Metastatic Colorectal Cancer
Conditions
Keywords
Colorectal Cancer, Metastasis, Stage IV, Liver Metastasis
Brief summary
To determine if sorafenib when added to chemotherapy will slow disease progression more than chemotherapy alone in patients previously untreated for metastatic colorectal cancer.
Interventions
DRUGSorafenib (Nexavar, BAY43-9006) + mFOLFOX6 (5-FU, levo-leucovorin, oxaliplatin)
Subjects will receive oral Sorafenib 400 mg twice daily (BID) continuously and intravenous (IV) mFOLFOX6 (5-FU 400 mg/m\^2 bolus and 2400 mg/m\^2 for 46-48 hrs; levo-leucovorin 200 mg/m\^2; 85 mg/m\^2 oxaliplatin) every 14 days until progressive disease (PD)
DRUGMatching placebo + mFOLFOX6 (5-FU, levo-leucovorin, oxaliplatin)
Subjects will receive oral matching placebo 2 tablets BID continuously and IV mFOLFOX6 (5-FU 400 mg/m\^2 bolus and 2400 mg/m\^2 for 46-48 hrs; levo-leucovorin 200 mg/m\^2; 85 mg/m\^2 oxaliplatin) every 14 days until progressive disease
Sponsors
Amgen
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histological confirmation of adenocarcinoma of the colon or rectum * Tumor tissue sample available for KRAS and BRAF assessment * Measurable metastatic Stage IV disease including at least one measurable lesion that has not previously been radiated * No prior chemotherapy for metastatic CRC * Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 * Life expectancy of at least 12 weeks * Adequate bone marrow, liver, and renal function; adequate clotting parameters
Exclusion criteria
* Prior treatment with sorafenib * Clinical or radiographic evidence of brain metastasis * Major surgery, surgical biopsy, or significant traumatic injury within 28 days of randomization; evidence or history of bleeding diathesis or coagulopathy * Red blood cell (RBC), white blood cell (WBC), or platelet transfusions and/or growth factor use within 28 days before randomization * Adjuvant therapy for CRC (Stage I, II, or III) completed within 12 months before randomization * Serious, non-healing wound, ulcer, or bone fracture; Grade 3 or 4 hemorrhage within 28 days before randomization * Use of anticoagulation therapy (low dose anticoagulation therapy to mitigate risk of thrombosis due to placement of a semi-permanent central venous port for administration of chemotherapy is allowed. The use of coumadin and related compounds is excluded.) * Uncontrolled hypertension (systolic blood pressure \> 150 mmHg or diastolic pressure \> 100 mmHg on repeated measurement) despite optimal medical management * Thrombolic, embolic, venous, or arterial events (eg, cerebrovascular accident, including transient ischemic attacks) within 6 months before randomization * Active cardiac disease including: * Congestive heart failure * Unstable angina or myocardial infarction within the 6 months before randomization * Cardiac ventricular arrhythmias requiring antiarrhythmic treatment * Peripheral neuropathy \> Grade 1 (CTCAE) * Known HIV infection or chronic hepatitis B or C infection * Any active infection \>/= Grade 2 (CTCAE) * Any medical, psychological, or social condition that may interfere with the subject's participation in the study or evaluation of the study results * Use of any investigational drug within 28 days or 5 half-lives of that drug, whichever is longer, before randomization * Subjects with metastatic CRC who are currently candidates for surgery with curative intent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | From randomization of the first subject until 23 months later, assessed every 8 weeks. | Progression-free Survival (PFS) was defined as the time from date of randomization to disease progression or death due to any cause, whichever occurred first. Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation. Disease progression was defined as an increase of at least 20% in the sum of tumor lesions sizes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From randomization of the first subject until 33 months later. | Overall Survival (OS) was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact. |
| Time to Progression (TTP) | From randomization of the first subject until 23 months later, assessed every 8 weeks. | Time to progression (TTP) was defined as the time from date of randomization to disease progression. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation. Disease progression was defined as an increase of at least 20% in the sum of tumor lesions sizes. |
| Overall Response | From randomization of the first subject until 23 months later, assessed every 8 weeks. | Overall response of a subject was defined as the best tumor response (Complete Response (CR) or Partial Response (PR)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes. |
