Conditions: Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase Primary Myelofibrosis Secondary Myelofibrosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 50
Healthy volunteers: no

Brief summary:
This phase II trial studies how well second mitochondrial-derived activator of caspases (SMAC) mimetic LCL161 (LCL161) works in treating patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocytosis myelofibrosis. SMAC mimetic LCL161 may help control the growth of abnormal cells by promoting apoptosis (programmed cell death).

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the efficacy of LCL161 as therapy for primary myelofibrosis (PMF), post-polycythemia vera (PV) myelofibrosis (MF) and post-essential thrombocytosis (ET) MF.

II. To determine the objective response which is defined as CR (complete remission) + PR (partial remission) + CI (clinical improvement) after three cycles of treatment.

SECONDARY OBJECTIVES:

I. To determine the safety of LCL161 as therapy for PMF, post-PV MF and post-ET MF.

II. To determine time to response and response duration. III. To assess changes in symptom burden as assessed by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) and M.D. Anderson Symptom Inventory (MDASI) questionnaires.

EXPLORATORY OBJECTIVE:

I. To assess the mechanisms of action of LCL161 in patients with MF; these studies will include the analysis of baculoviral IAP repeat containing 2 (cIAP1), X-linked inhibitor of apoptosis, E3 ubiquitin protein ligase (XIAP), and poly (adenosine diphosphate \[ADP\]-ribose) polymerase 1 (PARP) protein levels which will be determined by western blot (actin as loading control) and will be measured at baseline and at beginning of each cycle for first 3 cycles and at end of study.

OUTLINE:

Patients receive SMAC mimetic LCL161 orally (PO) on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Arms:
arm 1: Patients receive SMAC mimetic LCL161 PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Questionnaire Administration intervention 3: Smac Mimetic LCL161
Intervention descriptions: intervention 1: Correlative studies intervention 2: Ancillary studies intervention 3: Given PO

Protocol document:
Prot_SAP_000.pdf: 
1 
 
Open Label Phase 2 Single Agent Study of LCL-161 in Patients 
with Primary Myelofibrosis (PMF), Post-Polycythemia Vera 
Myelofibrosis (Post-PV MF), or Post-Essential Thrombocytosis 
Myelofibrosis (Post-ET MF) 
 
 
 
 
 
 
 
 
 
Novartis Study #: 
CLCL161AUS02T 
MDACC Protocol #: 
2013-0612 
Investigator Name: 
Naveen Pemmaraju, MD 
 
Assistant Professor, Dept of Leukemia, MD Anderson 
 
Investigator Contact 
Information: 
T: 713-792-4956, 
 
npemmaraju@mdanderson.org 
 
MD Anderson Cancer Center 
Unit 428 
PO BOX 301402 
 
Houston, TX 77230-1402 
 
Co-Investigator: 
Srdan Verstovsek, MD, PhD 
 
Professor, Dept of Leukemia, MD Anderson 
 
 
 
 
Amendment 10 
 
July 9, 2019 


2 
 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of abbreviations ............................................................................................................ 4 
Glossary of terms ................................................................................................................. 5 
1 
Background .......................................................................................................................... 6 
1.1 
Overview of disease pathogenesis, epidemiology and current treatments............... 6 
Treatment of PMF .................................................................................................... 7 
1.2 
Overview of LCL161 and apoptosis ........................................................................ 7 
1.2.2 Animal pharmacokinetics and drug metabolism ........................................... 9 
1.2.3 Animal toxicology ......................................................................................... 9 
1.2.4 Biomarkers  .................................................................................................. 11 
1.3 
Study purpose/rationale  ........................................................................................ 16 
2 
Objectives and endpoints  .................................................................................................. 16 
Primary Objectives  ........................................................................................................... 16 
Secondary Objectives  ....................................................................................................... 17 
Exploratory Objectives  ..................................................................................................... 17 
3 
Investigational plan ........................................................................................................... 17 
4 
Population  ......................................................................................................................... 18 
4.1 
Inclusion criteria  ................................................................................................... 18 
4.2 
Exclusion criteria  .................................................................................................. 19 
5 
Treatment  .......................................................................................................................... 20 
5.1 
Treating the patient  ............................................................................................... 20 
5.1.1 
Administration  ...................................................................................... 20 
5.1.2 
Dosing and treatment schedule  ............................................................ 23 
5.1.3 
Definitions of dose limiting toxicities (DLTs)  ..................................... 23 
5.1.4 
Follow-up for toxicities  ........................................................................ 24 
5.2 
Dose modifications  ............................................................................................... 25 
5.2.1 
Dose modification and dose delay  ....................................................... 25 
5.2.2 
Treatment interruption and treatment discontinuation  ......................... 26 
5.3 
Concomitant medications  ..................................................................................... 27 
5.3.1 
Packaging and labeling ......................................................................... 28 
Supply, receipt and storage  .................................................................. 28 
5.3.2 
Drug compliance and accountability  .................................................... 28 
5.3.3 
Disposal and destruction  ...................................................................... 28 
6 
Visit schedule and assessments  ........................................................................................ 28 
6.1 
Study flow and visit schedule  ............................................................................... 28 


3 
 
6.2 
Assessment Types  ................................................................................................. 28 
6.2.1 
Efficacy  ................................................................................................ 30 
6.2.2 
Safety  .................................................................................................... 30 
6.2.3 
Biomarkers  ........................................................................................... 30 
7 
Adverse Events  ................................................................................................................. 31 
7.1 
Adverse Events  ..................................................................................................... 31 
7.1.1 
Definitions and reporting  ..................................................................... 31 
7.2 
Serious Adverse Event Reporting (SAE)  .............................................................. 31 
7.2.1 
Investigator Communications with Novartis  ........................................ 33 
7.3 
Pregnancies  ........................................................................................................... 33 
8 
Statistical methods and data analysis  ................................................................................ 33 
8.1 
Sample size calculation  ......................................................................................... 33 
9 
Administrative procedures  ................................................................................................ 36 
9.1 
Discontinuation of study support  .......................................................................... 36 
9.2 
Amendments to the protocol  ................................................................................. 36 
9.2.1 
Publication of results  ............................................................................ 36 
9.2.2 
Disclosure and confidentiality  .............................................................. 36 
10 References (available upon request)  ................................................................................. 37 


4 
 
 
List of abbreviations 
 
 
ADME 
Absorption, distribution, metabolism, and excretion 
AE 
Adverse event 
ALT 
Alanine aminotransferase/serum glutamic pyruvic transaminase/SGPT 
AST 
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase/SGOT 
AUC 
Area under the plasma concentration-time curve 
CL/F 
Systemic clearance (where F is the fraction of the dose absorbed) 
CL/F 
Apparent oral clearance 
Cmax 
Maximum (peak) concentration of drug 
CNS 
Central nervous system 
DLT 
Dose limiting toxicity 
DS&E 
Drug Safety and Epidemiology 
ECG 
Electrocardiogram 
GLP 
Good laboratory practice 
Hr 
Hour 
IAP 
Inhibitor of Apoptosis proteins 
IC50 
Half maximal inhibitory concentration 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MTD 
Maximum tolerated dose 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
QD 
Once daily 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 


5 
 
 
Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cycle 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (eg: q28 days) 
Enrollment/Enrolled 
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 tested 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 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of 
the tumor, whether lymph nodes contain cancer, and whether the cancer 
has spread from the original site to other parts of the body 
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 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points 


6 
 
1 
Background 
 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatments 
Primary myelofibrosis (PMF) is a rare hematologic malignancy (approximately 0.4-1.3 cases 
per 100,000 people in United States/Australia/Europe). PMF is one of the three classical 
BCR/ABL 
negative 
myeloproliferative 
neoplasms 
(MPN), 
along 
with 
essential 
thrombocytosis (ET) and polycythemia vera (PV) Initially postulated as an MPN in the 1950’s 
by William Dameshek, PMF is now recognized as a clonal hematopoietic stem cell disorder in 
which 50% of patients have a constitutively activated mutation in the Janus kinase (JAK)2 
gene, most commonly at V617F. Patients with ET and PV can acquire over time features of 
myelofibrosis, then called Post-Polycythemia Vera Myelofibrosis (Post-PV MF), or Post- 
Essential Thrombocytosis Myelofibrosis (Post-ET MF). 
 
The primary pathogenic mechanism in MF is the unchecked proliferation of a pluripotent 
stem cell clone that leads to ineffective erythropoiesis, dysplastic-megakaryocyte hyperplasia, 
and an increase in the ratio of immature granulocytes to total granulocytes. This clonal 
myeloproliferation is characteristically accompanied by reactive myelofibrosis (bone marrow 
fibrosis) and by extramedullary hematopoiesis in the spleen or in multiple organs. The 
diagnosis is often suspected when teardrop-shaped red cells and myeloid precursors are 
detected in the peripheral blood. The typical clinical features include marked splenomegaly, 
progressive anemia, and constitutional symptoms. The terms “myeloid metaplasia” and 
“extramedullary hematopoiesis” are used interchangeably to describe a pathologic process of 
ectopic hematopoietic activity that may occur in any organ system but that affects primarily 
the liver and spleen. 
 
At the molecular level, a JAK2 tyrosine kinase mutation (JAK2V617F) can be demonstrated 
in MF in approximately half of patients, with most being homozygous for such mutation. To 
date, however, many other mutations have been discovered in patients with MPN (up to 20 at 
last count), sometimes few present in a single patient, in different cell clones. What has 
become clear over last two years is the relationship between dysregulated JAK-STAT (signal 
transducer and activator of transcription) signaling and the signs and symptoms of MPNs. The 
understanding of dysregulated JAK-STAT activity in MPNs as the basic pathophysiologic 
abnormality in practically all patients with MPNs has led to the clinical development of 
several JAK2 inhibitors. 
 
Adverse prognostic factors for survival include older age and anemia (hemoglobin < 10 
gm/dL). The etiology for the latter finding is usually multifactorial and related both to 
marrow failure and hypersplenism. Poor prognosis has also been correlated with 
leukocytosis, leukopenia, circulating blasts, increased numbers of granulocyte precursors, 
thrombocytopenia, abnormal karyotype, and hypercatabolic symptoms. The course of the 
disease is highly variable. Median survival from time of diagnosis ranges from 3 to 6 years; 
survival rates are 68% at 2 and 40% at 5 years. The usual causes of death are progressive 
marrow failure, body wasting, transformation into acute myeloid leukemia, and/or portal 
hypertension. 


7 
 
Treatment of PMF 
 
Patients with acceptable quality of life and no threatening hematologic abnormalities, such as 
erythrocytosis or thrombocytosis, are customarily observed without any therapy. Hydroxyurea 
is the most commonly used agent in the proliferative phases of the disease. Interferon-alpha 
had yielded hematologic responses and reductions in splenomegaly in 30% to 50% of subjects, 
especially those in a proliferative phase; however, conventional interferon-alpha therapy is 
frequently poorly tolerated. Therapies aimed at improving the anemia found in patients with 
MF include androgens and/or erythropoietin. Splenectomy and/or splenic irradiation have 
been used to manage symptomatic splenomegaly. Splenectomy has been associated with 
risk of leukemic transformation in some series, and splenic irradiation can result in severe 
myelosuppression. Benefit to a subset of subjects has been demonstrated for both allogeneic 
SCT and several novel drugs, including the thalidomide-derived immunomodulatory analogs 
known as immunomodulatory drugs (IMiDs; i.e. lenalidomide, pomalidomide). 
 
