Conditions: Non-small Cell Lung Cancer
Keywords: cancer metastatic locally advanced lung non-small cell lung cancer NSCLC epidermal growth factor receptor EGFR T790M CO-1686 unresectable recurrent EGFR-directed therapy irreversible EGFR inhibitor TIGER Rociletinib
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 149
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare the anti-tumor efficacy of oral single-agent rociletinib, as measured by investigator assessment of the PFS, with that of single-agent cytotoxic chemotherapy in patients with EGFR-mutated, advanced/metastatic NSCLC after failure of at least 1 previous EGFR-directed TKI and at least 1 line of platinum-containing doublet chemotherapy.

Detailed description:
This is a Phase 3, randomized, open-label, multicenter study evaluating the safety and efficacy of oral rociletinib at 500 mg BID and 625 mg BID compared with that of single-agent cytotoxic chemotherapy, in patients with previously treated mutant EGFR NSCLC. Eligible patients are those with mutant EGFR NSCLC previously treated with at least 1 EGFR inhibitor and at least 1 line of platinum-containing chemotherapy doublet for advanced/metastatic NSCLC.

After providing informed consent to participate and screening to confirm eligibility, patients will be randomized 1:1:1 to receive either oral rociletinib 500 mg BID, oral rociletinib 625 mg BID, or single-agent cytotoxic chemotherapy (investigator choice of pemetrexed, gemcitabine, docetaxel, or paclitaxel; choice of chemotherapy agent must be specified before randomization).

Arms:
arm 1: Daily oral rociletinib at 500 mg BID with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Treatment with rociletinib is continuous and each cycle will comprise of 21 days. arm 2: Daily oral rociletinib at 625 mg BID with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Treatment with rociletinib is continuous and each cycle will comprise of 21 days. arm 3: Pemetrexed

500 mg/m2 pemetrexed given intravenously on Day 1 of each 21-day cycle.

Gemcitabine

1250 mg/m2 gemcitabine given intravenously on Day 1 and 8 of each 21-day cycle.

Docetaxel

75 mg/m2 docetaxel (60 mg/m2 for patients residing in East-Asian territories) given intravenously on Day 1 of each 21-day cycle.

or 35 mg/m2 docetaxel given intravenously on a weekly basis as part of a continuous 21-day cycle; i.e. dosing will be on Days 1, 8, and 15 of each 21-day cycle.

Paclitaxel

80 mg/m2 paclitaxel given intravenously on a weekly basis as part of a continuous 21-day cycle; i.e. dosing will be on Days 1, 8, and 15 of each 21-day cycle.

Interventions: intervention 1: Rociletinib intervention 2: Pemetrexed or gemcitabine or paclitaxel or docetaxel
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
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TIGER-3: A Phase 3, Open-label, Multicenter, Randomized Study of Oral 
Rociletinib (CO-1686) Monotherapy Versus Single-agent Cytotoxic 
Chemotherapy in Patients with Mutant EGFR Non-small Cell Lung Cancer 
(NSCLC) After Failure of at Least 1 Previous EGFR-directed Tyrosine 
Kinase Inhibitor (TKI) and Platinum-doublet Chemotherapy 
Protocol Number: 
CO-1686-020 
Investigational Product: 
Rociletinib (CO-1686) 
IND Number: 
113,560 
EUDRA CT Number: 
2014-003437-26 
Development Phase: 
Phase 3 
Indication Studied: 
Locally advanced or metastatic NSCLC with mutant 
epidermal growth factor receptor (EGFR) 
Sponsor Name and Address: 
Clovis Oncology, Inc. 
5500 Flatiron Parkway, Suite 100 
Boulder, CO 80301 USA 
Phone Number: 
303-625-5000 
Facsimile Number: 303-245-0360 
Responsible Medical Officer: Sergey Yurasov, M.D., Ph.D.  
Compliance Statement: 
This study will be conducted in accordance with the 
ethical principles that have their origin in the Declaration 
of Helsinki, clinical research guidelines established by 
the Code of Federal Regulations (Title 21, CFR Parts 50, 
56, and 312), and International Conference on 
Harmonisation (ICH) Good Clinical Practices (GCP) 
Guidelines. Essential study documents will be archived 
in accordance with applicable regulations. 
Protocol Date: 
Amendment 1 Date: 
Amendment 2 Date: 
Amendment 3 Date: 
10 October 2014 
31 October 2014 
27 April 2015 
22 February 2016 
Amendment 4 Date: 
7 September 2016 
Version: 
5.0 
CONFIDENTIALITY STATEMENT 
The information in this document contains commercial information and trade secrets that are privileged 
or confidential and may not be disclosed unless such disclosure is required by applicable laws and 
regulations. In any event, persons to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed by them. These restrictions on 
disclosure will apply equally to all future information supplied to you which is indicated as privileged or 
confidential. 


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Protocol Approval Signature Page 
Protocol: 
CO-1686-020 
Title: 
TIGER-3: A Phase 3, Open-label, Multicenter, Randomized Study of 
Oral Rociletinib (CO-1686) Monotherapy Versus Single-agent Cytotoxic 
Chemotherapy in Patients with Mutant EGFR Non-small Cell Lung 
Cancer (NSCLC) After Failure of at Least 1 Previous EGFR-directed 
Tyrosine Kinase Inhibitor (TKI) and Platinum-doublet Chemotherapy 
Date: 
7 September 2016 
Version: 
5.0 
Reviewed and Approved by: 
 
 
 
 
 
 
Sergey Yurasov, M.D., Ph.D. 
Senior Vice President of Clinical Development 
Clovis Oncology, Inc. 
 
Date 
 
 
 
 
 
Alan Newlands, Ph.D. 
Head of Global Regulatory Affairs 
Clovis Oncology, Inc. 
 
Date 
 
 
 
 
 
Jeff Isaacson, Ph.D. 
Senior Director, Biostatistics and Data Management 
Clovis Oncology, Inc. 
 
Date 
 
 


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Protocol Acceptance Form 
Protocol: 
CO-1686-020 
Title: 
TIGER-3: A Phase 3, Open-label, Multicenter, Randomized Study of 
Oral Rociletinib (CO-1686) Monotherapy Versus Single-agent Cytotoxic 
Chemotherapy in Patients with Mutant EGFR Non-small Cell Lung 
Cancer (NSCLC) After Failure of at Least 1 Previous EGFR-directed 
Tyrosine Kinase Inhibitor (TKI) and Platinum-doublet Chemotherapy 
Date: 
7 September 2016 
Version: 
5.0 
Reviewed and Approved by: 
 
I have carefully read this protocol and agree that it contains all of the necessary information 
required to conduct this study. I agree to conduct this study as described and according to the 
Declaration of Helsinki, ICH Guidelines for GCP, and all applicable regulatory requirements. 
 
 
 
 
 
Investigator’s Signature 
 
Date 
 
 
 
 
 
Name (printed) 
 
 
 


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TABLE OF CONTENTS  
PROTOCOL APPROVAL SIGNATURE PAGE .......................................................................... 2 
LIST OF IN-TEXT TABLES ......................................................................................................... 8 
LIST OF IN-TEXT FIGURES........................................................................................................ 8 
1 
SYNOPSIS ........................................................................................................................... 9 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................... 21 
3 
INTRODUCTION .............................................................................................................. 24 
3.1 
Mutant EGFR Non-small Cell Lung Cancer .............................................................. 24 
3.2 
Nonclinical Overview ................................................................................................. 26 
3.2.1 
Pharmacology ................................................................................................... 27 
3.2.2 
Metabolism ....................................................................................................... 27 
3.2.3 
Safety Pharmacology and Toxicology .............................................................. 28 
3.3 
Clinical Experience with Rociletinib .......................................................................... 28 
3.3.1 
Safety of Rociletinib from Clinical Studies ...................................................... 29 
3.3.2 
Activity of Rociletinib from Clinical Studies ................................................... 34 
3.3.3 
Pharmacokinetics of Rociletinib ....................................................................... 36 
3.4 
Rationale for Current Study ........................................................................................ 37 
4 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................... 39 
4.1 
Objectives ................................................................................................................... 39 
4.1.1 
Primary Objective ............................................................................................. 39 
4.1.2 
Secondary Objectives........................................................................................ 39 
4.1.3 
Exploratory Objectives ..................................................................................... 39 
4.2 
Endpoints .................................................................................................................... 39 
4.2.1 
Primary Endpoint .............................................................................................. 39 
4.2.2 
Secondary Endpoints ........................................................................................ 40 
4.2.3 
Exploratory Endpoints ...................................................................................... 40 
5 
STUDY DESIGN ............................................................................................................... 41 
5.1 
Overall Study Design and Plan ................................................................................... 41 
5.1.1 
Screening Period ............................................................................................... 42 
5.1.2 
Randomization .................................................................................................. 42 
5.1.3 
Treatment Period ............................................................................................... 42 
5.1.4 
End-of-Treatment .............................................................................................. 44 
5.1.5 
Follow-up .......................................................................................................... 44 
5.1.6 
Extension Phase ................................................................................................ 44 
5.2 
Study Schema.............................................................................................................. 45 
6 
STUDY POPULATION..................................................................................................... 47 
6.1 
Number of Patients and Sites ...................................................................................... 47 
6.2 
Inclusion Criteria ........................................................................................................ 47 


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6.3 
Exclusion Criteria ....................................................................................................... 48 
6.4 
Criteria for Rociletinib Cross-over Treatment Eligibility Following Radiological 
Progression on or After Comparator Arm Therapy .................................................... 50 
6.5 
Patients or Partners of Patients of Reproductive Potential ......................................... 51 
6.6 
Waivers of Inclusion/Exclusion Criteria ..................................................................... 52 
7 
DESCRIPTION OF STUDY TREATMENTS AND DOSE MODIFICATIONS ............ 53 
7.1 
Description of Study Treatments ................................................................................ 53 
7.1.1 
Rociletinib ......................................................................................................... 53 
7.1.2 
Single-agent Cytotoxic Chemotherapy ............................................................. 53 
7.2 
Method of Assigning Patients to Treatment Groups................................................... 53 
7.3 
Preparation and Administration of Protocol-specified Treatment .............................. 54 
7.3.1 
Rociletinib ......................................................................................................... 54 
7.3.2 
Single-agent Cytotoxic Chemotherapy ............................................................. 54 
7.4 
Dose Modifications of Protocol-specified Treatment ................................................. 56 
7.4.1 
Rociletinib ......................................................................................................... 56 
7.4.2 
Single-agent Cytotoxic Chemotherapy ............................................................. 59 
7.5 
Accountability of Protocol-specified Treatment ......................................................... 62 
7.6 
Blinding/Masking of Treatment .................................................................................. 62 
7.7 
Treatment Compliance ................................................................................................ 63 
7.7.1 
Rociletinib ......................................................................................................... 63 
7.7.2 
Single-agent Cytotoxic Chemotherapy ............................................................. 63 
8 
PRIOR AND CONCOMITANT THERAPIES ................................................................. 64 
8.1 
Anticancer or Experimental Therapy .......................................................................... 64 
8.2 
Hematopoietic Growth Factors and Blood Products .................................................. 64 
8.3 
CYP450 Isozyme Inhibitors and Inducers .................................................................. 64 
8.4 
P-gp Substrates, Inhibitors, and Inducers ................................................................... 65 
8.5 
Other Concomitant Medications ................................................................................. 65 
9 
STUDY PROCEDURES .................................................................................................... 67 
9.1 
Screening Period (All Patients) ................................................................................... 85 
9.1.1 
Screening for Patients who Cross Over to Rociletinib Having Progressed 
On or After Comparator Arm Therapy ............................................................. 86 
9.2 
Randomization ............................................................................................................ 87 
9.3 
Treatment Period ......................................................................................................... 87 
9.3.1 
Patients Randomized to Rociletinib or Who Cross Over to Rociletinib 
Having Progressed On or After Comparator Arm Therapy .............................. 88 
9.3.2 
Patients Randomized to Single-agent Cytotoxic Chemotherapy ...................... 90 
9.4 
End-of-Treatment Visit (All Patients) ........................................................................ 91 
9.5 
Follow-up (All Patients) ............................................................................................. 92 
9.6 
Methods of Data Collection ........................................................................................ 92 


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9.6.1 
Safety Evaluations ............................................................................................ 92 
9.6.2 
Efficacy Evaluations ......................................................................................... 94 
9.6.3 
Pharmacokinetic Evaluations ............................................................................ 95 
9.6.4 
Pharmacogenomic Assessment ......................................................................... 96 
9.6.5 
Biomarker Assessments – FFPE Tumor Tissue................................................ 96 
9.6.6 
Pharmacodynamic Evaluations - ctDNA .......................................................... 96 
9.6.7 
Quality-of-Life Assessments ............................................................................ 97 
9.6.8 
Patient Diary ..................................................................................................... 97 
10 
ADVERSE EVENT MANAGEMENT.............................................................................. 98 
10.1 
Definition of an Adverse Event .................................................................................. 98 
10.2 
Definition of a Serious Adverse Event ....................................................................... 98 
10.3 
Definition of an Adverse Event of Special Interest .................................................... 99 
10.4 
Events or Outcomes Not Qualifying as Serious Adverse Events ............................... 99 
10.5 
Clinical Laboratory Assessments as Adverse Events and Serious Adverse Events ... 99 
10.6 
Pregnancy or Drug Exposure during Pregnancy ....................................................... 100 
10.7 
Recording of Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest .......................................................................................................... 100 
10.7.1 
Intensity of Adverse Events ............................................................................ 101 
10.7.2 
Causal Relationship of Adverse Events to Investigational Medicinal 
Products........................................................................................................... 101 
10.7.3 
Outcome and Action Taken ............................................................................ 102 
10.8 
Follow-up of Adverse Events, Serious Adverse Events, and Adverse Events of 
Special Interest .......................................................................................................... 102 
10.9 
Regulatory Aspects of Serious Adverse Event Reporting and Adverse Events of 
Special Interest .......................................................................................................... 102 
11 
STATISTICAL METHODS ............................................................................................ 104 
11.1 
Analysis Populations ................................................................................................. 104 
11.2 
Statistical Methods .................................................................................................... 104 
11.2.1 
General Considerations ................................................................................... 104 
11.2.2 
Patient Disposition .......................................................................................... 104 
11.2.3 
Baseline Characteristics .................................................................................. 104 
11.2.4 
Efficacy Analyses ........................................................................................... 104 
11.2.5 
Safety Analyses ............................................................................................... 108 
11.3 
Sample Size Considerations ...................................................................................... 110 
11.4 
Interim Analysis ........................................................................................................ 110 
12 
PATIENT DISPOSITION ................................................................................................ 111 
12.1 
Patient Discontinuations ........................................................................................... 111 
13 
STUDY ADMINISTRATION ......................................................................................... 112 
13.1 
Regulatory and Ethical Considerations ..................................................................... 112 


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13.1.1 
Regulatory Authority Approvals ..................................................................... 112 
13.1.2 
Independent Ethics Committee/Institutional Review Board........................... 112 
13.2 
Confidentiality of Information .................................................................................. 113 
13.3 
Patient Informed Consent ......................................................................................... 113 
13.4 
Study Monitoring ...................................................................................................... 114 
13.5 
Case Report Form ..................................................................................................... 114 
13.6 
Study Termination and Site Closure ......................................................................... 115 
13.7 
Modification of the Study Protocol........................................................................... 115 
13.8 
Retention of Study Documents ................................................................................. 115 
13.9 
Clinical Study Report ................................................................................................ 116 
13.10 Study Publication ...................................................................................................... 116 
13.11 Quality Assurance Audits ......................................................................................... 116 
14 
REFERENCES ................................................................................................................. 117 
15 
APPENDICES .................................................................................................................. 119 


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LIST OF IN-TEXT TABLES 
Table 3-1: 
Treatment-related Serious Adverse Events Reported in Patients in 
Study CO-1686-008 .............................................................................................. 31 
Table 3-2: 
Treatment-related Adverse Events Reported in at Least 5% of Patients in 
Study CO-1686-008 .............................................................................................. 33 
Table 3-3: 
Best Response, Objective Response, and Disease Control Rate in T790M+ 
Patients .................................................................................................................. 35 
Table 9-1: 
Schedule of Assessments for Patients Randomized to Rociletinib ....................... 68 
Table 9-2: 
Schedule of Assessments for Patients Randomized to Single-agent Cytotoxic 
Chemotherapy ....................................................................................................... 74 
Table 9-3: 
Schedule of Assessments for Patients who Cross Over to Rociletinib After 
Chemotherapy ....................................................................................................... 80 
 
LIST OF IN-TEXT FIGURES 
Figure 3-1: 
Rociletinib Generates Complete Responses in L858R/T790M Transgenic 
Model .................................................................................................................... 27 
Figure 3-2: 
Target Lesion Response in Centrally Confirmed T790M+ Patients ..................... 34 
Figure 3-3: 
Best Response for Target Lesions in T790M-negative Patients ........................... 36 
Figure 3-4: 
Individual Rociletinib AUC0–24 on Day 1 Following 500 mg to 1000 mg 
CO-1686 HBr BID ................................................................................................ 37 
Figure 5-1: 
Study Schema ........................................................................................................ 46 
Figure 7-1: 
Guidelines for Management of Hyperglycemiaa ................................................... 59 
 


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1 
SYNOPSIS 
Protocol 
Number 
CO-1686-020 
Title 
TIGER-3: A Phase 3, Open-label, Multicenter, Randomized Study of Oral 
Rociletinib (CO-1686) Monotherapy Versus Single-agent Cytotoxic 
Chemotherapy in Patients with Mutant EGFR Non-small Cell Lung Cancer 
(NSCLC) After Failure of at Least 1 Previous EGFR-directed Tyrosine Kinase 
Inhibitor (TKI) and Platinum-doublet Chemotherapy 
Phase 
Phase 3  
Introduction 
In mid-2015, Clovis submitted a New Drug Application for the use of rociletinib 
in patients with T790M-positive NSCLC. In June 2016, the FDA issued a 
Complete Response Letter to Clovis stating that more data is required to approve 
rociletinib for use outside of a clinical trial. Based on this outcome, Clovis 
decided to discontinue development of CO-1686 for NSCLC. Patients will be 
informed of this change in the development plans in an update to the informed 
consent form for this study. Those patients who continue to derive clinical benefit 
from study treatment, will be allowed to continue on study at the discretion of the 
Principal Investigator in an extension phase.  
The purpose of this protocol amendment is to add a new Extension Phase to allow 
patients to continue on study but to avoid unnecessary collection of data that will 
no longer be analyzed or required for regulatory purposes, whilst maintaining an 
appropriate level of safety monitoring. A new schedule of assessments for the 
Extension Phase as well as a complete description of procedures is provided in 
Appendix C. This schedule replaces all schedules of assessments in Section 9 and 
should be followed for all patients. 
In addition, this amendment also introduces the availability of 
N-acetyltransferase 2 (NAT2) testing for patients, an indirect indicator of the 
likelihood of developing hyperglycaemia or QTc prolongation. The availability 
and disclosure of this information to the patients’ treating physician will not 
affect the monitoring and associated treatment guidelines for these adverse 
events. 
For patients who wish to continue rociletinib treatment post progression or for 
patients wish to crossover to rociletinib treatment following progression on 
chemotherapy it is important that a full exploration of alternative treatment 
options between patients and their treating physicians takes place prior to making 
that decision. 
Investigators and their staff are directed to the current Investigator’s Brochure for 
the most current efficacy and safety data, in which integrated summaries of the 
latest available data can be found and supersedes all safety and efficacy data in 
this protocol. 
Rociletinib (CO-1686) is a novel, potent, small molecule irreversible TKI that 
selectively targets mutant forms of the epidermal growth factor receptor (EGFR) 
while sparing wild-type (WT) EGFR. Clovis Oncology, Inc. (Clovis) was 
developing rociletinib as a therapeutic agent to be administered orally to patients 
with mutant EGFR NSCLC. 
Activating EGFR mutations are key drivers of NSCLC in 10% to 15% of patients 
of European descent and approximately 30% of patients of East Asian descent.1 


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Patients with the most common EGFR mutations, exon 21 L858R and deletions 
in exon 19, typically have good responses to therapy with first-generation EGFR 
inhibitors such as erlotinib or gefitinib, and also with the second generation 
inhibitor afatinib.2-4 Toxicity associated with erlotinib, gefitinib, and afatinib 
includes skin rash and diarrhea related to inhibition of the WT-EGFR in skin and 
intestine, respectively.5-7  
Despite an impressive initial response to treatment, progression generally occurs 
after 9 to 14 months of erlotinib, gefitinib, or afatinib therapy, driven in 
approximately 60% of cases by a second site EGFR mutation in exon 20 called 
T790M (the “gatekeeper” mutation) which mediates resistance to first and second 
generation EGFR inhibitors.8-10 There are no approved therapies that target 
T790M specifically, and standard of care remains cytotoxic chemotherapy. Yu et 
al reported that T790M-positive (T790M+) disease is fatal, with a median overall 
survival (OS) of less than 2 years.10  
Nonclinical data demonstrate that rociletinib inhibits T790M as well as the 
common activating mutations (L858R, del19) and has minimal inhibitory activity 
towards WT-EGFR at therapeutic doses. It is anticipated that rociletinib will 
promote cell death in tumor cells with the T790M mutation, thus driving 
objective tumor responses and providing therapeutic benefit in patients who have 
acquired T790M-mediated resistance to first generation EGFR inhibitors. 
In the first-in-human study, CO-1686-008, in patients with advanced EGFR 
mutation positive NSCLC and previous treatment with an EGFR inhibitor, no 
maximum tolerated dose (MTD) was observed and 3 doses levels, 500 mg twice 
daily (BID), 625 mg BID, and 750 mg BID, were selected for further clinical 
evaluation of safety, tolerability and efficacy in the expansion cohorts. Maturing 
data from this study suggest that patients treated with rociletinib at 500 mg BID 
and 625 mg BID experience responses that are comparable in frequency, depth 
and duration, with an overall acceptable safety profile for this advanced cancer 
patient population. To further describe the risk/benefit profile of the rociletinib 
500 mg BID dose, patients enrolled under Protocol Amendment 2 will receive a 
starting dose of 500 mg BID. 
As expected, due to its selectivity for mutant EGFR, events typical of WT-EGFR 
inhibition (the combination of rash and chronic diarrhea) have not been observed 
with rociletinib. Furthermore, heavily pretreated patients have experienced 
durable Response Evaluation Criteria In Solid Tumors (RECIST) responses. The 
majority of these responders had most recently been treated with an EGFR-TKI. 
Moreover, initial clinical data suggest that rociletinib may provide clinical 
benefits to patients who test negative with respect to the T790M mutation and the 
study has been designed to specifically investigate the effectiveness of rociletinib 
in this group of patients.  
The goals of the current study (Protocol CO-1686-020) are to compare the 
anti-tumor efficacy and safety of oral single-agent rociletinib with that of single-
agent cytotoxic chemotherapy in patients with EGFR-mutated, 
advanced/metastatic NSCLC after failure of at least 1 previous EGFR-directed 
TKI and 1 line of platinum-containing doublet chemotherapy. An additional goal 
will be to determine the effectiveness of rociletinib in patients who test negative 
with respect to the T790M mutation. 
Rociletinib is being developed with a companion diagnostic (Qiagen, United 
Kingdom) to identify patients whose tumors express activating EGFR mutations 
as well as the T790M resistance mutation.  


