Axitinib is a potent and selective second generation in hibitor of VEGF receptors 1, 2, and 3 approved in the United States, European Union, Japan, and elsewhere for the treatment of advanced renal cell carcinoma after fail ure of one prior systemic ther

In phase II, eligible patients were stratified by gender and ECOG PS and, AP24534 FGFR 阻害剤 using a centralized, random ized permuted block allocation within strata generated by the central randomization administrator, assigned to receive axitinib bid continuously plus pemetrexed cis platin, axitinib in a modified dosing schedule plus pemetrexed cisplatin, or pemetrexed cisplatin alone. Axitinib was administered orally at a start ing dose of 5 mg bid in 21 day cycles. For the modified dosing schedule, axitinib was given on days 2 through 19, followed by a 3 day interruption, except the last cycle, during which it was given on days 2 through 21. Axitinib dose could be increased step wise to 7 mg bid, and then to a maximum of 10 mg bid, in patients who tolerated axitinib with no treatment related CTCAE Grade 3 AEs for 2 weeks, unless BP was greater than 150 90 mmHg or patient was taking antihypertensive medication.<br><br> Axi tinib dose was reduced step wise to 3 mg bid, and then to 2 mg bid, at the discretion of the investigator, in patients who experienced a treatment related CTCAE Grade 3 AE or BP 150 100 mmHg on maximal antihypertensive treatment. Axitinib treatment was temporarily interrupted in patients who had a treatment related CTCAE Grade 4 AE, BP 160 105 mmHg, AT-406 ic50 or urine protein creatinine ra tio 2. 0 and restarted at the next lower dose once im proved to CTCAE Grade 2, BP 150 100 mmHg, or urine protein creatinine ratio 2. 0, respectively. If a pa tient required a dose reduction below 2 mg bid, axitinib was to be discontinued.<br><br> Pemetrexed 500 mg m2 and cis platin 75 mg m2 were administered intravenously on day 1 of each of up to six 21 day cycles. Dose reductions were based on Akt1 阻害剤 nadir hematologic counts or maximum non hematologic toxicity from the preceding cycle. Vitamin B12 and folic acid were adminis tered 1 week prior to treatment and then every 9 weeks and daily, respectively, until 3 weeks after the last dose of chemotherapy. Patients randomized to arms I and II who completed four to six cycles of axitinib plus pemetrexed cisplatin and had stable disease or better continued to receive single agent axitinib maintenance therapy until disease progression, unacceptable toxicity, or withdrawal of patient consent. All patients were followed bimonthly for survival status following discontinuation of study treatment until at least 1 year after randomization of the last patient.<br><br> Crossover between treatment arms was not allowed. The study protocol was reviewed and approved by the institutional review board or independent ethics commit tee at each center. The names of all institutional review boards and independent ethics committees are listed under Appendix. The study was conducted in compliance with the Declaration of Helsinki, International Conference on Harmonization Good Clinical Practice Guidelines, and local regulatory requirements. This trial was registered at ClinicalTrials. gov on October 7, 2008. Assessments Radiologic tumor assessments were performed at screen ing and every 6 weeks thereafter, and whenever disease progression was suspected. Responses were evaluated ac cording to RECIST and required confirmation 4 weeks after initial documentation. Safety was evaluated through out the study. BP measurements were taken at screening and on day 1 of each cycle and thyroid function tests were conducted at screening and on day 1 of each chemother apy cycle and on day 1 of every other cycle thereafter.