Higher SUN exposure is associated with better outcomes but SUN PK on day 28 does not correlate with toxicity (# 363, ASCO-GU 2012).
Toxicity-driven dose/schedule individualization was tested in a prospective phase II study where all pts start on 50 mg/day (d). Pts with minimum toxicity on d 28 are dose escalated to 62.5 mg and then 75 mg. Samples for SU011248 and SU012662 were drawn on day 14 on the first course (100 pts) and again after the optimal dose/schedule had been established (58 pts). 11 patients had 2-3 more samples drawn during continued Rx on the optimal dose.
117 pts were enrolled. Of 108 pts evaluable for response, dose was escalated in 20 pts to 62.5 mg (12 pts) and then to 75 mg (8 pts). In 49 pts eligible for dose reduction by standard criteria, a 50 mg dose was maintained but for 7 - 24 d. Dose was reduced to 37.5 mg in 22 pts and to 25 mg in 10 pts with individualized days on Rx. For 100 pts sampled on the first course the mean concentration (standard error) was 93.8 (3.0) and 29.8 (1.4) ng/mL for SU011248 and SU012662 respectively. For 58 pts, sampled again when optimal dose was established, the mean change from the 1st course for SU011248 and SU012662 was significantly different between dose levels (P
While dose individualization corrects for some of the differences in PK values on the 1st Rx course, differences remain even after dose optimization emphasizing the importance of pharmacodynamics for toxicity and outcome. An ongoing dose optimization may be important to correct for the decline in PK over time.Table:
|Dose level (n pts)||SU011248 (standard error)||SU012662 (standard error)|
|During 1st course ng/mL||During 1st course ng/mL|
|mean change at optimal dose||mean change at optimal dose|
|50 mg (n = 27)||90.7 (5.2)||27.6 (2.6)|
|−11.8 (5.6)||0 (2.3)|
|< 50 mg (n = 13)||95.4 (10.1)||33.6 (4.6)|
|−22.6 (12.7)||−12.7 (4.4)|
|>50 mg (n = 18)||77.1 (5.7)||24.1 (2.6)|
|+29.6 (10.6)||+12.4 (2.5)|
|After optimization||SU011248 (SE) at optimal dose||SU012662 (SE) at optimal dose|
|50 mg (n = 27)||78.9 (4.7)||27.5 (2.3)|
|< 50 mg (n = 13)||72.8 (8.0)||21.7 (2.8)|
|>50 mg (n = 18)||106.7 (11.9)||36.5 (3.6)|
Clinical trial identification
Legal entity responsible for the study
Dr. Georg A Bjarnason and the Sunnybrook Research Institute
G.A. Bjarnason: Funding for this trial from Pfizer. Honoraria and support to attend meetings from Pfizer. C.K. Kollmannsberger: Pfizer: adboards, honoraria for presentations, participation in clinical trials. D. Soulieres: Pfizer Ad boards and honorarium for talks. P. Zalewski: Pfizer Advisory boards. C.M. Canil, R.J. Macfarlane: Pfizer advisory boards. S.J. Hotte: Pfizer advisory boards and CME talks. S.A. North: Honoraria from Pfizer. D.Y.C. Heng: Advisory boards: Pfizer, Novartis, Bristol-Myers Squib. A. Kapoor: Pfizer advisory boards and CME talks. A.R. Hansen: Advisory board with Pfizer. N.S. Basappa: Pfizer honoraria, advisory boards, travel support. All other authors have declared no conflicts of interest.