Publication Date:
2008-11-16
Description:
Background: Correlation between IM plasma level and clinical response has been previously reported [Larson et al., Picard et al.]. TOPS is an open-label, randomized, multicenter Phase III study investigating whether 800 mg of IM (400 mg twice daily) results in an improved efficacy compared with 400 mg daily IM in newly diagnosed, previously untreated CML-CP. This analysis reports IM trough plasma levels (Cmin) at both doses and their correlation with clinical response and safety parameters. Methods: IM PK trough samples were collected at time 0 (predose), and following 1, 6, 9, and 12 month treatment for both 400 mg/day (mg/d) and 800 mg/d arms. Plasma concentrations of IM and CGP74588 (major metabolite) were determined by a validated LC/MS/MS (liquid chromatography and tandem mass spectrometry) method. Correlation of IM exposure with clinical response (major molecular response [MMR] rates and time to first MMR) was assessed by grouping patients into quartiles based on their measured IM Cmin levels in month 1. For correlation with frequency of adverse events [AEs], an average Cmin (aCmin) over 12 months corrected for dose intensity was used for the analysis. Correlations were assessed for the entire evaluable population and for each dose group separately. Results: IM PK exposure was proportional to dose and stable over time. For the 400 mg/d dose (n=78–87), the median IM Cmin values at month 1, 6, 9, and 12 were 1190, 1060, 1210, and 1295 ng/mL, respectively; and for the 800 mg/d dose (n=148–167) the corresponding Cmin values for each month were 2720, 2340, 2170, and 2150 ng/mL, respectively. The intra-patient variability (CV%) was low and similar between the 400 mg/d and 800 mg/d doses, 25% and 27%, respectively. The inter-patient variability (CV%) was 38% for 400 mg/d and 58% for 800 mg/d. Despite this inter-patient variability there was a strong correlation between IM Cmin at month 1 (Table 1) and time to MMR or MMR at 3, 6, 9 and 12 months. Table 1: MMR rates over 12 months based on month 1 IM C min quartiles for evaluable patients with PK data MMR Rate* (%) Relative benefit (Fishers Exact Test p-value) Month of treatment (No. of evaluable patients) IM Cmin Q1 3180 ng/mL Q2-Q3 vs Q1 Q4 vs Q1 *No. of patients achieving MMR/total number of patients evaluable at each visit Month 3 (218) 0/54 (0%) 15/108 (14%) 10/56 (18%) NA (0.0027) NA (0.0013) Month 6 (208) 8/51 (16%) 38/103 (37%) 22/54 (41%) 2.35 (0.0084) 2.60 (0.0052) Month 9 (212) 21/57 (37%) 60/103 (58%) 29/52 (56%) 1.58 (0.013) 1.51 (0.0561) Month 12(214) 21/56 (38%) 62/107 (58%) 30/51 (59%) 1.55 (0.0142) 1.57 (0.0338) Based on the evaluable population at month 12, patients with higher Cmin at month 1 (〉1165 ng/mL, Q2-Q4) achieved MMR faster than patients with lower Cmin (
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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