Colorectal Cancer
Conditions
Brief summary
This study will evaluate the efficacy and safety of adding bevacizumab to crossover fluoropyrimidine-based chemotherapy in patients with metastatic colorectal cancer who have experienced disease progression under first line treatment with standard chemotherapy plus bevacizumab. Participants will receive chemotherapy alone, or in combination with bevacizumab. The anticipated time on study treatment is until disease progression or unacceptable toxicity occurs. Participants are allowed to continue on bevacizumab, even after stopping chemotherapy.
Interventions
DRUGChemotherapy
As prescribed
DRUGBevacizumab
Bevacizumab, 5 mg/kg intravenously (IV) on days 1 and 14 of each 4 week cycle, or 7.5 mg/kg IV on days 1 and 22 of each 6 week cycle.
Sponsors
Hoffmann-La Roche
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
* Adult patients, \>=18 years of age * Metastatic colorectal cancer and disease progression * Previously treated with first-line chemotherapy plus Avastin * Eastern Cooperative Oncology Group (ECOG) performance status \<=2.
Exclusion criteria
* Diagnosis of progression of disease more than 3 months after last Avastin administration * First-line patients with progression-free survival in first-line of \<3 months * Patients receiving less than 3 consecutive months of Avastin in first-line therapy * Past or current history (within the last 2 years prior to treatment start) of other malignancies, except for curatively treated basal and squamous cell cancer of the skin or in situ cancer of the cervix * Clinically significant cardiovascular disease within 6 months prior to start of study treatment * Known central nervous system (CNS) disease, except for treated CNS metastases as defined by protocol
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Overall Survival: Time From Randomization to Death From Any Cause | within 6.5 years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival: Time to Event | within 6.5 years | — |
| Response Rate: Percentage of Participants With Best Overall Response, Defined as Confirmed Complete Response (CR) or Partial Response (PR) According to RECIST Criteria | within 6.5 years | — |
| Overall Survival: Months From Time of First Line Therapy | within approximately 9.6 years | — |
| Participants With Progression Free Survival Event | within 6.5 years | — |
| Response Rate: Participants With Response Status Based on RECIST Criteria | within 6.5 years | Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. |
Countries
Austria, Belgium, Czechia, Denmark, Estonia, Finland, France, Germany, Netherlands, Norway, Portugal, Saudi Arabia, Spain, Sweden, Switzerland
Participant flow
Recruitment details
This study enrolled 820 patients at 220 sites located in 15 countries in Europe and Saudi Arabia. Study AIO KRK 0504 enrolled 261 patients, and 559 patients subsequently enrolled in Study ML18147 when the study was transferred to Hoffmann LaRoche (in 2008).
Participants by arm
| Arm | Count |
|---|---|
| Chemotherapy Chemotherapy alone until disease progression, unacceptable toxicity, or patient refusal
Chemotherapy: As prescribed | 411 |
| Chemotherapy + Bevacizumab Chemotherapy and Bevacizumab until disease progression, unacceptable toxicity, or patient refusal
Chemotherapy: As prescribed
Bevacizumab: Bevacizumab, 5 mg/kg intravenously (IV) on days 1 and 14 of each 4 week cycle, or 7.5 mg/kg IV on days 1 and 22 of each 6 week cycle. | 409 |
| Total | 820 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Died | 394 | 385 |
| Overall Study | Lost to Follow-up | 8 | 10 |
Baseline characteristics
| Characteristic | Chemotherapy | Chemotherapy + Bevacizumab | Total |
|---|---|---|---|
| Age, Continuous | 61.9 years STANDARD_DEVIATION 9.55 | 62.1 years STANDARD_DEVIATION 9.78 | 62.0 years STANDARD_DEVIATION 9.66 |
| Sex: Female, Male Female | 152 Participants | 142 Participants | 294 Participants |
| Sex: Female, Male Male | 259 Participants | 267 Participants | 526 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 379 / 409 | 382 / 401 |
| serious Total, serious adverse events | 137 / 409 | 130 / 401 |
Outcome results
Primary
Overall Survival: Time From Randomization to Death From Any Cause
Time frame: within 6.5 years
