Conditions: Ovarian Neoplasms Non-Small-Cell Lung Carcinoma Melanoma Other Solid Tumors
Keywords: LTT462 ERK MAPK solid tumor
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 65
Healthy volunteers: no

Brief summary:
A phase I study of LTT462 in patients with advanced solid tumors that harbor MAPK pathway alterations.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None

Interventions: intervention 1: LTT462
Intervention descriptions: intervention 1: ERK Inhibitor

Protocol document:
Prot_000.pdf: 
Clinical Development 
LTT462 
Oncology Clinical Trial Protocol CLTT462X2101 / NCT02711345
A phase I dose finding study of oral LTT462 in adult 
patients with advanced solid tumors harboring MAPK 
pathway alterations 
Document type 
Amended Protocol Version 
EUDRACT number 
2015-003614-24 
Version number 
03 (Clean) 
Development phase 
I 
Document status 
Final 
Release date 
13-Mar-2018
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Template version 17-Nov-2014 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of figures ...................................................................................................................... 7 
List of tables ........................................................................................................................ 7 
List of abbreviations ............................................................................................................ 9 
Glossary of terms ............................................................................................................... 12 
Amendment 3 (13-Mar-2018) ........................................................................................... 13 
Amendment 2 (14-Aug-2017) ........................................................................................... 16 
Amendment 1 (14-Jul-2016) ............................................................................................. 18 
Protocol summary .............................................................................................................. 21 
1 
Background ........................................................................................................................ 24 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 24 
 
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25 
 
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1.2 
Introduction to investigational treatment ............................................................... 27 
1.2.1 
Overview of LTT462 ............................................................................ 27 
 
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1.2.3 
Clinical experience ................................................................................ 31 
2 
Rationale ............................................................................................................................ 32 
2.1 
Study rationale and purpose ................................................................................... 32 
2.2 
Rationale for the study design ............................................................................... 32 
2.3 
Rationale for dose and regimen selection .............................................................. 35 
3 
Objectives and endpoints ................................................................................................... 35 
4 
Study design ...................................................................................................................... 38 
4.1 
Description of study design ................................................................................... 38 
4.1.1 
Dose escalation ...................................................................................... 38 
 
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4.2 
Timing of interim analyses and design adaptations ............................................... 42 
4.3 
Definition of end of the study ................................................................................ 42 
4.4 
Early study termination .......................................................................................... 42 
5 
Population .......................................................................................................................... 43 
5.1 
Patient population .................................................................................................. 43 
5.2 
Inclusion criteria .................................................................................................... 43 


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5.3 
Exclusion criteria ................................................................................................... 44 
6 
Treatment ........................................................................................................................... 48 
6.1 
Study treatment ...................................................................................................... 48 
6.1.1 
Dosing regimen ..................................................................................... 48 
6.1.2 
Treatment duration ................................................................................ 50 
6.2 
Dose escalation guidelines ..................................................................................... 50 
6.2.1 
Starting dose rationale ........................................................................... 50 
6.2.2 
Provisional dose levels .......................................................................... 50 
6.2.3 
Guidelines for dose escalation and determination of 
MTD(s)/RDE(s) .................................................................................... 51 
6.2.4 
Definitions of dose limiting toxicities (DLTs) ...................................... 54 
6.3 
Dose modifications ................................................................................................ 55 
6.3.1 
Dose modification and dose delay ........................................................ 55 
6.3.2 
Follow-up for toxicities ......................................................................... 63 
6.3.3 
Anticipated risks and safety concerns of the study drug ....................... 63 
6.4 
Concomitant medications ...................................................................................... 63 
6.4.1 
Permitted concomitant therapy ............................................................. 63 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ........... 63 
6.4.3 
Prohibited concomitant therapy ............................................................ 64 
6.5 
Patient numbering and treatment assignment ........................................................ 64 
6.5.1 
Patient numbering ................................................................................. 64 
6.5.2 
Treatment assignment ........................................................................... 64 
6.6 
Study treatment preparation and dispensation ....................................................... 64 
6.6.1 
Study treatment packaging and labeling ............................................... 65 
6.6.2 
Drug supply and storage ........................................................................ 65 
6.6.3 
Study drug compliance and accountability ........................................... 65 
6.6.4 
Disposal and destruction ....................................................................... 66 
7 
Visit schedule and assessments ......................................................................................... 66 
7.1 
Study flow and visit schedule ................................................................................ 66 
7.1.1 
Molecular pre-screening ........................................................................ 75 
7.1.2 
Screening ............................................................................................... 75 
 
 76 
7.1.4 
Treatment period ................................................................................... 76 
7.1.5 
Discontinuation of Study Treatment ..................................................... 77 
7.1.6 
Withdrawal of Consent ......................................................................... 78 
7.1.7 
Follow up for Safety Evaluations .......................................................... 78 


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7.1.8 
Lost to follow-up ................................................................................... 79 
7.2 
Assessment types ................................................................................................... 80 
7.2.1 
Efficacy assessments ............................................................................. 80 
7.2.2 
Safety and tolerability assessments ....................................................... 82 
7.2.3 
Pharmacokinetics .................................................................................. 86 
7.2.4 
Biomarkers ............................................................................................ 89 
8 
Safety monitoring and reporting ........................................................................................ 94 
8.1 
Adverse events ....................................................................................................... 94 
8.1.1 
Definitions and reporting ...................................................................... 94 
8.1.2 
Laboratory test abnormalities ................................................................ 96 
8.1.3 
Adverse events of special interest ......................................................... 96 
8.2 
Serious adverse events ........................................................................................... 96 
8.2.1 
Definitions ............................................................................................. 96 
8.2.2 
Reporting ............................................................................................... 97 
8.3 
Pregnancies ............................................................................................................ 98 
8.4 
Warnings and precautions ...................................................................................... 98 
8.5 
Data Monitoring Committee .................................................................................. 99 
 
 99 
9 
Data collection and management ..................................................................................... 100 
9.1 
Data confidentiality ............................................................................................. 100 
9.2 
Site monitoring .................................................................................................... 100 
9.3 
Data collection ..................................................................................................... 101 
9.4 
Database management and quality control .......................................................... 101 
10 Statistical methods and data analysis .............................................................................. 102 
10.1 
Analysis sets ........................................................................................................ 103 
10.1.1 
Full Analysis Set ................................................................................. 103 
10.1.2 
Safety Set ............................................................................................ 103 
 
 103 
10.1.4 
Dose-determining analysis set............................................................. 103 
10.1.5 
Pharmacokinetic analysis set ............................................................... 103 
10.2 
Patient demographics/other baseline characteristics ........................................... 104 
 
 104 
10.4 
Primary objective ................................................................................................. 105 
10.4.1 
Variable ............................................................................................... 105 
10.4.2 
Statistical hypothesis, model, and method of analysis ........................ 105 
10.4.3 
Handling of missing values/censoring/discontinuations ..................... 110 


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10.4.4 
Supportive analyses ............................................................................. 110 
10.5 
Secondary objectives ........................................................................................... 111 
10.5.1 
Secondary efficacy objectives ............................................................. 111 
10.5.2 
Secondary Safety objectives ............................................................... 112 
10.5.3 
Pharmacokinetics ................................................................................ 115 
10.5.4 
Biomarkers .......................................................................................... 117 
 
 118 
10.7 
Interim analysis .................................................................................................... 118 
10.8 
Sample size calculation ........................................................................................ 119 
10.8.1 
Dose-escalation part ............................................................................ 119 
 
 119 
 
 121 
11 Ethical considerations and administrative procedures .................................................... 121 
11.1 
Regulatory and ethical compliance ...................................................................... 121 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 121 
11.3 
Informed consent procedures ............................................................................... 121 
11.4 
Discontinuation of the study ................................................................................ 122 
11.5 
Publication of study protocol and results............................................................. 122 
11.6 
Study documentation, record keeping and retention of documents ..................... 123 
11.7 
Confidentiality of study documents and patient records ..................................... 123 
11.8 
Audits and inspections ......................................................................................... 124 
11.9 
Financial disclosures ............................................................................................ 124 
12 Protocol adherence .......................................................................................................... 124 
12.1 
Amendments to the protocol ................................................................................ 124 
13 References (available upon request) ................................................................................ 125 
14 Appendices ...................................................................................................................... 129 
 
 
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14.2 
Appendix 2: Drugs that are prohibited or to be used with caution ...................... 153 
 
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List of figures 
Figure 4-1 
Study design .......................................................................................... 41 
Figure 4-2 
Study visit flow ..................................................................................... 42 
 
List of tables 
Table 3-1 
Objectives and related endpoints .......................................................... 36 
Table 4-1 
LTT462 regimens .................................................................................. 39 
 
 43 
Table 6-1 
Dose and treatment schedule ................................................................. 48 
Table 6-2 
Provisional dose levels .......................................................................... 51 
 
 55 
 
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Table 6-5 
Supply and storage of study treatments ................................................ 65 
Table 7-1 
Visit evaluation schedule ...................................................................... 67 
 
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Table 7-3 
ECOG performance status ..................................................................... 82 
 
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Table 7-8 
Biomarker sample collection plan ......................................................... 90 
 
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Table 10-7 
Noncompartmental pharmacokinetic parameters ................................ 115 
 
 
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Table 14-6 
Drugs prohibited while on study ......................................................... 153 
Table 14-7 
Drugs to be used with caution while on study .................................... 155 
 
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List of abbreviations 
AE 
Adverse event 
ALK 
Anaplastic lymphoma kinase 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase/ glutamic pyruvic transaminase/ GPT 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase/ glutamic oxaloacetic transaminase/ SGOT 
AUC 
Overall exposure 
AUCinf 
Total plasma exposures 
BHLRM 
Bayesian hierarchical Logistic Regression Model 
BID 
Bis in diem/twice a day 
BLRM 
Bayesian Logistic Regression Model 
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
BUN 
Blood urea nitrogen  
BVN 
Bivariate normal 
 
 
CK 
Creatine kinase, also known as CPK 
Cmax 
Maximum concentration 
Cmin 
Minimum concentration 
CMO&PS 
Chief Medical Office and Patient Safety 
CNS 
Central nervous system 
CPK 
Creatine phosphokinase, also known as CK 
CR 
Complete response 
CRF 
Case report/record form; the term CRF can be applied to either EDC or Paper 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse events 
 
 
Ctrough  
Concentration at trough 
 
 
DCR 
Disease control rate 
DDS 
Dose-determining Set 
DLT 
Dose limiting toxicity 
DOR 
Duration of response 
DUSP6 
Dual specificity phosphatase 6 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern cooperative oncology group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
 
 
EoT 
End of treatment 
ERK 
Extracellular signal-regulated kinases 
EWOC 
Escalation with overdose control 
FAS 
Full analysis set  


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FDA 
Food and Drug Administration 
 
 
FFPE 
Formalin fixed paraffin embedded 
FIH 
First-in-human 
Fpo 
Oral bioavailability  
GGT 
Gamma-glutamyl-transferase  
GI 
Gastrointestinal 
GLP 
Good laboratory practice 
GTPase 
Small guanidine triphosphatase 
hCG 
Human chorionic gonadotropin  
Hgb 
Hemoglobin 
HGS 
High-grade serous 
HR 
Heart Rate  
HRAS 
Harvey rat sarcoma viral oncogene homolog 
IC50 
Inhibition concentration 50% 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IN 
Investigator notice 
INR 
International normalized ratio 
 
 
IRB 
Institutional Review Board 
Iv 
Intravenous 
KRAS 
Kirsten rat sarcoma viral oncogene homolog 
 
  
LDH 
Lactate dehydrogenase 
 
 
 
 
LVEF 
Left ventricular ejection fraction 
MAP 
Meta-analytic-predictive 
MAPK 
Mitogen activated protein kinase 
MedDRA 
Medical dictionary for regulatory activities 
MEK 
Mitogen-activated protein kinase kinase 
 
 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multiple gated acquisition 
NCI 
National Cancer Institute 
 
 
 
 
NRAS 
Neuroblastoma RAS viral (v-ras) oncogene homolog 
 
 
 
  
 
 
ORR 
Objective response rate 
 
 
PAS 
Pharmacokinetic analysis set 
PD 
Pharmacodynamic  


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PFS 
Progression free survival 
 
  
PHI 
Protected Health Information 
 
 
 
 
PPI 
Proton pump inhibitors 
PR 
Partial response 
 
 
PT 
Prothrombin time 
 
 
 
 
QD 
Once daily 
RAP 
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses 
RDE 
Recommended dose for expansion 
RDI 
Relative dose intensity 
REB 
Research Ethics Board 
RECIST 
Response evaluation criteria in solid tumors 
RVO 
Retinal vein occlusion 
SAE 
Serious Adverse Event 
SD 
Stable disease 
 
 
STL 
Standard tables listings 
SUSAR 
Suspected unexpected serious adverse reactions 
T½ 
Half-life  
 
 
 
 
ULN 
Upper limit of normal 
 
 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study subject or study patient 
Cohort 
A group of newly enrolled patients treated at a specific dose and regimen (i.e. treatment 
group) at the same time 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g. q28 days) 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.)  
Enrollment 
Point/time of patient entry into the study; the point at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol) 
Investigational 
drug 
The study treatment whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with “investigational new 
drug.” 
Investigational 
treatment 
Drug whose properties are being 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 
Medication number 
A unique identifier on the label of each study treatment package which is linked to one of 
the treatment groups of a study 
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 subject who enrolls in the study 
Period 
A subdivision of the study timeline; divides stages into smaller functional segments such 
as screening, baseline, titration, washout, etc. 
Stage related to 
study timeline 
A major subdivision of the study timeline; begins and ends with major study milestones 
such as enrollment, randomization, completion of treatment, etc. 
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 
Supportive 
treatment 
Refers to any treatment required by the exposure to a study treatment, e.g. 
premedication of vitamin supplementation and corticosteroid for pemetrexed disodium. 
Treatment group 
A treatment group defines the dose and regimen or the combination, and may consist of 
1 or more cohorts. Cohorts are not expanded, new cohorts are enrolled. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data collected using 
specified assessments at specified time points 
Withdrawal of 
Consent 
Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not 
want any further study related contact 


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Amendment 3 (13-Mar-2018) 
Amendment rationale  
The purpose of this amendment is to introduce the following changes into the protocol: 
The age of patients eligible for inclusion in this study has been reduced from ≥18 years to 
≥12 years to allow access to LTT462 treatment for adolescent patients who have the same 
risk/benefit as the adult population.  
 
  The inclusion of patients ≥12 years is supported by published 
literature showing that adolescents have similar toxicity profiles, maximum tolerated doses, and 
pharmacokinetic parameters compared to adults.  
• The following inclusion and exclusion criteria were amended to allow the recruitment of 
adolescent patients:     
• The informed consent inclusion criterion (inclusion criterion #1) was updated to state 
that in addition to the assent of any adolescent patients, the signature of at least one 
parent or guardian is required to allow the adolescent to participate in the trial. This is 
as per ICH guidelines for recruitment of adolescent patients.   
• The study age inclusion criterion (inclusion criterion #2) was amended to decrease the 
age of study participation from ≥18 to ≥12 years. 
• The study biopsy inclusion criterion (inclusion criterion #7) was amended to allow 
adolescent patients to participate in the study without having to provide the required 
new biopsy at screening or on treatment if not feasible.  This will be reviewed by the 
Investigator and will require written confirmation from Novartis prior to study 
inclusion.       
• Two PK samples have been added on Cycle 1 Day 8 at 2 hours and 4 hours post-dose, for 
all patients treated with a QD, BID 
 to better 
characterize the PK of LTT462.   
This amendment will also clarify any ambiguous protocol language, make minor 
changes/corrections for consistency, and amend any discrepancies that have been identified. 


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Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Protocol summary, Section 2.2, Section 2.3, Table 3-1, Section 4.1, Section 5.1, 
Section 5.2: Addition of language to show that the study will recruit both adult and 
adolescent patients.    
• Protocol summary, Section 5.2:  Changed age of patients in inclusion criterion #2 from 18 
years to ≥12 years to allow recruitment of adolescent patients.  
• Section 1.1.3, Section 1.1.4, Section 2.3: addition of supportive information/data for 
justification for inclusion of adolescent patients in the study.   
• Section 5.2: amended inclusion criterion #1 to include that a parent or legal guardian will 
need to consent for adolescent patients to be included.  
• Section 5.2 and Table 7-8: amended inclusion criterion #7 to allow adolescent patients to 
participate if it is not possible for a new biopsy to be performed at screening or on-
treatment. This will be possible only after written agreement between the Investigator and 
Novartis.  
• Section 6.1: Added language to clarify the administration instructions for BID dosing. 


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• Section 7.2.3.1 and Table 7-6: Clarification of when PK samples should be taken relative 
to the previous dose of LTT462 and next dose of LTT462.  
• Table 7-6: Addition of two PK sampling timepoints on Cycle 1 Day 8 for patients treated 
with a QD, BID 
 off regimen.   
• Table 7-8: removal of "if medically feasible" footnote for newly obtained tumor biopsy for 
biomarker analyses as this and is inconsistent with the inclusion criterion for adult 
patients. A new footnote applicable to adolescent patients has been added. 
• Section 13: Addition of references for adolescent studies.   
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Amendment 2 (14-Aug-2017) 
Amendment rationale 
The purpose of this amendment is to introduce the following changes into the protocol: 
 Update of the protocol language to allow the exploration of a BID regimen in addition to 
QD 
 that are 
already included in the protocol. 
 
 
 
This amendment will further clarify protocol phrases, minor changes/corrections for 
consistency and correct minor protocol discrepancies that have been identified. 
Study Status 
The first patient first visit occurred on 15th April 2016. 
 
 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• List of abbreviations, Section 8.2.2 and Section 8.3: Changed name of Drug Safety and 
Epidemiology department at Novartis to Chief Medical Office and Patient Safety. 
• Section 1.2.2.1: addition of information on BID dosing regimen in pre-clinical studies (as 
already available in the LTT462 Investigator’s Brochure). 


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• Section 2.2, Section 2.3, Section 4.1.1, Table 4-1, Section 4.1.3, Figure 4-1, Section 
6.2.3.1, Table 7-1, Section 10.1.4, Section 10.4.2.1, Section 13, Section 14.5.2, Section 
14.5.2.2, Section 14.5.2.2.2, Section 14.5.2.2.3, Section 14.5.2.2.4, Section 14.5.2.2.5, 
Table 14-20, Table 14-21, Table 14-22, Table 14-23: Update of protocol language and 
statistical sections to allow testing of BID regimen with LTT462. 
• Section 6.1.1 and Table 6-1: Update of administration instructions to include BID dosing 
 
 
• Table 7-1, Table 7-5, Section 7.2.3.1, Table 7-6, Section 7.2.4 and Table 7-8: Addition of 
a new PK and DUSP6 sample time-point at 12 hours on C1D15 to allow the testing of 
BID regimen with LTT462, and addition of ECG assessments for BID dosing in-line with 
existing time-points. Clarifications on existing regimens (QD,
 
) are made in the tables, but there are no new assessments/samples for these 
regimens. 
• Section 7.2.2.7: Removal of incorrect text. 
• Section 11.5: Updated publication policy in line with Novartis standards. 
IRBs/IECs and HA Approval 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Amendment 1 (14-Jul-2016) 
Amendment rationale 
This amendment addresses the following revision 
 
Additionally, the following revisions have been made: 
• Changed inclusion criteria from patient must be willing to undergo required study biopsies 
(if medically feasible) to patients must have a site of disease amenable to biopsy, and be a 
candidate for tumor biopsy according to the treating institution’s guidelines to be eligible 
for the study. These biopsies will be taken at screening/baseline and during therapy and 
used for assessment of secondary 
 objectives to answer translational 
research questions 
 
This amendment will further clarify protocol phrases, minor changes/corrections for 
consistency and correct minor protocol discrepancies that have been identified. 


