Clinical trial NCT02524119
Conditions: Hepatocellular Carcinoma
Sponsor: University of Texas Southwestern Medical Center
Start date: 2016-04-01; Completion date: 2020-09-01
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is determine whether the combination therapy with LEE011 and chemoembolization in patients with locally advanced Hepatocellular Carcinoma not amenable to curative therapies will provide greater efficacy than chemoembolization alone with a tolerable safety profile.

Detailed description:
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

Arms: arm 1: 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 lesion.
Interventions: intervention 1: LEE011 intervention 2: Chemoembolization
Intervention descriptions: intervention 1: 600 mg PO once daily will be given orally on days 1-21 of a 28 day cycle (3 weeks on / 1 week off) :until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason intervention 2: Patients will be treated with chemoembolization once every 4 weeks with up to 4 total chemoembolizations within the first 6 months from the initial chemoembolization.

Protocol documents:
Prot_SAP_000.pdf: 
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Title: LEE001 and Chemoembolization In Patients With Advanced Hepatocellular 
Carcinoma 
 
NCT02524119 
 
Document Date: 2/19/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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A Phase Ib/II Study of LEE011 and Chemoembolization In Patients With Advanced 
Hepatocellular Carcinoma  
 
IRB#: 052015-073 
Velos#: 19592 
IND#: 127,831 
 
 
 
 
 
 
 
 
 
Principal Investigator 
Muhammad Shaalan Beg, MD 
Assistant Professor of Hematology Oncology 
University of Texas Southwestern Medical Center 
Harold C. Simmons Comprehensive Cancer Center 
5323 Harry Hines Boulevard 
Dallas, TX 75390-9179 
Ph: 214-648-4180 
Fx: 214-648-1906 
Email: Muhammad.Beg@utsouthwestern.edu 
 
 
 
 
 
 
 
 
 
 
Study Chair 
Adam Yopp, MD  
Assistant Professor of Surgery 
 
University of Texas Southwestern Medical Center 
 
Harold C. Simmons Comprehensive Cancer Center 
 
5323 Harry Hines Boulevard 
 
Dallas, TX 75390-8852 
 
Ph: 214-648-5870 
 
Fx: 214-648-1118 
 
Email: adam.yopp@utsouthwestern.edu 
 
 
 
 
 
 
Sub-Investigator(s): 
 
 
 
Amit Singal, MD 
Medicine 
Purva Gopal, MD 
Pathology 
Hao Zhu, MD 
Medicine 
Sanjeeva Kalva, MD 
Aravind Sanjeevaiah 
Radiology 
Medicine 
 
 
 
 
 


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Biostatistician: 
Chul Ahn, Ph.D. 
 
UT Southwestern Medical Center 
 
5323 Harry Hines Blvd 
 
Dallas, TX 75390 
 
 
 
 
Initial Version: 
Amendment #1: 
Amendment #2: 
November 10, 2015 
April 11, 2016 
May 12, 2016 
 
Amendment #3: 
   
  August 6, 2017 
 
Funding Source:  
Investigator Initiated Program, Novartis Pharmaceuticals 
 
 
 
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 


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CONTACT INFORMATION 
 
 
PRINCIPAL INVESTIGATOR: 
 
Muhammad Shaalan Beg MD 
 
   
 
UT Southwestern Medical Center 
 
   
 
5323 Harry Hines Blvd, NB2.418 
 
   
 
Dallas, TX 75390-9179 
 
   
 
Phone: 214-648-4180 
 
   
 
Email: muhammad.beg@utsouthwestern.edu 
 
 
BIOSTATISTICIAN:  
 
 
Chul Ahn, Ph.D. 
 
 
 
 
 
 
Professor of Biostatistics and Director 
 
 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
 
 
Biostatistics Core 
 
 
 
 
 
 
5323 Harry Hines Blvd 
 
 
 
 
 
 
Dallas, TX 75390 
 
 
 
 
 
 
Phone: 214-648-9418  
 
 
 
 
 
 
Email: Chul.Ahn@UTSouthwestern.edu 
 
 
 
OFFICE INFORMATION: 
 
 
UT Southwestern Medical Center  
 
 
Harold C. Simmons Cancer Center 
 
 
Attn: Clinical Research Office; NB2.402 
 
 
5323 Harry Hines Blvd 
MC 9179 
 
 
 
 
 
 
Dallas, Texas 75390-9179 
 
 


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Signature Page 
IRB#: 052015-073 
 
Amendment #3 dated August 6, 2017 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
 
Principal Investigator (PI) Name: 
 
PI Signature: 
 
Date: 
 
 
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................ 1 
STUDY SCHEMA ........................................................................................................... 2 
STUDY SUMMARY ........................................................................................................ 3 
1.0 
BACKGROUND AND RATIONALE ................................................................. 4 
1.1 
HEPATOCELLULAR DISEASE BACKGROUND ............................................................ 4 
1.2 
HEPATOCELLULAR CARCINOMA MANAGEMENT ..................................................... 4 
1.3 
COMBINATION OF CHEMOEMBOLIZATION AND SYSTEMIC THERAPY IN ADVANCED 
HCC ................................................................................................................................. 5 
1.4 
ROLE OF CELL CYCLE RELATED GENES AND PROTEINS IN CANCER.................. 5 
1.5 
PROLIFERATION FOLLOWING CHEMOEMBOLIZATION IN HEPATOCELLULAR 
CARCINOMA ................................................................................................................... 7 
1.6 
CD4/6 INHIBITION AND REDUCTION OF PROLIFERATION IN PRE-CLINICAL 
HEPATOCELLULAR TUMOR MODELS AND EARLY STAGE CLINICAL TRIALS IN HCC
 7 
1.7 
INTRODUCTION OF INVESTIGATIONAL TREATMENT(S) AND OTHER STUDY 
TREATMENT(S) .............................................................................................................. 8 
1.8 
STUDY RATIONALE ..................................................................................................... 13 
2.0 
STUDY OBJECTIVES .................................................................................... 14 
2.1 
PRIMARY OBJECTIVE ................................................................................................. 14 
2.2 
SECONDARY OBJECTIVES ......................................................................................... 14 
3.0 
STUDY DESIGN ............................................................................................. 14 
3.1 
DESIGN. ........................................................................................................................ 14 
3.2 
ENDPOINTS .................................................................................................................. 15 
4.0 
STUDY POPULATION ................................................................................... 16 
5.0 
SUBJECT ELIGIBILITY ................................................................................. 16 
5.1 
INCLUSION CRITERIA ................................................................................................. 16 
5.2 
EXCLUSION CRITERIA ................................................................................................ 18 


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6.0 
TREATMENT ................................................................................................. 22 
6.1 
OVERVIEW .................................................................................................................... 22 
6.2 
STUDY TREATMENT .................................................................................................... 22 
6.3 
LEE011 ADMINISTRATION SCHEDULE AND DOSE ADJUSTMENTS ...................... 23 
6.4 
LEE011 DOSING ........................................................................................................... 23 
6.5 
TREATMENT DURATION ............................................................................................. 23 
6.6 
LEE011 DOSE MODIFICATION GUIDELINE ............................................................... 24 
6.7 
ADJUSTMENT OF STARTING DOSE IN SPECIAL POPULATIONS .......................... 37 
6.8 
CONCOMITANT MEDICATIONS .................................................................................. 37 
6.9 
DRUG SUPPLY AND STORAGE .................................................................................. 38 
6.10 
STUDY DRUG COMPLIANCE AND ACCOUNTABILITY ............................................. 39 
6.11 
CHEMOEMBOLIZATION ............................................................................................... 39 
6.12 
LEE011 ADMINISTRATION WITH CHEMOEMBOLIZATION ...................................... 42 
7.0 
VISIT SCHEDULE AND ASSESSMENTS ...................................................... 44 
7.1 
TABLE OF ASSESSMENTS ......................................................................................... 44 
7.2 
SCREENING PHASE .................................................................................................... 47 
7.3 
TREATMENT PHASE .................................................................................................... 48 
7.4 
POST – TREATMENT FOLLOW-UP PHASE ............................................................... 49 
7.5 
SURVIVAL PHASE ........................................................................................................ 50 
8.0 
MEASUREMENT OF EFFECT ....................................................................... 50 
8.1 
ANTITUMOR EFFECT- SOLID TUMORS ..................................................................... 50 
8.2 
SAFETY/TOLERABILITY .............................................................................................. 53 
9.0 
ADVERSE EVENTS ....................................................................................... 53 
9.1 
LEE001 TREATMENT RELATED EVENTS .................................................................. 53 
9.2 
CHEMOEMBOLIZATION TREATMENT RELATED EVENTS ...................................... 54 
9.3 
ADVERSE EVENT MONITORING ................................................................................ 54 
9.4 
STOPPING RULES ....................................................................................................... 58 


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9.5 
STEPS TO DETERMINE IF AN ADVERSE EVENT REQUIRES EXPEDITED REPORTING
 58 
10.0 
SAFETY AND TOLERABILITY ASSESSMENTS .......................................... 59 
10.1 
PHYSICAL EXAMINATION, VITAL SIGNS, HEIGHT AND WEIGHT ........................... 59 
10.2 
ECOG PERFORMANCE STATUS (PS) ........................................................................ 59 
10.3 
LABORATORY ASSESSMENTS .................................................................................. 59 
11.0 
CORRELATIVES STUDIES ........................................................................... 60 
12.0 
STATISTICAL CONSIDERATIONS ............................................................... 61 
12.1 
STUDY DESIGN/STUDY ENDPOINTS......................................................................... 61 
13.0 
STUDY MANAGEMENT ................................................................................ 63 
13.1 
CONFLICT OF INTEREST ............................................................................................ 63 
13.2 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT ..................... 63 
14.0 
RECRUITMENT AND REGISTRATION PROCEDURES ............................... 63 
14.1 
RECRUITMENT PLAN .................................................................................................. 63 
14.2 
STUDY SUBJECT IDENTIFICATION NUMBER ........................................................... 64 
14.3 
SUBJECT REGISTRATION ......................................................................................... 64 
15.0 
PROTECTION OF HUMAN SUBJECTS ........................................................ 65 
16.0 
DATA AND SAFETY MONITORING PLAN ................................................... 66 
17.0 
ADHERENCE TO THE PROTOCOL .............................................................. 66 
17.1 
EMERGENCY MODIFICATIONS .................................................................................. 67 
17.2 
OTHER PROTOCOL DEVIATIONS/VIOLATIONS ....................................................... 67 
17.3 
AMENDMENTS TO THE PROTOCOL .......................................................................... 68 
17.4 
RECORD RETENTION ................................................................................................. 68 
17.5 
OBLIGATIONS OF INVESTIGATORS .......................................................................... 68 
18.0 
REFERENCES ............................................................................................... 70 


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19.0 
APPENDICES ................................................................................................ 72 


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LIST OF ABBREVIATIONS  
AE 
 
Adverse Event 
ALT  
 
Alanine Aminotransferase 
ALC   
Absolute Lymphocyte Count 
AST 
 
Aspartate Aminotransferase 
BUN   
Blood Urea Nitrogen 
CBC 
 
Complete Blood Count 
CMP   
Comprehensive Metabolic Panel 
CR  
 
Complete Response 
CT 
 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT  
 
Dose Limiting Toxicity 
DSMB  
Data and Safety Monitoring Board 
ECOG  
Eastern Cooperative Oncology Group 
H&P 
 
History and Physical Exam 
HRPP  Human Research Protections Program 
IV 
 
Intravenously 
MTD 
 
Maximum Tolerated Dose 
NCI 
 
National Cancer Institute 
ORR  
Overall Response Rate 
OS 
 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
 
Progressive Disease 
PFS 
 
Progression Free Survival 
p.o 
 
Per os 
PR 
 
Partial Response 
SAE 
 
Serious Adverse Event 
SD 
 
Stable Disease 
WBC   
White Blood Count 
 
 


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STUDY SCHEMA 
Phase Ib 
 
 
 
Phase II 
 
 
 


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STUDY SUMMARY 
Title 
A Phase Ib/II Study of LEE011 and Chemoembolization In 
Patients With Advanced Hepatocellular Carcinoma (HCC) 
Protocol Number 
052015-073 
Phase 
Phase Ib/II 
Methodology 
Open label 
Study Duration 
Four Years (4) 
Study Center(s) 
Single institutional trial: UT Southwestern Medical Center (UTSW) 
and Parkland Health and Hospital System (PHHS) 
Objectives 
Primary objective: 
1. To determine the maximum tolerated dose (MTD) of LEE011 
in patients with locally advanced HCC treated with 
chemoembolization 
2. To determine the progression free survival (PFS) of 
combination LEE011 and chemoembolization in patients with 
locally advanced HCC.  
 
Secondary objectives: 
1. To determine overall survival of LEE011 combined with 
chemoembolization and compared to historical controls. 
2. To determine the safety and tolerability of LEE011 in 
combination with chemoembolization as measured by rates of 
adverse events according to the CTCAE v. 4.03. 
3. To determine treatment response with pre- and intra-treatment 
biopsies and plasma/serum.  
Number of Subjects 
Phase Ib: 9-18 
Phase II: 40 
Diagnosis and Main 
Inclusion Criteria 
1. Patients must have a histologically confirmed diagnosis of 
Hepatocellular carcinoma.  
2. RB positivity as defined by RB expression (score of 0.5 or 1) 
with concurrent p16in4a loss (score of 0-2);  
3. Patients must have HCC limited to the liver;  
4. Absence of occlusive main portal vein thrombus, branch 
venous thrombus is allowed; 
5. Patients with locally advanced HCC not eligible for curative 
therapies; 
6. Age ≥ 18 years; 
7. Child-Pugh Score A or B7 
Study Product(s), Dose, 
Route, Regimen 
Phase Ib: LEE011 (200, 400, or 600mg) by mouth daily (3 weeks 
on/1 week off) in combination with chemoembolization 
Phase II: LEE011 (MTD from phase Ib) by mouth daily (3 weeks 
on/1 week off) in combination with chemoembolization 
Duration of 
administration 
Study treatment will continue until disease progression, 
unacceptable toxicity, death or discontinuation from the study 
treatment for any other reason. 


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Statistical Methodology 
Phase Ib: The primary endpoint of this aspect will be to determine 
the MTD of LEE011 following chemoembolization utilizing a 
standard 3+3 dose escalation (200, 400, 600 mg). 
Phase II: 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. 
 
 
1.0 
BACKGROUND AND RATIONALE 
1.1 
HEPATOCELLULAR DISEASE BACKGROUND 
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is 
responsible for more than 500,000 deaths annually. (1) Previously considered 
uncommon in Western countries, the incidence and mortality of HCC have increased 
three-fold in the United States over the past two decades. (2) 
1.2 
HEPATOCELLULAR CARCINOMA MANAGEMENT 
Currently, the only potentially curative options available to patients with HCC are 
partial hepatectomy, liver transplantation, or ablative techniques, but only 15% of 
patients are likely to benefit from such options due to concomitant cirrhosis and 
donor organ shortages. (3) For patients who undergo transplantation, a 5-year 
survival of 70% is possible, provided they meet Milan criteria (one lesion less than 5 
cm or up to three lesion less than 3 cm). 
 
For patient with HCC limited to the liver that are not candidates for curative 
therapies, loco-regional therapies such as chemoembolization offer tumor control 
while minimizing systemic toxicity and are felt to be reasonable alternatives to 
systemic therapy according to the National Comprehensive Cancer Network 
guidelines. (4) Tumor directed hepatic artery chemoembolization is possible because 
normal liver receives blood flow from both the hepatic artery and the portal vein, 
whereas HCC receives almost all blood flow from the hepatic artery. By inserting an 
angiographic catheter into the branches of the hepatic artery supplying the tumor and 
injecting cytotoxic chemotherapeutic agents (eg. Doxorubicin and/or cisplatin) 
followed by injecting cytotoxic particles leading to cessation of blood flow in the 
hepatic artery branch, tumor necrosis may result from both exposure to cytotoxic 
agents as well as ischemia. 
 
While there have been multiple randomized trials of chemoembolization that have 
failed to demonstrate a survival advantage in favor of chemoembolization, all these 
studies were conducted in the 1980s and 1990s. Since then, interventional radiology 
techniques have improved and two randomized trials reported in 2002 demonstrated 
a survival advantage for chemoembolization. Llovet and colleagues randomized 112 
patients to chemoembolization, bland embolization, or best supportive care (BSC) 


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and reported a significant result in favor of chemoembolization. One and 2 year 
survival probabilities were 82% and 63% for chemoembolization; 63% and 27% for 
BSC, p=0.009. (5)  In a single institution study from Hong Kong, Lo and colleagues 
randomized 80 patients to either BSC or cisplatin based chemoembolization. 
Survival for the chemoembolization arm (1 year, 57%, 3 years, 26%) was superior to 
the BSC arm (1 year, 32%; 3 years, 3%, p=0.002).  A subsequent meta-analysis of 
randomized trials in HCC conducted between 1978 and 2002 with a combined total 
of 545 patients reported a significant improvement of 2 year survival in favor of 
chemoembolization, OR 0.42; 95% CI, 0.2-0.88. Multiple studies have demonstrated 
median progression free survival times ranging from 8-10 months. (6) Our 
institutional historical controls for chemoembolization demonstrate an 8.0 month 
median PFS. Chemoembolization has become the accepted standard of treatment 
option for local advanced HCC with no curative options. The NCCN, the American 
Association for the Study of Liver Diseases, and the Barcelona Clinic Liver Cancer 
Group, all recommend chemoembolization for the treatment of unresectable HCC. 
(7) 
 
1.3 
COMBINATION OF CHEMOEMBOLIZATION AND SYSTEMIC THERAPY IN 
ADVANCED HCC 
Combining systemic therapy with standard of care chemoembolization has been 
studied in multiple clinical trials utilizing sorafenib and brivanib as systemic therapy 
with disappointing rates of efficacy although good tolerability. The largest clinical trial 
combining sorafenib with chemoembolization was the randomized phase II SPACE 
trial.  A total of 307 patients were randomized to receive sorafenib or placebo 
continually; all patients received a first chemoembolization 3-7 days after the first 
dose of the studied drug, and subsequent chemoembolizations on defined time 
points. The primary endpoint of time to progression was not met following 
comparison with placebo. (8) Similar results were obtained when combining brivanib 
with chemoembolization in a randomized controlled phase III trial. (9) Currently 
despite a lack of significant long-term efficacy following chemoembolization alone 
there is no systemic therapy that when given in combination with chemoembolization 
that has demonstrated increased benefit. 
 
