Expanded Cohort for Metastatic Colorectal Cancer (MCRC) Using Bevacizumab + Everolimus
Condition: Colorectal Adenocarcinoma
MeSH terms: Adenocarcinoma
Intervention: Bevacizumab; Everolimus
Intervention description: 10 mg/kg intravenous bevacizumab given days 1 and 15 of each cycle; 10 mg Everolimus(RAD001) daily by mouth, days 1-28
Intervention MeSH terms: Bevacizumab; Everolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 50.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: colorectal; refractory; adenocarcinoma; bevacizumab; everolimus

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.
    

Eligibility criteria:

        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.