Colorectal Cancer
Conditions
Brief summary
This open-label single arm study will evaluate the efficacy and safety of Avastin added to XELOX or FOLFOX in patients with metastatic colorectal cancer and disease progression on 1st line therapy with FOLFIRI plus Avastin. Patients will receive either Avastin (7.5mg/kg iv infusion every 3 weeks) and standard XELOX (Xeloda \[capecitabine\] plus oxaliplatin) chemotherapy or Avastin (5 mg/kg iv infusion every 2 weeks) and standard FOLFOX (5-FU and leucovorin plus oxaliplatin) chemotherapy. The anticipated time on study treatment is until disease progression, and the target sample size is 100 individuals.
Interventions
standard FOLFOX regimen
DRUGleucovorin
standard FOLFOX regimen
DRUGbevacizumab [Avastin]
7.5 mg/kg iv infusion every 3 weeks OR 5 mg/kg iv infusion every 2 weeks
DRUGcapecitabine [Xeloda]
standard XELOX regimen
DRUGoxaliplatin
standard XELOX or FOLFOX regimen
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_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 * at least 1 measurable lesion according to RECIST v. 1.1 * patients with disease progression with prior FOLFIRI + Avastin therapy who are not candidates for primary metastasectomy * disease progression \</= 8 weeks after last dose of Avastin * ECOG \</=2 * No more than 8 weeks between 1st-line treatment with FOLFIRI + Avastin and 2nd-line treatment with XELOX or FOLFOX + Avastin
Exclusion criteria
* disease progression \> 8 weeks after last Avastin administration * clinically significant cardiovascular disease * CNS disease except for treated brain metastasis * history of other malignancies within 2 years prior to start of study treatment (with the exception of curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix) * major surgery, open biopsy, or significant traumatic injury within 28 days prior to start of study treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) From the Start of Treatment Beyond Progression | Baseline, every 9 weeks until disease progression, at end of treatment or withdrawal, for up to 24 months | PFS from the start of treatment beyond progression was defined as the interval between the start of beyond-progression therapy and the date at which disease progression was documented. Progression of disease was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 and abdominal/pelvic computerized tomography (CT) or magnetic resonance imaging (MRI) scanning as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The same method of assessment and the same technique were to be used to evaluate each lesion throughout the entire study. If more than one method was used, data from the most accurate method according to RECIST were recorded. Median PFS was estimated using the Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PFS From the Start of First-Line Therapy | Baseline, every 9 weeks until disease progression, at end of treatment or withdrawal, for up to 24 months | PFS from the start of first-line therapy was defined as the interval between the start of first-line therapy and the date at which second disease progression (after the start of beyond progression therapy) was documented. Progression of disease was evaluated using RECIST version 1.1 and abdominal/pelvic CT or MRI scanning. The same method of assessment and the same technique were to be used to evaluate each lesion throughout the entire study. If more than one method was used, data from the most accurate method according to RECIST were recorded. Median PFS was estimated using the Kaplan-Meier method. |
| Percentage of Participants With an Overall Response of Complete Response (CR) or Partial Response (PR) | Baseline, every 9 weeks until disease progression, at end of treatment or withdrawal, for up to 24 months | Percentage of participants with an overall response of CR or PR according to RECIST criteria. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must have decreased to normal (short axis less than \[\<\]10 millimeters \[mm\]). No new lesions. PR was defined as greater than or equal to (≥)30 percent (%) decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. |
| Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression | Baseline, every 9 weeks until disease progression, at final visit or at withdrawal, for up to 24 months | Pro-angiogenic cytokine concentrations of placental growth factor (PlGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF) in participant sera were measured and reported in units of picograms/milliliter (pg/mL). The geometric mean was calculated as exp10 (mean of log10 transformed concentration) and the standard deviation (SD) is SD of log10 transformed concentration. |
Countries
Belgium
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab + Oxaliplatin + Capecitabine Participants received bevacizumab 7.5 mg/kg IV on Day 1; oxaliplatin 130 mg/m\^2 IV on Day 1; and capecitabine 1000 mg/m\^2, PO, BID on Days 1 through 14 (followed by 1-week rest period). The cycle was repeated every 3 weeks until disease progression. | 25 |
| Bevacizumab + FOLFOX Participants received bevacizumab 5.0 mg/kg IV on Day 1 and FOLFOX (5-FU plus leucovorin and oxaliplatin) administered on Days 1 and 2 (followed by a rest period on Days 3 through 14); the specific FOLFOX regimen was determined on an individual participant basis by the investigator (5-FU and leucovorin dose was dependent on choice of FOLFOX regimen; oxaliplatin was administered at a dose ranging from 85 to 130 mg/m\^2 IV on Day 1 based on choice of FOLFOX regimen). The cycle was repeated every 2 weeks until disease progression. | 50 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 3 |
| Overall Study | Other | 2 | 2 |
| Overall Study | Premature withdrawal | 1 | 3 |
| Overall Study | Unacceptable toxicity | 1 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Bevacizumab + Oxaliplatin + Capecitabine | Bevacizumab + FOLFOX | Total |
|---|---|---|---|
| Age, Continuous | 59.6 years STANDARD_DEVIATION 8.9 | 64.9 years STANDARD_DEVIATION 8.7 | 63.1 years STANDARD_DEVIATION 9 |
| Sex: Female, Male Female | 8 Participants | 21 Participants | 29 Participants |
| Sex: Female, Male Male | 17 Participants | 29 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 25 | 49 / 50 |
| serious Total, serious adverse events | 12 / 25 | 18 / 50 |
Outcome results
Primary
Progression-Free Survival (PFS) From the Start of Treatment Beyond Progression
PFS from the start of treatment beyond progression was defined as the interval between the start of beyond-progression therapy and the date at which disease progression was documented. Progression of disease was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 and abdominal/pelvic computerized tomography (CT) or magnetic resonance imaging (MRI) scanning as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The same method of assessment and the same technique were to be used to evaluate each lesion throughout the entire study. If more than one method was used, data from the most accurate method according to RECIST were recorded. Median PFS was estimated using the Kaplan-Meier method.