1.4 
ROLE OF CELL CYCLE RELATED GENES AND PROTEINS IN CANCER 
In the mammalian cell cycle, entry into S phase is achieved by cyclin-dependent 
kinases 4 and 6 (CDK4/6). The cyclin D proteins act through the CDK4 and CDK6 
protein kinases to promote G1 progression. CDK4 and CDK6, in turn, 
hyperphosphorlyate and activate the retinoblastoma protein (RB) to promote cell 
cycle entry and cellular proliferation (Figure 1). (10,11) 
 
 
 


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Figure 1. The D-cyclin-CDK4/6-INK4a-pRb pathway  
 
Mitogenic signals converge at the level of cyclin D1 upregulation and CDK4/6 
association, localization, and kinase activity. CDK4/6 phosphorylates and inactivates 
RB tumor suppressor proteins, leading to dissociation of E2F transcription factors 
and subsequent expression of genes required for the G1/S transition and cell cycle 
progression. (10,11) 
 
D-cyclins are the positive regulators of these kinases, while the p16 protein encoded 
by the CDKN2A gene functions as their major inhibitor. Upon mitogen stimulation, 
signal transduction pathways including MAPK and PI3K increase cell proliferation by 
upregulating the expression of D-cyclins, which in turn activate the kinases. (10,11) 
 
A wide range of human tumors, including HCC, harbor genetic alterations that 
increase the activity of CDK4/6 via deregulated signaling pathways. (12)  
Furthermore, copy number abnormalities that result in increased CDK4/6 activity are 


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among the most commonly described genetic lesions observed in diverse tumor 
types.  Specifically, amplifications of the genes that encode cyclin D1 or CDK4/6, and 
homozygous deletions affecting the CDKN2A locus are particularly common.    The 
CDKN2A locus is also subject to frequent epigenetic silencing in multiple cancer 
subtypes including HCC.   Finally, RB is a tumor suppressor protein that is 
dysfunctional in multiple cancers. Direct analyses of primary HCC has revealed loss 
of RB expression in 10-15% of tumors, with genetic alterations observed in ~8% of 
cases. (12,13) Thus, the majority of HCC tumors represent a viable target for 
LEE011. (12) 
1.5 
PROLIFERATION FOLLOWING CHEMOEMBOLIZATION IN HEPATOCELLULAR 
CARCINOMA 
There are multiple pre-clinical and clinical studies suggesting that hepatic artery 
embolization leads to increased HCC tumoral cell proliferation. Kim et al reported a 
case series in which explanted livers from transplanted patients undergoing 
chemoembolization 3 to 4 weeks prior to transplant had an elevated Ki67 
proliferative index compared to non-treated controls.The increase in proliferative 
index within intratumoral endothelial and tumor cells was likely secondary to a post-
embolization ischemic necrosis. (14) Farris et al also demonstrated a statistically 
significant difference in proliferation, again measured by the Ki67 proliferative index, 
between patients undergoing chemoembolization and control patients. (15) 
1.6 
CD4/6 INHIBITION AND REDUCTION OF PROLIFERATION IN PRE-CLINICAL 
HEPATOCELLULAR TUMOR MODELS AND EARLY STAGE CLINICAL TRIALS 
IN HCC 
Our group previously demonstrated that inhibition of CDK4/CDK6 potently 
suppressed proliferation in HCC tumor models. For example, in a hepatoma 
xenograft model there was substantial suppression of proliferation following CDK4/6 
inhibition (Figure 2).   Similarly, in necrotic mouse livers following CCL4 
administration, CDK4/6 inhibition had a profound impact on aberrant proliferation 
(Figure 3).  These, and additional preclinical data served as the basis for a small 
single arm Phase II trial in advanced HCC using the CD4/6 inhibitior, palbociclib. 
This study used Rb and p16ink4 staining of tumor tissue as inclusion criteria. The 
immunohistochemical stains were developed and optimized by Dr. Agnieszka 
Witkiewicz, who assisted in developing this study This study treated 23 HCC patients 
who had failed on previous sorafenib therapy due to either intolerability or disease 
progression with palbociclib.  The safety profile was largely consistent with CDK4/6 
inhibition, the most common adverse event was bone marrow suppression. Grade 3 
and 4 adverse events included the following: thrombocytopenia, 43%; neutropenia, 
43%;leucopenia, 30%. (16) There was no evidence of liver related toxicity, including 
elevated AST and/or or AST and/or total bilirubin, following palbociclib administration 
in these patients with underlying cirrhosis. (Littman SJ, Gastrointestinal Cancers 
Symposium 2015, abstract 277) 
 
 


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1.7 
INTRODUCTION OF INVESTIGATIONAL TREATMENT(S) AND OTHER STUDY 
TREATMENT(S) 
1.7.1 Overview of LEE011 
LEE011 is an orally bioavailable and highly selective small molecule inhibitor 
of the CDK4/cyclin-D1 and CDK6-cyclin-D3 enzyme complexes with IC50s of 
0.01 and 0.039 mM in biochemical assays, respectively.  In preclinical 
models, LEE011 has potent cytostatic activity that is dependent on the 
presence of RB. 
 
The pharmacokinetics (PK) of LEE011 was investigated in mouse, rat, dog, 
and monkey. The absorption of LEE011 after oral administration was 
moderate for rats (48-84%). Oral bioavailability ranged from 10% and 65% 
across animal species. Time to maximum plasma drug concentration (Tmax) 
was between 2 and 4 hours. Terminal half-life (T1/2) of LEE011 was 
moderate in rodents and monkeys (2-7 hours), and was longer in dogs (18 
hours). LEE011 is moderately bound to plasma proteins in all animal species 
with unbound fractions in plasma ranging from 20-32%. [3H]LEE011 and 
metabolites were extensively distributed to tissues in male rates, but there 
was no uptake into the brain. 
 
In vitro metabolism studies showed that oxidative metabolism of LEE011 is 
dominated by CYP3A4 with a minor contribution of about 20% by flavin-
containing monoxygenase 3. In rate ADME studies, LEE011 was 
predominantly excreted in the bile as metabolites, with limited excretion of 
unchanged drug in urine. The bulk of the administered dose (87%) was 
excreted within 24 hours. LEQ803 is a prominent metabolite in rat, monkey, 
and human hepatocytes, and the only metabolite in dog hepatocytes. 
Fig 2.   Huh7 xenografts were treated with the 
vehicle control or the CDK4/6 inhibitor (PD-
0332991) by gavage.   Mice were sacrificed 
and tumor proliferation was determined by 
BrdU incorporation 
Fig 3.   Mice were treated with CCl4 to 
induce liver damage and CDK4/6 inhibitor 
by gavage.   Mice were sacrificed and 
hepatoic proliferation in the presence of 
necrotic damage was determined by BrdU 
incorporation. 


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LEQ803 is weakly pharmacologically active; however, it interacts with hERG 
channels in vitro. 
 
LEE011 is a time-dependent CYP3A4 inhibitor and a reversible inhibitor of 
CYP1A2 at higher concentrations. LEE011 is a low affinity substrate of P-
glycoprotein. LEE011 inhibits MDR1 mitoxantrone-resistant protein and 
human bile salt export pump, but not rat or dog BSEP. Overall, the 
elimination of LEE011 may potentially be affected by co-administered drugs 
that inhibit or induce CYP3A4. LEE011 may inhibit substrates of CYP3A4, 
CYP1A2, and BSEP, if sufficiently high concentrations are achieved in vivo. 
 
In GLP toxicology studies, LEE011 and LEQ803 exposure generally 
increased in a dose proportional manner in rates and dogs. Gender-different 
pharmacokinetics were observed in rats with higher exposure to LEE011 and 
LEQ803 in males as compared to females; however no gender differences 
were identified in dogs. 
1.7.2 Non-clinical Toxicokinetics 
Four week oral GLP toxicity studies with LEE011 (succinate salt) have been 
performed in the rat and dog. 
1.7.2.1 Rat 
Rats received qd oral doses of 25, 75 and 150 mg/kg/day in 0.5% 
methylcellulose aqueous solution (low dose) and suspension (mid 
and high dose). Maximum plasma concentrations of LEE011 and 
LEQ803 were reached between 0.5 and 7 hours after dosing. In 
general, plasma AUC0-24h of LEE011 and its metabolite LEQ803 
increased with increasing dose in a roughly proportional manner 
following single and multiple administrations of LEE011. This was 
less evident for the metabolite LEQ803 in the male rats. Following 
multiple administrations of LEE011 for 30 days no distinct increase 
in exposure was observed on day 30 when compared with Day 1. 
Overall, irrespective of the study days and gender, the exposure to 
the metabolite LEQ803 was substantially lower than LEE011 (3.9 to 
18.2% for Day 1 and 3.2 to 10.9% for Day 30). Gender-dependent 
toxicokinetics were identified, with higher exposure to LEE011 in 
males as compared to females (Cmax: 2.4 to 4.0-fold and AUC0-
24h: 3.2 to 7.0-fold) and higher exposure in males for the metabolite 
LEQ803 (Cmax: 3.9 to 14.0-fold and AUC0-24h: 6.2 to 17.8-fold), 
over the dosing regimen and study days. 
1.7.2.2 Dog 
Dogs received once daily oral doses of LEE011 of 5, 10 and 20 
mg/kg/day per gavage administered in 0.5% methylcellulose 
aqueous solution. The time to maximum plasma concentration 
(Tmax) generally occurred between 0.5 and 3 h post-dose for 


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LEE011 and LEQ803, irrespective of gender. In general, plasma 
AUC0-24h of LEE011 and its metabolite LEQ803 increased with 
increasing dose in a roughly proportional manner following single 
and multiple administrations of LEE011. Following multiple 
administrations of LEE011 a slight increase of the exposure was 
observed on Day 29 for LEE011 (1.2 to 1.9-fold) and for LEQ803 
(1.3 to 1.9-fold) when compared to Day 1 (single administration). The 
exposure to the metabolite LEQ803 was found to be lower than for 
LEE011 (6.0 to 8.5% for Day 1 and 5.6 to 9.5% for Day 29) following 
single and multiple administrations, regardless of the study day and 
gender. Generally, there was no apparent gender difference (based 
on AUC) over the dosing regimen or study day 
 
1.7.3 Overall Assessment of Non-clinical Studies 
LEE011 was profiled in a safety pharmacology receptor/enzyme panel and 
showed activity against PDE4D (IC50 0.88 µM and 0.39 µM). LEE011 
did not induce vasculitis or cardiovascular toxicity in the toxicology studies 
performed so far (up to 4 weeks). The impact of PDE4D inhibition in the 
clinic may include nausea and emesis. Rat safety pharmacology studies did 
not reveal any effects on CNS or respiratory functions. In the in vitro 
manual patch clamp assay, LEE011 had an IC50 of 53 µM and 
LEQ803, a metabolite of LEE011 that represents 6 to 10% of the parent 
drug in dogs, had an IC50  of 4.5 µM. In the dog telemetry study, 
prolongation of the average QT and QTc was observed with the potential 
to induce incidences of PVCs at higher exposure levels. LEE011 and 
LEQ803 likely contributed to the QT prolonging effects seen in vivo. 
Cardiac (ECG) monitoring in patients should be performed.  
Oral single dose toxicity studies were performed in dogs only. Oral 
multiple dose toxicity studies were performed in rats and dogs (up to 4 
weeks). 
In the 4-week toxicity studies, LEE011 was tolerated up to 150 mg/kg 
in rats and up to 20 mg/kg in dogs without mortality. Reversibility was 
assessed up to 4 weeks. 
In rats and dogs effects on bone marrow, lymphoid tissue (thymus, spleen, 
lymph nodes, gut- associated lymphoid tissues), hepatobiliary system, 
testes, adrenals and lungs were observed. In addition, in dogs, effects on 
intestinal mucosa, skin, bone/ribs and ovaries were also reported. 
The effects of LEE011 on the bone marrow (hypocellularity), lymphoid 
system (lymphoid depletion), intestinal mucosa (atrophy), skin (atrophy), 
bone (decreased bone formation) and testes (atrophy) can be regarded as 
related to the pharmacological inhibition of cell replication in these tissues 
due to CDK4/6 inhibition. An increased number of ovarian corpora lutea 
was observed in a single female dog at the highest dose tested (20 
mg/kg/day) and this effect could also be related to the pharmacology 


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(arrest of estrous cycle). The hepatobiliary system (proliferative changes, 
cholestasis, sand-like gallbladder calculi, and inspissated bile) was 
identified as an additional target organ of toxicity which is not likely related 
to the primary pharmacology of LEE011. Inflammatory changes in the lung 
of dogs were considered secondary to aspiration of test-article and are 
indicative of the irritant potential  of the formulated test-article in the 
respiratory tract. Correlating hematological and/or biochemistry changes 
were seen for the effects described in the bone marrow, lymphoid system 
and liver. 
In rats, the changes seen in the bone marrow and hematology 
demonstrated a clear tendency towards reversibility. All other findings fully 
reversed. In dogs, the changes seen in testes and lungs demonstrated a 
clear trend towards reversibility and all the other changes were fully 
reversible. It can be expected that after a prolonged recovery time 
incompletely recovered findings would have totally reversed in both species. 
It is advised to monitor carefully hematological and hepatobiliary 
parameters, as well as gastrointestinal effects in patients treated with 
LEE011. 
In vitro, LEE011 did not show an indication for mutagenic potential. 
In vitro, LEE011 did not show a phototoxic potential. 
In conclusion, multiple biological effects were observed in toxicology 
studies up to 4 weeks duration in rats and dogs. The observed toxicities 
can be considered clinically manageable. The critical nature of many of 
these effects and the potentially severe consequences for patients, 
however, warrant careful monitoring. 
LEE011 was moderately absorbed (48 to 84%) and rapidly absorbed after 
oral administration in rats, with Tmax ranging from 2 to 4 hr. Oral 
bioavailability ranged from 10 to 65% across animal species. The T1/2 of 
LEE011 was moderate in rodents and monkeys (3 to 5 h), and was 
comparatively longer (18 h) in dogs. LEE011 exhibited moderate binding 
to plasma proteins (human fu = 30%). LEE011 and its metabolites were 
extensively distributed into the organs and tissues of rats including the 
choroid, ciliary body, and meninges. The highest radioactivity 
concentrations were found in tissues such as the pituitary gland, pineal 
gland, spleen, kidney, and adrenal medulla, with remarkably high 
exposure in the thyroid gland. Distribution of LEE011 and/or its 
metabolites into melanin-containing structures was seen in pigmented rats. 
No radioactivity was detected in the brain after i.v. or p.o. dosing. 
Oxidative metabolism of LEE011 was dominated by CYP3A4 with a minor 
contribution of about 20% by FMO3. LEE011 is a low-affinity substrate of 
P-gp. LEE011 is a time- dependent CYP3A4 inhibitor and a reversible 


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inhibitor of CYP1A2. LEE011 was found to inhibit the MXR and human 
BSEP, but not the rat or dog BSEP. LEQ803 (N-demethylation) is a 
prominent metabolite found in rat, monkey and human hepatocytes, and the 
only metabolite formed in dog hepatocytes. This metabolite was found 
to interact with hERG channels in vitro.  
In rat ADME studies, LEE011 was predominantly excreted in the bile. 
The elimination of unchanged drug was limited. A minor proportion of the 
administered dose is excreted in urine. The bulk of the administered dose 
(87.3%) was excreted within 24 hr. 
1.7.4 Clinical Safety of LEE011 
Please see investigator’s brochure for up to date details on LEE011. As of 
June 15, 2015, 157 patients have been treated with LEE011 in the first-in 
human phase I study (CLEE011X2101). Patients with advanced solid tumors 
or lymphomas were treated with increasing doses of LEE011 orally, once 
daily for 21 days followed by a 1-week rest (28-day cycle).  
 
Evaluation of safety, tolerability, and PK from patients with advanced solid 
tumors and lymphoma in the FIH study was used to define the MTD and 
recommended dose for future development. The MTD was determined as 
900 mg/day on a 3-weeks-on/1-week-off schedule.  The recommended dose 
for further studies based on the expansion cohort is 600 mg/day with a 3 
weeks on/1 week off schedule, which has an acceptable safety profile, lower 
risk for QTcF prolongation, adequate exposures, and preliminary evidence of 
clinical activity. The most common hematologic and non-hematologic adverse 
events are in Tables 2-1 and 2-2.  
 
