Gastro-oesophageal Junction Cancer, Gastric Cancer
Conditions
Keywords
gastro-oesophageal junction cancer, gastric cancer, lower third oesophageal cancer, polysomy, amplification, FGFR
Brief summary
The purpose of this study is to assess the efficacy, safety and tolerability of AZD4547 compared with paclitaxel in patients with advanced gastric or lower-oesophageal cancer whose tumours are found to have FGFR2 polysomy or gene amplification.
Detailed description
A Randomised Open-Label Phase IIa Study to Assess the Efficacy and Safety of AZD4547 monotherapy versus paclitaxel in Patients with Advanced Gastric or Gastro-oesophageal Junction Cancer with FGFR2 Polysomy or Gene Amplification (SHINE study). Patients were to be assigned to strata by FGFR2 status of: polysomy, low or high gene amplification.
Interventions
DRUGAZD4547
Tablets taken, oral, twice daily, commencing with a 2 week on AZD4547, 1 week off AZD4547 schedule.
DRUGpaclitaxel
Infusion administered once a week, 3 weeks on and 1 week off
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
25 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Female or male aged 25 or over * Histological diagnosis of locally advanced or metastatic gastro adenocarcinoma (including adenocarcinoma of the lower third of the oesophagus or the gastro oesophageal junction ) * Radiographically confirmed progression after 1 prior chemotherapy or chemoradiotherapy for gastric cancer. Suitable for and expected to benefit from paclitaxel monotherapy. * At least one lesion, not previously irradiated, that has baseline at least 10mm in the longest diameter for non nodal lesions and is assessed by Computerised Tomography (CT) or Magnetic Resonance Imaging (MRI) * Provision of either an archival tumour sample or a fresh tumour sample for confirmation of FGFR2 polysomy/gene amplification
Exclusion criteria
* Prior exposure to AZD4547 or history of hypersensitivity other drugs similar in structure or class to AZD4547. Hypersensitivity to paclitaxel or formulated in cremophor EL (polyoxyethylated castor oil) * Prior taxane treatment for gastric cancer with the exception of adjuvant/neo-adjuvant therapy given \> 6 months; Major surgery, radiotherapy with wide field of radiation or any cancer treatment within 4 weeks before the first dose of the study treatment * With the exception of alopecia, any unresolved toxicities from prior therapy with a Common Terminology Criteria for AE (CTCAE) grade \>1 at the time of starting study treatment. * Blood and Echocardiogram (ECG) readings that are deemed to be abnormal by falling outside of the reference ranges in the protocol inclusion/exclusion section. * Taking other regular medication that are predicted to interact with AZD4547 due to their route of metabolism.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression Free Survival | Tumour size assessed at week 8 (±1 week) and then every 8 weeks (±1 week) | PFS is the time from randomisation until the date of objective disease progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) or death (by any cause in the absence of progression). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival : Number of Patients Who Had Died at DCO (Data Cut Off) | Tumour size assessed at week 8 (±1 week) and then every 8 weeks (±1 week) | — |
| Objective Response Rate | Week 8 (±1 week) and then every 8 weeks (±1 week) | ORR=Percentage of patients with at least one visit response of CR (complete response) or PR (partial response) that is confirmed at least 4 weeks later; CR:disappearance of target lesions and no new lesions; PR is at least 30% decrease in sum of diameters of lesions taking as a reference the smallest sum since treatment started. |
| Percentage Change From Baseline at Week 8 in Target Lesion Size | Baseline, Week 8 (±1 week) | A negative change denotes a reduction in target lesion size. Percentage change from baseline in tumour size at 8 weeks in target lesion size. |
| Percentage of Patients Without Progressive Disease at 8 Weeks | Week 8 (±1 week) | PD = A ≥ 20% increase in the sum of diameters of target lesions and an absolute increase of ≥ 5mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diamters |
Countries
Belgium, Bulgaria, Canada, Czechia, France, Germany, Hungary, India, Italy, Japan, Romania, South Korea, Spain, Taiwan, Ukraine, United Kingdom
Participant flow
Recruitment details
This study was conducted in 11 countries. Enrolment started in November 2011 and last patient visit was in August 2013. In total, 960 patients were enrolled out of which 71 were randomised. A total of 67 patients received treatment , 40 of these patients received AZD4547 and 27 received Paclitaxel.
