This is a first-in-man, phase I/II clinical research study with BEZ235, an inhibitor of phosphatidylinositol 3'-kinase (PI3K). The study consists of a Phase I dose escalation part followed by a safety expansion part and a Phase II expansion part:

Phase I dose escalation part (advanced solid tumors):

Patients receive oral BEZ235 once daily on days 1-28 of the first course. Courses will repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of at least 3 patients receive escalating doses of BEZ235 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose expected to produce during the first course of treatment dose-limiting toxicity in 33% of patients.

Once the MTD has been defined, the safety expansion and efficacy expansion parts of the trial will be opened for enrollment.

Phase I safety expansion part (advanced solid tumors):

Patients will be treated with BEZ235, given at the MTD, once daily. Treatment of patients will continue until disease progression or occurrence of unacceptable side effects.

Phase II expansion part (advanced breast cancer):

Patients will be treated with BEZ235, given at the MTD, once daily. Treatment of patients will continue until disease progression or occurrence of unacceptable side effects.

An effort will be made to enrich the trial population with Cowden Syndrome patients with advanced solid malignancies.

• Solid Tumors
• Breast Cancer

• Experimental: Dose Escalation
• Experimental: MTD Expansion

Inclusion Criteria:

Disease Characteristics:

All patients

• Histologic confirmation of the underlying malignancy
• Progressive, recurrent unresectable disease
• Absence of brain metastases or history of primary central nervous system tumor. Negative CT or MRI scan required if there are symptoms attributable to brain metastases
• No history of another primary cancer that is currently clinically significant, has potential for metastases, or currently requires active intervention
• Availability of a representative tumor tissue specimen

Phase II expansion part (advanced breast cancer)

• Confirmed positive hormone receptor (estrogen receptor and/or progesterone receptor) or positive HER2 expression status
• Disease progression/recurrence following hormonal or anti-HER-2 treatment for advanced disease
• At least one but not more than two prior chemotherapy regimens for the unresectable tumor
• Measurable disease by MRI or CT scan

Cowden Syndrome patients with an advanced malignancy

• Genetic confirmation of Cowden Syndrome

Patient Characteristics:

• Age ≥ 18
• World Health Organization (WHO) Performance Status of ≤ 2
• Life expectancy of ≥ 12 weeks
• Hematopoietic:
• Absolute neutrophil count at least 1,500/mm3
• Hemoglobin at least 9 g/dL
• Platelet count at least 100,000/mm3
• No diabetes mellitus or history of gestational diabetes mellitus
• Normal blood glucose tests
• No acute or chronic renal disease
• Creatinine ≤ 1.5 times the upper limit of normal or 24-hour clearance ≥ 50 mL/min
• No acute or chronic liver disease
• AST/SGOT and ALT/SGPT ≤ 2.5 times the upper limit of normal (ULN); ≤ 5 times ULN if liver metastases present
• Bilirubin ≤ 1.5 times ULN
• No acute or chronic pancreatitis
• Amylase and lipase within the upper limit of normal
• No peripheral neuropathy
• No unresolved diarrhea
• No impaired cardiac function or clinically significant cardiac diseases such as ventricular arrhythmia, congestive heart failure, uncontrolled hypertension
• No acute myocardial infarction or unstable angina pectoris within the past 3 months
• No progressive eye disease
• No impairment of gastrointestinal (GI) function or GI disease that may alter the absorption of BEZ235
• No other concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study
• Known HIV infection (HIV testing not mandatory)
• Not pregnant or nursing
• Fertile patients must use barrier contraceptives

Prior/Concurrent Therapy:

• Recovered from side effects of prior anticancer therapies
• No concurrent treatment with medication that could prolong the QT interval
• No concurrent treatment with calcium channel blockers
• No concurrent treatment with therapeutic doses of warfarin sodium
• At least 4 weeks since prior chemotherapy or other systemic anticancer therapy
• At least 6 weeks since prior antibody therapy
• At least 2 weeks since prior treatment with corticosteroids, or with colony stimulating growth factors such as G-CSF or GM-CSF
• At least 4 weeks since prior radiotherapy
• At least 2 weeks since prior major surgery No concurrent investigational drugs

Exclusion Criteria:

Patients who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases Prior treatment with a PI3K inhibitor Acute or chronic liver disease or renal disease Acute or chronic pancreatitis Patients with any peripheral neuropathy ≥ CTCAE grade 2 Patients with unresolved diarrhea ≥ CTCAE grade 2

Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study:

• Impaired cardiac function or clinically significant cardiac diseases
• Patients with diabetes mellitus requiring insulin treatment, history of gestational diabetes mellitus
• Patients with known coagulopathies (as per amendment 4)
• Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol Patients with a history of photosensitivity reactions to other drugs

Any of the following ophthalmological findings:

• Progressive eye disease that could lead to severe loss of visual acuity or visual field loss during the study period
• Inability to perform the ophthalmic procedures required in this protocol

Other protocol-defined inclusion/exclusion criteria may apply