Several JAK2 (or JAK1/JAK2) inhibitors are currently in clinical trials for MF. Ruxolitinib 
(formerly INCB018424; Incyte Corporation, Wilmington, DE, USA) recently became the first 
FDA-approved drug for the treatment of MF. Ruxolitinib is a potent and selective JAK1- and 
JAK2-inhibitor. Treatment with ruxolitinib is associated with a dramatic decrease in 
circulating levels of proinflammatory cytokines, IL-6, and tumor necrosis factor (TNF)-α, 
which have been implicated in the pathogenesis of MPNs. Proinflammatory cytokines are 
known to be at very high levels in MF and to contribute to the disease pathogenesis. Primary 
benefit of ruxolitinib in MF is significant decrease in organomegaly (splenomegaly and 
hepatomegaly) and significant improvement in quality of life and the therapy controls 
debilitating MF-related systemic symptoms, improves patients ability to walk, and patients 
gain weight. It does not improve anemia, and it does not improve the bone marrow fibrosis. 
 
 
 
1.2 
Overview of LCL161 and apoptosis 
 
LCL161 is a biostable, cell-permeable, small molecular weight SMAC-mimetic compound. It 
is an orally bioavailable pan-IAP inhibitor that demonstrates anti-tumor efficacy as a single 
agent in a small subset of cell lines, and in many more cell lines and xenograft models when 
given in combination with paclitaxel. 
 
 
Apoptosis, or programmed cell death, plays a critical role in regulating cell number and 
eliminating stressed or damaged cells from normal tissues and provides a major barrier to the 
development and progression of human cancer. Cancer cells have evolved mechanisms to 
ensure their survival, often including ways to avoid activation of apoptosis. Many commonly 
used antineoplastic therapies rely on overriding these mechanisms to trigger apoptosis. 
 
Apoptosis signaling networks are classified as either intrinsic and mediated by cellular stress 
and mitochondrial permeability, or extrinsic and mediated by death receptor-ligand interactions 
(Ashkenazi and Dixit 1998, Green and Reed 1998). Both pathways ultimately converge on 
caspases, the enzymatic mediators of cell destruction. One class of negative regulatory  
molecules  is  the  Inhibitor  of  Apoptosis  (IAPs)  proteins  (Tamm  et  al  2000, 


8 
 
Hofmann 2002, Krajewska et al 2003, Shiraki et al 2003, Tamm et al 2004). The ability of 
IAP proteins to buffer an apoptotic signal is regulated by SMAC/Diablo (Second 
mitochondrial activator of cytochrome c), a mitochondrial protein (Du et al 2000, Verhagen et 
al 2000). SMAC is released from mitochondria upon activation of the intrinsic apoptotic 
pathway, and it’s binding to IAPs promotes apoptosis. The observation that short SMAC- 
derived peptides could inhibit the caspase 9-XIAP interaction in vitro hinted at a therapeutic 
utility for SMAC (Chai et al 2000). Agents that, like SMAC, could disengage IAPs from 
caspases may potentially sensitize cancer cells to apoptotic stimuli. 
 
SMAC-mimetic agents developed by multiple groups have expanded our understanding of the 
roles of IAPs in cells, and have demonstrated activity as single agents in a subset of tumor cell 
lines (Li et al 2004, Gaither et al 2007, Varfolomeev et al 2007, Vince et al 2007). Analysis of 
the basis for the single agent activity has revealed the role of the cIAP1 and cIAP2 proteins as 
E3 ligases that modify the function of multiple proteins in the TNF/death receptor signaling 
cascade to control NF-κB activity. Treatment with SMAC-mimetic compounds disrupts 
signaling by stimulating auto-ubiquitination and degradation of cIAP1 and in the presence of 
TNFα, this promotes formation of a death-inducing signaling complex and apoptosis (Gyrd- 
Hansen and Meier 2010; Wu et al 2007). 
 
1.2.1 Preclinical experience 
 
In vitro pharmacology 
 
LCL161 binds with high affinity to XIAP, cIAP1, and cIAP2 through their BIR3 domains. 
LCL161 binding to cIAP1 causes cIAP1 autoubiquitination and degradation of cIAP1 and 
cIAP2 by the proteosome in a dose-dependent manner. Loss of cIAP1 occurs rapidly (within 
30 minutes) in both sensitive and insensitive cell lines. Since this phenomenon is also observed 
in human PBMCs, the measurement of cIAP1 protein levels is a useful pharmacodynamic 
biomarker. The binding of LCL161 to XIAP interferes with XIAP’s ability to interact with and 
repress caspase 9, but does not impact XIAP protein levels. 
 
LCL161 exhibits single agent cellular activity with an IC50 < 1 µM in ~5% of tumor cell lines 
representing a wide range of tumor histotypes. Single agent sensitive lines include, but are not 
limited, to SKOV-3 (ovarian), MDA-MB-231, EVSA-T and UACC732 (breast), HCC44 (lung, 
adenocarcinoma), Kym-1 (sarcoma), REh, HSB-2 and CCRF-CEM (ALL). SKOV-3 and 
MDA-MB-231 are among the most sensitive with IC50s in the 10 nM range. The basis for single 
agent activity is related to baseline and compound-induced NF-κB and TNF-α expression 
levels, but expression levels alone are insufficient to predict single agent activity (Gaither 
2007, Petersen 2007, Varfolomeev 2007, Vince 2007). 
 
In vivo pharmacology 
 
Since the MDA-MB-231 human breast cell line was highly sensitive to LCL161 in vitro, the 
single agent activity of LCL161 was assessed in an MDA-MB-231-based orthotopic nude 
mouse xenograft model. LCL161 demonstrated dose-dependent anti-tumor activity 
corresponding to a tumor over control (T/C) value of 24% and 9% for the two doses tested 
(28.9 mg/kg PO, BID and 57.8 mg/kg PO BID, respectively, p < 0.05). LCL161 dosed at 10.8 
mg/kg PO BID had no significant anti-tumor effect, corresponding to T/C value of 48% (p > 
0.05). For comparison, the positive reference compound paclitaxel, dosed at a maximum 


9 
 
tolerated dose of 12.5 mg/kg, iv, 2x/week, resulted in a T/C value of 19% at study termination 
(p < 0.05). 
 
Plasma and tumor exposure assessed at study termination were dose proportional over the 
tested range. The tumor-to-plasma ratios of LCL161 were approximately 1-2 fold in all three 
dose groups. The doses of LCL161 resulting in single agent anti-tumor activity, i.e., T/C 
values of 24% and 9%, provided estimated plasma AUC0-24h of approximately 18,600 nM.h 
(9,300 ng.h/mL) and 25,000 nM.h (12,500 ng.h/mL), respectively. 
 
1.2.2 Animal pharmacokinetics and drug metabolism 
 
The pharmacokinetics of LCL161 was investigated in the rat, dog, and monkey. LCL161 is 
rapidly and extensively absorbed in all animal species tested after an oral dose. The compound 
has a low to moderate plasma clearance and a moderate to high volume of distribution at 
steady state, indicating wide tissue distribution. LCL161 is highly bound to plasma protein 
across all species examined with saturable plasma protein binding at high 
concentrations. Results from the rat ADME study demonstrated that [14C]LCL161 is mainly 
excreted into feces, with minor renal excretion (~21%), and this was confirmed in orally 
dosed, bile duct cannulated animals. The major metabolic pathway for LCL161 based on in 
vitro studies in human hepatocytes involves cytosolic NADPH-dependent carbonyl 
reductase(s) (~60%), while a minor pathway exists for oxidative metabolism (~40%) by 
CYP2C8 and by CYP3A4. No unique, major metabolites were identified in human 
hepatocytes. LCL161 is a P-glycoprotein (P-gp) substrate, which may affect the distribution 
of LCL161 to tissues expressing this efflux transporter (e.g., brain). 
 
With respect to potential drug-drug interactions (DDI), in vitro data suggested that there is a 
high risk for clinically relevant CYP3A4/5 time-dependent inhibition (KI ~ 0.8 µM) and a 
clinical drug-drug interaction study with midazolam (CLCL161A2105) confirmed this finding 
in vivo. LCL161 is also a reversible CYP2B6 inhibitor (Ki ~ 0.2 µM) based on in vitro data; 
the clinical relevance has not been confirmed in vivo. 
 
1.2.3 Animal toxicology 
 
Safety pharmacology studies demonstrated that LCL161 had no significant effects on the 
function of the central nervous system (CNS), cardiovascular and respiratory systems. It is 
also considered non-genotoxic, as shown by the results of in vitro genetic toxicology studies. 
 
In the general toxicology studies, LCL161 was administered to rats and monkeys by oral 
(gavage) for up to 4-weeks with once daily dosing. The doses for the 4-week rat study were: 0 
(control), 3, 10 and 20 mg/kg/day, and the doses for the 4-week monkey study were 0 
(control), 10, 30 and 45 mg/kg/day. The following are considered the main target organs of 
toxicity: lymphoid hyperplasia and general inflammation in both rats and monkeys and 
bone/joint lesions in rats only. The STD10 in the rat was determined to be 10 mg/kg/day, with 
steady-state systemic exposure (AUC0-24h) of 19,800 ng.hr/mL (males and females combined), 
and the highest non-severely toxic dose (HNSTD) in monkeys was 30 mg/kg (360 mg/m2, males and 
females combined). General inflammation was the most prominent finding in the daily dosed 
toxicology studies. In rats, inflammatory changes were observed in mesenteric and 
mandibular lymph nodes, the spleen, the skin, bone/joints, bone marrow, serosa/adventitia of 
thoracic, abdominal and subcutaneous organs/tissues, lungs, gastrointestinal (GI) tract and 
liver. In general, the lesions were dose dependent and fully reversed, or showed a tendency 


10
 
towards reversibility upon drug withdrawal. Clinical pathology changes in rats were also 
indicative of inflammation, including decreases in lymphocytes and eosinophils, increases in 
neutrophils and monocytes, and abnormal neutrophil and lymphocyte morphology. In 
monkeys, evidence of inflammation was observed in the kidney, liver, lacrimal gland, salivary 
gland, lungs and stomach. The inflammation in the monkeys was reversed after a 4-week 
recovery period. Clinical pathology changes were also indicative of inflammation, including 
increases in peripheral leukocyte counts, increased fibrinogen and C-reactive proteins, and 
increased bone marrow myeloid: erythroid ratios, although the degree of clinical pathology 
findings was generally minor. Cytokine analysis identified sporadic increases in serum 
concentrations of IL-1 beta, IL-2, IL-6, TNF-α, and GM-CSF. 
 
