A Phase I/II Study of the HDAC Inhibitor LBH-589 in Combination With the mTOR Inhibitor Everolimus (RAD001) in Metastatic Renal Cell Carcinoma

Inclusion Criteria:

- Patients must have histologically confirmed metastatic or unresectable renal cell
carcinoma

- Predominant clear cell component is required

- Patients must have metastatic disease which has progressed on or within 6 months of
stopping treatment with VEGFR receptor tyrosine kinase inhibitors

- Previous therapy with bevacizumab, interleukin 2, or interferon alpha is also
permitted

- Ability to provide written informed consent obtained prior to participation in the
study and any related procedures being performed

- Serum albumin >= 3g/dL

- AST/SGOT and ALT/SGPT =< 2.5 x upper limit of normal (ULN)

- Serum bilirubin =< 1.5 x ULN

- Serum creatinine =< 1.5 x ULN or 24-hour creatinine clearance >= 50 ml/min

- Serum potassium >= LLN

- Serum phosphorous >= LLN

- Serum total calcium (corrected for serum albumin) or serum ionized calcium >= LLN

- Serum magnesium >= LLN

- TSH and free T4 within normal limits (WNL); patients may be on thyroid hormone
replacement

- ANC >= 1.5 x 10^9/L

- Platelets >= 100 x 10^9/L

- Hb > 9 g/dL

- INR < 1.3 (or < 3 on anticoagulants)

- Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =<
2.5 x ULN (in case one or both of these thresholds are exceeded, the patient can only
be included after initiation of appropriate lipid lowering medication

- Baseline MUGA or ECHO must demonstrate LVEF >= the lower limit of the institutional
normal

- ECOG Performance Status of =< 2

Exclusion Criteria:

- Pure papillary and chromophobe renal cell carcinoma, collecting duct tumors and
transitional cell carcinoma are not eligible

- Prior treatment with an HDAC or mTOR inhibitor

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

- Patients who have had a major surgery of significant traumatic injury within 4 weeks
of start of study drug and who have not recovered from the side effects of any major
surgery (defined as requiring general anesthesia) or patients that may require major
surgery during the course of the study

- Prior treatment with any investigational drug within the preceding 4 weeks

- Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent; topical or inhaled corticosteroids are allowed

- Patients should not receive immunization with attenuated live vaccines within one
weeks of study entry or during study period; close contact with those who have
received attenuated live vaccines should be avoided during treatment with everolimus
(Examples of live vaccines include intranasal influenza, measles, mumps, rubella,
oral polio, BCG, yellow fever, varicella and TY2a typhoid vaccines)

- Uncontrolled brain or leptomeningeal metastases, including patients who continue to
require glucocorticoids for brain or leptomeningeal metastases

- Other malignancies within the past 3 years except for adequately treated carcinoma of
the cervix or basal or squamous cell carcinomas of the skin

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

- 1) Symptomatic congestive heart failure of New York Heart Association Class III or 4

- 2) Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction within 6 months of start of study drug, serious uncontrolled cardiac
arrhythmia or any other clinically significant cardiac disease

- 3) Concomitant use of drugs with a risk of causing torsades de pointes

- 4) Severely impaired lung functions as defined as spirometry and DLCO that is 50% of
the normal predicted value and/or O2 saturation that is 88% or less at rest on room
air

- 5) Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN; optimal
glycemic control should be achieved before starting trial therapy

- 6) Active (acute or chronic) or uncontrolled severe infections

- 7) Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
hepatitis; a detailed assessment of Hepatitis B/C medical history and risk factors
must be done at screening for all patients; HBV DNA and HCV RNA PCR testing are
required at screening for all patients with a positive medical history based on risk
factors and/or confirmation of prior HBV/HCV infection

- A known HIV seropositivity

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

- Patients with an active, bleeding diathesis

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods; adequate contraception
must be used throughout the trial and for 8 weeks after the last dose of study drug
by both sexes

- Adults of reproductive potential who are not using effective birth control methods;
if barrier contraceptive are being used, these must be continued throughout this
trial by both sexes; hormonal contraceptives are not acceptable as a sole method of
contraception

- Women of childbearing potential must have a negative urine or serum pregnancy test
within 14 days prior to administration of everolimus

- Patients who have received prior treatment with an mTOR inhibitor (sirolimus,
temsirolimus, everolimus)

- Patients with a known hypersensitivity to everolimus (everolimus) or other rapamycins
(sirolimus, temsirolimus) or to its excipients

- History of noncompliance to medical regimens

- Male patient whose sexual partner(s) are WOCBP who are not willing to use adequate
contraception, during the study and for 8 weeks after the end of treatment

- Patients unwilling to or unable to comply with the protocol

- Patients currently receiving strong or moderate CYP3A4 inhibitors or inducers;
patients should not begin study drugs until at least 72 hours after the last dose (or
longer, as indicated) of the inhibitor or inducer