Conditions: Advanced Digestive System Neuroendocrine Neoplasm Duodenal Neuroendocrine Tumor G1 Functional Pancreatic Neuroendocrine Tumor Gastric Neuroendocrine Tumor Intermediate Grade Lung Neuroendocrine Neoplasm Low Grade Lung Neuroendocrine Neoplasm Nonfunctional Pancreatic Neuroendocrine Tumor Thymus Neoplasm
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
This phase II trial studies how well ribociclib works in treating patients with neuroendocrine tumors of the foregut, which includes the thymus, lung, stomach, and pancreas, that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced tumors). Ribociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the Response Evaluation Criteria in Solid Tumors (RECIST) (per version 1.1) objective response rate of LEE011 (ribociclib) among patients with advanced foregut neuroendocrine tumors (NETs).

SECONDARY OBJECTIVES:

I. To evaluate the progression free survival duration of LEE011 among patients with advanced foregut NETs.

II. To evaluate the safety and tolerability of LEE011 in patients with advanced foregut NETs.

III. To determine clinic benefit rate at 6 months (defined as complete response plus partial response plus stable disease) with LEE011 among patients with advanced foregut NETs.

EXPLORATORY OBJECTIVES:

I. To determine baseline molecular markers (mutations, deletions, and amplifications in multiple endocrine neoplasia \[MEN\]1, p27, p16 and cyclin D1 \[CCND1\]) in archival tumor that may predict clinical benefit at 6 months from LEE011.

II. To determine potential mechanisms/markers of resistance. III. To determine early chromogranin and neuron specific enolase responses in patients with elevated levels at baseline.

IV. To determine the pharmacodynamic changes including proliferation-related Ki-67 antigen (Ki-67) and phosphorylated retinoblastoma (pRb) upon treatment with LEE011 in patients with advanced foregut NETs.

OUTLINE:

Patients receive ribociclib orally (PO) once daily (QD) on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Arms:
arm 1: Patients receive ribociclib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Pharmacological Study intervention 3: Ribociclib
Intervention descriptions: intervention 1: Correlative studies intervention 2: Correlative studies intervention 3: Given PO

Protocol document:
Prot_SAP_000.pdf: 
 
 
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A phase II study of LEE011 (Ribociclib) in patients with advanced 
neuroendocrine tumors of foregut origin 
Study Supporter:  Novartis 
Novartis Study #: CLEE011XUS02T 
Institutional Study #: 2014-0371 
IND #: 125735 
Investigator Name: Nageshwara V. Dasari, M.D, MS 
Investigator Contact Information:  Nageshwara V. Dasari, M.D., M.S 
Department of Gastrointestinal Medical Oncology 
University of Texas MD Anderson Cancer Center 
1515 Holcombe Boulevard, Unit 426  
Houston, TX 77030 
Phone: 713-792-2828; Fax: 713-563-0541 
Email: adasari@mdanderson.org 
 
 
 
 
 
                                  Version#:3 
 
 


 
 
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Table of contents 
1 
Background .......................................................................................................................... 7 
1.1 
Overview of Neuroendocrine Tumors ..................................................................... 7 
1.2 
Overview of the G1 to S phase transition in mammalian cells ................................ 8 
1.3 
Alterations in the D-cyclin-CDK4/6-INK4a-pRb pathway in human 
malignancies: ........................................................................................................... 8 
1.4 
LEE011 .................................................................................................................... 9 
1.4.1 
Overview of LEE011 .............................................................................. 9 
1.5 
Study purpose/rationale ......................................................................................... 13 
2 
Objectives and endpoints ................................................................................................... 14 
3 
Investigational plan ........................................................................................................... 16 
3.1 
Overview of Study Design ..................................................................................... 16 
3.2 
Investigational treatment ....................................................................................... 16 
3.3 
Treatment arm ........................................................................................................ 17 
3.4 
Treatment duration ................................................................................................. 17 
3.5 
Rationale for the study design ............................................................................... 17 
4 
Population .......................................................................................................................... 17 
4.1 
Inclusion criteria .................................................................................................... 17 
4.2 
Exclusion criteria ................................................................................................... 19 
5 
Treatment ........................................................................................................................... 21 
5.1 
Treating the patient ................................................................................................ 21 
5.1.1 
Administration....................................................................................... 21 
5.1.2 
Dosing and treatment schedule ............................................................. 22 
5.1.3 
Dose modification and dose delay ........................................................ 22 
5.1.4 
Concomitant therapy ............................................................................. 25 
5.1.5 
Prohibited concomitant therapy ............................................................ 28 
5.2 
Study drug(s) ......................................................................................................... 30 
5.2.1 
Packaging and labeling ......................................................................... 30 
5.2.2 
Supply, receipt and storage ................................................................... 30 
5.2.3 
Drug compliance and accountability ..................................................... 30 
5.2.4 
Disposal and destruction ....................................................................... 31 
6 
Visit schedule and assessments ......................................................................................... 31 
6.1 
Study flow and visit schedule ................................................................................ 31 
6.1.1 
Screening Examination ......................................................................... 34 
6.2 
Assessment types ................................................................................................... 34 
6.2.1 
Electrocardiogram ................................................................................. 34 


 
 
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6.2.2 
Efficacy ................................................................................................. 34 
6.2.3 
Safety ..................................................................................................... 42 
6.2.4 
Biomarkers ............................................................................................ 42 
7 
Safety monitoring and reporting ........................................................................................ 44 
7.1 
Adverse Events ...................................................................................................... 44 
7.1.1 
Definitions and reporting ...................................................................... 44 
7.1.2 
Serious Adverse Event Reporting (SAE) .............................................. 46 
7.2 
Communications between Investigator and Novartis ............................................ 47 
7.2.1 
Reporting responsibility ........................................................................ 47 
7.2.2 
Reporting procedures to Novartis ......................................................... 48 
7.2.3 
Pregnancies ........................................................................................... 48 
8 
Statistical methods and data analysis ................................................................................ 48 
9 
Ethical considerations and administrative procedures ...................................................... 49 
9.1 
Ethics and good clinical practice ........................................................................... 49 
9.2 
Institutional Review Board/Independent Ethics Committee ................................. 50 
9.3 
Informed consent ................................................................................................... 50 
9.4 
Discontinuation of the study .................................................................................. 50 
9.5 
Amendments to the protocol .................................................................................. 50 
9.6 
Publication of results ............................................................................................. 51 
9.7 
Disclosure and confidentiality ............................................................................... 51 
9.8 
Declaration of Helsinki .......................................................................................... 51 
10 References ......................................................................................................................... 52 
 


 
 
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List of abbreviations 
ADME 
Absorption, distribution, metabolism, and excretion 
AE 
Adverse Event 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
BID 
bis in diem/twice a day 
CK 
Creatine Phosphokinase 
Cmax 
Maximum (peak) concentration of drug 
Cmin 
Minimum (peak) concentration of drug 
CR 
Complete Response 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria Adverse Events 
DLT 
Dose Limiting Toxicity 
DoR 
Duration of tumor Response 
DMC 
Data Monitoring Committee 
DS&E 
Drug Safety and Epidemiology 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FFPE 
Formalin-Fixed Paraffin-Embedded 
GCP 
Good Clinical Practice 
Hgb 
Hemoglobin 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LLOQ 
Lower limit of quantification 
PD 
Pharmacodynamics 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
QD 
Quaque die/ once a day 
REB 
Research Ethics Board 
RECIST 
Response Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum glutamic oxaloacetic transaminase; aspartate aminotransferase; AST 
SGPT 
Serum glutamic pyruvic transaminase; alanine aminotransferase; ALT 
TK 
Toxicokinetics 


 
 
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WBC 
White Blood cells 
WHO 
World Health Organization 


 
 
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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug.” 
Investigational treatment 
Drug whose properties are being testing in the study as well as their 
associated placebo and active treatment controls (when applicable). This 
also includes approved drugs used outside of their indication/approved 
dosage, or that are tested in a fixed combination. Investigational treatment 
generally does not include other study treatments administered as 
concomitant background therapy required or allowed by the protocol 
when used in within approved indication/dosage 
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
Subject Number (Subject No.) 
A unique identifying number assigned to each patient/healthy volunteer 
who enrolls in the study 
Phase 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at 
this time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for 
progression and/or survival 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when 
study treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered 
to the patient (subject) as part of the required study procedures, including 
placebo and active drug run-ins. 
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination. 
Study treatment discontinuation 
Point/time when patient permanently stops taking study treatment  for any 
reason; may or may not also be the point/time of premature patient 
withdrawal 


 
 
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1 
Background  
1.1 
Overview of Neuroendocrine Tumors  
Neuroendocrine tumors (NET) are thought to arise from cells at the interface of nerves and 
endocrine glands. While slow growing, these are nonetheless incurable and lethal when 
advanced. The incidence of these tumors is also steadily increasing. The traditional 
classification of these tumors is anatomical, based on site of origin into foregut, midgut and 
hindgut NETs. Foregut NETs include thymic, bronchopulmonary, gastric, duodenal and 
pancreatic NETs. Treatment options for metastatic pancreatic NETs (PNETs) continue to be 
limited as detailed below. Furthermore, treatment options for non-pancreatic metastatic 
foregut carcinoid tumors are severely limited with no FDA approved cytotoxic or targeted 
agents currently [1].  
The phase III, randomized, double-blind, placebo controlled study of lanreotide in patients 
with gastroenteropancreatic NETs (GEP-NETs)  randomized 204 patients with advanced, non-
functioning, SSA naive GEP-NETs (45% were PNETs)  with Ki-67 < 10% to lanreotide 
autogel 120 mg or placebo every 4 weeks for 96 weeks or until progressive disease or death. 
The primary endpoint was progression free survival (PFS). Secondary end points included 
percentage of patients without disease progression at weeks 48 and 96 and overall survival. At 
two years of treatment, median PFS was not reached with lanreotide vs 18 months with 
placebo (hazard ratio, HR 0.47; 95% CI 0.30-0.73; p = 0.0002). At end of 2 years of 
treatment, 62% of lanreotide treated patients vs 22% of placebo treated patients had not 
progressed or died. Very few serious treatment-related adverse events were noted [2]. 
The prospective, international, multicenter, randomized, placebo-controlled phase III 
RADIANT-3 trial randomized 410 patients with progressing low- or intermediate grade 
advanced PNET to everolimus 10 mg daily plus best supportive care (BSC) or placebo plus 
BSC.  The primary endpoint was PFS. Treatment with everolimus demonstrated a 6.4 months 
prolongation of median PFS as assessed by the local investigators (11 months vs 4.6 months, 
HR, 0.35; 95% CI, 0.27-0.45; p < 0.0001) [3].   
Sunitinib is an oral multi-tyrosine kinase vascular endothelial growth factor receptor inhibitor 
and was evaluated in a phase III prospective, multicenter, international, double-blind placebo 
controlled study of patients with advanced, well-differentiated PNETs who were randomized 
to best supportive care vs sunitinib 37.5 mg daily. The primary endpoint was PFS. The study 
was designed to enroll 340 patients but was terminated after 171 patients were accrued due to 
an unplanned interim analysis that showed more adverse events in the placebo arm. At the 
final analysis, PFS in the sunitinib arm was 11.4 months vs 5.5 months with placebo (HR 
0.42; 95% CI 0.26 – 0.66; p < 0.001) [4].  
The aim of this study is to evaluate the response rate of LEE011 in patients with metastatic 
foregut neuroendocrine tumors. 


