Clinical trial NCT03070301
Conditions: Neuroendocrine Tumors
Keywords: LEE011 Everolimus 16-1535
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2017-02-27; Completion date: 2024-01-31
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to test any good and bad effects of the combination of LEE011 with everolimus on the participant and the cancer.

Detailed description:

Arms: arm 1: Subjects will receive LEE011 200 mg daily, in combination with everolimus 5 mg daily; in the setting of toxicity, everolimus dosing will be changed to 2.5 mg daily or 2.5 mg every other day. Subjects will continue treatment until meeting one of the criteria for removal from study.
Interventions: intervention 1: LEE011 intervention 2: everolimus
Intervention descriptions: intervention 1: LEE011 200 mg daily intervention 2: everolimus 5 mg daily or 2.5mg daily

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1535 A(10) 
Approval date: 18-Apr-2019 
Page 1 of 68 
 
 
 
A phase II trial of LEE011 in combination with everolimus in the treatment of advanced 
well differentiated neuroendocrine tumors of foregut origin. 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal Investigator/Department: 
Diane Reidy-Lagunes, MD, MS 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Nitya Raj, MD 
Charles Rudin, MD, PhD 
Medicine 
Medicine 
Investigator(s)/Department: 
Ghassan Abou-Alfa, MD 
Philip Caron, MD, PhD 
Andrea Cercek, MD 
Luis A. Diaz, MD 
Andrew Epstein, MD 
Karuna Ganesh, MD, PhD 
James Harding, MD 
David Ilson, MD, PhD 
Yelena Janjigian, MD 
David Kelsen, MD 
Nancy Kemeny, MD 
Geoffrey Ku, MD 
Chung-Han Lee, MD, PhD 
Parisa Momtaz, MD 
Eileen O’Reilly, MD 
Armin Shahrokni, MD 
Leonard Saltz, MD 
Neil Segal, MD, PhD 
Zsofia Stadler, MD 
Anna Varghese, MD 
Rona Yaeger, MD 
Kenneth Yu, MD 
Elizabeth Won, MD 
Alice Zervoudakis, MD 
Jamie Chaft, MD 
Alexander Drilon, MD 
Matthew Hellmann, MD 
Mark Kris, MD 
Bob Li, MBBS 
Piro Lito, MD 
Paul Paik, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
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Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1535 A(10) 
Approval date: 18-Apr-2019 
Page 2 of 68 
 
 
Gregory Riely, MD, PhD 
Stephen Veach, MD 
Medicine 
Medicine 
Helena Yu, MD 
Marjorie Zauderer, MD 
Medicine 
Medicine 
Wungki Park, MD 
Juan Schvartzman, MD 
Imane El Dika, MD 
Medicine 
Medicine 
Medicine 
Louise Connell, MD 
Victoria Lai, MD 
Medicine 
Medicine 
Kathryn Arbour, MD 
Marinela Capanu, PhD 
Laura Tang, PhD 
Biostatistics 
Pathology 
Interventional Radiology 
Etay Ziv, MD, PhD 
Melanie Albano, NP 
Nursing 
Nursing 
Ellen Hollywood, NP 
Erica Kaufmann, NP 
Patricia Gabriel, NP 
Nursing 
Nursing 
Nursing 
Michal Segal, RN 
Jaclyn Norris, NP 
Nursing 
Nursing 
Alison Massey, NP 
Linda Ahn, NP 
Elizabeth Panora, NP 
Nursing 
Nursing 
Nursing 
Jad Bou Ayache, MD 
Peter Sawan, MD 
Natasha Pinheiro, NP 
Radiology 
Radiology 
Nursing 
Claudia Calderon, NP 
Nursing 
Consenting Professional(s)/Department: 
Ghassan Abou-Alfa, MD 
Medicine 
Philip Caron MD, PhD 
Andrea Cercek, MD 
Luis A. Diaz, MD 
Medicine 
Medicine 
Medicine 
Andrew Epstein, MD 
Karuna Ganesh, MD, PhD 
Medicine 
Medicine 
James Harding, MD 
David Ilson, MD, PhD 
Yelena Janjigian, MD 
Medicine 
Medicine 
Medicine 
David Kelsen, MD 
Nancy Kemeny, MD 
Medicine 
Medicine 
Geoffrey Ku, MD 
Chung-Han Lee, MD, PhD 
Bob Li, MD, MBBS 
Medicine 
Medicine 
Medicine 
Parisa Momtaz, MD 
Eileen O’Reilly, MD 
Medicine 
Medicine 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1535 A(10) 
Approval date: 18-Apr-2019 
Page 3 of 68 
 
 
Nitya Raj, MD 
Diane Reidy-Lagunes, MD, MS 
Armin Shahrokni, MD 
Leonard Saltz, MD 
Neil Segal, MD, PhD 
Zsofia Stadler, MD 
Anna Varghese, MD 
Rona Yaeger, MD 
Kenneth Yu, MD 
Elizabeth Won, MD 
Alice Zervoudakis, MD 
Jamie Chaft, MD 
Alexander Drilon, MD 
Matthew Hellmann, MD 
Mark Kris, MD 
Piro Lito, MD 
Paul Paik, MD 
Gregory Riely, MD, PhD 
Charles Rudin, MD, PhD 
Stephen Veach, MD 
Helena Yu, MD 
Marjorie Zauderer, MD 
Wungki Park, MD 
Juan Schvartzman, MD 
Imane El Dika, MD 
Louise Connell, MD 
Victoria Lai, MD 
Kathryn Arbour, MD 
Ellen Hollywood, NP 
Erica Kaufmann, NP 
Patricia Gabriel, NP 
Jaclyn Norris, NP 
Alison Massey, NP 
Linda Ahn, NP 
Elizabeth Panora, NP 
Natasha Pinheiro, NP 
Claudia Calderon, NP 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
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Medicine 
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Medicine 
Medicine 
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Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
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Medicine 
Medicine 
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Nursing 
Nursing 
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Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
OneMSK Sites 
Manhattan 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1535 A(10) 
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Participating Institutions 
PI's Name 
Site's Role 
Dana Farber Cancer Institute 
Dr. Kimberly Perez 
Data Collection 
MD Anderson Cancer Center 
Dr. Arvind Dasari 
Data Collection 
Beth Israel Medical Center 
Dr. Andrea J. Bullock 
Data Collection 
Massachusetts General Hospital 
Dr. Jeffrey Clark 
Data Collection 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ......................................................................... 6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 7 
3.0 
BACKGROUND AND RATIONALE ........................................................................................ 8 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION .............................................................. 19 
4.1 
Design ............................................................................................................................... 19 
4.2 
Intervention ........................................................................................................................ 19 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS.............................................................................. 20 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .............................................................................. 21 
6.1 
Subject Inclusion Criteria ................................................................................................... 21 
6.2 
Subject Exclusion Criteria .................................................................................................. 22 
7.0 
RECRUITMENT PLAN ......................................................................................................... 24 
8.0 
PRETREATMENT EVALUATION......................................................................................... 24 
9.0 
TREATMENT/INTERVENTION PLAN .................................................................................. 25 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION....................................................... 51 
11.0 
TOXICITIES/SIDE EFFECTS ................................................................................................ 53 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT .......................... 55 
13.0 
CRITERIA FOR REMOVAL FROM STUDY .......................................................................... 58 
14.0 
BIOSTATISTICS ................................................................................................................... 58 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ... 60 
15.1 
Research Participant Registration ...................................................................................... 60 
15.2 
Randomization................................................................................................................... 60 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................... 60 
16.1 
Quality Assurance ............................................................................................................. 61 
16.2 
Data and Safety Monitoring................................................................................................ 61 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................... 62 
17.1 
Privacy .............................................................................................................................. 62 
17.2 
Serious Adverse Event (SAE) Reporting ............................................................................ 62 
17.2.1 
Reporting to Novartis (MSK ONLY) ............................................................................. 63 
18.0 
INFORMED CONSENT PROCEDURES ............................................................................... 65 
19.0 
REFERENCES ..................................................................................................................... 66 
20.0 
APPENDICES ....................................................................................................................... 67 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1535 A(10) 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
Title of Study: A phase II trial of LEE011 in combination with everolimus in the treatment of 
advanced well differentiated neuroendocrine tumors of foregut origin. 
Trial Phase: Phase II. 
Patient Population: Advanced (unresectable or metastatic) well differentiated neuroendocrine 
tumors (WDNETs) of foregut origin (thymic, bronchopulmonary, gastric, duodenal, and 
pancreatic). 
Trial Type: Interventional 
 
Type of control: No treatment control 
 
Route of administration: LEE011 (oral), everolimus (oral) 
 
Trial blinding: Unblinded open-label 
Groups: One cohort - foregut WDNETs 
Number of trial subjects: 41 patients 
Estimated duration of trial: 5 to 6 years 
Study Design: This will be a multicenter, non-randomized, open-label phase II clinical trial.. This 
study will be conducted to determine the efficacy and safety of the combination of LEE011 and 
everolimus in subjects with advanced WDNETs of foregut origin (thymic, bronchopulmonary, 
gastric, duodenal, and pancreatic). 
 
The first 10 patients enrolled on this study were treated with a starting dose of LEE011 300 mg once 
daily for 3 weeks on/1 week off and everolimus 2.5mg daily, based on the results of CLEE011X2106 
in breast cancer. Given the toxicities noted in the WDNET patient population (see below), primarily 
with regards to cytopenias for these 10 patients treated on protocol, subsequent enrolled patients 
will receive the oral combination of LEE011 200 mg once daily and everolimus 5 mg daily, based 
on more recent data from CLEE011XUS29 (TRINITI-1) study in metastatic breast cancer. Subjects 
will continue treatment until meeting one of the criteria for removal from study. 
 
If patients have a functional NET, they are permitted to continue on a somatostatin analog for 
hormonal symptom control. 
 
The primary objective of this trial is to determine the progression free survival (PFS) in patients with 
WDNETs of foregut origin treated with LEE011 + everolimus using RECIST v1.1. 


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In this simon two stage design, a total of 41 patients will be enrolled; 21 patients will be enrolled in 
the first stage. If 10 or more patients are alive and progression free at 1 year, then we will enroll an 
additional 20 patients. If 23 or more out of 41 patients are alive and progression free at 1 year, then 
the combination is considered promising. 
 
The secondary objectives include establishing the safety of LEE011 + everolimus in this patient 
population, objective response rate (ORR), event free survival (EFS), and OS. Correlative 
objectives include investigating the associations between biomarkers related to the Rb pathway 
and/or the pathogenesis of foregut WDNETs and clinical response to the combination of LEE011 + 
everolimus. 
 
The study will be completed when all subjects have progressed or discontinued from the study for 
other reasons. The accrual time is estimated to be 1 to 2 years. The study is expected to take 
approximately 4 to 5 years to complete. The study duration is estimated at 5 to 6 years. 
 
Status of Study on 12/08/2017: Ten patients have been enrolled to date and initiated therapy on 
protocol. Two patients were taken off study due to infectious complications. Seven patients were taken 
off study in the setting of either clinical or radiographic disease progression. Of the 10 patients, 7 
patients underwent dose reductions (4 patients with 1 dose reduction, 3 patients with 2 dose 
reductions). 
 
4/10 (40%) patients experienced grade 1 thrombocytopenia, 2/10 (20%) patients experienced grade 
2 thrombocytopenia, and 2/10 (20%) patients experienced grade 3 thrombocytopenia. No patients 
experienced grade 1 neutropenia. 7/10 (70%) patients experienced grade 2 neutropenia and 2/10 
(20%) patients experienced grade 3 neutropenia. 
 
1/10 (10%) patients experienced grade 1 rash, 1/10 (10%) patients experienced grade 2 rash, and 
1/10 (10%) patients experienced grade 3 rash – the rash was maculopapular and acne-like in 
nature. 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
• 
The primary objective is to determine the PFS in patients with WDNETs of foregut 
origin treated with LEE011 + everolimus. 
• 
The secondary objectives are to: 
o Establish the safety of LEE011 + everolimus in foregut WDNETs. 
o Determine the ORR during treatment of foregut WDNETs with LEE011 + 
everolimus. 
o Determine the event free survival during treatment of foregut WDNETs with 
LEE011 + everolimus. 


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o Determine OS during treatment of foregut WDNETs with LEE011 + 
everolimus. 
• 
The exploratory objectives are to investigate the associations between biomarkers 
related to the Rb pathway and/or the pathogenesis of foregut WDNETs and clinical 
response to the combination of LEE011 + everolimus. 
3.0 
BACKGROUND AND RATIONALE 
3.1 
Overview of WDNETs 
3.1.1 
Epidemiology and clinical presentation of WDNETs 
 
WDNETs are an uncommon and heterogeneous group of neoplasms that arise in a variety of 
locations, most commonly in the lung and gastrointestinal tract.[1] WDNETs are subdivided into two 
groups: carcinoid tumors and panNETs. Carcinoid tumors develop from the neuroendocrine tissues 
of the aerodigestive tract, and panNETs develop from the endocrine tissues of the pancreas (i.e. 
islets of Langerhans). This group of WDNETs is both morphologically and clinically distinct from high 
grade neuroendocrine carcinomas, tumors that are characterized by an extremely aggressive 
behavior and are treated along small cell lung cancer paradigms with platinum-based 
chemotherapy.[2] Epidemiological data from the last 30 years has demonstrated that the incidence 
of neuroendocrine tumors continues to rise, while there have been no significant changes in survival 
from this disease.[3, 4] 
Although most WDNETs are slow growing, after the development of metastatic disease, most 
commonly to the liver, median survival is only a few years.[5] Metastatic disease is a common 
presentation for the majority of patients with WDNETs, especially those with non-functioning tumors 
given the absence of clinical symptoms that would warrant earlier clinical evaluation.[6] 
Asymptomatic patients diagnosed with WDNETs are often monitored initially, however with time, 
their disease will progress and these patients will require treatment. Typical indications for therapy 
are pain/symptoms due to tumor bulk, symptoms from hormone secretion, or progression of disease 
and increased tumor burden under observation.[6] Given the heterogeneous clinical presentations 
and complex spectrum of aggressiveness of WDNETs, their treatment is challenging, and requires 
multimodality management with surgeons, interventional radiologists, medical oncologists, 
endocrinologists, and gastroenterologists. 
3.1.2 
Treatment options for WDNETs 
 
The primary site of WDNETs is important when considering medical therapy, as panNETs generally 
respond better to therapies in comparison to carcinoid tumors. Treatment options for WDNETs 
include somatostatin analogs (SSA), peptide receptor radiation therapy (PRRT), targeted agents, 
and cytotoxic therapy. 
SSA (octreotide long-acting-release or octreotide LAR, lanreotide) act through a family of 5 G- 
protein couple receptors to exert many functions, including inhibition of endocrine and exocrine 
secretions and inhibition of tumor cell growth. For this reason, SSA is highly useful to treat 


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hormonally related NET symptoms.[7] In addition, it has been demonstrated in both the PROMID 
and CLARINET studies, that SSA have antiproliferative tumor effects and can offer cytostatic control 
of WDNETs.[8, 9] SSA generally serve as first-line therapy for WDNETs, however, once these 
tumors progress on SSA, there are few therapy options available, especially for extra-pancreatic 
WDNETs. 
The recognition that WDNETs highly express somatostatin receptors is the molecular basis for the 
use of tumor targeting with radiolabeled somatostatin analogs (PRRT). Several radioisotopes linked 
to a somatostatin analog have been used, and include indium-111 (111In-), yttrium-90 (90Y-), and 
lutetium-177 (177Lu); while many single-institution series as well as the multicenter MAURITIUS trial 
have demonstrated improved response in symptom control in both carcinoid tumors and in 
panNETs, the degree of activity and toxicity patients can expect from PRRT has not been 
adequately defined.[10-13] 
Targeted agents have undergone investigation in WDNETs. Both sunitinib (small multitargeted 
tyrosine kinase inhibitor) and everolimus (mammalian targeted of rapamycin/mTOR inhibitor) are 
FDA approved for the treatment and panNETs and have been demonstrated to offer a PFS benefit. 
[14, 15] In carcinoid tumors, sunitinib has no proven benefit, while the RADIANT-4 trial has provided 
evidence for a PFS benefit of everolimus in the carcinoid cohort. Despite a PFS benefit of these 
targeted agents, objective response rates are low, and although side effects are manageable, they 
can be persistent. 
Finally, cytotoxic therapy has been investigated in WDNETs, and while certain chemotherapy drugs 
(streptozocin, temozolomide, dacarbazine, platinum agents) can increase response rate in 
panNETs, these drugs are inactive in carcinoid tumors and do not represent treatment options. 
It is well understood in the scientific community, and has been defined within the World Health 
Organization classification of endocrine and digestive tumors, that NETs that arise from different 
anatomic sites are biologically different.[16] More recent data suggests that embryologic origin 
(foregut, midgut, hindgut) can classify these tumors genetically and clinically with foregut tumors 
(thymic, bronchopulmonary, gastric, duodenal, and pancreatic) sharing very similar genetic and 
clinical characteristics (as opposed to the midgut and hindgut tumors which appear different). 
3.1.3 
Cyclin-dependent kinases in WDNETs 
 
