Breast CarcinomaNCT01655004
Prospective Study of UDP-gluconoryltransferase 2B17 Genotype as a Predictive Marker of Exemestane PK and PD
A study testing Exemestane in people with Breast Carcinoma, run by National University Hospital, Singapore at 1 site in Singapore.
Trial 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… Read more about this study
- Who is it for?
- Ages 21 to 99 years, women only
- Conditions the study is for
- Breast Carcinoma
- What is being tested?
- Exemestane
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 110 participants
- Where
- 1 siteSingapore
- Study dates
- Aug 2012to Aug 2018
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 to 99 years
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Female, Age ≥ 21 years
- Histologically-proven hormone-receptor positive metastatic breast carcinoma
- A minimum of one prior line of endocrine therapy in the metastatic setting. First-line therapy is permitted if the patient relapses while on or within 6 months of adjuvant endocrine therapy.
- Patients with both measurable and non-measurable disease as per the Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 may be enrolled.
- Eastern co-operative group (ECOG) performance status of < 2 and estimated life expectancy of at least 12 weeks
- Post-menopausal women* or pre-menopausal women on ovarian suppression with FSH and plasma oestradiol levels in menopausal range within 21 days of study enrollment
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- Adequate organ function including the following:
- Bone marrow:
- Absolute neutrophil (segmented and bands) count (ANC) ≥ 1.5 x 109/L
- Platelets ≥ 100 x 109/L
- Hepatic:
- Bilirubin ≤ 1.5 x upper limit of normal (ULN),
- ALT and AST ≤ 2.5x ULN
- Renal:
- o Calculated creatinine clearance >35ml/minute
- Signed informed consent from patient or legal representative
- Pre-menopausal females must have a negative serum pregnancy test within 21 days of study enrollment
Who cannot join
- Concurrent administration of other anti-tumor therapies, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy are prohibited. Concomitant bisphosphonates and gonadotropin-releasing hormone therapy are allowed.
- Patients must have recovered from the toxicities of the previous anti-cancer therapy.
- Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
- Prior use of exemestane in the metastatic setting or relapse while on adjuvant exemestane or within 6 months of completing adjuvant exemestane.
- Major surgery within 28 days of study drug administration.
- Concomitant use of potent CYP3A4 inducers (Table 1, section 3.5.3); a washout period of 14 days is required for patients discontinuing these medications prior to study enrollment.
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- Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy.
- Pregnancy.
- Breast feeding.
- Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator.
- Symptomatic brain metastasis.
Trial locations and contacts
1 site in 1 country.
Singapore1 site, 1 recruiting
- Recruiting
National University Hospital
Singapore, Singapore, 119074
Andrea LA Wong, MBBS, (65) 6772 5934, andrea_la_wong@nuhs.edu.sg
Soo Chin Lee, MBBS
About this study
Official title: Prospective Study of UDP-gluconoryltransferase (UGT) 2B17 Genotype as a Predictive Marker of Exemestane Pharmacokinetics and Pharmacodynamics in Asian Women With Hormone Receptor-positive Advanced Breast Cancer
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.
Read the detailed description
This is a prospective non-randomised open-label study of exemestane in post-menopausal, hormone receptor positive advanced breast cancer patients, with pre-specified analysis of exemestane pharmacokinetics and pharmacodynamics according to UGT2B17 genotype (UGT2B17*2/*2 versus those with at least one wild-type allele). A total of 110 patients will be enrolled over a period of 30 months. Eligible patients will receive exemestane 25mg daily orally (as part of standard care) until progression of disease or intolerable toxicities. At the time of study entry, blood samples will be drawn for genotyping studies (for research purposes) but investigators will be blinded to the results. Pharmacokinetic sampling for exemestane and its metabolites will be performed at baseline and on day 29 (+/- 3 days) before dosing and 0.5, 1, 2, 4, 6, 8 and 24 hours after exemestane ingestion. Patients will be evaluated on an 8-weekly basis for toxicities and efficacy assessments during the first 6 months of treatment, followed by 12-weekly thereafter until disease progression, unacceptable toxicities, or patient withdrawal.
- Conditions
- Breast Carcinoma
- Being tested
- Exemestane
- Keywords
- hormone receptor positive, breast cancer
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ExemestaneDrug
Also called trade name Aromasin
Exemestane is commercially available and will be obtained locally from the manufacturer. There are no experimental treatments in this study.
| Study group | Role | What they receive |
|---|---|---|
| exemestane standard treatment | Experimental | Patients will receive exemestane 25mg daily orally after a meal until progression of disease, intolerable toxicities, voluntary withdrawal or termination of the study. Receives: Drug: Exemestane |
What is being measured
The primary outcome is the main question the study is designed to answer.