 
 
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1.2 
Overview of the G1 to S phase transition in mammalian cells  
Normal mammalian cells proliferate in response to extracellular signals by transitioning 
through a series of tightly controlled phases that culminate in cell division. The commitment 
to transition from G1 to S phase and the initiation of cell cycle progression is regulated by the 
retinoblastoma protein (pRb). In the absence of appropriate growth stimuli, pRb, in its 
unphosphorylated state, binds and inhibits the activity of the E2F family of transcription 
factors,  preventing these proteins from activating the genes required for  S phase transition 
[5].  Upon mitogen stimulation, signaling through pathways such as the MAPK and PI3K 
pathways increases the abundance of  D-cyclins, which bind and activate cyclin-dependent 
kinases (CDKs) 4 and 6 (CDK4/6).  Cyclin D-bound CDK4/6 then phosphorylates the pRb 
protein to deactivate it and release bound E2F. Once freed, E2F activates S phase-specific 
genes in order to start cell cycle progression.    Full deactivation of pRb requires its sequential 
phosphorylation at different sites by both cyclin D-CDK4/6 and cyclin E-CDK2.  The 
phosphorylation events mediated by CDK4/6 are prerequisites for those catalyzed by CDK2 
[6]. The kinase activity of CDK4/6 is in turn inhibited by p16, encoded by the INK4a gene [5, 
7].  The CIP/KIP proteins, inhibitors of cyclin E-CDK2, also bind to the cyclin D-CDK4/6 
complex, and this results in further activation of CDK2 by sequestering CIP/KIP proteins 
from their target [8]. Cyclin D-CDK4/6 is therefore a key enzyme complex that regulates the 
G1 to S phase transition. 
1.3 
Alterations in the D-cyclin-CDK4/6-INK4a-pRb pathway in human 
malignancies: 
The D-cyclin-CDK4/6-INK4a-pRb pathway is universally disrupted in cancer to favor cell 
proliferation. Eighty percent of human neoplasms maintain functional pRb but harbor 
aberrations that increase the activity of CDK4/6 to effectively inactivate pRb function.  These 
aberrations include genetic or epigenetic changes that directly increase the kinase activity of 
CDK4/6 or defects that activate the upstream regulators [5, 9].  One of the most common 
events is the inactivation of p16 via mutations, deletion and epigenetic silencing. p16 
inactivation is frequently observed in a significant portion of non-small cell lung cancer 
(NSCLC), melanoma, pancreatic cancer and mesothelioma [10-13]. Moreover, a specific 
mutation of the CDK4 gene (CDKR24C), that confers resistance to p16 binding, has been 
shown to play a causal role in rare cases of familial melanoma, suggesting that unchecked 
CDK4 activity  is a key event in these cancers [14]. 


 
 
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Translocations of the genes encoding D-cyclins to the immunoglobulin heavy chain locus are 
found in a majority of mantle cell lymphomas (MCLs) and in many cases of multiple 
myeloma [15]. These translocations lead to constitutive expression of D-cyclins, which result 
in enhanced CDK4/6 kinase activity and unchecked cell proliferation [16]. Amplification of  
cyclin D1 and overexpression of the protein have also been reported in approximately 50% of 
squamous cell esophageal cancers [17] and  in 20-30% of breast cancers [18, 19], suggesting 
that activation of this pathway may play a role in the growth of these tumors.  Furthermore, 
many of the receptor-mediated growth pathways that are activated in human cancers increase 
D-cyclin transcription and expression to drive cell proliferation.  In mouse breast cancers 
driven by activated Ras or Her2/Neu oncogenes, cyclin D1 and CDK4 have been shown to be 
necessary for the tumorigenic phenotype in both initiation and maintenance phases, 
demonstrating that Cyclin-D1/CDK4 is the key effector enzyme complex for Ras- or 
Her2/Neu-driven cancers [20, 21]. Other activating aberrations of mitogen pathways such as 
V600E B-Raf in the MAPK pathway and PTEN deletions in the PI3K pathway also increase 
D-cyclins to achieve unchecked proliferation, suggesting that CDK4/6 may also be crucial for 
the cancers bearing these alterations [22, 23]. Finally, the genes encoding CDK4 and 6 are 
amplified in a subset of human neoplasms. The CDK4 gene is amplified in 100% of 
liposarcomas along with the MDM2 gene, while CDK6 is frequently amplified in T-
lymphoblastic lymphoma and/or acute lymphoblastic leukemia [24]. 
1.4 
LEE011 
1.4.1 
Overview of LEE011 
LEE011 is an orally bioavailable, small molecule inhibitor of CDK4/6. LEE011 exhibits 
highly specific inhibitory activity against CDK4/cyclinD1 and CDK6/cylinD3 complexes, 
with concentration resulting in 50% inhibition (IC50) values of 10 nM and 39 nM, 
respectively, in isolated enzyme assays. It is inactive against the majority of other kinases. 
LEE011 is currently being tested in a first-in-human clinical study [CLEE011X2101] in adult 
patients with refractory cancer. 
Pharmacology of LEE011 
LEE011 inhibits the growth of many tumor cell types in vitro and in vivo including ER+ 
breast cancer. In a panel of human breast cancer cell lines, dose-dependent inhibition of 
proliferation was observed in ER+ breast cancer cell lines, with IC50 < 1µM being observed 
for most ER+ breast cancer lines. Regardless of the various genetic aberrations that may be 
present in the cancer cells, the anti-tumor activity of LEE011 requires the presence of 
functional retinoblastoma protein (Rb). 


 
 
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Nonclinical pharmacokinetics and metabolism of LEE011 
Four different species were used to investigate the pharmacokinetics (PK) of LEE011: mouse, 
rat, dog and monkey. The absorption of LEE011 after oral administration was moderate for 
rats (48 to 84%). Bioavailability ranged between 10% and 65% across animal species. Time to 
maximum plasma drug concentration (Cmax) was between 2 and 4 hours. Terminal half-life 
(T 1/2) of LEE011 was moderate in rodents and monkeys (2 to 7 h), and was longer (18 h) in 
dogs. 
The binding of LEE011 to plasma proteins was moderate (unbound fraction in human plasma 
for humans = 30). [3H]-LEE011 and its metabolites are extensively distributed into the organs 
and tissues of rats including choroid, ciliary body and meninges with the exception of the 
brain. Radioactivity concentrations were highest in tissues such as the pituitary gland, pineal 
gland, spleen, kidney and adrenal medulla with remarkably high exposure in the thyroid 
gland. Distribution of LEE011 and/or its metabolites into melanin-containing structures was 
seen in pigmented rats. 
Oxidative metabolism of LEE011 is dominated by CYP3A4 with a minor contribution of 
about 20% by flavin-containing monooxygenase 3 (FMO3). LEE011 is a moderate substrate 
of P-glycoprotein (P-gp). LEE011 is a time-dependent CYP3A4 inhibitor (KI 5.1 µM, kinact 
0.0245 min-1) and a reversible inhibitor of CYP1A2 at higher concentrations (Ki=16 µM). 
LEE011 inhibits the mitoxantrone-resistant protein (MXR; IC50=24 µM) and human bile salt 
export pump (BSEP; IC50=4.7 µM), but not the BSEP of rat or dog. LEQ803 (N-
demethylation) is the main metabolite in humans, a major metabolite in the rat and monkey, 
and the only metabolite in dogs. This metabolite is weakly pharmacologically active; 
however, it interacts with hERG channels in vitro.  
In rat ADME studies, LEE011 was predominantly excreted in the bile as metabolites, with 
limited excretion of unchanged drug in urine. The bulk of the administered dose (87%) was 
excreted within 24 h. 
Overall, the elimination of LEE011 may potentially be affected by co-administered drugs that 
inhibit or induce CYP3A4. LEE011 may inhibit substrates of CYP3A4, CYP1A2, and BSEP, 
if sufficiently high concentrations are achieved in vivo. 
Safety pharmacology and toxicology of LEE011 
In vitro, LEE011 did not show mutagenic or phototoxic potential. Safety pharmacology 
studies conducted did not reveal any effects on CNS or respiratory functions. In the dog 
telemetry study, prolongation of the average QT and QTc was observed with the potential to 
induce PVCs at higher exposure levels. LEE011 and LEQ803 likely contributed to the QT 
prolonging effects seen in vivo. 


 
 
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In rats and dogs, LEE011 induced bone marrow hypocellularity, lymphoid depletion, atrophy 
of the skin and intestinal mucosa, decreased bone formation and testicular atrophy. The liver, 
bile system and gall bladder (proliferative changes, cholestasis, sand-like gallbladder calculi, 
and inspissated bile) were identified as additional target organs of toxicity which are not likely 
related to the primary pharmacology of LEE011. Correlating hematological and/or 
biochemistry changes were seen for the effects described in the bone marrow, lymphoid 
system and liver. All of the described changes were fully reversible in rats and dogs. 
Based on the mechanism of action and preclinical toxicology studies conducted, the major 
potential toxicities for LEE011 include myelosuppression, hepatic toxicity, and prolongation 
of the QT interval. The risk of these toxicities may be amplified by concomitant 
administration of strong inhibitors of CYP3A4. 
Clinical Studies with LEE011 
LEE011 is currently being investigated in patients as a single agent in 3 phase I studies: 
CLEE011X1101, CLEE011X2101, CLEE011X2102 and in combination in 10 studies: 8 
phase Ib/II CLEE011X2105, CLEE011X2106, CLEE011X2107, CLEE011X2108, 
CLEE011A2112C, CMEK162X2114, CMEK162X2110, CLGX818X2102, a randomized 
phase II CLEE011A2201, and a randomized phase III CLEE011A2301. LEE011 is also being 
investigated in 3 clinical pharmacology studies in healthy subjects: CLEE011A2111, 
CLEE011A2101, and CLEE011A2106.  
 
