Colorectal Cancer, Colorectal Carcinoma, Liver Metastases
Conditions
Keywords
colon cancer, Colorectal carcinoma, liver metastases, SIR-Spheres microspheres, yttrium-90, FOLFOX, bevacizumab, metastatic colorectal cancer
Brief summary
This study is a randomized multi-center trial that will assess the effect of adding Selective Internal Radiation Therapy (SIRT), using SIR-Spheres microspheres®, to a standard chemotherapy regimen of FOLFOX as first line therapy in patients with non-resectable liver metastases from primary colorectal adenocarcinoma. Treatment with the biologic agent bevacizumab, if part of the standard of care at participating institutions, is allowed within this study at the discretion of the treating Investigator.
Interventions
DEVICESIR-Spheres yttrium-90 microspheres
SIR-Spheres microspheres (yttrium-90 \[Y-90\] labelled resin microspheres), hepatic artery injection administered on Day 3 or 4 of cycle 1. mFOLFOX6 administered on Day 1 and at the start of each cycle every 14 days: 85 or 60 mg/m2 oxaliplatin by 2-hour intravenous (IV) infusion + 200 mg/m2 leucovorin by 2-hour IV infusion + 400 mg/m2 5-fluorouracil (5-FU) by IV bolus + 2.4 g/m2 5-FU by 46-hour continuous IV infusion. Treatment with the biologic agent bevacizumab, if part of standard practice at the participating institution, was permitted at the discretion of the treating Investigator. In the event that leucovorin was not available, use of levofolinic acid (the active S enantiomer) was acceptable at half the dose of the racemic leucovorin i.e. 100 mg/m2.
DRUGSystemic chemotherapy (FOLFOX)
mFOLFOX6 administered on Day 1 and at the start of each cycle every 14 days: 85 or 60 mg/m2 oxaliplatin by 2-hour intravenous (IV) infusion + 200 mg/m2 leucovorin by 2-hour IV infusion + 400 mg/m2 5-fluorouracil (5-FU) by IV bolus + 2.4 g/m2 5-FU by 46-hour continuous IV infusion. Treatment with the biologic agent bevacizumab, if part of standard practice at the participating institution, was permitted at the discretion of the treating Investigator. In the event that leucovorin was not available, use of levofolinic acid (the active S enantiomer) was acceptable at half the dose of the racemic leucovorin i.e. 100 mg/m2.
Sponsors
Sirtex Medical
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
* Unequivocal and measurable CT evidence of liver metastases which are not treatable by surgical resection or local ablation. * Limited extra-hepatic metastases in the lung and/or lymph nodes are permitted (Lung: 5 lesions total, \< 1 cm, or 1 single lesion of up to 1.7 cm; Lymph nodules in one single anatomic area (pelvis, abdomen or chest): any number, \< 2 cm). * Suitable for either treatment regimen. * Prior chemotherapy for metastatic colorectal cancer is not allowed. * WHO performance status 0-1. * Adequate hematological, renal and hepatic function. * Age 18 years or older. * Willing and able to provide written informed consent. * Life expectancy of at least 3 months without any active treatment.
Exclusion criteria
* Evidence of ascites, cirrhosis, portal hypertension, main portal or venous tumor involvement or thrombosis as determined by clinical or radiologic assessment. * Previous radiotherapy delivered to the upper abdomen. * Non-malignant disease that would render the patient unsuitable for treatment according to the protocol. * Peripheral neuropathy \> grade 1 (NCI-CTC). * Dose limiting toxicity with previous adjuvant 5-FU or oxaliplatin chemotherapy. * Prior non-adjuvant chemotherapy for any malignancy. Adjuvant chemotherapy for colorectal cancer is not an
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) at Any Site | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months | PFS defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as an increase in the sum of the longest diameters of ≥ 20% and an absolute increase in the sum of the longest diameters of ≥ 5 mm, or the appearance of a new lesion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Overall Response | Through study completion, up to 60 months | Tumour Response Rate per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT: Complete Response (CR) - Disappearance of all target lesions which is confirmed if determined by two observations not less than 4 weeks apart; Partial Response (PR) - \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Countries
Australia, Belgium, France, Germany, Israel, Italy, New Zealand, Poland, Spain, Switzerland, United States
Participant flow
Recruitment details
Between 10 October 2006 and 26 April 2013, 561 patients were screened. 31 screen failures included 2 patients who were randomized twice. 530 patients were randomized in the Intent to treat (ITT) population from 87 centres in Australia, Europe including Belgium, France, Germany, Israel, Italy and Spain, New Zealand and the US.
