Metastatic Colorectal Cancer
Conditions
Keywords
Metastatic Colorectal Cancer
Brief summary
This is a randomized, double-blind, placebo-controlled multi-center phase III study to evaluate efficacy and safety of regorafenib in patients with metastatic colorectal cancer (CRC) who have progressed on/after all approved drugs for CRC
Detailed description
All participants received Best Supportive Care. Acronyms used in Adverse events section: Gastrointestinal (GI), Genitourinary (GU), Not Otherwise Specified (NOS), Absolute Neutrophil Count (ANC), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Common Terminology Criteria for Adverse Events (CTCAE), International Normalized Ratio (INR), Central nervous system (CNS), Acute respiratory distress syndrome (ARDS), Cranial nerves (CN), Disseminated Intravascular Coagulation (DIC), Cardiac troponin T (cTnT). Abbreviation used in Results section: Data Monitoring Committee (DMC). Adverse event collection will be covered in Adverse events section.
Interventions
DRUGRegorafenib (Stivarga, BAY73-4506)
160 mg per oral once daily for 3 weeks of every 4 week cycle (i.e., 3 weeks on, 1 week off)
DRUGPlacebo
matching placebo tablets for 3 weeks of every 4 week cycle (i.e., 3 weeks on, 1 week off)
OTHERBest Supportive Care (BSC)
BSC includes any concomitant medications or treatments: antibiotics, analgesics, radiation therapy for pain control (limited to bone metastases), corticosteroids, transfusions, psychotherapy, growth factors, palliative surgery, or any other symptomatic therapy necessary to provide BSC, except other investigational anti-tumor agents or anti-neoplastic chemo/hormonal/immuno-therapy.
Sponsors
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 or cytological documentation of adenocarcinoma of the colon or rectum * Progression during or within 3 months following the last administration of approved standard therapies. Patients treated with oxaliplatin in an adjuvant setting should have progressed during or within 6 months of completion of adjuvant therapy * Patients with measurable or non measurable disease * Eastern Cooperative Oncology Group (ECOG) Performance Status of \</= 1 * Life expectancy of at least 3 months * Adequate bone marrow, liver and renal function
Exclusion criteria
* Unstable/uncontrolled cardiac disease * History of arterial or venous thrombotic or embolic events * Symptomatic metastatic brain or meningeal tumors * Patients with evidence or history of bleeding diathesis * Interstitial lung disease - Persistent proteinuria \>/= grade 3 * Unresolved toxicity \> grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin induced neurotoxicity \</= Grade 2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis (IA). | Overall survival (OS) was defined as the time (days) from randomization to death due to any cause. Patients alive at the time of analysis were censored at the last date known to be alive. If a patient was lost to follow-up and there was no contact after randomization, this patient was censored at Day 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (Based on Investigator's Assessment) | From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. | Progression-free survival was defined as the time (days) from date of randomization to date of first observed disease progression (radiological or clinical) or death due to any cause, if death occurred before progression was documented. |
| Objective Tumor Response | From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. | The objective tumor response was defined as the percentage of patients with complete response (CR, tumor disappears) or partial response (PR, sum of lesion sizes decreased at least 30% from baseline) as best overall response. A best overall response was defined for all patients, using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1. Patients whose best overall response was not CR or PR, and any patients with no post-baseline assessments were considered nonresponders for the analysis. |
| Disease Control | From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. | Disease control was defined as the percentage of patients whose best response was not PD \[sum of lesion sizes increased at least 20% from smallest sum on study or new lesions\] (ie, CR \[tumor disappears\], PR \[sum of lesion sizes decreased at least 30% from baseline\] or SD (stable disease)). SD included if at least 6 weeks after randomization. |
