A Phase I/II Study of LEE011 Plus Everolimus in Patients With Metastatic Pancreatic Adenocarcinoma Refractory to Chemotherapy
Phase: PHASE1
Conditions: Metastatic Pancreatic Adenocarcinoma
Sponsor: Georgetown University

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Version 2.3, July 16, 2018 
A Phase I/II Study of LEE011 plus Everolimus in Patients with 
Metastatic Pancreatic Adenocarcinoma Refractory to Chemotherapy 
Georgetown Protocol #:       2016-0232 
Clinicaltrials.gov #:         NCT02985125 
Initial Concept Approval Date:  Version 1.0, July 15, 2015 
Initial Protocol Version Date:   Version 1.0, October 15, 2015 
Amended: 
Version 2.1, June 10, 2016 
Version 2.2, July 17, 2017 
Version 2.3, July 16, 2018 
Study Chair: 
Michael J. Pishvaian, MD, PhD 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
3800 Reservoir Road, NW 
Washington, DC 20057 
Telephone (202) 444-2144 
Fax (202) 444-9429 
E-Mail: pishvaim@georgetown.edu
Study Co-Chairs: 
Benjamin A. Weinberg, MD    
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
  Washington, DC 
  Erik S. Knudsen, PhD 
  Roswell Park Comprehensive Cancer Center 
Buffalo, NY 
Study Pathologist: 
Agnes Witkiewicz, MD 
Roswell Park Comprehensive Cancer Center 
Buffalo, NY 
Biostatistician: 
Hongkun Wang, PhD 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
Funding Sources: 
1) Novartis, Inc
2) Conquer Cancer Foundation (Young Investigator Award)

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Summary of Changes 
 
The full protocol was first approved by the Georgetown Scientific Review Committee (CRC) on 
02/17/2016, and by the IRB on 08/03/2016.  Version 2.2 07/17/2017 was the first major update 
since IRB approval, and the changes made are summarized below. Version 2.3 06/22/2018 is the 
second update in order to update protocol safety changes for LEE011 (ribociclib). (Please note, 
minor formatting, spelling and grammatical corrections, and pagination updates are not detailed 
below). 
 
Version 2.3, 07/XX/2018 
1) This protocol will be open at other sites.  As a result, the full list of sub-investigators has been 
removed, as it would be overly cumbersome.  
a. In addition, language in the protocol has been re-added throughout the protocol 
regarding oversight of the trial at other sites 
2) Dose adjustments for QTc prolongation have been added. 
3) Additional drugs have been added to the list of prohibited drugs and drugs to be used with 
caution. 
4) INR inclusion criteria was changed to ≤ 1.5 from < 1.5. 
5) Tumor biopsies are mandatory UNLESS the patient has been evaluated for a biopsy in 
consultation with radiology in good faith, and there is a determination that an attempt at a 
biopsy would cause undue risk to the patient. 
6) Corticosteroids should not be given during the study except for topical applications, inhaled 
sprays, eye drops, or local injections. A short duration (< 5 days) of systemic corticosteroids 
less than or equal to the potency of 4 mg dexamethasone daily is allowed (e.g. for chronic 
obstructive pulmonary disease, or an anti-emetic). 
7) Address of Dr. Knudsen (moved to Roswell Park Comprehensive Cancer Center) has been 
updated. 
8) The patient Drug Diary (Appendix A) was modified to clarify timing of each oral agent 
separately, and to clarify that the LEE-011 should only be taken 21 out of 28 days 
9) The pregnancy language in the Protocol and the Informed Consent Form has been clarified: 
a. In the protocol, the details of eligible patients, with regards to avoidance of 
pregnancy have been clarified (Section 3.2) 
b. The time frame for avoiding pregnancy after coming off of the study medications 
needs to only be 21 days, per Novartis standards 
c. The section on avoidance of pregnancy has been enhanced and clarified for 
patients  
 
Version 2.2, 07/17/2017 
1) The study was originally designed as a multi-institutional trial. However, we were unable to 
obtain support for a multi-institutional study, and thus, this will be a single institutional trial, at 
Georgetown only. 
a. Correspondingly, all external coinvestigators have been removed 
b. The list of internal (Georgetown) sub-investigators has been updated 
c. Dr. Erik Knudsen is a key scientific collaborator, and thus is now listed as a study 
Co-chair 
d. Because this is a single-site study, the sections on “Trial Coordination” have been 
removed entirely 
e. We have also updated the accrual timeline to allow for enrollment over 24-29 
months 
2) The collection of samples for correlative studies has been updated and clarified: 
a. Section 4.4.5 includes a clarification on collection of blood samples for ctDNA 
b. Section 8.1.1 includes a clarification that 2 cores will be collected for FFPE, and 2 

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cores will be frozen in tubes in liquid nitrogen. A lab manual has been updated 
(Version 2.5 05/12/2017) to reflect this as well 
3) The first patient enrolled experienced Grade 3 anemia during Cycle 1, which brought to light 
the fact that there was a lack of clarification of the timing of treatment holds and dose 
modifications in Section 6.  Thus, clarification was added to Section 6.7.1.2 regarding 
treatment holds and dose modifications for myelosuppression. 
4) The second patient enrolled in the trial had to go off study due to a Grade 3 allergic reaction 
to one or both of the study medications, manifest as a diffuse rash. In discussion with Novartis, 
the rash is not typical of the rash that can be observed with everolimus, and a rash with 
LEE011 is very rare. Furthermore, in the Phase I trial of everolimus and LEE011, there was 
no indication of an increased risk of a rash.  Thus, it has been our determination that this 
patient had a true “allergic” reaction, that was not dose dependent.  Therefore, the section on 
the definition of a DLT was modified to add a Grade 3 or 4 allergic reaction as an exception 
to a DLT. 
a. In compliance with the protocol version when the patient was enrolled, the rash 
was determined to be a DLT, and the cohort was expanded to six patients. 
 
 
 

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TABLE OF CONTENTS                                      PAGE 
 
Table of Contents                                                    5 
Figures and Tables                                                   6 
Glossary of Abbreviations and Definition of Terms                              7 
Study Synopsis                                                      9 
1.0 Background and Justification                                       16 
1.1 Cyclin Dependent Kinases                                      16 
1.2 Cell Cycle Inhibition in Pancreatic Cancer                            16 
1.3 LEE011                                                  19 
1.4 Everolimus                                                25 
1.5 Pancreatic Cancer                                           27 
2.0 Study Objectives                                                29 
2.1 Primary Objective                                            29 
2.2 Secondary Objectives                                         29 
2.3 Exploratory Objectives                                         29 
2.4 Primary Endpoint                                            29 
     2.5 Secondary Endpoints                                         29 
     2.6 Exploratory Endpoints                                         30 
     2.7 Indication                                                 30 
3.0 Subject Population                                               31 
3.1 Subject Population, Number of Subjects and Feasibility                   31 
3.2 Inclusion Criteria                                            31 
3.3 Exclusion Criteria                                            33 
3.4 Prior and Concomitant Therapy                                   34 
4.0 Trial Design and Detailed Study Procedures                             39 
4.1 Treatment Plan Overview                                       39 
 
4.2 Detailed Study Plan                                          40 
 
4.3 Tumor Biopsies                                             42 
 
4.4 Detailed Patient Assessments                                    44 
5.0 Dosages and Dispensation of Drugs                                   52 
 
5.1 Dispensation of Study Drugs and Treatments Administered                52 
 
5.2 Packaging and Labeling of LEE011 and Everolimus                     52 
 
5.3 Storage and Disposition of LEE011 and Everolimus                     52 
5.4 Treatment Compliance                                        52 
5.5 Drug Accountability                                           53 
5.6 Selection of Doses in the Study (LEE011 Investigator’s Brochure)            53 
6.0 Safety Variables and Toxicity Assessment                              54 
 
6.1 Adverse Event Assessments                                    54 
 
6.2 Study Monitoring                                            54 
 
6.3 Adverse Events and Toxicity Definitions                             55 
6.4 Adverse Events Collection Period                                 56 
6.5 Adverse Events Reporting                                      57 
6.6 Pregnancy                                                57 
6.7 Toxicity Management and Dose Adjustments                         57 
7.0 Efficacy Assessment                                             62 
7.1 Efficacy Variables                                            62 
     7.2 RECIST v1.1 Criteria for Tumor Response                           62 
     7.3 Evaluation of Best Overall Response                               63 
     7.4 Definition of Disease Progression                                 64 
8.0 Correlative Research and Tumor Biopsies                              65 
     8.1 Pharmacodynamic Assessment of the Efficacy of LEE011 and Everolimus      65 
     8.2 Mutational Analysis of Tumor Samples                              66 

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     8.3 Analysis of ctDNA                                            66 
     8.4 Tissue Prioritization                                          66 
9.0 Statistical Considerations                                          67 
      9.1 Objectives                                                67 
      9.2 Study Design                                              67 
      9.3 Sample Size Considerations                                    68 
      9.4 Endpoints                                                68 
      9.5 Analysis Plan                                              69 
10.0 Ethical Considerations                                           69 
      10.1 Institutional Review Board (IRB)                                71 
      10.2 Ethical Conduct of the Study                                   71 
      10.3 Subject Information and Consent                                71 
      10.4 Ethical Consideration for Enrollment                              71 
      10.5 Protection of Patient Confidentiality                              71 
Appendices 
Appendix A – Patient Drug Diary                                        72 
Appendix B – Patient Trial Events                                       73 
Appendix C – Study Eligibility Checklist                                  74 
Appendix D – Patient Registration Form                                  76 
Appendix E – References                                             77 
 
 
 
 
 
 
 

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FIGURES, TABLES, AND ABBREVIATIONS                        PAGE  
Figures  
Figure 1: Phase I Schema                                              14 
Figure 2: Phase II Schema                                             15 
Figure 3: The RB-pathway in Pancreatic Cancer                               16 
Figure 4: Potent Impact of CDK4/6 Inhibition in Patient-derived Xenografts             17 
Figure 5: Potent Impact of CDK4/6 Inhibition in Patient-derived Xenografts             17 
Figure 6: Schematic of the Explant Approach                                 17 
Figure 7: Response of 15 cases to CDK4/6 Inhibition                            18 
Figure 8: Established Pancreatic Lines Have Limited Response to CDK4/6 Inhibition       18 
Figure 9: MTOR Inhibitors are Synergistic with CDK4/6 Inhibition in Pancreatic Cancer Models  
                                                               18 
Figure 10: Molecular Structure of LEE011                                   19 
Figure 11: Molecular Structure of Everolimus                                 26 
Figure 12: (Figure 1 Repeated): Phase I schema                               39 
Figure 13: (Figure 2 Repeated): Phase II schema                              39 
 
Tables 
Table 1: Dose Escalation Schema                                        13 
Table 2: Pharmacokinetic Parameters of LEE011 and Everolimus at Steady State  
(Cycle 1, Day 15)                                                    23 
Table 3: LEE011X2106: Adverse Events (All grades ≥15% in All Patients Receiving Triplet 
Therapy) Suspected to Be Related to Treatments                              24 
Table 4: ECOG Performance Status                                       32 
Table 5. List of Medications to be Used with Caution During Study Drug Treatment        36 
Table 6. List of Prohibited Medications During Study Drug Treatment                 37 
Table 7: Study Activities                                               46 
Table 8: Study Activities Checklist                                        47 
Table 9: Dispensation of LEE011 by Dose Level                                 50 
Table 10: Criteria for Defining DLTs Related to LEE011 or Everolimus                56 
Table 11: Dose Modifications for Toxicities Related to LEE011 or Everolimus            57 
Table 12: Response Evaluation                                          62 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
4E-BP1      Eukaryotic initiation factor 4E-binding protein 1 
5-FU        5-fluorouracil 
ACE        Angiotensin-converting enzyme 
ADME       Absorption, distribution, metabolism, and excretion 
AE         Adverse event 
ALP        Alkaline phosphatase 
ALT         Alanine aminotransferase 
ANC        Absolute neutrophil count 
AST        Aspartate aminotransferase 
AUC        Area under the curve 
β-hCG       β-human chorionic gonadotropin 
BCS        Biopharmaceutics Classification System 
BrdU        Bromodeoxyuridine 
BUN        Blood urea nitrogen 
CBC        Complete blood count 
CDK        Cyclin-dependent kinase 
CDKN2A     Cyclin-dependent kinase inhibitor 2A (gene) 
CNS        Central nervous system 
CR         Complete response 
CRF        Case report form 
CT         Computed tomography 
ctDNA       Circulating tumor DNA 
CYP        Cytochrome P450 
DCR        Disease control rate 
DLT        Dose-limiting toxicity 
DNA        Deoxyribonucleic acid 
DSMB       Data and safety monitoring review board 
ECOG       Eastern Cooperative Oncology Group 
ECG        Electrocardiogram 
FOLFIRINOX  5-fluorouracil, irinotecan, oxaliplatin 
GEM        Gemcitabine 
GGT        Gamma-glutamyl transpeptidase 
HIF-1        Hypoxia-inducible factor 1 
HIV         Human immunodeficiency virus 
HR         Hazard ratio 
IHC         Immunohistochemistry 
IND         Investigational new drug 
INR         International normalized ratio 
IV          Intravenously 
LCCC       Lombardi Comprehensive Cancer Center 
LD         Longest diameter 
LFT         Liver profile 
LLN         Lower limit of normal 
MCL        Mantle cell lymphoma 
MEF        Mouse embryonic fibroblast 
MRI         Magnetic resonance imaging 
mOS        Median overall survival 
mPAC       Metastatic pancreatic adenocarcinoma 
mPFS       Median progression-free survival 
mTOR       Mammalian target of rapamycin 
mTORC1     Mammalian target of rapamycin complex 1 

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NGS        Next-generation Sequencing 
ORR        Overall response rate 
OS         Overall survival 
PCR        Polymerase chain reaction 
PD         Progression of disease 
PFS        Progression-free survival 
PFS8 weeks     Progression-free survival rate at 8 weeks 
PgP        P-glycoprotein 
PI          Principal investigator 
PK         Pharmacokinetics 
PO         By mouth 
PR         Partial response 
PS         Performance Status 
PT         Prothrombin time 
PTT        Partial thromboplastin time 
QD         Once daily 
RB         Retinoblastoma 
RECIST      Response Evaluation Criteria in Solid Tumors 
RNA        Ribonucleic acid 
RP2D       Recommended Phase II Dose 
RR         Response rate 
S6K1        S6 ribosomal protein kinase 
SAE        Significant adverse event 
SD         Stable disease 
SRS        Stereotactic radiosurgery 
ULN        Upper limit of normal 
VEGF       Vascular endothelial growth factor 
 
 
 
 
 
 

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STUDY SYNOPSIS 
Title 
A Phase I/II Study of LEE011 Plus Everolimus in Patients with Metastatic Pancreatic 
Adenocarcinoma Refractory to Chemotherapy 
 
Short Title 
LEE011 plus Everolimus in Refractory Pancreatic Cancer 
 
Protocol  
Number 
2016-0232 
 
Clinicaltrials.g
ov number: 
NCT02985125 
Phase 
Phase I/II 
 
Investigational 
Agents 
1) LEE011 (ribociclib), an oral CDK4/6 inhibitor (Novartis) 
2) Everolimus (Afinitor®), an oral mTOR inhibitor (Novartis) 
 
Indication 
Metastatic pancreatic adenocarcinoma (mPAC) refractory to gemcitabine (GEM)- 
and 5-fluorouracil (5-FU)-based chemotherapy 
 
Concept 
and 
Scientific 
Rationale 
Pancreatic adenocarcinoma has an overall poor prognosis, with an estimated five-
year survival rate around 7.2%(1). Approximately 53% of patients have metastatic 
disease at diagnosis, and their prognosis is even more dismal with an estimated 
five-year survival rate around 2.3%(1). In the past, single-agent gemcitabine (GEM) 
was the preferred treatment option for advanced pancreatic cancer as it was shown 
to have a survival benefit compared to single-agent 5-FU, although the median 
progression-free survival (mPFS) was only 2.3 months compared to 0.9 months 
(P=0.0002)(2). 
The two largest first-line trials in metastatic pancreatic adenocarcinoma 
(mPAC) that demonstrated a survival benefit over single-agent GEM used 
FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and 5-FU)(3) and GEM plus nab-
paclitaxel(4). Conroy et al. showed an improved disease control rate (DCR, the 
proportion of patients with a complete response (CR), partial response (PR), or 
stable disease (SD)) of 70.2% and mPFS of 6.4 months using FOLFIRINOX 
compared to 50.9% and 3.3 months using GEM (both P<0.001)(3). Using nab-
paclitaxel plus GEM, Von Hoff et al. also demonstrated an improved DCR (48% 
versus 33%, P<0.001) and mPFS, 5.5 versus 3.7 months (P<0.001), when 
compared to single-agent GEM(4). Recently, we have seen patients who have had 
progression of disease on both lines of therapy and retain an adequate performance 
status for further treatment. Previous studies of third-line therapy in mPAC are 
limited but reveal stable disease in 25-31% of patients with no partial or complete 
responses (31% of patients in the GVAX/CRS-207 combination vaccine study had 
stable disease but only 52% of these patients were treated in the third-line setting)(5, 
6). Therefore, novel therapeutic options are needed both for pancreatic cancer in 
general as well as for this subset of patients with refractory mPAC. 
We propose a therapeutic approach using agents that directly target the 
signaling pathways responsible for tumorigenesis. LEE011 (ribociclib, Novartis) is 
an oral small-molecule inhibitor of cyclin-dependent kinase 4 (CDK4) and cyclin-
dependent kinase 6 (CDK6). CDK4/6 acts by phosphorylating and inactivating the 
retinoblastoma protein (RB), allowing E2F family transcription factors to accelerate 
cell cycle progression from G1 to S phase(7). Pancreatic cancer is frequently 
associated with an alteration in the CDKN2A gene resulting in the loss of the 
p16INK4a protein that naturally inhibits CDK4/6(8). LEE011 as a single agent has not 

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Version 2.3, July 16, 2018 
shown significant activity, likely due to aberrant induction of Cyclin D and E1(9). The 
addition of an inhibitor of the mammalian target of rapamycin (mTOR) blocked this 
pathway and halted tumor cell proliferation when studied in pancreatic cancer cells 
xenograft models(9, 10). The combination of everolimus (Afinitor®, Novartis), an mTOR 
inhibitor, with LEE011 is currently under evaluation in a Phase Ib/II clinical trial of 
LEE011, everolimus, and exemestane in patients with locally advanced or 
metastatic 
hormone-receptor 
positive, 
HER2-negative 
breast 
cancer 
(CLEE011X2106). We aim to study the combination of LEE011 and everolimus as 
third-line therapy in patients with mPAC refractory to 5-FU- and GEM-based 
chemotherapy. 
 
Hypothesis: 
We hypothesize that the combination of LEE-011 and everolimus will improve the 
progression-free survival rate at 8 weeks from a historical baseline of 25% to a 
hypothesized rate of 50%. 
Study Duration 
24 – 29 months 
 
Objectives 
Primary Objective of the Phase I Portion: To determine the Recommended Phase 
II dose (RP2D) of LEE011 in the combination with everolimus in patients with 
mPAC refractory to 5-FU- and GEM-based chemotherapy 
 
Primary Objective of the Phase II Portion: To determine the progression-free survival 
(PFS) rate at 8 weeks (PFS8weeks) to assess the clinical efficacy of the combination 
of LEE011 and everolimus in patients with mPAC refractory to 5-FU- and GEM-
based chemotherapy 
 
Secondary Objectives: 
To determine, in patients with refractory mPAC treat with LEE011 and everolimus: 
▪ Median progression-free survival (mPFS) 
▪ Median overall survival (mOS) 
▪ Best overall response rate (ORR) 
▪ Change in serum tumor markers (CA 19-9 or CEA) 
▪ Safety and tolerability 
 
Exploratory Objectives: 
1) To correlate the PFS8 weeks to correlative scientific markers, including the analysis 
of tumor biopsies and blood-based markers, including RB, pRB, p16, cyclin D1, 
Ki67, MCM7, and pS6 levels by immunohistochemistry    
2) To screen for use a targeted sequencing approach for genetic lesions observed 
in pancreatic cancer that includes KRAS, SMAD4, TP53, CDKN2A as well as 
other commonly mutated cancer genes. 
3) To assess blood for the analysis of circulating tumor DNA as a surrogate marker 
of disease burden.   KRAS and other mutations will be used as the determinants 
of tumor selective DNA 
Number 
of 
Subjects 
 
A minimum of 12 and a maximum of 44 evaluable patients 
Diagnosis and 
Main Inclusion 
and Exclusion 
Criteria 
Key Inclusion Criteria 
1) Histologically confirmed metastatic adenocarcinoma of the pancreas with 
measurable disease per RECIST 1.1 
2) Patient must consent to two mandatory biopsies and have tumor amenable to 
biopsy 

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- Tumor biopsies are mandatory UNLESS the patient has been evaluated for a 
biopsy in consultation with radiology in good faith, and there is a determination 
that an attempt at a biopsy would cause undue risk to the patient. 
3) Documented progression of disease on at least one 5-FU-based regimen and 
at least one GEM-based regimen for metastatic disease (progression during or 
within 3 months of the completion of adjuvant therapy is acceptable) 
4) Age ≥ 18 years 
5) ECOG performance status 0 or 1 
6) Signed informed consent form 
7) Adequate hepatic, bone marrow, and renal function as defined below in the 
body of the protocol 
 
Key Exclusion Criteria 
1)  Patients previously exposed to, intolerant of, or ineligible for CDK inhibitors, 
mTOR inhibitors, and/or their combination 
2)  Prior anti-tumor therapy within 3 weeks of Cycle 1 Day 1 (anti-tumor therapy 
defined as, but is not limited to, anti-cancer agents (cytotoxic chemotherapy, 
immunotherapy, and biologic therapy), radiotherapy, and investigational 
agents), the “wash-out period” 
3)  Patients with known CNS metastases (that do not meet inclusion criteria, 
detailed below) 
4)  Active severe infection, or known chronic infection with HIV or hepatitis B virus 
5)  Cardiovascular disease problems including unstable angina, therapy for life-
threatening ventricular arrhythmia, or myocardial infarction, stroke within the 
last 6 months, or a diagnosis of congestive heart failure 
6)  Patient has a concurrent malignancy or malignancy within 3 years prior to 
starting study drug, with the exception of adequately treated, basal or squamous 
cell carcinoma, non-melanomatous skin cancer or curatively resected cervical 
cancer. 
7)  Women who are pregnant or breastfeeding 
8)  Patient is currently receiving or has received systemic corticosteroids ≤2 weeks 
prior to starting study drug, or who have not fully recovered from side effects of 
such treatment. 
 
Study Design 
 
This study is a multi-institutional single-arm, open-label, Phase I/II trial of the 
combination of LEE011 and everolimus in refractory mPAC.  
 
Phase I Portion 
The Phase I portion of the study will be used to determine the R2PD for LEE011 for 
the Phase II portion of the study. Patients will be evaluated every 2 weeks for the 
first 8 weeks and then every 4 weeks thereafter. The dose of everolimus will remain 
constant at 2.5 mg by mouth daily every day, and LEE011 will be given daily days 
1-21 out of a 28 day cycle with the dose determined by the patient cohort. A standard 

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3+3 design will be employed in which patients are enrolled in cohorts of 3 patients 
each (see figure 1): 
 
• 
3 patients are enrolled at dose level 1. 
o If 0 patients experience a DLT, 3 patients are enrolled at dose level 
2. 
o If 1 patient experiences a DLT, 3 additional patients are enrolled at 
dose level 1. If 1 of 6 patients at dose level 1 experiences a DLT, 3 
patients are enrolled at dose level 2. 
o If ≥ 2 patients experience a DLT, 3 patients are enrolled at dose level 
-1. 
• 
If 0-1 of 3 patients at dose level 2 experience a DLT, then 3 additional 
patients are enrolled at dose level 2. 
o If 0-1 of 6 patients at dose level 2 experience a DLT, dose level 2 is 
the RP2D. 
• 
If ≥ 2 of 3 patients at dose level 2 experience a DLT, 3 additional patients 
may be enrolled (to achieve 6 patients total) at dose level 1. 
o If 0-1 of 6 patients at dose level 1 experience a DLT, dose level 1 is 
the RP2D.  
o If ≥ 2 of 6 patients at dose level 1 experience a DLT, 3 patients are 
enrolled at dose level -1. 
• 
If 0-1 of 3 patients at dose level -1 experience a DLT, 3 additional patients 
are enrolled at dose level -1. 
o If 0-1 of 6 patients at dose level -1 experience a DLT, dose level -1 is 
the RP2D . 
o If ≥ 2 of 3 or 6 patients at dose level -1 experience a DLT, 3 patients 
are enrolled at dose level -2. 
• 
If 0-1 of 3 patients at dose level -2 experience a DLT, 3 additional patients 
are enrolled at dose level -2. 
o If 0-1 of 6 patients at dose level -2 experience a DLT, dose level -2 is 
the RP2D. 
o If ≥ 2 of 3 or 6 patients at dose level -2 experience a DLT, the study 
is terminated. 
 
