Recurrent Colon Cancer, Recurrent Rectal Cancer, Stage IV Colon Cancer, Stage IV Rectal Cancer
Conditions
Brief summary
This phase II trial is studying how well giving sorafenib together with bevacizumab works in treating patients with metastatic colorectal cancer. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Sorafenib and bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving sorafenib together with bevacizumab may kill more tumor cells
Detailed description
PRIMARY OBJECTIVES: I. Evaluate proportion of patients who are progression-free at 3 months (in historic comparison with results for single-agent bevacizumab in ECOG 3200). SECONDARY OBJECTIVES: I. Response rate (RR) II. Overall survival (OS) III. Safety IV. Feasibility OUTLINE: This is a multicenter study. Patients receive sorafenib tosylate orally twice daily on days 1-5 and 8-12 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and then periodically during study treatment for laboratory biomarker and pharmacogenetic studies. After completion of study treatment, patients are followed periodically for up to 2 years.
Interventions
DRUGsorafenib tosylate
Given orally
BIOLOGICALbevacizumab
Given IV
Sponsors
Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
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
* Diagnosis of stage IV colorectal cancer (histologic proof is not required) * Measurable disease * Spiral CT scan required for both pre- and post-treatment tumor assessments of lesions measuring 1-2 cm * Progressive disease during or within 6 months of most recent prior chemotherapy regimen (bevacizumab, fluoropyrimidine, oxaliplatin, or irinotecan-based treatment) OR considered ineligible for standard therapy * Documentation of submission of tumor material for Kirsten Rat Sarcoma (KRAS) testing available * Prior anti-epidermal growth factor receptor (EGFR) antibody therapy (e.g., cetuximab or panitumumab) required for patients with wild-type KRAS tumor * No known brain metastasis * Patients with neurological symptoms must undergo a CT scan or MRI of the brain to exclude brain metastasis * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Life expectancy ≥ 6 months * Hemoglobin ≥ 9.0 g/dL * Absolute neutrophil count (ANC) ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * White blood cell count (WBC) ≥ 3,400/mm³ * International normalized ratio (INR) \< 1.5 (≤ 3.0 if on anti-coagulation therapy \[e.g., warfarin or heparin\]) * Total bilirubin ≤ 1.5 times upper limit of normal (ULN) * Aspartate aminotransferase (AST) ≤ 2.5 times ULN (≤ 5 times ULN if there is liver involvement) * Alkaline phosphatase ≤ 3 times ULN * Creatinine ≤ 1.5 times ULN * Urine protein:creatinine ratio \< 1 OR urine dipstick \< 2+ OR urine protein \< 1,000 mg by 24-hour urine collection * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for ≥ 6 months after completion of study treatment (≥ 2 weeks after completion of treatment with sorafenib tosylate alone) * Willing to provide mandatory blood samples for translational research studies * Able to swallow whole pills * No inadequately controlled hypertension (i.e., systolic BP \> 150 mm Hg or diastolic BP \> 100 mm Hg on anti-hypertensive medications) * No prior hypertensive crisis or hypertensive encephalopathy * No myocardial infarction or unstable angina within the past 6 months * No congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias * No thrombolic or embolic events (e.g., cerebrovascular accident, including transient ischemic attacks) within the past 6 months * No hemorrhage or bleeding event \> grade 3 within the past 4 weeks * No evidence or history of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation) * No greater than normal risk of bleeding * No active or recent hemoptysis (≥ ½ teaspoon of bright red blood per episode) within the past 30 days * No concurrent uncontrolled illness including, but not limited to, any of the following: * Ongoing or active infection * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia requiring anti-arrhythmic drugs * Psychiatric illness or social situations that would limit compliance with study requirements * No known HIV infection or chronic hepatitis B or C infection * No serious, non-healing wound, active ulcer, or untreated bone fracture * Patients with fractures secondary to metastatic disease are eligible after appropriate radiotherapy * No significant traumatic injury within the past 4 weeks * No known or suspected allergy or hypersensitivity to any component of bevacizumab, sorafenib tosylate, or their excipients or to any other agent given in the course of this study * No malabsorption problem * None of the following within the past 6 months: * Significant vascular disease (e.g., aortic aneurysm or aortic dissection) * Peripheral arterial thrombosis * Symptomatic peripheral vascular disease * Abdominal fistula * Gastrointestinal perforation * Intra-abdominal abscess * No other active malignancy within the