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Planned 
Number of 
Patients 
Up to approximately 600 patients will be enrolled. 
Planned 
Number of Sites 
Up to 150 investigative sites in North America, Europe, Asia, and Australia. 
Study 
Objectives 
Primary Objective 
• 
To compare the anti-tumor efficacy of oral single-agent rociletinib, as 
measured by investigator assessment of the progression-free survival (PFS), 
with that of single-agent cytotoxic chemotherapy in patients with 
EGFR-mutated, advanced/metastatic NSCLC after failure of at least 1 
previous EGFR-directed TKI and at least 1 line of platinum-containing 
doublet chemotherapy 
Secondary Objectives 
• 
To compare secondary measures of clinical efficacy (duration of response 
[DR], objective response rate [ORR], and OS) between patients randomized 
to rociletinib or single-agent cytotoxic chemotherapy 
• 
To compare the safety and tolerability of rociletinib with that of single-agent 
cytotoxic chemotherapy 
• 
To determine pharmacokinetics (PK) of rociletinib using population PK 
(POPPK) methods and explore correlations between PK, exposure, response, 
and/or safety findings in patients randomized to rociletinib 
Exploratory Objectives 
• 
To evaluate clinical benefit of continued rociletinib treatment following 
disease progression in patients randomized to the rociletinib arm 
• 
To evaluate clinical benefit of rociletinib treatment following disease 
progression in patients randomized to the comparator arm who cross over to 
receive rociletinib 
• 
To compare quality of life (QoL) by patient-reported outcomes (PRO) 
between patients randomized to rociletinib or single-agent cytotoxic 
chemotherapy  
• 
To evaluate concordance of mutant EGFR detection between tissue and 
plasma and assess rociletinib mediated alterations in mutant EGFR levels 
over time using circulating tumor deoxynucleic acid (ctDNA) obtained from 
plasma; analyze clinical endpoints based on plasma EGFR mutation test 
results 
• 
To explore tissue and blood-based biomarkers that may be predictive of 
response or primary resistance to rociletinib and investigate mechanisms of 
acquired resistance in the tissue and blood of patients who experience clinical 
progression during treatment with rociletinib  
Study Endpoints Primary Endpoint: 
• 
PFS according to RECIST Version 1.111 as determined by investigator 
assessment (invPFS) 
Secondary Endpoints: 
• 
ORR and DR according to RECIST Version 1.1 as determined by 
investigator assessment 
• 
OS 


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• 
Treatment-emergent adverse events (AEs), laboratory abnormalities, and 
electrocardiogram (ECG) abnormalities 
• 
Plasma PK parameters for rociletinib based on sparse sampling 
Exploratory Endpoints: 
• 
DCR according to RECIST Version 1.1 as determined by investigator 
assessment 
• 
Time-to-treatment failure  
• 
OS, ORR, PFS, DR, and DCR in patients who cross over to receive 
rociletinib and in patients who continue to receive rociletinib beyond 
progression 
• 
Change from baseline in PROs using the European Organization for 
Research and Treatment of Cancer Core Quality of Life Questionnaire 
(EORTC QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 
module (EORTC QLQ-LC13)12 and the EQ-5D13  
• 
Change from baseline in mutant EGFR levels in ctDNA obtained from 
plasma 
• 
OS, ORR, PFS, DR, and DCR based on plasma EGFR mutation test results 
• 
Positive and negative percent agreement between blood and tissue results for 
T790M  
• 
Identify biomarkers associated with response or resistance to rociletinib 
Study Design 
In mid-2015, Clovis submitted a New Drug Application for the use of rociletinib 
in patients with T790M-positive NSCLC. In June 2016, the FDA issued a 
Complete Response Letter to Clovis stating that more data is required to approve 
rociletinib for use outside of a clinical trial. Based on this outcome, Clovis 
decided to discontinue development of CO-1686 for NSCLC. Patients will be 
informed of this change in the development plans in an update to the informed 
consent form for this study. Those patients who continue to derive clinical benefit 
from study treatment, will be allowed to continue on study at the discretion of the 
Principal Investigator in an extension phase.  
The purpose of this protocol amendment is to add a new Extension Phase to allow 
patients to continue on study but to avoid unnecessary collection of data that will 
no longer be analyzed or required for regulatory purposes, whilst maintaining an 
appropriate level of safety monitoring. A new schedule of assessments for the 
Extension Phase as well as a complete description of procedures is provided in 
Appendix C. This schedule replaces all schedules of assessments in Section 9 and 
should be followed for all patients. 
In addition, this amendment also introduces the availability of NAT2 testing for 
patients, an indirect indicator of the likelihood of developing hyperglycemia or 
QTc prolongation. The availability and disclosure of this information to the 
patient’s treating physician will not affect the monitoring and associated 
treatment guidelines for these adverse events. 
For patients who wish to continue rociletinib treatment post progression or for 
patients wish to crossover to rociletinib treatment following progression on 
chemotherapy it is important that a full exploration of alternative treatment 
options between patients and their treating physicians takes place prior to making 
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This is a Phase 3, randomized, open-label, multicenter study evaluating the safety 
and efficacy of oral rociletinib compared with that of single-agent cytotoxic 
chemotherapy, in patients with previously treated mutant EGFR NSCLC. Eligible 
patients are those with mutant EGFR NSCLC previously treated with at least 
1 EGFR inhibitor and at least 1 line of platinum-containing chemotherapy 
doublet for advanced/metastatic NSCLC. 
After providing informed consent to participate and screening to confirm 
eligibility, patients will be randomized 1:1 to receive rociletinib or single-agent 
cytotoxic chemotherapy (investigator choice of pemetrexed, gemcitabine, 
docetaxel, or paclitaxel; choice of chemotherapy agent must be specified before 
randomization). Randomization will be stratified according to: 
1. Brain metastases present versus no brain metastases present, 
2. Eastern Cooperative Oncology Group (ECOG) performance status 0 
versus ECOG performance status 1, 
3. Territory of residence at time of randomization (East Asian versus non-
East Asian). 
All patients will provide a tumor biopsy during screening for central 
determination of T790M mutation status, although the test results do not have to 
be available before randomization. Switching therapy after biopsy sampling is not 
permitted as this may impact on the T790M mutation status. However, dose 
reduction of the therapy adopted at that time is permitted. 
The treatment cycle length will be 21 days for all treatments. Treatment will 
continue, with tumor assessment every 6 ± 1 weeks, irrespective of regimen, until 
disease progression or until other withdrawal criteria are met (including 
completion of a single-agent chemotherapy regimen). If clinical progression is 
diagnosed then confirmation of disease progression with a computed tomography 
(CT) scan (per RECIST 1.1) will be required. Tumor scan at the End-of-
Treatment Visit is not required if patient had radiographic evidence of disease 
progression on study, or it has been < 2 weeks since last on-study scan. In 
addition, a magnetic resonance imaging (MRI) may be used in place of a CT at 
end-of-treatment scan if required per local authorities. 
Patients may opt to continue to receive treatment with rociletinib following 
radiographic progression as outlined in the National Comprehensive Cancer 
Network (NCCN) guidelines for treatment of NSCLC with EGFR-TKIs if: a) the 
patient provides additional consent, b) the investigator feels it is in the patient’s 
best interest, and c) the sponsor provides approval. In general, eligible patients 
may include those with asymptomatic systemic progression or locally 
symptomatic progression, such as brain metastases amenable to local treatment, 
with concomitant asymptomatic systemic progression or continued systemic 
disease control. 
Patients randomized to the comparator chemotherapy arm may choose to cross 
over to receive rociletinib upon radiological progression. As with all patients, if 
clinical progression is diagnosed then confirmation of disease progression with a 
CT/MRI scan (per RECIST 1.1) will be required along with sponsor approval 
before crossing over to treatment with rociletinib.  
When protocol-specified therapy is discontinued, and the patient has yet to 
progress, patients will continue to undergo scheduled tumor assessments for 


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monitoring of PFS. All patients will also be followed for survival status, and 
subsequent NSCLC cancer therapy. 
Dosing may be delayed or reduced according to protocol-specified toxicity 
criteria. 
Patients will undergo serial assessments for anti-tumor efficacy, drug safety, and 
PROs. Sparse blood sampling for POPPK analyses will be conducted in all 
patients treated with rociletinib. A central laboratory will confirm presence or 
absence of the T790M mutation in formalin-fixed paraffin embedded (FFPE) 
tumor tissue (results not required prior to randomization). Local laboratories will 
be used for hematology and chemistry. ECGs will be performed and interpreted 
locally for patient care decisions; however, tracings will be collected centrally for 
independent evaluation. Tumor scans will be acquired by the investigative site 
and evaluated locally for patient treatment decisions. Scans will also be collected 
and stored with a central vendor and quality control performed; central reading of 
scans will not be done unless requested by the sponsor. Following disease 
progression, patients who provide additional consent will undergo tumor biopsy 
before subsequent-line therapy is initiated.  
AEs will be collected from the time the first dose of study drug is administered 
through to 28 days after the last protocol-specified treatment administration. 
Study procedure-related AEs that occur after signing of the Informed Consent 
Form (ICF) but before administration of study drug will also be captured. 
Study 
Population 
Inclusion Criteria 
All patients must meet all of the following inclusion criteria: 
1. Histologically or cytologically confirmed metastatic or unresectable locally 
advanced NSCLC with radiological progression on the most recent therapy 
received 
2. Documented evidence of a tumor with 1 or more EGFR activating mutations 
excluding exon 20 insertion 
3. Disease progression confirmed by radiological assessment while receiving 
treatment with single-agent EGFR-TKI (eg, erlotinib, gefitinib, afatinib, or 
dacomitinib). The washout period for the single agent EGFR-TKI is a 
minimum of 3 days or 5 half-lives, whichever is more applicable, prior to 
start of treatment.  
4. Multiple lines of prior treatment are permitted and there is no specified order 
of treatment, but in the course of their treatment history, patients must have 
received and have radiologically documented disease progression following: 
− 
At least 1 line of prior treatment with a single-agent EGFR TKI (eg, 
erlotinib, gefitinib, afatinib, or dacomitinib)  
o 
If EGFR-TKI is a component of the most recent treatment line, the 
washout period for the EGFR-TKI is a minimum of 3 days before 
the start of rociletinib treatment 
AND 
− 
A platinum-containing doublet chemotherapy (either progressed during 
therapy or completed at least 4 cycles without progression with 
subsequent progression after a treatment-free interval or after a 
maintenance treatment). 
o 
If cytotoxic chemotherapy is a component of the most recent 
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completed at least 14 days prior to start of study treatment. When an 
EGFR-TKI is given in combination with platinum-containing 
doublet chemotherapy, treatment with the EGFR-TKI may continue 
until at least 3 days before start of treatment.  
5. Have undergone a biopsy of either primary or metastatic tumor tissue within 
60 days prior to start of treatment and have tissue available to send to sponsor 
laboratory or are able to undergo a biopsy during screening and provide 
tissue to sponsor laboratory 
6. Measureable disease according to RECIST Version 1.1 
7. Life expectancy of at least 3 months 
8. ECOG performance status of 0 to 1 
9. Age  18 years (in certain territories, the minimum age requirement may be 
higher eg, age  20 years in Japan and Taiwan, age  21 years in Singapore) 
10. Patients should have recovered to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Grade ≤ 1 from any 
significant chemotherapy-related toxicities 
11. Adequate hematological and biological function, confirmed by the following 
local laboratory values: 
Bone marrow function 
a. Absolute neutrophil count (ANC)  1.5 × 109/L 
b. Platelets > 100.0 × 109/L  
c. Hemoglobin  9 g/dL (or 5.6 mmol/L) 
Hepatic function 
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
 3 × upper limit of normal (ULN); if liver metastases,  5 × ULN 
e. Bilirubin  2 × ULN 
− Patients with documented Gilbert’s syndrome and conjugated 
bilirubin within the normal range may be allowed into the study. In 
this event, it will be documented that the patient was eligible based on 
conjugated bilirubin levels 
Renal function  
f. Creatinine clearance ≥ 45 mL/min 
Electrolytes 
g. Potassium and magnesium within normal range. Patients may receive 
supplements to meet this requirement. 
Glucose 
h. Fasting serum glucose within normal ranges 
12. Written consent on an Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)-approved ICF before any study-specific evaluation 
Exclusion Criteria 
Any of the following criteria will exclude patients from study participation: 


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1. Any other malignancy associated with a high mortality risk within the next 
5 years and for which the patients may be (but not necessarily) currently 
receiving treatment 
− 
Patients with a history of malignancy that has been completely treated, 
with no evidence of that cancer currently, are permitted to enroll in the 
trial provided all chemotherapy was completed > 6 months prior and/or 
bone marrow transplant > 2 years prior 
2. Known pre-existing interstitial lung disease 
3. Tumor small cell transformation by local assessment, irrespective of 
presence of T790M+ component 
4. Patients with leptomeningeal carcinomatosis are excluded. Other central 
nervous system (CNS) metastases are only permitted if treated, 
asymptomatic, and stable (not requiring steroids for at least 2 weeks prior to 
randomization and the patient is neurologically stable; ie, free from new 
symptoms of brain metastases). If a patient has had brain metastasis treated 
within the previous 8 weeks, a follow-up scan should have been performed to 
confirm that treated metastasis remain controlled without evidence of new 
lesions. 
5. Patients who are currently receiving treatment with any medications that 
have the potential to prolong the QT interval and that treatment cannot be 
either discontinued or switched to a different medication (known to have no 
effect on QT) before starting protocol-specified treatment (see 
http://crediblemeds.org/ for a list of QT-prolonging medications) 
6. Prior treatment with rociletinib, or other drugs that target T790M+ mutant 
EGFR with sparing of WT-EGFR including but not limited to AZD9291, 
HM61713, and TAS-121 
7. Any contraindications for therapy with pemetrexed, paclitaxel, gemcitabine 
or docetaxel unless a contraindication with respect to one of these drugs will 
not affect the use of any of the others as a comparator to rociletinib 
8. Any of the following cardiac abnormalities or history: 
a. Clinically significant abnormal 12-lead ECG, QT interval corrected using 
Fridericia’s method (QTCF) > 450 msec  
b. Inability to measure QT interval on ECG 
c. Personal or family history of long QT syndrome 
d. Implantable pacemaker or implantable cardioverter defibrillator 
e. Resting bradycardia < 55 beats/min 
9. Non-study related surgical procedures  7 days prior to randomization. In all 
cases, the patient must be sufficiently recovered and stable before treatment 
administration. 
10. Females who are pregnant or breastfeeding 
11. Refusal to use adequate contraception for fertile patients (females and males) 
while on treatment and for 6 months after the last dose of study treatment 
(rociletinib and chemotherapy irrespective of single cytotoxic agent used) 
12. Presence of any serious or unstable concomitant systemic disorder 
incompatible with the clinical study, eg, substance abuse, uncontrolled 
intercurrent illness including: 
• 
uncontrolled diabetes 


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• 
 active infection 
• 
arterial thrombosis, and  
• 
symptomatic pulmonary embolism 
13. Any other reason the investigator considers the patient should not participate 
in the study 
14. Treatment with live vaccines initiated less than 4 weeks prior to 
randomization 
Study 
Treatments 
Patients will be randomized 1:1 to receive either rociletinib or single-agent 
cytotoxic chemotherapy (investigator choice of pemetrexed, gemcitabine, 
docetaxel, or paclitaxel; choice of chemotherapy agent must be specified before 
randomization).  
Rociletinib 
Daily oral rociletinib at 500 mg BID with 8 oz (240 mL) of water and with a meal 
or within 30 minutes after a meal. Treatment with rociletinib is continuous and 
each cycle will comprise of 21 days. 
For patients who started therapy with rociletinib at 625 mg BID under Protocol 
Amendment 1, a dose reduction to 500 mg BID is allowed, only if necessitated by 
unacceptable toxicity. 
Pemetrexed 
500 mg/m2 pemetrexed given intravenously on Day 1 of each 21-day cycle.  
Gemcitabine 
1250 mg/m2 gemcitabine given intravenously on Days 1 and 8 of each 21-day 
cycle. 
 
Docetaxel 
75 mg/m2 docetaxel (60 mg/m2 in Asian patients) given intravenously on Day 1 
of each 21-day cycle, or 35 mg/m2 docetaxel given intravenously on a weekly 
basis as part of a continuous 21-day cycle; ie, dosing will be on Days 1, 8, and 15 
of each 21-day cycle.  
Paclitaxel 
80 mg/m2 paclitaxel given intravenously as a 1 hour infusion, on a weekly basis 
as part of a continuous 21-day cycle; ie, dosing will be on Days 1, 8, and 15 of 
each 21-day cycle. 
Concomitant 
Medications 
Premedication should be administered in accordance with standard of care 
associated with the comparator chemotherapy. Additional supportive care may be 
used at the investigator’s discretion and in accordance with institutional 
procedures.  
Withdrawal 
Criteria 
After stopping protocol-specified treatment, all patients will remain in the study 
and will be followed for safety (until 28 days after last dose for all AEs or until 
resolution for serious adverse events [SAEs]), and for survival status and 
subsequent therapy assessment (approximately every 2 months from the 
End-of-Treatment Visit until death or sponsor decision, whichever comes first). 
Patients who discontinue rociletinib or chemotherapy without progression should 
continue to be scanned every 6 weeks per protocol until disease progression 
occurs. Exceptions to this requirement based on local institutional or regulatory 
requests must be agreed in advance with the sponsor. A patient must be 
discontinued from protocol-prescribed therapy if any of the following apply: 


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• 
Consent withdrawal at the patient’s own request or at the request of their 
legally authorized representative 
• 
Radiographic progression of patient’s underlying disease per RECIST 1.1, 
except as described in Section 5.1.3 of the protocol. If clinical progression is 
diagnosed then confirmation with a CT scan will be required before patient 
withdrawal 
• 
Any event, adverse or otherwise, that, in the opinion of the investigator, 
would pose an unacceptable safety risk to the patient 
• 
An intercurrent illness that, in the opinion of the investigator, would affect 
assessments of the clinical status to a significant degree  
• 
A positive pregnancy test at any time during the study 
• 
Noncompliance as described in Section 7.7 of the protocol 
• 
Investigator decision 
Efficacy 
Assessments 
Efficacy measures will include tumor assessments, preferably by CT scans of the 
chest and abdomen with appropriate slice thickness per RECIST Version 1.1. 
Scans of the pelvis (CT or MRI) are required if there is prior evidence of local 
disease or if clinically indicated (symptomatic patients). MRI scans may be 
carried out in patients unable to undergo CT scan or if requested by local 
regulatory authorities. Brain imaging (CT/MRI) is required at baseline and 
follow-up scans should include the brain in patients with baseline brain lesions. 
All sites of disease should be followed and the same imaging methodology 
should be used throughout the study. 
Tumor assessments will be carried out at screening and every 6 weeks ± 1 week 
from the time of randomization thereafter until tumor progression. Patients are 
required to have an end-of-treatment tumor scan using the same methodology 
used at screening unless: 
• 
The patient has radiographic evidence of disease progression while on study, 
or  
• 
It has been < 2 weeks since their last on-study scan 
In addition, an MRI may be used in place of a CT at end-of-treatment scan if 
required per local authorities. 
Patients who discontinue rociletinib or chemotherapy without progression should 
continue to be scanned every 6 weeks per protocol until disease progression 
occurs. Exceptions to this requirement based on local institutional or regulatory 
requests must be agreed in advance with the sponsor. If a treatment cycle is 
delayed, the efficacy assessments should still follow the 6-weekly calendar 
schedule from the time of randomization. 
Safety 
Assessments 
Safety assessments will include:  
• 
AEs  
• 
Hematology including complete blood count (CBC) and differential, clinical 
chemistry including glycated HbA1c and c-peptide, and urinalysis 
• 
12-lead ECGs  
• 
Physical examination, vital signs, and body weight 
• 
Concomitant medications/procedures 
• 
ECOG performance status 
AEs will be classified according to the NCI CTCAE Version 4.03.14  


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Biomarker 
Assessments 
EGFR mutational status will be assessed in matching blood and tumor tissue 
collected at screening from each patient. Tumor tissue from the primary tumor, or 
an accessible local/distal metastatic lesion, will be obtained within 60 days prior 
to start of treatment with study drug. The corresponding blood specimen will be 
obtained immediately prior to tumor specimen collection where possible. 
EGFR-mutational status on collected tissue and blood will be assessed by the 
sponsor.  
If sufficient tissue is available from the baseline tumor biopsy, samples will be 
tested for other molecular alterations, that may modulate response or resistance to 
EGFR-targeted therapy including but not limited to EGFR gene amplification, 
MET proto-oncogene (MET) amplification, phosphatidylinositol-4,5-
bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations, and 
expression of other growth factor receptors and their ligands. Following disease 
progression, patients who provide additional consent will undergo a tumor biopsy 
before subsequent line therapy is initiated. This tissue will be analyzed for 
molecular alterations that modulate resistance to EGFR-targeted therapy. 
For patients who provide additional consent, genomic DNA will be extracted 
from a blood sample in order to detect genetic polymorphisms in cytochrome 
P450 (CYP) isozymes and to explore the possible correlation between CYP 
polymorphism and drug exposure. The extracted genomic DNA from blood may 
additionally be compared to tumor DNA so that molecular alterations unique to 
the tumor that may modulate response or resistance to EGFR-targeted therapy 
can be unambiguously identified. 
Patient-reported 
Outcome 
Assessments 
PROs will be measured using the EORTC QLQ-C30, EORTC QLQ-LC1312 and 
EQ-5D13 which will be administered at screening, pre-dosing on Cycle 1 Day 1 
(C1D1), then on Day 1 of every 2 cycles ± 1 week for the first 6 cycles. After 
Cycle 7, questionnaires will be collected every 3 cycles ± 1 week, and at the 
End-of-Treatment Visit. 
Statistical 
Procedures 
Sample Size Justification 
Up to approximately 600 patients will be randomized in a 1:1 ratio to receive 
treatment with rociletinib or single-agent cytotoxic chemotherapy.  
The primary objective of this study is to estimate the difference in PFS between 
rociletinib and single-agent cytotoxic chemotherapy. The median PFS for 
cytotoxic chemotherapy in this patient population is expected to be approximately 
4 months15 while the median PFS in all rociletinib patients (both T790M+ and 
negative) is expected to be at least 6 months.  
A step-down procedure will be used (see below) where PFS will first be 
evaluated in the T790M+ subgroup followed by all randomized patients.  
The total sample size for the study is based on the minimum anticipated treatment 
effect of 4 months versus 6 months median PFS in all patients. A total of 
600 patients should result in about 400 events of progression which provides 
90% power to detect a hazard ratio (HR) of 0.70 at a one-sided 0.025 significance 
level.  
The targeted number of T790M+ patients in this study is between 250 and 
275 patients. A sample size of 250 T790M+ patients should result in about 
170 events of progression which provides 90% power to detect a HR of 0.60 at a 
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In the event that the frequency of T790M+ patients in this trial is lower than 
expected, enrollment will continue until 250 T790M+ patients have been 
enrolled.  
Efficacy Analysis 
The primary and key secondary endpoints will be tested among the centrally 
confirmed T790M+ and all randomized patients, using an ordered step-down 
multiple comparisons procedure. InvPFS in the T790M+ subgroup will be tested 
first at a one-sided 0.025 significance level. If invPFS in the T790M+ subgroup is 
statistically significant then invPFS in all randomized patients will be tested at a 
one-sided 0.025 significance level. A sensitivity analysis of Independent 
Radiology Review of PFS (irrPFS) will also be conducted. The remaining key 
secondary efficacy analyses will also be tested using this step-down approach. 
Once statistical significance is not achieved for one test, the statistical 
significance will not be declared for all subsequent analyses in the ordered 
step-down procedure.  
Kaplan-Meier methodology will be used to summarize time to event variables. 
The stratified log-rank and the HR will be used for comparing the PFS 
distributions among the rociletinib and chemotherapy-treated patients. The 
stratification factors of brain metastases and territory will also be used for 
analysis.  
The ORR will be summarized with frequencies and percentages. The DR for 
complete response (CR) and partial response (PR) will be summarized with 
descriptive statistics (N, mean, standard deviation, median, minimum, and 
maximum) as well as categorically. 
Safety Analyses 
Data from all patients who receive 1 or more doses of study medication will be 
included in the safety analyses. AEs, clinical laboratory information, vital signs, 
ECGs, ECOG performance status, body weight, and concomitant 
medications/procedures will be summarized.  
Population PK  
Sparse blood sampling for POPPK analyses will be conducted in all patients 
treated with rociletinib (patients randomized to receive rociletinib or those who 
cross over to receive rociletinib following treatment with single-agent cytotoxic 
chemotherapy). A specific POPPK data analysis plan will be developed and will 
outline the detailed approach to data handling, model development and 
diagnostics, individual model parameter estimation, exploration of covariate 
effects, and final model evaluation techniques.  
Pharmacodynamic Assessment 
Blood may be tested for biomarkers of response or resistance to EGFR-targeted 
therapy. Analysis may be performed on a subset of patients if it becomes clear 
that the analysis will have limited scientific value in some or if there are not 
enough serially collected samples from individual patients to allow for adequate 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AAG 
alpha 1-acid glycoprotein 
AE 
adverse event 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUC0−24 
area under the curve from time zero to 24 hours 
BID 
twice daily 
BUN 
blood urea nitrogen 
C12h 
concentration at 12 hours post-dose 
C1D1 
Cycle 1 Day 1 
CBC 
complete blood count 
CFR 
Code of federal regulations 
CI 
confidence interval 
Cmax 
maximum concentration 
CNS 
central nervous system 
CO2 
carbon dioxide 
CO-1686 free base (Fb) 
free base form of CO-1686 
CO-1686 HBr 
hydrobromide salt formulation CO-1686 
CR 
complete response  
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events, Version 4.03 
ctDNA 
circulating tumor DNA 
CYP 
cytochrome P450 
DCR 
disease control rate 
DLT 
dose-limiting toxicity  
DNA 
deoxyribonucleic acid 
DR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 


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EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Core 
Quality of Life Questionnaire 
EORTC QLQ-LC13 
European Organization for the Research and Treatment of Cancer Quality 
of Life Questionnaire Lung Cancer module 
EURTAC 
EURopean TArceva® versus Chemotherapy study 
FACT-L 
Functional Assessment of Cancer Therapy-Lung 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FG 
fasting plasma or serum glucose 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
GRAS 
generally regarded as safe 
HbA1c 
glycated hemoglobin A1c 
HCP 
health care practitioner 
HIPAA 
Health Information Portability and Accountability Act  
HR 
hazard ratio 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IGF-1R 
insulin-like growth factor 1 receptor 
INR 
international normalized ratio 
invPFS 
investigator determined progression-free survival 
iPASS 
Iressa™ Pan-ASian Study 
IR 
insulin receptor 
IRB 
Institutional Review Board  
IRR 
Independent Radiology Review 
irrPFS 
Independent Radiology Review of PFS 
ITT 
intent-to-treat 
LD 
longest diameter 
MedDRA 
Medical Dictionary for Drug Regulatory Activities  
MET 
MET proto-oncogene 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NAT2 
N-acetyltransferase 2 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
not evaluable 
NSAID 
nonsteroidal anti-inflammatory drug 


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NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PIK3CA 
hosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha 
PK 
pharmacokinetic 
PMDA 
Pharmaceuticals and Medical Devices Agency 
POPPK 
population pharmacokinetics 
PR 
partial response 
PROs 
patient-reported outcomes 
PT 
preferred term 
QD 
once daily 
QoL 
quality of life 
QTCF 
QT interval corrected using Fridericia’s method 
RECIST 
Response Evaluation Criteria In Solid Tumors, Version 1.1 
SAE 
serious adverse event 
SAS 
statistical analysis software 
SD 
stable disease 
SGLT2 
sodium-glucose cotransporter 2 
SOC 
system organ class 
SOP 
standard operating procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
suspected unexpected serious adverse reaction 
T1/2 
elimination half-life 
T790M 
EGFR mutation in exon 20; “gatekeeper” mutation 
T790M+ 
T790M-positive 
TE 
treatment-emergent 
TKI 
tyrosine kinase inhibitor 
Tmax 
time to maximum concentration 
TOI 
trial outcome index 
ULN 
upper limit of normal 
WBC 
white blood cell 
WT 
wild-type 
β-hCG 
beta human chorionic gonadotropin 


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3 
INTRODUCTION 
CO-1686 Clinical Development Program Update 
In mid-2015, Clovis submitted a New Drug Application for the use of rociletinib in patients with 
T790M-positive NSCLC. In June 2016, the FDA issued a Complete Response Letter to Clovis 
stating that more data is required to approve rociletinib for use outside of a clinical trial. Based 
on this outcome, Clovis decided to discontinue development of CO-1686 for NSCLC. Patients 
will be informed of this change in the development plans in an update to the informed consent 
form for this study. Those patients who continue to derive clinical benefit from study treatment, 
will be allowed to continue on study at the discretion of the Principal Investigator in an extension 
phase.  
Extension Phase 
The purpose of this protocol amendment is to add a new Extension Phase to allow patients to 
continue on study but to avoid unnecessary collection of data that will no longer be analyzed or 
required for regulatory purposes, whilst maintaining an appropriate level of safety monitoring. A 
new schedule of assessments for the Extension Phase as well as a complete description of 
procedures is provided in Appendix C. This schedule replaces all schedules of assessments in 
Section 9 and should be followed for all patients. 
In addition, this amendment also introduces the availability of N-acetyltransferase 2 (NAT2) 
testing for patients, an indirect indicator of the likelihood of developing hyperglycaemia and QTc 
prolongation. The availability and disclosure of this information to the patient’s treating 
physician will not affect the monitoring and associated treatment guidelines for these adverse 
events. 
For patients who wish to continue rociletinib treatment post progression or for patients who wish 
to crossover to rociletinib treatment following progression on chemotherapy it is important that a 
full exploration of alternative treatment options between patients and their treating physicians 
takes place.  
Investigators and their staff are directed to the current Investigator’s Brochure for the most 
current efficacy and safety data, in which integrated summaries of the latest available data can be 
found and supersedes all safety and efficacy data in this protocol. 
3.1 
Mutant EGFR Non-small Cell Lung Cancer  
Despite years of research and prevention strategies, lung cancer remains the most common 
cancer worldwide with an incidence of 1.8 million in 2012 representing 13% of all cancers, and 
non-small cell lung cancer (NSCLC) accounts for almost 89% of all lung cancers.16,17 
Additionally, lung cancer continues to be the most common cause of cancer-related deaths 
worldwide with a 5-year survival rate of less than 10% in patients with advanced disease.18  
Cytotoxic chemotherapy has been the mainstay of treatment of patients with NSCLC; however, 
survival rates remain low and toxicity is significant. Recent breakthroughs in NSCLC treatment 