General inflammation is believed to be related to LCL161’s mechanism of action. Inhibition 
of IAPs leads to activation of the NF-κB pathway and to the increased production of 
inflammatory cytokines such as TNF-α in tumors. While TNF-α has not been demonstrated to 
be responsible for the inflammation observed in animals, other cytokines including GRO-KC 
(a rat-specific analog of IL-8) and MCP-1 have been characterized. Based on the 
understanding of the mechanism of action and on preclinical data, the inflammation is 
reversible upon discontinuation of drug. 
 
Based on the dose limiting toxicity for LCL161 of generalized inflammation, it was of interest 
to evaluate the impact on the in vivo safety profile of combining LCL161 with an anti- 
inflammatory corticosteroid. Dexamethasone, selected as the corticosteroid due to its common 
use in rodents, was assessed in three contexts. First, 0.3 mg/kg/day of dexamethasone (modeled 
from 20 mg of dexamethasone in humans daily) was administered to rats prior to LCL161 
and in combination with each LCL161 dose over a 2-week period. In this study, steroids 
in combination with LCL161 were able to prevent the majority of the inflammatory findings. 
In a second experiment, dexamethasone dosing was not started until LCL161- mediated 
inflammation had been allowed to fully develop in rats, and it was then given at 0.1 mg/kg 
daily for 5 days (modeled from 40 mg of prednisone in humans daily). In this context, 
dexamethasone suppressed the inflammation and bone changes. A 5-day drug holiday without 
the administration of dexamethasone also diminished inflammation and bone changes 
significantly, but not to the same degree as treatment with dexamethasone. In a third 
experiment designed to test whether treatment with dexamethasone impaired tumor killing, 
dexamethasone at 0.5 mg/kg/week was administered as a pre-dose (modeled from 3 mg 
dexamethasone in humans as a pre-dose) with 150 mg/kg of LCL161 given weekly to tumor- 
bearing mice (MDA-231 xenograft). In this study, steroids did not antagonize the anti-tumor 
activity of LCL161 (see Investigator’s Brochure). 
 
Lymphoid hyperplasia is consistently observed in animal studies with daily doses. In rats and 
monkeys, enlarged spleen and lymph nodes and microscopic evidence of lymphoid 
hyperplasia was observed. The spleen appears to be the most sensitive organ for LCL161 
induced lymphoid proliferative changes, and lymphoid hyperplasia was observed in spleen at 
all doses in the rat and monkey 4-week GLP studies. Hyperplastic changes of lymph nodes 
were also observed in multiple organs/tissues in rat and monkeys - often at higher doses. 
Lymphoid hyperplasia in spleen and lymph nodes were at least partially reversible in the 4- 
week studies, though 4 weeks may not be long enough for complete recovery for lymphoid 
hyperplasia. 


11
 
Effects on bone/joints were observed in toxicology studies with daily dosing in rats, but not in 
monkeys. The findings include: mesenchymal proliferation, outgrowth of mesenchymal 
tissues with destruction of cortical bone, periosteal proliferation, new bone formation, 
decrease in trabecular bone, growth plate thickening and/or disorganization of trabecular bone 
adjacent to growth plate. Articular findings include inflammation, fibroplasias, and/or 
necrosis of periarticular soft tissue and exudation in the articular cavity. The findings were 
dose-dependent. The bone findings were partially reversed during recovery, though it is 
unlikely that a 4- to 6-week recovery period is long enough for bone findings. It is not certain 
if the bone/joint findings are secondary to inflammation, or a direct effect, or both. It is 
suspected that the bone findings in rats are confounded by the continued presence of open 
epiphyses and high bone turnover rates. However, due to the lower exposures obtained in the 
monkey toxicology studies, these bone findings cannot be characterized as species-specific. 
Final data from the ongoing first-in-human trial suggest that LCL161 does not have clinically 
significant effects on bone turn over (see Investigator’s Brochure). 
 
1.2.4 Biomarkers 
 
Preclinical and clinical biomarker data from the first-in-human trial (CLCL161A2101) with 
LCL161 given as a single agent on a once-weekly schedule were used to select the biomarkers 
employed 
in 
this 
trial 
to 
explore 
the 
relationship 
between 
pharmacokinetics/ 
pharmacodynamics, efficacy, target modulation, molecular response, and immune 
modulation. Preclinical studies in MDA-MB-231 breast cancer cells treated with LCL161 in 
vitro demonstrated that cIAP1 is degraded within 30 minutes of drug treatment. In mouse 
studies, maximal degradation of cIAP1 in MDA-MB-231 tumor tissue occurred 
approximately 6 hours following PO administration of LCL161. Analysis of clinical data from 
the CLCL161A2101 trial suggest that cIAP1 is degraded in PBMCs within 2 hours of LCL161 
dosing, and variably recovers around 72 hours after dosing. 
 
The downstream impact of cIAP1 degradation is proteolytic activation of caspase-3 in sensitive 
models, which induces apoptosis. 
 
In addition to the activation of apoptosis, preclinical studies have also demonstrated that the 
degradation of cIAP1 leads to the transient activation of NF-κB. In LCL161-sensitive cell 
lines, NF-κB activation led to the production of TNF-α, which is weakly correlated with anti- 
tumor activity. Independent of the anti-tumor activity, preclinical studies have also shown that 
NF-κB activation plus antigen stimulation activates immune cells and stimulates the release of 
numerous cytokines into the circulation. These effects of LCL161 could underlie the 
inflammation observed with chronic dosing in rats and monkeys and to the cytokine release 
syndrome observed in patients, described below. 
 
1.2.5.1 Human clinical experience 
 
Two clinical trials with LCL161 have been completed and final data are available 
(Investigator’s Brochure). Two clinical trials with LCL161 are ongoing. 
 
1.2.5.2 CLCL161A2101, a first-in-human clinical trial 
CLCL161A2101 was a phase 1 dose escalation study designed to identify the maximum 
tolerated dose (MTD), safety and tolerability of LCL161 when given as a single oral dose 
once each week, and to seek preliminary evidence of activity. 


12
 
A total of 53 patients with advanced solid tumors (relapsed or refractory) were enrolled, and 
patients received oral LCL161 on Days 1, 8, and 15 of every 21-day cycle at doses ranging 
from 10-3000 mg. 
 
 
Clinical safety and tolerability 
The most common adverse events of any CTCAE grade observed that were suspected to be 
related to LCL161 included fatigue, nausea and vomiting. In general these toxicities were 
manageable and severe toxicity was unusual. Eight patients (15%) experienced grade 3 or 4 
toxicities that were considered to be related to LCL161. Three patients (5.6%) experienced 
DLTs (one each at doses of 1800 mg, 2100 mg and 3000mg). All DLTs were a clinical 
syndrome of cytokine release (CRS) that is consistent with the mechanism of action of 
LCL161 and that variably included vomiting, diarrhea, fever, flushing or pruritic rash, and in 
the most severe cases symptomatic hypotension. Symptoms occurred on the day of dosing 
within hours of having received LCL161. Two patients experienced grade 3 CRS (one each at 
1800 and 2100 mg), both of whom recovered within 24 hours of the development of symptoms. 
One patient (at 3000 mg) developed significant hypotension with grade 4 cytokine release 
syndrome. The severe hypotension experienced by this patient was unusual and may have 
been complicated by concomitant administration of three anti-hypertensive medications 
including amlodipine, which is metabolized by CYP3A4. In the 1800 mg dose group one 
patient (4%) among 24 developed grade 3 CRS as a DLT; this dose was selected as the dose 
recommended for further study. 
 
Laboratory abnormalities including hematological toxicity was uncommon. The most 
common severe hematological abnormality was lymphopenia, which occurred in 8 patients 
(15%), followed by anemia in 5 patients (9%) and grade 4 thrombocytopenia in 1 patient 
(1.8%). No severe or life threatening hematologic abnormalities were reported for WBC or 
absolute neutrophils (neutropenia). Neuropathy or pneumonitis was not reported as a new 
adverse event. 
 
 
Clinical pharmacokinetics 
LCL161 was rapidly absorbed after a single oral dose of a tablet formulation, with peak 
plasma concentrations occurring between 1.0 and 6.2 hours. LCL161 exhibited variable PK, 
with a large apparent volume of distribution (Vz/F) ranging from 190-1689 L, a moderate 
apparent total body clearance (CL/F) ranging from 13-151 L/h, and a terminal elimination 
half-life (T1/2) ranging from 4.4-15.5 hours. LCL161 Cmax and AUCinf generally increased 
with increasing doses; however, a slightly less than proportional increase was observed. 
Substantial inter-patient variability was observed in LCL161 PK at the RDE of 1800 mg with 
the percent coefficient of variation of 78% for Cmax and 84% for AUC(0-inf). There was no 
accumulation in LCL161 plasma Cmax or AUC(0-6) from Day 1 to Day 8 and no evidence for 
time-dependent effects on PK following weekly oral administration of LCL161. 
 
 
Clinical pharmacodynamics 
This study provided evidence that LCL161 is pharmacodynamically active at tolerable doses 
investigated in patients. The principal marker of pharmacodynamic activity was degradation 
of cIAP1. Target degradation was observed in all paired tumor biopsies obtained prior to and 
following a single dose of LCL161, including one case at 900 mg and five cases at 1800 mg. 
cIAP1 degradation was also observed in some paired skin biopsies at doses ≤160 mg and in 


13
 
22 of 24 the samples at doses ≥320 mg. cIAP1 depletion in skin was consistently evident 24 
hours after LCL161 dosing. The evidence of pharmacodynamic activity (cIAP1 degradation) 
at doses ≥320 mg suggests that 1800 mg, the dose chosen for further study, is well above that 
required for target inhibition. The time course of degradation and recovery of cIAP1 protein 
levels after a single weekly dose of LCL161 was characterized in PBMCs. The data 
demonstrated that cIAP1 is rapidly degraded within 2 hours of treatment with LCL161 and 
suggested that protein levels begin to recover in most patients approximately 72 hours after 
dosing. 
 
 
Clinical efficacy 
No evidence of anti-tumor activity was identified in this unselected population, which is 
consistent with the preclinical data that suggest a small proportion of malignant cell lines are 
sensitive to LCL161 as a single agent. 
 
For more information, refer to the [Investigator’s Brochure]. 
 
 
1.2.5.3 CLCL161A2105, a drug-drug interaction study with midazolam 
To  evaluate  the  clinical  risk  of  CYP3A4/5  inhibition  by  LCL16,  the  clinical  drug-drug 
interaction (DDI) study CLCL161A2105 was conducted in 16 healthy patients. This study 
evaluated the effect of a single 600 mg dose of LCL161 on the PK of the sensitive CYP3A 
probe substrate, midazolam. The study was also designed to evaluate the time-course of 
CYP3A4/5 recovery with repeat, single oral doses of midazolam (2 mg) given 3 and 7 days 
after LCL161. This study had no accompanying pharmacodynamic or efficacy endpoints. 
 
