Colorectal Cancer
Conditions
Brief summary
This single arm study will assess the resection rate of liver metastasis, time to disease progression, and safety of neoadjuvant treatment with Avastin in combination with oxaliplatin and capecitabine (XELOX) in patients with metastatic colorectal cancer with unresectable liver metastasis. Patients will receive Avastin 5mg/kg iv on day 1 of every 2 week cycle, oxaliplatin 85mg/m2 iv on day 1 of every 2 week cycle, and capecitabine 1000mg/m2 on days 1-5 and 8-12 of every 2 week cycle. The anticipated time on study treatment is 3-12 months, and the target sample size is \<100 individuals.
Interventions
DRUGcapecitabine [Xeloda]
1000mg/m2 iv on days 1-5 and 8-12 of each 2 week cycle
DRUGoxaliplatin
85mg/m2 iv on day 1 of each 2 week cycle
DRUGbevacizumab [Avastin]
5mg/kg iv on day 1 of each 2 week cycle.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 75 Years
Healthy volunteers
No
Inclusion criteria
* adult patients, \<=75 years of age; * chemotherapy-naive for stage IV colorectal cancer with unresectable liver metastasis; * \>=1 measurable lesion; * ECOG status 0-2.
Exclusion criteria
* prior exposure to Avastin; * clinical or radiological evidence of CNS metastases; * uncontrolled hypertension, or clinically significant cardiovascular disease; * ongoing treatment with aspirin (\>325mg/day) or other medications known to predispose to gastrointestinal ulceration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Conversion From Unresectable to Resectable Liver Metastases | After 5 cycles of neoadjuvant treatment (10 weeks) | Participants were assessed via microscopic and macroscopic examination for tumor resectability after completion of 5 cycles of neoadjuvant treatment. Unresectable participants exhibited any of the following criteria: greater than or equal to (≥) 4 liver metastases; location and/or distribution of metastatic disease within the liver considered unsuitable for resection with clear margins; liver involvement precluding resection, in the setting of adequate parenchymal volume for otherwise viable liver function in the immediate postoperative period; and inability to maintain adequate circulation for viable liver function. Participants who had not met any of the above criteria at the end of 5 cycles underwent surgical resection. The percentage of participants with conversion from initially unresectable to resectable liver metastases was calculated as \[number of participants eligible for surgical resection divided by the number analyzed\] multiplied by 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Disease Progression | Up to approximately 3 years (at Baseline, end of Cycle 5, time of surgery, and within 4 weeks of end of treatment [EOT]) | Objective tumor response was assessed using RECIST version 1.1. Disease progression was defined as a ≥20 percent (%) increase in the sum of longest diameters of target lesions, taking as reference the smallest sum obtained at previous tumor assessment, or the appearance of any new lesions. The percentage of participants with disease progression was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100. |
| Time to Disease Progression | Up to approximately 3 years (at Baseline, end of Cycle 5, time of surgery, and within 4 weeks of EOT) | Objective tumor response was assessed using RECIST version 1.1. Disease progression was defined as a ≥20% increase in the sum of longest diameters of target lesions, taking as reference the smallest sum obtained at previous tumor assessment, or the appearance of any new lesions. Time to disease progression was defined as the time from first dose to time of disease progression. Participants without progression were censored at the time of last tumor assessment. Time to disease progression was estimated using Kaplan-Meier analysis and expressed in months. |
| Percentage of Participants With a Best Overall Tumor Response of Complete Response (CR) or PR According to RECIST Version 1.1 | Up to approximately 3 years (at Baseline, end of Cycle 5, time of surgery, within 4 weeks of EOT, and at least 4 weeks after initial response) | Objective tumor response was assessed using RECIST version 1.1. CR was defined as the disappearance of all target lesions, and PR was defined as a ≥30% decrease in the sum of longest diameters compared to Baseline. Response was confirmed at a minimum of 4 weeks after the first documented response. The percentage of participants with confirmed CR or PR was calculated as \[number of participants meeting the respective criteria divided by the number analyzed\] multiplied by 100. |