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Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
 Protocol Summary and Section 5.2: Revised wording of inclusion criterion 7 to mandate 
that patients must have site of disease amenable to biopsy, 
 
 
• Section 5.3: Added in exclusion criterion 7 to confirm that any malignant disease other 
than that being treated in the study is considered a medical condition that would exclude a 
patient. 


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IRBs/IECs and HA Approval 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Protocol summary 
Title 
A phase I dose finding study of oral LTT462 in adult patients with advanced solid 
tumors harboring MAPK pathway alterations 
Brief title 
N/A 
Sponsor and 
Clinical Phase 
Novartis 
Phase I 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this first-in-human (FIH) trial is to characterize safety and tolerability 
of the ERK1/2 inhibitor LTT462 and identify a recommended dose and regimen for 
future studies in adult and adolescent patients with advanced solid tumors harboring 
mitogen activated protein kinase (MAPK) pathway alterations. 
MAPK pathway is frequently activated in human cancers with RAS genes (KRAS, 
NRAS and HRAS) being the most frequently mutated oncogenes in all cancers 
(>30%) with KRAS mutations being the most prevalent in 20% of all cancers. 
However, no effective therapies exist for KRAS mutant cancers. Inhibitors against 
BRAF or MEK suppress MAPK signaling and have demonstrated efficacy in BRAF 
mutant tumors, but these effects are almost always short-lived due to multiple 
acquired resistance mechanisms which commonly reactivate ERK1/2 signaling. In 
this setting, inhibition of ERK1/2, which are the most distal kinases in the MAPK 
signaling cascade, effectively inhibits MAPK signaling and demonstrates anti-tumor 
effects in preclinical studies (Morris et al. 2013). 
 
 
 
 Therefore it is expected that the ERK
 inhibitor LTT462 will result in 
anti-tumor activity in adult and adolescent patients with advanced solid tumors 
harboring documented MAPK pathway alterations. 
Primary Objective(s) 
and Key Secondary 
Objective 
To characterize safety and tolerability of LTT462 and identify a recommended dose 
and regimen for future studies in adult and adolescent patients with advanced solid 
tumors harboring MAPK pathway alterations. 
Secondary 
Objectives 
To evaluate the preliminary anti-tumor activity of LTT462 
To evaluate the pharmacokinetic (PK) profile of LTT462 
To assess the pharmacodynamic (PD) effect of LTT462 
Study design 
This study has been designed as a Phase I, open-label, dose finding study with a 
dose escalation part and a dose expansion part in adult and adolescent patients with 
advanced solid tumors harboring documented MAPK pathway alterations. The study 
treatment, LTT462, will be taken until patient experiences unacceptable toxicity, 
progressive disease and/or treatment is discontinued at the discretion of the 
investigator or the patient or due to withdrawal of consent. 
 
 
A cycle is defined as 28 days. 
Population 
The dose escalation part of the study will be conducted in adult and adolescent 
patients with advanced solid tumors harboring MAPK pathway alterations. 
 
 
 
 
 
Inclusion criteria 
1. Able to understand and voluntarily sign the ICF and ability to comply with the study 
visit schedule and the other protocol requirements. 
2. Patient (male or female) ≥12 years of age 
3. Must have progressed following standard therapy, or for whom, in the opinion of 
the Investigator, no effective standard therapy exists, is tolerated or appropriate. 
4. ECOG (Eastern cooperative oncology group) performance status ≤1 
5. Presence of at least one measurable lesion according to RECIST v1.1. 
 
 
 


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Dose escalation part: 
Patients must have advanced solid tumors harboring at least one of the MAPK 
pathway alterations. 
7. Patients must have a site of disease amenable to biopsy and be a candidate for 
tumor biopsy. Patients must be willing to undergo a new tumor biopsy 
 
. 
Exclusion criteria 
1. Prior treatment with ERK inhibitors. 
2. History or current evidence of retinal vein occlusion (RVO) or current risk factors 
for RVO. 
3. Any medical condition that would, in the investigator’s judgment, prevent the 
patient’s participation in the clinical study due to safety concerns or compliance with 
clinical study procedures. 
5. Patients receiving proton pump inhibitors (PPI) which cannot be discontinued 
3 days prior to the start of study treatment and for the duration of the study. 
6. Clinically significant cardiac disease 
 
 
 
Investigational and 
reference therapy 
LTT462 
Efficacy 
assessments 
Tumor assessment per RECIST v1.1 
Safety assessments 
Safety: 
● Incidence and severity of adverse events (AEs) and serious AEs, including 
changes in laboratory values, vital signs, electrocardiograms (ECGs) and cardiac 
imaging, and ophthalmological assessments. 
● Incidence and nature of dose limiting toxicities (DLTs; dose escalation only) 
Tolerability: Dose interruptions, reductions, and dose intensity 
Other assessments 
Plasma concentrations and derived PK parameters of LTT462 
Changes from baseline of PD markers in tumor tissue (DUSP6) and in blood 
(DUSP6). 
Data analysis 
The statistical analysis of the safety and tolerability primary endpoints other than 
incidence of DLTs (during the dose escalation part) will be descriptive, no hypotheses 
or models will be considered. Incidence of DLTs during the dose escalation part will 


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be analyzed using a Bayesian hierarchical logistic regression model (BHLRM), which 
is a hierarchical adaptation of the Bayesian logistic regression model (BLRM). 
Key words 
LTT462, ERK, MAPK alterations, KRAS, BRAF, solid tumor, BHLRM, BLRM. 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
The RAS/RAF/MEK/ERK or MAPK (mitogen activated protein kinase) pathway is a key 
signaling cascade that drives cell proliferation, differentiation, and survival. Dysregulation of 
this pathway underlies many instances of tumorigenesis (Kirkwood et al 2012). This pathway 
is comprised of the RAS small guanidine triphosphatase (GTPase), which, when activated, 
promotes the activation of the RAF family proteins. Activated RAF proteins lead to the 
phosphorylation and activation of mitogen-activated protein kinase kinase (MEK) 1/2 proteins, 
which subsequently phosphorylate and activate extracellular signal-regulated kinases (ERKs). 
ERKs phosphorylate a variety of substrates including multiple transcription factors, and 
regulate several key cellular activities, including proliferation, differentiation, migration, 
survival and angiogenesis. Aberrant signaling or inappropriate activation of the MAPK pathway 
has been shown in multiple tumor types, including melanoma, lung, ovarian and pancreatic 
cancer, and can occur through several distinct mechanisms, including activating mutations in 
RAS and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) (Lea et al 2007). 
The MAPK pathway is frequently mutated in human cancer. Kirsten rat sarcoma viral oncogene 
homolog (KRAS) and BRAF mutations occur most frequently, appearing in approximately 30% 
of human cancers (reviewed in Zhao and Adjei 2014). RAS genes (KRAS, neuroblastoma RAS 
viral (v-ras) oncogene homolog (NRAS) and Harvey rat sarcoma viral oncogene homolog 
(HRAS)) are mutated in numerous cancer types, including colorectal (50%), melanoma (20%), 
lung (19%), ovarian (18%) and pancreatic (90%) cancers. BRAF is mutated in melanoma (50%), 
thyroid (50%), low grade ovarian (36%) and colorectal (9%) cancers, with BRAFV600E 
accounting for greater than 90% of observed mutations in BRAF gene cancer (Cantwell-Dorris 
et al 2011). Although selective, BRAF and, to a lesser extent, MEK inhibitors have 
demonstrated clinical activity in BRAF-mutant tumors. However, there are currently no 
effective therapies for KRAS-mutant tumors (Cantwell-Dorris et al 2011). ERK1/2 is the most 
distal kinase in the MAPK signaling cascade and they are an attractive drug target to effectively 
suppress oncogenic MAPK signaling and cancer cell proliferation. 


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1.2 
Introduction to investigational treatment 
1.2.1 
Overview of LTT462 
LTT462 is a potent and selective, orally bioavailable, 
 
ERK
 inhibitor. 
 
 
 
 
 
 


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1.2.3 
Clinical experience 
In addition to LTT462X2101 (the first-in-human (FIH) study described in this protocol), 
LTT462 is currently being tested in [LXH254X2102] a Phase Ib, open-label, multicenter study 
of oral LXH254 
 in combination with oral LTT462 in adult patients with 
advanced or metastatic KRAS or BRAF mutant Non-Small Cell Lung Cancer. 
1.2.3.1 
Clinical Safety 
For LTT462x2101, the first patient first visit occurred on 15th April 2016. 
 
 
 
 
 
 


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In the ongoing clinical study LXH254X2102, the first patient first visit occurred on 24th 
February 2017. 
 
 
 
 
 
2 
Rationale 
2.1 
Study rationale and purpose 
MAPK pathway is frequently activated in human cancers. The RAS genes, including KRAS, 
NRAS and HRAS, are the most frequently mutated oncogenes in all cancers (>30%) with KRAS 
mutations being the most prevalent in 20% of all cancers, such as in pancreatic (90%), colorectal 
(40%), and lung (30%) cancers. However, no effective therapies exist for KRAS mutant cancers, 
largely because KRAS itself has proven difficult to target directly with small molecules (Young 
et al 2009). Inhibitors against BRAF or MEK suppress MAPK signaling and have demonstrated 
efficacy in BRAF mutant tumors; nonetheless these effects are almost always short-lived due to 
multiple acquired resistance mechanisms which commonly reactivate ERK
 signaling. In this 
setting, inhibition of ERK
, which are the most distal kinases in the MAPK signaling cascade, 
effectively inhibits MAPK signaling and demonstrates anti-tumor effects in preclinical studies 
(Morris et al 2013). 
 
2.2 
Rationale for the study design 


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The design of the phase I, open label, dose finding study, with a dose escalation part and a dose 
expansion part, was chosen in order to establish the safety and tolerability of LTT462 and 
identify a recommended dose and regimen for future studies in adult and adolescent patients 
with advanced solid tumors harboring documented MAPK pathway alterations. 
The age of patients eligible for inclusion in this study is ≥12 years to allow access to LTT462 
treatment for adolescent patients with MAPK pathway alterations who have the same 
risk/benefit as the adult population.  
 
  The inclusion of patients ≥12 years is supported by published 
literature showing that adolescents have similar toxicity profiles, maximum tolerated doses, and 
pharmacokinetic parameters compared to adults.  
The statistical analysis of the primary endpoints other than incidence of dose limiting toxicities 
(DLTs) during the dose escalation part 
 will be descriptive (Section 
10.4.2.1). No hypotheses or models will be considered. Incidence of DLTs during the dose 
escalation part will be analyzed using an adaptive Bayesian model. Sample size requirements 
are provided in Section 10.8. 
Dose Escalation Part 
All patients enrolled during the dose escalation part of the study, will receive LTT462 in order 
to evaluate its safety and tolerability. On C1D1 only 1 dose will be given (in the morning) for 
all regimens. The evening dose on C1D1 will be omitted for the BID regimen. In addition, 
dosing will be omitted on the second day of the first cycle (C1D2; a cycle is defined as 28 days) 
for all regimens. This is to allow for a 48 hour sampling to fully characterize LTT462 PK 
parameters, such as total plasma exposures (AUCinf) and T½, and PD. 
The dose escalation for the QD 
 regimens will be guided by a Bayesian hierarchical 
logistic regression model (BHLRM) based on the first cycle DLT data of the study treatment. 
This model estimates the relationship between dose and the probability of a patient experiencing 
a DLT in the different cohorts investigated in the escalation part, following different regimens 
. The model has the flexibility to allow for the case in which the dose-
toxicity relationship is similar for some strata and the case in which the relationship is different 
for one or more strata. In the event that the relationship is similar, then the model structure will 
allow borrowing of information between those strata identified as exchangeable, which will in 
turn lead to improved estimation of the dose-toxicity relationship. The BHLRM is a hierarchical 
adaptation of the Bayesian logistic regression model (BLRM), a well-established method to 
estimate the MTD and/or RDE in cancer patients. 
If, in addition, 
 BID regimen are 
explored, dose escalation decisions will be guided by a separate BLRM. Both Bayesian models, 
BHLRM and BLRM, will be guided by the escalation with overdose control (EWOC) principle 
to control the risk of DLT in future patients. The use of Bayesian response adaptive models for 
small datasets has been accepted by European Medicines Agency (Guideline on clinical trials 
in small populations, 2007) and endorsed by numerous publications (Babb et al 1998, 
Neuenschwander et al 2008), and its development and appropriate use is one aspect of the 
FDA’s Critical Path Initiative. 


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The dose(s) identified by the model as satisfying the EWOC criterion at any given time point 
in the trial will be based on the entire history of all DLT information from previous cohorts up 
to that point. The model then provides information on the risk of DLT at all doses for future 
patients. 
The decisions on new dose levels and regimens are made jointly by the Investigators and 
Novartis study personnel and will be based on patient tolerability and safety evaluations (for 
doses satisfying EWOC under the respective Bayesian model) and guided by PK, PD, and 
preliminary anti-tumor activity information available at the time of the decision making 
(Section 6.2.3). 


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2.3 
Rationale for dose and regimen selection 
In this study the selection of dose and regimen of LTT462 is based on the currently available 
non-clinical information (Section 1.2.2). 
The starting dose of LTT462 in the dose escalation part of the FIH trial is 45 mg QD. 
 
 
   
Provisional doses for dose escalation can be found in Table 6-2. 
In the dose expansion part, patients will be treated with LTT462 monotherapy at the 
recommended dose and regimen selected, which will be based on the dose escalation data. 
 
 
 
Initially the clinical regimen for this FIH study with LTT462 will be a continuous once daily 
dosing schedule. A QD regimen was demonstrated to be efficacious and tolerated in preclinical 
studies (Section 1.2.2.1). 
 
 
Depending on clinical experience with the starting regimen of QD dosing (in case emerging 
PK, PD, and/or safety data indicate that QD regimen is not optimal), the Novartis Clinical Study 
team may decide to additionally explore BID 
 
 for newly enrolled patients during the dose escalation part. 
 
BID 
 regimens are supported by preclinical findings, where efficacy was 
achieved with either QD, BID 
 regimens. 
 
 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 


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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 10.4 
To characterize safety and tolerability of LTT462 and 
identify a recommended dose and regimen for future 
studies in adult and adolescent patients with advanced solid 
tumors harboring MAPK pathway alterations. 
Safety: 
Incidence and severity of adverse events (AEs) and serious 
AEs (SAEs), including changes in laboratory values, vital signs, 
and ECGs. 
Incidence and nature of DLTs (dose escalation only) 
Tolerability: Dose interruptions, reductions, and dose intensity 
 
Secondary 
 
Refer to Section 10.5 
To evaluate the preliminary anti-tumor activity of LTT462  
For both parts: 
Overall response rate (ORR), Disease Control Rate (DCR), 
Duration of Response (DOR), and Progression Free Survival 
(PFS) as per Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 
 
 
 
To evaluate the pharmacokinetic (PK) profile of LTT462 
Plasma concentrations and derived PK parameters of LTT462 
 
To assess the pharmacodynamic (PD) effect of LTT462 
Changes from baseline of the PD marker DUSP6 in tumor 
tissue and in blood. 
 


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4 
Study design 
4.1 
Description of study design 
This study is a Phase I, open-label, dose finding study with a dose escalation part and a dose 
expansion part in adult and adolescent patients with advanced solid tumors harboring 
documented MAPK pathway alterations. The study treatment will be taken until the patient 
experiences unacceptable toxicity, progressive disease and/or has treatment discontinued at the 
discretion of the Investigator or the patient, or due to withdrawal of consent. 
   
4.1.1 
Dose escalation 
Initially all patients enrolled in the dose escalation part of the study will receive oral LTT462 
QD in fasted condition, with the exception of C1D2, when the dose will be omitted to allow for 
48h-PK and PD profile collection. 
The safety (including the dose-DLT relationship) and tolerability of LTT462 will be assessed, 
and dose(s) and regimen(s) will be identified for use in the expansion part based on the review 
of this data. The RDE will also be guided by the available information on PK, PD, and 
preliminary anti-tumor activity 
 
 
If emerging PK, PD, safety data and/or preliminary anti-tumor activity indicate that the QD 
regimen is not optimal, the Novartis Clinical Study team may recommend an alternative dosing 
regimen (see Table 4-1) for newly enrolled patients during the dose escalation part. In which 
case the starting total daily dose identified at that time for these alternative regimens will satisfy 
the EWOC criterion as per the statistical model for the alternative regimen and will not be higher 
than the highest tested safe QD dose. This decision will be formally documented in the dose 
escalation meeting minutes, which will be distributed to all relevant parties. QD, BID 
 
 may be explored in parallel. 
The dose escalation part plans to enroll at least 21 patients (Section 10.8.1) with advanced solid 
tumors harboring documented MAPK pathway alterations as listed in Table 5-1, with at least 
six patients treated at dose and regimen selected for dose expansion part (MTD or lower dose) 
(Section 6.2.3). Testing of additional regimens e.g. BID dosing in the dose escalation may 
increase patient numbers above those stated. Once RDE(s) has/have been identified, the dose 
expansion will be opened to patient enrollment. 


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Table 4-1 
LTT462 regimens 
Starting Regimen 
Provisional 
 Other Regimens 
QD 
 
 
BID 
(dosing two times a day for a 4 week cycle) 


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Figure 4-1 
Study design 
Dose Escalation and Dose Expansion 
 
* More than one dose level and /or regimen, in 
, may be investigated 
** No dosing on C1D2 to allow for 48h-PK and PD profile collection. Additionally the evening dose on 
C1D1 will be omitted for the BID regimen. 
 
  


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Study visit flow 
Patients will undergo clinical and laboratory assessments during screening/baseline and 
periodically during treatment as outlined in Table 7-1. 
For study visit flow detailed information is provided in Section 7.1. 
Figure 4-2 
Study visit flow 
 
*as applicable 
4.2 
Timing of interim analyses and design adaptations 
No formal interim analyses are planned for the study. However, the dose-escalation design 
foresees that decisions based on the current data are taken before the end of the study  
(Section 6.2.3). Adult and adolescent patients will be analyzed together as one population. 
During the dose expansion phase, cumulative study data (including safety, tolerability, 
preliminary anti-tumor activity, PK, and PD) will be reviewed on an ongoing basis by Novartis 
and study investigators. 
 