Table 2-1 Hematologic AEs in study CLEE011X2101 
Adverse Event, n (%) 
LEE011, 600 mg/day, 3 week 
on/1 week off schedule (n=67) 
Neutropenia 
All 
Grade 3/4 
22 (33%) 
15 (22) 
Leukopenia 
All 
Grade 3/4 
14 (21) 
7 (10) 
Thrombocytopenia All 
Grade 3/4 
13 (19) 
7 (10) 
Anemia 
All 
Grade 3/4 
16 (24) 
2 (3) 
Lymphopenia 
All 
Grade 3/4 
10 (15) 
8 (12) 
 
Table 2-2 Non-hematologic AEs in study CLEE011X2101 


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Adverse Event, n (%) 
LEE011, 600 mg/day, 3 
weekon/1 week off schedule 
(n=67) 
Fatigue 
All 
Grade 3/4 
20 (30) 
0 
Nausea 
All 
Grade 3/4 
32 (48) 
1 (2) 
Vomiting 
All 
Grade 3/4 
19 (28) 
0 
Diarrhea 
All 
Grade 3/4 
19 (28) 
2 (3) 
QT prolongation 
All 
Grade 3/4 
10 (15) 
0 
 
1.7.4.1 Clinical Pharmacokinetics of LEE011 
LEE011 is rapidly absorbed with median Tmax ranging from 2-5 hours in 
both adult and pediatric patients. Plasma concentrations increased 
approximately 2- to 3-fold from C1D1 to C1D18 due to accumulation, 
with steady state being reached by approximately day 8. Mean effective 
T1/2 was 32.6 hours in study CLEE011X2101. At steady state 
(C1D18/21), plasma exposure increases in LEE011 were slightly higher 
than dose proportional over the dose range 50-1200mg. 
1.8 
STUDY RATIONALE 
Combination therapy consisting of chemoembolization and LEE011 is attractive for 
patients with advanced HCC for the following reasons: 
 
• 
Based on the previously mentioned SPACE and brivanib trials there are no 
currently paired chemotherapy agents with chemoembolization demonstrating 
efficacy. The lack of significant long-term efficacy with chemoembolization 
alone coupled with significant post-procedure progression is an unmet need 
in the treatment of locally advanced HCC, the largest subset of HCC patients; 
• 
Following chemoembolization there is significant pre-clinical and clinical data 
demonstrating a proliferative affect both intra- and peri-tumoral.  Inhibition of 
CDK4 and CDK6 is associated with a reduction in proliferation both in in vitro 
and in vivo models; 
• 
Previous administration of a CDK4/6 inhibitor in patients with metastatic HCC 
has demonstrated efficacy with limited toxicity in early phase trials. 
It is our hypothesis that combination therapy with LEE011 and chemoembolization in 
patients with locally advanced HCC not amenable to curative therapies will provide 
greater efficacy than chemoembolization alone with a tolerable safety profile. 


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2.0 
STUDY OBJECTIVES 
2.1 
PRIMARY OBJECTIVE 
2.1.1 To determine the maximum tolerated dose (MTD) of LEE011 in patients with 
locally advanced HCC treated with chemoemolization.  (Phase Ib) 
 
2.1.2 To determine the progression free survival (PFS) of combination LEE011 and 
chemoembolization in patients with locally advanced HCC. PFS will be 
calculated from the date of enrollment on the study to appearance of new 
metastatic lesions or objective tumor progression using RECIST version 1.1 
guidelines and be compared with historical controls. (Phase II) 
2.2 
SECONDARY OBJECTIVES 
2.2.1 To determine overall survival of LEE011 combined with chemoembolization 
and compare to historical controls; 
 
2.2.2 To determine the safety and tolerability of LEE in combination with 
chemoembolization as measured by rates of adverse events according to the 
CTCAE v. 4.03; 
 
2.2.3 To determine treatment response with pre- and intra-treatment biopsies and 
plasma/serum. Correlative studies will be performed on the collected tissue 
and blood samples to determine if predictive markers of response can be 
generated.  
3.0 
STUDY DESIGN 
 
This is a single arm, open-label, single-institution phase Ib/II therapeutic trial of 
chemoembolization in combination with LEE011 in patients with locally advanced HCC. This 
study will enroll patientsat the UT Southwestern Medical Center and its affiliated hospitals 
and clinics, and Parkland Health and Hospital System.  
Immunohistochemistry testing: Prior to initiation on treatment, all patients will sign an 
informed consent form. Only patients with protocol defined RB-positivity will be eligible for 
treatment. Eligible patients should have RB expression  defined as a score of  0.5 or 1 with 
concurrent P16in4a loss of expression defined as a score of 0-2. TACE treatment can be 
initiated prior to confirmation of RB status provided an informed consent is signed. 
 Tissue, either from archival formalin fixed paraffin embedded samples or a new biopsy of a 
target lesion will be needed. RB-proficiency is determined by tumor biopsy demonstrating 
RB normal and p16in4a low by immunohistochemistry.  RB staining is scored on an absent 
(no nuclear staining), weak (nuclear staining less than observed in endothelial cells and 
stromal cells surrounding the tumor), positive (nuclear staining at or above surrounding 
tissue) (0, 0.5, 1 respectively).  P16ink4a is a routine clinical stain, wherein high expression 
is indicative of RB loss (ie. the markers are inversely correlated).  Staining is scored using 
absent, weak, positive, and strong (0, 1, 2, 3, respectively).  This determination will be made 


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by the study pathologist who has extensive experience with these markers in the context of 
HCC and breast cancer clinical studies.   
 
3.1 
ENDPOINTS 
Phase Ib:  
 
The primary endpoint of the phase Ib trial will be determination of the maximum 
tolerated dose of LEE011 administered following chemoembolization (section 6.6). 
 
Phase II:  
 
The primary endpoint of the phase II trial will be progression free survival (PFS) of 
HCC patients.  
 
Statistics and sample size justification: 
 
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 alone is 8-10 months. Our institutional median PFS for TACE 
based on similar chemoembolization procedures as outlined below is 8.0 months. 
This study will target a hazard ratio of 1.45 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 40 patients initiating LEE011 treatment with the median 
PFS for TACE alone is 8 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. The same 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 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 30 days following discontinuation of LEE011 or followed until 
resolution, whichever comes first. Response rate and toxicity rate will be estimated 


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using an exact binomial method along with the 95% confidence interval. 
 
Laboratory assessments will also be described according to the NCI CTCAE v.4.03 
criteria, with separate descriptions for Grade 3 or 4 laboratory abnormalities. 
Clinically significant laboratory abnormalities will be described as well. Serious 
adverse events will be summarized, including a causality assessment.   
 
The number of treatment cycles and doses administered will be summarized using 
descriptive statistics. Treatment delays will be summarized using counts and 
percentages.  
 
Patients’ disposition will be summarized in the following manner: 
 
• The number and percentage of patients selected, included, completed, withdrawn 
and lost to follow-up will be summarized using descriptive statistics.  
• Major protocol deviations will be summarized. 
• The reason for withdrawal (adverse events, lack of efficacy, major protocol 
deviation, non-medical reason, recovery or remission) will be summarized.  
 
For pathology-, laboratory- and imaging-correlative studies, Cox regression analysis 
will be conducted to investigate the association between PFS and parameters from 
correlative studies.  
 
4.0 
STUDY POPULATION 
This study will include patients with locally advanced HCC not amenable to curative 
treatments who have no evidence of metastatic disease. The investigator or designee must 
ensure that only patients who meet all the following inclusion and none of the exclusion 
criteria are offered treatment in the study. The study population will be the same for phase Ib 
and II. 
5.0 
SUBJECT ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion 
criteria to be registered and enrolled to the study. Study treatment may not begin until a 
subject is registered (See Section 14.3). 
 
5.1 
INCLUSION CRITERIA 
5.1.1 Histologically confirmed diagnosis of hepatocellular carcinoma (mixed 
HCC/cholangiocarcinoma is allowed). 
5.1.2 RB positivity as defined by RB expression (score of 0.5 or 1) with 
concurrent p16in4a loss (score of 0-2);  
5.1.3 Patients must have HCC limited to the liver. There must be no definitive 


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clinical or radiographic evidence of extrahepatic HCC. Portal 
lymphadenopathy is permitted as lymphadenopathy is commonly associated 
with cirrhosis unrelated to malignancy;  
5.1.4 Absence of occlusive main portal vein thrombus, branch venous thrombus is 
allowed; 
5.1.5  Patients with locally advanced HCC not eligible for curative therapies;  
5.1.6  Age ≥ 18 years; 
5.1.7  Child-Pugh Score A or B7; 
5.1.8  ECOG Performance score of 0-2; 
5.1.9  Anticipated life expectancy greater than 6 months; 
5.1.10 Following baseline laboratory values should be met: 
5.1.10.1 Total bilirubin ≤ 2.0 x ULN or direct bilirubin ≤1.5 x ULN in patients 
with well-documented Gilbert’s Syndrome; 
5.1.10.2 INR ≤ 1.7; 
5.1.10.3 Hgb ≥ 9.0 g/dl; 
5.1.10.4 Alkaline Phosphatase, AST, ALT <5 times ULN; 
5.1.10.5 Platelet count ≥ 75,000/mm3; 
5.1.10.6 Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min; 
5.1.10.7 Absolute neutrophil ≥ 1,500 cells/mm3; 
5.1.10.8 Potassium, total calcium (corrected for serum albumin), magnesium, 
and phosphorus within normal limits for the institution or corrected to 
within normal limits with supplements; 
5.1.11 Women of childbearing potential must have a negative pregnancy test;  
5.1.12 Prior therapy is allowed provided the following are met: at least 4 weeks since 
prior locoregional therapy including surgical resection, radiotherapy, or 


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ablation. Provided target lesion has increased in size by 25% or more or the 
target lesion was not treated with locoregional therapy; 
5.2 
EXCLUSION CRITERIA 
5.2.1 Patient who received any CDK4/6 inhibitor; 
5.2.2 Patient who has received previous systemic therapy or TACE for HCC; 
5.2.3 Clinically significant, uncontrolled heart disease and/or recent events 
including any of the following: 
5.2.3.1 History of acute coronary syndromes (including myocardial 
infarction, unstable angina, coronary artery bypass grafting,  
 
 


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5.2.3.2 coronary angioplasty, or stenting) or symptomatic pericarditis within 
12 months prior to screening; 
5.2.3.3 History of documented congestive heart failure (New York Heart 
Association functional classification III-IV); 
5.2.3.4 Documented cardiomyopathy; 
5.2.3.5 Patient has a left ventricular ejection fraction <50% as determined 
by MUGA scan or ECHO at screening; 
5.2.3.6 History of any cardiac arrhythmias, e.g., ventricular, 
supraventricular, nodal arrthymias, or conduction abnormality within 
12 months of screening; 
5.2.3.7 Bradycardia (heart rate <50 at rest), by ECG or pulse, at screening; 
5.2.3.8 Congenital long QT syndrome or family history of long QT 
syndrome; 
5.2.3.9 Systolic Blood Pressure (SBP) >160 or <90 mm Hg; 
5.2.4 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); 
5.2.5 Patient is currently receiving any of the following medications and cannot be 
discontinued 7 days prior to treatment (see appendix 1 for details): 
5.2.5.1 Known strong inducers or inhibitors of CYP3A4/5 or bile salt 
pump efflux, including grapefruit, grapefruit hybrids, pummelos, star-
fruit, and Seville oranges; 
5.2.5.2 That have a known risk to prolong the QT interval or induce 
Torsades de Pointes; 
5.2.5.3 Herbal preparations/medications, dietary supplements; 
5.2.5.4 That have a narrow therapeutic window and are 
predominantly metabolized through CYP3A4/5; 
5.2.6 Tumor involvement > 50% of the liver; 
5.2.7 Patient has a known history of HIV infection (testing is not required); 
5.2.8 Patient has any other concurrent severe and/or uncontrolled medical 
condition that would, in the investigator’s judgment, cause unacceptable 
safety risks, contraindicate patient participation in the study or compromise 


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compliance with the protocol (e.g. chronic pancreatitis, active untreated or 
uncontrolled fungal, bacterial, or viral infections, etc.); 
5.2.9 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); 
5.2.10 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;  
5.2.11 Participation in a prior investigational study within 30 days prior to enrollment 
or within 5 half-lives of the investigational product, whichever is longer;  
5.2.12 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; 
5.2.13 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); 
5.2.14 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); 
5.2.15 Patient has a known hypersensitivity to any of the excipients of LEE011; 
5.2.16 Prior ablative, radiation, resection, or transplant therapies less than 4 weeks 
before study registration; 
5.2.17 Active gastrointestinal bleeding; 
5.2.18 Allergy to iodine or gadolinium contrast that cannot be safely controlled with 
premedication; 
5.2.19 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; 
5.2.20 Contraindication to angiography or chemoembolization medications; 
5.2.21 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 laboratory test; 
5.2.22 Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective 


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methods of contraception throughout the study and for 8 weeks after study 
drug discontinuation. Highly effected contraception methods include: 
5.2.22.1 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 
5.2.22.2 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 
5.2.22.3 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.  
   5.2.22.4 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. 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. 
5.2.23 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. 
 
 
5.2.24 Any physical condition that can prevent ability to tolerate oral therapy 


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6.0 
TREATMENT  
6.1 
OVERVIEW 
Study subjects will sign an informed consent prior to initiation of screening 
processes. Following this, patients will undergo an image guided biopsy of liver 
tumor and the tissue will be collected and sent to: 1) The Pathology Department for 
histological confirmation of HCC and RB status through previously validated 
RB/p16ink4a staining; and 2) the pathology laboratory for correlative studies detailed 
in Section 11.  If the patient has archival formalin fixed paraffin embedded tissue, no 
additional baseline biopsy will be required. 
 
6.2 
STUDY TREATMENT 
For this study, the term “investigational drug” refers to Novartis study drug LEE011. 
The procedure, chemoembolization, is standard of care for locally, advanced, non-
metastatic HCC. Study treatment in this study refers to the combination of 
chemoembolization and LEE011. 
 
LEE011 will be supplied by Novartis or its designee as 200 mg hard gelatin capsules 
as individual patient supply packaged in bottles. Storage conditions are described in 
the medication label. Chemoembolization will be performed in usual standard of care 
practice by the interventional radiology division at UT Southwestern Medical Center 
as described in section 6.12 . 
All dosages prescribed and dispensed to the patient, and all dose changes during 
the study will be recorded in the drug accountability records. 
 
6.2.1 Description and Composition 
The LEE011 drug product is planned for oral administration. The available 
clinical forms are 10 mg, 50 mg and 200 mg hard gelatin capsules. The 
capsules only contain the drug substance; there are no excipients.  
6.2.2 Storage Condition 
The shelf life of the drug product is established based on ongoing stability 
studies and may be extended during the clinical study. The capsules are 
stored in HDPE bottles and the powder in bottle product is stored in amber 
glass bottles. Storage for the capsules and for the powder in bottle product is 
“Do not store above 25 °C, protect from moisture”. 
6.2.3 Hazards and Precautions 
LEE011 is a potent investigational new drug that has not been fully 
evaluated. Exercise appropriate hygiene and clinical practice precautions. 


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6.3 
LEE011 ADMINISTRATION SCHEDULE AND DOSE ADJUSTMENTS 
LEE011will be given orally once a day on days 1-21 of a 28 day cycle (3 weeks on / 
1 week off). Days 22-28 will be a “rest” from LEE011. 
 
Table 6.1 Dose and Treatment Schedule 
 
Study Treatment 
Pharmaceutical form 
and route of 
administration 
Total Dose 
Frequency 
and/or Regimen 
LEE011 
200 mg capsules by 
mouth 
200,400, or 
600 mg 
Once Daily on 
Days 1-21 of a 
28 day cycle. 
Rest Days 22-28 
 
LEE011 will be administered as a flat-fixed dose, and not by body weight or body 
surface area. 
 
The investigators will instruct the patient to take the study drug as per protocol.  
Patients must be instructed to return unused study drugs to the site at 
discontinuation or completion of treatment. The site personnel will ensure that 
dosing compliance is being performed by reviewing patient dosing diaries at each 
the end/start of a new treatment cycle.  
6.4 
LEE011 DOSING 
LEE011 must be taken as follows: 
• Patients should be instructed to take the LEE011 capsules with a large glass of 
water (~250 mL or 8 oz.) at the same time each day; 
• LEE011 can be taken without regard to meals; however dietary habits around the 
time of dosing should be as consistent as possible throughout the study; 
• Patients should be instructed to swallow the LEE011 capsules whole and not to 
chew, crush or open them; 
• If vomiting occurs during the course of treatment, no re-dosing of the patient is 
allowed before the next scheduled dose; 
• Any doses that are missed (not taken within 6 hours of the intended time) should 
be skipped and should not be replaced or made up on a subsequent day; 
• Patients must avoid consumption of grapefruit, Seville oranges or products 
containing the juice of each during the entire study and preferably 7 days before 
the first dose of study medication, due to potential CYP3A4 interaction with the 
study medications. Orange juice is allowed. 
6.5 
TREATMENT DURATION 
 
Patients will receive trial treatment until one of the following criteria applies: 
- 
disease progression,  
- 
unacceptable toxicity or toxicity that results in treatment interruption of >4 
 
weeks,  
- 
patient experiences DLT 


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- 
patient decides to withdraw from study, starts a new therapy or is lost to  
 
follow up 
- 
discontinuation from the study treatment for any other reason.  
- 
PI or study sponsor discretion 
 
Patients who come off therapy will be followed for survival regardless of cause of 
 
treatment discontinuation.” 
6.6 
DOSE LIMITING TOXICITIES-PHASE IB COMPONENT 
The phase Ib component of the study will consist of 3+3 dose escalation rule with the dose 
of LEE011 escalating up to 600mg daily to determine the maximum tolerated dose (MTD) 
that will be used during the phase II component. The dose levels for the phase Ib aspect will 
be 200 mg, 400 mg, or 600 mg daily. 
Only the first cycle of therapy (one cycle equals to one month) will be used to determine 
dose limiting toxicity (DLT). However, if two total grade 5 adverse events or 2 Grade 4 
adverse events (lasting ≥ 7days); occur at any time while the patient is still receiving study 
treatment that are either: definitely, probably, or possibly related to either LEE011 or TACE 
the study will be terminated to enrollment.  
Only patients started on the first dose of LEE011 will be included in the evaluation of DLT. If 
a patient has a DLT that patient will not receive further LEE011. Patients following initial 
chemoembolization who never receive LEE011 will not be included in the MTD analysis and 
will be replaced. The patients will be followed for thirty days following the initial 
chemoembolization for safety assessment. Patients will be enrolled into the next highest 
drug cohort only after 3 or 6 patients have completed the first cycle of therapy. Once the 
MTD is determined, patients at the MTD dose will continue with LEE011 and represent the 
first three patients accrued to the phase II aspect.  
Due to observed (TACE related, non DLT) toxicity on cohort 1 specific criteria for cohort 1 
has been developed after discussion with the FDA. Cohort 1 has been expanded to 6 
patients. Decision for dose escalation will be made using the following criteria:  
• 
No or one DLT: the next three patients will be assigned to next higher dose 
level (400 mg of LEE011). 
• 
At least two toxicities: the MTD is exceeded and the phase I component of 
the trial will be stopped with no continuation into the phase II component. 
 