Clinical safety and tolerability 
Among the 16 healthy patients treated with LCL161 and midazolam, one patient developed 
possible grade 1 CRS characterized by transient fever and neutrophilia approximately 12 
hours after dosing. 
 
Clinical pharmacokinetics 
LCL161 exhibited rapid absorption in healthy patients with a Tmax ranging from 1.0-4.0 
hours and a T1/2 ranging from 4.5-7.6 hours. A strong drug interaction was observed when 
LCL161 and midazolam were dosed on the same day: midazolam Cmax was increased 3-fold 
and AUC(0-inf) was increased 9-fold. The drug interaction was transient, however. 
CYP3A4/5 enzyme activity was greater 3 days after the single dose of LCL161 compared to 
baseline, with midazolam Cmax and AUC(0-inf) decreased by approximately 30%. Enzyme 
activity completely returned to baseline levels within 7 days of dosing. 
 
Based upon the preclinical and clinical data from this DDI study, caution should be used for 
patients receiving LCL161 who are taking medications that are substrates for CYP3A4/5. 
 
For more information, refer to the [Investigator’s Brochure]. 
 
 
1.2.5.4 CLCL161A2104: A combination study with weekly paclitaxel 
 
CLCL161A2104 is an ongoing phase Ib dose-escalation study of LCL161 with paclitaxel in 
which patients are treated with a fixed, standard dose of paclitaxel (80 mg/m2 IV once 


14
 
weekly) followed immediately by oral LCL161 once weekly at doses ranging from 600 mg to 
the RDE (recommended dose for expansion) of 1800 mg. The objectives of the study are to 
define the MTD, safety, tolerability, pharmacokinetics and pharmacodynamics of LCL161 in 
combination with paclitaxel. Eligible patients are aged ≥18 years, with advanced solid tumors 
that have progressed despite the use of standard therapies or for which no effective therapies 
are available. 
 
Clinical safety and tolerability 
As of July 31st, 2012, preliminary AE data are available from 52 patients receiving treatment 
with LCL161 + paclitaxel; 600 mg LCL161 (n=3), 1200 mg LCL161 (n=5), 1500 mg LCL161 
(n=5), and 1800 mg LCL161 (n=39). The most common AE regardless of relationship to 
LCL161 is anemia of any grade, occurring in 32 out of 52 (62%) patients. Other common 
AEs (greater than 10%) include diarrhea (58%); asthenia and nausea (48%); neutropenia 
(44%); pyrexia (37%); fatigue (33%); alopecia and constipation (31%); decreased appetite 
(29%); vomiting (25%); mucosal inflammation (23%); dyspnea, rash, and peripheral 
neuropathy (21%); abdominal pain (19%); dysgeusia (17%); peripheral oedema (15%); cough, 
dyspepsia, myalgia, peripheral sensory neuropathy, urinary tract infection (13%); dizziness, 
febrile neutropenia, headache, neutrophil count decreased, pruritus, and respiratory tract 
infection (12%). 
 
Neutropenia was the most common Grade 3 and Grade 4 adverse event (17% and 19% 
respectively). Ten of the 52 (19%) patients experienced Grade 3 anemia; no Grade 4 anemia 
was reported. 
 
Two patients (600 mg and 1800 mg) experienced a Grade 1 CRS. The incidence and severity 
of CRS is lower than that observed in patients treated with LCL161 as a single agent. This is 
consistent with the preclinical and extensive clinical experience with dexamethasone as a 
suppressant of cytokine release and inflammation. Dexamethasone is being given to all 
patients on the CLCL161A2104 study as a premedication to prevent hypersensitivity reactions 
to paclitaxel. To inhibit clinically significant CRS, dexamethasone is generally being 
continued for all patients at a dose of 4 mg prior to paclitaxel infusion. 
As of August 10th, 2012, 28 patients (54%) experienced SAEs. Three cases were suspected to 
be related to treatment with LCL161, including two cases of non-infectious pneumonitis and 
one case of asymptomatic ALT elevation; all three recovered fully. No deaths have occurred 
that were considered related to LCL161. 


15
 
Overall, five patients have developed non-infectious pneumonitis among 55 patients evaluable 
for this toxicity. Three patients experienced grade 3 pneumonitis and two patients 
experienced grade 2 pneumonitis; two patients experienced pneumonitis as a serious adverse 
event. One patient with grade 3 pneumonitis had twice received palliative radiation to the 
chest wall, most recently ten weeks prior to treatment with paclitaxel and LCL161. This 
patient developed radiation pneumonitis in the radiation field as an SAE. All cases have 
occurred at a single geographic location at which 25 of the 55 patients have been treated. All 
five patients responded promptly to treatment with corticosteroids and recovered fully. Of the 
three initial cases reported, two were rechallenged with LCL161 and paclitaxel. Both patients 
weaned off corticosteroids and remain on treatment. After at least six additional cycles of 
study treatment each, neither patient has had a recurrence of pneumonitis. The third patient 
withdrew consent. Pneumonitis did not occur as a toxicity of LCL161 as a single agent on the 
CLCL161A2101 study (section 1.2.2.1.1). Radiation pneumonitis as a toxicity of paclitaxel is 
listed on the drug label; nonetheless the incidence of pneumonitis observed in this study is 
higher than expected. 
 
Clinical pharmacokinetics 
Preliminary noncompartmental PK analysis was conducted on data from patients with full PK 
sampling (n=32) indicates LCL161 Cmax and AUCinf did not increase with increasing doses 
from 600 to 1800 mg. The lack of increase in exposure with increasing LCL161 doses is 
consistent with the first-in-human study where dose proportionality could not be definitively 
claimed due to the small sample sizes and the large inter-patient variability. Based on 
preliminary analysis, co-administration of paclitaxel and LCL161 does not appear to result in 
a PK interaction. At the 1800 mg dose level, the median LCL161 Cmax and AUCinf were 
comparable to values observed following single agent LCL161. Paclitaxel plasma PK 
parameters were unaffected by increasing doses of LCL161 and were consistent with 
published data for weekly paclitaxel dosed at 80 mg/m2 as a 1 hour infusion (Campone et al 
2009; Ready et al 2007), indicating LCL161 has no effect on the PK of paclitaxel. 
 
Clinical efficacy 
Among the 45 patients, 11 have confirmed PRs to study treatment. 
 
For more information, refer to the [Investigator’s Brochure]. 
 
1.2.5.4 CLCL161A2201: neoadjuvant, randomized weekly paclitaxel with or 
without LCL161 
CLCL161A2201 is an ongoing phase II open-label, neoadjuvant, randomized study of weekly 
paclitaxel with or without LCL161 in patients with triple negative breast cancer. Following a 
screening period to determine eligibility, patients will be randomized to either paclitaxel 80 
mg/m2 IV given weekly (the control arm) or paclitaxel 80 mg/m2 IV weekly immediately 
followed by LCL161 1800 mg PO once weekly (the experimental arm). Treatment will be 
administered each week for 12 weeks (4 cycles). The length of each treatment cycle is 21 
days. The objectives of this trial are to assess whether adding LCL161 to weekly paclitaxel 
enhances the efficacy of paclitaxel in women with triple negative breast cancer that are 
positive for the gene expression signature. 


16
 
1.3        Study purpose/rationale 
 
Multiple groups have demonstrated that targeting of inhibition of apoptosis pathways and use 
of Smac mimetics represents a novel therapeutic approach for patients with myeloid 
malignancies (Fulda S , Nat Rev Drug Discov 2012;11:109-124). Carter et al (Blood 2010 
Jan 14;115(2):306-14) demonstrated that inhibition of X-linked inhibitor of apoptosis protein 
(XIAP) leads to enhancement of apoptosis signaling pathways in AML by release of Smac 
from the mitochondria and leading to expression of  the caspase pathway.  Katragadda et al 
(Katragadda, Expert Opin Investig Drugs 2013 May;22(5):663-70) discuss an antisense 
oligonucleotide to (XIAP), that has shown evidence of anti-leukemic activity in AML and the 
authors suggest exploration of Smac mimetics and targeting of other inhibitors of 
apoptosis(IAPs) to be valid therapeutic considerations in AML and myeloid malignancies . 
 
In pre-clinical work in the area of Smac mimetics, Carter et al (Carter, personal 
communication and in press) have recently demonstrated synergistic targeting of AML 
stem/progenitor cells with a novel  IAP antagonist , birinapant (a different Smac mimetic 
compound), in combination with hypomethyaltor agent as Phase Ib/2a clinical trial (2013- 
0141, Dr Gautam Borthakur, PI, Dept of Leukemia).  Based on this group’s work, it has been 
shown that birinipant leads to induced death receptor /caspase-mediated apoptosis in AML 
cells.  With this background, a clinical trial in our group has recently been opened for accrual 
with the Smac mimetic birinipant, with addition of hypomethylator agent, for patients with 
myelodysplastic syndrome (MDS) after failure to standard hypomethylator alone frontline 
therapy. 
 
TNF-α has been previously shown to be involved in the clonal evolution to leukemia in 
Fanconi anemia in animal model systems. Based on the work by Fleishman and colleagues 
(Blood 2011), researchers have confirmed the overexpression of TNF-α, a pro-inflammatory 
cytokine, in PMF patients. The authors demonstrate that TNF-α plays a critical part in the 
promotion of clonal dominance of MPN cells expressing JAK2V617F mutation. Indeed, 
JAK2V617F allele level is correlated with TNF-α mRNA expression levels, which indicates 
that JAK2V617F leads to up-regulation of TNF-α mRNA. 
 
Therefore on the basis of preclinical data suggesting overexpression of TNF-α as a central 
mediator of clonal dominance of JAK2V617F expressing MPN cells, and the inhibition of 
LCL161 of tumor activity via inhibition of IAPs in high TNF-α expressing tumor models, we 
propose an open label, phase 2 single agent clinical trial of LCL161 in PMF patients including 
post-PV and post-ET MF patients. 
 
 
2 
Objectives and endpoints 
 
Primary Objectives 
 
To determine the efficacy of LCL161 as therapy for PMF, post-PV MF and post-ET MF. 
 
To determine the objective response which is defined as CR (complete remission) + PR 
(partial remission) + CI (clinical improvement) after three cycles of treatment. It will be 
categorized  according  to  the  International  Working  Group  (IWG)  consensus  criteria  for 


17
 
myelofibrosis (Blood. 2013 Aug 22;122(8):1395-8. doi: 10.1182/blood-2013-03-488098. 
Epub 2013 Jul 9). 
 
 
 
Secondary Objectives 
 
To determine the safety of LCL161 as therapy for PMF, post-PV MF and post-ET MF. 
To determine time to response and response duration 
To assess changes in symptom burden as assessed by Myeloproliferative Neoplasm Symptom 
Assessment Form (MPN-SAF TSS) and M. D. Anderson Symptom Inventory (MDASI) 
questionnaires. 
 
 
 
Exploratory Objectives 
 
Samples will be collected during the course of the study to assess the mechanisms of action of 
LCL161 in patients with MF. These studies will include the analysis of cIAP1, XIAP, and PARP 
protein levels which will be determined by western blot (actin as loading control) and will  be measured 
at baseline and at beginning of each cycle for first 3 cycles and at end of study. 
 
