Conditions: ALK-positive Non-small Cell Lung Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 14
Healthy volunteers: no

Brief summary:
The purpose of this study is to see if Ceritinib can target ALK in non-small cell lung cancer and slow down cancer growth and prevent it from spreading.

Detailed description:
This is an, open-label, two-cohort protocol designed to evaluate the activity of targeted therapy and SABR in ALK positive lung adenocarcinoma.

Cohort A will evaluate the combination in ALK-inhibitor naïve patients. Cohort B will evaluate the combination in patients who have received treatment with one prior ALK inhibitor.

Ceritinib will be administered to the patient until disease progression by RECIST 1.1, unacceptable toxicity, withdrawal of consent, or discontinuation of the trial for any other reason including death.

The primary focus of this protocol is identifying response in ALK+ lung cancer patients. Patients with Ventana assay and Vysis FISH probe positive tumors will be treated. Evidence of ALK gene rearrangement will also be considered eligible for the trial.

Primary Objective:

Cohort A: Superiority of ceritinib + SABR median PFS compared to historical control of 10 months (expected to be 20 months)

Endpoint:

Cohort A Median PFS defined as time from initiation of ceritinib until disease progression by RECIST 1.1, unacceptable toxicity, withdrawal of consent, or discontinuation of the trial for any other reason including death.

Primary:

Cohort B: Superiority of ceritinib + SABR median PFS compared to historical control of 7 months.

Endpoint:

Cohort B: Median PFS defined as time from initiation of ceritinib until disease progression by RECIST 1.1, unacceptable toxicity, withdrawal of consent, or discontinuation of the trial for any other reason including death.

Secondary:

* Report Overall survival Overall survival
* Report Time to 2nd SABR Time from start of systemic therapy to first day of second course of SABR
* Report Time to 3rd SABR Time from start of therapy to first day of third course of SABR
* Report proportion of patients CR/PR/stable disease at 6 and12 months Number of patients with CR/PR/stable disease for 6 and 12 months after initiation

Safety:

-Demonstrate safety of ceritinib followed by SABR Describe toxicity and adverse events (CTCAE v.4) compared to historical controls.

Arms:
arm 1: Patients will receive ceritinib at a dose of 750 mg (150 mg capsules times 5 capsules once a day) for 10 weeks. Patient will stop taking Ceritinib 72 hours before SABR (Stereotactic ablative body radiation). They could get 1, 3 ,or 5 treatments on consecutive days with 18 hours between each treatment or every other day (doctor's determination). The patient may start taking Ceritinib again 72 hours after radiation is complete. Patient will continue to take certinib for up to 8 months. At Follow-Up treatment, patients will be contacted every 3 months for 9 months. arm 2: Patients will receive ceritinib at a dose of 750 mg (150 mg capsules times 5 capsules once a day) for 10 weeks. Patient will stop taking Ceritinib 72 hours before SABR (Stereotactic ablative body radiation). They could get 1, 3 ,or 5 treatments on consecutive days with 18 hours between each treatment or every other day (doctor's determination). The patient may start taking Ceritinib again 72 hours after radiation is complete. Patient will continue to take certinib for up to 8 months. At Follow-Up treatment, patients will be contacted every 3 months for 9 months.

Interventions: intervention 1: Ceritinib intervention 2: Stereotactic ablative body radiation
Intervention descriptions: intervention 1: Patients will receive ceritinib at a dose of 750 mg (150 mg capsules times 5 capsules once a day) for 10 weeks. Patient will stop taking Ceritinib 72 hours before SABR radiation. The patient may start taking Ceritinib again 72 hours after radiation is complete. Patient will continue to take certinib for up to 8 months. intervention 2: Patients will receive study drug for 10 weeks. They could get 1, 3 ,or 5 treatments on consecutive days with 18 hours between each treatment or every other day (doctor's determination).

Protocol document:
Prot_SAP_000.pdf: 
Official title: Phase II trial of Ceritinib in combination with Stereotactic 
Ablative Radiation (SABR) in ALK-rearranged metastatic lung 
adenocarcinoma 
NCT number: NCT02513667 
Document date: 04-09-2020 


 
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                                       1 
 
 
Phase II trial of Ceritinib in combination with Stereotactic Ablative Radiation 
(SABR) in ALK-rearranged metastatic lung adenocarcinoma 
 
Principal investigator:  
 
 
 
Medical oncology co-chair 
Sawsan Rashdan, MD   
 
 
 
David Gerber, MD 
UT Southwestern Medical Center-Oncology 
 
UT Southwestern Medical Center-Oncology 
5323 Harry Hines Boulevard, Dallas, TX 75390  
5323 Harry Hines Boulevard, Dallas, TX 75390 
Telephone: (214) 648-4180.Fax: (214) 648-1955  
Telephone: (214) 648-4180.Fax: (214) 648-1955 
Email: Sawsan.Rashdan@UTSouthwestern.edu  
Email: David.Gerber@UTSouthwestern.edu 
 
Radiation Oncology co-chair  
 
 
 
Puneeth Iyengar, MD   
 
 
 
 
UT Southwestern Medical Center-Oncology 
 
 
5323 Harry Hines Boulevard, Dallas, TX 75390  
 
Telephone: (214) 648-4180.Fax: (214) 648-1955  
 
Email: Puneeth.Iyengar@UTSouthwestern.edu  
 
Co-Investigators: 
 
 
 
 
Hak Choy, MD 
UT Southwestern Medical Center-Oncology 
5323 Harry Hines Boulevard, Dallas, TX 75390 
Telephone: (214) 648-4180.Fax: (214) 648-1955 
Hak.Choy@UTSouthwestern.edu 
 
  
Biostatistician: 
 
 
 
 
 
Hong Zhu, PhD  
University of Texas, Southwestern Medical Center 
Department of Clinical Science 
5323 Harry Hines Boulevard, Dallas, TX 75390 
Phone:(214) 648-7438. Fax: (214) 648-5120 
 
Email: Hong.Zhu@UTSouthwestern.edu  
 
 
 
Study Drug: 
Ceritinib (LDK378) 
 
Funding Source:  
Novartis- funding and investigational agent 
 
Amended version: 
 
Version 6.0, 04.03.2020 
 
 
 
 
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 


 
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                                       2 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the necessary assurances 
that this trial will be conducted according to all stipulations of the protocol, including all statements regarding confidentiality, 
and according to local legal and regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date: ____________________ 


 
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                                       3 
 
 
 
List of abbreviations 
 
AE 
Adverse Event 
ALCL 
Anaplastic large cell lymphomas 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT  
BCRP 
multidrug transporter ABCG2 
b.i.d. 
bis in diem/twice a day  
CNS 
Central nervous system  
CR 
Complete Response  
CrCl 
creatinine clearance 
CRO 
Contract Research Organization 
DLT 
Dose Limiting Toxicity 
DS&E 
Drug Safety and Epidemiology 
ECG 
Electrocardiogram 
EIAED 
enzyme inducing anti-epileptic medication 
EGFR 
epidermal growth factor receptor 
EOT 
End of treatment 
FAS 
Full Analysis Set 
GI 
Gastric intestinal 
hERG 
human Ether-à-go-go-Related Gene 
IUD   
                intrauterine device  
IUS                        intrauterine system  
i.v. 
 
  intravenous (ly) 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IRB 
Institutional Review Board 
LLN 
Lower limit of normal  
LLNA 
local lymph node assay  
MTD 
Maximum Tolerated Dose 
NSCLC 
non-small cell lung cancer  
o.d. 
omnia die/once a day 
OS 
Overall survival  
OTC 
over-the counter  
QD 
once daily 
PD 
Progressive disease  
p.o. 
per os/by mouth/orally   
PFS 
Progression free survival 
PHI 
Protected Health Information 
PK 
Pharmacokinetics 
PPI 
proton pump inhibitors 
PR 
Partial response 


 
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                                       4 
 
 
Racc 
accumulation ratio 
RAP 
The Report and Analysis Plan (RAP) is a regulatory document which provides 
evidence of preplanned analyses 
RDE 
Recommended dose for expansion 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RR 
Response Rate 
SABR 
Stereotactic Ablative Radiation  
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
TDI                        time-dependent inhibition  
TKI                         tyrosine kinase inhibitors  
ULN  
                 upper limit of normal 
UV 
Ultraviolet radiation 
VATS 
Video-assisted thoracic surgery  
VEGF 
vascular endothelial growth factor 
WHO 
World Health Organization 


 
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Protocol  
 
Protocol No.  
 
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                                       5 
 
 
Table of Contents 
Protocol summary .......................................................................................................................... 10 
STUDY SUMMARY ............................................................................................................................... 11 
1.0 Background and Rationale ............................................................................................................ 12 
1.1 
Overview of lung adenocarcinoma pathology, epidemiology and current treatment ........ 12 
1.1.1 
Lung adenocarcinoma and molecular/genetic abnormalities ......................... 12 
1.1.2 
Treatment for ALK+ lung adenocarcinoma ..................................................... 12 
1.1.3 
Combination of targeted therapy with stereotactic radiation ........................... 12 
1.1.4 
Patterns of failure in non-small cell lung cancer ............................................. 13 
1.1.5 
Concept ........................................................................................................... 13 
1.2 
Immunologic effect of SABR and targeted therapy .......................................................... 13 
1.3 
Introduction to investigational treatment(s) and other study treatment(s) ........................ 14 
1.3.1 
Overview of Ceritinib ....................................................................................... 14 
1.3.2 
Rationale of continuing systemic therapy after oligoprogression ................... 16 
1.3.3 
Rationale of adding stereotactic ablative radiation therapy after targeted 
therapy ............................................................................................................ 17 
1.4 
Study rationale and purpose ............................................................................................. 18 
1.5 
Rationale for the protocol design ...................................................................................... 18 
1.6 
Rationale for dose and regimen selection ........................................................................ 18 
2.0 Study Objectives ............................................................................................................................ 19 
2.1 
Translational and exploratory objectives .......................................................................... 21 
2.2 
Description of protocol design .......................................................................................... 21 
2.2.1 
Treatment phase and duration of treatment ................................................... 21 
2.3 
Definition of end of the Study ............................................................................................ 22 
2.4 
Early Termination .............................................................................................................. 22 
3.0 Subject eligibility ............................................................................................................................ 22 
3.1 
Patient population ............................................................................................................. 22 
3.2 
Inclusion criteria ................................................................................................................ 22 
3.3 
Exclusion criteria ............................................................................................................... 23 
4.0 Treatment Plan .............................................................................................................................. 25 
4.1 
Treatment Dosage and Administration ............................................................................. 25 
4.1.1 
Dosing regimen ............................................................................................... 26 
4.1.2 
Treatment duration .......................................................................................... 27 
4.2 
Dose escalation guidelines ............................................................................................... 27 
4.3 
Dose modifications ............................................................................................................ 27 
4.3.1 
Dose modification and dose delay of Ceritinib................................................ 28 
4.3.2 
Follow-up for toxicities .................................................................................... 34 
4.3.3 
Anticipated risks and safety concerns of the ceritinib treatment ..................... 37 


 
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                                       6 
 
 
4.4 
Concomitant medications.................................................................................................. 37 
4.4.1 
Permitted concomitant therapy requiring caution and/or action with 
ceritinib ............................................................................................................ 38 
4.4.2 
Prohibited concomitant therapy with ceritinib ................................................. 39 
4.5 
Patient numbering, treatment assignment or randomization ............................................ 40 
4.5.1 
Patient numbering ........................................................................................... 40 
4.5.2 
Treatment assignment .................................................................................... 41 
4.5.3 
Treatment blinding .......................................................................................... 41 
4.6 
Study drug administration ................................................................................................. 41 
4.6.1 
Study drug compliance ................................................................................... 41 
5.0 Visit schedule and assessments ................................................................................................... 42 
5.1 
Screening/Baseline Procedures ....................................................................................... 42 
5.1.1 
Informed Consent ........................................................................................... 42 
5.1.2 
Medical history ................................................................................................ 42 
5.1.3 
Demographics ................................................................................................. 42 
5.1.4 
Review subject eligibility criteria ..................................................................... 42 
5.1.5 
Review previous and concomitant medications .............................................. 43 
5.1.6 
Physical exam including vital signs, height and weight .................................. 43 
5.1.7 
Performance status ......................................................................................... 43 
5.1.8 
Adverse event assessment ............................................................................. 43 
5.1.9 
Hematology ..................................................................................................... 43 
Hgb, platelets, white blood cells (WBC), red blood cells (RBC), differential 
(basophils, eosinophils, lymphocytes, monocytes, neutrophils (% or 
absolute)) ........................................................................................................ 43 
5.1.10 
Serum chemistries and coagulation ................................................................ 43 
5.1.11 
Immune profile ................................................................................................ 43 
5.1.12 
Urinalysis......................................................................................................... 43 
5.1.13 
ECG ................................................................................................................ 43 
5.1.14 
Pregnancy test (for females of child bearing potential) .................................. 43 
5.1.15 
Tumor assessment ......................................................................................... 43 
5.1.16 
Follow-up after Treatment ............................................................................... 44 
5.2 
Protocol flow and visit schedule ........................................................................................ 44 
5.2.1 
Screening/Baseline ......................................................................................... 49 
5.2.2 
Treatment period ............................................................................................. 50 
5.2.3 
End of treatment visit including study completion and premature 
withdrawal ....................................................................................................... 50 
5.3 
Assessment types ............................................................................................................. 51 
5.3.1 
Efficacy assessments ..................................................................................... 51 
5.3.2 
Safety and tolerability assessments ............................................................... 51 
6.0 Measurement of Effect ................................................................................................................... 55 


 
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                                       7 
 
 
6.1 
Antitumor Effect- Solid Tumors ......................................................................................... 55 
6.1.1 
Definitions ....................................................................................................... 55 
6.1.2 
Disease Parameters ....................................................................................... 55 
6.1.3 
Methods for Evaluation of Measurable Disease ............................................. 56 
6.1.4 
Response Criteria ........................................................................................... 56 
6.1.5 
Duration of Response ..................................................................................... 58 
6.1.6 
Progression-Free Survival .............................................................................. 58 
7.0 Adverse events .............................................................................................................................. 58 
7.1.1 
Contraindications: ........................................................................................... 58 
7.1.2 
Special Warnings and Precautions for Use: ................................................... 58 
7.1.3 
Interaction with other medications .................................................................. 59 
7.1.4 
Adverse Reactions .......................................................................................... 59 
7.2 
Adverse Event Monitoring ................................................................................................. 60 
7.2.1 
Definition ......................................................................................................... 60 
Unanticipated Problems .................................................................................................... 61 
7.2.2 
Reporting ........................................................................................................ 61 
7.2.2.1 
SAEs ............................................................................................................... 62 
Reporting 62 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting ......................... 63 
7.3.1 
Laboratory test abnormalities ......................................................................... 64 
7.3.2 
Adverse events of special interest (AESI) ...................................................... 64 
7.4 
Pregnancies ...................................................................................................................... 64 
7.5 
Warnings and precautions ................................................................................................ 65 
8.0 Study agents and therapies ........................................................................................................... 65 
8.1 
Agent Ceritinib .................................................................................................................. 65 
8.1.1 
Return and Retention of Study Drug ............................................................... 65 
8.2 
Therapy Stereotactic Ablation Body Radiation (SABR) .................................................... 65 
8.3 
SABR DOSE AND TECHNIQUES .................................................................................... 66 
8.3.1 
Ceritinib during SABR ..................................................................................... 66 
8.3.2 
SABR Prescription .......................................................................................... 66 
8.3.3 
Planning Constraints and Concerns ............................................................... 66 
8.4 
Technical Factors .............................................................................................................. 67 
8.4.1 
Physical Factors .............................................................................................. 67 
8.4.2 
Dose Verification at Treatment ....................................................................... 67 
8.4.3 
Treatment Platforms ....................................................................................... 67 
8.4.4 
Simulation/Image Guidance ............................................................................ 67 
8.4.5 
Patient Positioning .......................................................................................... 67 
8.4.6 
Image Guidance .............................................................................................. 68 
8.5 
Treatment Planning/Target volumes ................................................................................. 68 


 
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8.5.1 
Image Acquisition ............................................................................................ 68 
8.5.2 
Target Volumes ............................................................................................... 68 
8.6 
Dosimetry .......................................................................................................................... 69 
8.6.1 
3D-Conformal Planning ................................................................................... 69 
8.6.2 
Intensity Modulated Radiation Therapy (IMRT) .............................................. 69 
8.6.3 
Dose Calculations ........................................................................................... 69 
8.6.4 
Normal Tissue Dose Constraints .................................................................... 70 
8.7 
Intracranial Stereotactic Radiosurgery Dose (SRS) for and Technique ........................... 72 
8.7.1 
SRS Dose ....................................................................................................... 73 
8.7.2 
SRS Technique, Pre-SRS Image acquisition and target planning with 
Conformality Index .......................................................................................... 73 
CI = Rx Isodose Vol / (Target Vol) ......................................................................................................... 73 
8.7.3 
Normal Tissue Dose Constraints .................................................................... 74 
8.8 
Radiation Therapy Quality Assurance .............................................................................. 74 
9.0 STATISTICAL CONSIDERATIONS .............................................................................................. 74 
9.1 
Study Design/Study Endpoints ......................................................................................... 74 
9.2 
Sample Size and Accrual .................................................................................................. 76 
9.3 
Data Analyses Plans ......................................................................................................... 76 
9.3.1 
Treatment phase and duration of treatment ................................................... 77 
9.4 
Definition of end of the Study ............................................................................................ 77 
9.5 
Early Termination .............................................................................................................. 77 
9.6 
Data confidentiality ............................................................................................................ 77 
9.7 
Statistical methods and data analysis ............................................................................... 77 
9.8 
Analysis sets ..................................................................................................................... 77 
9.8.1 
Full Analysis Set ............................................................................................. 77 
9.8.2 
Safety Set ....................................................................................................... 77 
9.9 
Patient demographics/other baseline characteristics ....................................................... 78 
9.10 
Treatments (ceritinib treatment, concomitant therapies, compliance) .............................. 78 
9.10.1 
Handling of missing values/censoring/discontinuations ................................. 78 
9.10.2 
Safety objectives ............................................................................................. 78 
10.0 Ethical considerations and administrative procedures .................................................................. 79 
10.1 
Regulatory and ethical compliance ................................................................................... 79 
10.2 
Informed consent procedures ........................................................................................... 79 
10.3 
Discontinuation of the study .............................................................................................. 79 
10.4 
Publication of the study and results .................................................................................. 79 
10.4.1 
Communication and Publication of Clinical Trial Results ............................... 79 
10.5 
Study documentation, record keeping and retention of documents ................................. 79 
10.6 
Confidentiality of study documents and patient records ................................................... 79 
10.7 
Audits and inspections ...................................................................................................... 79 


 
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                                       9 
 
 
11.0 STUDY MANAGEMENT ................................................................................................................ 80 
11.1 
Conflict of Interest ............................................................................................................. 80 
11.2 
Institutional Review Board (IRB) Approval and Consent .................................................. 80 
11.3 
Registration Procedures ................................................................................................... 80 
11.4 
Data Management and Monitoring/Auditing ..................................................................... 80 
11.5 
Adherence to the Protocol ................................................................................................ 81 
11.5.1 
Emergency Modifications ................................................................................ 81 
11.5.2 
Other Protocol Deviations/Violations .............................................................. 81 
11.6 
Amendments to the Protocol ............................................................................................ 82 
11.7 
Record Retention .............................................................................................................. 82 
11.8 
Obligations of Investigators .............................................................................................. 82 
12.0 Protocol adherence .......................................................................... Error! Bookmark not defined. 
12.1 
Amendments to the protocol ............................................... Error! Bookmark not defined. 
13.0 References (available upon request) ............................................................................................. 83 
14.0 Appendices .................................................................................................................................... 85 
14.1 
Appendix 1: List of prohibited concomitant medications and concomitant medications 
requiring caution for ceritinib ............................................................................................. 85 
 
e 1-1 
Trial Schema   
 
 
 
 
 
 
 
11 
 
 
List of figures 
Figure 1-1 
Trial Schema   
 
 
 
 
 
 
 
11 
 
List of tables 
Table 4-1 
Dose and treatment schedule   
 
 
 
 
 
28 
Table 4-2 
Dose reduction steps for Ceritinib  
 
 
 
 
 
30 
Table 4-3 
Criteria for interruption and re-initiation of Ceritinib treatment  
 
 
31 
Table 4-4 
Follow-up recommendations for specific toxicities  
 
 
 
36 
Table 5-1 
Visit evaluation schedule  
 
 
 
 
 
 
47 
Table 5-2 
WHO Performance status scale   
 
 
 
 
 
52 
Table 5-3 
Local Clinical laboratory parameters collection plan  
 
 
 
53 
Table 5-4 
ECG collection plan  
 
 
 
 
 
 
 
54 
Table 14-1 
Prohibited medications that are strong inducers or inhibitors of CYP3A, 
or CYP3A substrates with narrow therapeutic index, or sensitive CYP2C  
substrates with narrow therapeutic index  
 
 
 
 
77 
Table 14-2 
List of medications to be used with caution 
 
 
 
 
77 
Table 14-3 
List of prohibited enzyme-inducing anti-epileptic drugs 
 
 
 
78 
Table 14-4 
List of prohibited QT prolonging drugs 
 
 
 
 
 
78 
 


 
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Protocol summary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Cohort A: ALK-naïve: 
450 mg PO daily 
Cohort A: ALK-resistant: 
450 mg PO daily 


 
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Protocol No.  
 
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                                       11 
 
 
 
 
 
 
 
 
 
 
 
STUDY SUMMARY 
Title 
Phase II trial of Ceritinib in combination with Stereotactic Ablative 
Radiation in ALK-rearranged metastatic lung adenocarcinoma 
Short Title 
Ceritinib and SABR in ALK + lung adenocarcinoma 
Protocol Number 
XXX 
Phase 
II 
Methodology 
Open label, Dual arm 
Study Duration 
Three years 
Study Center(s) 
single center 
Objectives 
Prolongation of progression free survival in lung adenocarcinoma with  
targeted therapy and radiation 
Number of Subjects 
33 
Diagnosis and Main 
Inclusion Criteria 
Metastatic/locally advanced lung adenocarcinoma harboring a ALK 
rearrangement 
Study Product(s), Dose, 
Route, Regimen 
Ceritinib (LDK378)  450 mg PO daily 
Duration of administration 
Until progression/intolerance of therapy. Projected  14 months for 
patients who progressed on crizotinib therapy and 20 months for those 
who have not been treated previously with an ALK inhibitor. 
Reference therapy 
Published progression free survival with ceritinib (LDK378) alone 
Statistical Methodology 
Sample size calculated on the basis of prolongation of progression free 
survival of patients treated on this protocol compared to published 
survival data. Kaplan Meier Methods will be used to estimate 
progression-free survival and overall survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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                                       12 
 
 
1.0 
Background and Rationale 
1.1 
Overview of lung adenocarcinoma pathology, epidemiology and current treatment 
1.1.1 
Lung adenocarcinoma and molecular/genetic abnormalities 
Lung cancer is the most common cancer worldwide. There are over 1.5 million cases annually, leading 
to more than 1 million deaths every year [1]. In the US, 160,000 deaths occur from lung cancer annually 
[2]. 
Lung cancer is classified broadly into small cell and non-small cell. Non-small cell lung cancer is further 
classified into squamous cell cancer and adenocarcinoma. Treatment for each classification varies, as 
well as their clinical behavior and molecular/genetic profile. 
Lung adenocarcinoma has been found to harbor mutations that can be targeted with specific anti-cancer 
agents. These have dramatically improved the outlook for the minority of patients that do harbor an 
actionable mutation. These drugs are much better tolerated than traditional chemotherapies, with fewer 
side effects and also easier to take. However the duration of response to these targeted therapies is 
limited by the development of clinical resistance. 
1.1.2 
Treatment for ALK+ lung adenocarcinoma 
Patients with lung adenocarcinoma now routinely have molecular/genetic testing performed on their 
tumor. Approximately 2-8% of patients with lung adenocarcinoma demonstrate a rearrangement in the 
anaplastic lymphoma kinase (ALK) gene [3, 4]. Due to the large number of lung cancer cases annually, 
this small percentage represents thousands of patients every year in the US. 
ALK was identified as a chromosome translocation-produced protein in anaplastic large cell lymphomas 
(ALCL). In lung cancer, a fusion was identified between ALK and the echinoderm microtubule-associated 
protein like 4 (EML4-ALK) [3]. 
Patients with ALK rearrangements tend to be younger with less smoking history. The exact cause of the 
rearrangement is unclear. ALK rearrangements are rarely found in squamous cell cancer. 
Crizotinib has been tested as an oral ALK-inhibitor. This compound has dramatically transformed 
treatment for ALK positive lung cancer. Crizotinib resulted in clinical response rates in more than 50% 
of 255 patients treated [5]. The median duration of response was 9-11 months. Crizotinib is FDA 
approved for the treatment of ALK positive lung cancer. 
The NCCN guidelines recommend ALK inhibitor therapy be the first treatment for patients with ALK 
positive lung cancer [6]. However, the response to crizotinib is not durable, with many patients 
demonstrating progression within one year of treatment initiation. The central nervous system is a 
common site of progression [7].  
Ceritinib is a second generation ALK inhibitor with 20 times greater potency. 246 patients were treated 
with ceritinib in a phase I trial [8]. 163 had previously been treated with an ALK inhibitor and 83 were 
ALK-inhibitor naïve. The overall response rate was 58%, with median duration of response being 10 
months for those not previously treated with an ALK inhibitor, and 6.9 months for those previously treated 
 
1.1.3 
Combination of targeted therapy with stereotactic radiation 
Stereotactic ablative body radiation (SABR) is a technique of delivering precisely targeted radiation to 
tumors while minimizing the dose given to adjacent normal tissue. Large doses of radiation are 
delivered in a small of number of treatments. Due to the radio-biological response to this type of 
radiation, there can be dramatic tumor responses leading to the ablative terminology.  