For Cohort 2 and 3 the following traditional 3+3 dose escalation rules will be used:  
• 
If a dose limiting toxicity (DLT) is observed in 1 out of 3 patients at a given dose level, up 
 to 3 additional patients will be enrolled and treated at that dose level. 
• 
If 2 out of 3-6 patients at that dose level have DLTs, the dose will be decreased to the  
previous dose level, and up to 3 additional patients will be enrolled at that dose level for 
a total of 6 patients. 
• 
When up to 3 additional patients are added to a given dose level, if 0-1 of 6 patients has 
a DLT then the dose will be increased to the next dose level.  
• 
Additional dose levels may be explored per investigator discretion to define the safety 
profile of the treatment. 
 


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The recommended Phase II dose (RP2D) will be the highest cohort level in which one or 
fewer subjects of 6 develops a first cycle DLT.   
 
 
 
 
 
 
The Data and Safety Monitoring Committee as described below will regularly review all serious 
adverse events and any local adverse events, which are unanticipated problems. The study will 
utilize the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 for grading of all 
adverse events related to treatment. 
 
Table 6.2: Dose-limiting toxicity: phase Ib component 
The following will be considered a DLT if they occur  within the first cycle of therapy with LEE011 
and are determined to be possibly, probably or definitely related to LEE011 
 
 
Grade 4 neutropenia lasting more than 7 consecutive days 
Grade 3 or 4 febrile neutropenia 
≥ Grade 3 vomiting ≥ 48 hours despite optimal anti-emetic therapy 
≥ Grade 3 diarrhea ≥ 48 hours despite optimal anti-diarrhea therapy 
Clinical signs of cardiac disease, such as unstable angina or myocardial infarction, or Troponin ≥ 
grade 3 
Grade 4 serum alkaline phosphatase > 7 days 
≥ Grade 3 serum creatinine 
≥ Grade 3 adverse event for any non-hematologic toxicity unless otherwise specified as below 
(excluding alopecia, fatigue< 5 days, laboratory abnormalities that are responsive to oral 
supplementation or deemed by the investigator to be clinically insignificant).  
 
 
 


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THROMBOCYTOPENIA 
 
Toxicity/Grade 
Dose Limiting Toxicity and Management 
Recommendations 
Grade 3 
( ≥ 25 x 109/L - <50 x 109/L) 
without clinically significant 
bleeding 
Dose interruption until recovery to grade ≤2. 
 
Re-initiate LEE011 at the same dose level. 
 
• If toxicity recurs at grade 3: dose limiting toxicity 
Grade 3 
( ≥ 25 x 109/L - <50 x 109/L) 
with clinically significant 
bleeding 
Dose limiting toxicity 
Grade 4 
(<25 x 109/L) 
Dose limiting toxicity 
 
HEPATOTOXICITY (BILIRUBIN, ALT, AST) 
TOTAL BILIRUBIN without ALT/AST increase above baseline value 
Toxicity/Grade 
 
Dose Limiting Toxicity and Management Recommendations 
Same grade as baseline or 
increase from baseline grade 
0 to grade 1 
Maintain dose level with LFTs monitored every other-week 
Increase from baseline grade 
0 or 1 to grade 2 (1.5-3.0 x 
ULN) or from baseline grade 
2 to grade 3 (>3.0 -10 x ULN) 
Dose interruption of LEE011 
 
If resolved to ≤ grade 1 in ≤ 21 days, then maintain dose 
level 
 
If resolved to ≤ grade 1 in > 21 days or toxicity recurs, then dose 
limiting toxicity 
Increase from baseline grade 
0 or 1 to grade 3 (>3.0-10 
xULN) 
Dose limiting toxicity 
Grade 4 (> 10.0 x ULN) 
Dose limiting toxicity 


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HEPATOTOXICITY (BILIRUBIN, ALT, AST) 
AST or ALT without bilirubin elevation > 2 x ULN 
AST or ALT 
Toxicity/Grade 
 Dose Limiting Toxicity and Management Recommendations 
Same grade as baseline 
or increase from baseline 
grade 0 to grade 1 
(confirmed 48 to 72 hrs later) 
No dose adjustment required with LFTs monitored per protocol if 
same grade as baseline or bi-weekly in case of increase from 
baseline grade 0 to 1 
Increase from baseline grade 
0 or 1 to grade 2 (> 3.0 
– 5.0 x ULN) 
or 
from baseline grade 2 to 
grade 3 (> 5.0 – 20.0 x ULN) 
Dose interruption of LEE011 
 
If resolved to ≤ baseline value in ≤ 21 days, then maintain 
dose level 
 
If resolved to ≤ baseline value in > 21 days or toxicity recurs, 
then dose limiting toxicity 
 
 
Increase from baseline grade 
0 or 1 to grade 3 (> 5.0 – 20.0 
x ULN)  
Dose limiting  toxicity 
Grade 4 (> 20.0 x ULN) 
Dose limiting toxicity 
 
 
Confounding factors and/or alternative causes for increase of total bilirubin should be excluded 
before dose interruption/reduction. They include but are not limited to: evidence of obstruction, 
such as elevated ALP and GGT typical of gall bladder or bile duct disease, hyperbilirubinemia due 
to the indirect component only (i.e. direct bilirubin component ≤ 1 x ULN) due to hemolysis or 
Gilbert Syndrome, pharmacologic treatment, viral hepatitis, alcoholic or autoimmune hepatitis, 
other hepatotoxic drugs. 
 
For patients with Gilbert Syndrome, these dose modifications apply to changes in direct 
bilirubin only. Bilirubin will be fractionated if elevated. 


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AST or ALT and concurrent Bilirubin 
AST or ALT ≥ grade 2 (> 3 x 
ULN) in patients with normal 
values at baseline and total 
bilirubin  > 2 x ULN 
or AST or ALT ≥ grade 3 (> 5 
x ULN) in patients with grade  
 
Dose limiting toxicity 
 
 
 
 
 
Confounding factors and/or alternative causes for increased transaminases should be excluded 
before dose interruption/reduction. They include but are not limited to: concomitant medications, 
herbal preparations or dietary supplements, infection, hepato-biliary disorder or obstruction, new 
or progressive liver metastasis, and alcohol intake. 
 
QTC 
Toxicity/Grade 
Dose Limiting Toxicity and Management Recommendations 
For all 
grades 
• Check the quality of the ECG 
• Perform analysis of serum electrolytes (K+, Ca++, Phos, Mg++). If 
below the lower limit of normal, interrupt LEE011 administration, 
correct with supplements or appropriate therapy as soon as 
possible, and repeat electrolytes until documented as normal 
• Review concomitant medication usage for the potential to inhibit 
CYP3A4 and/or to prolong the QT interval 
• Check compliance with correct dose and administration of LEE011  
2 
QTc 481-500 ms 
Interrupt LEE011 
 
Perform a repeat ECG one hour after the first QTcF of ≥481ms 
 
If QTcF < 481 ms, restart LEE011 at the same dose.  No dose 
adjustment for the first occurrence 
 
If QTcF remains ≥481 ms, restart LEE011 at the same dose level. No 
dose adjustments required for the first occurrence 
 
If QTcF ≥481 ms recurs, dose limiting toxicity 
 
Repeat ECGs 7 days and 14 days after dose resumption (then as 
clinically indicated) for any patient who has therapy interrupted due to 
QTcF ≥481 ms 
 
3 
QTc ≥ 501 ms on at least 
two separate ECGs 
Interrupt LEE011 
• 
Consider consulting a local cardiologist 
 


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• 
Perform a repeat ECG one hour after the first QTcF of ≥501 ms 
 
• 
If QTcF remains ≥ 501 ms, repeat ECG as clinically indicated, but 
at least once a day until the QTcF returns to < 481 ms. 
 
• 
If QTcF returns to < 481 ms, LEE011 should be reduced by 
1 dose level. (please refer to the dosing schedule table) 
 
Repeat ECGs 7 days and 14 days after dose resumption for any 
patient who has therapy interrupted due to QTcF ≥501 ms 
 
• 
If QTcF of ≥ 501 ms recurs, discontinue LEE011- Dose limiting 
toxicity 
4 
QT/QTc ≥ 501 or > 
60 ms change from 
baseline 
 
And 
 
Torsades de pointes 
or polymorphic 
ventricular tachycardia, 
or signs/symptoms of 
serious arrhythmia 
Dose limiting toxicity 
 
6.7 LEE011 DOSE MODIFICATION GUIDELINE- PHASE IB CYCLE 2+ AND PHASE II 
COMPONENTS 
Management of severe or intolerable adverse reactions requires temporary dose reduction 
and/or interruption of LEE011 therapy. Refer to Table 6.3 for guidance. Dose increases once 
LEE011 has been reduced are not allowed.  
 
Table 6.3 Dose Modification Guidelines 
 
Dose Level 
LEE011 
Dose 
Number of capsules & 
strength 
Highest dose (0) 
600 mg 
3 x 200 mg capsules 
First dose reduction (-1) 
400 mg 
2 x 200 mg capsules 
Second dose reduction (-2) 
200 mg 
1 x 200 mg capsules 
Third dose reduction (-3) 
Discontinue Treatment of LEE011 


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Recommendations for dose reduction, interruption, of discontinuation of LEE011 in the 
management of adverse reactions are summarized in Table 6-4, Table 6-5, Table 6-6, and 
Table 6-7. Clinical judgment and discretion of the treating physician should guide the 
management plan of each patient based on individual benefit and risk assessment. 
 
Table 6-4 LEE011 Dose Adjustment and Management Recommendations for  
 
HEMATOLOGICAL ADVERSE REACTIONS 
 
 
THROMBOCYTOPENIA 
 
Toxicity/Grade 
Dose Adjustment and Management Recommendations 
Grade 1 
( ≥ 75 x 109/L) 
No dose adjustment required. 
Grade 2 
( ≥ 50 x 109/L - <75 x 
109/L) 
No dose adjustment required. 
 
Grade 3 
( ≥ 25 x 109/L - <50 x 
109/L) 
Dose interruption until recovery to grade ≤2. 
 
Re-initiate LEE011 at the same dose level.If toxicity recurs at grade 3: 
discontinue LEE011 
Grade 4 
(<25 x 109/L) 
Discontinue LEE011. 
 
 


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Toxicity/Grade 
Dose Adjustment and Management Recommendations 
 
Absolute neutrophil count (ANC) 
 
Grade 1 
(≥1.5 x 109/L) 
No dose adjustment required. 
Grade 2 
(≥1.0 - <1.5 x 109/L) 
No dose adjustment required. 
Grade 3 
(≥0.5 - <1.0 x 109/L) 
Dose interruption until recovery to ≥1.0 x 109/L. 
Re-initiate LEE011 at the same dose level. 
 
• If toxicity recurs at grade 3: temporary dose interruption until 
recovery to ≥1.0 x 109/L and reduce LEE011 dose to the next 
lower dose level. 
Grade 4 
(<0.5 x 109/L) 
Dose interruption until recovery to 
 ≥ 1.0 x 109/L. 
 
Re-initiate LEE011 at the next lower dose level. 
• If toxicity recurs at grade 4: temporary dose interruption until 
recovery to ≥ 1.0 x 109/L and reduce LEE011 at the next lower 
dose level. 
 
Febrile Neutropenia 
 
Grade 3 
ANC <1.0 x 109/L with 
[a single temperature 
of >38.3°C (101°F) or a 
sustained temperature 
of ≥38°C (100.4°F) for 
more than one hour] 
Dose interruption until improvement of ANC ≥ 1.0 x 109/L and no 
fever. 
 
Restart at the next lower dose level. 
• If febrile neutropenia recurs, discontinue LEE011. 
Grade 4 
Life-threatening 
consequences; urgent 
intervention indicated 
Discontinue LEE011. 
 
Anemia (Hemoglobin) 
 
Grade 1 
(≥ 10.0 g/dL) 
No dose adjustment required. 
Grade 2 
( ≥ 8.0 – <10.0 g/dL) 
No dose adjustment required. 
Grade 3 
(<8.0 g/dL) 
Dose interruption until recovery to grade ≤ 2. 
 
Re-initiate LEE011 at the same dose. 


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Grade 4 
Life-threatening 
consequences; urgent 
intervention indicated 
Discontinue LEE011. 
 
 
 
 
Table 6-5 LEE011 Dose Adjustment and Management Recommendations for  
 
HEPATIC ADVERSE REACTIONS 
 
 
HEPATOTOXICITY (BILIRUBIN, ALT, AST) 
TOTAL BILIRUBIN without ALT/AST increase above baseline value 
Grade 
Dose Adjustment and Management Recommendations 
Same grade as baseline or 
increase from baseline grade 0 
to grade 1 
Maintain dose level with LFTs monitored every other-week 
Increase from baseline grade 0 
or 1 to grade 2 (1.5-3.0 x ULN) 
or from baseline grade 2 to grade
3 (>3.0 -10 x ULN) 
Dose interruption of LEE011 
 
If resolved to ≤ grade 1 in ≤ 21 days, then maintain dose 
level 
 
If resolved to ≤ grade 1 in > 21 days or toxicity recurs, 
discontinue LEE011  


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HEPATOTOXICITY (BILIRUBIN, ALT, AST) 
AST or ALT without bilirubin elevation > 2 x ULN 
AST or ALT 
Toxicity/Grade 
Dose Adjustment and Management Recommendations 
Same grade as baseline or 
increase from baseline grade 
0 to grade 1 
(confirmed 48 to 72 hrs later) 
No dose adjustment required with LFTs monitored per 
protocol if same grade as baseline or bi-weekly in case of 
increase from baseline grade 0 to 1 
Increase from baseline grade 0 
or 1 to grade 3 (>3.0-10 xULN) 
Discontinue LEE011 
Grade 4 (> 10.0 x ULN) 
Discontinue LEE011 
Confounding factors and/or alternative causes for increase of total bilirubin should be excluded 
before dose interruption/reduction. They include but are not limited to: evidence of obstruction, 
such as elevated ALP and GGT typical of gall bladder or bile duct disease, hyperbilirubinemia due 
to the indirect component only (i.e. direct bilirubin component ≤ 1 x ULN) due to hemolysis or 
Gilbert Syndrome, pharmacologic treatment, viral hepatitis, alcoholic or autoimmune hepatitis, 
other hepatotoxic drugs. 
 
For patients with Gilbert Syndrome, these dose modifications apply to changes in direct 
bilirubin only. Bilirubin will be fractionated if elevated. 


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Increase from baseline grade 0 or 
1 to grade 2 (> 3.0 
– 5.0 x ULN) 
or 
from baseline grade 2 to grade 3 
(> 5.0 – 20.0 x ULN) 
Dose interruption of LEE011 
 
If resolved to ≤ baseline value in ≤ 21 days, then 
maintain dose level 
 
If resolved to ≤ baseline value in > 21 days or toxicity 
recurs, discontinue LEE011 
 
 
 Increase from baseline grade 0 
or 1 to grade 3 (> 5.0 
– 20.0 x ULN) 
Discontinue LEE011 
Grade 4 (> 20.0 x ULN) 
Discontinue LEE011 
AST or ALT and concurrent Bilirubin 
AST or ALT ≥ grade 2 (> 3 x 
ULN) in patients with normal 
values at baseline and total 
bilirubin  > 2 x ULN 
o
r 
AST or ALT ≥ grade 3 (> 5 x 
ULN) in patients with grade 1 or 
2 at baseline, and total bilirubin  
> 2 x ULN 
Discontinue LEE011 
Confounding factors and/or alternative causes for increased transaminases should be excluded 
before dose interruption/reduction. They include but are not limited to: concomitant medications, 
herbal preparations or dietary supplements, infection, hepato-biliary disorder or obstruction, new 
or progressive liver metastasis, and alcohol intake. 
 
 
 
 
 
 
 
 
 
 


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Table 6-6 LEE011 dose modification guidance in case of QT PROLONGATION 
 
The ECG are done based on scheduled assessment as detailed in table 7.1. 
 
