2 . administration of cisplatin / capecitabine resulted in slightly increased axitinib plasma exposure , as indicated by a higher auc24 and cmax . axitinib did not appear to alter cisplatin ( platinum in puf ) exposure , but it did decrease plasma exposure of capecitabine and 5-fu , as suggested by lower auc24 and cmax ( table 4 ) . the overall investigator - assessed objective response rate ( orr ) was 36.4% ( 95% ci , 17.2% to 59.3% ) . eight patients ( 36.4% ) each had partial response or stable disease (  6 weeks ) . maximum percent change in tumor size from baseline in target lesions is shown in fig . median duration of response in patients with partial response was 9.1 months ( 95% ci , 6.4 to 20.2 months ) ; median pfs was 3.8 months ( 95% ci , 2.9 to 9.4 months ) . a total of 22 patients were enrolled in dl1 between april 2009 and april 2010 . all patients discontinued the study because of either disease progression ( n=16 ; leading to death in two patients during the study period ) , death ( n=1 ; due to ruptured abdominal aortic aneurysm ) , aes ( n=2 ) , refusal of further follow - up or treatment ( n=1 each ) , or enrollment in an ongoing extension study ( n=1 ; nct00828919 ) . patients started a median of four cycles of combination therapy ( range , 1 to 31 for axitinib , 1 to 10 for cisplatin , and 1 to 31 for capecitabine ) . dose delays for axitinib , cisplatin , or capecitabine occurred in 15 patients ( 68.2% ) . dose reductions for axitinib , cisplatin , and capecitabine were required in 19 patients ( 86.4% ) , 10 ( 45.5% ) , and 17 ( 77.3% ) , respectively . median ( range ) relative dose intensity ( percent of actual / intended dose intensity ) was 70.1% ( 33.3% to 95.2 % ) for axitinib , 76.5% ( 42.1% to 103.1% ) for cisplatin , and 67.5% ( 38.7% to 93.9% ) for capecitabine . three dlts occurred during cycle 1 in three ( 25% ) of the first 12 patients treated at dl1 . in the first cohort of six patients , one patient had a dlt of ruptured abdominal aortic aneurysm ( grade 5 ) , which was considered to be related to all three study drugs . in the second cohort of six patients , one patient experienced a dlt of acute renal failure ( grade 3 ) lasting 21 days , which was considered to be related to axitinib and cisplatin , and another patient missed > 5 consecutive days of axitinib doses due to thrombocytopenia ( grade 3 ) , which was considered to be related to all three study drugs . per the definition of mtd in this study , axitinib 5 mg twice a day on days 1 - 21 in combination with cisplatin 80 mg / m on day 1 and capecitabine 1,000 mg / m twice a day on days 1 - 14 of each 21-day cycle was established as the mtd . in addition , gastrointestinal perforation ( grade 3 ) , which was considered to be related to all three study drugs , was reported as a dlt in one of the 10 patients in the mtd expansion cohort . the most frequently reported all - causality , all - grade , non - hematologic aes ( table 3 ) included decreased appetite ( n=20 , 90.9% ) , nausea and fatigue ( n=17 , 77.3% each ) , and hypertension and stomatitis ( n=16 , 72.7% each ) . the most common all - causality , grade 3/4 , non - hematologic aes were hypertension ( n=8 , 36.4% ) and decreased appetite and stomatitis ( n=4 , 18.2% each ) . during the study , a total of 12 patients experienced 18 serious aes : thrombosis , headache , hypoesthesia , enterocolitis , diarrhea , pneumonia , acute prerenal failure , ruptured abdominal aortic aneurysm , bradycardia , hypertension , nausea , vomiting , gastrointestinal hemorrhage , acute renal failure , decreased appetite , and gastrointestinal perforation ( n=1 each ) , and disease progression leading to death ( n=2 ) . the most common grade 3/4 laboratory abnormalities included neutropenia ( n=8 , 36.4% ) and thrombocytopenia ( n=4 , 18.2% ) . pk parameters for axitinib at steady - state , cisplatin , and capecitabine and its metabolite 5-fu in the absence and presence of each other are summarized in table 4 , and the respective plasma concentration - time profiles are shown in fig . 