 
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SABR has an increasing role in metastatic non-small lung cancer, as demonstrated by a recently 
concluded Phase II trial of targeted therapy with SABR [11]. This trial was conducted at UT 
Southwestern and enrolled 24 patients with advanced, metastatic non-small cell lung who had 
progressed on standard chemotherapy. These patients were with the targeted therapy erlotinib 
combined with stereotactic ablative radiation to sites of visible disease. In a previous trial, patients with 
advanced non-small cell lung cancer who had progressed after one cycle of chemotherapy and were 
then treated with erlotinib had a progression free survival (PFS) of 2.3 months and overall survival 
(OS) of 6.7 months [12]. Combining SABR with erlotinib trial prolonged the median PFS to 14.7 
months and median OS to 20.7 months. 
 
This combination of SABR with targeted therapy greatly prolonged the duration of time that targeted 
therapy was beneficial for patients. The study population was enriched for patients with limited 
metastatic disease, though it is plausible that patients with more advanced disease would also receive 
some benefit of the combined therapy. 
1.1.4 
Patterns of failure in non-small cell lung cancer 
Reasons for discontinuing anti-cancer therapy include ineffective control of existing lesions or the 
development of new lesions. The patterns of failure in non-small lung cancer were evaluated in 64 
patients with advanced non-small lung cancer [13]. 64% of patients in this study demonstrated 
progression in already known sites of disease. This suggests that enhanced control of existing lesions 
will result in prolongation of the benefit from systemic therapy. 
1.1.5 
Concept 
The proposed study is designed to prolong the clinical benefit of ALK-inhibitor targeted therapy in 
patients with ALK+ lung cancer. This will evaluate the combination of two well-tolerated therapies, 
ceritinib and SABR. This dual therapy is expected to be more effective than either alone in destroying 
sensitive tumor cells and also in preventing the development of resistant cells.  
 
Based on current studies, patients derive benefit from ALK inhibitors for less than a year before they 
need to be switched to another treatment, usually chemotherapy. 
  
Ceritinib alone is active therapy, however resistance and progression will develop as with all ALK 
inhibitors. Tumors that remain after 10 weeks of ceritinib monotherapy may harbor weakly sensitive or 
resistant clones. While on systemic therapy, progression usually occurs at sites of known disease. 
Therefore targeting known and visible disease may delay progression that requires a change in 
systemic therapy. 
 
This study will treat lesions that persist after 10 weeks of targeted therapy with ceritinib with 
stereotactic ablative radiation. Limited progression after that period will also be considered for repeat 
SABR if possible, instead of discontinuing the ceritinib that is keeping the majority of the disease under 
control. This accurately reflects current clinical practice and recommendations from the national 
authorities such as the NCCN, which recommend continuing targeted therapy after progression in 
some cases. 
 
1.2 
Immunologic effect of SABR and targeted therapy 
The exact mechanism is not well defined, but the combination of an effective drug with ablative 
radiotherapy demonstrates a synergistic immune response. 
 


 
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Ablative radiotherapy to a primary tumor leads to recruitment of CD8+ cells of the immune system in 
destroying cancer cells. Other mechanisms include disruption of immunologic barriers, enhanced 
antigen presentation to dendritic cells and potentially reversing tumor cell unresponsiveness in patients 
[14]. The decrease in size of untreated metastatic lesions after primary site ablative radiotherapy is 
termed the “abscopal effect” and has been demonstrated in solid tumors such as melanoma [15, 16]. 
 
The immunologic impact of administering radiation with ceritinib will be evaluated in tumor specimens. 
These would include modulators of immune response such as myeloid derived suppressor cells, 
macrophages, CD4/CD8 T-cells and NK cells. Analysis of blood specimens for myeloid derived 
suppressor cells and macrophages that are VEGF-R2 positive will also done to determine if serum 
changes correlate with response. 
Research at UT Southwestern has demonstrated that ALK signaling leads to a pro-metastatic phenotype 
in breast cancer [17]. Macrophages are constituents of blood that can be divided into two broad subtypes 
M1 and M2. M1-like macrophages produce inflammatory cytokines and are capable of destroying tumor 
cells. M2-like macrophages promote collagen deposition and angiogenesis. They also secrete 
angiogenic and anti-inflammatory cytokines such as IL-10, TGF-β and VEGF which promote tumor 
progression. 
Induction of the ALK pathway by pleiotropin is associated with macrophages that promote anti-
inflammation, angiogenesis, immune tolerance and metastasis. These data suggested that ALK 
inhibition may be an effective in reducing metastatic spread from primary lung cancer. This also suggests 
that blood monitoring of M1 and M2 like macrophages may predict for the subsequent development of 
metastases. 
1.3 
Introduction to investigational treatment(s) and other study treatment(s) 
1.3.1 
Overview of Ceritinib 
Ceritinib [5-Chloro-N2-[2-isopropoxy-5-methyl-4-(4-piperidinyl)phenyl]-N4-[2 (isopropylsulfonyl) phenyl]-
2,4-pyrimidinediamine] is an orally available ALK inhibitor. Ceritinib in pre-clinical studies is an 
approximately 20-fold more potent ALK inhibitor than crizotinib, it is more selective for ALK and does 
not inhibit MET. In addition, ceritinib shows potent antitumor activity in crizotinib-resistant animal models 
(as described below) and the efficacy seen in the Phase I clinical trial in patients who failed crizotinib 
has been extremely encouraging (Mehra et al 2012; unpublished data summarized below). These 
features support the use of ceritinib in NSCLC patients whose disease has progressed on crizotinib. 
1.3.1.1 
Non-clinical experience 
1.3.1.1.1 
Pharmacology 
Ceritinib inhibits ALK and ALK-mediated signaling pathways in a dose-dependent manner. It inhibits 
autophosphorylation of ALK, ALK-mediated phosphorylation of downstream signaling proteins, and 
proliferation of ALK-dependent cancer cells both in vitro and in vivo. Ceritinib is approximately 20-fold 
more potent than crizotinib in enzymatic inhibition assays of the ALK kinase activity (IC50 of 0.15 nM for 
ceritinib and 3 nM for crizotinib). In a kinase panel of 35 additional enzymes,   demonstrated a high 
degree of selectivity for ALK inhibition by inhibiting only 2 other kinases (INSR and IGF1R) but with 
approximately 50-fold less potency than ALK inhibition. 
Preclinical data showed inhibition of the kinase activity of the NPM-ALK fusion oncogene (in Karpas299 
human ALCL cells) and of the EML4-ALK fusion oncogene (in H2228 human NSCLC cells) with ceritinib, 
which led to inhibition of cancer cell proliferation in vitro. The inhibition of the downstream signaling 
pathway by ceritinib correlated with the inhibition of proliferation. In addition, inhibition of NPM-ALK and 
EML4-ALK in mouse and rat xenograft models resulted in inhibition of tumor growth and tumor 


 
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regression in vivo. Ceritinib was also active in cell lines with ALK amplification or expression of activating 
point mutations. A single dose pharmacodynamic study and multiple daily dose efficacy study performed 
in Karpas299 and H2228 tumor models indicated that a 70% to 80% reduction in the ALK signaling 
pathway is required to achieve complete tumor regression. 
1.3.1.1.2 
Nonclinical pharmacokinetics (PKs) and metabolism 
Ceritinib showed good oral bioavailability (48%-100%) in various animal species. Ceritinib is highly 
bound to plasma protein (>94%) in all species. Following oral administration of [14C]ceritinib to LEH male 
rats, radioactivity was widely distributed. The highest tissue exposures were found in intestine wall, uveal 
tract, pituitary gland, bile, adrenal cortex, harderian gland, liver, spleen, lymph node, lung, kidney, 
thyroid, bone marrow, adrenal medulla and pancreas (25 to 710-fold higher exposure relative to blood) 
[DMPK R0900773B]. Unchanged ceritinib was the major component in feces and bile of intact and bile 
duct-cannulated rats. In the rat, ceritinib underwent oxidation leading to the formation of five oxygenated 
metabolites (designated as M23.6, M30.6, M35.8, and M33.4). In addition, ceritinib underwent sulfation 
leading to M36.8 and oxidation followed by sulfation resulting in the presence of M29.5. Ceritinib also 
underwent glucuronidation leading to M26.8 and M27.6. The major metabolite in feces was designated 
M33.4 (oxygenation) accounting for approximately 7% of the dose. All other metabolites in feces and 
bile were minor (<5% of the dose). In rats dosed with [14C]-ceritinib, ceritinib-derived radioactivity was 
excreted predominantly via the fecal route (>99%), and renal excretion was a minor pathway for 
excretion (<1%) [DMPK R0900773A]. Fecal excretion was the result of biliary excretion (69%) and 
gastrointestinal (GI) secretion (31%). Since parent drug was the major component in bile and feces after 
IV administration, enterohepatic circulation may occur. 
CYP3A4/5 is the major hepatic enzyme metabolizing ceritinib in a human in vitro system. The compound 
is a time-dependent CYP3A4/5 inhibitor (KI: 1.47 μM and kinact 0.0642 min-1), and a potent reversible 
inhibitor of CYP2A6 (Ki: 0.0316 μM), 2B6 (IC50 2 μM), 2C8 (IC50 2 μM), 2C9 (Ki: 0.241 μM) and 3A4/5 
(Ki: 0.161 μM). These data suggest a high potential of drug-drug interaction between ceritinib and 
compounds metabolized by these CYP isoforms if sufficiently high concentrations of ceritinib are 
achieved. Ceritinib is likely a P-gp, but not BCRP or MRP2 substrate. It does not inhibit P-gp, BCRP or 
MRP2 up to 1.5 μM in vitro. 
Kinetic PK/pharmacodynamic modeling was performed in the nude rat H2228 model (constitutively 
expressing ELM4-ALK gene) and the nude rat Karpas 299 model (expressing NPM-ALK). The minimal 
pharmacologic dose in humans was estimated to be 100 mg/day for tumor stasis. 
1.3.1.1.3 
Safety pharmacology and toxicology 
Ceritinib was evaluated for safety in 2- and 4-week studies in rats and monkeys. The principal toxicity 
induced by ceritinib was a systemic inflammation characterized by increased neutrophil counts in the 
peripheral blood and mixed cell/neutrophilic inflammation of the biliopancreatic ducts, pancreas, and/or 
duodenum. Gastrointestinal toxicity was observed in both species characterized by body weight loss, 
decreased food consumption, emesis (monkey), diarrhea, and at high doses, by histopathologic lesions 
including erosion, mucosal inflammation, and foamy macrophages in the duodenal crypts and ampullae 
of rats and monkeys, respectively. Liver (bile duct) was also affected in both species only at the highest 
dose levels studied (100 mg/kg/day in the 2-week studies for both rat and monkeys and 50 and 30 
mg/kg/day in the 4-weeks studies in rat and monkeys, respectively), and included increases in liver 
transaminases in a few animals at high doses, and mixed cell inflammation, erosion and cytoplasmic 
vacuolation of the bile duct epithelium. The pancreas was a target organ in the rat, but not the monkey, 
with acinar cell atrophy and mixed cell inflammation noted at mid- and high doses. Target organ effects 
showed partial to complete recovery during the 4-week non-dosing period. No effects in the rat central 
nervous system or on the respiratory system were observed at single, high doses (100 mg/kg). 


 
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Ceritinib has potent activity on the hERG channel with an IC50 of 0.4 μM. However, there were no 
ceritinib-related effects in vivo in monkeys at doses as high as 100 mg/kg (human equivalent dose [HED] 
of 1950 mg). 
Preclinical studies (in vitro 3T3 NRU assay, refer to [Investigators Brochure]) indicate a low risk of photo 
toxicity with use of ceritinib. In addition, a preliminary analysis from an in vivo UV LLNA assay 
demonstrates no significant phototoxic potential with ceritinib. 
1.3.1.2 
Clinical experience 
1.3.1.2.1 Clinical safety, efficacy and tolerability 
The phase I study of ceritinib demonstrated preliminary evidence of antitumor activity in ALK-positive 
NSCLC. The majority of these patients in this trial had received prior chemotherapy (median of 3 
regimens) and the majority also received prior crizotinib.  Among 114 response-evaluable patients with 
at least 18 weeks of follow-up, or who discontinued study earlier, and were treated with ceritinib doses 
of 400 mg daily or higher, 66 (58%) patients have responded. The response rate to ceritinib is similar 
regardless of prior ALK inhibitor therapy. In patients with NSCLC treated at ≥400 mg daily, who had 
previously received crizotinib, the response rate was 57%, and in those who had not previously received 
crizotinib it was 60%. Post-baseline tumor measurements are available for 104 of the 114 response 
evaluable patients. A waterfall plot displaying the maximum decrease from baseline in the sum of the 
longest tumor diameters (Figure 1-1) shows that the large majority of patients treated with ceritinib had 
a reduction in tumor burden. The median duration of response in patients who responded and were 
treated at ≥400 mg daily was 8.2 months (95% CI: 6.9, not estimable), and 71% had a duration of 
response of 6 months or longer. 
After treatment with ceritinib, responses were seen in the CNS in lesions that were not treated with any 
other modality. The available data from the phase I study indicate that ceritinib has substantial antitumor 
activity in chemotherapy-treated ALK-positive NSCLC patients regardless of prior ALK inhibitor therapy. 
In the Phase I trial of ceritinib [8], dose-limiting toxicities included diarrhea, vomiting, nausea, 
dehydration, hypophosphatemia and elevated alanine transferase. The most common adverse events 
included nausea (82%), diarrhea (75%), vomiting (65%), fatigue (47%), and increased alanine 
aminotransferase levels (21%). The common grade 3 or 4 adverse events were increased alanine 
aminotransferase (21%), increased aspartate aminotransferase (11%), diarrhea (7%), and increased 
lipase levels (7%). 
1.3.2 
Rationale of continuing systemic therapy after oligoprogression 
This continuation of erlotinib beyond progression is recommended by the NCCN guidelines for the 
following benefits; delayed symptoms, reduction in tumor size and FDG avidity on PET [6, 18]. 
Similarly the continuation of ALK-inhibitors after the development of progressive disease has also 
been associated with clinical benefit. However the optimal therapy to combine with targeted therapy 
beyond progression is ill-defined as adding systemic chemotherapy is often too toxic. 
 
In select patients continuing crizotinib beyond progression resulted in an overall survival of 29.6 
months compared to 10.8 months for patients who did not continue crizotinib [19]. These data suggest 
that for a carefully selected group of patients, continuing ALK inhibitors even in the setting of limited 
progressive disease results in clinically meaningful benefit. 
 
The decision to continue ceritinib at the time of oligoprogression will be at the discretion of treating 
oncologist in line with standard clinical practice. If, in the opinion of the treating oncologist, the patient 
would benefit from continued ceritinib this will be allowed even after documented oligoprogression. 


 
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1.3.3 
Rationale of adding stereotactic ablative radiation therapy after targeted therapy 
 
SABR will be added as a cytoreductive agent after major cancer cell killing is achieved with ceritinib. 
This proposed study will evaluate the combination of two well-tolerated therapies, ceritinib and 
Stereotactic Ablative Radiotherapy (SABR). This dual therapy is expected to be more effective than 
either alone in destroying sensitive tumor cells and also in preventing the development of resistant 
cells.  
 
Ceritinib alone is active therapy, however resistance and progression will develop as with all ALK 
inhibitors. Tumors that remain after 10 weeks of ceritinib monotherapy are likely to harbor weakly 
sensitive or resistant clones. The Goldie-Coldman hypothesis of tumor resistance [20] suggests that 
any detectable tumor will contain some resistant clones. According to this hypothesis, the probability of 
resistance developing in a tumor depends on i. the number of cancer cells and ii. the mutation rate of 
the constituent cells [21].  
 
Stereotactic radiation to lesions that persist despite ceritinib therapy will effectively provide a non-
invasive tumor “debulking” and reduction in tumor cell number. Fewer cancer cells may then result in a 
smaller chance of resistant clones developing according to the Goldie-Coldman hypothesis. Because 
of the reduced cancer cell number, this approach may prolong the time that ceritinib will be effective as 
the sole systemic therapy for ALK-rearranged patients. This will likely delay the development of 
clinically significant resistance that necessitates a switch from ceritinib to another systemic therapy. 
 
Larger tumors are more heterogeneous and therefore more likely to contain some resistant cells, 
decreasing the chance of cure. To prevent resistance, according to Goldie-Coldman, it is suggested 
that multiple therapies should be used in combination whenever possible [21]. This allows for the 
therapies to achieve maximum efficacy against heterogeneous cell populations. 
 
At study entry: 
Patients on this trial who have lesions requiring radiation prior to initiation of systemic therapy in the 
view of the treating physician will be allowed to get such radiation. This will not limit their trial 
participation, though the lesion will be noted as having been radiated. 
 
After 10 weeks of ceritinib monotherapy: 
Lesions that persist after ceritinib monotherapy will receive stereotactic radiation. These include 
lesions that may have progressed during ceritinib monotherapy alone. As long as no change in 
systemic therapy is indicated, these patients will continue on the trial. Up to 6 sites or organs will 
receive stereotactic radiation, at the discretion of the treating physician.  All sites of gross tumor 
(typically defined by CT and PET) should be treated for patients to continue on study. 
 
Subsequent areas of progression: 
As long as the study participant is on ceritinib as the sole systemic therapy, further stereotactic 
radiation may be delivered to up to 6 sites or organs at a time. When ceritinib is no longer the systemic 
agent or when new progressive sites cannot feasibly be treated with stereotactic radiation (e.g., 
malignant pleural effusion or site previously irradiated), study participation will end. The primary 
endpoint of progression-free survival will be calculated from the start of treatment to the first episode of 
progression. 
 
Ceritinib during stereotactic radiation: 
Currently there are limited data about the safety of concurrent ceritinib and stereotactic radiation, 
though studies are ongoing. If there is a concern for the safety of the patient, ceritinib will be held for 3 


 
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days prior to and 3 days after the stereotactic radiation. The total expected duration of the stereotactic 
radiation is expected to range between 1-5 treatments, generally not exceeding 21 days from first to 
last radiation therapy.  
 
CNS metastases: 
Stereotactic radiation to CNS lesions that require therapy will be allowed. At study entry the presence 
of CNS lesions or their treatment with radiation will not constitute a restriction to study participation. 
Subsequently, progression in the CNS will not terminate study participation, and patients may receive 
stereotactic radiation to those areas. 
 
Evaluation of CNS metastases will consist of an MRI or contrast enhanced CT performed at baseline 
and then as clinically indicated, but at least every 3 months . Patients without CNS involvement will not 
be required to have mandatory CNS imaging. All patients with new symptoms suspicious of CNS 
involvement will have urgent CNS imaging performed. 
1.4 
Study rationale and purpose 
Patients with ALK+ non small cell lung cancer will receive the current optimal therapy with ceritinib. After 
10 weeks of targeted therapy, there will likely be some persisting lesions that would not have completely 
regressed. These persisting lesions would likely consist of cells that are less sensitive to targeted 
therapy. From the data summarized above [13], these persisting lesions are most to subsequently 
develop resistance and demonstrate progression. 
To delay the onset of clinical progression, lesions that persist after 10 weeks of ceritinib therapy and are 
amenable to stereotactic ablative radiation will be radiated. Ceritinib will be held for 3 days before the 
first dose of radiation and resumed 3 days after the last dose. There is no specific window for radiation. 
SABR should be initiated as feasible following at least 10 weeks of ceritinib treatment.  
After radiation, all patients will continue ceritinib therapy. If subsequently there is any evidence of 
progression, there will be an assessment of whether a repeat course of radiation is feasible. If it is 
feasible to repeat SABR to sites of progression, this will be performed and ceritinib resumed. If SABR is 
not possible, then a change in systemic therapy will be required. 
1.5 
Rationale for the protocol design 
The purpose of the trial is to determine if the addition of SABR to ceritinib can prolong the clinical benefit 
of targeted therapy.  This will be an open-label, non-randomized, two arm trial in ALK + lung 
adenocarcinoma. The protocol will also report the safety of treating with SABR and ceritinib, though both 
are widely used in clinical practice. 
Crizotinib is widely used for ALK + lung adenocarcinoma. Ceritinib is FDA approved as subsequent 
therapy for ALK + lung adenocarcinoma. As both are excellent options for treatment of ALK+ lung 
cancer, the trial will consist of two cohorts. The first will be for patients who have never been treated with 
an ALK inhibitor, the other will be for patients who have progressed on one ALK inhibitor. 
1.6 
Rationale for dose and regimen selection 
The package insert for ceritinib recommends a starting dose of 750 mg daily. There are 
recommendations for dose adjustments for toxicity and renal/hepatic impairment. This dose has been 
associated with gastrointestinal toxicities often necessitating a dose reduction, In clinical practice, the 
starting dose is lower and side effects mitigated by the addition of food with the dose. 
In a phase I study of Ceritinib 450 mg or 600 mg with a low fat meal was compared to 750 mg in ALK+ 
non small cell lung cancer. In this ASCEND-8 study, 137 patients were randomized to 750 mg daily with 
no food, 600 mg daily with food or 450 mg daily with food. The 750 mg dose patients showed similar 


 
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steady state pharmacokinetics, while the 600 mg arm shows a 25% higher PK. The incidences of GI 
related AE’s were lowest in the 450 mg arm with no grade 3 or 4 toxicities, while the remaining toxicities 
were similar. These data were presented in the Journal of Thoracic Oncology in 2017 (s1184, vol.12, 
No 1S). 
2.0 
Study Objectives  
The hypothesis is that delivering SABR to patients with persisting tumors 10 weeks after ceritinib will 
result in superior overall tumor control, prolong PFS for patients and lengthen the duration of ceritinib 
activity in patients with ALK+ lung adenocarcinoma.  
 
Published experience suggests that median PFS for patients who have previously been treated with 
crizotinib is less with ceritinib than those who have never been treated with crizotinib (7 months vs 10 
months) (Shaw et al, NEJM 2014). As a result patients enrolled on this study will be divided into 
cohorts on the basis of prior exposure to crizotinib. 
 
The primary endpoint of this study will be Progression-Free Survival (PFS); defined as time from 
initiation of ceritinib to evidence of disease progression by RECIST 1.1, unacceptable toxicity, 
withdrawal of consent, or discontinuation of the trial for any other reason.  
 
There may be progression in a specific localized region that is amenable to stereotactic radiation. If all 
existing lesions that enlarge and any new lesions that develop can still be effectively treated with 
stereotactic radiation, patients will be evaluated for repeat SABR therapy and ceritinib resumed. This 
will be at the recommendation of the treating physician according to standard practice. This will be 
defined as Time to 2nd SABR therapy and will be one of the secondary endpoints. 
 
Similarly, if 3rd round of SABR can be safely provided with subsequent resumption of ceritinib, it will be 
defined as the Time to 3rd SABR therapy. 
 
Cohort A (ALK inhibitor naive): 
 
Primary Objective:  
To demonstrate the superiority of ceritinib combined with SABR in prolonging 
median PFS compared to historical control of 10 months  
 
Primary Endpoint:   
Median PFS (as described in section 2.0) for study cohort, expected to be 20 
months  
 
 
Hypothesis: 
The addition of stereotactic radiation in patients with ALK+ lung 
adenocarcinoma receiving ceritinib will enhance efficacy leading to 
prolongation of time on ceritinib monotherapy.  
 
 
Secondary Objectives:To describe overall survival in study participants 
To describe the time to 2nd and 3rd SABR therapy 
To determine the number of patients with CR, PR or stable disease by 
RECIST 1.1 criteria at 6 and 12 months 
 
 
Secondary Endpoints: Overall survival 
Time to 2nd SABR treatment, Time to 3rd SABR treatment 


 
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PFS at 6 and 12 months from study initiation 
therapy 
 
Safety Objectives:  
Demonstrate safety of ceritinib followed by SABR. 
 