 There will be no intra-patient dose escalation or de-escalation. 
Patients enrolled in the Phase I portion of the trial who have received the 
recommended Phase II dose of LEE011 will be counted towards the Phase II 
efficacy analysis. 
Table 1. Dose Escalation Schema 
 
 

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Figure 1. Phase I Schema 
 
Phase II Portion 
 
Stage 1 – Initial Stage 
The first stage of the Phase II portion of the study will be performed to establish a 
minimum level of clinical efficacy to warrant the enrollment of more patients in the 
second stage of the study. Using a Simon’s Minimax two-stage design, 11 patients 
will be enrolled and will undergo baseline imaging and a pre-treatment biopsy. The 
patients will then be started on treatment with LEE011 at the RP2D by mouth daily 
for the first 21 days out of a 28 day cycle in combination with everolimus 2.5 mg by 
mouth daily continuously. 
 
- LEE011 at the RP2D by mouth once daily Days 1-21 
- Everolimus 2.5 mg by mouth once daily Days 1-28 (continuously) 
 
Patients will be evaluated, including laboratory testing at screening, on Cycle 1 Day 
1, and every 2 weeks until the first response assessment at 8 weeks, then every 4 
weeks thereafter. Response assessment will occur every 8 weeks regardless of 
treatment cycle. If at the first response assessment there is no evidence of 
progression of disease (PD), as determined by RECIST v1.1 criteria, and the patient 
is tolerating therapy, then the patient may be seen only every 4 weeks, unless 
clinically indicated. Patients will continue to remain on study as long as there is no 
evidence of PD (according to RECIST v1.1 criteria) and the therapy is adequately 
tolerated.   
 Patients will have a tumor biopsy prior to treatment, a second biopsy at 2 weeks 
on treatment, and an optional final biopsy at the time of progression of disease (PD). 
 
3.6.1.2 Stage 2 – Final Stage 
After all 11 patients from the initial stage have undergone their 8 week response 
assessment, an interim analysis will be conducted to determine how many had a 
PR, CR, SD, or PD. The study will be stopped prematurely if 2 or fewer patients 
obtain a PR, CR, or SD at 8 weeks. If 3 or more patients obtain a PR, CR, or SD at 
8 weeks, then 15 additional patients will be enrolled on the study for a total of 26 
patients. Assuming a dropout rate of 10% in this refractory patient population, up to 
3 additional patients may replace patients whose come off study prior to being 
evaluable for the primary endpoint (for reasons other than disease progression).  
Thus, up to 29 patients may be screened for the Phase II portion of this study. 

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Figure 2: Phase II Schema 
Multi-
Institutional 
Trial 
Coordination 
Personnel 
At each site, personnel dedicated to this protocol will be: 
 
- A site PI 
 
- A research coordinator/data manager 
In addition, at Lombardi-Georgetown, there will be a dedicated “multi-institutional” 
research coordinator who will play the primary role in coordinating the trial between 
Lombardi-Georgetown and additional sites.  This coordinator will be the main point 
of contact for Dr. Pishvaian and the other site PIs for any study related concerns, 
and to screen each patient being considered for enrollment (Including “remote” 
screening for the patients being screened at other sites). This coordinator will also 
be the point of contact for the data managers for data entry questions. Finally, this 
coordinator will play a major role in regulatory coordination of the study, specifically 
by: 1) reviewing and confirming all study-related adverse events; 2) submitting all 
SAE reports to the Georgetown IRB; and  (the research coordinators at the other 
sites will prepare SAE reports for patients treated at their respective sites, but the 
“multi-institutional” coordinator will submit the final report); 3) gathering and 
preparing all primary source data for review/audit. 
 
Patient Enrollment 
Enrollment at the sites will be competitive.  If a patient is being screened for 
enrollment, the local research coordinator must send a secure/encrypted email 
within 24 hours containing the patient’s name, to the local PI, to Dr. Pishvaian, and 
to the multi-institutional coordinator.  If a patient is successfully screened, the local 
research coordinator must send all supporting documentation to the multi-
institutional research coordinator (by email or fax).  Patients should not start therapy 
until both Dr. Pishvaian and the multi-institutional coordinator have reviewed the 
patient’s records and confirmed that the patient is indeed eligible for enrollment. 
 
Data Collection and Management  
Patient data will be entered into the online accessible database.  This database is 
housed at Lombardi-Georgetown, but is accessible anywhere there is Internet 
access.  The data manager and research coordinator at each site will attend an 
online training session so that they may learn how to enroll data into the database.  
All screening data should be entered prior to starting therapy, and all ongoing patient 
data should be entered within one week of each patient visit.   
 
Conference Calls 
A monthly conference call will be held between Lombardi-Georgetown and the other 
sites meeting will be held to review patient enrollment, toxicity, and response 
assessment.   
 

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Trial Auditing 
The multi-institutional coordinator will arrange all primary source documents for the 
patients to be audited.  This will include collecting copies of the primary source data 
for any patients treated at other sites. 
 
Statistical 
Design,  
Feasibility, and 
Trial Duration 
This is a multi-institutional single arm, open label Phase I/II study to evaluate the 
PFS8weeks of the combination of LEE-011 plus everolimus, in patients with metastatic 
pancreatic cancer refractory to 5-fluorouracil (5-FU) and gemcitabine-based 
chemotherapy.  Previous studies of third-line therapy in mPAC are limited but reveal 
stable disease in 25-31% of patients with no partial or complete responses (31% of 
patients in the GVAX/CRS-207 combination vaccine study had stable disease but 
only 52% of these patients were treated in the third-line setting)(5, 6).  It is hoped that 
the combination of LEE-011 plus everolimus can increase the PFS8weeks to at least 
50%, though early stopping rules are in place for lack of efficacy.  
       All patients meeting the eligibility criteria and who have signed a consent form, 
have begun treatment, are not lost to follow-up, and are not taken off study for 
reasons other than progression or death before 8 weeks will be considered 
evaluable for the assessment of the DCR.   
       Between 12 and 24 patients will be enrolled in the Phase I portion of the study, 
depending on whether DLTs occur and dose de-escalation is required. The 6 
patients treated at the RP2D will be included in the Phase II portion of the study. We 
anticipate the combination will be well tolerated such that all of the patients in the 
Phase I portion are likely to be evaluable for the Phase II efficacy analysis. 
       26 evaluable patients will be enrolled in the Phase II portion of the study (though 
the potential drop-out rate is 10%), which will provide a 90% power to detect an 
improvement in the DCR from 25% (based on historical control) to 50%, assuming 
a 1-sided significance level of 0.1 and an accrual rate of 2 patients per month.  A 
Simon's optimal two-stage design will be used to test the null hypothesis that the 
DCR P<=0.25 versus the alternative that P>=0.5.  For the first stage, 11 patients will 
be entered to the study. The trial will be terminated if 2 or fewer patients achieve a 
PR, CR, or SD at 8 weeks.  If at least 3 patients in the first stage achieve a PR, CR, 
or SD at 8 weeks, the trial goes on to the second stage.  A total of 26 patients will 
be enrolled.  If the total number of patients who achieve a PR, CR, or SD at 8 weeks 
is less than or equal to 9, the combination therapy will be rejected.  If however, 10 
or more patients achieve a PR, CR, or SD at 8 weeks the combination therapy will 
be considered for further analysis.  
       With 26 evaluable patients in the Phase II portion, combined with a minimum of 
12 to a maximum of 18 patients enrolled strictly in the Phase I portion of the trial, 
there will be up to 44 patients enrolled.  At an expected accrual rate of 3 patients per 
month, the expected accrual duration will be approximately 15 months.   
       Descriptive statistics will be used to summarize patients’ demographics, toxicity, 
and quality of life. The PFS8weeks will be estimated from the observed data with 95% 
exact binomial confidence interval. The nonparametric Kaplan-Meier method will be 
used to estimate the survival function and calculate the PFS and OS. The ORR will 
be estimated from the observed data with 95% exact binomial confidence intervals. 
 
 
 

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1.0 BACKGROUND AND JUSTIFICATION      
1.1 Cyclin Dependent Kinases 
Cell cycle progression is a tightly regulated process, and aberrant cell cycle regulation is a 
hallmark of most cancers(11). G1 to S-phase progression is regulated by the cyclins and cyclin-
dependent kinases (CDKs). CDK4 is activated by the D-type cyclins, enabling progression in early 
G1, and CDK2 is activated by the A and E-type cyclins enabling progression through late G1 and 
into S-phase(11). CDK4 and CDK2 activity are inhibited by the cyclin dependent kinase inhibitors, 
p16INK4 and p21Cip/Kip, respectively. CDK4 and other CDKs and cyclins are often overexpressed in 
tumor cells, and activating mutations in CDK4 are oncogenic(11-19). For example, mice that carry 
a CDK4 activating mutation, CDK4R24C/R24C develop multiple tumors and have a significantly 
decreased life span(20). By contrast, mouse embryonic fibroblasts (MEFs) in which either CDK4 
or all three cyclin D subtypes have been knocked out are resistant to oncogenic transformation(21, 
22). CDK4 classically exerts its effects on the cell cycle by phosphorylating retinoblastoma (Rb) 
enabling the release of the E2F transcription factor, resulting in the transcription of genes required 
for subsequent cell cycle events, such as cyclins E and A(11).  However, data demonstrates that 
CDK4-regulated cell cycle activation also occurs through the inhibition of TGF-β signaling(23). 
 
1.2 Cell Cycle Inhibition in Pancreatic Caner 
The activity of CDK4/6 is frequently deregulated in pancreatic cancer due to the loss of CDKN2A 
via either homozygous deletion or epigenetic silencing. The signature driver of pancreatic cancer 
(KRAS) drives cells into senescence through activation of CDKN2A. Thus, there is a potent 
hypothetical rationale for pharmaceutically mimicking the function of CDKN2A based on a 
plethora of published data. Most recently, in the sequencing of over 109 cases, we discovered 
amplification of CCND1 and CDK4 also occurs in pancreatic adenocarcinoma (Figure 2), while 
the loss of RB is rare(8). Therefore from a genetic perspective one would anticipate that pancreatic 
cancers could respond efficiently to CDK4/6 inhibition.  
 
Figure 
3. 
The 
RB-pathway 
in 
Pancreatic 
Cancer. 109 
dissected 
pancreatic cancers were subjected to 
whole exome sequencing.  Frequent loss 
of CDKN2A/2B was observed, and 
amplification of CCND1 and CDK4 was 
found in select cases. RB1 loss that 
compromises the action of CDK4/6 
inhibitors was observed in ~3% of cases. 
(Blue 
boxes 
denote 
homozygous 
deletion, green boxes denote mutation, 
and red boxes denote amplification).  
Data and figure from Witkiewicz, et al.(8) 
 
In patient-derived patient derived xenografts we found that CDK4/6 inhibition was highly effective 
at limiting tumor growth, and had a profound impact on proliferative index (Figures 3 and 4). This 
finding was also recapitulated in the analysis of primary tumor explants (Figures 5 and 6). Both of 
these patient-derived models recapitulate the histology and tumor microenvironment of pancreatic 
cancer. Interestingly, we did identify a single case (out of 15 tested) that failed to response to 
CDK4/6 inhibition. We could show that the basis for the lack of response is loss of RB; therefore 
select biomarkers can be deployed to define rare tumors which fail to respond (Figure 6). Overall, 
these data suggest that the vast majority of primary pancreatic cancers would have the capacity 
to response to CDK4/6 inhibition.  

17 
Version 2.3, July 16, 2018 
 
 
 
Figure 4. Potent Impact of CDK4/6 Inhibition in Patient-derived Xenografts: (A) Three patient 
derived xenograft models were employed that maintained the tissue architecture consistent with 
the primary tumor. (B) Xenograft models were treated with CDK4/6 inhibitor by oral gavage daily. 
Tumor volume was determined by daily measuring and lead to a substantial impact on tumor size. 
 
 
 
Figure 5. Potent Impact of CDK4/6 Inhibition in Patient-derived Xenografts: Xenograft 
models were treated with CDK4/6 inhibitor by oral gavage daily. At sacrifice tissue were stained 
with Ki67. Data show significant cytostatic activity across the models employed. 
 
 
 
Figure 6. Schematic of the Explant Approach: Surgical tissue is cultured ex vivo and treated 
with specific drugs. Samples are processed and stained for specific markers. In this fashion the 
model recapitulates serial biopsying of primary tumor during treatment. 
 

18 
Version 2.3, July 16, 2018 
 
 
Figure 7. Response of 15 cases to CDK4/6 Inhibition: (A) Surgical tissues from 15 different 
patients were exposed ex vivo to CDK4/6 inhibition and impact on Ki67 was determined. >95% 
of cases could respond. (B) Staining for RB and p16ink4a demonstrated that the vast majority of 
cases have low p16ink4a levels and robust nuclear RB staining. The one case that failed to 
respond had very high p16ink4a and loss of nuclear RB in the tumor compartment. 
 
In the context of this clinical trial the disease will be advanced and perhaps more indicative of 
aggressive models of disease. In evaluation of such models, our group and others found that 
while some models respond very effectively, others can develop resistance to CDK4/6 inhibition 
in spite of loss of CDKN2A (Figure 7). We explored the mechanism and found that there is 
deregulation of parallel pathways that facilitate the bypass which involves signaling to other 
CDK/Cyclins and involves the mTOR pathway(9, 10). In drug screening, our group and others found 
that mTOR inhibitors were particularly potent cooperative agents with CDK4/6 inhibitors across 
all models(9, 10) and served to broaden the efficacy of CDK4/6 inhibition into resistant models 
(Figure 8).  
 
 
Figure 8. Established Pancreatic Lines have Limited Response to CDK4/6 Inhibition: 
Bromodeoxyuridine (BrdU) incorporation was determined in the presence of CDK4/6 inhibition, 
demonstrating substantial residual cell cycle progression. These cells were further able to 
proliferate in spite of treatment as determined by crystal violet staining. 
 
 
 
Figure 9. MTOR Inhibitors are Synergistic with CDK4/6 Inhibition in Pancreatic Cancer 
Models.  

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Version 2.3, July 16, 2018 
Treatment with CDK4/6 inhibitors can lead to an accumulation or maintenance of mTOR activity 
as measured by phosphorylated S6 kinase. While phosphatidylinositol 3-kinase (PI3K) inhibitors 
have modest effects, mTOR inhibitors are synergistic for the suppression of proliferation and lead 
to active cell killing. In contrast, MEK inhibitors suppress proliferation but do not induce apoptosis 
in these models. Identical results were observed by independent groups using different cell lines 
and xenograft models(9, 10). 
 
Together the genetic rationale, the findings in patient-derived models, and aggressive established 
models of metastatic disease suggest that CDK4/6 inhibitors in combination with mTOR inhibitors 
can have a highly significant impact on a broad range of pancreatic cancers. The use of 
combination approaches is particularly important since resistance to CDK4/6 inhibition as a single 
agent can develop in pancreatic adenocarcinoma models, and by all accounts mTOR inhibitors 
are particularly effective at countering the acquisition of resistance and actively leading to the 
death of cell treated with CDK4/6 inhibitors(9, 10). 
 
1.3 LEE011 (Investigator’s Brochure(24)) 
1.3.1 LEE011 Overview 
LEE011 is an oral small molecule inhibitor that inhibits the CDK4/CCND1 and CDK6/cyclin-D3 
complexes.  Cell cycle proliferation is upregulated by signaling pathways including the mitogen-
activated protein kinase (MAPK) and PI3K pathways by increasing expression of D-cyclins.  D-
cyclins promote CDK4/6 which acts by phosphorylating the RB protein, resulting in its deactivation.  
In turn, this activates the E2F family of transcription factors, resulting in cell cycle proliferation 
through the checkpoint from G1 to S phase.  The p16 protein encoded by INK4A normally inhibits 
CDK4/6. Loss of p16 activity due to overexpression of D-cyclins, CDK4/6, decreased p16 binding, 
or INK4a gene mutations are frequently seen in human malignant cells.  Thus, LEE011 causes 
cell cycle arrest at G1 by inhibiting CDK4/6 in malignancies associated with phosphorylated RB. 
 
Figure 10: Molecular Structure of LEE011 
 
 
 
1.3.2 LEE011 in vitro Pharmacology 
LEE011 inhibits the CDK4/CCND1 and CDK6/cyclin-D3 enzyme complexes with concentration 
resulting in 50% inhibition (IC50) values of 0.01 and 0.039 μM in biochemical assays, respectively. 
In Jeko-1 cells, the compound inhibits CDK4/6-dependent pRb phosphorylation with an average 
IC50 of 0.06 μM. Consistent with the observed inhibition of pRb phosphorylation, LEE011 also 
inhibited G1 to S phase cell cycle progression in Jeko-1 cells as judged by both the inhibition of 
BrdU uptake (IC50 of 0.1 μM) and fluorescence activated cell sorting (FACS) analysis (half-
maximal increase in cells in G1 at 0.11 μM). 
 
The effect of LEE011 on pRb phosphorylation, BrdU uptake and cell cycle progression has been 
assessed in > 40 cell lines derived from hematological, esophageal, liposarcoma and breast 
cancers. In pRb+ cell lines, LEE011 inhibits pRb phosphorylation with a median IC50 value of 
0.275 μM (range: 0.06 to 8.8 μM). Similarly, LEE011 interferes with G1 to S phase cell cycle 
progression in these cells as determined by either BrdU uptake or FACS analysis with a median 
IC50 value of 0.46 μM. In contrast, in lineage-matched pRb- cell lines no effect of LEE011 on either 
pRb phosphorylation or cell cycle progression is observed. Thus, LEE011 is able to impact cell 
cycle progression in cell lines derived from a variety of tumor types that harbor a diversity of 
genetic alterations in a manner dependent on intact pRb. 
 
1.3.3 LEE011 in vivo Pharmacology 
LEE011 was well-tolerated in mice and rats with body weight loss not exceeding 12.5% at doses 
up to 250 mg/kg QD PO or 150 mg/kg QD PO, respectively, for up to 28 days. However, 

20 
Version 2.3, July 16, 2018 
myelosuppression was observed and correlated with pRb phosphorylation inhibition.  Treatment 
with LEE011 resulted in tumor regression in the Jeko-1 MCL xenograft model at doses greater 
than or equal to 75 mg/kg QD PO. In vivo pharmacokinetics (PK)/pharmacodynamics (PD) studies 
demonstrated dose-related inhibition of pRb phosphorylation in tumors, with continuous dosing 
over at least 3-5 days being required to achieve optimal target inhibition. In male nude rats, a 
PK/PD/efficacy study indicated that plasma levels corresponding to approximately 0.5 - 4 μM over 
a 24 h dose interval are sufficient to obtain near complete inhibition of pRb phosphorylation and 
complete regression in the Jeko-1 MCL xenograft model. 
 
LEE011 has demonstrated in vivo anti-tumor activity in subsets of tumor xenograft models. 
Consistent with the compounds mechanism of action, efficacy was only observed in tumors 
expressing pRb. Tumor types where LEE011 has demonstrated robust anti-tumor activities 
include but are not limited to breast, melanoma, neuroblastoma, malignant rhabdoid, lung, 
pancreas and hematological malignancies. In addition, LEE011 has shown anti-tumor activity 
when combined with targeted agents which inhibit signaling pathways known to regulate D-cyclin 
levels, including inhibitors of the RAF/mitogen-activated protein kinase kinase (MEK)/extracellular 
signal-regulated kinase (ERK), phosphoinositide 3-kinase (PIK3) and mammalian target of 
rapamycin (mTOR) pathways. 
 
1.3.4 Safety Pharmacology and Toxicology LEE011 
In vivo cardiac safety studies demonstrated a signal for QT prolongation with the potential to 
induce incidences of premature ventricular contractions (PVCs) at higher exposure levels.  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) 
are considered to be 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 in the 4-week toxicity study at the highest dose tested (20 mg/kg/day) and this effect 
could also be related to the pharmacology of LEE011 (arrest of estrous cycle). The liver, bile 
system and gall bladder (proliferative changes, cholestasis, sand-like gallbladder calculi and 
inspissated bile) and the kidney (concurrent degeneration and regeneration of tubular epithelial 
cells) were identified as additional target organs of toxicity which are not likely related to the 
primary pharmacology of LEE011.  Inflammatory changes in the lungs 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. Generally all 
changes demonstrated either reversibility or a clear tendency towards reversibility. 
 
1.3.5 Non-clinical Pharmacokinetics and Metabolism of LEE011 
Pharmacokinetics of LEE011 and its metabolite LEQ803 in plasma were investigated in mouse 
(RD-2009-50082), rat (DMPK R0800526), dog (RD-2009-50081) and cynomolgus monkey 
(DMPK R0800755) after a single PO or IV dose.  Following IV dosing, LEE011 showed high 
plasma clearance (CL) in the mouse (43 mL/min/kg), rat (46 mL/min/kg), dog (32 mL/min/kg) and 
monkey (35 mL/min/kg) compared to hepatic blood flow. The plasma volume of distribution at 
steady-state (Vss) was large across species (7.9 to 28 L/kg) and the terminal elimination T1/2 was 
moderate in rodents and monkeys (~2 to 5 h) and longer in dogs (18 h) after IV administration.  
Following oral dosing, Tmax occurred between 2 and 4 hours in mice, rats, dogs and cynomolgus 
monkeys. In the rat, absorption (66.0%) was higher than bioavailability (37.1%), indicating a 
moderate first-pass effect. Oral bioavailability was moderate in mouse (65%) and dog (64%) and 
low to moderate in cynomolgus monkey (17%).  After oral dosing, systemic exposure of metabolite 
LEQ803 was lower than parent exposure in all species investigated. LEQ803 AUC was 29% of 
parent AUC in the rat, 3 to 6% in the dog (DMPK R1370291) and 26% in the monkey. 
 
1.3.6 Human Pharmacokinetics and Metabolism of LEE011 

21 
Version 2.3, July 16, 2018 
The available clinical form that has been used in different clinical trials is hard gelatin capsules 
(10 mg, 50 mg and 200 mg). An oral solution (30 mg/mL) has also been developed for clinical 
use, and film coated tablets are utilized in the current formulation.  In vitro, LEE011 exhibits pH-
dependent solubility with decreased solubility with increased pH and is moderately permeable in 
Caco-2 cell monolayers (DMPK R0800504).  According to the Biopharmaceutics Classification 
System (BCS), LEE011 can be classified as a low solubility drug substance with moderate 
permeability (BCS class II or BCS class IV).  This classification is subject to change pending new 
data on permeability (e.g., from absorption data from the human ADME study). 
 
The PK of LEE011 have been evaluated following single and repeat daily doses in the ongoing 
single agent, Phase I study in patients with advanced solid tumors or lymphomas 
CLEE011X2101. Patients in all but one cohort received escalating doses of LEE011 once daily 
for 3 weeks followed by 1 week off schedule. In one cohort, patients received once daily 
continuous dosing of 600 mg LEE011. PK sampling (pre-dose and 0.5, 1, 2, 4, 6, 8, and 24 hours 
post-dose) was conducted on Days 1 and 18 or 21 of Cycle 1. Additional PK sampling (predose 
and 1, 2, and 4 hours post-dose) was conducted on Days 8 and 15 of Cycle 1. Sparse samples 
were collected in Cycle 2 and subsequent cycles. Following oral dosing, LEE011 was rapidly 
absorbed with median Tmax ranging from 1 to 4 hours. LEE011 exhibited slightly over-proportional 
increases in exposure (Cmax and AUC) across the dose range tested (50 to 1200 mg), with no 
clear evidence of time-dependent auto-inhibition of its clearance mediated by CYP3A4. Steady 
state was generally reached by Day 8 and mean T1/2,acc ranged from 15.9 to 32.6 hours across 
the dose range (50 to 1200 mg). Mean Racc across the studied doses ranged from 1.55 to 2.52. 
At the 600 mg dose level, LEQ803, an active metabolite of LEE011, accounted for approximately 
8% (geometric mean) of the LEE011 AUC0-24h after a single dose and after multiple doses. 
A food effect study conducted in healthy subjects (CLEE011A2111) indicated that LEE011 
administered as drug-in-capsule (DiC) can be taken without regard to meals. 
 