| Tumor Response | From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals. | A tumor response (best overall response) was defined for all patients, using the RECIST criteria, version 1.1. Categories: complete response (CR, tumor disappears), partial response (PR, sum of lesion sizes decreased at least 30% from baseline), stable disease (SD, steady state of disease), progressive disease (PD, sum of lesion sizes increased at least 20% from smallest sum on study or new lesions). Clinical PD considered when radiographic imaging not possible. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, China, Czechia, France, Germany, Hungary, Israel, Italy, Japan, Netherlands, Portugal, Spain, Switzerland, Turkey (Türkiye), United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Regorafenib (Stivarga, BAY73-4506)+BSC Participants received Regorafenib 160 mg per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC). | 505 |
| Placebo+BSC Participants received matching placebo tablets per oral once daily for 3 weeks on 1 week off of every 4 week cycle plus best supportive care (BSC). | 255 |
| Total | 760 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Switched From Placebo to Regorafenib | Adverse Event | 0 | 1 |
| Without/Before Drug Switch | Adverse Event | 50 | 7 |
| Without/Before Drug Switch | did not receive study treatment | 5 | 2 |
| Without/Before Drug Switch | Physician Decision | 2 | 0 |
| Without/Before Drug Switch | Protocol Violation | 2 | 0 |
| Without/Before Drug Switch | Switch to Regorafenib | 0 | 4 |
| Without/Before Drug Switch | Withdrawal by Subject | 17 | 5 |
Baseline characteristics
| Characteristic | Placebo+BSC | Total | Regorafenib (Stivarga, BAY73-4506)+BSC |
|---|---|---|---|
| Age, Continuous | 60.1 Years | 60.5 Years | 60.7 Years |
| Eastern Cooperative Oncology Group (ECOG) performance status (PS) before treatment 0 | 146 Participants | 411 Participants | 265 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status (PS) before treatment 1 | 109 Participants | 349 Participants | 240 Participants |
| KRAS mutation No | 94 Participants | 299 Participants | 205 Participants |
| KRAS mutation Unknown | 4 Participants | 31 Participants | 27 Participants |
| KRAS mutation Yes | 157 Participants | 430 Participants | 273 Participants |
| Sex: Female, Male Female | 102 Participants | 296 Participants | 194 Participants |
| Sex: Female, Male Male | 153 Participants | 464 Participants | 311 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 489 / 500 | 229 / 253 | 4 / 4 |
| serious Total, serious adverse events | 232 / 500 | 103 / 253 | 2 / 4 |
Outcome results
Primary
Overall Survival
Overall survival (OS) was defined as the time (days) from randomization to death due to any cause. Patients alive at the time of analysis were censored at the last date known to be alive. If a patient was lost to follow-up and there was no contact after randomization, this patient was censored at Day 1.
Time frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis (IA).
Population: Intent to treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regorafenib (Stivarga, BAY73-4506)+BSC | Overall Survival | 196 Days |
| Placebo+BSC | Overall Survival | 151 Days |
Comparison: Sample size based on primary efficacy endpoint of OS. The study was designed to have 90% power to detect 33.3% increase in median OS (i.e. hazard ratio of 0.75, Regorafenib / Placebo). Assuming 1-sided overall alpha of 0.025, randomization ratio of 2:1 for Regorafenib and Placebo, and 2 formal interim analyses of OS using an O'Brien-Fleming-type error spending function, a total of 582 death events were required for primary completion. Results based on 2nd planned formal IA with 432 total events.p-value: 0.00517895% CI: [0.636, 0.942]Log Rank
Secondary
Disease Control
Disease control was defined as the percentage of patients whose best response was not PD \[sum of lesion sizes increased at least 20% from smallest sum on study or new lesions\] (ie, CR \[tumor disappears\], PR \[sum of lesion sizes decreased at least 30% from baseline\] or SD (stable disease)). SD included if at least 6 weeks after randomization.
