Clinical trial NCT01055795 (phase 1, status: completed)
Conditions: advanced solid tumors
ICD codes: K74.02, G47.22, H35.3133, H35.3134, H35.3113, H35.3114, H35.3123
Drugs: bevacizumab, everolimus and lbh589
SMILES: [H]\C(=C(\[H])C1=CC=C(CNCCC2=C(C)NC3=CC=CC=C23)C=C1)C(O)=NO
Eligibility criteria:

        Inclusion Criteria:

          1. Histologically and/or cytologically confirmed malignant solid tumor that is refractory
             to standard therapies, or for which no standard therapies exist.

          2. Patients must have at least one measurable site of disease according to RECIST (see
             Appendix 1) criteria that has not been previously irradiated. If the patient has had
             previous radiation to the marker lesion(s), there must be evidence of progression
             since the radiation

          3. Age ≥ 18 years

          4. Karnofsky Performance status ≥ 80% (see Appendix 2)

          5. Adequate bone marrow function as shown by:

               1. ANC ≥ 1.5 x 109/L

               2. Platelets ≥ 100 x 109/L

               3. Hemoglobin >9 g/dL; Erythropoietin and transfusion support is permitted provided
                  treatments are not required more than every 8 weeks.

          6. Adequate liver function as shown by:

               1. serum bilirubin ≤ 1.5 x ULN

               2. INR ≤ 1.5

               3. ALT and AST ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases)

          7. Adequate renal function: creatinine clearance (estimated) ≥ 40 cc/min

          8. Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5
             x ULN. NOTE: Use of standard lipid lowering agents (see Section 10.3.6 for guidance)
             is permitted to meet eligibility.

          9. Fasting blood sugar <160 mg/dL.

         10. Baseline MUGA or ECHO must demonstrate LVEF ≥ 50%

         11. TSH and free T4 within normal limits; Patients are permitted to receive thyroid
             hormone supplements to treat underlying hypothyroidism.

         12. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
             within 7 days from day 1 of study drug and must be willing to use two methods of
             contraception, one of them being a barrier method during the study and for 3 months
             after last study drug administration

         13. Signed informed consent

        Exclusion Criteria:

          1. Patients currently receiving anticancer therapies or who have received anticancer
             therapies within 4 weeks from day 1 of study drug (including chemotherapy, radiation
             therapy, antibody based therapy, etc.)

          2. Patients who:

               1. have had a major surgery or significant traumatic injury within 4 weeks from day
                  1 of study drug,

               2. have not recovered from the side effects of any major surgery (defined as
                  requiring general anesthesia) or

               3. are anticipated to require major surgery during the course of the study.

          3. Patients with a known hypersensitivity to experimental drugs (or classes of drugs) or
             their excipients

          4. Patients receiving chronic, systemic treatment with corticosteroids or another
             immunosuppressive agent with the following exceptions:

               -  Intermittent steroids ( not to exceed 4 mg every day) may be used on an as-needed
                  basis (e.g. treatment for chemotherapy-related nausea.)

               -  Patients on physiologic replacement doses of steroids due to adrenal
                  insufficiency for any reason may remain on these medications.

               -  Topical, inhaled or intra-articular corticosteroids

          5. Patients should not receive immunization with attenuated live vaccines within one week
             of day 1 of study drug or during study period

          6. Active brain or leptomeningeal metastases, including patients who continue to require
             glucocorticoids for brain or leptomeningeal metastases. Treated, asymptomatic
             metastases are permitted provided the patient has been off steroids for at least 1
             month prior to day 1 of study drug.

          7. Clinically significant arrhythmias including complete left bundle branch block or use
             of a permanent cardiac pacemaker, congenital long QT syndrome, history or presence of
             ventricular tachyarrhythmias, 2nd degree AV block type II, 3rd degree AV block
             clinically significant resting bradycardia (<50 beats per minute), QTcF > 450 msec on
             screening ECG.

          8. Presence of poorly controlled atrial fibrillation (ventricular heart rate >100 bpm)

          9. Previous history of CVA, TIA, angina pectoris, acute MI or history of recent
             re-perfusion procedures (e.g. PTCA) within 6 months from day 1 of study drug.

         10. Congestive heart failure (New York Heart Association (NYHA classification, see
             Appendix 4 functional classification III-IV).

         11. Fasting blood sugar > 160 mg/dL despite standard of supportive care. Patients may
             start or adjust anti-diabetic medications to meet eligibility.

         12. Patients who have any severe and/or uncontrolled medical conditions or other
             conditions that could affect their participation in the study as so judged by the
             treating physician. Examples include but are not limited to:

               1. Severely impaired lung function (e.g. use of home O2, history of Idiopathic Lung
                  Disease (ILD), any evidence of ILD on scan.

               2. Active (acute or chronic) or uncontrolled severe infections requiring treatment
                  with antibiotics

               3. Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
                  hepatitis

               4. Uncontrolled hypertension, BP>150/100 despite medical management

               5. Impairment of gastrointestinal function or gastrointestinal disease that may
                  significantly alter the absorption of oral medications (e.g., ulcerative disease,
                  uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
                  resection)

         13. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
             recent peripheral arterial thrombosis) within 6 months prior to day 1 of study drug

         14. History of hemoptysis (>/= 1/2 teaspoon of bright red blood per episode) within 1
             month prior to day 1 of study drug

         15. History of abdominal fistula or gastrointestinal perforation at any point within 6
             months prior to day 1 of study drug, unless surgically repaired.

         16. Use or need for full dose anticoagulation other than low molecular weight heparin
             (i.e. Lovenox only with and no other bleeding risk)..

         17. Invasion or encasement of a major artery. Abutment without invasion or encasement is
             permitted. Abutment is defined as loss of the tissue plane between tumor and vessel
             but without invasion of the soft tissues or lumen of the vessel. Encasement is defined
             as more than 180 degrees of involvement

         18. Serious, non-healing wound, active ulcer, or untreated bone fracture as judged by
             treating physician

         19. Active, bleeding diathesis

         20. Known history of HIV or Hepatitis B or C seropositivity

         21. Female patients who are pregnant or breast feeding, or adults of reproductive
             potential who are not using effective birth control methods. Two acceptable forms of
             contraceptives must be continued throughout the trial by both sexes. Hormonal
             contraceptives are not acceptable as a sole method of contraception. (Women of
             childbearing potential must have a negative serum pregnancy test within 7 days prior
             to day 1 of study drug)

         22. Concomitant use of drugs with a risk of causing torsades de pointes (See Appendix 5 )

         23. Concomitant use of CYP3A4 inhibitors (See Appendix 6)

         24. Patients unwilling to or unable to comply with the protocol

         25. Intrathoracic lung carcinoma of squamous cell histology. Mixed tumors will be
             categorized by the predominant cell type unless small cell elements are present, in
             which case the patient is ineligible; sputum cytology alone is acceptable. Patients
             with extrathoracic-only squamous cell NSCLC are eligible. Patients with only
             peripheral lung lesions (of any NSCLC histology) will also be eligible (a peripheral
             lesion is defined as a lesion in which the epicenter of the tumor is </= 2 cm from the
             costal or diaphragmatic pleura in a three-dimensional orientation based on each lobe
             of the lung and is </= 2 cm from the trachea, main, and lobar bronchi).