Recent investigation has suggested a role of the retinoblastoma (Rb) tumor suppressor pathway in 
NET development. The Rb1 tumor suppressor normally regulates and prevents entry of cells into the 
S-phase of the cell cycle.[17] Rb1 inactivation can result from either loss of Rb1 protein through 
gene mutations, or by alterations in the Rb1 pathway that increases Rb1 protein 
phosphorylation.[17] In fact, a majority of cancers have intact Rb1 protein despite genetic alterations 
in components of the Rb1 pathway.[17] One mechanism of Rb1 inactivation is through 
phosphorylation by cyclin-dependent kinases Cdk4 and Cdk6 (both which are activated by cyclin 
D1).[17] Tumors with intact Rb1 gene may have loss or downregulation of p16INK4a, a Cdk inhibitor 
that specifically inhibits Cdk4 and Cdk6; this mechanism is thought to play a role in tumor 
development when the Rb1 gene is intact.[17, 18]Early mouse models demonstrated a role of the 


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G1 to S-phase transition in pancreatic endocrine cell proliferation.[18] Based on the initial pre-clinical 
data, further investigation of human tissue samples corroborated these findings, and inactivation of 
p16INK4a has been observed in a variety gastrointestinal NETs.[18] A study of 12 gastrinoma and 
nonfunctioning panNET specimens was notable for inactivating p16INK4a gene alterations in 91.7% of 
the specimens.[19] The p16INK4a gene was homozygously deleted in 3 of 8 gastrinomas and 2 of 4 
nonfunctional panNETs; methylation of the gene was seen in 58.3% of the specimens.[19] A later 
study evaluating the CpG island methylator phenotype in 11 primary panNETs observed a large 
proportion of tumor-specific methylation or deletion in p16INK4a in nonfunctional panNETs, as well as 
lack of p16INK4a nuclear staining in almost half of the tumors without obvious p16INK4a alterations.[20] 
The findings from this study suggested that there is an unknown mechanism for loss of p16INK4a in 
panNETs.[20] More recent studies corroborated this data, demonstrating the presence of p16INK4a 
inactivation in panNETs.[21, 22] Taken together, these findings implicated a role for p16INK4a and the 
Rb tumor suppressor pathway in panNET development. 
Recently, a study at MSK investigated abnormalities in the Rb1 pathway in panNETs.[17] In this 
study, panNETs from 92 patients underwent staining by immunohistochemistry (IHC) for markers of 
the Rb pathway. It was demonstrated that a majority of tumors expressed high amounts of Cdk4 or 
cyclin D1. Specifically, 100% of patients stained positive for RB1 by IHC, 58% of samples stained for 
Cdk4, 68% of samples stained for phospho-Rb1, and 68% of samples stained for Cyclin D1; in 
addition, there was a significant correlation between phospho-Rb1 and Cdk4 protein expression as 
well as cyclin D1 and Rb1 phosphorylation. In this study, genomic DNAs from 26 tumors were then 
subjected to copy number analysis to search for amplifications of Rb genes, and the copy numbers 
of Cdk4 or Cdk6 were increased in 19% of the tumors. Subsequently, the investigators observed 
that growth of the human panNET cell line QGP1 was inhibited in a xenograft mouse model by the 
Cdk4/6 inhibitor, PD 0332991, which reactivates the Rb pathway. This data suggests that patients 
with panNETs may strongly respond to Cdk4/6 inhibitors such as LEE011. 
Looking specifically at carcinoid tumors, unpublished data from next-generation sequencing utilizing 
the institutional MSK-IMPACT platform (MSK IRB protocol #12-245) has identified CdkN2A/B 
alterations in a large proportion of sequenced patients. To date, we have observed CDKN2A/B 
alterations in approximately 20% of patients with WDNETs (including pancreatic and extra- 
pancreatic primary tumors) who have consented to MSK-IMPACT testing of their tissue. CdkN2A 
encodes tumor suppressor proteins that bind and inhibit Cdk4 and Cdk6. With CdkN2A/B loss, this 
inhibition does not occur, leading to dysregulation of the Cdk4/6-cyclin-Rb pathway and loss of cell 
cycle control. This data demonstrating CdkN2A/B loss in patients with carcinoid tumors suggests 
that Cdk4/6 inhibitors such as LEE011 may be beneficial in this patient population as well. 
3.1.4 
Rationale for combination cyclin-dependent kinase inhibition with everolimus in 
WDNETs 
Everolimus, an inhibitor of mTOR, is approved for panNET treatment, and in comparison to placebo, 
doubles PFS from 5 to 11 months.[15] Its benefit in carcinoid tumors was tested in the RADIANT-2 
trial where median PFS was 16.4 months versus 11.3 months.[23] However, the PFS did not 
achieve its primary endpoint of PFS based on adjudicated central radiologic review and the 


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difference was not statistically different. Many in the NET community felt strongly that there was a 
signal in RADIANT-2. 
As a result, RADIANT-4 was conducted to test the hypothesis that mTOR inhibitors are active in 
WDNETs of the lung and gastrointestinal tract. RADIANT-4 has recently returned a positive trial with 
PFS of 11.0 months in the everolimus arm, versus 3.9 months in the placebo arm; in addition, tumor 
shrinkage was seen in 64% of patients receiving everolimus, in comparison to 26% of patients 
receiving placebo. Based on these recent results from RADIANT-4, everolimus is now the first 
targeted agent to show robust antitumor activity across a broad spectrum of WDNETs, including 
those arising from the pancreas, lung, and gastrointestinal tract. 
Everolimus has unequivocally proven to be helpful in patients with WDNETs. Preclinical data 
(discussed below in section 3.2 of protocol) suggests that everolimus and LEE011 are synergistically 
active. In addition, there in an ongoing trial looking at the anti-tumor effects of LEE011 in this patient 
population (NCT02420691). Based on this foundation, we hypothesize that the combination of 
LEE011 and everolimus will prolong PFS in WDNETs. 
3.2 
Introduction to investigational treatments and other study treatments 
3.2.1 
Overview of LEE011 
In the mammalian cell cycle, entry into S phase is achieved by CDK 4/6. LEE011 is an orally 
bioavailable, highly selective small molecule inhibitor of CDK4/6 that induces G1 arrest at sub- 
micromolar concentrations in a variety of pRb-positive cancer cells in vitro. LEE011 has proven 
efficacious when combined with other targeted therapies in vitro and in vivo in cancers driven by a 
variety of oncogenic signaling pathways. LEE011 may therefore be an effective anti-cancer agent in 
a variety of pRb-positive human neoplasms, especially in those that contain activated CDK4/6-pRb 
pathway. LEE011 is currently being developed in phase III clinical studies for the treatment of 
hormone receptor positive breast cancer patients; several other phase I or II clinical studies are 
being conducted. 
3.2.1.1 
Pharmacology of LEE011 
3.2.1.1.1 
In vitro pharmacology (Per LEE011 Investigators Brochure) 
 
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 
bromodeoxyuridine (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 more than 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 


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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. 
3.2.1.1.2 
In vivo pharmacology (Per LEE011 Investigators Brochure) 
 
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, 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 compound 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 (MEK)/extracellular signal-regulated kinase (ERK), phosphoinositide 3- 
kinase (PIK3) and mammalian target of rapamycin (mTOR) pathways. 
3.2.1.2 
Synergy with everolimus and LEE011 (Per LEE011 Investigators Brochure) 
 
LEE011, when combined with everolimus (RAD001), induced synergistic growth inhibitions in 
multiple tumor models, including cell lines derived from MCL, ER+ breast cancer, and MRTs (RD - 
2012-50383). The combination of LEE011 with the PI3K inhibitor, alpelisib (BYL719), showed similar 
synergistic effects in ER+ breast cancer, neuroblastoma and colorectal cancer cell lines (RD -2013- 
50144). Table 1 shows synergy scores which demonstrate that co-treatment of LEE011 and 
everolimus or alpelisib leads to synergistic growth inhibition. 
Table 1: Synergy scores for LEE011 / everolimus combination in cancer cells 
 
Cell Line 
Type 
Combination partner 
Synergy Score* 


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T-47D 
MCF-7 
A-204 
G-401 
T-47D 
MCF-7 
MDA-MB-453 
HCT116 
SIMA 
ER+/HER2- breast 
ER+/HER2- breast 
Rhabdoid 
Rhabdoid 
ER+/HER2- breast 
ER+/HER2- breast 
ER-/HER+ breast 
Colorectal 
Neuroblastoma 
everolimus (RAD001) 
everolimus (RAD001) 
everolimus (RAD001) 
everolimus (RAD001) 
alpelisib (BYL719) 
alpelisib (BYL719) 
alpelisib (BYL719) 
alpelisib (BYL719) 
alpelisib (BYL719) 
7.6 
8.0 
7.8 
5.6 
2.0 
7.6 
3.2 
5.0 
3.3 
*Shown are synergy scores for the combination of LEE011 and everolimus or alpelisib in tumor cell lines. Synergy scores 
are described in Lehar et al (2009) with scores >2 representing real synergy. All 3 breast cancer and the neuroblastoma 
derived cell lines harbor activating mutations in the PIK3CA gene, both rhabdoid derived cell lines have bi-allelic 
inactivation of SMARCB1, and the neuroblastoma cell line displays high levels of N-Myc. 
 
3.2.1.3 
Safety, pharmacology, and toxicology of LEE011 (Per LEE011 Investigators 
Brochure) 
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 
gallbladder (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. 
Nonclinical studies in pregnant animals have shown that LEE011 can harm an unborn fetus. Data 
from a rabbit embryofetal development study shows that LEE011 is teratogenic in the rabbit in the 
absence of maternal toxicity. In rabbits, LEE011 also demonstrates embryotoxicity and fetotoxicity. 
Reproductive studies have also demonstrated that LEE011 induced embryotoxicity and fetotoxicity 
in rats. 


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3.2.1.4 
Nonclinical pharmacokinetics and metabolism of LEE011 (Per LEE011 
Investigators Brochure) 
LEE011 showed high clearance (CL) in the mouse, rat, dog and monkey. The volume of distribution 
was large across species and the terminal elimination half-life (T1/2) was moderate in rodents and 
monkey (~2 to 5 h) and longer in dog (18 h). 
Bioavailability was low to moderate in rat (37%) and cynomolgus monkey (17%), and moderate in 
mouse (65%) and dog (64%). Following oral administration, time to reach maximal plasma 
concentrations (Tmax) occurred between 2 to 4 h across species. Gender-dependent toxicokinetics 
were observed in rats with higher exposure to LEE011 in males as compared to females and with 
higher exposure to the metabolite, LEQ803. 
Plasma protein binding was moderate in all species (unbound fraction (fu) in human: 30%). 
In a rat ADME (absorption, distribution, metabolism and excretion) study, extensive distribution of 
[3H]LEE011 and its metabolites was seen. In pigmented rats, radioactivity was specifically found in 
melanin-containing structures, and the highest exposure to total radiolabeled components was 
observed in eye ciliary body, eye choroid, meninges, tactile hair and hair follicles. Radioactivity was 
not detected in the brain. Tlast (last observation timepoint) was ≤ 48h for most tissues, but long (168 
to 840h) for lymph nodes, preputial gland, testis, eye and meninges. At one week ≤ 0.04% of the 
dose was retained in the carcass. 
LEQ803 (N-demethylation) was a prominent metabolite found in mouse, rat, dog, monkey and 
human hepatocytes. This metabolite retains some pharmacologic activity and interacts with human 
Ether-a-go-go Related Gene (hERG) channels in vitro. In male rats, unchanged LEE011 (24.7% of 
[3H]AUC0-24h) and its metabolite M11 (26.3% of [3H]AUC0-24h) were the major components in 
plasma. In rats, LEE011 was eliminated mainly by metabolism with direct sulfation as the major 
pathway. Direct LEE011 secretion accounted for 18.2% of the total plasma clearance. In male dogs, 
metabolism was the major elimination route. The most prominent components in plasma were 
LEE011 (55.9% of [14C]AUC0-48h) and its metabolite LEQ803 (1.61% of [14C]AUC0-48h). 
Results from the ADME (male rats) study showed that 3H-components were predominantly excreted 
with bile (61.4% of dose). Minor urinary excretion was observed (5.9% of dose after p.o.). The 
majority of the administered dose (87.3%) was excreted within 24 h via urine, feces (enteric 
secretion) and bile. 
In vitro, LEE011 was a reversible inhibitor of cytochrome P450 (CYP) enzymes CYP1A2, CYP2E1 
and CYP3A4 and a time-dependent inhibitor of CYP3A4. LEE011 may inhibit CYP3A4 under 
therapeutic conditions. No induction of CYP1A2, CYP2B6 or CYP3A4 was observed. The in vitro 
inhibitory potency of LEE011 observed for the transporters OATP1B1 (organic anion transporting 
polypeptide 1B1), BCRP (breast cancer resistance protein), OCT1 (organic cation transporter 1), 
OCT2, MATE1 (multidrug and toxin extrusion protein 1), MATE2K and BSEP (bile salt export pump) 
may translate into clinically relevant inhibition at therapeutic doses. 


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Elimination of LEE011 is dominated by oxidative metabolism mainly via CYP3A4 with a minor 
contribution by flavin-containing monooxygenase 3 (FMO3). The elimination of LEE011 may be 
affected by co-administered drugs that inhibit or induce CYP3A4. Although LEE011 is a substrate of 
the P-glycoprotein (P-gp) efflux transporter, this process is likely not clinically relevant due to the 
high passive permeability of LEE011. 
3.2.1.5 
Clinical Experience with LEE011 
 
LEE011 is currently being investigated in patients as a single agent in 3 phase I studies: 
CLEE011X1101, CLEE011X2101, CLEE011X2102; in 2 phase II studies: CLEE011X2201, 
CLEE011XUS03; and in combination in 15 studies: 12 phase Ib/II CLEE011X2105, CLEE011X2106, 
CLEE011X2107, CLEE011X2108, CLEE011A2115C, CLEE011X2110C, CMEK162X2114, 
CMEK162X2110, CLGX818X2102, CLGX818X2109, HDM201X2103C, PIM447X2104C and 3 
randomized phase III studies: CLEE011A2301, CLEE011F2301 and CLEE011E2301. Four studies, 
were closed to enrolment: CLEE011A2201, a randomized phase II study; CLEE011A2112C, a 
phase I dose finding study; CLEE011X2102, a phase I study in malignant rhabdoid tumors and 
neuroblastomas; and CLEE011X2105, a phase Ib/II study in BRAF mutant melanoma. LEE011 is 
also being investigated in 4 clinical pharmacology studies: CLEE011A2102, CLEE011A2103, 
CLEE011A2109, and, CLEE011A2116. Three clinical pharmacology studies in healthy subjects 
have been completed: CLEE011A2101, CLEE011A2106 and CLEE011A2111. 
To date, one study treatment related death occurred in study [CMEK162X2114] and one death 
suspected to be related occurred in study [CLEE011X2106]. 
Please refer to the LEE011 Investigator’s Brochure for a summary of the current clinical experience 
in the above trials. 
3.2.2 
Overview of everolimus 
 
Everolimus has been in clinical development since 1996 as an immunosuppressant in solid organ 
transplantation. Everolimus is a derivative of rapamycin. It is a selective mTOR inhibitor, specifically 
targeting the mTOR-raptor (regulatory-associated protein of mTOR, Raptor) signal transduction 
complex 1 (mTORC1). Everolimus potently inhibits proliferation of endothelial cells and has 
antiangiogenic activity in vivo.[24-28]. 
Everolimus is approved in Europe and other global markets for cardiac and renal transplantation, 
and in the United States for the prevention of organ rejection of kidney transplantation. Everolimus is 
currently approved for advanced kidney cancer, subependymal giant cell astrocytoma, pancreatic 
neuroendocrine tumors, progressive, well-differentiated, non-functional neuroendocrine tumors of 
gastrointestinal or lung origin (that are unresectable, locally advanced or metastatic), and breast 
cancer (in combination with exemestane). 
The following is a brief summary of the main characteristics of everolimus. More detailed information 
can be obtained from the Everolimus Prescribing Information. 
3.2.2.1 
Non-clinical experience 


