A Trial of LEE011 in Patients With Advanced Solid Tumors or Lymphoma

• Safety and tolerability of LEE011, as assessed by grade and frequency of Adverse events, serious adverse events, and changes in lab values, vital signs and ECGs. [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
• The pharmacokinetics (PK) of LEE011 (AUC inf, Cmax, Tmax, T1/2) [ Time Frame: 18 months ] [ Designated as safety issue: No ]
• Any pharmacodynamic activity of LEE011 treatment, as assessed by changes from baseline in biomarkers associated with the pharmacologic activity of LEE011 [ Time Frame: 18 months ] [ Designated as safety issue: No ]
• Antitumor activity that may be associated with LEE011 treatment, as assessed by CT/MRI Response Evaluation Criteria for Solid Tumors (RECIST) Criteria v1.0 or Cheson Criteria 2007 for lymphomas. [ Time Frame: 18 months ] [ Designated as safety issue: No ]

LEE011 is a new oral drug designed to inhibit the activity of an enzyme known as CDK4/6. CDK4/6 is involved in the process that allows both normal and cancer cells to divide and multiply. Cancer cells are often driven to divide and multiply by abnormalities that increase the activity of CDK4. Hence there is hope that blocking the activity of CDK4 may slow the growth of some cancers. LEE011 has shown anti-cancer activity in several different tumor models in animals.

Because CDK4 is important in both normal and cancerous cells, LEE011 is expected to decrease the ability of the bone marrow to make white blood cells, platelets, and red blood cells. Although these effects are expected to be reversible, they can increase the risk of infection, bleeding and fatigue.

The primary purpose of this study is to find the highest dose of LEE011 that can be safely given to adult patients with advanced solid tumors or lymphomas for which no further effective standard treatment is available. It will provide information about the side effects that may occur following treatment. The study will also possibly provide early evidence for LEE011's anti-tumor activity.

• Advanced Solid Tumor
• Lymphomas

Inclusion Criteria:

1. Patients aged ≥18 years with a histologically or cytologically confirmed diagnosis of a solid tumor or lymphoma for which no further effective standard treatment is available
2. Patients must have an ECOG performance status of 0 - 1
3. Patients enrolled in the dose expansion phase must have at least one measurable lesion as defined by RECIST criteria for solid tumors or Measurable nodal disease at baseline as defined by Cheson criteria for Lymphoma.

4. A sufficient interval must have elapsed between the last dose of prior anti-cancer therapy (including cytotoxic and biological therapies and major surgery) and enrollment in this study, to allow the effects of prior therapy to have abated:

   • Cytotoxic chemotherapy: ≥ the duration of the cycle of the most recent treatment regimen (a minimum of 2 weeks for all regimens, except 6 weeks for nitrosoureas and mitomycin-C).
   • Biologic therapy (e.g., antibodies): ≥ 4 weeks.

5. Patients must have adequate organ function, as defined by the following parameters:

   • Bone marrow: Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L, Hemoglobin (Hgb) ≥ 9 g/dL, Platelets ≥ 100 x 109/L
   • Hepatic function: Serum total bilirubin ≤ 1.5 x ULN (upper limit of normal); AST (SGOT) and ALT (SGPT) ≤ 3 x ULN, except in patients with tumor involvement of the liver who must have AST and ALT ≤ 5 x ULN
   • Renal function: Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 40 ml/min, Serum potassium, magnesium and calcium must be within normal limits

Exclusion Criteria:

1. Patients with primary central nervous system tumors or brain metastases. However, if radiation therapy and/or surgery has been completed and serial evaluation by CT (with contrast enhancement) or MRI over a minimum of 3 months demonstrates the disease to be stable and if the patient remains asymptomatic, then the patient may be enrolled. Such patients must have no need for treatment with steroids or anti-epileptic medications.
2. Impairment of gastro-intestinal (GI) function or GI disease that may significantly alter the absorption of LEE011 such as patients with a history of GI surgery which may result in intestinal blind loops and patients with clinically significant gastroparesis, unresolved nausea, vomiting, or diarrhea of CTCAE grade > 1
3. Prior hematopoietic stem cell or bone marrow transplantation

4. Impaired cardiac function or clinically significant cardiac diseases, including any of the following:

   • LVEF <45% as determined by MUGA or echo
   • Complete left bundle branch block
   • Obligate use of a cardiac pacemaker or implantable cardioverter defibrillator
   • Congenital long QT syndrome or family history of unexpected sudden cardiac death
   • History or presence of ventricular tachyarrhythmia
   • Presence of unstable atrial fibrillation (ventricular response > 100 bpm
   • Clinically significant resting bradycardia
   • QTcF >450 ms for males and >470 ms for females on screening ECG
   • Right bundle branch block and left anterior hemiblock (bifascicular block)
   • Angina pectoris ≤ 3 months prior to dosing with study drug
   • Acute MI ≤ 3 months prior to dosing with study drug
   • Other clinically significant heart disease
5. Acute myocardial infarction or angina pectoris ≤ 3 months prior to starting study drug
6. Patients with concurrent severe and/or uncontrolled concurrent medical conditions that could compromise participation in the study (e.g. uncontrolled hypertension and/or diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection).

Known diagnosis of HIV or hepatitis C

Other protocol-defined inclusion/exclusion criteria may apply