 
 
 
 
 
4.3 
Definition of end of the study 
The study will end when the treatment period and 30-day safety follow-up have been completed 
for all patients, when survival follow-up (for expansion patients only) has additionally has been 
completed, as described in Section 7.1.7, or when the study is terminated early. 
Refer to Section 10 for details of timing of the primary analysis and final reporting of data. 
4.4 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient(s) should be seen as soon as possible for an end of treatment (EoT) visit and the 
same assessments for EoT, as described in Section 7.1.5 for a patient who discontinued 
treatment or a withdrawn patient, should be performed. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
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Institutional Review Boards (IRBs) and/or Ethics Committees of the early termination of the 
trial. 
5 
Population 
5.1 
Patient population 
In this study, LTT462 will be administered to adult and adolescent (≥12 years old) patients with 
advanced solid tumors harboring MAPK alteration(s) 
 Patients identified to 
have other molecular alterations in MAPK pathway may be eligible pending documented 
agreement between Novartis and Investigator. 
The Investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. All data for the inclusion 
and exclusion criteria must be verifiable in the patient’s source documents. 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Able to understand and voluntarily sign the ICF and ability to comply with the study visit 
schedule and the other protocol requirements. Written informed consent must be obtained 
prior to any study specific procedures that are not part of standard of care. If consent 
cannot be expressed in writing, it must be formally documented and witnessed, ideally via 
an independent trusted witness. 
For adolescent patients: consent will be obtained from parent(s) or legal guardian(s) and 
the signature of at least 1 parent or guardian will be required. Investigators will also obtain 
assent of patients according to local, regional or national guidelines. 
For Japan only: written consent is necessary both from the patient and his/her legal 
representative if he/she is under the age of 20 years. 
2. Patient (male or female) ≥ 12 years of age 


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3. All patients participating in this clinical trial must have progressed following standard 
therapy, or for whom, in the opinion of the Investigator, no effective standard therapy 
exists, is tolerated or appropriate. 
4. ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1 
5. Presence of at least one measurable lesion according to RECIST v1.1 (Appendix 1). 
Dose escalation part: 
Patients must have advanced solid tumors harboring at least one of the MAPK pathway 
alterations listed in Table 5-1. 
Dose expansion part: 
Group 1:
Group 2:
Group 3:
 Group 4: 
 
Note: Enrollment of patients with MAPK alteration(s) other than listed in Table 5-1 may 
be possible (dose expansion and dose escalation), but only after documented agreement 
between Novartis and the Investigator. 
 
 
7. Patients must have a site of disease amenable to biopsy and be a candidate for tumor 
biopsy according to treating institution’s guidelines. Patients must be willing to undergo a 
new tumor biopsy 
.   
For adolescent patients: new tumor biopsies 
 should be 
performed when feasible.  However, exceptions may be granted after documented 
agreement between Novartis and the Investigator. 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Prior treatment with ERK inhibitors. 


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4. History or current evidence of retinal vein occlusion (RVO) or current risk factors for 
RVO 
 
 
 Any medical condition that would, in the investigator’s judgment, prevent the patient’s 
participation in the clinical study due to safety concerns or compliance with clinical study 
procedures. 
 
 
 
 
 Patients with malignant disease, other than that being treated in this study. 
 
 
 
 
 


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10. Patients receiving proton pump inhibitors (PPI) which cannot be discontinued 3 days prior 
to the start study treatment and for the duration of the study (Appendix 2). 
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6 
Treatment 
6.1 
Study treatment 
The investigational drug to be used as the study treatment in this study is LTT462. 
6.1.1 
Dosing regimen 
Table 6-1 
Dose and treatment schedule 
Study treatments 
Pharmaceutical form and 
route of administration 
Dose 
Frequency and/or 
Regimen* 
LTT462 
Capsule for oral use 
As assigned 
Daily ** 
* If emerging PK and/or safety data indicate that this regimen is not optimal, the Novartis Clinical Study team 
may recommend an alternative dosing regimen in the treatment period for newly enrolled patients such as 
, BID 
 (Section 4.1). 
** Study treatment will be omitted on C1D2 of the treatment period for all dosing regimens, see Section 4.1 or 
Table 7-1. Additionally the C1D1 evening dose will be omitted for BID dosing. 
LTT462 should be taken as follows: 
• LTT462 will be administered orally at flat-fixed doses (not by body weight or body 
surface area). 
• Adolescent patients will be treated with the same dose as adult patients (see Section 2.3).   
• Patients should take their dose at approximately the same time 
 
 on each day of dosing 
with a glass of water 
 
• Study treatment should be taken in the morning (for BID dosing, the study treatment 
should be taken in the morning and in the evening. 
 
 
• The C1D2 should be omitted for all dosing regimens. Additionally the C1D1 evening dose 
should be omitted for the BID regimen. 
• On the days of PK sampling, the patients should take their doses in the clinic where the 
administration of LTT462 will be supervised and administration time recorded. 
• The capsules should be ingested whole and should not be chewed or crushed. 
• If multiple capsules are required for a dosage, then all capsules for that dose should be 
ingested in a short period of time as possible (i.e., not slower than 1 capsule every 
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• If vomiting occurs following the dosing of study treatment, re-dosing is not permitted and 
dosing should resume at the next scheduled dose. If the vomiting occurs on full PK 
sampling days within the first 4 hours post-dosing, this event should to be recorded on the 
dose administration PK electronic Case Report Form (eCRF) page, as well as on the 
adverse event page, as appropriate. 
• If the patient forgets to take the scheduled dose and more than 4 hours has passed since the 
scheduled time of study treatment intake, that dose should be skipped and treatment 
should continue with the next scheduled dose at the prescribed level (missed doses should 
not be replaced or made up at the next scheduled dosing). 
• All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF. 
The investigator or responsible site personnel should instruct the patient to take the study drug 
exactly as prescribed to promote compliance. 
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6.1.2 
Treatment duration 
Patients may be discontinued from study treatment earlier due to unacceptable toxicity, 
progressive disease, if treatment is discontinued at the discretion of the investigator or the 
patient and/or the patient withdraws consent. Refer to Section 7.1.3 and Section 7.1.4. 
6.2 
Dose escalation guidelines 
6.2.1 
Starting dose rationale 
The selection of the starting dose follows the ICH S9 guidelines for choosing a starting dose for 
a FIH trial conducted in patients with cancer. 
6.2.2 
Provisional dose levels 
Table 6-2 describes the starting dose and the dose levels that may be evaluated during the study. 


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Table 6-2 
Provisional dose levels 
Dose level 
Proposed daily dose* 
Increment from previous dose 
-1** 
30 mg 
-33% 
1  
45 mg 
(starting dose) 
2 
100 mg 
122% 
3 
200 mg 
100% 
4 
300 mg 
50% 
5 
400 mg 
33% 
6 
500 mg 
25% 
7 
600 mg 
20% 
*It is possible for additional and/or intermediate dose levels to be added during the course of the study. Cohorts 
may be added at any dose level below the MTD in order to better understand safety, PK or PD. 
**Dose level -1 represents treatment doses for patients requiring a dose reduction from the starting dose level. 
No dose reduction below dose level -1 is permitted for this study. 
Dose escalation will continue until a recommended dose (MTD(s) or lower dose(s)) and 
regimen is determined. At all decision time points, the adaptive Bayesian models permits 
alterations in the dose increments based on the observed DLTs. Multiple cohorts may be opened 
simultaneously in order to study more than one dose or dose regimen in order to better 
understand safety, PK and or PD, as long as selected dose levels satisfy the EWOC criterion 
and satisfy the rules for escalation described in Section 6.2.3 (e.g., at most 100% increase from 
previous dose, with the exception of the first dose escalation for which an increase of up to 
122% will be considered. 
 
 
 
 
 
 
6.2.3 
Guidelines for dose escalation and determination of MTD(s)/RDE(s) 
6.2.3.1 
MTD definition 
The MTD is defined as the highest drug dosage not expected to cause DLT in 33% or more of 
the treated patients in the first cycle of LTT462 treatment during the escalation part of the study. 
AEs and laboratory abnormalities considered to be DLTs are defined in Table 6-3. If different 
dose regimens are tested in addition to QD (such as BID, 
 a 
different dose for each regimen may correspond to this definition. 
The recommended dose(s) selected for study in the dose expansion part will be identified based 
on the review of all study data, including the estimated MTD if achieved. The recommended 
dose(s) will not exceed the MTD but may be a lower dose if supported by the review of safety, 
PK, PD and preliminary anti-tumor activity at all doses. 
6.2.3.2 
Dose cohort modification 
For the purposes of dose escalation decisions, each cohort will consist of 1 to 6 newly enrolled 
patients who will be treated at the specified dose level. The first cohort will be treated with the 
starting dose of 45 mg QD. 


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Patients must complete a minimum of 1 cycle of treatment with the minimum safety evaluation 
and drug exposure or have had a DLT within the first cycle of treatment to be considered 
evaluable for dose escalation decisions (Section 10.1.4). Dose escalation decisions will occur 
when the cohort of patients has met these criteria. 
If two patients (who may be in different cohorts) have experienced a toxicity of Common 
Terminology Criteria for Adverse events (CTCAE) grade 2, for which relationship to study 
drug cannot be ruled out; or when any single patient experiences a DLT or adverse event (AE) 
of CTCAE grade 3 or greater during Cycle 1, the cohort size will be increased to between 3 and 
6 evaluable patients for the current and subsequent cohorts. 
If a minimum of 3 patients are required in a cohort and only 2 of these patients are evaluable 
and neither subject has experienced a treatment-related toxicity > CTCAE grade 1, dose 
escalation decisions may be considered. 
Dose escalation decisions will be made by the Investigators and Novartis study personnel. 
Decisions will be based on a synthesis of all relevant data available from all dose levels 
evaluated in the ongoing study including safety information, DLTs, all CTCAE Grade ≥ 2 
toxicity data during Cycle 1, PK, and PD data from evaluable patients. The recommended dose 
for the next cohort of subjects will be guided by the BHLRM subject to the EWOC principle 
(Section 10.4.2). 
The adaptive Bayesian methodology provides an estimate of all dose levels of LTT462 that do 
not exceed the MTD for each regimen and incorporates all DLT information at all dose levels 
for this estimation. In general, the next dose will have the highest chance that the DLT rate will 
fall in the target interval (16-33%) and will always satisfy the EWOC principle. The dose for 
the next cohort will not exceed a 100% increase from the previous dose, with the exception of 
the first dose escalation in which increases of up to 122% will be considered (see Section 6.2.2). 
Smaller increases in dose may be recommended by the Investigators and Novartis upon 
consideration of all of the available clinical data. Any dose escalation decision made by 
Investigators and Novartis personnel will not exceed the dose level permissible following the 
application of the EWOC principle to inference from the Bayesian model. If needed to better 
define the dose-toxicity relationship additional patients may be enrolled to the current dose 
level, to a preceding dose level, or to an intermediate dose level before proceeding with further 
dose escalation. 
If 2 patients in a previously untested dose level experience a DLT, further enrollment to that 
cohort will stop and the Bayesian model will be updated with this new information. The next 
cohort will be opened at the next lower dose level or an intermediate dose level (see Table 6-2 
and Appendix 5) that satisfies the EWOC criteria. However, if 2 patients in a new cohort at a 
previously tested dose level experience a DLT (e.g., a total of 8 patients are treated on this dose 
level with 2 DLTs observed), further enrollment to that cohort will stop, the Bayesian model 
will be updated with this new information and re-evaluation of the available safety, PK, and PD 
data will occur. By incorporating information gained at the preceding dose cohorts, additional 
patients may be enrolled into the current dose level or a lower dose level as agreed by 
Investigators and Novartis personnel and if the Bayesian model predicts that the risk for this 
dose to exceed the MTD(s) remains below 25% (EWOC). Re-escalation may then occur if data 


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in subsequent cohorts supports this EWOC criteria are satisfied and Investigators and Novartis 
personnel agree. 
To better understand the safety, tolerability, and PK of LTT462 additional cohorts of patients 
may be enrolled at preceding dose levels, or to intermediate dose levels, before or while 
proceeding with further dose escalation. 
If a decision is made to escalate to a higher dose level but one or more additional patient(s) 
treated at the preceding dose level experiences a DLT during the first cycle of treatment, then 
the Bayesian model will be updated with this new information before any additional patients 
are enrolled at that higher dose level. Patients ongoing will continue treatment at their assigned 
dose levels. 
Dose escalation will continue until identification of the MTD(s) or until Novartis and 
Investigators reach a consensus that based on the clinical data, a suitable lower dose is 
recommended for use in the expansion part for one or more of the dose and regimen (schedule 
). This will occur when the following conditions are met: 
1. at least 6 patients have been treated with this dose, schedule, 
 
2. this dose satisfies one of the following conditions: 
a. the posterior probability of targeted toxicity at this dose exceeds 50% and is the 
highest among potential doses. 
b. a minimum of 21 patients have already been treated on the trial. 
c. significant activity is seen early in the dose escalation part, in which case a 
recommended dose/regimen may be identified and the dose expansion part may be 
initiated without determination of the MTD. 
3. it is the dose recommended for patients, either per the model or by review of all clinical data 
by 
Novartis 
and 
Investigators 
in 
a 
dose-escalation 
teleconference,  
see Section 6.2.3.1. 
6.2.3.3 
Implementation of Dose Escalation Decisions 
To implement dose escalation decisions, the available toxicity information (including AEs and 
laboratory abnormalities that are not DLTs), the recommendations from the Bayesian model 
after all patients in the cohort are assessed as evaluable, and the available PK and PD 
information will all be evaluated by the Investigators and Novartis study personnel (including 
the study physician and statistician) during a dose decision meeting by teleconference. Drug 
administration at the next higher dose level may not proceed until the investigator receives 
written confirmation from Novartis indicating that the results of the previous dose level were 
evaluated and that it is permissible to proceed to a higher dose level. 


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6.2.3.4 
Intra-Patient dose escalation 
Intra-patient dose escalation is not permitted at any time within the first 4 cycles of treatment. 
After the 4th cycle is completed, individual patients may be considered for treatment at a dose 
of LTT462 higher than the dose to which they were initially assigned. In order for a patient to 
be treated at a higher dose of LTT462, he or she must have tolerated the lower dose for at least 
4 cycles of therapy (i.e. he or she must not have experienced any LTT462-related toxicity 
CTCAE grade ≥ 2 at the lower dose originally assigned). Moreover, the new, higher dose with 
which the patient is to be treated must be a dose that has completed evaluation and has not 
exceeded the MTD estimated by the Bayesian model given all available data. 
There is no limit to the number of times a patient may have his or her dose of LTT462 increased. 
Further increase after the initial intra-patient dose escalation will be subject to the same rule as 
for the initial intra-patient dose escalation. Consultation and agreement with Novartis must 
occur prior to any intra-patient dose escalation occurring. These changes must be recorded on 
the Dosage Administration Record eCRF. 
Data from the first cycle of treatment at the new dose level will not be formally included into 
the statistical model describing the relationship between dose and occurrence of DLT. However, 
this data will be incorporated into the clinical assessment of safety within a dose escalation 
teleconference. 
With the exception of ophthalmological assessments (see Section 7.2.2.7), patients will 
continue with the visit schedule in line with the duration of their treatment (i.e. they would not 
have to restart at C1D1 assessments but continue from C5D1 if they). 
6.2.4 
Definitions of dose limiting toxicities (DLTs) 
A dose-limiting toxicity (DLT) is defined as an AE or abnormal laboratory value where the 
relationship to LTT462 cannot be ruled out, and is assessed as not primarily related to disease, 
disease progression, inter-current illness, or concomitant medications that occurs within the first 
28 days of treatment with LTT462 and meets any of the criteria 
 National 
Cancer Institute (NCI) CTCAE version 4.03 will be used for all grading. 
The investigator must notify the Sponsor immediately of any unexpected CTCAE grade ≥ 3 
AEs or laboratory abnormalities. Prior to enrolling patients into a higher dose level, CTCAE 
grade ≥ 2 AEs will be reviewed for all patients at the current dose level. 


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6.3 
Dose modifications 
6.3.1 
Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule due to DLT(s), dose 
adjustments are permitted in order to allow the patient to continue the study treatment. For the 


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dose escalation part of the study, dose reductions during Cycle 1 are only allowed if a DLT is 
observed and recorded. 
The following guidelines need to be considered: 
• The criteria for dose modifications and dose interruptions (i.e., interruption and re-
initiation criteria for LTT462 treatment) for toxicities considered at least possibly related 
to the study treatment are outlined in Table 6-4. All dose modifications should be based on 
the worst preceding toxicity (CTCAE version 4.03). 
• A patient must discontinue treatment with LTT462 if, after treatment is resumed at a lower 
dose, the toxicity recurs with the same or worse severity, unless in the opinion of the 
investigator it is in the patient’s best interest to continue LTT462, and upon documented 
agreement with Novartis. 
• For each patient, once a dose level reduction has occurred, the dose level may not be re-
escalated during subsequent treatment cycles with LTT462. 
• If, due to study drug related toxicity, a patient requires a dose interruption of > 21 days 
from the intended day of the next scheduled dose, then the patient should be discontinued 
from the study treatment. However, if the patient with a dose interruption of > 21 days is 
clearly benefiting from the study treatment and in the opinion of the investigator it is in 
the patient’s best interest to continue LTT462, upon documented agreement with Novartis, 
the patient may remain on study treatment. This decision must be available in the source 
documentation and described as an investigator comment in the eCRF. 
In case of study treatment interruption, visit schedule should still be followed and assessments 
performed as per Table 7-1. 
Any dose modification and dose delay must be recorded on the Dosage Administration Record 
eCRF. 


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6.3.2 
Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4 week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologist, endocrinologist, 
dermatologist, psychiatrists etc. should be consulted as deemed necessary. 
All patients must be followed up for adverse events and serious adverse events for 30 days 
following the last dose of LTT462 
6.3.3 
Anticipated risks and safety concerns of the study drug 
Appropriate eligibility criteria and specific DLT definitions, as well as specific dose 
modification and stopping rules are included in this protocol. Recommended guidelines for 
prophylactic or supportive treatment for expected toxicities, including management of study 
drug induced adverse events will be as per institutional guidelines. Refer to preclinical toxicity 
(Section 1.2.2.4) and/or the [LTT462 Investigator’s Brochure]. 
6.4 
Concomitant medications 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Prior and Concomitant 
Medications or the Surgical and Medical procedures eCRF. 
6.4.1 
Permitted concomitant therapy 
In general, the use of any concomitant medication/therapy, including over-the-counter 
medications deemed necessary for the care of the patient or to treat AEs is permitted during the 
study except for those specified as prohibited in Section 6.4.3. 
6.4.2 
Permitted concomitant therapy requiring caution and/or action 
Permitted therapy to be used with caution in this study includes: 
 
• Agents that modify gastric pH: If antacids and/or H2 receptor antagonists are indicated, 
follow guideline provided in Appendix 2 regarding timing of administration of these 
agents relative to LTT462 dosing. 
If any of the above drugs cannot be avoided, caution should be used during concomitant 
administration with LTT462. The patient and the Investigator should be aware of potential signs 
of overdose of the concomitant medication and in the event of suspected toxicity; administration 
of either the substrate or LTT462 should be discontinued according to Investigator judgment. 
Refer to (Appendix 2) for a list of medications that are to be used with caution. 