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Everolimus inhibits the proliferation of a wide range of human tumor cell lines in vitro at IC50s 
ranging from sub/low nM to μM. 
The antitumor efficacy of everolimus was compared to other compounds in a panel of six breast 
cancer xenograft models established after direct transplantation of patients’ tumors onto nude mice 
[Report RD-2011-50492]; this panel included an ER+ model, HBCx-3 (XTS-181).[29] Everolimus 
given daily by oral gavage for 21 to 35 days at 20 mg/kg was well tolerated with no significant mean 
body weight loss. In all breast cancer models tested, tumor growth was significantly inhibited, and 
was particularly evident in the HBCx-3 (XTS-181) model with nine partial regressions in ten mice 
tested (-13.5% mean tumor volume regression, p<0.001). 
Based on data generated using human liver microsomes and microsomes from cells expressing 
single human cytochrome P450s enzymes, CYP3A4 was identified as the major enzyme involved in 
the microsomal biotransformation of everolimus. Everolimus inhibited competitively the metabolism 
of the CYP3A4 substrate cyclosporine with a Ki value of 2.3 μmol/L (2204 ng/mL) under in vitro 
conditions. 
Further details can be found in the Everolimus Investigator’s Brochure. 
3.2.2.2 
Clinical experience 
3.2.2.2.1 
Everolimus pharmacokinetics 
Everolimus is rapidly absorbed with a median tmax of one to two hours. The steady-state AUC0-τ is 
dose-proportional over the dose range between 5 to 70 mg when given weekly and 5 and 10 mg 
when given daily. Steady-state was achieved within two weeks with the daily dosing regimen. Cmax 
is dose-proportional between 5 and 10 mg for both the weekly and daily regimens. 
In healthy subjects, high fat meals reduced systemic exposure to a 10 mg dose of everolimus (as 
measured by AUC) by 22% and the peak plasma concentration Cmax by 54%. Light fat meals 
reduced AUC by 32% and Cmax by 42%. Food had no apparent effect on the post absorption phase 
concentration-time profile ([Study RAD001C2120]). The blood-to-plasma ratio of everolimus, which 
is concentration-dependent over the range of 5 to 5,000 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 [DMPK R303044]. Plasma protein binding is similar in healthy 
patients and in subjects with moderate hepatic impairment (approximately 74%, [Study 
RAD001A2303]). 
The major and nearly exclusive enzyme responsible for the metabolism of everolimus in man was 
CYP3A4 (DMPK(US)1998/005; DMPK(CH) R99-2448).[30] Other CYP isoenzymes either do not 
metabolize everolimus or do so at very low rates. Everolimus is a moderate inhibitor of P- 
glycoprotein-like mediated efflux systems, although the compound has a high intrinsic permeability 
when P-glycoprotein is inhibited.[31, 32][DMPK(CH) 1997/417] Following oral administration, 
everolimus is the main circulating component in human blood and contributes the majority of the 
overall pharmacologic activity (Study W107). 


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No specific excretion studies have been undertaken in cancer patients; however, data available from 
the transplantation setting found the drug to be mainly eliminated through the feces. 
3.2.2.2.2 
Everolimus monotherapy in WDNETs 
 
Everolimus monotherapy in WDNETs has been evaluated in multicenter, randomized phase III 
studies. 
RADIANT-3 was a randomized phase III double-blind placebo-controlled study of 410 patients with 
low or intermediate-grade, progressive and advanced panNETs.[15] Patients were randomized to 
receive everolimus plus best supportive care or placebo plus best supportive care. The results 
demonstrated significantly improved median PFS of 11.0 months with everolimus compared with 4.6 
months with placebo. Response rate was 5% in the everolimus arm compared with 2% in the 
placebo arm. 
A subsequent phase III study, RADIANT-2, evaluated the efficacy of everolimus plus octreotide LAR 
versus placebo plus octreotide LAR in 429 patients with functional carcinoid tumors.[23] The primary 
end point was PFS, and patients in the placebo arm were allowed to cross over to everolimus upon 
disease progression. By central review, median PFS was 16.4 months in the everolimus group 
versus 11.3 months in the placebo group but did not meet its statistical predefined end point. 
Therefore, the study was considered negative. 
Given the findings of RADIANT-2, with suggestion that there may be a role for everolimus in the 
management of carcinoid tumors, RADIANT-4 was conducted. RADIANT-4 was a study of 302 
patients with advanced, progressive, nonfunctional WDNETs of the lung and gastrointestinal trac t. 
RADIANT-4 has recently returned a positive trial with PFS of 11.0 months in the everolimus arm, 
versus 3.9 months in the placebo arm; in addition, tumor shrinkage was seen in 64% of patients 
receiving everolimus, in comparison to 26% of patients receiving placebo. Based on these findings, 
everolimus is now the first targeted agent to show robust antitumor activity across a broad spectrum 
of WDNETs, including those arising from the pancreas, lung, and gastrointestinal tract. 
3.2.2.2.3 
Safety profile of everolimus 
The following adverse events are considered to be class-effects of mTOR inhibitors: stomatitis/oral 
mucositis/ulcers, infections and infestations, rash and similar events, cytopenia, hemorrhages, non- 
infectious pneumonitis, hyperglycemia/new-onset diabetes mellitus, renal events, and 
thromboembolism. The more common metabolic side effects reported with mTOR inhibitors result 
from inhibitory effects on mTOR-regulated lipid and glucose pathways, while infections stem from 
the immunosuppressive properties of these agents. Virtually all of the side effects associated with 
mTOR inhibitors can be managed effectively with dose modification and/or supportive intervention. 
Further details related to everolimus safety can be found in the Everolimus Investigator’s Brochure, 
Everolimus Prescribing Information, and the Everolimus Package Insert. 
3.2.2.3 
Potential for drug interaction (LEE011 and everolimus) 


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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 pharmacokinetic drug-drug interaction was possible with 
the combination of everolimus and LEE011. 
As of March 2, 2015, 84 patients have been treated with the combination of LEE011 + everolimus + 
exemestane in a Phase Ib/II study(CLEE011X2106). Everolimus was administered at 2.5 mg (daily) 
concurrently with 200, 250 and 300 mg of LEE011 (daily, 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 (daily) was administered in each combination. 
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 daily) 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.[33-35][RAD001 IB] 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 (daily) with 300 mg LEE011 (daily, 3 weeks on/1 week off) with 
food is ongoing. 
Results from CLEE011X2106 were presented amongst 70 evaluable patients in 12/2015 at the 2015 
San Antonio Breast Symposium.(Bardia 2015, Publication Number P6-13-01) In this cohort, grade 3/4 
treatment-related 
adverse 
events 
were 
neutropenia 
(45.7%), 
leukopenia 
(8.6%), 
and 
thrombocytopenia (5.7%), with 2 patients (2.9%) discontinuing treatment due to adverse events. Six 
patients (8.6%) treated with LEE011 (300 mg) and everolimus (2.5 mg) experienced grade 3 dose- 
limiting toxicities: increased alanine aminotransferase/aspartate aminotransferase (2 patients, 2.9%), 
febrile neutropenia and hypophosphatemia (1 patient, 1.4%), oral mucositis (1 patient, 1.4%), rash 
and thrombocytopenia (1 patient, 1.4%), and thrombocytopenia with bleeding (1 patient, 1.4%). 
 
In the more recent CLEE011XUS29 (TRINITI-1) study in breast cancer, the dose de-escalation cohort 
C has been included, where patients initiate therapy with a starting dose of LEE011 200 mg daily and 
everolimus 5 mg daily. To date, the dosing regimen has been better tolerated with regards to 
hematologic toxicities, and also allows for maximum exposure of everolimus. To date, five patients 
have been treated as part of cohort C in CLEE011XUS29 for a period of more than one month and no 
dose limiting toxicities have been observed. 
 
3.2.2.4 
Ongoing clinical experience with Treatment of WDNETs with LEE011 and 
everolimus 
 
Our experience at MSKCC with treatment of WDNETs on this protocol (as of 12/08/2017) with 
LEE011 + everolimus with starting dose of LEE011 300mg once daily 3 weeks on/1 week off and 
everolimus 2.5mg daily are as follows. Ten patients have been enrolled to date and initiated therapy 
on protocol. Two patients were taken off study due to infectious complications; one patient had 


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recurrent urinary tract infections and elected to come off of study and the second patient had colitis 
in the setting of febrile neutropenia and was taken off of study. For both of these patients, the 
infectious complications occurred during the first cycle of treatment. Seven patients were taken off 
study in the setting of either clinical or radiographic disease progression. One patient continues on 
therapy at this time. 
Of the 10 patients, 7 patients underwent dose reductions (4 patients with 1 dose reduction, 3 
patients with 2 dose reductions). 
4/10 (40%) patients experienced grade 1 thrombocytopenia, 2/10 (20%) patients experienced grade 
2 thrombocytopenia, and 2/10 (20%) patients experienced grade 3 thrombocytopenia. No patients 
experienced grade 1 neutropenia. 7/10 (70%) patients experienced grade 2 neutropenia and 2/10 
(20%) patients experienced grade 3 neutropenia. 
1/10 (10%) patients experienced grade 1 rash, 1/10 (10%) patients experienced grade 2 rash, and 
1/10 (10%) patients experienced grade 3 rash – the rash was maculopapular and acne-like in 
nature. 
Given our results after enrollment of 10 patients on this study, based on the dose de-escalation 
cohort C of CLEE011XUS29, for any patients enrolled in the future, the decision has been made to 
initiate treatment with a starting dose of LEE011 200mg daily and everolimus 5 mg daily. The 
expectation is that with this dosing schema, we will allow for additional safety for patients with 
maximum exposure of everolimus, a known effective therapy for WDNETs. Additionally, we believe 
that a higher dose of everolimus (already an FDA approved drug in foregut WDNETs as discussed 
in this protocol) will allow for more promising efficacy. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a multicenter, non-randomized, phase II clinical trial. This study will be conducted to 
determine the efficacy and safety of the combination of LEE011 and everolimus in subjects with 
advanced WDNETs of foregut origin. 
The primary objective of this trial is to determine the PFS in patients with WDNETs treated with the 
combination of LEE011 and everolimus using RECIST v1.1. 
A total of 41 patients will be enrolled in this study. A simon two stage design will be employed. 
 
4.2 
Intervention 
All subjects will receive the oral combination of LEE011 and everolimus, with dosing based on the 
Cohort C of of CLEE011XUS29 (TRINITI-1), currently enrolling for the treatment of patients with breast 
cancer. Subjects will receive LEE011 200 mg daily, in combination with everolimus 5 mg daily; in the 
setting of toxicity, everolimus dosing will be changed to 2.5 mg daily or 2.5 mg every other day. 
Subjects will continue treatment until meeting one of the criteria for removal from study. 


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Subjects will be evaluated by physical exam and routine blood tests every 2 weeks for cycles 1 and 
2, and monthly for every cycle thereafter during the study period. CT or MRI will be performed during 
screening, and then at 12 week intervals. Evaluation of tumor responses will be performed according 
to RECIST v1.1. 
Subjects who discontinue treatment for reasons other than disease progression will have 
posttreatment follow-up for disease status until disease progression, initiating a non-study cancer 
treatment, withdrawing consent, or becoming lost to follow-up. All subjects will be followed by 
telephone contact for OS until death or withdrawal of consent. 
The study will be completed when all subjects have progressed or discontinued from the study for 
other reasons. The accrual time is estimated to be 1 to 2 years. The study is expected to take 
approximately 4 to 5 years to complete. The study duration is estimated at 5 to 6 years. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 
LEE011 (LEE011) 
LEE011 will be provided by Novartis. LEE011 will be administered orally at the dose of 200 mg daily. 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. Clinical supplies will be 
affixed with a clinical label in accordance with regulatory requirements. 
5.1.1 
Description and composition of LEE011 
 
The LEE011 drug product is planned for oral administration. The available clinical forms are 
capsules/tablets (50 mg, 200 mg). LEE011 will be administered as a flat-fixed dose, and not by body 
weight or surface area. 
5.1.2 
Storage condition of LEE011 
 
Study treatments will be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated site 
personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the medication label. Medication labels will comply with the legal 
requirements of the United States and be printed in the local language. 
The shelf-lives of the drug products are established based on ongoing stability studies and may be 
extended during the clinical study. 
Please refer to the clinical labels for current shelf-life, in-use and storage conditions for the 
capsules/tablets. 
5.2 
Everolimus 


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Everolimus will be provided for study use and will be supplied by Novartis. Everolimus was 
administered orally at the dose of 2.5 mg daily, as established in LEE011X2106 for the first 10 
patients enrolled to this study. For subsequently enrolled patients, given the toxcities observed in the 
WDNET population, everolimus will be administered orally at the dose of 5 mg daily, as established 
in CLEE011XUS29 (TRINITI-1), cohort C dose de-escalation. 
Complete guidelines for the management and administration of everolimus can be found in the 
Everolimus Investigator’s Brochure and Everolimus Package Insert. 
5.3 
Study drug compliance and accountability 
 
Compliance should be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver. Records of study medication used, dosages 
administered, and intervals between visits and the completion of the study should be captured in the 
Pill Diary. This information must be captured in the source document at each patient visit. 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
 
1. Patient has signed the Informed Consent prior to any screening procedures being 
performed and is able to comply with the protocol requirements. 
2. Adults > 18 years old. 
3. Histologic or cytologic diagnosis of a WDNET, Ki67 ≤ 30%, unresectable, of foregut origin 
(thymic, bronchopulmonary, gastric, duodenal, and pancreatic) confirmed by the enrolling 
institution. 
• 
Note: If patients have a functional NET, they are permitted to continue on a 
somatostatin analog for hormonal symptom control. 
4. MSK patient has tissue available from a previous biopsy for the evaluation of potential 
predictive biomarkers. If tissue is not available for MSK patient, a new tumor specimen 
will need to be obtained prior to the start of study treatment. If archived tissue is 
available, participating site patient will provide for the evaluation of potential predictive 
biomarkers. If tissue is not available for participating site patient, a new tumor specimen 
is optional prior to the start of study treatment. 
5. Documented radiological evidence for disease progression (measurable or 
nonmeasurable) ≤12 months prior to enrollment. 
6. Disease that is currently not amenable to surgical resection with curative intent as 
determined by the treating investigator 
7. Measurable disease as defined by RECIST v1.1. 
8. ECOG performance status 0 or 1 or KPS performance status 100 to 70. 
9. Patient has adequate bone marrow and organ function as defined by the following 
laboratory values at screening: 
• 
Absolute neutrophil count >1.5 x 109/L 


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• 
Platelets >100 x 109/L 
• 
Hemoglobin >9.0 g/dL 
• 
INR <1.5 
• 
Serum creatinine <1.5mg/dL or creatinine clearance >50 mL/min 
• 
In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) <2.5 x ULN. If a patient has liver metastases, ALT and 
AST <5 x ULN 
• 
Total bilirubin < ULN; or total bilirubin ≤3.0 x ULN or direct bilirubin ≤1.5 x ULN in 
patients with well-documented Gilbert’s Syndrome 
10. Negative serum pregnancy test done ≤14 days prior to registration, for women of 
childbearing potential only. A serum pregnancy test will be conducted < 72 hours prior to 
treatment start as a pre-treatment parameter. All women of reproductive potential and 
their partners must agree to use adequate methods of birth control (e.g. latex condoms) 
throughout the study and for 30 days after the last dose of study drug. 
† A female of reproductive potential is a sexually mature female who: has not undergone 
a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for 
at least 24 consecutive months (i.e. has had menses at any time in the preceding 24 
consecutive months). 
11. Patient with standard 12-lead ECG with the following parameters at screening (defined as 
the mean of the triplicate ECGs): 
• 
QTcF interval at screening <450msec (using Fridericia’s correction) 
12. Must be able to swallow LEE011 and everolimus capsules/tablets. 
13. Recovered from adverse events (to grade 1 or less toxicity according to CTCAE 4.0) due 
to agents administered previously. 
a. NOTE: Chemotherapy-induced alopecia and grade 2 neuropathy are acceptable. 
6.2 
Subject Exclusion Criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patient has a known hypersensitivity to any of the excipients of LEE011 or everolimus. 
2. Previous treatment with a CDK 4/6 inhibitor or an mTOR inhibitor. 
3. Has had prior chemotherapy, targeted small molecule therapy within 2 weeks prior to 
study Day 1 or who has not recovered (i.e. < Grade 1 or at baseline) from adverse events 
due to a previously administered agent. 
• 
Note: Subjects with < Grade 2 neuropathy or chemotherapy-induced alopecia are 
an exception to this criterion and may qualify for the study. 
4. 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. 
5. Patients with central nervous system (CNS) involvement unless they meet ALL of the 
following criteria: 


