Abstract

Abstract 1127

Poster Board I-149

Background

In the TOPS study, IM trough levels (Cmin) were collected from different race groups, mainly Caucasian and Asian, but also Black and others. Inter-ethnic differences in the PK of a drug are known to be important factors accounting for inter-individual variation in drug responsiveness. This analysis reports the comparison between Caucasian and Asian CML patients (pts) treated at doses of 400 mg QD and 400 mg bid (800 mg daily) of IM Cmin on Day 29 of initial treatment, clinical response, safety and tolerability.

Methods

Steady state IM Cmin on Day 29 and clinical response and safety data obtained during the first 12 months (mos) of treatment were obtained from pts randomized 2:1 to 800 mg or 400 mg daily IM. The steady-state Cmin was defined as predose concentration collected approximately within ±3 hours of the scheduled dosing time on Day 29. The associations of race with the rates of major molecular response (MMR) and complete cytogenetic response (CCyR) were evaluated. Correlation of IM exposure with clinical response (MMR and CCyR) was assessed by grouping pts into quartiles based on their measured IM Cmin levels at Day 29. The safety endpoint for each pt was the presence or absence of an adverse event (AE) of grade 3 or higher in the first 12 mos from the first dose.

Results

IM Cmin levels were available from 229 pts in TOPS including 54 Caucasians, 18 Asians, and 14 Black and others at 400 mg (total 86) and 103 Caucasians, 29 Asians, and 11 Black and others at 800 mg (total 143). For the first 12 mos, the means of the average dose intensities for Asian (mean [range], 362 [267-400] in 400 mg and 666 [226-800] in 800 mg) were not significantly different from Caucasian (386 [204-597] in 400 mg and 666 [289-800] in 800 mg) (P=0.070 and P=0.995 for the 400 mg and 800 mg arms, respectively). Mean (± SD) of IM Cmin levels (ng/mL) with respect to race are shown in Table 1. IM Cmin was slightly over-proportional to dose and showed large interpatient variability (CV=42-60%) for both dose groups regardless of the race group.

Table 1.

Summary of IM Cmin values (ng/mL, Mean (±SD)) in Caucasian, Asian and Others

 Caucasian (C) Asian (A) Others Between C and A 
400 mg 1383 ± 716 (n=54) 1298 ± 593 (n=18) 1569 ± 823 (n=14) P=0.589 
800 mg 2954 ± 1349 (n=103) 3298 ± 1547 (n=29) 3279 ± 1999 (n=11) P=0.359 
 Caucasian (C) Asian (A) Others Between C and A 
400 mg 1383 ± 716 (n=54) 1298 ± 593 (n=18) 1569 ± 823 (n=14) P=0.589 
800 mg 2954 ± 1349 (n=103) 3298 ± 1547 (n=29) 3279 ± 1999 (n=11) P=0.359 

The percentages of pts who achieve MMR and CCyR by 12 mos in 400 mg are 59% and 78% for Caucasian compared with 44% and 56% (P=0.290 and 0.126 for MMR and CCyR respectively) for Asian. In the 800 mg arm, the percentages of pts who achieve MMR and CCyR by 12 mos are 69% and 79% for Caucasian compared with 62% and 79% for Asian (P=0.507 and >0.999 for MMR and CCyR respectively). There was no evidence to conclude any overall difference between Caucasian and Asian (P=0.229 and 0.247, for MMR and CCyR respectively) when both treatment arms were combined. Association between Cmin based on the quartiles and MMR and CCyR by 12 mos by race was explored and shown in Table 2.

Table 2.

Summary of CCyR and MMR rates by Cmin Quartiles for Caucasian and Asian pts

 Rate (%) IM Cmin Q1 IM Cmin Q2–Q3 IM Cmin Q4 
Race  <1290 ng/mL 1290 to < 3260 ng/mL 3260+ ng/mL 
Caucasian CCyR 29/36 (80.6%) 63/83 (75.9%) 31/38 (81.6%) 
(n=157) MMR 23/36 (63.9%) 55/83 (66.3%) 25/38 (65.8%) 
Asian CCyR 6/13 (46.2%) 15/19 (79.0%) 12/15 (80.0%) 
(n=47) MMR 3/13 (23.1%) 11/19 (57.9%) 12/15 (80.0%) 
 Rate (%) IM Cmin Q1 IM Cmin Q2–Q3 IM Cmin Q4 
Race  <1290 ng/mL 1290 to < 3260 ng/mL 3260+ ng/mL 
Caucasian CCyR 29/36 (80.6%) 63/83 (75.9%) 31/38 (81.6%) 
(n=157) MMR 23/36 (63.9%) 55/83 (66.3%) 25/38 (65.8%) 
Asian CCyR 6/13 (46.2%) 15/19 (79.0%) 12/15 (80.0%) 
(n=47) MMR 3/13 (23.1%) 11/19 (57.9%) 12/15 (80.0%) 

In the lower quartile Cmin group (Cmin<1290 ng/mL), the differences in CCyR and MMR rates between Asian and Caucasian pts were significant (P=0.031 and P=0.022 respectively), which was probably due to a higher rate of dose interruptions in the 1st 12 mos in Asian pts. A definitive conclusion cannot be drawn due to the small number of Asian pts. Occurrences of at least one grade 3 or 4 adverse event were found to be significantly higher in Asian pts (69% and 75% in the 1st 6 and 12 mos respectively) compared to Caucasian pts (53% and 57% in the 1st 6 and 12 mos respectively) (P=0.028 and P=0.008 respectively).

Conclusion

The results of this analysis from TOPS show that IM Cmin levels were similar between Caucasian and Asian CML pts in each treatment arm. There were no major differences in efficacy, as measured by MMR and CCyR rates by 12 mos, between Asian and Caucasian pts. There were no unexpected differences in patterns of AEs between Caucasian and Asian pts; however, occurrences of one or more grade 3 AEs were higher in Asian. Further analysis on a larger group of CML pts will be needed to evaluate the impact of AE rate differences between Caucasian and Asian pts.

Disclosures

Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Granvil:Novartis: Employment. Demirhan:Novartis: Employment. Reynolds:Novartis: Employment. Jin:Novartis: Employment. Wang:Novartis: Employment, Equity Ownership. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cortes-Franco:Novartis: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Guilhot:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria.

Author notes

*

Asterisk with author names denotes non-ASH members.