Single agent experience: 
In single agent trials, a total of 179 patients have been treated: 132 in study CLEE011X2101 
(in a Caucasian population, including 85 in the dose escalation), 15 in CLEE011X1101 (in 
Japanese patients, all in the dose escalation) and 32 in CLEE011X2102 (in patients under the 
age of 21 years, all in the dose escalation). 
 
A total of 18 patients presented toxicities meeting the dose limiting toxicity (DLT) criteria (10 
in CLEE011X2101, 4 in CLEE011X1101 and 4 in CLEE011X2102): these consisted of 
Grade 3 stomatitis, Grade 3 pulmonary embolism, Grade 3 hyponatremia, prolonged Grade 
3/4 neutropenia (x2), prolonged Grade 2 elevated creatinine, Grade 4 thrombocytopenia (x5), 
Grade 3 asymptomatic QTcF prolongation with Grade 3 neutropenia, Grade 4 febrile 
neutropenia, Grade 3 febrile neutropenia (x2), Grade 3 electrocardiogram QT prolonged, 
Grade 3 fatigue, and Grade 3 asymptomatic QTcF prolongation with grade 4 neutropenia. 
The maximum tolerated dose (MTD) and recommended dose for expansion (RDE) from study 
CLEE011X2101 were declared as 900 mg qd and 600 mg qd on a 3 weeks on/1 week off 
schedule, respectively. At the RDE, the most common (in at least 2 patients) adverse events 
(AEs) related to study treatment were (all grades, Grade 3/4): neutropenia (46.3%, 28.4%), 
leukopenia (46.3%, 19.4%), nausea (44.8%, 1.5%), thrombocytopenia (34.3%, 9%), fatigue 
(32.8%, 3%), anaemia (28.4%, 3%), diarrhoea (26.9%, 3%), lymphopenia (22.4%, 17.9%), 
electrocardiogram QT prolonged (9%, 0%), hyponatremia (3%, 1.5%), and febrile 
neutropenia (1.5%, 1.5%). Preliminary data for clinical activity from study CLEE011X2101 
show that out of 114 evaluable patients, 3 partial responses were seen at the 600 mg qd dose 
level: one in a BRAF/NRAS wild type, CCDN1 amplified melanoma patient, one in a 
CDKN2A loss head and neck acinar carcinoma patient, and one in an ER+/HER2-, PIK3CA 


 
 
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mutant, CCDN1 amplified breast cancer. 
 
As of 28-Mar-2014, PK data were available from approximately 128 patients from the first-in 
human (FIH) study CLEE011X2101. Following oral dosing, LEE011 was rapidly absorbed 
with median Tmax ranging from 1 to 5 hours. LEE011 plasma exposure exhibited slightly 
over-proportional increases in exposure across the dose range tested (50 to 1200 mg), with no 
clear evidence of time-dependent auto-inhibition of its clearance mediated by CYP3A4. 
Steady-state was generally reached by Day 8 and the mean effective T1/2 based on 
accumulation ratio (i.e., T1/2,acc) ranged from 15.9 to 32.6 hours across the dose range tested. 
The accumulation ratio based on AUC obtained in a dosing interval (Racc) across the studied 
doses ranged from 1.55 to 2.52.  
 
The MTD and RDE are still under evaluation for study CLEE011X1101 at the dose of 600 mg 
qd. In study CLEE011X2102, the MTD was determined to be 470 mg/m2 qd and the RDE 
was determined to be 350 mg/m2 qd on a 3 week on/1 week off schedule in pediatric patients. 
A food effect study conducted in healthy subjects CLEE011A2111 indicated that LEE011 
administered as drug-in-capsule (DiC) can be taken without regard to meals.  
A drug-drug interaction (DDI) study with ritonavir (a strong CYP3A4 inhibitor) and 
rifampicin (a strong CYP3A4 inducer) conducted in healthy subjects CLEE011A2101 
indicated that concurrent use of strong CYP3A4 inhibitors or strong CYP3A4 inducers may 
markedly affect LEE011 exposure and should be avoided.  
A DDI cocktail study with midazolam (a sensitive CYP3A4 substrate) and caffeine (a 
sensitive CYP1A2 substrate) was conducted in healthy subjects CLEE011A2106. Preliminary 
PK data indicate that LEE011 (400 mg) is a moderate inhibitor of CYP3A4, but did not have a 
substantial effect on CYP1A2 substrates in humans. Concurrent use of sensitive CYP3A4 
substrates with a narrow therapeutic index should be avoided. Concurrent use of CYP1A2 
substrates is not expected to lead to clinically important DDIs.  
 
Combination trial experience: 
LEE011 is being evaluated in several combination trials: letrozole (CLEE011A2201, 
CLEE011A2301]), letrozole and BYL719 CLEE011X2107, letrozole and buparlisib 
CLEE011A2112C, fulvestrant and buparlisib CLEE011X2108, everolimus and exemestane 
CLEE011X2106, LGX818 (CLEE011X2105, CLGX818X2102), MEK162 CMEK162X2114, 
or MEK162 and LGX818 CMEK162X2110. These trials are ongoing with the exception of 
CLEE011A2201 whose recruitment has been stopped on 28-July-2014. Phase I trials are still 
in the dose escalation phase. CLEE011A2201 and CLEE011A2301 are blinded trials and 
no safety data are available at the time of this update. The most recent DMC meeting was held 
for study CLEE011A2301 on 03-Sep-2014 after 86 patients have started treatment, and the 
IDMC recommended continuing the study without any changes. 
Clinical pharmacokinetics of LEE011 
The PK of LEE011 have been evaluated following single and repeat daily doses in the 
ongoing single agent, phase I study in patients with advanced solid tumors or lymphomas 
CLEE011X2101. Patients in all but one cohort received escalating doses of LEE011 once 
daily for 3 weeks followed by 1 week off schedule. In one cohort, patients received once daily 


 
 
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continuous dosing of 600 mg LEE011. PK sampling (pre-dose and 0.5, 1, 2, 4, 6, 8, and 24 h 
post-dose) was conducted on Days 1 and 18 or 21 of Cycle 1. Additional PK sampling 
(predose and 1, 2, and 4 h post-dose) was conducted on Days 8 and 15 of Cycle 1. Sparse 
samples were collected in Cycle 2 and subsequent cycles. Following oral dosing, LEE011 was 
rapidly absorbed with median Tmax ranging from 1 to 4 h. LEE011 exhibited slightly over-
proportional increases in exposure (Cmax and AUC) across the dose range tested (50 to 1200 
mg), with no clear evidence of time-dependent auto-inhibition of its clearance mediated by 
CYP3A4. Steady state was generally reached by Day 8 and mean T1/2, acc ranged from 15.9 
to 32.6 h across the dose range (50 to 1200 mg). Mean Racc across the studied doses ranged 
from 1.55 to 2.52. At the 600 mg dose level, LEQ803, an active metabolite of LEE011, 
accounted for approximately 8% (geometric mean) of the LEE011 AUC0-24h after a single 
dose and after multiple doses. Further details regarding pharmacokinetics of single agent 
LEE011 and in combination with other agents is available in the IB.  
1.5 
     Study purpose/rationale 
Recent advances in molecular genetics have shed new light on the carcinogenesis of NETs. 
Evidence suggests aberrant cell cycle regulation due to aberrations in MENIN (MEN1), p27 
(CDKN1B), p16 (CDKN2A), and Cyclin D1 (CCND1) is critical in the carcinogenesis and 
malignant progression of NETs. 
 
The most common genetic cancer syndrome leading to the development of NETs is 
MEN1.[25] Germline mutation in MEN1 leads to the development of lung, thymic, and 
pancreatic NETs. Mutations in MEN1 appear to mediate carcinogenesis of NETs through 
dysregulation of p27, and p18.[26] Indeed, families with MEN1 phenotype without 
identifiable germline mutations in MEN1 have been found to have mutations in p27 (now 
called MENX syndrome).[27] This is further supported by the role of MENIN in regulating 
normal pancreatic islets. A study in mice showed that a physiologic function of MENIN is to 
regulate endocrine mass through p27.[28] During pregnancy, a down regulation of MENIN 
leads to suppression of p27, cell cycle progression, and an increase in pancreatic endocrine 
mass which serves to prevent gestational diabetes.  
 
Somatic mutation in MENIN is also the most common genetic abnormality in sporadic foregut 
NETs and have been identified in approximately 40% of pancreatic and lung NETs.[29-32] 
We recently conducted exome sequencing of approximate 200 genes among 23 cases of 
advanced NETs treated with everolimus in our prior investigator-initiated phase 2 studies 
conducted at MDACC (unpublished data). In addition to confirming the presence of mutation 
in MEN1, we also identified the homozygous deletion of CDKN2A, CDKN2B (p15), as well 
as copy number amplification of CCND1. In addition, alterations in p16 may also be mediated 
by epigenetic modification. We previously also reported the methylation of p16 in 26% of 
NETs.  
 
Studies have suggested that intact Rb function is a prerequisite for CDK 4/6 inhibitors 
activity. Multiple studies using various methods have documented this in foregut tumors [33-
36] 


 
 
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Taken together, evidence suggests germ line mutations, somatic mutations and epigenetic 
silencing in NETs lead to dysregulation of CDK 4 and CDK 6 in a majority of patients with 
foregut NETs. This dysregulation leads to cell cycle progression, carcinogenesis and 
malignant progression. LEE011 is an inhibitor of CDK 4 and CDK 6. There is strong 
scientific rationale to study LEE011 in advanced NETs. 
 