The human ADME study for LEE011 has not been conducted. Circulating metabolites of LEE011 
in human plasma samples from study CLEE011X2101 were identified and semi-quantified, when 
possible, by LC-MS analysis. In plasma samples from 9 patients treated for 21 days with 600 mg 
QD, 24 metabolites were identified (DMPK R1400226). Of these metabolites, 13 were not 
previously identified in vitro or in the rat in vivo. In addition, 24 not fully structurally characterized 
components were identified, which were all isomers of identified metabolites. A qualitative 
analysis showed that LEE011 was the major component in plasma at steady-state (~46% of drug-
related material). Phase I metabolites constituted ~50% of drug-related material. Of these, 
metabolites M9 (oxidation and desaturation) and M13 (oxygenation) represented ~47% of Phase 
I metabolism. Phase II metabolites were minor components in plasma (~4%). LEQ803, an active 
metabolite of LEE011, accounted for approximately 8% (geometric mean) of the LEE011 AUC0-
24h following dosing at 600 mg. The human ADME study for LEE011 has not been conducted. 
1.3.7 LEE011 Drug-Drug Interactions 
At the therapeutic dose, the determined in vitro inhibition potential of LEE011 towards CYP1A2, 
CYP2E1 and CYP3A may translate into clinical significance. The predicted net exposure changes 
following CYP1A2, CYP2E1 and CYP3A4/5 inhibition are 1.4- (for the specific probe substrate 
theophylline), 1.3- (worst case assessment) and 8.8-fold (for the specific probe substrate 
midazolam), respectively). As LEE011 is mainly eliminated via CYP3A, it is likely subject to 
autoinhibition which could lead to an increase in LEE011 exposure over time.  The observed 
mean accumulation (Racc) of LEE011 was 2.5 in study CLEE011X2101 upon multiple dosing of 
600 mg and could be a combined effect of drug accumulation and auto-inhibition. Induction of 
CYP3A4 is not expected. Preliminary PK data from a clinical DDI study with midazolam (a 
CYP3A4 substrate) and caffeine (a CYP1A2 substrate) indicated LEE011 (400 mg) is a moderate 
CYP3A4 inhibitor, but did not have a substantial effect on CYP1A2 in humans. Based on these 
results, concomitant use of LEE011 with CYP3A4/5 substrates with narrow therapeutic index 

22 
Version 2.3, July 16, 2018 
should be avoided. Based on the minimal interaction observed with a sensitive CYP1A2 substrate 
in humans, LEE011 is unlikely to result in clinical interactions with CYP2E1 substrates (Ki,u for 
CYP2E1 > Ki,u for CYP1A2).The overall conclusions from this assessment are that caution is 
recommended for concomitant administration of LEE011 with sensitive substrates of renal 
transporters (OCT2 and MATE1) or sensitive substrates of BCRP. In addition, caution is 
recommended for BSEP inhibitors. Preliminary PK data from a DDI study with midazolam 
CLEE011A2106 indicate concomitant use of LEE011 with CYP3A4 substrates with a narrow 
therapeutic index should be avoided in patients receiving LEE011.  
 
1.3.8 Drug Interactions (LEE011 and everolimus) 
In vitro experiments observed time-dependent inhibition of CYP3A4 by LEE011 with a KI value 
of 5 μM and a kinact value of 0.0245 min-1; a clinical DDI confirmed these in vitro results. 
Everolimus is a sensitive CYP3A4 substrate. Therefore, a PK DDI was possible with the 
combination of everolimus and LEE011.(24) As of March 2, 2015, 84 patients have been treated 
with the combination of LEE011 + everolimus + exemestane in a Phase Ib study 
(CLEE011X2106). Everolimus (RAD001) was administered at 2.5 mg (QD) concurrently with 200 
mg, 250 mg and 300 mg of LEE011 (QD, 3 weeks on/1 week off) with or without food. Additionally 
350 mg of LEE011 was administered with 1 mg of everolimus without food or 2.5 mg everolimus 
with food and 200 mg of LEE011 was administered with 5 mg of everolimus with food. A fixed 
dose of 25 mg of exemestane (QD) was administered in each combination.(25)  
Preliminary PK data for Cmax and AUC0-24h for LEE011 and everolimus were available on Day 1 
and after multiple doses on Day 15. Everolimus (2.5 mg QD) exposure (AUC0-24h) was increased 
in the presence of LEE011 (200-350 mg) to levels of 5 to 10 mg when compared to historical 
single agent data.(26-29) In general, mean steady state exposure for LEE011 and everolimus 
appeared to be lower in the presence of food at the same dose level; however, individual Cmax 
and AUC0-24h values with food were within the range of values observed without food. Further 
evaluation of 2.5 mg of everolimus (RAD001) (QD) with 300 mg LEE011 (QD, 3 weeks on/1 week 
off) with food is ongoing in CLEE011X2106 dose expansion.(25) See Table 2 for full PK 
parameters. 
 
 
 

23 
Version 2.3, July 16, 2018 
Table 2. Pharmacokinetic Parameters of LEE011 and Everolimus at Steady State (Cycle 1, 
Day 15) 
Analyte 
Dose (LEE011 + 
EVE + EXE, mg 
Fasted/Fed 
N 
Cmax (ng/mL), 
Mean (SD) [n] 
AUC0-24h 
(h*ng/mL), mean 
(SD) [n] 
LEE011 
200 + 2.5 + 25 
Fasted 
6 
473 (305) [6] 
5200 (3540) [5] 
200 + 2.5 + 25 
Fed 
3 
315 (163) [3] 
4330 (3920) [3] 
250 + 2.5 + 25 
Fasted 
16 
818 (549) [14] 
9460 (6280) [11] 
250 + 2.5 + 25 
Fed 
5 
720 (301) [2] 
10 000 (4960) [2] 
300 + 2.5 + 25 
Fasted 
11 
1250 (690) [8] 
14 800 (9390) [8] 
300 + 2.5 + 25 
Fed 
12 
924 (505) [11] 
13 500 (7680) [8] 
350 + 1 + 25 
Fasted 
6 
989 (362) [5] 
11 900 (3390) [4] 
350 + 2.5 + 25 
Fed 
5 
896 (376) [5] 
12 700 (5640) [5] 
200 + 5 + 25 
Fed 
6 
580 (216) [5] 
6860 (2470) [5] 
EVE 
200 + 2.5 + 25 
Fasted 
6 
20 (5) [5] 
170 (47) [5] 
200 + 2.5 + 25 
Fed 
3 
8 (2) [3] 
1120 (32) [3] 
250 + 2.5 + 25 
Fasted 
16 
33 (14) [13] 
327 (161) [10] 
250 + 2.5 + 25 
Fed 
5 
24 (17) [2] 
257 (182) [2] 
300 + 2.5 + 25 
Fasted 
11 
35 (18) [7] 
365 (197) [7] 
300 + 2.5 + 25 
Fed 
12 
26 (9) [11] 
305 (135) [9] 
350 + 1 + 25 
Fasted 
6 
13 (3) [4] 
106 (30) [3] 
350 + 2.5 + 25 
Fed 
5 
26 (8) [5] 
287 (103) [5] 
200 + 5 + 25 
Fed 
6 
40 (12) [5] 
403 (124) [5] 
Historical single-agent data (steady state) 
EVE 
5 mg13 
 
4 
32 (9) [4] 
223 (74) [4] 
10 mg13 
 
7 
60 (17) [7] 
560 (283) [7] 
5 mg14 
 
23 
54 (12) [23] 
418 (87) [23] 
AUC0-24h, area under the curve from time zero to 24 h;   Cmax maximum plasma 
concentration; EVE, everolimus; EXE, exemestane; SD, standard deviation 
 
1.3.9 Clinical Safety of LEE011 when Combined with Everolimus and Exemestane 
In the ongoing Phase Ib/II clinical trial (CLEE011X2106), out of 70 patients treated with the triplet 
combination, LEE011 (200–350 mg 3 weeks on, 1 week off), everolimus (most at 2.5 mg), and 
exemestane (25 mg), the median number of prior regimens was 4, and 18 (25.7%) pts had 
received prior PI3K/AKT/mTOR or CDK4/6 inhibitors for metastatic disease. Grade 3/4 treatment-
related AEs (≥5% patients) were neutropenia (45.7%), leukopenia (8.6%), and thrombocytopenia 
(5.7%). Two (2.9%) patients discontinued due to AEs. Grade 3 AST/ALT AEs were appreciated 
in 2 patients, febrile neutropenia and hypophosphatemia (1 patient), oral mucositis (1 patient), 
rash and thrombocytopenia (1 patient), and thrombocytopenia with bleeding (1 patient). MTD and 
RDE were declared at LEE011 300 mg 3 weeks on, 1 week off, everolimus 2.5 mg daily and 
exemestane 25 mg daily. This combination dose appeared to be tolerable and safe.(25) See Table 
3 for full AE listing. 
 
 

24 
Version 2.3, July 16, 2018 
Table 3. LEE011X2106: Adverse Events (All grades ≥15% in All Patients Receiving Triplet 
Therapy) Suspected to Be Related to Treatments 
Adverse 
Event 
Grade 
R 200 mg + E 
2.5 mg 
R 250 mg + 
E 2.5 mg 
R 300 mg + E 
2.5 mg 
R 350 
mg + E 
1 mg 
 
R 350 
mg + E 
2.5 mg 
R 200 
mg + E 
5 mg 
All 
Patients 
With 
Triplet 
Therapy 
Fasted 
/Fed N 
 
Fasted 
n=6 
Fed 
n=3 
Fasted 
n=18 
Fed 
n=6 
Fasted 
n=11 
Fed 
n=12 
Fasted 
n=6 
Fed  
n=9 
Fed  
n=6 
N/A  
N=77 
Total 
All 
6 (100) 
3 
(10
0) 
17 
(94) 
5 
(83) 
11 
(100) 
12 
(100) 
6 (100) 
9 (100) 
6 (100) 
75 (97) 
G3/4 
2 (33) 
0 
11 
(61) 
1 
(17) 
10 
(91) 
10 
(83) 
2 (33) 
8 (89) 
4 (67) 
48 (62) 
Stomatitis 
All 
4(67) 
3 
(10
0) 
8 (44) 
5 
(83) 
7 (64) 
6 (50) 
2 (33) 
5 (56) 
2 (33) 
42 (55) 
G3/4 
0 
0 
0 
0 
0 
1 (8) 
0 
0 
0 
1 (1) 
Anemia 
All 
3 (50) 
1 
(33) 
9 (50) 
2 
(33) 
7 (64) 
6 (50) 
2 (33) 
3 (33) 
3 (50) 
36 (47) 
G3/4 
0 
0 
2 (11) 
1 
(17) 
1 (9) 
0 
0 
0 
1 (17) 
5 (7) 
Neutro-
penia 
All 
4 (67) 
0 
5 (28) 
1 
(17) 
6 (55) 
6 (50) 
3 (50) 
8 (89) 
3 (50) 
36 (47) 
G3/4 
2 (33) 
0 
2 (11) 
1 
(17) 
6 (55) 
4 (33) 
0 
7 (78) 
2 (33) 
24 (31) 
Neutrophil 
count 
decreased 
All 
0 
1 
(33) 
10 
(56) 
1 
(17) 
5 (46) 
5 (42) 
1 (17) 
2 (22) 
2 (33) 
27 (35) 
G3/4 
0 
0 
6 (33) 
0 
3 (27) 
4 (33) 
0 
0 
1 (17) 
14 (18) 
White 
blood cell 
count 
decreased 
All 
1 (17) 
2 
(67) 
5 (28) 
1 
(17) 
7 (64) 
3 (25) 
4 (67) 
1 (11) 
1 (17) 
25 (33) 
G3/4 
0 
0 
2 (11) 
0 
3 (27) 
2 (17) 
1 (17) 
1 (11) 
0 
9 (12) 
Thrombo-
cytopenia 
All 
1 (17) 
0 
6 (33) 
1 
(17) 
5 (46) 
6 (50) 
1 (17) 
4 (44) 
1 (17) 
25 (33) 
G3/4 
0 
0 
0 
1 
(17) 
2 (18) 
1 (8) 
0 
1 (11) 
0 
5 (7) 
AST 
increase 
All 
2 (33) 
1 
(33) 
5 (28) 
0 
4 (36) 
4 (33) 
1 (17) 
2 (22) 
2 (33) 
21 (27) 
G3/4 
0 
0 
0 
0 
2 (18) 
0 
0 
1 (11) 
0 
3 (4) 
ALT 
increase 
All 
3 (50) 
0 
2 (11) 
1 
(17) 
6 (55) 
5 (42) 
0 
1 (11) 
3 (50) 
21 (27) 
G3/4 
0 
0 
0 
0 
2 (18) 
1 (8) 
0 
0 
1 (17) 
4 (5) 
Nausea 
All 
1 (17) 
1 
(33) 
6 (33) 
1 
(17) 
3 (27) 
3 (25) 
1 (17) 
2 (22) 
1 (17) 
19 (25) 
G3/4 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 

25 
Version 2.3, July 16, 2018 
Adverse 
Event 
Grade 
R 200 mg + E 
2.5 mg 
R 250 mg + 
E 2.5 mg 
R 300 mg + E 
2.5 mg 
R 350 
mg + E 
1 mg 
 
R 350 
mg + E 
2.5 mg 
R 200 
mg + E 
5 mg 
All 
Patients 
With 
Triplet 
Therapy 
Rash 
All 
1 (17) 
1 
(33) 
2 (11) 
1 
(17) 
5 (46) 
2 (17) 
0 
2 (22) 
2 (33) 
16 (21) 
G3/4 
0 
0 
0 
0 
1 (9) 
0 
0 
0 
0 
1 (1) 
Platelet 
count 
decrease 
All 
2 (33) 
0 
3 (17) 
1 
(17) 
3 (27) 
2 (17) 
0 
2 (22) 
2 (33) 
15 (20) 
G3/4 
1 (17) 
0 
0 
0 
0 
0 
0 
0 
0 
1 (1) 
Diarrhea 
All 
1 (17) 
1 
(33) 
4 (22) 
0 
2 (18) 
2 (17) 
0 
1 (11) 
3 (50) 
14 (18) 
G3/4 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Lympho-
penia 
All 
3 (50) 
1 
(33) 
4 (22) 
0 
1 (9) 
2 (17) 
2 (33) 
0 
1 (17) 
14 (18) 
G3/4 
1 (17) 
0 
3 (17) 
0 
0 
1 (8) 
0 
0 
0 
5 (7) 
Fatigue 
All 
0 
1 
(33) 
3 (17) 
1 
(17) 
2 (18) 
2 (17) 
2 (33) 
1 (11) 
1 (17) 
13 (17) 
G3/4 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Lympho-
cyte count 
decreased 
All 
0 
0 
5 (28) 
1 
(17) 
4 (36) 
1 (8) 
1 (17) 
0 
1 (17) 
13 (17) 
G3/4 
0 
0 
3 (17) 
0 
0 
0 
0 
0 
0 
3 (4) 
 ALT, alanine aminotransferase; AST, aspartate aminotransferase; E, everolimus; G, Grade; R, LEE011. 
 
1.4  Everolimus (Afinitor® Package Insert(29)) 
1.4.1 Chemical Structure of Everolimus 
Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase 
downstream of the phosphoinositide 3-kinase (PI3K)/AKT pathway.  Its chemical name is 
(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(1R)-
2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-
15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-
16,24,26,28-tetraene-2,3,10,14,20-pentaone. The molecular formula is C53H83NO14 and the 
molecular weight is 958.2 grams per mole. The tablets also contain anhydrous lactose, butylated 
hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate as 
inactive ingredients. 
 
 
 

26 
Version 2.3, July 16, 2018 
Figure 11: Molecular Structure of Everolimus 
 
 
 
1.4.2 Everolimus Mechanism of Action 
Everolimus inhibits mTOR kinase activity by binding to FKBP-12 intracellularly forming a complex 
with mTOR complex 1 (mTORC1).  This inhibition has been demonstrated to decrease cell 
proliferation and angiogenesis through decreased expression of hypoxia-inducible factor 1 (HIF-
1) and vascular endothelial growth factor (VEGF).  It also reduces protein synthesis by decreasing 
activity of S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein 
1 (4E-BP1). 
 
1.4.3 Everolimus Pharmacokinetics  
Peak serum concentrations are observed within 1-2 hours and are proportional to dosing between 
5 and 10 mg daily.  Above 20 mg the maximum concentration is less than dose-proportional, but 
the AUC demonstrates a maintenance of dose-proportionality up to 70 mg.  Steady-state 
concentration is reached in 2 weeks.  Fatty meals may reduce serum concentrations, and it is 
recommended that patients take the medication consistently either with or without food.  Blood-
to-plasma ratio is 17-73%, with about 20% confined to plasma, and 74% plasma protein binding. 
 
Everolimus is a potent competitive inhibitor of CYP3A4, a mixed inhibitor of CYP2D6, and a 
substrate of PgP.  Thus, avoidance of co-administration with strong CYP3A4/PgP inhibitors and 
dose-reduction with moderate CYP3A4/PgP inhibitors is recommended.  80% of the drug is 
excreted in the feces and 5% in the urine, with a mean half-life of elimination of about 30 hours.  
Clearance of everolimus does not vary based on creatinine clearance (as low as 25 mL/min) and 
no dose adjustment is recommended; however, no clinical studies were conducted in patients 
with decreased renal function.  There are notable increases in serum concentration of everolimus 
in patients with impaired liver function, with relative increases in AUC by 1.8-, 3.2-, and 3.6-fold 
in patients with Child-Pugh classes A, B, and C respectively. Recommended dose adjustments 
include decreasing to 7.5 mg daily, 5 mg daily, and 2.5 mg daily in Child-Pugh classes A, B, and 
C respectively, with further dose reductions for tolerability.  Use in Child-Pugh class C is only 
recommended if the benefits outweigh the risks of administration. 
 
QTc prolongation was not seen in a trial of 59 healthy subjects given doses up to 50 mg in a single 
dose, and carcinogenesis was not observed in animal studies.  Animal studies do suggest that 
everolimus may impair male and female fertility. 
 
After administration of AFINITOR tablets in patients with advanced solid tumors, peak everolimus 
concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 

27 
Version 2.3, July 16, 2018 
70 mg. Following single doses, Cmax is dose-proportional with daily dosing between 5 mg and 10 
mg. With single doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, 
however AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was 
achieved within 2 weeks following once-daily dosing.  
 
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 
5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 
20% at blood concentrations observed in cancer patients given everolimus 10 mg/day. Plasma 
protein binding is approximately 74% both in healthy subjects and in patients with moderate 
hepatic impairment.  
 
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the 
main circulating component in human blood. Six main metabolites of everolimus have been 
detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-
opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were 
also identified in animal species used in toxicity studies, and showed approximately 100-times 
less activity than everolimus itself.  
 
In vitro, everolimus competitively inhibited the metabolism of CYP3A4 and was a mixed inhibitor 
of the CYP2D6 substrate dextromethorphan.  
 
No specific elimination studies have been undertaken in cancer patients. Following the 
administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving 
cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in 
the urine. The parent substance was not detected in urine or feces. The mean elimination half-life 
of everolimus is approximately 30 hours. 
 
1.4.4 Everolimus Drug Approval 
Everolimus (Afinitor®) is currently approved by the Food and Drug Administration (FDA) for 
multiple indications: postmenopausal advanced hormone-receptor positive, HER2-negative 
breast cancer in combination with exemestane after failure with letrozole or anastrozole, 
pancreatic neuroendocrine tumors (PNET) that are unresectable, locally advanced, or metastatic, 
advanced renal cell carcinoma (RCC) after failure with sutininib or sorafenib, renal 
angiomyolipoma and tuberous sclerosis complex (TSC) not requiring immediate surgery, and 
TSC with subependymal giant cell astrocytoma (SEGA) that is unresectable.  Everolimus 
(Zortress®) is also approved for organ rejection prophylaxis in kidney and liver transplant patients. 
 
1.5 Pancreatic Cancer 
Cancer of the pancreas is the fourth leading cause of cancer death in the United States, with an 
estimated 48,960 new diagnoses and 40,560 deaths attributable to the disease in 2015(30).  
Presently, surgical resection offers the only chance of cure.  However only 15 to 20 percent of 
patients have resectable disease at initial diagnosis; the majority have either locally advanced or 
metastatic cancer.  Of those who are surgical candidates, most will have disease relapse after 
curative surgery.  Reported five-year survival rates following pancreaticoduodenectomy for node-
negative and node-positive disease are 25 to 30, and 10 percent, respectively(31, 32).  For those 
who are unresectable at diagnosis, the outcomes are even poorer. Median survival is 12-15 
months for patients with locally advanced unresectable disease, and only 8-11 months for those 
who present with metastases(2-4, 33-36).  Thus, better medical intervention is desperately needed. 
 
 
1.5.1 First Line Therapy in Pancreatic Cancer 
Only recently have there been improvements in systemic therapy for advanced pancreatic cancer.  
Originally, gemcitabine became the standard front line therapy after a head to head comparison 

28 
Version 2.3, July 16, 2018 
with 5-fluorouracil (5-FU) showed gemcitabine to be superior(2). Gemcitabine and 5-FU were 
found to yield an 18 percent versus 2 percent one-year survival and a 24 percent versus 4.8 
percent improvement in clinical benefit response, respectively.  For over 10 years, no clinically 
meaningful improvement in survival was achieved for any regimen compared to gemcitabine 
alone. Finally in 2011, the combination of 5-FU, oxaliplatin, and irinotecan (FOLFIRINOX) was 
compared against gemcitabine in a phase III trial with promising results, and FOLFIRINOX is 
considered the standard first-line treatment option in patients with a good performance status (PS 
0-1)(3). The median overall survival (mOS) was 11.1 months in the FOLFIRINOX group as 
compared with 6.8 months in the gemcitabine group.  The mPFS was 6.4 months in the 
FOLFIRINOX group as compared with 3.3 months in the gemcitabine group.  The objective 
response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group 
(P<0.001). More adverse events were noted in the FOLFIRINOX group including 5.4% of patients 
in this group who had febrile neutropenia.  More recently, in a 2013 Phase III trial, the combination 
of gemcitabine and nab-paclitaxel was also demonstrated to be superior over gemcitabine alone(4). 
The median overall survival of gemcitabine and nab-paclitaxel was 8.5 months, which was 
statistically superior to the 6.7 month survival seen with single agent gemcitabine. The mPFS was 
5.5 months in the gemcitabine plus nab-paclitaxel group as compared with 3.7 months in the 
gemcitabine group.  The objective response rate was 23% in the gemcitabine plus nab-paclitaxel 
group versus 7% in the gemcitabine group (P<0.001). More adverse events were noted in the 
gemcitabine plus nab-paclitaxel group including 3% of patients in this group who had febrile 
neutropenia.   This trial has effectively established gemcitabine plus nab-paclitaxel as another 
definitive first-line treatment option for patients with metastatic pancreatic cancer.  These two trials 
now form the standard for comparison for first line treatment for metastatic pancreatic cancer, and 
it should be noted that, based on these data, patients on the study proposed herein who are 
receiving first line therapy will be expected to remain on first line therapy for an average of ~6 
months.  
 
1.5.2 Second Line Therapy in Pancreatic Cancer 
Research into second line therapy for pancreatic cancers is yet to reveal an obvious choice that 
shows efficacy above and beyond its comparators.  Second line trials have demonstrated 
response rates of 2.5 to 24% and mOS rates of 4 to 6 months(37-55).  The best mOS rate from 
combination therapy for second line treatment is typically around six months (range 3-9 months). 
Promising data came from the results of the CONKO-003 trial(37).  Patients who had progressed 
on gemcitabine were randomized to 5-FU plus oxaliplatin vs. best supportive care (which could 
include 5–FU alone).  Patients treated with a combination of 5-FU and oxaliplatin had a mOS of 
~11 months as measured from the start of gemcitabine therapy.  Additionally, Conroy, et al 
reported the mOS in patients receiving second-line therapy in the FOLFIRINOX vs. gemcitabine 
trial(3).  In both arms, the mOS for second line therapy was 4.4 months.  There are no prospective 
trials of FOLFORINOX in patients whose disease had progressed on first line treatment, but a 
single-institution retrospective study of 27 patients treated with second-line FOLFIRINOX showed 
an ORR of 19 percent, and 12 others had stable disease (44%), and the median time to tumor 
progression was 5.4 months(38). Finally, the recently presented NAPOLI-1 Phase III trial 
demonstrated an improvement in overall survival of the combination of MM-398 plus 5-FU over 
5-FU alone and it is anticipated this trial will lead to the first approved agent in the second line 
setting for metastatic pancreatic cancer(55). In the NAPOLI-1 trial, the median PFS for MM-398 
plus 5FU was 3.1 months vs. 1.5 months for 5-FU alone.  
 