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have been a result of molecular characterization of NSCLC and development of molecularly 
targeted agents that have demonstrated superiority to chemotherapy in those patients whose 
tumors express the targeted genetic mutation.  
One timely example is the recent approval of crizotinib, used to treat NSCLC patients whose 
tumors harbor anaplastic lymphoma kinase (ALK) rearrangements. In 2 single-arm studies of 
crizotinib in previously treated ALK-positive patients, the tumor response rates were 50% and 
61% and the duration of responses (DR) were 42 and 48 weeks, respectively.19,20 These response 
rates and the DR are significantly higher that what would be expected with chemotherapy in this 
patient population.21  
Molecularly targeted therapies also have proven to be superior to chemotherapy for NSCLC 
patients whose tumors have mutations in the epidermal growth factor receptor (EGFR). 
Activating EGFR mutations are key drivers of NSCLC malignancy in 10% to 15% of patients of 
European descent and approximately 30% of patients of East Asian descent.1 Two recent Phase 3 
trials comparing EGFR tyrosine kinase inhibitors (TKIs) versus chemotherapy have established 
TKIs as the gold standard for treating EGFR-mutation-positive NCSLC. In the Iressa™ Pan-ASia 
Study (iPASS), treatment with gefitinib was compared with treatment with carboplatin/paclitaxel 
in previously-untreated NSCLC patients. In EGFR-mutation-positive patients, the response rate 
was significantly higher with gefitinib treatment (71.2%) than with chemotherapy (47.3%).2 
Furthermore, EGFR-mutation-positive patients experienced a significantly longer progression 
free survival (PFS) of 9.5 months compared with 6.3 months for those on chemotherapy.22 
Quality of life (QoL) was also evaluated in this study; more patients treated with gefitinib versus 
chemotherapy had clinically meaningful improvement in QoL, as assessed by the Functional 
Assessment of Cancer Therapy-Lung (FACT-L) questionnaire and the Trial Outcome Index 
(TOI). Although survival was an endpoint of the study, the analysis of overall survival (OS) was 
complicated by the fact that EGFR-mutation-positive patients assigned to the chemotherapy arm 
crossed over to gefitinib upon progression. A second Phase 3 randomized trial, the EURopean 
TArceva® (erlotinib) versus Chemotherapy (EURTAC) study, compared erlotinib treatment with 
chemotherapy in previously untreated patients with EGFR-mutation-positive NSCLC. Patients 
demonstrated a response rate of 58% in the erlotinib arm compared with 15% in the 
chemotherapy arm (p < 0.0001). Furthermore, PFS was 9.7 months in the erlotinib arm versus 
5.2 months in the chemotherapy arm (hazard ratio [HR] = 0.37; p < 0.0001).23 At an interim 
analysis, OS was 22.9 months in the erlotinib arm and 18.8 months in the chemotherapy arm 
(HR = 0.80; p = 0.42). Again, cross over from chemotherapy to erlotinib confounds 
interpretation of survival data in this study. These data demonstrate that gefitinib and erlotinib 
improve response rates and PFS compared with chemotherapy.  
While the toxicity profile is also improved with first-generation TKIs compared with 
chemotherapy, significant toxicities do occur. Toxicities associated with both erlotinib and 
gefitinib includes skin rash and diarrhea related to inhibition of the wild-type (WT) EGFR in 
skin and intestine, respectively.5-7  
Despite the initial response, progression occurs in most patients. In the most comprehensive 
analysis to date, Sequist et al analyzed serial biopsies from EGFR-mutation-positive NSCLC 
patients who progressed on TKIs.24 Through this research, Sequist demonstrated that acquired 
resistance occurs through a number of different mechanisms, while the activating mutation is 


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maintained. The most common cause of progression (in 60% of patients) was found to be a 
second site EGFR mutation in exon 20 called T790M (the “gatekeeper” mutation), which 
prevents drug from binding to the receptor.3,8,9,24 This mutation was sometimes associated with 
amplification of the EGFR gene as well. Some patients developed amplification of another gene 
that drives tumor growth (MET proto-oncogene (MET) amplification). Still others showed 
mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha 
(PIK3CA) gene. Interestingly, a few patients had tumors that transitioned to a small-cell lung 
cancer, or to a more aggressive mesenchymal cell morphology.24  
The differences in the mechanisms of resistance have a direct impact on patient treatment 
algorithms; specific therapies are needed to target these different mutations or changes in cellular 
morphology. For patients with the T790M mutation, there are currently no approved therapies. 
Several compounds that target the T790M mutation are in development. Second generation TKIs 
such as neratinib and afatinib have been shown to be more potent than erlotinib and gefitinib 
against the T790M mutation in vitro, but only at concentrations higher than the drug 
concentration required to maximally inhibit WT-EGFR.25 Consequently, although there are 
several compounds in development, to date they have failed to demonstrate significant 
anti-T790M activity in the clinic, likely because of dosing limitations caused by toxicity from 
WT-EGFR inhibition. Hence, patients who have progressed on first generation TKIs have limited 
treatment options. Assessment of post-progression survival in patients treated with EGFR-TKI 
indicated patients with EGFR T790M-positive (T790M+) tumors had a median post-progression 
survival of 1.9 years (95% confidence interval [CI], 1.6–2.6 years).10 These patients are usually 
offered chemotherapy, which is known to cause increased toxicities compared with targeted 
therapies and does not offer a cure; progression eventually occurs. Thus, NSCLC patients who 
have failed treatment with TKIs and whose tumors express T790M mutation represent a group 
with fatal disease and unmet need. 
In this patient population, rociletinib (CO-1686) was expected to provide improved activity by 
inhibiting a key resistance pathway. Furthermore, as rociletinib has only minimal activity against 
WT-EGFR, patients receiving rociletinib may not experience the toxicities noted with first 
generation TKIs (eg, skin rash and diarrhea). In addition, this study aims to confirm and extend 
in a larger cohort of patients, early findings of activity in patients who test negative for the 
T790M mutation.  
3.2 
Nonclinical Overview 
Rociletinib is a novel, potent, small molecule irreversible TKI that selectively targets mutant 
forms of the EGFR. Clovis Oncology, Inc. (Clovis) is developing rociletinib as a therapeutic 
agent to be administered orally to patients with mutant EGFR NSCLC. Rociletinib inhibits the 
EGFR gatekeeper mutation (T790M) which is associated with clinical resistance to Tarceva® 
(erlotinib) and Iressa™ (gefitinib) as well as the common EGFR activating mutations (L858R, 
del19) and has minimal inhibitory activity towards the WT-EGFR at clinically relevant doses. 
Rociletinib has been evaluated as a free base formulation (CO-1686 free base) and as a 
hydrobromide salt formulation (CO-1686 HBr). The pharmacologically active moiety, 
irrespective of formulation, is CO-1686. 


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3.2.1 
Pharmacology 
Rociletinib exhibits nonclinical antitumor activity as a single agent in cell lines expressing the 
most common activating and T790M EGFR mutations. The in vitro activity of rociletinib was 
evaluated against common and rare lung-cancer associated EGFR mutants. Rociletinib was 
active against del19, L858R, G719S (an exon 19 insertion mutant), and L861Q, but not against 
an exon 20 insertion. Therefore, patients with exon 20 insertions have been excluded from 
participation in this study.  
At clinically achievable doses, rociletinib shows potent activity in the NCI-H1975 
(EGFRL858R/T790M) and primary LUM1868 (EGFRL858R/T790M) subcutaneous xenograft models.26 
In addition, the efficacy of rociletinib was examined in an EGFRL858R/T790M transgenic model and 
compared with that of afatinib. Complete responses (CRs) were observed in all mice treated with 
rociletinib, with very limited activity in the afatinib group (Figure 3-1). 
Figure 3-1: Rociletinib Generates Complete Responses in L858R/T790M 
Transgenic Model 
 
Abbreviations: BID = twice daily; CR = complete response; PD = progressive disease; PR = partial response; 
SD = stable disease. 
3.2.2 
Metabolism 
In liver microsomes, rociletinib was slowly metabolized, with cytochrome P450 (CYP) 2C8 
playing a role, and CYP2D6 playing a minor role at most. There is no evidence to suggest the 
involvement of the polymorphically-expressed CYP2C9 and CYP2C19 in rociletinib 
metabolism, implying a low potential for ethnic sensitivity variability in humans. Rociletinib is a 
substrate and an inhibitor of P-glycoprotein (P-gp) and caution should be exercised when 
rociletinib is co-administered with P-gp inhibitors and inducers (see Section 8.4 for further 
information). Caution should also be exercised in patients receiving oral rociletinib and requiring 
concomitant medication with warfarin (Coumadin), nonsteroidal anti-inflammatory drugs 
(NSAIDs), or clopidogrel, as rociletinib moderately inhibited CYP2C8, CYP2C9, and CYP2C19 
activities in vitro (see Section 8.3 for further information).  
-1 0 0
-8 0
-6 0
-4 0
-2 0
0
2 0
4 0
6 0
8 0
1 0 0
2 0 0
4 0 0
6 0 0
C h a n g e  fro m  B a s e lin e  (% )
P D
S D
P R
C R
A fa tin ib
2 0 m g /k g
C O -1 6 8 6
5 0 m g /k g  B ID
L 8 5 8 R /T 7 9 0 M
T ra n s g e n ic  M o d e l
CO-1686: Baseline
CO-1686: 3W
Afatinib: Baseline 
Afatinib : 3W


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3.2.3 
Safety Pharmacology and Toxicology 
Safety pharmacology and toxicology studies were carried out in rats and dogs with the rociletinib 
formulation of CO-1686 HBr. 
Primary indices of toxicity in rats included dose-dependent clinical signs (thinning haircoat 
[females], squinting, pale ears or body, and hunched posture), loss in body weight, and decreased 
body weight gain and food consumption. Increased neutrophil count, decreased white blood cell 
(WBC) count, lymphocyte count, and red blood cell parameters were also noteworthy. Squinting 
was observed in high dose rats administered rociletinib and was associated with atrophy of 
meibomian gland in the eyelid; both effects were reversible. The correlate of this finding in 
humans is dry eye. Other microscopic findings after 28 days of repeated-dosing in rats included 
minimal-to-moderate atrophy of other glands (Harderian gland, mammary gland, and prostate). 
Pathological findings were minor glandular atrophy in all 4 tissues which was reversible and 
principally occurred in the high-dose group. Only minor effects were observed with rociletinib 
on hematopoietic tissue.  
Primary indices of toxicity in dogs included dose-related clinical signs which included abnormal 
feces (liquid and/or non-formed feces), vomiting, and redness of gingiva and lips. These 
observations were not considered adverse due to the overall good health of the animals. All 
clinical observations were reversible, except for non-formed feces. There was no microscopic 
correlation associated with the redness of gingiva or lips.  
No evidence of elevated serum glucose levels were observed in the rat and dog studies. There 
were no rociletinib-related cardiac safety or neurobehavioral findings from the Good Laboratory 
Practice (GLP) repeat-dose toxicity studies. Rociletinib did not have any genotoxic activity in 
2 in vitro assays, and was not phototoxic when evaluated in a phototoxicity study with Long 
Evans pigmented rats. 
Please refer to the Investigator’s Brochure for detailed information on the nonclinical program.  
3.3 
Clinical Experience with Rociletinib  
Four studies are currently ongoing (CO-1686-008, CO-1686-018, CO-1686-019, CO-1686-022) 
and 1 clinical study has been completed (CO-1686-016).  
Ongoing studies: 
• CO-1686-008 (TIGER-X) is a 2-part, open-label, safety, pharmacokinetic (PK), and 
preliminary efficacy study of rociletinib in patients with advanced NSCLC. The study 
consists of 2 parts. Part 1 is a Phase 1 dose escalation phase to determine the maximum 
tolerated dose (MTD) and is fully enrolled. The Phase 2 part of the study is the expansion 
portion in previously-treated NSCLC patients who have documented evidence of an 
activating mutation in the EGFR gene and evidence of the T790M mutation based on 
prospective testing for T790M, and is currently enrolling 
• CO-1686-018 is a Phase 1, open-label, safety, PK, and preliminary efficacy study of 
rociletinib in Japanese patients with advanced NSCLC 


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• CO-1686-019 (TIGER-2) is a single arm, open-label, safety and efficacy study of rociletinib 
as second line EGFR-directed TKI therapy in patients with mutant EGFR NSCLC with the 
T790M mutation 
• CO-1686-022 (TIGER-1) is a randomized, open-label, Phase II study of CO-1686 or erlotinib 
as first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer 
(NSCLC) 
Completed study: 
• CO-1686-016 was a Phase 1, PK, safety and tolerability study in healthy adult male subjects 
that was completed in order to evaluate 3 formulations of rociletinib CO-1686 HBr, and to 
support introduction of the CO-1686 HBr formulation into protocol CO-1686-008 
3.3.1 
Safety of Rociletinib from Clinical Studies 
Preliminary safety data are presented for the ongoing CO-1686-008 and completed CO-1686-016 
studies. One hundred and ninety patients have received at least 1 dose of rociletinib as of 
04 June 2014; 42 healthy male volunteers (Study CO-1686-016) and 148 patients with advanced 
NSCLC (Study CO-1686-008). The overall safety data presented here are for patients who 
received rociletinib in Study CO-1686-008 and included in the clinical database, as of the cut-off 
date of 04 June 2014.  
3.3.1.1 
Study CO-1686-008 – Ongoing Phase 1/2 Study 
CO-1686-008 is an ongoing 2-part, open-label, safety, PK, and preliminary efficacy study of 
rociletinib in patients with advanced NSCLC. As of 04 June 2014, 148 patients with advanced 
NSCLC have received at least 1 dose of rociletinib. In the initial stage of the study, 57 patients 
were treated with rociletinib administered as CO-1686 free base capsules at doses ranging from 
150 mg up to 1800 mg daily. Subsequently, CO-1686 HBr tablets were introduced into the study 
to be used in the later dose escalation cohorts. Ninety-one patients have been treated with 
rociletinib administered as HBr tablets at doses of 500 mg twice daily (BID; N = 18), 625 mg 
BID (N = 17), 750 mg BID (N = 50) and 1000 mg BID (N = 6). At the time of this summary, 
preliminary safety data are available in the clinical database for 148 patients.  
DOSE-LIMITING TOXICITIES (DLTS) 
Enrollment of patients to the dose escalation phase was completed in February 2014 with a DLT 
rate of < 33% at all evaluated doses. The DLT evaluable population included all patients who 
had completed Cycle 1, and who were enrolled while the dose escalation part of the study was 
ongoing. The most frequently reported DLT was hyperglycemia/glucose tolerance impaired 
which occurred at a similar frequency (11% to 25%) across all rociletinib dose levels with the 
CO-1686 HBr formulation (500 mg BID, 625 mg BID, 750 mg BID, and 1000 mg BID). 
Hyperglycemia can be effectively managed with the addition of anti-hyperglycemic therapy 
and/or dose reductions. Guidance for the management of hyperglycemia associated with 
rociletinib treatment is provided in Section 7.4.1. 


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SERIOUS ADVERSE EVENTS (SAES) AND DEATHS 
A total of 43 patients experienced at least 1 SAE and 17 patients have reported an SAE assessed 
as related to study drug. Treatment-related SAEs are summarized in Table 3-1. The most 
commonly reported treatment-related SAE was hyperglycemia (reported in 6% of patients). Four 
patients (3%) experienced an SAE of vomiting and 3 patients (2%) experienced an SAE of 
nausea. All other treatment-related SAEs occurred in 2 or fewer patients. 
To date, there have been 11 deaths while on study or within 28 days after the last dose of 
rociletinib. Eight deaths were reported as due to progression of NSCLC, 1 death due to 
pulmonary embolism, 1 death due to pneumonia, and 1 death of unknown cause. At this stage, a 
causal relationship with rociletinib cannot be ruled out for the death of unknown cause, all other 
deaths were reported as unrelated to study drug. 


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Table 3-1: 
Treatment-related Serious Adverse Events Reported in Patients in Study CO-1686-008 
System Organ Class 
Preferred Term 
< 900 BID FB 
(N = 38) 
900 BID FB 
(N = 19) 
500 BID HBr 
(N = 18) 
625 BID HBr 
(N = 17) 
750 BID HBr 
(N = 50) 
1000 BID HBr 
(N = 6) 
Overall 
(N = 148) 
Number of Patients with at Least 1 Treatment-related Treatment-emergent SAE 
Overall 
4 (10.5%) 
1 (5.3%) 
4 (22.2%) 
3 (17.6%) 
4 (8.0%) 
1 (16.7%) 
17 (11.5%) 
Cardiac Disorders 
Pericarditis 
1 (2.6%) 
0 
0 
0 
0 
0 
1 (0.7%) 
Gastrointestinal Disorders 
Diarrhea 
1 (2.6%) 
1 (5.3%) 
0 
0 
0 
0 
2 (1.4%) 
Nausea 
1 (2.6%) 
0 
1 (5.6%) 
0 
1 (2.0%) 
0 
3 (2.0%) 
Pancreatitis 
0 
0 
1 (5.6%) 
0 
0 
0 
1 (0.7%) 
Vomiting 
2 (5.3%) 
0 
1 (5.6%) 
0 
1 (2.0%) 
0 
4 (2.7%) 
Infections and Infestations 
Gastroenteritis 
0 
0 
0 
0 
1 (2.0%) 
0 
1 (0.7%) 
Investigations 
ECG QT prolonged 
0 
0 
0 
1 (5.9%) 
1 (2.0%) 
0 
2 (1.4%) 
ECG T wave 
inversion 
0 
0 
0 
0 
1 (2.0%) 
0 
1 (0.7%) 
Transaminases 
increased 
0 
1 (5.3%) 
0 
0 
0 
0 
1 (0.7%) 
Metabolism and Nutrition Disorders 
Combined terms of 
hyperglycemia 
1 (2.6%) 
0 
4 (22.2%) 
1 (5.9%) 
2 (4.0%) 
1 (16.7%) 
9 (6.1%) 
Decreased appetite 
0 
1 (5.3%) 
0 
0 
0 
0 
1 (0.7%) 
Hypoglycemia 
1 (2.6%) 
0 
0 
0 
0 
0 
1 (0.7%) 
Hypokalemia 
0 
0 
0 
1 (5.9%) 
0 
0 
1 (0.7%) 
Respiratory, Thoracic, and Mediastinal Disorders 
Pneumonitis 
0 
0 
0 
1 (5.9%) 
0 
0 
1 (0.7%) 
Abbreviations: BID = twice daily; ECG = electrocardiogram; FB = CO-1686 free base; HBr = CO-1686 hydrobromide; N = number of patients; SAE = serious 
adverse event; TE = treatment-emergent. 


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TREATMENT-RELATED ADVERSE EVENTS (AES) 
Of the 148 patients treated with rociletinib as of the data cut-off date, 124 patients (84%) had at 
least 1 AE and 111 patients (75%) had an AE considered to be possibly, probably, or definitely 
related to rociletinib. 
The most frequently reported AEs (≥ 20% of patients), regardless of causality or severity, were 
nausea (40%); AEs associated with blood glucose increases (39%; including Medical 
Dictionary for Regulatory Activities [MedDRA] preferred terms [PTs] blood glucose elevated, 
glucose tolerance impaired, and hyperglycemia); fatigue (26%); diarrhea (26%); and decreased 
appetite (22%). 
AEs considered to be related to rociletinib and reported in > 5% of patients overall are 
summarized by system organ class (SOC), PT, and dose level in Table 3-2. The most 
frequently reported treatment-related AEs (≥ 20% of patients), regardless of severity, were 
nausea (28%); increased blood glucose, combined terms as in previous paragraph (33%); and 
fatigue (20%). 
The majority of AEs have been mild or moderate in severity. Rociletinib selectively inhibits 
mutant EGFR, and as expected, the syndrome of dose related WT-driven rash and diarrhea has 
not been observed. All reported events of diarrhea were either Grade 1 or Grade 2. 
The most common skin reaction reported in patients treated with EGFR-TKIs is a follicular 
acneiform eruption. In Study CO-1686-008, rash, irrespective of causality, was reported 
infrequently (overall 6 patients [4%]) and all events were mild. In Study CO-1686-008, only 
1 report of dermatitis acneiform and 1 report of follicular rash have been reported to date. 
There have been 2 AEs of pneumonitis and 1 SAE of pneumonitis, all assessed as related to 
rociletinib by the investigator. Patients recovered after steroid therapy, and patients were not 
rechallenged with rociletinib. 
ELECTROCARDIOGRAM (ECG) CHANGES 
Rociletinib exposure is associated with QTC prolongation. The effect takes several days to 
develop, and is not seen on Day 1 of therapy. Patients with low baseline resting heart rates 
appear to be at a higher risk for QTC prolongation during treatment with rociletinib. Typically, 
the abnormality is evident by Day 15 of therapy, and the increase remains stable with 
continued dosing. QTC intervals longer than 500 msec have been observed in 10 patients 
(7.6%). In clinical studies of rociletinib, all cases of QTC prolongation have been asymptomatic 
and no cases of ventricular dysrhythmia or torsades de pointes have been observed.  
Prolonged QTC is managed effectively by dose reduction.  


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Table 3-2: 
Treatment-related Adverse Events Reported in at Least 5% of Patients in Study CO-1686-008 
System Organ Class 
Preferred Term 
< 900 BID FB 
(N = 38) 
900 BID FB 
(N = 19) 
500 BID HBr 
(N = 18) 
625 BID HBr 
(N = 17) 
750 BID HBr 
(N = 50) 
1000 BID HBr 
(N = 6) 
Overall 
(N = 148) 
Number of Patients with at Least 1 Treatment-related TEAE 
Overall 
28 (73.7%) 
18 (94.7%) 
16 (88.9%) 
15 (88.2%) 
28 (56.0%) 
6 (100.0%) 
111 (75.0%) 
Gastrointestinal Disorders 
Diarrhea 
6 (15.8%) 
6 (31.6%) 
4 (22.2%) 
4 (23.5%) 
6 (12.0%) 
2 (33.3%) 
28 (18.9%) 
Nausea 
8 (21.1%) 
6 (31.6%) 
6 (33.3%) 
7 (41.2%) 
12 (24.0%) 
3 (50.0%) 
42 (28.4%) 
Vomiting 
5 (13.2%) 
2 (10.5%) 
3 (16.7%) 
4 (23.5%) 
4 (8.0%) 
0 
18 (12.2%) 
General Disorders and Administration Site Conditions 
Fatigue 
9 (23.7%) 
6 (31.6%) 
5 (27.8%) 
3 (17.6%) 
5 (10.0%) 
1 (16.7%) 
29 (19.6%) 
Investigations 
Electrocardiogram QT prolonged 
0 
2 (10.5%) 
0 
2 (11.8%) 
5 (10.0%) 
3 (50.0%) 
12 (8.1%) 
Metabolism and Nutrition Disorders 
Combined terms of hyperglycemia 
4 (10.5%) 
6 (31.6%) 
11 (61.1%) 
10 (58.8%) 
14 (28.0%) 
4 (66.7%) 
49 (33.1%) 
Decreased appetite 
1 (2.6%) 
6 (31.6%) 
4 (22.2%) 
3 (17.6%) 
2 (4.0%) 
2 (33.3%) 
18 (12.2%) 
Musculoskeletal and Connective Tissue Disorders 
Muscle spasms 
3 (7.9%) 
4 (21.1%) 
3 (16.7%) 
0 
3 (6.0%) 
0 
13 (8.8%) 
Myalgia 
3 (7.9%) 
4 (21.1%) 
2 (11.1%) 
0 
1 (2.0%) 
1 (16.7%) 
11 (7.4%) 
Abbreviations: BID = twice daily; FB = CO-1686 free base; HBr = CO-1686 hydrobromide; N = number of patients; TEAE = treatment-emergent adverse 
event. 


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3.3.2 
Activity of Rociletinib from Clinical Studies 
3.3.2.1 
Study CO-1686-008 – Ongoing Phase 1/2 Study 
CO-1686-008 is a 2-part, open-label, safety, PK, and preliminary efficacy study of rociletinib in 
patients with advanced NSCLC. The dose escalation phase of the study has been completed.  
Although the primary objectives of Phase 1 of Study CO-1686-008 were to evaluate the safety, 
toxicity, and PK profile of rociletinib, encouraging signals of activity have been observed in an 
EGFR-mutation-positive patient population previously treated with one or more lines of an 
EGFR-TKI (eg, erlotinib, gefitinib, afatinib) and chemotherapy. A preliminary analysis of 
efficacy has been conducted using objective response rate (ORR), DR, and PFS as efficacy 
parameters. There is robust evidence of activity for rociletinib across the therapeutic doses 
(Figure 3-2) for patients confirmed as T790M+ by central testing, with 22 of 40 patients 
achieving a Response Evaluation Criteria In Solid Tumors (RECIST) partial response (PR) as of 
the data cut-off date (Table 3-3). The ORR in this group of patients is 55% and the disease 
control rate (DCR) is approximately 92%.  
Figure 3-2: Target Lesion Response in Centrally Confirmed T790M+ Patients 
 
Abbreviations: BID = twice daily; FB = CO-1686 free base; HBr = CO-1686 hydrobromide; T790M+ = T790M-
positive; T = last prior therapy was a tyrosine kinase inhibitor; + = ongoing. 


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Table 3-3: 
Best Response, Objective Response, and Disease Control Rate in 
T790M+ Patients 
 
900 mg 
BID FB 
(N = 8) 
500 mg 
BID HBr 
(N = 6) 
625 mg 
BID HBr 
(N = 9) 
750 mg 
BID HBr 
(N = 13) 
1000 mg 
BID HBr 
(N = 4) 
Overall 
 
(N = 40) 
Best Response 
PR 
6 (75.0%) 
3 (50.0%) 
5 (55.6%) 
5 (38.5%) 
3 (75.0%) 
22 (55%) 
SD 
2 (25.0%) 
2 (33.3%) 
2 (22.2%) 
8 (61.5%) 
1 (25.0%) 
15 (45.5%) 
PD 
0 (0.0%) 
1 (16.7%) 
2 (22.2%) 
0 (0.0%) 
0 (0.0%) 
3 (9.0%) 
Objective Response 
(CR, PR) 
6 (75.0%) 
3 (50.0%) 
5 (55.6%) 
5 (38.5%) 
3 (75.0%) 
22 (55%) 
Disease Control Rate 
(CR, PR, SD)  
8 (100.0%) 
5 (83.3%) 
7 (77.8%) 
13 
(100.0%) 
4 (100.0%) 
37 (92.5%) 
Abbreviations: BID = twice daily; CR = complete response; FB = CO-1686 free base; HBr = CO-1686 
hydrobromide; N= number of patients; PD = progressive disease; PR = partial response; SD = stable disease; 
T790M+ = T790M-positive. 
Data shown are for patients with measurable disease at baseline. 
 
Some (29.4%) evaluable T790M-negative patients, with at least a Cycle 2 scan measurement, 
achieved a target lesion response as of the data cut-off date (Figure 3-3). These data suggest that 
although the benefit is more modest than in patients with T790M+ disease, rociletinib is active in 
patients with T790M-negative disease. Response rate and PFS in the T790M-negative group are 
longer than would be expected for single-agent cytotoxic chemotherapy in relapsed disease in an 
unselected population (data specific to T790M-negative patients are not available). Response 
rates of less than 10% with PFS under 3 months have been described for pemetrexed and 
docetaxel monotherapy (Alimta® label).  
Rociletinib activity in T790M-negative patients could be explained by several factors including 
heterogeneous clones of cells within the tumor, with only T790M-negative clones captured 
within the biopsy sample, or a small fraction of T790M+ cells falling out with the sensitivity 
limit of the assay.  
The data support including T790M-negative patients in randomized studies, to characterize the 
signal further, and to establish whether rociletinib is more active than available therapies. 