QTC 
Grade 
Dose Modification 
For all grades 
• Check the quality of the ECG 
• Perform analysis of serum electrolytes (K+, Ca++, Phos, 
Mg++). If below the lower limit of normal, interrupt LEE011 
administration, correct with supplements or appropriate 
therapy as soon as possible, and repeat electrolytes until 
documented as normal 
• Review concomitant medication usage for the potential to 
inhibit CYP3A4 and/or to prolong the QT interval 
• Check compliance with correct dose and administration of 
LEE011  
1 
QTc 450-480 ms 
No dose adjustment required. 
2 
QTc 481-500 ms 
Interrupt LEE011 
 
Perform a repeat ECG one hour after the first QTcF of 
≥481ms 
 
If QTcF < 481 ms, restart LEE011 at the same dose.  No dose 
adjustment for the first occurrence 
 
If QTcF remains ≥481 ms, restart LEE011 at the same dose 
level. No dose adjustments required for the first occurrence 
 
If QTcF ≥481 ms recurs, discontinue LEE011 
 
Repeat ECGs 7 days and 14 days after dose resumption (then 
as clinically indicated) for any patient who has therapy 
interrupted due to QTcF ≥481 ms 
 
3 
QTc ≥ 501 ms on at least two 
separate ECGs 
Interrupt LEE011 
• 
Consider consulting a local cardiologist 
 
• 
Perform a repeat ECG one hour after the first QTcF of 
≥501 ms 
 
• 
If QTcF remains ≥ 501 ms, repeat ECG as clinically 
indicated, but at least once a day until the QTcF returns 
to < 481 ms. 


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• 
If QTcF returns to < 481 ms, LEE011 should be reduced 
by 
1 dose level. (please refer to the dosing schedule table) 
 
Repeat ECGs 7 days and 14 days after dose resumption 
for any patient who has therapy interrupted due to QTcF 
≥501 ms 
 
• 
If QTcF of ≥ 501 ms recurs, discontinue LEE011 
4 
QT/QTc ≥ 501 or > 60 ms 
change from baseline 
 
And 
 
Torsades de pointes or 
polymorphic ventricular 
tachycardia, or 
signs/symptoms of serious 
arrhythmia 
Discontinue LEE011 
 
Table 6-7 LEE011 Dose Adjustment and Management Recommendations for  
 
ALL OTHER ADVERSE REACTIONS 
 
Grade 
Dose Adjustment and Management Recommendations 
1 
No dose adjustment recommended. Initiate appropriate medical therapy and 
monitor. 
2 
Dose interruption until recovery to grade ≤1. Initiate appropriate 
medical therapy and monitor. 
 
Re-initiate LEE011 at the same dose. 
 
• 
If the same toxicity recurs at grade 2, interrupt LEE011 until recovery to 
grade ≤1. Re-initiate LEE011 at the next lower dose level. 


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3 
Dose interruption until recovery to grade ≤1. Initiate appropriate 
medical therapy and monitor. 
 
Re-initiate LEE011 at the next lower dose level. 
 
• 
If toxicity recurs at grade 2: temporary dose interruption until recovery to 
grade ≤1 and reduce LEE011 dose the next lower dose level. 
• 
If toxicity recurs at grade 3, discontinue LEE011. 
4 
Discontinue LEE011 and treat with appropriate medical therapy. 
 
6.8 
ADJUSTMENT OF STARTING DOSE IN SPECIAL POPULATIONS  
 
Renal impairment 
Insufficient data are available to provide a dosage recommendation for LEE011 in patients 
with renal impairment.  
Patients with baseline renal impairment are excluded from the study (serum creatinine > 1.5 
or creatinine clearance < 50 mL/min). Patients who experience serum creatinine impairment 
of grade 3 or higher during the treatment period should discontinue treatment and should be 
followed for safety assessments. 
6.9 
CONCOMITANT MEDICATIONS 
Permitted Concomitant Therapy 
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and 
supportive care agents, such as pain medications, anti-emetics and anti-diarrheal are 
allowed. 
 
The patient must be told to notify the investigational site about any new medications s/he 
takes after the start of the study treatment.  All medications (other than study drugs) and 
significant non-drug therapies (including vitamins, physical therapy and blood transfusions) 
administered within 30 days of study entry and during the study must be listed on the 
Concomitant medications/Significant non-drug therapies section of the patient record. 
 
Bisphosphonates and Denosumab 
Bisphosphonates and denosumab are permitted for the treatment of osteoporosis and 
prevention of skeletal related events for patients with bone metastases. Chronic concomitant 
bisphosphonate/denosumab therapy for the prevention of bone metastasis is not permitted. 
 
Hematopoietic Growth Factors 
Hematopoietic growth factors may be used according to ASCO guidelines. 
 
Palliative Radiotherapy 


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Palliative radiation is permitted if done solely for bone pain relief. It should not be delivered 
to a target lesion and it should not encompass more than 25% of irradiated bone marrow 
Refer to the LEE011 (LEE011) Investigator’s Brochure, Appendix table 1, and Appendix 
table 2 for information on possible interactions with other drugs. 
 
Permitted Concomitant Therapy Requiring Caution 
Medications to be used with caution during LEE011 in this study are listed below (see Table 
2). This list is not comprehensive and is only meant to be used as a guide. Concurrent use 
of CYP1A2 substrates is not expected to lead to clinically important drug-drug interactions, 
therefore their use is not regulated. These medications should be excluded from patient use 
if possible. If they must be given, then use with caution and consider a LEE011 interruption 
if the concomitant medication is only needed for a short time (See Appendix Table 1): 
 
• Moderate inhibitors or inducers of CYP3A4/5; 
• Sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index; 
• Strong inhibitors of BSEP; 
• Sensitive substrates of the renal transporters, MATE1 and OCT2; 
• Sensitive substrates of BCRP; 
• Medications that carry a possible risk for QT prolongation 
 
Prohibited Concomitant Therapy 
The following medications are prohibited during study treatment in the study (see Appendix 
Table 2). This list is not comprehensive and is only meant to be used as a guide: 
 
• Strong inhibitors or inducers of CYP3A4/5; 
• Substrates of CYP3A4/5 with a narrow therapeutic index; 
• Medications that carry a known risk for QT prolongation; 
• Herbal medications/preparations, herbal dietary supplements; 
• Other investigational and antineoplastic therapies not part of the study; 
• Herbal medications include, but are not limited to: St. John’s Wort, Kava, ephedra 
(ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, black cohosh and ginseng. Patients should stop using all herbal 
medications and dietary supplements at least 7 days prior to first dose of study 
treatment. 
6.10 
DRUG SUPPLY AND STORAGE 
Study drug must be received by the designated personnel at the study site, handled 
and stored safely and properly, and kept in a secured location to which only 
designated personnel have access. Upon receipt, the study drug should be stored 
according to the instructions specified on the drug labels and in the Investigators 
Brochure. Medication labels will comply with the legal requirements of each country 
and be printed in the local language. 


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6.11 
STUDY DRUG COMPLIANCE AND ACCOUNTABILITY 
6.11.1 Compliance 
Compliance will be assessed by the investigator and/or study personnel at 
each patient visit and information provided by the patient via patient drug 
diary. Records of the study medication used, dosages administered, and 
intervals between visits and completion of the study will be captured in the 
Drug Accountability Form. 
6.11.2 Accountability 
The investigator or designee must maintain an accurate record of the 
shipment and dispensing of study treatment in a drug accountability log at the 
study close-out visit, and as appropriate during the course of the study.  
6.12 
DRUG ELUTING BEAD-CHEMOEMBOLIZATION 
Chemoembolization is considered standard of care for locally advanced, non- 
metastatic HCC.  
 
6.12.1 DC Bead description 
a) DC bead comprise a range of hydrogel microspheres that are biocompatible, 
hydrophilic, non resorbable, precisely calibrated and capable of loading doxorubicin. 
DC bead is produced from polyvinyl alcohol and are available in the following size 
ranges: 
 
Nominal bead size 
Label color 
Upon loading with 
doxorubicin, DC bead 
undergo a slight 
decrease in size, up to 
20% when loading at 25 
mg/ml 
100-300 um 
Yellow 
300-500 um 
Blue 
500-700 um 
Red 
700-900 um 
Green 
 
b) How supplied: 
• 
10 ml glass vial 
• 
Each vial contains approximately 2 ml of DC bead in non-pyrogenic, sterile, 
physiological buffered saline. Total volume of saline and DC bead is 
approximately 8 ml. 
• 
The vial is stopper sealed by an aluminum cap equipped with a color-coded lid 
• 
Each vial is intended for single patient use only. Do not resterilize. Discard any 
unused material 
C) Contraindications-DC bead 
• 
Patients intolerant to vascular occlusion procedures 
• 
Vascular anatomy that precludes catheter placement or emboli injection 
• 
Presence or likely onset of vasospasm 


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• 
Presence of likely onset of hemorrhage 
• 
Presence of severe atheromatous disease 
• 
Presence of feeding arteries smaller than distal branches from which they 
emerge 
• 
Presence of patent extra-to-intracranial anastomoses or shunts 
• 
Presence of collateral vessel pathways potentially endangering normal 
territories during embolization 
• 
Presence of end arteries leading directly to cranial nerves 
• 
Presence of arteries supplying the lesion not large enough to accept DC bead 
• 
Vascular resistance peripheral to the feeding arteries precluding passage of 
DC bead into the lesion 
• 
Do not use DC bead for embolization of large diameter arteriovenous shunts 
6.12.2 DRUG LOADING INSTRUCTIONS 
DC bead is suitable for loading doxorubicin-HCL only. Liposomal formulations of 
doxorubicin are not suitable for loading into DC bead. 
To obtain final loading of 50 mg per 2 ml vial of DC bead; 
I. Reconstitute a vial containing 50 mg of doxorubicin with 2 ml of sterile water 
for injection. Mix well to obtain a clear red solution (25 mg/ml). 
II. Remove as much saline as possible from vial of DC bead using a syringe 
with a small gauge needle. 
III. Using a syringe and needle add the 2 ml of reconstituted doxorubicin solution 
directly to the vial of DC bead. 
IV. Agitate the DC bead/doxorubicin solution occasionally to encourage mixing 
until the DC bead is red. Although the solution retains a red color, doxorubicin 
will be loaded. 
V. Loading will take a minimum of 20 minutes for the smallest size DC bead and 
up to 120 minutes for the larges DC bead. 
VI. Prior to use, transfer the DC bead loaded with doxorubicin to a syringe and 
add 1 to 4 times the volume of the non-ionic contrast media, Omnipaque 350. 
Invert the syringe gently to obtain an even suspension of DC bead. A dose of 
up to 37.5 doxorubicin per ml DC bead can be loaded. 
VII. The maximum recommended total dose of doxorubicin per procedure is 150 
mg. 
6.12.3 PATIENT PRE-PROCEDURAL PREPARATION 
a) IV normal saline 
b) Pre-medications 
a. Versed and Fentanyl titrated for moderate sedation 
6.12.4 CHEMOEMBOLIZATION PROCEDURAL PREPARATION 
a) The patient is prepped and draped in a sterile fashion. 
b) Carefully evaluate the vascular network associated with the lesion with high 
resolution imaging prior to beginning the embolization procedure. 


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c) DC beads are available in a range of sizes, but only 100 to 500 um particles 
should be utilized. Care should also be taken to choose the appropriate size 
of DC bead athat bases matches the vascular target or vessel size. 
d) Choose a delivery catheter based on the size of the target vessel. DC bead 
can tolerate temporary compression of 20% to 30% in order to facilitate 
passage through the delivery catheter. 
e) Introduce the delivery catheter into the target vessel according to standard 
techniques. Position the catheter tip as close as possible to the treatment site 
to avoid inadvertent occlusion of normal vessels. 
f) DC are not radio-opaque. It is recommended to monitor the embolization 
under fluoroscopic visualization by adding the desired amount of contrast 
medium to the suspension fluid. 
a. Take care to ensure proper suspension of the DC bead in the contrast 
medium to enhance distribution during injection. 
b. Draw the DC bead into a syringe needle of a size greater than or 
equal to 19 gauge. 
c. At a rate no faster than 1ml/minute, slowly inject DC bead into the 
delivery catheter under fluoroscopic visualization while observing the 
contrast flow rate. Exercise conservative judgment in determining the 
embolization endpoint. 
g) Upon completion of the treatment, remove the catheter while maintaining 
gentle suction so as not to dislodge the DC bead still within the catheter 
lumen. 
h) Discard any unused DC bead loaded with doxorubicin. 
6.12.5 POST-CHEMOEMBOLIZATION PROCEDURE ORDERS AND CARE 
a) Admit patients overnight for observation. 
b) Hydration with IV normal saline 
c) Patient controlled analgesia for pain control. 
6.12.6 POST-PROCEDURE CARE 
a) Post-arteriography bedrest with monitoring of vital signs and pulses. 
b) Patient can be discharged as soon as they demonstrate adequate oral intake 
or liquids, no longer require parenteral narcotics or antiemetics. 
c) Fevers <103 degrees F are normal during the first week following treatment 
and do not require cultures. 
d) Following institutional guidelines, patients will be seen in the HCC 
multidisciplinary clinic 7-10 days following chemoembolization and will have 
the following evaluations completed: 
• 
Physical examination 
• 
Comprehensive metabolic panel 
• 
Complete blood count without differential 
• 
Prothrombin time/INR 
 


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At this time the decision will be made to initiate LEE011 treatment.   
LEE011 ADMINISTRATION WITH CHEMOEMBOLIZATION 
Subjects are to be evaluated from toxicity with: 
 
• 
Physical Examination (PE) 
• 
Comprehensive Metabolic Panel (CMP) 
• 
CBC 
• 
ECG’s 
LEE011 will be initiated at the earliest of 7 days following embolization 
chemoembolization provided the following criteria are met: 
 
• 
Serum bilirubin elevation < 2.0 x ULN. If serum bilirubin ≥ 2.0 x ULN then 
subjects will be assessed weekly and LEE011 will be initiated once bilirubin < 
2.0 x ULN. 
 
• 
Resolution of Grade < 3 non-hematologic toxicity (other than bilirubin criteria 
above). If non-hematologic toxicity ≥ Grade 3 then subjects will be assessed 
weekly and LEE011 will be initiated once < Grade 2; 
 
• 
Hematological toxicity of ≤ Grade 2. If hematologic toxicity ≥ Grade 3 then 
subjects will be assessed weekly and LEE011 will be initiated once ≤ Grade 
2.  
 
If baseline AST, ALT and alkaline phosphate are elevated post 
chemoembolization decrease to baseline grade is necessary to 
continue/initiate LEE011; 
 
• 
ECOG performance status ≤ 2; 
 
• 
Serum AST, ALT, and/or Alkaline Phosphate < 5 x ULN. 
 
If criteria is not met, subjects will be reevaluated in 5-7 day intervals. If study 
subjects are unable to meet the above LEE011 starting criteria following initial 
chemoembolization treatment within 28 days after treatment, they will be 
removed from the study.  
6.12.7 Subsequent Chemoembolizations 
To proceed with subsequent chemoembolization, study subjects must meet 
the following criteria: 
 
≤ Grade 2 hematologic toxicity with the exception of: 
• serum creatinine ≤ 1.5 mg/dl; 
• serum bilirubin ≤ 3.0 mg/dl. 


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Repeat Chemoembolization (for either ipsilateral or contralateral disease) if 
indicated, should be performed at least 4 weeks apart. Up to 4 
chemoembolizations can be performed in 6 months of the first 
chemoembolization. Additional chemoembolizations, if clinically indicated can 
occur after the first 6 months  
 


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7.0 
VISIT SCHEDULE AND ASSESSMENTS 
Table 7.1, lists all of the assessments and indicates with an “X”, the visits and when they are performed. For the phase Ib 
component only the first cycle will be utilized for determination of dose limiting toxicities. All data obtained from these 
assessments must be supported by the proper source documentation and placed in the patient’s chart. 
7.1 TABLE OF ASSESSMENTS 
Treatment Days  
Screening 
Phase1 
Treatment 
Phase: 
Chemoembolization 
Treatment Phase: LEE011 
Post Treatment Follow-up 
Survival 
Phase 
Day 
-28 
– 
Day 
-1 
Day 
-7 –  
 
Day -
1 
7-14 days  
Following 
chemoembolization 
Cycle 1 
Cycle 2 
C3 
C4+ 
End of 
Treatment 
or Early 
Withdrawal 
  
(Within 15 
Days of 
Last 
LEE011 
Dose) 
Safety 
Follow-
Up  
 
(Within 
30 
Days of 
Last 
LEE011 
Dose) 
Efficacy 
Follow-
Up 
Survival 
Follow-
Up  
 
Every 
12 
weeks 
 
Day 
   12,13 
Day 
15 
Day 
1 
Day 
15 
Day 
1 
Day 
1 
Visit 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Checklist  
- Inclusion / 
Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Med History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dx and Extent of 
Cancer (Staging) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CBC 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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Chemistry (CMP) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Cholesterol/Lipid 
Panel 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PT/INR 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum Pregnancy 
Test (WOCBP 
Only) 
 
X 
 
 
 
 
 
X 
X 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
Tumor 
Assessments with 
RECIST 1.15 
X 
 
 
-------------------------------
Every 8 weeks5--------------------
------------- 
 
X5 
 
ECHO/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECG (12 – Lead) 
 
X3 
 
X 
X 
X 
X3 
X 
X 
X 
X 
 
 
Adverse Events6 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Conmeds6 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Biomarker Tissue 
Collection 
(Biopsy)7 
X7 
 
 
 
 
X7 
 
 
 
 
 
 
 