Safety Endpoints:  
toxicity and adverse events (CTCAE v.4)  
 
Hypothesis: 
the safety of this combination of targeted therapy and radiation will be as safe 
as published experience of both these agents. 
 
Cohort B (treated with one prior ALK-inhibitor): 
 
Primary Objective:  
To demonstrate the superiority of ceritinib combined with SABR in prolonging 
median PFS compared to historical control of 7 months  
 
Primary Endpoint:   
Median PFS (Time to subsequent systemic therapy) for study cohort, 
expected to be 14 months.  
 
 
Hypothesis: 
the addition of stereotactic radiation in patients with ALK+ lung 
adenocarcinoma receiving ceritinib will enhance efficacy and prolongation of 
time on ceritinib monotherapy.  
 
 
Secondary Objectives:To describe overall survival in study participants 
To describe the time to 2nd and 3rd SABR therapy 
To determine the number of patients with CR, PR or stable disease by 
RECIST 1.1 criteria at 6 and 12 months 
 
Secondary Endpoints: Overall survival 
Time to 2nd SABR treatment, Time to 3rd SABR treatment 
PFS at 6 and 12 months from study initiation 
 
 
 
Hypothesis: 
The combination of SABR and ceritinib will result in a clinically meaningful 
overall survival in study participants. 
 
The early application of SABR will be effective in delaying progression which 
is amenable to SABR but does not require a change in systemic therapy 
 
Safety Objectives:  
Demonstrate safety of ceritinib followed by SABR. 
 
Safety Endpoints:  
toxicity and adverse events (CTCAE v.4)  
 
Hypothesis: 
 
 
The primary objective is to describe the PFS in patients undergoing study therapy. This is defined as 
evidence of disease progression by RECIST, unacceptable toxicity, withdrawal of consent, or 
discontinuation of the trial for any other reason.  


 
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Additional SABR to enlarging lesions will be permitted while on ceritinib, but no change in systemic 
therapy will be allowed. Patients who demonstrate oligo progression and have disease amenable to 
repeat courses of radiation therapy may resume ceritinib at the discretion of the treating oncologist 
until a change in systemic therapy is indicated.  
 
The secondary objective of the study is to report overall survival and in ALK-positive lung 
adenocarcinoma. We will use Kaplan-Meier methods to estimate the overall survival. 
The rate of overall response and its 95% confidence interval will be estimated using exact binomial 
method. Response duration will be summarized for patients who responded. Descriptive summary 
statistics like median, 25% and 75% percentiles will be used.   
 
The secondary objective is also to describe the time to subsequent SABR in patients undergoing study 
therapy. Patients will be retreated with SABR if feasible. After the initial SABR to persisting lesions, if 
new lesions appear or if existing lesions enlarge but are amenable to SABR, patients will remain on 
study and listed as not having progressed. This time to 2nd and 3rd SABR will be recorded and 
reported. The secondary endpoint will be recorded as time to 2nd and (if applicable) 3rd SABR therapy. 
 
The safety objective of this study to report the toxicity profile of the combination of ceritinib and SABR 
therapy. Both are well tolerated and routinely used in non-small cell lung cancer.  
2.1 
Translational and exploratory objectives 
Radiation can potentially reverse tumor cell unresponsiveness in patients, even in sites that are have 
not been radiated. As noted above[17] (and in press), M1 and M2 macrophages play different roles in 
the tumor metastasis. ALK inhibition impacts the immunologic profile and potentially the subsequent 
development of metastases. 
The exploratory objectives of this study would be to determine the impact of ALK inhibition and radiation 
on immune cell such as VEGFR2 expression, CD4/CD8 T-cells, NK cells and macrophages,. Blood will 
be collected at various time points during the study to determine any association with ceritinib or 
radiation. 
2.2 
Description of protocol design 
 
This is an, open-label, two-cohort protocol designed to evaluate the activity of targeted therapy and 
SABR in ALK+ lung adenocarcinoma. Study participants will have to be eligible for both radiation and 
targeted therapy with ceritinib. 
2.2.1 
Treatment phase and duration of treatment  
Patients eligible for treatment will receive  450 mg daily of ceritinib as part of a 28 day cycle. The first 
dose of each cycle will be administered after evaluation at the study center. Patients will remain on study 
and take ceritinib until there is evidence of disease progression by RECIST 1.1, unacceptable toxicity, 
withdrawal of consent, or discontinuation of the trial for any other reason. In case of oligoprogression 
amenable to repeat courses of SABR, the treating oncologist may resume ceritinib if it is indicated per 
standard clinical practice.  Patients must continue to be followed for safety and efficacy assessments as 
per the schedule of assessments. 
After 2 treatment cycles, lesions will be assessed by treating physician per RECIST 1.1.  Persisting 
lesions will be treated with a course of SABR as feasible following at least 10 weeks of ceritinib 
treatment. Ceritinib will be held 3 days before the start of radiation. Patients will resume ceritinib 3 days 


 
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                                       22 
 
 
after completion of the SABR. Regular surveillance will follow and any new or enlarging lesions that 
develop will be assessed for repeat SABR. 
 
2.3 
Definition of end of the Study 
The study will end when all 33 patients have evidence of disease progression by RECIST1.1, 
unacceptable toxicity, withdrawal of consent, or discontinuation of the trial for any other reason.  
 
At the completion or discontinuation of study medication, all patients will be seen within 30 days for an 
end of therapy evaluation. This will include a safety assessment for AE’s SAE’s. Any unused medication 
will be returned.  
2.4 
Early Termination 
Treatment on protocol may be terminated early if the Principal investigator or institution assess that the 
safety of the enrolled subjects will be compromised by continuation of the trial. The procedure followed 
will be that of the premature withdrawal patient and any patients on treatment will be seen as soon as 
possible. 
3.0 
Subject eligibility  
3.1 
Patient population 
Subjects for this study will be selected from those with ALK+ lung adenocarcinoma. ALK analysis by 
Ventana or Vysis assay is routinely performed on lung adenocarcinoma to determine ALK status. 
Patients who are positive for an ALK rearrangement by gene sequencing will also be considered eligible 
for the study.  
Patients will be informed about their potential eligibility status for this trial. None of these patients will be 
given any therapy or undergo any study related assessments/procedures until they have successfully 
screened and enrolled on to the therapeutic portion of the study. 
Patients enrolled to the therapeutic portion of the study will have histologically proven lung 
adenocarcinoma with ALK abnormality detected by gene sequencing or assay as described above. 
3.2 
Inclusion criteria 
Patients eligible for inclusion in this early treatment protocol have to meet all of the following criteria: 
1. Histologically or cytologically confirmed diagnosis of lung adenocarcinoma that demonstrates ALK 
rearrangement as detected by the approved FISH test (Abbott Molecular Inc), using Vysis 
breakapart probes (defined as 15% or more positive tumor cells); or the Ventana IHC test. 
Evidence of rearrangement by gene sequencing tests such as FoundationOne or Caris will also be 
seen as evidence of ALK abnormality and meeting eligibility requirement. 
2. Patients with no prior ALK-inhibitor therapy will be placed in cohort A, those treated with one prior 
line of ALK-inhibitor (at any time) will enter cohort B.  
3. Patients will not have any other curative therapeutic option, such as radiation or surgery. 
4. WHO performance status 0-2.  
5. Age ≥18 years. 
6. Patients must have recovered from all toxicities related to any prior anticancer therapies to ≤ 
Grade 2 (CTCAE v 4.03), provided that any concomitant medication is given prior to initiation of 


 
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study sponsor. 
                                       23 
 
 
treatment with ceritinib. Exception to this criterion: patients with any grade of alopecia are allowed 
to enter the treatment. 
7. Adequate organ function: the following laboratory criteria have been met: 
• 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
• 
Hemoglobin (Hgb) ≥ 8 g/dL 
• 
Platelets ≥ 75 x 109/L 
• 
Serum creatinine <1.5 mg/dL and /or calculated creatinine clearance (using Cockcroft-Gault 
formula) ≥30 mL/min 
• 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN), except for patients with Gilbert’s syndrome 
who may be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN 
• 
Aspartate transaminase (AST) < 2.0 x ULN, except for patients with liver metastasis, who are 
only included if AST < 3 x ULN; alanine transaminase (ALT) < 2.0 x ULN, except for patients 
with liver metastasis, who are only included if ALT < 3 x ULN 
• 
Alkaline phosphatase (ALP) ≤5.0 x ULN  
• 
Fasting plasma glucose ≤175 mg/dL (≤9.8 mmol/L) 
• 
Serum amylase ≤ 2 x ULN  
• 
Serum lipase ≤ ULN  
 
8. Patient must have the following laboratory values or have the following laboratory values corrected 
with supplements to be above the lower limit of normal before the first dose of ceritinib: 
• 
Potassium 
• 
Magnesium 
• 
Phosphorus 
• 
Total calcium (corrected for serum albumin) 
9. Written informed consent for the protocol must be obtained prior to any screening procedures.  
10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other 
procedures. 
 
3.3 
Exclusion criteria 
Patients eligible must not meet any of the following criteria: 
1. Patients with known hypersensitivity to any of the excipients of ceritinib (microcrystalline cellulose, 
mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate). 
2. History of carcinomatous meningitis. 
3. Prior therapy with ceritinib.  
4. Presence or history of a malignant disease other than lung adenocarcinoma that has been 
diagnosed and/or required therapy within the past year and is undergoing active anticancer 
treatment. Exceptions to this exclusion include the following: completely resected basal cell and 
squamous cell skin cancers, and completely resected carcinoma in situ of any type. 
5. Patient has history of interstitial lung disease or interstitial pneumonitis, including clinically 
significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic 
intervention). 
6. Patient who has received thoracic radiotherapy to lung fields ≤4 weeks prior to starting the study 
treatment or patients who have not recovered from radiotherapy-related toxicities. For all other 
anatomic sites (including radiotherapy to thoracic vertebrae and ribs) radiotherapy ≤2 weeks prior 


 
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                                       24 
 
 
to starting the study treatment or has not recovered from radiotherapy-related toxicities. Palliative 
radiotherapy for bone lesions ≤2 weeks prior to starting study treatment is allowed. 
7. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 
months), such as: 
• 
unstable angina within 6 months prior to screening; 
• 
myocardial infarction within 6 months prior to screening; 
• 
history of documented congestive heart failure (New York Heart Association functional 
classification III-IV); 
• 
uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg and/or 
Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive medication  
• 
initiation or adjustment of antihypertensive medication(s) is allowed prior to screening; 
• 
ventricular arrhythmias; supraventricular and nodal arrhythmias not controlled with 
medication; 
• 
other cardiac arrhythmia not controlled with medication; 
• 
Corrected QT (QTcF) >470 ms using Fridericia’s correction on the screening ECG 
8. Impaired GI function or GI disease that may alter absorption of ceritinib or inability to swallow up to 
five ceritinib capsules daily. Although, patients unable to swallow capsules will be allowed to 
participate in this study, by following the specific instructions on making a slurry of the medication. 
9. Patient has impairment of GI function or GI disease that may significantly alter the absorption of 
ceritinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption 
syndrome). 
10. Receiving medications that meet one of the following criteria and that cannot be discontinued at 
least 1 week prior to the start of treatment with ceritinib and for the duration of participation (see 
Appendix 1 Tables): 
• 
Medication with a known high risk of prolonging the QT interval or inducing Torsades de 
Pointes (please refer to http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm) 
• 
Strong inhibitors or strong inducers of CYP3A4/5 (please refer to 
http://medicine.iupui.edu/flockhart/table.htm or http://www.druginteractioninfo.org) 
• 
Medications with a low therapeutic index that are primarily metabolized by CYP3A4/5, 
CYP2C8 and/or CYP2C9 (please refer to http://medicine.iupui.edu/flockhart/table.htm or 
http://www.druginteractioninfo.org) 
• 
Therapeutic doses of warfarin sodium (Coumadin) or any other coumadin-derived anti-
coagulant. Anticoagulants not derived from warfarin are allowed (eg, dabigatran, rivaroxaban, 
apixaban). 
• 
Unstable or increasing doses of corticosteroids; If patients are on corticosteroids for 
endocrine deficiencies or tumor-associated symptoms (non-CNS), dose must have been 
stabilized (or decreasing) for at least 5 days before first dose of study treatment. 
• 
Enzyme-inducing anticonvulsive agents 
• 
Herbal supplements 
11. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive hCG laboratory test. 
12. Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, unless they are using highly effective methods of contraception during dosing and agree 
to continue for 3 months after the last dose of study treatment. Highly effective contraception 
methods include: 


 
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                                       25 
 
 
• 
Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
• 
Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) 
or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment. 
• 
Male sterilization (at least 6 months prior to screening) with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate. For female subjects on the study the 
vasectomized male partner should be the sole partner for that subject. 
• 
Combination of any two of the following (a+b or a+c or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or other forms of 
hormonal contraception that have comparable efficacy (failure rate < 1%), for example 
hormone vaginal ring or transdermal hormone contraception. 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/vaginal suppository. 
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or 
without hysterectomy) or tubal ligation at least six weeks prior to screening. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of child bearing potential. 
13. Sexually active males unless they agree to use a condom during intercourse while taking drug and 
agree to continue for 3 months after the last dose of study treatment. Male patients for 3 months 
should not father a child in this period. A condom is required to be used also by vasectomized men 
in order to prevent delivery of the drug via seminal fluid. 
14. Patient has a history of pancreatitis or history of increased amylase or lipase that was due to 
pancreatic disease. 
15. Patient has other severe, acute, or chronic medical conditions including uncontrolled diabetes 
mellitus or psychiatric conditions or laboratory abnormalities that, in the opinion of the investigator, 
may increase the risk associated with study participation or may interfere with the interpretation of 
study results. 
16. Patient has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks 
prior to starting study treatment or has not recovered from side effects of such procedure. Video-
assisted thoracic surgery (VATS) and mediastinoscopy will not be counted as major surgery and 
patients can receive study treatment ≥1 week after these procedures. 
4.0 
Treatment Plan 
4.1 
Treatment Dosage and Administration 
For this protocol, the term “treatment” refers to ceritinib. The dose and schedule are listed under table 
4-1. 
Each cycle of therapy will be 28 days long. A completed cycle will be 28 days of once daily continuous 
treatment. Day 1 will be the first day that ceritinib is taken, and the last day of a completed treatment 


 
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                                       26 
 
 
cycle will be day 28. All doses prescribed to and taken by patients, any dose adjustments and interruption 
or discontinuations will be recorded in the clinical trial record. 
Table 4-1 
Dose and treatment schedule 
Study 
treatments 
Pharmaceutical form and route 
of administration 
Dose 
Frequency and/or 
Regimen 
Ceritinib 
Hard gelatin capsule for oral use 
450 mg (3 x 150 mg 
capsule) 
Once daily 
(28-day cycle) 
4.1.1 
Dosing regimen 
Patients on this trial will begin therapy on day 1 of Cycle 1 with the first administration of ceritinib. 
4.1.1.1 
Ceritinib 
Patients will self-administer the doses of ceritinib for the cycle. 
Ceritinib will be administered orally once daily at a dose of 450 mg ( 3 capsules of 150mg ceritinib) on a 
continuous dosing schedule. The investigator must instruct the patient to take the ceritinib treatment 
exactly as prescribed. 
• 
Patients should take ceritinib once daily at approximately the same time each day, in the morning, 
afternoon, or evening. 
• 
Patients should take ceritinib  with food.  
• 
Each dose of ceritinib should be taken with a glass of water and consumed over as short a time as 
possible (i.e., not slower than 1 capsule every 2 minutes).  
• 
For patients with a gastrostomy tube who are unable to swallow capsules, patient will be instructed 
on how to prepare mixture. For patients that are unable to swallow capsules, administration can 
occur through a nasogastric (NG) or gastric (G) tube: 
1. Put on gloves and mask before opening containers. Take the appropriate number of capsules that 
are needed, out of the containers. 
2. Place a glass bowl in an area with smooth surfaces that is easy to clean. 
3. Carefully open each capsule, one at a time, and pour or tip the contents out of each capsule in the 
glass bowl. 
4. Carefully check to make sure that both parts of each capsule are empty. Some of the contents may 
stick to the inside of the capsules. If this happens, use a toothpick (or similar tool) to remove the stuck 
contents into the glass bowl; work over the bowl. 
5. Fill the glass bowl with at least 40 mL (eight teaspoons) of water. If taking a dose that is 200 mg or 
less, then use at least 20 mL (four teaspoons of water). 
6. Mix the drug powder with water carefully with the spoon. 
7. Put the end of the syringe in the glass bowl and slowly pull back on the plunger drawing the mixture 
into the syringe. 
8. Make sure patient is sitting relatively upright, connect the syringe to the patient’s NG or G-tube and 
empty the mixture by slowly pushing the plunger into the syringe until all contents are empty. 
9. Repeat steps 7-8 if necessary, making sure the entire dose is administered. 
10. Once the entire dose is given, rinse the tube by syringing in 20 mL (four teaspoons) twice. If dose 
is 200 mg or less, then use at least 10 mL (two teaspoons) of water twice for rinsing. 
11. Dispose empty capsule shells, mask and gloves as per the hospital or institutions’ guidelines 
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed before the next 
scheduled dose. 


 
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                                       27 
 
 
Patients should be instructed not to make up missed doses or partial doses (i.e., when the entire dose 
is not taken as instructed). A missed or partial dose will be defined as a case when the full dose is not 
taken within 8 hours after the approximate time of the usual daily dosing. That day’s dose (or partial 
remaining dose) should be omitted, and the patient should continue treatment with the next scheduled 
dose on the following day. The patient should record this in the medication diary. 
4.1.2 
Treatment duration 
 
Patients will continue ceritinib treatment until they experience any of the following: 
 
-Disease progression not amenable to SABR and necessitating change in systemic therapy 
determined by the treating physician. 
-Unacceptable toxicity that precludes further treatment. 
-Start of a new anti-cancer therapy. 
-Pregnancy. 
-Treatment is discontinued at the discretion of the investigator or patient. 
-Lost to follow-up. 
-Death.  
-Completed. 
4.2 
Dose escalation guidelines 
No doses escalation will be permitted on this study. 
4.3 
Dose modifications 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are permitted 
in order to allow the patients to continue the ceritinib treatment. Any changes in ceritinib administration 
will be recorded in the clinical trial record. 
General guidelines for dose modifications  
• 
For grade 1 and tolerable grade 2 treatment-related toxicities, patients are encouraged to continue 
at the current dose of study treatment. For intolerable grade 2 treatment-related toxicities, dosing 
should be interrupted until resolution to grade 1 or lower followed by dose reduction to the next dose 
level. 
• 
For grade 3 or grade 4 treatment-related toxicity that is not considered by the investigator to be life-
threatening, patients should interrupt study treatment until resolution to grade 1 or lower; then study 
treatment may continue following a dose reduction to the next dose level, if, in the opinion of the 
Investigator, the patient continues to experience clinical benefit. For any grade 3 or 4 treatment-
related toxicity that is considered by the investigator to be life-threatening, permanently discontinue 
study treatment. 
 
More detailed ceritinib dose modification guidelines are described in Section 4.3.1 respectively for 
selected toxicities.  
All dose modifications, interruptions or discontinuations must be based on the worst preceding toxicity 
as graded by the NCI Clinical Toxicity Criteria version 4.03. 
Patients whose treatment is interrupted or permanently discontinued due to an AE must be followed until 
resolution or stabilization of the event. Patients requiring interruptions greater than 1 cycle (28 days) 


 
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                                       28 
 
 
should be discontinued from ceritinib treatment unless the treating physician and Principle investigator 
agree that the patient should resume treatment. 
All patients will be followed for safety until 30 days after the last dose of ceritinib. 
 
4.3.1 
Dose modification and dose delay of Ceritinib 
Guidelines for dose interruptions and re-initiation of ceritinib treatment (with or without dose reduction) 
are described in Table 4-2. Dosing adjustment guidelines are in Table 4-3 
 
Table 4-2 
 Dose reduction steps for ceritinib 
Ceritinib dose levels  
 
 Dose* and schedule 
Starting dose level 
 
 
450 mg QD continuously 
Dose level - 1   
 
 
300 mg QD continuously 
Dose level – 2**  
 
 
 
150 mg QD continuously 
 
*Dose reduction will be based on the worst preceding toxicity as per NCI-CTCAE version 4.03. 
**Dose reduction below 150 mg/day is not allowed. If a dose reduction below 150 mg/day is required, 
the patient will be permanently discontinued from ceritinib.  
Table 4-3 
Criteria for interruption and re-initiation of Ceritinib treatment 
 
Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for Ceritinib 
HEMATOLOGICAL 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1.5 x 109/L) 
Maintain dose level 
Grade 2 (ANC < 1.5 and ≥ 1.0 x 109/L) 
Maintain dose level 
Grade 3 (ANC < 1.0 and ≥ 0.5 x 109/L) 
Omit dose until resolved to ≤ Grade 2, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 4 (ANC < 0.5 x 109/L) 
Omit dose until resolved to ≤ Grade 2, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Febrile neutropenia 
(ANC < 1.0 x 109/L, with a single 
temperature of ≥ 38.3 °C or a sustained 
temperature of ≥ 38 °C for more than one 
hour ) 
Omit dose until clinically resolved and neutropenia ≤ 
Grade 2, then  1 dose level 


 
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Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for Ceritinib 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75 x 109/L) 
Maintain dose level 
Grade 2 (PLT < 75 and ≥ 50 x 109/L) 
Maintain dose level 
Grade 3 (PLT < 50 and ≥ 25 x 109/L) 
Omit dose until resolved to ≤ Grade 2, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 4 (PLT < 25 x 109/L) 
Omit dose until resolved to ≤ Grade 2, then  1 
dose level 
HEPATIC 
alkaline phosphatase and/or Gamma-glutamyl transpeptidase (GGT) 
Isolated elevations of any grade 
Maintain dose level 
Total Bilirubin** 
(for patients with Gilbert Syndrome these 
dose modifications apply to changes in 
direct (conjugated) bilirubin only) 
 
Grade 1 (> ULN and ≤ 1.5 x ULN) 
Maintain dose level with liver function test (LFTs)*** 
monitored as per protocol 
Grade 2 (> 1.5 and ≤ 3.0 x ULN) with ALT or 
AST ≤ 3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 3 (> 3.0 and ≤ 10.0 x ULN) with ALT 
or AST ≤ 3.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days,  1 dose level 
If resolved in > 7 days discontinue patient from 
ceritinib 
Grade 4 (> 10.0 x ULN) 
Permanently discontinue patient from ceritinib 
AST or ALT 
Grade 1 (> ULN and ≤ 3.0 x ULN) 
Maintain dose level with LFTs*** monitored per 
protocol 
Grade 2 (> 3.0 and ≤ 5.0 x ULN) without 
total bilirubin elevation to > 1.5 x ULN 
Omit dose until resolved to ≤ Grade 1, then 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 3 (> 5.0 and ≤ 20.0 x ULN) without 
total bilirubin elevation to > 1.5 x ULN 
Omit dose until resolved to ≤ Grade 1, then 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 4 (> 20.0 x ULN) without bilirubin 
elevation to > 2.0 x ULN 
Omit dose until resolved to ≤ Grade 1, then  1 
dose level 
AST or ALT and concurrent Total Bilirubin 
AST or ALT > 3.0 x ULN with total bilirubin > 
2.0 x ULN in the absence of cholestasis or 
hemolysis 
Permanently discontinue patient from ceritinib 


 
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Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for Ceritinib 
RENAL 
Serum creatinine 
Grade 1 (>1 and ≤1.5 x baseline; > ULN and  
≤1.5 x ULN) 
Maintain dose level 
Grade 2 (>1.5 and ≤3.0 x baseline; >1.5 and 
≤3.0 x ULN) 
Omit dose until resolved to ≤ Grade 1, then: 
If resolved in ≤ 7 days, then maintain dose level 
If resolved in > 7 days, then  1 dose level 
Grade 3 (>3.0 x baseline; >3.0 and ≤6.0 x 
ULN) 
Omit dose until resolved to ≤ Grade 1, then  1 
dose level 
Grade 4 (> 6.0 x ULN) 
Permanently discontinue patient from ceritinib 
GASTROINTESTINAL 
Diarrhea**** 
Grade 1 (despite maximal anti-diarrheal 
medication) 
Maintain dose level but adjust anti-diarrhea 
treatment (may change anti-diarrhea treatment) 
Grade 2 (despite maximal anti-diarrheal 
medication) 
Omit dose until resolved to ≤ Grade 1, then maintain 
dose level. 
If diarrhea returns as ≥ Grade 2, then suspend dose 
until resolved to ≤ Grade 1, then ↓ 1 dose level 
Grade 3 (despite maximal anti-diarrheal 
medication) 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose 
level 
Grade 4 (despite maximal anti-diarrheal 
medication) 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose 
level 
Nausea***** 
Grade 1 (despite standard anti-emetics) 
Maintain dose level but adjust anti-emetic treatment 
Grade 2 (despite standard anti-emetics) 
Maintain dose level but adjust anti-emetic treatment 
Grade 3 (despite standard anti-emetics) 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose 
level  
Vomiting***** 
Grade 1 (despite standard anti-emetics) 
Maintain dose level but adjust anti-emetic treatment 
Grade 2 (despite standard anti-emetics) 
Omit dose until resolved to ≤ Grade 1, then maintain 
dose level. 
If vomiting returns as ≥ Grade 2, then suspend dose 
until resolved to ≤ Grade 1, then ↓ 1 dose level  
Grade 3 (despite standard anti-emetics) 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose 
level 
Grade 4 (despite standard anti-emetics) 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 dose 
level 
METABOLIC 
Any Grade hypophosphatemia 
Treatment with phosphate supplements as clinically 
indicated and maintain dose level 
Hyperglycemia 