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• 
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 
6. 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 res ection). 
7. Patient has a known history of HIV infection (testing not mandatory). 
8. Patient has any other concurrent severe and/or uncontrolled medical condition that 
would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate 
patient participation in the clinical study or compromise compliance with the protocol (e.g. 
chronic pancreatitis, active untreated or uncontrolled fungal, bacterial or viral infections, 
etc.). 
9. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. 
Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may 
be included, however blood glucose and antidiabetic treatment must be monitored closely 
throughout the trial and adjusted as necessary 
10. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, 
including any of the following: 
• 
History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or 
coronary artery bypass graft (CABG) within 6 months prior to study entry 
• 
Documented cardiomyopathy 
• 
Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated 
acquisition (MUGA) scan or echocardiogram (ECHO) 
• 
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 
• 
Concomitant medication(s) with a known risk to prolong the QT interval and/or 
known to cause Torsades de Pointe that cannot be discontinued or replaced by 
safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting study 
drug) 
• 
Inability to determine the QTcF interval 
• 
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) 
11. Patient is currently receiving any of the following medications and cannot be discontinued 
7 days prior to starting study drug (see Table 1 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 


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• 
Herbal preparations/medications, dietary supplements 
12. 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. 
• 
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) 
13. Participation in a prior investigational study within 30 days prior to enrollment or within 5 
half-lives of the investigational product, whichever is longer 
14. Patient who has received radiotherapy ≤4 weeks or limited field radiation for palliation ≤2 
weeks prior to starting study drug, and who has not recovered to grade 1 or better from 
related side effects of such therapy (exceptions include alopecia) or in whom ≥25% of the 
bone marrow (Ellis, 1961) was irradiated. 
15. Patient has had major surgery within 14 days prior to starting study drug or has not 
recovered from major side effects (tumor biopsy is not considered as major surgery). 
16. Patient with a Child-Pugh score B or C (see Appendix D). 
17. Patient has a history of non-compliance to medical regimen or inability to grant consent. 
18. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
 
 
7.0 
RECRUITMENT PLAN 
Potential research subjects will be identified by members of the patient’s treatment team, the 
protocol investigator or research team at participating institutions. If the investigator is a member of 
the treatment team, s/he will screen their patient’s medical records for suitable research study 
participants. The investigator will use information provided by the patient and/or medical record to 
confirm that the patient is eligible and contact the patient regarding study enrollment. All eligible 
patients, regardless of sex and race, will be approached for participation. The investigators are 
aware of the NIH policy concerning inclusion of women and minorities in clinical research 
populations. 
Participation in the study is completely voluntary. Patients will be required to read, agree to, and sign 
an IRB-approved informed consent form prior to registration on this trial. Patients will not receive 
payment for their participation on this study. Patients are free to withdraw from the study without 
consequence at any time. 
8.0 
PRETREATMENT EVALUATION 
The following must be completed within 28 days of starting LEE011 + everolimus: 
1. CT scan of the chest, abdomen, and pelvis with contrast. If patient is unable to receive 
CT contrast, or the abdominal/pelvic target lesion is indeterminate on CT scan then MRI 
abdomen and pelvis with contrast plus CT chest without contrast may be perfromed. 


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Non-contrast CT chest, abdomen, and pelvis may be used if the target lesion(s) do not 
require contrast for accurate measurements. 
2. 12-lead Electrocardiogram (EKG). 
3. Signed informed consent for study participation. 
4. History and physical examination, including height, weight, vital signs (temperature, pulse 
rate, respiration rate, blood pressure), and ECOG performance status. 
5. Serum pregnancy test for all women of childbearing potential (within 72 hours prior to 
receiving first dose of study medication). If the test result is positive related to pregnancy, 
the patient will not be allowed to participate in this study. 
6. CBC with differential and platelet count, serum chemistries (Na, K, Cl, CO2, BUN, 
creatinine, glucose, calcium, albumin, and total protein), liver function tests (AST, ALT, 
alkaline phosphatase, total bilirubin), coagulation panel (PT/INR and PTT), lipid panel, 
and urinalysis. 
7. Serology for hepatitis B (HepBsAg, and HepBcAb) and hepatitis C antibody (negative 
test acceptable prior to screening period). HepB PCR will be performed if HepB core 
antibody or HepB surface antigen is reactive. 
8. Transthoracic echocardiogram (TTE) or multigated acquisition (MUGA) scan. 
9. Perform baseline tumor biopsy for MSK patients without archived tissue or obtain 
archived tissue for research purposes for MSK patients. Performing baseline tumor 
biopsy for participating site patients is optional. Obtain archived tissue for research 
purpoes for participating site patients if available. 
9.0 
TREATMENT/INTERVENTION PLAN 
9.1 
Study drug preparation and dispensation 
 
The investigator or responsible site personnel must instruct the patient or caregiver to take the study 
drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site personnel 
only. All dosages prescribed and dispensed to the patient and all dose modifications during the 
study must be recorded on the Dosage Administration Record Form. 
LEE011 will be supplied by Novartis or its designee in the form of 50mg and 200mg capsules/tablets 
as individual patient supply packaged in bottles. Storage conditions are described in the medication 
label. 
Everolimus will be supplied for study use and will be supplied by Novartis as tablets for oral use. 
LEE011 and everolimus will be administered as a flat-fixed dose and not by body weight or body 
surface area. 


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9.1.1 
Study drug packaging and labeling 
LEE011 capsules/tablets are packaged in high density polyethylene (HDPE) bottles with child 
resistant closures. Everolimus tablets are packaged in blister packs (4 blisters per pack per 
strength). 
Medication labels will be in English. They will include storage conditions for the drug but no 
information about the patient. The study drug will be labeled and packaged under the responsibility 
of the Novartis drug supply management department. The medication will be supplied as open label 
supply in a way which allows the patient to take medication at home. 
9.1.2 
Drug supply and storage 
 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated site 
personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels, the LEE011 Investigator’s Brochure, and in the Everolimus 
Package Insert. 
9.1.3 
Study drug compliance and accountability 
 
Patients will be instructed to return unused study drugs to the site at discontinuation or completion of 
treatment. The site personnel must ensure that the appropriate dose of each study drug is 
administered and that the drug accountability is performed. Compliance should be assessed by the 
investigator and/or study personnel at each patient visit and information provided by the patient 
and/or caregiver will be captured in the Pill Diary. 
9.1.4 
Disposal and destruction 
 
The LEE011 and everolimus supply can be destroyed at the local Novartis facility, Drug Supply 
group or third party, as appropriate, or if pre-arranged between Novartis and study site, destruction 
of used and unused LEE011 and everolimus will be performed at the study site if permitted by local 
regulations. 
9.2 
Dosing Instructions and Schedule 
The dosing regimen to be used in this trial is outlined below in Table 2. For the first 10 patients 
enrolled on this study, the doses of LEE011 and everolimus were based on the final results of 
LEE011X2106. Given the toxicities observed in our first 10 WDNET patients, for subsequently e 
nrolled patients, the doses of LEE011 and everolimus are based on cohort C of CLEE011XUS29 
(LEE011 200 mg daily and everolimus 5 mg daily. The investigator will instruct the patient to take 
the study drug as per protocol. Patients will be instructed to return unused study drugs to the 
investigator at the end of each cycle. The investigator will ensure that the appropriate dose of each 
study drug is administered at each visit and will provide the patient with the correct amount of drugs 
for subsequent dosing. 


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Table 2: Dosing regimen 
 
Study treatments 
Pharmaceutical 
Form 
Dose 
Route of 
Administration 
Regimen/ Treatment 
Period 
LEE 011 
Capsule/Tablet 
200 mg 
Oral 
Daily (continuous) 
Everolimus 
Tablet 
5 mg 
Oral 
Daily (continuous) 
Everolimus (first 
dose reduction) 
Tablet 
2.5 mg 
Oral 
Daily (continuous) 
Everolimus 
(second dose 
reduction) 
Tablet 
2.5 mg 
Oral 
Every other day 
(continuous) 
 
Day 1 is considered the first day of dosing. Each treatment cycle is 28 days. The study drugs will be 
administered as a flat-fixed dose, and not by body weight or by body surface area. LEE011 and 
everolimus will be taken orally, once a day, or every other day if the patient develops toxicity that 
requires a second dose reduction as per Table 2.. All trial treatments will be administered in an 
outpatient setting. 
9.3 
LEE011 and everolimus administration 
 
Patients will take the LEE011 and everolimus combination at home. Patients will be asked to record 
in a diary the date and time that the study medication was taken on a Pill Diary. 
LEE011 and everolimus must be taken as follows (also noted on the Pill Diary): 
• 
Patients should be instructed to take the study drug combination of LEE011 and everolimus 
with a large glass of water (~250 ml) at approximately the same time each day. 
• 
Patients should be instructed to swallow the LEE011 capsules/tablets and everolimus tablets 
whole and not to chew, crush, or open them. 
• 
LEE011 and everolimus can be taken after eating a light, low fat meal. 
• 
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting and/or 
diarrhea (or increase stool frequency) during a treatment cycle must be noted on the Pill 
Diary. 
• 
Any doses that are missed (not taken within 6 hours of the intended time) should be skipped 
and should not be replaced or made up on a subsequent day. 
• 
Patients must avoid consumption of grapefruit, grapefruit hybrids, pummelos, star-fruit, 
Seville oranges, or products containing the juice of each during the entire study and 
preferably 7 days before the first dose of study medications, due to potential CYP3A4 
interaction with the study medications. Orange juice is allowed. 
• 
No herbal or dietary supplements are permitted, due to potential interactions with LEE011; 
multivitamins are allowed. 


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9.4 
Treatment duration 
During the treatment period, the patient must follow the investigators instructions with regards to 
contraception, concomitant medications, and dosing regimen. There is no fixed treatment duration; 
patients may continue treatment with the LEE011 and everolimus combination until disease 
progression, unacceptable toxicity occurs that precludes any further treatment, and/or treatment is 
discontinued at the discretion of the investigator or by patient refusal (withdrawal of consent). 
For details of the frequency of the visits and assessments during the treatment period, refer to the 
study calendar (Table 7). 
9.5 
Dose modifications 
For patients who do not tolerate the protocol-specified dosing schedule, LEE011/everolimus 
adjustments are permitted in order to allow the patient to continue the study treatment. Any changes 
to the dose or interruption of dosing must be recorded on the Pill Diary. Patients who require a drug 
hold of more than 28 days will be discontinued from the study unless discussed and approved by the 
MSK PI. Once dose-reduced the dose may not be re-escalated. 
Management of severe or intolerable adverse reactions (sections 9.5.1 to 9.5.7) requires temporary 
interruption, and/or discontinuation of LEE011 therapy and in the case of everolimus requires dose 
reduction, temporary interruption, and/or discontinuation of everolimus therapy.. Each patient is 
allowed a maximum of two dose reductions for everolimus. After this, the patient will be discontinued 
from the study treatment. For each patient, once a dose level reduction for everolimus has occurred 
for toxicity meeting the criteria for dose interruption and/or adjustment, the dose level cannot be re- 
escalated during subsequent treatment cycles. If a dose reduction is required, everolimusshould be 
reduced one dose level. Dose levels for everolimus are provided in Table 3. 
A dose-dependent drug-drug interaction was observed between LEE011 and everolimus based on 
clinical PK analyses in a separate dose escalation trial, where everolimus exposure increased 2- to 
4-fold in the presence of LEE011. The dose de-escalation modification of everolimus, which we are 
adopting given our experience in treating our first 10 patients enrolled to this study, allows for 
additional safety with maximum exposure of everolimus. After permanent discontinuation of either 
LEE011 or everolimus, patients should be discontinued from study treatment. 
Table 3: Dose modification guidelines for LEE011 and everolimus 
 
LEE011 
Everolimus 
Dose 
Dose 
Starting dose 
200 mg 
5 mg daily 
First dose reduction 
200 mg 
2.5 mg daily 


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Second dose reduction 
200 mg 
2.5 mg every other day 
Anticipated risks and safety considerations of the study drug combination 
 
Preclinical and Phase I clinical data available from ongoing studies with LEE011 and everolimus 
suggest few overlapping toxicities for the proposed combinations. Special attention will be paid to 
blood counts (cytopenias), mucositis, liver function test abnormalities and QTc prolongation. Clinical 
data from the CLEE011X2101 study do not show marked accumulation in LEE011 with time, 
suggesting that it does not substantially inhibit its own metabolism or clearance. 
Everolimus and LEE011 are in vitro inhibitors and substrates of CYP3A4, and the latter is also a 
time-dependent CYP3A4 inactivator. The available preclinical and clinical data therefore suggest the 
possibility of a drug interaction, specifically one that may increase exposure to everolimus. Based on 
simulation using Simcyp software (Simcyp Version 12, release 1), the projected increase in the AUC 
0-6h of everolimus was 3.5-fold following the starting daily dose of 200 mg LEE011 co-administered 
with 2.5 mg of everolimus for 14 days. No significant effect on LEE011 metabolism was predicted 
when co-administered with everolimus. Appropriate eligibility criteria, dose modification guidelines 
and stopping rules are included in this protocol. 
 
9.5.1 Dose modifications and management recommendations for hematologic adverse 
reactions (see Table 3 for dose reduction guide) 


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Toxicity 
Grade 
Dose Adjustment and Management 
Recommendations 
Thrombocytopenia 
Thrombocytopenia 
Grade 1(≥75 x 109/L) 
No dose adjustment required. 
Grade 2 (≥50 x 109/L – <75 x 
109/L) 
Dose interruption of LEE011 and 
everolimus until recovery to grade 1. 
CBC will be repeated weekly (± 3 day 
window) until toxicity has recovered to 
grade 1. Re-initiate study treatment 
at the same dose. 
Grade 3 (≥25 x 109/L - <50 x 
109/L) 
Dose interruption of LEE011 and 
everolimus until recovery to grade 1. 
CBC will be repeated weekly (± 3 day 
window) until toxicity has recovered to 
grade 1. Re-initiate study treatment 
at the same dose level. 
If toxicity recurs at grade 3: temporary 
dose interruption of LEE011 and 
everolimus until recovery to grade 1 
and reduce everolimus to the next 
lower dose level. Maintain LEE011 at 
same dose. 
Grade 4(<25 x 109/L) 
Dose interruption of LEE011 and 
everolimus until recovery to grade 1. 
CBC will be repeated weekly (± 3 day 
window) until toxicity has recovered to 
grade 1. Re-initiate study everolimus 
at the next lower dose level. Maintain 
LEE011 at the same dose. If toxicity 
recurs at grade 4: discontinue study 
treatment. 
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) 
Dose interruption of LEE011 and 
everolimus until recovery to ≥1.0 x 
109/L. 
CBC will be repeated weekly (± 3 day 
window) until toxicity has recovered 
to grade 1.Re-initiate study treatment 
at the same dose level. 
If toxicity recurs at grade 3: temporary 
dose interruption of LEE011 and 
everolimus until recovery to ≥1.0 x 
109/L. 
If resolved in ≤7 days, then maintain 
dose level. 
If resolved in >7 days, consider 
growth factors then reduce everolimus 
dose to the next lower dose level. 
Maintain LEE011 at same dose. 


