LEE001 and Chemoembolization In Patients With Advanced Hepatocellular Carcinoma

Single-arm, single-institution, non-randomized, open-label phase II study to determine the
efficacy and safety of treatment with LEE011 and chemoembolization in patients with advanced
HCC (Hepatocellular Carcinoma) not amenable to curative therapies. A total of 40 patients
will be enrolled and undergo chemoembolization. Patients will receive LEE011 (600 mg PO once
daily, 3 weeks on/1 week off) on Day 1 with chemoembolization. Patients can receive a total
of 4 chemoembolization treatments within 6 month following first treatment as needed to treat
initial HCC (Hepatocellular Carcinoma) lesion.

Progression free survival will be based on tumor assessment using RECIST 1.1 criteria
(Response Evaluation Criteria in Solid Tumors) Patients will receive trial treatment until
disease progression, unacceptable toxicity, death or discontinuation from the study treatment
for any other reason. Patients will be followed for survival regardless of treatment
discontinuation for any reason.

The study will include men and women with locally advanced HCC (Hepatocellular Carcinoma) not
amenable to curative therapy who have received no prior therapy for advanced disease.

Investigational Therapy:

LEE011 oral (3 weeks on/1 week off) in combination with chemoembolization.

Efficacy Assessments:

1. Dynamic contrasted abdominal computed tomography or magnetic resonance imaging will be
done at baseline, every 8 weeks, and every 3 months thereafter following initial
chemoembolization.

2. Chest CT imaging as clinically indicated

3. Survival status every 12 months (or earlier if required) regardless of treatment
discontinuation reason

Data Analysis:

The primary endpoint of the trial will be progression free survival (PFS) of HCC patients.
PFS is defined to be the time from initiation of treatment to progression or death without
evidence of progression. For cases without documentation of progression, follow-up will be
censored at the date of last disease assessment without progression, unless death occurs
within 4 months following the date of last progression-free, in which case death will be
counted as an event. The historical median PFS for TACE (Transcatheter arterial
chemoembolization) alone is 8-10 months. This study will target a hazard ratio of 0.69 with
an 80% power and a one-sided significance level of 10%. Assuming a 24-month accrual and an
18-month follow-up period the study requires 38 patients initiating LEE011 treatment with the
median PFS for TACE alone is 8 months, and 41 patients with the median PFS for
TACE(Transcatheter arterial chemoembolization) alone is 10 months. PFS will be estimated
using the Kaplan-Meier method, and Greenwood's formula will be used to calculate the standard
error of the corresponding Kaplan-Meier estimate and 95% confidence interval. Survival curves
will be estimated using Kaplan-Meier methodology.

Secondary endpoints of efficacy are to evaluate OS (Overall Survival). The statistical
methods used for the analysis of PFS will be used for the analysis of OS.

Other secondary objectives will include description of toxicity of the therapy regimen. These
data will be analyzed separately. The safety analyses will be performed on all patients who
receive any dose of therapy. Adverse events will be described using the NCI CTCAE v 4.03
criteria (ctep.cancer.gov/forms.CTCAEv4.pdf). Frequency and severity of adverse events
according to the NCI CTCAE ) v 4.03 (Common Terminology Criteria for Adverse Events) body
system and severity criteria will be described. In addition, frequency of Grade 3 or 4
adverse events will be described separately. Causality will also be noted. Adverse events
will be recorded for up to 1 year following discontinuation from study. Response rate and
toxicity rate will be estimated using an exact binomial method along with the 95% confidence
interval

Inclusion Criteria:

1. Patient must have a histologically confirmed diagnosis of RB positive hepatocellular
carcinoma

2. Patients must have HCC limited to the liver. There must be no clinical or radiographic
evidence of extrahepatic HCC. Portal lymphadenopathy is permitted as lymphadenopathy
is commonly associated with cirrhosis unrelated to malignancy;

3. Absence of occlusive main portal vein thrombus, branch venous thrombus is allowed;

4. Patients with locally advanced HCC not eligible for curative therapies;

5. Age ≥ 18 years;

6. Child-Pugh Score A or B7;

7. ECOG (Eastern Cooperative Oncology Group) Performance score of 0-2;

8. Life expectancy greater than 6 months;

9. Following baseline laboratory values:

10. Total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤1.5 x ULN in patients with
well-documented Gilbert's Syndrome;

11. INR (international normalized ratio) ≤ 1.7;

12. Hgb ≥ 9.0 g/dl;

13. Alkaline Phosphatase, AST (Aspartate Aminotransferase), ALT (Alanine Aminotransferase)
<7 times ULN;

14. Platelet count ≥ 75,000/mm3;

15. Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min;

16. Absolute neutrophil ≥ 1,500 cells/mm3;

17. Potassium, total calcium (corrected for serum albumin), magnesium, and phosphorus
within normal limits for the institution or corrected to within normal limits with
supplements before first dose of study medication