 
 
 
 
 
 
Figure 1: Regulation of CDK4, CDK6 and cell cycle by MENIN, p27, p18, and p16 
2 
Objectives and endpoints 
 
Primary objective 
• To estimate the RECIST (per version 1.1) objective response rate of LEE011 among 
patients with advanced foregut NETs 
Secondary objectives 
• To evaluate the progression free survival duration of LEE011 among patients with 
advanced foregut NETs 
• To evaluate the safety and tolerability of LEE011 in patients with advanced foregut 
NETs 


 
 
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• To determine clinic benefit rate at 6 months (defined as complete response plus partial 
response plus stable disease) with LEE011 among patients with advanced foregut 
NETs  
Explorative objectives 
• To determine baseline molecular markers (mutations, deletions, and amplifications in 
MEN1, p27, p16 and CCND1) in archival tumor that may predict clinical benefit  at 6 
months from LEE011 
• To determine potential mechanisms / markers of resistance 
• To determine early chromogranin and neuron specific enolase responses in patients 
with elevated levels at baseline 
• To determine the pharmacodynamic changes including Ki-67 and pRb upon treatment 
with LEE011 in patients with advanced foregut NETs 
 
Objectives and related endpoints are described in the table below. 
Table  
Objectives and related endpoints 
 
Objective 
Endpoint 
Analysis 
Primary 
RECIST 
objective 
response rate of LEE011 
among 
patients 
with 
advanced foregut NETs 
Radiographic RECIST 
(ver 1.1) response rate, 
ORR 
 
Response 
rate 
with 
corresponding confidence 
interval 
Secondary 
Progression free survival 
duration 
of 
LEE011 
among 
patients 
with 
advanced foregut NETs 
PFS 
Kaplan Meier estimate of 
median 
PFS 
with 
corresponding confidence 
interval 
 
Safety and tolerability 
CTCAE v 4.0 
Descriptive statistics of 
event rates for all grade 
and G3/4 events 
Exploratory 
Early CgA response rate 
Early 
response 
as 
defined 
by 
a 
30% 
decrease from baseline 
at 
week 
4 
among 
patients with elevated 
values at baseline 
Response 
rate 
with 
corresponding confidence 
interval 
 
Early NSE response rate 
Early 
response 
as 
defined 
by 
a 
30% 
decrease from baseline 
at 
week 
4 
among 
Response 
rate 
with 
corresponding confidence 
interval 


 
 
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3 
Investigational plan 
3.1 
Overview of Study Design 
This is an open-label, single center, phase II study of LEE011. Patients with advanced, 
progressive pancreatic NET and foregut carcinoids and adequate organ function, 
performance status will be recruited. Patients will be treated with LEE011 600 mg po daily 
3 weeks on/1 week off in 28 day cycles. This dose is based on prior phase I trials of this drug. 
Patients will be allowed to remain on study until disease progression or unacceptable 
toxicities. Toxicity evaluations will be conducted at the beginning of each cycle while 
radiographic tumor evaluations will be carried out at baseline and every 3 cycles thereafter.   
The primary objective of the study is objective response rate and secondary objectives 
include progression free survival, safety analyses. Baseline molecular markers in archival 
tumor tissue will be evaluated for potential predictive markers to LEE011 therapy as 
exploratory objectives. A response rate of <5% will be considered unacceptable i.e. the signal 
for further, larger studies with LEE011 in this patient population is ≥ 1 response.  Refer to the 
statistical analysis section for greater detail.  
 
3.2 
Investigational treatment 
The investigational study drug used in this trial is LEE011, which is supplied as capsules. 
patients with elevated 
values at baseline 
 
Baseline 
molecular 
markers 
in 
archival 
tumor that may predict 
clinical benefit at 6 
months from LEE011 
Mutations, 
deletions, 
and amplifications in 
MEN1, p27, p16 and 
CCND1 
Descriptive statistics 
 
Pharmacodynamic effect 
of LEE011 on Ki 67, 
pRB 
Paired measurement of 
Ki 67, pRB 
Descriptive 
statistics 
including 
mean 
and 
median. Comparison will 
be made with paired-
sample T-test or non-
parametric 
test 
as 
appropriate 


 
 
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3.3 
Treatment arm 
Patients with histologically or cytologically confirmed, advanced, unresectable well 
differentiated neuroendocrine tumors (low or intermediate grade) that have progressed in the 
last 12 months will be accrued. They will consist of patients with advanced PNET who have 
progressed on prior therapy or (non-pancreatic) advanced foregut carcinoids with progressive 
disease in the last 12 months.  
3.4 
Treatment duration 
Patients will continue on therapy until progressive disease or unacceptable toxicities or other 
criteria as listed below: 
-Evidence of recurrent or progressive disease 
-Second malignancy 
-Development of unacceptable toxicity during treatment 
-Anaphylactic reactions to LEE011 
-Non-adherence to the protocol 
-Refusal of therapy 
-Physician decides it is in the best medical interest of the patient 
-Positive pregnancy test after receipt of study agent 
-Completed all planned therapy 
 
Off Study Criteria: 
-Death 
-Lost to follow-up 
-Enrollment on another therapeutic study or non-protocol therapy for disease 
-Withdrawal of consent 
-Authorizes consent but does not receive study agent(s) due to development of 
significant health disorder or change in health status 
3.5 
Rationale for the study design 
This is a single center, exploratory study evaluating the activity of LEE011 in patients with 
advanced foregut neuroendocrine tumors i.e. carcinoid tumors and pancreatic NETs.  
4 
Population 
Patients with radiographically measurable, advanced, unresectable PNETs with progression 
after prior therapy, and other foregut carcinoids with evidence of progression in the past 12 
months prior to screening will be eligible for this study.  
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 


 
 
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1. Histologically or cytologically confirmed low or intermediate grade, unresectable well 
differentiated foregut neuroendocrine tumors (thymic, bronchopulmonary, gastric, 
duodenal and pancreatic). Patients with multiple neuroendocrine tumors associated with 
MEN1 syndrome will be eligible.  
2. Patients must have radiographically measurable disease. 
3. Pancreatic neuroendocrine patients must have had progression after prior therapy. Patients 
with other foregut neuroendocrine tumors must have had progressive disease over the last 
12 months, irrespective of prior therapy. Patients with both functional (who may continue 
somatostatin analogues as required for control of related symptoms) and non-functional 
tumors are eligible. In patients who have previously received therapy, the number of prior 
lines of therapy should not be more than 2 lines of systemic therapy not including 
somatostatin analogues.  
4. Written informed consent must be obtained prior to any screening procedures 
5. Age ≥ 18 years.  
6. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status 
of 0 - 1. 
7. A sufficient interval must have elapsed between the last dose of prior anti-cancer therapy 
(including cytotoxic and biological therapies and major surgery) and enrollment, to allow 
the effects of prior therapy to have abated: 
a. Cytotoxic or targeted chemotherapy: ≥ the duration of the cycle of the most recent 
treatment regimen (a minimum of 3 weeks for all regimens, except 6 weeks for 
nitrosoureas and mitomycin-C) 
b. Biologic therapy (e.g., antibodies): ≥ 4 weeks 
8. Patients must have adequate organ function, as defined by the following parameters: 
a. Bone marrow:  
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L  
• Hemoglobin (Hgb) ≥ 9 g/dL 
• Platelets ≥ 100 x 109/L 
b. Hepatic function:  
• Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) Aspartate 
aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) 
and ALT (SGPT) ≤ 2.5 x ULN, except in patients with tumor involvement of 
the liver who must have AST and ALT ≤ 5 x ULN 
c. Renal function:  
• Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50 mL/min  
• Serum potassium, sodium, magnesium, phosphorus and total calcium (corrected 
for serum albumin) must be within clinically relevant limits (e.g., a patient can 
be enrolled if a lab value may be outside the normal laboratory range but the 
abnormality is not clinically relevant or can be repleted.) 


 
 
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9. Negative pregnancy test (serum β-HCG) within 7 days of starting study treatment is 
required in women of childbearing potential. β-HCG may be secreted by a small 
percentage of NETs and be a tumor marker. Thus, NET patients with positive β-HCG are 
eligible if pregnancy can be excluded by vaginal ultrasound or lack of expected doubling 
of β-HCG.  
 
4.2 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patient has a known hypersensitivity to LEE011 or any of its excipients. 
2. Patients with known or suspected brain metastases. However,  if radiation therapy and/or 
surgery has been completed and serial evaluation by CT (with contrast enhancement) or 
MRI over a minimum of 3 months demonstrates the disease to be stable and if the patient 
remains asymptomatic, then the patient may be enrolled. Such patients must have no need 
for treatment with steroids or anti-epileptic medications. 
3. Patients with concurrent malignancies or malignancies within 3 years prior to starting 
study drug (with the exception of tumors common to a single genetic cancer syndrome, i.e.  
MEN1, MEN2, vHL, TSC etc., or adequately treated, basal cell skin cancer, squamous cell 
carcinoma, non-melanoma skin cancer or curatively resected cervical cancer). 
4. Patient is not able to swallow oral medication and/or has impairment of gastrointestinal 
(GI) function or GI disease that may significantly alter the absorption of the study drugs 
(e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption 
syndrome, or small bowel resection). 
5. Known diagnosis of human immunodeficiency virus (HIV) or hepatitis C (testing is not 
mandatory) 
6. Patient has any other concurrent severe and/or uncontrolled medical condition that 
would, in the investigator’s judgment, contraindicate patient participation in the clinical 
study (e.g. chronic pancreatitis, chronic active hepatitis, etc.). 
7. Patient who has received radiotherapy within ≤ 4 weeks or limited field radiation for 
palliation within ≤ 2 weeks prior to starting study drug, and who has not recovered to grade 
1 or better from related side effects of such therapy (exceptions include alopecia) and/or in 
whom ≥ 30% of the bone marrow was irradiated. 
8. Patient has had major surgery within 14 days prior to starting study drug or has not 
recovered from major side effects (tumor biopsy is not considered as major 
surgery). 
9. Impaired cardiac function or clinically significant cardiac diseases, including any of the 
following: 
a. History of acute coronary syndromes (including myocardial infarction, unstable 
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or 
symptomatic pericarditis < 12 months prior to screening 
b. History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 
c. Documented cardiomyopathy 


 
 
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d. Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by 
Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening 
e. History of ventricular, supraventricular, nodal arrhythmias, or any other cardiac 
arrhythmias, long QT Syndrome or conduction abnormality within 12 months prior to 
starting study drug 
f. Congenital long QT syndrome or a family history of QTc prolongation  
g. On screening, inability to determine the QTcF interval on the ECG (i.e.: unreadable or not 
interpretable) or QTcF >450 msec (using Fridericia’s correction). All as determined by 
screening ECG (mean of triplicate ECGs) 
10. Systolic blood pressure >160 mmHg or <90 mmHg at screening.  
11. Patients who are currently receiving treatment with agents that are known to cause QTc 
prolongation or inducing Torsades de Pointes in humans and are unable to discontinue or 
switch to an alternate medication.  
12. Patients who are currently receiving treatment (within 5 days prior to starting study drug) 
with agents that are known strong inducers or inhibitors of CYP3A4/5, or that have a 
narrow therapeutic window and are predominantly metabolized through CYP3A4/5.   
13. Patients with concurrent severe and/or uncontrolled concurrent medical conditions that 
could compromise participation in the study (e.g., uncontrolled diabetes mellitus defined 
by a glucose > 1.5 ULN in spite of adequate medical treatment, clinically significant 
pulmonary disease, clinically significant neurological disorder, active or uncontrolled 
infection) 
14. Patient has a history of non-compliance to medical regimen or inability to grant consent. 
15. Pregnant or lactating women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive hCG laboratory 
test (> 5 mIU/mL). 
16. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
throughout the study and for 8 weeks after study drug discontinuation. Highly effective 
contraception methods include: 
• 
Total abstinence when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception 
• 
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment 
• 
Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient 
• 
Combination of any of the two following (a+b or a+c or b+c) 
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone 
contraception 