2 . administration of cisplatin / capecitabine resulted in slightly increased axitinib plasma exposure , as indicated by a higher auc24 and cmax . axitinib did not appear to alter cisplatin ( platinum in puf ) exposure , but it did decrease plasma exposure of capecitabine and 5-fu , as suggested by lower auc24 and cmax ( table 4 ) . the overall investigator - assessed objective response rate ( orr ) was 36.4% ( 95% ci , 17.2% to 59.3% ) . eight patients ( 36.4% ) each had partial response or stable disease (  6 weeks ) . maximum percent change in tumor size from baseline in target lesions is shown in fig . median duration of response in patients with partial response was 9.1 months ( 95% ci , 6.4 to 20.2 months ) ; median pfs was 3.8 months ( 95% ci , 2.9 to 9.4 months ) . cisplatin/5-fu has long been a standard first - line treatment option for patients with advanced gastric cancer ; cisplatin / capecitabine has also become an acceptable alternative . we evaluated axitinib in combination with cisplatin / capecitabine as first - line therapy in patients with advanced gastric cancer . because dls higher than dl1 were not planned in this trial , all patients were started at dl1 consisting of axitinib 5 mg twice a day on days 1 to 21 in combination with cisplatin 80 mg / m on day 1 and capecitabine 1,000 mg / m twice a day on days 1 to 14 of each 21-day cycle . three dlts were observed during cycle 1 in three ( 25% ) of the first 12 patients ( ruptured abdominal aortic aneurysm , acute renal failure , and > 5 consecutive days of missed axitinib doses due to thrombocytopenia ) . as per the trial s definition , we established that dl1 was the mtd . one additional event ( gastrointestinal perforation ) was reported as a dlt in the mtd expansion cohort . the combination appeared to be generally tolerated with a manageable safety profile . compared with cytotoxic chemotherapy , most molecularly targeted agents , such as axitinib , are relatively well tolerated , with most aes reported as grade 1 or 2 . however , chronic administration of these agents with relatively short - term or no holidays may result in new challenges in terms of cumulative toxicity . the combination of molecularly targeted agents with chemotherapy may augment this fundamental issue associated with chronic administration . although potentially manageable during the first cycle , when chronic , overlapping toxicities and delayed recovery from chemotherapy - related toxicity , as a result of molecularly targeted agents chronically altering physiologic cellsignaling pathways in normal tissue can become unacceptable . we determined tolerable doses to be the standard starting dose of axitinib and therapeutic doses of cisplatin / capecitabine , but median relative dose intensity was only ~70% for both axitinib and chemotherapy . the low median relative dose intensities for axitinib , cisplatin , and capecitabine reflect the number of patients experiencing dose delays or reductions due to aes for all three drugs . given the importance of maintaining the dose intensity of chemotherapy to preserve efficacy , a new paradigm is urgently needed for determining the optimal dosing schedule in phase i studies of molecularly targeted agents combined with chemotherapy . in terms of pk interaction , axitinib is primarily metabolized by cyp3a4/5 , and to a lesser extent ( < 10% each ) by cyp1a2 , cyp2c19 , and uridine diphosphate glucuronosyltransferase 1a1 . cisplatin does not undergo substantial enzymatic biotransformation in the liver and is mainly eliminated through renal excretion ; hence , induction or inhibition of cyp450 activity by concomitant medications is not likely to affect platinum cl . capecitabine , a pro - drug , undergoes a three - step metabolic process to its active component 5-fu . overall , interactions between axitinib and cisplatin or capecitabine are considered unlikely as axitinib is metabolized via pathways that are distinct from those for cisplatin and capecitabine . our data indicate that coadministration of axitinib did not overtly affect the pk of cisplatin . this is consistent with expectations , based on knowledge of the disposition of the two drugs . although the sample size for pk evaluation was small in this study ( n=6 for assessment of capecitabine and n=3 for 5-fu plasma exposure ) , there is a suggestion of decreased plasma exposure for