| Duration of Response | From randomization of the first subject until 23 months later, assessed every 8 weeks | Duration of Response was defined as the time from date of first response (Complete Response (CR) or Partial Response (PR)) to the date when Progressive Disease (PD) was first documented or to the date of death, whichever occurred first according to Response Evaluation Criteria in Solid Tumors (RECIST). Subjects still having CR or PR and alive at the time of analysis were censored at their last date of tumor evaluation. CR was defined as disappearance of tumor lesions, PR as a decrease of at least 30% and PD as an increase of at least 20% in the sum of tumor lesions sizes. |
Countries
Belgium, Hungary, Italy, Poland, Romania, Russia, Spain, Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib (Nexavar, BAY43-9006) + mFOLFOX6 Subjects will receive oral Sorafenib 400 mg twice daily (BID) continuously and intravenous (IV) mFOLFOX6 (5-FU 400 mg/m\^2 bolus and 2400 mg/m\^2 for 46-48 hrs; levo-leucovorin 200 mg/m\^2; 85 mg/m\^2 oxaliplatin) every 14 days until progressive disease (PD) | 97 |
| Matching Placebo + mFOLFOX6 Subjects will receive oral matching placebo 2 tablets BID continuously and IV mFOLFOX6 (5-FU 400 mg/m\^2 bolus and 2400 mg/m\^2 for 46-48 hrs; levo-leucovorin 200 mg/m\^2; 85 mg/m\^2 oxaliplatin) every 14 days until progressive disease | 101 |
| Total | 198 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment | Adverse Event | 9 | 6 |
| Treatment | Physician Decision | 3 | 2 |
| Treatment | Surgery | 8 | 3 |
| Treatment | Withdrawal by Subject | 10 | 7 |
Baseline characteristics
| Characteristic | Sorafenib (Nexavar, BAY43-9006) + mFOLFOX6 | Matching Placebo + mFOLFOX6 | Total |
|---|---|---|---|
| Age, Continuous | 59.2 years STANDARD_DEVIATION 10.3 | 60.3 years STANDARD_DEVIATION 8.3 | 59.8 years STANDARD_DEVIATION 9.3 |
| ECOG (Eastern Cooperative Oncology Group) Performance Status 0=Fully active without restriction | 34 Participants | 36 Participants | 70 Participants |
| ECOG (Eastern Cooperative Oncology Group) Performance Status 1= Restricted in physically strenuous activity | 63 Participants | 65 Participants | 128 Participants |
| ECOG (Eastern Cooperative Oncology Group) Performance Status 2= Ambulatory, capable of all selfcare | 0 Participants | 0 Participants | 0 Participants |
| ECOG (Eastern Cooperative Oncology Group) Performance Status 3= Capable of limited selfcare | 0 Participants | 0 Participants | 0 Participants |
| ECOG (Eastern Cooperative Oncology Group) Performance Status 4= Completely disabled | 0 Participants | 0 Participants | 0 Participants |
| ECOG (Eastern Cooperative Oncology Group) Performance Status 5= Dead | 0 Participants | 0 Participants | 0 Participants |
| KRAS Missing | 22 Participants | 17 Participants | 39 Participants |
| KRAS Mutant | 33 Participants | 43 Participants | 76 Participants |
| KRAS Wild-Type | 42 Participants | 41 Participants | 83 Participants |
| Liver metastases by Principal Investigator No | 18 Participants | 20 Participants | 38 Participants |
| Liver metastases by Principal Investigator Yes | 79 Participants | 81 Participants | 160 Participants |
| Number of metastatic sites by Principal Investigator <3 | 71 Participants | 71 Participants | 142 Participants |
| Number of metastatic sites by Principal Investigator >=3 | 26 Participants | 30 Participants | 56 Participants |
| Region of Enrollment Belgium | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Romania | 3 participants | 8 participants | 11 participants |
| Region of Enrollment Russian Federation | 54 participants | 52 participants | 106 participants |
| Region of Enrollment Spain | 25 participants | 25 participants | 50 participants |
| Region of Enrollment United Kingdom | 12 participants | 14 participants | 26 participants |
| Region of Enrollment United States | 2 participants | 2 participants | 4 participants |
| Sex: Female, Male Female | 55 Participants | 38 Participants | 93 Participants |
| Sex: Female, Male Male | 42 Participants | 63 Participants | 105 Participants |
| Stage of Disease at study entry (TNM Classification, Stage IV) | 97 Participants | 101 Participants | 198 Participants |
| Time since initial diagnosis | 9.8 Months STANDARD_DEVIATION 16.2 | 9.2 Months STANDARD_DEVIATION 16.9 | 9.5 Months STANDARD_DEVIATION 16.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 96 / 97 | 99 / 101 | 96 / 97 | 99 / 101 |
| serious Total, serious adverse events | 30 / 97 | 27 / 101 | 33 / 97 | 30 / 101 |
Outcome results
Primary
Progression-Free Survival (PFS)
Progression-free Survival (PFS) was defined as the time from date of randomization to disease progression or death due to any cause, whichever occurred first. Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation. Disease progression was defined as an increase of at least 20% in the sum of tumor lesions sizes.