 
3 
Investigational plan 
 
Overview of Study Design 
 
This is a phase 2, non-randomized, prospective, open-label study to determine the efficacy 
and safety of LCL161 in subjects with PMF and post ET/PV MF. Potential subjects will be 
screened for participation in the study. In general, screening assessments will include review 
of past medical history and transfusion history, review of current medication and prior MF- 
directed therapies, complete physical exam and vital signs, including spleen and liver 
measurements, ECOG performance status assessment, complete blood count (CBC) with 
differential, serum chemistries, 12-lead ECG, pregnancy test, bone marrow biopsy and aspirate 
(including cytogenetics), as well as testing for JAK2 mutation (by quantitative polymerase 
chain reaction [PCR]), and PCR or fluorescent in situ hybridization (FISH) for BCR-ABL1, 
if not previously done. 
 
Twenty-eight days (4 weeks) will be considered one cycle of therapy. Subjects will remain on 
study treatment, in the absence of disease progression or toxicity warranting discontinuation 
of therapy, as long as there is evidence of clinical benefit, as judged by the treating physician. 
Dose reduction is allowed in case of intolerance; guidelines for drug dose decrease or 
interruption will be provided. 
 
Study assessments and serial measurements of safety and efficacy will be performed. All 
scheduled visits will have a ±5-day window. Study visits at MD Anderson Cancer Center will 
occur at minimum (more often if judged necessary by the treating physician) for the initial 
dose of LCL161  then at the start of cycles 2, 3, 4, 7 and 10, and then every 6 cycles (cycle 
16, 22 etc.) thereafter while participating in the study. 


18
 
Only patients who have been on study for at least 3 cycles, and on a stable dose of LCL161 
for at least 2 cycles without grade 3-4 toxicity, will be allowed to extend their visits to M.D. 
Anderson to every 3 cycles.  Bone marrow biopsy sample will be collected before therapy, 
Cycle 4 Day 1, and then every 3-6 cycles at the discretion of the treating physician. All planned 
study visits should occur whether or not the study drug has been interrupted for an adverse 
event. The patient will be contacted by the principal investigator or research staff 30 days 
after discontinuation of protocol +/-5 days to assess for AE’s. All treatment decisions related 
to study drug are to be made by treating physician at MD Anderson and discussed with principal 
investigator. 
 
Females of childbearing potential (FCBP) and males participating in the study must agree to 
use a reliable form of contraception or to practice complete abstinence from heterosexual 
intercourse while participating in the study and for at least 90 days after discontinuation from 
the study. If pregnancy or a positive pregnancy test does occur in a study subject, treatment 
with the study drug must be immediately discontinued. 
 
 
 
4 
Population 
 
This is a phase 2, prospective, open-label study to determine the efficacy and safety of 
LCL161 in subjects with PMF and post ET/PV MF. 
 
4.1 
Inclusion criteria 
 
The investigator or his/her designee must ensure that all patients offered enrollment in this 
study meet the inclusion and exclusion criteria outlined below. 
 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Patients must provide written informed consent. 
2. Age 18 years or older. 
3. Willing and able to comply with scheduled visits, treatment plan and laboratory tests 
4. Patient is able to swallow and retain oral medication 
 
5. Must be diagnosed with treatment requiring PMF or post ET/PV MF with intermediate-1, 
intermediate -2 or high risk disease according to the IWG prognostic scoring system, or if 
with low risk disease then with symptomatic splenomegaly that is ≥5 cm below left costal 
margin by physical exam. 
 
6. Patients who are not candidates for, intolerant, or relapsed/refractory to Ruxolitinib 
7. ECOG performance status 0-2 
8. Required baseline laboratory status: 
• 
Absolute neutrophil count (ANC) 0.5 x 109/L (1500/mm3) 
• 
Serum direct bilirubin ≤ 2.0 x ULN (upper limit of normal) 
• 
AST (SGOT) and ALT (SGPT) 2.5 x ULN, except for patients with MF 
involvement of the liver who must have AST and ALT 5 x ULN 
• 
Serum creatinine ≤ 1.5 x ULN 
 
9. Treatment-related toxicities from prior therapies must have resolved to Grade ≤ 1 
 


19
 
10. At least 2 weeks from prior MF-directed treatment (till the start of study drug) 
 
4.2 
Exclusion criteria 
 
Patients eligible for this study must not meet any of the following criteria: 
1. Any concurrent severe and/or uncontrolled medical conditions that could increase the 
patient’s risk for toxicity while in the study or that could confound discrimination between 
disease- and study treatment-related toxicities. 
2. Impaired cardiac function or clinically significant cardiac diseases, including any of the 
following: 
 History or presence of ventricular tachyarrhythmia 
 Presence of unstable atrial fibrillation (ventricular response > 100 bpm); Patients with 
stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac 
exclusion criteria. 
 Clinically significant resting bradycardia (< 50 bpm) 
 Angina pectoris or acute myocardial infarction ≤ 3 months prior to starting study drug 
 Other clinically significant heart disease (e.g., symptomatic congestive heart failure; 
uncontrolled arrhythmia or hypertension; history of labile hypertension or poor 
compliance with an antihypertensive regimen) 
3. Patients who are currently receiving chronic (>14 days) treatment with corticosteroids at a 
dose ≥ 10 mg of prednisone (or its glucocorticoid equivalent) per day, or any other chronic 
immunosuppressive treatment that cannot be discontinued prior to starting study drug 
4. Patients who are currently receiving treatment with agents that are metabolized solely 
through CYP3A4/5 and have a narrow therapeutic index or are strong CYP2C8 inhibitors; 
or are receiving treatment with agents that carry a risk for QT prolongation and are 
CYP3A substrates.  
5. Patients with impairment of GI function or GI disease that may significantly alter the 
absorption of LCL161 as per physicians opinion 
6. Pregnant or breast feeding (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive β- 
HCG laboratory test. 
7. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing and for 90 days after study treatment. Highly effective contraception methods 
include: 
• 
Total abstinence or 
• 
Male partner or female sterilization or 
• 
Combination of any two of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system 
(IUS) 
c. Barrier methods of contraception: condom for male partner or occlusive 
cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/vaginal suppository. 
Note: Postmenopausal women are allowed to participate in this study. Women are 
considered post-menopausal and not of child bearing potential if they have had 12 months 


20
 
of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of asomotor 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, a woman is considered to be of not child bearing potential only 
when her reproductive status has been confirmed by follow-up hormone level assessment. 
8. Sexually active males must use a condom during intercourse while taking the drug and 
for 3 months after stopping study drug 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 
 
 
 
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 appropriately. 
 
Labs (chemistry and hematology) will be performed per visit evaluation schedule and as 
needed if clinically indicated and at the discretion of the PI and treating physician.  
 
5.1.1 
Administration 
 
Table                         Treatment and treatment schedule 
 
Study 
treatments 
Pharmaceutical form and route of 
administration 
Dose Level 
Dose 
Frequency 
and/or regimen 
LCL161 
Tablets for oral use 
-4 
-3 
-2 
-1 
0 
300 mg 
600 mg 
900 mg 
1200 mg 
1500 mg 
Weekly 
 
LCL161 will be dosed on a flat milligram per dose scale. LCL161 tablets will be administered 
orally on a weekly schedule, every 7 days (+/- 3 days). Responsible site personnel will ensure 
that the appropriate dose of study drug is administered at the clinic for the initial dose and will 
provide the patient with the correct amount of LCL161 for subsequent dosing at home. Patients 
will be instructed to return unused LCL161 study drug to the site at each visit.  Study visits at 
MD Anderson Cancer Center will occur at minimum at the start of cycles 1, 2, 3, 4, 7, and 
10, and then every 6 months thereafter while participating in the study. 
 
Patients will be given LCL161 at a flat milligram per dose scale of 1500 mg weekly. 
 
LCL161 administration 
 
Due to the unknown effect of food on its absorption, patients should be instructed to fast for 2 
hours prior to taking LCL161 and 2 hours after. Light meals (e.g. cereal, toast and jam for 
breakfast) and/or liquids (e.g. milk, non-citrus juice) can be taken outside of the fasting 
periods on days of LCL161 dosing. 


21
 
 For example, if a light meal was completed at 08:00 am, then study drug administration 
should begin at 10:00 am and the next meal could begin at 12:00 pm. Water and regularly 
prescribed medications are allowed during the fasting periods. 
 
If vomiting occurs during the course of the treatment, no re-dosing of LCL161 is allowed 
before the next scheduled dose. 
 
Due to a theoretical potential for LCL161 sensitizing skin to toxicity from UV exposure, 
patients should be instructed to refrain from excessive sun exposure and other forms of UV 
radiation (e.g., tanning beds) while taking LCL161. 
 
The investigator should instruct the patient to take the study drug exactly as prescribed 
(promote compliance). All dosages prescribed and dispensed to the patient and all dose 
changes during the study must be recorded appropriately. 
 
the first dose of LCL161 be administered in the clinic under the supervision of the 
investigator, treating physician, or clinic staff. Dexamethasone administration will be optional 
for first dose and for subsequent doses at discretion of treating physician and PI. For at home 
dosing, patients must be provided with appropriate patient education to ensure awareness of 
recognizing symptoms of cytokine release syndrome, and an informed action plan in the event 
of CRS onset. Patients must also be provided with adequate supply of dexamethasone in the 
event of cytokine release syndrome occurrence. 
 
5.1.1.2 Known undesirable effects of LCL161 
See Section 1.2.2.1 and the Investigator’s  Brochure.  The most common toxicities of LCL161 
are diarrhea, asthenia and rash; grade 3 and 4 toxicity is rare. Diarrhea is common, typically 
as one or two loose stools within hours of taking LCL161. A complex of symptoms consistent 
with cytokine release syndrome (CRS) was the principle dose limiting toxicity for patients 
treated in the first in human study, where use of concomitant dexamethasone was prohibited. 
The symptoms of CRS variably included fever, flushing/rash, diarrhea, vomiting, asthenia and 
in the most severe cases, hypotension. Clinically significant CRS has not been reported to 
date on the ongoing study with paclitaxel + LCL161, where dexamethasone is used as a 
premedication for paclitaxel. Two principal toxicities characteristic of paclitaxel, neutropenia 
and peripheral neuropathy, have not generally been observed with LCL161, suggesting that it 
does not cause these toxicities. Pneumonitis, a toxicity observed for some patients treated 
with LCL161 + paclitaxel, was not observed in patients treated with LCL161 as a single agent. 
5.1.1.3 Ancillary treatments for LCL161 
Cytokine release syndrome 
Cytokine release syndrome variably includes signs of flushing or pruritic rash, fever, diarrhea, 
asthenia/extreme weakness, and in more severe cases, symptomatic hypotension. The 
symptoms have typically occurred within twelve hours of LCL161 administration, and if they 
occur then consideration should be given to increased monitoring/hospitalization, IV fluids, 
IV dexamethasone, and H1/ H2 receptor antagonists. 
 