 
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Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for Ceritinib 
Persistent hyperglycemia  (glucose > 250 
mg/dL despite optimal anti-hyperglycemic 
therapy) 
Omit dose until hyperglycemia is adequately 
controlled then resume ceritinib at ↓ 1 dose level 
If adequate hyperglycemic control cannot be 
achieved with optimal medical management 
permanently discontinue patient from ceritinib. 
GENERAL DISORDERS 
Fatigue (asthenia) 
Grade 1  
Maintain dose level 
Grade 2 
Maintain dose level 
Grade 3 
If grade 3 fatigue resolves in ≤ 7 days, maintain dose 
level 
If grade 3 fatigue lasts > 7 days, omit dose until 
resolved to ≤ Grade 2 and then  dose level 
CARDIAC INVESTIGATIONS 
Electrocardiogram QT corrected (QTc) interval prolonged 
Grade 1 (QTc 450-480 ms) 
Maintain dose level 
Grade 2 (QTc 481-500 ms) 
Maintain dose level 
Grade 3 (QTc ≥ 501 ms on at least two 
separate ECGs) 
When QTc ≥ 501 ms is identified at the site, 
interrupt ceritinib treatment and perform the 
following: 
Perform an analysis of serum potassium, calcium, 
phosphorus, and magnesium, and if below lower 
limit of normal, correct with supplements to within 
normal limits. 
Review concomitant medication usage for the 
potential to inhibit CYP3A4/5 and/or to prolong the 
QT-interval. 
Check compliance with correct dose and 
administration of ceritinib. 
Perform a repeat ECG within one hour of the first 
QTc of ≥ 501 ms. 
If QTc remains ≥ 501 ms, repeat ECG as clinically 
indicated, but at least once a day until the QTc 
returns to < 501 ms. 
If QTc returns to ≤ grade 1 (< 481 ms), ceritinib will 
be reduced by 1 dose level (i.e., 600 mg QD or 
lower). 
Repeat ECG in 24 hours, or less, as clinically 
indicated; continue monitoring as clinically 
indicated until QTc < 481 ms 


 
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Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for Ceritinib 
Repeat ECGs 7 days and 14 days (and then every 
21 days) after dose resumption for all patients 
who had therapy interrupted due to QTc ≥ 501 
ms. 
If QTc of ≥ 501 ms recurs, interrupt ceritinib 
treatment. If QTc returns to ≤ grade 1 (< 481 ms), 
ceritinib may be reduced again by 1 dose level (i.e., 
450 mg QD or 300mg QD). Repeat ECGs as 
described above. 
If QTc of ≥ 501 ms recurs after 2nd dose 
reduction for QTc prolongation, the patient must 
be discontinued from study. 
QTc of >480 ms should be reported as an adverse 
event (AE) 
Grade 4 (QTc ≥ 501 or > 60ms change from 
baseline and Torsades de pointes or 
polymorphic ventricular tachycardia or 
signs/symptoms of serious arrhythmia) 
Permanently discontinue patient from ceritinib 
PULMONARY 
Notes:  
• 
Withhold ceritinib for acute onset of new or progressive unexplained pulmonary symptoms, 
such as dyspnea, cough and fever and during diagnostic workup for pneumonitis/ILD. 
• 
During evaluation of potential grade 2, 3, and 4 pneumonitis, if an infectious etiology is 
confirmed (i.e., pneumonia) and pneumonitis is excluded, then consider resuming ceritinib 
at current dose level after the pneumonia resolves. 
PNEUMONITIS 
Any Grade treatment-related 
ILD/pneumonitis 
Permanently discontinue patient from ceritinib. 
BRADYCARDIA 
Grade 1  
Omit dose until recovery to asymptomatic 
bradycardia or to a heart rate ≥ 60 bpm 
Evaluate concomitant medications known to cause 
bradycardia and adjust the dose of ceritinib 
Grade 2 
Omit dose until recovery to asymptomatic 
bradycardia or to a heart rate ≥ 60 bpm 
Evaluate concomitant medications known to cause 
bradycardia and adjust the dose of ceritinib 
Grade 3 
Grade 4 (in patients taking a concomitant 
medication also known to cause bradycardia 
or a medication known to cause 
hypotension) 
Omit dose until recovery to asymptomatic 
bradycardia or to a heart rate ≥ 60 bpm 
If the concomitant medication can be adjusted or 
discontinued, resume ceritinib at ↓ 1 dose level with 
frequent monitoring 
Grade 4 (in patients who are not taking a 
concomitant medication also known to 
cause bradycardia or known to cause 
hypotension) 
Permanently discontinue ceritinib 


 
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Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for Ceritinib 
PANCREATIC 
Amylase and/or lipase elevations (in the absence of clinical symptoms) 
Grade 1 (> ULN and ≤1.5 x ULN) 
Maintain dose level 
Grade 2 (>1.5 - 2.0 x ULN) 
Maintain dose level 
Grade ≥3 (> 2.0 x  ULN)  
Omit dose until resolved to ≤ Grade 1, then  1 
dose level 
Note: Withhold ceritinib for acute onset of new or progressive unexplained abdominal symptoms, 
such as severe pain or vomiting; perform diagnostic procedures (e.g., abdominal CT scan or 
ultrasound) to exclude pancreatic pathology.     
* Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. All dose modifications 
should be based on the worst preceding toxicity. 
** If Grade 3 or 4 hyperbilirubinemia is due to the indirect (non-conjugated) component only, and 
hemolysis as the etiology has been ruled out as per institutional guidelines (e.g., review of 
peripheral blood smear and haptoglobin determination), then ↓ 1 dose level and continue treatment 
at the discretion of the Investigator. 
***LFTs include albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), Alkaline 
phosphatase and GGT. 
**** Dose modifications apply to patients who experience diarrhea despite appropriate antidiarrheal 
medication. This medication should be started at the first sign of abdominal cramping, loose stools 
or overt diarrhea (see Section 4.3.2.5). 
***** Dose modifications apply to patients who experience nausea and/or vomiting despite 
appropriate antiemetic medication. This medication should be started at the first sign of nausea 
and/or vomiting (see Section 4.3.2.6). 
 
 
 
 
 
 
 
 
 
 


 
 
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4.3.2 
Follow-up for toxicities 
An unscheduled visit should be performed in all cases below where toxicity monitoring is recommended 
more frequently than defined by the schedule of assessments (table 5-1). 
Ongoing SAEs at the final safety evaluation visit or the end of study treatment visit (whichever is later) 
should be followed until they improve becoming non serious events, stabilize, or return to baseline levels. 
Refer to Section 7.2 for SAE. 
A summary of selected toxicity follow-up recommendations is listed in table 4-4. For full toxicity 
information and dosing adjustments please refer to Table 4-3. 
Table 4-4  
Follow-up recommendations for specific toxicities 
 
Toxicity 
Follow-up evaluation* 
 
Investigations 
(hematologic) 
 
Febrile neutropenia, neutropenia or thrombocytopenia ≥ CTCAE Grade 3 
Test weekly (or more frequently) until ≤ Grade 2 
Subsequent monitoring must be performed every 3 weeks (or more frequently) 
 
 
Investigations 
(hepatic) 
 
Total ALT/AST/total bilirubin Grade 2: 
Test weekly (or more frequently) until ≤ Grade 1 
Thereafter, continue to test every 2 weeks (or more frequently) for 2 cycles (8 
weeks). If 
no recurrence of ≥ Grade 2 event, continue monitoring every cycle (4 weeks) 
Total ALT/AST/total bilirubin ≥ Grade 3: 
Test weekly (or more frequently) until ≤ Grade 1 
Thereafter, continue to test every 2 weeks (or more frequently) for 4 cycles (16 
weeks). If 
no recurrence of ≥ grade 2 event, continue monitoring every cycle (4 weeks) 
Discontinuation due to liver toxicity: 
Test weekly (or more frequently) until ≤ Grade 1 or stabilization 
 
 
Investigations 
(renal) 
 
Serum creatinine Grade 2: 
Test weekly (or more frequently) until Grade 1 
Thereafter, test every cycle (4 weeks) 
Serum creatinine ≥ Grade 3: 
Test twice weekly (or more frequently) until ≤ Grade 1 
Thereafter, test every cycle (4 weeks) 
 
Investigations 
(Metabolic) 
 
Hyperglycemia ≥ Grade 3 
Test weekly (or more frequently) until Grade 1 
 
Investigations 
(pancreatic) 
Amylase/lipase ≥ Grade 3: 
Test weekly (or more frequently) until ≤ Grade 1. After resumption of dosing, 
continue to test weekly for one additional cycle (4 weeks). If no reoccurrence of ≥ 
Grade 2 event, continue monitoring every cycle (4 weeks). 


 
 
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*Note: this table refers only to the evaluation schedule to monitor selected toxicities. Refer to Table 
4-3 for dose modifications required for applicable toxicities 
 
 
4.3.2.1 
Guidelines for the follow-up of laboratory hematologic abnormalities 
In case of any occurrence of febrile neutropenia, neutropenia ≥ grade 3, or thrombocytopenia ≥ grade 
3, hematology tests must be performed weekly (or more frequently if clinically indicated) until the event 
resolves to ≤ grade 2. Subsequent monitoring must be performed at least every 4 weeks. 
 
4.3.2.2 
Guidelines for the follow-up of laboratory liver abnormalities 
In patients with any clinically relevant laboratory liver abnormality, as defined below, hepatic toxicity 
monitoring must include ALL of the following liver function tests (LFTs): albumin, ALT, AST, total bilirubin 
(fractionated if total bilirubin > 2.0 x ULN), alkaline phosphatase and GGT. Note: for patients with Gilbert 
Syndrome, total and direct bilirubin must be monitored, but intensified monitoring applies to changes in 
direct bilirubin only. 
In case of any occurrence of ALT/AST/total bilirubin increase to grade 2 the LFTs must be monitored 
weekly (or more frequently if clinically indicated) until the event resolves to ≤ grade 1. Thereafter 
monitoring must be continued every 2 weeks (or more frequently if clinically indicated) for two additional 
cycles (e.g. 8 weeks). If there is no recurrence of ≥ grade 2 ALT/AST/total bilirubin elevations during this 
period, subsequent monitoring must be performed at least every 4 weeks. 
In case of any occurrence of ALT/ AST/ bilirubin increase to grade 3 or 4, LFTs must be monitored 
weekly (or more frequently if clinically indicated) until the event resolves to ≤ grade 1. Thereafter 
monitoring must be continued every 2 weeks (or more frequently if clinically indicated) for four additional 
cycles (e.g. 16 weeks). If there is no recurrence of ≥ grade 2 ALT/AST/total bilirubin elevations during 
this period, subsequent monitoring must be performed at least every 4 weeks. 
Patients who discontinue ceritinib treatment due to liver toxicity must be monitored weekly (or more 
frequently if clinically indicated) until the event resolves to ≤ grade 1 or stabilization occurs (no CTCAE 
grade change over 4 weeks). 
4.3.2.3 
Guidelines for the follow-up of laboratory renal abnormalities 
In case of any occurrence of serum creatinine results of grade 2 or greater, tests must be performed 
weekly (or more frequently if clinically indicated) until the event resolves to ≤ grade 1. Subsequent 
monitoring must be performed at least every 4 weeks. 
In case of any occurrence of serum creatinine ≥ grade 3, tests must be performed twice weekly (or more 
frequently if clinically indicated) until the event resolves to ≤ grade 1. Subsequent monitoring must be 
performed at least every 4 weeks.  
4.3.2.4 
Guidelines for the follow-up of laboratory pancreatic abnormalities 
In case of any occurrence of lipase or amylase increase to grade 3 or 4, both lipase and amylase must 
be monitored weekly (or more frequently if clinically indicated) until the event resolves to ≤ grade 1 (or 
to baseline).  


 
 
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After resumption of dosing, monitoring must be continued weekly (or more frequently if clinically 
indicated) for one additional cycle (i.e. 4 weeks). If there is no recurrence of ≥ grade 2 amylase or lipase 
elevations during this period, subsequent monitoring must be performed every 4 weeks. 
Patients who discontinue study treatment due to pancreatic toxicity must be monitored weekly (or more 
frequently if clinically indicated) until the event resolves to ≤ grade 1 or stabilization occurs (no CTCAE 
grade change over 4 weeks). 
If amylase and/or lipase elevations are accompanied by new or progressive unexplained abdominal 
symptoms such as severe pain or vomiting, withhold ceritinib, then perform diagnostic procedures (e.g., 
abdominal CT scan or ultrasound) to exclude pancreatic pathology.  
See also dose modification guidelines descried in Table 4-3. 
4.3.2.5 
Guidelines for monitoring pneumonitis 
Monitor patients for pulmonary symptoms indicative of pneumonitis. In addition, withhold ceritinib for 
acute onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever 
and during diagnostic workup for pneumonitis/ILD. 
4.3.2.6 
Guidelines for the treatment of study drug induced diarrhea 
The investigator should consider/investigate potential concomitant medication, food or comorbidity 
driven causes of diarrhea (including infectious causes) and remedy these causes if possible (e.g. 
discontinuation of concomitant medication, dietary modification, treatment of comorbidity). 
The patient should be monitored for signs of dehydration and instructed to take preventive measures 
against dehydration as soon as diarrhea occurs. Antidiarrheal medication must be initiated at the first 
sign of abdominal cramping, loose stools or overt diarrhea. Concomitant medication for the treatment of 
diarrhea should follow local practice and the investigator’s best judgment and may follow “the 
recommended guidelines for the treatment of cancer treatment-induced diarrhea” (Benson et al 2004).  
 
For example: 
• 
For uncomplicated diarrhea (grade 1 or 2 without complicating signs or symptoms), loperamide 
given at a standard dose (e.g. initial administration of 4 mg, then 2 mg every 2-4 hours, maximum 
of 16 mg/day), along with oral hydration and dietetic measures should be considered.  
• 
For complicated diarrhea (all grade 3 or 4, grade 1-2 with complicating signs or symptoms - 
moderate to severe cramping, decreased performance status, fever, neutropenia, frank bleeding 
or dehydration), management should involve intravenous (IV) fluids, and consider treatment with 
octreotide (at starting dose of 100 to 150 µg sub-cutaneous tid or 25 to 50 µg IV) and antibiotics 
(e.g. fluoroquinolone) should be given. 
• 
Dose adaptation of ceritinib in case of treatment related diarrhea must follow the guidelines 
presented above in the Criteria for interruption and re-initiation of ceritinib Treatment table. 
4.3.2.7 
Guidelines for the treatment of study drug induced nausea and vomiting 
Nausea and vomiting are among the most frequently reported AEs following treatment with ceritinib and 
patients must therefore be closely monitored for the appearance of these AEs. 
The investigator should consider/investigate potential concomitant medication, food or comorbidity 
driven causes of nausea and/or vomiting and remedy these causes if possible (e.g. discontinuation of 


 
 
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concomitant medication, dietary modification, treatment of comorbidity). Adjusting the time of ingestion 
of ceritinib may influence perception and management of nausea (eg. taking it at bedtime). 
Individualized supportive and anti-emetic treatment should be initiated, as appropriate, at the first signs 
and/or symptoms of these AEs. In patients with vomiting, the patient should be monitored for signs of 
dehydration and instructed to take preventive measures against dehydration. Concomitant medication 
for the treatment of nausea and/or vomiting should follow local practice and the investigator’s best 
judgment. For moderate emetogenic drugs, such as ceritinib, International Guidelines for anti-emetic 
treatment recommend early treatment with 5-HT3-receptor antagonists (5-HT3RAs). 
• 
Dose adaptation of ceritinib in case of treatment related nausea and/or vomiting must follow 
the guidelines presented above in the Criteria for interruption and re-initiation of ceritinib Treatment 
table. 
4.3.2.8 
Guidelines for treatment of hypophosphatemia 
Hypophosphatemia was not among the commonly reported AEs (i.e., < 15%), regardless of relationship 
to ceritinib treatment. 
Therefore, phosphate levels should be checked at baseline and during treatment. In cases of 
hypophosphatemia at screening, phosphate supplements should be started and phosphate levels must 
be normalized before treatment is commenced with ceritinib. For any grade of hypophosphatemia during 
the study, treatment with phosphate supplements should be given as clinically indicated, and the ceritinib 
dose can be maintained. 
4.3.3 
Anticipated risks and safety concerns of the ceritinib treatment 
Appropriate eligibility criteria and 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 AEs, e.g., diarrhea are provided in Section above. Refer 
to preclinical toxicity and or clinical data found in the Investigator’s Brochure. 
 
4.4 
Concomitant medications 
In general, the use of any concomitant medication/therapy deemed necessary for the care of the patient 
(e.g., anti-emetics, anti-diarrheal agents) is permitted, except when specifically prohibited. The patient 
must be told to notify the investigational site about any new medications he/she takes after the start of 
the ceritinib treatment. All medications, including herbal/natural medications (excluding ceritinib 
treatment and prior antineoplastic treatments and blood transfusions), surgeries and procedures 
(including physical therapy) administered within 30 days prior to the first dose of administration of 
ceritinib treatment through 30 days after the last dose of ceritinib treatment will be recorded. Medications 
include not only physician prescribed medications, but also all over-the counter (OTC) medications, 
herbal medications (prohibited, see Section 4.4.2), food or vitamin supplements, and blood transfusions. 
For up to date information on prohibited medications please refer to the following websites: 
• 
Medication with a known High risk of prolonging the QT interval or inducing Torsades de Pointes 
(please refer to http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm ) 
• 
Strong inhibitors or strong inducers of CYP3A4/5 (please refer to 
http://medicine.iupui.edu/flockhart/table.htm or http://www.druginteractioninfo.org ) 


 
 
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• 
Medications with a low therapeutic index that are primarily metabolized by CYP3A4/5, CYP2C8 
and/or CYP2C9 (please refer to http://medicine.iupui.edu/flockhart/table.htm or 
http://www.druginteractioninfo.org) 
 
4.4.1 
Permitted concomitant therapy requiring caution and/or action with ceritinib 
4.4.1.1 
Corticosteroids 
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to induce CYP3A 
enzymes, thereby increasing the risk of reducing ceritinib drug exposure to sub-therapeutic levels. 
Systemic corticosteroid treatment must not be given during the study, except for stable doses of 
corticosteroid therapy such as dexamethasone and prednisone (e.g. for tumor associated symptoms) 
that are permitted during the course of the study. The corticosteroid dose must have been stabilized (or 
decreasing) for at least 5 days before initiating ceritinib therapy or 2 weeks when used for CNS related 
symptoms. High dose pulses of steroids are not allowed. 
Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local 
injections (e.g. intra-articular) are allowed. 
Bisphosphonates 
The use of bisphosphonates regardless of indication is allowed provided patients have been on stable 
doses for at least 4 weeks prior to the start of treatment.  Patients requiring initiation of bisphosphonate 
treatment during the course of the study should be evaluated for progressive disease (result of 
evaluation should be clearly documented in the patient’ source documentation) and will be subject to 
the same evaluation for stereotactic radiation to those areas. If the disease can be effectively controlled 
with radiation, initiation of bisphosphonates will be allowed. If bone involvement requires a change in 
systemic the patient will be recorded as having undergone progressive disease. 
No drug-drug interaction is expected between LDK378 and bisphosphonates as the two drugs are 
eliminated through different elimination pathways. Bisphosphonates are not inhibitors of human CYP450 
enzymes involved in the metabolism of LDK378 and do not undergo metabolism in vivo. 
The same guidelines apply to the use of denosumab for the treatment of bone metastatic disease 
4.4.1.2 
Drugs that are metabolized by CYP450 enzymes 
In vitro drug metabolism studies show that the metabolism of ceritinib is mediated by CYP3A4/5. Ceritinib 
is a time-dependent CYP3A4/5 inhibitor and is also a potent reversible inhibitor of CYP2A6, 2B6, 2C8, 
2C9 and 3A4/5 and may consequently increase exposure to drugs metabolized by these enzymes. 
Clinical studies have not yet been performed to confirm the potential effect of ceritinib onsubstrate drugs 
metabolized by these enzymes in patients. Also, the potential effect of low and moderate CYP3A4/5 
inhibitors and inducers on ceritinib clearance is not known. 
Concomitant treatment of ceritinib with weak inhibitors or inducers of CYP3A4/5 is permitted. Caution is 
advised when ceritinib is co-administered with drugs that are moderate inhibitors or inducers of 
CYP3A4/5 (Appendix 1). Duration of concomitant treatment should be kept as short as possible, or 
completely avoided whenever possible. Patients receiving such medications must be monitored closely 
for any potentiation of toxicity or decrease of clinical benefit due to any individual concomitant 
medications, and may require dose titration or adjustment. Note that co-administration of ceritinib with 
strong inducers or inhibitors of CYP3A4/5 is prohibited (Section 4.4.2.5). 


 
 
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Concomitant treatment of ceritinib with medications known to be metabolized by CYP2A6, 2B6, 2C8 and 
2C9 is allowed with caution (Appendix 1), except for drugs which have narrow therapeutic 
index/sensitive substrates for these CYP isoforms (Section 4.4.2.6 and Appendix 1). 
 
4.4.1.3 
Non-enzyme inducing anti-epileptic drugs 
Non-enzyme inducing anti-epileptic medication (Non-EIAED) is allowed. 
4.4.1.4 
Gastric protection agents 
The use of gastric protection agents including antacids, H2-antagonists, and proton pump inhibitors 
(PPIs; Appendix I) is allowed. However, PPIs should be used with caution due to the theoretical effects 
of long-acting pH elevating agents (i.e., prolonged acid suppression) on reducing ceritinib absorption. 
When the concurrent use of a H2-antagonist or an antacid with ceritinib is necessary, the H2 blocker 
must be administered 10 hours before or 2 hours after the ceritinib dose, and the antacid must be 
administered 2 hours before or 2 hours after the ceritinib dose. Time restrictions for the concurrent use 
of PPIs and ceritinib are not applicable due to the long-acting effects of PPIs on gastric pH (i.e., 
separation of doses will not likely impact this interaction). 
 
4.4.2 
Prohibited concomitant therapy with ceritinib 
4.4.2.1 
Other anticancer therapy 
Anticancer therapy (chemotherapy, targeted therapy or biologic therapy, and anti-cancer surgery) other 
than the ceritinib treatment must not be given to patients while they are enrolled in the treatment portion 
of the trial. If such agents are required then the patient must be permanently discontinued from the 
treatment portion of the study. 
The only radiation permitted will be SABR therapy given at the study institution as part of the trial. No 
other radiation will be allowed for patients.  
4.4.2.2 
Other investigational therapies 
Other investigational therapies must not be used while the patient is on the study. 
4.4.2.3 
Warfarin and coumadin derivatives  
Warfarin sodium or any other coumadin-derivative anticoagulants are not permitted. Ceritinib is an 
inhibitor of CYP2C8 and 2C9, the major metabolizing enzyme of warfarin. A clinically relevant increase 
in warfarin exposure is possible. Anticoagulants not derived from warfarin are allowed (eg, dabigatran, 
rivaroxaban, apixaban). 
4.4.2.4 
Enzyme inducing anti-epileptic drug (EIAED) 
Use of EIAEDs is not permitted. Refer to Appendix 1 for a list of prohibited EIAED. 
If a patient is currently taking an EIAED, he/she must have discontinued the EIAED therapy for at least 
1 week prior to starting ceritinib treatment. 
If a patient was previously on a non-EIAED and needs to permanently change anticonvulsant agent but 
cannot change to another non-EIAED, the patient will be taken off ceritinib. 


