Clinical trial NCT01058655 (phase 1/phase 2, status: completed)
Conditions: gastrointestinal cancer
ICD codes: C49.A0, C49.A1, C49.A2, C49.A5, C49.A3, C49.A4, C49.A9
Drugs: everolimus, tivozanib
SMILES: [H][C@@]1(C[C@@H](C)[C@]2([H])CC(=O)[C@H](C)\C=C(C)\[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)\C=C\C=C\C=C(C)\[C@H](C[C@]3([H])CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@@]3([H])C(=O)O2)OC)CC[C@@H](OCCO)[C@@H](C1)OC, COC1=C(OC)C=C2C(OC3=CC(Cl)=C(C=C3)N=C(O)N=C3NOC(C)=C3)=CC=NC2=C1
Eligibility criteria:

        For the Phase I component:

        Inclusion Criteria:

          -  18 years of age or older

          -  Histologic confirmation of a gastrointestinal malignancy, limited to cancer of the
             esophagus, stomach, small bowel, liver, biliary tract, gallbladder, pancreas, large
             bowel, appendix, rectum and anus.

          -  Locally advanced or metastatic disease

          -  Disease that: a) has recurred or progressed following standard therapy, b) for which
             no standard therapy currently exists, or c) for which the subject is not a candidate
             for or unwilling to undergo standard therapy. There is no limit to the number of prior
             regimens received by the patient.

          -  ECOG Performance Status of 0, 1 or 2

          -  Life expectancy of at least 12 weeks

          -  Adequate organ function as outlined in the protocol

          -  At least 4 weeks is required from : a) previous regimen of chemotherapy, b)
             immunotherapy or biological therapy, c) other investigational agents, and d)
             radiotherapy.

          -  At least 4 weeks is required from treatment of bevacizumab

          -  At least 4 weeks is required from prior systemic hormonal therapy or treatment with
             strong CYP3A4 inducers or inhibitors

          -  If female and of child bearing potential, documentation of negative pregnancy test
             prior to enrollment.

        Exclusion Criteria:

          -  Prior therapy with inhibitors of mTOR or VEGFR (prior treatment with bevacizumab is
             allowed).

          -  Clinically apparent CNS metastases or carcinomatous meningitis

          -  Clinically significant cardiovascular disease

          -  Major surgery within 4 weeks of the start of study treatment or patients who have not
             recovered from the side effects of any major surgery.

          -  Active bleeding diathesis or history of Grade 2 or greater clinically significant
             bleeding within 3 months of enrollment

          -  Active infection requiring antibiotics

          -  Participants with a known positive history of chronic Hepatitis B viral infection or
             known positive HBV-DNA test are excluded.

          -  History of interstitial pneumonitis or severely impaired lung function defined as 88%
             or less O2 saturation at rest in room air

          -  Immunocompromise or chronic use of immunosuppressant medications

          -  Uncontrolled serious medical or psychiatric illness

          -  Subjects with non-healing wounds, active peptic ulcers, or unhealed bone fractures

          -  Significant proteinuria, defined as urine dipstick protein of 3+ or greater

          -  Concurrent malignancy (other than non-melanoma skin cancer) diagnosed within the past
             3 years or any currently active malignancy

          -  Elevated fasting levels of the following: serum cholesterol, serum triglycerides, and
             serum glucose

          -  Patients who are pregnant or lactating

          -  Malabsorption, uncontrolled vomiting or diarrhea, or any disease significantly
             affecting gastrointestinal function that could interfere with absorption of study
             drugs

          -  Inability to swallow pills

        For the phase II component, only patients with metastatic colorectal cancer will be
        enrolled.

        For the Phase II component:

        Inclusion Criteria (Phase II):

          -  18 years of age or older

          -  Histologic confirmation of colorectal cancer

          -  Stage IV disease

          -  At least one site of disease measurable by RECIST criteria

          -  Receipt of or intolerance to a fluoropyrimidine (fluorouracil or capecitabine),
             irinotecan, oxaliplatin, bevacizumab, and a monoclonal antibody to epidermal growth
             factor receptor (cetuximab or panitumumab). If a patient's tumor was K-RAS mutation
             positive, then previous treatment with cetuximab or panitumumab is not required.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

          -  Life expectancy of at least 12 weeks

          -  Adequate organ function as outlined in the protocol

          -  At least 3 weeks is required from: (a) previous regimen of chemotherapy,
             (b)immunotherapy or biological therapy, (c) other investigational agents, and (d)
             radiotherapy. Of note, concomitant radiotherapy is NOT allowed, while a patient is on
             protocol.

          -  At least 3 weeks is required from prior treatment with bevacizumab

          -  At least 3 weeks is required since prior systemic hormonal therapy or treatment with
             strong CYP3A4 inducers or inhibitors.

          -  Negative pregnancy test for women of child bearing potential

        Exclusion Criteria (Phase II):

          -  Prior therapy with inhibitors of mTOR or VEGFR (prior treatment with bevacizumab is
             allowed)

          -  Clinically apparent CNS metastases or carcinomatous meningitis, as determined by
             physical examination and imaging studies

          -  Clinically significant cardiovascular disease, defined as follows:

        (A)Symptomatic congestive heart failure, (B)Symptomatic coronary artery disease or
        myocardial infarction within 3 months of enrollment, (C)Cardiac arrhythmias not controlled
        with medication, (D)Deep venous thrombosis or pulmonary embolus within the last 6 months,
        (E) Cerebrovascular accident within the last 12 months, (F)Poorly controlled hypertension,
        defined as systolic pressure > 150 mmHg or diastolic pressure > 100 mmHg documented on 2
        consecutive measurements taken at least 24 hours apart, (G)Symptomatic peripheral vascular
        disease, defined as claudication on walking ≤

        1 block

          -  Major surgery within 4 weeks of the start of study treatment or patients who have not
             recovered from the side effects of any major surgery. Major surgery defined as those
             surgeries that require general anesthesia

          -  Active bleeding diathesis or history of grade 2 or higher clinically significant
             bleeding (hemoptysis, hematemesis, hematochezia, or melena) within 3 months of
             enrollment

          -  Active infection requiring antibiotics

          -  Participants with a known positive history of chronic Hepatitis B viral infection or
             known positive HBV-DNA test are excluded.

          -  History of interstitial pneumonitis or severely impaired lung function defined as less
             than or equal to 88% O2 saturation at rest in room air.

          -  Immunocompromise or chronic use of immunosuppressant medications (prednisone ≤ 10 mg
             daily or the equivalent of a comparable steroid is allowed, if deemed necessary by a
             study investigator)

          -  Uncontrolled serious medical or psychiatric illness

          -  Subjects with non-healing wounds, active peptic ulcers, or unhealed bone fractures

          -  Significant proteinuria, defined as urine dipstick protein 3+ or greater

          -  Concurrent malignancy (other than non-melanoma skin cancer) diagnosed within the past
             3 years or any currently active malignancy.

          -  Elevated fasting levels of the following: serum cholesterol, serum triglycerides, and
             serum glucose.

          -  Patients who are pregnant or lactating

          -  Malabsorption, uncontrolled vomiting or diarrhea, or any disease significantly
             affecting gastrointestinal function that could interfere with absorption of study
             drugs

          -  Inability to swallow pills