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Figure 3-3: Best Response for Target Lesions in T790M-negative Patients 
 
Abbreviations: BID = twice daily; FB = CO-1686 free base; HBr = CO-1686 hydrobromide; T = last prior therapy 
was a tyrosine kinase inhibitor; + = ongoing. 
3.3.3 
Pharmacokinetics of Rociletinib 
3.3.3.1 
Study CO-1686-016 – Completed Phase 1 Study 
In healthy volunteers (Study CO-1686-016), maximum concentration (Cmax) and area under the 
curve from time zero to 24 hours (AUC0–24) of rociletinib increased with ascending single doses 
of the rociletinib formulation of CO-1686 HBr (50 mg to 1000 mg), with rociletinib plasma 
levels increasing in a less than dose proportional manner above 125 mg. 
The single-dose PK of rociletinib was compared in the fasted and fed state, and it was concluded 
that a high-fat meal increased the plasma drug concentrations from 3 to 12 hours postdose with a 
mean increase of 172% at 12 hours postdose (C12h: –22% to +400%) and a mean increase of 77% 
in AUC0–24 (+10% to 146%) with no change in half-life (T1/2); a slight mean increase of 12% in 
Cmax was observed and a delayed time to maximum concentration (Tmax) was seen in a majority 
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Six healthy subjects were dosed, in the fed state, with 500 mg BID rociletinib for 4 days. PK 
profiles of rociletinib following morning and evening dosing were similar, with low intra-subject 
variability (Day 1 and Day 4 comparison). There was no accumulation of rociletinib. 
3.3.3.2 
Study CO-1686-008 – Ongoing Phase 1/2 Study 
In the patient study (CO-1686-008), PK following HBr salt administration were available from a 
total of 51 patients (11 started at 500 mg BID, 10 switched from CO-1686 free base to 500 mg 
BID HBr, 15 started at 625 mg BID, 9 started at 750 mg BID, and 6 started at 1000 mg BID). 
CO-1686 HBr showed increased absorption and thus higher exposure than free base. The median 
Tmax was 1.5 to 3.25 hours and T1/2 ranged from 1.7 to 4.7 hours. Following CO-1686 HBr 
administration, exposure (measured as Cmax and AUC0–24) increased approximately 
dose-proportionally from 500 mg to 1000 mg BID (Figure 3-4). 
Figure 3-4: Individual Rociletinib AUC0–24 on Day 1 Following 500 mg to 1000 mg 
CO-1686 HBr BID 
 
Abbreviations: AUC = area under the curve; BID = twice daily; HBr = CO-1686 hydrobromide. 
3.4 
Rationale for Current Study 
As noted previously, there are limited treatment options for mutant EGFR NSCLC patients who 
have failed treatment with first generation TKIs and platinum-containing cytotoxic 
chemotherapy. Single-agent cytotoxic chemotherapy has limited efficacy and significant toxicity 
in the second or third-line setting. Consequently, these patients represent a group with fatal 
disease and unmet need. 
With potent nonclinical activity against activating EGFR mutations and the T790M resistance 
mutation, minimal inhibitory activity towards the WT, and with activity in clinical studies in 
500
750
1000
0
12500
25000
37500
50000
62500
75000
100000
125000
H B r D o s e  v s  A U C
B ID  D o s e  (m g )
6 2 5
C O -16 86  A U C 0 -2 4 (n g .h /m L )


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both T790M+ and T790M-negative populations, rociletinib may provide a tolerable and effective 
therapy for a patient population with few alternative treatment options.  
The goals of the current study (Protocol CO-1686-020) are to compare the anti-tumor efficacy 
and safety of oral single-agent rociletinib with that of single-agent cytotoxic chemotherapy in 
patients with EGFR-mutated advanced/metastatic NSCLC after failure of at least 1 previous 
EGFR-directed TKI and one line of platinum-containing doublet chemotherapy.  
An additional goal will be to determine the effectiveness of rociletinib in patients who test 
negative with respect to the T790M mutation, given initial findings suggestive of a clinical 
benefit of rociletinib in these patients.  
In the first-in-human study, CO-1686-008, in patients with advanced EGFR mutation positive 
NSCLC and previous treatment with an EGFR inhibitor, no MTD was observed and 3 dose 
levels, 500 mg BID, 625 mg BID, and 750 mg BID, were selected for further clinical evaluation 
of safety, tolerability and efficacy in the expansion cohorts. Maturing data from this study 
suggest that patients treated with rociletinib at 500 mg BID and 625 mg BID experience 
responses that are comparable in frequency, depth and duration, with an overall acceptable safety 
profile for this advanced cancer patient population. To further describe the risk/benefit profile of 
the rociletinib 500 mg BID dose, patients enrolled under Protocol Amendment 2 will receive a 
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4 
STUDY OBJECTIVES AND ENDPOINTS 
4.1 
Objectives 
4.1.1 
Primary Objective 
• To compare the anti-tumor efficacy of oral single-agent rociletinib, as measured by 
investigator assessment of the PFS, with that of single-agent cytotoxic chemotherapy in 
patients with EGFR-mutated, advanced/metastatic NSCLC after failure of at least 1 previous 
EGFR-directed TKI and at least 1 line of platinum-containing doublet chemotherapy 
4.1.2 
Secondary Objectives 
• To compare secondary measures of clinical efficacy (DR, ORR and OS) between patients 
randomized to rociletinib or single-agent cytotoxic chemotherapy 
• To compare the safety and tolerability of rociletinib with that of single-agent cytotoxic 
chemotherapy 
• To determine PK of rociletinib using population PK (POPPK) methods and explore 
correlations between PK, exposure, response, and/or safety findings in patients randomized 
to rociletinib 
4.1.3 
Exploratory Objectives 
• To evaluate clinical benefit of continued rociletinib treatment following disease progression 
in patients randomized to the rociletinib arm 
• To evaluate clinical benefit of rociletinib treatment following disease progression in patients 
randomized to the comparator arm who cross over to receive rociletinib 
• To compare QoL by patient-reported outcomes (PRO) between patients randomized to 
rociletinib or single-agent cytotoxic chemotherapy  
• To evaluate concordance of mutant EGFR detection between tissue and plasma and assess 
rociletinib mediated alterations in mutant EGFR levels over time using circulating tumor 
DNA (ctDNA) obtained from plasma; analyze clinical endpoints based on plasma EGFR 
mutation test results 
• To explore tissue and blood-based biomarkers that may be predictive of response or primary 
resistance to rociletinib and investigate mechanisms of acquired resistance in the tissue and 
blood of patients who experience clinical progression during treatment with rociletinib  
4.2 
Endpoints 
4.2.1 
Primary Endpoint 
• Progression-free survival (PFS) according to RECIST Version 1.1 as determined by 
investigator assessment (invPFS) 


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4.2.2 
Secondary Endpoints 
• ORR and DR according to RECIST Version 1.1 as determined by investigator assessment 
• OS 
• Treatment-emergent AEs, laboratory abnormalities, and ECG abnormalities 
• Plasma PK parameters for rociletinib based on sparse sampling 
4.2.3 
Exploratory Endpoints 
• DCR according to RECIST Version 1.1 as determined by investigator assessment 
• Time–to-treatment failure  
• OS, ORR, PFS, DR, and DCR in patients who cross over to receive rociletinib and in patients 
who continue to receive rociletinib beyond progression 
• Change from baseline in PROs using the European Organization for Research and Treatment 
of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30), the EORTC Quality of 
Life Questionnaire Lung Cancer module (EORTC QLQ-LC13) and the EQ-5D 
• Change from baseline in mutant EGFR levels in ctDNA obtained from plasma 
• OS, ORR, PFS, DR, and DCR based on plasma EGFR mutation test results 
• Positive and negative percent agreement between blood and tissue results for T790M  
• Identify biomarkers associated with response or resistance to rociletinib 


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5 
STUDY DESIGN 
5.1 
Overall Study Design and Plan 
This is a Phase 3, randomized, open-label, multicenter study evaluating the safety and efficacy of 
oral rociletinib compared with single-agent cytotoxic chemotherapy in patients with previously 
treated mutant EGFR NSCLC. Eligible patients are those with mutant EGFR NSCLC previously 
treated with at least 1 EGFR inhibitor and at least 1 line of platinum-containing chemotherapy 
doublet for advanced/metastatic NSCLC.  
After providing consent to participate and screening to confirm eligibility for participation in the 
study, patients will be randomized 1:1 to receive either oral rociletinib or single-agent cytotoxic 
chemotherapy (investigator choice of pemetrexed, gemcitabine, docetaxel, or paclitaxel; choice 
of chemotherapy agent must be specified before randomization). Randomization will be stratified 
according to:  
1. Brain metastases present versus no brain metastases present 
2. Eastern Cooperative Oncology Group (ECOG) performance status 0 versus ECOG 
performance status 1 
3. Territory of residence at time of randomization (East Asian versus non-East Asian). 
All patients will provide a tumor biopsy during screening for central determination of T790M 
mutation status in formalin-fixed paraffin-embedded (FFPE) tumor tissue, although the test result 
does not have to be available before randomization. Switching therapy after biopsy sampling is 
not permitted as this may impact on the T790M mutation status. However, dose reduction of the 
therapy adopted at that time is permitted. 
The treatment cycle length will be 21 days for all treatments. See Section 7.3 for further details 
of the dosing schedules. Dosing may be delayed or reduced according to protocol-specified 
toxicity criteria. Protocol-specified treatment will continue, with tumor assessment every 
6 ± 1 weeks, irrespective of regimen, until there is disease progression by RECIST Version 1.1 
or unacceptable toxicity as assessed by the investigator or until other withdrawal criteria are met 
(including completion of a single agent chemotherapy regimen). If clinical progression is 
diagnosed then confirmation of disease progression with a computed tomography (CT) scan (per 
RECIST 1.1) will be required. Patients may opt to continue to receive treatment with rociletinib 
following radiographic progression as outlined in the National Comprehensive Cancer Network 
(NCCN) guidelines for treatment of NSCLC with EGFR-TKIs if: a) the patient provides 
additional consent, b) the investigator feels it is in the patient’s best interest, and c) the sponsor 
provides approval. In general, eligible patients may include those with asymptomatic systemic 
progression or locally symptomatic progression, such as brain metastases amenable to local 
treatment, with concomitant asymptomatic systemic progression or continued systemic disease 
control.  
Patients randomized to the comparator chemotherapy arm may choose to cross over to receive 
rociletinib upon radiological progression. As with all patients, if clinical progression is diagnosed 
then confirmation of disease progression with a CT/magnetic resonance imaging (MRI) scan (per 


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RECIST Version 1.1) will be required along with sponsor approval before crossing over to 
treatment with rociletinib.  
When protocol-specified therapy is discontinued, and the patient has yet to progress, patients will 
continue undergo scheduled tumor assessments for monitoring of PFS. All patients will also be 
followed for survival status, and subsequent NSCLC cancer therapy until death or sponsor 
decision, whichever comes first.  
5.1.1 
Screening Period 
After providing consent to participate, patients will undergo screening assessments within 
35 days prior to randomization to rociletinib or single-agent cytotoxic chemotherapy. Patients 
will be monitored for AEs from the time the first dose of study medication is administered 
through to 28 days after the last protocol-specified treatment administration. Study-procedure-
related AEs that occur after signing of the Informed Consent Form (ICF) but before 
administration of study treatment will also be collected. 
5.1.2 
Randomization 
Following confirmation of patient eligibility by the investigator, patients will be centrally 
randomized in a 1:1 ratio to receive oral rociletinib or single-agent cytotoxic chemotherapy 
(investigator choice of pemetrexed, gemcitabine, docetaxel, or paclitaxel). The choice of 
chemotherapy agent must be specified by the investigator before randomization. At least 5 daily 
doses of folic acid must be taken preceding the first dose of pemetrexed. If the investigator 
selects pemetrexed as the comparator option for a patient, then folic acid supplementation may 
begin prior to randomization, if necessary, to ensure that Cycle 1 Day 1 (C1D1) is not delayed 
while premedication is completed. Patients can continue receiving treatment with a single-agent 
EGFR-TKI (eg, erlotinib, gefitinib, afatinib, or dacomitinib) until 3 days before C1D1. 
5.1.3 
Treatment Period 
During the treatment period, patients will receive either oral single agent rociletinib or 
investigator choice of single-agent pemetrexed, gemcitabine, docetaxel, or paclitaxel 
chemotherapy. Treatment cycles are 21 days long, with dosing initiating within 3 days after 
randomization (C1D–3), on C1D1. 
Rociletinib will be administered daily to patients at 500 mg BID (see Section 7.3.1). Treatment 
with rociletinib is continuous and each cycle will comprise of 21 days. In each cycle, the first 
dose of rociletinib will be taken in clinic, with the remaining doses self-administered by the 
patient at home. Patients will take rociletinib with 8 oz (240 mL) of water and with a meal or 
within 30 minutes after a meal. No dose escalation above the starting dose is allowed.  
For patients who started therapy with rociletinib at 625 mg BID under Protocol Amendment 1, a 
reduction in dose to 500 mg BID is allowed, only if necessitated by unacceptable toxicity. 
The choice of single-agent cytotoxic chemotherapy is at the discretion of the investigator from 
amongst the regimens described in this protocol. The treatment cycle length will be 21 days. The 
dosing regimens for the 4 chemotherapy comparators are as follows: 


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Chemotherapy Agent 
Dosing Regimen 
Pemetrexed 
500 mg/m2 intravenously on Day 1 of each 21-day cycle 
Gemcitabine 
1250 mg/m2 intravenously on Days 1 and 8 of each 21-day cycle 
Docetaxel 
Two possible dosing regimens: 
75 mg/m2 intravenously on Day 1 of each 21-day cycle (Note: dose 
will be 60 mg/m2 in Asian patients) 
35 mg/m2 intravenously on a weekly basis as part of a continuous 
21-day cycle; (ie, dosing will be on Days 1, 8, and 15 of each 21-day 
cycle) 
Paclitaxel 
80 mg/m2 intravenously as a 1 hour infusion, on a weekly basis as part 
of a continuous 21-day cycle; (ie, dosing will be on Days 1, 8, and 15 
of each 21-day cycle) 
 
See Section 7.3.2 for further dosing details. 
All patients will undergo serial assessments for anti-tumor efficacy, drug safety, and PRO. 
Sparse blood sampling for POPPK analyses will be conducted in all patients treated with 
rociletinib. Tumor scans will be acquired by the investigative site and evaluated locally for 
patient treatment decisions. Scans will also be collected and stored with a central vendor and 
quality control performed; central reading of scans will not be done unless requested by the 
sponsor. AEs will be collected from the time of first dose of study treatment until 28 days after 
the last protocol-specified treatment administration. Study procedure-related AEs that occur after 
signing of the ICF but before administration of study treatment will also be collected. Local 
laboratories will be used for hematology and chemistry. ECGs will be performed and interpreted 
locally for patient care decisions; however, tracings will be collected centrally for independent 
evaluation. ECGs will be read by the central ECG reader, within 1 day for screening ECGs and 
within 3 days for ECGs at other times. 
Protocol-specified treatment will continue until there is disease progression by RECIST 
Version 1.1 or unacceptable toxicity as assessed by the investigator. If clinical progression is 
diagnosed then confirmation of disease progression with a CT scan (per RECIST Version 1.1) 
will be required.  
Patients may opt to continue to receive treatment with CO-1686 following radiographic 
progression, as outlined in the NCCN guidelines for treatment of NSCLC with EGFR-TKIs27 
if the patient provides additional consent and the investigator believes it is in the best interest of 
the patient, in consideration of the potential risks and benefits, the current status of the rociletinib 
development program, and alternative treatment options. The investigator should inform the 
sponsor of their decision prior to starting post-progression treatment. In general, eligible patients 
may include those with asymptomatic systemic progression or locally symptomatic progression, 
such as brain metastases amenable to local treatment, with concomitant asymptomatic systemic 
progression or continued systemic disease control. This must be discussed with, and approved 
by, the sponsor and will be reviewed on a case-by-case basis. If a patient continues treatment 
post-progression, all study assessments including efficacy assessments, safety assessments, QoL 


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administration, and blood collection for biomarker analysis and companion diagnostic 
development should continue per protocol. The patient should be discontinued from treatment 
once it is clear that no further clinical benefit can be achieved.  
Following disease progression, patients who provide additional consent will undergo tumor 
biopsy before subsequent-line therapy is initiated. 
5.1.4 
End-of-Treatment 
All patients should return to the clinic for end-of-treatment assessments 28 ± 7 days after the last 
dose of oral rociletinib or single-agent cytotoxic chemotherapy has been administered. Patients 
in the cross over portion of the study will only have 1 End-of-Treatment Visit after 
discontinuation of cross over rociletinib. Patients who continue treatment with rociletinib after 
radiological progression will likewise only have 1 End-of-Treatment Visit after discontinuation 
of rociletinib. 
The trial will be completed when all enrolled patients have discontinued treatment in this 
protocol and completed the End-of-Treatment follow-up Visit.  
5.1.5 
Follow-up 
All patients will be followed up at approximately every 2 months, starting at the End-of-
Treatment Visit, to monitor survival status until death or sponsor decision, whichever comes 
first. After discontinuation of protocol-specified treatment, subsequent anticancer therapy use 
will be recorded. If the patient discontinues treatment before progression, then scans should 
continue until progression according to the protocol schedule of every 6 ± 1 weeks. 
5.1.6 
Extension Phase 
In mid-2015, Clovis submitted a New Drug Application for the use of rociletinib in patients with 
T790M-positive NSCLC. In June 2016, the FDA issued a Complete Response Letter to Clovis 
stating that more data is required to approve rociletinib for use outside of a clinical trial. Based 
on this outcome, Clovis decided to discontinue development of CO-1686 for NSCLC. Patients 
will be informed of this change in the development plans in an update to the informed consent 
form for this study. Those patients who continue to derive clinical benefit from study treatment 
will be allowed to continue on study at the discretion of the Principal Investigator in an extension 
phase.  
The purpose of this protocol amendment is to add a new Extension Phase to allow patients to 
continue on study but to avoid unnecessary collection of data that will no longer be analyzed or 
required for regulatory purposes, whilst maintaining an appropriate level of safety monitoring. A 
new schedule of assessments for the Extension Phase as well as a complete description of 
procedures has been provided in Appendix C. This schedule will replace all schedules of 
assessments in Section 9 and should be followed for all patients. 
For patients who wish to continue rociletinib treatment post progression or for patients who wish 
to crossover to rociletinib treatment following progression on chemotherapy it is important that a 


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full exploration of alternative treatment options between patients and their treating physicians 
takes place.  
5.2 
Study Schema 
The study schema in Figure 5-1 summarizes the treatment design of the study. 


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Figure 5-1: Study Schema 
 
Abbreviations: OS = overall survival; PD = progressive disease per RECIST Version 1.1; R = randomization; RECIST = Response Evaluation Criteria In Solid 
Tumors, Version 1.1. 
Screening: Biopsy or surgical resection of primary or metastatic lesions within 60 days prior to start of treatment.  
Randomization: Patients will be allocated to rociletinib or comparator on 1:1 ratio. 
 
  
  
             
            
            
           
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6 
STUDY POPULATION 
6.1 
Number of Patients and Sites 
The total enrollment planned for this study is up to approximately 600 patients. There will be up 
to 150 investigative sites in North America, Europe, Asia, and Australia.  
6.2 
Inclusion Criteria 
All patients must meet all of the following inclusion criteria: 
1. Histologically or cytologically confirmed metastatic or unresectable locally advanced 
NSCLC with radiological progression on the most recent therapy received 
2. Documented evidence of a tumor with 1 or more EGFR activating mutations excluding exon 
20 insertion 
3. Disease progression confirmed by radiological assessment while receiving treatment with 
single agent EGFR-TKI (eg, erlotinib, gefitinib, afatinib, or dacomitinib). The washout 
period for the single agent EGFR-TKI is a minimum of 3 days or 5 half-lives, whichever is 
more applicable, prior to start of treatment. 
4. Multiple lines of prior treatment are permitted and there is no specified order of treatment, 
but in the course of their treatment history, patients must have received and have 
radiologically documented disease progression following: 
− At least 1 line of prior treatment with a single-agent EGFR TKI (eg, erlotinib, gefitinib, 
afatinib, or dacomitinib)  
o 
If EGFR-TKI is a component of the most recent treatment line, the washout period 
for the EGFR-TKI is a minimum of 3 days before the start of rociletinib treatment 
AND 
− A platinum-containing doublet chemotherapy (either progressed during therapy or 
completed at least 4 cycles without progression with subsequent progression after a 
treatment-free interval or after a maintenance treatment). 
o 
If cytotoxic chemotherapy is a component of the most recent treatment line, 
treatment with chemotherapy should have been completed at least 14 days prior to 
start of study treatment. When an EGFR-TKI is given in combination with platinum-
containing doublet chemotherapy, treatment with the EGFR-TKI may continue until 
at least 3 days before start of treatment.  
5. Have undergone a biopsy of either primary or metastatic tumor tissue within 60 days prior to 
start of treatment and have tissue available to send to sponsor laboratory or are able to 
undergo a biopsy during screening and provide tissue to sponsor laboratory  
6. Measureable disease according to RECIST Version 1.1 
7. Life expectancy of at least 3 months 
8. ECOG performance status of 0 to 1 


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9. Age  18 years (in certain territories, the minimum age requirement may be higher eg, age 
 20 years in Japan and Taiwan, age  21 years in Singapore) 
10. Patients should have recovered to National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) Grade ≤ 1 from any significant chemotherapy-related 
toxicities. 
11. Adequate hematological and biological function, confirmed by the following local laboratory 
values: 
Bone marrow function 
a. 
Absolute neutrophil count (ANC)  1.5 × 109/L 
b. Platelets > 100.0 × 109/L  
c. 
Hemoglobin  9 g/dL (or 5.6 mmol/L) 
Hepatic function 
d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)  3 × upper limit 
of normal (ULN); if liver metastases,  5 × ULN 
e. 
Bilirubin  2 × ULN 
− Patients with documented Gilbert’s syndrome and conjugated bilirubin within the 
normal range may be allowed into the study. In this event, it will be documented that 
the patient was eligible based on conjugated bilirubin levels 
Renal function  
f. 
Creatinine clearance ≥ 45 mL/min 
Electrolytes 
g. Potassium and magnesium within normal range. Patients may receive supplements to 
meet this requirement 
Glucose 
h. Fasting serum glucose within normal ranges 
12. Written consent on an Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)-approved ICF before any study specific evaluation 
6.3 
Exclusion Criteria 
Any of the following criteria will exclude patients from study participation: 
1. Any other malignancy associated with a high mortality risk within the next 5 years and for 
which the patients may be (but not necessarily) currently receiving treatment 
− Patients with a history of malignancy that has been completely treated, with no evidence 
of that cancer currently, are permitted to enroll in the trial provided all chemotherapy was 
completed > 6 months prior and/or bone marrow transplant > 2 years prior 


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2. Known pre-existing interstitial lung disease 
3. Tumor small cell transformation by local assessment, irrespective of presence of T790M+ 
component 
4. Patients with leptomeningeal carcinomatosis are excluded. Other central nervous system 
(CNS) metastases are only permitted if treated, asymptomatic, and stable (not requiring 
steroids for at least 2 weeks prior to randomization and the patient is neurologically stable; ie, 
free from new symptoms of brain metastases). If a patient has had brain metastasis treated 
within the previous 8 weeks, a follow up scan should have been performed to confirm that 
treated metastasis remain controlled without evidence of new lesions. 
5. Patients who are currently receiving treatment with any medications that have the potential to 
prolong the QT interval and that treatment cannot be either discontinued or switched to a 
different medication (known to have no effect on QT) before starting protocol-specified 
treatment (see http://crediblemeds.org/ for a list of QT-prolonging medications) 
6. Prior treatment with rociletinib, or other drugs that target T790M+ mutant EGFR with 
sparing of WT-EGFR including but not limited to AZD9291, HM61713, and TAS-121 
7. Any contraindications for therapy with pemetrexed, paclitaxel, gemcitabine or docetaxel 
unless a contraindication with respect to one of these drugs will not affect the use of any of 
the others as a comparator to rociletinib 
8. Any of the following cardiac abnormalities or history: 
a. 
Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia’s 
method (QTCF) > 450 msec  
b. Inability to measure QT interval on ECG 
c. 
Personal or family history of long QT syndrome 
d. Implantable pacemaker or implantable cardioverter defibrillator 
e. 
Resting bradycardia < 55 beats/min 
9. Non-study related surgical procedures  7 days prior to randomization. In all cases, the 
patient must be sufficiently recovered and stable before treatment administration 
10. Females who are pregnant or breastfeeding 
11. Refusal to use adequate contraception for fertile patients (females and males) while on 
treatment and for 6 months after the last dose of study treatment (rociletinib and 
chemotherapy irrespective of single cytotoxic agent used) 
12. Presence of any serious or unstable concomitant systemic disorder incompatible with the 
clinical study, eg, substance abuse, uncontrolled intercurrent illness including: 
• uncontrolled diabetes 
• active infection 
• arterial thrombosis, and  
• symptomatic pulmonary embolism 


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13. Any other reason the investigator considers the patient should not participate in the study 
14. Treatment with live vaccines initiated less than 4 weeks prior to randomization 
6.4 
Criteria for Rociletinib Cross-over Treatment Eligibility Following 
Radiological Progression on or After Comparator Arm Therapy 
To be eligible for participation in the cross over part of the study, patients must fulfil the 
following criteria: 
1. Have documented radiological progression per RECIST 1.1 during or following completion 
of comparator arm therapy (single agent cytotoxic chemotherapy)  
2. Have adequate hematological and biological function, confirmed by the following local 
laboratory values: 
Bone marrow function 
a. 
ANC  1.5 × 109/L 
b. Platelets > 100.0 × 109/L  
c. 
Hemoglobin  9 g/dL (or 5.6 mmol/L) 
Hepatic function 
d. AST and ALT  3 × ULN; if liver metastases,  5 × ULN  
e. 
Bilirubin  2 × ULN (except for patients with documented Gilbert’s disease and 
conjugated bilirubin) 
Renal function  
f. 
Creatinine clearance ≥ 45 mL/min 
Electrolytes 
g. Potassium and magnesium within normal range. Patients may receive supplements to 
meet this requirement. 
Glucose 
h. Fasting serum glucose within normal ranges 
3. Written consent on an IRB/IEC-approved ICF  
In addition, any of the following will exclude patients from participation in the cross over part: 
1. Patients who are currently receiving treatment with any medications that have the potential to 
prolong the QT interval and that treatment cannot be either discontinued or switched to a 
different medication (known to have no effect on QT) before starting rociletinib (see 
http://crediblemeds.org/ for a list of QT-prolonging medications) 
2. Any of the following cardiac abnormalities or history: 
a. 
Clinically significant abnormal 12-lead ECG, QTCF > 450 msec  


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b. Inability to measure QT interval on ECG 
c. 
Personal or family history of long QT syndrome 
d. Implantable pacemaker or implantable cardioverter defibrillator 
e. 
Resting bradycardia < 55 beats/min 
3. Presence of any serious or unstable concomitant systemic disorder incompatible with the 
clinical study, eg, substance abuse, uncontrolled intercurrent illness including: 
• uncontrolled diabetes 
• active infection 
• arterial thrombosis, and 
•  symptomatic pulmonary embolism 
4. A positive pregnancy test in females of childbearing potential 
5. Any other reason the Investigator considers the patient should not participate in the cross 
over study 
6.5 
Patients or Partners of Patients of Reproductive Potential 
Pregnancy is an exclusion criterion and women of childbearing potential must not be considering 
getting pregnant during the study. Female patients who are more than 2 years postmenopausal or 
have had a hysterectomy will not be considered of childbearing potential. Female patients of 
childbearing potential must have a negative serum pregnancy less than 3 days before 
randomization. Since there is a 3 day window between randomization and C1D1, a urine 
pregnancy test must be performed on C1D1 to confirm that the patient is not pregnant before 
dosing. Both values should be entered in the electronic case report form (eCRF). Another serum 
pregnancy test will be performed at the End-of-Treatment Visit, and during screening for patients 
who chose to cross over from comparator arm therapy to receive rociletinib. 
Patients of reproductive potential (males and females) must practice an adequate method of 
contraception during treatment and for 6 months after the last dose of study treatment (rociletinib 
and chemotherapy irrespective of the single cytotoxic agent used). Adequate contraception is 
defined as: 
• Abstinence - Complete abstinence, acceptable only when it is the usual and preferred lifestyle 
of the patient, periodic abstinence (eg, calendar, symptothermal, post-ovulation methods) is 
not acceptable; or 
• Double-barrier protection (ie, condom plus spermicide in combination with a diaphragm, 
cervical/vault cap, or intrauterine device).  
Patients will be instructed to notify the investigator if pregnancy is discovered either during or 
within 6 months of completing treatment. This also applies to male patients whose partners 
become pregnant while the patient is on study or within the 6-month period after the last dose of 
study drug. 