 
 
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b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository 
In case of use of oral contraception, women should have been stable on the same pill 
before taking study treatment. 
Note: Oral contraceptives are allowed but should be used in conjunction with a barrier 
method of contraception due to unknown effect of drug-drug interaction. 
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential. 
17. Sexually active males unless they use a condom during intercourse while taking the drug 
and for 21 days after stopping treatment and should not father a child in this period. A 
condom is required to be used also by vasectomized men in order to prevent delivery of 
the drug via seminal fluid.  
18. Patients unwilling or unable to comply with the protocol. 
19. Patient is currently receiving warfarin or other coumarin-derived anticoagulant for 
treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin 
(LMWH) or fondaparinux is allowed. 
5 
Treatment 
5.1 
Treating the patient 
The investigator needs to instruct the patient to take the study drug as per protocol.  All 
dosages prescribed and dispensed to the patient and any dose change or interruption must be 
recorded as appropriately. 
5.1.1 
Administration 
Table 5-1 
 
Treatment and treatment schedule 
Study treatment 
Pharmaceutical form and route of 
administration 
Dose 
Frequency and/or 
regimen 
LEE011 
Capsule for oral use 
 600 mg 
Daily (21 days with 
7 days of rest) 
LEE011 will be taken orally, once a day for 21 consecutive days followed by a 7 day planned 
break. LEE011 will be dosed on a flat dosing scale of 600 mg/day, irrespective of size and 
weight. Medication labels will be in the local language and comply with the legal 
requirements. 


 
 
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5.1.2 
Dosing and treatment schedule 
The following general guidelines should be followed for LEE011 administration: 
• Patients should be instructed to take their once-a-day dose at approximately the same time 
each day. LEE011 can be taken without regard to meals. 
• Each daily dose of LEE011 should be taken with a glass of water and consumed over as 
short a time as possible unless otherwise instructed 
• Patients should be instructed to swallow capsules whole and to not chew or open them 
unless otherwise instructed.  
• If vomiting occurs during the course of the treatment, then no re-dosing of the patient is 
allowed before the next scheduled dose 
• Any doses that are missed (not taken within 6 hours of the intended time) should be 
skipped and should not be replaced or made up on a subsequent day. 
• Patients should inform the  study team of any missed or delayed doses 
• Patients must avoid grapefruit products/juice, and Seville (sour) oranges/juice during the 
entire study. Orange juice is allowed.  
• On a day of lipid panel sampling, patients must be fasting from all food and drink for at 
least 8 hours overnight. Water is allowed during all fasting periods; however coffee, tea 
and juice are not permitted during the fasting period.  
 
5.1.3 
Dose modification and dose delay 
 
Investigators should follow the guidelines described below for the modification of LEE011 
treatment.  Toxicities will be graded per the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. Any plan to deviate from these guidelines in view of 
the patient safety must be previously discussed with Novartis unless there is an urgent need 
for action.  
All dose modifications should be based on the worst preceding toxicity. If study treatment is 
being held due to toxicity, scheduled visits and all assessments should continue to occur 
except the dosing of the study drug. If the patient requires a dose interruption of > 21 days 
from the previous dose, then the patient must be discontinued from study treatment. Patients 
who discontinue the treatment due to an adverse event or an abnormal laboratory value must 
be followed until resolution or stabilization of the event. All dose changes or interruptions 
must be recorded appropriately. Provisional dose levels can be found in the table below. 
 
 
 


 
 
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Table 5-2 
Dose Modification Guidelines 
 
LEE011 
Dose 
Number of capsules & strength 
 
 
Starting dose 
600 mg 
3 x 200 mg capsules 
 
 
First dose reduction 
400 mg 
2 x 200 mg capsules 
 
 
Second dose reduction 
200 mg 
1 x 200 mg capsules 
 
 
 
Table 5-3 
Recommended Dose Modifications and Dose Delays for suspected 
LEE011 treatment-related toxicities (except for Hematologic toxicities 
& QTC Prolongation as outlined in subsequent tables) 
Grade 
Dose Adjustment and Management Recommendations 
1 
No dose adjustment required. Initiate appropriate medical therapy and monitor. 
2 
Dose interruption until recovery to grade ≤1. Initiate appropriate medical therapy and monitor. 
Re-initiate LEE011 at the same dose. 
• 
If the same toxicity recurs at grade 2, interrupt LEE011 until recovery to grade ≤1. Re-initiate LEE011 at 
the next lower dose level. 
3 
Dose interruption until recovery to grade ≤1. Initiate appropriate medical therapy and monitor. 
Re-initiate LEE011 at the next lower dose level. 
• 
If toxicity recurs at grade 2: temporary dose interruption until recovery to grade ≤1 and reduce LEE011 
dose the next lower dose level. 
• 
If toxicity recurs at grade 3, discontinue LEE011. 
4 
Discontinue LEE011 and treat with appropriate medical therapy. 
 
 
 


 
 
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Table 5-4 
Study drug dose modification and management recommendation for 
hematological AEs  
Toxicity 
Grade 
Dose Adjustment and Management Recommendations 
Thrombocytopenia 
1 
≥75 x 109/L 
No dose adjustment required. 
 
2 
50 x 109/L - <75 x 109/L 
Dose interruption until recovery to grade ≤1. 
Re-initiate LEE011 at the same dose. 
 
3 
25 x 109/L - <50 x 109/L 
Dose interruption until recovery to grade ≤1. 
Re-initiate LEE011 at the same dose level. 
• If toxicity recurs at grade 3: temporary dose interruption 
until recovery to grade ≤1 and reduce LEE011 to the 
next lower dose level. 
 
4 
<25 x 109/L 
Dose interruption until recovery to grade ≤1.  
Re-initiate LEE011 at the next lower dose level. 
• If toxicity recurs at grade 4: discontinue LEE011. 
Absolute neutrophil 
count (ANC) 
1 
≥1.5 x 109/L 
No dose adjustment required. 
 
2 
1.0 - <1.5 x 109/L 
No dose adjustment required. 
 
3 
0.5 - <1.0 x 109/L 
Dose interruption until recovery to >1.0 x 109/L. 
Re-initiate LEE011 at the same dose level. 
• If toxicity recurs at grade 3: temporary dose 
interruption until recovery to >1.0 x 109/L and 
reduce LEE011 dose to the next lower dose level. 
 
4 
<0.5 x 109/L 
Dose interruption until recovery to >1.0 x 109/L. 
Re-initiate LEE011 at the next lower dose level. 
• If toxicity recurs at grade 4: temporary dose 
interruption until recovery to >1.0 x 109/L and 
reduce LEE011 at the next lower dose level. 
Febrile neutropenia 
3 
ANC <1.0 x 109/L with [a 
single temperature of 
>38.3°C (101°F) or a 
sustained temperature 
≥38°C (100.4°F) for more 
than one hour] 
Dose interruption until improvement of ANC ≥ 1.0 x 
109/L and no fever.  Restart at the next lower dose 
level. 
• If febrile neutropenia recurs, discontinue 
LEE011. 
 
4 
Life-threatening 
consequences; urgent 
intervention indicated 
Discontinue LEE011. 
Anemia 
(Hemoglobin) 
1 
10.0 – LLN g/dL 
No dose adjustment required. 
 
2 
8.0 – 10.0 g/dL 
No dose adjustment required. 
 
3 
<8.0 g/dL 
Dose interruption until recovery to grade ≤ 2. 
Re-initiate LEE at the same dose. 
 
4 
Life-threatening 
consequences; urgent 
intervention indicated 
Discontinue LEE011. 
 
 


 
 
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Table 5-5 
 
Recommended Dose Modification guidance in case of QT prolongation  
Grade 
Dose Modification 
For all grades 
• 
Check the quality of the ECG. 
• 
Perform analysis of serum electrolytes (K+, Ca++, Phos, Mg++). If below the 
lower limit of normal, interrupt LEE011 administration, correct with 
supplements or appropriate therapy as soon as possible, and repeat 
electrolytes until documented as normal. 
• 
Review concomitant medication usage for the potential to inhibit CYP3A4 
and/or to prolong the QT interval. 
• 
Check compliance with correct dose and administration of LEE011. 
1 
QTc 450-480 ms 
No dose adjustment required. 
2 
QTc 481-500 ms 
Interrupt LEE011 
Perform a repeat ECG one hour after the first QTcF of ≥418ms 
• If QTcF <481 ms, restart LEE011 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 at the same dose level. No dose 
adjustments required for first occurrence.  
• If QTcF ≥481 ms recurs, LEE011 should be reduced by 1 dose level (please 
refer to the dosing schedule table)  
• Repeat ECGs 7 days and 14 days after dose resumption (then as clinically 
indicated) for any patient who has therapy interrupted due to QTcF ≥481 ms 
3 
QTc ≥501 ms on at least two 
separate ECGs 
Interrupt LEE011 
• Consider consulting a local cardiologist. Perform a repeat ECG one hour after 
the first QTcF of ≥501 ms. 
• If QTcF remains ≥501 ms, repeat ECG as clinically indicated, but at least once 
a day until the QTcF returns to <481 ms. 
• If QTcF returns to <481 ms, LEE011 should be reduced by 1 dose level (please 
refer to the dosing schedule table) 
• Repeat ECGs 7 days and 14 days after dose resumption for any patient who 
has therapy interrupted due to QTcF ≥501 ms 
• If QTcF of ≥501 ms recurs, discontinue LEE011 
4 
QT/QTc ≥501 or >60 ms 
change from baseline 
and 
Torsades de pointes or 
polymorphic ventricular 
tachycardia, or 
signs/symptoms of serious 
arrhythmia 
Discontinue LEE011 
• Obtain local cardiologist consultation 
• Perform a repeat ECG one hour after the first QTcF of ≥501 ms 
• If QTcF remains ≥501 ms, repeat ECG as clinically indicated, but at least 
once a day until the QTcF returns to <501 ms. 
5.1.4 
Concomitant therapy 
The investigator should instruct the patient to notify the study team about any new 
medications including herbals and supplements he/she takes after the start of the study drug. 
All medications (other than study drug) and significant non-drug therapies (including physical 
therapy and blood transfusions) administered after the patient starts treatment with study drug 
must be recorded appropriately.  