1.5.3 Third Line Therapy in Pancreatic Cancer 
Previous studies of third-line therapy in mPAC are limited but reveal stable disease in 25-31% of 
patients with no partial or complete responses (31% of patients in the GVAX/CRS-207 
combination vaccine study had stable disease but only 52% of these patients were treated in the 
third-line setting)(5, 6).  
 

29 
Version 2.3, July 16, 2018 
2.0 STUDY OBJECTIVES 
2.1 Primary Objective:  
2.1.1 Primary Objective of the Phase I Portion: To determine the Recommended Phase II dose 
(RP2D) of LEE011 in the combination with everolimus in patients with mPAC refractory to 5-FU- 
and GEM-based chemotherapy 
 
2.1.2 Primary Objective of the Phase II Portion: To determine the progression-free survival (PFS) 
rate at 8 weeks (PFS8 weeks) to assess the clinical efficacy of the combination of LEE011 and 
everolimus in patients with mPAC refractory to 5-FU- and GEM-based chemotherapy 
 
2.2 Secondary Objectives 
2.2.1 To determine the mPFS of patients treated with the combination of LEE011 and everolimus 
in patients with mPAC refractory to chemotherapy 
 
2.2.2 To determine the mOS of patients treated with the combination of LEE011 and everolimus 
in patients with mPAC refractory to chemotherapy 
 
2.2.3 To determine the best ORR, the largest percent decrease in tumor size from baseline as 
measured by expert radiologists using RECIST v1.1 criteria, defined as the proportion of patients 
with a CR or PR, of the combination of LEE011 and everolimus in patients with mPAC refractory 
to chemotherapy 
 
2.2.4 To determine the safety and tolerability of the combination of LEE011 and everolimus in 
patients with mPAC refractory to chemotherapy 
 
2.3 Exploratory Objectives: 
2.3.1 To correlate the PFS8 weeks to correlative scientific markers, including the analysis of tumor 
biopsies and blood-based markers, including RB, pRB, p16, cyclin D1, Ki67, MCM7, and pS6 
levels by immunohistochemistry    
 
2.3.2 To screen for use a targeted sequencing approach for genetic lesions observed in 
pancreatic cancer that includes KRAS, SMAD4, TP53, CDKN2A as well as other commonly 
mutated cancer genes 
 
2.3.3 To assess blood for the analysis of circulating tumor DNA as a surrogate marker of disease 
burden.   KRAS and other mutations will be used as the determinants of tumor selective DNA 
 
2.4 Primary Endpoint:  
PFS at 8 weeks in a patient with refractory mPAC treated with LEE011 and everolimus, defined 
as positive if a patient does not have evidence of PD at 8 weeks as measured by expert 
radiologists using RECIST v1.1 criteria 
 
2.5 Secondary Endpoints: 
2.5.1 PFS in a patient with refractory mPAC treated with LEE011 and everolimus, defined as the 
time from Cycle 1, Day 1 to PD (as measured by expert radiologists using RECIST v1.1 criteria), 
death from any cause, or last follow-up, as determined by the investigator 
 
2.5.2 Overall survival (OS) in a patient with refractory mPAC treated with LEE011 and everolimus, 
defined as the time from Cycle 1, Day 1 to death from any cause or last follow-up 
 
2.5.3 Best response in a patient, defined as the largest percent decrease in tumor size from 
baseline and categorized as a CR, PR, or SD by imaging studies, measured by expert radiologists 
using RECIST v1.1 criteria  

30 
Version 2.3, July 16, 2018 
2.5.4 Adverse events in a patient with refractory mPAC treated with LEE011 and everolimus, 
defined as the number of grade 3 and 4 toxicities according to National Cancer Institute Common 
Toxicity Criteria for Adverse Events (NCI CTCAE v4.03) that occur after Cycle 1, Day 1  
 
2.6 Exploratory Endpoints: 
2.6.1 Measurements of tumor cell proliferation, apoptosis, and RB-related gene expression by 
immunohistochemistry 
(IHC) 
in 
the 
pre-treatment 
and 
on-treatment 
biopsies: 
 
2.6.1.1 RB, defined as positive if any tumor cells have RB nuclear staining  
 
2.6.1.2 pRB, defined as positive if any tumor cells have phosphorylated-RB nuclear staining  
 
2.6.1.3 p16, defined as positive if there is positive nuclear staining in 5% or more of tumor cells 
 
2.6.1.4 Cyclin D1, defined as positive if any tumor cells have cyclin D1 nuclear staining  
 
2.6.1.5 Ki67, defined as a percentage of positively stained cells (nuclear staining and mitotic 
figures) among the total number of malignant cells viewed in at least 3 randomly-selected high-
power (x40 objective) fields 
 
2.6.1.6 MCM7, defined as a percentage of positively stained cells (nuclei) among the total number 
of malignant cells viewed in at least 3 randomly-selected high-power (x40 objective) fields 
 
2.6.1.7 pS6, defined using a histoscore of intensity and percent of tumor cells staining 
 
2.6.2 Frequency of mutations (including, for example, KRAS, CDKN2A, SMAD4, and TP53) in the 
initial biopsy specimen from targeted NGS analyses from pre-treatment and on-treatment biopsy 
specimens 
 
2.6.3 Frequency of mutations (including, for example, KRAS, CDKN2A, SMAD4, and TP53) from 
ctDNA as measured by quantitative PCR collected as detected in 5mL of serial blood samples 
collected every 8 weeks  
 
2.7 Indication: 
Patients with mPAC who have progressed on 5-FU- and GEM-based chemotherapy 
 
 
 
 
 

31 
Version 2.3, July 16, 2018 
3.0 SUBJECT POPULATION 
3.1 Subject Population, Number of Subjects and Feasibility 
(See Appendix C for Study Eligibility Checklist) 
 
3.1.1 Subject Population 
Patients with metastatic pancreatic adenocarcinoma whose disease has progressed on at least 
one 5-FU-based regimen and at least one GEM-based regimen for metastatic disease 
(progression during or within 3 months of the completion of adjuvant therapy is acceptable), and  
who have biopsiable disease, and who have an adequate performance status (PS), bone marrow, 
hepatic, and renal function 
 
3.1.2 Number of Subjects 
26 evaluable patients for the Phase II portion 
 
3.1.3 Feasibility 
Patients will be enrolled from the Lombardi Comprehensive Cancer Center (LCCC) at 
Georgetown University, and from partner institutions involved in this protocol. Only patients with 
mPAC will be eligible for enrollment.  At our centers, over 300 new cases of pancreatic cancer 
are seen annually, at least one-half are metastatic, and around 25% of these patients would be 
eligible for further treatment after progression on 5-FU- and gemcitabine-based chemotherapy 
regimens.  Therefore, around 18 patients would be eligible for enrollment in this trial each year.  
Based on this, we expect to accrue 1.5 patients per month, completing accrual in about 29 months. 
 
3.2 Inclusion Criteria 
1. Histologically confirmed mPAC (mixed histology is acceptable as long as the predominant 
histology is pancreatic adenocarcinoma) 
2. Patient must consent to two mandatory biopsies and have tumor amenable to biopsy 
o Tumor biopsies are mandatory UNLESS the patient has been evaluated for a biopsy 
in consultation with radiology in good faith, and there is a determination that an attempt 
at a biopsy would cause undue risk to the patient. 
3. Measurable disease by RECIST v1.1 criteria (tumor ≥ 1 cm in longest diameter on axial 
image on CT or MRI and/or lymph node(s) ≥ 1.5 cm in short axis on CT or MRI) on baseline 
imaging 
4. Documented progression of disease on at least one 5-FU-based regimen and at least one 
GEM-based regimen for metastatic disease (progression during or within 3 months of the 
completion of adjuvant therapy is acceptable) 
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 (see Table 
2) 
6. Age ≥ 18 years 
7. Subjects with no brain metastases or a history of previously treated brain metastases who 
have been treated by surgery or stereotactic radiosurgery (SRS) at least 4 weeks prior to 
enrollment and have a baseline MRI that shows no evidence of active intracranial disease 
8. Patients with available standard 12-lead ECG with the following parameters at screening 
(defined as the mean of the triplicate ECGs): 
• 
QTcF interval at screening <450msec 
• 
Resting heart rate 50-90bpm 

32 
Version 2.3, July 16, 2018 
9. Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm3; Platelets ≥100 × 
109/L; hemoglobin ≥ 9.0 g/dL 
• 
Patients may have a transfusion of red blood cells to meet the hemoglobin requirement 
10. Renal function: serum creatinine ≤ 1.5 × upper normal limit of institution's normal range or 
creatinine clearance ≥ 50 mL/min/1.73 m2 for subjects with creatinine levels above 
institutional normal 
11. Hepatic function: AST and ALT ≤ 3.0 × the upper normal limit of institution's normal range. 
Total bilirubin ≤ 1.5 × the upper normal limit of institution's normal range. For subjects with 
liver metastases, AST and ALT < 5 × the upper normal limit of institution's normal range, 
and total bilirubin >1.5 - 3.0 x the upper normal limit of institution's normal range are 
acceptable as long as there is no persistent nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash, or eosinophilia. 
12. Partial Thromboplastin Time (PTT) must be ≤ 1.5 × upper normal limit of institution's 
normal range and INR (International Normalized Ratio) ≤ 1.5. Subjects on anticoagulant 
(such as warfarin) will be permitted to enroll as long s the INR is in the acceptable 
therapeutic range as determined by the investigator. 
13. Potassium, total calcium (corrected for serum albumin), magnesium, sodium and 
phosphorus within normal limits for the institution or corrected to within normal limits with 
supplements before first dose of study medication 
14. Patients must have fully recovered from all effects of surgery.  Patients must have had at 
least two weeks after minor surgery and four weeks after major surgery before starting 
therapy.  Minor procedures requiring “Twilight” sedation such as endoscopies or mediport 
placement may only require a 24-hour waiting period, but this must be discussed with an 
investigator. 
15. Patients and their partners must avoid pregnancy during the trial, and for 21 days after 
stopping the study medications 
o Avoidance of pregnancy may include total abstinence when this is in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception 
o Eligible female patients may have undergone surgical bilateral oophorectomy with 
or without hysterectomy, total hysterectomy, or tubal ligation at least six weeks 
before taking study treatment. In case of oophorectomy alone, patients are eligible 
only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment  
o Eligible male patients and male partners of patients must also agree to avoid 
pregnancy during the trial, and for 21 days after stopping the study medications 
o Women of childbearing potential must have a negative serum pregnancy test 
within 14 days prior to initiation of treatment and/or postmenopausal women must 
be amenorrheic for at least 12 months to be considered of non-childbearing 
potential 
16. Patient is capable of swallowing pills whole 
17. Patient is capable of understanding and complying with parameters as outlined in the 
protocol and able to sign and date the informed consent, approved by the Institutional 
Review Board (IRB), prior to the initiation of any screening or study-specific procedures 
 
 

33 
Version 2.3, July 16, 2018 
Table 4. ECOG Performance Status 
 
 
 
3.3 Exclusion Criteria 
1. Patients previously exposed to, intolerant of, or ineligible for CDK inhibitors, mTOR 
inhibitors, and/or their combination 
2. Prior anti-tumor therapy within 3 weeks of Cycle 1 Day 1 (anti-tumor therapy defined as, 
but is not limited to, anti-cancer agents (cytotoxic chemotherapy, immunotherapy, and 
biologic therapy), radiotherapy, and investigational agents), the “wash-out period” 
3. 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 clinical study or compromise compliance with the protocol (e.g. chronic 
pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or 
viral infections, etc.). 
4. Women who are pregnant or breastfeeding 
5. Concurrent use of CYP3A4 inhibiting or activating medications 
6. Concurrent use of an ACE inhibitor (increased risk of angioedema with ACE inhibitors 
administered in combination with everolimus, seen in approximately 6.8% of patients) 
7. Psychiatric illness or social situation that would limit compliance with study requirements 
8. Patient has a concurrent malignancy or malignancy within 3 years prior to starting study 
drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-
melanomatous skin cancer or curatively resected cervical cancer. 
9. Patients with central nervous system (CNS) involvement unless they meet ALL of the 
following criteria: 
• 
At least 4 weeks from prior therapy completion (including radiation and/or surgery) to 
starting the study treatment 
• 
Clinically stable CNS tumor at the time of screening and not receiving steroids and/or 
enzyme-inducing anti-epileptic medications for brain metastases. 
10. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly 
alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome, or small bowel resection). 
11. Patient has a known history of HIV infection or chronic, active Hepatitis B (testing not 
mandatory). 
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
Ambulatory and capable of all self-care but unable to carry out any
work activities. Up and about more than 50% of waking hours.
2
Restricted in physically strenuous activity but ambulatory and able to  carry 
out work of a light or sedentary nature, e.g., light housework, office work.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
Ambulatory and capable of all self-care but unable to carry out any
work activities. Up and about more than 50% of waking hours.
2
Restricted in physically strenuous activity but ambulatory and able to  carry 
out work of a light or sedentary nature, e.g., light housework, office work.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade

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Version 2.3, July 16, 2018 
12. 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 clinical study or compromise compliance with the protocol (e.g. chronic 
pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or 
viral infections, etc.). 
13. Clinically significant, uncontrolled heart disease and/or cardiac repolarization 
abnormalities, including any of the following: 
• 
History of acute coronary syndromes (including myocardial infarction, unstable angina, 
coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic 
pericarditis within 6 months prior to screening 
• 
History of documented congestive heart failure (New York Heart Association functional 
classification III-IV) 
• 
Documented cardiomyopathy 
• 
Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated 
acquisition (MUGA) scan or echocardiogram (ECHO) at screening 
• 
Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz type II and 
third-degree AV block) 
• 
Long QT syndrome or family history of idiopathic sudden death or congenital long QT 
syndrome, or any of the following: 
• 
Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or 
hypomagnesemia, 
history 
of 
cardiac 
failure, 
or 
history 
of 
clinically 
significant/symptomatic bradycardia. 
o Concomitant use of medication(s) with a known risk to prolong the QT interval 
and/or known to cause Torsades de Pointe that cannot be discontinued (within 5 
half-lives or 7 days prior to starting study drug) or replaced by safe alternative 
medication 
o Inability to determine the QT interval on screening (QTcF, using Fridericia’s 
correction) 
o Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening 
14. Patient is currently receiving any of the following medications and cannot be discontinued 
7 days prior to starting study drug (see Table 4 for details): 
• 
Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit 
hybrids, pummelos, star-fruit, and Seville oranges 
• 
That have a narrow therapeutic window and are predominantly metabolized through 
CYP3A4/5 
• 
Herbal preparations/medications, dietary supplements. 
15. Patient is currently receiving or has received systemic corticosteroids ≤2 weeks prior to 
starting study drug, or who have not fully recovered from side effects of such treatment. 
• 
Note: 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).  
 
 

35 
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3.4 Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins and/or 
herbal supplements) that the subject is receiving at Screening up to the Final Visit must be 
recorded in source documents and the case report forms (CRFs). The reason for use, date(s) of 
administration (including start and end dates), and dosage information (including dose and 
frequency) must be recorded. Any change in concomitant therapy during the study period must 
be similarly recorded. Questions regarding prior or concomitant therapy should be directed to one 
of the investigators. 
 
3.4.1 Prior Anti-cancer Therapy 
For purposes of this protocol, anti-tumor treatment may be defined as, but is not limited to, anti-
cancer agents (cytotoxic chemotherapy, immunotherapy, or biologic therapy), radiotherapy, and 
investigational agents. An investigational agent is any drug or therapy not currently approved for 
use in humans. 
 
3.4.2 Prior Surgery 
Patients must have fully recovered from all effects of surgery.  Patients must have had at least 
two weeks after minor surgery and four weeks after major surgery before starting therapy.  Minor 
procedures requiring “Twilight” sedation such as endoscopies or mediport placement may only 
require a 24 hour waiting period, but this must be discussed with an investigator. 
 
3.4.3 Supportive Care 
Subjects should receive best supportive care and treatment of symptoms during the study as 
appropriate, including transfusion of blood and blood products, oxygen therapy, nutritional support, 
intravenous fluids, and treatment with appropriate medications (antibiotics, antiemetics, 
antidiarrheals, and analgesics, etc.).  Medications which are given for supportive care, such as 
appetite stimulation, may be given concurrently. 
 
3.4.3.1 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. 
 
3.4.3.2 Hematopoietic growth factors 
Hematopoietic growth factors may be used according to ASCO guidelines. 
 
3.4.3.3 Palliative radiotherapy 
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. No dose 
modification of study treatment is needed during palliative radiotherapy. 
 
3.4.3.4 Corticosteroids 
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to lead to 
induction of CYP3A enzymes, thereby potentially increasing the risk of reducing LEE011 drug 
exposure to subtherapeutic levels. Systemic corticosteroid treatment should not be given during 
the study, except for: 
• 
Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways diseases), eye 
drops or local injections (e.g., intra-articular); 
A short duration (< 5 days) of systemic corticosteroids ≤ to the anti-inflammatory potency of 4 mg 
dexamethasone (e.g. for chronic obstructive   pulmonary disease, or as an antiemetic) 
 
 

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Version 2.3, July 16, 2018 
3.4.4 Drugs with QT prolongation 
As far as possible, avoid co-administration of QT prolonging drugs or any other drugs with the 
potential to increase the risk of drug-related QT prolongation (e.g., via a potential DDI that 
increases the exposure of LEE011 or the exposure of the QT prolonging drug). A definitive list of 
drugs with a known risk, possible risk, or conditional risk of QT prolongation and/or Torsades de 
Pointes (TdP) is available online at www.qtdrug.org. 
 
Medications with a known risk for QT prolongation are prohibited during study treatment. 
 
3.4.5 Permitted concomitant therapy requiring caution 
Medications to be used with caution during LEE011 and everolimus in this study are listed below 
(see Table 3). This list is not comprehensive and is only meant to be used as a guide. These 
medications should be excluded from patient use if possible. If they must be given, then use with 
caution and consider a LEE011 and everolimus interruption if the concomitant medication is only 
needed for a short time. 
• 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 
 
 
 

37 
Version 2.3, July 16, 2018 
Table 5. List of Medications to be Used with Caution During Study Drug Treatment 
Category 
Drug Name 
Moderate CYP3A4/5 
inhibitors 
Aprepitant, amprenavir, asafoetida resin (Ferula asafoetida) cimetidine, crizotinib, 
diltiazem, faldaprevir,  imatinib,  isavuconazole, netupitant, nilotinib, tofisopam, 
Schisandra sphenanthera (nan wu wei zi), verapamil 
Moderate CYP3A4/5 
inducers 
Bosentan, dabrafenib, efavirenz, etravirine, genistein,lopinavir5, modafinil, 
nafcillin, telotristat 
Sensitive CYP3A4/5 
substrates1 
Alpha-dihydroergocryptine,  aprepitant,  atorvastatin, avanafil, 
bosutinib,brotizolam, budesonide, buspirone,  cobimetinib,   darifenacin, 
dasatininb, ebastine, eletriptan, eplerenone, everolimus, felodipine, fluticasone, 
grazoprevir, ibrutnib, isavuconazole, ivabradine, ivacaftor, , levomethadyl (LAAM), 
lomitapide, lovastatin, lumefantrine, lurasidone, maraviroc, midazolam, 
midostaurin, naloxegol, neratinib, nisoldipine, perospirone, quetiapine, 
ridaforolimus, sildenafil, simeprevir, simvastatin, ticagrelor, tilidine,  tolvaptan, 
triazolam, ulipristal, vardenafil, venetoclax, vicriviroc, voclosporin 
BSEP inhibitors 
Alectinib, atorvastatin,  bromocriptine, candesartan, clobetasol, clofaziminie, 
dabigatran, dipyridamole, glyburide, grazoprevir, ledipasvir, 
mifepristone,pioglitazone, reserpine,rifamycin, simeprevir, telmisartan,timcodar, 
troglitazone, valinomycin, velpatasvir 
Medications that carry a 
possible risk for QT 
prolongation2 
Alfuzosin, apomorphine, aripiprazole, artenimol+piperaquine , asenapine, 
atomoxetine,  bedaquiline, bendamustine, bortezomib, bosutinib, buprenorphine, 
cabozantinib, capecitabine, ceritinib, clomipramine, crizotinib,clozapine, 
cyamemazine (cyamepromazine), dabrafenib, dasatinib, degarilix, delamanid, 
desipramine, dexmedetomidine, dolasetron, efavirenz, eliglustat, epirubicin, 
eribulin mesylate, ezogabine(retigabine), famotidine, felbamate, fingolimod, 
flupentixol,  gemifloxacin, granisetron, hydrocodone-ER, iloperidone, imipramine 
(melipramine), isradipine, ketanserin, lapatinib, lenvatinib, leuprolide, lithium, 
melperone, midostaurin, mifepristone, mirabegron, mirtazapine, moexipril/HCTZ, 
necitumumab, nicardipine, nilotinib, norfloxacin, nortriptyline, nusinersen, 
ofloxacin, osimertinib,  oxytocin, paliperidone, palonosetron,  panabinostat, 
pasireotide, pazopanib, perflutren lipid microspheres, perphenazine, pilsicainide, 
pimavanserin, pipamperone, promethazine, prothipendyl,  rilpivirine, risperidone, 
romidepsin, sertindole, sorafenib, sunitinib, tamoxifen, tipiracil/trifluridine, 
tizanidine, tolterodine, toremifene,trimipramine, tropisetron, vardenafil, 
vemurafenib, venlafaxine, vorinostat, ziprasidone 
MATE1/2 substrates3 
Acyclovir, cephalexin, cimetidine, fexofenadine, ganciclovir, glycopyrronium, 
metformin, pindolol, plisicainide, ranitidine, topotecan, varenicline 
OCT1/2 substrates4 
Amantadine,  6-beta-hydroxycortisol, carboplatin, cisplatin, cephalexin, 
cephradine, ipratropium, lamivudine, linagliptin, metformin, oxyplatin, oxybutynin, 
phenformin, picoplatin, pilsicainide, pindolol, ranitidine, sorafenib,  tropisetron, 
trospium, umeclidinium, and zidovudine 
BCRP substrates 
Daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, imatinib, methotrexate, 
mitoxantrone, pitavastatin, rosuvastatin, irinotecan, ethinyl estradiol, simvastatin, 
sulfasalazine, sofosbuvir, tenofovir, topotecan, venetoclax 
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  The list provided is as of January 2018. Check https www 
crediblemeds.org/healthcare-providers/drug-list for the most updated list. 
3 MATE1 and MATE2 share considerable substrate specificity.  
4 OCT1 and OCT2 share considerable substrate specificity. 
5 Lopinavir is prohibited when combined with ritonavir  
 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations for 
Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” Flockhart 
Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug Interactions: 
Table of Substrates, Inhibitors and Inducers. 
 
3.4.6 Prohibited concomitant therapy 
The following medications are prohibited during study treatment in the study (see Table 4). 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 

38 
Version 2.3, July 16, 2018 
• Medications that carry a known risk for QT prolongation 
• Other investigational and antineoplastic therapies not part of the study 
• Herbal medications/preparations, dietary supplements (except for vitamins) including, but 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. 
 