| Percentage of Participants by Best Overall Tumor Response According to RECIST Version 1.1 | Up to approximately 3 years (at Baseline, end of Cycle 5, time of surgery, within 4 weeks of EOT, and at least 4 weeks after initial response) | Objective tumor response was assessed using RECIST version 1.1. CR was defined as the disappearance of all target lesions, and PR was defined as a ≥30% decrease in the sum of longest diameters compared to Baseline. Response was to be confirmed at a minimum of 4 weeks after the first documented response. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, as well as no new target lesions. Disease progression or PD was defined as a ≥20% increase in the sum of longest diameters of target lesions, taking as reference the smallest sum obtained at previous tumor assessment, or the appearance of any new lesions. Non-evaluability for tumor assessment was also documented when applicable. The percentage of participants with each level of response was calculated as \[number of participants meeting the respective criteria divided by the number analyzed\] multiplied by 100. |
Countries
Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Resected Participants with unresectable liver metastases secondary to CRC were assigned to receive neoadjuvant treatment of IV bevacizumab with XELOX. Bevacizumab was given as 5 mg/kg on Day 1 of each 14-day cycle during Cycles 1 to 5 and/or Cycles 8 to 12. During Cycles 1 to 12, IV oxaliplatin was given as 85 mg/m\^2 on Day 1, and PO capecitabine as 1000 mg/m\^2 twice daily on Days 1 to 5 and 8 to 12. Resectability was assessed at completion of Cycle 5. Resectable participants followed a new algorithm: complete Cycle 6 (XELOX), rest for 4 weeks, undergo surgery, rest for 4 weeks, complete adjuvant therapy during Cycles 7 (XELOX) and 8 to 12 (bevacizumab plus XELOX), and continue an additional 6 cycles with capecitabine and bevacizumab per Investigator discretion. Participants could be withdrawn at any point for unacceptable toxicity. | 19 |
| Unresected Participants with unresectable liver metastases secondary to CRC were assigned to receive neoadjuvant treatment of IV bevacizumab with XELOX. Bevacizumab was given as 5 mg/kg on Day 1 of each 14-day cycle during Cycles 1 to 5 and/or Cycles 8 to 12. During Cycles 1 to 12, IV oxaliplatin was given as 85 mg/m\^2 on Day 1, and PO capecitabine as 1000 mg/m\^2 twice daily on Days 1 to 5 and 8 to 12. Resectability was assessed at completion of Cycle 5. Unresectable participants with PR or SD, according to RECIST version 1.1, repeated neoadjuvant treatment until documented resectability or PD. Participants could be withdrawn at any point for unacceptable toxicity. | 26 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 6 |
| Overall Study | Discretion of Investigator or Sponsor | 0 | 3 |
| Overall Study | Disease Progression | 8 | 11 |
| Overall Study | Withdrawal by Subject | 1 | 6 |
Baseline characteristics
| Characteristic | Resected | Unresected | Total |
|---|---|---|---|
| Age, Continuous | 55.0 years STANDARD_DEVIATION 11.6 | 55.1 years STANDARD_DEVIATION 10.4 | 55.08 years STANDARD_DEVIATION 11.2 |
| Gender Female | 6 Participants | 12 Participants | 18 Participants |
| Gender Male | 13 Participants | 14 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 45 / 45 |
| serious Total, serious adverse events | 11 / 45 |
Outcome results
Primary
Percentage of Participants With Conversion From Unresectable to Resectable Liver Metastases
Participants were assessed via microscopic and macroscopic examination for tumor resectability after completion of 5 cycles of neoadjuvant treatment. Unresectable participants exhibited any of the following criteria: greater than or equal to (≥) 4 liver metastases; location and/or distribution of metastatic disease within the liver considered unsuitable for resection with clear margins; liver involvement precluding resection, in the setting of adequate parenchymal volume for otherwise viable liver function in the immediate postoperative period; and inability to maintain adequate circulation for viable liver function. Participants who had not met any of the above criteria at the end of 5 cycles underwent surgical resection. The percentage of participants with conversion from initially unresectable to resectable liver metastases was calculated as \[number of participants eligible for surgical resection divided by the number analyzed\] multiplied by 100.
Time frame: After 5 cycles of neoadjuvant treatment (10 weeks)
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Percentage of Participants With Conversion From Unresectable to Resectable Liver Metastases | 42.2 percentage of participants |
Secondary
Percentage of Participants by Best Overall Tumor Response According to RECIST Version 1.1
Objective tumor response was assessed using RECIST version 1.1. CR was defined as the disappearance of all target lesions, and PR was defined as a ≥30% decrease in the sum of longest diameters compared to Baseline. Response was to be confirmed at a minimum of 4 weeks after the first documented response. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, as well as no new target lesions. Disease progression or PD was defined as a ≥20% increase in the sum of longest diameters of target lesions, taking as reference the smallest sum obtained at previous tumor assessment, or the appearance of any new lesions. Non-evaluability for tumor assessment was also documented when applicable. The percentage of participants with each level of response was calculated as \[number of participants meeting the respective criteria divided by the number analyzed\] multiplied by 100.