Biomarker Blood 
Collection8 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
LEE011 Study 
Drug (Oral)9 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
Patient Dosing 
Diary for LEE0119 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
Chemoembolizatio
n (TACE)10 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
Discontinuation11 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Survival Follow-
Up12 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1. 
Screening assessments, apart from those listed above, must occur within 28 days of registration as per Table 7.1; 
2. 
Vital Signs, ECOG Performance Status, Physical Exam, ECG, CBC, CMP, PT/INR, Lipid Panel, Serum Pregnancy Test (WOCBP Only), and Urinalysis 
should be performed within 7 days of the first treatment day (Cycle 1, Day 1).  If there are any dose modifications or halting of drug in the phase II 
aspect, weekly hematology, comprehensive metabolic panels, and PT/INR laboratory investigations will be performed until the grade of adverse event 
leading to the modification or cessation is stable or a grade reduction occurs. In addition, following each chemoembolization the following will be done 
every other week for two cycles after each chemoembolization: physical examination, CMP, CBC, and PT/INR. 
3. 
In order for an accurate evaluation of baseline QTc, a total of three (triplicate) 12-lead ECGs will be performed after resting in a supine position for 5-10 
min, with a 2 minute interval between each ECG (triplicate ECG’s at screening only). Subsequent ECG’s will be performed after resting in a supine 
position for 5-10 min, on Day 1, C1D15, and C2D15 of each treatment cycle (single ECG’s )prior to chemoembolization and LEE011; 


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4. 
For all treatment visits there is a general +/- 3 day window on assessments to take into account scheduling over public holidays, if not specifically 
specified otherwise; 
5. 
Baseline scans can be completed within 28 days prior to registration. After baseline, radiological assessments (CT –chest/abdomen/pelvis or MRI – 
abdomen/pelvis) must be performed as outline in Table 7.1 (Every 8 weeks during the treatment phase). CT Chest must be performed at baseline. CT 
Chest during treatment will be performed if clinically indicated. A visit window of +/- 7 days is allowed. Once the patient has been discontinued from the 
study and enters the efficacy phase, radiological assessments (CT or MRI) will continue on the every 8 weeks schedule until progression or for the first 
12 months, whichever comes first. After a year, radiological (CT or MRI) assessments will be performed every 12 weeks until progression.  
6. 
AE/Conmeds will be assessed from consent until up to 30 days last dose of LEE001 or until resolution, whichever comes first. Conmeds will recorded up 
to30 day prior to consent; 
7. 
The biopsy performed during screening is for HCC diagnosis and RB positive status and must be performed for the subject to be eligible for the study. 
However, initial TACE can be performed following agreement of informed consent while RB proficiency is being determined. If patient is not RB proficient 
patient will be removed from the study as a screen failed and offered other treatment. If the patient has archival formalin fixed paraffin embedded tissue 
no additional baseline biopsy will be done. The post treatment biopsy is optional and for research purposes only (phase 2 only). If the subject consented 
to the research biopsy during the consent process, it will be performed during the 8th and 9th week of after initiating treatment of LEE011 and at least one 
chemoembolization. NOTE: LEE011 should be held for 24-48 hours prior to and after the second biopsy. These held doses will not be made up and 
noted on the patient’s diary. 
8. 
Biomarker blood collection is also an optional research procedure and the patient must have consented to the additional blood collection to participate 
(phase II only). Blood will be collected according to the schedule in table 7.1; 
9. 
Patients will be treated with LEE011 (3 weeks on / 1 week off of a 28 day cycle) until disease progression, unacceptable toxicity, death, or 
discontinuation from the study treatment due to any other reason. The patient will complete a subject dosing log in order to ensure drug compliance. The 
patient will be provided a new dosing diary at each new treatment cycle and reviewed at the end of each cycle for compliance.  
10. Patients will be treated with chemoembolization with up to 4 total chemoembolizations within the first 6 months from the initial chemoembolization. 
11. Patients who discontinue treatment for reasons other than disease progression, death, start of new anti-neoplastic therapies, lost to follow-up, or 
withdrawal of consent to efficacy follow-up, then tumor assessments and patient reported outcomes must continue to be performed every 8 weeks during 
the first 12 months and every 12 weeks thereafter until the start of new anti-cancer therapy, disease progression, death, lost to follow-up, or withdrawn 
consent to efficacy follow-up; 
12. All patients will be followed for survival status every 12 weeks regardless of treatment discontinuation until death, lost to follow-up, or withdrawal of 
consent to survival follow-up. Survival follow-up assessment may be made by a phone call to the patient or designated PHI, EPIC medical record review, 
or certified mail. At least 3 documented attempts should be made to contact the patient before the patient is considered lost to follow-up.  
13. The follow-up visit after chemoembolization can be used as day 1 visit of each cycle if the decision is made to continue with LEE011 treatments.  
 
 


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7.2 
SCREENING PHASE 
Assessments performed exclusively to determine eligibility for this study will be done 
only after obtaining informed consent. Assessments performed for clinical 
indications (not exclusively to determine study eligibility) may be used for 
baseline values even if the studies were done before informed consent was 
obtained. 
 
All screening procedures must be performed within 28 days prior to registration, 
unless otherwise stated. The screening procedures include the following: (See Table 
7.1 above for the list of assessments to be performed.) 
7.2.1 Informed Consent 
Patients must provide a signed inform consent form prior to any study specific 
evaluations including screening. Eligibility will be determined according to the 
inclusion/exclusion criteria as described in Section 5. A list of procedures to 
be performed at time of screening is summarized in Table 7.1. Patients must 
meet all eligibility criteria to be considered for enrollment in the study.  
7.2.2 Eligibility Checklist (Inclusion/Exclusion) 
In order to determine and confirm the eligibility of the patient, once all 
screening procedures are completed, an eligibility checklist must be 
completed by the research team prior to chemoembolization. 
7.2.3 Patient Demographics and other Baseline Characteristics 
The data that will be collected on patient characteristics at screening 
includes: 
• Demographic (name, date of birth, age), sex, race/ethnicity; 
• Diagnosis, RB status, and extent of cancer (staging) – tissue biopsy 
(required); 
• Pertinent Medical History; 
• Prior cancer treatment; 
• All medications taken within 30 days before first treatment. If there are 
any changes, medications are to be updated on a continual basis. 
 
Furthermore the following assessments will be performed: 
• Vital Signs (BP, HR, T, RR); 
• Adverse Events / Conmeds 
• Height and Weight; 
• Physical Examination (PE); 
• ECOG Performance Status (PS); 
• Laboratory Evaluations (chemistry, CBC, PT/INR, Lipid Panel, and UA) 
• ECG (in Triplicate – baseline only) 
• ECHO or MUGA; 


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• Radiological Assessments (RECIST 1.1) (CT - chest/abdomen/pelvis or 
MRI – abdomen/pelvis). Chest CT will be performed at baseline only. 
During the treatment phase, a Chest CT will be performed as clinically 
indicated; 
• 
Pregnancy Test (Women of Child-bearing Potential Only). 
7.2.4 Pre-Treatment - Biomarker Tissue Biopsy (Required) 
After signing the treatment and biopsy informed consent, the screening 
biopsy, confirming HCC diagnosis, staging, and (RB+) result, must be 
complete within 28 days prior to  registration unless the patient has archival 
formalin fixed paraffin embedded tissue to determine RB status. This biopsy 
is required to confirm patient eligibility. However, initial TACE procedure can 
be initiated prior to determination of RB status provided informed consent is 
signed and biopsy tissue is available for analysis. 
7.2.5 Biomarker / DNA Blood Collection (Optional – Phase II only) 
After signing the optional biomarker / DNA consent for future biomarker and 
DNA blood, samples will be collected at baseline, during treatment, and at the 
end of treatment or early-term visit. This procedure is for research and will not 
be used to make medical decisions regarding the patient’s treatment. 
7.3 
TREATMENT PHASE 
7.3.1 Study Treatment 
Patients will be treated with chemoembolization once every 4 weeks (or every 
28 Days), for a total of up to 4 chemoembolizations within the first 6 months.  
 
In addition, patients will be treated with 200, 400, or 600 mg LEE011 once 
daily by mouth (3 Weeks on / 1 Week off in a 28 day cycle) until disease 
progression, unacceptable toxicity, death, or discontinuation from the study 
treatment due to any other reason. For details of assessment, refer to Table 
7.1. 
7.3.2 Post-Treatment – Biomarker Tissue Biopsy (Optional – Phase II only) 
The post treatment biopsy is optional and the patient must have consented to 
this second procedure during the initial consenting process. The second 
biopsy, for research purposes only, will be performed between Weeks 8 and 
9 post initial treatment of LEE011. To qualify for the second biopsy, patients 
must have taken LEE011 for 21 consecutive days (21 days on treatment / 7 
days off in a 28 day cycle) and had at least one chemoembolization. 
7.3.3 Additional Treatment Phase Assessments will be performed: 
• Vital Signs (BP, HR, T, RR); 
• Adverse Events / Conmeds 
• Weight; 


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• Physical Examination (PE); 
• ECOG Performance Status (PS); 
• Laboratory Evaluations (chemistry, CBC, PT/INR, and Lipid Panel); 
• ECG; 
• Radiological Assessments (RECIST 1.1) (CT - chest/abdomen/pelvis 
or MRI – abdomen/pelvis). During the treatment phase, a Chest CT 
will be performed as clinically indicated; 
7.4 
POST – TREATMENT FOLLOW-UP PHASE 
7.4.1 End of Treatment and Early Withdrawal Visit 
Patients who completely discontinue study treatment should be scheduled for 
an End of Treatment (EOT) visit within 15 days following the last dose date of 
LEE011, at which time all of the assessments listed for the EOT visit will be 
performed. For details of the assessment, see Table 7-1.  
 
At a minimum, all patients who discontinue study treatment, including those 
who refuse to return for a final visit, will be contacted for AE evaluations 
during the 30 days following the last dose date of LEE011. 
7.4.1.1 Criteria for Early Withdrawal 
Patients may voluntarily withdraw from the study treatment or be 
dropped from it at the discretion of the investigator at any time. 
Patients may be withdrawn from the study treatment if any of the 
following occur: 
• Adverse event 
• Lost to follow-up 
• Physician decision 
• Progressive disease 
• Protocol deviation 
• Study terminated by the sponsor 
• Technical problems 
7.4.2 Safety Follow-Up 
All patients will be followed up for safety up to 30 days after last dose of study 
drug (LEE011) treatment. Patients whose treatment is interrupted or 
permanently discontinued due to an AE, including abnormal laboratory value, 
must be followed until resolution or stabilization of the event, whichever 
comes first. 
7.4.3 Efficacy Follow-Up 
Patients who discontinue treatment for reasons other than disease 
progression, death, start of new anti-neoplastic therapies, lost to follow-up, or 
withdrawal of consent -- Tumor Assessments and scans (CT or MRI) (See 
Section 8) must continue to be performed every 8 weeks during the first 12 


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months, then thereafter, every 3 months (every 12 Weeks) until the start of 
new anti-cancer therapy, disease progression, death, lost to follow-up, or 
withdrawn of consent. 
7.5 
SURVIVAL PHASE 
7.5.1 Survival Follow-Up 
All patients will be followed for survival status every 12 weeks, starting from 
the Safety Follow-Up visit, regardless of treatment discontinuation, until 
death, lost to follow-up, or withdrawal of consent to survival follow-up.  
 
Survival follow-up assessment may be made by a phone call to the patient or 
designated PHI, EPIC medical record review, or certified mail. At least 3 
documented attempts should be made to contact the patient before the 
patient is considered lost to follow-up. 
8.0 
MEASUREMENT OF EFFECT 
For the purposes of this study, patients will be evaluated for progression every 8 weeks for 
the first 12 months, then every 12 weeks (3 months) thereafter following the initial 
chemoembolization. Imaging will consist of a CT or MRI abdomen with liver protocol. The 
same imaging modality used at baseline will be used for further scans unless documented 
by primary investigator.  CT Chest or additional imaging will be at the discretion of the 
investigator based on clinical suspicion of additional progressive disease. 
8.1 
ANTITUMOR EFFECT- SOLID TUMORS 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [JNCI 92(3):205-216, 2000].  Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST criteria. 
Note:  Lesions are either measurable or non-measurable using the criteria provided 
below. The term “evaluable” in reference to measurability will not be used because it 
does not provide additional meaning or accuracy. 
8.1.1 Disease Parameters 
Measurable Disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 20 mm with conventional techniques (CT, MRI, x-ray) or as ≥ 
10 mm with spiral CT scan. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). A “high-resolution” CT scan 
is one in which images are recorded at least every 5 mm. 
 
Non-Measurable Disease. All other lesions (or sites of disease), including 
small lesions (longest diameter <20 mm with conventional techniques or <10 
mm using spiral CT scan), are considered non-measurable disease. Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 


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lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses 
(not followed by CT or MRI), and cystic lesions are all non-measurable. 
 
Target Lesions. All measurable lesions up to a maximum of 5 lesions per 
organ and 10 lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). A sum of the longest diameter (LD) for all 
target lesions will be calculated and reported as the baseline sum LD. The 
baseline sum LD will be used as reference by which to characterize the 
objective tumor response. 
 
Non-Target Lesions. All other lesions (or sites of disease) that are not target 
lesions, as defined in the section above, will be identified as non-target 
lesions and should also be recorded at baseline. Non-target lesions include 
measurable lesions that exceed the maximum numbers per organ or total of 
all involved organs as well as non-measurable lesions. Measurements of 
these lesions are required when feasible, since a patient may have 
progressive disease on the basis of larger non-target lesions. The presence 
or absence of each non-target lesion should be noted throughout follow-up. 
8.1.2 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a 
ruler or calipers. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 28 days before 
the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-
up. Imaging-based evaluation is preferred to evaluation by clinical 
examination when both methods have been used to assess the antitumor 
effect of a treatment. 
8.1.3 Response Criteria 
8.1.3.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the 
baseline sum LD. There can be no appearance of new lesions. 


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Progressive Disease (PD): At least a 20% increase in the sum of the 
LD of target lesions, taking as reference the smallest sum LD 
recorded since the treatment started, or the appearance of one or 
more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started. 
8.1.3.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions 
and normalization of tumor marker level. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or 
more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions 
8.1.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the 
start of the treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient’s best response 
assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
 
Target 
Lesions 
Non-
Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best 
Response 
for this 
Category 
Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non-
CR/Non-
PD 
No 
PR 
 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented 
at least once 
>4 wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
 


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Any 
PD* 
Yes or No 
PD 
no prior SD, 
PR or CR 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-
target lesions may be accepted as disease progression. 
 
Note: Subjects with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to 
document the objective progression even after discontinuation 
of treatment. 
 
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 
8.1.4 Duration of Response 
Duration of overall response: The duration of overall response is measured 
from the time measurement criteria are met for CR or PR (whichever is first 
recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria 
are first met for CR until the first date that recurrent disease is objectively 
documented.  
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
8.1.5 Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression. 
8.2 
SAFETY/TOLERABILITY 
 
Analyses will be performed for all subjects having received at least one dose of study 
drug. The study will use the CTCAE version 4.03 for reporting of non-hematologic 
adverse events (http://ctep.cancer.gov/reporting/ctc.html) and modified criteria for 
hematologic adverse events (Appendix #/letter). 
9.0 
ADVERSE EVENTS 
9.1 
LEE001 TREATMENT RELATED EVENTS 
The following grade 3 and 4 AEs are suspected to be related to LEE011 treatment 
for reporting purposes: 


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• 
Anemia, febrile neutropenia, leukopenia, lymphopenia, neutropenia, 
thrombocytopenia; 
• 
Electrocardiogram QT prolonged, hypertension; 
• 
Diarrhea, nausea, vomiting, stomatitis, mucositis; abdominal pain; 
• 
Pneumonia 
• 
Asthenia/fatigue; decreased appetite 
• 
Hepatocellular injury; Hepatic function abnormalities (elevated transaminases); 
elevated creatinine 
• 
Rash; 
• 
Hyponatremia 
9.2 
CHEMOEMBOLIZATION TREATMENT RELATED EVENTS 
The following events are considered to be expected for reporting purposes following 
chemoembolization: 
• 
Abdominal pain; 
• 
Fever; 
• 
Fatigue; 
• 
Nausea; 
• 
Elevated liver enzymes; 
• 
Infection; 
• 
Cholecystitis; 
• 
Hemorrhage; 
• 
Thromboembolic events; 
• 
Alopecia; 
• 
Hyperpigmentation; 
• 
Mucositis; 
• 
Hepatocellular injury; hepatic function abnormalities (elevated transaminases) 
9.3 
ADVERSE EVENT MONITORING 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of subjects enrolled in the studies as well 
as those who will enroll in future studies using similar agents. Adverse events are 
reported in a routine manner at scheduled times during a trial. Additionally, certain 
adverse events must be reported in an expedited manner to allow for optimal 
monitoring of subject safety and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study 
drug, will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the 
adverse event return to baseline;  
 any abnormal laboratory values have returned to baseline;  


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 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 
 
9.3.1 Definition  
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, 
abnormal physical exam or laboratory finding), symptom, clinical event, or disease, 
temporarily associated with the subject’s participation in the research, whether or not 
it is considered related to the subject’s participation in the research. 
 
Adverse events encompass clinical, physical and psychological harms. Adverse 
events occur most commonly in the context of biomedical research, although on 
occasion, they can occur in the context of social and behavioral research. Adverse 
events may be expected or unexpected. 
 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) and version number 
specified in the protocol. Adverse events not specifically defined in the NCI CTCAE 
will be scored on the Adverse Event log according to the general guidelines provided 
by the NCI CTCAE and as outlined below.   
 
• Grade 1: Mild;  
• Grade 2: Moderate; 
• Grade 3: Severe or medically significant but not immediately life threatening; 
• Grade 4: Life threatening consequences; 
• Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those 
events, occurring at any dose, which meets any of the following criteria:  
 
• Results in death;   
• Immediately life-threatening;  
• Results in inpatient hospitalization or prolongation of existing hospitalization;  
• Results in persistent or significant disability/incapacity;  
• Results in a congenital anomaly/birth defect;  
• Based upon appropriate medical judgment, may jeopardize the subject’s 
health and may require medical or surgical intervention to prevent one of the 
other outcomes listed in this definition. 
 