Table 6. List of Prohibited Medications During Study Drug Treatment 
Category 
Drug Name 
Strong CYP3A4/5 inhibitors 
Atazanavir/ritonavir, boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, darunavir/ritonavir, elvitegravir/ritonavir, grapefruit juice, 
idelalisib, indinavir, indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir,ombitasvir/paritaprevir/dasabuvir/ritonavir (VIEKIRA PAK), 
posaconazole, ritonavir,  saquinavir/ritonavir, telaprevir, telithromycin, 
tipranavir/ritonavir, troleandomycinvoriconazole 
Strong CYP3A4/5 inducers 
carbamazepine3, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin3, 
rifabutin, rifampin (rifampicin)3, St. John's wort (hypericum perforatum)2,3 
CYP3A4/5 substrates with 
NTI1 
Alfentanil, astemizole, cisapride, cyclosporine, diergotamine 
(dihydroergotamine), ergotamine, fentanyl,  pimozide, quinidine,  sirolimus, 
tacrolimus 
Medications with a known risk 
for QT prolongation4 
Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, chloroquine,  
chlorpromazine, cilostazol, ciprofloxacin, cisapride, citalopram, clarithromycin, 
disopyramide, dofetilide, domperidone, donepezil, dronedarone, droperidol, 
erythromycin, escitalopram, flecainide, fluconazole, gatifloxacine, grepafloxacin, 
halofantrine, haloperidol, ibutilide, levofloxacin, levomepromazine, levosulpiride, 
methadone, moxifloxacin, ondansetron, oxaliplatin, papaverine HCl (intra-
coronary), pentamidine, pimozide,  procainamide, propofol, quinidine, 
roxithromycin, sevoflurane, sotalol,  sulpiride, sultopride, terlipressin, terodiline,  
thioridazine, vandetanib 
Herbal preparations/ 
medications 
Herbal preparations/medications known as strong inducers or inhibitors of 
CYP3A4/5 or those with a known risk of QT prolongation 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, all SERMS (including raloxifene), 
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) or 
drugs which have <2-fold difference in the minimum toxic concentrations and minimum effective concentrations in 
the blood. 
2 Herbal product 
3 P-gp inducer 
4 The list provided is as of January 2018.Check https www crediblemeds.org/healthcare-providers/drug-list for the 
most updated list.  
As far as possible, avoid co-administration of QT prolonging drugs or any other drugs with the potential to 
increase the risk of drug-related QT prolongation (e.g., via a potential DDI that increases the exposure of ribociclib 
or the exposure of the QT prolonging drug). A definitive list of drugs with a known risk, possible risk, or conditional 
risk of QT prolongation and/or Torsades de Pointes (TdP) is available online at qtdrugs.org. 
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication Considerations for 
Novartis Clinical Trials (January 2018), which is compiled from Indiana University “Clinically Relevant” Flockhart 
Table™, University of Washington Drug Interaction Database, and FDA Drug Development and Drug Interactions: 
Table of Substrates, Inhibitors and Inducers. 

39 
Version 2.3, July 16, 2018 
4.0 TRIAL DESIGN AND DETAILED STUDY PROCEDURES 
4.1 Treatment Plan Overview 
We propose a single arm, open-label Phase I/II study to evaluate the clinical activity of the 
combination of LEE011, a novel inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), and the 
mTOR inhibitor everolimus in patients with mPAC refractory to chemotherapy.  We will also 
analyze the pharmacodynamics effects of this combination on tumor cells through serial biopsies. 
 
4.1.1 Phase I Portion (Dose Escalation Procedures) 
During the Phase I Portion of the study, patients will receive everolimus 2.5 mg once daily days 
1-28 continuously and a dose of LEE011 by mouth once daily days 1-21 according to their dose 
level (see below): 
• 
3 patients are enrolled at dose level 1. 
o If 0 patients experience a DLT, 3 patients are enrolled at dose level 2. 
o If 1 patient experiences a DLT, 3 additional patients are enrolled at dose level 1. If 
1 of 6 patients at dose level 1 experiences a DLT, 3 patients are enrolled at dose 
level 2. 
o If ≥ 2 patients experience a DLT, 3 patients are enrolled at dose level -1. 
• 
If 0-1 of 3 patients at dose level 2 experience a DLT, then 3 additional patients are enrolled 
at dose level 2. 
o If 0-1 of 6 patients at dose level 2 experience a DLT, dose level 2 is the RP2D. 
• 
If ≥ 2 of 3 patients at dose level 2 experience a DLT, 3 additional patients may be enrolled 
(to achieve 6 patients total) at dose level 1. 
o If 0-1 of 6 patients at dose level 1 experience a DLT, dose level 1 is the RP2D.  
o If ≥ 2 of 6 patients at dose level 1 experience a DLT, 3 patients are enrolled at 
dose level -1. 
• 
If 0-1 of 3 patients at dose level -1 experience a DLT, 3 additional patients are enrolled at 
dose level -1. 
o If 0-1 of 6 patients at dose level -1 experience a DLT, dose level -1 is the RP2D . 
o If ≥ 2 of 3 or 6 patients at dose level -1 experience a DLT, 3 patients are enrolled 
at dose level -2. 
• 
If 0-1 of 3 patients at dose level -2 experience a DLT, 3 additional patients are enrolled at 
dose level -2. 
o If 0-1 of 6 patients at dose level -2 experience a DLT, dose level -2 is the RP2D. 
o If ≥ 2 of 3 or 6 patients at dose level -2 experience a DLT, the study is terminated. 
 
There will be no intrapatient dose de-escalation. 
 
4.1.2 Phase II Portion, Stage 1 – Initial Stage 
The first stage of the study will be performed to establish a minimum level of clinical efficacy to 
warrant the enrollment of more patients in the second stage of the study.  11 patients will be 
enrolled and will undergo baseline imaging and a pre-treatment biopsy.  The patients will then be 
started on treatment with at the RP2D by mouth daily for the first 21 days out of a 28 day cycle in 
combination with everolimus 2.5 mg by mouth daily continuously. 
 
- LEE011 at the RP2D by mouth once daily days 1-21 
- Everolimus 2.5 mg by mouth once daily days 1-28 (continuously) 
 
Patients will be evaluated, including laboratory testing, every 2 weeks until the first restaging 
analysis.  Restaging will occur every 8 weeks regardless of treatment cycle. If at first restaging 
there is no evidence of PD, as determined by RECIST v1.1 criteria, and the patient is tolerating 
therapy, then patients may be seen only on Day 1 of future cycles, unless clinically indicated. 

40 
Version 2.3, July 16, 2018 
Patients will continue to remain on study as long as there is no evidence of PD (according to 
RECIST v1.1 criteria) and the therapy is adequately tolerated.   
 
Patients will have a tumor biopsy prior to treatment, a second biopsy at 2 weeks on treatment, 
and an optional final biopsy at the time of PD. 
 
4.1.3 Phase II Portion, Stage 2 – Final Stage 
After all 11 patients from the initial stage have undergone their 8 week response assessment, an 
interim analysis will be conducted to determine how many had a PR, CR, SD, or PD. The study 
will be stopped early if 2 or fewer patients obtain a PR, CR, or SD at 8 weeks.  If 3 or more patients 
obtain a PR, CR, or SD at 8 weeks, then 15 additional patients will be enrolled on the study for a 
total of 26 patients. Up to 3 additional patients may be screened and may be used to replace up 
to 3 patients in the initial 26 patients, provided those initial patients undergo screening but do not 
start study treatment within 3 weeks of screening. Thus, up to 29 patients may be screened for 
the Phase II portion of this study. 
 
Figure 12 (Figure 1 Repeated): Phase I Schema 
 
 
Figure 13 (Figure 2 Repeated): Phase II Schema 
 
 
 
4.2 Detailed Study Plan 
4.2.1 Screening 
Study activities are detailed in Table 5, and a study activity checklist in Table 6. Screening will 
occur within 21 days prior to administration of the first doses of LEE011 and everolimus on Cycle 
1 Day 1. Signed informed consent will be obtained from the subject or the subject's legally 
acceptable representative before any study-specific procedures are undertaken.  For procedures 

41 
Version 2.3, July 16, 2018 
performed at screening and repeated, the later procedure performed prior to dosing, will serve as 
a baseline for clinical assessment.  A complete history and physical will be obtained at the 
screening visit.  Additionally, labs will be reviewed/ordered during the screening visit, prior to the 
initiation of therapy.   
 
Patients who pass screening will again undergo a full evaluation on Cycle 1 Day 1, including a 
physical examination, vital signs, performance status, chemistry, hematology, medication review, 
and adverse event evaluation.  If any abnormality is identified at subject assessment on Cycle 1 
Day 1, prior to initiating therapy, the patient will be deemed a screen failure and will not start 
treatment.   
 
For patients being considered for enrollment outside of Georgetown-Lombardi, all primary source 
documentation should be sent to the multi-institutional coordinator and the Study Chair, Dr. 
Pishvaian for review and approval.  Patients must be approved for accrual prior to starting study 
medications.  Faxed records should be sent to 202-687-3821, with an email to the multi-
institutional coordinator and Dr. Pishvaian to confirm receipt of those records. 
 
The screening procedures include the following listed below. 
 
4.2.1.1 Informed Consent 
Signed informed consent will be obtained from the subject or the subject's legally acceptable 
representative before any study-specific procedures are undertaken.   
 
4.2.1.2 Medical History 
The following information will be collected during the Screening Period: 
1) Complete medical history, including documentation of any clinically significant medical 
conditions  
2) History of tobacco and alcohol use 
3) Presence and severity of any symptoms/conditions associated with metastatic pancreatic 
cancer 
4) Detailed oncology history, including: 
a. Date of primary cancer diagnosis 
b. Pathology (histology or cytology) of primary tumor 
c. Metastasis information (including the location) 
d. Surgical history 
e. Anti-cancer and radiation treatments administered (including dates and type of 
modality) 
5) At each visit, the subject's medical history will be reviewed and any changes from baseline 
will be recorded in the case report form (CRF). On C1D1 any changes observed from the 
screening assessments, prior to dosing, will be recorded in the subject's medical history. 
All medications (prescription or over-the-counter, including vitamins and/or herbal 
supplements) will be recorded beginning with the Screening Visit and continuing up 
through the date of the off study visit. 
 
4.2.1.3 Demographics 
Age, gender, race and ethnicity will be recorded. 
 
4.2.1.4 Review subject eligibility criteria 
 
4.2.1.5 Review previous and concomitant medications 
 
4.2.1.6 Physical exam including vital signs, height, and weight 

42 
Version 2.3, July 16, 2018 
A complete physical examination will be performed at the Screening Visit.  Body weight will be 
recorded during every physical exam. The subject will wear lightweight clothing and no shoes 
during weighing.  Height will be measured at the Screening Visit only; the subject will not wear 
shoes. 
 
4.2.1.7 Vital sign determinations 
Vital sign determinations of heart rate, blood pressure and body temperature will be obtained at 
the Screening Visit. If possible, blood pressure and heart rate measurements should not 
immediately follow scheduled blood collections. 
 
4.2.1.8 Performance Status 
Performance status will be evaluated prior to study entry according to Table 2. 
 
4.2.1.9 Hematology 
Hematology samples (CBC) will be collected and assessed using a certified laboratory.  The 
Investigator will review, initial and date all laboratory results. Any laboratory value outside the 
reference range stated in the inclusion criteria will preclude the patient from study participation. 
 
4.2.1.10 Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, ALT, AST, 
BUN, creatinine, electrolytes (sodium, potassium, calcium, chloride, bicarbonate), glucose, total 
bilirubin, phosphorous, and magnesium. Any laboratory value outside the reference range stated 
in the inclusion criteria will preclude the patient from study participation. 
 
4.2.1.11 Pregnancy Test 
For female subjects of childbearing potential, a serum pregnancy test will be performed at the 
Screening Visit within 14 days of C1D1 and a urine pregnancy test will be done at the C1D1 visit 
prior to the first dose of study drug. Subjects considered not of childbearing potential must be 
documented as being surgically sterile or post-menopausal (for at least 1 year).  The test results 
must be reviewed and determined to be negative prior to dosing. If the urine pregnancy test is 
positive at C1D1, it should be confirmed by a serum pregnancy test. The test may be repeated at 
the discretion of the investigator at any time during the study.  Should a female study subject 
become pregnant or suspect she is pregnant while participating in this study, she should inform 
the treating Investigator immediately. 
 
4.2.1.12 Tumor assessment 
Only patients with metastatic pancreatic cancer not eligible for resection will be considered for 
entry.  Subjects must have measurable disease, defined as at least 1 unidimensionally 
measurable lesion as defined by RECIST 1.1. Imaging for screening will be reviewed to prepare 
for tumor biopsies and molecular assessment.   
 
4.3 Tumor Biopsies 
Upon signing consent, patients will undergo a fresh tumor core biopsy by interventional 
radiologists. Tumor biopsies are mandatory UNLESS the patient has been evaluated for a biopsy 
in consultation with radiology in good faith, and there is a determination that an attempt at a biopsy 
would cause undue risk to the patient. Tumor samples will be sent to Dr. Erik Knudsen at: 
 
Roswell Park Comprehensive Cancer Center 
c/o Dr. Erik S. Knudsen 
Elm & Carlton Streets 
Buffalo, NY 14263 
 
 

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4.3.1 Patient Study Number Assignment and Sample Labeling 
An additional scientific objective is to assess the pharmacodynamic effects of LEE011 and 
everolimus on tumor tissue and to correlate those effects to PFS.  Thus, for all patients, we will 
require 2 core biopsies of a primary pancreatic tumor or metastatic lesion, and a third core biopsy 
will be optional:  
- 
A fresh core biopsy prior to treatment (within 3 weeks of Cycle 1 Day 1) 
- 
A repeat core biopsy on Cycle 1 Day 15 (± 3 days), preferably on the same tumor site if 
possible 
- 
An optional final core biopsy after PD or off study, preferably on the same tumor site if 
possible 
The first (pre-treatment) biopsy should be performed as soon as possible after consent is signed. 
For this reason, patients will be screened for accessibility of tumor tissue. Specifically, our 
radiologists will review the most recent images for each patient prior to enrollment. Only patients 
who, in their best estimation, have a tumor deposit(s), that are easily accessible by ultrasound or 
CT guidance in order to obtain serial core needle biopsies, will be eligible for study.   
 
Patients will undergo core biopsies, as per standard protocol in the Department of Radiology.  An 
18-20 gauge needle will be used.  At least three 1-2 cM core biopsies should be obtained with 
each biopsy.  All samples should be labeled with the date, protocol number, protocol assigned 
patient number, and biopsy number (1 – pre-treatment; 2 – on-treatment; 3 – after PD or off study). 
The samples will be immediately placed in formalin and then embedded in paraffin.  
 
Samples collected must be shipped at room temperature to Dr. Knudsen at: 
 
Roswell Park Comprehensive Cancer Center 
c/o Dr. Erik S. Knudsen 
Elm & Carlton Streets 
Buffalo, NY 14263 
 
Of note, patients who are on chronic anticoagulation will be required to hold anticoagulation prior 
to the biopsies being performed.  Patients on warfarin must hold treatment for 5 days, but will be 
on low-molecular weight heparin (LMWH), 1mg/kg subcutaneously twice a day. The LMWH will 
continue until the last biopsy is complete.  Patients may then resume warfarin the day after the 
last biopsy.  Additionally, patients on LMWH will hold (i.e., not receive) the dose of LMWH the 
morning of the procedure, but will resume the LMWH the evening of the day of the biopsy. 
 
Throughout the study, the following labelling procedures will be followed 
 
4.3.1.1 Patient Study Number Assignment 
Patients will be de-identified and labelled with a 5 digit study label (X-XXX-X): 
- 
The first number will be the site from which the patient was enrolled (single digit) 
o 1 = Georgetown 
o 2 = Additional Sites as Added 
- 
The second number will be the site-assigned patient number (three digit) 
- 
The third number will indicate the collection timing  
o 1 = Pre-treatment 
o 2 = On treatment 
 
4.3.1.2 Labeling of Serial Blood Samples 
Serial blood samples will be labeled in a similar fashion, except that the collection timing will 
labelled by week number (e.g. week 0 = pretreatment; week 8; week 16) 
 
 

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4.4 Detailed Patient Assessments 
Subject assessments (physical examinations, vital signs, performance status, chemistry, 
hematology, medication review, and adverse event evaluations) will be conducted at screening, 
Cycle 1 Day 1, every 2 weeks thereafter until the first response assessment at 8 weeks, and then 
every 4 weeks thereafter. Study visits and the on-treatment tumor biopsy may be performed 3 
days before or after the scheduled date due to unforeseen or unavoidable circumstances, and 
attempts should be made to schedule visits to line up with the start of a new cycle (within the 
constraints of the above parameters). Study drugs will be dispensed at the last visit prior to the 
start of the next 28 day cycle. The radiologic first response assessment at 8 weeks, and 
subsequent radiologic response assessments every 8 weeks thereafter, may be performed up to 
7 days before or after the scheduled date due to unforeseen or unavoidable circumstances. 
Details are provided in Table 5, and a checklist highlighting the important events for screening 
through the completion of the trial is provided below, as Table 6.   
 
4.4.1 Physical Examinations 
A complete physical examination will be performed at the screening visit, on Cycle 1 Day 1, then 
every 2 weeks up to the first response assessment at 8 weeks, then every 4 weeks thereafter. 
Any significant physical examination findings after the administration of the first doses of LEE011 
and everolimus will be recorded as adverse events.  Body weight will be recorded during every 
physical exam. The subject will wear lightweight clothing and no shoes during weighing.  Weight 
will be measured on the same scale at each visit. Height will be measured at the screening visit 
only; the subject will not wear shoes. 
 
4.4.2 Medical History 
At each visit, the subject's medical history will be reviewed and any changes from baseline will be 
recorded as an adverse event.  On Day 1, any changes observed from the screening assessments, 
prior to dosing, will be recorded in the subject's medical history. All medications (prescription or 
over-the-counter, including vitamins and/or herbal supplements) will be recorded beginning with 
the screening visit and continuing up through the date of the final visit. 
 
4.4.3 Vital Signs 
Vital sign determinations of body temperature (in degrees Celsius), heart rate, respiratory rate, 
blood pressure and pain (using a 0-10 Numeric Ranking Scale) will be obtained at the screening 
visit, on each day the subject is seen by the treating physician, and at the final visit. If possible, 
blood pressure and heart rate measurements should not immediately follow scheduled blood 
collections. 
 
4.4.4 Clinical Laboratory Tests 
All subjects will undergo the laboratory assessments outlined in Table 5.  
1) A complete blood count (CBC) with differential will be collected at the screening visit, on 
Cycle 1 Day 1, Cycle 1 Day 15, then every 2 weeks until the first response assessment, 
at the first response assessment at 8 weeks, then every 4 weeks thereafter. 
2) Serum chemistries (total protein, albumin, total bilirubin, AST, ALT, alkaline phosphatase, 
sodium, potassium, chloride, bicarbonate, BUN, creatinine, calcium, magnesium, and 
phosphorous) will be collected at the screening visit, on Cycle 1 Day 1, Cycle 1 Day 15, 
then every 2 weeks until the first response assessment, at the first response assessment 
at 8 weeks, then every 4 weeks thereafter. 
3) PT/PTT/INR will be collected at the screening visit, on Cycle 1 Day 15, and at final visit if 
the patient agrees to the optional third biopsy 
4) Additionally, a tumor marker (serum CA19-9 or CEA level) and research blood samples 
for ctDNA will be sampled on Cycle 1 Day 1 and every 8 weeks thereafter. 
Laboratory samples for this study will be assessed using the certified laboratory at the 
investigators’ institutions, or at a clinical laboratory such as Quest or LabCorp and these data will 

45 
Version 2.3, July 16, 2018 
be used for all data analysis.  The Principal Investigator or sub-investigator will review, initial and 
date all laboratory results. Any laboratory value outside the reference range that is considered 
clinically significant by the investigator will be followed as appropriate. Clinically significant 
laboratory values will be recorded as adverse events if they meet the criteria as specified in 
Section 8. 
 
4.4.5 Collection and Processing of ctDNA 
For collection of ctDNA on Cycle 1 Day and every 8 weeks thereafter, 4 mL of patient blood will 
be collected via venipuncture (venipuncture is preferred, however if an indwelling catheter must 
be used, 3 catheter volumes of blood must be collected and discarded prior to collection of the 
sample) into 2 evacuated Streck tubes.  Immediately after collection, the tubes will be inverted 8 
to 10 times to ensure good mixing of blood and placed in an ice bath. The date and time of 
collection for each sample will be recorded.  The complete process of centrifugation, transfer to 
polypropylene tubes and freezing should be accomplished within 60 minutes from blood draw. 
The processing of samples should be performed as described below: 
 
1. Immediately invert the collection tubes 8 to 10 times and placed in an ice bath. 
2. Centrifuge the sample at 1,200 g for 10 minutes at 4°C to separate the plasma. 
3. Isolate supernatants in sterile 1.5 mL Eppendorf tubes and centrifuge at 1,600 g for 10 minutes 
at 4°C 
4. Transfer supernatants (plasma) using plastic pipettes into screw-capped polypropylene tubes 
labeled with the patient number, the protocol number, and the study week. 
5. Store samples at –20°C or colder and ship on dry ice to Dr. Knudsen to: 
 
Roswell Park Comprehensive Cancer Center 
c/o Dr. Erik S. Knudsen 
Elm & Carlton Streets 
Buffalo, NY 14263 
 
4.4.6 Cardiac Evaluation 
All subjects will undergo a baseline ECG prior to enrollment.  An ECG will also be performed on 
Cycle 1 Day 15. ECGs will be reviewed by the investigator and confirmed by a cardiologist. 
Standard triplicate 12-Lead ECG (2 minutes apart) is recommended in all visits; the combined 
QTcF values from these triplicate ECGs will be averaged to provide a single value for each time 
point. For patients with QTcF ≥481 ms at any time, interrupt study treatment and follow the 
procedures described in Table 9. If treatment is resumed, repeat ECGs 7 days and 14 days after 
dose resumption (and then as clinically indicated). During subsequent cycles, a predose ECG will 
be performed for every cycle starting at cycle 6, and predose and 2-4 postdose starting at cycle 
9 and every 3rd cycle thereafter. 
 
4.4.7 Adverse Event Evaluation 
The Principal Investigator or sub-investigators will assess adverse events, laboratory data and 
vital signs throughout the study.  Adverse events will be assessed by NCI CTCAE Version 4.03. 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
The 
investigators will monitor each subject for clinical and laboratory evidence of adverse events on 
a routine basis throughout the study. The investigator will assess and record any adverse event 
in detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, time 
course, duration and outcome, relationship of the adverse event to study drug, and any action(s) 
taken. For serious adverse events not considered "probably related" to study drug, the 
investigator will provide an "Other" cause of the event. For adverse events to be considered 
intermittent, the events must be of similar nature and severity. Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject will be 
recorded. All adverse events will be followed to a satisfactory conclusion. 

46 
Version 2.3, July 16, 2018 
 
4.4.8 Imaging and Response Evaluation 
Patients will undergo a baseline tumor evaluation with imaging studies within 3 weeks prior to 
Cycle 1 Day 1. Imaging studies should include a diagnostic CT scan of the chest, abdomen, and 
pelvis with PO and IV contrast (unless medically contraindicated). If a patient has an allergy to IV 
contrast, appropriate pre-medication can be given to prevent a contrast reaction. Patients may 
undergo other modalities such as an MRI instead of a CT scan at the treating physician’s 
discretion if appropriate (such as severe allergy to CT contrast, extremity tumors, bone 
metastases requiring bone scans, etc.).   
 
Response evaluation will occur every 8 weeks (regardless of treatment cycle) and at the final visit, 
if not performed within the last 4 weeks. Tumor response and/or disease progression will be 
assessed by the modality(ies) used prior to treatment. Patients will continue to remain on study 
as long as there is no evidence of PD and the therapy is adequately tolerated.   
 
4.4.9 Removal of Subjects from Therapy or Assessment 
4.4.9.1 Reasons for Removal of Subjects from Therapy or Assessment 
Each subject has the right to withdraw from study treatment at any time. In addition, the 
investigator may discontinue a subject from the study treatment at any time for any reason if the 
investigator considers it necessary, including the occurrence of an adverse event or 
noncompliance with the protocol.  Each subject will be withdrawn from the study if any of the 
following occur: 
1) The subject experiences either clinical or radiographic progressive disease.  
2) The subject requires radiotherapy or alternate antineoplastic agents during the study 
period. 
3) The investigator believes it is in the best interest of the subject. 
4) Clinically significant deterioration of the subject's medical status as determined by the 
investigator. 
5) Subject becomes pregnant or begins breastfeeding during the treatment portion of the 
study. 
6) The subject or subject's legally acceptable representative decides to withdraw consent for 
any reason.  
7) Any other medical reason that the study investigator deems appropriate. 
 