Time frame: Baseline, every 9 weeks until disease progression, at end of treatment or withdrawal, for up to 24 months
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Oxaliplatin + Capecitabine | Progression-Free Survival (PFS) From the Start of Treatment Beyond Progression | 6.3 months |
| Bevacizumab + FOLFOX | Progression-Free Survival (PFS) From the Start of Treatment Beyond Progression | 5.1 months |
Secondary
Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression
Pro-angiogenic cytokine concentrations of placental growth factor (PlGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF) in participant sera were measured and reported in units of picograms/milliliter (pg/mL). The geometric mean was calculated as exp10 (mean of log10 transformed concentration) and the standard deviation (SD) is SD of log10 transformed concentration.
Time frame: Baseline, every 9 weeks until disease progression, at final visit or at withdrawal, for up to 24 months
Population: ITT Population. Number (n) equals (=) number of participants assessed for the given parameter at the specified visit.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Bevacizumab + Oxaliplatin + Capecitabine | Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression | Baseline bFGF (n=13,23) | 6.8 pg/mL | Standard Deviation 0.7 |
| Bevacizumab + Oxaliplatin + Capecitabine | Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression | bFGF, Prior to progression levels (n=12,18) | 3.6 pg/mL | Standard Deviation 0.9 |
| Bevacizumab + Oxaliplatin + Capecitabine | Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression | Baseline HGF (n=13,23) | 133.0 pg/mL | Standard Deviation 0.3 |
| Bevacizumab + Oxaliplatin + Capecitabine | Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression | HGF, Prior to progression levels (n=12,18) | 187.3 pg/mL | Standard Deviation 0.4 |
| Bevacizumab + Oxaliplatin + Capecitabine | Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression | Baseline PIGF (n=13,23) | 29.8 pg/mL | Standard Deviation 0.1 |
| Bevacizumab + Oxaliplatin + Capecitabine | Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression | PIGF, Prior to progression levels (n=12,18) | 34.7 pg/mL | Standard Deviation 0.1 |
| Bevacizumab + FOLFOX | Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression | Baseline PIGF (n=13,23) | 26.3 pg/mL | Standard Deviation 0.2 |
| Bevacizumab + FOLFOX | Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression | Baseline bFGF (n=13,23) | 6.1 pg/mL | Standard Deviation 0.6 |
| Bevacizumab + FOLFOX | Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression | HGF, Prior to progression levels (n=12,18) | 230.3 pg/mL | Standard Deviation 0.4 |
| Bevacizumab + FOLFOX | Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression | bFGF, Prior to progression levels (n=12,18) | 4.2 pg/mL | Standard Deviation 0.7 |
| Bevacizumab + FOLFOX | Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression | PIGF, Prior to progression levels (n=12,18) | 37.1 pg/mL | Standard Deviation 0.2 |
| Bevacizumab + FOLFOX | Geometric Mean Values of Pro-Angiogenic Cytokine Concentrations at Baseline and Prior to Progression | Baseline HGF (n=13,23) | 186.0 pg/mL | Standard Deviation 0.4 |
Secondary
Percentage of Participants With an Overall Response of Complete Response (CR) or Partial Response (PR)
Percentage of participants with an overall response of CR or PR according to RECIST criteria. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must have decreased to normal (short axis less than \[\<\]10 millimeters \[mm\]). No new lesions. PR was defined as greater than or equal to (≥)30 percent (%) decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.
Time frame: Baseline, every 9 weeks until disease progression, at end of treatment or withdrawal, for up to 24 months
Population: ITT population; only participants with RECIST evaluations were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Oxaliplatin + Capecitabine | Percentage of Participants With an Overall Response of Complete Response (CR) or Partial Response (PR) | 27.3 percentage of participants |
| Bevacizumab + FOLFOX | Percentage of Participants With an Overall Response of Complete Response (CR) or Partial Response (PR) | 6.4 percentage of participants |
Secondary
PFS From the Start of First-Line Therapy
PFS from the start of first-line therapy was defined as the interval between the start of first-line therapy and the date at which second disease progression (after the start of beyond progression therapy) was documented. Progression of disease was evaluated using RECIST version 1.1 and abdominal/pelvic CT or MRI scanning. The same method of assessment and the same technique were to be used to evaluate each lesion throughout the entire study. If more than one method was used, data from the most accurate method according to RECIST were recorded. Median PFS was estimated using the Kaplan-Meier method.
Time frame: Baseline, every 9 weeks until disease progression, at end of treatment or withdrawal, for up to 24 months
Population: ITT population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Oxaliplatin + Capecitabine | PFS From the Start of First-Line Therapy | 17.8 months |
| Bevacizumab + FOLFOX | PFS From the Start of First-Line Therapy | 18.0 months |