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6.4.3 
Prohibited concomitant therapy 
 
 
 
 In addition, the following classes of medications or herbs are prohibited: 
• PPIs are prohibited. 
 
• Refer to Appendix 2 for a list of medications that are prohibited. 
6.5 
Patient numbering and treatment assignment 
6.5.1 
Patient numbering 
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for pre-screening (if applicable) or when they are enrolled for 
screening. The subject number is retained as the primary identifier for the patient throughout 
his/her entire participation in the trial. The Subject No. consists of the Center Number (Center 
No.) (as assigned by Novartis to the investigative site) and a sequential patient number suffixed 
to it, so that each subject is numbered uniquely across the entire database. Upon signing the 
informed consent form, the patient is assigned to the next sequential Subject No. available to 
the investigator 
. 
Patients who do not meet all of the inclusion or exclusion criteria may potentially be re-screened 
for consideration in the trial. If a patient is re-screened, the same Subject No. should be used. 
6.5.2 
Treatment assignment 
This is a non-randomized trial. The assignment of a patient to a particular cohort or group will 
be coordinated by the sponsor. 
6.6 
Study treatment preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s), including instructions for administration, will be 
dispensed to the patient by authorized site personnel only, on an outpatient basis. Patients will 
be provided with adequate supply of study treatment for self-administration at home until at 
least their next scheduled study visit. 
 
 
 All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF. 


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6.6.1 
Study treatment packaging and labeling 
The study medication packaging has a 2-part label. Site personnel will add the patient number 
on the label. Immediately before dispensing the package to the patient, site personnel will detach 
the outer part of the label from the packaging and affix it to the source document (Drug Label 
Form) for that patient’s unique patient number. 
Study treatment labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the drug. 
Study treatment will be packed under the responsibility of the Novartis Drug Supply 
Management department and will be supplied as open label supply which allows the patient to 
take medication at home. 
6.6.2 
Drug supply and storage 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels and in the LTT462 Investigator’s Brochure. 
Table 6-5 
Supply and storage of study treatments 
Study treatments 
Supply 
Storage 
LTT462 
Centrally supplied by Novartis 
Refer to study treatment label 
6.6.3 
Study drug compliance and accountability 
6.6.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit. 
6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 


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6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. 
Study drugs destruction at the investigational site will only take place if permitted by local 
regulations and authorized by Novartis in a prior agreement. 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 lists all of the assessments and indicates with an “X” the visits at which they are 
performed. 
All data obtained from these assessments must be supported in the patient’s source 
documentation. The “Category” column of the table indicates which assessments produce data 
to be entered into the clinical database (D) and those which will remain in source documents 
only (S). 
No case report form (CRF) will be used as a source document. 
For Japan only, patients are required to be hospitalized in Cycle 1 of the dose escalation part. 
Visits and schedule windows 
During the course of the study visits, test and/or procedures should occur on schedule whenever 
possible. 
• Screening evaluations must be performed ≤ 14 days prior to first dose of study treatment 
(≤ 28 days for baseline radiological assessments). 
 Laboratory assessments performed as part of the screening evaluations that are within 
72 hours of the first dose of study treatment, are not required to be repeated on the first 
dosing day. 
 
 
 
 
 
 
 
• Full PK sampling should be performed on the specified day of dosing and time point (see 
Table 7-6 and Table 7-7 for sample windows). 
• For imaging assessments, a ±7 day window is allowed; however, confirmatory scan must 
be performed at least 4 weeks after the initial scan indicating response. 
In any case, if the dosing schedule is changed, the visit evaluation schedule will follow 
Table 7-1 without changes. 


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Table 7-1 
Visit evaluation schedule 
 
Category 
Protoco
l 
Section 
Screening 
Period 
Treatment Period 
End of study treatment (EoT) 
Follow-up 
period 
Visit Name 
 
Molecular Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
to 
Cycle 6 
Subsequent cycles 
30 days safety follow-up 
Disease progression F/U 
Day of cycle 
 
 
 
-14 
to -1 
1 
2 
3 
8 
1
5 
1
6 
1
7 
2
2 
1 
8 
1
5 
2
2 
1 
15 
1 
 
 
 
 
Informed 
Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain Molecular 
Pre-Screening 
Informed Consent 
D 
7.1.1 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain informed 
consent 
D 
7.1.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
D 
7.1.2.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
D 
5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
D 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and 
extent of cancer 
D 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
D 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Category 
Protoco
l 
Section 
Screening 
Period 
Treatment Period 
End of study treatment (EoT) 
Follow-up 
period 
Visit Name 
 
Molecular Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
to 
Cycle 6 
Subsequent cycles 
30 days safety follow-up 
Disease progression F/U 
Day of cycle 
 
 
 
-14 
to -1 
1 
2 
3 
8 
1
5 
1
6 
1
7 
2
2 
1 
8 
1
5 
2
2 
1 
15 
1 
 
 
 
 
Prior 
antineoplastic 
therapy 
D 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
D 
7.1.2.2 
 
X 
 
 
 
Tumor progression 
status at study 
enrollment 
D 
7.1.2.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor evaluation 
D 
7.2.1 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
C3
, 
C5 
 
C7
b 
X 
 
X 
 
Safety 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
S 
7.2.2.1 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
Vital signs 
D 
7.2.2.2 
 
X 
X 
X 
X 
X 
X 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Height  
D 
7.2.2.3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Category 
Protoco
l 
Section 
Screening 
Period 
Treatment Period 
End of study treatment (EoT) 
Follow-up 
period 
Visit Name 
 
Molecular Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
to 
Cycle 6 
Subsequent cycles 
30 days safety follow-up 
Disease progression F/U 
Day of cycle 
 
 
 
-14 
to -1 
1 
2 
3 
8 
1
5 
1
6 
1
7 
2
2 
1 
8 
1
5 
2
2 
1 
15 
1 
 
 
 
 
Weight 
D 
7.2.2.3 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
 
Performance 
status 
D 
7.2.2.4 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
 


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Category 
Protoco
l 
Section 
Screening 
Period 
Treatment Period 
End of study treatment (EoT) 
Follow-up 
period 
Visit Name 
 
Molecular Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
to 
Cycle 6 
Subsequent cycles 
30 days safety follow-up 
Disease progression F/U 
Day of cycle 
 
 
 
-14 
to -1 
1 
2 
3 
8 
1
5 
1
6 
1
7 
2
2 
1 
8 
1
5 
2
2 
1 
15 
1 
 
 
 
 
Laboratory 
evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
D 
7.2.2.5.1 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Chemistry 
D 
7.2.2.5.2 
 
X 
X 
 
 
X  X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Coagulation 
D 
7.2.2.5.3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Pregnancy test  
D 
7.2.2.5.4 
 
X 
Xd 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
 
 
Adverse events 
D 
8 
 
Xe 
Continuously 
 
 
Cardiac 
assessments 
 
7.2.2.6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
D 
7.2.2.6.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QD 
 
 
 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
BID 
 
 
 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
Cardiac imaging 
(MUGA or ECHO) 
D 
7.2.2.6.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 


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Category 
Protoco
l 
Section 
Screening 
Period 
Treatment Period 
End of study treatment (EoT) 
Follow-up 
period 
Visit Name 
 
Molecular Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
to 
Cycle 6 
Subsequent cycles 
30 days safety follow-up 
Disease progression F/U 
Day of cycle 
 
 
 
-14 
to -1 
1 
2 
3 
8 
1
5 
1
6 
1
7 
2
2 
1 
8 
1
5 
2
2 
1 
15 
1 
 
 
 
 
PK sampling 
D 
7.2.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QD 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
C3, 
C5 
 
 
X 
 
 
 
BID 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
C3, 
C5 
 
 
X 
 
 
 


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Category 
Protoco
l 
Section 
Screening 
Period 
Treatment Period 
End of study treatment (EoT) 
Follow-up 
period 
Visit Name 
 
Molecular Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
to 
Cycle 6 
Subsequent cycles 
30 days safety follow-up 
Disease progression F/U 
Day of cycle 
 
 
 
-14 
to -1 
1 
2 
3 
8 
1
5 
1
6 
1
7 
2
2 
1 
8 
1
5 
2
2 
1 
15 
1 
 
 
 
 
Biomarkers 
 
7.2.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole Blood for 
DUSP6 
D 
7.2.4.1.1 
 
 
X 
X 
X 
 
X 
X 
Xc 
 
 
 
 
 
 
 
 
Xf 
 
Xf 
 


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Category 
Protoco
l 
Section 
Screening 
Period 
Treatment Period 
End of study treatment (EoT) 
Follow-up 
period 
Visit Name 
 
Molecular Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
to 
Cycle 6 
Subsequent cycles 
30 days safety follow-up 
Disease progression F/U 
Day of cycle 
 
 
 
-14 
to -1 
1 
2 
3 
8 
1
5 
1
6 
1
7 
2
2 
1 
8 
1
5 
2
2 
1 
15 
1 
 
 
 
 
Collection of 
archival paraffin 
blocks/slides or 
newly obtained 
tumor sample for 
molecular pre-
screening (as 
applicable). 
D 
7.1.1 
7.2.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of newly 
obtained tumor 
sample from 
biopsy/resection 
D 
7.2.4.1.1 
7.2.4.3.1 
 
X 
 
 
 
 
Study drug 
administration  
D 
6.1 
 
 
Xh 
 
Continuously 
 
 
 
 
Antineoplastic 
therapies since 
discontinuation of 
study treatment 
D 
7.1.7.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 


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Category 
Protoco
l 
Section 
Screening 
Period 
Treatment Period 
End of study treatment (EoT) 
Follow-up 
period 
Visit Name 
 
Molecular Pre-screening 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
to 
Cycle 6 
Subsequent cycles 
30 days safety follow-up 
Disease progression F/U 
Day of cycle 
 
 
 
-14 
to -1 
1 
2 
3 
8 
1
5 
1
6 
1
7 
2
2 
1 
8 
1
5 
2
2 
1 
15 
1 
 
 
 
 


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7.1.1 
Molecular pre-screening 
All patients will be asked to sign a “molecular pre-screening informed consent” prior to the 
collection and analysis of an archival or newly obtained tumor sample to determine the 
molecular status of the tumor, unless existing local data can be used for inclusion in the study. 
For inclusion in the dose escalation part, evidence of a MAPK pathway alteration may be 
obtained from existing local data for the patient or local testing of a tumor sample may be 
performed. 
The results of existing local data must be captured on the appropriate eCRF upon enrollment 
onto the study after the patient has signed the main study ICF. Evidence of local data must be 
present in the source documentation. 
7.1.2 
Screening 
When the patient is considered eligible for screening, the investigator should complete the 
Patient Registration Form and send it to Novartis. The allocation of patients to treatment cohorts 
and groups will be handled by the Novartis clinical study team. 
A written ICF will be obtained from each patient before any study procedures not considered 
part of standard of care procedures are initiated. 
The patients should be evaluated against the study inclusion and exclusion criteria of the study. 
The clinical screening period starts once the MAPK pathway alteration(s) status of the patient 
is known, meets the eligibility requirements, and the patient has provided written ICF to 
participate in the study. Screening assessments have to be done within 14 days prior to the first 
dose of study treatment. Radiological tumor assessment by RECIST v1.1 (Appendix 1) should 
be conducted preferably within 7 days prior to the first dose of the study treatment; however 
tumor assessments up to 28 days prior to the first dose will be acceptable. The tumor assessment 
made during the screening period will provide the baseline tumor measurements, which will be 
used to determine future responses and/or progression. A complete list of screening evaluations 
is provided in the visit of assessments table (Table 7-1). 
7.1.2.1 
Information to be collected on screening failures 
Patients who signed an Informed Consent Form but failed to be started on treatment for any 
reason will be considered a screen failure. Both subjects who signed a molecular pre-screening 
ICF but are considered ineligible after molecular pre-screening, as well as subjects who are 
found not eligible after signing the main study consent will be considered as screening failures, 
and data will be handled in the same manner. 
The reason for molecular pre-screening failure or screening failure will be entered on the 
Screening Phase Disposition Page. 


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The demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for Screen Failure patients. No other data will be entered into the clinical database 
for patients who are screen failures, unless the subject experienced a Serious Adverse Event 
during the Screening Phase (see Section 8 for serious adverse event (SAE) reporting details). 
For molecular pre-screening failures, only SAEs possibly related to a study procedure (i.e., 
tumor biopsy collection) will be reported. 
7.1.2.2 
Patient demographics and other baseline characteristics 
Data will be collected on patient characteristics at baseline, including demographic information 
(age, gender, and race), smoking history and relevant medical history (history of disease and 
current disease status, staging, sites of disease, prior anticancer therapies, prior medication/ 
significant non-drug therapies) and any other assessments that are done for the purposes of 
determining eligibility for inclusion in the study. 
Additionally, the rate at which the tumor was progressing at study enrollment (determined by 
comparing the sum of target lesions diameters of baseline scan to scan obtained prior to baseline 
– if available from patient’s records) will be assessed to support 
 PK, PD, and/or 
preliminary anti-tumor activity based objectives. 
All medications and significant non-drug therapies (including herbal medicines, physical 
therapy and blood transfusions) that are taken by the patient within the 4 weeks prior to their 
first dose of study drug must be recorded on the eCRF. 
7.1.4 
Treatment period 
Treatment period is applicable for both dose escalation and dose expansion parts. 
The treatment period will begin on the first day when patient receives LTT462. 
 
 
 
 
A treatment period cycle is defined as 28 days (4 calendar weeks) for the purposes of scheduling 
procedures and evaluations. Please refer to Table 7-1 for details of the timing of required 
assessments and Section 7.1 for visit windows. 


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Patients will be treated until the patient experiences progression of disease, development of 
unacceptable toxicity, withdrawal of informed consent, or death, whichever occurs first as 
described in Section 7.1.5 and Section 7.1.6. 
Patients who have disease progression and have evidence of clinical benefit, such as disease 
shrinkage at other sites or symptomatic improvement, may continue treatment with LTT462. In 
addition, LTT462 treatment may be temporarily interrupted to permit local therapy for 
symptomatic metastases after disease progression has been documented. Patients who continue 
on treatment after disease progression should discontinue study treatment once they are no 
longer deriving benefit as assessed by the investigator. These decisions can only be taken upon 
documented agreement with the Novartis Medical monitor and a report of the discussions with 
Novartis must be recorded in the source documentation and in a comment in the eCRF. 
7.1.5 
Discontinuation of Study Treatment 
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator must make every 
effort (e.g. telephone, e-mail, letter) to determine the primary reason for this decision and 
record this information in the patient’s chart and on the appropriate eCRF pages. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason. 
The investigator should discontinue study treatment for a given patient if, he/she believes that 
continuation would be detrimental to the patient’s well-being. 
Study treatment may be discontinued under the following circumstances: 
• Adverse Event 
• Investigator’s decision 
• Progressive disease 
• Lost to follow-up 
• Technical problems 
• Study terminated by Novartis 
• Patient/guardian decision 
• Study treatment interruption of > 21 consecutive days; unless the investigator feels there is 
clinical benefit 
• Protocol deviations 
Study treatment must be discontinued under the following circumstances: 
• Pregnancy 
• Death 
Patients who discontinue study treatment should NOT be considered withdrawn from the 
study. They should return for the EoT visit assessments indicated in Table 7-1. If they fail to 
return for these assessments for unknown reasons, every effort (e.g. telephone, email, letter) 
should be made to contact them as specified in Section 7.1.8. 


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At the time patients discontinue study treatment, a visit should be scheduled as soon as possible 
and within 14 days of the last dose of study treatment or within 14 days of the decision to 
permanently discontinue study treatment, at which time all of the assessments listed for the EoT 
visit will be performed. If the decision to discontinue study treatment occurs at a regularly 
scheduled visit, that visit may become the EoT visit rather than having the patient return for an 
additional visit. 
7.1.6 
Withdrawal of Consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want any 
further study related contact. 
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations). 
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information. 
Study treatment must be discontinued and no further assessments conducted. 
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up. 
7.1.7 
Follow up for Safety Evaluations 
7.1.7.1 
30-day safety FU period 
All patients must have safety evaluations for 30 days, after the last dose of study treatment. 
Information related to AEs (including concomitant medication taken for ongoing AEs) and 
ongoing anti-neoplastic treatments will be collected. Data collected should be added to the 


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Adverse Events eCRF, the Prior and Concomitant Medications eCRF, and the Antineoplastic 
Therapy Since Discontinuation of Study Treatment eCRF. 
All AEs suspected to be related to study drug should be followed up weekly, or as clinically 
indicated, until resolution or stability (see also Section 8.2.2). 
7.1.7.2 
Disease progression FU 
Any patient who discontinues from study treatment for any reason (except for disease 
progression, death, withdrawal of consent, lost to follow-up, or study termination) will continue 
to have tumor assessments, performed every 8 weeks, in the follow-up period until disease 
progression or start of new anticancer therapy. 
Antineoplastic therapies since discontinuation of study drug will be collected during this 
follow-up period. 
7.1.8 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition eCRF. 


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7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Tumor response will be assessed locally according to the Novartis guideline version 3.1 
 based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
(Eisenhauer et al 2009). 
 