Correlation of UGT2B17*2 deletion genotype with clinical benefit rate (CBR)
The correlation of genotype (UGT2B17 *2/*2 versus those with at least one wild-type allele) with clinical benefit rate (CBR), defined as the percentage achieving CR, PR and SD in patients with measurable disease or the absence of disease progression in patients with non-measurable disease, lasting at least 24 weeks.
Measured: 24 weeks
Secondary outcomes (1)
Correlation of UGT2B17*2 deletion genotype with exemestane pharmacokinetics, objective response rates (ORR), progression-free survival (PFS), overall survival (OS) and musculoskeletal toxicities
The correlation of genotype (UGT2B17 *2/*2 versus those with at least one wild-type allele) with:
- Objective response rates (ORR), as defined by a best overall response of CR or PR.
- Progression-free survival (PFS), as defined by the time from the date of study enrollment until the first date of documented disease progression or death due to any cause, whichever occurs first.
- Overall survival (OS) as defined by the time from the date of study enrollment until the date of death due to any cause.
- Grade 2 and above musculoskeletal toxicities, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0.
- Pharmacokinetic parameters, in particular, AUC of exemestane-17-O-glucuronide, 17-dihydroexemestane and their ratio.
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Aug 2012 (estimated)
- Study startAug 2012
- Primary completionJun 2017 (estimated)
- Study completionAug 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Breast CarcinomaStudies of the same condition, open and under way.
- More trials run by National University Hospital, SingaporeThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 110 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National University Hospital, Singapore
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Andrea LA Wong, MBBS, Principal investigator, National University Hospital, Singapore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01655004
- Sponsor's protocol ID
- BR05/14/12
- Other IDs
- 2012/00428
- Status last verified
- Jun 2016
- First submitted
- 30 Jul 2012
- Last updated
- 22 Jun 2016
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Dowsett M, Cuzick J, Ingle J, Coates A, Forbes J, Bliss J, Buyse M, Baum M, Buzdar A, Colleoni M, Coombes C, Snowdon C, Gnant M, Jakesz R, Kaufmann M, Boccardo F, Godwin J, Davies C, Peto R. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol. 2010 Jan 20;28(3):509-18. doi: 10.1200/JCO.2009.23.1274. Epub 2009 Nov 30.
PubMed 19949017Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Janicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Lassus M, Verbeek JA, Staffler B, Chaudri-Ross HA, Dugan M. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol. 2001 May 15;19(10):2596-606. doi: 10.1200/JCO.2001.19.10.2596.
PubMed 11352951Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler M. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol. 2000 Nov 15;18(22):3758-67. doi: 10.1200/JCO.2000.18.22.3758.
PubMed 11078488Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, Piccart MJ, Bogaerts J, Therasse P. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol. 2008 Oct 20;26(30):4883-90. doi: 10.1200/JCO.2007.14.4659. Epub 2008 Sep 15.
PubMed 18794551
Study at a glance
From the registry record, last updated by the sponsor on 22 Jun 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prospective Study of UDP-gluconoryltransferase (UGT) 2B17 Genotype as a Predictive Marker of Exemestane Pharmacokinetics and Pharmacodynamics in Asian Women With Hormone Receptor-positive Advanced Breast Cancer
- ClinicalTrials.gov ID
- NCT01655004
- Acronym / sponsor ID
- BR05/14/12
- Conditions
- Breast Carcinoma
- Keywords
- hormone receptor positive, breast cancer
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 110 participants (estimated)
- Lead sponsor
- National University Hospital, SingaporeUniversity, hospital or other
- Study start
- Aug 2012
- Primary completion
- Jun 2017 (estimated)
- Study completion
- Aug 2018 (estimated)
- First posted
- 1 Aug 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
This is a prospective non-randomised open-label study of exemestane in post-menopausal, hormone receptor positive advanced breast cancer patients, with pre-specified analysis of exemestane pharmacokinetics and pharmacodynamics according to UGT2B17 genotype (UGT2B17*2/*2 versus those with at least one wild-type allele). A total of 110 patients will be enrolled over a period of 30 months. Eligible patients will receive exemestane 25mg daily orally (as part of standard care) until progression of disease or intolerable toxicities. At the time of study entry, blood samples will be drawn for genotyping studies (for research purposes) but investigators will be blinded to the results. Pharmacokinetic sampling for exemestane and its metabolites will be performed at baseline and on day 29 (+/- 3 days) before dosing and 0.5, 1, 2, 4, 6, 8 and 24 hours after exemestane ingestion. Patients will be evaluated on an 8-weekly basis for toxicities and efficacy assessments during the first 6 months of treatment, followed by 12-weekly thereafter until disease progression, unacceptable toxicities, or patient withdrawal.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| exemestane standard treatment | Experimental | Drug: ExemestanePatients will receive exemestane 25mg daily orally after a meal until progression of disease, intolerable toxicities, voluntary withdrawal or termination of the study. |
Who may qualify
- Ages
- 21 to 99 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- Female, Age ≥ 21 years
- Histologically-proven hormone-receptor positive metastatic breast carcinoma
- A minimum of one prior line of endocrine therapy in the metastatic setting. First-line therapy is permitted if the patient relapses while on or within 6 months of adjuvant endocrine therapy.