past 3 years except non melanoma skin cancer or carcinoma in situ of the cervix * Prior malignancy allowed provided patient is not receiving other specific treatment for that malignancy (other than hormonal therapy) * No other concurrent investigational agent for this cancer * Prior radiotherapy allowed * No prior sorafenib tosylate * No prior discontinuation of bevacizumab due to adverse events * More than 4 weeks since prior and no concurrent participation in any other experimental drug study * More than 4 weeks since prior St. John's wort or rifampin * More than 4 weeks since prior and no concurrent major surgical procedure or open biopsy * More than 7 days since prior core biopsy or minor surgical procedure, including placement of a vascular access device * No concurrent anticoagulant, except low-dose warfarin or heparin for deep venous thrombosis prophylaxis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival Rate | At 3 months | The primary endpoint of this trial is progression free survival at 3 months. All patients meeting the eligibility criteria who have signed a consent form and have begun treatment will be considered evaluable. Patients lost to follow-up before 3 months (e.g., progression, refusing further treatment, etc.) will be considered treatment failures. All eligible patients will be followed until death or a minimum of 3 years. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Progression is defined as at least a 20% increase in the sum of longest liameter of target lesions taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate | 2 years | Number of patients reporting a partial response or complete response while on treatment |
| Overall Survival | 2 years | The distribution of overall survival will be estimated using Kaplan-Meier methodology. |
| Feasibility of Study Treatment | 2 years | Will be evaluated based on the number of patients who delayed treatment, omitted doses of treatment, or reduced treatment dose. |
Countries
United States
Contacts
STUDY_CHAIRAxel Grothey, MD
North Central Cancer Treatment Group
Participant flow
Recruitment details
83 patients were registered between 06/03/2009 and 10/20/2009 from 25 North Central Cancer Treatment Group (NCCTG) sites.
Pre-assignment details
One patient withdrew from the study and three patients were ineligible, therefore, these patients were excluded from all results.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Sorafenib Tosylate and Bevacizumab) Patients receive sorafenib tosylate orally twice daily on days 1-5 and 8-12 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and then periodically during study treatment for laboratory biomarker and pharmacogenetic studies\> \> sorafenib tosylate: Given orally\>
\> bevacizumab: Given IV | 79 |
| Total | 79 |
Baseline characteristics
| Characteristic | Treatment (Sorafenib Tosylate and Bevacizumab) |
|---|---|
| Age, Continuous | 62 years |
| Kirsten rat sarcoma (KRAS) Mutated | 40 participants |
| Kirsten rat sarcoma (KRAS) Wild-type | 39 participants |
| Performance Score 0 (Fully active) | 44 participants |
| Performance Score 1 (Restricted in physically strenuous activity) | 35 participants |
| Sex: Female, Male Female | 36 Participants |
| Sex: Female, Male Male | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| other Total, other adverse events | 78 / 79 |
| serious Total, serious adverse events | 13 / 79 |
Outcome results
Primary
Progression-free Survival Rate
The primary endpoint of this trial is progression free survival at 3 months. All patients meeting the eligibility criteria who have signed a consent form and have begun treatment will be considered evaluable. Patients lost to follow-up before 3 months (e.g., progression, refusing further treatment, etc.) will be considered treatment failures. All eligible patients will be followed until death or a minimum of 3 years. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Progression is defined as at least a 20% increase in the sum of longest liameter of target lesions taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.
Time frame: At 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Sorafenib Tosylate and Bevacizumab) | Progression-free Survival Rate | 53.2 percentage of participants |
Secondary
Feasibility of Study Treatment
Will be evaluated based on the number of patients who are able to\> tolerate the regimen, how long they tolerate it and whether they elect to stop treatment.
Time frame: Up to 2 years
Secondary
Overall Survival
The distribution of overall survival will be estimated using Kaplan-Meier methodology.
Time frame: Time from registration to death, assessed up to 2 years
Secondary
Response Rate
Simple frequency analysis will be conducted to see if response rate is related to prior treatment and the selected tumor biomarkers. Descriptive statistics will be used to investigate how prior treatment affects various other measures as well.
Time frame: Up to 2 years