 
 


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7.2.2 
Safety and tolerability assessments 
Safety will be monitored by performing physical examinations and assessing vital signs, height 
and weight, performance status, laboratory evaluations, 
 
 
 
 as well as collecting of the adverse events at every visit. For 
details on AE collection and reporting, refer to Section 8. 
7.2.2.1 
Physical examination 
A complete physical examination will be performed according to the standards at each 
institution and must be performed as indicated in Table 7-1. 
Information about the physical examination must be present in source documentation at the 
study site. Significant findings that were present prior to the signing of informed consent must 
be included in the Medical History page on the patient’s eCRF. Significant new findings that 
begin or worsen after informed consent must be recorded on the Adverse Event page of the 
patient’s eCRF. 
7.2.2.2 
Vital signs 
Vital signs (including body temperature, pulse rate and blood pressure) must be performed 
before and at 1, 3 and 6 hours after dosing, per institutional standards on C1D1, C1D15, 
 
 For all other visits that coincide with PK samples, vital signs should 
be taken at pre-dose and 1 hour post-dose. For all other visits indicated in Table 7-1, vital signs 
should be recorded only at pre-dose. Blood pressure and pulse rate measurements should be 
assessed while the patient is sitting. On the days of blood sampling for PK, the vital signs should 
be collected prior to the blood collection. 
7.2.2.3 
Height and weight 
Height and body weight (indoor clothing, but without shoes) will be measured. Height will be 
collected at screening only. Weight will be measured at the visits indicated in Table 7-1. More 
frequent examinations may be performed at the discretion of the Investigator and if medically 
indicated. 
7.2.2.4 
Performance status 
ECOG performance status will be assessed as indicated in Table 7-1. The ECOG performance 
status scale is summarized in Table 7-3. 
Table 7-3 
ECOG performance status 
Grade 
ECOG Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 


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7.2.2.5 
Laboratory evaluations 
All laboratory parameters assessed for safety purposes will be evaluated locally, at the site. 
Refer to Table 7-4 for a summary of the parameters to be evaluated according to Table 7-1. 
At any time during the study, abnormal laboratory parameters which are clinically relevant (e.g., 
require dose modification and/or interruption of study treatment, lead to clinical symptoms or 
signs, or require therapeutic intervention), whether specifically requested in the protocol or not, 
will be recorded on the Adverse Events eCRF page. Laboratory data will be summarized using 
the CTCAE (version 4.03). 
In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria is 
outside of a protocol-specified range at Screening, the assessment may be repeated prior to first 
treatment. If the repeat value remains outside of protocol-specified ranges, the patient is 
excluded from the study. 
Novartis must be provided with a copy of the laboratory’s certification, and normal ranges for 
each parameter measured. In addition, if at any time a patient has laboratory parameters 
obtained from a different outside laboratory, Novartis must be provided with a copy of the 
certification and normal ranges for that laboratory. 
Unscheduled assessment can be performed if clinically indicated. 
7.2.2.5.1 Hematology 
Hematology panel outlined in Table 7-4 will be performed as per the assessment schedule in 
Table 7-1. 
7.2.2.5.2 Clinical chemistry 
Clinical chemistry panel outlined in Table 7-4 will be performed as per the assessment schedule 
in Table 7-1. 


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7.2.2.5.3 Coagulation 
Coagulation panel outlined in Table 7-4 will be performed as per the assessment schedule in 
Table 7-1. 
An unscheduled coagulation sample may be collected as clinically needed. 
7.2.2.5.4 Pregnancy and assessments of fertility 
Serum hCG pregnancy tests will be conducted for all female patients of childbearing potential 
at all visits in the assessment schedule in Table 7-1. The 30 day safety follow up pregnancy test 
may either be performed by a serum hCG or urine test. 
For female adolescent patients of childbearing potential, a urine pregnancy test may be 
conducted at visits, per the assessment schedule in Table 7-1, when a serum hCG pregnancy 
test is not permitted due to local regulations. 
The pre-dose pregnancy test on C1D1 does not have to be performed if the screening serum 
pregnancy test was done within 72 hours prior to the first dose and was negative. 
 
 
 If a patient becomes pregnant, 
study treatment must be stopped immediately. If a pregnancy test is positive, but the patient is 
thought not to be pregnant, study treatment should be stopped until it is determined that the test 
was falsely positive, and pregnancy is excluded. 
7.2.2.6 
Cardiac assessments 
7.2.2.6.1 Electrocardiogram (ECG) 
Standard 12 lead ECG will be performed as per the assessment schedule in Table 7-1 and Table 
7-5. For all patients, 3 sequential 12-lead ECGs must be performed during the trial. 
 
 


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Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
eCRF page. Each ECG tracing should be labeled with the study number, patient initials (where 
regulations permit), patient number, date, and kept in the source documents at the study site. 
Clinically significant abnormalities present when the patient signed informed consent should 
be reported on the Medical History eCRF page. Clinically significant findings must be 
discussed with Novartis prior to enrolling the patient in the study. New or worsened clinically 
significant findings occurring after informed consent must be recorded on the Adverse Events 
eCRF page. 
All ECGs will be independently reviewed by a central laboratory. Instructions for the collection 
and transmission of ECGs to the central ECG laboratory will be provided in the ECG Manual. 


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Clinically significant abnormalities present at screening should be reported on the Medical 
History eCRF page. New or worsened clinically significant findings occurring after informed 
consent must be recorded on the Adverse Events eCRF page. All eligibility and patient 
management decisions could be made based on the local reading of the ECG exceptionally if 
the results of the central ECG can’t be received in a timely manner (prior to first dose). 
7.2.2.6.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram 
MUGA scans or ECHO to assess LVEF will be performed as outlined in Table 7-1, within the 
windows outlined in Section 7.1. Additional assessments may be performed if clinically 
indicated. A MUGA scan or ECHO will be performed at end of study treatment only if an 
assessment of LVEF has not been performed ≤ 14 days prior to EoT. 
7.2.3 
Pharmacokinetics 
Serial blood samples should be collected from all patients in dose escalation and dose expansion 
parts of the study in order to characterize the single dose and steady-state plasma PK of LTT462 
after oral administration to patients. 


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A detailed description of the planned pharmacokinetic analyses is given in Section 10.5.3. 
7.2.3.1 
Pharmacokinetics and blood collection and handling 
PK blood samples will be taken by either direct venipuncture or an indwelling cannula inserted 
in a forearm vein. At each time point, specified in Table 7-6 and Table 7-7, about 2 mL of blood 
will be collected into tubes containing K2 EDTA. These tubes should then be gently inverted 
several times to thoroughly mix the blood with the anticoagulant. Refer to the [CLTT462X2101 
Laboratory Manual] for detailed instructions for the collection, handling, and shipment of PK 
samples. 
All sampling time points in Table 7-6 and Table 7-7 are relative to the previous time of LTT462 
administration. If the dosing schedule is changed to BID 
 (Section 4.1) 
the time points will follow the same collection plan unless otherwise indicated in the tables. 
On the days of PK assessments, the following information should be recorded in the appropriate 
eCRF and source documents: 
• date and times of drug administration prior to first post-dose blood collection 
• date and actual time of PK blood draw 
 
 
• time of vomiting, if it occurs within 4 hours following LTT462 administration 
• any sampling problems. 
On days and time points where blood PD samples are to be drawn, the PK sample should be 
drawn first. 
The date and time of the unscheduled blood sample collection, and the date, time and dose of 
the LTT462 dose taken prior to the unscheduled blood sample collection should be entered in 
the appropriate eCRF page. 


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7.2.4 
Biomarkers 
In this study biomarker analyses will be used to investigate the effect of LTT462 at the 
molecular and cellular level as well as to determine how changes in the markers may relate to 


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exposure and clinical outcomes. 
 
 The sample collection information, as required, should be 
recorded on the relevant eCRF page(s) and central laboratory requisition form(s). 
To the extent possible, actual date of biomarker samples collection should be on the same day 
as the tumor evaluation when scheduled coincidently. Table 7-8 summarizes the biomarker 
collections for this study. On days and time points when biomarker and PK blood samples are 
being collected, the PK sample must be drawn first. If the dosing schedule is changed to BID 
 the time points will follow the same collection plan unless otherwise 
indicated in the table. 
Detailed instructions for the collection, handling, and shipping of biomarker samples are 
outlined in the study [Laboratory Manual]. 
While the goal of the biomarker assessments is to provide supportive data for the clinical study, 
there may be circumstances when a decision is made to stop a collection, or not perform or 
discontinue an analysis due to either practical or strategic reasons (e.g., inadequate sample 
number, issues related to the quality of the sample or issues related to the assay that preclude 
analysis, impossibility to perform correlative analyses, etc.). Therefore, depending on the 
results obtained during the study, sample collection analysis may be omitted at the discretion 
of Novartis. 
Table 7-8 
Biomarker sample collection plan 
Sample Type 
Volume 
Visit / Time point 
Marker 
Purpose 
Tumor samples 
Archival Tumor 
(preferably collected 
after last antineoplastic 
treatment)* 
or 
Newly obtained Tumor 
biopsy 
FFPE block / 
11 tissue 
sections at 4 µm 
Or 
Newly obtained 
formalin fixed 
tumor biopsy in 
ethanol (3-6 
passes) 
Molecular pre-screening 
(Section 7.1.1) 
 
 
 
 
 
 
 
 
 
 
Determine patient 
eligibility  
 
 
 
 
* If existing local data or local testing is used for patient selection, any remaining tumor sample used for patient 
selection is requested for retrospective analysis if an adequate amount remains. If available, FFPE (formalin 
fixed paraffin embedded) tissue block (preferred) or 11 unstained slides (4µM) should be submitted at C1D1 
after the patient has received their first dose. 
Newly obtained tumor 
biopsy for biomarker 
analyses**  
 
 
 
 
 
 
Newly obtained 
formalin fixed 
tumor biopsy in 
ethanol (3-
6 passes/visit) 
Screening 
(newly obtained tumor 
sample collected at pre-
screening may be used 
if an adequate amount 
remains) 
DUSP6  
and/or 
 
 
 
 
 
 
Pharmacodynamic 
effect in tumor 
and/or 
 
 
 
 
 
 
 


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Sample Type 
Volume 
Visit / Time point 
Marker 
Purpose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
**For adolescent patients only: screening and on treatment biopsies are requested, however exceptions may 
be granted following documented agreement between Novartis and Investigator.  
Blood samples 
Whole Blood  
DUSP6 
Pharmacodynamic 
effect. 


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Sample Type 
Volume 
Visit / Time point 
Marker 
Purpose 
7.2.4.1 
LTT462 pharmacodynamic assessments 
PD effects of LTT462 will be assessed directly in tumor and surrogate tissue. 


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8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. 
For patients whose MAPK pathway alteration(s) status is unknown and who sign the molecular 
pre-screening ICF, AEs which occur after signature of this consent will only be captured if they 
meet the definition of serious as outlined in Section 8.2 and are reported to be causally related 
with study procedures (e.g. an invasive procedure such as biopsy). Once the main study ICF is 
signed, all AEs per the descriptions below will be captured in the Adverse Event eCRF. 
Patients for whom the MAPK pathway alteration(s) status is known, and confers eligibility to 
the study, will sign the main study ICF only. All AEs per the descriptions below will be captured 
in the Adverse Event eCRF. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 


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Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s eCRF. Adverse event monitoring should 
be continued for at least 30 days following the last dose of study treatment. Adverse events 
(including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate Adverse 
Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03, unless otherwise stated. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study (but is collected as a seriousness criterion); rather, information about 
deaths will be collected though a Death form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine: 
• The severity grade (CTCAE Grade 1-4) 
• Its duration (Start and end dates) or Ongoing after the 30 Day safety follow-up 
• Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
• Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
• Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
• Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) 
• Whether it is serious, where a SAE is defined as in Section 8.2.1 and which seriousness 
criteria have been met. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as a 
serious adverse event. 


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Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events eCRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe), as per CTCAE, does not 
automatically indicate a SAE unless it meets the definition of serious, as defined below and/or 
as per investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in which case the lab abnormality would still, by definition, be an 
adverse event and must be reported as such. 
8.1.3 
Adverse events of special interest 
These will be determined at a program level on an ongoing basis. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
Note that hospitalizations for the following reasons should NOT be reported as serious 
adverse events: 
• Routine treatment or monitoring of the study indication, not associated with any 
deterioration in condition. 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent. 


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• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition. 
• Note: Treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event. 
Progression of underlying malignancy is not reported as an adverse event if it is clearly 
consistent with the suspected progression of the underlying cancer as defined by RECIST 
criteria. Hospitalization due solely to the progression of underlying malignancy should NOT be 
reported as a serious adverse event. 
Clinical symptoms of progression may be reported as adverse events if the symptom cannot be 
determined as exclusively due to the progression of the underlying malignancy, or does not fit 
the expected pattern of progression for the disease under study. 
Symptomatic deterioration may occur in some patients. In this situation, progression is evident 
in the patient’s clinical symptoms, but is not supported by the tumor measurements. Or, the 
disease progression is so evident that the investigator may elect not to perform further disease 
assessments. In such cases, the determination of clinical progression is based on symptomatic 
deterioration. These determinations should be a rare exception as every effort should be made 
to document the objective progression of underlying malignancy. 
If there is any uncertainty about an adverse event being due only to the disease under study, it 
should be reported as an AE or SAE. 
8.2.2 
Reporting 
For patients with unknown MAPK alteration(s) status and who sign the molecular pre-screening 
ICF, SAE collection will start upon signing the molecular pre-screening ICF. SAEs will only 
be reported if the event is suspected to be causally related to a study procedure as assessed by 
the investigator (e.g. an invasive procedure such as biopsy). SAEs will be followed until 
resolution or until clinically relevant improvement or stabilization. If the main ICF is not signed 
(molecular screen failure), SAE collection ends 30 days after the last study related procedure. 
For patients with known MAPK alteration(s) status who sign the main study ICF, SAE 
collection starts at time of main study informed consent whether the patient is a screen failure 
or not. 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided main informed consent and until at least 30 days after the patient has 
stopped study treatment must be reported to Novartis within 24 hours of learning of its 
occurrence. 
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event. 


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Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours Novartis. Detailed instructions 
regarding the submission process and requirements for signatures are to be found in the 
investigator folder provided to each site. 
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The 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 withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Chief Medical Office and Patient Safety (CMO&PS) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
8.3 
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 Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis CMO&PS. Pregnancy follow-up should be recorded on 
the same form and should include an assessment of the possible relationship to the study 
treatment any pregnancy outcome. Any SAE experienced during pregnancy must be reported 
on the SAE Report Form. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
8.4 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [LTT462 


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Investigator Brochure]. Additional safety information collected between Investigator’s 
Brochure updates will be communicated in the form of Investigator Notifications. This 
information will be included in the patient informed consent and should be discussed with the 
patient during the study as needed. 
8.5 
Data Monitoring Committee 
A data monitoring board will not be used for this study. 
 


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9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated Contract Research Organization (CRO)) will review the protocol and 
CRFs with the investigators and their staff. During the study, the field monitor will visit the site 
regularly to check the completeness of patient records, the accuracy of entries on the CRFs, the 
adherence to the protocol to Good Clinical Practice, the progress of enrollment, and to ensure 
that study treatment is being stored, dispensed, and accounted for according to specifications. 
Key study personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 


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assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the CRFs 
are performed according to the study-specific monitoring plan. 
9.3 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the eCRF. The eCRFs have been built using fully validated 
secure web-enabled software that conforms to 21 CFR Part 11 requirements, Investigator site 
staff will not be given access to the EDC system until they have been trained. Automatic 
validation programs check for data discrepancies in the eCRFs and, allow modification or 
verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
PK and biomarker (blood, serum, plasma and/or tissue) samples obtained during the course of 
the study will be collected from the Investigator sites and analyzed by Novartis designated 
laboratories. ECG data collected during the study will be reviewed and processed centrally by 
a specialist CRO. Radiological and photography data will be acquired by the sites and 
interpreted locally, however, during the course of the study, Novartis may decide to have a 
central review of the radiological assessments performed. In such case, the investigator’s staff 
will be instructed on how to send data from these radiological assessments to a CRO for central 
review when needed. Details regarding all CRO procedures including collection and shipment 
of data will be described in the manual provided by the respective CRO. Designated 
investigational site staff will enter the information required by the protocol into the appropriate 
eCRF and/or designated laboratory requisition forms. Field monitors will review the eCRFs and 
laboratory paper requisition forms for accuracy and completeness and instruct site personnel to 
make any required corrections or additions. One copy of the requisition form will be forwarded 
to each analytical laboratory with the respective sample(s) by the field monitor or by the 
designated investigational site staff; and one copy will be retained at the investigational site. 
9.4 
Database management and quality control 
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 


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system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
ECG, PK, and biomarker samples and/or data will be processed centrally and the results will be 
sent electronically to Novartis (or a designated CRO). 
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked. Authorization is required prior to making any 
database changes to locked data, by joint written agreement between the Global Head of 
Biostatistics and Data Management and the Global Head of Clinical Development. 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site. 
10 
Statistical methods and data analysis 
Study data will be analyzed by Novartis and/or designated CRO. Any data analysis carried out 
independently by the investigator must be submitted to Novartis before publication or 
presentation. 
Study data will be summarized with respect to demographic and baseline characteristics, 
efficacy observations and measurements, safety observations and measurements, 
pharmacokinetics and PD measurements, using descriptive statistics (quantitative data) and 
contingency tables (qualitative data). All data from participating centers in this protocol will be 
combined, so that an adequate number of patients will be available for analysis. 
Summaries will be produced by treatment group for the dose escalation part, by study arm for 
the expansion part, and overall. Categorical data will be presented as frequencies and 
percentages. For continuous data, mean, standard deviation, median, minimum, and maximum 
will be presented. 
The primary CSR will include all patients’ data reported in the study up to the time when all 
patients have had the opportunity to complete at least 6 cycles of treatment or discontinued the 
study. Any additional data reported past this data cutoff date for the primary CSR will be 
reported in a closeout CSR once all study patients have discontinued the study  
(refer to Section 4.3). 
The following rules will be followed for reporting results unless stated otherwise: 
a. Dose escalation: cohorts with the same dose level , regimen, 
 will 
be pooled into a single treatment group. All tables, figures and analyses will be produced 
by treatment group. 


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10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) includes all patients who received at least one dose (full or partial) 
of LTT462. Patients will be analyzed according to the treatment assigned. 
10.1.2 
Safety Set 
The Safety Set includes all patients who received at least one dose (full or partial) of LTT462. 
Patients will be analyzed according to the treatment received, where treatment received is 
defined as: 
• The treatment assigned, if it was received at least once or 
• The first study treatment received, if the treatment assigned was never received. 
10.1.4 
Dose-determining analysis set 
The DDS includes all patients from the Safety Set (escalation part) who met the minimum 
exposure criterion and had sufficient safety evaluations, or experienced a DLT during the first 
28 days of dosing. 
A patient has met the minimum exposure criterion when exposed to the received study treatment 
(as defined in the Safety Set definition above) for at least 75% of the planned LTT462 total 
daily doses in the first cycle of treatment. 
• For QD: at least 75% percent of the planned daily doses means at least 21/27, given that 
the C1D2 dose will be omitted. 
• For BID: at least 75% of planned BID daily doses means at least 20/26 full days of dosing 
of the planned doses, given the C1D2 dose will be omitted and a single dose will be 
administered on the first day of treatment. 
Patients who do not experience a DLT during the first cycle of dosing are considered to have 
sufficient safety evaluations if they have been observed for ≥ 28 days following the first dose, 
and are considered by both the Sponsor and Investigators to have enough safety data to conclude 
that a DLT did not occur. 
10.1.5 
Pharmacokinetic analysis set 
• The Pharmacokinetic Analysis Set (PAS) consists of all patients who have at least one PK 
blood sample providing measurable LTT462 and who satisfy the bullets below: Patient 
received at least one dose of study treatment 
• Patient followed the dosing recommendation (Section 6.1.1) and took the drug 1 hour 
before or 2 hours after the meal 


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• Patient did not vomit within 4 hours of dose administration 
• Patient provided at least one primary PK parameter 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data will be presented descriptively. Demographic data 
includes age, gender, race, height, weight, ECOG performance status. Baseline data includes 
diagnosis and extend of cancer, smoking and medical history, and current (ongoing) medical 
conditions, including cancer-related conditions and symptoms, and prior anti-neoplastic therapy 
(medication, radiotherapy, or surgery summarized separately). 
Medical history and current medical conditions are coded using the latest MedDRA 
terminology. 
Summary tables and listings will be based on the FAS. 