 
 
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4.4.2.5 
Strong CYP3A inhibitors and inducers 
In vitro metabolism studies suggest that oxidative metabolism of ceritinib is predominantly mediated by 
CYP3A4/5. 
Strong inhibitors or inducers of CYP3A4/5 are prohibited. Patients receiving concomitant medications 
known to strongly inhibit and/or induce CYP3A4/5 that are deemed medically necessary should be 
excluded from the study. Refer to Appendix 1 for a list of these medications. Please note that this list 
may not be comprehensive. 
4.4.2.6 
Medications that are CYP2C8, CYP2C9 and CYP3A4/5 substrates with narrow 
therapeutic index 
Ceritinib is a potent inhibitor of drugs metabolized by the cytochromes CYP2C8, CYP2C9 and CYP3A4/5 
in vitro. Because of the potential risk for drug-drug interactions, using medications known to be 
metabolized by these enzymes and that have a narrow therapeutic index is not permitted concomitantly 
with ceritinib. Refer to Appendix 1 for a list of these medications. Please note that this list may not be 
comprehensive. 
4.4.2.7 
Herbal medications 
Herbal preparations/medications are not allowed throughout the study, as a potential drug-drug 
interaction is always possible. These herbal medications include, but are not limited to: St. John’s wort, 
Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, 
and ginseng. 
Patients should stop using herbal medications at least 7 days prior to first dose of ceritinib treatment. 
4.4.2.8 
Medications that may prolong the QT interval or have a known risk of inducing 
Torsades de Pointes 
Ceritinib has potent activity on the hERG channel with an IC50 of 0.4 μM. However, there were no 
ceritinib-related effects in vivo in monkeys at doses as high as 100 mg/kg (human equivalent dose (HED) 
of 1950 mg). Preliminary data from patients treated in the phase 1 study ([CLDK378X2101]) at doses of 
50-750 mg suggest that ceritinib may have an effect on the QT interval. One patient (700 mg QD dose; 
<1%) had a QTc > 500 ms and 9 patients had an increase from baseline QTc > 60 ms. 
Concomitant administration of ceritinib with drugs known to have a high risk of increasing the QTc 
interval and drugs known to increase the QTc interval that are also primarily metabolized by CYP3A4/5 
should be avoided. Concomitant use of ceritinib and any medication included in Appendix 1 titled “List 
of prohibited QT prolonging drugs” (i.e., drugs that are generally accepted by the Qtdrugs.org Advisory 
Board of the Arizona CERT to have a known risk of causing Torsades de Pointes) is not permitted. 
 
4.5 
Patient numbering, treatment assignment or randomization  
4.5.1 
Patient numbering 
Each patient will be assigned a subject number at the time of screening which shall be the primary 
identifier for the patient throughout the entire trial. This number will not be reassigned if a patient is not 
enrolled on to the therapeutic portion of the trial. Once assigned a number, the patient will not be given 
a new number if enrollment is delayed behind other patients.  


 
 
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4.5.2 
Treatment assignment 
Before the first dose of ceritinib, the investigator will confirm that the patient meets all eligibility criteria. 
The patient will be assigned to the treatment arm and the Investigator or delegate will update the trial 
record accordingly.  
4.5.3 
Treatment blinding 
Not applicable. 
 
4.6 
Study drug administration 
The investigator and delegates, as well as other study personnel will instruct the patient to take ceritinib 
according to protocol. This will only be after confirmation by the investigator or co-investigator that the 
patient is to continue and has received instructions on how to take the medicine per protocol. 
For patients that are unable to swallow capsules, administration can occur through a nasogastric (NG) 
or gastric (G) tube: 
1. Put on gloves and mask before opening containers. Take the appropriate number of capsules that 
are needed, out of the containers. 
2. Place a glass bowl in an area with smooth surfaces that is easy to clean. 
3. Carefully open each capsule, one at a time, and pour or tip the contents out of each capsule in the 
glass bowl. 
4. Carefully check to make sure that both parts of each capsule are empty. Some of the contents may 
stick to the inside of the capsules. If this happens, use a toothpick (or similar tool) to remove the stuck 
contents into the glass bowl; work over the bowl. 
5. Fill the glass bowl with at least 40 mL (eight teaspoons) of water. If taking a dose that is 200 mg or 
less, then use at least 20 mL (four teaspoons of water). 
6. Mix the drug powder with water carefully with the spoon. 
7. Put the end of the syringe in the glass bowl and slowly pull back on the plunger drawing the mixture 
into the syringe. 
8. Make sure patient is sitting relatively upright, connect the syringe to the patient’s NG or G-tube and 
empty the mixture by slowly pushing the plunger into the syringe until all contents are empty. 
9. Repeat steps 7-8 if necessary, making sure the entire dose is administered. 
10. Once the entire dose is given, rinse the tube by syringing in 20 mL (four teaspoons) twice. If dose 
is 200 mg or less, then use at least 10 mL (two teaspoons) of water twice for rinsing. 
11. Dispose empty capsule shells, mask and gloves as per the hospital or institutions’ guidelines 
 
4.6.1 
Study drug compliance  
4.6.1.1 
Study drug compliance 
At each visit, the patient’s compliance in study medication according to protocol will be assessed by the 
investigator and/or study personnel. This information will be entered into the Drug Accountability Form 
and captured into the source document at each visit, in their medication diary. 


 
 
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5.0 
Visit schedule and assessments 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for therapy on this study 
will be done only after obtaining informed consent. Assessments performed for clinical 
indications (not exclusively to determine study eligibility) may be used for baseline 
values even if the studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 30 days prior to registration unless 
otherwise stated. The screening procedures include: 
5.1.1 Informed Consent 
Screening assessments to confirm eligibility will be performed as per the schedule of assessments. 
Documented Informed consent must be obtained before any study specific procedure will be performed. 
 
For treatment on the trial, the patient must have a documented ALK abnormality either by sequencing 
or assay and meet the remainder of the eligibility criteria. This must be done at the treating center and 
all study required testing must be completed within the 30 day period prior to day of initiating therapy. 
 
Re-screening of patients will be allowed, if all entry criteria are met during the re-screening phase time 
period (-30 days to -1 day). 
5.1.2 Medical history 
Complete medical and surgical history, history of infections 
5.1.3 Demographics 
Data to be collected on patient characteristics at screening include: 
 
-Demography (including: date of birth, age, patient initials, gender, childbearing potential, race and 
ethnicity, or as allowed by local regulations) 
 
-lung adenocarcinoma diagnosis and extent of disease, including: 
Date of diagnosis 
Site of active disease 
Prior antineoplastic therapies (medications, radiation, surgeries) 
Prior and Concomitant Medications, surgical and medical procedures 
 
All other medications taken within 30 days before the first dose of ceritinib treatment is administered will 
be noted in the clinical trial medication record and updated on a continual basis if there is new change 
to the medication. 
 
5.1.4 Review subject eligibility criteria  
According to section 3 


 
 
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5.1.5 Review previous and concomitant medications 
5.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
5.1.7 Performance status 
Performance status evaluated prior to study entry  
5.1.8 Adverse event assessment 
Baseline adverse events will be assessed. See section 7.1 for Adverse Event 
monitoring and reporting. 
5.1.9 Hematology 
 Hgb, platelets, white blood cells (WBC), red blood cells (RBC), differential 
(basophils, eosinophils, lymphocytes, monocytes, neutrophils (% or absolute)) 
5.1.10 
Serum chemistries and coagulation 
Albumin, ALT, AST, calcium, creatinine, total bilirubin, direct bilirubin (only if 
total bilirubin is ≥ grade 2), blood urea nitrogen (BUN) or urea, magnesium, 
potassium, sodium, glucose, phosphate (inorganic phosphorus), alkaline 
phosphatase, GGT, lipase, amylase. Creatinine clearance will be calculated 
using the serum creatinine value. Coagulation tests will be Prothrombin Time 
(PT) and Partial Thromboplastin Time. 
5.1.11 
Immune profile 
M1/M2/VEGFR2 macrophages, NK cells, CD4/CD8 ratio, ALK in immune cells 
and others 
5.1.12 Urinalysis 
Macroscopic panel (dipstick)(color, total bilirubin, blood, glucose, ketones, leukocyte esterase, nitrite, 
pH, protein, specific gravity, urobilinogen)  
Microscopic panel (RBC, WBC, casts, crystals, bacteria, epithelial cells) 
5.1.13 ECG 
A standard 12 lead ECG should be used for assessments. 
5.1.14 Pregnancy test (for females of child bearing potential) 
At screening visit, serum pregnancy test will be performed. Following the screening assessment, urine 
pregnancy tests should be performed. 
5.1.15 Tumor assessment 
To be performed using radiographic imaging according to section 5.3.1. 


 
 
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5.1.16 Follow-up after Treatment 
The study team will attempt to collect survival status and new therapy information for patients who are 
enrolled. Public sources may be searched for survival status information.  
5.2 
Protocol flow and visit schedule 
Table 5-1 lists the protocol schedule and assessments and indicates when particular assessments will 
be performed with an “X”. The cycle length is fixed at 28 days, and will be maintained regardless of 
whether there were dose modifications or interruptions in therapy. If treatment with ceritinib is 
interrupted, future visits and assessments will continue as listed from cycle 1 day as Day#1 for the 
purpose of scheduling. Screening procedures may overlap with Cycle 1 Day 1 procedures only if all 
eligibility criteria is met and confirmed prior to dosing. A physician visit is not needed on C1D1 if 
performed within 7 days prior to starting treatment. In this case, delegated study personnel may assess 
performance status (WHO) on Cycle 1 Day 1.There will be variation of up to +/- 3 days allowed in visits 
and assessments.  A delay of Cycle Day 1 for subsequent cycles beyond cycle 2, due to holiday, 
inclement weather, or other unforeseen circumstances will be permitted for a maximum of 7 days. 


 
 
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Table 5-1  
Visit evaluation Schedule 
Protocol 
Section 
ALK 
abnormality 
Screening / 
Baseline 
Day 1 of 
Cycle 1 
(28d) +/-3 
Day 15 of 
Cycle 1 
(28d) +/-3 
Day 1 of 
Cycle 2 
(28d) +/-3 
Day 1 of 
Subsequent 
cycles 
(28d) +/-3 
End of study 
treatment (EoT) 
(at last visit, or 
up to 30 days 
f
)
Long Term 
Follow up Q3 
mo following 
EOT   
Visit Number 
 
1 
2 
3 
4 
5, 6.. 
Last 
Day of cycle 
  
-180 to -1 
-30 to -1 
D1 
D15 
D29 
D57, D85.. 
Last 
Obtain Informed Consent 
ICF 
X 
X 
Patient history 
 
Inclusion/exclusion criteria 
3.2 & 3.3 
 
X 
Documentation of ALK/ positivity by 
sequencing, FISH or IHC 
5.1.1 
X 
X 
Diagnosis and extent of cancer 
5.1.2 
 
X 
Demography 
5.1.3 
 
X 
Relevant medical history/current 
medical conditions 
5.1.4 
 
X 
Prior antineoplastic therapy 
(meds, surgery, radiation) 
5.1.5 
 
X 
Prior/concomitant medications 
5.1.5 
 
X 
Continuous 
 
Surgical and Medical Procedures 
4.4 
 
X 
Continuous 
 
Eligibility Screening  
5.1.4 
 
X 
End of Phase Disposition 
5.1.1.
1 and 
5.1.3 
 
X 
Screening 
Phase 
Disposition  
X 
End of Treatment 
Phase  
 
Physical examination 
5.1.6 
 
X 
 
X 
X 
X 
Performance status (WHO) 
5.1.7 
 
X 
X 
 
 
X 
X 
Height 
5.1.6 
 
X 
Weight 
5.1.6 
 
X 
X 
 
X 
X 
X 
Vital signs 
5.1.6 
 
X 
X 
 
X 
X 
X 
Survival Assessment 
5.1.16 
 
 
 
 
 
X 
 


 
 
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                                       47 
 
 
Table 5-1. 
Visit evaluation Schedule 
(continued) 
Protocol 
Section 
ALK 
abnormality 
Screening / 
Baseline 
Day 1 of Cycle 1
(28d) +/- 3 
Day 15 of 
Cycle 1 (28d) 
+/-3 
Day 1 of Cycle 
2 (28d) +/- 3 
Day 1 of 
Subsequent 
cycles 
(28d) +/- 3 
End of 
study 
treatment 
(EoT) (at 
last visit, 
or up to 
30 d
Long 
Term 
Follow Up 
Q3 mo 
following 
EOT 
Visit Number 
 
1 
2 
3 
4 
5, 6,… 
Last 
Day of cycle 
-180 to -1 
-30 to-1 
1 
D15 
D29 
D57, D85.. 
Last 
Lab assessments* 
 
 
X 
X * 
X 
X 
X 
X 
CBC 
5.1.9 
 
X 
X 
X 
X 
X 
X 
Chemistry, lipase,  amylase 
5.1.10 
 
X 
X 
X 
X 
X 
X 
Coagulation 
5.1.10 
 
X 
 
 
 
 
Creatinine clearance 
5.1.10 
 
X 
 X 
Urinalysis (dipstick) with 
microscopic analysis 
5.1.12 
 
X 
 X 
X 
Immune profile/correlatives,  
5.1.11 
 
 
X 
X 
 
X(Cycle 3 and 6 
only)) 
X 
circulating biomarker levels, resistance 
markers, CTC biomarker analysis 
5.1.11 
 
 
X 
X 
 
X (Cycle 3 and 6 
only) 
X 
Pregnancy test 
5.1.14 
 
X 
 
 
X 
X 
X 
Imaging 
Standard of care imaging of 
neck/chest/abdomen (CT, MRI) as 
indicated to areas of known/ suspected 
disease 
5.2.1 
 
X 
 
 
 
X (Every 2 cycles 
or 8 weeks) 
Standard of Care Imaging of the brain as 
clinically indicated (MRI/CT) 
5.2.1 
 
X (if known or 
suspected brain 
metastases) 
 
 
 
X  
(every 12 weeks 
or 3 cycles) 
Safety 
 
Adverse events 
7.1 
 
X 
Continuous 
 
ECG 
5.1 
 
X 
X 
 
X 
X (Every even 
cycle) 
X 
Drug administration 
4.1 
Continuous 


 
 
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 * Baseline laboratory assessments must be performed on Cycle 1 Day 1 or within 24 hours prior to dosing. 
• 
Please refer to Table 5-3 for local Clinical laboratory parameters 


 
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5.2.1 
Screening/Baseline 
Screening assessments to confirm eligibility will be performed as per the schedule of 
assessments. Documented Informed consent must be obtained before any study specific procedure will 
be performed.  
 
The patient must have a documented ALK abnormality either by sequencing or assay and meet the 
remainder of the eligibility criteria. All study required testing must be completed within the 30 day period 
prior to day of initiating therapy. 
 
Re-screening of patients will be allowed, if all entry criteria are met during the re-screening phase time 
period (-30 days to -1 day). 
5.2.1.1 
Biomarker required for Eligibility on this trial arm 
Patient eligibility will be checked once all screening procedures are completed. 
5.2.1.1.1 
ALK positivity 
Histologically or cytologically confirmed diagnosis of lung adenocarcinoma with ALK positivity will be 
required to be considered eligible for the therapeutic portion of the trial. ALK testing will be via: 
i. 
FISH test for ALK rearrangement using the FDA-approved FISH test (Abbott Molecular Inc), 
using Vysis breakapart probes (defined as 15% or more positive tumor cells). or  
ii. 
ALK positivity by protein expression, as determined by positive immunohistochemistry (IHC) 
assay. or 
iii. 
Next generation sequencing using a CLIA certified laboratory demonstrating positivity for 
ALK translocations.  
Documentation of ALK positivity using one of the above tests is required. 
5.2.1.2 
Patient demographics and other baseline characteristics 
Data to be collected on patient characteristics at screening include: 
 
-Demography (including: date of birth, age, patient initials, gender, childbearing potential, 
race and ethnicity, or as allowed by local regulations) 
 
-Relevant medical history 
 
-lung adenocarcinoma diagnosis and extent of disease, including: 
Date of diagnosis 
Site of active disease 
Prior antineoplastic therapies (medications, radiation, surgeries) 
Prior and Concomitant Medications, surgical and medical procedures 
 
All other medications taken within 30 days before the first dose of ceritinib treatment is administered will 
be noted in the clinical trial medication record and updated on a continual basis if there is new change 
to the medication. 
5.2.1.3 
Information to be collected on screening failures 
 
A patient who signs an informed consent but fails to satisfy all eligibility criteria for any 
reason will be considered a screen failure. The reason for not entering the treatment protocol will be 
recorded. The demographic information, informed consent, and Inclusion/Exclusion pages will be 
completed for Screen Failure patients. No other data will be entered into the clinical database for patients 


 
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who are screen failures, unless the patient experienced a Serious Adverse Event during the Screening 
Phase (see Section 7 for SAE reporting details). 
 
Subjects who signed ICF but are considered ineligible after signing the study consent will be 
considered as screening failures, and data will be handled in the same manner. 
 
The following information will be recorded for screening failure patients: 
 
-Screening Phase Disposition page (including reason for not satisfying eligibility criteria 
and being started on treatment). 
-Informed consent. 
-Demography. 
-Adverse Events (only if an SAE occurs). 
-Inclusion/Exclusion Criteria. 
 
5.2.2 
Treatment period 
Following completion of screening procedures and verifying patient eligibility, the patient 
will be approved for treatment  per protocol. 
 
The study treatment phase begins on Cycle 1, Day 1 with the first administration of ceritinib and will 
continue to receive ceritinib treatment until disease progression by RECIST1.1  not amenable to SABR 
necessitating a change in systemic therapy, unacceptable toxicity, withdrawal of consent, or 
discontinuation of the trial for any other reason whichever occurs first.  Patients who have RECIST-
defined PD as assessed by the investigator but who, in the opinion of the investigator, have evidence of 
continued clinical benefit from ceritinib may continue to receive the study medication upon approval by 
the principal investigator. In such cases, these patients must continue to be followed for safety and 
efficacy assessments as per the schedule of assessments.  Patients will be assessed as per visit 
schedule in Table 5-1. 
 
There is a visit windows of ± 3 days for scheduled study assessments. 
5.2.3 
End of treatment visit including study completion and premature withdrawal 
5.2.3.1 
End of Phase Disposition 
Patients will be evaluated upon discontinuation of the ceritinib by a clinic visit. At that time all 
assessments listed for End Of Treatment will be performed. A note will be entered into the clinical trial 
record will be completed, giving the date and reason for stopping the ceritinib treatment. 
At a minimum, all patients who discontinue ceritinib treatment, including those who refuse to return for 
a final visit, will be contacted for safety evaluations during the 30 days following the last dose of 
treatment. 
5.2.3.2 
Criteria for patient withdrawal 
Patients may voluntarily withdraw from the study (no further study data to be collected) at any time. 
Patient death will be considered as a withdrawal from the study. Patients may also be withdrawn (the 
physician may decide to remove the patient from any further study activity) if any of the following occur: 
• 
Adverse event(s) (see Section 7.1) 
• 
Disease progression 
• 
Major protocol deviation 
• 
Technical problems 
• 
Physician decision 


 
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• 
Non-compliance with study treatment. 
• 
Death 
• 
Completed 
Patients must be withdrawn if any of the following occur: 
• 
Lost to follow-up 
• 
Subject/guardian decision 
• 
Pregnancy (Pregnancy will be followed for outcome) 
 
Patients lost to follow up should be recorded as such in the clinical trial record. For patients who are lost 
to follow-up, the investigator will record the attempts at “due diligence” by documenting in the source 
documents steps taken to contact the patient, e.g. dates of telephone calls, registered letters, etc. 
5.2.3.3 
Replacement policy 
If an eligible patient is unable to start therapy with ceritinib, they may be replaced with another eligible 
patient if they have not received any study drug. 
Apart from the above, patients will not be replaced on this study.  
 
5.3 
Assessment types 
5.3.1 
Efficacy assessments 
Efficacy evaluations will be via revised RECIST 1.1 criteria on imaging performed at the conclusion of 
every 2 cycles. Target lesions will be identified prior to initiation of therapy on imaging and will be 
followed on subsequent imaging.  
Physical exam findings of progressive disease will be considered as sufficient for documented 
progression if the record records biopsy proven tumor measurements in 2 dimensions and shows an 
increase in both dimensions of 20%. If the progression is amenable to SABR, the patient will receive 
SABR and be maintained on ceritinib. If the progression is not amenable to SABR and a change in 
systemic therapy is needed, the patient will be considered to have progressed and have reached the 
end of the study. 
Imaging exams will be according to standard of care guidelines to areas of known/suspected disease. 
These will include CT of the neck, chest, abdomen and pelvis as well as MRI of the brain. Other tests 
may be clinically indicated, these will be ordered according to disease and patient specific guidelines. 
Imaging of the brain will be performed at baseline by CT or MRI per standard of care for lung 
adenocarcinoma. 
Subjects with known CNS metastases must have an MRI of the brain performed every 3 cycles while 
on study. If an MRI cannot be performed, CT of the brain would be an acceptable alternative. Subjects 
without documented CNS metastases will not have mandated CNS imaging requirements. 
5.3.2 
Safety and tolerability assessments 
 
Safety will be monitored by the assessments described below as well as the collection of AEs 
at every visit. For details on AE collection and reporting, refer to Section 7. Significant 
findings that were present prior to the signing of informed consent must be included in the 
relevant medical history/current medical conditions in the clinical trial record. Significant 
new findings that begin or worsen after informed consent must be recorded in the clinical trial record. 


 
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5.3.2.1 
Physical examination 
Physical examinations will include an examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, and a basic nervous system evaluation. Information about the physical examination will be 
present in the source documentation. For the assessment schedule refer to Table 5-1. 
Significant findings that were present prior to the signing of informed consent must be 
included in the clinical trial record. Significant new findings that begin or worsen after informed consent 
must be recorded in the clinical trial record. 
5.3.2.2 
Vital signs 
Vital signs include body temperature, blood pressure and pulse measurements. Blood pressure 
(systolic and diastolic) and pulse should be measured. 
For the assessment schedule refer to Table 5-1. 
5.3.2.3 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured. Height will be measured at screening only.  
For the assessment schedule for weight refer to Table 5-1. 
5.3.2.4 
Performance status 
WHO performance status will be assessed as per the assessment schedule (refer to Table 5-1). 
Assessment of WHO performance status (Table 5-2) will be performed within the time 
windows described above of the scheduled assessment, even if ceritinib medication is being 
held. More frequent examinations may be performed at the investigator’s discretion, if medically 
indicated. 
 
 
Table 5-2 
WHO Performance status scale 
Score 
Performance 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 housework, 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 
5 
Dead 
5.3.2.5 
Laboratory evaluations 
 
Local site laboratories will be used for the analysis of scheduled hematology, biochemistry, 
urine, and other blood specimens collected as part of safety monitoring. All unscheduled 
blood testing will be performed locally, with exceptions for emergency conditions. The time windows 
granted for laboratory evaluations are identical to the corresponding visit time windows for each visit 
(refer to Section 5.1). 
Laboratory abnormalities that are considered clinically significant, induce clinical signs or 


 
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symptoms, require concomitant therapy or require changes in ceritinib treatment  constitute an 
adverse event (AE) and must be reported as an AE in the clinical trial record. 
Laboratory values obtained at the screening visit will be used to assess eligibility to meet inclusion 
criteria. In addition, eligible patients must have baseline laboratory assessments performed on Cycle 1 
Day 1 or within 24 hours prior to dosing. 
 
5.3.2.5.1 Hematology 
Hematology assessments of the parameters listed in Table 5-3 will be tested as per the schedule of 
assessments (Table 5-1). 
 
