Colorectal Neoplasms
Conditions
Brief summary
This Phase II study is open to patients with metastatic colorectal cancer who have tried but failed chemotherapy regimens containing oxaliplatin and irinotecan. Patients must not have received anti-EGFR (Epidermal Growth Factor Receptor) treatment (for example, cetuximab, panitumumab) in the past. Patients with wild-type KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) colorectal cancer will be randomised to receive either BIBW 2992 or cetuximab. Patients with KRAS mutated colorectal cancer will not be randomised, but will all receive BIBW 2992. The main objectives of the study are: to compare the effectiveness of BIBW 2992 with that of cetuximab in patients with KRAS wild type cancer, and to assess the effectiveness of BIBW 2992 in patients with KRAS mutated cancer.
Interventions
DRUGBIBW 2992
Patients receive BIBW 2992 tablets once daily, and can reduce dose for adverse event management
DRUGCetuximab
Patients receive cetuximab intravenously, once a week, every week
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with metastatic colorectal cancer who have failed both oxaliplatin- and irinotecan-based regimens 2. Tumour sample available for KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation testing and other biomarker analyses.
Exclusion criteria
1. Prior treatment with Epidermal Growth Factor Receptor (EGFR) targeting small molecules or antibodies. 2. Biological treatment (including Bevacizumab or any other antiangiogenic agents) during the trial is not allowed. 3. Known pre-existing interstitial lung disease. 4. Planned major surgical procedures during the trial period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Objective Response | Baseline till progression or death, whichever came first, assessed up to 23 months | Percentage of participants with objective response: complete response (CR) or partial response (PR) according to RECIST (version 1.1) without confirmation criteria applied. |
| Percentage of Participants With Disease Control (DC) | Baseline till progression or death, whichever came first, assessed up to 23 months | Percentage of participants with objective response or stable disease (SD) as determined by RECIST (version 1.1) with confirmation criteria applied. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Baseline till progression or death, whichever came first, assessed up to 23 months | PFS time is defined as time from randomisation (wild-type group) or start of treatment (mutated group) to tumor progression evaluated according to RECIST (version 1.1) or death whichever occurs earlier. Median and confidence interval estimated using product-limit Kaplan-Meier method. |
| Overall Survival (OS) Time | Baseline till death, assessed up to 23 months | OS time is defined as time from the date of randomisation (wild-type group) or date of start of treatment (mutated group) to the date of death. Median and confidence interval estimated using product-limit Kaplan-Meier method. |
| Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 8 (Cpre,ss,8) | day 8 | Cpre,ss,8 represents the pre-dose concentration of afatinib in plasma at steady state on day 8. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Afatinib (Wild-type) Afatinib tablets once daily in patients with KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) wild-type metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated. | 36 |
| Cetuximab (Wild-type) Cetuximab 400 mg/m² on Day 1 and then 250mg/m² once a week, every week, intravenous (i.v.) in patients with KRAS wild-type metastatic colorectal cancer. | 14 |
| Afatinib (Mutated) Afatinib tablets once daily in patients with KRAS mutated metastatic colorectal cancer. Patients started on 40 mg and then increased to 50 mg after 4 weeks if well tolerated. | 41 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Not treated | 0 | 1 | 2 |
| Overall Study | Other Adverse Event | 8 | 1 | 7 |
| Overall Study | Progressive disease | 27 | 13 | 32 |
| Overall Study | Refusal to continue taking trial medicat | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | Afatinib (Wild-type) | Cetuximab (Wild-type) | Afatinib (Mutated) | Total |
|---|---|---|---|---|
| Age, Continuous | 62.5 years STANDARD_DEVIATION 10.4 | 62.6 years STANDARD_DEVIATION 7.7 | 60.0 years STANDARD_DEVIATION 11.9 | 61.4 years STANDARD_DEVIATION 10.8 |
| Sex: Female, Male Female | 9 Participants | 5 Participants | 22 Participants | 36 Participants |
| Sex: Female, Male Male | 27 Participants | 9 Participants | 19 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 35 / 36 | 14 / 14 | 40 / 41 |
| serious Total, serious adverse events | 15 / 36 | 5 / 14 | 18 / 41 |
Outcome results
Primary
Percentage of Participants With Disease Control (DC)
Percentage of participants with objective response or stable disease (SD) as determined by RECIST (version 1.1) with confirmation criteria applied.