4.4.9.2 Discontinuation of Individual Subjects 
When a subject discontinuation from the study (without reaching a protocol-defined endpoint) is 
planned, the investigator will notify the PI as soon as possible (provided, in each case, subject 
care and safety are not compromised).  When a subject discontinues the study, a final visit will be 
conducted (preferably prior to the initiation of another anticancer therapy). However, these 
procedures should not interfere with the initiation of any new treatments or therapeutic modalities 
that the investigator feels are necessary to treat the subject's condition. Following discontinuation 
of the study drug, the subject will be treated in accordance with the investigator's best clinical 
judgment.  At the final visit, the reason(s) for the discontinuation from the study will be recorded 
and a physical examination, body weight, vital signs measurement, laboratory analyses, 
performance status, tumor assessment, collection of unused study drug and an assessment of 
adverse events will be performed as soon as possible after discontinuation from the study.  All 
subjects will have one final visit, which does not need to be performed for subjects who have had 
a visit greater than 30 days after discontinuation of the study drugs.  If a subject is discontinued 
from the study with an ongoing adverse event or an unresolved clinically significant laboratory 
result, personnel will attempt to provide follow-up until a satisfactory clinical resolution of the 
laboratory result or adverse event is achieved.  In the event that a positive result is obtained on a 
pregnancy test for a subject during the study, the administration of study drug to that subject must 
be discontinued immediately.   

47 
Version 2.3, July 16, 2018 
 
4.4.9.3 Discontinuation of Entire Study 
The investigators may terminate this study provided that written notice is submitted at a 
reasonable time in advance of the intended termination.  The following procedures for 
discontinuation will be followed:  
1) If the investigators have decided to prematurely discontinue the study, the investigators 
will promptly notify in writing the IRB of the decision and give detailed reasons for the 
discontinuation. 
2) The PI must promptly notify enrolled subjects of the premature discontinuation and 
administer appropriate treatments such as replacement of protocol therapy by other 
appropriate regimens. 
 
4.4.10 Longitudinal Outcomes Assessment 
Subsequent therapies will be administered at the discretion of the treating physician.  Patients will 
be followed after progression until death (or up to 24 months) to assess overall survival.  
Information pertaining to survival and post-treatment therapy will be collected approximately every 
12 weeks (Month 3, 6, 9, 12, 15 and 18) beginning after the final visit, for a period up to 24 months. 
 
4.4.11 Multi-Institution Study Coordination 
4.4.11.1 Personnel 
At each site, personnel dedicated to this protocol will be: 
 - A study PI 
 - A research coordinator/data manager 
 
This coordinator will be the main point of contact for Dr. Pishvaian and the other PIs for any study 
related concerns, and to screen each patient being considered for enrollment. This coordinator 
will also be the point of contact for the data managers for data entry questions. Finally, this 
coordinator will play a major role in regulatory coordination of the study, specifically by: 1) 
reviewing and confirming all study-related adverse events; 2) submitting all SAE reports to the 
Georgetown IRB; and 3) gathering and preparing all primary source data for review/audit. 
 
In addition, at Lombardi-Georgetown, there will be a dedicated “multi-institutional” research 
coordinator who will play the primary role in coordinating the trial between Lombardi-Georgetown 
and additional sites.  This coordinator will be the main point of contact for Dr. Pishvaian and the 
other site PIs for any study related concerns, and to screen each patient being considered for 
enrollment (Including “remote” screening for the patients being screened at other sites). This 
coordinator will also be the point of contact for the data managers for data entry questions. Finally, 
this coordinator will play a major role in regulatory coordination of the study, specifically by: 1) 
reviewing and confirming all study-related adverse events; 2) submitting all SAE reports to the 
Georgetown IRB (the research coordinators at the other sites will prepare SAE reports for patients 
treated at their respective sites, but the “multi-institutional” coordinator will submit the final report); 
3) gathering and preparing all primary source data for review/audit. 
 
4.4.11.2 Patient Enrollment 
Enrollment at the sites will be competitive.  If a patient is being screened for enrollment, the local 
research coordinator must send a secure/encrypted email within 24 hours containing the patient’s 
name, to the local PI, to Dr. Pishvaian, and to the multi-institutional coordinator.  If a patient is 
successfully screened, the local research coordinator must send all supporting documentation to 
the multi-institutional research coordinator (by email or fax).  Patients should not start therapy 
until both Dr. Pishvaian and the multi-institutional coordinator have reviewed the patient’s records 
and confirmed that the patient is indeed eligible for enrollment. 
 
 

48 
Version 2.3, July 16, 2018 
4.4.11.32 Data Collection and Management  
Patient data will be entered into the online accessible database.  This database is housed at 
Lombardi-Georgetown, but is accessible anywhere there is Internet access.  The data manager 
and research coordinator will attend an online training session so that they may learn how to enroll 
data into the database.  All screening data should be entered prior to starting therapy, and all 
ongoing patient data should be entered within one week of each patient visit.   
 
4.4.11.4 3 Conference Calls/Meetings 
A monthly meeting will be held to review patient enrollment, toxicity, and response assessment.   
A monthly conference call will be held between Lombardi-Georgetown and the other sites to 
review patient enrollment, toxicity, and response assessment.   
 
4.4.11.54 Trial Auditing 
The coordinator will arrange all primary source documents for the patients to be audited.  This will 
include collecting copies of the primary source data. 
 
4.4.12 Protocol Deviations 
The investigator should not implement any deviation from the protocol without prior review and 
agreement by the Sponsor and in accordance with the IRB and local regulations, except when 
necessary to eliminate an immediate hazard to study subjects.  
 
Table 7. Study Activities 
 
 
 
 
 

49 
Version 2.3, July 16, 2018 
Table 8. Study Activities Checklist 
Screening 
Subject assessment           _______ 
Eligibility criteria met          _______ 
Informed consent             _______ 
Demographics              _______ 
Medical History              _______ 
Concurrent medications        _______ 
ECG                     _______ 
Pregnancy test (if appropriate)    _______ 
Vital signs                 _______ 
Height                    _______ 
Weight                    _______ 
History and physical           _______ 
Performance status           _______ 
CBC with differential           _______ 
Serum chemistries            _______ 
PT/PTT/INR                _______ 
Radiologic Assessment        _______ 
Tumor amenable to biopsy      _______ 
Pre-treatment biopsy          _______ 
 
Cycle 1, Day 1 
Subject assessment           _______ 
Concurrent medications        _______ 
Pregnancy test (if appropriate)    _______ 
Vital signs                 _______ 
Weight                    _______ 
History and physical           _______ 
Performance status           _______ 
Adverse event evaluation       _______ 
CBC with differential           _______ 
Serum chemistries            _______ 
Serum Tumor Marker          _______ 
Research serum sample for ctDNA _______ 
Dispense study drugs          _______ 
 
Cycle 1, Day 15 
Subject assessment           _______ 
Concurrent medications        _______ 
ECG                     _______ 
Vital signs                 _______ 
Weight                    _______ 
History and physical           _______ 
Performance status           _______ 
Adverse event evaluation       _______ 
CBC with differential           _______ 
Serum chemistries            _______ 
PT/PTT/INR                _______ 
On-treatment tumor biopsy      _______ 
 
 
 

50 
Version 2.3, July 16, 2018 
Cycle 2, Day 1 
Subject assessment           _______ 
Concurrent medications        _______ 
ECG                     _______ 
Vital signs                 _______ 
Weight                    _______ 
History and physical           _______ 
Performance status           _______ 
Adverse event evaluation       _______ 
CBC with differential           _______ 
Serum chemistries            _______ 
PT/PTT/INR                _______ 
Serum Tumor Marker          _______ 
Dispense study drugs          _______ 
 
Every 2 weeks until first response assessment 
Subject assessment           _______ 
Concurrent medications        _______ 
Vital signs                 _______ 
Weight                    _______ 
History and physical           _______ 
Performance status           _______ 
Adverse event evaluation       _______ 
CBC with differential           _______ 
Serum chemistries            _______ 
 
First response assessment (at 8 weeks on treatment) 
Subject assessment           _______ 
Concurrent medications        _______ 
Vital signs                 _______ 
Weight                    _______ 
History and physical           _______ 
Performance status           _______ 
Adverse event evaluation       _______ 
CBC with differential           _______ 
Serum chemistries            _______ 
Serum Tumor Marker          _______ 
Radiologic Assessment        _______ 
Research serum sample for ctDNA _______ 
Dispense study drugs          _______ 
 
Every 4 weeks after first response assessment 
Subject assessment           _______ 
Concurrent medications        _______ 
Vital signs                 _______ 
Weight                    _______ 
History and physical           _______ 
Performance status           _______ 
Adverse event evaluation       _______ 
CBC with differential           _______ 
Serum chemistries            _______ 
Dispense study drugs          _______ 
 

51 
Version 2.3, July 16, 2018 
Every 8 weeks after first response assessment 
Subject assessment           _______ 
Concurrent medications        _______ 
Vital signs                 _______ 
Weight                    _______ 
History and physical           _______ 
Performance status           _______ 
Adverse event evaluation       _______ 
CBC with differential           _______ 
Serum chemistries            _______ 
Serum Tumor Marker          _______ 
Radiologic Assessment        _______ 
Research serum sample for ctDNA _______ 
Dispense study drugs          _______ 
 
Upon disease progression or off study 
Subject assessment           _______ 
Concurrent medications        _______ 
Vital signs                 _______ 
Weight                    _______ 
History and physical           _______ 
Performance status           _______ 
Adverse event evaluation       _______ 
CBC with differential           _______ 
Serum chemistries            _______ 
Serum Tumor Marker          _______ 
Radiologic Assessment        _______ 
Research serum sample for ctDNA _______ 
Tumor biopsy (optional)        _______ 
 
Follow-up assessment(s) 
Subject assessment (may be done via phone)_______ 
Vital status data collection       _______ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

52 
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5.0 DOSAGES AND DISPENSATION OF DRUGS   
5.1 Dispensation of Study Drug and Treatments Administered 
The study drugs are defined as LEE011 and everolimus.  Patients will receive both drugs by 
mouth.  Patients will receive sufficient quantities of LEE011 and everolimus for 1 cycle of 
administration on Day 1 of each cycle.  Patients will receive bottles of LEE011 and everolimus 
and will be provided with drug diaries (see Appendix A) to record the date and time they took the 
drugs. LEE011 should specifically be taken WITH FOOD. Everolimus can be taken with or without 
food. LEE011 and everolimus should be taken with a large glass of water (~250 mL) at the same 
time each day and should be swallowed whole without crushing, chewing, or opening the pills.  If 
vomiting occurs, no re-dosing of the patient is allowed prior to the next scheduled dose.  If doses 
are not taken within 6 hours of the intended time, the dose should be skipped and not replaced 
or made up on a subsequent day. Patients will be instructed to store LEE011 and everolimus at 
room temperature. Subjects should return bottles of LEE011 and everolimus (empty, partially filled, 
or full) and their diaries (See Appendix A) prior to each cycle and at the final visit. 
 
5.2 Packaging and Labeling of LEE011 and Everolimus 
Film coated tablets of LEE011 will be packaged in bottles containing 200 mg and 50 mg tablets 
(75 tablets per bottle), and patients will be supplied with sufficient tablets for one cycle, plus 
enough for one extra day (see Table 7). 
 
Table 9. Dispensation of LEE011 by Dose Level 
Dose Level  
Dose 
200 mg Tablets Dispensed 
50 mg Tablets Dispensed 
2 
300 mg 
22 
44 
1 
250 mg 
22 
22 
-1 
200 mg 
22 
0 
-2 
150 mg 
0 
66 
 
Everolimus will be packaged in bottles containing 2.5 mg tablets with sufficient tablets in the bottle 
for once cycle, plus enough for one extra day (29 pills). Each bottle will be labeled with an open-
label white single panel or booklet label that will include, but is not limited to, the following 
information: 
1) Protocol number 
2) Drug identification 
3) Number of capsules 
4) Storage conditions 
5) Dosing instructions 
6) Blank spaces to write the subject's identification number, initials and date dispensed 
Each bottle label must remain affixed to the bottle.   
 
5.3 Storage and Disposition of LEE011 and Everolimus 
LEE011 is not to be stored at temperatures above 25°C and should be protected from moisture. 
Everolimus is to be stored at 25°C (excursions permitted between 15-30°C) and should be 
protected from light and moisture. All clinical supplies must be stored in a secure place until they 
are dispensed for subject use or are returned to the Georgetown Pharmacy.  Investigational 
products are for investigational use only, and are to be used only within the context of this study. 
The clinical supplies supplied for this study must be maintained under adequate security and 
stored under conditions specified on the label. Destruction of used and unused study drug will be 
performed. 
 
5.4 Treatment Compliance 
Subjects will be instructed to return all bottles of LEE011 and everolimus (empty, partially filled or 
full) to the study personnel prior to each cycle and at the final visit.  The study personnel will 

53 
Version 2.3, July 16, 2018 
document the bottles of study drug returned and the number of capsules per bottle, according to 
institutional policy.  If the number of capsules taken and the number of capsules returned do not 
add up to the number of capsules dispensed, an explanation will be provided.  Unless otherwise 
directed by the principal investigator, a subject will be considered compliant with study drug, if 85% 
of the assigned dose is taken during a cycle.   
 
5.5 Drug Accountability 
The investigator or designee will verify that LEE011 and everolimus supplies are received intact 
and in the correct amounts. A signed and dated Proof of Receipt (POR) or similar document will 
support documentation of the receipt of supplies.  An accurate running inventory of LEE011 and 
everolimus will be maintained, and will include the lot number, POR number(s), the bottle numbers, 
and the date study drug was dispensed for each subject. Upon completion or termination of the 
study, all original containers (empty or containing unused study drug) will be returned to the 
manufacturer or destruction of used and unused study drug will be performed. Labels must remain 
attached to the containers. The investigator or his/her designated representative agrees not to 
supply study medication to any persons not enrolled in the study or not named as a sub-
investigator.  Personnel will record the lot number(s) and doses of LEE011 and everolimus given 
to each subject. 
 
5.6 Selection of Doses in the Study (LEE011 Investigator’s Brochure{Novartis, 2015 #16}) 
Initial doses of LEE011 and everolimus are based on the ongoing CLEE011X2106 study, a Phase 
Ib/II trial evaluating LEE011 in combination with everolimus and exemestane in postmenopausal 
women with estrogen receptor positive HER2 negative locally advanced or metastatic breast 
cancer. As of 21-Mar-2014, 16 patients have been enrolled and treated with at least one LEE011 
dose. The median age of 16 patients was 56.5 (range: 41–84) years, the male/female ratio was 
0/16 patients, and the distribution of ECOG performance status of 0/1 at baseline was 7/9 patients, 
respectively. As of 21-Mar-2014, 5 patients were discontinued from the study and 11 patients 
were still ongoing. Reasons for discontinuation were disease progression (4 patients, 25% of total 
enrolled) and death (one patient, 6.3% of total enrolled). Patients were enrolled to one of the 
following four cohorts: (1) LEE011 (600 mg) + exemestane (25 mg), n=3, (2) LEE011 (200 mg) + 
everolimus (2.5 mg) + exemestane (25 mg), n=6, (3) LEE011 (250 mg) + everolimus (2.5 mg) + 
exemestane (25 mg), n=1 or (4) LEE011 (300 mg) + everolimus (2.5 mg) + exemestane (25 mg), 
n=6. Three dose-limiting toxicities (DLTs) were observed in the LEE011 (300 mg) + everolimus 
(2.5 mg) + exemestane (25 mg) cohort of one Grade 3 febrile neutropenia and two Grade 3 
alanine aminotransferase elevations.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Version 2.3, July 16, 2018 
6.0 SAFETY VARIABLES AND TOXICITY ASSESSMENT 
The Principal Investigator or sub-investigators will assess adverse events, laboratory data and 
vital signs throughout the study.  Adverse events will be assessed by NCI CTCAE Version 4.03. 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 
6.1 Adverse Event Assessment 
The investigators will monitor each subject for clinical and laboratory evidence of adverse events 
on a routine basis throughout the study. The investigator will assess and record any adverse 
event in detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, 
time course, duration and outcome, relationship of the adverse event to study drug, and any 
action(s) taken. For serious adverse events not considered "probably related" to study drug, the 
investigator will provide an "Other" cause of the event. For adverse events to be considered 
intermittent, the events must be of similar nature and severity. Adverse events, whether in 
response to a query, observed by personnel, or reported spontaneously by the subject will be 
recorded. All adverse events will be followed to a satisfactory conclusion. 
 
6.2 Study Monitoring 
6.2.1 Data Safety Monitoring Committee at Georgetown 
The Georgetown Lombardi Comprehensive Cancer Center will be responsible for the data and 
safety monitoring of this trial.  As this study is an investigator initiated Phase I/II study utilizing 
FDA-approved on label, and off label therapies, it is considered a high risk study which requires 
real-time monitoring by the PI and study team and quarterly reviews by the LCCC Data and Safety 
Monitoring Committee (DSMC). 
 
The Study Chair and the other investigators will review the data including safety monitoring at 
their monthly teleconferences with participating sites.   
 
All Severe Adverse Events (SAEs) are required to be reported to the Georgetown IRB.  Based on 
SAEs, the IRB retains the authority to suspend further accrual pending more detailed reporting 
and/or modifications to further reduce risk and maximize the safety of participating patients. 
 
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data and Safety 
Monitoring Committee every 3 months from the time the first patient is enrolled on the study. 
Results of the DSMC meetings will be forwarded to the IRB with recommendations regarding 
need for study closure. 
 
DSMC recommendations should be based not only on results for the trial being monitored as well 
as on data available to the DSMC from other studies.  It is the responsibility of the PI to ensure 
that the DSMC is kept apprised of non-confidential results from related studies that become 
available.  It is the responsibility of the DSMC to determine the extent to which this information is 
relevant to its decisions related to the specific trial being monitored. 
 
A written copy of the DSMC recommendations will be given to the trial PI and the IRB.  If the 
DSMC recommends a study change for patient safety or efficacy reasons the trial PI must act to 
implement the change as expeditiously as possible.  In the unlikely event that the trial PI does not 
concur with the DSMC recommendations, then the LCCC Associate Director of Clinical Research 
must be informed of the reason for the disagreement.  The trial PI, DSMC Chair, and the LCCC 
AD for Clinical Research will be responsible for reaching a mutually acceptable decision about 
the study and providing details of that decision to the IRB.  Confidentiality must be preserved 
during these discussions.  However, in some cases, relevant data may be shared with other 
selected trial investigators and staff to seek advice to assist in reaching a mutually acceptable 
decision. 
 

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If a recommendation is made to change a trial for reasons other than patient safety or efficacy the 
DSMC will provide an adequate rationale for its decision. If the DSMC recommends that the trial 
be closed for any reason, the recommendation will be reviewed by the Associate Director for 
Clinical Research at G-LCCC.  Authority to close a trial for safety reasons lies with the IRB, with 
the above described input from DSMC and the AD for Clinical Research.   
 
Of note, the DSMC will also review the safety data of the patients enrolled outside of Georgetown 
University.  The multi-institutional coordinator will be tasked with the job of collecting all primary 
source documentation for patients enrolled outside of Georgetown University.  In addition, the 
data managers at each site will be entering data into the Georgetown database, so that all data 
will be available for the DSMC at Georgetown to review.  Faxed records should be sent to 202-
687-2399, with an email to the multi-institutional coordinator and Dr. Pishvaian to confirm receipt 
of those records. 
 
6.2.2 Study Monitoring with Novartis 
The Study Chair and when available, the responsible research coordinator will hold a phone 
conference with Novartis monthly to discuss trial management, safety concerns, response 
assessment and correlative studies.  More frequent conferences may be held as necessary. 
 
6.3 Adverse Event and Toxicity Definitions 
6.3.1 Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
a causal relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not the event is 
considered causally related to the use of the product.  Such an event can result from use of the 
drug as stipulated in the protocol or labeling, as well as from accidental or intentional overdose, 
drug abuse, or drug withdrawal. Any worsening of a pre-existing condition or illness is considered 
an adverse event.  Laboratory abnormalities and changes in vital signs are considered to be 
adverse events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, and/or if the investigator considers them to be adverse events. 
An elective surgery/procedure scheduled to occur during a study will not be considered 
an adverse event if the surgery/procedure is being performed for a pre-existing condition and the 
surgery/procedure has been pre-planned prior to study entry.  However, if the pre-existing 
condition deteriorates unexpectedly during the study (e.g., surgery performed earlier than 
planned), then the deterioration of the condition for which the elective surgery/procedure is being 
done will be considered an adverse event. 
 
6.3.2 Serious Adverse Events 
If an adverse event meets any of the following criteria, it is to be reported to the DSMC as a 
serious adverse event (SAE) within 24 hours of the study personnel being made aware of the 
serious adverse event. 
1) Death of Subject An event that results in the death of a subject. 
2) Life-Threatening An event that, in the opinion of the investigator, would have resulted in 
immediate fatality if medical intervention had not been taken. This does not include an 
event that would have been fatal if it had occurred in a more severe form. 
3) Hospitalization or 
4) Prolongation of Hospitalization An event that results in an admission to the hospital for 
any length of time or prolongs the subject's hospital stay. This does not include an 
emergency room visit or admission to an outpatient facility. 
5) Congenital Anomaly An anomaly detected at or after birth, or any anomaly that results 
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6) Persistent or Significant Disability/Incapacity An event that results in a condition that 
substantially interferes with the activities of daily living of a study subject. Disability is not 
intended to include experiences of relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle). 
7) Important Medical Event Requiring Medical or Surgical Intervention to Prevent 
Serious Outcome An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on medical judgment may 
jeopardize the subject and may require medical or surgical intervention to prevent any of 
the outcomes listed above (i.e., death of subject, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or significant 
disability/incapacity). Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse. 
8) Spontaneous Abortion Miscarriage experienced by study subject.  
9) Elective Abortion Elective abortion performed on study subject. 
 
6.3.3 Adverse Event Severity 
The study investigator will rate the severity of each adverse event according to the NCI CTCAE 
Version 4.03.  For adverse events not captured by the NCI CTCAE Version 4.03, the following 
should be used: 
1) Grade 1 (Mild) The adverse event is transient and easily tolerated by the subject. 
2) Grade 2 (Moderate) The adverse event causes the subject discomfort and interrupts the 
subject's usual activities.  
3) Grade 3/4 (Severe or Life Threatening) The adverse event causes considerable 
interference with the subject's usual activities and may be incapacitating or life-threatening. 
4) Grade 5 (Death) The adverse event resulted in death of the subject. 
 
6.3.4 Relationship to Study Drug 
The investigator will use the following definitions to assess the relationship of the adverse event 
to the use of study drug: 
1) Definitely Related An adverse has a clear temporal relationship to study drug and/or 
recurs on re-challenge and an Other cause of event is extremely unlikely. 
2) Probably Related An adverse event has a strong temporal relationship to study drug or 
recurs on re-challenge and an Other cause of event is unlikely or significantly less likely. 
3) Possibly Related An adverse event has a strong temporal relationship to the study drug 
and an Other cause of event is equally or less likely compared to the potential relationship 
to study drug.  
4) Probably Not Related An adverse event has little or no temporal relationship to the study 
drug and/or a more likely Other cause of event exists.   
5) Not Related An adverse event is due to an underlying or concurrent illness or effect of 
another drug and is not related to the study drug (e.g., has no temporal relationship to 
study drug or has a much more likely Other cause of event). 
If an investigator's opinion of possibly, probably not, or not related to study drug is given, an Other 
cause of event must be provided by the investigator for the serious adverse event. 
 
6.4 Adverse Event Collection Period 
All adverse events reported from the time of study drug administration until 30 days following 
discontinuation of study drug administration have elapsed will be collected, whether elicited or 
spontaneously reported by the subject. In addition, serious adverse events will be collected from 
the time the subject signed the study-specific informed consent. 
 
 

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6.5 Adverse Event Reporting 
In the event of a serious adverse event, whether related to study drug, study procedure such as 
a biopsy, or even if not directly related to any study intervention, the investigator will notify the 
IRB within 72 hours of being made aware of the serious adverse event.  Furthermore, all serious 
adverse events, in addition to being reported to the FDA by the investigator, must be reported by 
facsimile within 24 hours to Novartis DS&E at 877-778-9739.  Forms can be obtained from, and 
returned to e-mail: usdrugsafety.operations@novartis.com. 
The SAE report should comprise a full written summary, detailing relevant aspects of the 
adverse events in question.  Where applicable, information from relevant hospital case records 
and autopsy reports should be included.  Follow-up information should be forwarded to Novartis 
within 24 hours. 
SAEs brought to the attention of the investigator at any time after cessation of LEE011 or 
everolimus and considered by the investigator to be related or possibly related to LEE011 or 
everolimus must be reported to Novartis if and when they occur. Additionally, in order to fulfill 
international reporting obligations, SAEs that are related to study participation (e.g., procedures, 
invasive tests, change from existing therapy) or are related to a concurrent medication will be 
collected and recorded from the time the subject consents to participate in the study until he/she 
is discharged. 
For patients enrolled outside of Georgetown University, serious adverse events will also 
be reported, and all supporting documentation sent (faxed or emailed) to the multi-institutional 
coordinator and to the Study Chair, Dr. Pishvaian, as well as to Novartis (as above) within 24 
hours.  Faxed records should be sent to 202-687-3821, with an email to the multi-institutional 
coordinator and Dr. Pishvaian to confirm receipt of those records. 
 