Participants by arm
| Arm | Count |
|---|---|
| mFOLFOX6 Plus SIRT A single injection of SIR-Spheres microspheres into the liver plus systemic chemotherapy consisting of Oxaliplatin + Leucovorin + 5-Fluorouracil (FOLFOX) | 267 |
| mFOLFOX6 Alone Systemic chemotherapy consisting of Oxaliplatin + Leucovorin + 5-Fluorouracil (FOLFOX) | 263 |
| Total | 530 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 190 | 182 |
| Overall Study | Lost to Follow-up | 4 | 8 |
| Overall Study | Not otherwise specified | 4 | 7 |
| Overall Study | Withdrawal by Subject | 11 | 23 |
Baseline characteristics
| Characteristic | Total | mFOLFOX6 Plus SIRT | mFOLFOX6 Alone |
|---|---|---|---|
| Age, Continuous | 63 years | 63 years | 63 years |
| Extra-hepatic metastases at randomization No | 319 participants | 160 participants | 159 participants |
| Extra-hepatic metastases at randomization Yes | 211 participants | 107 participants | 104 participants |
| Primary tumor in situ No | 289 Participants | 148 Participants | 141 Participants |
| Primary tumor in situ Unknown | 1 Participants | 0 Participants | 1 Participants |
| Primary tumor in situ Yes | 240 Participants | 119 Participants | 121 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 8 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 6 Participants | 5 Participants |
| Race (NIH/OMB) White | 491 Participants | 248 Participants | 243 Participants |
| Sex: Female, Male Female | 173 Participants | 85 Participants | 88 Participants |
| Sex: Female, Male Male | 356 Participants | 182 Participants | 174 Participants |
| Synchronous metastases | 474 Participants | 241 Participants | 233 Participants |
| Tumor liver involvement % <=25% | 377 Participants | 185 Participants | 192 Participants |
| Tumor liver involvement % >25% | 151 Participants | 81 Participants | 70 Participants |
| Tumor liver involvement % Unknown | 2 Participants | 1 Participants | 1 Participants |
| WHO performance status 0 | 351 participants | 176 participants | 175 participants |
| WHO performance status 1 | 177 participants | 90 participants | 87 participants |
| WHO performance status Unknown | 2 participants | 1 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 190 / 246 | 182 / 270 |
| other Total, other adverse events | 112 / 246 | 157 / 270 |
| serious Total, serious adverse events | 134 / 246 | 112 / 270 |
Outcome results
Primary
Progression-Free Survival (PFS) at Any Site
PFS defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as an increase in the sum of the longest diameters of ≥ 20% and an absolute increase in the sum of the longest diameters of ≥ 5 mm, or the appearance of a new lesion.
Time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| mFOLFOX6 Plus SIRT | Progression-Free Survival (PFS) at Any Site | 10.7 Months |
| mFOLFOX6 Alone | Progression-Free Survival (PFS) at Any Site | 10.2 Months |
Comparison: The null hypothesis tested for the primary efficacy endpoint is rate of progression (months) of SIRT/FOLFOX treatment versus FOLFOX is equal for both groups. The two-sided alternative hypothesis tested with 95% confidence is PFS rate for SIRT/FOLFOX treatment lower to that of FOLFOX.p-value: 0.55195% CI: [0.77, 1.12]Log Rank
Secondary
Percentage of Participants With Overall Response
Tumour Response Rate per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT: Complete Response (CR) - Disappearance of all target lesions which is confirmed if determined by two observations not less than 4 weeks apart; Partial Response (PR) - \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Through study completion, up to 60 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| mFOLFOX6 Plus SIRT | Percentage of Participants With Overall Response | 76.4 percentage of participants |
| mFOLFOX6 Alone | Percentage of Participants With Overall Response | 68.1 percentage of participants |
Comparison: A sample size of at least 450 patients for the SIRFLOX study was estimated to be needed to detect an increase in the median PFS at any site from 9.4 months to 12.5 months with 80% power and 95% confidence. Taking into account the number of patients who might receive the alternative treatment or lack of imaging data, the sample size was increased to 530. The Null hypothesis is no difference between the treatment arms with respect to PFS.p-value: <0.05Log Rank