Thymidylate synthase genotype specific dosing of capecitabine: Proof of concept phase I study.

Abstract

2551 Background: Thymidylate synthase (TYMS) is the target of fluoropyrimidines (FP). TYMS 3R3R is the predominant genotype in East Asian (EA) patients and is associated with increased TYMS expression, reduced FP related toxicity and relative FP resistance. Dose finding studies for FP were developed in Caucasians, a population that typically harbors TYMS 2R2R and 2R3R genotypes. We hypothesize the recommended phase II dose (RP2D) of capecitabine is higher in 3R3R and similar for 2R allele carriers compared to the FDA approved dose. Objectives 1) To determine the maximal tolerated dose (MTD) and RP2D of capecitabine in EA patients with advanced stage malignancy 2) To determine the safety and toxicity of this regimen and 3) To perform plasma pharmacokinetics (PK) of capecitabine and its metabolites. Methods: EA patients with advanced stage cancer were prospectively allocated into two cohorts: Group A (3R3R) and Group B (2R3R, 2R2R). In each cohort, dose escalation followed a standard phase I 3+3 design. Additional patients were treated at the R2P2 dose level (DL). Initial dose was 1250/m2 bd for 14 days q3w (DL 1) with 125 mg/m2 bd increments subsequently. Pharmacokinetics (PK) of capecitabine and its metabolites were performed using a LC-MS/MS method. Results: 23 patients (Group A=18; group B=5) received 94 cycles (median 2.5, range 1-8). Median age was 58 (range 34-74) years. Median turnaround time for TYMS genotyping was 1 day. In group A, grade 3-4 DLTs were seen in 3 patients: diarhoea, neutropenic fever, hand-foot syndrome, and mucositis. MTD was at DL 4 (1625mg/m2 bd) and the RP2D was 1500mg/m2 bd (DL 3). DL 3 was expanded to n=9. At DL 3, day 1 mean (± SD) capecitabine and 5FU Cmax was 12.3 ± 9.9 and 0.91 ± 0.73 µg/mL, respectively and AUC0 – t was 9.84 ± 5.53 and 1.21 ± 0.54 h*µg/mL, respectively. Compared with DL1, Cmax for capecitabine and 5FU was 2 and 2.02 fold higher and AUC 0-t was 1.49 and 1.59 fold higher at DL3. Accrual in group B was ceased at DL2 due to lack of patient enrolment; no DLT was seen. By ROC analysis, day 1 5FU AUC0 – t of 1.74 h*µg/mL predicted for DLT (p=0.022, sensitivity 100%, specificity 90%). Conclusions: In EA patients with TSER 3R3R, the RP2D was 1500 mg/m2 bd. The D1 5FU AUC0 – t at RP2D was 59% more than the FDA approved dose (DL1).