Time frame: From randomization of the first subject until 23 months later, assessed every 8 weeks.
Population: The test was conducted using the intent-to-treat (ITT) population (all subjects who were randomized).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + mFOLFOX6 | Progression-Free Survival (PFS) | 9.1 Months |
| Matching Placebo + mFOLFOX6 | Progression-Free Survival (PFS) | 8.7 Months |
Comparison: A sample size of 120 PFS events would provide a \> 85% power at a target HR = 0.65 between sorafenib and matching placebo, with a 1-sided alpha = 0.10, for testing the null hypothesis H0: HR ≥ 1 versus the alternative hypothesis H1: HR \< 1 based on the log-rank test. The test was conducted using the intent-to-treat (ITT) population, defined as all subjects who were randomized to treatment.p-value: 0.230995% CI: [0.635, 1.231]Log Rank
Secondary
Duration of Response
Duration of Response was defined as the time from date of first response (Complete Response (CR) or Partial Response (PR)) to the date when Progressive Disease (PD) was first documented or to the date of death, whichever occurred first according to Response Evaluation Criteria in Solid Tumors (RECIST). Subjects still having CR or PR and alive at the time of analysis were censored at their last date of tumor evaluation. CR was defined as disappearance of tumor lesions, PR as a decrease of at least 30% and PD as an increase of at least 20% in the sum of tumor lesions sizes.
Time frame: From randomization of the first subject until 23 months later, assessed every 8 weeks
Population: Duration of response was the time from the first documented CR or PR until the first documented PD or death (if before progression). Only responders (CR or PR) were included in the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + mFOLFOX6 | Duration of Response | 7.5 months |
| Matching Placebo + mFOLFOX6 | Duration of Response | 6.7 months |
Secondary
Overall Response
Overall response of a subject was defined as the best tumor response (Complete Response (CR) or Partial Response (PR)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes.
Time frame: From randomization of the first subject until 23 months later, assessed every 8 weeks.
Population: The test was conducted using the intent-to-treat (ITT) population (all subjects who were randomized).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + mFOLFOX6 | Overall Response | 45 participants |
| Matching Placebo + mFOLFOX6 | Overall Response | 61 participants |
Comparison: The proportion of subjects achieving overall response (CR or PR), when confirmation of response was not required, was estimated with a 95% confidence interval for each treatment group. The treatment groups were compared with respect to overall response rate using the Cochran-Mantel-Haenszel test, adjusting for the stratification factors.p-value: 0.023Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS)
Overall Survival (OS) was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact.
Time frame: From randomization of the first subject until 33 months later.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + mFOLFOX6 | Overall Survival (OS) | 535 days |
| Matching Placebo + mFOLFOX6 | Overall Survival (OS) | 552 days |
Secondary
Time to Progression (TTP)
Time to progression (TTP) was defined as the time from date of randomization to disease progression. Subjects without progression at the time of analysis were censored at their last date of tumor evaluation. Disease progression was defined as an increase of at least 20% in the sum of tumor lesions sizes.
Time frame: From randomization of the first subject until 23 months later, assessed every 8 weeks.
Population: The test was conducted using the intent-to-treat (ITT) population (all subjects who were randomized).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib (Nexavar, BAY43-9006) + mFOLFOX6 | Time to Progression (TTP) | 9.2 Months |
| Matching Placebo + mFOLFOX6 | Time to Progression (TTP) | 9.0 Months |
Comparison: A sample size of 120 PDs would provide a \> 85% power at a target HR = 0.65 between sorafenib and matching placebo, with a 1-sided alpha = 0.10, for testing H0: HR ≥ 1 versus H1: HR \< 1 based on the log-rank test. The test was conducted using the intent-to-treat (ITT) population (all subjects who were randomized).p-value: 0.143795% CI: [0.586, 1.174]Log Rank