Pre-assignment details
Patients ≥ 25 years with locally advanced or metastatic gastric adenocarcinoma that had FGFR2 polysomy or FGFR2 gene amplification and whose disease had progressed during or after 1st line therapy. Patients whose disease had progressed within 6 months following adjuvant or neo-adjuvant therapy could be included at the discretion of the investigator
Participants by arm
| Arm | Count |
|---|---|
| Paclitaxel 80mg / m\^2 | 30 |
| AZD4547 80mg BD 2 weeks on/1 week off | 41 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 27 | 16 |
| Overall Study | Death before treatment | 1 | 2 |
| Overall Study | Did not receive treatment | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Unclassified reason for not completed | 11 | 10 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Paclitaxel | AZD4547 | Total |
|---|---|---|---|
| Age, Continuous | 61.9 years STANDARD_DEVIATION 10.65 | 60.6 years STANDARD_DEVIATION 11.38 | 61.2 years STANDARD_DEVIATION 11.02 |
| Age, Customized >=50 - < 65 years | 13 Participants | 20 Participants | 33 Participants |
| Age, Customized <50 years | 4 Participants | 7 Participants | 11 Participants |
| Age, Customized >= 65 years | 13 Participants | 14 Participants | 27 Participants |
| Gender Female | 8 Participants | 12 Participants | 20 Participants |
| Gender Male | 22 Participants | 29 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 39 / 40 | 26 / 27 |
| serious Total, serious adverse events | 8 / 40 | 6 / 27 |
Outcome results
Primary
Median Progression Free Survival
PFS is the time from randomisation until the date of objective disease progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) or death (by any cause in the absence of progression).
Time frame: Tumour size assessed at week 8 (±1 week) and then every 8 weeks (±1 week)
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD4547 | Median Progression Free Survival | 1.8 months |
| Paclitaxel | Median Progression Free Survival | 3.5 months |
p-value: 0.958180% CI: [1.12, 2.21]Regression, Cox
Secondary
Objective Response Rate
ORR=Percentage of patients with at least one visit response of CR (complete response) or PR (partial response) that is confirmed at least 4 weeks later; CR:disappearance of target lesions and no new lesions; PR is at least 30% decrease in sum of diameters of lesions taking as a reference the smallest sum since treatment started.
Time frame: Week 8 (±1 week) and then every 8 weeks (±1 week)
Population: The analysis included factors for treatment and FGFR2 FISH score (4/5 versus 6) and is based on the Full analysis set (all treated patients).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD4547 | Objective Response Rate | 2.6 Patients (%) |
| Paclitaxel | Objective Response Rate | 23.3 Patients (%) |
p-value: 0.99780% CI: [0.02, 0.35]Regression, Logistic
Secondary
Overall Survival : Number of Patients Who Had Died at DCO (Data Cut Off)
Time frame: Tumour size assessed at week 8 (±1 week) and then every 8 weeks (±1 week)
Population: This secondary analysis included factors for treatment and FGFR2 FISH score (4/5 versus 6) and is based on the Full analysis set (all treated patients).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD4547 | Overall Survival : Number of Patients Who Had Died at DCO (Data Cut Off) | 27 Patients |
| Paclitaxel | Overall Survival : Number of Patients Who Had Died at DCO (Data Cut Off) | 18 Patients |
p-value: 0.815680% CI: [0.89, 1.95]Regression, Cox
Secondary
Percentage Change From Baseline at Week 8 in Target Lesion Size
A negative change denotes a reduction in target lesion size. Percentage change from baseline in tumour size at 8 weeks in target lesion size.
Time frame: Baseline, Week 8 (±1 week)
Population: Full analysis set - all treated patients with at least one post baseline RECIST target lesion assessment scan
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AZD4547 | Percentage Change From Baseline at Week 8 in Target Lesion Size | 28.4 Percentage change | Standard Deviation 44.4 |
| Paclitaxel | Percentage Change From Baseline at Week 8 in Target Lesion Size | -1.1 Percentage change | Standard Deviation 36.18 |
Secondary
Percentage of Patients Without Progressive Disease at 8 Weeks
PD = A ≥ 20% increase in the sum of diameters of target lesions and an absolute increase of ≥ 5mm, taking as reference the smallest sum of diameters since treatment started including the baseline sum of diamters
Time frame: Week 8 (±1 week)
Population: Full analysis set - all treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD4547 | Percentage of Patients Without Progressive Disease at 8 Weeks | 24.4 Percentage of patients |
| Paclitaxel | Percentage of Patients Without Progressive Disease at 8 Weeks | 53.3 Percentage of patients |