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10.4 
Primary objective 
The primary objective of this study is to characterize the safety and tolerability of LTT462 and 
identify a recommended dose and regimen for future studies. 
10.4.1 
Variable 
The primary endpoints defined to evaluate the safety of LTT462 are incidence and severity of 
AEs, changes in hematology and chemistry laboratory values, changes vital signs, changes in 
ECG and incidence and nature of DLTs (dose escalation only). Tolerability will be evaluated 
in terms of dose interruptions, dose reductions, and dose intensity. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
DLTs will be analyzed using a Bayesian model. The incidence of DLTs will be summarized by 
system organ class and preferred term. The DDS will be used to analyze DLTs. Statistical 
analysis of endpoints other than DLTs will be descriptive, based on the safety analysis set, no 
hypotheses or models will be considered. Descriptive statistics will be provided on: 
• The incidence by patients of AEs, independent of relationship to study drug, and also 
considering severity 
• The incidence by patient of serious AE, independent of relationship to study drug 
• Changes from baseline to worst post-baseline hematology and chemistry laboratory values 
• Changes from baseline to worst post-baseline values of ECG parameters 
• Changes in vital signs from baseline to worst post-baseline values 
• Summary of dose intensity, and number and percentage of dose interruptions and 
reductions. 
10.4.2.1 Dose limiting toxicities (dose escalation) 
Dosing regimens QD
The dose escalation will be guided by a BHLRM based on the first Cycle DLT data of the study 
treatment. This model estimates the relationship between dose and the probability of a patient 
experiencing a DLT following a QD regimen 
 


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Additional dosing regimen 
Should emergent data support the investigation of 
 
 a separate BLRM, guided by the EWOC principle, will be used to make dose 
recommendations. 
Dose recommendation 
After each cohort of patients, the posterior distributions for the probabilities of DLT rates at 
different dose levels will be obtained. Dose recommendation will be based on posterior 
summaries including the mean, median, standard deviation, 95%-credible interval, and the 
probability that the true DLT rate for each dose lies in one of the following categories: 
• [0,16%) under-dosing 
• [16%,33%) targeted toxicity 
• [33%,100%] excessive toxicity 
Dose recommendation will also be guided by the EWOC principle, which mandates the dose 
for the next cohort to have less than 25% chance of excessive toxicity. The final estimate of the 
MTD/RDE will also satisfy this condition. 
Summary of DLTs 
A summary of the posterior probabilities of DLT rates in the different toxicity categories and 
the corresponding illustration will be presented at each dose escalation meeting. For the CSR, 
DLTs will be listed and the incidence summarized by primary system organ class and preferred 
term. The dose-determining analysis set will be used. 
10.4.2.2 Adverse events 
Data handling 
AEs will be coded using the latest version of the MedDRA and graded using the CTCAE version 
4.03. The CTCAE grade 5 (death) will not be used in this study. 
A patient with multiple CTCAE grades for an AE will be summarized under the maximum 
grade recorded for the event. A subject with multiple occurrences of an AE is counted only once 
in the AE category (e.g. system organ class, preferred term). 


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10.4.2.3 Laboratory parameters 
Data handling 
All laboratory values will be converted into SI units, as appropriate, and the severity grade 
calculated using CTCAE, version 4.03. For laboratory tests covered by CTCAE, a Grade 0 will 
be assigned for all non-missing values not graded as 1 or higher. Grade 5 will not be used. For 
laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on local laboratory normal ranges. The list of parameters 
with CTCAE grading and LNR is presented in Section 10.5.3. 
 
 


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10.4.2.4 Electrocardiograms 
Data handling 
• Unscheduled ECGs are included in the analysis of notable value. 
• Triplicate 12 lead sequential readings will be performed at baseline and post-baseline for a 
patient at the given time points (Section 7.2.2.6), all individual values are transferred, in 
which case, ECGs are averaged over the patient and then across patients for change from 
baseline analysis. 
• No adjustment (in the variance) is made to account for different patients having differing 
number of ECGs being averaged at a given time point. (It is assumed that the scheduled 
assessments for each patient are the same and any deviations are sporadic and minor). 


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10.4.2.5 Vital signs 
Data handling 
Change from baseline will only be summarized for patients with both baseline and post-baseline 
values. 
10.4.2.6 Tolerability 
Tolerability of study drug treatment will be assessed by summarizing the number and 
percentage of dose interruptions and dose reductions per patient, together with reasons for dose 
interruption and dose reductions. Dose intensity and relative dose intensity of LTT462 per 
patient will be summarized. For relative dose intensity, the number and proportion of patients 
within the following categories will be presented: < 0.5, ≥ 0.5 - < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - 
< 1.1 and ≥ 1.1. 
10.4.3 
Handling of missing values/censoring/discontinuations 
No imputation for missing data will be performed. Patients with missing baseline assessments 
will be excluded from analyses where a baseline value is required to compute the corresponding 
endpoint. 
10.4.4 
Supportive analyses 
During the course of the study, additional analyses may be identified based on emerging safety 
data, to support the primary analyses. These analyses will be defined in the statistical analysis 
plan prior to clinical database lock. 


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10.5 
Secondary objectives 
10.5.1 
Secondary efficacy objectives 
Tumor response will be determined locally according to RECIST v1.1 (refer to Appendix 1) 
per local investigators’ assessment. The FAS will be used for all efficacy analyses. 
Efficacy endpoints are progression free survival (PFS), ORR, duration of response (DOR), and 
DCR. 
 
Dose escalation part 
For the dose escalation part, the best overall response (BOR) and individual lesions, and the 
PFS time will be presented for each patient in a listing. 


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10.5.2 
Secondary Safety objectives 
10.5.2.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used. All tables will be presented by treatment 
group for the dose escalation part and by study group for the dose expansion part. 
The overall observation period will be divided into three mutually exclusive segments: 
• pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
• on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
• post-treatment period: starting at day 30+1 after last dose of study medication. 
10.5.2.2 Adverse events (AEs) 
Analysis of adverse events will be described similar to the primary endpoint. Summary tables 
for adverse events (AEs) will include only on-treatment events. The listing of all AE will 
include all AE reported in the study, without date restrictions. 
The incidence of the following treatment-emergent adverse events will be summarized by 
maximum severity (based on CTCAE grades), system organ class and/or preferred term: AE 
suspected to be study drug related, AE leading to study drug discontinuation, AE requiring drug 
dosage adjustments/temporarily interrupted, SAE suspected to be study drug related. 
Deaths with onset on-treatment and also all deaths occurring during the study will be 
summarized by system organ class and/or preferred term. AE which are not SAE will be 
summarized by primary system organ class and preferred term. 
LTT462 specific safety event categories (SEC) may be considered. Such categories consist of 
one or more well-defined safety events which are similar in nature and for which there is a 
specific clinical interest in connection with the study treatment. 
For each specified SEC, number and percentage of patients with at least one event part of the 
SEC will be reported. 
10.5.2.3 Laboratory abnormalities 
All laboratory values will be converted into SI units, as appropriate, and the severity grade 
calculated using CTCAE, version 4.03. Data handling will be as described in Section 10.4.2. 
Analysis of chemistry and hematology tests results are described in Section 10.4.2. A listing of 
patients with abnormal values of CTCAE grade 3 or 4 will be presented (for all laboratory 
parameters measured). For parameters (independent of the test category) with no CTCAE grade, 
a listing of patients with abnormal values will be provided, with low/high values flagged. 
 
 
 


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10.5.2.4 Hepatic abnormalities 
Hepatic abnormalities will be assessed based on the following liver function tests: ALT, AST, 
ALP, and total bilirubin (TBL). The number and percentage of patients with newly occurring 


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notable hepatic laboratory values within the categories presented below will be provided. For 
the combined criteria, shift tables to compare baseline to the worst post-baseline will be 
presented. A listing of patients with at least one newly occurring notable event will be provided. 
10.5.2.5 Other safety data 
Other safety assessments include ECOG performance status, physical examinations, height, 
pregnancy test, MUGA scan or ECHO, 
 


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10.5.2.6 Supportive analyses for secondary objectives 
Refer to Section 10.4.4. 
10.5.3 
Pharmacokinetics 
Pharmacokinetic parameters will be determined by non-compartmental method(s) using the 
pharmacokinetic profile of LTT462. PK parameters listed in Table 10-7 will be derived and 
reported, when feasible. 
Further analyses may be conducted using population PK approaches. In addition, a model based 
approach may be used to explore the potential relationship between efficacy, safety, and/or 
biomarker endpoints and LTT462 concentration and/or exposure metrics. Any analyses 
performed will be specified either in the study analysis plan or in a stand-alone analysis plan 
document. All analyses will be reported either in the CSR or a stand-alone report. 
Table 10-7 
Noncompartmental pharmacokinetic parameters 
AUClast 
The AUC from time zero to the last measurable concentration sampling time (Tlast) (mass x 
time x volume-1) 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x 
volume-1) 
AUCinf 
The AUC from time zero to infinity (mass x time x volume-1) 
Cmax 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration 
after single dose administration (mass x volume-1) 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time) 
Cmin 
Observed concentration at the end of a dosing interval (taken directly before next 
administration) 
CL/F 
The total body clearance of drug from the plasma (volume x time-1) 
Racc 
Accumulation ratio calculated using AUCtau at steady state divided by AUCtau at Day 1 
T½ 
Effective elimination half-life 
10.5.3.1 Data handling principles 
All concentrations below the lower limit of quantitation (LLOQ) or missing data will be labeled 
as such in the concentration data listings. Concentrations below the LLOQ will be treated as 
zero in summary statistics and for the calculation of pharmacokinetic parameters, unless 
otherwise stated under the Pharmacokinetic Analysis Set. 
At the time of analysis, concentration data from patients may be removed from the estimation 
of certain PK parameters depending on the number of available blood samples, concomitant 
medications, vomiting, etc. Specific time points might be removed from the analysis set if 


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technical issues with the sample are reported (e.g. sampling issues, missing information). These 
patients and concentration data points will be identified at the time of analysis 
10.5.3.1.1 
Data analysis set 
All pharmacokinetic data analyses and PK summary statistics will be based on PAS. Only PK 
blood samples with date and time and for which the last prior dose dates and times are 
adequately recorded will be included in the PK analyses. 
10.5.3.1.2 
Basic tables, figures, and listing 
Descriptive statistics such as arithmetic and/or geometric mean and CV%, median and range, 
will be presented for all pharmacokinetic parameters, as applicable. Zero concentrations will 
not be included in the geometric mean calculations. Tmax will be summarized in terms of median 
values and ranges. Missing concentrations or PK parameter values will not be imputed. A listing 
of derived PK parameters per patient will be produced by treatment group. 
Mean plasma concentration versus time profile plots will be generated for LTT462. Further 
graphical exploratory analyses (such as individual plasma concentration versus time) will be 
carried out if deemed appropriate. 
10.5.3.2 Dose proportionality 
The analysis of dose proportionality will be conducted for AUC and Cmax of LTT462 using a 
power model on log-transformed scale. The log-transformed PK parameters will each be 
regressed onto a fixed factor for log (dose). The 90% confidence interval (CI) of the slope for 
each PK parameter will be computed from the model and presented in a summary table. Dose-
proportionality will only be investigated if at least three doses of LTT462 are investigated. 
Exploratory analysis will be carried out if deemed necessary. 
10.5.3.4 Time-dependency 
If AUCinf can be reliably estimated on Day 1, the time dependence of the PK (comparison within 
subject of Day 1 AUCinf with Day 15 AUCtau with point estimates and CI) will be analyzed. 
Details will be included in the study analysis plan. 


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10.5.4 
Biomarkers 
Since this clinical trial was not designed to address specific biomarkers-related hypotheses, the 
analysis of this data should be viewed as 
 hypotheses generating. 
Secondary objectives include the assessment of the PD effect of LTT462 in both tumor and 
blood of LTT462. For assessment of PD effects of LTT462 in tumor, pre- and post- treatment 
tumor biopsies will be examined for expression of DUSP6. For assessment of PD effects in 
blood, levels of DUSP6 will be measured in samples isolated concomitantly with those 
collected for PK measurements. 
10.5.4.1 Outline of the data analysis 
Changes in biomarkers in blood and tumor samples may be summarized by means of descriptive 
analysis and correlation with clinical response and exposure where feasible. If the number of 
samples is inadequate to perform a rigorous data analysis, then the available data will only be 
listed. 
Additional analyses will be specified in a separate analysis plan and may be reported in the 
CSR. These analyses may include but are not limited to the meta-analysis of data from this 
study combined with data from other studies or the analysis of biomarkers generated from 
samples collected during the study but analyzed after the database lock and completion of the 
CSR. 
10.5.4.2 Data handling principles 
For change from baseline analyses, calculations will only be performed on patients with 
measurable samples and pre- and post- treatment time points. If both the baseline and post 
baseline values are below the LLOQ, percent change, absolute change, or fold-change from 
baseline will not be imputed. 
10.5.4.3 Data analysis principles 
10.5.4.3.1 
Analysis sets 
The FAS will be used for all biomarker related analyses. The number of patients with 
measureable samples will be identified in the summaries and relevant proportions will be 
calculated against this number. 
10.5.4.3.2 
Basic tables, figures and listings 
Baseline and percentage change from baseline in delta Ct (ΔCT) values of DUSP6 expression 
will be summarized by treatment. 
A waterfall plot will be used to depict the change from baseline in ΔCT values of DUSP6 
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The best percentage change in tumor size and best overall response will also be displayed as a 
waterfall plot, annotated with MAPK pathway gene alterations at baseline. 
Change from baseline in Dual Specificity Phosphatase 6 (DUSP6) expression 
To assess the drug effect on MAPK signaling and correlation to preliminary anti-tumor 
response, changes of molecular status of DUSP6 in pre- and post-treatment tumor biopsies and 
blood samples will be analyzed. Percentage and fold changes will be listed. 
10.5.4.3.3 
Advanced analysis methods 
Additional analyses that may be performed after the completion of the final CSR will be 
documented in separate analysis reports. These analyses may include but are not limited to the 
meta-analysis of data from this study combined with data from other studies or the analysis of 
biomarkers generated from samples collected during the study but analyzed after the database 
lock and completion of the CSR. The data analysis will be described in a separate analysis plan 
document and may be included in the CSR. 
10.7 
Interim analysis 
No formal interim analyses are planned. However, the dose escalation design foresees that 
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each cohort in the dose escalation part, the next dose of LTT462 has to be chosen depending on 
the observed data. Details of this procedure and the process for communication with 
Investigators are provided in Section 6.2.3. 
 
 
 Cumulative study 
data (including safety, tolerability, preliminary anti-tumor activity, PK, and PD) will be 
reviewed on an ongoing basis by Novartis and study investigators. 
10.8 
Sample size calculation 
10.8.1 
Dose-escalation part 
Initially, cohorts of 1 to 3 evaluable patients will be enrolled in the dose-escalation part. Upon 
observation of specific toxicities (see Section 6.2.3 for details), cohorts of 3 to 6 evaluable 
patients will be enrolled including at least six patients at the MTD/RDE level, as described in 
Section 6.2.3. Multiple cohorts may be sequentially enrolled to the same dose level. Additional 
cohorts of 1 to 6 patients may be enrolled at any dose level below the estimated MTD/RDE for 
further elaboration of safety and pharmacokinetic parameters as required. At least 21 patients 
are expected to be treated in the dose escalation part, for the model to have reasonable operating 
characteristics relating to its MTD recommendation. In the event that a lower dose is 
recommended for the use in the dose expansion without identification of the MTD, then the 
sample size may be smaller than 21. 


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11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. 
For Japan only, written consent is necessary both from the patient and his/her legal 
representative if he/she is under the age of 20 years. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 


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documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their CRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in  
Section 4.4. 
11.5 
Publication of study protocol and results 
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted in a publicly accessible database such as www.clinicaltrials.gov before study 
start. In addition, results of interventional clinical trials in adult patients are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1 year of study completion (i.e., LPLV), those for interventional clinical trials involving 
pediatric patients within 6 months of study completion. 
Novartis follows the ICMJE authorship guidelines (www.icmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted 
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations. 
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable. 
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com. 


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11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
eCRFs an audit trail will be maintained by the system. The investigator should retain records of 
the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site. 


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11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days. 


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13 
References (available upon request) 
Babb J, Rogatko A and Zacks S (1998) Cancer Phase I clinical trials; efficient dose escalation 
with overdose control. Statist.Med.17, 1103-1120 
Cantwell-Dorris ER, O'Leary JJ, Sheils OM (2011) BRAFV600E: implications for 
carcinogenesis and molecular therapy. Mol Cancer Ther. Mar; 10(3): 385-94 
Eisenhauer EA, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer, 45(2): 228-47 


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EMEA (February 1, 2007). Guideline on clinical trials in small populations. Document 
reference: CHMP/EWP/83561/2005. 
Food and Drug Administration (February 2012). Drug Interaction Studies - Study Design, 
Data Analysis and Implications for Dosing and Labeling. Rockville, Md. 
Kirkwood JM, Bastholt L, Robert C et al (2012). Phase II, open-label, randomized trial of the 
MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with 
advanced melanoma. Clinical Cancer Research ;18(2): 555-67. 
Lea IA, Jackson MA, Li X, et al (2007) Genetic pathways and mutation profiles of human 
cancers: site- and exposure-specific patterns. Carcinogenesis; 28(9): 1851-8. 


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Morris EJ, Jha S, Restaino CR, et al. (2013) Discovery of a novel ERK inhibitor with activity 
in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov Jul; 3(7): 
742-50. 
Neuenschwander B, Branson M, Gsponer T (2008) Critical aspects of the Bayesian approach 
to phase I cancer trials. Statist. Med.; 27: 2420-2439 


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Young A, Lyons J, Miller AL, et al (2009) Ras signaling and therapies. Adv Cancer Res., 102: 
1-17 
Zhao and Adjei (2014). The clinical development of MEK inhibitors. Nat Rev Clin Oncol; 
11(7): 385-400 


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14 
Appendices 


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14.2 
Appendix 2: Drugs that are prohibited or to be used with caution 
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited below. Combination administration 
of study drugs could result in drug-drug interactions (DDI) that could potentially lead to reduced 
activity or enhanced toxicity of the concomitant medication and/or LTT462. 
The following lists are based on the Oncology Clinical Pharmacology Drug-Drug Interaction 
memo (released in April 2015). The FDA’s Guidance for Industry, Drug Interaction Studies - 
Study Design, Data Analysis and Implications for Dosing and Labeling (February 2012), is the 
basis of the OCP DDI List, and it was supplemented with the data from the Indiana University 
School of Medicine’s “Clinically Relevant” Table and the University of Washington’s Drug 
Interaction Database. 
The list of medications in Table 14-6 and Table 14-7 is meant to provide guidance and it is not 
a comprehensive list. If the patient requires to take a medication that is not in the list, but there 
might be a risk of DDI, please contact Novartis. 
If a drug appears in Table 14-6 (prohibited) as well as in Table 14-7 (drugs to be used with 
caution), the drug should be considered as prohibited. 
Please contact the Novartis Medical monitor with any questions. 
Table 14-6 
Drugs prohibited while on study 
Category 
Drug Names 
Proton pump Inhibitor 
Omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazol, 
rabeprazole 


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Category 
Drug Names 


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Table 14-7 
Drugs to be used with caution while on study 
Category 
Drug Names 
In the event that a drug appears in both the listings of prohibited and drugs to be used with caution, the drug is 
prohibited. 
1 
LTT462 should be administered at least 1 hour before or 2 hours after an antacid 
2 
LTT462 should be administered at least 3 hours before or 6 hours after an H2 receptor antagonist. 


