FGFR Inhibition, Pharmacokinetics, Biomarkers, ER+ Breast Cancer
Conditions
Keywords
Breast Cancer, ER+, FGFR1, Exemestane, AZD4547, Fulvestrant
Brief summary
The purpose of this study is to assess the safety and effectiveness of AZD4547 in combination with fulvestrant vs. fulvestrant alone in ER+ breast cancer patients with FGFR1 polysomy (FISH4/5) or gene amplification (FISH 6)
Interventions
DRUGAZD4547
Tablet oral twice daily
DRUGExemestane
Tablet oral once daily
DRUGPlacebo
Tablet oral twice daily
DRUGFulvestrant
A monthly intramuscular injection of a depot formulation with a loading dose 14 days after initial administration
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Post-menopausal women (either through bilateral oophorectomy or amenorrhoeic for 24 months) * Histological confirmation of Breast Cancer with documented ER+ receptor status * Safety run-in: Relapsing during/within 12 months of completion of a single regimen of adjuvant endocrine therapy with non-steroidal AI and/ tamoxifen or progression following 1st line endocrine therapy with non-steroidal AL * Rand phase IIa: Received at least 1 prior endocrine therapy in the metastatic setting or have relapsed during/ within 6 months of completion of adjuvant endocrine therapy (either non-steroidal AI or tamoxifen or a combination of both). Chemotherapy administered in the adjuvant setting is permitted. * Rand phase IIa: Mandatory provision of tumour sample to confirm FGFR1 polysomy or gene amplification. At least one measurable lesion that can be accurately assessed by CT/MRI/x-ray at baseline and follow up visits
Exclusion criteria
* Prior exposure to exemestane (safety run-in) / fulvestrant (randomized phase IIa), or any agent known to inhibit FGFRs. * More than 1 prior regimen of chemotherapy for breast cancer * ECG recordings that demonstrate significant abnormalities in cardiac rate, rhythm or conduction * History of hypersensitivity to active or inactive excipients of AZD4547 or exemestane (safety run-in ) or fulvestrant (Randomized phase), including castor oil, or drugs with a similar chemical structure or class to AZD4547 or exemestane or fulvestrant. * Randomized phase IIa: bleeding/blood clotting conditions that would prevent the administration of the fulvestrant injection into the buttocks
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety and Tolerability in Terms of Number of Patients With Adverse Events (Serious and Non-serious) | 3 years, 10 months (Adverse events recorded from patient screening to discontinuation plus 28 days safety follow-up). |
Countries
Belgium, Czechia, France, Germany, Hungary, Italy, Romania, United Kingdom
Participant flow
Recruitment details
First patient was enrolled on 8 Dec 2010 and Last patient last visit was on 21 Oct 2014. Recruitment was slow, leading to concerns about the feasibility of completing enrolment. Moreover, the limited evidence of clinical activity of AZD4547 monotherapy in FGFR gastric cancer and NSCLC has resulted in a business decision to terminate enrolment.