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Grade 4 (<0.5 x 109/L) 
Dose interruption of LEE011 and 
everolimus until recovery to ≥1.0 x 
109/L. 
CBC will be repeated weekly (± 3 day 
window) until toxicity has recovered to 
grade 1. Re-initiate everolimus at the 
next lower dose level (first dose 
reduction level). Maintain LEE011 at 
same dose 
If toxicity recurs at grade 4: temporary 
dose interruption of LEE011 and 
everolimus until recovery to ≥1.0 x 
109/L and reduceeverolimus at the 
next lower dose level. Maintain 
LEE011 at same dose. 
Febrile Neutropenia 
Grade 3: ANC<1.0 x 109/L with 
[a single temperature of >38.3 
degrees C (101 degrees F) or a 
sustained temperature of >=38 
degrees C (100.4 degrees F) 
for more than one hour] 
. 
Dose interruption of both LEE011 and 
everolimus until improvement of ANC 
≥1.0 x 109/L and no fever. 
CBC will be repeated weekly (± 3 day 
window) until toxicity has recovered to 
grade 1. Restart everolimus at the 
next lower dose level. Maintain 
LEE011 at the same dose. 
If febrile neutropenia recurs, 
discontinue study treatment. 
Colony Stimulating Factors should be 
considered in patients with fever and 
profound neutropenia (<1.0 x 109/L). 
Grade 4 Life-threatening 
consequences; urgent 
intervention indicated 
Discontinue study treatment. 
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 
Dose interruption of LEE011 and 
everolimus until recovery to grade 1. 
CBC will be repeated weekly (± 3 day 
window) until toxicity has recovered to 
grade 1. Re-initiate study treatment 
at the same dose. 
Grade 4: Life-threatening 
consequences; 
urgent intervention 
indicated 
Discontinue study treatment 
PRBC transfusion to be considered 
per NCCN guidelines. 


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9.5.2 LEE011/everolimus dose modification and management for QTcF prolongation (see 
Table 3 for dose reduction guide) 


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Adverse drug reaction 
Severity 
Dose adjustment and management 
recommendations 
QTcF prolongation 
For All Grades 
Check the quality of the ECG and the QT 
value and repeat if needed. 
Perform analysis of serum electrolytes (K+, 
Ca++, Phosphorus, Mg++). If outside of 
normal range, hold LEE011 and everolimus, 
correct with supplements or appropriate 
therapy as soon as possible, and repeat 
electrolytes until documented as normal. 
Review concomitant medication usage for 
the potential to inhibit CYP3A4 and/or to 
prolong the QT interval. 
Check compliance with correct dose and 
administration of study treatment 
Consider collecting a time matched PK 
sample; record date and time of last study 
drug intake. 
Grade 1 
QTc 450-480 ms 
No dose adjustment required. 
Grade 2 
QTc 481-500 ms 
Hold LEE011 and everolimus. 
Perform a repeat ECG one hour after the 
first QTcF of ≥481 ms. 
If QTcF <481 ms, restart LEE011 and 
everolimus at the same dose. No dose 
adjustment required for first occurrence. 
If QTcF remains ≥481 ms, repeat ECG as 
clinically indicated until the QTcF returns to 
<481 ms. Restart LEE011 and everolimus at 
the same dose. No dose adjustment 
required for first occurrence. 
If QTcF ≥481 ms recurs, everolimus should 
be reduced 
by 1 dose level; continue with LEE011 at 
same dose. 
Repeat ECGs 7 days and 14 days after 
dose. 
Resumption of study treatment (then as 
clinically indicated ) for any patients who had 
therapy interrupted due to QTcF ≥481 ms. 


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Grade 3 
QTc ≥501 ms on at least two 
separate ECGs 
Hold LEE011 and everolimus. 
Transmit ECG immediately and confirm 
prolongation/ abnormalities with central 
assessment. 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, everolimus will 
be reduced by 1 dose level. Maintain 
LEE011 at same dose. 
Repeat ECGs 7 days and 14 days after dose 
resumption (then as clinically indicated) for 
any patients who had therapy interrupted 
due to QTcF ≥501ms 
If QTcF of ≥501 ms recurs, discontinue 
study treatment. Perform frequent ECGs 
until the QTcF is <500 msec. Address 
electrolyte, calcium and magnesium 
abnormalities. 
Grade 4 
QT/QTc ≥501 or >60 ms change 
from baseline and 
Torsades de pointes or 
polymorphic ventricular 
tachycardia, or signs/symptoms 
of serious arrhythmia 
Discontinue study treatment. Transmit ECG 
immediately and confirm prolongation/ 
abnormalities with central assessment. 
Obtain local cardiologist (or qualified 
specialist) consultation and repeat cardiac 
monitoring as indicated until the QTcF 
returns to <481 ms. 
 
9.5.3 LEE011/everolimus dose modification and management for cardiac dysfunction (see 
Table 3 for dose reduction guide) 
 
Adverse drug reaction 
Severity 
Dose adjustment and management 
recommendations 
Cardiac - Left Ventricular 
Systolic Dysfunction 
Asymptomatic, 
resting ejection fraction 40-50%; 
or 10-20% drop from baseline 
Maintain dose level, and continue 
LEE011 and everolimus with caution. 
Repeat LVEF within 4 weeks or as 
clinically appropriate. 
Symptomatic, 
responsive to intervention, 
ejection fraction 20-39% 
or >20% drop from baseline 
Hold LEE011 and everolimus until 
resolved, then reduce everolimus by 
one dose level. Maintain LEE011 at 
same dose. 
Referral to cardiologist mandatory for 
management of heart failure 
symptoms. 
LVEF measurement to be repeated, 
if not resolved within 28 days 
permanently discontinue LEE011 
and everolimus if applicable. 


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9.5.4 LEE011/everolimus dose modification and management for hepatotoxicity (see Table 3 
for dose reduction guide) 
 
HEPATOTOXICITY (BILIRUBIN, SGPT/ALT, SGOT/AST) 
TOTAL BILIRUBIN without ALT/AST increase above baseline value 
Grade 1 (> ULN – 1.5 x ULN) 
(confirmed 48 to 72hrs later) 
If confirmed, maintain dose level with LFTs monitored bi-weekly until 
normalizes. 
Grade 2 (>1.5 – 3.0 x ULN) 
Dose interruption of LEE011 and everolimus. 
Liver enzymes and bilirubin tests will be repeated twice weekly (± 3 
day window) until toxicity has recovered to grade 1. 
If resolved to ≤grade 1 in ≤21 days, then maintain dose level. 
If resolved to ≤grade 1 in >21 days or toxicity recurs, reduce 
everolimus by 1 dose level. Maintain LEE011 at same dose. 
Repeat liver enzymes and bilirubin tests twice weekly for 2 weeks 
after dose resumption. 
If toxicity recurs after two dose reductions of everolimus, discontinue 
study treatment. 
Grade 3 (>3.0 – 10.0 x ULN) 
Dose interruption of LEE011 and everolimus. 
Liver enzymes and bilirubin tests will be repeated twice weekly (± 3 
day window) until toxicity has recovered to grade 1. 
If resolved to ≤ Grade 1 in ≤21 days, lower 1 dose level of 
everolimus, maintain LEE011 at same dose. 
Repeat liver enzymes and bilirubin tests twice weekly for 2 weeks 
after dose resumption. 
If resolved to ≤grade 1 in >21 days or toxicity recurs, discontinue 
study treatment. 
Grade 4 (>10.0 x ULN) 
Discontinue LEE011 
Confounding  factors and/or alternative  causes for increase of total bilirubin should be excluded before 
dose interruption/reduction. They include but are not limited to: evidence of obstruction, such as elevated ALP 
and GGT typical of gall bladder or bile duct disease, hyperbilirubinemia due to the indirect component only 
(i.e. direct bilirubin component ≤1 x ULN) due to hemolysis or Gilbert’s Syndrome, pharmacologic treatment, 
viral hepatitis, alcoholic or autoimmune hepatitis, other hepatotoxic drugs. For patients with Gilbert’s 
Syndrome, these dose modifications apply to changes in direct bilirubin only. Bilirubin will be fractionated if 
elevated. 
 
 
HEPATOTOXICITY (AST or ALT) 
AST or ALT without bilirubin elevation >2 x ULN 
Same grade as baseline or 
increase from 
baseline grade 0 to grade 1 
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) 
Dose interruption of LEE011 and everolimus until recovery to ≤baseline. 
Liver enzymes and bilirubin tests will be repeated twice weekly (± 3 day 
window) until toxicity has recovered to grade 1. 
If resolved to ≤baseline in ≤21 days, then maintain dose level. 
If resolved to ≤baseline in >21 days or toxicity recurs, then reduce 
everolimus by 1 dose level. Maintain LEE011 at same dose. Repeat liver 
enzyme and bilirubin tests twice weekly for 2 weeks after dose resumption. 
If toxicity recurs after two dose reductions of everolimus or recovery to 
≤baseline grade is >28 days, discontinue study treatment. 


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Increase from baseline grade 0 
or 1 to 
grade 3 (>5.0 – 20.0 x ULN) 
Dose interruption of LEE011 and everolimus until resolved to ≤baseline 
grade, then lower 1 dose level of study treatment. 
Liver enzymes and bilirubin tests will be repeated twice weekly (± 3 day 
window) until toxicity has recovered to grade 1. 
Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks after 
dose resumption. 
If recovery to ≤baseline grade is >28 days, discontinue study treatment. 
If toxicity recurs after two dose reductions of everolimus or recovery to 
≤ baseline grade is > 28 days, discontinue study treatment. 
Increase from baseline grade 2 
to grade 3 
(>5.0 – 20.0 x ULN) 
Dose interruption of LEE011 and everolimus until resolved to ≤baseline 
grade, then lower everolimus by 1 dose level. Maintain LEE011 at same 
dose 
Liver enzymes and bilirubin tests will be repeated twice weekly (± 3 day 
window) until toxicity has recovered to grade 1. 
Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks after 
dose resumption. 
If toxicity recurs after two dose reductions of everolimus or recovery to 
≤baseline grade is >28 days, discontinue study treatment. 
Grade 4 (>10.0 x ULN) 
Discontinue study treatment. 
AST or ALT and concurrent Bilirubin 
For patients with normal ALT 
and AST and total 
bilirubin at baseline: AST or 
ALT > 3 x ULN combined 
with total bilirubin > 2 x ULN 
without evidence of cholestasis 
or 
For patient with elevated AST or 
ALT or total bilirubin at baseline: 
baseline : [AST or ALT >2 x 
baseline AND >3.0x ULN] OR 
[AST or ALT 8.0 x ULN]- 
whichever is lower- combined 
with [total bilirubin 2 x 
baseline AND >2.0 x ULN] 
Discontinue study treatment. 
Confounding factors and/or alternative causes for increased transaminases should be excluded before dose 
interruption/reduction. They include but are not limited to: concomitant medications, herbal preparations or 
dietary supplements, infection, hepato-biliary disorder or obstruction, new or progressive liver metastasis, and 
alcohol intake. 
 
Additional follow-up for hepatic toxicities 
 
Hepatic toxicity monitoring includes assessment of the following liver function tests (LFTs): albumin, 
ALT, AST, total bilirubin, direct and indirect bilirubin alkaline phosphatase (fractionated if alkaline 
phosphatase is grade 2 or higher), creatinine kinase, prothrombin time (PT)/(PTT), international 
normalized ratio (INR) and Gamma-glutamyl transpeptidase (GGT). For patients with Gilbert’s 
Syndrome: total and direct bilirubin must be monitored, intensified monitoring applies to changes in 
direct bilirubin only. 


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Close observation is recommended in case of AST, ALT, and/or bilirubin increase requiring dose 
interruption, which involves: 
• 
Repeating liver enzyme and serum bilirubin tests approximately two times weekly. Frequency 
of re-testing can decrease to once a week or less if abnormalities stabilize or return to normal 
values. 
• 
Obtaining a more detailed history of current symptoms. 
• 
Obtaining a more detailed history of prior and/or concurrent diseases including history of any 
pre-existing liver conditions or risk factors. 
• 
Obtaining a history of concomitant drug use (including non-prescription medications, herbal 
and dietary supplements), alcohol use, recreational drug use, and special diets. 
• 
Ruling out acute viral hepatitis types A, B, C, D, and E; hepatotropic virus infections 
cytomegalovirus (CMV), Epstein-Barr virus (EBV), or herpes simplex virus (HSV); 
autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic hepatopathy; and biliary tract 
disease. 
• 
Obtaining a history of exposure to environmental chemical agents. 
• 
Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct bilirubin). 
• 
Considering gastroenterology or hepatology consultations. 
• 
Assessing cardiovascular dysfunction or impaired liver oxygenation, including hypotension or 
right heart failure as possible etiologies for liver dysfunction. 
• 
Obtaining a PK sample, as close as possible to last dose of study drug. 
• 
Liver biopsy as clinically indicated to assess pathological change and degree of potential 
liver injury. 
Increase in transaminases combined with total bilirubin (TBIL) increase may be indicative of drug- 
induced liver injury (DILI), and should be considered as clinically important events. The threshold for 
potential DILI may depend on the patient’s baseline AST/ALT and TBIL value; patients meeting any 
of the following criteria will require further follow-up as outlined below: 
• 
For patients with normal ALT AND AST AND TBIL value at baseline: AST or ALT >3.0 x ULN 
combined with TBIL >2.0 x ULN. 
• 
For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT >2 x baseline AND 
>3.0 x ULN] OR [AST or ALT >8.0 x ULN], whichever is lower, combined with [TBIL >2 x 
baseline AND >2.0 x ULN]. 
 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined as: 
Alkaline phosphatase (ALP) elevation >2.0 x ULN with R value <2 in patients without bone 
metastasis, or elevation of ALP liver fraction in patients with bone metastasis. 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both 
values [R value = ALT/ULN)/(ALP/ULN)]. It denotes the relative pattern of ALT and/or ALP elevation 
is due to cholesteric or hepatocellular liver injury or mixed type injury. 


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In the absence of cholestasis, these patients should be immediately discontinued from study drug 
treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed history, 
physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no other 
alternative cause for LFT abnormalities identified, should be considered as “medically significant”, 
thus meeting the definition of SAE, and reported as SAE using the term “potential drug-induced liver 
injury”. All events should be followed up with the outcome clearly documented. 
9.5.5 Dose modification and management for everolimus specific toxicities (Refer to dose 
modification Table 3) 


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Adverse drug reaction 
Severity 
Dose adjustment and management 
recommendations 
Stomatitis 
Grade 1 
Minimal symptoms, normal diet 
No dose adjustment required. 
Manage with non-alcoholic steroid 
mouthwash and salt water (0.9%) 
mouth wash four times a day. 
Grade 2 
Symptomatic but can eat and 
swallow modified diet 
Interrupt everolimus and LEE011 until 
recovery to grade 1. 
Re-initiate study treatment at the same 
dose. 
If stomatitis recurs, interrupt LEE011 
and everolimus until recovery to grade 
1. Re-initiate study treatment at a one 
dose lower. 
Manage with topical analgesic mouth 
treatments (e.g. benzocaine, butyl 
minobenzoate, tetracaine 
hydrochloride, menthol or phenol) with 
or without topical corticosteroids (i.e. 
triamcinolone oral paste). 
Grade 3 
Symptomatic and unable to 
adequately aliment or hydrate 
orally 
Interrupt everolimus and LEE011 until 
recovery to grade ≤1.Re-initiate study 
treatment of everolimus at a reduced 
dose. Maintain LEE011 at the same 
dose. 
If reoccurs, interrupt LEE011 and 
everolimus until recovery to grade 
≤1.Re-initiate everolimus study 
treatment at second dose level. 
Maintain LEE011 at the same dose. 
Manage with topical analgesic mouth 
treatments (i.e. benzocaine, butyl 
aminobenzoate, tetracaine 
hydrochloride, menthol or phenol) with 
or without topical corticosteroids (i.e. 
triamcinolone oral paste). 
Grade 4 
Symptoms associated with life- 
threatening consequences 
Hold LEE011 and everolimus and 
provide appropriate medical therapy. If 
recovered to ≤grade 1 within 3 weeks, 
Re-initiate study treatment with 
everolimus at a reduced dose. Maintain 
LEE011 at same dose. If >3 weeks, 
then discontinue study treatment. 
Serum creatinine 
Grade 1 
No dose adjustment required. Initiate 
appropriate monitoring. 
Grade 2 
Hold LEE011 and everolimus until 
resolved to grade ≤1, then re-initiate 
study treatment at the same dose level. 
If toxicity recurs at Grade 2, interrupt 
LEE011 and everolimus until recovery 
to grade ≤1, re-initiate and 
reduceeverolimus by one dose level. 
Maintain LEE011 at same dose. 