 
 
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In general, medications required to treat AEs, manage cancer-related symptoms including pain 
medications are allowed at investigator’s discretion. Medications which are being used to 
manage underlying medical conditions (except for those medications specifically mentioned 
in the inclusion/exclusion criteria) at study entry will be allowed to continue at investigator’s 
discretion.  Concomitant medications will be recorded in PDMS/CORe.  
Concomitant therapy requiring caution 
The following therapies are permitted when used with caution: 
• 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, and sensitive substrates 
of BCRP. 
 


 
 
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Table 5-6 : Medications to be used with caution during LEE011 therapy 
Category 
Drug Name 
Moderate CYP3A4/5 
inhibitors 
Amprenavir, aprepitant, atazanavir, casopitant, cimetidine, 
ciprofloxacin, darunavir, diltiazem, dronedarone, fluconazole, 
fosamprenavir, grapefruit juice (citrus paradisi fruit juice), imatinib, 
Schisandra sphenanthera1, tofisopam, verapamil 
Moderate CYP3A4/5 
inducers 
Bosentan, efavirenz, etravirine, genistein, modafinil, nafcillin, 
talviraline, thioridazine 
Sensitive CYP3A4/5 
substrates1 
Alfentanil, aAlpha-dihydroergocryptine, aplaviroc, aprepitant, 
atorvastatin, brecanavir, brotizolam, budesonide, buspirone, 
capravirine, casopitant, darifenacin, darunavir, dasatinib, 
dronedarone, ebastine, eletriptan, eplerenone, everolimus, 
felodipine, fluticasone, lovastatin, lumefantrine, lurasidone, 
maraviroc, midazolam, neratinib, nisoldipine, perospirone, 
quetiapine, ridaforolimus, sildenafil, simvastatin, ticagrelor, 
tolvaptan, triazolam, vardenafil, vicriviroc 
Strong BSEP inhibitors 
Bosentan, fusidate, glibenclamide, lovastatin, sulindac, troglitazone 
(TGZ-sulfate) 
MATE1 Medications 
that carry a possible 
risk for QT 
prolongation2 
Alfuzosin, amantadine, atazanavir, chloral hydrate, clozapine, 
dolasetron, dronedarone, eribulin, escitalopram, famotidine, 
felbamate, fingolimod, foscarnet, fosphenytoin, gatifloxacin, 
gemifloxacin, granisertron, iloperidone, indapamide, isradipine, 
lapatinib, levofloxacin, lithium, moexipril, nicardipine, nilotinib, 
octreotide, ofloxacin, ondansetron, oxytocin, paliperidone, 
pasireotide, quetiapine, ranolazine, risperidone, roxithromycin, 
sertindole, sunitinib, tamoxifen, tizanidine, vardenafil, venlafaxine, 
ziprasidone 
MATE1 and OCT2 
substrates3 
Acyclovir, amantadine, amiloride, cephalexin, cephradine, 
cimetidine, famotidine, fexofenadine, memantine, metformin (also 
a substrate for OCT1, MATE1, and MATE2K), pindolol, 
procainamide, ranitidine, and varencicline 
BCRP substrates 
Daunorubicin, doxorubicin, rosuvastatin, sulfasalazine, topotecan 
1 Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold 
or higher when co-administered with a potent inhibitor. 
2 Source: www.crediblemeds.org 
3 Source: FDA Draft Guidance for Industry, Drug Interaction Studies – Study Design, Data 
Analysis, and implications for Dosing and Labeling (February 2012) and Yonezawa and Inui 
(2011) Importance of the multidrug and toxin extrusion MATE/SLC47A family to 
pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics. Br J 
Pharmacology 164:1817-25 
• 
 


 
 
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5.1.5 
Prohibited concomitant therapy 
Other anti-neoplastic therapy is prohibited. Concurrent somatostatin analogue given for 
control of hormonal syndrome is allowed.  
  
Other investigational 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 
treatment must not be given to patients while the patient is on the study medication. 
Strong CYP3A inhibitors and inducers 
Patients receiving concomitant medications including vitamins, supplements and herbal 
supplements known to strongly inhibit and/or induce CYP3A4/5 and that are deemed 
medically necessary should be excluded from the study. Patients should be instructed not to 
take grapefruit, Seville oranges or products containing the juice of each while receiving 
LEE011 treatment throughout the study due to its potential for CYP3A4/5 inhibition.  


 
 
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Table 5-7 
List of prohibited medications during LEE011 treatment  
 
Category 
Drug Name 
Strong CYP3A4/5 
inhibitors 
Boceprevir, clarithromycin, cobicistat, conivaptan, elvitegravir, 
indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin, tipranavir, troleandomycin, voriconazole 
Strong CYP3A4/5 
inducers 
Avasimibe2,3, carbamazepine, mitotane, phenobarbital, phenytoin, 
rifabutin, rifampin (rifampicin)3, St. John's wort (hypericum 
perforatum)3 
CYP3A4/5 substrates 
with NTI1 
Alfentanil, astemizole, cisapride, cyclosporine, diergotamine 
(dihydroergotamine), ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, terfenadine 
Medications with a 
known risk for QT 
prolongation4 
Amiodarone, arsenic trioxide, astemizole, azithromycin, bepridil, 
chloroquine, chlorpromazine, cisapride, citalopram, 
clarithromycin, disopyramide, dofetilide, domperidone, droperidol, 
erythromycin, flecainide, halofantrine, haloperidol, ibutilide, 
levomethadyl, mesoridazine, methadone, moxifloxacin, 
pentamidine, pimozide, probucol, procainamide, quinidine, sotalol, 
sparfloxacin, terfenadine, thioridazine, vavdetanib 
Herbal preparations/ 
medications/dietary 
supplements 
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 from the study drug. 


 
 
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Category 
Drug Name 
1 NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in 
their exposure levels by the concomitant use of potent inhibitors may lead to serious safety 
concerns (e.g., Torsades de Pointes). 
2 Herbal product 
3 P-gp inducer 
4 Source: www.crediblemeds.org 
 
5.2 
Study drug(s) 
5.2.1 
Packaging and labeling 
LEE011 hard gelatin capsule will be supplied by Novartis as 200-mg hard gelatin capsules for 
oral use, packaged in bottles, and will be administered on a flat scale of mg/day.  
Medication will be labeled for Clinical Trial use and will include storage conditions for the 
drug and the medication number but no information about the patient. 
Table  
 
Packaging and labeling 
Study drugs 
Packaging 
Labeling (and dosing frequency) 
LEE011 
 
hard gelatin capsules in bottles 
(200 mg) 
 
Labeled as ”LEE011” 
 
5.2.2 
Supply, receipt and storage 
Study drug must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated assistants have access. Upon receipt, LEE011 should be stored according to the 
instructions specified on the drug labels. Study medication will be dispensed by an authorized 
person at the investigator’s site.  
Patients will be provided with adequate supply of LEE011 for self-administration at home 
until at least their next scheduled study visit. 
5.2.3 
Drug compliance and accountability 
Drug accountability 
Clinical drug supply must be accounted for and patients will be asked to return all unused 
study drug and packaging on a regular basis, at the end of the study or at the time of study 
drug discontinuation. 


 
 
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At the conclusion of the study, and, as appropriate during the course of the study, the 
Investigator will return all unused study drug (except as indicated in section 5.2.4), packaging, 
drug labels, and a copy of the completed drug accountability ledger to Novartis.  
5.2.4 
Disposal and destruction  
The drug supply will be destroyed at a Novartis facility, or at MD Anderson, as appropriate.  
Study drug destruction at MD Anderson will only be permitted if authorized by Novartis. The 
unused study drug will be destroyed per MD Anderson Cancer Center standard policy. 
 
6 
Visit schedule and assessments 
6.1 
Study flow and visit schedule 
The table below lists all of the assessments and indicates with an “X” the visits when they are 
performed. 
 
Note:  All assessments should be performed within ± 3 days, unless otherwise specified as in 
the case of restaging radiographic evaluation which may be done within 7 days of the end of 
every 3rd cycle.  On treatment days, all assessments should be performed prior to dosing, 
unless otherwise specified. Screening tests may be done between days -28 to -1. For cycle 1 
day 1 treatment, screening laboratory values, medical history, physical exam may be used if 
done within 10 days                                 . 


 
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Table 6-1 
Visit evaluation schedule 
 
Screening 
Treatment 
 
 
Subseque
nt cycles 
 
End of 
Treatment 
End of 
Post  
Treatment 
Follow-Up 
 
 
Cycle 1 
Cycle 2 
Cycle 3 +  
 
 
Day of cycle 
Screening 
1 
 
15 
 
 
 
1 
 
 
15 
 
 
1 
EOT 
30 days after last dose 
Informed 
consent 
X 
 
 
 
 
 
 
 
Inclusion/ 
exclusion 
criteria 
X 
 
 
 
 
 
 
 
Relevant 
medical 
history9 
 
X 
X 
 
X 
 
X 
 
 
Physical exam9 
X 
X 
X 
X 
 
X 
X 
 
Vitals9 
X 
X 
X 
X 
 
X 
X 
 
Hematology9 
X 
X 
X 
X 
 
X 
X 
 
Biochemistry9 
X 
X 
X 
X 
 
X 
X 
 
Coagulation1 
X 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis2 
X 
 
 
 
 
 
X 
 
Lipid Panel13 
X 
 
 
 
 
X 
X 
 
ECG11 
X 
 
X 
 
X 
 
X 
X 
X 
 
Echo / MUGA12 
X 
 
 
 
 
 
X 
 
Pregnancy 
Test3 
X 
 
 
 
 
 
 
 
Archival Tumor 
Tissue4 
X 
 
 
 
 
 
 
 
Tumor Biopsy5 
X 
 
 
X 
 
 
X6 
 
Blood for 
genomic DNA10 
X 
 
 
 
 
 
 
 
Radiographic 
Evaluation7 
X 
 
 
 
 
X7 
 
 
Serum Tumor 
Markers8 
X 
 
 
X 
 
X 
 
 
LEE011 dosing  
 
Continuous (21 days with 7 days of rest) 
 
Concomitant  
medications 
 
Continuous monitoring 
 
Progression 
free survival 
 
Continuous monitoring 


 
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Screening 
Treatment 
 
 
Subseque
nt cycles 
 
End of 
Treatment 
End of 
Post  
Treatment 
Follow-Up 
 
 
Cycle 1 
Cycle 2 
Cycle 3 +  
 
 
Day of cycle 
Screening 
1 
 
15 
 
 
 
1 
 
 
15 
 
 
1 
EOT 
30 days after last dose 
Adverse events 
 
Continuous Monitoring (up to 30 days post treatment discontinuation) 
 