For at home dosing of study drug after the initial dose, patients must be provided with 
adequate supply of dexamethasone along with instruction on self-administration. Adequate 
education on how to recognize the symptoms of cytokine release syndrome should be provided 


22
 
to patients at every cycle. Should CRS onset symptoms occur, patients should be instructed 
on how to manage the symptoms and to contact the investigator. 
 
Medications metabolized by CYP3A4/5 
Results from the clinical DDI study with midazolam CLCL161A2105 showed that LCL161 is 
a potent time-dependent inhibitor of CYP3A4 activity. For patients taking medications 
metabolized by CYP3A4/5 and where increased exposure to these medications may put the 
patient at risk, the medication may be withheld on the day of LCL161 dosing and resumed on 
the following day. This could include, for example, blood pressure medications metabolized 
primarily by CYP3A4/5. High levels of anti-hypertensive medication after LCL161 dosing 
could exacerbate clinical symptoms of hypotension for patients who develop CRS. The risk of 
CRS appears to be limited to the day of LCL161 dosing and CYP enzyme activity returns 
quickly. 
 
Rash 
Preclinical data indicate that LCL161 induces apoptosis of basal and suprabasal epidermal 
cells. Rash, often described as acneiform and sometimes associated with pruritus or some 
peeling, has been observed in patients treated with LCL161. Symptomatic treatment with 
topical agents may include steroids. 
 
Anti-emetics 
Patients may be treated prophylactically with anti-5-HT3-emetics. 
 
Anti-diarrheals 
Patients should have medication available in case LCL161-induced diarrhea occurs. The 
commonly  used  anti-diarrheal  medication  loperamide  is  metabolized  by  CYP2C8  and 
CYP3A4, and based upon DDI studies performed to date, LCL161 may affect the metabolism 
of loperamide. However, extensive clinical experience with loperamide has demonstrated a 
wide safety margin for dosing, with very few serious consequences of overdosing. 
Nonetheless, caution should be used and patients taking LCL161 should be made aware of the 
risk of constipation. 
 
Pneumonitis 
All patients reporting respiratory symptoms should be evaluated for possible infectious causes 
and for non-infectious pneumonitis. Such symptoms might include cough, dyspnea and fever, 
hypoxia can occur in the more severe cases hypoxia. Radiographic confirmation and an 
appropriate evaluation for infectious causes are required for those patients in whom a diagnosis 
of pneumonitis is being considered. Bronchoscopy and pulmonary function testing may be 
helpful in evaluating the causes and severity of lung disease. Initial treatment for pneumonitis 
should include prednisone at 1 mg/kg/day or similar corticosteroid to be tapered as symptoms 
resolve. 
 
5.1.2 
Dosing and treatment schedule 
 
Twenty-eight days (4 weeks) will be considered one cycle of therapy. Subjects will remain on 
study treatment, in the absence of disease progression or toxicity warranting discontinuation 
of therapy, as long as there is evidence of clinical benefit, as judged by the treating physician. 
Dose reduction is allowed in case of intolerance; guidelines for drug dose decrease or 
interruption will be provided. 


23
 
 
5.1.3 
Definitions of dose limiting toxicities (DLTs) 
 
DLT will be defined as an AE or abnormal laboratory value related to study treatment (i.e., 
assessed as unrelated to disease, intercurrent illness, or concomitant medications), including 
those AEs and abnormal laboratory values that result in a failure to meet the criteria for re- 
treatment. If at any time during the study a patient experiences a DLT, the study treatment 
must be stopped and the toxicity(ies) in question must be followed until resolution or 
stabilization. If treatment is to be resumed administration must be resumed at a lower dose. 
 
Prior to advancing/changing dose levels a cohort summary must be completed and submitted 
to the IND Office/Medical Monitor. 
 
Table 5-1 
Criteria for defining dose-limiting toxicities (DLTs) 
 
Toxicity 
Criteria 
Hematology 
Febrile neutropenia (ANC, including bands, of < 1.0 x 109/L (1000/mm3) 
and fever of ≥38.5°C) 
Grade 4 thrombocytopenia or anemia or neutropenia without fever 
Neurotoxicity 
≥ Grade 3 peripheral motor neuropathy or 
≥ Grade 3 peripheral sensory neuropathy 
Gastrointestinal 
≥ Grade 3 vomiting or nausea despite the optimal use of anti-emetics 
≥ Grade 3 diarrhea despite the use of optimal anti-diarrheal treatments 
Fatigue 
Grade 3 or higher 
Renal 
Serum creatinine 2.0 X ULN to 3.0 X ULN for > 7 consecutive days 
CTCAE grade ≥ 3 serum creatinine 
Hepatic* 
Direct Bilirubin ≥ 3.0 x ULN 
Direct Bilirubin 2.0-3.0 x ULN and ≥ Grade 2 ALT 
AST or ALT ≥ Grade 3 or > 5 x ULN for > 2 weeks for patients with 
involvement of liver with myelofibrosis at baseline 
Allergic 
≥Grade 2 hypersensitivity reaction despite optimal use of prophylaxis 
Dermatologic/ Skin 
Any grade ≥ 2 skin toxicity resulting in a > 72 hour delay in, or interruption 
of LCL161 treatment; any CTCAE grade ≥ 3 
Other adverse events 
not listed above 
Non-hematologic toxicities of ≥ Grade 3 
Any adverse event that requires a dose reduction as determined by the 
investigator 
 
5.1.4 
Follow-up for toxicities 
 
Patients who experience study treatment-related toxicity must be evaluated at least once 
a week until resolution of the toxicity in question to Grade 1, to the patient’s baseline value, 
or until it is deemed irreversible. Assessments used to follow treatment-related toxicities 
are directed by symptoms and signs and include physical examination, vital signs 
(including weight), performance status, and evaluation of adverse events and concomitant 
medications. 
 
Patients who experience toxicities should be followed as outlined in Table 5-2. 
 


24
 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or abnormal laboratory value must be followed at least once a week for 4 weeks, and 
subsequently at 4-week intervals until resolution or stabilization of the event, whichever 
comes first. If a patient requires a dose delay of > 28 days from the intended day of the 
next scheduled dose of LCL161 because of inadequate recovery from LCL161 related 
toxicity, then the patient must be discontinued from the study. However, the patient will 
continue to be followed for resolution of the toxicity in question, as previously described. All 
patients will be followed for adverse events and serious adverse events for 30 days following 
the last dose of study treatment. 
 
Table 5-2 
General guidelines for follow-up of study treatment-related toxicity 
 
Toxicity 
Follow-up evaluation 
Hematology 
If CTCAE Grade ≥ 4 neutropenia or thrombocytopenia has been demonstrated, 
these parameters should be re-evaluated at least twice a week until resolution to 
CTCAE Grade ≤ 1 or the patient’s baseline. 
Cardiac 
Patients who experience ECG abnormalities indicative of an ischemic cardiac event 
should be managed according to standard medical practice. 
Renal 
If serum creatinine ≥ 2 x baseline occurs, this parameter should be repeated at least 
twice a week until resolution to Grade ≤ 1 or the patient’s baseline, and then at least 
weekly following reinitiation of treatment once creatinine returns to baseline/normal, 
or to document stabilization at an elevated level. 
Neurotoxicity/ 
Pain 
Patients who experience Grade ≥ 2 sensory neuropathy or neuropathic pain or 
Grade ≥ 1 motor neuropathy should be examined at least once a week until 
improvement with resolution to Grade ≤ 1 or the patient’s new baseline. 
Hepatic 
If direct bilirubin ≥ 2 x ULN or Grade ≥ 3 AST/ALT has been demonstrated, these 
parameters should be repeated at least twice a week until resolution to Grade ≤ 1 or 
the patient’s baseline (i.e. Grade ≤ 2 if liver infiltration with tumor present), and then 
at least weekly until either resolution or stabilization. 
Allergy/ 
Autoimmunity 
If a Grade ≥ 3 allergic reaction/hypersensitivity or autoimmunity event occurs and is 
suspected to be related to LCL161, no further LCL161 should be given and the 
patient should be discontinued from the study. 
Inflammation 
Whenever an inflammatory adverse event is suspected, the investigator is 
encouraged to obtain a biopsy of the affected organ as long as it does not place the 
patient at a significantly higher medical risk (e.g., skin biopsies for rash,GI biopsy for 
chronic diarrhea or bronchoscopic biopsy for suspected pneumonitis are 
appropriate). 
Pulmonary 
Potential study treatment-related pulmonary adverse events (i.e., Grade ≥ 2) should 
be evaluated at a minimum by re-evaluation of the chest CT and oxygen saturation 
measurements, as is standard of care. The standard of care oxygen saturation 
measurements should be repeated at least twice a week until resolution to Grade ≤ 1 
or the patient’s baseline. Bronchoscopy for those patients with suspected pneumonia 
or pneumonitis should be considered to evaluate infectious causes and potentially for 
biopsy of lung tissue. Pulmonary function testing may be helpful to evaluate the 
severity of lung disease. 
A chest radiograph may be used for immediate evaluation; however, it will not 
replace the need for a follow-up chest CT scan. PFTs may also be obtained at the 
discretion of the investigator to investigate pulmonary toxicity. 
Non-laboratory
Patients who experience non-laboratory DLTs or any additional toxicity that the 
investigator deems significant  will be evaluated  at  least once a week following 
demonstration of the toxicity, until resolution or stabilization of the toxicity. 
 


25
 
5.2 
Dose modifications 
 
5.2.1 
Dose modification and dose delay 
 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted in order to allow the patient to continue the study treatment. All dose 
modifications should be based on the worst preceding toxicity (CTCAE version 4.03). 
If a patient experiences a DLT, study treatment should be interrupted and the toxicity 
should be followed. 
 
5.2.2 
Treatment interruption and treatment discontinuation 
 
5.2.2.1 
Dose reductions for DLTs possibly associated with LCL161 
 
Table 5-3 
Dose modifications for toxicities suspected related to LCL161 
 
Toxicity 
Grade 
Actions 
Non-hematological 
1 or 2 
- Continue LCL161 therapy at full dose, with optimal supportive care. 
 
- For prolonged (> 1 week) toxicity that interferes significantly with 
quality of life, two dose level reductions of LCL161 are allowed 
 
-See Table 5-4 for dose level reductions 
3 or 4 
- Delay LCL161 until recovery to grade ≤ 1 with optimal supportive care. 
Reduce LCL161 dose one dose level. 
 
- If symptoms recur, reduce one dose level 
 
-See Table 5-4 for dose level reductions 
Hematological (not observed 
with LCL161 as a single agent)
1 or 2 
- Continue LCL161 therapy at full dose, with optimal supportive care 
3 or 4 
- Delay study treatment until neutrophils ≥1.5 x109/L (1,500/mm3), 
platelets ≥100 x109/L (100,000/mm3) and Hgb ≥ 9.0 g/dL 
 
- Reduce LCL161 dose one dose level 
- If toxicity recurs, reduce LCL161 dose one dose level 
 
-See Table 5-4 for dose level reductions 
 
Table 5-4 
Dose level reduction (weekly dose) 
Dose Level 
LCL161 Dose 
0 
1500 mg 
-1 
1200 mg 
-2 
900 mg 
-3 
600 mg 
-4 
300 mg 
 
5.2.2.2 Discontinuation of therapy due to study treatment-related toxicity 
 
Study treatment should not be resumed in the case of the following study treatment-
related events. 