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Protocol No. CLTT462X2101 

SAP_001.pdf: 
Clinical Development 
LTT462 
Oncology Clinical Trial Protocol CLTT462X2101 / NCT02711345
A phase I dose finding study of oral LTT462 in adult 
patients with advanced solid tumors harboring MAPK 
pathway alterations 
Statistical Analysis Plan (SAP) 
Author: 
 Statistician 
Document type: 
SAP Documentation 
Document status: 
Amendment 1 
Release date: 
13-May-2019
Number of pages: 
29 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Table of contents 
1 
Introduction ......................................................................................................................... 4 
1.1 
Study design............................................................................................................. 4 
1.2 
Study objectives and endpoints ............................................................................... 5 
2 
Statistical Methods .............................................................................................................. 6 
2.1 
Data analysis general information ........................................................................... 6 
2.2 
General definitions ................................................................................................... 7 
2.3 
Analysis sets ............................................................................................................ 8 
2.3.1 
Exclusion from analysis sets ................................................................... 9 
2.4 
Subgroup analyses ................................................................................................. 10 
2.5 
Patient demographics and other baseline characteristics ....................................... 10 
2.5.1 
Basic demographic and background data .............................................. 10 
2.5.2 
Medical History ..................................................................................... 10 
2.5.3 
Prior antineoplastic therapy ................................................................... 10 
2.5.4 
Diagnosis and extent of cancer ............................................................. 10 
2.6 
Patient disposition .................................................................................................. 11 
2.7 
Protocol deviations ................................................................................................ 11 
2.8 
Treatments (study treatment, concomitant therapies, compliance) ....................... 11 
2.8.1 
Study treatment ..................................................................................... 11 
2.8.2 
Concomitant therapies ........................................................................... 12 
2.9 
Analysis of the primary variables .......................................................................... 12 
2.9.1 
Primary variables .................................................................................. 12 
2.9.2 
Statistical model and method of analysis .............................................. 12 
2.10 
Analysis of efficacy variable(s) ............................................................................. 15 
2.10.1 
Confidence intervals for ORR ............................................................... 15 
2.11 
Analysis of safety variables ................................................................................... 15 
2.11.1 
Adverse events ...................................................................................... 16 
2.11.2 
Laboratory data ..................................................................................... 17 
2.11.3 
Other safety data ................................................................................... 19 
2.12 
Tolerability ............................................................................................................ 19 
2.13 
Pharmacokinetic data ............................................................................................. 20 
2.13.1 
Data handling principles ....................................................................... 20 
2.13.2 
Data analysis set .................................................................................... 20 
2.13.3 
Basic tables, figures, and listing ............................................................ 20 
2.13.4 
Dose proportionality .............................................................................. 21 
2.14 
Biomarkers ............................................................................................................. 22 


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2.14.1 
Outline of data analysis ......................................................................... 22 
2.14.2 
Analysis data set .................................................................................... 22 
2.14.3 
General data handling ........................................................................... 22 
2.14.4 
Dual specificity phosphatase 6 (DUSP6) .............................................. 22 
2.14.5 
Advanced analysis methods .................................................................. 24 
3 
Interim analysis ................................................................................................................. 24 
4 
Sample size calculation ..................................................................................................... 24 
4.1 
Dose-escalation part ............................................................................................... 24 
 
24 
5 
Changes in planned analysis .............................................................................................. 26 
6 
Appendix ........................................................................................................................... 26 
6.1 
Baseline .................................................................................................................. 26 
6.2 
Handling of missing and partial dates ................................................................... 27 
 
 27 
7 
References ......................................................................................................................... 29 
 


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1 
Introduction 
This Statistical Analysis Plan (SAP) provides detailed statistical methodology for the analysis 
of data from study CLTT462X2101 that will be presented in the Clinical Study Report (CSR). 
The output shells (in-text and post-text) accompanying this document can be found in the TFL 
shells document. The specifications for derived variable and datasets can be found in the 
Programming Datasets Specifications (PDS) document. 
All changes to the planned analysis described in this document required before or after database 
lock will be made through an amendment or addendum, respectively. Note that obvious 
corrections will be made at the time of analysis to address minor formatting or spelling mistakes 
present in the TFL shells document without the need to amend. 
The SAP, TFL shells and PDS documents may also serve as a reference for the creation of any 
outputs required outside of the CSR, e.g., MTD/RDE declaration, IB updates, abstracts, posters, 
presentations, manuscripts and management updates. Data used for these analyses will have a 
status aligned to the database lock guidance. 
1.1 
Study design 
 
 
 
 


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1.2 
Study objectives and endpoints 
Table 1-1 
Primary and secondary objectives 
 


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2 
Statistical Methods 
2.1 
Data analysis general information 
Study data will be analyzed by Novartis personnel and/or designated CRO(s) using R 
 
. The most updated SAS® version 
available in the programming environment 
 
PK parameters will be calculated using non-compartmental methods available
 
 
The primary clinical study report (CSR), if final DBL has not occurred, will include all patients’ 
data reported during the dose escalation and dose expansion parts up to the time when all 
patients have potentially completed at least six cycles of treatment or discontinued the study. 
The primary CSR will include all outputs planned within the TFL shells document. A final (or 
closeout) CSR will be produced once all patients have discontinued the study.  
Data from participating centers will be combined, so that an adequate number of patients will 
be available for analysis. No center effect will be assessed. The data will be summarized with 
respect to demographic and baseline characteristics, efficacy observations and measurements, 
safety observations and measurements, and all relevant pharmacokinetic (PK) and 
pharmacodynamics (PD) measurements using descriptive statistics (n, mean, standard 


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deviation, median, minimum, and maximum) for quantitative data and contingency tables 
(frequencies and percentages) for qualitative data. 
Both pre and post intra-patient dose escalation data will be listed and summarized together 
under the one dose level/treatment group. 
Cohorts of patients treated during the dose escalation part with the same dose levels, regimen 
 will be pooled into one single treatment group.
 
 
 Below an illustration of the grouping, there will be no difference between safety and 
efficacy layout of outputs (more details are included in the TFL shells document).   
Table 2-1 
General display of information  
 
 
Dose Escalation 
 
Treat 
A 
N=xx 
n   (%) 
Treat 
B 
N=xx 
n   (%) 
Treat 
C 
N=xx 
n   (%) 
All  
patients 
N=xx 
n   (%) 
variable 
xx 
(xx.x) 
xx 
(xx.x) 
xx 
(xx.x) 
xx 
(xx.x) 
variable 
xx 
(xx.x) 
xx 
(xx.x) 
xx 
(xx.x) 
xx 
(xx.x) 
variable 
xx 
(xx.x) 
xx 
(xx.x) 
xx 
(xx.x) 
xx 
(xx.x) 
If during the course of the study different groups of interest are identified, the SAP will be 
updated accordingly.  
2.2 
General definitions 
Study drug and study treatment 
Study drug and study treatment refer to LTT462 and are used interchangeable. 
Date of first/last administration of study drug and study treatment 
The date of first (last) administration of study treatment is derived as the first (last) date when 
a non-zero dose of study treatment LTT462 was administered and recorded on the Dosage 
Administration Record panel. For the sake of simplicity, the date of first (last) administration 
of study treatment will also be referred as start (last) date of study treatment. 
Study day 
The study day for all assessments/onset of events will be calculated using the start date of study 
treatment as reference. For assessments/events occurring on or after the start date of study 
treatment, study day will be calculated as: 


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Study day (days) = Event date – Start date of study treatment + 1 
Therefore, the first day of study treatment is study day 1. 
For all assessment/onset of events occurring prior to the start of the study treatment, study day 
will be negative and will be calculated as: 
Study day (days) = Event date – Start date of study treatment 
On-treatment assessment/event 
An on-treatment assessment/event is defined as any assessment/event in the time interval from 
the start date of LTT462 treatment 
 until 
the last date of LTT462 treatment + 30 days inclusive. 
LTT462 dose interruption 
Study drug dose interruption is defined as a “total daily dose” equal to zero, between the first 
and last non-zero doses, following a non-zero total daily dose. This applies to any regimen, in 
our case QD 
 and independently of the reason for interruptions. 
 
LTT462 dose reduction 
Time points at which the dose change flag is checked and the total daily dose is nonzero.  
If the total daily dose at that time point is lower than the total daily dose at the time that the last 
non-zero dose was administered then the dose change is identified as a dose reduction. 
2.3 
Analysis sets  
Full Analysis Set (FAS) 
The FAS will be the default to be used for all efficacy analyses.  Listings of raw data will use 
the FAS, unless otherwise noted. It includes all patients who received at least one dose of study 
drug (full or partial). Patients will be classified according to the planned (i.e., assigned) 
treatment (dose level, regimen, 
). 
Safety Set 
The safety set will be the primary population for all safety related endpoints except 
determination of the dose-DLT relationship. It includes all patients who received at least one 
dose (full or partial) of study treatment. The statement that a patient did not experience an 
adverse event constitutes a valid safety assessment. Patients will be analyzed according to the 
treatment received, where treatment received is defined as: 
• The treatment assigned, if it was received at least once, or 
• The first study treatment received, if the treatment assigned was never received.  
Dose-determining Set 
The DDS consists of all patients from the safety set in the dose escalation part of the trial who 
either meet the following minimum exposure criterion and have sufficient safety evaluations 


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during the first 28 days of dosing or discontinue earlier due to a DLT during the first 28 days 
of dosing. This constitutes an evaluable patient for the determination of MTD. Patients in the 
DDS will be identified prior to each dose escalation meeting and will be confirmed prior to 
database lock. 
In this study, if data on AEs, vital signs, Labs, and dose administration is collected at least at 
study visits C1D1, C1D8 and C1D15, patient is considered as having sufficient safety 
evaluations. The statement that a patient did not experience an adverse event constitutes a valid 
safety assessment. 
A patient is considered to have met the minimum exposure requirement if they have received 
at least 75% of the planned doses of each of the assigned combination drugs during the first 
cycle (the first 28 days of dosing). For all regimens proposed this equates to at least 21 of the 
planned 28 doses LTT462. 
Patients who do not experience a DLT during the first 28 days of dosing are considered to have 
sufficient safety evaluations if they have been observed for 28 days or more following the first 
dose, and are considered by both Novartis and Investigators (at the dose escalation meetings) 
to have enough safety data to conclude that a DLT did not occur. 
PK analysis set for the treatment period 
The Pharmacokinetic Analysis Set (PAS) includes all patients who have at least one PK blood 
sample providing measurable LTT462 and who satisfy the bullets below: 
• received at least one dose of LTT462, 
• 
patient provided at least one primary PK parameters,  
• 
patient did not vomit within 4 hr of dose administration,  
The PAS will be used for summaries of PK data (tables and figures) as well as for listings of 
derived parameters. 
 
2.3.1 
Exclusion from analysis sets 
In general, a patient must have provided written informed consent before inclusion into any 
analysis set, as specified in section 5.2 of the study protocol. 
Table 2-2 
Reasons for excluding a patient from an analysis set 
Analysis set 
Deviation 
Full analysis 
Patient did not receive at least one dose of LTT462 
Safety  
Patient did not receive at least one dose of LTT462. 
Patient without at least one post-baseline safety assessment. 


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Analysis set 
Deviation 
Dose-determining  
Patient did not experience a DLT, however, the requirement of a minimum 
exposure to the planned study treatment was not met.  
PK analysis,  
 
If any of the conditions detailed above are violated, patient will be exclude 
from PAS 
 
2.4 
Subgroup analyses 
None identified to date. 
2.5 
Patient demographics and other baseline characteristics 
Unless noted otherwise, summaries and listings described in this section will be based on the 
FAS. 
2.5.1 
Basic demographic and background data 
Demographic data including age, age categories (<65, ≥65 years), sex, race, ethnicity, height, 
weight, LVEF, and ECOG performance status at baseline will be listed and summarized.  
2.5.2 
Medical History 
Medical history and current medical conditions will be coded using the latest Medical 
Dictionary for Regulatory Activities (MedDRA) terminology available at the time of reporting. 
Medical history and current (ongoing) medical conditions, including cancer-related conditions 
and symptoms will be available as listing.  
2.5.3 
Prior antineoplastic therapy 
The number (%) of patients who received prior anti-neoplastic medications will be summarized 
and listed. 
The summary of prior anti-neoplastic medications will include the total number of regimens 
(note: there can be more than one medication per regimen), therapy type at last medication, 
setting at last medication, best response at last medication (defined to be the best response 
during the last treatment regimens recorded), time (in months) from (end of) last medication to 
Progression,. The last medication is defined based on the last end date of all prior regimen 
components. Prior antineoplastic medications will also be summarized by Anatomical 
Therapeutic Chemical (ATC) class, and preferred term. 
All Prior anti-neoplastic therapies (medications, surgery and radiotherapy) will be available at 
a patient level (listing). 
2.5.4 
Diagnosis and extent of cancer 
The summary and listing of diagnosis and extent of cancer (disease history) will include primary 
site of cancer, details of tumor histology/cytology, histological grade, stage at initial diagnosis, 
stage at time of study entry time (in months) from initial diagnosis of primary site to start of 
study treatment, time (in months) since most recent recurrence/relapse or progression to start of 


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study treatment, time (in months) from initial diagnosis of primary site to first 
recurrence/relapse or progression, current stage of cancer, current extent of disease (metastatic 
sites), and type of lesions (target and non-target lesions) at baseline. 
2.6 
Patient disposition 
The FAS will be used for the patient disposition summary tables and listings. The following 
will be tabulated: 
• Number (%) of patients who are still on-treatment, 
• Number (%) of patients who discontinued treatment, 
• Primary reasons for study treatment discontinuation, 
• Number (%) of patients who are still on study, 
• Number (%) of patients who discontinued from study, 
• Primary reasons for study discontinuation. 
2.7 
Protocol deviations 
The FAS will be used for the protocol deviation listing. The full list of protocol deviations is 
documented in the Study Specification Document (SSD). 
2.8 
Treatments (study treatment, concomitant therapies, 
compliance) 
Unless otherwise noted, the safety set will be used for all summaries and listings described in 
this section.  
2.8.1 
Study treatment 
Last date of exposure to LTT462 is the last date of study treatment. 
Study treatment will be summarized in terms of duration of exposure to study treatment, 
cumulative/average daily study drug dose, study drug intensity (DI).  
• Duration of exposure (days): last date of exposure to study treatment − first date of study 
treatment + 1 (periods of interruption are not excluded) 
• Cumulative dose (mg): sum of all total daily doses of study drug taken by a patient 
• Cumulative planned dose (mg): sum of all doses of study drug that was intended to have 
been taken during the treated period by a patient 
• DI (mg/day): cumulative dose (mg) ⁄ number of doses scheduled per protocol during 
treatment period 
• Relative DI: Cumulative dose (mg) ⁄ Cumulative planned dose (mg) 
The duration of exposure to study treatment will also be summarized following the categories: 
<4, <=4, <=8, <=12, <=16, <=24 weeks.  
Relative RDI will also be summarized following the categories: <0.5, 0.5-<0.75, 0.75-<0.9, 0.9-
<1.1, ≥1.1 for each study drug.  
A listing of patient’s dose administration records will be presented. 


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2.8.2 
Concomitant therapies 
Concomitant therapies are defined as any medications (excluding study treatment, prior 
antineoplastic treatments) and significant non-drug therapies (including physical therapy and 
blood transfusions) administered in the study and are recorded in the Concomitant 
Medications/significant non-drug therapies eCRF. These therapies will be coded using the 
WHO Drug Reference Listing (WHO DRL) dictionary that employs the WHO Anatomical 
Therapeutic Chemical (WHO ATC) classification system. 
Any concomitant therapies starting prior to or after the start of study treatment will be available 
at a patient level (listing). 
The imputation of a concomitant medication start date will follow the same conventions as for 
an AE start date (see Section 2.11.1 Adverse events). No imputation will be performed for 
concomitant medication end dates. 
 
2.9 
Analysis of the primary variables 
2.9.1 
Primary variables 
The primary endpoints defined to evaluate the safety of LTT462 are incidence and severity of 
AEs/SAEs, changes in hematology and chemistry laboratory values, changes in vital signs, 
changes in ECG, and incidence and nature of DLTs (dose escalation only). Tolerability will be 
evaluated in terms of dose interruptions, dose reductions, and dose intensity. 
2.9.2 
Statistical model and method of analysis 
DLTs (in the dose escalation part) will be analyzed using a BHLRM. The incidence of DLTs 
will be summarized by system organ class (SOC) and preferred term. The DDS will be used to 
analyze DLTs. 
 