1 Coagulation profile includes a prothrombin time (PT) or International normalized ratio (INR), 
activated partial thromboplastin time (aPTT) and fibrinogen at baseline and as required per 
treating physician discretion every cycle in patients on anticoagulation 
2 Urinalysis includes specific gravity, pH, glucose, protein, bilirubin, ketones, leukocytes and 
blood 
3 Women with child-bearing potential will be screened with serum β-HCG. In patients with 
positive serum β-HCG, pregnancy can be excluded by vaginal ultrasound or lack of expected 
doubling of β-HCG (every 3 days).  
4 Treatment need not be held until procurement of archival tissue 
5 Mandatory pre-treatment and cycle 2 day 1 tumor biopsies in all patients in whom they may be 
obtained safely. Post treatment biopsies may be obtained +/- 3 days of cycle 2 day 1.  
6 Optional EOT biopsies will be obtained in patients with initial response or prolonged stable 
disease (>6 months) 
7 Radiographic evaluation will be with CT, MRI and/or Octreoscan and will be obtained at 
baseline and at the end of every 3 cycles subsequently. Choice of radiographic test (including 
octreoscans) per discretion of physician; For patients with known or suspected brain metastases, 
CT head with contrast or MRI at baseline and as clinically indicated thereafter. Confirmatory 
scans should also be obtained at least 4 weeks following initial documentation of objective 
response. 
8 Serum tumor markers including chromogranin-A, neuron specific enolase will be obtained at 
baseline, cycle 2, Day 1, cycle 4 day 1 and every 3 cycles thereafter. These tests may be 
obtained more frequently per treating physician’s discretion 
9Physical exam with vitals, weight and performance status will be obtained at each clinic visit. All 
evaluations during and after cycle 3 will be obtained on day 1 +/- 3 days except for radiographic 
evaluations which will be obtained at the end of every 3 cycles within  a window of 7 days. 
Hematology tests: CBC with platelets and differential; Serum biochemistry tests: BUN, 
Creatinine, direct and indirect bilirubin, total protein, alkaline phosphatase, albumin, ALT, AST, 
glucose, electrolytes including, sodium, potassium, chloride, bicarbonate, calcium, magnesium, 
phosphorus.   
10Blood for genomic DNA will be obtained at baseline.  
11 ECGs will be performed as per section 6.2.1 and Table 6.2 after the patient has been resting 
for 5-10 minutes prior to each time point. If an abnormal ECG is obtained at any time, patient’s 
electrolytes must be reviewed and repeat ECG measurements must be done after correction of 
electrolyte abnormalities. For patients with QTcF ≥481 ms, interrupt study treatment and follow 
the procedures described in the “LEE011 Dose Modification” section. If treatment is resumed, 
repeat ECGs 7 days and 14 days after dose resumption (and then as clinically indicated). ECGs 
will be performed according to the schedule in (Table 6-2).  
12 Echocardiogram or MUGA scan in patients with prior history of heart failure who have not had 
LVEF evaluated in the past 6 months or in patients with clinical signs / symptoms suggestive of 
heart failure.  
13. Fasting lipid panel including triglycerides, total cholesterol, HDL, LDL at baseline and every 4 
cycles.  
 


 
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6.1.1 
Screening Examination 
The screening examination must start with the Informed Consent procedure. The investigator 
is obliged to give the patient thorough information about the study and the study related 
assessments, and the patient should be given ample time to consider his or her participation. 
The investigator must not start any study related procedure before ICF is signed and dated by 
both patient (and impartial witness, if applicable) and investigator.  
6.2 
Assessment types 
6.2.1 
Electrocardiogram 
Standard twelve-lead ECGs should be obtained after the patient has been resting for 5-10 
minutes prior to each time point indicated. All ECGs should be recorded with the patient in 
the same physical position. Screening ECGs should be obtained in triplicate approximately 2 
minutes apart.  
If an abnormal ECG is obtained at any time, patient’s electrolytes must be reviewed and 
repeat ECG measurements must be done after correction of electrolyte abnormalities. For 
patients with QTcF ≥481 ms, interrupt study treatment and follow the procedures described in 
the “LEE011 Dose Modification” section. If treatment is resumed, repeat ECGs 7 days and 14 
days after dose resumption (and then as clinically indicated). ECGs will be performed 
according to the schedule in (Table 6-2).  
Table 6-2 
ECG Collection Schedule 
Scheduled time points  
Screening 
Anytime during the screening period. Triplicate ECGs approximately 2 
minutes apart 
Cycle 
Day 
Sampling time 
1 
15 
pre-dose 
2 
1 
pre-dose 
2 
15 
pre-dose, 2-4 hours post dose 
3 
1 
pre-dose, 2-4 hours post dose 
4 -6  
1 
Predose up to cycle 6  
Unscheduled  
 
As clinically indicated 
End of Treatment 
 
Within 14 days of last dose 
All measurement times are relative to dose of LEE011 unless otherwise specified. 
 
6.2.2 
Efficacy 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response after 3 cycles 
+/- 1 week.  In addition to a baseline scan, confirmatory scans should also be obtained at 
least 4 weeks following initial documentation of objective response. The PI will be 
responsible for determining each participants’ response to treatment.  The PI will document 
the response to treatment on a protocol-specific response form. The PI will sign the form 
and it will be included as part of the patient’s medical record.  


 
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Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria. 
 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment. 
 
Evaluable for objective response.  Only those patients who have measurable disease present 
at baseline, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for response.  These patients will have their response 
classified according to the definitions stated below.  (Note:  Patients who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable 
for non-target disease.  The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  
 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter for non-nodal lesions and short axis 
for nodal lesions to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, 
or >10 mm with calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  In order for such lesions to be considered measurable, the radiation 
must be greater than 6 months prior to the study initiation, and there must have been 
subsequent evidence of disease progression in the radiated tumor lesions. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed.  At baseline and in follow-up, only the 
short axis will be measured and followed. 
 


 
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Non-measurable disease.  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), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements.  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.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 


 
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Clinical lesions  Clinical lesions will only be considered measurable when 
they are superficial (e.g., skin nodules and palpable lymph nodes) and 
≥10 mm diameter as assessed using calipers (e.g., skin nodules).  In the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  However, 
CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 
mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, 
and temporal resolution; however, there are many image acquisition 
variables involved in MRI, which greatly impact image quality, lesion 
conspicuity, and measurement.  Furthermore, the availability of MRI is 
variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the 
modality used at follow-up should be the same as was used at baseline 
and the lesions should be measured/assessed on the same pulse sequence.  
It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  
Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use 
with RECIST measurements.  However, if the site can document that the 
CT performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer 
lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should 


 
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Page 38 
not be used as a method of measurement.  Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a later 
date and, because they are operator dependent, it cannot be guaranteed 
that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the 
course of the study, confirmation by CT or MRI is advised.  If there is 
concern about radiation exposure at CT, MRI may be used instead of CT 
in selected instances. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may be 
a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
 
a. 
Negative FDG-PET at baseline, with a positive 
FDG-PET at follow-up is a sign of PD based on a new lesion. 


 
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Page 39 
b. 
No FDG-PET at baseline and a positive FDG-
PET at follow-up:  If the positive FDG-PET at follow-up corresponds 
to a new site of disease confirmed by CT, this is PD.  If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on 
CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be 
the date of the initial abnormal FDG-PET scan).  If the positive FDG-
PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. 
FDG-PET may be used to upgrade a response 
to a CR in a manner similar to a biopsy in cases where a residual 
radiographic abnormality is thought to represent fibrosis or scarring.  
The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
d. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
Response Criteria 
 
Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the 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 progressions). 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
 


 
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Complete Response (CR): 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). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
 
Non-CR/Non-PD:  
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not a 
single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
        For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best 
Overall Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 


 
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Page 41 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of 
a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time 
should be reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
 
 For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target 
disease since SD is increasingly used as an endpoint for assessment of efficacy in some trials 
so to assign this category when no lesions can be measured is not advised 
 
 
Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that progressive disease is objectively documented.  
 


 
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Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements.  
 
Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
Response Review 
 
The PI will be responsible for determining each participant’s response to treatment.  All 
imaging will be done with no thicker than 2.5 mm reconstruction as per the standard of care 
for our institutional imaging. 
 
6.2.3 
Safety  
Safety assessments will consist of monitoring and recording all adverse events, including 
serious adverse events, the monitoring of hematology, blood chemistry, ECG and the regular 
monitoring of vital signs, and physical exam including weight; and performance status.  
 
6.2.4 
Biomarkers 
Biomarkers (from blood and/or tissue as indicated on Table 6.1) will be obtained for the 
following objectives: 
1) To evaluate efficacy of target inhibition with LEE011 therapy 
2) To evaluate for predictors of response to LEE011  
3) To evaluate for markers of resistance to LEE011 therapy  
 
Archival tumor tissue equivalent to at least 2 core biopsies will be collected prior to initiation 
of treatment. Paired pre- and post- treatment tumor biopsy will be obtained from all patients 
(required).  Pre-treatment biopsy will be obtained within 4 weeks before initiating therapy. 
Post-treatment tumor biopsy will be obtained on day 1 (+ / - 3 days) of cycle 2.  All FNA 
biopsies to be used for molecular profiling will be frozen immediately. Tissue will be picked-
up by the laboratory personnel of Funda Meric-Bernstam. Tissue biomarker studies will be 
performed at the laboratory of Funda Meric-Bernstam, University of Texas M. D. Anderson 
Cancer Center. 


 
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Page 43 
This tumor tissue will be used to asses Ki67 and levels of pharmacodynamics markers 
including but not limited to pRB and cyclin D1 cyclin E, p16, p21 and p27 at baseline and at 
cycle 2 day 1. Marker expression will be assessed by a pathologist blinded to outcomes and 
treatment status.  Level of marker expression will be assessed by H score, incorporating both 
intensity (0 to 3), and percentage of cells stained; thus providing a score of 0-300.  For IHC, 
we will compare the H-score at baseline to H-scores on-treatment.  
In addition, genomic profiling including methylation, mutations, deletions and amplifications 
in the CDK 4/6 pathway genes including but not limited to MEN1, Cip/Kip protein genes such 
as CDKN1B (coding for p27), INK4 protein genes such as CDKN2A (coding for p16), D-
cyclin genes such as CCND1, CCND2, CCND3 (coding for cyclins D 1-3), CDK4, CDK6 will 
be also be performed.  
 
Optional biopsies will be taken at the end of study in patients who are willing and have 
demonstrated  partial response or prolonged progression free survival. These biopsies will be 
analyzed with additional targeted sequencing in addition to other assays such as FISH, RNA 
seq, IHC, RPPA, methylation assays, rearrangement assays through the MD Anderson 
unusual responders program.  
 
Blood for genomic DNA will be collected at baseline.  
 
