Colorectal Adenocarcinoma
Conditions
Keywords
colorectal, refractory, adenocarcinoma, bevacizumab, everolimus
Brief summary
The purpose of this study is to find the safest and most effective dose of the drugs bevacizumab and everolimus given in combination for the treatment of metastatic colorectal cancer. Bevacizumab (also called Avastin™) is a drug that is given intravenously (through a vein). Everolimus (also called RAD001) is a tablet that is taken by mouth. Bevacizumab is a protein that is thought to prevent the formation of blood vessels tumors need to grow. RAD001 has multiple capabilities, like bevacizumab it may prevent the formation of blood vessels needed by tumors and it also may stop tumor growth. This study will try to find the safest dose of these drugs that can be tolerated when taken in combination. The study will look at how the drugs work in the body, and will see if there is any effect on metastatic colorectal cancer.
Detailed description
This open-label, non-randomized expanded cohort trial of bevacizumab and RAD001 for patients with refractory metastatic colorectal cancer is designed to assess preliminary efficacy as well as the safety and tolerability of this combination. Patients will be accrued to this study at Duke University Medical Center and The Duke Oncology Outreach Network (DON) After satisfying eligibility and screening criteria, patients will be treated on 28 day cycles. * The treatment regimen is as follows: 10 mg/kg Bevacizumab intravenous on days 1 and 15 and 10mg everolimus (RAD001) daily by mouth * Toxicity will be assessed every visit, and as clinically indicated. * Efficacy will be assessed every 2 cycles, and as clinically indicated. * Patients may remain on treatment as long as they are deemed to be clinically benefiting from treatment, do not have progressive disease on restaging imaging (Section 6.0), or do not have any other reason for discontinuation of treatment as outlined in Section 3.4. * Patients will undergo correlative studies as outlined in the study protocol
Interventions
DRUGBevacizumab
10 mg/kg intravenous bevacizumab given days 1 and 15 of each cycle
DRUGEverolimus
10 mg Everolimus(RAD001) daily by mouth, days 1-28
Sponsors
Novartis Pharmaceuticals
Genentech, Inc.
Herbert Hurwitz
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically confirmed adenocarcinoma of the colon or rectum that has progressed on, or patient could not tolerate, fluoropyrimidine, oxaliplatin, irinotecan, and cetuximab and/or panitumumab chemotherapy. Disease must be measurable or evaluable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria * Patients must not have had radiation therapy, hormonal therapy, biologic therapy or chemotherapy for cancer within the 28 days prior to study day 1. Patients must not have had major surgery within the 28 days prior to study day 1 or minor surgical procedures within the 7 days prior to study day 1. * Age \>18 years. * Karnofsky performance status \> 70 percent * Life expectancy of at least 3 months. * Patients must have normal organ and marrow function as defined in the protocol * The effect of the investigational drugs on the developing human fetus is not known, but these drugs are likely to be embryo- and feto- toxic. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study, she should inform her treating physician and study PI immediately. Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study. Patients who are pregnant and/or lactating are excluded from this study. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Patients who have had radiation therapy, hormonal therapy, biologic therapy, or chemotherapy for cancer within the 28 days prior to day 1 of the study. * Patients who have received any other investigational agents within the 28 days prior to day 1 of the study. * Patients with known central nervous system (CNS) metastases. * Inadequately controlled hypertension (defined as systolic blood pressure \>150 and/or diastolic blood pressure \> 100 mmHg). Initiation of antihypertensive is permitted provided adequate control is documented over at least 1 week before starting treatment. * Significant vascular disease (e.g., aortic aneurysm, aortic dissection) * Symptomatic peripheral vascular disease * Evidence of bleeding diathesis or coagulopathy. Patients on therapeutic anticoagulation may be enrolled provided that they have been clinically stable on anti-coagulation for at least 2 weeks. * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment (56 days for hepatectomy, open thoracotomy, major neurosurgery) or anticipation of need for major surgical procedure during the course of the study * Core biopsy or other minor surgical procedure excluding study-related procedures or placement of a vascular access device, within 7 days prior to expected start of treatment. * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment * Serious, non-healing wound, ulcer, or bone fracture * Proteinuria at screening as demonstrated by either Urine protein:creatinine (UPC) ratio greater than or