Metastatic, Gastric or Gastro-oesophageal Junction, Cancer
Conditions
Keywords
Metastatic Gastric Cancer who progress following First Line Therapy and are Ineligible for Treatment with trastuzumab by HER2 Status
Brief summary
The purpose of the study is to assess the efficacy and safety and PK of AZD8931 plus paclitaxel versus paclitaxel alone in patients with metastatic, gastric or gastro-oesophageal junction, cancer.
Detailed description
A Phase IIa Multi-centre Randomised Double-Blind Placebo-controlled Study to Assess the Efficacy, Safety and Pharmacokinetics of AZD8931 in Combination with Paclitaxel versus Paclitaxel alone in Patients with Metastatic, Gastric or Gastro-oesophageal Junction, Cancer who progress following First Line Therapy and are Ineligible for Treatment with trastuzumab by HER2 Status (SAGE)
Interventions
DRUGAZD8931
40 mg, oral dose twice daily
DRUGPlacebo
Placebo, oral dose twice daily
DRUGPaclitaxel
IV once weekly for 3 weeks followed by a week off.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female aged 18 years or older (20 years or older in Japan) * Patients must have radiologically confirmed progression following 1st line fluoropyrimidine and platinum based treatment for metastatic gastric cancer (the date of progression and start of first line treatment to be captured on the database) * Suitable for paclitaxel therapy. * At least one lesion, not previously irradiated and not chosen for a mandatory fresh tumour biopsy during the study screening period, that can be accurately measured at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for accurate repeat assessment. * Ineligible for trastuzumab treatment by local assessment. This should include IHC analysis to determine HER2 status with further testing by FISH/CISH when considered part of local practice. Eligible patients are defined as; HER2 IHC 0, HER2 IHC +1 and +2
Exclusion criteria
* Have received more than 1 prior chemotherapy regimen for metastatic gastric cancer. (chemotherapy as adjuvant treatment is permitted). * Any prior taxane therapy (at any time from diagnosis of gastric cancer) * Any prior therapy with an inhibitor of ErbB1 (EGFR) or ErbB2 (HER2) (eg, lapatinib) * Resting ECG with measurable QTc(F) interval of greater than 480 msec at 2 or more time points within a 24 hour period (see section 6.4.9.1 ) * Unresolved toxicity grater than CTCAE grade 2 (except alopecia) from previous anti-cancer therapy
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in Tumour Size at 8 Weeks Were Analyzed for Comparing Relative Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone | Baseline and 8 weeks, accessed up to data cut off on 4 December 2012 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Were Analysed for Comparing Relative Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone | Baseline and every 8 weeks, accessed up to data cut off on 4 December 2012 | Time from the date of randomization until the date of objective disease progression (as per RECIST1.1) or the date of death (by any cause in absence of progression). |
| The Objective Response Rate (ORR) Was Analysed for Investigating the Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone | Baseline and 8 weeks, accessed up to data cut off on 4 December 2012 | The number of subjects with at least one visit response of CR or PR. (Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive disease (PD), A ≥ 20% increase in the sum of diameters of target lesions and an absolute increase of ≥ 5mm; Stable disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; Not Evaluable (NE), All target lesion measurements are missing or \>1/3 target lesion measurements are missing and sum of diameters of non-missing target lesions does not qualify for PD; Not applicable (NA), No target lesions are recorded at baseline) |
Countries
Germany, Japan, South Korea, Spain, Taiwan
Participant flow
Recruitment details
Due to the early stopping of this study as a result of the AZD8931 program being stopped, the full planned enrolment was not carried out. This study was stopped after 39 were enrolled, 25 of whom were treated, which is less than the number planned in the protocol.
Pre-assignment details
Due to the early stopping of this study as a result of the AZD8931 program being stopped, the full planned enrolment was not carried out. This study was stopped after 39 were enrolled, 25 of whom were treated, which is less than the number planned in the protocol.