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Grade 3 
Hold LEE011 and everolimus until 
resolved to grade ≤1, then reduce 
everolimus by 1 dose level. Maintain 
LEE011 at the same dose. If toxicity 
recurs after two everolimus dose 
reductions, discontinue study 
treatment. 
Grade 4 
Discontinue study treatment and 
manage appropriately. 
Metabolic events (e.g. 
hyperglycemia, dyslipidemia) 
Grade 1 
No dose adjustment required. 
Initiate appropriate medical therapy 
and closely monitor. Consider 
metformin for hyperglycemia. 
Grade 2 
No dose adjustment required. 
Manage with appropriate medical 
therapy and monitor. 
For hyperglycemia, consider metformin 
and follow up with endocrinologist. 
Grade 3 
Hold LEE011 and everolimus until 
resolved to grade ≤1, then reduce 
everolimusby 1 dose level. Maintain 
LEE011 at the same dose. 
Manage with appropriate medical 
therapy and monitor. 
Grade 4 
Hold LEE011 and everolimus until 
resolved to grade ≤1 then discontinue 
study treatment 
 
9.5.6 Management of non-infection pneumonitis 


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Worst Grade 
Pneumonitis 
Required 
Investigations 
Management of 
Pneumonitis 
Dose Adjustment 
Grade 1 
Asymptomatic 
radiographic 
findings only 
CT scans with lung 
windows 
Repeat at least every 
8-12 weeks until return 
to within normal limits. 
No specific therapy is 
required 
Administer 100% of 
study treatment 
dose. 
Grade 2 
Symptomatic, 
not interfering 
with ADL 
CT scan with lung 
windows. 
Consider pulmonary 
function 
testing includes: 
spirometry, 
DLCO, and room air O2 
Saturation at rest 
Repeat at least every 
8-12 weeks until return 
to within normal limits. 
Consider a 
bronchoscopy with 
biopsy and / or BAL 
Symptomatic only. 
Consider 
corticosteroids if 
symptoms are 
troublesome. 
Reduce everolimus 
dose by 1 dose level 
until recovery to 
≤Grade 1.* Patient will 
continue at LEE011 at 
current dose. 
Grade 3 
Symptomatic, 
interfering with 
ADL; O2 
indicated 
CT scan with lung 
windows 
and pulmonary function 
testing includes: 
spirometry, DLCO, and 
room air O2 saturation 
at rest. 
Repeat at least every 6 
weeks until return to 
within normal limits. 
Bronchoscopy with 
biopsy and / or BAL is 
recommended. 
Consider 
corticosteroids if 
infective origin is ruled 
out. 
Taper as 
medically indicated. 
Hold everolimus until 
recovery to Grade ≤1. 
May restart everolimus 
treatment within 3 
weeks at 1 lower dose 
level if evidence of 
clinical benefit. Patient 
will continue LEE011 at 
current dose. 
Grade 4 
Life threatening; 
ventilatory 
support 
indicated 
CT scan with lung 
windows 
and required 
pulmonary 
function testing, if 
possible, 
includes: spirometry, 
DLCO, and room air 
O2 saturation at rest. 
Repeat at least every 6 
weeks until return to 
within normal limits. 
Bronchoscopy with 
biopsy and / or BAL is 
recommended if 
possible. 
Consider 
corticosteroids if 
infective origin is ruled 
out. Taper as 
medically indicated. 
Discontinue study 
treatment. 


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*If patient is minimally symptomatic, everolimus can be continued at 5 mg daily at the discretion of the treating 
oncologist and after discussion with the principle investigator. Everolimus may also be completely interrupted if 
symptoms are troublesome. 
 
 
9.5.7 Recommended actions to be taken for positive baseline hepatitis B test 
 
Test 
Result 
Result 
Result 
Result 
Result 
HBV-DNA 
+ 
+ or - 
- 
- 
- 
HBsAg 
+ or - 
+ 
- 
- 
- 
HBs Ab 
+ or - 
+ or - 
+ 
and no prior HBV 
vaccination 
+ or - 
- 
or + with 
prior HBV 
vaccination 
HBc Ab 
+ or - 
+ or - 
+ or - 
+ 
- 
Recommendation 
Prophylaxis treatment should be started 
1-2 weeks prior to first dose of study 
drug. 
Monitor HBV-DNA approximately every 
6 weeks. 
No prophylaxis. Monitor HBV- 
DNA approximately every 4 
weeks at the end of treatment 
and until EOT + 30 days. 
No specific 
action. 
 
Antiviral prophylaxis therapy should continue for at least 4 weeks after last dose of study drug. For 
hepatitis B reactivation, definition and management guidelines see Table 4: Guidelines for 
management of hepatitis B. 
Table 4: Guidelines for management of hepatitis B 
 
Reactivation is Defined as: 
Treatment 
Increase of 1 log in HBV- 
DNA relative to baseline 
HBV- DNA value OR new 
appearance of measurable 
HBV-DNA 
AND 
ALT elevation x 5 ULN 
Start appropriate antiviral therapy. 
AND 
Interrupt LEE011 and everolimus administration until resolution: 
≤grade 1 ALT (or baseline ALT, if >grade 1) and ≤baseline HBV-DNA 
levels. 
If resolution occurs within ≤21 days study treatment should be re- 
started at one dose lower, if applicable. If the patient is already 
receiving the lowest dose of study drug according to the protocol, the 
patient should restart at the same dose after resolution. Both antiviral 
therapies should continue at least 4 weeks after last dose of study 
drug. 
If resolution occurs >21 days patients should discontinue study 
treatment but continue both antiviral therapies at least 4 weeks after 
last dose of study treatment. 
 
9.5.8 Guidance for all other adverse reactions 


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Consider performing an analysis of serum potassium, calcium, phosphorus, and magnesium for all 
adverse reactions, if indicated. If electrolyte values are outside of the normal range, interrupt 
LEE011/everolimus administration, correct electrolytes with supplements or appropriate therapy as 
soon as possible, and repeat electrolyte testing until documented normalization of the electrolytes. 
Table 5: LEE011/everolimus dose adjustment and management recommendation for all other 
adverse reactions (see Table 3 for dose reduction guide) 
 
Grade/Severity 
Dose adjustment and management recommendations 
Grade 1 
No dose adjustment- maximize AE management. 
Grade 2 
Dose interruption of LEE011/everolimus until recovery to 
Grade ≤1 (28 days allowed for toxicity to return to ≤ grade 1). 
Initiate appropriate medical therapy and monitor. 
Re-initiate study treatment at the same dose. If the same 
toxicity recurs at Grade 2, interrupt LEE011/everolimus until 
recovery to Grade ≤1. Re-initiate everolimus treatment at the 
next lower dose level. Maintain LEE011 at same dose. 
Grade 3 
Hold both everolimus and LEE011 until it resolves to Grade ≤ 
1 (28 days allowed for toxicity to return to ≤ grade 1).. Initiate 
appropriate medical management and monitor. 
Re-initiate study treatment at the next lower everolimus dose 
level. Maintain LEE011 at same dose. 
If toxicity recurs at grade 3, discontinue study treatment. 
Grade 4 
Discontinue study treatment. 
Additional recommendations: 
Nausea: Ensure adequate hydration or fluid repletion. Consider performing an analysis of serum 
potassium, calcium, phosphorus and magnesium, if indicated. If electrolyte values are below the lower 
limits of normal, interrupt LEE011, correct electrolytes with supplements as soon as possible, and 
repeat electrolyte testing until documented normalization. 
Diarrhea: At the first sign of loose stools (Grade 1), initiate loperamide. Patient should remain well 
hydrated. Fluids and electrolytes should be replaced as needed. Consider performing an analysis of 
serum potassium, calcium, phosphorus and magnesium, if indicated. If electrolyte values are below 
the lower limits of normal, interrupt LEE011, correct electrolytes with supplements as soon as 
possible, and repeat electrolyte testing until documented normalization. 
 
9.5.9 
Dose Adjustments in Special Populations 
9.5.9.1 Renal impairment 
 
Insufficient data are available to provide a dosage recommendation for LEE011 in patients with renal 
impairment. 
Patients with baseline renal impairment are excluded from the study (serum creatinine > ULN or 
creatinine clearance <50 mL/min). Patients who experience renal impairment of grade 2 or higher 
during the treatment period should discontinue treatment and should be followed for safety 
assessments. 


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9.5.9.2 
Elderly 
Physicians should exercise caution in monitoring the effects of LEE011 in the elderly. Insufficient 
data are available to provide a dosage recommendation. 
9.6 
Concomitant medications 
9.6.1 
Permitted concomitant therapy for all treatment groups 
 
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and supportive 
care agents, such as packed red blood cells (PRBCs), pain medications, anti-emetics, short courses 
of steroids, chronic use of a low dose steroid for physiologic replacement, topical treatments for 
stomatitis and anti-diarrheal are allowed. The use of any other potential new concomitant 
medications may be discussed between the investigator and the MSK PI on a case by case basis. 
The patient must be told to notify the treating physician about any new medications he/she takes 
after the start of the study drug combination. All medications (other than study drugs) and significant 
non-drug therapies (including vitamins, herbal medicines, physical therapy and blood transfusions) 
administered within 30 days of study entry and during the study must be listed on the Concomitant 
medications/Significant non-drug therapies eCRF. 
Patients taking concomitant medication chronically should be maintained on the same dose and 
dose schedule throughout the study period, as medically feasible. 
Refer to the LEE011 and Everolimus Investigator’s Brochures for concomitant medications. 
Hematopoietic growth factors 
 
The use of Transfusions or Hematopoietic growth factor support (e.g. erythropoietins, G-CSF and 
GM-CSF) should be according to ASCO guidelines. 
Bisphosphonates and denosumab 
 
Bisphosphonates and denosumab are generally allowed with the following comments: 
• 
Bisphosphonate/denosumab therapy for the treatment of osteoporosis is permitted. 
• 
Bisphosphonate/denosumab therapy for the prevention of skeletal related events for patients 
with existing bone metastases is permitted. 
• 
If bisphosphonate therapy is to be started after the first dose of study drug, prior consultation and 
approval by Novartis is required and the reason for its use must be clearly documented. 
 
Palliative radiotherapy 
 
Palliative radiation is permitted while on study after discussion with sponsor. It should not be 
delivered to a target lesion and it should not encompass more than 25% of irradiated bone marrow. 


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If palliative radiotherapy is initiated after the start of study treatment, the reason for its use must be 
clearly documented and progression as per RECIST v1.1 must be ruled out. 
No dose modification of study treatment is needed during palliative radiotherapy. 
9.6.2 
Prohibited concomitant therapy 
The following medications are prohibited during study treatment in the study (see Table 6). This list 
is not comprehensive and is only meant to be used as a guide. Please contact the medical monitor 
with any questions. 
• 
Strong and moderate inhibitors or inducers of CYP3A4/5. 
• 
Substrates of CYP3A4/5 with a narrow therapeutic index. 
• 
Medications with a known risk for QT prolongation. 
• 
Other investigational and anti-neoplastic therapies, including chemotherapy, immunotherapy, 
target therapy, biological response modifiers, or endocrine therapy. 
• 
Hormone replacement therapy, topical estrogens (including any intra-vaginal preparations), 
megestrol acetate and selective estrogen-receptor modulators (e.g. raloxifene). 
• 
Prolonged systemic corticosteroid treatment (≥2 weeks), except for topical applications (e.g. 
rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. 
intraarticular) should not be given. A short duration of systemic corticosteroids is allowed (e.g. 
chronic obstructive pulmonary disease, LFT abnormality). 
• 
Herbal preparations/medications (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. 
 
9.6.3 
Permitted concomitant therapy requiring caution and/or action while on study 
 
Permitted medications to be used with caution combined LEE011 and everolimus in this study are 
listed below (see Table 7). These medications should be excluded from patient use if possible. If 
they must be given based on the investigator’s judgment, then use with caution and consider a 
LEE011 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. 
• 
Medications that carry a possible risk for QT prolongation. 
• 
Sensitive substrates of the renal transporters, MATE1 and OCT2. 
• 
Sensitive substrates of BCRP. 
 
 
9.6.4 
Drugs with QTc prolongation 


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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 drug-drug 
interaction 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. 
Table 6: List of prohibited medications during study drug treatment 
 
Category 
Drug Name 
Strong CYP3A4/5 inhibitors 
voriconazole, boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, eltegravir/ritonavir, grapefruit juice, 
indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
saquinavir/ritonavir, telaprevir, telithromycin, tipranavir/ritonavir, 
troleandomycin, voriconazole 
Strong CYP3A4/5 inducers 
Avasimibe2,3, carbamazepine, mitotane, phenobarbital, phenytoin, 
rifabutin, rifampin (rifampicin)3, St. John's wort (hypericum perforatum)3 
CYP3A4/5 substrates with NTI1 
Terfenadine, alfentanil, apixaban (doses >2.5 mg only), aprepitant, 
astemizole, cisapride, cyclosporine, diergotamine, dihydroergotamine, 
ergotamine, fentanyl, lovastatin, nicardipine, nisoldipine, pimozide, 
quinidine, rivaroxaban, simvastatin, sirolimus, tacrolimus, terfenadine, 
thioridazine 
Medications with a known risk for 
QT prolongation4 
vavdetanib, amiodarone, anagrelide, arsenic trioxide, astemizole, 
azithromycin, bepridil, chloroquine, chlorpromazine, cilostazol, 
ciprofloxacin, cisapride, citalopram, clarithromycin, disopyramide, 
dofetilide, domperidone, donepezil, dronedarone, droperidol, 
erythromycin, escitalopram, flecainide, fluconazole, halofantrine, 
haloperidol, ibutilide, levofloxacin, levomethadyl, mesoridazine, 
methadone, moxifloxacin, ondansetron (intravenous only), pentamidine, 
pimozide, probucol, procainamide, propofol, quinidine, sevoflurane, 
sotalol, sparfloxacin, sulpiride, terfenadine, thioridazine, vandetanib, 
venlafaxine 
Herbal preparations/ medications 
Herbal preparations/medications are prohibited throughout the study. 
These herbal medications include, but are not limited to: St. John’s 
wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. 
Patients should stop using these herbal medications 7 days prior to first 
dose of study drug. 
Other investigational and 
antineoplastic therapies 
Other investigational therapies must not be used while the patient is on 
the study. Anticancer therapy (chemotherapy, biologic or radiation 
therapy, and surgery) other than the study treatments must not be given 
to patients while the patient is on the study medication. If such agents 
are required for a patient then the patient must be discontinued study 
drug. 
1NTI = 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). 
2Herbal product 
3P-gp inducer 
4Source: www.qtdrugs.org (as of Apt 7, 2015) 


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Table 7: List of medications to be used with caution during study drug treatment 
 
Category 
Drug Name 
Moderate CYP3A4/5 inhibitors 
Amprenavir, atazanavir, casopitant, cimetidine, darunavir, diltiazem, 
fosamprenavir, lomitapide, netupitant, tofisopam, verapamil 
Moderate CYP3A4/5 inducers 
Bosentan, efavirenz, etravirine, genistein, lersivirine, modafinil, nafcillin, 
Talviraline 
Sensitive CYP3A4/5 substrates1 
Alpha-dihydroergocryptine, almorexant, alpaviroc, apixaban (doses < 
2.5 mg only), atazanavir, atorvastatin, avanafil, bosutinib, brecanavir, 
brotizolam, budesonide, buspirone, capravirine, casopitant, darifenacin, 
darunavir, ebastine, eletriptan, eplerenone, felodipine, fluticasone, 
ivacaftor, lomitapide, lumefantrine, lurasidone, maraviroc, midazolam, 
perospirone, quetiapine, ridaforolimus, sildenafil, ticagrelor, tilidine, 
tolvaptan, triazolam, vardenafil, vicriviroc, voclosporin 
Strong BSEP inhibitors 
Bosentan, fusidate, glibenclamide, sulindac, troglitazone (TGZ-sulfate) 
Medications that carry a possible 
risk for QT prolongation2 
Alfuzosin, apomorphine, aripiprazole, atazanavir, atomoxetine, 
bedaquiline, clozapine, dexmedetomidine, dolasetron, eribulin, 
famotidine, felbamate, fingolimod, foscarnet, gatifloxacin, gemifloxacin, 
granisetron, iloperidone, isradipine, lithium, mirabegron, mirtazapine, 
moexipril, norfloxacin, ofloxacin, olanzapine, ondansetron (p.o. only at 4 
mg or 8 mg), oxytocin, paliperidone, pasireotide, pipamperone, 
promethazine, quetiapine, ranolazine, rilpivirine, risperidone, 
roxithromycin, sertindole, telavancin, tetrabenazine, tizanidine, 
tolterodine, vardenafil, ziprasidone 
MATE1 and OCT2 substrates3 
Acyclovir, amantadine, amiloride, cephalexin, cephradine, cimetidine, 
famotidine, fexofenadine, memantine, metformin (also a substrate for 
OCT1, MATE1, and MATE2K), pindolol, procainamide, ranitidine, and 
varencicline 
BCRP substrates 
Rosuvastatin, sulfasalazine 
1Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when 
co-administered with a potent inhibitor. 
2Source: www.qtdrugs.org (as of Apr 7, 2015) 
3Source: FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
implications for Dosing and Labeling (February 2012) and Yonezawa and Inui (2011) Importance of the 
multidrug and toxin extrusion MATE/SLC47A family to pharmacokinetics, 
pharmacodynamics/toxicodynamics and pharmacogenomics. Br J Pharmacology 164:1817 -25 
 
9.7 
Biomarkers 
 
The biomarker collections for this study are summarized in Table 8 below. 
9.7.1 
Potential predictive biomarkers 
MSK patients must supply a tumor specimen that may be from a previous biopsy (archival tumor 
specimen) or from a newly obtained tumor specimen before beginning treatment with LEE011 and 
everolimus. Participating site patients can supply an archival tumor specimen if available. The most 
recent biopsy is preferred. The availability of tumor specimens must be confirmed before MSK 
patients receive treatment. Additionally, a pathology report must be submitted along with the 
patient’s archival tumor block/slides for MSK patients and for applicable participating site patients. 