Population: Intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemotherapy | Overall Survival: Time From Randomization to Death From Any Cause | 9.8 months |
| Chemotherapy + Bevacizumab | Overall Survival: Time From Randomization to Death From Any Cause | 11.2 months |
p-value: 0.006295% CI: [0.69, 0.94]Log Rank
Secondary
Overall Survival: Months From Time of First Line Therapy
Time frame: within approximately 9.6 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemotherapy | Overall Survival: Months From Time of First Line Therapy | 22.5 months |
| Chemotherapy + Bevacizumab | Overall Survival: Months From Time of First Line Therapy | 23.9 months |
Comparison: Kaplan Meier Estimatep-value: 0.171395% CI: [0.77, 1.05]Log Rank
Secondary
Participants With Progression Free Survival Event
Time frame: within 6.5 years
Population: Unstratified intention to treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy | Participants With Progression Free Survival Event | 394 participants |
| Chemotherapy + Bevacizumab | Participants With Progression Free Survival Event | 386 participants |
Secondary
Progression Free Survival: Time to Event
Time frame: within 6.5 years
Population: Unstratified intention to treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Chemotherapy | Progression Free Survival: Time to Event | 4.1 Months |
| Chemotherapy + Bevacizumab | Progression Free Survival: Time to Event | 5.7 Months |
p-value: <0.000195% CI: [0.59, 0.78]Log Rank
Secondary
Response Rate: Participants With Response Status Based on RECIST Criteria
Response Evaluation Criteria In Solid Tumors (RECIST) is a set of published rules that define when tumors in cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment.
Time frame: within 6.5 years
Population: Participants with measurable disease
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Chemotherapy | Response Rate: Participants With Response Status Based on RECIST Criteria | Partial response | 3.4 percentage of participants |
| Chemotherapy | Response Rate: Participants With Response Status Based on RECIST Criteria | Progressive Disease | 35.0 percentage of participants |
| Chemotherapy | Response Rate: Participants With Response Status Based on RECIST Criteria | Stable Disease | 50.2 percentage of participants |
| Chemotherapy | Response Rate: Participants With Response Status Based on RECIST Criteria | Missing (No Response Assessment) | 10.8 percentage of participants |
| Chemotherapy | Response Rate: Participants With Response Status Based on RECIST Criteria | Complete response | 0.5 percentage of participants |
| Chemotherapy + Bevacizumab | Response Rate: Participants With Response Status Based on RECIST Criteria | Missing (No Response Assessment) | 10.4 percentage of participants |
| Chemotherapy + Bevacizumab | Response Rate: Participants With Response Status Based on RECIST Criteria | Complete response | 0.2 percentage of participants |
| Chemotherapy + Bevacizumab | Response Rate: Participants With Response Status Based on RECIST Criteria | Partial response | 5.2 percentage of participants |
| Chemotherapy + Bevacizumab | Response Rate: Participants With Response Status Based on RECIST Criteria | Stable Disease | 62.6 percentage of participants |
| Chemotherapy + Bevacizumab | Response Rate: Participants With Response Status Based on RECIST Criteria | Progressive Disease | 21.5 percentage of participants |
Secondary
Response Rate: Percentage of Participants With Best Overall Response, Defined as Confirmed Complete Response (CR) or Partial Response (PR) According to RECIST Criteria
Time frame: within 6.5 years
Population: Participants with measurable disease
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Chemotherapy | Response Rate: Percentage of Participants With Best Overall Response, Defined as Confirmed Complete Response (CR) or Partial Response (PR) According to RECIST Criteria | 3.9 percentage of participants |
| Chemotherapy + Bevacizumab | Response Rate: Percentage of Participants With Best Overall Response, Defined as Confirmed Complete Response (CR) or Partial Response (PR) According to RECIST Criteria | 5.4 percentage of participants |
p-value: 0.311395% CI: [-1.5, 4.5]Chi-squared
p-value: 0.4315Cochran-Mantel-Haenszel