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Prospective Study of UDP-gluconoryltransferase 2B17 Genotype as a Predictive Marker of Exemestane PK and PD

NCT01655004 · Status: UNKNOWN · Phase: NA · Type: INTERVENTIONAL · Enrollment: 110

Last updated 2016-06-22

No results posted yet for this study

Summary

Aromatase inhibitors have led to significant improvements in clinical outcomes for women with postmenopausal hormone receptor-positive advanced breast cancer. However, there is a notable absence of phase III comparisons among the three agents and therefore no clear indication of the superiority of one AI over the others. Furthermore, there remains a distinct lack of predictive biomarkers of AI efficacy and toxicity to inform clinical decisions. The metabolic pathways of exemestane have recently been delineated and UGT2B17 is the most active hepatic gluconoryltransferase responsible for the glucuronidation of the crucial active exemestane metabolite, 17-dihydroxyexemestane. The UGT2B17\*2/\*2 deletion genotype is associated with markedly reduced glucuronidation of 17-dihydroxyexemestane in vitro and is found more commonly in Asians than Caucasians (60-70% vs less than 10%). Our research group recently demonstrated significant reduction in glucuronidation of vorinostat, a UGT2B17 substrate, with a trend towards improved clinical benefit rate and progression-free survival in Asian breast cancer patients who were UGT2B17\*2 homozygotes treated with this compound. In-vivo studies correlating UGT2B17\*2 genotype with exemestane pharmacokinetics and pharmacodynamics are lacking. We hypothesize that individuals with UGT2B17\*2/\*2 genotype have reduced glucuronidation of 17-dihydroxyexemestane and therefore have increased exposure to the active drug, resulting in improved treatment efficacy. We propose a study of exemestane in hormone receptor positive post-menopausal advanced breast cancer patients with prospective correlation of treatment outcome by UGT2B17 genotype. The primary endpoint is the correlation of genotype (UGT2B17\*2/\*2 vs those with at least one wild-type variant) with clinical benefit rate, and secondary endpoints include its association with exemestane pharmacokinetics, progression-free survival, overall survival and musculoskeletal toxicities.

Conditions

  • Breast Carcinoma

Interventions

DRUG

Exemestane

Exemestane is commercially available and will be obtained locally from the manufacturer. There are no experimental treatments in this study.

Sponsors & Collaborators

  • National University Hospital, Singapore

    lead OTHER

Principal Investigators

  • Andrea LA Wong, MBBS · National University Hospital, Singapore

Study Design

Allocation
NA
Purpose
TREATMENT
Masking
NONE
Model
SINGLE_GROUP

Eligibility

Min Age
21 Years
Max Age
99 Years
Sex
FEMALE
Healthy Volunteers
No

Timeline & Regulatory

Start
2012-08-31
Primary Completion
2017-06-30
Completion
2018-08-31

Countries

  • Singapore

Study Locations

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Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT01655004 on ClinicalTrials.gov