Table 5-3 
Local Clinical laboratory parameters collection plan 
Test 
Category 
Data 
Results 
Test Name 
Hematology 
 
Hgb, platelets, white blood cells (WBC), red blood cells (RBC), 
differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils (% or absolute)) 
Chemistry 
 
Albumin, ALT, AST, calcium, creatinine, total bilirubin, direct 
bilirubin (only if total bilirubin is ≥ grade 2), blood urea nitrogen 
(BUN) or urea, magnesium, potassium, sodium, glucose, 
phosphate (inorganic phosphorus), alkaline phosphatase, GGT, 
lipase, amylase 
Coagulation 
 
PT/PTT 
Creatinine 
clearance 
 
Creatinine clearance 
Urinalysis 
 
Macroscopic panel (dipstick)(color, total bilirubin, blood, glucose, 
ketones, leukocyte esterase, nitrite, pH, protein, specific gravity, 
urobilinogen)  
Microscopic panel (RBC, WBC, casts, crystals, bacteria, epithelial 
cells) 
Pregnancy 
test 
 
For women of childbearing potential : 
At screening visit, serum pregnancy test 
At subsequent cycles, urinary pregnancy test. 
If local requirements dictate otherwise, local regulations should be 
followed 
5.3.2.5.1 
Hematology 
Hematology assessments of the parameters listed in Table 5-3 will be tested as per the schedule of 
assessments (Table 5-1). 
5.3.2.5.2 
Clinical chemistry and Creatinine clearance 
Clinical chemistry and Creatinine clearance assessments of the parameters listed in Table 5-3 will be 
tested as per the schedule of assessments (Table 5-1). 
5.3.2.5.3 
Urinalysis 
Dipstick measurements will be performed as per Table 5-3 and according to the schedule of 
assessments (Table 5-1). Any significant findings on dipstick will be followed up with microscopic 
evaluation as per Table 5-3. 
5.3.2.5.4 
Pregnancy and assessments of fertility 
During screening, a serum pregnancy test will be completed. Starting on day 1 of Cycle 2, and at EOT, 
urinary pregnancy test (dipstick) will be performed. The time windows granted for pregnancy testing are 


 
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identical to the corresponding visit time windows for each visit. If local requirements dictate otherwise, 
local regulations should be followed. 
Women who are determined not to be of child bearing potential before the study will only be tested at 
screening. When non-child bearing potential status is determined during the study, further pregnancy 
testing will not be continued. Women are considered post-menopausal if they have had 12 months of 
natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of 
vasomotor symptoms), and otherwise not of child bearing potential if they have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment is she considered not of child bearing potential. 
The time windows granted for pregnancy testing are identical to the corresponding visit time windows 
for each visit.  
If a positive pregnancy test is performed in between study visits, the patients must immediately notify 
the investigator. 
 
5.3.2.6 
Translational analysis 
To analyze the immunologic impact of SABR and ceritinib, 16 ml of whole blood (8ml X 2 tubes) will be 
drawn from patients into BD Vacutainer Whole Blood Tube, ACD A, (Yellow, 8.5 mL), at Cycle 1 Day 1, 
Cycle 1 Day 15, Cycle 3 and Cycle 6 day 1, and end of treatment.  
For circulating ALK biomarker and resistance mechanism analysis, 30 ml of whole blood (10 X 3 tubes) 
will be drawn into Streck CELL-FREE DNA BCT® at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 and Cycle 
6 day 1, and end of treatment. Plasma will be processed and frozen for ALK and resistance mechanism 
analysis. CTCs will be enriched and captured and interrogated for biomarker analysis.  
Blood will not be drawn if the investigator is concerned that doing so may harm the patient. 
5.3.2.7 
Cardiac assessments 
5.3.2.7.1 
Electrocardiogram (ECG) 
A standard 12 lead ECG should be used for assessments. 
All ECGs will be performed locally and reviewed by investigator prior to ceritinib treatment 
administration. Please refer to Table 5-4 for cardiac assessment monitoring schedule. 
 
Table 5-4 
ECG collection plan 
Cycle 
Day of 
cycle 
ECG monitoringa 
 
Screeningb 
1 single ECG 
Cycle 1 
1 
Pre-dose: 3 sequential ECGs separated by at least 2-4 minutes 
 
Cycle 2 
1 
Pre-dose: 1 single ECG 
Even 
numbered 
cycles 
(4,6,8…) 
1 
Pre-dose: 1 single ECG 
EOT 
N/A 
1 single ECGs recorded 


 
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a Refer to Table Criteria for interruption and re-initiation of ceritinib treatment for the recommended 
dose modifications due to QTc interval prolongation 
b The screening ECGs will be reviewed by investigator for eligibility of the patient. (Note: the mean 
QTc interval at baseline must be ≤ 450msec for the patient to be eligible for participation in the trial) 
Note: Additional monitoring performed at the Investigator’s discretion, if medically indicated. 
Interpretation of the tracing must be made by a qualified physician and documented. Clinically significant 
abnormalities present when the patient signs the informed consent should be reported. New or worsened 
clinically significant findings occurring after informed consent must be recorded. 
 
6.0 
Measurement of Effect 
6.1 
Antitumor Effect- Solid Tumors 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 
criteria. 
6.1.1 
Definitions 
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of 
their first treatment with study drug. 
 
Evaluable for objective response.  Only those subjects who have measurable 
disease present at baseline, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for 
response. These subjects will have their response classified according to the 
definitions stated below. (Note: Subjects who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
6.1.2 
Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as >20 mm with conventional techniques (CT, MRI, x-ray) or as >10 
mm with spiral CT scan. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Note: Previously irradiated lesions are non-measurable except in cases of 
documented progression of the lesion since the completion of radiation 
therapy. 
 
Non-measurable disease. All other lesions (or sites of disease), including 
small lesions (longest diameter <20 mm with conventional techniques or <10 
mm using spiral CT scan), are considered non-measurable disease. Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses 
(not followed by CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions. All measurable lesions up to a maximum of 3 lesions per 
organ and 6 lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline. Target 


 
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lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). A sum of the longest diameter (LD) for all 
target lesions will be calculated and reported as the baseline sum LD. The 
baseline sum LD will be used as reference by which to characterize the 
objective tumor response. 
 
Non-target lesions. All other lesions (or sites of disease) including any 
measurable lesions over and above the 6 target lesions should be identified 
as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence or absence 
of each should be noted throughout follow-up.  
6.1.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a 
ruler or calipers. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 30 days before 
the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-
up. Imaging-based evaluation is preferred to evaluation by clinical 
examination when both methods have been used to assess the antitumor 
effect of a treatment. 
 
Conventional CT and MRI. These should be performed with cuts of 10 mm or 
less in slice thickness contiguously. Spiral CT should be performed using a 5 
mm contiguous reconstruction algorithm.  
 
CT scans of the neck, chest, abdomen and pelvis will be performed at 
baseline and every two cycles according to standard of care. Other imaging of 
these areas such as PET/MRI will be allowed if CT cannot be performed. 
MRI of the brain will be performed at baseline and as clinically indicated. 
Wherever it can be safely given, radiographic contrast agents should be given 
for the imaging studies. 
 
6.1.4 
Response Criteria 
6.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, 
determined by two separate observations conducted not less than 4 
weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the 
baseline sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the 
LD of target lesions, taking as reference the smallest sum LD 
recorded since the treatment started, or the appearance of one or 
more new lesions. 
 


 
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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started. 
6.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions 
and normalization of tumor marker level. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or 
more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions 
6.1.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the 
start of the treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements 
recorded since the treatment started). The subject’s best response 
assignment will depend on the achievement of both measurement 
and confirmation criteria. 
 
 
Target 
Lesions 
Non-
Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Response for 
this Category 
Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. 
confirmation 
CR 
Non-
CR/Non-
PD 
No 
PR 
 
>4 wks. 
confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
Documented 
at least once 
>4 wks. from 
baseline 
PD 
Any 
    Yes or No 
PD 
 
no prior SD, 
PR or CR 
Any 
PD* 
     Yes or No 
PD 
Any 
Any 
 Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: 
Subjects with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration”. Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
Note: If subjects respond to treatment and are able to have their disease 
resected, the patient’s response will be assessed prior to the surgery. 


 
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6.1.5 
Duration of Response 
Duration of overall response: The duration of overall response is measured 
from the time measurement criteria are met for CR or PR (whichever is first 
recorded) until the first date that: 
i. recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since 
the treatment started) AND is amenable to SABR. This will be defined as time 
to subsequent SABR. 
ii. recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since 
the treatment started) and is NOT amenable to SABR. This will be defined as 
progression on systemic therapy. 
 
The duration of overall CR is measured from the time measurement criteria 
are first met for CR until the first date that recurrent disease is objectively 
documented. 
 
 
6.1.6 
Progression-Free Survival 
Progression Free Survival will be the primary endpoint for this study. If 
oligoprogression occurs that is amenable to repeat treatment with SABR, the 
ceritinib will be held and SABR therapy delivered. If the treating oncologist 
then feels the patient would benefit from continuing the ceritinib that will be 
permitted. The patient will however be have been deemed as having 
progressed even if ceritinib is resumed. 
 
After the initial SABR to persisting lesions if new lesions appear or if existing 
lesions enlarge but are NOT amenable to SABR (necessitating a change in 
systemic therapy), the patient will have completed the therapeutic portion of 
the study. 
Time to 2nd SABR is defined as the duration of time from the start of treatment 
to the time of development of new or enlarging lesions that are amenable to 
SABR and the progression does not require a discontinuation of ceritinib. 
 
Time to 3rd SABR is defined in patients who have already received two rounds 
of SABR while on this study as the duration of time from the start of treatment 
to the time of development of new or enlarging lesions that are amenable to 
SABR and the progression does not require a discontinuation of ceritinib. 
 
7.0 
Adverse events 
7.1.1 
Contraindications: 
 Known allergy to ceritinib, no specific contraindications listed in package insert. 
7.1.2 
Special Warnings and Precautions for Use:  
Cardiac: symptomatic bradycardia can occur with heart rate <50/min. If possible, will avoid concurrent 
use of agents that may cause bradycardia (eg, beta blockers, nondihydropyridine calcium channel 
blockers, clonidine, digoxin). Will monitor heart rate and blood pressure regularly. Dose will be held for 
symptomatic bradycardia. 


 
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QTc prolongation: QTc interval prolongation has occurred in clinical studies, and may be concentration-
dependent. Will periodically monitor ECG and electrolytes in patients with heart failure, 
bradyarrhythmias, electrolyte abnormalities, or who are taking medications known to prolong the QTc 
interval. May require treatment interruption, dosage reduction, or discontinuation. Will permanently 
discontinue in patients who develop QTc interval prolongation in combination with torsades de pointes 
or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia. 
Gastrointestinal toxicity: Diarrhea, nausea, vomiting, or abdominal pain occurred in the majority of 
patients in clinical trials; over one-third of patients required dose reductions due to severe or persistent 
gastrointestinal toxicity. Symptomatic management will be with antiemetics and antidiarrheals. 
Hepatotoxicity: Hepatotoxicity has been observed in patients treated with ceritinib in clinical trials, 
including ALT levels >5 times ULN in over one-quarter of patients.  
Hyperglycemia: Hyperglycemia, including grade 3 and 4 toxicity, has been observed in ceritinib-treated 
patients. Close monitoring of blood sugars in patients with baseline random blood sugar greater than 
180, with addition of insulin or other medication to correct hyperglycemia. 
Pulmonary toxicity: Severe and life-threatening interstitial lung disease (ILD)/pneumonitis (some fatal) 
may occur. Monitor for signs/symptoms of pulmonary toxicity; permanently discontinue in patients 
diagnosed with treatment related ILD/pneumonitis. 
 
7.1.3 
Interaction with other medications 
CYP3A inducers and inhibitors: these should be avoided while patients are receiving ceritinib. If a strong 
CYP3A inhibitor must be given concurrently, the dose of ceritinib should be reduced. Similarly concurrent 
administration of substrates of CYP3A and CYP2C9 should also be avoided. 
Please note Section 14.1 for a full list of medications that require caution. 
7.1.4 
Adverse Reactions 
In the dose escalation phase patients were treated on a once daily schedule at the following dose levels: 
50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg and 750 mg. The MTD was 
determined to be 750 mg daily. Following determination of the MTD in May-2012 the expansion part of 
the study opened at the 750 mg daily dose level.  
During the dose escalation part of the study, first cycle dose-limiting toxicities (DLTs) that contributed to 
the definition of the MTD included hypophosphatemia (400 mg), ALT elevation (400 mg), nausea with 
dehydration (600 mg), diarrhea (600 mg and 750 mg), and vomiting (750 mg). There were 3 cases of 
grade 3 hypophosphatemia, one of which was a DLT that contributed to the MTD determination – this 
patient was able to continue ceritinib at the same dose. In all cases patients were able to continue 
therapy without dose modification. Hypophosphatemia was not among the most commonly reported AEs 
(i.e., < 10%), regardless of relationship to ceritinib treatment. 
The majority of adverse events, regardless of relationship to study drug, have been Grade 1-2, and have 
not required dose interruption or reduction. The most common adverse events were gastrointestinal 
toxicities, including nausea, diarrhea and vomiting, occurring in 72.7%, 72.7%, and 55.5% of patients, 
respectively. Other adverse events occurring in more than 20% of patients included fatigue (30.9%), 
abdominal pain (27.3%), decreased appetite (25.9%), ALT increased (25.0%) and constipation (21.4%). 
Grade 3 and 4 adverse events were much less common, with none occurring in 16% or more of patients. 
ALT increase, AST increase and diarrhea were the most common grade 3 or 4 events, occurring in 


 
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15.5%, 7.3% and 5.9% of patients, respectively. All other grade 3 or 4 events occurred in less than 5% 
of patients. 
Preliminary ECG data from 220 patients treated at doses of 50-750 mg suggest that ceritinib may have 
an effect on the QT interval. One patient (700 mg QD dose; <1%) had a QTc > 500 msec and 2 (1.6%) 
patients (1 at 700 mg QD dose, 1 at 750 mg QD dose) had an increase from baseline QTc > 60 msec. 
Interstitial lung disease/pneumonitis has been reported in some patients treated with ceritinib. Five cases 
improved or resolved with interruption of ceritinib and treatment with antibiotics and/or steroids. In one 
case, ceritinib was resumed at a reduced dose without recurrence of pneumonitis. Recurrent 
pneumonitis has also been reported following re-challenge of cases at a lower dose of ceritinib. Two 
fatal outcome of treatment-related pneumonitis has been reported.  
In summary, ceritinib has been generally well tolerated by patients with ALK-rearranged NSCLC at 
doses up to the MTD of 750 mg daily. GI toxicities are common, but they are generally grade 1-2, and 
resolve with holding ceritinib and reducing the dose in the setting of grade 3-4 events. 
 
7.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done 
to ensure the safety of subjects enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Adverse events are reported in a routine manner at scheduled times during a 
trial. Additionally, certain adverse events must be reported in an expedited manner to allow for optimal 
monitoring of subject safety and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study drug, will be 
monitored until:  
 
the adverse event resolves or the symptoms or signs that constitute the adverse event return 
to baseline;  
 
any abnormal laboratory values have returned to baseline;  
 
there is a satisfactory explanation other than the study drug for the changes observed; or 
 
death 
 
7.2.1 
Definition  
An adverse event is defined as any untoward or unfavorable medical occurrence in a human research 
study participant, including any abnormal sign (for example, abnormal physical exam or laboratory 
finding), symptom, clinical event, or disease, temporarily associated with the subject’s participation in 
the research, whether or not it is considered related to the subject’s participation in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events occur most 
commonly in the context of biomedical research, although on occasion, they can occur in the context 
of social and behavioral research. Adverse events may be expected or unexpected. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI Common 
Terminology Criteria for Adverse Events (NCI CTCAE) and version number specified in the protocol. 
Adverse events not specifically defined in the NCI CTCAE will be scored on the Adverse Event log 
according to the general guidelines provided by the NCI CTCAE and as outlined below.   
• 
Grade 1: Mild  
• 
Grade 2: Moderate 
• 
Grade 3: Severe or medically significant but not immediately life threatening 
• 
Grade 4: Life threatening consequences 
• 
Grade 5: Death related to the adverse event 


 
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Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, occurring at 
any dose, which meets any of the following criteria:  
• 
Results in death   
• 
Immediately life-threatening  
• 
Results in inpatient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity  
• 
Results in a congenital anomaly/birth defect  
• 
Based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above criteria. Serious 
adverse events may or may not be related to the research project. A serious adverse event 
determination does not require the event to be related to the research. That is, both events completely 
unrelated to the condition under study and events that are expected in the context of the condition 
under study may be serious adverse events, independent of relatedness to the study itself. As 
examples, a car accident requiring overnight hospitalization would be a serious adverse event for any 
research participant; likewise, in a study investigating end-stage cancer care, any hospitalization or 
death would be a serious adverse event, even if the event observed is a primary clinical endpoint of 
the study. Refer to the UTSW IRB website at 
http://www.utsouthwestern.net/intranet/research/research-administration/irb/study-
management/adverse-events.html to determine when a serious adverse event requires reporting to the 
IRB. 
Unanticipated Problems 
The term “unanticipated problem” is found, but not defined in the regulations for the Protection of 
Human Subjects at 45 CFR 46, and the FDA regulations at 21 CFR 56. Guidance from the regulatory 
agencies considers unanticipated problems to include any incident, experience, or outcome that meets 
each of the following criteria: 
• 
Unexpected (in terms of nature, severity or frequency) AND 
• 
Definitely, probably, or possibly related to participation in the research AND  
• 
Serious or a possible unexpected problem in that the research places subjects or 
others at greater risk of harm than was previously known or recognized. Note: Any serious adverse 
event would always suggest a greater risk of harm. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
7.2.2 
Reporting 
Local unanticipated problems require expedited reporting, and are submitted to the UTSW IRB through 
the UTSW eIRB and to the SCC DSMC Coordinator.  Hardcopies or electronic versions of the eIRB 
report; FDA Form #3500A forms, or other sponsor forms, if applicable; and/or any other supporting 
documentation available should be forwarded to the DSMC Coordinator.  The DSMC Coordinator 
forwards the information onto the DSMC Chairman who determines if immediate action is required.  
Follow-up eIRB reports, and all subsequent SAE documentation that is available are also submitted to 
the DSMC Chair who determines if further action is required. (See Appendix IV of the SCC DSMC 
Plan for a template Serious Adverse Event Form which may be utilized when a sponsor form is 
unavailable and SAE submission to the eIRB in not required). 


 
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All local serious adverse events which occur on research subjects on protocols for which the SCC is 
the DSMC of record require reporting to the DSMC regardless of whether IRB reporting is required. 
Hardcopies or electronic versions of the FDA Form #3500A forms, or other sponsor forms, if 
applicable; and/or any other supporting documentation available should be forwarded to the DSMC 
Coordinator.   
 
If the event occurs on this clinical trial coordinated by the Cancer Center, the DOT Manager or lead 
coordinator ensures that all participating staff are notified of the event and resulting action, according 
to FDA guidance for expedited reporting. DSMC Chairperson reviews all serious adverse events upon 
receipt from the DSMC Coordinator.  The DSMC Chairperson determines whether action is required 
and either takes action immediately, convenes a special DSMC session (physical or electronic), or 
defers the action until a regularly scheduled DSMC meeting.  
  
Telephone reports to: 
(Investigator: Sawsan Rashdan, office # 214 6484180, pager 972-229-3813) 
 
UTSW SCC Data Safety Monitoring Committee Coordinator (if fax report is not 
available) within 2 working days to 214-648-7097. 
 
Written reports to: 
(Investigator: Sawsan Rashdan, office fax # 214 6481955, 5323 Harry Hines Blvd, 
Dallas, TX 75390-8852) 
 
UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-7018 or deliver to NB 2.418 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation 
 
7.2.2.1 SAEs 
 
Local serious adverse events (SAEs) for studies where SCC DSMC is the DSMC of record require 
reporting to the DSMC coordinator within 2 working days of PI awareness, or as described in the 
protocol.   
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient has 
provided informed consent and until at least 30 days after the patient has stopped LDK378 treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAE experienced after this 30 days period should only be reported to Novartis if the investigator 
suspects a causal relationship to the LDK378 treatment. Recurrent episodes, complications, or 
progression of the initial SAE 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. 
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 send the 


 
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completed, signed form by FAX (1-877-778-9739) within 24 hours of learning of its occurrence along 
with Novartis SAE Report Fax Coversheet to the oncology Novartis Drug Safety and Epidemiology 
(DS&E) department. 
The original copy of the SAE Report Form and the fax confirmation sheet must be kept at the study site. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form was sent, 
using a new SAE Report Form stating that this is a follow-up to the previously reported SAE and giving 
the date of the original 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 LDK378 treatment, an oncology Novartis DS&E 
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 (EC) in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
 
 
 
7.2.2.2 Unanticipated Problems  
Local unanticipated problems require reporting to the UTSW IRB within 2 working days of PI 
awareness of the event.   
Unanticipated problems, including those that occur as non-local events, require reporting to the UTSW 
IRB within 10 working days of PI awareness of the event. 
For further guidance for Investigators regarding safety reporting requirements for INDs and BA/BE 
studies, refer to FDA Draft Guidance document: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227
351.pdf 
7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: 
Identify the type of adverse event using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE v4).  
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol treatment. Any 
event that occurs more than 30 days after the last dose of treatment and is attributed (possibly, 
probably, or definitely) to the agent(s) must also be reported accordingly. 
 
Step 4: 
Determine the prior experience of the adverse event.  


 
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Expected events are those that have been previously identified as resulting from administration of the 
agent. An adverse event is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in: 
• 
the current known adverse events listed in the Agent Information Section of this 
protocol; 
• 
the drug package insert; 
• 
the current Investigator’s Brochure 
7.3.1 
Laboratory test abnormalities 
7.3.1.1 
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 ceritinib 
treatment), should be record. 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. 
7.3.2 
Adverse events of special interest (AESI) 
Adverse events of special interest to be monitored for ceritinib have now also been identified and include: 
hepatotoxicity, 
interstitial 
lung 
disease/pneumonitis, 
QT 
interval 
prolongation, 
bradycardia, 
hyperglycemia, gastrointestinal toxicity (nausea, vomiting and diarrhea) and pancreatitis (including 
lipase and amylase elevations).  
 
7.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be 
reported to Novartis immediately (within 24 hours) of learning of its occurrence. Patients who become 
pregnant during the trial must be withdrawn. The pregnancy will be followed up from the estimated date 
of delivery plus 3 months 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 DS&E. Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the investigational treatment of any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study treatment. 
A pregnancy outcome informed consent will be provided by Novartis. Consent to report information 
regarding these pregnancy outcomes should be obtained from the mother. 
Women of childbearing potential should be advised to use highly effective contraception methods while 
they are receiving study treatment and up to 3 months after treatment has been stopped. 
If a pregnancy occurs while on LDK378 treatment, the newborn will be followed for at least 3 months. 


 
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7.5 
Warnings and precautions 
Additional safety information collected between IB updates will be noted and added to the protocol. This 
information will be included in the patient informed consent and should be discussed with the patient 
during the study as needed. The package insert for ceritinib does not contain any specific 
contraindication. 
8.0 
Study agents and therapies 
8.1 
Agent Ceritinib  
• 
Other names for the drug(s): Ceritinib, Zykadia, LDK378 
 
• 
Classification - type of agent: Targeted cancer therapy 
 
• 
Mode of action: ALK inhibitor 
 
• 
Storage and stability: should be stored at 25 C, with a range of 15-30C. 
 
• 
Protocol dose:  450 mg 
 
• 
Preparation: 150 mg Hard gelatin capsule 
 
• 
Route of administration for this study: Oral 
 
• 
Incompatibilities: none 
 
• 
Availability: FDA-approved 
 
• 
Side effects: Please refer to the ceritinib package insert for a comprehensive list of 
adverse events. 
 
Commonly reported adverse events include Gastrointestinal symptoms such as diarrhea, nausea and 
vomiting, anorexia, and constipation. Fatigue is also commonly reported. Decreased hemoglobin and 
serum phosphate, increased serum glucose, ALT and bilirubin have also been reported. 
Cardiovascular side effects include bradycardia and prolonged Q-T interval on ECG. Visual 
disturbances and interstitial pulmonary disease have also been reported. 
 
• 
Nursing implications: none 
8.1.1 
Return and Retention of Study Drug 
The study drug ceritinib will be destroyed by the UT Southwestern designated 
investigational drug service pharmacy in accordance with institutional 
protocols. No patient returned drug will be re-assigned to other patients or 
diverted to another person. 
 
8.1.2 
Study Drug compliance  
 
The patient will be asked to keep a diary of taking the medication, as well as 
bringing pill bottles to each clinic visit. 
 
8.2 
Therapy Stereotactic Ablation Body Radiation (SABR) 
 


 
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8.3 
SABR DOSE AND TECHNIQUES 
  
SABR will begin 10 weeks after initiation of ceritinib for consolidation of residual disease sites. 
Additional SABR treatments will be delivered to new distinct areas of disease that develop after that 
period at the discretion of the treating medical oncology/radiation oncology teams.  PFS will at that 
point already been established, but patients will be followed for OS.  
Stereotactic treatment is the targeting, planning, and directing of treatment fields guided to a target 
based on known 3-D coordinates related to reliable fiducial markers. This differs from conventional 
radiation therapy in which treatment is guided by skin or bony landmarks assumed to correlate to the 
target volume based on the initial simulation.  SABR in this study will be delivered with an ablative 
range of dose per fraction. Treatment will account for inter/intra-fractional errors with careful dosimetry 
that delivers an ablative dose to the metastatic lesion(s) while respecting normal tissue constraints. 
8.3.1 
Ceritinib during SABR 
It is not expected ceritinib and SABR would have significant toxicity if given concurrently. 
However to minimize risk to the patient, ceritinib will be held for 72 hours before the first radiation 
treatment and resumed 72 hours after the last radiation dose. While radiation is being delivered, 
concurrent treatment with ceritinib is not allowed. 
 
