Colorectal Cancer Metastatic
Conditions
Keywords
Metastatic, Colon Cancer, Rectal Cancer
Brief summary
Combining Sorafenib with standard cytotoxic fluoropyrimidine therapy for advanced colorectal cancer may provide clinical benefit when no other treatment remains.
Detailed description
The Raf/MEK/ERK pathway is an important mediator of responses to growth factors, and a strong inducer of genes involved in tumorigenesis, angiogenesis, apoptosis, and tumorigenesis in metastatic colorectal cancer (mCRC). Inhibition of this pathway has been previously proven to be highly clinically beneficial for patients with this disease. It has also been clearly demonstrated that the inhibition of VEGF, when coupled with cytotoxic therapy and/or continued beyond initial response, can improve clinical outcomes and survival in this same cohort of patients. Safety and pharmacokinetic data have already been established for this novel doublet oral chemotherapy. This study is intended to determine the activity of a combination of oral fluoropyrimidine plus sorafenib in an advanced mCRC patient population for whom limited treatment options remain.
Interventions
DRUGSorafenib Plus Capecitabine (SorCape)
Sorafenib 200-400 mg PO twice daily on days 1-21 (dose escalation schema) plus Capecitabine 1000 mg/m2 PO twice daily on days 1-14 repeated every 21 days
Sponsors
Bayer
University of Florida
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically proven adenocarcinoma of the colon or rectum. * Metastatic disease that is not amenable to potentially curative treatment. * Measurable disease (as per RECIST 1.1 criteria). * At least one prior chemotherapeutic regimen for metastatic disease. Patients must have progressed following oxaliplatin based therapy (in either the adjuvant or metastatic setting) and irinotecan based therapy (in the metastatic setting). * Adequate bone marrow, liver and renal function. * Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate, provided stability in anticoagulation therapy is documented at the treating provider's discretion. For patients on warfarin, the INR should be measured prior to the initiation of study treatment and should be monitored at least weekly, or as defined by the local standard of care, until INR is stable. * Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment. * Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Men should use adequate birth control for at least three months after the last administration of sorafenib. * Patients may have had a history of other (non-colorectal) malignancies if there is no current evidence of persistent or recurrent disease and they are not undergoing any active therapy (including hormonal). * Patients should have paraffin-embedded tissue from initial diagnosis or prior colorectal cancer surgery available for molecular analysis. * Patients must consent to participate in the study and must have signed and dated an IRB-approved consent form conforming to federal and institutional guidelines. Consent must be obtained prior to any study specific procedures.
Exclusion criteria
* Prior therapy with a tyrosine kinase inhibitor. * Age \< 18 years * ECOG Performance Status \> 2 * Less than 28 days elapsed from prior radiation therapy, surgery or chemotherapy to the time of registration. * History of known brain metastasis. Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis. * History of clinically significant cardiac disease (severe/unstable angina pectoris, NYHA class III or IV congestive heart failure, symptomatic coronary artery disease) or myocardial infarction, cerebrovascular accident or transient ischemic attack within the last 12 months. * Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. Uncontrolled hypertension defined as systolic blood pressure \> 140 mmHg or diastolic pressure \> 90 mmHg, as measured on 3 consecutive pre-enrollment assessments, despite optimal medical management. * Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C. * Active clinically serious infection \> CTCAE Grade 2. * Pulmonary hemorrhage/bleeding event \> CTCAE Grade 2 within 4 weeks of first dose of study drug. * Any other hemorrhage/bleeding event \> CTCAE Grade 3 within 4 weeks of first dose of study drug. * Pulmonary embolism or any other uncontrolled thromboembolic event within 3 months prior to registration or occurrence of deep vein thrombosis within 4 weeks of registration. * Serious non-healing wound, ulcer, or bone fracture. * Evidence or history of a clinically significant bleeding diathesis or coagulopathy (without vitamin K antagonist therapy). * Use of St. John's Wort or rifampin (rifampicin). * Known or suspected allergy to sorafenib or capecitabine. * Any condition that impairs patient's ability to swallow whole pills. * Any known malabsorption problem. * History of chronic or inflammatory bowel disorders, clinically significant chronic diarrhea refractory to medical management, or unresolved bowel obstruction.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sorafenib Activity | 2 years | Determine activity of sorafenib plus capecitabine on progression free survival (PFS) in patients with advanced colorectal cancer. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 5 years | Evaluate overall survival after treatment. |
| Response Rate | 3 months | This is the percentage of subjects that achieved either a complete response or a partial response per RECIST 1.1 criteria |
| Response Duration | up to 12 months | This is the median response duration (median time from date of a complete or partial response to date of disease progression per RECIST 1.1 criteria) and includes only subjects that achieved either a complete or partial response to treatment per RECIST 1.1 criteria. |
| Toxicity (Percentage of Subjects That Experienced an Adverse Event) | 12 months | Evaluate acute toxicity of treatment. The toxicity assessments were graded by the NCI CTCAE (Clinical Trial Common Adverse Event) grading system - a global standard for assessments of clinical and laboratory toxicities. All toxicities are scored 1(mild) through 5 (death related to the event) based upon well-defined and reproducible definitions. |
| Correlative Tissue Analysis | 6 months | Exploratory tissue analysis in patients receiving sorafenib plus capecitabine |
Countries
United States
Participant flow
Pre-assignment details
43 Patients were consented and enrolled; however, only 42 were dosed. The one patient that was not dosed was removed due to progression of disease prior to treatment initiation.