6.6 Pregnancy 
In the event of a positive pregnancy test result, study drugs will be immediately discontinued. The 
investigator must report the positive pregnancy test within 72 hours of the study personnel 
becoming aware of the pregnancy to the IRB and to Novartis.  Patients should also notify the 
investigator if it is determined after completion of the study that they become pregnant either 
during the treatment phase of the study or within five days after the treatment period.  Information 
regarding a pregnancy occurrence in a study subject and the outcome of the pregnancy will be 
collected, and the status of the mother and child should be reported to the IRB and to Novartis 
after delivery.  Pregnancy in a study subject is not considered an adverse event but does require 
discontinuation of the subject from the study. However, the medical outcome of an elective or a 
spontaneous abortion, stillbirth or congenital anomaly is considered a serious adverse event and 
must be reported to the IRB and to Novartis within 72 hours of study personnel becoming aware 
of the event.  Male subjects should also notify the investigators if the subject's partner should 
become pregnant during the study, this should also be reported within 72 hours of study personnel 
awareness. 
 
6.7 Toxicity Management and Dose Adjustments 
6.7.1 Dose Reduction and Delays 
6.7.1.1 Known toxicities of LEE011 and/or everolimus defined as dose-limiting toxicities (DLTs) 
For the Phase I portion of the trial, toxicities will be defined as DLTs if they are included below (as 
defined by CTCAE v.4.03) AND they occur during the first 4 weeks of therapy AND are deemed 
related to the study regimen as assessed by the investigator: 
 
 
 
 
 
 
 

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Table 10. Criteria for Defining DLTs Related to LEE011 or everolimus 
Toxicity 
DLT (per CTCAE v. 4.03) 
Hematology 
≥ Grade 4 neutropenia (ANC < 500/µL) lasting ≥ 7 consecutive 
days 
≥ Grade 4 thrombocytopenia 
Grade 3 thrombocytopenia with clinically significant bleeding 
Grade 3 or 4 febrile neutropenia 
ECG QT interval 
QTc interval ≥ 501 ms on at least 2 separate ECGs 
Cardiac 
≥ Grade 3 cardiac toxicity, clinical signs of cardiac disease such as 
unstable angina, myocardial infarction, or troponin ≥ Grade 3 
Gastrointestinal 
≥ Grade 3 vomiting ≥ 48 hours despite optimal anti-emetic therapy 
≥ Grade 3 diarrhea ≥ 48 hours despite optimal anti-diarrheal 
therapy 
(Optimal therapy for vomiting and diarrhea should be based on 
institutional guidelines with consideration of the prohibited 
medications listed in these protocol guidelines). 
Hepatobiliary 
≥ Grade 2 total bilirubin > 7 consecutive days 
≥ Grade 3 total bilirubin 
≥ Grade 2 ALT with a ≥ Grade 2 bilirubin elevation of any duration 
in the absence of liver metastases 
≥ Grade 3 ALT for > 4 consecutive days 
Grade 4 ALT or AST 
Grade 4 serum alkaline phosphatase > 7 consecutive days 
Renal 
≥ Grade 3 serum creatinine 
Stomatitis 
≥ Grade 3 – everolimus is associated with stomatitis. Per the 
Afinitor® package insert, topical treatments are recommended, but 
alcohol-, hydrogen peroxide-, iodine-, or thyme- containing 
mouthwashes should be avoided as they may exacerbate the 
condition. Antifungal agents should not be used unless fungal 
infection has been diagnosed. 
Pneumonitis 
Non-infectious pneumonitis – everolimus is associated with 
pneumonitis.  The use of corticosteroids is suggested for Grade 1-
2 pneumonitis, recommended for Grade 3 pneumonitis, and Grade 
4 pneumonitis should result in the cessation of everolimus. 
Non-hematologic, non-
hepatic adverse events 
≥ Grade 3 except for the following exceptions: 
Exceptions to DLT 
criteria 
Grade 3 or 4 Allergic Reaction 
Grade 3 alopecia 
< 5 days of Grade 3 fatigue 
Grade 3 fever or infection without neutropenia < 5 days duration 
Grade 3 laboratory abnormalities that are responsive to oral 
supplementation or deemed by the investigator to be clinically 
insignificant 
 
6.7.1.2 Dose reduction and delays due to toxicities related to known toxicities of LEE011 or 
everolimus 
If a subject experiences a DLT, as defined above in Table 10, the subject will complete the 
planned activities of the cycle as scheduled (i.e., CT scans and lab tests will be performed per 
standard of care).  The following are guidelines for dose delay and discontinuation of the study 
drugs: 
1) All treatment drugs should be discontinued/delayed concurrently until the toxicity resolves to 
Grade 1 or lower or to baseline if Grade 2 at the time of study entry.  

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a. Of note, LEE011 is known to be associated with myelosuppression. Thus, for Grade 2 
or 3 neutropenia, anemia, or thrombocytopenia which do NOT meet the definition of a 
DLT as detailed in Table 10, then treatment will continue without modification. 
i. Patients who experience Grade 2 or 3 neutropenia, anemia, or 
thrombocytopenia, while continuing treatment without modification for that 
cycle, will be followed with weekly CBCs to track the recovery (or worsening) 
of the myelosuppression 
ii. Dose modifications for Grade 2 or 3 neutropenia, anemia, or thrombocytopenia 
as detailed in Table 11 below will then be instituted FOR SUBSEQUENT 
CYCLES of therapy 
1. Thus, 
for 
example, 
a 
patient 
who 
experiences 
Grade 
3 
thrombocytopenia without bleeding at Cycle 1, Day 15 will continue 
treatment without modification.  CBCs will be checked weekly 
a. If the thrombocytopenia worsens to Grade 4, for example Cycle 
1, Day 22, then treatment will be held, and dose reductions will 
be instituted starting Cycle 2 
b. If the thrombocytopenia does NOT worsen through Cycle 1, 
then treatment hold and dose modifications will be followed for 
Cycle 2, as per Table 11 below  
iii. For clarity, for any hematologic toxicity that meets the definition of a DLT (even 
in the Phase II portion), treatment will be held, and doses modified as per Table 
11, even within a cycle.  
2) Subjects may delay retreatment for up to 3 weeks to allow the toxicity to resolve.  
In the Phase II portion of the study, dose adjustments will be followed, as per Table 11.  One dose 
adjustment is allowed, as delineated in Table 11. 
 
Table 11. Dose Modifications for Toxicities Related to LEE011 or everolimus 
Hematologic 
Thrombocytopenia 
Grade 1 (≥ 75 x 109/L) 
No dose adjustment required 
Grade 2 (≥ 50 x 109/L – < 75 x 109/L) 
Hold LEE011 and everolimus until recovery ≤ Grade 1, re-initiate at same dose 
Grade 3 (≥ 25 x 109/L – < 50 x 109/L) 
Hold LEE011 and everolimus until recovery ≤ Grade 1, re-initiate at same dose 
If recurs at Grade 3: 
Hold LEE011 and everolimus until recovery ≤ Grade 1,  
re-initiate LEE011 at one dose level lower, everolimus 2.5 mg 
Grade 4 (< 25 x 109/L) 
Hold LEE011 and everolimus until recovery ≤ Grade 1,  
re-initiate LEE011 at one dose level lower, everolimus 2.5 mg 
If recurs at Grade 4: 
Discontinue all therapy (off study) 
Neutropenia (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) 
Hold LEE011 and everolimus until recovery ≥ 1.0 x 109/L, re-initiate at same dose 
If recurs at Grade 3: 
Hold LEE011 and everolimus until recovery ≥ 1.0 x 109/L 
If resolved ≤ 7 days, re-initiate at same dose 
If resolved > 7 days, re-initiate LEE011 at one dose level lower, everolimus 2.5 mg 
Grade 4 (≥ 1.5 x 109/L) 
Hold LEE011 and everolimus until recovery ≥ 1.0 x 109/L,  
re-initiate LEE011 at one dose level lower, everolimus 2.5 mg 
If recurs at Grade 4: 
Discontinue all therapy (off study) 
Febrile neutropenia 
Grade 3 (ANC < 1.0 x 109/L with a 
single temperature > 38.3 °C 
(101 °F) or a sustained temperature 
of ≥ 38.3 °C (101 °F) for more than 1 
hour 
Hold LEE011 and everolimus until recovery ≥ 1.0 x 109/L and afebrile,  
re-initiate LEE011 at one dose level lower, everolimus 2.5 mg 
If recurs: 
Discontinue all therapy (off study) 
Grade 4 (life-threatening 
consequences, urgent intervention 
indicated) 
 
 
Discontinue all therapy (off study) 
 

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Anemia (hemoglobin) 
Grade 1 (≥ 10.0 – LLN g/dL) 
No dose adjustment required 
Grade 2 (≥ 8.0 – < 10.0 g/dL) 
No dose adjustment required 
Grade 3 (< 8.0 g/dL) 
Hold LEE011 and everolimus until recovery to ≤ Grade 2, re-initiate at same dose 
Grade 4 (life-threatening 
consequences, urgent intervention 
indicated) 
Discontinue all therapy (off study) 
Hepatotoxicity 
Total bilirubin elevation without AST/ALT increase above baseline value 
Grade 1 (> ULN – 1.5 x ULN) 
confirmed on repeat 48-72 hours 
later 
Maintain dose level with LFTs monitored bi-weekly 
Grade 2 (> 1.5 – 3.0 x ULN) 
Hold LEE011 and everolimus 
If resolved to ≤ Grade 1 in ≤ 21 days, then re-initiate at same dose 
If resolved to ≤ Grade 1 in > 21 days or toxicity recurs, 
Re-initiate LEE011 at one dose level lower, everolimus 2.5 mg 
Repeat liver enzymes and bilirubin tests twice weekly for 2 weeks following re-initiation 
If recurs at reduced dose level, discontinue all therapy (off study) 
Grade 3 (> 3.0 – 10.0 x ULN) 
Hold LEE011 and everolimus 
If resolved to ≤ Grade 1 in ≤ 21 days,  
Re-initiate LEE011 at one dose level lower, everolimus 2.5 mg 
Repeat liver enzymes and bilirubin tests twice weekly for 2 weeks following re-initiation 
If resolved to ≤ Grade 1 in > 21 days or toxicity recurs, discontinue all therapy (off study) 
Grade 4 (> 10.0 x ULN) 
Discontinue all therapy (off study) 
AST or ALT elevation without bilirubin elevation > 2 x ULN 
Same grade as baseline or increase 
from baseline Grade 0 to Grade 1 
confirmed 48-72 hours 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) 
Hold LEE011 and everolimus 
If resolved to ≤ baseline value in ≤ 21 days, then re-initiate at same dose 
If resolved to ≤ baseline value in > 21 days or toxicity recurs, 
Re-initiate LEE011 at one dose level lower, everolimus 2.5 mg 
Repeat liver enzymes and bilirubin tests twice weekly for 2 weeks following re-initiation 
If recurs at reduced dose level or recovery to ≤ baseline value in > 28 days,  
Discontinue all therapy (off study) 
Increase from baseline Grade 0 or 1 
to Grade 3 (> 5.0 – 20.0 x ULN) 
Hold LEE011 and everolimus 
If resolved to ≤ baseline value in ≤ 28 days,  
Re-initiate LEE011 at one dose level lower, everolimus 2.5 mg 
Repeat liver enzymes and bilirubin tests twice weekly for 2 weeks following re-initiation 
If recurs at reduced dose level or recovery to ≤ baseline value in > 28 days,  
Discontinue all therapy (off study) 
Increase from baseline Grade 2 to 
Grade 3 (> 5.0 – 20.0 x ULN) 
Hold LEE011 and everolimus 
If resolved to ≤ baseline value in ≤ 28 days,  
Re-initiate LEE011 at one dose level lower, everolimus 2.5 mg 
Repeat liver enzymes and bilirubin tests twice weekly for 2 weeks following re-initiation 
If recurs at reduced dose level or recovery to ≤ baseline value in > 28 days,  
Discontinue all therapy (off study) 
Grade 4 (> 20.0 x ULN) 
Discontinue all therapy (off study) 
AST or ALT and concurrent bilirubin elevation 
Normal ALT or AST or total bilirubin 
at baseline:  
AST or ALT ≥ Grade 2 with total 
bilirubin > 2 x ULN without evidence 
of cholestasis 
OR 
Elevated AST or ALT or total 
bilirubin at baseline: baseline: [AST 
Discontinue all therapy (off study) 

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or ALT >2 x baseline AND > 3.0 x 
ULN] OR [AST or ALT 8.0 x ULN]- 
whichever is lower-combined with 
[total bilirubin 2x baseline AND > 2.0 
x ULN]  
QT Prolongation 
For All Grades 
1. 
Check the quality of the ECG and the QT value, repeat if needed 
2. 
Check serum electrolytes (potassium, calcium, phosphorus, and magnesium), 
if abnormal: hold LEE011 and everolimus, correct with supplements as soon 
as possible and repeat electrolytes until within normal range, then re-initiate at 
same dose 
3. 
Review concomitant medications for propensity to prolong the QT interval and 
CYP3A4 inhibitors  
4. 
Check compliance with correct dose and administration of LEE011 
QTcF 450-480 ms 
Perform steps 1-4 as directed in “For All Grades.” No dose adjustment required 
QTcF 481-500 ms 
Hold LEE011 and everolimus. Perform steps 1-4 as directed in “For All Grades.” 
Repeat ECG one hour after the first QTcF of ≥ 481 ms.  
• 
Repeat ECG as clinically indicated until the QTcF returns to < 481 ms, restart 
LEE011with dose reduced by 1 dose level. Refer to Table 1 for dosing 
schedule. 
• 
If QTcF ≥ 481 ms recurs, LEE011 should be reduced again by 1 dose level. 
• 
Repeat ECGs 7 and 14 days after dose resumption and as clinically indicated 
QTcF ≥ 501 ms on at least 2 
separate ECGs 
Hold LEE011 and everolimus. Perform steps 1-4 as directed in “For All Grades.” 
Transmit ECG immediately and confirm prolongation/abnormalities with central 
assessment (if applicable). 
Perform a repeat ECG within one hour of the first QTcF of ≥ 501 ms. 
If QTcF remains ≥ 501 ms, consult with a cardiologist (or qualified specialist) and repeat 
cardiac monitoring as indicated until the QTcF returns to < 481 ms. 
• If QTcF returns to < 481 ms, LEE011 will be reduced by 1 dose level. Refer to Table 
1 for dosing schedule. 
• If QTcF remains ≥ 481 ms after performing steps 1-4 as directed in “For All 
Grades,” discontinue LEE011. 
Repeat ECGs 7 days and 14 days after dose resumption (then as clinically indicated) for 
any patients who had therapy interrupted due to QTcF ≥ 501 ms 
If QTcF of ≥ 501 ms recurs, discontinue LEE011. 
QT/QTcF ≥ 501 ms or > 60 ms 
increase from baseline 
AND 
Torsades de pointes or polymorphic 
ventricular tachycardia, or 
signs/symptoms of serious 
arrhythmia 
Discontinue all therapy (off study). Perform steps 1-4 as directed in “For All Grades.” 
Obtain local cardiologist consultation (or qualified specialist), repeat cardiac monitoring 
as indicated until QTcF returns to < 481 ms 
Non-infectious Pneumonitis 
Grade 1-2 
Consider steroids, hold LEE011 and everolimus until below Grade 1, re-initiate at same 
dose 
Grade 3 
Trial of steroids, hold LEE011 and everolimus until below Grade 1 
If recurs, discontinue all therapy (off study) 
Grade 4 
Discontinue all therapy (off study) 
All Other Adverse Reactions 
Grade 1 
No dose adjustment recommended, initiate appropriate medical therapy and monitor 
Grade 2 
Hold LEE011 and everolimus until ≤ Grade 1, treat with appropriate medical therapy and 
monitor, re-initiate at same dose 
If recurs at Grade 2, hold LEE011 and everolimus until ≤ Grade 1,  
Re-initiate LEE011 at one dose level lower, everolimus 2.5 mg 
Grade 3 
Hold LEE011 and everolimus until ≤ Grade 1, treat with appropriate medical therapy and 
monitor, re-initiate LEE011 at one dose level lower, everolimus 2.5 mg 
If recurs at Grade 3, discontinue all therapy (off study) 
Grade 4 
Discontinue all therapy (off study), treat with appropriate medical therapy 
 
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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7.0 EFFICACY ASSESMENT    
7.1 Efficacy Variables 
Tumor response and/or disease progression will be assessed by a CT scan (or other appropriate 
modalities such by way of MRI consistent with the modality used prior to treatment) utilizing 
RECIST v1.1 criteria. Assessments will be performed within 3 weeks before screening every 8 
weeks thereafter, and at the final visit, if not performed within the last four weeks. If subjects 
respond to treatment and are able to have their disease resected, the patient’s response will be 
assessed prior to the surgery.  The primary clinical efficacy endpoint is PFS8 weeks as determined 
by RECIST v1.1 criteria.  Analyses of these endpoints are described in Section 13. 
 
7.2 RECIST v1.1 Criteria for Tumor Response 
Changes in the measurable lesions over the course of therapy will be evaluated using the RECIST 
v1.1 criteria. 
 
7.2.1 Definition of Lesions 
7.2.1.1 Measurable Disease  
The presence of at least one measurable lesion. If the measurable disease is restricted to a 
solitary lesion, its neoplastic nature should be confirmed by cytology/histology. 
 
7.2.1.2 Measurable Lesions 
Lesions that can be accurately measured in at least one dimension with longest diameter ≥ 20 
mm using conventional techniques or ≥ 10 mm with CT scan.  
 
7.2.1.3 Non-measurable Lesions 
All other lesions, including small lesions (longest diameter < 20 mm with conventional techniques 
or < 10 mm with a CT scan), bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions and also 
abdominal masses that are suspicious though may or may not be confirmed and followed by 
imaging techniques. 
 
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 14 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.  Clinical lesions will only be considered measurable when 
they are superficial (e.g., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is required. 
 
7.2.2 Methods of Measurement 
CT and MRI are the best currently available and reproducible methods to measure target lesions 
selected for response assessment. Conventional CT and MRI should be performed with cuts of 
10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm. This applies to tumors of the chest, abdomen and pelvis. For 
accurate objective response evaluation, ultrasound should not be used to measure tumor lesions. 
However, ultrasound is a possible alternative to clinical measurements of superficial palpable 
lymph nodes, subcutaneous lesions and thyroid nodules. Ultrasound might also be useful to 
confirm the complete disappearance of superficial lesions usually assessed by clinical 
examination.  Cytology and histology can be used to differentiate between PR and CR in rare 
cases (e.g., after treatment to differentiate between residual benign lesions and residual 
malignant lesions in tumor types such as germ cell tumors).   
 
 
 

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7.2.3 Baseline Documentation of "Target" and "Non-Target" Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 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.  All other lesions (or sites of disease) should be 
identified as non-target lesions and should also be recorded at baseline. Measurements of these 
lesions are not required, but the presence or absence of each should be noted throughout follow-
up. 
 
7.2.4 Definitions of Tumor Response-Measurable Disease 
7.2.4.1 Complete Response (CR) 
The disappearance of all known disease, determined by two observations not less than 4 weeks 
apart. There can be no appearance of new lesions. 
 
7.2.4.2 Partial Response (PR) 
A 30% or more decrease in the sum of the LD of target lesions that have been measured to 
determine the effect of therapy by two observations not less than 4 weeks apart. There can be no 
appearance of new lesions or progression of any lesion. 
 
7.2.4.3 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, the appearance of one or more new lesions and/or 
an unequivocal progression of non-target lesions. 
 
7.2.4.4 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. 
 
7.3 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 12. Response Evaluation.  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. 
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 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
Note: Patients 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. 
 
7.4 Definition of Disease Progression 
Disease progression will be defined as: 
1) Radiologic progression of disease by RECIST v1.1 criteria. 
2) Clinical progression as determined by the investigator, which may be characterized as, 
but is not limited to: 
a. Increase of at least 2 points in ECOG performance status attributable to cancer 
progression. 
b. Requirement for palliative radiation, chemotherapy or surgery. 
3) Death from disease progression 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8.0 CORRELATIVE RESEARCH AND TUMOR BIOPSIES  
8.1 Pharmacodynamic Assessment of the Efficacy of LEE011 and Everolimus 
8.1.1 Introduction 
The primary objective of this trial is to determine the efficacy of LEE011 and everolimus in patients 
with refractory mPAC. However, an important secondary endpoint is to assess the 
pharmacodynamic effects of the combination treatment on cell cycle, the retinoblastoma 
pathways and MTOR pathways, and to correlate those effects to the PFS.  Thus, for all patients, 
we will require at least 2 serial biopsies.   
- 
A fresh biopsy prior to treatment  
- 
A repeat biopsy on the Cycle 1 Day 15 
- 
An optional final biopsy after PD or off study 
The first (pre-treatment) biopsy should be performed as soon as possible after consent is signed. 
For this reason, patients will be screened for accessibility of tumor tissue.  Specifically, our 
radiologists will review the most recent images for each patient prior to enrollment.  Only patients 
who, in their best estimation, have a tumor deposit(s), that are easily accessible by ultrasound or 
CT guidance in order to obtain serial core needle biopsies, will be eligible for study 
 
With regards to the timing of the second biopsy, the pharmacokinetics of both LEE011 and 
everolimus suggest that the LEE011 reaches steady state by Day 8, and the everolimus by 2 
weeks.  Thus, the second biopsy was requested at a time point wherein both agents have 
achieved steady state, but before the week off of LEE011. 
 
Patients will undergo core biopsies, as per standard protocol in the Department of Radiology.  An 
18-20 gauge needle will be used.  At least four 1-2 cM core biopsies should be obtained with each 
biopsy.  All samples should be labeled with the date, protocol number, protocol assigned patient 
number, and biopsy number (1 – pre-treatment; 2 – on-treatment; 3 – after PD or off study).  
 
2 cores should be placed in screw-top tubes and frozen in liquid nitrogen. 
The other 2 cores should be immediately placed in formalin and then embedded in paraffin.  
 
Throughout the study, the following labeling procedures will be followed 
 
8.1.1.1 Patient Study Number Assignment 
Patients will be de-identified and labeled with a 5 digit study label (X-XXX-X): 
- 
The first number will be the site from which the patient was enrolled (single digit) 
o 1 = Georgetown 
- 
The second number will be the site-assigned patient number (three digit) 
- 
The third number will indicate the collection timing  
o 1 = Pre-treatment 
o 2 = On treatment 
 
8.1.1.2 Labeling of Serial Blood Samples 
Serial blood samples will be labeled in a similar fashion, except that the collection timing will 
labeled by week number (e.g. week 0 = pretreatment; week 8; week 16) 
 
8.1.1.3 Sample Shipment 
Samples collected must be shipped at room temperature to Dr. Erik Knudsen at: 
 
Roswell Park Comprehensive Cancer Center 
c/o Dr. Erik S. Knudsen 
Elm & Carlton Streets 
Buffalo, NY 14263 

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8.1.2 
Assessment 
of 
Pharmacodynamic 
Effects 
of 
LEE011 
and 
Everolimus 
A formalin-fixed, paraffin embedded core sample from the pre-treatment and on-treatment tumor 
biopsies will be used to make slides to stain for the following markers by IHC with the indicated 
cutpoints: 
a. RB, defined as negative if tumor cells are devoid of nuclear staining, while 
lymphocytes and stromal cells have positive nuclear staining.  
b. pRB (phosphorylated Ser780), defined using a histoscore of intensity and percent 
of tumor cell nuclei staining.  
c. p16 levels are defined using established clinical staining criteria (0-3+) 
d. Cyclin 
D1, 
defined 
using 
intensity 
and 
predominant 
localization 
(nuclear/cytoplasmic) 
e. Ki67, defined as a percentage of positively stained nuclei in the tumor 
compartment 
f. MCM7, defined as a percentage of positively stained cells nuclei in the tumor 
compartment 
g. pS6 (Ser235/236) defined using a histoscore of intensity and percent of tumor cells 
staining 
 
LEE011 directly suppresses the phosphorylation of RB which provides an assessment of on-
target activity.   Ki67 and MCM7 are markers of proliferation and are expected to diminish with 
treatment associated with response.   RB, Cyclin D1, and p16 could be predictive markers of 
response, and the absence of RB and high-levels of p16 are associated with resistance.   
Phosphorylation of s6 protein is mediated by MTOR and provides a marker for the efficacy of 
MTOR inhibition by everolimus.  
 