26
 
 ≥ Grade 3 cardiac event 
 ≥ Grade 3 allergic/hyper-sensitivity, cytokine release syndrome or autoimmune reaction or 
other non-hematologic events of Grade 4 severity 
 > 28-day dose delay due to study treatment-related toxicity. 
 
Patients who discontinue from the study for a study treatment-related adverse event or an 
abnormal laboratory value must be followed as described in Table 5-2. All interruptions and 
changes to study drug administration or dose must be recorded appropriately. 
 
5.3 
Concomitant medications 
 
The investigator should instruct the patient to notify the study site about any new medications 
including herbals and supplements he/she takes after the start of the study drug. All 
concomitant medications and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after patient consent and through end of study participation 
for patients enrolled on protocol will be captured. 
 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient is allowed, including drugs given prophylactically, with the following exceptions: 
 Other investigational therapies must not be used while the patient is on study. 
 Anticancer therapy (e.g., chemotherapy, biologic, immunologic or radiation therapy, and 
surgery) other than the study treatment (LCL161) must not be given while the patient is on 
the study with the exception of Hydroxyurea for baseline proliferative patients. For these 
patients, Hydroxyurea will be allowed at the discretion of the attending physician or PI at 
a maximum dose of 5 Grams per day. 
 Routine use of granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage 
colony stimulating factor (GM-CSF) must be used in accordance with the American 
Society of Clinical Oncology’s (ASCO) 
 Patients receiving recombinant erythropoietin or darbepoetin alfa prior to starting study 
drug may continue their pre-treatment doses throughout the study. 
 Subjects should not receive h i g h  d o s e ,  o n g o i n g  corticosteroids therapy or any 
other immunosuppressive treatment while enrolled in this study except as instructed per 
study protocol and at the discretion of the PI. 
 Any immune stimulating agents (e.g., cytokines, vaccines), must not be used while the 
patient is on the study except inactivated (killed) or component vaccines (e.g. influenza 
vaccine). 
 Acute reactions (e.g., hypersensitivity reactions) should be managed according to standard 
medical practice, as determined by the investigator. 
 Results from the clinical DDI study with midazolam indicate that LCL161 is a potent 
time-dependent inhibitor of the metabolizing enzyme CYP3A4/5. Therefore, use of 
medications that have a narrow therapeutic index and that are primarily metabolized by 
CYP3A4/5 will be discouraged and may only be used with PI approval. In addition, the 
use of medications that carry a risk for QT prolongation and that are substrates for 
CYP3A4/5 will be discouraged and may only be used with PI approval. LCL161 is 
primarily metabolized by cytosolic NADPH-dependent carbonyl reductase(s) (~60%), with 
a minor contribution of oxidative metabolism (~40%) (mainly CYP2C8, followed by 
CYP3A). Therefore, use of medications that are strong inhibitors of CYP2C8 will be 


27
 
discouraged in this study and will require PI approval to use. Caution is recommended 
when combining LCL161 with any other CYP2C8 or CYP3A4/5-interacting medication. 
 
Patients taking chronic medication should be maintained on the same dose and dose schedule 
throughout the study period, as medically feasible. Certain medications metabolized primarily 
by CYP3A4/5 that may pose a safety risk on the day of LCL161 dosing can be held and 
resumed the following day, at the investigator’s discretion. 
 
5.3.1 
Packaging and labeling 
 
LCL161 will be supplied as tablets for oral use of 300 mg dosage strength. LCL161 will be 
dosed on a flat scale and not adjusted to body weight or body surface area. 
 
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, LCL161 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. For at home dosing after the initial dose Patients will be 
provided with adequate supply of LCL161 for self-administration at home until at least their 
next scheduled study visit. 
 
The film-coated LCL161 tablets are stored in a standard high density plastic bottle with child 
resistant closure. LCL161 should be stored according to the following conditions: “Do not 
store above 25°C, protect from moisture, protect from light.” 
 
5.3.2 
Drug compliance and accountability 
 
5.3.2.1     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. 
 
At the conclusion of the study, and, as appropriate during the course of the study, the 
Investigational Pharmacy will return all used and unused study drug, packaging, drug labels, 
and a copy of the completed drug accountability ledger to Novartis. 
 
5.3.3       Disposal and destruction 
 
The drug supply will be destroyed at a Novartis facility, or Novartis will provide guidelines 
for destruction, if investigational site is approved to destroy drug per prior agreement with 
Novartis. 
 
 
 
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. 


28
 
 
Table 6-1 Visit evaluation schedule 
 
Category 
Screening 
Cycle 1 Cycles 2-4
Cycle 7 
Cycles 10+ 
(Every 6 cycles 
starting with 
cycle 10) 
 
End of 
Treatment 
(EOT) 
Study 
Evaluation 
Completion 
Day of Cycle 
-28 to 
-1 
1 
1 
Day 1 
(+/- 5 days)
Day 1 
(+/- 5 days) 
Within 7 days 
of last dose 
30 days after 
last dose 
Informed consent 
X 
Demography 
X 
Inclusion/exclusion criteria
X 
Relevant medical history/ 
Current Medical 
Conditions
X 
 
 
 
 
 
 
Concomitant medications1
X 
Continuous
Adverse events 
X 
Continuous (up to 30 days post study discontinuation)
X 
LCL161 dosing 
Once weekly dosing8
Vitals 
X 
X 
X 
X 
X 
X 
 
Physical Exam2, 9 
X 
X 
X 
X 
X 
X 
 
Serum Pregnancy Test 
for WCBP3 
X 
 
 
 
 
 
 
Biochemistry4 
X
X
X 
X
X
Hematology 
X
X
X 
X
X
Urinalysis 
X 
 
As needed 
As needed 
 
 
ECOG performance7 
status 
X 
 
X 
X 
X 
X 
 
EKG 
X 
Bone marrow 
aspiration/biopsy5 
X 
 
Cycle 4* 
X* 
X* 
 
 
MPN-SAFTSS and 
MDASI6, 7 
X 
 
X 
X 
X 
X 
 
Correlative Studies 
(Optional) 
X** 
 
X** 
 
 
X** 
 
* 
Bone marrow biopsy sample will be collected at Screening, Day 1 of Cycle 4, and then every 3-6 cycles thereafter at 
the discretion of the treating physician.  
** 
Correlative Studies at Screening, Day 1 of Cycles 2 and 3 and End-of-Treatment Visits 
1 Within 14 days of study day 1 
2 History and physical exam including body weight, spleen and liver measurements. This also includes a transfusion history 
for 3 months prior to day 1 
3 Pregnancy test (for Females of Child Bearing Potential - FCBP only; within 3 days of day 1) 
4 CBC and differential, electrolytes (Na, K, Cl, HCO3), creatinine, uric acid, BUN, glucose, direct and total bilirubin, uric 
acid, SGOT and SGPT (within 14 days of study day 1) at screening and per visit evaluation schedule 
5 Bone marrow biopsy and/ or aspirate (within 3 month of study day 1) with cytogenetics (if not done before) and 
JAK2V617F status and allele burden (if not done before) 
6 Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF TSS) and M. D. Anderson Symptom Inventory 
(MDASI) questionnaire (within 3 days of study day 1) 
7 ECOG performance status and MPN-SAFTSS and MDSAI questionnaires will be performed/administered if the patient is 
seen at MDACC but not if seen by their local physician in cycles 4 and beyond 
8 Weekly doses will be administered every 7 days (+/- 3days) 
9 Cycle 1 Day 1 physical exam may be waived if screening exam is done within 3 days prior to Cycle 1 Day 1. 
 
 
 
 


29
 
 
6.2 
Assessment types 
 
6.2.1 
Efficacy 
 
Descriptive statistics will be utilized to assess time to response and response duration. 
 
Duration of response: duration of response is defined as the date at which the subject’s 
objective status is first noted to be a CR or PR to the date progression is documented (if one 
has occurred) or to the date of last follow-up (for those subjects who have not progressed). 
 
Time to response: The time to response is defined as the time from study registration to the 
first date at which the subject’s objective status was classified as a response (CR or PR). In 
subjects who do not achieve a response, time to response will be censored at the subject’s last 
evaluation date. The distribution for each of these event-time variables (duration of response 
and time to response) will be estimated by Kaplan-Meier curves. 
 
6.2.2 
Safety 
 
Safety assessments will consist of the following: monitoring and recording of all adverse 
events and serious adverse events; the regular monitoring of hematology, blood chemistry, 
urinalysis; regular measurement of vital signs, physical examination, including weight; and 
performance status. 
 
These assessments should be performed periodically throughout the study, except for adverse 
events that will be evaluated continuously. 
 
Data from all subjects who receive any study drug will be included in the safety analyses. 
Subjects who entered the study and did not take any of the study drug and had this confirmed, 
will not be evaluated for safety. The severity of the toxicities will be graded according to the 
NCI CTCAE v4.03 whenever possible. We will follow standard reporting guidelines for 
adverse events. 
 
6.2.3 
Biomarkers 
 
Samples will be collected during the course of the study to assess the mechanisms of action of 
LCL161 in patients with MF. Correlative studies will not be mandatory for patient accrual. 
These studies will include the analysis of cIAP1, XIAP, and PARP protein levels which will 
be determined by western blot (actin as loading control) at the following timepoints: baseline, 
beginning of each cycle for the 1st  3 cycles, and the end of study.  All samples will be 
collected at the time or regularly performed blood draws or bone marrow biopsies so no 
additional procedures will be required.  The samples will be batched and stored for analysis at 
a later date in the lab of Dr. Bing Carter, MD.  In case a collection of blood is missed for 
correlative studies, this will not be reported as a violation of the study. 


30
 
7 
Adverse Events 
 
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 (or therapy) 
even if the event is not considered to be related to study drug (or therapy). Study drug (or 
therapy) includes the drug (or therapy) under evaluation, and any reference or placebo drug 
(or therapy) given during any phase of the trial. 
 if it is unclear what study treatment includes, list all drug(s), other therapies, changes to 
existing therapy, diagnostic procedure, etc. that are specified by the protocol 
 
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. 
 
All “suspected adverse reactions” (as defined in 21 CFR 312.32(a)) will be captured in the 
case report forms. For abnormal chemical values grade 3 or 4, the apogee will be reported per 
course in the CRF. To ensure patient safety each serious adverse event must also be reported 
to Novartis within 24 hours of learning of its occurrence. 
 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 Adverse events and specific data will be entered into CORe/PDMS. 
CORe/PDMS will be used as the electronic case report form for this protocol. 
 
7.2 
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. 
 