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6.6 
Waivers of Inclusion/Exclusion Criteria 
No waivers of these inclusion or exclusion criteria will be granted by the investigator and the 
sponsor or its designee for any patient enrolling into the study.  


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7 
DESCRIPTION OF STUDY TREATMENTS AND DOSE 
MODIFICATIONS 
7.1 
Description of Study Treatments 
7.1.1 
Rociletinib  
Rociletinib is provided as yellow, film-coated tablets for oral administration in two dosage 
strengths made from the same drug blend. The strengths are achieved by adjusting the total tablet 
weight. The strengths are differentiated by tablet shapes: the 125 mg strength is a round tablet 
and the 250 mg strength is an oval tablet. Each tablet consists of CO-1686 HBr drug substance, 
silicified microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, 
copovidone, magnesium stearate and hypromellose based film coat. Excipients used are 
generally regarded as safe (GRAS). Tablets are packaged along with desiccant in high density 
polyethylene bottles closed with a child-resistant cap. Tablets will be supplied to the study sites 
by the sponsor. Rociletinib tablets should be stored in their original packaging at 15°C to 30°C 
(59°F to 86°F). 
Child-resistant bottles containing rociletinib tablets are labeled according to applicable 
regulations for investigational products. Patients should be advised not to split or crush tablets. 
Additionally, patients should be advised not to take tablets with chips or other gross visual 
defects. Defective tablets should be returned to the study site and reported to the sponsor. 
7.1.2 
Single-agent Cytotoxic Chemotherapy 
The comparator product is single agent cytotoxic chemotherapy: investigator choice of 
pemetrexed, gemcitabine, docetaxel, or paclitaxel. Commercially available pemetrexed, 
gemcitabine, docetaxel, and paclitaxel will be either procured by investigational centers or be 
supplied by the sponsor. Each product will be stored in accordance with manufacturer’s product 
labeling. 
7.2 
Method of Assigning Patients to Treatment Groups 
Patients will be randomized 1:1 to receive oral rociletinib or single-agent cytotoxic 
chemotherapy (investigator choice of pemetrexed, gemcitabine, docetaxel, or paclitaxel; choice 
of chemotherapy agent must be specified before randomization). Randomization will be stratified 
according to:  
1. Brain metastases present versus no brain metastases present 
2. ECOG performance status 0 versus ECOG performance status 1 
3. Territory of residence at time of randomization (East Asian versus non-East Asian). 


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7.3 
Preparation and Administration of Protocol-specified Treatment 
7.3.1 
Rociletinib 
Rociletinib will be administered daily at 500 mg BID. Treatment with rociletinib is continuous 
and each cycle will comprise of 21 days. The first dose will be administered at the clinic during 
the visit on Day 1 of each cycle, then the patient should take rociletinib at home, at 
approximately the same time each day. Patients should take rociletinib as directed by the treating 
physician. Each dose should be taken with 8 oz (240 mL) of water and with a meal or within 
30 minutes after a meal. Tablets should be swallowed whole.  
For patients who started therapy with rociletinib at 625 mg BID under Protocol Amendment 1, a 
reduction in dose to 500 mg BID is allowed, only if necessitated by unacceptable toxicity. 
If a patient misses a dose (ie, does not take it within 6 hours of the scheduled time), he or she 
should resume taking rociletinib with their next scheduled dose. Missed or vomited doses will 
not be made up. 
The investigator or designee will be responsible for distributing the appropriate strength(s) of 
oral rociletinib tablets to all patients. A sufficient number of tablets will be provided to the 
patient to last until the next scheduled visit. Patients will be instructed to record daily doses taken 
or not taken at home in a patient diary, and will be instructed to bring their rociletinib tablets and 
diary to the next scheduled clinic visit for reconciliation by site personnel. 
Supportive care should be given if required to manage AEs per institutional guidelines. 
Prophylactic treatment is not required. 
7.3.2 
Single-agent Cytotoxic Chemotherapy 
The choice of single-agent cytotoxic chemotherapy is at the discretion of the investigator from 
amongst the regimens described in this protocol and must be specified and documented before 
randomization. The following treatment and premedication regimens are recommended for the 
comparator regimens; however, locally approved premedication protocols may be followed at the 
investigator’s discretion. 
7.3.2.1 
Pemetrexed 
Pemetrexed will be administered to patients intravenously in clinic at 500 mg/m2 over 
10 minutes on Day 1 of each 21-day cycle.  
A corticosteroid should be given the day before, on the day of, and on the day after pemetrexed 
administration. The corticosteroid should be equivalent to 4 mg of dexamethasone administered 
orally BID.  
Patients treated with pemetrexed should also receive vitamin supplementation. Patients should 
take oral folic acid or a multivitamin containing folic acid (350 to 1000 micrograms) on a daily 
basis. At least 5 daily doses of folic acid must be taken preceding the first dose of pemetrexed. If 
pemetrexed is considered as a chemotherapy choice, then folic acid supplementation may begin 


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prior to randomization to minimize treatment delay. Dosing should continue during the full 
course of therapy and for 21 days after the last dose of pemetrexed. Patients should also receive 
an intramuscular injection of vitamin B12 (1000 micrograms) in the week preceding the first 
dose of pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may 
be given on the same day as pemetrexed. 
Complete blood counts (CBC), including platelet counts, should be performed on all patients 
receiving pemetrexed. Patients should be monitored before each dose and on Days 8 and 15 of 
each cycle. Patients should not begin a new cycle of treatment unless the ANC is 
≥ 1500 cells/mm3, the platelet count is ≥ 100,000 cells/mm3, and creatinine clearance is 
≥ 45 mL/min. Pemetrexed should not be administered to patients whose creatinine clearance is 
< 45 mL/min using the standard Cockcroft and Gault formula: 
 
Caution should be exercised when administering pemetrexed concurrently with NSAIDs to 
patients whose creatinine clearance is < 80 mL/min. 
7.3.2.2 
Gemcitabine 
Gemcitabine will be administered to patients intravenously in clinic at 1250 mg/m2 over 
30 minutes on Days 1 and 8 of each 21-day cycle.  
Patients receiving gemcitabine should be monitored prior to each dose with a CBC, including 
differential and platelet count. Laboratory evaluation of renal and hepatic function, including 
transaminases and serum creatinine, should be performed prior to initiation of therapy and 
periodically thereafter. Gemcitabine should be administered with caution in patients with 
evidence of significant renal or hepatic impairment. 
7.3.2.3 
Docetaxel 
There is a choice of 2 dosing regimens for docetaxel: 
• Docetaxel administered intravenously in clinic at 75 mg/m2 (60 mg/m2 for Asian patients) 
over 1 hour on Day 1 of each 21-day cycle  
Or  
• Docetaxel administered intravenously in clinic at 35 mg/m2 over 1 hour on a weekly basis as 
part of a continuous 21-day cycle; ie, dosing will be on Days 1, 8, and 15 of each 21-day 
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All patients should be premedicated with corticosteroids, such as oral dexamethasone 16 mg per 
day (eg, 8 mg BID) for 3 days starting 1 day prior to docetaxel administration, in order to reduce 
the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions. 
7.3.2.4 
Paclitaxel 
Paclitaxel will be administered to patients intravenously in clinic at 80 mg/m2 as a 1 hour 
infusion, on a weekly basis as part of a continuous 21-day cycle; ie, dosing will be on Days 1, 8, 
and 15 of each 21-day cycle. 
All patients should be premedicated prior to paclitaxel administration in order to prevent severe 
hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg 
administered orally approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its 
equivalent) 50 mg intravenously, 30 to 60 minutes prior to paclitaxel, and cimetidine 300 mg or 
ranitidine 50 mg intravenously, 30 to 60 minutes before paclitaxel. 
Patients who experienced severe hypersensitivity reactions to paclitaxel should not be 
rechallenged with the drug. Paclitaxel should not be administered to patients with baseline 
neutrophil counts of less than 1500 cells/mm3. Frequent monitoring of blood counts should be 
performed during paclitaxel treatment. Patients should not be re-treated with subsequent cycles 
of paclitaxel until neutrophils recover to a level > 1500 cells/mm3 and platelets recover to a level 
> 100,000 cells/mm3. 
If a patient develops significant conduction abnormalities during paclitaxel infusion, appropriate 
therapy should be administered and continuous cardiac monitoring should be performed during 
subsequent therapy with paclitaxel. 
7.4 
Dose Modifications of Protocol-specified Treatment 
7.4.1 
Rociletinib 
No dose escalation above the starting dose is allowed. Two dose reduction steps are allowed for 
each patient. The dose reductions are from 500 mg BID (starting dose) to 375 mg BID, then to 
250 mg BID. The dose of rociletinib should not be reduced below 250 mg BID without prior 
sponsor approval. 
For NCI CTCAE Version 4.03 Grade 3 or 4 hematologic and non-hematologic toxicities (except 
for nausea/vomiting, alopecia, QTc prolongation and hyperglycemia), the dose should be initially 
reduced to 375 mg BID and, if persistent, to 250 mg BID for subsequent doses if the investigator 
and sponsor do not believe treatment discontinuation is required. Re-escalation of dose after 
resolution of AEs must be discussed and approved by sponsor prospectively. 
If a patient continues to experience toxicity after these dose reduction steps, or if dosing with 
rociletinib is interrupted for > 14 consecutive days due to toxicity, treatment should be 
discontinued unless otherwise agreed between the investigator and the sponsor before 
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7.4.1.1 
Management of Prolonged QTC 
ECGs will be measured throughout the study as described in the protocol. Readings for QTC 
prolongation will be based on the average seen in the ECGs for each time point. Patients are 
required to have within-normal-range potassium and magnesium at enrollment, and these 
electrolytes should be maintained within range during rocilenitib treatment, if necessary using 
supplementation. If QTC prolongation of CTCAE Grade 3 is observed, rociletinib will be 
withheld until the event has improved to Grade 1. Rociletinib can then be re-started at a reduced 
dose after sponsor approval. After 2 dose reduction evaluations, if CTCAE Grade 3 or above 
QTC prolongation recurs, then rociletinib will be discontinued unless agreed with the sponsor 
that additional dose reductions can be evaluated. If QTC prolongation changes of CTCAE Grade 
4 are observed at any time, rociletinib will be discontinued permanently. 
7.4.1.2 
Management of Hyperglycemia 
Rociletinib causes hyperglycemia in some patients secondary to inhibition of the insulin-like 
growth factor 1 receptor (IGF-1R) and insulin receptor (IR) kinases by a metabolite. Therefore, 
some patients will require addition of a glucose lowering medication and patients with 
pre-existing diabetes may require more frequent monitoring and/or adjustments of diabetic 
medication. Clinical experience with rociletinib suggests hyperglycemia generally occurs within 
the first 3 weeks of treatment, leading to the need for more intensive glucose monitoring during 
the first several weeks of the study. In Phase 1/2 clinical trial experience, increased nausea, 
vomiting, decreased appetite, diarrhea, muscle cramps and fatigue have been reported in patients 
with hyperglycemia. Such patients must be closely monitored including assessment of fasting 
glucose levels and early initiation of anti-hyperglycemic therapy. As rociletinib-induced 
hyperglycemia is mediated through insulin resistance, agents that suppress glucose synthesis 
(metformin), increase sensitivity to insulin (glitazones) or increase glucose excretion 
(sodium-glucose cotransporter 2 [SGLT2] inhibitors) are expected to be more effective than 
those that increase plasma insulin (sulphonylureas or exogenous insulin). Metformin has been 
used most frequently in rociletinib clinical studies and is, therefore, recommended as the initial 
agent to manage hyperglycemia in patients with normal renal function. In addition, preliminary 
data from the ongoing Study CO-1686-008 suggest that starting metformin at the same time 
rociletinib therapy is initiated may prevent development of rociletinib-induced hyperglycemia. 
For all patients, irrespective of whether they are receiving metformin prophylactically or 
therapeutically, glucose monitoring should be conducted according to the following schedule: 
Fasting glucose will be measured at the following visits: screening, C1D1, C1D4 (± 1 day), 
C1D8 (± 1 day), C1D15 (± 1 day), C2D1, C2D15 (± 1 day), C3D1, C4D1, C5D1, CND1… and 
End-of-Treatment Visit.  
The following guidelines for management of hyperglycemia are based on experience in the 
Phase 1 study. Whilst the blood glucose thresholds for intervention outlined below should be 
followed, management of individual patients should be based on local practices and the treating 
physician’s judgment. In all cases, the prescribing information should be followed and maximum 
approved dose of anti-hyperglycemic agent should not be exceeded. 


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1. Additional monitoring outside of per protocol schedule is not needed if fasting glucose is 
< 125 mg/dL (< 6.94 mmol/L). 
2. If fasting glucose ≥ 125 mg/dL (≥ 6.94 mmol/L) and ≤ 160 mg/dL (≤ 8.88 mmol/L), patients 
will be asked to perform self-monitoring of blood glucose using finger stick blood testing 
(preferred choice) or urine dipstick testing (a urine dipstick can show a false-positive 
glucosuria in patients taking SGLT2 inhibitors). Initiation of anti-hyperglycemic therapy 
with metformin or anti-hyperglycemic agent of choice should be considered at this time, 
particularly for patients with symptoms of increased nausea, vomiting, decreased appetite, 
diarrhea, muscle cramps and fatigue. Tests should be performed at home QD for at least 
2 weeks, taking note of time, fasted/fed state, and glucose levels in a monitoring log 
provided. Patients should bring this monitoring log to scheduled visits and review with the 
treating physician. If patient observes at home 2 or more fasting blood glucose measurements 
> 160 mg/dL (> 8.88 mmol/L), and/or 2 or more random blood glucose measurements 
> 200 mg/dL (> 11.01 mmol/L) (or a combination of the 2), or 2 or more positive urine 
glucose tests before their next scheduled clinic visit, they should call their health care 
practitioner (HCP), inform the study site, and schedule a visit as soon as possible with the 
treating physician. Treatment with metformin or anti-hyperglycemic agent of choice should 
be started.  
3. If fasting blood glucose > 160 mg/dL (≥ 8.88 mmol/L) and ≤ 250 mg/dL (≤ 13.87 mmol/L) 
on more than 2 occasions, start metformin or anti-hyperglycemic agent of choice. Patients 
should perform self-monitoring of blood glucose using finger stick blood testing or urine 
dipstick testing. Finger stick tests should be performed at home QD for at least 2 weeks, 
making note of time, fasted/fed state and glucose levels in a monitoring log provided. 
Patients should bring this monitoring log to scheduled visits and review with treating 
physician. 
4. If fasting glucose > 250 mg/dL (> 13.87 mmol/L), and the patient is not symptomatic, 
manage as for Step 3 above. If the patient is symptomatic, then hold rociletinib and bring 
glucose under control acutely, if necessary using insulin with conversion to metformin or 
anti-hyperglycemic agent of choice once plasma glucose is controlled. Once patient is 
asymptomatic and deemed appropriate for additional therapy, rociletinib may be 
re-introduced at a reduced dose, with concomitant metformin/anti-hyperglycemic agent of 
choice. Patients should perform self-monitoring of blood glucose using finger stick blood 
testing or urine dipstick testing. Finger stick tests should be performed at home BID for at 
least 2 weeks, before breakfast and before dinner, taking note of time, fasted/fed state and 
glucose levels in a monitoring log provided. Patients should bring this monitoring log to 
scheduled visits and review with the treating physician.  
Metformin is contraindicated in patients with renal disease or renal dysfunction, among others, 
and use should follow the package insert and approved label. In order to minimize known 
gastrointestinal (GI) toxicity associated with metformin use, the extended release form and 
taking medication at bedtime are recommended to improve tolerability.28 Additional 
recommendations to avoid GI toxicity with metformin include starting treatment at a reduced 
dose (500 mg QD) for 72 hours, increasing to 500 mg BID for 72 hours, and if necessary, and 
increasing up to 1000 mg BID. If plasma glucose is not adequately controlled with the regimen 
outlined above, then consider adding pioglitazone or an SGLT-2 inhibitor and consider 
consultation with an endocrinologist. 


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End-of-Treatment 
When rociletinib is discontinued, the need and use of anti-diabetic medications should be 
reassessed and the patient monitored and treated appropriately in order to minimize the possible 
hypoglycemia which may result. 
Figure 7-1: Guidelines for Management of Hyperglycemiaa 
 
Abbreviations: FG = fasting plasma or serum glucose (in mg/dL); HCP = health care practitioner; QD = once daily. 
a Guidelines intend to assist in managing patients that are non-diabetic at study start only.  
b Consider initiation of anti-hyperglycemic therapy, particularly for patients with symptoms of increased nausea, 
vomiting, decreased appetite, diarrhea, muscle cramps and fatigue. 
c For patients with a single elevation, fasting glucose can be repeated at the next regularly scheduled assessment. 
 
7.4.2 
Single-agent Cytotoxic Chemotherapy 
Investigators can follow institutional guidelines or local dose reduction protocols for the 
comparator chemotherapy agents, otherwise investigators must follow the guidelines indicated in 
the protocol. 


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7.4.2.1 
Pemetrexed 
Hematological toxicities should be managed as follows: 
Hematological Toxicity 
Dose of Pemetrexed 
Nadir ANC < 500/mm3 and nadir platelets 
≥ 50,000/mm3 
75% of previous dose 
Nadir platelets < 50,000/mm3 regardless of nadir 
ANC 
75% of previous dose 
Nadir platelets < 50,000/mm3 with bleeding 
(CTCAE Grade 2) regardless of nadir ANC 
50% of previous dose 
Abbreviations: ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for Adverse Events, 
Version 4.03. 
If patients develop non-hematological toxicities ≥ Grade 3 (excluding neurotoxicity), pemetrexed 
should be withheld until resolution to less than or equal to the patient’s pretherapy value. 
Treatment should be resumed according to the guidelines in the table below. 
Non-hematological Toxicity 
Dose of Pemetrexed 
Any Grade 3 or 4 toxicity, except mucositis and 
neurotoxicity 
75% previous dose 
Any diarrhea requiring hospitalization 
(irrespective of grade) or Grade 3 or 4 diarrhea 
75% previous dose 
Grade 3 or 4 mucositis 
50% previous dose 
 
If patients develop neurotoxicity, treatment should be modified as follows: 
CTCAE Grade 
Dose of Pemetrexed 
1 
100% previous dose 
2 
100% previous dose 
3, 4 
Discontinue 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events, Version 4.03. 
Pemetrexed therapy should be discontinued if a patient experiences any hematological or 
non-hematological Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 
neurotoxicity is observed. 
7.4.2.2 
Gemcitabine 
Dose reduction within a treatment cycle should proceed as follows: 
When the Day 8 dose is delayed more than 5 days because of toxicity, then that dose will be 
omitted and the next scheduled dose will be administered on time. 


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The criteria for step-wise dose reduction during a treatment cycle are as follows: 
Within Cycle Dose Reduction Steps 
ANC, × 109/L 
 
Platelet Count, × 109/L 
Percent of Full Dose 
During Cycle 
 1.0 
And 
 100 
100 
0.5 to 0.99 
And/or 
50 to 99 
75 
< 0.5 
And/or 
< 50 
Hold 
Abbreviations: ANC = absolute neutrophil count. 
For other hematological and non-hematological toxicities of Grade 3/4 (except for 
nausea/vomiting and alopecia), the investigator should consider a dose reduction to 75%, and, if 
persistent, to 50% for subsequent doses. Once the dose has been reduced within a treatment 
cycle, treatment continues at that dose level; no dose escalation is possible during that cycle.  
Dose reduction between treatment cycles should proceed as follows: 
Treatment cycles may be delayed owing to drug-related toxicity or in the event of either 
ANC < 1.5 × 109/L or platelet count < 100 × 109/L. Delays of > 3 weeks require treatment to be 
permanently discontinued. 
Occurrence of Grade 4 neutropenia lasting  7 days, febrile neutropenia, Grade 4 
thrombocytopenia, or Grade 3 with clinically significant coagulopathy in the previous cycle 
require new cycles to start at 75% of the starting dose; recurrent febrile neutropenia requires 
starting new cycles at 50% of the starting dose. 
7.4.2.3 
Docetaxel 
Docetaxel should be administered when the neutrophil count is ≥ 1500 cells/mm3.  
Three-weekly schedule: 
In patients who experience either febrile neutropenia, neutrophil count < 500 cells/mm3 for more 
than 1 week, severe or cumulative cutaneous reactions, severe peripheral neuropathy, or Grade 3 
non-hematological toxicity during docetaxel therapy, treatment should be withheld until 
resolution of the toxicity and the subsequent dose of docetaxel should be reduced from 75 to 
55 mg/m². If the patient continues to experience these reactions at 55 mg/m², the treatment 
should be discontinued.  
If ≥ Grade 3 neuropathy occurs, docetaxel should be permanently discontinued 
Weekly schedule: 
If Grade 3 toxicity occurs, the dose of docetaxel should be reduced to 75 to 50% of the initial 
dose based on investigator assessment. If the patient continues to experience toxicity at a reduced 
dose, the treatment should be discontinued. 


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7.4.2.4 
Paclitaxel 
Adjust dose according to the following schedule: 
Toxicity 
CTCAE Grade 
Adjustment 
Febrile neutropenia 
Any 
Reduce paclitaxel to 65 mg/m2 
Peripheral neuropathy 
Grade 2 
Reduce paclitaxel to 65 mg/m2 
Peripheral neuropathy 
Grade 3 
Discontinue 
Other 
 Grade 3 excluding alopecia, 
nausea/vomiting/ diarrhea 
controlled by medication 
Hold until Grade 1. If toxicity 
recurs on re-starting, reduce 
dose to 65 mg/m2 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events, Version 4.03. 
In addition, if any other Grade 3 AEs occur, the dose of paclitaxel should be reduced to 75 to 
50% of the of the initial dose. Paclitaxel should not be repeated until the neutrophil count is at 
least 1500 cells/mm3 and the platelet count is at least 100,000 cells/mm3. 
For all treatment regimens, additional supportive care may be used at the investigator’s 
discretion and in accordance with institutional procedures. 
7.4.2.5 
For All Chemotherapy Regimens 
If febrile neutropenia, Grade 4 thrombocytopenia for ≥ 7 days, or thrombocytopenia with 
bleeding occurs then no dose re-escalation is permitted.  
7.5 
Accountability of Protocol-specified Treatment 
Study personnel will maintain accurate records of rociletinib and single-agent cytotoxic 
chemotherapy shipments/receipts (if provided by sponsor), administration, and drug 
reconciliation. The study site is responsible for the return or destruction of the study drugs as 
required. A drug management system will manage sponsor supplied study drug inventory at all 
sites. The system will be required to manage study treatment requests and shipments. 
Any rociletinib or sponsor-provided cytotoxic chemotherapy accidentally or deliberately 
destroyed must be accounted for. All bottles of sponsor-provided study drug must be accounted 
for before their destruction at the study center. Unused bottles of sponsor-provided study drug 
should be destroyed locally. If destruction at the site is not possible, supply should be returned to 
the drug depot. During the course of the study and at completion of the study, the number of 
bottles of sponsor-provided study drug shipped, destroyed, and returned must be reconciled.  
7.6 
Blinding/Masking of Treatment 
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7.7 
Treatment Compliance 
7.7.1 
Rociletinib 
Documentation of dosing will be recorded in a study specific diary card provided by the sponsor 
(or designee). Study site personnel will enter the scheduled daily doses and the number of tablets 
to be taken each day. Study site personnel will review the dosing information with the patient (or 
legally authorized representative) on scheduled clinic visit days. Patients (or legally authorized 
representative) will be asked to record dosing information for oral rociletinib taken at home in 
the diary card and to bring the diary card and all unused tablets with them to scheduled clinic 
visits. A compliance check and tablet count for returned material will be performed by study 
personnel. Study site personnel will record compliance information on the eCRF and retain the 
diary card in the patient’s medical record.  
7.7.2 
Single-agent Cytotoxic Chemotherapy 
Chemotherapy (investigator choice of single-agent pemetrexed, gemcitabine, docetaxel, or 
paclitaxel) will be administered in the study clinic by study personnel and therefore treatment 
compliance is assured. 


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8 
PRIOR AND CONCOMITANT THERAPIES 
Medications known to produce QT prolongation should be avoided during the study whilst 
treatment is ongoing. If a drug that has the potential to cause QT prolongation is indicated to 
control AEs (eg, 5HT3 inhibitor for nausea/vomiting) and the investigator believes that the 
patient is benefiting from study therapy, then additional ECGs should be done to monitor for 
potential QTC changes. The use of such concomitant medications and an appropriate ECG 
monitoring plan should be agreed between the investigator and sponsor. Acceptable antiemetics 
with low potential to affect QTC include phenothiazines and corticosteroids. 
All procedures performed and medications used during the study must be documented on the 
eCRF.  
8.1 
Anticancer or Experimental Therapy 
No other anticancer therapies (including radiation, hormonal treatment [except corticosteroids 
and megestrol acetate], antibody or other immunotherapy or other experimental drugs) of any 
kind will be permitted while the patient is participating in the study.  
Palliative radiation therapy intended to provide relief of cancer-related symptoms is permitted 
while the patient is on study, as long as there is no evidence of disease progression according to 
RECIST Version 1.1. Treatment should be withheld while the patient is undergoing 
radiotherapy.  
Additionally, a patient who continues treatment post-progression may undergo radiation or other 
procedures to specific lesions post-progression, if the patient continues to benefit from treatment 
overall. See Section 5.1.3 for more details. 
8.2 
Hematopoietic Growth Factors and Blood Products 
Erythropoietin, darbepoetin alfa, and/or hematopoietic colony-stimulating factors for treatment 
of cytopenias should be administered according to institutional guidelines. Prophylactic use of 
these agents is not permitted. 
Transfusion thresholds for blood product support will be in accordance with institutional 
guidelines. 
8.3 
CYP450 Isozyme Inhibitors and Inducers  
Caution should be exercised in patients receiving oral rociletinib and requiring concomitant 
medication with warfarin (Coumadin), NSAIDs, or clopidogrel, as rociletinib moderately 
inhibited CYP2C8, CYP2C9, and CYP2C19 activities in vitro. Patients taking warfarin who are 
enrolled in the study are required to have international normalized ratio (INR) monitored 
regularly per standard clinical practice. Preliminary data from an ongoing definitive CYP 
inhibition study revealed that rociletinib also moderately inhibited CYP3A4. As such, caution 
should be exercised in patients receiving rociletinib and the following CYP3A4 substrates with 


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narrow therapeutic range: alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimis, and terfenadine.  
8.4 
P-gp Substrates, Inhibitors, and Inducers 
Because rociletinib is a P-gp inhibitor in vitro, caution should be exercised in patients receiving 
oral rociletinib and requiring concomitant medication with digoxin, a P-gp substrate. Patients 
taking digoxin who are enrolled in the study are required to have digoxin levels monitored 
regularly via standard clinical practice. 
Rociletinib is a P-gp substrate and thus, P-gp inhibitors have the potential to increase rociletinib 
exposure. As such, caution should be exercised in patients receiving rociletinib and the following 
P-gp inhibitors: amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, 
cyclosporine, diltiazem, dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, 
lopinavir and ritonavir, quercetin, quinidine, ranolazine, and verapamil. 
Conversely, P-gp inducers have the potential to decrease rociletinib exposure. Caution should be 
exercised in patients receiving rociletinib and the following P-gp inducers: avasimibe, 
carbamazepine, phenytoin, rifampin, St John’s wort, and tipranavir/ritonavir. 
8.5 
Other Concomitant Medications 
Therapies considered necessary for the patient’s well-being may be given at the discretion of the 
investigator and in accordance with institutional procedures, and should be documented on the 
eCRF. Other concomitant medications, except for analgesics, chronic treatments for concomitant 
medical conditions, or agents required for life-threatening medical problems, should be avoided.  
Medications for nausea to consider, that are not associated with QT prolongation, include: 
• Steroids (dexamethasone, methylprednisolone) 
• Benzodiazepines 
• Aprepitant  
• Select anticholinergic agents (scopolamine) 
• Trimethobenzamide  
• Cannabinoids 
Palonosetron is currently not listed on crediblemeds.org and a thorough QTc study showed no 
QTc effect. However, as rare cases of QTc prolongation have been reported, a more frequent 
ECG monitoring schedule should be adopted if used with rociletinib. 
Because rociletinib is absorbed optimally in an acidic environment, proton pump inhibitors or H2 
blockers should be used with caution. If gastric acid blockade is required, short acting antacids 
are preferred.  


