A Phase I PK/PD Study of the PI3 Kinase/mTOR Inhibitor BEZ235 Given Twice Daily for the Treatment of Patients With Advanced Solid Tumors

Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of solid tumor malignancy that is
metastatic or unresectable and not responsive to standard therapies or for which
there is no effective therapy.

2. Eastern Cooperative Group (ECOG) Performance Status score of 0 or 1.

3. Patient has recovered (to grade ≤ 1) from all clinically significant toxicities
related to prior antineoplastic therapies with the exception of alopecia and bone
marrow and organ functions (described separately).

4. Adequate organ system function, defined as follows:

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

• Platelets ≥ 100 x 109/L

- Hemoglobin ≥ 9 g/dL

- INR ≤ 2

- Fasting plasma glucose ≤ 140 mg/dL

- Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x the
upper limit of normal (ULN) if no liver involvement or ≤ 5 x the upper limit of
normal with liver involvement.

- Creatinine ≤ 1.5 x ULN, OR calculated creatinine clearance ≥ 50 mL/min as
calculated by the Cockcroft-Gault method, OR 24-hour measured urine creatinine
clearance ≥ 50 mL/min.

5. Ability to swallow and retain oral medication.

6. Life expectancy of ≥ 3 months.

7. Male patients willing to use adequate contraceptive measures.

8. Female patients who are not of child-bearing potential, and female patients of
child-bearing potential who agree to use adequate contraceptive measures and who
have a negative serum or urine pregnancy test within 72 hours prior to initial trial
treatment.

9. Patients must have measurable or evaluable disease.

10. Patients must be ≥18 years of age.

11. Patients entering this study must be willing to provide tissue from a previous tumor
biopsy (if available) for correlative testing. If tissue is not available, a patient
will still be eligible for enrollment into the study.

12. Ability to understand the nature of this trial and give written informed consent.

Exclusion Criteria:

1. Patients currently receiving cancer therapy (i.e., chemotherapy, radiation therapy,
immunotherapy, biologic therapy, hormonal therapy [with the exception of LHRH
agonists for prostate cancer], surgery and/or tumor embolization).

2. Use of an investigational drug within 21 days or 5 half-lives (whichever is shorter)
prior to the first dose of BEZ235. For investigational drugs for which 5 half-lives
is less than 21 days, a minimum of 10 days between termination of the investigational
drug and administration of BEZ235 is required. In addition, any drug-related
toxicity should have recovered to grade 1 or less.

3. Any major surgery, radiotherapy, or immunotherapy within the last 28 days (limited
palliative radiation is allowed ≥ 2 weeks). Chemotherapy regimens with delayed
toxicity within the last 4 weeks (or within the last 6 weeks for prior nitrosourea or
mitomycin C). Chemotherapy regimens given continuously or on a weekly basis with
limited potential for delayed toxicity within the last 2 weeks.

4. Patient has received wide field radiotherapy (including therapeutic radioisotopes
such as strontium 89) ≤ 28 days or limited field radiation for palliation ≤ 14 days
prior to starting study drug or has not recovered from side effects of such therapy.

5. Leptomeningeal metastases or spinal cord compression due to disease.

6. Patients with previously untreated brain metastases. Patients who have received
radiation or surgery for brain metastases are eligible if there is no evidence of
central nervous system (CNS) disease progression, and at least 2 weeks have elapsed
since treatment. Patients are not permitted to receive enzyme inducing
anti-epileptic drugs (EIAEDs) during the study and should not be receiving chronic
corticosteroid therapy for CNS metastases.

7. Patients with acute or chronic pancreatitis.

8. Patients with diabetes mellitus requiring insulin treatment or a history of
gestational diabetes mellitus.

9. Presence of active gastrointestinal (GI) disease or other condition that will
interfere significantly with the absorption, distribution, metabolism, or excretion
of BEZ235 (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea ≥ grade
2, and malabsorption syndrome).