Time frame: Up to approximately 3 years (at Baseline, end of Cycle 5, time of surgery, within 4 weeks of EOT, and at least 4 weeks after initial response)
Population: ITT Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants | Percentage of Participants by Best Overall Tumor Response According to RECIST Version 1.1 | CR | 36.8 percentage of participants |
| All Participants | Percentage of Participants by Best Overall Tumor Response According to RECIST Version 1.1 | PD | 52.6 percentage of participants |
| All Participants | Percentage of Participants by Best Overall Tumor Response According to RECIST Version 1.1 | PR | 10.5 percentage of participants |
| All Participants | Percentage of Participants by Best Overall Tumor Response According to RECIST Version 1.1 | Non-evaluable | 0 percentage of participants |
| All Participants | Percentage of Participants by Best Overall Tumor Response According to RECIST Version 1.1 | SD | 0 percentage of participants |
| Unresected | Percentage of Participants by Best Overall Tumor Response According to RECIST Version 1.1 | Non-evaluable | 3.8 percentage of participants |
| Unresected | Percentage of Participants by Best Overall Tumor Response According to RECIST Version 1.1 | CR | 0 percentage of participants |
| Unresected | Percentage of Participants by Best Overall Tumor Response According to RECIST Version 1.1 | SD | 15.4 percentage of participants |
| Unresected | Percentage of Participants by Best Overall Tumor Response According to RECIST Version 1.1 | PD | 46.2 percentage of participants |
| Unresected | Percentage of Participants by Best Overall Tumor Response According to RECIST Version 1.1 | PR | 34.6 percentage of participants |
p-value: 0.001Fisher Exact
Secondary
Percentage of Participants With a Best Overall Tumor Response of Complete Response (CR) or PR According to RECIST Version 1.1
Objective tumor response was assessed using RECIST version 1.1. CR was defined as the disappearance of all target lesions, and PR was defined as a ≥30% decrease in the sum of longest diameters compared to Baseline. Response was confirmed at a minimum of 4 weeks after the first documented response. The percentage of participants with confirmed CR or PR was calculated as \[number of participants meeting the respective criteria divided by the number analyzed\] multiplied by 100.
Time frame: Up to approximately 3 years (at Baseline, end of Cycle 5, time of surgery, within 4 weeks of EOT, and at least 4 weeks after initial response)
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Percentage of Participants With a Best Overall Tumor Response of Complete Response (CR) or PR According to RECIST Version 1.1 | 47.4 percentage of participants |
| Unresected | Percentage of Participants With a Best Overall Tumor Response of Complete Response (CR) or PR According to RECIST Version 1.1 | 34.6 percentage of participants |
Secondary
Percentage of Participants With Disease Progression
Objective tumor response was assessed using RECIST version 1.1. Disease progression was defined as a ≥20 percent (%) increase in the sum of longest diameters of target lesions, taking as reference the smallest sum obtained at previous tumor assessment, or the appearance of any new lesions. The percentage of participants with disease progression was calculated as \[number of participants meeting the above criteria divided by the number analyzed\] multiplied by 100.
Time frame: Up to approximately 3 years (at Baseline, end of Cycle 5, time of surgery, and within 4 weeks of end of treatment [EOT])
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Percentage of Participants With Disease Progression | 52.6 percentage of participants |
| Unresected | Percentage of Participants With Disease Progression | 46.2 percentage of participants |
Secondary
Time to Disease Progression
Objective tumor response was assessed using RECIST version 1.1. Disease progression was defined as a ≥20% increase in the sum of longest diameters of target lesions, taking as reference the smallest sum obtained at previous tumor assessment, or the appearance of any new lesions. Time to disease progression was defined as the time from first dose to time of disease progression. Participants without progression were censored at the time of last tumor assessment. Time to disease progression was estimated using Kaplan-Meier analysis and expressed in months.
Time frame: Up to approximately 3 years (at Baseline, end of Cycle 5, time of surgery, and within 4 weeks of EOT)
Population: ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Participants | Time to Disease Progression | 10.1 months |
| Unresected | Time to Disease Progression | 8.7 months |
p-value: 0.1341Log Rank