Note: A “Serious adverse event” is by definition an event that meets any of the above 


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criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 
adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring overnight hospitalization would be a serious adverse event for any 
research participant; likewise, in a study investigating end-stage cancer care, any 
hospitalization or death would be a serious adverse event, even if the event 
observed is a primary clinical endpoint of the study.  
 
Refer to the UTSW IRB website at 
http://www.utsouthwestern.net/intranet/research/research-administration/irb/study-
management/adverse-events.html to determine when a serious adverse event 
requires reporting to the IRB. 
 
9.3.2 Unanticipated Problems: 
The term “unanticipated problem” is found, but not defined in the regulations for the 
Protection of Human Subjects at 45 CFR 46, and the FDA regulations at 21 CFR 56. 
Guidance from the regulatory agencies considers unanticipated problems to include 
any incident, experience, or outcome that meets each of the following criteria: 
 
• 
Unexpected (in terms of nature, severity or frequency); 
 
AND 
 
• 
Definitely, probably, or possibly related to participation in the research; 
 
 AND  
 
• 
Serious or a possible unexpected problem in that the research places subjects or 
others at greater risk of harm than was previously known or recognized. Note: 
Any serious adverse event would always suggest a greater risk of harm. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
9.3.3 Reporting 
 
Local unanticipated problems require expedited reporting, and are submitted to the 
UTSW IRB through the UTSW eIRB and to the SCC DSMC Coordinator.  
Hardcopies or electronic versions of the eIRB report; FDA Form #3500A forms, or 
other sponsor forms, if applicable; and/or any other supporting documentation 


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available should be forwarded to the DSMC Coordinator.  The DSMC Coordinator 
forwards the information onto the DSMC Chairman who determines if immediate 
action is required.  Follow-up eIRB reports, and all subsequent SAE documentation 
that is available are also submitted to the DSMC Chair who determines if further 
action is required. (See Appendix IV of the SCC DSMC Plan for a template Serious 
Adverse Event Form which may be utilized when a sponsor form is unavailable and 
SAE submission to the eIRB in not required). 
  
All local serious adverse events which occur on research subjects on protocols for 
which the SCC is the DSMC of record require reporting to the DSMC regardless of 
whether IRB reporting is required. Hardcopies or electronic versions of the FDA 
Form #3500A forms, or other sponsor forms, if applicable; and/or any other 
supporting documentation available should be forwarded to the DSMC Coordinator.   
 
If the event occurs on a multi-institutional clinical trial coordinated by the Cancer 
Center, the Disease Oriented Team (DOT) Manager or lead coordinator ensures that 
all participating sites are notified of the event and resulting action, according to FDA 
guidance for expedited reporting. DSMC Chairperson reviews all serious adverse 
events within upon receipt from the DSMC Coordinator.  The DSMC Chairperson 
determines whether action is required and either takes action immediately, convenes 
a special DSMC session (physical or electronic), or defers the action until a regularly 
scheduled DSMC meeting.  
 
  
Written reports to: 
 
Muhammad Shaalan Beg, MD 
c/o   
QA Coordinator 
5323 Harry Hines Blvd, NB2.418 
Dallas, Texas 75390 
Phone: 214-648-5919 
Fax: 214-648-1875 
Email: silvia.pilarski@utsouthwestern.edu 
 
UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation. 
 
 


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1. SAEs 
Local serious adverse events (SAEs) for studies where SCC DSMC is the DSMC of 
record require reporting to the DSMC coordinator within 2 working days of PI 
awareness, or as described in the protocol.   
2. Unanticipated Problems  
Local unanticipated problems require reporting to the UTSW IRB within 2 working 
days of PI awareness of the event.   
Unanticipated problems, including those that occur as non-local events, require 
reporting to the UTSW IRB within 10 working days of PI awareness of the event. 
For further guidance for Investigators regarding safety reporting requirements for 
INDs and BA/BE studies, refer to FDA Draft Guidance document: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gu
idances/UCM227351.pdf 
9.4 
STOPPING RULES 
There is no interim analysis planned. 
 
Simmons Cancer Center Data and Safety Monitoring Board (DSMB) will oversee this 
study and will determine if early stoppage of the trial is needed due to unacceptable 
rates of drug related serious adverse events. 
 
To assess for aggregate severe hepatobiliary toxicity and severe events that occur at 
any time during the study, if 2 total grade 5 or 2 grade 4 adverse events (lasting ≥ 7 
days) occur while at patient is receiving study treatment and the adverse events are 
attributed to either being definitely, probably, or possible related to the study 
treatment then the study will terminate with no further patients entered. 
9.5 
STEPS TO DETERMINE IF AN ADVERSE EVENT REQUIRES EXPEDITED 
REPORTING 
Step 1: Identify the type of adverse event using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE v. 4.03).  
 
Step 2: Grade the adverse event using the NCI CTCAE v. 4.03. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is unlikely related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 


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Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment 
and is attributed (possibly, probably, or definitely) to the agent(s) must also be 
reported accordingly. 
 
Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for 
expedited reporting purposes only, when either the type of event or the severity of 
the event is not listed in: 
• 
the current known adverse events listed in the Agent Information Section of 
this protocol; 
• 
the drug package insert; 
• 
the current Investigator’s Brochure 
10.0 
SAFETY AND TOLERABILITY ASSESSMENTS 
Safety will be monitored by assessing physical examinations, ECOG performance status, 
height and weight, vital signs, ECG, patient reported outcomes, laboratory assessments 
including hematology, chemistry, cholesterol and lipid panel, PT, INR, and urine as well as 
collecting adverse events at every visit. For details on AE collection and reporting, refer to 
Section 9. 
10.1 
PHYSICAL EXAMINATION, VITAL SIGNS, HEIGHT AND WEIGHT 
A total body examination, vital signs, height and weight should be performed 
according to the visit schedule as outline in Table 7.1. 
10.2 
ECOG PERFORMANCE STATUS (PS) 
The performance status will be assessed according to the ECOG performance status 
scale following the schedule in Table 7.1. See Appendix A. 
10.3 
LABORATORY ASSESSMENTS 
Hematology, chemistry, coagulation, urinalysis, and cholesterol panels are to be 
performed according to the visit schedule outlined in Table 7.1 and 10.1. 
 
Table: 10.1: Clinical Laboratory Parameters Collection Plan 
Test Category 
Test Name 
Hematology 
Hemoglobin, Platelets, white blood 
cells with differential (neutrophils, 
lymphocytes, basophils, 
eosinophils, monocytes) 
Chemistry 
Albumin, alkaline phosphatase, 
ALT, AST, creatinine, potassium, 
sodium, glucose, direct bilirubin, 


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total bilirubin, total protein, 
magnesium, phosphorus 
Cholesterol and Lipid Panel 
Total cholesterol, LDL, HDL, 
triglycerides 
Coagulation 
PT, INR 
Urinalysis 
Glucose, protein, bilirubin, red 
blood cells, white blood cells, 
crystals, and bacteria. 
 
11.0 
CORRELATIVES STUDIES 
Pathology Correlative Studies 
 A major obstacle to molecularly targeted chemotherapeutic agents has been obtaining 
relevant tumor tissue to measure the agents’ biologic effects on target molecules or cellular 
pathways within the tumor.  The utilization of sequential tumor biopsies to obtain tissue 
following treatment is well established in breast and colorectal carcinoma. (17) However, 
sequential tumor biopsies of liver tumors are less established due to a fear of procedural 
complications.  The fear of bleeding events following liver biopsy of HCC appears 
unfounded and based on anecdotal evidence.  A large, multi-institutional trial where patients 
with advanced chronic Hepatitis C underwent sequential liver biopsies demonstrated 16 
cases (0.6%) of bleeding following 2740 liver biopsies. There were no deaths from peri-
procedural bleeding and a platelet count under 60000 was identified as a risk factor. (18) 
Two large published series of core needle biopsy of HCC as a diagnostic measure report 
bleeding events in less than 1% of patients with no reported mortalities. In both series 
capsular location of HCC was associated with increased incidence of bleeding event. (19, 
20) In this study all patients will potentially undergo up to two image-guided (either CT or 
Ultrasound) core needle biopsy of a single site of HCC at baseline (for clinical care) and 
between eight and nine weeks after the initiation of LEE011 (research only). The biopsy 
between eight and nine weeks following LEE011 initiation is not mandatory to initiate or 
continue with therapy and is subject to a separate informed consent.  The baseline biopsy is 
needed to confirm HCC and RB positivity as an eligibility criterion.  If archival formalin fixed 
paraffin embedded tissue is available for RB status analysis, a pre-treatment biopsy will not 
be required.To increase patient safety the following conditions must be met prior to liver 
biopsy: 
• 
Platelet count ≥ 70,000 
• 
INR ≤ 1.8 
• 
Target lesion not subcapsular in nature as determined by the participating 
interventional radiology team 
• 
LEE011 will be discontinued for a period of 24-48 hours prior to biopsy 
 


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There is no evidence that an image-guided liver biopsy following TACE increases risk of 
bleeding or tumor seeding. Due to the consideration that TACE is not considered a curative 
procedure and viable tumor tissue remains after an initial biopsy it is anticipated that enough 
tumor tissue will be available for the planned studies. (21) 
The patient will sign the informed consent for participation in research liver biopsy prior to 
the procedure. The liver biopsy will be performed by radiologists and the ancillary staff of 
Department of Radiology following the standard clinical protocol, which includes obtaining a 
separate informed consent for the procedure itself.  The core samples will be provided to the 
Department of Pathology for histological and RB status confirmation in addition to the 
pathology laboratory. If a core biopsy is performed as a part of the patient’s clinical care, 
extra cores will be obtained for surgical oncology laboratory, in addition to the cores 
necessary for clinical care.  All cores will be obtained through the same needle to avoid the 
need of additional punctures and to minimize associated risks. 
Tumor tissue will be used for several specific purposes.  Pre-treatment biopsies will be used 
to evaluate potential markers of durable response, in addition to staining for p16inkin4a and 
RB.   This will include the analysis of phospho-RB, Cyclin D1, Cyclin E1, Cyclin E2, and 
p27Kip1 by immunohistochemistry. These proteins have been functionally associated with 
the response to CDK4/6 inhibitors.  We will also assess baseline features of tumor 
proliferation by Ki67 and phospho-histone H3 staining and cleaved caspase 3 as a marker 
of tumor cell death.  In parallel, if there is sufficient material we will employ RNA sequencing 
to delineate baseline features of tumor tissue. The molecular features of the tumor from 
RNA sequencing will be analyzed for association with PFS and other clinical features of 
disease to explore markers of response. We will use the post-treatment biopsies to 
determine the effect of LEE011 on tumor markers discussed above and by RNA 
sequencing.  These studies will enable us to evaluate whether LEE011 is acting upon its 
targets in the tumor and to infer response markers with clinical outcome. 
Plasma and serum samples (2 x 5 mL red tops and 2 x 6mL lavender tops) will also be 
collected at baseline and at the beginning of every cycle following initiation of LEE011. The 
blood samples will be used to measure circulating tumor DNA or other features of tumor 
burden that can be correlated with disease response. Storage and processing of the blood 
samples will be at the discretion of the pathology laboratory. 
12.0 
STATISTICAL CONSIDERATIONS 
12.1 
STUDY DESIGN/STUDY ENDPOINTS 
The study is an open-label, non-randomized single-arm, single institution phase Ib/II 
therapeutic clinical trial.  The study population will be patients with advanced hepatocellular 
carcinoma. 
 
The phase Ib component of the study will consist of a traditional 3+3 dose escalation rule 
with 3 or 6 patients in each cohort, the process for dose escalation is outline in section 6.4. 
 
 
The primary endpoint of the phase II component will be progression free survival (PFS) of 


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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 alone is 8-10 months. Our 
institutional median PFS following the TACE protocol outlined is 8.0 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 40 patients 
with the median PFS for TACE 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. Forty total patients will be enrolled in the phase 
II aspect of the trial. This includes only patients who undergo chemoembolization and initiate 
LEE011 therapy. 
 
Secondary endpoints of efficacy are to evaluate OS. 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# 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. 
 
Laboratory assessments will also be described according to the NCI CTCAE v. 4.03 criteria, 
with separate descriptions for Grade 3 or 4 laboratory abnormalities.  Clinically significant 
laboratory abnormalities will be described as well. Serious adverse events will be 
summarized, including a causality assessment.   
The number of treatment cycles and doses administered will be summarized using 
descriptive statistics. Treatment delays will be summarized using counts and percentages.  
 
Patients’ disposition will be summarized in the following manner: 
 
• The number and percentage of patients selected, included, completed, 
withdrawn and lost to follow-up will be summarized using descriptive 
statistics; 
• Major protocol deviations will be summarized; 
• The reason for withdrawal (adverse events, lack of efficacy, major protocol 
deviation, non-medical reason, recovery or remission) will be summarized. 
 
For pathology-, laboratory- and imaging-correlative studies, Cox regression analysis will be 


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conducted to investigate the association between PFS and parameters from correlative 
studies. 
 
Approximately 175-200 patients with HCC are seen annually at UT Southwestern Medical 
Center with 80-90 chemoembolizations performed.  We anticipate no potential problems 
meeting the accrual deadlines with the proposed trial.  In addition, there are no competing 
trials either nationally or at UT Southwestern for this patient population that would potential 
limit accrual. 
13.0 
STUDY MANAGEMENT 
13.1 
CONFLICT OF INTEREST 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy on 
Conflicts of Interest. All investigators will follow the University conflict of interest policy. 
13.2 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL AND CONSENT 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations. The IRB must approve the consent 
form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with 
the applicable regulatory requirement(s), and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration of 
Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the 
FDA Regulations and local or state regulations. Once this essential information has 
been provided to the subject and the investigator is assured that the subject 
understands the implications of participating in the study, the subject will be asked to 
give consent to participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should 
be signed and personally dated by the subject  and by the person who conducted the 
informed consent discussion. 
14.0 
RECRUITMENT AND REGISTRATION PROCEDURES 
14.1 
RECRUITMENT PLAN 
The study will be open to all patients seen at the UT Southwestern Medical Center 
(including Parkland Health & Hospital System, University Hospital-Clements and 


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Zale, and the Harold C. Simmons Cancer Center) who meet the eligibility criteria 
outlined in Section 5.0. 
 
In addition, a description of the study and the enrollment criteria will placed on the 
UT Southwestern Medical Center website to maximize patient recruitment. Patients 
will be identified from surgical, hepatology, gastroenterology, radiology and medical 
oncology clinics for treatment of their disease.  After a discussion of the patient’s 
disease and a formulation of the initial treatment plan, the physician-investigator will 
describe the study to the patient.  The protocol will be discussed in a private clinic 
room or office.  Details including the risks and obligations of the subjects will be 
explained.  For non-English speaking patients, an independent translator will be 
available to communicate the details of the protocol.  A research coordinator will be 
available either in the clinic or by phone to answer any additional questions.  
 
Upon completion of the informed consent form and confirmation of protocol eligibility, 
the Clinical Research Office (CRO) at the Harold C. Simmons Cancer Center will be 
notified of the new enrollment.  All patients will be entered into the Velos Clinical 
Trials Management System for ongoing monitoring. All data collected will be entered 
into the password protected REDCap electronic data capture system. 
 
The investigators take due notice of the NIH policy concerning inclusion of women 
and minorities in clinical research populations.  There will be no limitation to access 
with regard to race or gender.  Patients will be required to read, agree to and sign an 
IRB-approved informed consent form prior to registration on this trial.  The 
registration procedure will be conducted as described above.  Patients will not 
receive payment for their participation on this study.  
14.2 
STUDY SUBJECT IDENTIFICATION NUMBER 
All subjects will be assigned a study number that is not linked to their personal 
identifiers to prevent loss of confidentiality. The number will be the Site 
Number, 01, 02, etc. followed by a sequential number starting with number 
001. For example, the first subject enrolled from site # 01 will be assigned 
study subject number 01-001; the next will be 01-002, and so forth. For this 
protocol, current sites are: 01 – UTSW and 02 – PHHS. Any additional sites 
added to this protocol will be numbered sequentially…03, 04, etc. This 
number will be assigned by the UTSW - Clinical Research Manager or QA 
Coordinator  or delegate upon confirmation of subject eligibility during the 
subject registration process.  
14.3 
SUBJECT REGISTRATION 
Following completion of baseline assessments and confirmation of subject 
eligibility, patients will be assigned a subject identification number by the 
UTSW - CRM or delegate and registered into Velos, the UTSW Clinical Trial 
Management System (CTMS). Subject registration will be confirmed (within 


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24 hours) once the following documents have been received by the UTSW-
CRM or delegate.  
 
• Signed copy of the Informed Consent signature page; 
• Inclusion/Exclusion worksheet signed by the coordinator and treating 
physician; 
 
All subjects must be registered with the UTSW - CRM before enrollment to study. To 
register a subject, email the above supporting documents to the UTSW – QA 
Coordinatorsilvia.pilarski@utsouthwestern.edu or call 214-648-5919, Monday 
through Friday, 8:00a.m. - 4:00p.m. CST. 
15.0 
PROTECTION OF HUMAN SUBJECTS 
Participation in this trial is voluntary.  All patients will be required to sign a statement of 
informed consent, which must conform to IRB guidelines. 
 
 
Inclusion of Women and Minorities:  Patients of all races, both male and female, will be 
accepted into the protocol. 
 
Exclusion of Lactating or Pregnant Women:  Children have been excluded from this study.  
Hepatocellular carcinoma is an adult cancer.  Thus, the relevance of this drug to the 
pediatric population has not been established.  Lactating and pregnant women are also 
excluded because of potential anti-proliferative effects of therapy that may be harmful to the 
developing fetus or nursing infant. 
 