- Patients with both measurable and non-measurable disease as per the Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 may be enrolled.
- Eastern co-operative group (ECOG) performance status of < 2 and estimated life expectancy of at least 12 weeks
Key exclusion criteria (11 listed)
- Concurrent administration of other anti-tumor therapies, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy are prohibited. Concomitant bisphosphonates and gonadotropin-releasing hormone therapy are allowed.
- Patients must have recovered from the toxicities of the previous anti-cancer therapy.
- Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
- Prior use of exemestane in the metastatic setting or relapse while on adjuvant exemestane or within 6 months of completing adjuvant exemestane.
- Major surgery within 28 days of study drug administration.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ExemestaneAlso: trade name AromasinExemestane is commercially available and will be obtained locally from the manufacturer. There are no experimental treatments in this study. | Drug | exemestane standard treatment |
Primary outcome
Correlation of UGT2B17*2 deletion genotype with clinical benefit rate (CBR)
Time frame: 24 weeks
The correlation of genotype (UGT2B17 *2/*2 versus those with at least one wild-type allele) with clinical benefit rate (CBR), defined as the percentage achieving CR, PR and SD in patients with measurable disease or the absence of disease progression in patients with non-measurable disease, lasting at least 24 weeks.
1 secondary outcome
Correlation of UGT2B17*2 deletion genotype with exemestane pharmacokinetics, objective response rates (ORR), progression-free survival (PFS), overall survival (OS) and musculoskeletal toxicities
Time frame: 24 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Jun 2016.
- Background: PubMed 19949017Dowsett M, Cuzick J, Ingle J, Coates A, Forbes J, Bliss J, Buyse M, Baum M, Buzdar A, Colleoni M, Coombes C, Snowdon C, Gnant M, Jakesz R, Kaufmann M, Boccardo F, Godwin J, Davies C, Peto R. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol. 2010 Jan 20;28(3):509-18. doi: 10.1200/JCO.2009.23.1274. Epub 2009 Nov 30.
- Background: PubMed 11352951Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Janicke F, Pluzanska A, Dank M, Becquart D, Bapsy PP, Salminen E, Snyder R, Lassus M, Verbeek JA, Staffler B, Chaudri-Ross HA, Dugan M. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol. 2001 May 15;19(10):2596-606. doi: 10.1200/JCO.2001.19.10.2596.
- Background: PubMed 11078488Nabholtz JM, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A, von Euler M. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol. 2000 Nov 15;18(22):3758-67. doi: 10.1200/JCO.2000.18.22.3758.
- Background: PubMed 18794551Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, Piccart MJ, Bogaerts J, Therasse P. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol. 2008 Oct 20;26(30):4883-90. doi: 10.1200/JCO.2007.14.4659. Epub 2008 Sep 15.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Andrea LA Wong, MBBS principal investigator
National University Hospital, Singapore
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Exemestane in people with Breast Carcinoma, run by National University Hospital, Singapore at 1 site in Singapore.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 22 Jun 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Singapore. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Andrea LA Wong, MBBS ((65) 6772 5934, andrea_la_wong@nuhs.edu.sg), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Correlation of UGT2B17*2 deletion genotype with clinical benefit rate (CBR) (time frame: 24 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01655004, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jun 2016.