Time frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regorafenib (Stivarga, BAY73-4506)+BSC | Disease Control | 41.0 Percentage of participants |
| Placebo+BSC | Disease Control | 14.9 Percentage of participants |
Comparison: Two treatment groups compared using Cochran-Mantel-Haenszel (CMH) test adjusting for same stratification factors as at randomization.p-value: <0.00000195% CI: [-32.06, -19.82]Cochran-Mantel-Haenszel
Secondary
Objective Tumor Response
The objective tumor response was defined as the percentage of patients with complete response (CR, tumor disappears) or partial response (PR, sum of lesion sizes decreased at least 30% from baseline) as best overall response. A best overall response was defined for all patients, using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1. Patients whose best overall response was not CR or PR, and any patients with no post-baseline assessments were considered nonresponders for the analysis.
Time frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regorafenib (Stivarga, BAY73-4506)+BSC | Objective Tumor Response | 1.0 Percentage of participants |
| Placebo+BSC | Objective Tumor Response | 0.4 Percentage of participants |
Comparison: Two treatment groups compared using Cochran-Mantel-Haenszel (CMH) test adjusting for same stratification factors as at randomization.p-value: 0.18843295% CI: [-1.74, 0.53]Cochran-Mantel-Haenszel
Secondary
Progression-free Survival (Based on Investigator's Assessment)
Progression-free survival was defined as the time (days) from date of randomization to date of first observed disease progression (radiological or clinical) or death due to any cause, if death occurred before progression was documented.
Time frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regorafenib (Stivarga, BAY73-4506)+BSC | Progression-free Survival (Based on Investigator's Assessment) | 59 Days |
| Placebo+BSC | Progression-free Survival (Based on Investigator's Assessment) | 52 Days |
Comparison: Two treatment groups compared using a stratified log-rank test, stratified by same stratification factors as randomization. Hazard ratio (Regorafenib / Placebo) and its 95% confidence interval calculated using Cox model, stratified by same factors.p-value: <0.00000195% CI: [0.419, 0.582]Log Rank
Secondary
Tumor Response
A tumor response (best overall response) was defined for all patients, using the RECIST criteria, version 1.1. Categories: complete response (CR, tumor disappears), partial response (PR, sum of lesion sizes decreased at least 30% from baseline), stable disease (SD, steady state of disease), progressive disease (PD, sum of lesion sizes increased at least 20% from smallest sum on study or new lesions). Clinical PD considered when radiographic imaging not possible.
Time frame: From randomization of the first subject until the database cut-off approximately 14 months later (19May2010 - 21Jul2011) used for 2nd planned formal interim analysis. Tumor assessed at 8 week intervals.
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regorafenib (Stivarga, BAY73-4506)+BSC | Tumor Response | Not assessed | 5.7 Percentage of participants |
| Regorafenib (Stivarga, BAY73-4506)+BSC | Tumor Response | Progressive Disease (PD) | 49.5 Percentage of participants |
| Regorafenib (Stivarga, BAY73-4506)+BSC | Tumor Response | Complete Response (CR) | 0 Percentage of participants |
| Regorafenib (Stivarga, BAY73-4506)+BSC | Tumor Response | Non CR/Non PD | 0.8 Percentage of participants |
| Regorafenib (Stivarga, BAY73-4506)+BSC | Tumor Response | Stable Disease (SD) | 42.8 Percentage of participants |
| Regorafenib (Stivarga, BAY73-4506)+BSC | Tumor Response | Not applicable | 0.2 Percentage of participants |
| Regorafenib (Stivarga, BAY73-4506)+BSC | Tumor Response | Partial Response (PR) | 1.0 Percentage of participants |
| Placebo+BSC | Tumor Response | Not assessed | 4.7 Percentage of participants |
| Placebo+BSC | Tumor Response | Not applicable | 0 Percentage of participants |
| Placebo+BSC | Tumor Response | Complete Response (CR) | 0 Percentage of participants |
| Placebo+BSC | Tumor Response | Stable Disease (SD) | 14.5 Percentage of participants |
| Placebo+BSC | Tumor Response | Progressive Disease (PD) | 80.0 Percentage of participants |
| Placebo+BSC | Tumor Response | Non CR/Non PD | 0.4 Percentage of participants |
| Placebo+BSC | Tumor Response | Partial Response (PR) | 0.4 Percentage of participants |