capecitabine and its metabolite 5-fu in the presence of axitinib . results also indicate that axitinib plasma exposure was increased in the presence of cisplatin / capecitabine . although the current study was not statistically powered for pk evaluations , the ~30% higher axitinib exposure in the presence of cisplatin / capecitabine was within the typical intersubject variability in axitinib exposure ( % coefficient of variation for axitinib auc24=79% to 83% ) observed in this study . in patients with advanced gastric cancer , preliminary antitumor activity of axitinib with other vegf - targeted agents have been evaluated in patients with advanced gastric cancer [ 6 - 11 ] . sunitinib , sorafenib , and bevacizumab   have been combined with cisplatin / capecitabine . in a phase i trial , patients receiving sunitinib with cisplatin / capecitabine had a 5.5-month median pfs and 33% orr . in the phase i trial of sorafenib with cisplatin / capecitabine , patients had a 10-month median pfs and a 62.5% orr . the addition of bevacizumab 7.5 mg / kg to cisplatin 80 mg / m ( day 1 ) plus capecitabine 1,000 mg / m twice a day ( days 1 - 14 ) every 3 weeks in the phase iii avagast trial   improved median pfs ( 6.7 months vs. 5.3 months ; hazard ratio , 0.80 ; 95% ci , 0.68 to 0.93 ; p=0.0037 ) and orr ( 46.0% vs. 37.4% , p=0.0315 ) in patients with previously untreated advanced gastric cancer . this small , exploratory phase i study has limitations , and definitive conclusions can not be drawn regarding the synergistic effect of this combination on antitumor activity . in addition , we currently lack definitive biomarkers for use in predicting which patients will experience long durations of response . because standard prescribing doses for individual drugs were used in dl1 and higher dl cohorts were not planned in this study , we know that the doses evaluated were tolerable but we may not know the true mtd . larger prospective studies may be needed in order to further investigate the safety and antitumor activity of axitinib in combination with cisplatin and capecitabine in patients with advanced gastric cancer . in conclusion , in patients with advanced gastric cancer , standard doses of axitinib ( 5 mg twice a day continuously ) plus therapeutic doses of cisplatin ( 80 mg / m on day 1 ) and capecitabine ( 1,000 mg / m twice a day on days 1 - 14 ) could be administered in 21-day cycles in combination .
purposethis phase i trial evaluated the question of whether the standard starting dose of axitinib could be administered in combination with therapeutic doses of cisplatin / capecitabine in patients with previously untreated advanced gastric cancer , and assessed overall safety , pharmacokinetics , and preliminary antitumor activity of this combination.materials and methodspatients in dose level ( dl ) 1 received axitinib 5 mg twice a day ( days 1 to 21 ) with cisplatin 80 mg / m2 ( day 1 ) and capecitabine 1,000 mg / m2 twice a day ( days 1 to 14 ) in 21-day cycles . 
 maximum tolerated dose ( mtd ) was the highest dose at which  30% of the first 12 patients experienced a dose - limiting toxicity ( dlt ) during cycle 1 . 
 ten additional patients were enrolled and treated at the mtd in order to obtain additional safety and pharmacokinetic data.resultsthree dlts occurred during cycle 1 in three ( 25% ) of the first 12 patients : ruptured abdominal aortic aneurysm , acute renal failure , and > 5 consecutive days of missed axitinib due to thrombocytopenia . 
 dl1 was established as the mtd , since higher dl cohorts were not planned . 
 common grade 3/4 non - hematologic adverse events in 22 patients treated at dl1 included hypertension ( 36.4% ) and decreased appetite and stomatitis ( 18.2% each ) . 
 cisplatin / capecitabine slightly increased axitinib exposure ; axitinib decreased capecitabine and 5-fluorouracil exposure . 
 eight patients ( 36.4% ) each had partial response or stable disease . 
 median response duration was 9.1 months ; median progression - free survival was 3.8 months.conclusionin patients with advanced gastric cancer , standard doses of axitinib plus therapeutic doses of cisplatin and capecitabine could be administered in combination . 
 adverse events were manageable .