8.2 Mutational Analysis of Tumor Samples 
Pre-treatment biopsy samples will be used for targeted next generation sequencing using a panel 
that includes 196 genes commonly altered in cancer with a specific emphasis on genes that are 
altered in pancreatic cancer.   This platform will allow >500x coverage across the genes and 
provide both single nucleotide variant and copy number information.   Each common gene 
mutation will be evaluated for association with PFS.    The presence of a CDKN2A mutation or 
deletion will be correlated with PFS, given the hypothesis that derangement in this pathway results 
in p16 loss, creating a therapeutic target of CDK4/6 (naturally inhibited by p16). 
 
8.3 Analysis of ctDNA 
ctDNA will be collected from patient serum at Cycle 1 Day 1 and every 8 weeks thereafter.   
Mutations identified by the targeted sequencing will be evaluated in the circulating DNA 
specimens using PCR (predominantly focused around KRAS, TP53, or CDKN2A mutations). We 
will correlate changes in the ctDNA abundance with PFS and tumor marker levels.  The data will 
determine if ctDNA may be a possible surrogate marker for disease burden. 
 
8.4 Tissue Prioritization 
We anticipate that the biopsies will provide sufficient tissue for all the studies to be performed 
above.  One good core of tissue should be sufficient for all the IHC stains, and one good core 
should be sufficient for the NGS.  However, should there be insufficient tissue, the priority will be 
as follows: 
- 
The IHC will take priority, with the specific priority order following the order of markers 
listed above (a through g) 
- 
The NGS will be the second priority. For the NGS, there is no “priority” order of the genes 
analyzed, as the entire panel will be run at once.  
 
 
 

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9.0 STATISTICAL CONSIDERATIONS 
9.1 Objectives:  
9.1.1 Primary Objective of the Phase I Portion: 
To determine the Recommended Phase II dose (RP2D) of LEE011 in the combination with 
everolimus in patients with mPAC refractory to 5-FU- and GEM-based chemotherapy 
 
9.1.2 Primary Objective of the Phase II Portion: 
 
To determine the progression-free survival (PFS) rate at 8 weeks (PFS8 weeks) to assess the clinical 
efficacy of the combination of LEE011 and everolimus in patients with mPAC refractory to 5-FU- 
and GEM-based chemotherapy 
 
9.1.3 Secondary Objectives 
9.1.3.1 To determine the mPFS of patients treated with the combination of LEE011 and 
everolimus in patients with mPAC refractory to chemotherapy 
 
9.1.3.2 To determine the mOS of patients treated with the combination of LEE011 and everolimus 
in patients with mPAC refractory to chemotherapy 
 
9.1.3.3 To determine the best ORR, the largest percent decrease in tumor size from baseline as 
measured by expert radiologists using RECIST v1.1 criteria, defined as the proportion of patients 
with a CR or PR, of the combination of LEE011 and everolimus in patients with mPAC refractory 
to chemotherapy 
 
9.1.3.4 To determine the safety and tolerability of the combination of LEE011 and everolimus in 
patients with mPAC refractory to chemotherapy 
 
9.1.4 Exploratory Objectives 
9.1.4.1 To correlate the PFS8 weeks to correlative scientific markers, including the analysis of tumor 
biopsies and blood-based markers, including RB, pRB, p16, cyclin D1, Ki67, MCM7, and pS6 
levels by immunohistochemistry    
 
9.1.4.2 To screen for use a targeted sequencing approach for genetic lesions observed in 
pancreatic cancer that includes KRAS, SMAD4, TP53, CDKN2A as well as other commonly 
mutated cancer genes 
 
9.1.4.1 To assess blood for the analysis of circulating tumor DNA as a surrogate marker of disease 
burden.   KRAS and other mutations will be used as the determinants of tumor selective DNA 
 
9.2 Study Design 
This study is a single-arm, open-label, Phase I/II trial of the combination of LEE011 and 
everolimus in refractory mPAC. The Phase I portion of the trial will be conducted in a 3+3 design, 
enrolling patients in cohorts of 3 patients each. If 0-1 DLTs occur in a cohort of 3 patients, the 
cohort will be expanded to 6 patients.  If 0-1 DLTs occur in the group of 6 patients, the RP2D will 
be that dose level.  Otherwise, 3 patients will be enrolled at the next lowest dose level and the 
process continued until the RP2D is determined (0-1 DLTs within the 6 patients at that dose level) 
or the study is terminated (if there are 2 or more DLTs at Dose Level -3).  
 
The Phase II study will be conducted using a Simon’s Minimax two-stage design. In the initial 
stage 11 patients will be enrolled, and if at least 3 patients are progression-free at 8 weeks, then 
an additional 15 patients will be enrolled in the second stage for a total of 26 patients on study. If 
2 or fewer patients are progression-free at 8 weeks, then the study will be terminated for futility. 
3 additional patients will be screened and may be used to replace up to 3 of the 26 patients, 

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provided those initial patients undergo screening but do not start study treatment within 3 weeks 
of screening. Thus, a total of 29 patients are expected to be screened for the Phase II portion of 
this study. 
 
9.3 Sample Size Considerations 
Using a Simon Minimax 2-stage design with a null hypothesis of 25% and an alternative 
hypothesis of 50% (or greater) a total of 26 evaluable patients are needed (assuming 90% power 
and alpha=0.1 (one-sided)). 
 
For the Phase I portion, there may be as few as 12, and as many as 18 patients enrolled strictly 
in the Phase I portion (and not treated at the RP2D of LEE011, thus not counted towards the 
Phase II portion of the study).  Thus, as many as 44 patients may be accrued for this trial.  
Anticipating an accrual rate of 3 patients per month, the trial is expected to complete accrual in 
approximately 15 months. 
 
9.4 Endpoints 
9.4.1 Primary Endpoint  
PFS at 8 weeks is a complete response (CR), partial response (PR), or stable disease (SD) by 
imaging study (CT or MRI), evaluated by expert radiologists using RECIST v1.1 criteria, at the 8 
week response assessment. Each patient will be categorized as either success/failure for being 
progression free at 8 weeks. 
 
9.4.2 Secondary Endpoints 
9.4.2.1 PFS is the time from Cycle 1, Day 1 to PD, death from any cause, or last follow-up, as 
determined by the investigator. If a patient dies on study they will be censored at the time of death 
for the purposes of the PFS endpoint. 
 
9.4.2.2 OS is the time from Cycle 1, Day 1 to death from any cause or last follow-up.  
 
9.4.2.3 Best response is the largest percent decrease in tumor size from baseline and is 
categorized as a CR, PR, or SD by imaging studies, evaluated by expert radiologists using 
RECIST v1.1 criteria.  
 
9.4.2.4 The number of grade 3 and 4 toxicities according to National Cancer Institute Common 
Toxicity Criteria for Adverse Events (NCI CTCAE; Version 4.0) that occur after Cycle 1, Day 1 will 
be recorded at each study visit.  
 
9.4.2.5 Pharmacodynamic effects of therapy will be evaluated by comparison of expression levels 
obtained by IHC in the pre-treatment biopsy and the on-treatment biopsy of: 
9.4.2.5.1 RB, defined as positive if any tumor cells have RB nuclear staining  
 
9.4.2.5.2 pRB, defined as positive if any tumor cells have phosphorylated-RB nuclear staining  
 
9.4.2.5.3 p16, defined as positive if nuclear staining in 5% or more of tumor cells 
 
9.4.2.5.4 Cyclin D1, defined as positive if any tumor cells have cyclin D1 nuclear staining 
 
9.4.2.5.5 Ki67, defined as a percentage of positively stained cells (nuclear staining and mitotic 
figures) among the total number of malignant cells viewed in at least 3 randomly-selected high-
power (x40 objective) fields 
 
9.4.2.5.6 MCM7, defined as a percentage of positively stained cells (nuclei) among the total 
number of malignant cells viewed in at least 3 randomly-selected high-power (x40 objective) fields 

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9.4.2.5.7 pS6 (Ser235/236) defined using a histoscore of intensity and percent of tumor cells 
staining 
 
9.4.2.6 Frequency of mutations from targeted NGS analyses from pre-treatment biopsy 
specimens will be ranked. 
 
9.4.2.7 ctDNA will be collected via serial blood samples with frequency as described above and 
quantitatively measured, defined as the number of mutant fragments in 5 mL by quantitative PCR. 
 
9.5 Analysis Plan 
9.5.1 Analytic plan for primary objective 
The null hypothesis is that the PFS rate at 8 weeks is 25% (based on historical controls wherein 
third-line therapy in mPAC revealed stable disease in 25-31% of patients5,6.) versus an alternative 
hypothesis that the rate is 50% or higher.  The plan is to use a Simon’s Minimax two-stage design 
with 11 patients enrolled during the first stage.  If 3 or more (out of 11) patients are progression 
free the trial will continue with an additional 15 patients being enrolled during the second stage 
(for a total of 26 patients).  If 10 or more patients are progression free at 8 weeks the trial will 
declare that the intervention has met the pre-specified criteria for success.     
 
9.5.2 Analytic plan for secondary objectives 
9.5.2.1 Survival and response endpoints: 
9.5.2.1.1 The nonparametric Kaplan-Meier method will be used to estimate median PFS. 
 
9.5.2.1.2 The nonparametric Kaplan-Meier method will be used to estimate median OS. 
 
9.5.2.1.3 We plan to determine the ORR within a ± 20% range based on our sample size.  
 
9.5.2.2 Adverse event data will be compiled and tabulated using descriptive statistics. 
 
9.5.2.3 Pharmacodynamic analyses are exploratory, but we hypothesize that proliferation indices 
(Ki67 and MCM7) will be decreased in the on-treatment sample compared to the pre-treatment 
sample and could correlate with PFS. Similarly, expected decreases in levels of pRB, cyclin D1, 
p16, and increases in RB could correlate with PFS.  Cox proportional hazard regression models 
will be fit to determine whether these secondary endpoints are associated with PFS. 
 
9.5.2.4 NGS analysis is also exploratory in nature. Using results from these analyses will examine 
whether median PFS is different with patients with mutations in CDKN2A compared to those 
without these mutations.   
 
9.5.2.5 ctDNA studies are exploratory and overall trends in serial measurements may support a 
response (or lack of response) signal to treatment and could be correlated with PFS as a 
surrogate marker of disease burden. 
 
9.5.2 Safety Assessments 
 
9.5.2.1 Safety Assessments 
The safety of LEE011 and everolimus will be assessed by evaluating study drug exposure, 
adverse events, serious adverse events, oncology-related events, all deaths, as well as changes 
in laboratory determinations and vital sign parameters.   
 
 
 

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9.5.2.2 Duration of Study Drug 
A summarization of the number of days and/or cycles subjects were exposed to study drug will 
be provided. 
 
9.5.2.3 Adverse Events   
Analyses of adverse events (and serious adverse events) will include only "treatment-emergent" 
events, i.e., those that have an onset on or after the day of the first dose of study drug. Analyses 
will not include those that have an onset greater than 30 days after the last dose of study drug. 
Treatment emergent adverse events will be summarized by system organ class and preferred 
term according to the MedDRA adverse event coding dictionary. The percentage of subjects 
experiencing an adverse event at a given severity, NCI CTCAE toxicity grade, and relationship to 
study drug will be provided.  
 
9.5.2.4 Deaths 
The number of subject deaths will be summarized (1) for deaths occurring while the subject was 
still receiving study drug in this study, (2) for deaths occurring off treatment within 30 days after 
the last dose of study drug, and (3) for all deaths in this study regardless of the number of days 
after the last dose of study drug.  The relatedness of the deaths to the study drugs will also be 
provided. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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10.0 ETHICAL CONSIDERATIONS 
10.1 Institutional Review Board (IRB) 
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, the 
Investigator's Brochure, the informed consent and all other forms of subject information related to 
the study (e.g., advertisements used to recruit subjects) and any other necessary documents be 
reviewed by an IRB. IRB approval of the protocol, informed consent and subject information 
and/or advertising, as relevant, will be obtained prior to the authorization of drug shipment to the 
study site.  Any amendments to the protocol will require IRB approval prior to implementation of 
any changes made to the study design.  Any serious adverse events that meet the reporting 
criteria, as dictated by local regulations, will be reported to the IRB. During the conduct of the 
study, the investigator should promptly provide written reports to the IRB of any changes that 
affect the conduct of the study and/or increase the risk to subjects.  
 
10.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical study 
conduct and the ethical Principals that have their origin in the Declaration of Helsinki.  
 
10.3 Subject Information and Consent 
Prior to the initiation of any screening or study-specific procedures, the investigator or his/her 
representative will explain the nature of the study to the subject and answer all questions 
regarding this study. A separate informed consent is also required from subjects who provide 
blood for genetic testing or fresh biopsy tissue samples for analyses. Each informed consent will 
be reviewed, signed and dated by the subject and the person who administered the informed 
consent. A copy of each informed consent will be given to the subject and each original will be 
placed in the subject's medical record. An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related procedures 
and that the subject received a signed copy.  Tissue sample collection for analysis will only be 
performed if the subject has voluntarily consented to participate after the nature of the testing has 
been explained and the subject has had the opportunity to ask questions. If the subject does not 
consent to the tissue sample collection, it will not impact the subject's participation in the study. 
 
10.4 Ethical Consideration for Enrollment 
Only patients with advanced cancer, for whom no curative therapy exists, will be considered for 
enrollment.  The only treatment options for these patients are enrollment in a Phase I clinical trial, 
or treatment off protocol, with a non-standard therapy.  As described above, the combination of 
LEE011 and everolimus is a rational and promising combination for such patients 
 
10.5 Protection of Patient Confidentiality 
All patient records, questionnaires, and tissue specimens will be de-identified using a letter and 
number assigned to their case at the time of enrollment on study.  No record or specimen will 
contain information which could identify the patient.  The key which connects patient identifiable 
information with this assigned number will be held by the Principal investigator.  For computer 
records, the key will be protected by a double password protection system.  Any paper records 
will be contained in a locked cabinet within a locked office to ensure patient’s privacy is protected.  
 
 
 

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Version 2.3, July 16, 2018 
APPENDIX A – PATIENT DRUG DIARY 
 
Cycle Number: ________  Day 1 Date: ___/____/_____ 
 
 
 
Day 1 
LEE011 
time: 
____:____ 
 
Everolimus 
time: 
____:____ 
 
Day 2 
LEE011  
time: 
____:____ 
Everolimus 
time: 
____:____ 
Day 3 
LEE011  
time: 
____:____ 
 Everolimus 
time: 
____:____ 
Day 4 
LEE011  
time: 
____:____ 
Everolimus 
time: 
____:____ 
Day 5 
LEE011  
time: 
____:____ 
Everolimus 
time: 
____:____ 
Day 6 
LEE011  
time: 
____:____ 
 Everolimus 
time: 
____:____ 
Day 7 
LEE011  
time: 
____:____ 
 Everolimus 
time: 
____:____ 
Day 8 
LEE011  
time: 
____:____ 
 Everolimus 
time: 
____:____ 
Day 9 
LEE011  
time: 
____:____ 
Everolimus 
time: 
____:____ 
Day 10 
LEE011  
time: 
____:____ 
Everolimus 
time: 
____:____ 
Day 11 
LEE011  
time: 
____:____ 
Everolimus 
time: 
____:____ 
Day 12 
LEE011  
time: 
____:____ 
Everolimus 
time: 
____:____ 
Day 13 
LEE011  
time: 
____:____ 
Everolimus 
time: 
____:____ 
Day 14 
LEE011  
time: 
____:____ 
Everolimus 
time: 
____:____ 
 
Day 15 
LEE011  
time: 
____:____ 
 
Everolimus 
time: 
____:____ 
Day 16 
LEE011  
time: 
____:____ 
Everolimus 
time: 
____:____ 
 
Day 17 
LEE011  
time: 
____:____ 
 
Everolimus 
time: 
____:____ 
Day 18 
LEE011  
time: 
____:____ 
Everolimus 
time: 
____:____ 
Day 19 
LEE011  
time: 
____:____ 
Everolimus 
time: 
____:____ 
Day 20 
LEE011  
time: 
____:____ 
Everolimus 
time: 
____:____ 
Day 21 
LEE011  
time: 
____:____ 
Everolimus 
time: 
____:____ 
Day 22 
Everolimus 
time: 
____:____ 
Day 23 
Everolimus 
time: 
____:____ 
Day 24 
Everolimus 
time: 
____:____ 
Day 25 
Everolimus 
time: 
____:____ 
Day 26 
Everolimus 
time: 
____:____ 
Day 27 
Everolimus 
time: 
____:____ 
Day 28 
Everolimus 
time: 
____:____ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX B – PATIENT TRIAL EVENTS 
 
 
 
 
 
 

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APPENDIX C: STUDY ELIGIBILITY CHECKLIST 
A Phase I/II Study of LEE011 plus Everolimus in Patients with Metastatic 
Pancreatic Adenocarcinoma Refractory to Chemotherapy 
Patient Initials: _________  Study ID: _________ 
Instructions: This form should be completed by the research staff before registering the patient into the trial. 
Completed form can be faxed to 202-687-3821 or scanned/emailed to pishvaim@georgetown.edu. 
□Georgetown University Medical Center     □ Other site: _____________________________________________ 
 
 
INCLUSION CRITERIA (ALL ITEMS MUST BE CHECKED YES) 
YES | NO 
 
□ | □ 
Histologically proven pancreatic adenocarcinoma with radiographically measurable disease 
□ | □ 
Documented progression of disease on at least one 5-FU-based regimen and at least one GEM-based regimen for metastatic 
disease (progression during or within 3 months of the completion of adjuvant therapy is acceptable) 
□ | □ 
Biopsy accessible tumor deposits (as can best be determined by imaging) - A patient’s biopsied lesion must be at least 1cm in 
diameter (in at least one dimension) 
□ | □ 
Age ≥ 18 years 
□ | □ 
ECOG performance status 0 or 1 (see Table 2 below) 
□ | □ 
Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to initiation of treatment 
and/or postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. 
□ | □ 
Subject is capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the 
informed consent, approved by the Institutional Review Board (IRB), prior to the initiation of any screening or study-specific 
procedures 
□ | □ 
Patients must have fully recovered from all effects of surgery.  Patients must have had at least two weeks after minor surgery and 
four weeks after major surgery before starting therapy.  Minor procedures requiring “Twilight” sedation such as endoscopies or 
mediport placement may only require a 24-hour waiting period, but this must be discussed with an investigator. 
□ | □ 
Subjects with no brain metastases or a history of previously treated brain metastases who have been treated by surgery or 
stereotactic radiosurgery (SRS) at least 4 weeks prior to enrollment and have a baseline MRI that shows no evidence of active 
intracranial disease 
□ | □ 
Patients with available standard 12-lead ECG with the following parameters at screening (defined as the mean of the triplicate 
ECGs): 
• QTcF interval at screening <450msec 
• Resting heart rate 50-90bpm 
LAB VALUES (ALL MUST BE CHECKED YES) 
YES | NO 
 
□ | □ 
Absolute neutrophil count (ANC) ≥ 1,500/mm3 
□ | □ 
Platelets ≥ 100,000/mm3 
□ | □ 
Hemoglobin ≥ 9.0 g/dL 
□ | □ 
Serum creatinine ≤ 1.5 X the upper limit of normal of the institution’s normal range OR creatinine clearance ≥ 50 mL/min/1.73 
m2 for subjects with creatinine level above the upper limit of normal 
□ | □ 
Hepatic function: AST and ALT ≤ 3.0 × the upper normal limit of institution's normal range. Total bilirubin ≤ 1.5 × the upper 
normal limit of institution's normal range. For subjects with liver metastases, AST and ALT < 5 × the upper normal limit of 
institution's normal range, and total bilirubin >1.5 - 3.0 x the upper normal limit of institution's normal range are acceptable as 
long as there is no persistent nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia. 
□ | □ 
Potassium, total calcium (corrected for serum albumin), magnesium, sodium and phosphorus within normal limits for the 
institution or corrected to within normal limits with supplements before first dose of study medication 
□ | □ 
Prothrombin Time and Partial Thromboplastin Time (PTT) ≤ 2 X the upper limit of the institution’s normal range 
□ | □ 
INR (International Normalized Ratio) < 2, subjects on anticoagulation will be permitted as long as the INR is in an acceptable 
therapeutic range as determined by the investigator 

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EXCLUSION CRITERIA (ELIGIBLE PATIENTS MUST ALL BE CHECKED NO) 
 
□ | □ 
Prior anti-tumor therapy within 3 weeks of Cycle 1 Day 1 (anti-tumor therapy defined as, but is not limited to, anti-cancer 
agents (cytotoxic chemotherapy, immunotherapy, and biologic therapy), radiotherapy, and investigational agents), the “wash-
out period” 
□ | □ 
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 clinical study or compromise compliance with the 
protocol (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral 
infections, etc.). 
□ | □ 
Concurrent use of CYP3A4 inhibiting or activating medications; or concurrent use of an ACE inhibitor (increased risk of 
angioedema with ACE inhibitors administered in combination with everolimus, seen in approximately 6.8% of patients) 
□ | □ 
Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of 
adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer. 
□ | □ 
Active severe infection or known chronic infection with HIV or hepatitis B virus 
□ | □ 
Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study 
drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). 
□ | □ 
Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, as detailed in full exclusion 
criteria in Section 3.3 
□ | □ 
Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug 
(see Table 4 for details): 
• Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville 
oranges 
• That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5 
• Herbal preparations/medications, dietary supplements. 
OR Patient is currently receiving or has received systemic corticosteroids ≤2 weeks prior to starting study drug, or who have 
not fully recovered from side effects of such treatment. 
□ | □ 
Woman who is pregnant or breast feeding 
 
Table 4 (repeated): ECOG Performance Status Scale 
 
 
 
 
 
 
 
 
 
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
Ambulatory and capable of all self-care but unable to carry out any
work activities. Up and about more than 50% of waking hours.
2
Restricted in physically strenuous activity but ambulatory and able to  carry 
out work of a light or sedentary nature, e.g., light housework, office work.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
Ambulatory and capable of all self-care but unable to carry out any
work activities. Up and about more than 50% of waking hours.
2
Restricted in physically strenuous activity but ambulatory and able to  carry 
out work of a light or sedentary nature, e.g., light housework, office work.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade

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Version 2.3, July 16, 2018 
APPENDIX D: PATIENT REGISTRATION FORM 
A Phase I/II Study of LEE011 plus Everolimus in Patients with Metastatic 
Pancreatic Adenocarcinoma Refractory to Chemotherapy 
Patient Initials: _________  Study ID: _________ 
Instructions: This form should be completed by the research staff before registering the patient into the trial. 
Completed form can be faxed to 202-687-3821 or scanned/emailed to pishvaim@georgetown.edu. 
□Georgetown University Medical Center     □ Other site: _____________________________________________ 
 
 
1.  Date Informed Consent signed: ____/____/________ 
 
2.  Start date for treatment: ____/____/_______ 
 
3.  Prior therapies (date initiated/type): 
 
 
 
 
 
4.  Please fax the following documentation: 
□ Pathology Report 
□ Physicians Note validating: 
  ▪Previous treatments 
□ CT showing RECIST criteria 
□ Laboratory Results 
□ Past Medical History 
 
ON-STUDY CARD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRN: __________________ 
DOB:   ____/____/________ 
Zip Code: _______________ 
Race: □ African American 
 □ Asian 
 □ Caucasian 
 □ Hispanic 
 □ Native American 
 □ Pacific Islander 
 □ Other 
 □ Unknown 
Gender:   □ Male  □ Female   □ Unknown 
Treating Physician: __________________ 
RN: _______________________________ 
Ethnicity:         □ Hispanic or Latino 
                                    □ Not Hispanic or Latino 
                                    □ Unknown 
Consent Approval Date:   
____/____/________ 
Screen Failure:      □ Yes    □ No 
Screening Date:  ____/____/________ 
On Study Date:   ____/____/________ 
Protocol Waiver:   □ Yes    □ No 
Reason: _______________________ 
Registration Site:  _______________ 
 
First Treatment Date:   ____/____/________ 

77 
Version 2.3, July 16, 2018 
 
 
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