Colorectal Cancer Metastatic
Conditions
Keywords
colon, rectum, metastatic colorectal cancer, liver metastases
Brief summary
This study is a randomized, multi-center study that will compare the efficacy and safety of selective internal radiation therapy (SIRT) using SIR-Spheres microspheres plus a standard chemotherapy regimen of FOLFOX6m versus FOLFOX6m alone as first-line therapy in patients with non-resectable liver metastases from primary colorectal carcinoma. 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 Investigator.
Interventions
DRUGFOLFOX6m
DEVICESIR-Spheres microspheres
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
* Age 18 years or older * Willing and able to provide written informed consent * 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) * All imaging evidence used as part of the screening process must be within 28 days * Suitable for either treatment regimen * WHO performance status 0-1 * Adequate hematological, renal and hepatic function * Life expectancy of at least 3 months without any active treatment
Exclusion criteria
* Evidence of ascites, cirrhosis, portal hypertension, main portal or venous involvement or thrombosis as determined by clinical or radiologic assessment * Previous radiotherapy delivered to the liver * Non-malignant disease that would render the patient unsuitable for treatment according to the protocol * Peripheral neuropathy \> grade 2 (NCI-CTC) * Dose-limiting toxicity associated with previous adjuvant 5-FU or oxaliplatin chemotherapy * Prior non-adjuvant chemotherapy for any malignancy. Adjuvant chemotherapy for colorectal cancer is permitted provided that it was completed more than 6 months before entry into the study * Pregnant or breast feeding * Concurrent or prior history of cancer other than adequately treated non-melanoma skin cancer or carcinoma in situ of the cervix * Allergy to contrast media that would preclude angiography of the hepatic arteries
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From date of randomization until the date of death from any cause assessed up 3 yrs 8 months | OS defined as the time interval between the date of randomization and the date of death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years 8 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. |
Countries
Australia, Belgium, France, Germany, Israel, Italy, New Zealand, Portugal, Singapore, South Korea, Spain, Taiwan, United States
Participant flow
Recruitment details
Between 01May2013&24Dec2014,209 patients were screened&randomised from 87centres in Australia, Belgium,France, Germany, Israel, Italy, Korea, New Zealand, Portugal, Singapore, Spain,Taiwan &the US. 209 patients randomized in the Intent to treat (ITT) population. 5 patients who did not receive study medication were not included in safety population.
Participants by arm
| Arm | Count |
|---|---|
| mFOLFOX6 Plus SIRT Systemic chemotherapy with FOLFOX6m plus or minus bevacizumab plus SIR-Spheres microspheres.
FOLFOX6m
SIR-Spheres microspheres | 105 |
| mFOLFOX6 Alone Systemic chemotherapy with FOLFOX6m plus or minus bevacizumab repeated every two weeks until evidence of treatment failure.
FOLFOX6m | 104 |
| Total | 209 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Death | 58 | 64 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 4 |
Baseline characteristics
| Characteristic | mFOLFOX6 Plus SIRT | mFOLFOX6 Alone | Total |
|---|---|---|---|
| Age, Continuous | 62.6 years STANDARD_DEVIATION 11.28 | 62.4 years STANDARD_DEVIATION 10.06 | 62.5 years STANDARD_DEVIATION 10.66 |
| Age, Customized Age, Categorical Below 65 years | 60 Participants | 57 Participants | 117 Participants |
| Age, Customized Age, Categorical Greater than or equal to 65 years | 45 Participants | 47 Participants | 92 Participants |
| Extra-hepatic Disease No | 73 participants | 77 participants | 150 participants |
| Extra-hepatic Disease Yes | 32 participants | 27 participants | 59 participants |
| ITT bevacizumab No | 18 Participants | 17 Participants | 35 Participants |
| ITT bevacizumab Yes | 87 Participants | 87 Participants | 174 Participants |
| Liver Involvement % <=25% | 74 participants | 74 participants | 148 participants |
| Liver Involvement % >25% | 31 participants | 30 participants | 61 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 6 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) White | 88 Participants | 93 Participants | 181 Participants |
| Sex: Female, Male Female | 41 Participants | 44 Participants | 85 Participants |
| Sex: Female, Male Male | 64 Participants | 60 Participants | 124 Participants |
| Tumor volume | 18.5 percentage of liver STANDARD_DEVIATION 17.77 | 17.9 percentage of liver STANDARD_DEVIATION 16.18 | 18.2 percentage of liver STANDARD_DEVIATION 16.96 |
| WHO performance status 0 | 61 Participants | 53 Participants | 114 Participants |
| WHO performance status 1 | 44 Participants | 50 Participants | 94 Participants |
| WHO performance status Unknown | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 58 / 92 | 64 / 112 |
| other Total, other adverse events | 92 / 92 | 111 / 112 |
| serious Total, serious adverse events | 47 / 92 | 47 / 112 |
Outcome results
Primary
Overall Survival (OS)
OS defined as the time interval between the date of randomization and the date of death from any cause.
Time frame: From date of randomization until the date of death from any cause assessed up 3 yrs 8 months
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| mFOLFOX6 Plus SIRT | Overall Survival (OS) | 25.9 months |
| mFOLFOX6 Alone | Overall Survival (OS) | 25.0 months |
Comparison: The null hypothesis tested for the primary efficacy endpoint is overall survival (months) of SIRT/FOLFOX treatment versus FOLFOX is equal for both groups. The two-sided alternative hypothesis tested with 95% confidence is OS time for SIRT/FOLFOX treatment lower to that of FOLFOX.p-value: 0.43Log Rank
Secondary
Progression-free Survival
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 3 years 8 months.
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| mFOLFOX6 Plus SIRT | Progression-free Survival | 11.8 months |
| mFOLFOX6 Alone | Progression-free Survival | 11.2 months |
Comparison: A sample size of at least 209 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 14.5 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 209. The Null hypothesis is no difference between the treatment arms with respect to PFS.p-value: <0.05Log Rank