Participants by arm
| Arm | Count |
|---|---|
| AZD8931 40mg + Paclitaxel AZD8931 40 mg bd (Twice daily) administered orally in combination with paclitaxel 80 mg/m2 administered intravenously \[approximately 1 hour duration\] on D1, 8 and 15 of each 28 day treatment cycle | 13 |
| Placebo + Paclitaxel AZD8931 matching placebo bd administered orally in combination with paclitaxel 80 mg/m2 administered intravenously \[approximately 1 hour duration\] on D1, 8 and 15 of each 28 day treatment cycle | 12 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 4 | 1 |
| Overall Study | Eligibility criteria | 3 | 9 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Ongoing | 3 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | AZD8931 40mg + Paclitaxel | Placebo + Paclitaxel | Total |
|---|---|---|---|
| Age, Continuous | 57.9 Years STANDARD_DEVIATION 8.71 | 62.7 Years STANDARD_DEVIATION 13.6 | 60.2 Years STANDARD_DEVIATION 11.34 |
| Age, Customized 18 - < 50 years | 3 Participants | 2 Participants | 5 Participants |
| Age, Customized 50 - < 65 years | 7 Participants | 4 Participants | 11 Participants |
| Age, Customized 65 - < 75 years | 3 Participants | 5 Participants | 8 Participants |
| Age, Customized >= 75 years | 0 Participants | 1 Participants | 1 Participants |
| HER2 Status: HER2/IHC (Local Assessment) HER2 0 No staining/membrane staining <10% of cells | 8 Participants | 6 Participants | 14 Participants |
| HER2 Status: HER2/IHC (Local Assessment) HER2 1+ Faint membrane staining ≥10% of cells | 3 Participants | 5 Participants | 8 Participants |
| HER2 Status: HER2/IHC (Local Assessment) HER2 2+ Weak/moderate membrane staining ≥10% cells | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 13 Participants | 12 Participants | 25 Participants |
| Race/Ethnicity, Customized Asian (Other Than Chinese or Japanese) | 8 Participants | 7 Participants | 15 Participants |
| Race/Ethnicity, Customized Chinese | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Japanese | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 9 Participants | 9 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 13 | 12 / 12 |
| serious Total, serious adverse events | 6 / 13 | 3 / 12 |
Outcome results
Primary
Change in Tumour Size at 8 Weeks Were Analyzed for Comparing Relative Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone
Time frame: Baseline and 8 weeks, accessed up to data cut off on 4 December 2012
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AZD8931 + Paclitaxel | Change in Tumour Size at 8 Weeks Were Analyzed for Comparing Relative Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone | -7.7 percentage change | Standard Error 8.6 |
| Placebo + Paclitaxel | Change in Tumour Size at 8 Weeks Were Analyzed for Comparing Relative Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone | -2.7 percentage change | Standard Error 8.64 |
Comparison: 60 patients had been considered to detect a -20% difference in the estimated average percentage change in tumour size at 8 weeks for AZD8931 plus paclitaxel compared to paclitaxel alone at a one-sided significance level of 10% with 90% power. This is based on a standard deviation of 30% for tumour data (on an absolute scale)p-value: 0.68895% CI: [-30.81, 20.81]ANCOVA
Secondary
Progression-free Survival (PFS) Were Analysed for Comparing Relative Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone
Time from the date of randomization until the date of objective disease progression (as per RECIST1.1) or the date of death (by any cause in absence of progression).
Time frame: Baseline and every 8 weeks, accessed up to data cut off on 4 December 2012
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD8931 + Paclitaxel | Progression-free Survival (PFS) Were Analysed for Comparing Relative Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone | 3.7 months |
| Placebo + Paclitaxel | Progression-free Survival (PFS) Were Analysed for Comparing Relative Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone | 3.5 months |
Secondary
The Objective Response Rate (ORR) Was Analysed for Investigating the Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone
The number of subjects with at least one visit response of CR or PR. (Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive disease (PD), A ≥ 20% increase in the sum of diameters of target lesions and an absolute increase of ≥ 5mm; Stable disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; Not Evaluable (NE), All target lesion measurements are missing or \>1/3 target lesion measurements are missing and sum of diameters of non-missing target lesions does not qualify for PD; Not applicable (NA), No target lesions are recorded at baseline)
Time frame: Baseline and 8 weeks, accessed up to data cut off on 4 December 2012
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AZD8931 + Paclitaxel | The Objective Response Rate (ORR) Was Analysed for Investigating the Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone | Total | 3 Participants |
| AZD8931 + Paclitaxel | The Objective Response Rate (ORR) Was Analysed for Investigating the Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone | Complete Response | 0 Participants |
| AZD8931 + Paclitaxel | The Objective Response Rate (ORR) Was Analysed for Investigating the Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone | Partial Response | 3 Participants |
| Placebo + Paclitaxel | The Objective Response Rate (ORR) Was Analysed for Investigating the Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone | Total | 0 Participants |
| Placebo + Paclitaxel | The Objective Response Rate (ORR) Was Analysed for Investigating the Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone | Complete Response | 0 Participants |
| Placebo + Paclitaxel | The Objective Response Rate (ORR) Was Analysed for Investigating the Efficacy of AZD8931 Plus Paclitaxel With Paclitaxel Alone | Partial Response | 0 Participants |