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Page 49 of 68 
 
 
 
While on protocol, all patients will also be given the opportunity to consent to an optional biopsy 
(regardless of disease response) for further evaluation of predictive biomarkers. 
Baseline tumor samples (archival or newly obtained) will be tested for p-Akt, p-S6K, p-pRb and PTEN 
protein as well as Ki-67 by immunohistochemistry at each participating site as per institutional 
guidelines. The status of molecules (e.g., gene expression, mutations, amplifications, deletions 
and/or protein expression/activation etc.) that are involved in the D-cyclin-CDK4/6-INK4a-Rb and 
mTOR pathways, such as mutations of CCND1, PIK3CA, PTEN and CDK4; gene amplification of 
CCND1 and CDK4, deletion of CDKN2, as well as other cancer associated genes, will also be 
investigated in the tumor tissue from all patients (provided that acceptable assays exist), with the 
intention to identify potential predictive markers related to therapeutic responses or resistant 
disease. Other pathways that may interact with D-cyclin-CDK4/6-INK4a-Rb and/or mTOR, or 
thought to be important in cancer may also be assessed, depending on sample and assay 
availability. Tumor samples obtained while on protocol (through an optional biopsy after patient 
consent for any patient on protocol) will be tested for total pRb and p-pRB, Ki-67, p-Akt, and p-S6K 
expression by IHC. The results from these exploratory analyses will be correlated with clinical 
outcome to determine potential predictive biomarkers of LEE0011/everolimus response/resistance. 
Biomarker analysis will be performed by each participating site for their respective patients. 
Next-generation sequencing 
Next-generation sequencing of tumor tissue may be considered for all patients on this protocol, 
however if next-generation sequencing is pursued, patients must be separately consented. 
At MSK, patients will be offered the opportunity to participate in MSK IRB# 12-245 to have MSK- 
IMPACT testing performed through our institutional protocol. Similarly, each participating site will be 
asked to consent their patients to the appropriate institution protocol as per their site IRB guidelines. 
Participation within these next-generation sequencing is not mandatory for patients to participate in 
this study. Participating sites will be responsible for submitting available sequencing data to MSK as 
per institutional guidelines. 
Table 8: Biomarker sample collection schedule 
 
Sample 
Tissue 
Visit 
Biomarker assay 
FFPE or newly obtained 
tumor (required for MSK 
patients, optional for 
participating site patients 
without archived tissue) 
Tumor 
Screening 
p-Akt, p-S6K, p-pRB, 
PTEN, Ki-67 by IHC 
DNA sequence of 
PIK3CA, CDK4, PTEN, 
CCND1 
Copy number 
assessment (by next- 
generation sequencing) 


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Page 50 of 68 
 
 
 
of CDK4, CCND1, 
CDKN2 
Newly obtained on- 
therapy tumor samples 
(optional) 
Tumor 
On therapy or in follow- 
up after therapy 
Total pRb and p-pRB, Ki- 
67, p-Akt, and p-S6K 
expression by IHC 
Other biomarkers related 
to Rb pathway and 
WDNET pathogenesis 


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10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Assessment 
Screenin 
g 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 onwards 
End of 
treatment8 
Follow- 
up 
Day of cycle 
-28 to -1 
11 
151 
11 
151 
11 
11 
within 15 
days of last 
dose 
Informed Consent 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
Height and Weight 
X 
X 
Vital signs 
(ECOG, temp, pulse, respiration rate, blood 
pressure) 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
EKG (12-Lead) 
X2 
X2 
X2 
As clinically indicated2 
ECHO/MUGA 
X 
As clinically indicated 
CBC with diff and platelet count 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistries3 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Function Tests3 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Panel 
(PT/INR and PTT) 
X 
X 
X 
X 
X 
X 
X 
Lipid panel 
X 
X4 
Urinalysis/BUN 
X 
X 
X 
X 
X 
X 
X 
X 
HepBsAg, HepBcAb and Hepatitis C Antibody5 
X 
Pregnancy test if female (Serum) 
X6 
CT/MRI scan 
X 
X7 
Archival Tissue 
X8 
Research Tumor Biopsy (optional) 
X8 
After initiating therapy for any patient on protocol 
Concomitant Medications 
Continuous8 
Adverse Events 
Continuous8 
LEE011 dosing 
Continuous 


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Everolimus dosing 
Continuous 
Survival Follow-up 
X9 
1. All study assessments, with the exception of CT/MRI scans, must be performed as per the above schedule of events ± 3 days. CT/MRI 
scans must be performed as per the above schedule of events ± 7 days. 
2. Triplicate 12-lead EKG (2 minutes apart) will be used and the combined QTcF values from these EKGs 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 the “LEE011 Dose 
Modification section.” If treatment is resumed, repeat EKGs 7 days and 14 days after dose resumption (and then as clinically indicated). 
3. Serum chemistries must include the following: Na, K, Cl, CO2, BUN, creatinine, glucose, calcium, albumin, and total protein. Liver 
function tests must include the following: AST, ALT, alkaline phosphatase, total bilirubin. 
4. Lipid panel must be performed every 4th cycle. 
5. Hepatitis B PCR will be done if the Hepatitis B core antibody or Hepatitis B surface antigen is reactive. 
6. Serum pregnancy test must be performed for all women of childbearing potential within 72 hours prior to receiving first dose of study 
medication. If the test result is positive related to pregnancy, the patient will not be allowed to participate in this study. 
7. Disease assessments must be performed every 12 weeks ± 7 days or sooner if there is clinical evidence of disease progression. All 
patients who discontinue treatment for reasons other than disease progression will have post-treatment follow-up for disease status until 
disease progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to follow-up. 
8. If archival tissue is not available, a baseline tumor biopsy must be done. Patients will also be given the opportunity to consent to an 
optional biopsy (regardless of disease response for any patient on protocol) for further evaluation of predictive biomarkers. This optional 
biopsy may be performed on therapy or in follow-up after therapy. 
9. All patients who discontinue study treatment should be contacted for safety evaluations for 30 days after the last dose. Patients whose 
treatment is interrupted or permanently discontinued due to an adverse event, including abnormal laboratory values, should be followed 
at least once a week for 4 weeks and subsequently at 4-week intervals until resolution or stabilization of the event, whichever comes 
first. 
10. All patients enrolled in the study will be followed for survival every 3 months with phone call until death, lost to follow-up, or withdrawal of 
consent, whichever occurs first. 


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11.0 
TOXICITIES/SIDE EFFECTS 
11.1 
Adverse Events (AE) Definition 
 
Definition 
An adverse event is defined as the appearance of (or worsening of) any unintended or undesirable 
symptom(s), sign(s) or medical condition(s) which may be associated with the use of the 
investigational study drug, whether considered related to the drug or not and presenting any time after 
formal written consent has been obtained. 
 
An abnormal laboratory value or test result occurring after obtained consent is considered an adverse 
event only if it results in a clinically significant change in signs or symptoms, requires therapy, or 
results in a change in the study medication. 
 
Adverse events may include, but are not limited to: 
• 
Subjective or objective symptoms provided by the subject and/or observed by the Investigator 
or study staff including laboratory abnormalities of clinical significance. 
• 
Any AEs experienced by the subject through the completion of final study procedures. 
• 
AEs not previously observed in the subject that emerge during the protocol- specified AE 
reporting period, including signs or symptoms associated with the underlying disease that were 
not present before the AE reporting period 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as biopsies). 
 
The following are NOT considered AEs: 
• 
Pre-existing condition: A pre-existing condition (documented on the medical history CRF) is 
not considered an AE unless the severity, frequency, or character of the event worsens during 
the study period. 
• 
Pre-planned or elective hospitalization: A hospitalization planned before signing the informed 
consent form is not considered an SAE, but rather a therapeutic intervention. However, if 
during the pre-planned hospitalization an event occurs, which prolongs the hospitalization or 
meets any other SAE criteria, the event will be considered an SAE. Surgeries or interventions 
that were under consideration, but not performed before enrollment in the study, will not be 
considered serious if they are performed after enrollment in the study for a condition that has 
not changed from its baseline level. Elective hospitalizations for social reasons, solely for the 
administration of chemotherapy, or due to long travel distances are also not SAEs. 
• 
Diagnostic Testing and Procedures: Testing and procedures should not to be reported as AEs 
or SAEs, but rather the cause for the test or procedure should be reported. 
 
11.2 
Adverse Event Reporting 
Adverse events will be monitored throughout the trial and graded in severity according to the 
guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 


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Approval date: 18-Apr-2019 
Page 54 of 68 
 
 
After the end of treatment, subjects will be followed for 30 days for adverse event monitoring 
(serious adverse events and events of clinical interest will be collected for 90 days after the end of 
treatment or 30 days after the end of treatment if the subject initiates new cancer therapy, whichever 
is earlier). 
11.3 End of treatment visit, including premature withdrawal and study safety follow up 
All patients who discontinue treatment for reasons other than disease progression will have post- 
treatment follow-up for disease status until disease progression, initiating a non-study cancer 
treatment, withdrawing consent, or becoming lost to follow-up. 
All patients who discontinue study treatment, including those who refuse to return for a final visit, 
should be contacted for safety evaluations (i.e., assessment of AEs and/or SAEs, concomitant 
medications) for 30 days after the last dose of study treatment. Patients whose treatment is 
interrupted or permanently discontinued due to an adverse event, including abnormal laboratory 
value, should be followed at least once a week for 4 weeks and subsequently at 4-week intervals 
until resolution or stabilization of the event, whichever comes first. 
11.4 Possible Side Effects of LEE011 and everolimus combination 
Likely 
• 
Lowering of red blood cell counts which can lead to tiredness and weakness (anemia) 
• 
Lowering of white blood cell counts which can increase the risk for infection 
• 
Lowering of platelet counts which can lead to easy bruising and bleeding 
• 
Inflammation of the mouth and lip 
• 
Mouth and tongue ulcers 
• 
Evidence of liver or kidney damage 
• 
Nausea 
• 
Diarrhea 
• 
Fever 
• 
Muscle aches and spasms 
• 
Headaches 
• 
Difficulty sleeping 
• 
Shortness of breath 
• 
Hair loss 
• 
Itching 
Less likely 
 
• Rash 
• Weakness/lack of energy 
• Fatigue 
• Vomiting 
• Decreased appetite 
• Change in taste 
• Nosebleeds 


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• Headache 
• Elevated blood sugar levels 
• Constipation 
• Shortness of breath 
• Low potassium levels which may cause your muscles to feel weak, cramp or twitch 
• Low phosphate levels which may cause your muscles to feel weak, cramp, or twitch 
• Low calcium levels which may cause your muscles to feel weak, cramp, or twitch 
• Elevated cholesterol 
• Abnormal kidney function (increase in creatinine) 
• Swelling 
• Inflammation of the lung (pneumonitis) 
• Hot flashes 
• Low magnesium levels 
• Weight loss 
• High blood pressure 
• Syncope 
• Increased eye tearing 
• Dry eye 
• Change in taste 
• Heartburn 
Rare but serious 
 
• Bleeding 
• Low white blood cell count with a fever which can result in life-threatening infection (pneumonia, 
urinary tract infection) 
• Skin infection (cellulitis) 
• Difficulty breathing with low levels of oxygen in the blood 
• Irregular heart rhythms (arrhythmia) 
• Liver inflammation that could result in liver failure 
• Inflammation of the colon (colitis) 
• Disorders of the bone marrow (leukemia) 
• Cardiac arrest 
• Sudden cardiac death 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
For the purposes of this study, patients will be evaluated for response every 12 weeks, or as 
clinically indicated if interim toxicity occurs mandating cancer staging re-assessment. RECIST v1.1 
criteria will be used. 
CT scan with contrast of the chest, abdomen, and pelvis 
CT scans should be performed with contiguous cuts in slice thickness of 5 mm or less. Spiral CT 
should be performed using a 5-mm contiguous reconstruction algorithm. 
MRI scans 


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MRI of the abdomen and pelvis is acceptable for measurement of lesions provided that the same 
anatomical plane is used for serial assessments. If possible, the same imaging device should be 
used for serial evaluations. In case of MRI, measurements will be preferably performed in the axial 
(transverse) plane on contrast-enhanced T1-weighted images. However, there are no specific 
sequence recommendations. 
Measurability of Tumor Lesions 
Tumor lesions will be categorized as follows: 
• 
Measurable Lesions - Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
• 
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the 
slice thickness and a minimum of 10 mm) 
• 
10 mm caliper measurement by clinical exam (when superficial) 
• 
Malignant lymph nodes are considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). 
• 
Nonmeasurable Lesions - Nonmeasurable lesions are defined as all other lesions (or sites 
of disease), including small lesions (longest diameter < 10 mm or pathological lymph nodes 
with ≥ 10 to < 15 mm short axis). Lesions considered truly nonmeasurable include the 
following: leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible imaging 
techniques. 
• 
Target Lesions - All lesions up to a maximum of 5 lesions total (and a maximum of 2 lesions 
per organ) representative of all involved organs should be identified as target lesions. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. 
• 
Non-target Lesions - It is possible to record multiple nontarget lesions involving the same 
organ as a single item on the case record form (e.g., “multiple enlarged pelvic lymph nodes” 
or “multiple liver metastases”) 
Response Criteria 
Evaluation of Target Lesions 
• 
Complete Response - Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm (the sum may 
not be “0” if there are target nodes). 


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• 
Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
• 
Progressive Disease - At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more 
new lesions is also considered progression.) 
• 
Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
Evaluation of Non-target Lesions 
• 
Complete Response - Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• 
Non-complete response/Non-progressive disease - Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits. 
• 
Progressive Disease - Unequivocal progression of existing non-target lesions will be 
defined as the overall level of substantial worsening in non-target disease such that, even in 
presence of SD or PR in target disease, the overall tumor burden has increased sufficiently 
to merit discontinuation of therapy. In the absence of measurable disease, change in non- 
measurable disease comparable in magnitude to the increase that would be required to 
declare PD for measurable disease. Examples include an increase in a pleural effusion from 
‘trace’ to ‘large,’ an increase in lymphangitic disease from localized to widespread. 
Appearance of New Lesions 
The appearance of new lesions is considered PD according to RECIST v1.1 guidelines. 
Evaluation of Overall Response 
Table 8 provides overall responses for all possible combinations of tumor responses in target and 
non-target lesions with or without the appearance of new lesions. 
 
Table 10: Evaluation of Overall Response 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Complete response 
Complete response 
No 
Complete response 
Complete response 
Not evaluable 
No 
Partial response 


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Table 10: Evaluation of Overall Response 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Complete response 
Non-complete response / 
non-progressive disease 
No 
Partial response 
Partial response 
Non-progressive disease and 
not evaluable1 
No 
Partial response 
Stable disease 
Non-progressive disease and 
not evaluable1 
No 
Stable disease 
Not all evaluated 
Non-progressive disease 
No 
Not evaluable 
Progressive disease 
Any 
Yes/No 
Progressive disease 
Any 
Progressive disease 
Yes/No 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
1 Not evaluable is defined as either when no or only a subset of lesion measurements are made at an 
assessment. 
 