Time frame: Baseline till progression or death, whichever came first, assessed up to 23 months
Population: Treated Set. Primary endpoint for the population of patients with KRAS mutated tumours.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib (Wild-type) | Percentage of Participants With Disease Control (DC) | 12 Percentage of Participants |
Comparison: Null hypothesis is that the disease control rate is 10% in patients with KRAS mutation. Sample size calculation based on a 2-sided exact binomial test at 10% significance level to distinguish between the historical disease control rate of 10% and a desirable disease control rate for afatinib of 25%.p-value: 0.639490% CI: [4.9, 23.9]Exact binomial test
Primary
Percentage of Participants With Objective Response
Percentage of participants with objective response: complete response (CR) or partial response (PR) according to RECIST (version 1.1) without confirmation criteria applied.
Time frame: Baseline till progression or death, whichever came first, assessed up to 23 months
Population: Randomised set. Primary endpoint for the population of patients with KRAS wildtype tumours.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Afatinib (Wild-type) | Percentage of Participants With Objective Response | 3 Percentage of Participants |
| Cetuximab (Wild-type) | Percentage of Participants With Objective Response | 20 Percentage of Participants |
Comparison: Null hypothesis is that the objective response rate (ORR) in KRAS wild-type patients treated with afatinib is less than or equal to the ORR in KRAS wild-type patients treated with cetuximab. Sample size is based on a 'pick the winner' approach assuming ORR for cetuximab of 12%, undesirable ORR for afatinib of 11% and desirable ORR for afatinib of 16%. As per 'pick the winner' approach, afatinib would be considered 'the winner' if the ORR for afatinib was greater than the ORR for cetuximab.p-value: 0.073590% CI: [0.018, 0.844]Regression, Logistic
Secondary
Overall Survival (OS) Time
OS time is defined as time from the date of randomisation (wild-type group) or date of start of treatment (mutated group) to the date of death. Median and confidence interval estimated using product-limit Kaplan-Meier method.
Time frame: Baseline till death, assessed up to 23 months
Population: Randomised set for wild-type group and treated set for mutated group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib (Wild-type) | Overall Survival (OS) Time | 355.0 Days |
| Cetuximab (Wild-type) | Overall Survival (OS) Time | NA Days |
| Afatinib (Mutated) | Overall Survival (OS) Time | 173.0 Days |
Secondary
Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 8 (Cpre,ss,8)
Cpre,ss,8 represents the pre-dose concentration of afatinib in plasma at steady state on day 8.
Time frame: day 8
Population: Randomised set for wild-type group and treated set for mutated group.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Afatinib (Wild-type) | Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 8 (Cpre,ss,8) | 16.6 ng/mL | Geometric Coefficient of Variation 80.3 |
| Cetuximab (Wild-type) | Pre-dose Concentration of Afatinib in Plasma at Steady State on Day 8 (Cpre,ss,8) | 21.4 ng/mL | Geometric Coefficient of Variation 91 |
Secondary
Progression Free Survival (PFS)
PFS time is defined as time from randomisation (wild-type group) or start of treatment (mutated group) to tumor progression evaluated according to RECIST (version 1.1) or death whichever occurs earlier. Median and confidence interval estimated using product-limit Kaplan-Meier method.
Time frame: Baseline till progression or death, whichever came first, assessed up to 23 months
Population: Randomised set for wild-type group and treated set for mutated group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Afatinib (Wild-type) | Progression Free Survival (PFS) | 46.0 Days |
| Cetuximab (Wild-type) | Progression Free Survival (PFS) | 144.5 Days |
| Afatinib (Mutated) | Progression Free Survival (PFS) | 41.0 Days |