18. Sodium >130 meq/L;

19. Women of childbearing potential must have a negative pregnancy test;

20. Prior therapy is allowed provided the following are met: at least 4 weeks since prior
locoregional therapy including surgical resection, chemoembolization, radiotherapy, or
ablation. Provided target lesion has increased in size by 25% or more or the target
lesion was not treated with locoregional therapy;

21. Must be able to swallow LEE011 capsules.

Exclusion Criteria:

1. Patient who received any CDK4/6 inhibitor (cyclin-dependent kinase 4);

2. Patient who has received previous systemic therapy;

3. Patients with central nervous system (CNS) involvement, unless they meet ALL of the
following criteria:

4. At least 4 weeks from prior therapy completion (including ration and/or surgery) to
starting the study treatment;

5. Clinically stable CNS tumor at the time of screening and not receiving steroids and/or
enzyme-inducing anti-epileptic medications for brain metastases;

6. Clinically significant, uncontrolled heart disease and/or recent events including any
of the following:

7. History of acute coronary syndromes (including myocardial infarction, unstable angina,
coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic
pericarditis within 12 months prior to screening;

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

9. Documented cardiomyopathy;

10. Patient has a left ventricular ejection fraction <50% as determined by MUGA (Multi
Gated Acquisition scan) or ECHO at screening;

11. History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal
arrythmias, or conduction abnormality within 12 months of screening;

12. Bradycardia (heart rate <50 at rest), by ECG or pulse, at screening;

13. Congenital long QT syndrome or family history of long QT syndrome;

14. Systolic Blood Pressure (SBP) >160 or <90 mm Hg;

15. On screening inability to determine the QTcF (Fridericia Correction Formula) 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);

16. Patient is currently receiving any of the following medications and cannot be
discontinued 7 days prior to treatment (see appendix 1 for details):

17. Known strong inducers or inhibitors of CYP3A4/5 (a member of the cytochrome P450),
including grapefruit, grapefruit hybrids, pomelo, star-fruit, and Seville oranges;

18. That have a known risk to prolong the QT interval or induce Torsades de Pointes

19. Herbal preparations/medications, dietary supplements;

20. That have a narrow therapeutic window and are predominantly metabolized through
CYP3A4/5;

21. Tumor involvement > 50% of the liver;

22. Patient has a known history of HIV infection (testing is not required);

23. Patient has any other concurrent sever and/or uncontrolled medical condition that
would, in the investigator's judgment, cause unacceptable safety risks, contraindicate
patient participation in the study or compromise compliance with the protocol (e.g.
chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled
fungal, bacterial, or viral infections, etc.);

24. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks to
starting study drug, or who have not fully recovered from side effects of such
treatment

25. The following uses of corticosteroids are permitted: single doses, topical
applications (e.g.: for rash), inhaled sprays (e.g.: for obstructive airways
diseases), eye drops or local injections (e.g.: intra-articular);

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

27. Participation in a prior investigational study within 30 days prior to enrollment or
within 5 half-lives of the investigational product, whichever is longer;

28. Patient who has received radiotherapy ≤ 4 weeks or limited field radiation for
palliation ≤ 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 ≥ 30-25% of the bone marrow was irradiated;

29. 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);

30. Patient has not recovered from all toxicities related to prior anticancer therapies to
NCI-CTCAE version 4.03 Grade <1 (Exception to this criterion: patients with any grade
of alopecia are allowed to enter the study);

31. Patient has a known hypersensitivity to any of the excipients of LEE011;

32. Prior ablative, radiation, resection, or transplant therapies less than 4 weeks before
study registration;

33. Active gastrointestinal bleeding;

34. Allergy to iodine or gadolinium contrast that cannot be safely controlled with
premedication;

35. Concurrent malignancy or malignancy within 3 years of study entry, with the exception
of adequately treated basal or squamous cell carcinoma, non-melanomatous skin cancer
or treated cervical cancer;

36. Contraindication to angiography or chemoembolization medications;

37. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after contraception and until the termination of gestation, confirmed by a
positive hCG (Human chorionic gonadotropin) laboratory test;

38. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
throughout the study and for 8 weeks after study drug discontinuation. Highly effected
contraception methods include:

39. 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

40. 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

41. 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.

42. Combination of any of the two following (a+b or a+c or b+c) 43A-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; 45 B-Placement of an intrauterine
device (IUD) or intrauterine system (IUS); 45 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. 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.

46-Sexually active males, unless they use a condom during intercourse while taking the
drug, and for 21 days after stopping treatment of LEE011 -- should not father a child in
this period. A condom is required to be used also by vasectomized male in order to prevent
delivery of the drug via seminal fluid.