Pre-assignment details
Part A: 38 patients enrolled, 31 patients received AZD4547+exemestane; 7 patients did not receive (5 patients were not eligible, 1 patient due to patient decision, 1 patient due to Other) Part B: 89 patients enrolled; 80 were not eligible, 9 patients received the treatment
Participants by arm
| Arm | Count |
|---|---|
| AZD4547 80mg bd Cont + Ex 25mg 80 mg AZD4547 bd continuous + 25 mg exemestane | 5 |
| AZD4547 40mg bd Cont + Ex 25mg 40 mg AZD4547 BD continuous + 25 mg exemestane | 5 |
| AZD4547 80mg bd 1w/1w + Ex 25mg 80 mg AZD4547 BD one week on/one week off + 25 mg exemestane | 12 |
| AZD4547 80mg bd 2w/1w + Ex 25mg 80 mg AZD4547 bd two week on/one week off + 25 mg exemestane | 9 |
| Part B: AZD4547 + Fulvestrant 80 mg AZD4547 BD + 500 mg Fulvestrant | 5 |
| Part B: Placebo + Fulvestrant 80 mg Placebo BD + 500 mg Fulvestrant | 4 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 4 | 4 | 0 | 0 |
| Overall Study | Objective Disease Progression | 0 | 0 | 0 | 0 | 2 | 0 |
| Overall Study | Other reason as per investigator | 3 | 4 | 7 | 3 | 1 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | AZD4547 80mg bd Cont + Ex 25mg | AZD4547 40mg bd Cont + Ex 25mg | AZD4547 80mg bd 1w/1w + Ex 25mg | AZD4547 80mg bd 2w/1w + Ex 25mg | Part B: AZD4547 + Fulvestrant | Part B: Placebo + Fulvestrant | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 58.4 Years STANDARD_DEVIATION 16.7 | 61.2 Years STANDARD_DEVIATION 9.36 | 66.5 Years STANDARD_DEVIATION 8.46 | 67.3 Years STANDARD_DEVIATION 9.66 | 61.0 Years STANDARD_DEVIATION 6.82 | 67.3 Years STANDARD_DEVIATION 9.46 | 64.6 Years STANDARD_DEVIATION 10.58 |
| Age, Customized < 35 | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Customized 35 >= - < 50 | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Age, Customized 50 >= - <65 | 2 Participants | 2 Participants | 3 Participants | 3 Participants | 4 Participants | 1 Participants | 15 Participants |
| Age, Customized >= 65 | 2 Participants | 2 Participants | 8 Participants | 6 Participants | 1 Participants | 3 Participants | 22 Participants |
| Race/Ethnicity, Customized Asian (Other Than Chinese And Japanese) | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Applicable | 2 Participants | 0 Participants | 8 Participants | 4 Participants | 2 Participants | 0 Participants | 16 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 5 Participants | 4 Participants | 5 Participants | 3 Participants | 4 Participants | 23 Participants |
| Race/Ethnicity, Customized White | 4 Participants | 5 Participants | 11 Participants | 9 Participants | 5 Participants | 4 Participants | 38 Participants |
| Sex/Gender, Customized Female | 5 Participants | 5 Participants | 12 Participants | 9 Participants | 5 Participants | 4 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 5 | 5 / 5 | 12 / 12 | 9 / 9 | 5 / 5 | 2 / 4 |
| serious Total, serious adverse events | 2 / 5 | 2 / 5 | 5 / 12 | 1 / 9 | 1 / 5 | 1 / 4 |
Outcome results
Primary
Safety and Tolerability in Terms of Number of Patients With Adverse Events (Serious and Non-serious)
Time frame: 3 years, 10 months (Adverse events recorded from patient screening to discontinuation plus 28 days safety follow-up).
Population: All patients who receive at least one dose of study treatment (AZD4547 or exemestane)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD4547 80mg bd Cont + Ex 25mg | Safety and Tolerability in Terms of Number of Patients With Adverse Events (Serious and Non-serious) | 5 Participants |
| AZD4547 40mg Cont + Ex 25mg | Safety and Tolerability in Terms of Number of Patients With Adverse Events (Serious and Non-serious) | 5 Participants |
| AZD4547 80mg bd 1w/1w + Ex 25mg | Safety and Tolerability in Terms of Number of Patients With Adverse Events (Serious and Non-serious) | 12 Participants |
| AZD4547 80mg bd 2w/1w + Ex 25mg | Safety and Tolerability in Terms of Number of Patients With Adverse Events (Serious and Non-serious) | 9 Participants |
| Part B: AZD4547 + Fulvestrant | Safety and Tolerability in Terms of Number of Patients With Adverse Events (Serious and Non-serious) | 5 Participants |
| Part B: Placebo + Fulvestrant | Safety and Tolerability in Terms of Number of Patients With Adverse Events (Serious and Non-serious) | 2 Participants |