8.3.2 
SABR Prescription 
Patients randomized to the SABR arm will be evaluated by the treating Radiation Oncologist. Based 
on location of the metastatic lesion(s), dose fractionation will be determined by clinical appropriateness 
that balances ablation of the lesion(s) while respecting normal tissue constraints.  
 
Prescription Dose 
  
Total Cumulative Dose Encompassing 95% of Planning Target Volume  
Number of 
Fractions 
Protocol Compliant 
Variation Acceptable 
Deviation Unacceptable 
1 
21-27 Gy 
<21 Gy but ≥16 Gy  
<16 Gy or >27 Gy  
3 
26.5-33 Gy 
<26.5 Gy but ≥24.5 Gy 
<24.5 Gy or >33 Gy,  
5 
30-37.5 Gy 
≥28 Gy, <30 Gy 
<28 Gy  or >37.5 Gy,  
 
Treatment may be delivered on consecutive days with 18 hours between fraction or every other day as 
deemed appropriate by the treating Radiation Oncologist. 
 
If there is residual disease not amenable to SABR fractionation schemes proposed in the study, 
especially for bulky hilar or mediastinal disease, a fractionation schema of 45 Gy in 15 fractions may 
be employed, with adherence to standard normal tissue constraints outlined in the trial.  This treatment 
will be delivered daily for three weeks. 
 
8.3.3 
Planning Constraints and Concerns  
The tolerance dose of SABR to the gastrointestinal tract is not established, and patients with 
metastatic disease involving the esophagus, stomach, intestines, or mesenteric lymph nodes will not 
be eligible. Patients with renal or adrenal metastases are potentially eligible if normal tissue constraints 
are otherwise met.  
 
Cutaneous metastases are an uncommon manifestation of non-small cell lung cancer that are typically 
associated with poor prognosis [22] . Patients with cutaneous metastases will be ineligible. As this may 
represent a group of patients with particularly poor prognosis, again this will be considered within any 
comparison with historical controls. 


 
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It is well established that for palliative effect for a painful bone metastasis, a single dose of 8 Gy is 
usually as effective as 30 Gy. Long term survival after bone metastasectomy has been reported [23]. 
Irradiation of non-spinal skeletal sites does not generally require specialized techniques of treatment. 
Metastases in major lower extremity weight-bearing bones should undergo surgical stabilization if 
there is plain film evidence of cortical erosion. 
 
Corticosteroid premedication will not be mandated, although it can be used at the discretion of 
the treating oncologist. Analgesic premedication to 
avoid general discomfort during long treatment durations is recommended when appropriate. 
 
8.4 
Technical Factors 
 
8.4.1 
Physical Factors 
Only photon (x-ray) beams produced by linear accelerators with photon energies of 4-15 MV will be 
allowed. Cobalt-60 and charged particle beams (including electrons, protons, and heavier ions) are not 
allowed. Restriction of photon beam energies > 10 MV but less than 15 MV will be based on clinical 
appropriateness taking into account distance the beam must travel to the target. 
 
8.4.2 
Dose Verification at Treatment 
In-vivo dosimeter measurements (e.g., diode, TLD) may be obtained for surface dose 
verification for accessible beams. This information is not required by the protocol. 
 
8.4.3 
Treatment Platforms 
The trial allows most commercially available photon producing treatment units except the 
exclusion of units described in Section 4.3.1 (e.g., cobalt units and charge particle 
accelerators). Conventional linear accelerators and specialized linear accelerators with 
image guidance (e.g., Novalis, Trilogy, Synergy, Artiste) are allowed. These units can be used 
with conformal dose delivery or IMRT. Other specialized accelerators (e.g., the CyberKnife® 
or Tomotherapy) are allowed as long as they meet the technical specifications of the protocol. 
 
8.4.4 
Simulation/Image Guidance 
 
8.4.5 
Patient Positioning 
Patients will be positioned in a stable position that allows accurate reproducibility of the target between 
treatments.  Positions uncomfortable for the patient should be avoided so as to prevent uncontrolled 
movement during treatments.  A variety of immobilization systems may be utilized including 
stereotactic frames that surround the patient on three sides and large rigid pillows (conforming to 
patients external contours) with reference to the stereotactic coordinate system.  Patient 
immobilization must be reliable enough to insure that the Gross Tumor Volume (GTV) does not deviate 
beyond the confines of the Planning Treatment Volume (PTV) with any significant probability (i.e., < 
5%). 
 
At the time of simulation for patients who will receive SABR to the lung and/or liver, the movement of 
the dome of the diaphragm (superior portion of the liver) is to be observed under fluoroscopy or other 
acceptable means to estimate respiratory movement during treatment if no breathing control device is 
used.  Patients will be assessed for suitability for tolerance of a respiratory control device using a 
breath-hold technique, respiratory gating, or abdominal compression to limit diaphragmatic excursion 


 
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during respiration. Patients with severe lung disease and patients who cannot tolerate diaphragmatic 
or breathing control devices for other reasons will be treated without them. A larger margin to account 
for breathing related intra-fractional organ movement is required. 
 
8.4.6 
Image Guidance 
Isocenter or reference point port localization images should be obtained on the treatment unit 
immediately before treatment to ensure proper alignment of the geometric center (i.e., 
isocenter) of the simulated fields. These IGRT images can be obtained with planar kV imaging 
devices or cone-beam CT equipment. For treatment systems that use kV imaging but also allow EPID 
imaging using the treatment beam, orthogonal images verifying the isocenter also should be obtained.  
 
8.5 
Treatment Planning/Target volumes 
 
8.5.1 
Image Acquisition 
Computed tomography will be the primary image platform for targeting and treatment planning. The 
planning CT scans must allow simultaneous view of the patient anatomy and fiducial system for 
stereotactic targeting. CT scan with IV contrast is recommended unless the patient has allergy to 
contrast or renal insufficiency.  Oral GI contrast to highlight the stomach and duodenum is 
recommended for patients with medial liver lesions or lesions of the caudate lobe. Axial acquisitions 
will be required with spacing ≤ 3.0 mm between scans. Images will be transferred to the treatment 
planning computers.  
 
8.5.2 
Target Volumes 
The target lesion will be outlined by an appropriately trained physician and designated the gross tumor 
volume (GTV). The target will generally be drawn using appropriate windowing based on location of 
the metastatic lesion(s). 4-dimensional CT image guided GTV delineation to take tumor motion into 
consideration will be allowed.  
 
For treatment to the lung, the target will generally be drawn using CT pulmonary windows; however, 
soft tissue windows with contrast may be used to avoid inclusion of adjacent vessels, atelectasis, or 
mediastinal or chest wall structures within the GTV. This target will not be enlarged whatsoever for 
prophylactic treatment (including no “margin” for presumed microscopic 
extension); rather, include only abnormal CT signal consistent with gross tumor (i.e., the GTV and the 
clinical target volume [CTV] are identical). An additional 0.5 cm in the axial plane and 1.0 cm in the 
longitudinal plane (craniocaudal) will be added to the GTV to constitute the PTV.  
 
For treatment to the liver, the following structures are contoured: entire liver, each individual liver gross 
tumor volume (GTV), each kidney, and the spinal cord. The planning target volume (PTV) is 
constructed to account for the positional uncertainty of the GTV during treatment. The PTV for each 
contoured GTV should be at least 5mm larger than the GTV in the axial plane and 1.0 cm larger than 
the GTV in the craniocaudal plane. Larger margins may be used in cases where greater motion of the 
hemidiaphragm is observed in simulation despite standard maneuvers to diminish motion.   
 
Treatment to skeletal and paraspinous lesions may be accomplished with any 3D conformal 
radiotherapy or intensity-modulated radiotherapy technique suitable for this application with 
performance specifications adequate to provide proper tumor dose distribution and normal tissue 
sparing. 
 


 
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8.6 
Dosimetry 
 
8.6.1 
3D-Conformal Planning 
Three-dimensional coplanar or non-coplanar beam arrangements will be custom designed for each 
case to deliver highly conformal prescription dose distributions. Non-opposing, non-coplanar beams 
are preferable. Generally, more beams are used for larger lesion sizes. For this protocol, the isocenter 
is defined as the common point of gantry and couch rotation for the treatment unit. Prescription lines 
covering the PTV will typically be the 60-90% line (rather than 95-100%); however, higher isodoses 
(hotspots) must be manipulated to occur within the target and not in adjacent normal tissue. The 
isocenter in stereotactic coordinates will be determined from system fiducials (or directly from the 
tumor in the case of volumetric imaging) and translated to the treatment record.  
 
The treatment dose plan will be made up of multiple static beams or arcs as described 
above. The plan should be normalized to a defined point corresponding closely to the 
center of mass of the PTV (COMPTV). Typically, this point will be the isocenter of the beam rotation; 
however, it is not a protocol requirement for this point to be the isocenter. 
Regardless, the point identified as COMPTV must have defined stereotactic coordinates and receive 
100% of the normalized dose. Because the beam apertures coincide nearly directly with the edge of 
the PTV (little or no added margin), the external border of the PTV will be covered by a lower isodose 
surface than usually used in conventional radiotherapy planning typically around 80% but ranging from 
60-90%. The prescription dose will be delivered to the margin of the PTV. As such, a “hotspot” will 
exist within the PTV centrally at the COMPTV with a magnitude of prescribed dose times the reciprocal 
of the chosen prescription isodose line (i.e., 60-90%). 
 
8.6.2 
Intensity Modulated Radiation Therapy (IMRT) 
IMRT is allowed in this study. The use of IMRT in this study is at the discretion of the treating 
physician. However, IMRT should be considered only when target coverage, OAR dose limits, or dose 
spillage are not achievable with 3D conformal planning. In addition, IMRT plans should follow the 
same planning principles as discussed above for 3D conformal planning. The number of segments 
(control points) and the area of each segment should be optimized to ensure deliverability and avoid 
complex beam fluences. Ideally, the number of segments should be minimized (2-3 segments per 
beam should be adequate), and the area of each segment 
should be maximized (the aperture of one segment from each beam should correspond to 
the projection of the PTV along a beam’s eye view). 
 
8.6.3 
Dose Calculations 
For purposes of dose planning and calculation of monitor units for actual treatment, this 
protocol will require tissue density heterogeneity correction.  
 
Successful treatment planning will require accomplishment of all of the following criteria: 
Maximum dose: The treatment plan should be created such that 100% corresponds to the maximum 
dose delivered to the patient. This point must exist within the PTV. 
Prescription isodose: The prescription isodose surface must be ≥ 60% and < 90% of the maximum 
dose. 
Prescription Isodose Surface Coverage: The prescription isodose surface will be 
chosen such that 95% of the target volume (PTV) is conformally covered by the prescription isodose 
surface (PTV V95%RX = 100%) and 99% of the target volume (PTV) receives a minimum of 90% of 
the prescription dose (PTV V90%RX > 99%). 
 
 


 
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8.6.4 
Normal Tissue Dose Constraints 
In accordance with the prior Phase I studies [7, 8], certain normal tissue dose constraints must be 
respected.  
 
The possibility that SABR-induced fibrosis might cause occlusion of large central airways, thus 
impeding ventilation distal to the occlusion has been well considered. An adjustment to the 
fractionation scheme may be made if, in the opinion of the treating radiation oncologist, the following 
conditions apply: (1) the location of a lung lesion is close enough to a large proximal bronchial airway 
such that occlusion might occur, and (2) compromised ventilation to the segment(s) of lung potentially 
affected would cause clinically significant adverse consequences.  
 
The same special condition applies in the setting of a patient whose primary lung disease has not 
been irradiated previously but is present as a PET-positive site of disease, often in proximity to 
mediastinal structures which is a dose-limiting concern.  These patients will be considered by the PI on 
a case-by-case basis.   
 
The following table lists the specific organ and dose fractionation constraints on normal tissues. 
 
One Fraction 
 
 
 
 
 
 
 
 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Endpoint (≥Grade 3) 
Spinal Cord and medulla 
<0.35 cc 
<1.2 cc 
10 Gy 
8 Gy 
14 Gy 
myelitis 
Spinal Cord Subvolume (5-
6 mm above and below 
level treated per Ryu) 
<10% of 
subvolume 
10 Gy 
14 Gy 
myelitis 
Cauda Equina 
<5 cc 
14 Gy 
16 Gy 
neuritis 
Sacral Plexus 
<5 cc 
14.4 Gy 
16 Gy 
neuropathy 
Esophagus* 
<5 cc 
11.9 Gy 
15.4 Gy 
stenosis/fistula 
Brachial Plexus 
<3 cc 
13.6 Gy 
16.4  Gy 
neuropathy 
Heart/Pericardium 
<15 cc 
16 Gy 
22 Gy 
pericarditis 
Great vessels 
<10 cc 
31 Gy 
37 Gy 
aneurysm 
Trachea and Large 
Bronchus* 
<4 cc 
17.4 Gy 
20.2 Gy 
stenosis/fistula 
Bronchus- smaller airways 
<0.5 cc 
12.4 Gy 
13.3 Gy 
stenosis with atelectasis 
Rib 
<5 cc 
28 Gy 
33 Gy 
Pain or fracture 
Skin 
<10 cc 
25.5 Gy 
27.5 Gy 
ulceration 
Stomach 
<5 cc 
17.4 Gy 
22 Gy 
ulceration/fistula 
Bile duct 
 
 
30 Gy 
stenosis 
Duodenum* 
<5 cc 
<10 cc 
11.2 Gy 
9 Gy 
17 Gy 
ulceration 
Jejunum/Ileum* 
<30 cc 
12.5 Gy 
22 Gy 
enteritis/obstruction 
Colon* 
<20 cc 
18 Gy 
29.2 Gy 
colitis/fistula 
Rectum* 
<3.5 cc 
<20 cc 
39 Gy 
22 Gy 
44.2 Gy 
proctitis/fistula 
Ureter 
 
 
35 Gy 
stenosis 
Bladder wall 
<15 cc 
12 Gy 
25 Gy 
cystitis/fistula 
Penile bulb 
<3 cc 
16 Gy 
 
impotence 
Femoral Heads  
<10 cc 
15 Gy 
 
necrosis 
Renal hilum/vascular trunk 
15 cc 
14 Gy 
 
malignant hypertension 
 
 
 
 
 
Parallel Tissue 
Critical 
Volume (cc) 
Critical Volume 
Dose Max (Gy) 
 
Endpoint (≥Grade 3) 


 
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Lung (Right & Left) 
1500 cc 
7 Gy 
 
Basic Lung Function 
Lung (Right & Left) 
1000 cc 
7.6 Gy 
V-8Gy <37% 
Pneumonitis 
Liver 
700 cc 
11 Gy 
 
Basic Liver Function 
Renal cortex (Right & Left) 
200 cc 
9.5 Gy 
 
Basic renal function 
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
 
Three Fractions  
 
 
 
 
 
 
 
 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Endpoint (≥Grade 3) 
Spinal Cord and medulla 
<0.35 cc 
<1.2 cc 
15.9 Gy 
13 Gy 
22.5 Gy 
myelitis 
Spinal Cord Subvolume (5-
6 mm above and below 
level treated per Ryu) 
<10% of 
subvolume 
18 Gy 
22.5 Gy 
myelitis 
Cauda Equina 
<5 cc 
21.9 Gy  
25.5 Gy 
neuritis 
Sacral Plexus 
<5 cc 
22.5 Gy 
24 Gy 
neuropathy 
Esophagus* 
<5 cc 
17.7 Gy 
25.2 Gy 
stenosis/fistula 
Brachial Plexus 
<3 cc 
22 Gy 
26  Gy 
neuropathy 
Heart/Pericardium 
<15 cc 
24 Gy 
30 Gy 
pericarditis 
Great vessels 
<10 cc 
39 Gy 
45 Gy 
aneurysm 
Trachea and Large 
Bronchus* 
<5 cc 
25.8 Gy 
30 Gy 
stenosis/fistula 
Bronchus- smaller airways 
<0.5 cc 
18.9 Gy 
23.1 Gy 
stenosis with atelectasis 
Rib 
<5 cc 
40 Gy 
50 Gy 
Pain or fracture 
Skin 
<10 cc 
31 Gy 
33 Gy 
ulceration 
Stomach 
<5 cc 
22.5 Gy 
30 Gy 
ulceration/fistula 
Bile duct 
 
 
36 Gy 
stenosis 
Duodenum* 
<5 cc 
<10 cc 
15.6 Gy 
12.9 Gy 
22.2 Gy 
ulceration 
Jejunum/Ileum* 
<30 cc 
17.4 Gy 
27 Gy 
enteritis/obstruction 
Colon* 
<20 cc 
24 Gy 
34.5 Gy 
colitis/fistula 
Rectum* 
<3.5 cc 
<20 cc 
45 Gy 
27.5 Gy 
49.5 Gy 
proctitis/fistula 
Ureter 
 
 
40 Gy 
stenosis 
Bladder wall 
<15 cc 
17 Gy 
33 Gy 
cystitis/fistula 
Penile bulb 
<3 cc 
25 Gy 
 
impotence 
Femoral Heads  
<10 cc 
24 Gy 
 
necrosis 
Renal hilum/vascular trunk 
15 cc 
19.5 Gy 
 
malignant hypertension 
 
 
 
 
 
Parallel Tissue 
Critical 
Volume (cc) 
Critical Volume 
Dose Max (Gy) 
 
Endpoint (≥Grade 3) 
Lung (Right & Left) 
1500 cc 
10.5 Gy 
 
Basic Lung Function 
Lung (Right & Left) 
1000 cc 
11.4 Gy 
V-11Gy<37% 
Pneumonitis 
Liver 
700 cc 
17.1 Gy 
 
Basic Liver Function 
Renal cortex (Right & Left) 
200 cc 
15 Gy 
 
Basic renal function 
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
 
Five Fractions 
 
 
 
 
 
 
 
 
 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose 
(Gy)** 
Endpoint (≥Grade 3) 


 
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Spinal Cord and medulla 
<0.35 cc 
<1.2 cc 
22 Gy 
15.6 Gy 
28 Gy 
myelitis 
Spinal Cord Subvolume (5-
6 mm above and below 
level treated per Ryu) 
<10% of 
subvolume 
22 Gy 
28 Gy 
myelitis 
Cauda Equina 
<5 cc 
30 Gy 
31.5 Gy 
neuritis 
Sacral Plexus 
<5 cc 
30 Gy 
32 Gy 
neuropathy 
Esophagus* 
<5 cc 
19.5 Gy 
35 Gy 
stenosis/fistula 
Brachial Plexus 
<3 cc 
27 Gy 
32.5 Gy 
neuropathy 
Heart/Pericardium 
<15 cc 
32 Gy 
38 Gy 
pericarditis 
Great vessels 
<10 cc 
47 Gy 
53 Gy 
aneurysm 
Trachea and Large 
Bronchus* 
<5 cc 
32 Gy 
40 Gy 
stenosis/fistula 
Bronchus- smaller airways 
<0.5 cc 
21 Gy 
33 Gy 
stenosis with atelectasis 
Rib 
<5 cc 
45 Gy 
57 Gy 
Pain or fracture 
Skin 
<10 cc 
36.5 Gy 
38.5 Gy 
ulceration 
Stomach 
<5cc 
26.5 Gy 
35 Gy 
ulceration/fistula 
Bile duct 
 
 
41 Gy 
stenosis 
Duodenum* 
<5 cc 
<10 cc 
18.5 Gy 
14.5 Gy 
26 Gy 
ulceration 
Jejunum/Ileum* 
<30 cc 
20 Gy 
32 Gy 
enteritis/obstruction 
Colon* 
<20 cc 
28.5 Gy 
40 Gy 
colitis/fistula 
Rectum* 
<3.5 cc 
<20 cc 
50 Gy 
32.5 Gy 
55 Gy 
proctitis/fistula 
Ureter 
 
 
45 Gy 
stenosis 
Bladder wall 
<15 cc 
20 Gy 
38 Gy 
cystitis/fistula 
Penile Bulb 
<3 cc 
30 Gy 
 
impotence 
Femoral Heads  
<10 cc 
30 Gy 
 
necrosis 
Renal hilum/vascular trunk 
15 cc 
23 Gy  
 
malignant hypertension 
 
 
 
 
 
Parallel Tissue 
Critical 
Volume (cc) 
Critical Volume 
Dose Max (Gy) 
 
Endpoint (≥Grade 3) 
Lung (Right & Left) 
1500 cc 
12.5 Gy 
 
Basic Lung Function 
Lung (Right & Left) 
1000 cc 
13.5 Gy 
V-13.5Gy<37% 
Pneumonitis 
Liver 
700 cc 
21 Gy 
 
Basic Liver Function 
Renal cortex (Right & Left) 
200 cc 
18 Gy 
 
Basic renal function 
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
 
Exceeding these dose tolerances by more than 2.5% constitutes a minor protocol violation.  Exceeding 
these dose tolerances by more than 5% constitutes a major protocol violation. 
 
 
 
 
 
8.7 
Intracranial Stereotactic Radiosurgery Dose (SRS) for and 
Technique 
 


 
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Patients with up to 10 brain metastases with the maximal size <= 4cm will be treated by SRS 
in a single fraction.  If there are more than 10 intracranial lesions or the size of the 
largest lesion is >4cm, such patients will be ineligible.    
 
8.7.1 
SRS Dose  
 
 
All supratentorial lesions are treated to the prescribed dose below.   
 
 
SRS Dose by lesion diameter  
Diameter (cm) 
<= 2.0 cm 
>2.0 - 3.0 cm 
>3.0 - 4.0 cm 
Dose (Gy) 
20-24 
18 
15 
 
For lesions within the brainstem (pons, medulla, and midbrain), the prescription dose 
will be 10-13 Gy in a single fraction.  
 
Multiple SRS sessions are allowed, as long as all intracranial lesions are treated 
within 14 days.   
 
 
8.7.2 
SRS Technique, Pre-SRS Image acquisition and target planning with Conformality Index 
 
Protocol SRS will be administered with a linear accelerator (LINAC), Vero ® (BrainLab, 
Feldkirchen, Germany), CyberKnife ® (Accuray, Sunnyvale, CA) or Gamma Knife® 
Perfexion (Elektra Instruments, Inc., Atlanta, GA). Fixed-frame stereotactic localization 
and planning will be used for SRS.  
 
Pre-SRS Image Acquisition: MRI with gadolinium contrast is the recommended imaging 
method for stereotactic localization.  In the case of LINAC, Vero or CyberKnife, MRI 
with contrast has to be obtained within 14 days of SRS with an acquisition of <= 1.5 mm 
slice thickness. The stereotactic target is the contrast-enhancing tumor as defined on 
MRI with contrast.  
 
In patients who cannot tolerate the contrast, other MR sequences may be utilized 
without the contrast, as long as the target lesion can be clearly demarcated for treatment 
and follow up. 
 
Conformality Index (CI) is derived from dividing the volume encompassed by the 
prescription isodose line by the target volume.   
 
CI = Rx Isodose Vol / (Target Vol)  
 
The target lesion in the SRS planning MRI will be contoured, and its volume will be 
calculated. Planning should achieve a conformity index specified below.   
 
Size of 
Target 
Prescription 
Isodose 
Conformality 
Index 
<=1cm    
35-100% 
< 2 
1-2cm     
< 2 


 
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2-3cm     
< 1.5 
3-4cm  
< 1.25 
 
At least 95% of the target volume must receive the prescription dose; the plan should 
be adjusted to achieve such coverage by the isodose line between 40-100%.  No part 
of the target should receive less than 90% of the prescription dose.  
 
 
8.7.3 
Normal Tissue Dose Constraints 
 
The following table lists maximum dose limits, in one fraction, to a point or volume within 
several critical structures of the cranium.  These are absolute limits, and treatment 
delivery that exceeds these limits will constitute a major protocol violation. 
 
Critical Structure and 
margin 
Volume 
Volume Max 
(Gy) 
Max Point Dose 
(Gy)* 
Endpoint 
(≥Grade 3) 
Optic Pathway 
<0.2 cc 
8 Gy 
10 Gy 
neuritis 
Brainstem (not medulla) 
<0.5 cc 
10 Gy 
15 Gy 
cranial 
neuropathy 
Spinal Cord and medulla 
<0.35cc 
<1.2 cc 
10 Gy 
8 Gy 
14 Gy 
myelitis 
 
* “point” defined as 0.035cc or less 
 
Patients with lesions within or near the above structures and the dose constraints 
cannot be satisfied, will be deemed ineligible. 
 
 
8.8 
Radiation Therapy Quality Assurance 
 
The radiation oncologist will perform an RT Quality Assurance Review after complete data for the first 
half of cases (18) enrolled at the University of Texas Southwestern Medical Center. They will perform 
the final review after complete data for the subsequent 19 cases at the University of Texas 
Southwestern Medical Center are completed. These cases will be reviewed within 3 months after this 
study has reached the target accrual or as soon as complete data for all cases enrolled has been 
received, whichever occurs first. 
  