Participants by arm
| Arm | Count |
|---|---|
| Sorafenib Plus Capecitabine (SorCape) Sorafenib 200-400 mg PO twice daily on days 1-21 (dose escalation schema) plus Capecitabine 1000 mg/m2 PO twice daily on days 1-14 repeated every 21 days. Single arm study.
Sorafenib Plus Capecitabine (SorCape): Sorafenib 200-400 mg PO twice daily on days 1-21 (dose escalation schema) plus Capecitabine 1000 mg/m2 PO twice daily on days 1-14 repeated every 21 days | 42 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | remain on study | 3 |
Baseline characteristics
| Characteristic | Sorafenib Plus Capecitabine (SorCape) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 13 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants |
| Age, Continuous | 57 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 31 Participants |
| Region of Enrollment United States | 42 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 42 / 42 |
| serious Total, serious adverse events | 13 / 42 |
Outcome results
Primary
Sorafenib Activity
Determine activity of sorafenib plus capecitabine on progression free survival (PFS) in patients with advanced colorectal cancer. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), 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
Time frame: 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib Plus Capecitabine (SorCape) | Sorafenib Activity | 123 days |
Secondary
Correlative Tissue Analysis
Exploratory tissue analysis in patients receiving sorafenib plus capecitabine
Time frame: 6 months
Population: Data were not collected.
Secondary
Overall Survival
Evaluate overall survival after treatment.
Time frame: 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib Plus Capecitabine (SorCape) | Overall Survival | 261 days |
Secondary
Response Duration
This is the median response duration (median time from date of a complete or partial response to date of disease progression per RECIST 1.1 criteria) and includes only subjects that achieved either a complete or partial response to treatment per RECIST 1.1 criteria.
Time frame: up to 12 months
Population: No data are available for this outcome measure since only 1 participant achieved a partial or complete response.
Secondary
Response Rate
This is the percentage of subjects that achieved either a complete response or a partial response per RECIST 1.1 criteria
Time frame: 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sorafenib Plus Capecitabine (SorCape) | Response Rate | 2.38 percentage of participants |
Secondary
Toxicity (Percentage of Subjects That Experienced an Adverse Event)
Evaluate acute toxicity of treatment. The toxicity assessments were graded by the NCI CTCAE (Clinical Trial Common Adverse Event) grading system - a global standard for assessments of clinical and laboratory toxicities. All toxicities are scored 1(mild) through 5 (death related to the event) based upon well-defined and reproducible definitions.
Time frame: 12 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib Plus Capecitabine (SorCape) | Toxicity (Percentage of Subjects That Experienced an Adverse Event) | Adverse Events - Any Grade | 100 percentage of participants |
| Sorafenib Plus Capecitabine (SorCape) | Toxicity (Percentage of Subjects That Experienced an Adverse Event) | Adverse Events - Grade 3 | 74 percentage of participants |
| Sorafenib Plus Capecitabine (SorCape) | Toxicity (Percentage of Subjects That Experienced an Adverse Event) | Adverse Events - Grade 4 | 2 percentage of participants |