Serum tumor markers including chromogranin-A, neuron specific enolase will be obtained at 
baseline, cycle 2, Day 1, cycle 4 day 1 and every 3 cycles thereafter. These tests may be 
obtained more frequently per treating physician’s discretion. 
 
Descriptive statistics will be presented by response category in an attempt to characterize 
these changes with respect to efficacy. 
 
 


 
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7 
Safety monitoring and reporting 
7.1 
Adverse Events 
7.1.1 
Definitions and reporting 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. An adverse event is any 
undesirable sign, symptom or medical condition occurring after starting study drug 
( LEE011), even if the event is not considered to be related to study drug. Medical 
conditions/diseases present before starting study treatment are only considered adverse events 
if they worsen after starting study treatment (any procedures specified in the protocol). 
Adverse events occurring before starting study treatment but after signing the informed 
consent form are recorded. Abnormal laboratory values or test results constitute adverse 
events only if they induce clinical signs or symptoms or require therapy, and are recorded.  
Information about all serious adverse events will be collected and recorded on the FDA 
MedWatch 3500a form for reporting to the supporting drug company, Novartis. To ensure 
patient safety each serious adverse event must also be reported to Novartis within 24 hours of 
learning of its occurrence. Please refer to Section 7.1.2 for the definition of a  serious adverse 
event.  
Events not considered to be serious adverse events are hospitalizations for the:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition. 
• treatment, which was elective or pre-planned, for a pre-existing condition that did not 
worsen 
• treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of serious given above and not resulting in hospital admission.  
Pregnancy, although not itself a serious adverse event, should also be reported on the  serious 
adverse event form and Novartis Clinical Study Pregnancy Form and be followed up to 
determine outcome, including spontaneous or voluntary termination, details of birth, and the 
presence or absence of any birth defects or congenital abnormalities. 
Safety monitoring and reporting 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. 
The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all 
subjects enrolled on the trial.  
Protocol specific data and adverse events will be documented in the medical record and 
entered into PDMS/CORe.  PDMS/CORe will be used as the electronic case report form 
(CRF)  for this protocol. 


 
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Adverse events 
Definitions and reporting 
Adverse events that begin or worsen after informed consent should be recorded in 
PDMS/CORe. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History  section of PDMS/CORe. . Adverse event monitoring should 
be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose 
of study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity Grade (CTCAE Grade 1-4) 
2. Its duration (Start and end dates or if continuing at the Safety Follow-up Visit) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)  
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, hospitalized, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Outcome 
(not 
recovered/not 
resolved, 
recovered/resolved, 
recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section7.1.2. 
All adverse events should be treated appropriately. Such treatment may include changes in 
study drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or 
any other medically required intervention. Once an adverse event is detected, it should be 
followed until its resolution, and assessment should be made at each visit (or more frequently, 
if necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drugs can be 
found in the [Investigators’ Brochure]. This information should be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment 
Laboratory test abnormalities 


 
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Page 46 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded in PDMS/CORe. Whenever possible, 
a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an 
already reported adverse event, it is not necessary to separately record the lab/test result as an 
additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol and is still, by definition, an adverse event. 
7.1.2 
Serious Adverse Event Reporting (SAE) 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred in 
a more severe form, might have caused death. 
• 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 that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate 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. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
• Important medical events as defined above may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if 
deemed appropriate by the Principal Investigator or the IND Sponsor, IND Office. 


 
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Page 47 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must 
be reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 
 
• All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of 
the event to the Safety Project Manager in the IND Office. 
 
• (Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB.  
 
• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last study treatment/intervention, unless the 
participant withdraws consent. Serious adverse events must be followed until clinical 
recovery is complete and laboratory tests have returned to baseline, progression of 
the event has stabilized, or there has been acceptable resolution of the event. 
 
• Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
 
Reporting to FDA: 
 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure that serious adverse 
events are reported according to the Code of Federal Regulations, Good Clinical 
Practices, the protocol guidelines, the sponsor’s guidelines, and Institutional Review 
Board policy. 
 
7.2 
Communications between Investigator and Novartis 
7.2.1 
Reporting responsibility 
The principal investigator has the obligation to report all serious adverse events to Novartis 
Drug Safety and Epidemiology (DS&E) 


 
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7.2.2 
Reporting procedures to Novartis 
The investigator must complete the FDA MedWatch 3500a form and Novartis SAE 
coversheet in English, assess the relationship to study treatment and send the initial completed 
MedWatch form and Novartis SAE coversheet by fax 1.888.299.4565 within 24 hours to the 
local Novartis Drug Safety and Epidemiology (DS&E).  The investigator must then ensure 
that the form and coversheet are accurately and fully completed with follow-up information 
and fax those to Novartis Drug Safety and Epidemiology (DS&E) within 2 to 3 calendar days 
for deaths or life-threatening events and 5 calendar days for other serious adverse events. The 
original and the duplicate copies of the FDA MedWatch form, Novartis SAE coversheet, and 
the fax confirmation sheet must be kept with the case report forms at the study site.  
Follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, and whether the patient continued or discontinued study participation. The 
MedWatch form, Novartis SAE coversheet, and fax confirmation sheet must be retained. 
Pregnancy follow-up should describe the outcome of the pregnancy, including any voluntary 
or spontaneous termination, details of the birth, and the presence or absence of any congenital 
abnormalities or birth defects. 
7.2.3 
Pregnancies 
Any pregnancy that occurs during study participation should be reported. To ensure patient 
safety each pregnancy must also be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any 
birth defects, congenital abnormalities or maternal and newborn complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator 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. 
8 
Statistical methods and data analysis 
This is a single arm, open-label exploratory/ phase II study.  Since no effective treatments are 
available in this setting, a response rate of 15% (within 95% CI) is considered acceptable – 
i.e., the signal for launching further, larger studies with LEE011 in this patient population is ≥ 
1 response in the current study.  If no response is observed, the treatment LEE011 is 
considered ineffective. A total of 20 patients will be enrolled and treated to rule out a response 
rate of 15% of less when at least one response is observed with 96% power.  In other words, 
with twenty patients treated, the probability of observing at least one response is more than 
96% if the response rate is at least 15%.  Descriptive statistics including with 90% confidence 
interval will be computed. Observed response profile, clinical benefit rate at 6 months and 
PFS along with relevant confidence intervals will be used to guide future development 
decisions. 
 
 


 
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Total evaluable 
patients 
Number of 
responders 
Response rate 
Lower 90% CI 
Upper 90% CI 
20 
0 
0% 
0 
13.9 
20 
1 
5% 
0.3 
21.6 
20 
2 
10% 
1.8 
28.3 
20 
3 
15% 
4.2 
34.4 
20 
4 
20% 
7.1 
40.1 
20 
5 
25% 
10.4 
45.6 
20 
6 
30% 
14 
50.8 
20 
7 
35% 
17.7 
55.8 
20 
8 
40% 
21.7 
60.6 
20 
9 
45% 
25.9 
65.3 
20 
10 
50% 
30.2 
69.8 
20 
>10* 
>50% 
>34.7% 
>74.1% 
 
* Actual response rate with corresponding CI will be calculated.  Exact confidence interval 
was calculated for all responses.  
 
Kaplan-Meier method will be used to compute the survival rate for the time-to-event 
endpoints such as PFS.  The efficacy in biomarker subgroups will be summarized by 
descriptive statistics.  
 
.  
9 
Ethical considerations and administrative procedures 
9.1 
Ethics and good clinical practice 
This study must be carried out in compliance with the protocol and Good Clinical Practice, as 
described in:  
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. Directive 91/507/EEC, The Rules Governing Medicinal Products in the European 
Community. 
3. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations). 
4. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 


 
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The investigator agrees, when signing the protocol, to adhere to the instructions and 
procedures described in it and thereby to adhere to the principles of Good Clinical Practice 
that it conforms to. 
9.2 
Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee (IRB/IEC/REB). A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. Any amendments to the protocol, must be approved by 
Novartis, the IND office, and this committee. 
9.3 
Informed consent 
The investigator must explain to each subject (or legally authorized representative) the nature 
of the study, its purpose, the procedures involved, the expected duration, the potential risks 
and benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any 
time and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before signing 
and dating it, and should be given a copy of the signed document. If the subject cannot read or 
sign the documents, oral presentation may be made or signature given by the subject’s legally 
appointed representative, if witnessed by a person not involved in the study, mentioning that 
the patient could not read or sign the documents. No patient can enter the study before his/her 
informed consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by 
the investigator with it for IRB/IEC/REB approval.  
Fertile men and women of child bearing potential should be informed that taking the study 
medication may involve unknown risks to the fetus if pregnancy were to occur during the 
study and agree that in order to participate in the study they must adhere to the contraception 
requirement for the duration of the study. If there is any question that the patient will not 
reliably comply, they should not be entered in the study. 
9.4 
Discontinuation of the study 
Novartis reserves the right to discontinue support for any study under the conditions specified 
in the clinical trial agreement. 
9.5 
Amendments to the protocol 
Any change or addition, including administrative aspects, to this protocol requires a written 
protocol amendment that must be approved by Novartis, the IND office and the IRB  before 
implementation. A copy of the written approval of the IRB/IEC/REB, must be sent to 
Novartis. 


 
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9.6 
Publication of results 
Any formal presentation or publication of data from this trial may be published after review 
and comment by Novartis and prior to any outside submission.  Novartis must receive copies 
of any intended communication in advance of publication (at least twenty-one working days 
for presentational materials and abstracts and thirty working days for manuscripts).   These 
requirements acknowledge Novartis’ responsibility to provide peer input regarding the 
scientific content and conclusions of such publications or presentations.  Principal 
Investigation/Institution shall have the final authority to determine the scope and content of its 
publications, provided such authority shall be exercised with reasonable regard for the 
interests of Novartis and, in accord with the trial contract and shall not permit disclosure of 
Novartis confidential or proprietary information. 
9.7 
Disclosure and confidentiality 
The investigator agrees to keep all information provided by Novartis in strict confidence and 
to request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents 
provided by Novartis (investigators' brochures and other material) will be stored appropriately 
to ensure their confidentiality. The information provided by Novartis to the investigator may 
not be disclosed to others without direct written authorization from Novartis, except to the 
extent necessary to obtain informed consent from patients who wish to participate in the trial. 
9.8 
Declaration of Helsinki 
The investigator must conduct the trial in accordance with the principles of the Declaration of 
Helsinki. Copies of the Declaration of Helsinki and amendments will be provided upon 
request or can be accessed via the website of the World Medical Association at 
http://www.wma.net/e/policy/17-c_e.html. 
 


 
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10 
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