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Design/Study Endpoints 
 
This is an, open-label, two-cohort protocol designed to evaluate the activity of targeted therapy and 
SABR in ALK positive lung adenocarcinoma.  
 
Cohort A will evaluate the combination in ALK-inhibitor naïve patients. 
Cohort B will evaluate the combination in patients who have received treatment with one prior ALK 
inhibitor. 
 


 
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Ceritinib will be administered to the patient until disease progression by RECIST 1.1, unacceptable 
toxicity, withdrawal of consent, or discontinuation of the trial for any other reason including death.   
The primary focus of this protocol is identifying response in ALK+ lung cancer patients. Patients with 
IHC positive or FISH probe positive tumors will be treated. Evidence of ALK gene rearrangement will 
also be considered eligible for the trial.  
 
Study Design:   
Purpose: of this prospective, single-center, two cohort, non-randomized trial is to evaluate the impact 
of the combination of ceritinib and stereotactic radiation delivered to patients with ALK-rearranged 
adenocarcinoma. The enhanced efficacy of this combination is to be evaluated specifically with 
regards to prolongation of clinical benefit of ceritinib. We will also evaluate the safety of this 
combination of targeted therapy and radiation.  
 
 
For ALK-rearranged patients started on ceritinib and treated with SABR to persisting lesions: 
-PFS compared to published historical results with ceritinib alone PFS=7 month for prior crizotinib 
treated and 10 month for no previous crizotinib therapy (Shaw et al, NEJM 2014). 
PFS will be defined as Time to Subsequent Systemic Therapy. 
 
As secondary objectives, we will also report overall survival and time to 2nd and 3rd SABR for each 
cohort. 
 
 
Objective 
Endpoint 
Primary: 
Cohort A: Superiority of ceritinib + 
SABR median PFS compared to 
historical control of  10 months  
(expected to be 20 months) 
 
Cohort  B: Superiority of ceritinib + 
SABR median PFS compared to 
historical control of  7 months 
Cohort  A Median PFS defined as time from 
initiation of ceritinib  until disease progression 
by RECIST 1.1, unacceptable toxicity, 
withdrawal of consent, or discontinuation of 
the trial for any other reason including death.   
 
Cohort  B: Median PFS defined as time from 
initiation of ceritinib  until disease progression 
by RECIST 1.1, unacceptable toxicity, 
withdrawal of consent, or discontinuation of 
the trial for any other reason including death.   
Secondary: 
Report Overall survival 
 
Report Time to 2nd SABR 
 
 
Report Time to 3rd SABR 
 
 
Report proportion of patients 
CR/PR/stable disease at 6 and12 
months 
Overall survival 
 
Time from start of systemic therapy to first 
day of second course of SABR 
 
Time from start of therapy to first day of third 
course of SABR 
 
Number of patients with CR/PR/stable 
disease for 6 and 12 months after initiation  
Safety: 
Demonstrate safety of ceritinib 
followed by SABR 
Describe toxicity and adverse events (CTCAE 
v.4) compared to historical controls. 


 
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9.2 
Sample Size and Accrual 
 
The results of a Phase I trial of ceritinib in ALK-rearranged metastatic adenocarcinoma 
were reported recently (Shaw et al., 2014). Ceritinib demonstrated activity in patients 
with an overall response rate of 57% at doses of 400 mg or greater. The PFS reported 
was 7  months for those with prior crizotinib treatment and 10 months for those who had 
not received any crizotinib. Toxicities and adverse events were also reported. This study 
offers contemporary, relevant historical control data for comparison purposes.  
 
The sample size calculation is based on the primary endpoint, progression-free survival, and the 
assumption that patients are randomized until the end of accrual. The sample size is calculated 
separately for each cohort. 
  
Cohort A (no prior ALK-inhibitor): 
  
A sample size of 18 patients achieves 80% power to detect the difference between the null hypothesis 
of median PFS of 10 months and the alternative hypothesis of median PFS of 20 months at two-sided 
significance level of 0.1. We assume the patient accrual period of 36 months and the follow-up period 
of 12 months. The assumption that patients are randomized until the end of accrual. The sample size 
was estimated using SWOG (https://www.swogstat.org/stat/public/one_survival.htm) sample size 
calculator. 
  
  
Cohort B (treated with one prior ALK inhibitor): 
  
A sample size of 15 patients achieves 80% power to detect the difference between the null hypothesis 
of median PFS of 7 months and the alternative hypothesis of median PFS of 14 months at two-sided 
significance level of 0.1. We assume the patient accrual period of 36 months and the follow-up period 
of 12 months. The assumption that patients are randomized until the end of accrual. The sample size 
was estimated using SWOG (https://www.swogstat.org/stat/public/one_survival.htm) sample size 
calculator.  
  
9.3 
Data Analyses Plans 
 
We will use Kaplan-Meier methods to estimate the progression-free survival, time to 
2nd and 3rd SABR and overall survival. 
 
Duration of response (defined in 6.1.5)  duration will be summarized for patients who 
responded. Descriptive summary statistics like median, 25% and 75% percentiles will 
be used.  
 
Toxicities are dichotomized as none versus any, or none and mild versus moderate to 
severe.   
 
The rates of overall response, toxicity and adverse events as well as their 95% 
confidence intervals will be estimated using exact binomial method.  
We will compare the rates of toxicity and adverse events in this study with those of 
historical controls by the Fisher's exact test.  
  


 
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9.3.1 
Treatment phase and duration of treatment  
Patients eligible for treatment will receive 450 mg daily of ceritinib as part of a 28 day cycle. The first 
dose of each cycle will be administered after evaluation at the study center. Patients will remain on study 
and take ceritinib until there is evidence of disease progression by RECIST, unacceptable toxicity, 
withdrawal of consent, or discontinuation of the trial for any other reason.   
 
If there is oligoprogression amenable to SABR, resumption of ceritinib after SABR will be permitted if 
the treating oncologist feels the patient would benefit. 
9.4 
Definition of end of the Study 
Cohort A will be completed when 20 patients and cohort B will be completed when 17 patients have 
evidence of disease progression by RECIST not amenable to SABR requiring discontinuation of ceritinib, 
unacceptable toxicity, withdrawal of consent, or discontinuation of the trial for any other reason.   
At the completion or discontinuation of study medication, all patients will be seen within 30 days for an 
end of therapy evaluation. This will include a safety assessment for AE’s SAE’s. Any unused medication 
will be returned. 
9.5 
Early Termination 
Treatment on protocol may be terminated early if the Principal investigator or institution assess that the 
safety of the enrolled subjects will be compromised by continuation of the trial. The procedure followed 
will be that of the premature withdrawal patient and any patients on treatment will be seen as soon as 
possible. 
 
9.6 
Data confidentiality 
Information about protocol 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 protocol 
- 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 protocol treatment period. 
 
9.7 
Statistical methods and data analysis 
9.8 
Analysis sets 
9.8.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all enrolled patients. 
9.8.2 
Safety Set 
The Safety Set includes all patients who received at least one dose of ceritinib medication. 


 
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9.9 
Patient demographics/other baseline characteristics 
Demographic, disease characteristics and other baseline data will be summarized descriptively for the 
FAS. 
9.10 
Treatments (ceritinib treatment, concomitant therapies, compliance) 
All analyses from this section will be performed on all patients from the safety set. Duration of ceritinib 
treatment exposure will be summarized. 
9.10.1 Handling of missing values/censoring/discontinuations 
All attempts will be made to ensure that the database contains full information for the safety set. No 
imputation will be applied for missing data. 
9.10.2 Safety objectives 
The safety objective is to describe toxicities in patients treated with ceritinib. 
 
9.10.2.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used. Toxicities will be dichotomized as none versus any 
adverse event, or none and mild versus moderate to severe adverse event.   
The safety summary tables will include assessments from the on-treatment period, unless otherwise 
specified.  
All safety data collected in the study will be listed regardless of the study period with data collected 
during the pre-treatment and post-treatment period flagged. 
9.10.2.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during the on-
treatment period, the treatment-emergent AEs. However, all safety data (including those from the pre 
and post-treatment periods) will be listed and those collected during the pre-treatment and post-
treatment period are to be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), type of 
adverse event, relation to study treatment by 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and tabulated 
by type of adverse event and. 
Specific safety event categories (SEC) will 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(s). 
For each specified category, number and percentage of patients with at least one event per category 
will be summarized. 
9.10.2.3 Other safety data 
Other safety data (including ECGs, vital signs and weight) will be summarized and listed, notable 
values will be flagged, and any other information collected will be listed as appropriate. 
 


 
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10.0 
Ethical considerations and administrative procedures 
10.1 
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. 
 
10.2 
Informed consent procedures 
Eligible patients will only be included on this after providing written IRB/IEC/REB-approved informed 
consent. 
Informed consent must be obtained before conducting any protocol-specific procedures (i.e. all of the 
procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in the clinical trial record. The informed consent document will be 
approved by the IRB. 
10.3 
Discontinuation of the study 
This study will discontinue if terminated by the Institutional Review Board or at the discretion of the 
Principal Investigator. 
 
10.4 
Publication of the study and results 
The results of this study will be updated and posted per regulatory requirements, including (but not 
limited) to databases such as clinicaltrials.gov.  
10.4.1 Communication and Publication of Clinical Trial Results 
All submitted manuscripts will comply with institutional guidelines and with authorship guidelines of the 
International Committee of Medical Journal Editors. 
 
10.5 
Study documentation, record keeping and retention of documents 
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. 
 
10.6 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names in any 
trial documents. Signed informed consent forms and patient enrollment log must be kept strictly 
confidential to enable patient identification. 
 
10.7 
Audits and inspections 
Source data/documents must be available to inspections by Health Authorities. 
 


 
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11.0 
STUDY MANAGEMENT 
11.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by 
the UTSW COI Committee and IRB according to UTSW Policy on Conflicts of Interest.  All 
investigators will follow the University conflict of interest policy. 
 
11.2 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations. The IRB must approve the consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and to ethical principles 
that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full explanation of the 
study and will be given the opportunity to review the consent form. Each consent form must include all 
the relevant elements currently required by the FDA Regulations and local or state regulations. Once 
this essential information has been provided to the subject and the investigator is assured that the 
subject understands the implications of participating in the study, the subject will be asked to give 
consent to participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed and 
personally dated by the subject  and by the person who conducted the informed consent discussion. 
 
 
11.3 
Registration Procedures 
All subjects must be registered with the Clinical Research Office before enrollment to study. Prior to 
registration, eligibility criteria must be confirmed with the Clinical Research Office Study Coordinator or 
Manager. To register a subject, call 214 648 5874 Monday through Friday, 9:00AM-5:00PM.  
 
11.4 
Data Management and Monitoring/Auditing 
Trial monitoring will be conducted no less than annually and refers to a regular interval review of trial 
related activity and documentation performed by the DOT, which includes but is not limited to accuracy 
of case report forms, protocol compliance, timeless and accuracy of Velos entries and AE/SAE 
management and reporting. Documentation of trial monitoring will be maintained along with other 
protocol related documents and will be reviewed during internal audit.   
 
Toxicity  review will be performed at the annual monitoring review.  These reviews will be documented 
by a written audit report, within 2 weeks of audit completion. The findings are reviewed with the 
research team to review any discrepancies and discuss corrective action. Audit reports and responses 
are distributed for review to the Deputy Director of the Cancer Center, DSMC Chairman, PI, DOT 
Leader and Associate Direction of the CRO. 
 
The DOT will review all local serious adverse events and unanticipated problems at monthly DOT 
research meetings.  The discussion of such events is documented in the meeting minutes.  Events are 
reported by the research coordinator to the DSMC per the DSMC plan. 
 


 
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The UTSW Simmons Cancer Center (SCC) Data and Safety Monitoring Committee (DSMC) is 
responsible for overall monitoring of data quality and patient safety.  As part of that responsibility, the 
DSMC reviews all local serious adverse events and unanticipated problems in real time as they are 
reported and reviews adverse events on a quarterly basis.   The Quality Assurance activity of the 
Clinical Research Office provides for periodic auditing of clinical research documents to ensure data 
integrity and regulatory compliance based on risk.  
 
The SCC-DSMC meets quarterly and conducts annual comprehensive reviews of ongoing clinical 
trials, for which it is the DSMC of record. 
 
Further detail may be found in the SCC-DSMC Plan.  
 
11.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-being of the 
study subject requires alternative treatment, the study shall be conducted exactly as described in the 
approved protocol.  
11.5.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, an IRB modification form must be completed 
within five (5) business days of making the change. 
11.5.2 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the Principal Investigator 
and the IRB. According to the IRB, a protocol deviation is any unplanned variance from an IRB 
approved protocol that:  
• 
Is generally noted or recognized after it occurs 
• 
Has no substantive effect on the risks to research participants 
• 
Has no substantive effect on the scientific integrity of the research plan or the value of 
the data collected  
• 
Did not result from willful or knowing misconduct on the part of the investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
• 
Has harmed or increased the risk of harm to one or more research participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, State 
laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal Investigator, please follow 
the guidelines below: 
 
 
Protocol Deviations: Personnel will report to any sponsor or data and safety monitoring committee 
in accordance with their policies. Deviations should be summarized and reported to the IRB at the time 
of continuing review. 
 
Protocol Violations: Study personnel should report violations within two (2) weeks of the investigator 
becoming aware of the event using the same IRB online mechanism used to report Unanticipated 
Problems.  


 
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11.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and documented 
by the Principal Investigator.  A summary of changes document outlining proposed changes as well as 
rationale for changes, when appropriate, is highly recommended.  When an amendment to the 
protocol substantially alters the study design or the potential risk to the patient, a revised consent form 
might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the IRB for 
approval prior to implementation.  
 
11.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, source 
documents, Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents 
(e.g., protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that the study investigator retain all study 
documentation pertaining to the conduct of a clinical trial. In the case of a study with a drug seeking 
regulatory approval and marketing, these documents shall be retained for at least two years after the 
last approval of marketing application in an International Conference on Harmonization (ICH) region. In 
all other cases, study documents should be kept on file until three years after the completion and final 
study report of this investigational study. 
 
11.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance 
with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The Principal 
Investigator is responsible for personally overseeing the treatment of all study patients. The Principal 
Investigator must assure that all study site personnel, including sub-investigators and other study staff 
members, adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines regarding 
clinical trials both during and after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all the required 
data will be collected and entered onto the Case Report Forms. Periodically, monitoring visits may be 
conducted and the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. At the completion of the study, all case report forms will be 
reviewed by the Principal Investigator and will require his/her final signature to verify the accuracy of 
the data. 
 


 
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12.0 
References (available upon request) 
 
1. 
Ferlay, J., et al., Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. 
Int J Cancer, 2010. 127(12): p. 2893-917. 
2. 
Siegel, R., D. Naishadham, and A. Jemal, Cancer statistics for Hispanics/Latinos, 2012. 
CA Cancer J Clin, 2012. 62(5): p. 283-98. 
3. 
Soda, M., et al., Identification of the transforming EML4-ALK fusion gene in non-small-
cell lung cancer. Nature, 2007. 448(7153): p. 561-6. 
4. 
Scagliotti, G., et al., ALK translocation and crizotinib in non-small cell lung cancer: an 
evolving paradigm in oncology drug development. Eur J Cancer, 2012. 48(7): p. 961-
73. 
5. 
Ou, S.H., et al., Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial 
transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell 
lung cancer patient with de novo MET amplification. J Thorac Oncol, 2011. 6(5): p. 
942-6. 
6. 
NCCN-NSCL;, Clinical Practice Guidelines, non small cell lung cancer 2015. 
http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. 
7. 
Chun, S.G., et al., Isolated central nervous system progression on Crizotinib: an 
Achilles heel of non-small cell lung cancer with EML4-ALK translocation? Cancer Biol 
Ther, 2012. 13(14): p. 1376-83. 
8. 
Shaw, A.T., et al., Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J 
Med, 2014. 370(13): p. 1189-97. 
9. 
Lim, S., et al., Ceritinib in ROS1-rearranged non-small-cell lung cancer: a Korean 
nationwide phase II study. Annals of Oncology, 2016. 27(suppl 6): p. 1205PD. 
10. 
Subbiah, V., D.S. Hong, and F. Meric-Bernstam, Clinical activity of ceritinib in ROS1-
rearranged non-small cell lung cancer: Bench to bedside report. Proceedings of the 
National Academy of Sciences, 2016: p. 201522052. 
11. 
Iyengar, P., et al., Phase II trial of stereotactic body radiation therapy combined with 
erlotinib for patients with limited but progressive metastatic non-small-cell lung cancer. 
J Clin Oncol, 2014. 32(34): p. 3824-30. 
12. 
Shepherd, F.A., et al., Erlotinib in previously treated non-small-cell lung cancer. N Engl 
J Med, 2005. 353(2): p. 123-32. 
13. 
Rusthoven, K.E., et al., Is there a role for consolidative stereotactic body radiation 
therapy following first-line systemic therapy for metastatic lung cancer? A patterns-of-
failure analysis. Acta Oncol, 2009. 48(4): p. 578-83. 
14. 
Lee, Y., et al., Therapeutic effects of ablative radiation on local tumor require CD8+ T 
cells: changing strategies for cancer treatment. Blood, 2009. 114(3): p. 589-95. 
15. 
Stamell, E.F., et al., The abscopal effect associated with a systemic anti-melanoma 
immune response. Int J Radiat Oncol Biol Phys, 2013. 85(2): p. 293-5. 
16. 
Postow, M.A., et al., Immunologic correlates of the abscopal effect in a patient with 
melanoma. N Engl J Med, 2012. 366(10): p. 925-31. 
17. 
Lynn, K.D. and R.A. Brekken, Abstract A23: ALK activity in macrophages drives 
metastasis in murine models of breast cancer. Cancer Research, 2015. 75(1 
Supplement): p. A23-A23. 


 
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18. 
Riely, G.J., et al., Prospective assessment of discontinuation and reinitiation of erlotinib 
or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the 
addition of everolimus. Clin Cancer Res, 2007. 13(17): p. 5150-5. 
19. 
Ou, S.H., et al., Clinical benefit of continuing ALK inhibition with crizotinib beyond 
initial disease progression in patients with advanced ALK-positive NSCLC. Ann Oncol, 
2014. 25(2): p. 415-22. 
20. 
Goldie, J.H. and A.J. Coldman, The genetic origin of drug resistance in neoplasms: 
implications for systemic therapy. Cancer Res, 1984. 44(9): p. 3643-53. 
21. 
Foo, J. and F. Michor, Evolution of acquired resistance to anti-cancer therapy. J Theor 
Biol, 2014. 355: p. 10-20. 
22. 
Potters, L., et al., American Society for Therapeutic Radiology and Oncology (ASTRO) 
and American College of Radiology (ACR) practice guideline for the performance of 
stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys, 2010. 76(2): p. 326-
32. 
23. 
Hasselle, M.D., et al., Hypofractionated image-guided radiation therapy for patients 
with limited volume metastatic non-small cell lung cancer. J Thorac Oncol, 2012. 7(2): 
p. 376-81. 
 
 


 
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13.0 
Appendices 
13.1 
Appendix 1: List of prohibited concomitant medications and concomitant medications 
requiring caution for ceritinib 
Table 14-1 
Prohibited medications that are strong inducers or inhibitors of CYP3A, 
or CYP3A substrates with narrow therapeutic index, or sensitive CYP2C substrates 
with narrow therapeutic index** 
CYP2C8 substrates with narrow therapeutic index 
Paclitaxel 
 
 
 
CYP2C9 substrates with narrow therapeutic index 
Warfarin 
phenytoin 
 
 
CYP3A4/5 substrates with narrow therapeutic index 
astemizole* 
cisapride* 
cyclosporine 
diergotamine 
ergotamine 
fentanyl 
pimozide 
quinidine* 
tacrolimus 
alfentanil 
terfenadine* 
sirolimus 
Strong CYP3A4/5 inhibitors 
Macrolide antibiotics: 
Antivirals: 
Antifungals: 
Others: 
clarithromycin 
telithromycin 
troleandomycin 
indinavir 
lopinavir 
nelfinavir 
ritonavir 
saquinavir 
tipranavir 
itraconazole 
ketoconazole 
posaconazole 
voriconazole 
conivaptan 
elvitegravir 
mibefradil 
nefazodone 
Strong CYP3A/5 inducers 
avasimibe 
rifabutin 
carbamazepine 
rifampin 
phenobarbital 
St. John’s wort 
Phenytoin 
* Compounds with risk of QT prolongation 
For an updated list of CYP2C substrates, CYP3A substrates, inhibitors and inducers, please 
reference the Novartis Oncology Clinical Pharmacology internal memo: drug-drug interactions (DDI) 
database, Oct 2010, which is compiled primarily from the FDA’s “Guidance for Industry, Drug 
Interaction Studies”, the Indiana University School of Medicine’s Drug Interactions Database, and 
the University of Washington’s Drug Interaction Database. 
**Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-
administered with a known potent inhibitor. 
Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that 
increases in their exposure levels by the concomitant use of potent inhibitors may lead to serious 
safety concerns (e.g., Torsades de Pointes). 
Table 14-2 
List of medications to be used with caution 
CYP2B6 substrates 
cyclophosphamide 
efavirenz 
ifosfamide 
methadone 
thiotepa 
Bupropion 
CYP2C8 substrates 
amodiaquine 
torsemide 
cerivastatin 
repaglinide 
Rosiglitazone 
CYP2C9 substrates 


 
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losartan 
piroxicam 
celecoxib 
irbesartan 
tolbutamide 
sulfamethoxazole 
diclofenac 
glipizide 
tolbutamide 
ibuprofen 
acenocoumarol 
torsemide 


 
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CYP3A4/5 substrates 
dronedarone 
alprazolam 
diazepam 
amlodipine 
diltiazem 
nifedipine 
nisoldipine 
nitrendipine 
capravirine 
ritonavir 
telaprevir 
atorvastatin 
everolimus 
clarithromycin 
erythromycin 
telithromycin 
aripiprazole 
haloperidol 
imatinib 
nilotinib 
methadone 
boceprevir 
brecanavir 
casopitant 
quinine 
tamoxifen 
tolvaptan 
trazodone 
vincristine 
verapamil 
Moderate CYP3A4/5 inhibitors 
ciprofloxacin 
erythromycin 
amprenavir 
atazanavir 
darunavir 
fosamprenavir 
diltiazem 
verapamil 
grapefruit juice 
aprepitant 
casopitant 
cimetidine 
dronedarone 
tofisopam 
Moderate CYP3A4/5 inducers 
bosentan 
nafcillin 
efavirenz 
ritonavir 
etravirine 
talviraline 
modafinil 
tipranavir 
Proton pump inhibitors 
esomeprazole 
rabeprazole 
lansoprazole 
omeprazole 
Pantoprazole 
This database of CYP 2B6, 2C8, 2C9 and 3A4/5 substrates, 3A4/5 inhibitors and inducers is from 
the Novartis Oncology Clinical Pharmacology internal memo: drug-drug interactions (DDI) database, 
Oct 2010, which is compiled primarily from the Indiana University School of Medicine’s “Clinically 
Relevant” Table (http://medicine.iupui.edu/flockhart/table.htm), the University of Washington’s Drug 
Interaction Database (www.druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug 
Interaction Studies” 
Table 14-3 
List of prohibited enzyme-inducing anti-epileptic drugs 
Prohibited enzyme-inducing anti-epileptic drugs 
carbamazepine 
phenobarbital 
ethotoin 
phenytoin 
felbamate 
primidone 
fosphenytoin 
topiramate 
Table 14-4 
List of prohibited QT prolonging drugs 
Prohibited medications causing QTc prolongation 
Antiarrhythmic: 
Anticancer: 
Antibiotic: 
Antianginal: 
amiodarone 
arsenic trioxide 
azithromycin 
bepridil 
disopyramide 
vavdetanib 
clarithromycin* 
Antipsychotic: 
dofetilide 
Antihistamine: 
erythromycin* 
chlorpromazine 
flecainide 
astemizole* 
moxifloxacin 
haloperidol* 
ibutilide 
terfenadine* 
sparfloxacin 
mesoridazine 
procainamide 
Antimalarial: 
Antinausea: 
pimozide 
quinidine* 
chloroquine 
domperidone 
thioridazine 
sotalol 
halofantrine 
droperidol 
Opiate 
agonist: 
Antilipemic: 
Anti-infective: 
GI stimulant: 
levomethadyl 
probucol 
pentamidine 
cisapride* 
methadone 
Antidepressant: 
 
 
 


 
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citalopram 
 
 
 
Please note: *CYP3A substrate 
Source: Arizona Center for Education and Research on Therapeutics (CERT), Drugs that prolong 
the QT interval and/or induce Torsades de Pointes, http://www.azcert.org/medical-pros/drug-
lists/drug-lists.cfm