13.0 
CRITERIAFOR REMOVAL FROM STUDY 
In the absence of serious toxicity or complications, all patients will continue treatment until evidence 
of disease progression. In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies: 
• 
Progression of disease. 
• 
Development of an intercurrent medical condition or need for concomitant treatment that 
precludes further participation in the trial. 
• 
Unacceptable toxicity or any adverse event that precludes further participation in the trial. 
• 
The investigator removes the patient from the trial in the best interests of the patient. 
• 
Patient death. 
• 
Study completion or discontinuation for any reason. 
• 
Patient withdraws consent to continued participation in the trial or is lost to follow up. 
Subjects who are permanently discontinued from receiving investigational product will return for end 
of study visit, unless consent is withdrawn, the subject is lost to follow-up or begins another 
treatment. All subjects will be followed for survival by phone every 3 months until death or withdrawal 
of consent. 
 
If consent is withdrawn, the subject will not receive any further investigational product or further 
study observation. 
14.0 
BIOSTATISTICS 


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IRB Number: 16-1535 A(10) 
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PFS: The primary endpoint will be PFS, using RECIST v1.1. An exact binomial single stage design 
will be employed. 
The below statistics are generated based on the PFS results from the RADIANT-2 and RADIANT-3 
trials (local PFS review; discussed in section 3 of protocol). 
With a simon two stage design, we can show an improvement from 45% to 65% with a total of 41 
patients with type I and II error rates of 10% each. In the first stage, we will enroll 21 patients and if 
10 or more are alive and progression free at 1 year, we will enroll an additional 20 patients for a total 
of 41 patients. If at the end we have 23 or more out of 41 patients alive and progression free at 1 
year then we would consider the study promising The accrual rate is approximately 2 patients per 
month. Patients lost to follow up without document progression prior to 1 year follow-up will be 
included as events for the primary endpoint of PFS.Secondary outcomes, including safety, ORR, 
EFS, and OS, as well as exploratory objectives, will also be summarized. 
Safety and Tolerability Analyses 
 
All recorded adverse events will be listed and tabulated by system organ class, preferred term and 
treatment. Any significant vital signs and clinical laboratory test results will be listed and summarized. 
Any significant physical examination findings and clinical laboratory results will be listed. 
Antitumor Activity (objective response rate - ORR) 
Assessments of antitumor activity will be based on ORR using RECIST v1.1. The ORR is defined as 
the proportion of subjects with CR or PR based on RECIST criteria. The exact 95% CI of ORR will be 
estimated using the binomial distribution. 
Event free survival (EFS) 
 
EFS will be measured from the start of treatment with LEE011 + everolimus until the documentation 
of disease recurrence, progression, or death due to any cause, whichever occurs first. EFS will be 
evaluated using the Kaplan-Meier method.EFS will be censored on the date of last tumor assessment 
documenting absence of tumor progression for subjects who are still alive prior to data cutoff, dropout, 
or the initiation of alternate anticancer treatment. Subjects having no tumor assessments after the 
start of treatment with LEE011 + everolimus will have EFS censored on the first date of treatment with 
LEE011 + everolimus. 
Overall survival (OS) 
 
OS will be determined as the time from the start of treatment with LEE011 + everolimus until death. 
For subjects who are alive at the end of study or lost to follow-up, OS will be censored on the last date 
when subjects are known to be alive. The OS will be evaluated using the Kaplan-Meier method. 
Exploratory objectives 


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Categorical biomarkers will be associated with response using Fisher’s exact test and with PFS using 
the log-rank test while continuous markers will be associated with response using Wilcoxon rank sum 
test and Cox model for PFS. 
Stopping rules 
 
In order to reduce patient risk, the study design includes early termination of the trial in the event of 
excessive toxicities defined as treatment related toxicities leading to a treatment delay of more than 
6 weeks as well as any delayed or irreversible grade 3 or 4 toxicities. The stopping rules are derived 
using repeated significance testing and are given in the table below. 
 
 
Toxicity 
# of toxicities needed to stop 
the study 
Toxicity 
rate 
Probability 
boundary is crossed 
Excessive 
toxicity 
2 within the first 6 patients 
3 within the first 15 patients 
4 within the first 30 patients 
5 within 42 patients 
0.05 
0.1 
0.2 
0.96 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a protocol specific 
Eligibility Checklist. 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility Checklist 
is confirming whether or not the participant is eligible to enroll in the study. Study staff are 
responsible for ensuring that all institutional requirements necessary to enroll a participant to 
the study have been completed. See related Clinical Research Policy and Procedure #401 
(Protocol Participant Registration). 
15.2 
Randomization 
 
This research study does not require randomization. 
16.0 
DATA MANAGEMENT ISSUES 


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A MSK Research Study Assistant (RSA) will be assigned to the study. The responsibilities of 
the MSK RSA include project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and coordinate the 
activities of the protocol study team. 
 
The data collected for this study will be entered remotely into electronic Case Report Forms 
(eCRFs) using the internet base system, Medidata Rave. Source documentation will be 
available to support the computerized patient record. 
 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent, and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team for discussion and action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute 
for 
Data 
and 
Safety  Monitoring 
of 
Clinical  Trials” 
which 
can 
be 
found 
at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSK were 
established and are monitored by the Office of Clinical Research. The MSK Data and Safety 
Monitoring  
Plans 
can 
be 
 found 
on 
the MSK 
Intranet 
 at: 
http://mskweb5.mskcc.org/intranet/_assets/_tables/content/359689/Data_safety%20Monitori 
ng07.pdf 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education 
on clinical research QA) and departmental procedures for quality control, and there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, 
report to the Center’s Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and 
the monitoring procedures will be established at the time of protocol activation. 


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17.0 
PROTECTION OF HUMAN SUBJECTS 
 
All the patients will be required to sign an IRB-approved informed consent and will have all 
their questions fully addressed before enrolling in the study. During informed consent, it will be 
made clear to the patient that participation is voluntary. All the data will be confidential, 
maintained in a password protected electronic database and will comply with all HIPAA 
guidelines. 
 
Every effort will be made to maintain patient confidentiality. Research and hospital records are 
confidential. Patient’s name or any other personally identifying information will not be used in 
reports or publications resulting from this study. The Food and Drug Administration or other 
authorized agencies (e.g., qualified monitors) may review patients’ records and pathology 
slides, as required. 
17.1 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
17.2 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant’s last 


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Approval date: 18-Apr-2019 
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investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted 
within 5 calendar days of the event. All other SAEs must be submitted within 30 calendar 
days of the event. 
The report should contain the following information: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
For IND/IDE protocols: 
The SAE report should be completed as per above instructions. If appropriate, the report will 
be forwarded to the FDA by the IND Office 
 
17.2.1 Reporting to Novartis (MSK ONLY) 
Serious Adverse Events 
The principal investigator has the obligation to report all serious adverse events to the FDA 
(if applicable), IRB, and Novartis Pharmaceuticals Drug Safety and Epidemiology 
Department (DS&E) (if applicable). 
Per Novartis guidelines, an adverse event is considered serious if it results in ANY of the 
following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
Results in persistent or significant disability/incapacity 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 


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IRB Number: 16-1535 A(10) 
Approval date: 18-Apr-2019 
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• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
• 
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• 
Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
 
• 
Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above is 
not a serious adverse event 
Information about all SAEs is collected and recorded on a Serious Adverse Event Report 
Form. The investigator must assess and record the relationship of each SAE to each specific 
study treatment (if there is more than one study treatment), complete the SAE Report Form 
in English, and send the completed, signed form along with the Novartis provided fax cover 
sheet to the Novartis Oncology Drug Safety and Epidemiology (DS&E) department by fax 
(fax: 877-778-9739) or email (email: clinicalsafetyop.phuseh@novartis.com) within 24 hours. 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has 
stopped study treatment must be reported to Novartis by MSK within 24 hours of MSK 
learning of the event. 
Any SAEs experienced after this 30 days period should only be reported to Novartis by MSK 
if the investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of MSK receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one should be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from MSK for Health Authority reporting. Novartis may need to issue an 
Investigator Notification (IN), to inform all investigators involved in any study with the same 
drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 


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Approval date: 18-Apr-2019 
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(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
Pregnancies 
 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to 
Novartis by MSK within 24 hours of MSK learning of the event. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by MSK to 
the oncology Novartis Drug Safety and Epidemiology (DS&E) department. Pregnancy follow- 
up should be recorded on the same form and should include an assessment of the possible 
relationship to the Novartis study treatment of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form using the Novartis 
provided fax cover sheet to the Novartis Oncology Drug Safety and Epidemiology (DS&E) 
department by fax (fax: 877-778-9739) or email (email: 
clinicalsafetyop.phuseh@novartis.com) within 24 hours. 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 


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Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
19.0 
REFERENCES 
 
1. 
Kunz, P.L., et al., Consensus guidelines for the management and treatment of 
neuroendocrine tumors. Pancreas, 2013. 42(4): p. 557-77. 
2. 
Moertel, C.G., et al., Treatment of Neuroendocrine Carcinomas with Combined Etoposide 
and Cisplatin - Evidence of Major Therapeutic Activity in the Anaplastic Variants of These 
Neoplasms. Cancer, 1991. 68(2): p. 227-232. 
3. 
Modlin, I.M., et al., Gastroenteropancreatic neuroendocrine tumours. Lancet Oncology, 2008. 
9(1): p. 61-72. 
4. 
Modlin, I.M., K.D. Lye, and M. Kidd, A 5-decade analysis of 13,715 carcinoid tumors. Cancer, 
2003. 97(4): p. 934-959. 
5. 
Yao, J.C., et al., One hundred years after "Carcinoid": Epidemiology of and prognostic factors 
for neuroendocrine tumors in 35,825 cases in the United States. Journal of Clinical 
Oncology, 2008. 26(18): p. 3063-3072. 
6. 
Reidy-Lagunes, D. and R. Thornton, Pancreatic neuroendocrine and carcinoid tumors: what's 
new, what's old, and what's different? Curr Oncol Rep, 2012. 14(3): p. 249-56. 
7. 
Kraenzlin, M.E., et al., Long-Term Treatment of a Vipoma with Somatostatin Analog 
Resulting in Remission of Symptoms and Possible Shrinkage of Metastases. 
Gastroenterology, 1985. 88(1): p. 185-187. 
8. 
Rinke, A., et al., Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the 
Effect of Octreotide LAR in the Control of Tumor Growth in Patients With Metastatic 
Neuroendocrine Midgut Tumors: A Report From the PROMID Study Group. Journal of 
Clinical Oncology, 2009. 27(28): p. 4656-4663. 
9. 
Caplin, M.E., et al., Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl 
J Med, 2014. 371(3): p. 224-33. 
10. 
Waldherr, C., et al., The clinical value of [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y- 
DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study. Ann Oncol, 
2001. 12(7): p. 941-5. 
11. 
Waldherr, C., et al., Tumor response and clinical benefit in neuroendocrine tumors after 7.4 
GBq (90)Y-DOTATOC. J Nucl Med, 2002. 43(5): p. 610-6. 
12. 
Virgolini, I., et al., In- and Y-DOTA-lanreotide: results and implications of the MAURITIUS 
trial. Semin Nucl Med, 2002. 32(2): p. 148-55. 
13. 
Kwekkeboom, D.J., et al., Treatment with the radiolabeled somatostatin analog [177 Lu- 
DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol, 2008. 26(13): p. 2124- 
30. 
14. 
Raymond, E., et al., Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. 
N Engl J Med, 2011. 364(6): p. 501-13. 
15. 
Yao, J.C., et al., Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med, 
2011. 364(6): p. 514-23. 
16. 
Rindi, G., et al., TNM staging of foregut (neuro)endocrine tumors: a consensus proposal 
including a grading system. Virchows Archiv, 2006. 449(4): p. 395-401. 
17. 
Tang, L.H., et al., Attenuation of the retinoblastoma pathway in pancreatic neuroendocrine 
tumors due to increased cdk4/cdk6. Clin Cancer Res, 2012. 18(17): p. 4612-20. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1535 A(10) 
Approval date: 18-Apr-2019 
Page 67 of 68 
 
 
18. 
Simon, B. and N. Lubomierski, Implication of the INK4a/ARF locus in gastroenteropancreatic 
neuroendocrine tumorigenesis. Gastroenteropancreatic Neuroendocrine Tumor Disease: 
Molecular and Cell Biological Aspects, 2004. 1014: p. 284-299. 
19. 
Muscarella, P., et al., Genetic alterations in gastrinomas and nonfunctioning pancreatic 
neuroendocrine tumors: An analysis of p16/MTS1 tumor suppressor gene inactivation. 
Cancer Research, 1998. 58(2): p. 237-240. 
20. 
Chan, A.O.O., et al., CpG island methylation in carcinoid and pancreatic endocrine tumors. 
Oncogene, 2003. 22(6): p. 924-934. 
21. 
Dammann, R., et al., Frequent RASSF1A promoter hypermethylation and K-ras mutations in 
pancreatic carcinoma. Oncogene, 2003. 22(24): p. 3806-3812. 
22. 
House, M.G., et al., Aberrant hypermethylation of tumor suppressor genes in pancreatic 
endocrine neoplasms. Annals of Surgery, 2003. 238(3): p. 423-431. 
23. 
Pavel, M.E., et al., Everolimus plus octreotide long-acting repeatable for the treatment of 
advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a 
randomised, placebo-controlled, phase 3 study. Lancet, 2011. 378(9808): p. 2005-2012. 
24. 
Yu, Y. and J.D. Sato, MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase 
mediate the mitogenic response of human endothelial cells to vascular endothelial growth 
factor. Journal of Cellular Physiology, 1999. 178(2): p. 235-246. 
25. 
Lane, H.A., et al., mTOR Inhibitor RAD001 (Everolimus) Has Antiangiogenic/Vascular 
Properties Distinct from a VEGFR Tyrosine Kinase Inhibitor. Clinical Cancer Research, 2009. 
15(5): p. 1612-1622. 
26. 
Guba, M., et al., Rapamycin inhibits primary and metastatic tumor growth by 
antiangiogenesis: involvement of vascular endothelial growth factor. Nature Medicine, 2002. 
8(2): p. 128-135. 
27. 
Tsutsumi, N., et al., Essential role of PDGFR alpha-p70S6K signaling in mesenchymal cells 
during therapeutic and tumor angiogenesis in vivo - Role of PDGFR alpha during 
angiogenesis. Circulation Research, 2004. 94(9): p. 1186-1194. 
28. 
Mabuchi, S., et al., RAD001 (everolimus) delays tumor onset and progression in a transgenic 
mouse model of ovarian cancer. Cancer Research, 2007. 67(6): p. 2408-2413. 
29. 
Marangoni, E., et al., A new model of patient tumor-derived breast cancer Xenografts for 
preclinical assays. Clinical Cancer Research, 2007. 13(13): p. 3989-3998. 
30. 
Kuhn, B., et al., Metabolism of sirolimus and its derivative everolimus by cytochrome P450 
3A4: Insights from docking, molecular dynamics, and quantum chemical calculations. Journal 
of Medicinal Chemistry, 2001. 44(12): p. 2027-2034. 
31. 
Crowe, A. and M. Lemaire, In vitro and in situ absorption of SDZ-RAD using a human 
intestinal cell line (Caco-2) and a single pass perfusion model in rats: Comparison with 
rapamycin. Pharmaceutical Research, 1998. 15(11): p. 1666-1672. 
32. 
Laplante, A., et al., Interaction of immunosuppressive agents rapamycin and its analogue 
SDZ-RAD with endothelial P-GP. Transplantation Proceedings, 2002. 34(8): p. 3393-3395. 
33. 
Kovarik, J.M., et al., Effect of rifampin on apparent clearance of everolimus. Annals of 
Pharmacotherapy, 2002. 36(6): p. 981-985. 
34. 
Kovarik, J.M., et al., Effect of multiple-dose erythromycin on everolimus pharmacokinetics. 
European Journal of Clinical Pharmacology, 2005. 61(1): p. 35-38. 
35. 
Urva, S., et al., A Phase I Study Evaluating the Effect of Everolimus on the Pharmacokinetics 
of Midazolam in Healthy Subjects. Journal of Clinical Pharmacology, 2013. 53(4): p. 444-450. 
 
 
20.0 
APPENDICES 


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IRB Number: 16-1535 A(10) 
Approval date: 18-Apr-2019 
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Appendix A: Pill Diary 
Appendix B: Multicenter Addendum 
Appendix C: SAE Report Form For Participating Sites 
Appendix D: Child Pugh Classification 
Appendix E: ECOG to KPS Conversion Table