LEE011 in Neuroendocrine Tumors of Foregut Origin

Study Drug Administration:

Each study cycle is 28 days.

If you are found to be eligible to take part in this study, you will take LEE011 capsules by
mouth 1 time on Days 1-21 of each cycle. You will take LEE011 capsules whole, at about the
same time each morning, with or without food, with at least 1 cup (8 ounces) of water. Do not
chew or open the capsules unless a member of the study staff tells you to do so.

If you forget to take your dose, you can still take the study drug up to 6 hours later. If
you are more than 6 hours late, wait until your next scheduled dose. If you vomit after
taking a dose, do not take an extra dose. Tell the study doctor or nurse if you vomit after
taking LEE011.

Study Visits:

On Day 1 of Cycle 1:

- You will have a physical exam.

- Blood (about 3 teaspoons) will be drawn for routine tests. If you are taking drugs to
prevent blood clots, this blood draw will also be used to check how well your blood
clots.

On Day 15 of Cycle 1:

- You will have a physical exam.

- Blood (about 2 teaspoons) will be drawn for routine tests.

- You will have an EKG before your dose of LEE011.

On Day 1 of Cycle 2:

- You will have a physical exam.

- You will have an EKG before your dose of LEE011.

- Blood (about 2 teaspoons) will be drawn for routine tests. If you are taking drugs to
prevent blood clots, this blood draw will also be used to check how well your blood
clots.

- You will have an image-guided tumor biopsy for PD testing.

On Day 15 of Cycle 2 and Day 1 of Cycle 3, you will have an EKG before and up to 4 hours
after your dose of LEE011.

On Day 1 of Cycles 3 and beyond:

- You will have a physical exam.

- Blood (about 2 teaspoons) will be drawn for routine tests. If you are taking drugs to
prevent blood clots, this blood draw will also be used to check how well your blood
clots.

On Day 1 of Cycle 2, Day 1 of Cycle 4, and then every 3 cycles after that (Cycles 7, 10, 13,
and so on), blood (about 2 teaspoons) will be drawn for tumor marker testing. If the study
doctor thinks it is needed, you may have this blood draw performed more frequently. The study
doctor will discuss this with you.

Every 3 cycles (Cycles 3, 6, 9, and so on), you will have an MRI, CT, and/or Octreoscan to
check the status of the disease.

On Day 1 of Cycles 4-6, you will have an EKG before your dose of LEE011.

Every 4 cycles (Cycles 4, 8, 12, and so on), blood (about 2 teaspoons) will be drawn to check
how much fat and cholesterol is in your blood. You should fast for at least 8 hours before
this blood draw.

Length of Treatment:

You may continue taking the study drug for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drug if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.

Your participation on this study will be over after the end-of-treatment visit, unless you
have side effects.

End-of-Treatment Visit:

Within 28 days after your last dose of study drug:

- You will have a physical exam.

- You will have an EKG and either an ECHO or a MUGA scan.

- Blood (about 2 tablespoons) and urine will be collected for routine tests, including a
test to to check how much fat and cholesterol is in your blood. You should fast for at
least 8 hours before this blood draw. If you are taking drugs to prevent blood clots,
this blood draw will also be used to check how well your blood clots.

If you have any side effects or symptoms, you will either be called by a member of the study
staff or asked to come into the clinic until the side effects or symptoms are gone or become
stable. If you are called, each call should last about 10 minutes.

This is an investigational study. LEE011 is not FDA approved or commercially available. It is
currently being used for research purposes. The study doctor can explain how the study drug
is designed to work.

Up to 20 participants will be enrolled in this study. All will take part at MD Anderson.

Inclusion Criteria:

1. Histologically or cytologically confirmed low or intermediate grade, unresectable well
differentiated foregut neuroendocrine tumors (thymic, bronchopulmonary, gastric,
duodenal and pancreatic). Patients with multiple neuroendocrine tumors associated with
MEN1 syndrome will be eligible.

2. Patients must have radiographically measurable disease.

3. Pancreatic neuroendocrine patients must have had progression after prior therapy.
Patients with other foregut neuroendocrine tumors must have had progressive disease
over the last 12 months, irrespective of prior therapy. Patients with both functional
(who may continue somatostatin analogues as required for control of related symptoms)
and non-functional tumors are eligible. In patients who have previously received
therapy, the number of prior lines of therapy should not be more than 2 lines of
systemic therapy not including somatostatin analogues.

4. Written informed consent must be obtained prior to any screening procedures.

5. Age greater than or equal to 18 years.

6. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 - 1.

7. 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, to allow the effects of prior therapy to have abated: a) Cytotoxic or
targeted chemotherapy: greater than or equal to the duration of the cycle of the most
recent treatment regimen (a minimum of 3 weeks for all regimens, except 6 weeks for
nitrosoureas and mitomycin-C). b) Biologic therapy (e.g., antibodies): greater than or
equal to 4 weeks.

8. Patients must have adequate organ function, as defined by the following parameters: a.
Bone marrow: Absolute Neutrophil Count (ANC) greater than or equal to 1.5 x 10^9/L;
Hemoglobin (Hgb) greater than or equal to 9 g/dL; Platelets greater than or equal to
100 x 10^9/L. b. Hepatic function: Serum total bilirubin less than or equal to 1.5 x
upper limit of normal (ULN); Aspartate aminotransferase (AST) (serum glutamic
oxaloacetic transaminase [SGOT]) and ALT (SGPT) less than or equal to 2.5 x ULN,
except in patients with tumor involvement of the liver who must have AST and ALT less
than or equal to 5 x ULN.