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Herbal and complementary therapies should not be encouraged because of unknown side effects 
and potential drug interactions, but any taken by the patient should be documented appropriately 
on the eCRF. 
Yellow fever vaccine is strictly contraindicated in accordance with the pemetrexed Summary of 
Product Characteristics (SPC). 


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9 
STUDY PROCEDURES 
Table 9-1 summarizes the schedule of assessments for patients randomized to receive treatment 
with oral rociletinib. For patients randomized to receive single agent cytotoxic chemotherapy, the 
schedules of assessments are summarized in Table 9-2. Table 9-3 summarizes the schedule of 
assessments for patients who cross over to receive oral rociletinib after progressing on 
single-agent cytotoxic chemotherapy. Patients who continue to receive rociletinib after 
radiological progression should continue to follow the procedures as outlined in Table 9-1 
without change. 
All procedures and assessments are to be completed within ± 1 day of the scheduled time point 
and are synchronized with administration day (C1D1) of oral rociletinib or single-agent cytotoxic 
chemotherapy unless otherwise indicated. 


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Table 9-1: 
Schedule of Assessments for Patients Randomized to Rociletinib 
 
Consent 
Screening 
Randomizationa 
Treatment Period 
(Daily dosing)b 
Post-treatment Period 
Procedurec 
Before Any 
Screening 
Procedures 
Cycle 1 
Day -35 
to 
Day -3 
Cycle 1 
Day -14 
to  
Day –3 
Cycle 1 
Day –3 
(C1D–3) 
Cycle 1 
Day 1 
(C1D1)c 
Cycle 
1 
Day 4  
± 1 
Day 
Cycle 
1 Day 
8  
± 1 
Day 
Cycle 
1 Day 
15  
± 1 
Day 
Cycle 
2  
Day 1 
(21 ± 
3 days 
after 
C1D1) 
Cycle 
2 Day 
15 
± 1 
Day 
Cycle 
3 +,  
Day 1 
(every 
21 ± 3 
days) 
End of 
Treatment 
Visit 
(28 ± 7 
days after 
last dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Random-
izationa 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Medical/ 
oncology 
history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination  
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
Vital signsd, 
height 
(screening 
only), weight, 
ECOG PS 
 
 
X 
(includin
g height) 
 
X 
 
 
 
X 
 
X 
X 
 
Previous/ 
concomitant 
medications 
and 
procedures 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
 
Contraceptive 
counselinge 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Local serum 
pregnancy 
testf 
 
 
X 
 
 
 
 
 
 
 
 
X 
 


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Table 9-1: 
Schedule of Assessments for Patients Randomized to Rociletinib (Cont.) 
 
Consent 
Screening 
Randomizationa 
Treatment Period 
(Daily dosing)b 
Post-treatment Period 
Procedurec 
Before Any 
Screening 
Procedures 
Cycle 1 
Day -35 
to 
Day -3 
Cycle 1 
Day -14 
to  
Day –3 
Cycle 1 
Day –3 
(C1D–3) 
Cycle 1 
Day 1 
(C1D1)c 
Cycle 
1 
Day 4  
± 1 
Day 
Cycle 
1 Day 
8  
± 1 
Day 
Cycle 
1 Day 
15  
± 1 
Day 
Cycle 
2  
Day 1 
(21 ± 
3 days 
after 
C1D1) 
Cycle 
2 Day 
15 
± 1 
Day 
Cycle 
3 +,  
Day 1 
(every 
21 ± 3 
days) 
End of 
Treatment 
Visit 
(28 ± 7 
days after 
last dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
Local urine 
pregnancy 
testf 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Local 
hematology 
(CBC and 
differential)  
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
Local fasting 
serum 
chemistryh 
 
 
X 
 
X 
Fasting 
glucose 
only 
Fasting 
glucose 
only 
Fasting 
glucose 
only 
X 
Fasting 
glucose 
only 
X 
X 
 
Local 
urinalysisi 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Tumor scans, 
including 
brain imaging 
at screeningj 
 
X 
 
 
Tumor scans performed every 6 ± 1 weeks during treatment, from C1D1 
X 
(X - if 
patient 
discontinues 
before 
progression) 
PGx blood 
sample 
 
 
 
 
X 
(optional; 
additiona
l consent 
required) 
 
 
 
 
 
 
 
 


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Table 9-1: 
Schedule of Assessments for Patients Randomized to Rociletinib (Cont.) 
 
Consent 
Screening 
Randomizationa 
Treatment Period 
(Daily dosing)b 
Post-treatment Period 
Procedurec 
Before Any 
Screening 
Procedures 
Cycle 1 
Day -35 
to 
Day -3 
Cycle 1 
Day -14 
to  
Day –3 
Cycle 1 
Day –3 
(C1D–3) 
Cycle 1 
Day 1 
(C1D1)c 
Cycle 
1 
Day 4  
± 1 
Day 
Cycle 
1 Day 
8  
± 1 
Day 
Cycle 
1 Day 
15  
± 1 
Day 
Cycle 
2  
Day 1 
(21 ± 
3 days 
after 
C1D1) 
Cycle 
2 Day 
15 
± 1 
Day 
Cycle 
3 +,  
Day 1 
(every 
21 ± 3 
days) 
End of 
Treatment 
Visit 
(28 ± 7 
days after 
last dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
Tumor/ 
metastasis 
biopsy for 
biomarker/ 
EGFR 
mutational 
statusk 
 
X 
(within 
60 days 
of 
C1D1) 
 
 
 
 
 
 
 
 
 
X (optional; 
additional 
consent 
required) 
 
Blood for 
biomarker 
testing and 
exploratory 
researchl 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
 
Adverse 
eventsm 
 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
 
Rociletinib 
dispensing/ 
administration 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Patient diaryn  
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
ECGo 
 
X 
 
 
X 
 
 
X 
X 
 
X 
X 
 
Blood for 
sparse PK 
sampling and 
AAG serum 
levelsp 
 
 
 
 
 
 
 
 
X 
 
X (Cycle 
3 to 7 
inclusive 
only) 
 
 


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Table 9-1: 
Schedule of Assessments for Patients Randomized to Rociletinib (Cont.) 
 
Consent 
Screening 
Randomizationa 
Treatment Period 
(Daily dosing)b 
Post-treatment Period 
Procedurec 
Before Any 
Screening 
Procedures 
Cycle 1 
Day -35 
to 
Day -3 
Cycle 1 
Day -14 
to  
Day –3 
Cycle 1 
Day –3 
(C1D–3) 
Cycle 1 
Day 1 
(C1D1)c 
Cycle 
1 
Day 4  
± 1 
Day 
Cycle 
1 Day 
8  
± 1 
Day 
Cycle 
1 Day 
15  
± 1 
Day 
Cycle 
2  
Day 1 
(21 ± 
3 days 
after 
C1D1) 
Cycle 
2 Day 
15 
± 1 
Day 
Cycle 
3 +,  
Day 1 
(every 
21 ± 3 
days) 
End of 
Treatment 
Visit 
(28 ± 7 
days after 
last dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
Quality of life 
questionnaires
q 
 
 
X 
 
X 
 
 
 
 
 
X (every 
2 cycles 
± 1 week 
until 
C7D1, 
then 
every 3 
cycles ± 
1 week) 
X 
 
Survival 
status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Subsequent 
therapies for 
NSCLC 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: AAG = alpha 1-acid glycoprotein; AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
β-hCG = beta human chorionic gonadotropin; BUN = blood urea nitrogen; C1D1 = Cycle 1 Day 1; CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern 
Cooperative Oncology Group performance status; EGFR = epidermal growth factor receptor; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer 
core quality of life questionnaire; EORTC QLQ-L13 = European Organisation for Research and Treatment of Cancer quality of life questionnaire lung cancer module; FFPE = 
formalin-fixed paraffin-embedded; HbA1c = glycated hemoglobin (A1c); ICF = informed consent form; PD = pharmacodynamic; PGx = pharmacogenomic; PK = 
pharmacokinetic; POPPK = population pharmacokinetics; MRI = magnetic resonance imaging; NSCLC = non-small cell lung cancer; QoL = quality of life; RECIST = Response 
Evaluation Criteria in Solid Tumors, Version 1.1; TKI = tyrosine kinase inhibitor; WBC = white blood cells. 
a 
C1D1 must be 3 days after randomization to allow patients in the pemetrexed chemotherapy arm enough time for folic acid and B12 treatment prior to therapy. 
b 
Rociletinib will be administered orally BID at 500 mg/dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. 
c 
Unless specified, procedure is completed ± 1 day of scheduled time point and is synchronized with C1D1 of rociletinib. 
d 
Vital signs (blood pressure, pulse, and temperature) taken pre-dose on C1D1, and without reference to dose at every subsequent visit. All vital signs will be obtained after the 
patient has been resting for at least 5 minutes. Height is only required once at screening. 


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Table 9-1: 
Schedule of Assessments for Patients Randomized to Rociletinib (Cont.) 
 
Consent 
Screening 
Randomizationa 
Treatment Period 
(Daily dosing)b 
Post-treatment Period 
Procedurec 
Before Any 
Screening 
Procedures 
Cycle 1 
Day -35 
to 
Day -3 
Cycle 1 
Day -14 
to  
Day –3 
Cycle 1 
Day –3 
(C1D–3) 
Cycle 1 
Day 1 
(C1D1)c 
Cycle 
1 
Day 4  
± 1 
Day 
Cycle 
1 Day 
8  
± 1 
Day 
Cycle 
1 Day 
15  
± 1 
Day 
Cycle 
2  
Day 1 
(21 ± 
3 days 
after 
C1D1) 
Cycle 
2 Day 
15 
± 1 
Day 
Cycle 
3 +,  
Day 1 
(every 
21 ± 3 
days) 
End of 
Treatment 
Visit 
(28 ± 7 
days after 
last dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
e 
Fertile male patients and female patients of childbearing potential are to continue using effective contraception for 6 months after the last dose of rociletinib and report any 
pregnancies during this period. 
f 
Serum β-hCG (evaluated by local laboratories) will be performed only on women of childbearing potential  3 days before randomization. An additional urine pregnancy test 
must be performed locally and results obtained prior to dosing on C1D1 to confirm that the patient is not pregnant before dosing. 
g 
Includes hemoglobin, hematocrit, CBC, and differential (with ANC), and platelet count ≤ 14 days before randomization. Blood will be analyzed at a local laboratory and must 
be reviewed by the investigator before starting each new cycle of rociletinib administration. Additional tests may be performed at the investigator’s discretion.  
h 
Includes c-peptide, total protein, albumin, creatinine, BUN or urea, total bilirubin, alkaline phosphatase, ALT, AST, fasting glucose, sodium, potassium, magnesium, chloride, 
CO2, calcium, phosphorus, and total cholesterol ≤ 14 days before randomization during screening and prior to starting each new cycle of rociletinib administration. Fasting 
glucose required on Cycle 1 Day 4 ± 1 day, Cycle 1 Day 8 ± 1 day, Cycle 1 Day 15 ± 1 day, and Cycle 2 Day 15 ± 1 day for patients taking rociletinib only (not required for 
patients taking chemotherapy). HbA1c will be measured ≤ 14 days before randomization during screening and on Day 1 of every other treatment cycle (Cycles 3, 5, 7, etc.). 
Samples will be analyzed by a local laboratory. Glucose must be measured following an 8 hour fast (no food or liquid other than water). 
i 
Includes dipstick for protein, glucose, blood, pH, and ketones. If dipstick findings are abnormal, then a microscopic evaluation will be performed to assess the abnormal 
findings. 
j 
Tumor scans obtained within 35 days before randomization may be used as the baseline scans. Scans will include the chest and abdomen (preferably CT scans with 
appropriate slice thickness per RECIST Version 1.1), using the same methods throughout the study that were used to detect lesions at baseline. Scans of the pelvis (CT or 
MRI) are required if there is prior evidence of local disease or if clinically indicated (symptomatic patients). Other studies (MRI, X-ray) may be performed if required. Brain 
imaging (CT/MRI) is required at baseline. Patients with brain lesions at screening should have the brain lesions followed throughout the study at the scheduled time points. 
Tumor scans will be performed during screening, then every 6 weeks ± 1 week from the time of randomization thereafter (Day 1 of Cycles 3, 5, 7, etc.) until tumor 
progression. Patients are required to have an end-of-treatment tumor scan using the same methodology used at screening unless the patient has radiographic evidence of 
disease progression while on study or it has been < 2 weeks since their last on-study scan. In addition, an MRI may be used in place of a CT for the end-of-treatment scan if 
required per local authorities. For patients with clinical progression, radiographic assessment should be performed to document evidence of radiographic progression. Patients 
who discontinue treatment without progression should continue to be scanned every 6 weeks per protocol until disease progression occurs. Exceptions to this requirement 
based on local institutional or regulatory requests must be agreed in advance with the sponsor. If a treatment cycle is delayed, the tumor scans should still follow the 6-weekly 
calendar schedule from the time of randomization. Scans will be evaluated locally for patient treatment decisions. Scans will also be stored with a central vendor and quality 
control performed; central reading of scans will not be done unless requested by the sponsor.  


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Table 9-1: 
Schedule of Assessments for Patients Randomized to Rociletinib (Cont.) 
 
Consent 
Screening 
Randomizationa 
Treatment Period 
(Daily dosing)b 
Post-treatment Period 
Procedurec 
Before Any 
Screening 
Procedures 
Cycle 1 
Day -35 
to 
Day -3 
Cycle 1 
Day -14 
to  
Day –3 
Cycle 1 
Day –3 
(C1D–3) 
Cycle 1 
Day 1 
(C1D1)c 
Cycle 
1 
Day 4  
± 1 
Day 
Cycle 
1 Day 
8  
± 1 
Day 
Cycle 
1 Day 
15  
± 1 
Day 
Cycle 
2  
Day 1 
(21 ± 
3 days 
after 
C1D1) 
Cycle 
2 Day 
15 
± 1 
Day 
Cycle 
3+,  
Day 1 
(every 
21 ± 3 
days) 
End of 
Treatment 
Visit 
(28 ± 7 
days after 
last dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
k 
Biopsy of either primary or metastatic tissue to confirm EGFR mutational status, including EGFR T790M, and for the development of a validated tissue-based EGFR T790M 
test. Randomization of a given patient will be based on local mutational testing and independent of the patient’s T790M status. Tissue material must be obtained within 60 
days prior to start of treatment and following progression on the most recent EGFR-TKI therapy and at least 1 previous platinum-based chemotherapy. T790M assessment 
will be performed by a central laboratory. At progression and/or end of treatment (prior to initiating a new line of treatment), a tumor biopsy will be performed if the patient 
provides additional consent. All tumor tissue will be processed locally as FFPE tissue. Exploratory biomarker analysis will be done if FFPE tissue is available after T790M 
testing and diagnostic test validation. Refer to the Laboratory Manual for specimen handling instructions.  
l 
Blood sampling for biomarker testing and exploratory research/pharmacodynamic assessment will be collected at screening (before biopsy, or at least 7 days AFTER the 
biopsy); predose on C1D1, then predose on Day 1 of every subsequent cycle, and at the End-of-Treatment Visit. Refer to the Laboratory Manual for sample processing 
details. 
m 
Patients will be monitored for AEs from the time the first dose of rociletinib is administered through to 28 days after the last dose. Study procedure-related AEs that occur 
after signing of the ICF but before administration of rociletinib will also be collected. On C1D1, AEs will be monitored pre- and postdose. 
n 
Patient diaries will be dispensed on C1D1. They should be collected and reviewed for compliance at each visit. No diary will be dispensed at end of treatment. 
o 
ECGs in triplicate, 10-second tracings > 2 minutes apart. Taken anytime during screening, predose on C1D1, predose and 2 hours after dose on C1D15, then predose on Day 1 
of every subsequent cycle (every 21 ± 3 days), and at end of treatment after treatment is discontinued. ECGs will be performed and interpreted locally for patient care 
decisions; however, tracings will be collected centrally for independent evaluation.  
p 
Blood samples will be drawn for POPPK analysis at 21 ± 3 day intervals for the first 6 months (Day 1 of Cycles 2 to 7 inclusive) in all patients treated with rociletinib. The 
sample can be predose (eg, if the study visit is early in the day) or postdose (if the visit is late in the morning or in the afternoon). The blood draw time relative to the last 
rociletinib dosing time will be recorded at each PK sample occasion for each patient. Serum samples for AAG analysis will be collected on the same day as PK samples. 
Central laboratories will be used for bioanalysis of plasma rociletinib and 3 metabolites levels and AAG measurement. Refer to the Laboratory Manual for details on 
collection and processing of blood PK and AAG samples. 
q 
QoL questionnaires (EORTC QLQ-C30 and EORTC QLQ-L13) and the EQ-5D preference-based health instrument will be collected at screening, predose on C1D1, then 
every 2 cycles ± 1 week for the first 6 cycles (Day 1 of Cycles 3, 5, 7 ± 1 week inclusive). After Cycle 7, questionnaires will be collected every 3 cycles ± 1 week (Day 1 of 
Cycle 10, 13, 16, etc. ± 1 week), and at the End-of-Treatment Visit. 
 


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Table 9-2: 
Schedule of Assessments for Patients Randomized to Single-agent Cytotoxic Chemotherapy 
 
Consent 
Screening 
Randomization 
Chemotherapy Cyclesa 
Post-treatment Period 
Procedureb 
Before Any 
Screening 
Procedures 
Cycle 1 
Day –35 
to Day –3 
Cycle 1 
Day −14 
to Day −3 
Cycle 1 
Day -3 
(C1D–3) 
Cycle 1  
Day 1 
(C1D1)c 
Cycle 
1  
Day 8  
± 
1 Day 
Cycle 
1  
Day 15 
± 1 
Day 
Cycle X+,  
Day 1 
(every 
21 ± 3 
days) 
Cycle X+ 
Day 8 
± 1 Day 
Cycle 
X+ 
Day 15  
± 1 Day 
End-of-
Treatment 
Visit 
(28 ± 7 
days after 
last dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
Begin folic 
acid/plan B12 
injectionp 
 
 
 
X 
 
 
 
 
 
 
 
 
Medical/onco-
logy history 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical 
examination  
 
 
X 
 
X 
 
 
X 
 
 
X 
 
Vital signsd, 
height 
(screening 
only), weight, 
ECOG PS 
 
 
X 
(including 
height) 
 
X 
 
 
X 
 
 
X 
 
Previous/ 
concomitant 
medications  
and procedures 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Contraceptive 
counselinge 
 
X 
 
 
 
 
 
 
 
 
X 
 
Local serum 
pregnancy testf 
 
 
X 
 
 
 
 
 
 
 
X 
 
Local urine 
pregnancy testf 
 
 
 
 
X 
 
 
 
 
 
 
 


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Table 9-2: 
Schedule of Assessments for Patients Randomized to Single-agent Cytotoxic Chemotherapy (Cont.) 
 
Consent 
Screening 
Randomization 
Chemotherapy Cyclesa 
Post-treatment Period 
Procedureb 
Before Any 
Screening 
Procedures 
Cycle 1 
Day –35 
to Day –3 
Cycle 1 
Day −14 
to Day −3 
Cycle 1 
Day -3 
(C1D–3) 
Cycle 1  
Day 1 
(C1D1)c 
Cycle 
1  
Day 8  
± 
1 Day 
Cycle 
1  
Day 15 
± 1 
Day 
Cycle X+,  
Day 1 
(every 
21 ± 3 
days) 
Cycle X+ 
Day 8 
± 1 Day 
Cycle 
X+ 
Day 15  
± 1 Day 
End-of-
Treatment 
Visit 
(28 ± 7 
days after 
last dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
Local 
hematology  
CBC and 
differentialg 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Local fasting 
serum 
chemistryh 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
Local 
urinalysisi 
 
 
X 
 
 
 
 
 
 
 
 
 
Tumor scans, 
including brain 
imaging at 
screeningj 
 
X 
 
 
Tumor scans performed every 6 ± 1 weeks during treatment, from 
C1D1 
X 
(X - if 
patient 
discontinues 
before 
progression) 
Tumor/ 
metastasis 
biopsy for 
biomarker/EGF
R mutational 
statusk 
 
X  
(within 
60 days of 
C1D1) 
 
 
 
 
 
 
 
 
X (optional; 
additional 
consent 
required) 
 
Blood for 
biomarker 
testing and 
exploratory 
researchl 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Adverse 
eventsm 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Table 9-2: 
Schedule of Assessments for Patients Randomized to Single-agent Cytotoxic Chemotherapy (Cont.) 
 
Consent 
Screening 
Randomization 
Chemotherapy Cyclesa 
Post-treatment Period 
Procedureb 
Before Any 
Screening 
Procedures 
Cycle 1 
Day –35 
to Day –3 
Cycle 1 
Day −14 
to Day −3 
Cycle 1 
Day -3 
(C1D–3) 
Cycle 1  
Day 1 
(C1D1)c 
Cycle 
1  
Day 8  
± 
1 Day 
Cycle 
1  
Day 15 
± 1 
Day 
Cycle X+,  
Day 1 
(every 
21 ± 3 
days) 
Cycle X+ 
Day 8 
± 1 Day 
Cycle 
X+ 
Day 15  
± 1 Day 
End-of-
Treatment 
Visit 
(28 ± 7 
days after 
last dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
Chemotherapy 
administration 
 
 
 
 
X 
Xq 
Xq 
X 
Xq 
Xq 
 
 
ECGn 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Quality of life 
questionnaireso 
 
 
X 
 
X 
 
 
X (every 
2 cycles 
± 1 week 
until 
C7D1, 
then 
every 3 
cycles ± 
1 week) 
 
 
X 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
X 
X 
Subsequent 
therapies for 
NSCLC 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; β-hCG = beta human chorionic 
gonadotropin; BUN = blood urea nitrogen; C1D1 = Cycle 1 Day 1; CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group 
performance status; EGFR = epidermal growth factor receptor; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer core quality of life 
questionnaire; EORTC QLQ-L13 = European Organisation for Research and Treatment of Cancer quality of life questionnaire lung cancer module; FFPE = formalin-fixed 
paraffin-embedded; HbA1c = glycated hemoglobin (A1c); ICF = informed consent form; PD = pharmacodynamic; PK = pharmacokinetic; MRI = magnetic resonance imaging; 
NSCLC = non-small cell lung cancer; QoL = quality of life; RECIST = Response Evaluation Criteria in Solid Tumors, Version 1.1; TKI = tyrosine kinase inhibitor; WBC = white 
blood cells. 
 


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Table 9-2: 
Schedule of Assessments for Patients Randomized to Single-agent Cytotoxic Chemotherapy (Cont.) 
 
Consent 
Screening 
Randomization 
Chemotherapy Cyclesa 
Post-treatment Period 
Procedureb 
Before Any 
Screening 
Procedures 
Cycle 1 
Day –35 
to Day –3 
Cycle 1 
Day −14 
to Day −3 
Cycle 1 
Day -3 
(C1D–3) 
Cycle 1  
Day 1 
(C1D1)c 
Cycle 
1  
Day 8  
± 
1 Day 
Cycle 
1  
Day 15 
± 1 
Day 
Cycle X+,  
Day 1 
(every 
21 ± 3 
days) 
Cycle X+ 
Day 8 
± 1 Day 
Cycle 
X+ 
Day 15  
± 1 Day 
End-of-
Treatment 
Visit 
(28 ± 7 
days after 
last dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
a 
Pemetrexed will be administered to patients intravenously at 500 mg/m2 on Day 1 of each 21-day cycle. 
Gemcitabine will be administered to patients intravenously at 1250 mg/m2 on Days 1 and 8 of each 21-day cycle. 
Docetaxel will be administered to patients intravenously at 75 mg/m2 (60 mg/m2 in Asian patients) on Day 1 of each 21-day cycle, or at 35 mg/m2 on a weekly basis as part of 
a continuous 21-day cycle (ie, dosing will be on Days 1, 8, and 15 of each 21-day cycle).  
Paclitaxel will be administered to patients intravenously at 80 mg/m2 as a 1 hour infusion, on a weekly basis as part of a continuous 21-day cycle (ie, dosing will be on 
Days 1, 8, and 15 of each 21-day cycle). 
b 
Unless specified, procedure is completed ± 1 day of scheduled time point and is synchronized with administration day C1D1 of chemotherapy. 
c 
C1D1 must be 3 days after randomization to allow patients in the pemetrexed chemotherapy arm enough time for folic acid and B12 treatment prior to therapy.  
d 
Vital signs (blood pressure, pulse, and temperature, ECOG PS) taken pre-dose on C1D1, and without reference to dose at every subsequent visit. All vital signs will be 
obtained after the patient has been resting for at least 5 minutes. Height is only required once at screening. 
e 
Fertile male patients and female patients of childbearing potential are to continue using effective contraception for 6 months after the last dose of chemotherapy and report any 
pregnancies during this period. 
f 
Serum β-hCG (evaluated by local laboratories) will be performed only on women of childbearing potential  3 days before randomization. An additional urine pregnancy test 
must be performed locally and results obtained prior to dosing on C1D1 to confirm that the patient is not pregnant before dosing. 
g 
Includes hemoglobin, hematocrit, CBC, and differential (with ANC), and platelet count ≤ 14 days before randomization. Blood will be analyzed at a local laboratory and must 
be reviewed by the investigator before starting each new cycle of chemotherapy administration. Additional tests may be performed at the investigator’s discretion. 
h 
Includes c-peptide, total protein, albumin, creatinine, BUN or urea, total bilirubin, alkaline phosphatase, ALT, AST, fasting glucose, sodium, potassium, magnesium, chloride, 
CO2, calcium, phosphorus, and total cholesterol ≤ 14 days before randomization during screening and prior to starting each new cycle of chemotherapy. HbA1c will be 
measured ≤ 14 days before randomization during screening and on Day 1 of every other treatment cycle (Cycles 3, 5, 7, etc.). Samples will be analyzed by a local laboratory. 
Glucose must be measured following an 8 hour fast (no food or liquid other than water). 
i 
Includes dipstick for protein, glucose, blood, pH, and ketones. If dipstick findings are abnormal, then a microscopic evaluation will be performed to assess the abnormal 
findings. 
 