10. Patient has active cardiac disease including any of the following:

• Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated
acquisition (MUGA) scan or echocardiogram (ECHO)

• QTcF > 480 msec on screening ECG

- Unstable angina pectoris

- Ventricular arrhythmias except for benign premature ventricular contractions

- Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled
with medication

- Conduction abnormality requiring a pacemaker

- Valvular disease with documented compromise in cardiac function

- Symptomatic pericarditis

11. Patient has a history of cardiac dysfunction including any of the following:

- Myocardial infarction within the last 6 months, documented by persistent
elevated cardiac enzymes or persistent regional wall abnormalities on assessment
of LVEF function

- History of documented congestive heart failure (New York Heart Association
functional classification III-IV).

- Documented cardiomyopathy

12. Family history of congenital long or short QT, or known history of QT/QTc
prolongation or Torsades de Pointes (TdP). Patients who are currently receiving
treatment with medication that has the potential to prolong the QT interval or
inducing Torsades de Pointes and the treatment cannot either be discontinued or
switched to a different medication prior to starting study drug.

13. Inadequately controlled hypertension (i.e., SBP > 180 mmHg or DBP>100mmHg).

14. Patient is receiving chronic treatment with systemic steroids or another
immuno-suppressive agent at the start of study treatment.

Note: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways
diseases), eye drops, or local injections (e.g. intra-articular) are allowed.

15. Patient is consuming Seville oranges, grapefruit, grapefruit hybrids, pummelos or
exotic citrus fruits (as well as their juices) during the last 7 days prior to start
of treatment. Regular orange juice is permitted.

16. Patients who are receiving a strong CYP3A4 inhibitor or inducer.

17. Patients who are currently receiving treatment with therapeutic doses of warfarin
sodium. Patients receiving low molecular weight heparin are allowed.

18. A serious active infection at the time of treatment, or another serious underlying
medical condition that would impair the ability of the patient to receive protocol
treatment.

19. Known diagnosis of human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C.

20. Psychological, familial, sociological, or geographical conditions that do not permit
compliance with the protocol.

21. Concurrent condition that in the investigator's opinion would jeopardize compliance
with the protocol.

22. Inability or unwillingness to comply with study and/or follow-up procedures outlined
in the protocol.

23. Women of child-bearing potential who are pregnant or breastfeeding or adults of
reproductive potential not employing an effective method of birth control.

- Women are considered post-menopausal and not of child bearing potential if they
have had 12 months of natural (spontaneous) amenorrhea with an appropriate
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six
months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol
< 20 pg/mL] or have had surgical bilateral oophorectomy (with or without
hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only
when the reproductive status of the woman has been confirmed by follow up
hormone level assessment is she considered not of child bearing potential.

- Women of child-bearing potential, defined as all women physiologically capable
of becoming pregnant, must use highly effective contraception during the study
and for 5 T1/2 (8 days) after stopping treatment. The highly effective
contraception is defined as either:

1. True abstinence: When this is in line with the preferred and usual lifestyle of the
subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception.

2. Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy)
or tubal ligation at least six weeks ago. In case of oophorectomy alone, only when the
reproductive status of the woman has been confirmed by follow up hormone level assessment.

3. Male partner sterilization: (with the appropriate post-vasectomy documentation of the
absence of sperm in the ejaculate). For female subjects on the study, the vasectomised
male partner should be the sole partner for that patient.

4. Use of a combination of any two of the following (a+b):

1. Placement of an intrauterine device (IUD) or intrauterine system (IUS).

2. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.

Oral contraception, injected or implanted hormonal methods are not allowed as BEZ235
potentially decreases the effectiveness of hormonal contraceptives.

- Women of child-bearing potential must have a negative serum or urine pregnancy test ≤
72 hours prior to initiating treatment.

- Fertile males, defined as all males physiologically capable of conceiving offspring
must use condom during treatment, for 5 T1/2 (8 days) after stopping treatment and
for additional 12 weeks (3 months in total after study drug discontinuation) and
should not father a child in this period.