31
 
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. 
 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 Serious 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 dose of drug, 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. 
 
The following SAEs are not subject to expedited reporting, but would still be included in the 
annual report via the SAE log. 
a. 
Infection or cytopenias leading to hospitalization or prolongation of hospitalization 
Disease progression leading to death, life-threating AE, hospitalization or 
prolongation of hospitalization, or disability. 
 
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 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. 
 


32
 
7.2.1 
Investigator Communications with Novartis 
 
The Investigator will assess the relationship to study treatment and send the initial SAE form 
and Novartis SAE coversheet by fax or email within 24 hours to the local Novartis Drug 
Safety & Epidemiology (DS&E) Department: 
FAX: 
1.888.299.4565 
EMAIL: 
clinicalsafetyop.phuseh@novartis.com 
copy Mark Szarszewski:  mark.szarszewski@novartis.com 
 
The investigator must then ensure that the SAE form and coversheet are accurately and fully 
completed with follow-up information and fax those to Novartis DS&E Department within 2 
to 3 calendar days for deaths or life-threatening events and 5 calendar days for other serious 
adverse events. Follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or discontinued study participation. The SAE form, Novartis SAE 
coversheet, and fax confirmation sheet must be retained in the regulatory binder. 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. 
 
7.3 
Pregnancies 
 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must 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 the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
 
Pregnancy should be recorded on a MD Anderson SAE 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 
 
8.1 
Sample size calculation 
 
A maximum of 50 patients will be enrolled in the study. All patients will be registered 
through the Clinical Oncology Research System (CORe) at MDACC, and the estimated 
accrual rate is approximately 2 patients per month. 
Based on the solid tumor trial experience, at dosage level of 1800 mg for LCL161, one patient 
among 24 developing a grade 3 cytokine release syndrome which is non-hematologic. With 
the consideration of the safety issue, patients will be given the LCL161 at a lower dose of 
1500 mg. The length of each treatment cycle is 28 days. If there are at least 2 out of 6 
experiencing DLT or at least 2 out of 3 experiencing DLT at dosage of 1500mg during the 
first cycle, the trial will be stopped for further investigation. 
 


33
 
The primary efficacy endpoint is objective response (OR), defined as CR (complete 
remission)+PR (partial remission)+CI (clinical improvement) for MF patients  after 3 cycles 
of treatment. The primary objective of this study is to assess efficacy in terms of the objective 
response rate after 3 cycles of treatment.  The two-stage design will be implemented.  We 
assume a target ORR of 35% and a response rate of 18% or lower will be considered not 
desirable. With a type I error rate of 4% and 80% power, we will enroll 16 patients in the first 
stage. If 3 or fewer patients achieve OR, the trial will be stopped. If 4 or more out of the first 
16 patients have OR, accrual will continue until a total of 50 patients have been enrolled. 
After the first 16 patients have enrolled, the study will not enroll new patient until enough 
responses (at least 4 responses out of 16 patients) are observed to warrant the continuation of 
the study. At the end of the study, if 14 or more out of these 50 patients achieve OR, the 
treatment of LCL161 will be considered efficacious and is worth further investigation. Under 
this two-stage design, the probability of early termination is 68% if the true ORR is 18% and 
the expected sample size is 26.96 patients. NCSS-PASS 2005 software was used to create the 
design details.  
 
The method of Thall, Simon and Estey [1995] will be used for toxicity monitoring for this 
study. 
 
Toxicity will be monitored among the 50 patients. Denote the probability of toxicity by p(T), 
where toxicity is defined as Grade 3-4 clinically relevant non-hematologic toxicity or a 
serious adverse event that is at least possibly drug related (Common Terminology Criteria for 
Adverse Events CTCAE version 4.03) and occurs anytime during the treatment. We assume 
as a priori, p(T) ~ beta (0.6, 1.4).  We will stop treating patients if Pr(p(T)> 0.30 | data)  >0.9. 
That is, we will stop the trial for new patient enrollment if at any time during the study, we 
determine that there is more than 90% chance that the toxicity rate is more than 30%. This 
toxicity stopping rule will be applied by cohort size of 5, starting from the 5th patient. 
Stopping boundaries corresponding to this stopping rule are listed in table 8.3a. The 
operating characteristics are summarized in Table 8.3b. Multc Lean Desktop (version 2.1) 
was used to generate the toxicity stopping boundaries and the OC table.  
Table 8.3a Boundary table for toxicity monitoring 
# of patients ( in cohort of 5, 
starting from the 5th patient)
Stop the trial if there are this 
many patients with toxicities:
5 
4-5 
10 
6-10 
15 
8-15 
20 
9-20 
25 
11-25 
30 
13-30 
35 
15-35 
40 
16-40 
45 
18-45 
 


34
 
Table 8.3b. Operating characteristics for toxicity monitoring 
 
True toxicity rate
Prob(stop the trial early)
Average sample size
0.2 
0.02 
49.21 
0.25 
0.08 
47.43 
0.3 
0.22 
43.59 
0.35 
0.44 
37.48 
0.4 
0.69 
30.12 
 
Analysis Plan 
 
Summary statistics will be provided for continuous variables. Frequency tables will be used 
to summarize categorical variables. The objective response rate (ORR) will be estimated 
along with the Bayesian 95% credible interval. 
 
Data from all subjects who receive any study drug will be included in the safety analyses. 
Subjects who entered the study and did not take any of the study drugs and had this confirmed, 
will not be evaluated for safety. The severity of the toxicities will be graded according 
to the NCI CTCAE v4.03 whenever possible. We will follow standard reporting guidelines 
for adverse events. Safety data will be summarized by category, severity and frequency. 
The proportion of patients with AEs will be estimated, along with the Bayesian 95% 
credible interval. 
 
Duration of response: duration of response is defined as the date, at which the subject’s 
objective status is first noted, to the date progression (no longer meeting criteria for any type 
of response). Patients who continue to respond as of the data cut-off date will be censored as 
of the date of their last assessment documenting continued response. 
 
Time to response: The time to response is defined as the time from study registration to the 
first date at which the subject’s objective status was classified as a response. In subjects who 
do not achieve a response, time to response will be censored at the subject’s last evaluation 
date. The distribution for each of these event-time variables (duration of response and time to 
response) will be estimated by Kaplan-Meier curves. 
 
 
 
9 
Administrative procedures 
 
9.1 
Discontinuation of study support 
 
Novartis and the IND Office reserves the right to discontinue support for any study under the 
conditions specified in the clinical trial agreement. 
 
9.2 
Amendments to the protocol 
 
Any change or addition to this protocol requires a written protocol amendment that must be 
approved by Novartis, the investigator, and the IND office before implementation. 
Amendments significantly affecting the safety of subjects, the scope of the investigation or the 


35
 
scientific quality of the study, require additional approval by the IRB/IEC/REB. A copy of the 
written approval of the IRB/IEC/REB, must be sent to Novartis. 
 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB/IEC/REB approval but the IRB/IEC/REB of each center must be kept 
informed of such administrative changes. 
 
9.2.1 
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 
Investigator/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. 
 
9.2.2 
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. 


36
 
10 
References (available upon request) 
 
Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science; 281 
 
Chai J, Du C, Wu JW, et al (2000) Structural and biochemical basis of apoptotic activation by 
Smac/DIABLO Nature; 406 (6798):855-62. 
 
Du C, Fang M, Li Y, et al (2000) Smac, a mitochondrial protein that promotes cytochrome 
cdependent caspase activation by eliminating IAP inhibition. Cell; 102(1):33-42. 
 
Fleischman AG, Aichberger KJ, Luty SB, et al (2011) TNF-alpha facilitates clonal expansion 
of JAK2V617F positive cells in myeloproliferative neoplasms. Blood; 118(24):6392-8. 
 
Green DR, Reed JC (1998) Mitochondria and apoptosis. Science; 281(5381):1309-12. 
Gyrd-Hansen M, and Meier P (2010) IAPs: from caspase inhibitors to modulators of NF-kB, 
inflammation and cancer. Nature reviews/cancer; 10:561-74. 
 
Hofmann  HS,  Simm  A,  Hammer  A  (2002)  Expression  of  inhibitors  of  apoptosis  (IAP) 
proteins in non-small cell human lung cancer. J Cancer Res Clin Oncol; 128(10): 554-60. 
 
Krajewska  M,  Krajewski S, Banares S, et al (2003)  Elevated expression  of  inhibitor of 
apoptosis proteins in prostate cancer. Clin Cancer Res; 9(13):4914-25. 
 
Li L, Thomas RM, Suzuki H, et al (2004) A small molecule Smac mimic potentiates TRAIL 
and TNFalpha-mediated cell death. Science; 305(5689):1471-4 
 
Shiraki K, Sugimoto K, Yamanaka Y, et al (2003) Overexpression of X-linked inhibitor of 
apoptosis in human hepatocellular carcinoma. Int J Mol Med; 12(5):705-8. 
 
Tamm I, Richter S, Oltersdorf D, et al (2004) High expression levels of x-linked inhibitor of 
apoptosis protein and survivin correlate with poor overall survival in childhood de novo acute 
myeloid leukemia. Clin Cancer Res; 10(11):3737-44. 
 
Tamm I, Kornblau SM, Segall H, et al (2000) Expression and prognostic significance of 
IAPfamily genes in human cancers and myeloid leukemias. Clin.Cancer Res; 6(5):1796-803. 
 
Van Schaik RH (2008) CYP450 pharmacogenetics for personalizing cancer therapy. Drug 
Resist Update; 11(3): 77-98 
 
Varfolomeev  E,  Blankenship  JW,  Wayson  SM,  et  al  (2007)  IAP  Antagonists  Induce 
Autoubiquitination of c-IAPs, NFKB Activation and TNFa-Dependent Apoptosis. Cell; 
131(4): 669-681. 
 
Verhagen AM, Ekert PG, Pakusch M, et al (2000) Identification of DIABLO, a mammalian 
protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell; 102(1):43-
53. 


37
 
Vince JE, Wong W, Khan N, et al (2007) IAP antagonists target cIAP1 to induce 
TNFalphadependent apoptosis. Cell; 131(4):682-693. 
 
Wu H, Tschopp J and Lin SC (2007) Smac mimetics and TNFalpha: a dangerous liaison? 
Cell; 131(4): 655-658. 
 
Food and Drug Administration (FDA) (2006). Guidance for Industry, Drug Interaction Studies 
- Study Design, Data Analysis and Implications for Dosing and Labeling, Center for Drug 
Evaluation and Research (CDER), Draft Guidance (Internet) Available from: 
US Department of Health and Human Services (2007) Guidance for Industry Clinical Trial 
Endpoints for the Approval of Cancer Drugs and Biologics. FDA 
 
 
Simon, R (1989) Optimal two-stage designs for phase II clinical trials. Controlled Clinical 
Trials, 10: 1-10 , 1989 
 
 
Thall, PF, Simon, R, Estey, EH (1995)  Bayesian sequential monitoring designs for single- 
arm clinical trials with multiple outcomes.  Statistics in Medicine 14:357-379