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Table 9-2: 
Schedule of Assessments for Patients Randomized to Single-agent Cytotoxic Chemotherapy (Cont.) 
 
Consent 
Screening 
Randomization 
Chemotherapy Cyclesa 
Post-treatment Period 
Procedureb 
Before Any 
Screening 
Procedures 
Cycle 1 
Day –35 
to Day –3 
Cycle 1 
Day −14 
to Day −3 
Cycle 1 
Day -3 
(C1D–3) 
Cycle 1  
Day 1 
(C1D1)c 
Cycle 
1  
Day 8  
± 
1 Day 
Cycle 
1  
Day 15 
± 1 
Day 
Cycle X+,  
Day 1 
(every 
21 ± 3 
days) 
Cycle X+ 
Day 8 
± 1 Day 
Cycle 
X+ 
Day 15  
± 1 Day 
End-of-
Treatment 
Visit 
(28 ± 7 
days after 
last dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
j 
Tumor scans obtained within 35 days before randomization may be used as the baseline scans. Scans will include the chest and abdomen (preferably CT scans with 
appropriate slice thickness per RECIST Version 1.1), using the same methods throughout the study that were used to detect lesions at baseline. Scans of the pelvis (CT or 
MRI) are required if there is prior evidence of local disease or if clinically indicated (symptomatic patients). Other studies (MRI, X-ray) may be performed if required. Brain 
imaging (CT/MRI) is required at baseline. Patients with brain lesions at screening should have the brain lesions followed throughout the study at the scheduled time points. 
Tumor scans will be performed during screening, then every 6 weeks ± 1 week from the time of randomization thereafter (Day 1 of Cycles 3, 5, 7, etc.) until tumor 
progression. Patients are required to have an end-of-treatment tumor scan using the same methodology used at screening unless the patient has radiographic evidence of 
disease progression while on study or it has been < 2 weeks since their last on-study scan. In addition, an MRI may be used in place of a CT for the end-of-treatment scan if 
required per local authorities. For patients with clinical progression, radiographic assessment should be performed to document evidence of radiographic progression. Patients 
who discontinue treatment without progression should continue to be scanned every 6 weeks per protocol until disease progression occurs. Exceptions to this requirement 
based on local institutional or regulatory requests must be agreed in advance with the sponsor. If a treatment cycle is delayed, the tumor scans should still follow the 6-weekly 
calendar schedule from the time of randomization. Scans will be evaluated locally for patient treatment decisions. Scans will also be stored with a central vendor and quality 
control performed; central reading of scans will not be done unless requested by the sponsor.  
k 
Biopsy of either primary or metastatic tissue to confirm EGFR mutational status, including EGFR T790M, and for the development of a validated tissue-based EGFR T790M 
test. Randomization of a given patient will be based on local mutational testing and independent of the patient’s T790M status. Tissue material must be obtained within 
60 days prior to start of treatment and following progression on the most recent EGFR-TKI therapy and at least one previous platinum-based chemotherapy. T790M 
assessment will be performed by a central laboratory. At progression and/or end of treatment (prior to initiating a new line of therapy), a tumor biopsy will be performed if the 
patient provides additional consent. All tumor tissue will be processed locally as FFPE tissue. Exploratory biomarker analysis will be done if FFPE tissue is available after 
T790M testing and diagnostic test validation. Refer to the Laboratory Manual for specimen handling instructions. 
l 
Blood sampling for biomarker testing and exploratory research/PD assessment will be collected at screening (before biopsy, or at least 7 days AFTER the biopsy); pre-dose on 
C1D1, then pre-dose on Day 1 of every subsequent cycle, and at the End-of-Treatment Visit. Refer to the Laboratory Manual for sample processing details. 
m 
Patients will be monitored for AEs from the time the first dose of chemotherapy is administered through to 28 days after the last dose. Study procedure-related AEs that occur 
after signing of the ICF but before administration of chemotherapy will also be collected. On C1D1, AEs will be monitored pre- and postdose. 
n 
ECGs in triplicate, 10-second tracings > 2 minutes apart. Taken anytime during screening, predose on C1D1, then predose on Day 1 of every subsequent cycle (every 
21 ± 3 days), and at end of treatment after treatment is discontinued. ECGs will be performed and interpreted locally for patient care decisions; however, tracings will be 
collected centrally for independent evaluation. 
o 
QoL questionnaires (EORTC QLQ-C30 and EORTC QLQ-L13) and the EQ-5D preference-based health instrument will be collected at screening, predose on C1D1, then 
every 2 cycles ± 1 week for the first 6 cycles (Day 1 of Cycles 3, 5, 7 ± 1 week inclusive). After Cycle 7, questionnaires will be collected every 3 cycles ± 1 week (Day 1 of 
Cycle 10, 13, 16, etc. ± 1 week), and at end of treatment. 


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Table 9-2: 
Schedule of Assessments for Patients Randomized to Single-agent Cytotoxic Chemotherapy (Cont.) 
 
Consent 
Screening 
Randomization 
Chemotherapy Cyclesa 
Post-treatment Period 
Procedureb 
Before Any 
Screening 
Procedures 
Cycle 1 
Day –35 
to Day –3 
Cycle 1 
Day −14 
to Day −3 
Cycle 1 
Day -3 
(C1D–3) 
Cycle 1  
Day 1 
(C1D1)c 
Cycle 
1  
Day 8  
± 
1 Day 
Cycle 
1  
Day 15 
± 1 
Day 
Cycle X+,  
Day 1 
(every 
21 ± 3 
days) 
Cycle X+ 
Day 8 
± 1 Day 
Cycle 
X+ 
Day 15  
± 1 Day 
End-of-
Treatment 
Visit 
(28 ± 7 
days after 
last dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
p 
At least 5 daily doses of folic acid must be taken preceding the first dose of pemetrexed and dosing must continue during the full course of therapy and for 21 days after the 
last dose of pemetrexed. Folic acid must be taken before starting pemetrexed. If the investigator selects pemetrexed as the comparator option for a patient, then folic acid 
supplementation may begin prior to randomization, if necessary, to ensure that C1D1 is not delayed while premedication is completed. Patients should also receive an 
intramuscular injection of vitamin B12 (1000 micrograms) in the week preceding the first dose of pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 
injections may be given on the same day as pemetrexed. 
q 
All chemotherapy agents will be administered on Day 1 of each 21-day cycle. In addition, gemcitabine, docetaxel at the 35 mg/m2 dose, and paclitaxel will be administered on 
Day 8 of each 21-day cycle; and docetaxel at the 35 mg/m2 dose and paclitaxel will also be administered on Day 15 of each 21-day cycle. This does not apply to pemetrexed 
and docetaxel at the 75 mg/m2 dose, which will only be administered on Day 1 of each 21-day cycle. 
 


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Table 9-3: 
Schedule of Assessments for Patients who Cross Over to Rociletinib After Chemotherapy 
 
Consent 
Screening 
Treatment Period 
(Daily dosing)a 
Post-treatment Period 
Procedureb 
Before 
Any 
Screening 
Procedures 
Day −35 
to Day −1 
Day −14 
to Day −1 
XO-
Cycle 1 
Day 1 
(XO-
C1D1)c 
XO-
Cycle 1 
Day 4 
± 1 Day 
XO-
Cycle 1 
Day 8  
± 1 Day 
XO- 
Cycle 1 
Day 15 
± 1 Day 
XO-
Cycle 
2 
Day 1 
(21 ± 3 
days 
after 
C1D1) 
XO-
Cycle 2 
Day 15 
± 1 day 
XO- 
Cycle 3+, 
Day 1 
(every 21 
± 3 days) 
End of 
Treatment 
visit 
(28 ± 7 days 
after last 
dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
Cross over informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
 
 
X 
X 
 
 
 
X 
 
X 
X 
 
Vital signsd, height 
(screening only), weight, 
ECOG PS 
 
 
X 
(including 
height) 
X 
 
 
 
X 
 
X 
X 
 
Previous/concomitant 
medications and 
procedures 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
Contraceptive 
counselinge 
 
X 
 
 
 
 
 
 
 
 
X 
 
Local serum pregnancy 
testf 
 
 
X 
 
 
 
 
 
 
 
X 
 
Local urine pregnancy 
testf 
 
 
 
X 
 
 
 
 
 
 
 
 
Local hematology, CBC 
and differentialg 
 
 
X 
X 
 
 
 
X 
 
X 
X 
 
Local fasting serum 
chemistryh 
 
 
X 
X 
Fasting 
glucose 
only 
Fasting 
glucose 
only 
Fasting 
glucose 
only 
X 
Fasting 
glucose 
only 
X 
X 
 
Tumor scans, including 
brain imaging at 
screeningi 
 
X 
 
Tumor scans performed every 6 ± 1 weeks during treatment, from XO-
C1D1 
X 
(X - if 
patient 
discontinues 
before 
progression 


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Table 9-3: 
Schedule of Assessments for Patients who Cross Over to Rociletinib After Chemotherapy (Cont.) 
 
Consent 
Screening 
Treatment Period 
(Daily dosing)a 
Post-treatment Period 
Procedureb 
Before 
Any 
Screening 
Procedures 
Day −35 
to Day −1 
Day −14 
to Day −1 
XO-
Cycle 1 
Day 1 
(XO-
C1D1)c 
XO-
Cycle 1 
Day 4 
± 1 Day 
XO-
Cycle 1 
Day 8  
± 1 Day 
XO- 
Cycle 1 
Day 15 
± 1 Day 
XO-
Cycle 
2 
Day 1 
(21 ± 3 
days 
after 
C1D1) 
XO-
Cycle 2 
Day 15 
± 1 day 
XO- 
Cycle 3+, 
Day 1 
(every 21 
± 3 days) 
End of 
Treatment 
visit 
(28 ± 7 days 
after last 
dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
PGx blood sample 
 
 
 
X 
(optional; 
additional 
consent 
required) 
 
 
 
 
 
 
 
 
Tumor/metastasis biopsy 
for biomarker/EGFR 
mutational statusj 
 
 
 
 
 
 
 
 
 
 
X (optional; 
additional 
consent 
required) 
 
Blood for biomarker 
testing and exploratory 
researchk 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
Adverse eventsl 
 
X 
X 
X 
 
 
 
X 
 
X 
X 
 
Rociletinib 
dispensing/administration 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Patient diarym 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
ECGn 
 
X 
 
X 
 
 
X 
X 
 
X 
X 
 
Blood for sparse PK 
sampling and AAG 
serum levelso 
 
 
 
 
 
 
 
X 
 
X 
(Cycle 3 
to 7 
inclusive 
only) 
 
 


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Table 9-3: 
Schedule of Assessments for Patients who Cross Over to Rociletinib After Chemotherapy (Cont.) 
 
Consent 
Screening 
Treatment Period 
(Daily dosing)a 
Post-treatment Period 
Procedureb 
Before 
Any 
Screening 
Procedures 
Day −35 
to Day −1 
Day −14 
to Day −1 
XO-
Cycle 1 
Day 1 
(XO-
C1D1)c 
XO-
Cycle 1 
Day 4 
± 1 Day 
XO-
Cycle 1 
Day 8  
± 1 Day 
XO- 
Cycle 1 
Day 15 
± 1 Day 
XO-
Cycle 
2 
Day 1 
(21 ± 3 
days 
after 
C1D1) 
XO-
Cycle 2 
Day 15 
± 1 day 
XO- 
Cycle 3+, 
Day 1 
(every 21 
± 3 days) 
End of 
Treatment 
visit 
(28 ± 7 days 
after last 
dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
Quality of life 
questionnairesp 
 
 
X 
X 
 
 
 
 
 
X 
(every 2 
cycles ± 
1 week 
until 
XO-
C7D1, 
then 
every 3 
cycles ± 
1 week) 
X 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
X 
X 
Subsequent therapies for 
NSCLC 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: AAG = alpha 1-acid glycoprotein; AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
β-hCG = beta human chorionic gonadotropin; BUN = blood urea nitrogen; C1D1 = Cycle 1 Day 1; CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern 
Cooperative Oncology Group performance status; EGFR = epidermal growth factor receptor; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer 
core quality of life questionnaire; EORTC QLQ-L13 = European Organisation for Research and Treatment of Cancer quality of life questionnaire lung cancer module; FFPE = 
formalin-fixed paraffin-embedded; HbA1c = glycated hemoglobin (A1c); ICF = informed consent form; PD = pharmacodynamic; PGx = pharmacogenomic; PK = 
pharmacokinetic; POPPK = population pharmacokinetics; MRI = magnetic resonance imaging; NSCLC = non-small cell lung cancer; QoL = quality of life; RECIST = Response 
Evaluation Criteria in Solid Tumors, Version 1.1; WBC = white blood cells, XO = cross over. 
a 
Rociletinib will be administered BID at 500 mg/dose with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. 
b 
Unless specified, procedure is completed ± 1 day of scheduled time point and is synchronized with administration day of rociletinib (XO-C1D1). 
c 
Procedures required on XO-C1D1 may be omitted if completed  3 days earlier during the screening period. 
d 
Vital signs (blood pressure, pulse, and temperature, and ECOG PS) taken predose on XO-C1D1, and without reference to dose at every subsequent visit. All vital signs will be 
obtained after the patient has been resting for at least 5 minutes. Height is only required once at screening. 


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Table 9-3: 
Schedule of Assessments for Patients who Cross Over to Rociletinib After Chemotherapy (Cont.) 
 
Consent 
Screening 
Treatment Period 
(Daily dosing)a 
Post-treatment Period 
Procedureb 
Before 
Any 
Screening 
Procedures 
Day −35 
to Day −1 
Day −14 
to Day −1 
XO-
Cycle 1 
Day 1 
(XO-
C1D1)c 
XO-
Cycle 1 
Day 4 
± 1 Day 
XO-
Cycle 1 
Day 8  
± 1 Day 
XO- 
Cycle 1 
Day 15 
± 1 Day 
XO-
Cycle 
2 
Day 1 
(21 ± 3 
days 
after 
C1D1) 
XO-
Cycle 2 
Day 15 
± 1 day 
XO- 
Cycle 3+, 
Day 1 
(every 21 
± 3 days) 
End of 
Treatment 
visit 
(28 ± 7 days 
after last 
dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
e 
Fertile male patients and female patients of childbearing potential are to continue using effective contraception for 6 months after the last dose of rociletinib and report any 
pregnancies during this period. 
f 
Serum β-hCG (evaluated by local laboratories) will be performed only on women of childbearing potential  3 days before XO-C1D1. An additional urine pregnancy test 
must be performed locally and results obtained prior to dosing on XO-C1D1 to confirm that the patient is not pregnant before dosing. 
g 
Includes hemoglobin, hematocrit, CBC, and differential (with ANC), and platelet count ≤ 14 days before XO-C1D1. Blood will be analyzed at a local laboratory and must be 
reviewed by the investigator before start of each new cycle of rociletinib administration. Additional tests may be performed at the investigator’s discretion. 
h 
Includes c-peptide, total protein, albumin, creatinine, BUN or urea, total bilirubin, alkaline phosphatase, ALT, AST, fasting glucose, sodium, potassium, magnesium, chloride, 
CO2, calcium, phosphorus, and total cholesterol ≤ 14 days before XO-C1D1 and prior to starting each new cycle of rociletinib administration. Fasting glucose required on 
XO-Cycle 1 Day 4 ± 1 day, XO-Cycle 1 Day 8 ± 1 day, XO-Cycle 1 Day 15 ± 1 day, and XO-Cycle 2 Day 15 ± 1 day. HbA1c will be measured ≤ 14 days before XO-C1D1 
and on Day 1 of every other treatment cycle (XO-Cycles 3, 5, 7, etc.). Samples will be analyzed by a local laboratory. Glucose must be measured following an 8 hour fast (no 
food or liquid other than water). 
i 
Tumor scans obtained at progression on/after comparator arm treatment should be used as XO-screening scans. Scans will include the chest and abdomen (preferably CT 
scans with appropriate slice thickness per RECIST Version 1.1), using the same methods throughout the study that were used to detect lesions at baseline. Scans of the pelvis 
(CT or MRI) are required if there is prior evidence of local disease or if clinically indicated (symptomatic patients). Other studies (MRI, X-ray) may be performed if required. 
Tumor scans will then be performed every 6 weeks ± 1 week from the time of crossover (Day 1 of XO-Cycles 3, 5, 7, etc.) until tumor progression. Patients are required to 
have an end of treatment tumor scan using the same methodology used at screening unless the patient has radiographic evidence of disease progression while on study or it 
has been < 2 weeks since their last on-study scan. In addition, an MRI may be used in place of a CT for the end-of-treatment scan if required per local authorities. For patients 
with clinical progression, radiographic assessment should be performed to document evidence of radiographic progression. Patients who discontinue treatment without 
progression should continue to be scanned every 6 weeks per protocol until disease progression occurs. Exceptions to this requirement based on local institutional or 
regulatory requests must be agreed in advance with the sponsor. If an XO-treatment cycle is delayed, the tumor scans should still follow the 6-weekly calendar schedule from 
the time of crossover. Scans will be evaluated locally for patient treatment decisions. Scans will also be stored with a central vendor and quality control performed; central 
reading of scans will not be done unless requested by the sponsor.  
j 
A tumor biopsy will be performed (prior to initiating a new line of therapy) if the patient provides additional consent. All tumor tissue will be processed locally as FFPE 
tissue. Exploratory biomarker analysis will be done if FFPE tissue is available after T790M testing and diagnostic test validation. Refer to the Laboratory manual for 
specimen handling instructions. 
k 
Blood sampling for biomarker testing and exploratory research/PD assessment will be collected at screening, predose on XO-C1D1, then pre-dose on Day 1 of every 
subsequent cycle, and at the End of Treatment Visit. Refer to the Laboratory Manual for sample processing details. 


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Table 9-3: 
Schedule of Assessments for Patients who Cross Over to Rociletinib After Chemotherapy (Cont.) 
 
Consent 
Screening 
Treatment Period 
(Daily dosing)a 
Post-treatment Period 
Procedureb 
Before 
Any 
Screening 
Procedures 
Day −35 
to Day −1 
Day −14 
to Day −1 
XO-
Cycle 1 
Day 1 
(XO-
C1D1)c 
XO-
Cycle 1 
Day 4 
± 1 Day 
XO-
Cycle 1 
Day 8  
± 1 Day 
XO- 
Cycle 1 
Day 15 
± 1 Day 
XO-
Cycle 
2 
Day 1 
(21 ± 3 
days 
after 
C1D1) 
XO-
Cycle 2 
Day 15 
± 1 day 
XO- 
Cycle 3+, 
Day 1 
(every 21 
± 3 days) 
End of 
Treatment 
visit 
(28 ± 7 days 
after last 
dose) 
Follow-up 
(every 
2 months for 
survival and 
subsequent 
therapy 
starting at 
end of 
treatment) 
l 
AEs will be collected from the time of the first dose of study therapy through to 28 days after the last dose of rociletinib. 
m 
Patient diaries should be collected and reviewed for compliance at each visit. No diary will be dispensed at end of treatment. 
n 
ECGs in triplicate, 10-second tracings > 2 minutes apart. Taken anytime during screening, pre-dose on XO-C1D1, pre-dose and 2 hours after dose on XO-C1D15, then pre-
dose on Day 1 of every subsequent XO-cycle (every 21 ± 3 days), and at end of treatment after treatment is discontinued. ECGs will be performed and interpreted locally for 
patient care decisions; however, tracings will be collected centrally for independent evaluation. 
o 
Blood samples will be drawn for POPPK analysis at 21 ± 3 day intervals for the first 6 months (Day 1 of Cycles 2 to 7 inclusive) in all patients treated with rociletinib. The 
sample can be pre-dose (eg, if the study visit is early in the day) or post-dose (if the visit is late in the morning or in the afternoon). The blood draw time relative to the last 
rociletinib dosing time will be recorded at each PK sample occasion for each patient. Serum samples for AAG analysis will be collected on the same day as PK samples. 
Central laboratories will be used for bioanalysis of plasma rociletinib and 3 metabolites levels and AAG measurement. Refer to the Laboratory Manual for details on 
collection and processing of blood PK and AAG samples. 
p 
QoL questionnaires (EORTC QLQ-C30, and EORTC QLQ-L13) and the EQ-5D preference-based health instrument will be collected at screening, pre-dose on XO-C1D1, 
then every 2 cycles ± 1 week for the first 6 cycles (Day 1 of XO-Cycles 3, 5, 7 ± 1 week inclusive). After XO-Cycle 7, questionnaires will be collected every 3 cycles ± 1 
week (Day 1 of XO-Cycle 10, 13, 16, etc. ± 1 week), and at end of treatment. 
 


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9.1 
Screening Period (All Patients) 
Following written informed consent, and unless otherwise specified, the following assessments 
should be carried out during the 35-day period before randomization. Assessments carried out 
before the patient signs informed consent are acceptable only if confirmed to have been standard 
of care. 
To be performed ≤ 60 days prior to start of treatment: 
• Biopsy or surgical resection of primary or metastatic lesions ≤ 60 days prior to start of 
treatment. To ensure adequate viable tumor tissue is obtained, image-guided biopsies should 
be achieved with 18- to 20-gauge cutting needles to provide 1 to 3 cores measuring 1 to 
1.5 cm in length. In addition, the biopsy must be of solid tumor tissue; ascites is not 
acceptable.  
To be performed ≤ 35 days prior to randomization: 
• Documented evidence of a tumor with an EGFR activating mutation known to be associated 
with rociletinib drug sensitivity (exon 19 deletion, L858R, G719X, L861Q, T790M, and 
S768I) as determined by testing of the NSCLC tumor using an appropriate laboratory 
technique 
• Medical history, including demographic information (birth date, race, gender, etc.) smoking 
status, and oncology history including date of cancer diagnosis, prior cancer treatment, and 
any surgical procedures 
• Prior and concomitant medications 
• Prior treatment for NSCLC 
• Contraceptive counseling 
• Study procedure-related AEs 
• 12-lead ECG (in triplicate, 10-second tracings > 2 minutes apart) 
• Tumor assessments of the chest and abdomen (preferably CT scans with appropriate slice 
thickness per RECIST Version 1.1), using the same methods throughout the study that were 
used to detect lesions at baseline. Scans of the pelvis (CT or MRI) are required if there is 
prior evidence of local disease or if clinically indicated (symptomatic patients). Assessments 
should consist of clinical examination and appropriate imaging techniques (CT scans with 
appropriate slice thickness per RECIST Version 1.1); MRI scans may be carried out in 
patients unable undergo CT scan or if requested by local regulatory authorities. The same 
methods used to detect lesions at baseline are to be used to follow the same lesions 
throughout the clinical study. 
• Brain imaging (CT/MRI) is required at baseline. Baseline brain lesions are only permitted if 
treated, asymptomatic, and stable (not requiring steroids for at least 2 weeks prior to 
randomization and the patient is neurologically stable; ie, free from new symptoms of brain 
metastases).  
• Blood sampling for biomarker/EGFR mutational testing and exploratory research that may 
lead to development of a plasma-based EGFR test. Detailed sample handling instructions are 
provided in the Laboratory Manual.  