9. (continued from above) c. Renal function: Serum creatinine less than or equal to 1.5 x
ULN or 24-hour clearance greater than or equal to 50 mL/min; Serum potassium, sodium,
magnesium, phosphorus, and total calcium (corrected for serum albumin) must be within
clinically relevant limits (e.g., a patient can be enrolled if a lab value may be
outside the normal laboratory range but the abnormality is not clinically relevant or
can be repleted.)

10. Negative pregnancy test (serum B-HCG) within 7 days of starting study treatment is
required in women of childbearing potential. B-HCG may be secreted by a small
percentage of NETs and be a tumor marker. Thus, NET patients with positive B-HCG are
eligible if pregnancy can be excluded by vaginal ultrasound or lack of expected
doubling of B-HCG.

Exclusion Criteria:

1. Patient has a known hypersensitivity to LEE011 or any of its excipients.

2. Patients with known or suspected 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.

3. Patients with concurrent malignancies or malignancies within 3 years prior to starting
study drug (with the exception of tumors common to a single genetic cancer syndrome,
i.e. MEN1, MEN2, vHL, TSC etc., or adequately treated, basal cell skin cancer,
squamous cell carcinoma, non-melanoma skin cancer or curatively resected cervical
cancer).

4. Patient is not able to swallow oral medication and/or has impairment of
gastrointestinal (GI) function or GI disease that may significantly alter the
absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea,
vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

5. Known diagnosis of human immunodeficiency virus (HIV) or hepatitis C (testing is not
mandatory).

6. Patient has any other concurrent severe and/or uncontrolled medical condition that
would, in the investigator's judgment, contraindicate patient participation in the
clinical study (e.g. chronic pancreatitis, chronic active hepatitis, etc.).

7. Patient who has received radiotherapy within less than or equal to 4 weeks or limited
field radiation for palliation within less than or equal to 2 weeks prior to starting
study drug, and who has not recovered to grade 1 or better from related side effects
of such therapy (exceptions include alopecia) and/or in whom greater than or equal to
30% of the bone marrow was irradiated.

8. Patient has had major surgery within 14 days prior to starting study drug or has not
recovered from major side effects (tumor biopsy is not considered as major surgery).

9. Impaired cardiac function or clinically significant cardiac diseases, including any of
the following: a) History of acute coronary syndromes (including myocardial
infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or
stenting) or symptomatic pericarditis less than 12 months prior to screening b)
History of documented congestive heart failure (New York Heart Association functional
classification III-IV) c) Documented cardiomyopathy d) Patient has a Left Ventricular
Ejection Fraction (LVEF) less than 50% as determined by Multiple Gated acquisition
(MUGA) scan or echocardiogram (ECHO) at screening e) History of ventricular,
supraventricular, nodal arrhythmias, or any other cardiac arrhythmias, long QT
Syndrome or conduction abnormality within 12 months prior to starting study drug

10. (continued from above) f) Congenital long QT syndrome or a family history of QTc
prolongation g) On screening, inability to determine the QTcF interval on the ECG
(i.e.: unreadable or not interpretable) or QTcF >450 msec (using Fridericia's
correction). All as determined by screening ECG (mean of triplicate ECGs)

11. Systolic blood pressure greater than 160 mmHg or less than 90 mmHg at screening.

12. Patients who are currently receiving treatment with agents that are known to cause QTc
prolongation or inducing Torsades de Pointes in humans and are unable to discontinue
or switch to an alternate medication.

13. Patients who are currently receiving treatment (within 5 days prior to starting study
drug) with agents that are known strong inducers or inhibitors of CYP3A4/5, or that
have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.

14. Patients with concurrent severe and/or uncontrolled concurrent medical conditions that
could compromise participation in the study (e.g., uncontrolled diabetes mellitus
defined by a glucose greater than 1.5 ULN in spite of adequate medical treatment,
clinically significant pulmonary disease, clinically significant neurological
disorder, active or uncontrolled infection)

15. Patient has a history of non-compliance to medical regimen or inability to grant
consent.

16. Pregnant or lactating women, where pregnancy is defined as the state of a female after
conception and until the termination of gestation, confirmed by a positive hCG
laboratory test (greater than 5 mIU/mL).

17. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using effective methods of contraception throughout
the study and for 8 weeks after study drug discontinuation. Highly effective
contraception methods include: Total abstinence when this is in line with the
preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar,
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable
methods of contraception; Female sterilization (have had surgical bilateral
oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before
taking study treatment. In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment.

18. (continued from above) Male sterilization (at least 6 months prior to screening). For
female patients on the study, the vasectomized male partner should be the sole partner
for that patient; Combination of any of the two following (a+b or a+c or b+c) a. Use
of oral, injected or implanted hormonal methods of contraception or other forms of
hormonal contraception that have comparable efficacy (failure rate <1%), for example
hormone vaginal ring or transdermal hormone contraception b. Placement of an
intrauterine device (IUD) or intrauterine system (IUS) c. Barrier methods of
contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with
spermicidal foam/gel/film/cream/ vaginal suppository. In case of use of oral
contraception, women should have been stable on the same pill before taking study
treatment.Note: Oral contraceptives are allowed but should be used in conjunction with
a barrier method of contraception due to unknown effect of drug-drug interaction.

19. (continued from above) 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
have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal
ligation 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.

20. Sexually active males unless they use a condom during intercourse while taking the
drug and for 21 days after stopping treatment and should not father a child in this
period. A condom is required to be used also by vasectomized men in order to prevent
delivery of the drug via seminal fluid.

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

22. Patient is currently receiving warfarin or other coumarin-derived anticoagulant for
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight
heparin (LMWH) or fondaparinux is allowed.