equal to 1.0 at screening * Any prior history of hypertensive crisis or hypertensive encephalopathy * New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix G) * History of myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or surgery within 6 months prior to study enrollment * History of stroke or transient ischemic attack within 6 months prior to study enrollment * History of intolerance or hypersensitivity to prior treatment with bevacizumab or RAD001. * Chronic treatment with systemic steroids or another immunosuppressive agent, though steroids may be used on an as-needed basis - ie - for treatment of nausea. Treatment with megace or low dose glucocorticoids is permitted for treatment of anorexia. * Other concurrent severe and/or uncontrolled medical disease which could compromise safety of treatment as so judged by treating physician * A known history of HIV seropositivity, hepatitis C virus, acute or chronic active hepatitis B infection, or other serious chronic infection requiring ongoing treatment. * Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter drug absorption (e.g., inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or significant small bowel resection) * Patients with an active, bleeding diathesis or on oral anti-vitamin K medication (except coumadin). No history of active GI bleeding or other major bleeding within previous 6 months. * Patients unwilling to or unable to comply with the protocol * Medical need for the continuous administration of any drugs which affect Cytochrome P450, family 3, subfamily A (CYP3A), though the use of low dose glucocorticoids for anorexia and /or nausea is permitted. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit safety or compliance with study requirements or may interfere with the interpretation of the results. * History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or any evidence of interstitial lung disease on baseline chest CT scan.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response | Measured 1 month after the last treated subject came off treatment | Overall response is composed of complete responses and partial responses. Complete response (CR): disappearance of all target lesions; Partial response: at least a 30 percent decrease in the sum of the longest diameter of the target lesions taking as reference the baseline sum longest diameter. Response is assessed at each subject's restaging, approximately ever 2 months. |
| Progression Free Survival (PFS) | interval between start of treatment and 8-week | 8 week PFS |
Countries
United States
Participant flow
Recruitment details
The recruitment process started in October 2007 and was complete in April 2009. All subjects except one were enrolled at the Morris Cancer Clinic at Duke University Medical Center. One subject was enrolled at the Community Memorial Healthcenter in South Hill, Virgina which is a Duke Oncology Network clinical research site.
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab and Everolimus Expanded Cohort of Patients with Refractory Metastatic Colorectal Cancer Treated With Bevacizumab and Everolimus | 50 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Subject is being followed for survival | 1 |
Baseline characteristics
| Characteristic | Bevacizumab and Everolimus |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 40 Participants |
| Age Continuous | 56 years STANDARD_DEVIATION 10.8 |
| Region of Enrollment United States | 50 participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 48 / 50 |
| serious Total, serious adverse events | 27 / 50 |
Outcome results
Primary
Overall Response
Overall response is composed of complete responses and partial responses. Complete response (CR): disappearance of all target lesions; Partial response: at least a 30 percent decrease in the sum of the longest diameter of the target lesions taking as reference the baseline sum longest diameter. Response is assessed at each subject's restaging, approximately ever 2 months.
Time frame: Measured 1 month after the last treated subject came off treatment
Population: 50 patients were enrolled and received bevacizumab at 10mg/kg every 2 weeks and everolimus at 10mg orally daily. However, only 49 patients were evaluable for progression. One patient who received less than 1 cycle of the regimen and died from a non-treatment-related illness was not included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab and Everolimus | Overall Response | 0 percentage of participants |
Primary
Progression Free Survival (PFS)
8 week PFS
Time frame: interval between start of treatment and 8-week
Population: 50 patients were enrolled and received bevacizumab at 10mg/kg every 2 weeks and everolimus at 10mg orally daily. However, only 49 patients were evaluable for progression. One patient who received less than 1 cycle of the regimen and died from a non-treatment-related illness was not included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab and Everolimus | Progression Free Survival (PFS) | 0.58 proportion of participants |