Statistical analysis of endpoints other than incidence of DLTs will be descriptive, based on the 
safety analysis set, no hypotheses or models will be considered. Details of analysis are provided 
in the safety and tolerability sections, respectively. Descriptive statistics will be provided on: 
• The incidence by patients of AEs, independent of relationship to study drug, and also 
considering severity 
• The incidence by patient of serious AE, independent of relationship to study drug 
• Changes from baseline to worst post-baseline hematology and chemistry laboratory values 
• Changes from baseline to worst post-baseline values of ECG parameters 
• Changes in vital signs from baseline to worst post-baseline values 
• Summary of dose intensity, and number and percentage of dose interruptions and reductions 


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2.9.2.1 
Dose limiting toxicities (dose escalation) 
Statistical model 
The dose escalation will be guided by a BHLRM based on the first Cycle DLT data of the study 
treatment. This model estimates the relationship between dose and the probability of a patient 
experiencing a DLT following a QD regimen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Dose recommendation 
After each cohort of patients, the posterior distributions for the probabilities of DLT rates at 
different dose levels will be obtained for each stratum. Dose recommendation will be based on 
posterior summaries including the mean, median, standard deviation, 95%-credible interval, 
and the probability that the true DLT rate for each dose lies in one of the following categories: 
• [0,16%) under-dosing 
• [16%,33%) targeted toxicity 
• [33%,100%] excessive toxicity 
Dose recommendation will also be guided by the EWOC principle, which mandates the dose 
for the next cohort to have less than 25% chance of excessive toxicity. The final estimate of the 
MTD/recommended dose for expansion will also satisfy this condition. 
Reports 
The dose determining set will be used in the following outputs: 
• A heatmap (in-text) of the posterior distribution of DLT rates, 
• a listing (CSR appendix 16.1.9) of inferential results from the BLRM at the time of the 
MTD declaration,  
• a summary of the DLTs with onset during the first cycle of treatment (dose escalation part 
only)  by primary system organ class, preferred term, and treatment group 
• a listing of patients with DLTs reported during the first cycle of treatment. 
2.9.2.2 
Analysis of other primary Endpoints 
Refer to sections 2.11 and 2.12  
 


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2.10 
Analysis of efficacy variable(s) 
Tumor response will be determined locally according to RECIST v1.1 (Appendix 1.1 of the  
study protocol), as per local investigators’ assessment. The FAS will be used for all efficacy 
analyses. 
Dose escalation part 
For the dose escalation part, the best overall response (BOR) and individual lesions, DOR (if 
applicable) and the PFS time will be presented for each patient in a listing. PFS, ORR and DCR 
will be summarized by treatment group. 
2.10.1 
Confidence intervals for ORR 
An exact binomial confidence interval (implemented using the SAS procedure FREQ with the 
EXACT statement for one-way tables) will be calculated (Clopper CJ, 1934). 
 
 
 
 
 
 
 
2.11 
Analysis of safety variables 
The assessment of safety is based on the type and frequency of Adverse Events (AEs) as well 
as on the number of laboratory values that fall outside of pre-determined ranges (Common 
Toxicity Criteria for Adverse Events (CTCAE version 4.03) grading limits or normal ranges as 
appropriate). Other safety data include ECOG performance status, electrocardiogram and vital 
signs. 
The Safety set will be used for summaries and listings of safety data with the exception of dose 
limiting toxicities (DLTs) for which the DDS will be used. 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of LTT462,  
2. On-treatment period: from day of first dose of LTT462 to 30 days after last dose of study 
medication, 
3. Post-treatment period: starting at Day 31 after last dose of LTT462. 
Safety summary tables described in the following sections will include assessments collected 
during the treatment period, unless otherwise stated. 


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2.11.1 
Adverse events 
Data handling 
AEs will be coded and graded using the latest version of MedDRA and CTCAE, respectively, 
available at the time of reporting. If CTCAE grading does not exist for an AE, grades 1, 2, 3, or 
4 corresponding to the severity of mild, moderate, severe, and life-threatening, respectively, 
will be used. CTCAE grade 5 (death) will not be used in this study. Death information will be 
collected during treatment, safety follow up, and post-treatment follow up . 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors, should not be reported as a 
serious adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
A patient with multiple CTCAE grades for an AE will be summarized under the maximum 
grade recorded for the event. A subject with multiple occurrences of an AE is counted only once 
in the AE category (e.g. SOC, preferred term). 
The incidence of a given AE is defined as the ratio of total number of patients experiencing the 
given AE at least once (defined by its preferred term [PT]) divided by the total number of 
patients at risk (i.e. part of the safety set). The incidence of AEs will be performed on treatment-
emergent events only, i.e., AE that first occurs or worsens during treatment up to 30 days 
following the last treatment administration.  The listing of adverse events will include all events 
reported during the study conduct.  
Reports 
The following AE summaries will be produced, including maximum CTC grade 3/ 4, in addition 
to the primary analyses: 
• AEs regardless of study drug relationship 
• AEs suspected to be study drug related  
• AEs leading to discontinuation of study drug, regardless of study drug relationship  
• AEs which are not SAEs regardless of study drug relationship 
• All SAEs regardless of study drug relationship 
• On-treatment deaths with cause of death by preferred term 
• All deaths, with cause of death by primary system organ class and preferred term  
 
A missing AE start date will be imputed using the following logic matrix described below. 


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Table 2-3 
Imputation rules for a partially missing AE start date 
 
AEM MISSING 
AEM < TRTM 
AEM = TRTM 
AEM > TRTM 
AEY MISSING 
No imputation 
No imputation 
No imputation 
No imputation 
AEY < TRTY 
 
(D) 
 
(C) 
 
(C) 
 
(C) 
 
AEY = TRTY 
 
(B) 
 
(C) 
 
(B) 
(A) 
 
AEY > TRTY 
 
(E) 
(A) 
(A) 
(A) 
 
AEM: Month AE started; AEY: Year AE started 
TRTM: Month treatment started; TRTY: Year treatment started 
Table 2-2 is the legend to the logic matrix shown in Table 2-1 and details the relationship of 
AE start date to study treatment start date. 
Table 2-4 
Imputation legend and AE/treatment start date relationship 
 
AE start date relationship 
Imputation 
(A) 
After treatment start or Uncertain 
MAX( 01MONYYYY, TRTSTD+1 ) 
(B) 
Uncertain 
TRTSTD+1 
(C) 
Before treatment start 
15MONYYYY 
(D) 
Before treatment start 
01JULYYYY 
(E) 
After treatment start 
01JANYYYY 
Before treatment start: Partial date indicates AE start date is prior to treatment start date. 
After treatment start: Partial date indicates AE start date is after treatment start date. 
Uncertain: Partial date insufficient to determine relationship of AE start date to treatment start date. 
No imputation will be performed for AE end dates. 
2.11.2 
Laboratory data 
Data handling 
All laboratory values will be converted into SI units, as appropriate, and the severity grade 
calculated using Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on local laboratory normal ranges.  
Laboratory parameters with CTCAE grading will follow the EASE Lab CTC grade derivations: 
• Lab values will be analyzed using programmable numeric CTCAE criteria , therefore not 
considering clinical components (e.g., life-threatening consequences).  It is therefore 
understood that  AEs on lab toxicities might not correspond fully with lab toxicities on lab 
values 
The new Novartis Oncology standard definitions of lab CTC grades (including direction of 
severity) are given in Appendix 6.3.  Of note this is the current version of the EASE report, at 
the time of the CSR, the most updated version will be applied, 


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Data analysis 
A listing of patients with abnormal laboratory values of CTCAE grade 3 or 4will be produced 
for the hematology and chemistry laboratory data. 


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2.11.3 
Other safety data 
2.11.3.1 Electrocardiograms 
Data handling 
• Unscheduled ECGs are included in the analysis of notable value. 
• Triplicate 12 lead sequential readings will be performed at baseline and post-baseline for a 
patient at the given time points, refer to section 7.2.2.6.1 of the study protocol, all 
individual values are transferred, in which case, ECGs are averaged over the patient and 
then across patients for change from baseline analysis. 
• No adjustment (in the variance) is made to account for different patients having differing 
number of ECGs being averaged at a given time point. (It is assumed that the scheduled 
assessments for each patient are the same and any deviations are sporadic and minor.) 
Data Analysis 
A listing of ECG intervals will be presented, by treatment group for the dose escalation part. 
2.11.3.2 Vital signs 
A listing of patients with abnormal vital signs will be provided. 
2.12 
Tolerability 
Tolerability of study drug treatment will be assessed by summarizing the number and 
percentage of dose interruptions and dose reductions per patient, together with reasons for dose 
interruption and dose reductions. Dose intensity and relative dose intensity of LTT462 per 
patient will be summarized. For relative dose intensity, the number and proportion of patients 


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within the following categories will be presented: < 0.5, ≥ 0.5 - < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - < 
1.1 and ≥ 1.1. 
 
2.13 
Pharmacokinetic data 
Pharmacokinetic parameters will be determined by non-compartmental method(s) using the 
pharmacokinetic profile of LTT462. PK parameters listed below will be derived and reported, 
when feasible. 
Table 2-8 
Non-compartmental pharmacokinetic parameters 
AUClast 
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x 
time x volume-1) 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x 
volume-1) 
AUCinf 
The AUC from time zero to infinity (mass x time x volume-1) 
Cmax 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass x volume-1) 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time) 
Cmin 
Observed concentration at the end of a dosing interval (taken directly before next 
administration) 
CL/F 
The total body clearance of drug from the plasma (volume x time-1) 
Racc 
Accumulation ratio calculated using AUCtau at steady state divided by AUCtau at Day 1 
T1/2 
Effective elimination half-life 
2.13.1 
Data handling principles 
All concentrations below the lower limit of quantitation (LLOQ) or missing data will be labeled 
as such in the concentration data listings. Concentrations below the LLOQ will be treated as 
zero in summary statistics and for the calculation of pharmacokinetic parameters, unless 
otherwise stated under the Pharmacokinetic Analysis Set.  
At the time of analysis, concentration data from patients may be removed from the estimation 
of certain PK parameters depending on the number of available blood samples, concomitant 
medications, vomiting, etc. Specific time points might be removed from the analysis, if 
technical issues with the sample are reported (e.g. sampling issues, missing information). These 
patients and concentration data points will be identified at the time of analysis. 
2.13.2 
Data analysis set 
All pharmacokinetic data analyses and PK summary statistics will be based on PAS. Only PK 
blood samples with date and time and for which the last prior dose dates and times are 
adequately recorded will be included in the PK analyses. 
2.13.3 
Basic tables, figures, and listing 
Descriptive statistics will be presented for all pharmacokinetic parameters, as described below. 


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Table 2-9 
Descriptive analysis 
Parameters 
Descriptive statistics 
AUC(1) , Cmin, Cmax, CL/F,  
accumulation ratio Racc, T1/2 
Mean standard deviation, CV% mean, geometric mean, 
CV% geo-mean, median, minimum, and maximum.  
90% CI for Racc. 
Tmax 
Median, minimum, and maximum. 
<Other parameters> 
None 
(1) Includes AUCinf, AUCtau, AUClast (or all AUC parameters) 
CV% = coefficient of variation (%) = sd/mean*100 
CV% geo-mean = sqrt (exp (variance for log transformed data)-1)*100 
 
 Zero concentrations will not be included in the geometric mean calculations. Tmax will be 
summarized in terms of median values and ranges. Missing concentrations or PK parameter 
values will not be imputed. A listing of derived PK parameters per patient will be produced by 
treatment group. 
Arithmetic and geometric mean plasma concentration versus time profile plots will be generated 
for LTT462. Further graphical exploratory analyses (such as individual plasma concentration 
versus time) will be carried out if deemed appropriate. 
2.13.4 
Dose proportionality 
Analysis of dose-proportionality will be performed if at least three doses of LTT462 are 
investigated. 
Cmax and AUC will be used for dose proportionality analysis using the power model (Gough 
1995). The power model empirical relationship between a PK parameter and dose is of the form 
( )(
)

dose
Exp
PK =
, 
where “PK” represents the PK parameter AUCinf or Cmax. For analysis, this equation is log-
transformed (natural log), obtaining the equation 
(
)
(
)
Dose
PK
e
e
log
log

+
=
, 
The slope beta measures the dose-proportionality between Dose and the PK parameter 
To test for dose proportionality, the confidence interval criteria for assessment of dose 
proportionality from Smith et al. (2000) will be used.  The a priori acceptance range for the 
slope, according to Smith, is given by 
(
)
(
)
(
)
(
)
ratio
dose
Ln
Ln
ratio
dose
Ln
Ln
_
25
.1
1
  
  
_
8.0
1
+


+

 
Where 1.25 and 0.8 are the critical a priori values suggested by regulatory authorities for any 
bioequivalence problem after a data log transformation, and “dose_ratio” is the ratio of the 
largest to the smallest dose.  Dose proportionality can be claimed if the 90% confidence interval 
for the slope is entirely contained within this a priori range.   


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2.14 
Biomarkers 
As a project standard, Novartis Oncology BDM will analyze only biomarkers collected in the 
clinical database. 
 
 
. 
 
 
 
 
 
  
There may be circumstances when a decision is made to stop sample collection, or not perform 
or discontinue the analysis of blood / archival tumor samples / fresh tumor biopsies / fine needle 
aspirates due to either practical or strategic reasons (e.g. issues related to the quality and/or 
quantity of the samples or issues related to the assay). Under such circumstances, the number 
of samples may be inadequate to perform a rigorous data analysis and the available data will 
only be listed and potentially summarized. 
2.14.1 
Outline of data analysis 
Additional analyses that may be performed after the completion of the end-of-study CSR will 
be documented in separate reports. These analyses may include but are not limited to the 
meta-analysis of data from this study combined with data from other studies or the analysis of 
biomarkers generated from samples collected during the study but analyzed after the database 
lock and completion of the CSR. The data analysis will be described in an addendum of the 
SAP or in a stand-alone analysis plan document, as appropriate.  
2.14.2 
Analysis data set 
The Full Analysis Set will be used for all biomarker analysis. Assessment of association 
between biomarker and safety data will be conducted using the Safety Set.   
2.14.3 
General data handling 
The last assessment before the first dose administration  (pre-dose) will be used as baseline 
value.  For assessments performed in tumor biopsies, fresh biopsy  results will be used for 
baseline when both archived and fresh tumor samples are available. When more than one 
biomarker data are available for a subject at any time point, the mean of the replicate values 
will be used for all statistical analyses.   
2.14.4 
Dual specificity phosphatase 6 (DUSP6) 
For assessment of PD effects of LTT462 in tumor, pre- and post- treatment tumor biopsies will 
be examined for expression of DUSP6. For assessment of PD effects in blood, levels of DUSP6 
will be measured in samples isolated concomitantly with those collected for PK measurements. 


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2.14.4.1 Handling of 
 data 
Percent Change in DUSP6 Expression is derived from the Relative Expression Ratio (RER), 
calculated according to the ‘Comparative CT Method’ described in Applied Biosystems User 
Bulletin #13 (2001) and consistent with the model described in (Pfaffl and Hageleit 2001). In 
this method, CT is computed by subtracting the CT of a Reference Gene from the CT of 
DUSP6 for both Baseline and Post-Baseline Samples. RER is calculated by raising 2.0 to an 
exponent computed by subtracting the (CT) of the Baseline Sample from (CT) of the Post-
Baseline Sample. RER is transformed by subtracting 1.0, such that expression increases and 
decreases are indicated when %Change is greater than or less than zero, respectively. 
2.14.4.2 Deriving change from baseline in DUSP6 expression 
Denoting the baseline (CT) of one patient as B and the post-baseline as PB, then  
• RER = 2^(B-PB) 
% Change in expression relative to Baseline = (RER -1)*100 
2.14.4.3 Biomarker data reports 
Table 2-10 
Biomarker data reports 
Type of sample 
(time point) 
Biomarker 
Biomarker 
assay  
Table 
Figure 
Tumor 
 
 
 
 
DUSP6 
 
- Summary of baseline  
 and percentage change 
(absolute and fold) from 
baseline in 
 
 DUSP6 
expression. 
(descriptive statistics 
include: mean, geometric 
mean, std, %CV, median, 
min-max) 
-  
 
- Waterfall plot to 
depict the change  
from baseline in 
 
 
DUSP6 expression 
annotated with the 
BOR 
- longitudinal plot of 
DUSP6 expression 
levels over time 
Blood 
DUSP6 
 
- Summary of baseline  
 and percentage change 
(absolute and fold) from 
baseline in 
 
DUSP6 
expression. 
(descriptive statistics 
include: mean, geometric 
mean, std, %CV, median, 
min-max) 
 
- Waterfall plot to 
depict the change  
from baseline in 
 
 
DUSP6 expression 
annotated with the 
BOR 
- longitudinal plot of 
DUSP6 expression 
levels over time 
 


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2.14.5 
Advanced analysis methods 
Additional analyses that may be performed after the completion of the final CSR will be documented in 
separate analysis reports. These analyses may include but are not limited to the meta-analysis of data 
from this study combined with data from other studies or the analysis of biomarkers generated from 
samples collected during the study but analyzed after the database lock and completion of the CSR. The 
data analysis will be described in a separate analysis plan document and may be included in the CSR. 
3 
Interim analysis 
No formal interim analyses are planned. However, the dose escalation design foresees that 
decisions based on the current data are taken before the end of the study. More precisely, after 
each cohort in the dose escalation part, the next dose of LTT462 has to be chosen depending on 
the observed data. Details of this procedure and the process for communication with 
Investigators are provided in Section 6.2.3 of the study protocol.  
 
 
 Cumulative study 
data (including safety, tolerability, preliminary anti-tumor activity, PK, and PD) will be 
reviewed on an ongoing basis by Novartis and study investigators. 
4 
Sample size calculation 
4.1 
Dose-escalation part  
Initially, cohorts of 1 to 3 evaluable patients will be enrolled in the dose-escalation part. Upon 
observation of specific toxicities, cohorts of 3 to 6 evaluable patients will be enrolled including 
at least six patients at the MTD/RDE level, as described in Section 6.2.3. Multiple cohorts may 
be sequentially enrolled to the same dose level. Additional cohorts of 1 to 6 patients may be 
enrolled at any dose level below the estimated MTD/RDE for further elaboration of safety and 
pharmacokinetic parameters as required. At least 21 patients are expected to be treated in the 
dose escalation part, for the model to have reasonable operating characteristics relating to its 
MTD recommendation. In the event that a lower dose is recommended for the use in the dose 
expansion without identification of the MTD, then the sample size may be smaller than 21. 


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5 
Changes in planned analysis 
Changes to planned analyses will be documented in section 9.8.3 of the CSR.. 
6 
Appendix 
6.1 
Baseline 
Baseline is the last available and valid assessment performed or value measured before the first 
administration of LTT462, unless otherwise stated under the related assessment section. 
Baseline can be the day before first treatment administration or the same day as first treatment 
administration if a pre-dose assessment/value is available (e.g., PK samples, samples for 
biomarkers). 


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If time is recorded for the first treatment dose and for a specific assessment performed the day 
of first dose, this assessment will be considered as baseline only if it is actually performed 
before the first dose, as checked using both times. 
If time is not recorded, a specific assessment performed the day of first dose administration will 
be considered as baseline if, according to protocol, it should be performed before the first dose. 
Patients with no data on a particular parameter before the first treatment administration will 
have a missing baseline for this parameter. 
6.2 
Handling of missing and partial dates 
For patients not known to have died prior to the cut-off date: 
All events (e.g. AEs and concomitant medications) that started before or on the cut-off date, 
and with end date missing or after the cut-off date will be reported as continuing at the cut-off 
date. For these events, the end date will not be imputed. 
For patients known to have died prior to or on the cut-off date: 
All events (e.g. AEs and concomitant medications) that started before or on the cut-off date, 
and with end date missing or after the cut-off date will have the end date imputed to the date of 
death. For these events, the imputed end date will not appear in the listings. 
If imputation of an end date is required for a specific analysis (e.g. a dose administration record 
with missing end date, or last date of study treatment is after the cut-off date), the end date will 
be imputed to the cut-off date in order to calculate e.g., the duration of exposure to study 
treatment. The imputed date will be displayed and flagged in the listings. 
 
 
 


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7 
References 
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time, 
Biometrics 38, 29 - 41.