Benefits:  It is possible that this treatment will result in shrinkage of hepatocellular carcinoma 
or in a stabilization of an otherwise progressing disease.  It is not known, of course, whether 
these or any other favorable events will occur.  It is not known whether this treatment will 
affect overall survival of the patients. 
 
Costs:  The patient will be responsible for the costs of standard medical care, including, all 
hospitalizations, even for complications of treatment.  LEE011 will be supplied to patients 
without costs from Novartis Pharmaceuticals.  Patients will not be responsible for the costs 
of tissue or serum procurement (including image guided biopsies) obtained for research 
purposes. 
 
Incentives:  No incentives will be offered to patients/subjects for participation in this study. 
 
Alternatives:  For patients with advanced hepatocellular carcinoma, alternative treatments 
may include other chemotherapy regimens or loco-regional therapies including transarterial 
chemoembolization and radiofrequency ablation.  At present, no specific treatment approach 
is considered standard of care for the disease.  Patients may be eligible for other 
investigational studies. 
 


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Confidentiality:  Every effort will be made to maintain patient confidentiality.  Research and 
hospital records are confidential.  Patient’s name or any personally identifying information 
will not be used in reports or publications resulting from this study.  The Food and Drug 
Administration or other authorized agencies (i.e., qualified monitors from UT Southwestern 
Medical Center, the NCI, etc.), may review patients records and pathology slides, as 
required. 
16.0 
DATA AND SAFETY MONITORING PLAN 
Trial monitoring will be conducted no less than annually and refers to a regular interval 
review of trial related activity and documentation performed by the DOT, which includes but 
is not limited to accuracy of case report forms, protocol compliance, timeless and accuracy 
of Velos entries and AE/SAE management and reporting. Documentation of trial monitoring 
will be maintained along with other protocol related documents and will be reviewed during 
internal audit.   
 
Study PI or designated Co-investigator and the research coordinator will attend the weekly 
Phase I research meeting during the dose escalation phase. Toxicity and dose escalation 
reviews will be performed in real-time by the Phase I DOT and DSMC.  As the study 
transitions to the Phase II stage, toxicity will be reviewed at the GI DOT research meetings 
and by DSMC. These reviews will be documented by distributing reports of the findings to 
the members of the GI DOT and investigators. 
 
The UTSW Simmons Cancer Center (SCC) Data Safety Monitoring Committee (DSMC) is 
responsible for monitoring data quality and patient safety for all UTSW SCC clinical trials.  
As part of that responsibility, the DSMC reviews all local serious adverse events and 
unanticipated problems in real time as they are reported and reviews adverse events on a 
quarterly basis. The quality assurance activity for the Clinical Research Office provides for 
periodic auditing of clinical research documents to ensure data integrity and regulatory 
compliance.  A copy of the DSMC plan is available upon request. 
The SCC DSMC meets quarterly and conducts annual comprehensive reviews of ongoing 
clinical trials, for which it serves as the DSMC of record. The QAC works as part of the 
DSMC to conduct regular audits based on the level of risk. Audit findings are reviewed at the 
next available DSMC meeting.  In this way, frequency of DSMC monitoring is dependent 
upon the level of risk.  Risk level is determined by the DSMC Chairman and a number of 
factors such as the phase of the study; the type of investigational agent, device or 
intervention being studied; and monitoring required to ensure the safety of study subjects 
based on the associated risks of the study. Protocol-specific DSMC plans must be 
consistent with these principles. Safety is monitored in real-time as serious adverse events 
and adverse events, which are unanticipated problems, are submitted to the DSMC and IRB 
with attributions. 
17.0 
ADHERENCE TO THE PROTOCOL 


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Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study subject requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol.  
17.1 
EMERGENCY MODIFICATIONS 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, an IRB modification form must 
be completed within five (5) business days of making the change. 
17.2 
OTHER PROTOCOL DEVIATIONS/VIOLATIONS 
All other planned deviations from the protocol must have prior approval by the 
Principal Investigator and the IRB. According to the IRB, a protocol deviation is any 
unplanned variance from an IRB approved protocol that:  
• 
Is generally noted or recognized after it occurs 
• 
Has no substantive effect on the risks to research participants 
• 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected  
• 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
• 
Has harmed or increased the risk of harm to one or more research participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal Investigator, 
please follow the guidelines below: 
 
If {non-Research Office} managed study, please maintain the following language in 
your protocol: 
 
Protocol Deviations: Personnel will report to any sponsor or data and safety 
monitoring committee in accordance with their policies. Deviations should be 
summarized and reported to the IRB at the time of continuing review. 
 
Protocol Violations: Study personnel should report violations within two (2) week of 
the investigator becoming aware of the event using the same IRB online mechanism 
used to report Unanticipated Problems.  


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17.3 
AMENDMENTS TO THE PROTOCOL 
Should amendments to the protocol be required, the amendments will be originated 
and documented by the Principal Investigator.  A summary of changes document 
outlining proposed changes as well as rationale for changes, when appropriate, is 
highly recommended.  When an amendment to the protocol substantially alters the 
study design or the potential risk to the patient, a revised consent form might be 
required.  
 
The written amendment, and if required the amended consent form, must be sent to 
the IRB for approval prior to implementation.  
17.4 
RECORD RETENTION 
Study documentation includes all Case Report Forms, data correction forms or 
queries, source documents, Sponsor-Investigator correspondence, monitoring 
logs/letters, and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction 
of the clinical research study. 
 
Government agency regulations and directives require that the study investigator 
retain all study documentation pertaining to the conduct of a clinical trial. In the case 
of a study with a drug seeking regulatory approval and marketing, these documents 
shall be retained for at least two years after the last approval of marketing application 
in an International Conference on Harmonization (ICH) region. In all other cases, 
study documents should be kept on file until three years after the completion and 
final study report of this investigational study. 
17.5 
OBLIGATIONS OF INVESTIGATORS 
The Principal Investigator is responsible for the conduct of the clinical trial at the site 
in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki. The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients. The Principal Investigator must assure 
that all study site personnel, including sub-investigators and other study staff 
members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring 
that all the required data will be collected and entered onto the Case Report Forms. 
Periodically, monitoring visits may be conducted and the Principal Investigator will 
provide access to his/her original records to permit verification of proper entry of 
data. At the completion of the study, all case report forms will be reviewed by the 


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Principal Investigator and will require his/her final signature to verify the accuracy of 
the data. 


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18.0 
REFERENCES 
1. Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden: Globocan 
2000. Int J Cancer 2001; 94(2):153-6. 
 
2. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, 
mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 
2009; 27(9):1485-91. 
 
3. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United 
States. N Engl J Med 1999; 340(10):745-50. 
 
4. Benson AB, D’Angelica MI, Abrams TA, et al. Hepatobiliary Cancers. NCCN 
Guidelines 2.2015. 
 
5. Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation 
versus symptomatic treatment in patients with unresectable hepatocellular 
carcinoma: a randomised controlled trial. Lancet 2002; 359(9319):1734-9. 
 
6. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol 
chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 
35(5):1164-71. 
 
7. Bruix J, Sherman M, American Association for the Study of Liver D: Management of 
hepatocellular carcinoma: an update. Hepatology 53:1020-2, 2011 
 
8. Lencioni R, Llovet JM, Han G, et al. Sorafenib or placebo in combination with 
transarterial chemoembolization (TACE) with doxorubicin eluting beads (DEBOX) for 
intermediate stage hepatocellular carcinoma: Phase II, randomized double-blind 
SPACE trial. J Clin Onc 2012; 30 (supple4;abstr LBA 154). 
 
9. Kudo M, Han G, Finn RS, et al. Brivanib as adjuvant therapy to transarterial 
chemoembolization in patients with hepatocellular carcinoma: a randomized phase III 
trial. Hepatology 2014;60:1697-1707. 
 
10. Ortega S, Malumbres M, Baracid M. Cyclin D-dependent kinases, INK4 inhibitors 
and cancer. Biochimica et Biophysica Acta-Reviews on Cancer 2002;1602:73-87. 
 
11. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES.   The history and future of 
targeting cyclin-dependent kinases in cancer therapy.  Nat Rev Drug Discov. 2015 
Feb;14(2):130-46. 
 
12. Rivadeneira DB, Mayhew CN, Thangavel C, Sotillo E, Reed CA, Graña X, Knudsen 
ES.   Proliferative suppression by CDK4/6 inhibition: complex function of the 
retinoblastoma pathway in liver tissue and hepatoma cells.Gastroenterology. 2010 
May;138(5):1920-30. 
 
13. Borg A, Zhang QX, Alm P, et al. The retinoblastoms gene in breast cancer: allele 
loss is not correlated with loss of gene protein expression Cancer Res1992;52:2991-
4. 


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14. Kim YB, Park YN, Park C. Increased proliferation activities of vascular endothelial 
cells and tumor cells in residual hepatocellular carcinoma following transcatheter 
arterial embolization. Histopathology 200;38:160-166. 
 
15. Farris AB 3rd, Dursun N, Dhanasekaran R, et al. Tumoral and angiogenesis factors 
in hepatocellular carcinoma after locoregional therapy. Pathol Res Pract 2012 208: 
15-21. 
 
16. Littman SJ, Brus C, Burkhart A. A phase II study of PD-0332991 in adults patients 
with advanced hepatocellular carcinoma. J Clin Onc 2015 (suppl 3, abstract 277). 
 
17. Dowlati A, Haaga J, Remick SC, et al. Sequential tumor biopsies in early phase 
clinical trial of anticancer agents for pharmacodynamic evaluation. Cancer Res 
2001;7(10);2971-6. 
 
18. Seeff LB, Everson GT, Morgan TR, et al. Complication rate of percutaneous liver 
biopsies among persons with advanced chronic liver disease in the HALT-C trial. Am 
J Gastro doi:10.1016lj.cgh.2010.03.025. 
 
19. Giorgio A, Tarantino L, de Stefano, et al. Complications after interventional 
sonography of focal liver lesions: a 22-year single-center experience. J Ultrasound 
Med 2003;22:193-205. 
 
20. Caturelli E, Solmi L, Anti M, et al. Ultrasound guided fine needle biopsy of early 
hepatocellular carcinoma complicating liver cirrhosis: a multicentre study. Gut 
2004;53:1356-62. 
 
 
 
 
 


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19.0 
APPENDICES 
 
In general, the use of any concomitant medication deemed necessary for the care of the 
patient is permitted in this study, except as specifically prohibited below. Combination 
administration of study drugs could result in drug-drug interactions (DDI) that could 
potentially lead to reduced activity or enhanced toxicity of the concomitant medication and/or 
LEE011. 
 
The following lists are not comprehensive and are only meant to be used as a guide. The 
lists are based on the Oncology Clinical Pharmacology Drug-Drug Interaction Database 
(release date: 29 Oct 2012), which was compiled from the Indiana University School of 
Medicine’s P450 Drug Interaction Table (http://medicine.iupui.edu/clinpharm/ddis/main-
table/) and supplemented with the FDA Draft Guidance for Industry, Drug Interaction Studies 
– Study Design, Data Analysis, and Implications for Dosing and Labeling (February 2012) 
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u
cm292362.pdf), and the University of Washington’s Drug Interaction Database 
(http://www.druginteractioninfo.org/). For current lists of medications that may cause QT 
prolongation and/or torsades de pointes (TdP), refer to the CredibleMeds® website 
(https://crediblemeds.org/). Please contact the medical monitor with any questions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix Table 1: List of medications to be used with caution during study drug treatment 
Category 
Drug Name 
Moderate CYP3A4/5 
inhibitors 
Amprenavir, aprepitant, atazanavir, casopitant, cimetidine, 
ciprofloxacin, darunavir, diltiazem, dronedarone, fluconazole, 
fosamprenavir, grapefruit juice (citrus paradisi fruit juice), imatinib, 
Schisandra sphenanthera1, tofisopam, verapamil 
Moderate CYP3A4/5 
inducers 
Bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, 
talviraline, thioridazine 
Sensitive CYP3A4/5 
substrates1 
Alpha-dihydroergocryptine, aplaviroc, aprepitant, atorvastatin, 
brecanavir, brotizolam, budesonide, buspirone, capravirine, 
casopitant, darifenacin, darunavir, dasatinib, dronedarone, 
ebastine, eletriptan, eplerenone, everolimus, felodipine, 
fluticasone, lovastatin, lumefantrine, lurasidone, maraviroc, 
midazolam, neratinib, nisoldipine, perospirone, quetiapine, 
ridaforolimus, sildenafil, simvastatin, ticagrelor, tolvaptan, 
triazolam, vardenafil, vicriviroc 
Strong BSEP inhibitors 
Bosentan, fusidate, glibenclamide, lovastatin, sulindac, troglitazone 
(TGZ-sulfate) 
Medications that carry 
a possible risk for QT 
prolongation2 
Alfuzosin, amantadine, atazanavir, chloral hydrate, clozapine, 
dolasetron, dronedarone, eribulin, escitalopram, famotidine, 
felbamate, fingolimod, foscarnet, fosphenytoin, gatifloxacin, 
gemifloxacin, granisertron, iloperidone, indapamide, isradipine, 
lapatinib, levofloxacin, lithium, moexipril, nicardipine, nilotinib, 
octreotide, ofloxacin, ondansetron, oxytocin, paliperidone, 
pasireotide, quetiapine, ranolazine, risperidone, roxithromycin, 
sertindole, sunitinib, tamoxifen, tizanidine, vardenafil, venlafaxine, 
ziprasidone 
MATE1 and OCT2 
substrates3 
Acyclovir, amantadine, amiloride, cephalexin, cephradine, 
cimetidine, famotidine, fexofenadine, memantine, metformin (also a 
substrate for OCT1, MATE1, and MATE2K), pindolol, 
procainamide, ranitidine, and varencicline 
BCRP substrates 
Daunorubicin, doxorubicin, rosuvastatin, sulfasalazine, topotecan 
1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold 
or higher when co-administered with a potent inhibitor. 
2 Source: www.crediblemeds.org 
3 Source: FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data 
Analysis, and implications for Dosing and Labeling (February 2012) and Yonezawa and Inui 
(2011) Importance of the multidrug and toxin extrusion MATE/SLC47A family to 
pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics. Br J 
Pharmacology 164:1817-25 
 


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Appendix Table 2: List of prohibited medications during study drug treatment 
Category 
Drug Name 
Strong CYP3A4/5 
inhibitors 
Boceprevir, clarithromycin, cobicistat, conivaptan, 
elvitegravir, indinavir, itraconazole, ketoconazole, lopinavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, telaprevir, telithromycin, tipranavir, 
troleandomycin, voriconazole 
Strong CYP3A4/5 
inducers 
Avasimibe2,3, carbamazepine, mitotane, phenobarbital, 
phenytoin, rifabutin, rifampin (rifampicin)3, St. John's wort 
(hypericum perforatum)3 
CYP3A4/5 substrates 
with NTI1 
Alfentanil, astemizole, cisapride, cyclosporine, 
diergotamine (dihydroergotamine), ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus, terfenadine 
Medications with a 
known risk for QT 
prolongation4 
Amiodarone, arsenic trioxide, astemizole, azithromycin, 
bepridil, chloroquine, chlorpromazine, cisapride, 
citalopram, clarithromycin, disopyramide, dofetilide, 
domperidone, droperidol, erythromycin, flecainide, 
halofantrine, haloperidol, ibutilide, levomethadyl, 
mesoridazine, methadone, moxifloxacin, pentamidine, 
pimozide, probucol, procainamide, quinidine, sotalol, 
sparfloxacin, terfenadine, thioridazine, vavdetanib 
Herbal preparations/ 
medications 
Herbal preparations/medications are prohibited throughout 
the study. These herbal medications include, but are not 
limited to: St. John’s wort, Kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, 
saw palmetto, and ginseng. Patients should stop using 
these herbal medications 7 days prior to first dose of study 
drug. 
Other investigational 
and antineoplastic 
therapies 
Other investigational therapies must not be used while the 
patient is on the study. Anticancer therapy (chemotherapy, 
biologic or radiation therapy, and surgery) other than the 
study treatments must not be given to patients while the 
patient is on the study medication. If such agents are 
required for a patient then the patient must be 
discontinued study drug. 
1 NTI = narrow therapeutic index drugs whose exposure-response indicates that 
increases in their exposure levels by the concomitant use of potent inhibitors may 
lead to serious safety concerns (e.g., Torsades de Pointes). 
2 Herbal product 
3 P-gp inducer 
4 Source: www.crediblemeds.org 


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Appendix A: ECOG Performance Status 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, i.e., light house work, 
office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours.   
3 
Capable of only limited self-care, confined to be or chair more than 
50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care. Totally confined 
to bed or chair. 
5 
Dead 
 
 
 
 
 
 
 
 
 
 
 


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Appendix B: Child-Pugh Score 
 
Measure 
1 point 
2 points 
3 points 
Total bilirubin 
(mg/dl) 
<2.0 
2.0-3.0 
>3.0 
Serum albumin (g/l) 
>3.5 
2.8-3.5 
<3.5 
INR  
<1.7 
1.7-2.2 
>2.2 
Ascites 
None 
Mild (based on 
clinical findings) 
Severe (based on 
clinical findings) 
Hepatic 
Encephalopathy 
None 
Controlled Medically 
Refractory 
 
5-6 points  
Child-Pugh A 
7-9 points  
Child-Pugh B 
10-15 points Child-Pugh C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix C: NYHA Classification 
 
Class 
Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, or dyspnea (shortness of 
breath). 
II 
Slight limitation of physical activity. Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation, or dyspnea. 
III 
Marked limitation of physical activity. Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity is 
undertaken, discomfort is increased 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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