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To be performed ≤ 14 days prior to randomization: 
• Physical examination by body system, height, and weight 
• ECOG performance status 
• Vital signs (blood pressure, pulse, and temperature) 
• Local hematology (hemoglobin, hematocrit, CBC and differential [with ANC], and platelet 
count) 
• Local fasting serum chemistry (c-peptide, total protein, albumin, creatinine, blood urea 
nitrogen [BUN] or urea, total bilirubin, alkaline phosphatase, ALT, AST, fasting glucose, 
sodium, potassium, magnesium, chloride, carbon dioxide [CO2], calcium, phosphorus, total 
cholesterol and glycated HbA1c  
• Local urinalysis performed on freshly voided clean sample (dipstick for protein, glucose, 
blood, pH, and ketones). If dipstick findings are abnormal based on Investigator judgment, 
then a microscopic evaluation will be performed to assess the abnormal findings 
• Study procedure-related AEs  
• QoL Questionnaires (EORTC QLQ-C30 and EORTC QLQ-LC13) and the EQ-5D 
To be performed ≤ 3 days prior to randomization: 
• Serum pregnancy test (by local laboratory)  3 days prior to randomization for women of 
childbearing potential 
9.1.1 
Screening for Patients who Cross Over to Rociletinib Having Progressed On or 
After Comparator Arm Therapy 
The following baseline assessments will be established prior to the first dose of oral rociletinib 
and ≤ 35 days following radiographic progression on single-agent cytotoxic chemotherapy. 
Patients will be required to sign a cross over ICF before screening procedures begin. 
To be performed ≤ 35 days prior to XO-C1D1: 
• Prior and concomitant medications 
• Contraceptive counseling 
• Study procedure-related AEs 
• 12-lead ECG (in triplicate, 10-second tracings > 2 min apart) 
• Tumor scans, including brain imaging at screening: scans used to determine radiographic 
progression on single agent cytotoxic chemotherapy will be used as baseline scans in cross 
over 
• Blood sampling for biomarker/EGFR mutational testing and exploratory research 
To be performed ≤ 14 days prior to XO-C1D1: 
• Physical examination by body system, height, and weight 


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• ECOG performance status 
• Vital signs (blood pressure, pulse, and temperature) 
• Local hematology (CBC and differential) and fasting serum chemistry (including HbA1c and 
a fasting glucose measurement) 
• Study procedure-related AEs 
• QoL Questionnaires (EORTC QLQ-C30 and EORTC QLQ-L13) and EQ-5D 
To be performed ≤ 3 days prior to XO-C1D1: 
• Serum pregnancy test (by local laboratory)  3 days prior to randomization for women of 
childbearing potential 
9.2 
Randomization 
Randomization will occur 3 days before initiation of study treatment (C1D1). All patients 
randomized to the comparator arm and selected to receive pemetrexed are required to take at 
least 5 doses of folic acid preceding the first dose of pemetrexed. Folic acid must be taken before 
starting pemetrexed. If the investigator selects pemetrexed as the comparator option for a patient, 
then folic acid supplementation may begin prior to randomization, if necessary, to ensure that 
C1D1 is not delayed while premedication is completed. 
Patients are not required to be present in the clinic for randomization to occur but sites should be 
mindful of the 3 day difference between randomization and C1D1 for all patients when planning 
visits. Patients can continue receiving treatment with a single-agent EGFR-TKI (eg, erlotinib, 
gefitinib, afatinib, or dacomitinib) until 3 days before C1D1. 
Before enrolling a patient, all eligibility criteria must be satisfied. Before enrolling a patient onto 
the rociletinib cross-over period following progression on or after comparator arm chemotherapy 
treatment, all eligibility criteria for entry to the cross over period must be satisfied.  
9.3 
Treatment Period  
During the treatment period, patients will receive either oral rociletinib tablets or infusions of a 
single agent cytotoxic chemotherapy, as directed.  
Oral rociletinib should be taken BID at 500 mg/dose with 8 oz (240 mL) of water and with a 
meal or within 30 minutes after a meal. In each cycle, the first dose of rociletinib will be taken in 
clinic, with the remaining doses self-administered by the patient at home. Patients will record the 
dose and timing of administration of oral rociletinib whilst at home in their daily dosing diary.  
For patients who started therapy with rociletinib at 625 mg BID under Protocol Amendment 1, a 
reduction in dose to 500 mg BID is allowed, only if necessitated by unacceptable toxicity. 
The choice of single-agent cytotoxic chemotherapy is at the discretion of the investigator from 
amongst the regimens described in this protocol. See the table in Section 5.1.3 and Section 7.3.2 
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Unless otherwise specified, all patients will undergo the following procedures and assessments. 
9.3.1 
Patients Randomized to Rociletinib or Who Cross Over to Rociletinib Having 
Progressed On or After Comparator Arm Therapy 
9.3.1.1 
Cycle 1 Day 1 (C1D1) and Cross Over Cycle 1 Day 1 (XO-C1D1) 
Patients will be required to take their first dose of rociletinib at the clinic with 8 oz (240 mL) of 
water and with a meal or within 30 minutes after a meal. The following procedures will be 
carried out pre- and post-dose. 
Predose Assessments 
Postdose Assessments 
Physical examination 
Weight 
ECOG performance status 
Vital signs (blood pressure, pulse, and temperature) 
Urine pregnancy test (with negative result) 
Concomitant medications and procedures 
Local hematology (CBC and differential and fasting 
serum chemistry (includes fasting glucose)  
Blood sampling for biomarker/EGFR mutational 
testing and exploratory research  
Pharmacogenomic blood sample 
Rociletinib tablets will be dispensed to the patient 
Patient diary dispensed 
12-lead ECG, 5 to 10 minutes before dosing (in 
triplicate, 10-second tracings > 2 minutes apart) 
QoL questionnaires (EORTC QLQ-C30, EORTC 
QLQ-LC13) and EQ-5D 
AEs experienced by the patient since dosing 
will be documented 
Concomitant medications administered since 
dosing will be recorded 
 
 
Enough rociletinib tablets (and diary cards) will be dispensed to the patient for daily dosing until 
the next study clinic visit. 
9.3.1.2 
Cycle 1 Day 4 and Cross Over Cycle 1 Day 4 (XO-C1D4) (± 1 Day) 
The following procedures will be carried out: 
• Fasting glucose 
9.3.1.3 
Cycle 1 Day 8 and Cross Over Cycle 1 Day 8 (XO-C1D8) (± 1 Day) 
The following procedures will be carried out: 
• Fasting glucose 


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9.3.1.4 
Cycle 1 and Cycle 2 Day 15 and Cross Over Cycle 1 and Cycle 2 Day 15 
(XO-C1D15 and XO-C2D15) (± 1 Day) 
The following procedures will be carried out: 
• Fasting glucose 
• 12-lead ECG (in triplicate, 10-second tracings > 2 minutes apart; Cycle 1 Day 15 and cross 
over Cycle 1 Day 15 only) 
9.3.1.5 
Cycle 2 Day 1 and Cross Over Cycle 2 Day 1 (21 ± 3 Days After C1D1 and 
XO-C1D1) and Cycle 3+ Day 1 and Cross Over Cycle 3+ Day 1 (every 21 ± 3 Days 
Thereafter) 
The following procedures will be carried out at 21 ± 3 day intervals: 
• Physical examination 
• Weight 
• ECOG performance status 
• Vital signs (blood pressure, pulse, and temperature) 
• 12-lead ECG (in triplicate, 10-second tracings > 2 minutes apart) 
• Local hematology (CBC and differential) and fasting serum chemistry (includes fasting 
glucose). HbA1c will be measured every other cycle (Day 1 of Cycles 3, 5, 7, etc.) after 
initiating rociletinib treatment. 
• Blood sampling for biomarker/EGFR mutational testing and exploratory research  
• Serum alpha 1-acid glycoprotein (AAG) samples and PK blood sample (Cycles 2 to 7 and 
cross over Cycles 2 to 7 inclusive only; Section 9.6.3) 
• Concomitant medication and procedures since last visit 
• AE monitoring 
• Collection and review of patient diary 
• QoL questionnaires (EORTC QLQ-C30 and EORTC QLQ-LC13) and the EQ-5D will be 
collected at screening, predose on C1D1 and XO-C1D1, then every 2 cycles ± 1 week for the 
first 6 cycles (Day 1 of Cycles 3, 5, 7 ± 1 week inclusive). After Cycle 7, questionnaires will 
be collected every 3 cycles ± 1 week (Day 1 of Cycle 10, 13, 16 ± 1 week, etc) and at end of 
treatment. 
• Rociletinib tablets will be dispensed to the patient 
• Patient diary will be dispensed to the patient 
• Tumor assessments will be carried out every 6 weeks ± 1 week from the time of 
randomization until tumor progression (see Section 9.6.2.1) 


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9.3.2 
Patients Randomized to Single-agent Cytotoxic Chemotherapy 
9.3.2.1 
Cycle X Day 1 
The choice of single-agent cytotoxic chemotherapy is at the discretion of the investigator 
(pemetrexed, gemcitabine, docetaxel or paclitaxel). All chemotherapy agents will be 
administered to the patients at the clinic intravenously on Day 1 of each 21-day cycle: 
• Pemetrexed will be administered at 500 mg/m2 
• Gemcitabine will be administered at 1250 mg/m2 
• Docetaxel will be administered either at 75 mg/m2 (60 mg/m2 for Asian patients) or at 
35 mg/m2 
• Paclitaxel will be administered at 80 mg/m2 as a 1 hour infusion 
The following procedures will be carried out pre and postdose. 
Predose Assessments 
Postdose Assessments 
Physical examination 
Weight 
ECOG performance status 
Vital signs (blood pressure, pulse, and 
temperature) 
Urine pregnancy test (with negative result) 
Concomitant medications and procedures 
Local hematology (CBC and differential ) and 
fasting serum chemistry (includes fasting glucose)  
Blood sampling for biomarker/EGFR mutational 
testing and exploratory research  
AE monitoring 
12-lead ECG, 5 to 10 minutes before dosing (in 
triplicate, 10-second tracings > 2 minutes apart) 
QoL questionnaires (EORTC QLQ-C30, EORTC 
QLQ-LC13) and EQ-5D 
Chemotherapy administration 
AEs experienced by the patient since dosing 
will be documented 
Concomitant medications administered since 
dosing will be recorded 
 
Tumor assessments will be carried out every 6 weeks ± 1 week from the time of randomization 
until tumor progression (see Section 9.6.2.1).  
9.3.2.2 
Cycle X Day 8 (± 1 Day) 
If selected as the comparator option, gemcitabine, docetaxel, and paclitaxel will be administered 
at the clinic intravenously on Day 8 of each 21-day cycle: 
• Gemcitabine will be administered at 1250 mg/m2 


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• Docetaxel will be administered at 35 mg/m2 (in patients randomized to this docetaxel dosing 
regimen) 
• Paclitaxel will be administered at 80 mg/m2 as a 1 hour infusion 
Please note, the other chemotherapy agents (pemetrexed and docetaxel 75 mg/m2 [60 mg/m2 in 
Asian patients]) will not be administered on this day. 
In addition, the following procedures will be carried out for all patients randomized to receive 
single agent cytotoxic chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel): 
• Hematology (CBC and differential ) 
• AE monitoring 
9.3.2.3 
Cycle X Day 15 (± 1 Day) 
If selected as the comparator option, docetaxel and paclitaxel will be administered at the clinic 
intravenously on Day 15 of each 21-day cycle: 
• Docetaxel will be administered at 35 mg/m2 (in patients randomized to this docetaxel dosing 
regimen) 
• Paclitaxel will be administered at 80 mg/m2 as a 1 hour infusion 
Please note, the other chemotherapy agents (pemetrexed, gemcitabine, and docetaxel 75 mg/m2 
[60 mg/m2 in Asian patients]) will not be administered on this day. 
In addition, the following procedures will be carried out for all patients randomized to receive 
single-agent cytotoxic chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel): 
• Hematology (CBC and differential) 
• AE monitoring 
9.4 
End-of-Treatment Visit (All Patients) 
The following procedures will be carried out for all patients 28 (± 7) days after the last dose of 
study treatment (initial study treatment or cross-over treatment, whichever comes last): 
• Physical examination 
• Weight 
• ECOG performance status 
• Vital signs (blood pressure, pulse, and temperature) 
• Concomitant medications and procedures 
• Contraceptive counseling 
• Serum pregnancy test for women of childbearing potential 


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• Local hematology (CBC and differential) and fasting serum chemistry (including fasting 
glucose) 
• Tumor scans (using the same methodology as was used at screening) unless it has been 
< 2 weeks since last scan or disease progression was noted on the last scan. In addition, an 
MRI may be used in place of a CT at end-of-treatment scan if required per local authorities. 
For patients with clinical progression, radiographic assessment should be performed to 
document evidence of radiographic progression. 
• Optional tumor biopsy (requires additional consent) 
• Blood sampling for biomarker/EGFR mutational testing and exploratory research  
• AE monitoring (until 28 days after last dose of study treatment; then only ongoing SAEs will 
be followed until resolution or stabilization); after the 28-day specified window, only 
treatment-related SAEs should be reported 
• Collection and review of patient diary (patients randomized to rociletinib only) 
• 12-lead ECG (in triplicate, 10-second tracings > 2 minutes apart) 
• QoL questionnaires (EORTC QLQ-C30 and EORTC QLQ-LC13) and the EQ-5D 
• Survival status 
• Subsequent therapies for NSCLC 
9.5 
Follow-up (All Patients) 
The following procedures will be carried out for all patients every 2 months for survival and 
subsequent therapy (unless otherwise specified) following the End-of-Treatment Visit:  
• Survival status – this may be done during routine clinic visits or by telephone contact  
• Subsequent therapies for NSCLC will be documented during routine clinic visits or by 
telephone contact 
• For patients who discontinue treatment prior to progression, tumor scans should be assessed 
approximately every 6 weeks (± 1 week) until progression 
9.6 
Methods of Data Collection 
9.6.1 
Safety Evaluations 
9.6.1.1 
Adverse Events Assessment 
The investigator has the responsibility for assessing the safety of the patients and for compliance 
with the protocol to ensure study integrity. Patients will be monitored for AEs from the time the 
first dose of rociletinib or chemotherapy is administered through to 28 days after the last dose of 
protocol-specified treatment. Study procedure-related AEs that occur after signing of the ICF but 
before administration of study treatment will also be collected. Any ongoing SAEs will be 
followed until resolution or stabilization. AEs and laboratory abnormalities will be graded 
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Complete details for monitoring AEs, including the definition of drug-related AEs, are provided 
in Section 10. 
9.6.1.2 
Clinical Laboratory Investigations 
Local laboratories will be used for hematology and chemistry and must be reviewed by the 
investigator before starting each new treatment cycle. Additional tests may be carried out at the 
investigator’s discretion. The panels of laboratory tests to be done are shown below: 
Hematology: Hemoglobin, hematocrit, CBC and differential (with ANC), and platelet count as 
per the schedule of assessments at screening, during treatment (Day 1 of each cycle; and Days 8 
and 15 of each cycle in patients randomized to single agent cytotoxic chemotherapy), and at the 
End-of-Treatment Visit. Hematology results must be reviewed by the investigator before the start 
of treatment. 
Patients known to require concomitant therapy with anticoagulant therapy such as warfarin 
should have coagulation markers monitored at screening and during the study. 
Clinical chemistry: C-peptide, total protein, albumin, creatinine, BUN or urea, total bilirubin, 
alkaline phosphatase, ALT, AST, fasting glucose, sodium, potassium, magnesium, chloride, 
CO2, calcium, phosphorus, and total cholesterol, as per the schedule of assessments at screening, 
during treatment (Day 1 of each cycle), and at the End-of-Treatment Visit. HbA1c will be 
measured at screening and Day 1 of every other cycle (Cycles 3, 5, 7, etc.) while the patient is on 
study.  
For patients randomized to rociletinib or crossed over to rociletinib only: Fasting glucose 
must be measured following an 8 hour fast (no food or liquid other than water) at screening, 
C1D1, C1D4, C1D8, C1D15, C2D1, C2D15, XO-C1D1, XO-C1D4, XO-C1D8, XO-C1D15, 
XO-C2D1, XO-C2D15, and every Cycle N D1 thereafter, and at the End-of-Treatment Visit, also 
if clinically indicated on study. Fasting glucose is measured as part of the clinical chemistry 
panel (see above) on all Cycles Day 1 visits, and measured individually C1D4, C1D8, C1D15, 
C2D15, XO-C1D4, XO-C1D8, XO-C1D15, and XO-C2D15. Serum levels of AAG will be 
determined on PK sampling days.  
Urinalysis: On freshly voided clean sample by dipstick for protein, glucose, blood, pH, and 
ketones as per the schedule of assessments. If dipstick findings are abnormal, then a microscopic 
evaluation will be done to assess the abnormal findings. Urinalysis will be carried out at 
screening only. 
Serum beta human chorionic gonadotropin (β-hCG) pregnancy test: Performed on women 
of childbearing potential  3 days before randomization,  3 days before XO-C1D1 (as 
applicable), and at the End–of-Treatment Visit. A urine pregnancy test will be performed on 
C1D1 and XO-C1D1 (as applicable) to confirm that the patient is not pregnant before dosing. 
Both values should be entered in the eCRF. A negative result must be confirmed by a physician 
before the first dose of study treatment can be administered. 
Laboratory reports will be reviewed by the investigator or delegated physician who will then 
comment on out-of-range values and assess their clinical significance. Clinically significant 


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abnormalities and associated panel results, as well as results of any additional tests carried out as 
follow-up to the abnormalities, will be documented on the eCRF as an AE. 
9.6.1.3 
Vital Signs 
Vital signs will include blood pressure, pulse, and body temperature. All vital signs will be 
obtained after the patient has been resting for at least 5 minutes. Vital signs will be carried out at 
screening, at Day 1 of each Cycle (predose), and the End-of-Treatment Visit.  
9.6.1.4 
12-lead Electrocardiograms 
Serial 12-lead ECGs will be taken at screening and at predose on Day 1 of each cycle 
(comparator arm); at screening, predose on C1D1, predose and 2 hours postdose on Cycle 1 
Day 15, and predose on Day 1 of each subsequent cycle (rociletinib arm and cross over); at the 
End-of-Treatment Visit; and as clinically indicated. ECGs must be done in triplicate, 10-second 
tracings > 2 minutes apart. 
ECGs should be carried out after the patient has been resting for at least 5 minutes. The 12-lead 
ECGs collected will be analyzed and interpreted locally for patient care decisions; however, 
tracings will be collected centrally for independent evaluation. Details on recording ECGs and 
preparation for central interpretation will be included in the Investigator’s File.  
9.6.1.5 
Body Weight and Height 
Height will be measured during the screening visit only. Weight will be measured at all clinic 
visits (the patient should be in light indoor clothes).  
9.6.1.6 
Physical Examinations 
Physical examinations will include an assessment of all the major body systems. Complete 
physical examinations will be carried out at screening and at all clinic visits.  
9.6.1.7 
ECOG Performance Status 
ECOG performance status (Appendix B) will be assessed at screening, Day 1 of each cycle, and 
at the End-of-Treatment Visit. ECOG performance status should be assessed by the same study 
personnel at each visit, if possible. Care will be taken to accurately score performance status, 
especially during screening for study eligibility purposes. Additional consideration should be 
given to borderline ECOG performance status to avoid enrolling patients with significant 
impairment. 
9.6.2 
Efficacy Evaluations 
9.6.2.1 
Tumor Assessments 
Tumor assessments should consist of clinical examination and appropriate imaging techniques 
(preferably by CT scans of the chest and abdomen with appropriate slice thickness per RECIST 
Version 1.1). Scans of the pelvis (CT or MRI) are required if there is prior evidence of local 
disease or if clinically indicated (symptomatic patients). MRI scans may be carried out in 


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patients unable to undergo CT scan or if requested by local regulatory authorities. The same 
methods used to detect lesions at baseline are to be used to follow the same lesions throughout 
the clinical study. An MRI may be used in place of a CT at end-of-treatment scan if required per 
local authorities.  
Tumor assessments will be carried out at screening and every 6 weeks ± 1 week from the time of 
randomization thereafter (Day 1 of Cycles 3, 5, 7, etc.) until tumor progression, including at the 
End-of-Treatment Visit if disease progression has not been documented previously. For patients 
with clinical progression, radiographic assessment should be performed to document evidence of 
radiographic progression. Tumor scans do not need to be repeated at end of treatment if 
< 2 weeks since the last scan or the patient had disease progression at the last scan. Scans will be 
evaluated locally for patient treatment decisions. Scans will also be collected and stored with a 
central vendor and quality control performed; central reading of scans will not be done unless 
requested by the sponsor. Tumor response will be interpreted using RECIST Version 1.1 
(Appendix A).11  
If a treatment cycle is delayed, the efficacy assessments should still follow the 6-weekly calendar 
schedule from the time of randomization. 
Patients who discontinue rociletinib or chemotherapy without progression should continue to be 
scanned every 6 weeks (± 1 week) per protocol until disease progression occurs. Exceptions to 
this requirement based on local institutional or regulatory requests must be agreed in advance 
with the sponsor. In these patients, a scan should be performed at the End-of-Treatment Visit. In 
this circumstance the end-of-treatment scan could be an MRI scan. 
Patients who continue rociletinib treatment post-progression or patients who crossover to 
rociletinib should continue to be scanned according to the protocol (ie, every 6 ± 1 weeks) until 
they discontinue from the study. 
Brain imaging (CT/MRI) is required at baseline. Patients with brain lesions at screening should 
have the brain lesions followed throughout the study at the scheduled time points.  
9.6.3 
Pharmacokinetic Evaluations  
Blood samples will be drawn for POPPK analysis at 21 ± 3 day intervals for the first 6 months 
(Day 1 of Cycles 2 to 7 inclusive) in all patients treated with rociletinib (ie, only in patients 
randomized to receive rociletinib or those who cross over to receive rociletinib following 
treatment with single agent cytotoxic chemotherapy). The sample can be taken predose (for 
example, if the study visit is early in the day) or postdose (if the visit is late in the morning or in 
the afternoon). The blood draw time relative to the last dosing time will be recorded at each PK 
sample occasion for each patient.  
Serum samples for AAG analysis will be collected on the same day as PK samples. 
Central laboratories will be used for bioanalysis of plasma rociletinib and 3 metabolites levels 
and AAG measurement. Please refer to the Laboratory Manual for details on collection and 
processing of blood PK and AAG samples. 


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9.6.4 
Pharmacogenomic Assessment 
For patients randomized to the rociletinib treatment arm or who cross over to rociletinib after 
progression on chemotherapy, and who provide additional consent, a pharmacogenomic blood 
sample will be collected from each patient on C1D1 or XO-C1D1 in order to detect genetic 
polymorphisms in CYP isoenzymes and to explore the possible correlation between potential 
polymorphisms and drug exposure.  
9.6.5 
Biomarker Assessments – FFPE Tumor Tissue 
If available, archival FFPE tumor tissue derived from the primary tumor, or an accessible 
local/distal metastatic lesion, will be obtained within 60 days before start of treatment. If archival 
tumor tissue is not available, a biopsy should be obtained during the screening period. Blood 
samples (ctDNA analysis; see Section 9.6.6 below) should be collected immediately before the 
biopsy procedure if possible; otherwise, the screening blood sample can be collected 7 days after 
the biopsy. To ensure adequate viable tumor tissue is obtained for mutational testing and 
diagnostic kit development, image-guided biopsies should be achieved with 18- to 20-gauge 
cutting needles to provide 1 to 3 cores measuring 1 to 1.5 cm in length. Tumor samples will be 
processed locally to yield FFPE tissue blocks. Entire FFPE blocks should be submitted when 
possible. Blocks will be returned upon request if required for legal or medical treatment 
purposes. 
If sufficient tissue is available from the baseline tumor biopsy, samples will be tested for other 
molecular alterations, that may modulate response or resistance to EGFR-targeted therapy 
including but not limited to EGFR gene amplification, MET gene amplification, PIK3CA 
mutations, and expression of other growth factor receptors and their ligands. 
Following disease progression, patients who provide additional consent will undergo a tumor 
biopsy before subsequent line therapy is initiated. This tissue will be analyzed for molecular 
alterations that modulate resistance to the study-assigned therapy.  
Sample handling instructions will be provided in a separate Laboratory Manual.  
9.6.6 
Pharmacodynamic Evaluations - ctDNA 
Whole blood will be collected from all patients at screening, at Day 1 of each cycle, and at the 
End-of-Treatment Visit for detection and quantification of cell-free ctDNA biomarkers of 
response or resistance to therapy, including but not limited to EGFR mutations, MET gene 
amplification, PIK3CA mutations, and alterations in other components of the EGFR signaling 
pathway. Blood samples will be processed locally to yield plasma (ctDNA fraction) and buffy 
coats (genomic DNA fraction). Genomic DNA extracted from the buffy coat may be compared 
to tumor DNA so that molecular alterations unique to the tumor that may modulate response or 
resistance to study-assigned therapy can be unambiguously identified. 
Samples may be used for the development of a blood-based diagnostic test.  
Please refer to the Laboratory Manual for details on collecting and processing of blood 
pharmacodynamics samples. 


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Analysis may be performed on a subset of patients if it becomes clear that the analysis will have 
limited scientific value in some patients (eg, because of a very low titer of ctDNA), or if there are 
not enough serially collected samples from individual patients to allow for adequate biomarker 
evaluation. 
9.6.7 
Quality-of-Life Assessments 
Patient reported outcomes will be measured using the EORTC QLQ-C30, EORTC QLQ-LC13,12 
and EQ-5D, which will be collected at screening, predose on C1D1, then every 2 
cycles ± 1 week for the first 6 cycles. After Cycle 7, questionnaires will be collected every 
3 cycles ± 1 week and at the end of treatment.  
9.6.8 
Patient Diary  
Patient diary cards will be provided to patients randomized to rociletinib treatment at clinic 
visits. Patients will use the diary cards to note the date, time, and dose of rociletinib 
administration whilst at home. Diary cards should be returned at each visit and reviewed by 
study personnel for completeness and accuracy versus study drug returned. 


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10 ADVERSE EVENT MANAGEMENT 
10.1 Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product that does not necessarily have a causal relationship with this treatment. An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, whether or 
not related to the investigational medicinal product. This includes an exacerbation of pre-existing 
conditions or events, intercurrent illnesses, drug interaction, or the significant worsening of the 
indication under investigation that is not recorded elsewhere on the eCRF under specific efficacy 
assessments. Anticipated fluctuations of pre-existing conditions, including the disease under 
study, that do not represent a clinically significant exacerbation or worsening are not considered 
AEs. 
It is the responsibility of the investigator to document all AEs that occur during the study. AEs 
should be elicited by asking the patient a nonleading question (eg, “Have you experienced any 
new or changed symptoms since we last asked/since your last visit?”). AEs will be reported on 
the AE eCRF. Symptoms reported spontaneously by the patient during the physical examination 
will also be documented on the AE eCRF (not on the physical examination eCRF, which is 
reserved for physical signs or findings). 
10.2 Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that occurs at any dose (including after informed 
consent is given and before dosing) that: 
• Results in death. Death may occur as a result of the underlying disease process. Nevertheless, 
any event resulting in death during the reporting period must be treated as an SAE and 
reported as such. All deaths occurring within 28 days of the last administration of study 
treatment should be reported as SAEs. 
• Is life-threatening (patient is at immediate risk of death from the event as it occurred) 
• Requires in-patient hospitalization (formal admission to a hospital for medical reasons) or 
prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect 
Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or seizures that 
do not result in in-patient hospitalization, or the development of drug dependency or drug abuse. 


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10.3 Definition of an Adverse Event of Special Interest 
An adverse event of special interest (AESI [serious or nonserious]) is one of scientific and 
medical concern specific to the sponsor’s product or program, for which ongoing monitoring and 
rapid communication by the investigator to the sponsor can be appropriate. Such an event might 
warrant further investigation in order to characterize and understand it. Depending on the nature 
of the event, rapid communication by the trial sponsor to other parties (eg, health authorities or 
ethics committees) might also be warranted.  
Details on the sponsor’s currently agreed list of AESIs for rociletinib can be found in the current 
rociletinib Investigator’s Brochure. These AESIs are to be reported to the sponsor expeditiously 
(see Section 10.9 for reporting instructions). 
10.4 Events or Outcomes Not Qualifying as Serious Adverse Events 
The following are not considered SAEs: 
• Pre-planned or elective hospitalization including social and/or convenience situations 
(eg, respite care) 
• Overdose of either Clovis study drug/chemotherapy comparators or concomitant medication 
unless the event meets SAE criteria (eg, hospitalization). However, the event should still be 
captured as a non-serious AE on the appropriate eCRF page. In addition, if there are other 
signs or symptoms which satisfy criteria for SAEs associated with the overdose, they should 
be reported as SAEs. 
• Events of progression of the patient’s underlying cancer as well as events clearly related to 
progression of the patient’s cancer (signs and symptoms of progression) should not be 
reported as an SAE unless the outcome is fatal during the study or within the safety reporting 
period. If the event has a fatal outcome during the study or within the safety reporting period, 
then the event of Progression of Disease must be recorded as an AE and as an SAE with 
CTCAE Grade 5 (fatal outcome) indicated. 
• Diagnosis of progression of disease or hospitalization due to signs and symptoms of disease 
progression alone should not be reported as SAEs 
10.5 Clinical Laboratory Assessments as Adverse Events and Serious 
Adverse Events 
It is the responsibility of the investigator to assess the clinical significance of all abnormal values 
as defined by the list of reference ranges from the local laboratory. In some cases, significant 
changes in laboratory values within the normal range will require similar judgment. 
An abnormal laboratory value that is not already associated with an AE is to be recorded as an 
AE only if any one of the following criteria is met: 
• An action on the study drug is made as a result of the abnormality 
• Intervention for management of the abnormality is required 


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• At the discretion of the investigator should the abnormality be deemed clinically significant 
10.6 Pregnancy or Drug Exposure during Pregnancy 
If a patient becomes pregnant during the study the investigator is to stop dosing with study 
drug(s) immediately. 
A pregnancy is not considered to be an AE or SAE; however, it must be reported to the sponsor 
using the Pregnancy Report Form within the same timelines as an SAE (Section 10.9). This 
applies to female patients as well as female partners of male patients. 
A pregnancy should be followed through to outcome, whenever possible. Once the outcome of 
the pregnancy is known, the Pregnancy Outcome Report Form should be completed and reported 
to the sponsor. 
AEs or SAEs that occur during pregnancy will be assessed and processed according to the AE or 
SAE processes using the appropriate AE or SAE forms.  
10.7 Recording of Adverse Events, Serious Adverse Events, and Adverse 
Events of Special Interest 
Any AE from the time the first dose of rociletinib or chemotherapy is administered through to 
28 days after the last dose, will be recorded on the AE eCRF. In addition, study 
procedure-related AEs that occur after signing of the ICF and before the first dose of rociletinib 
or chemotherapy will also be captured on the AE eCRF. Any other AE that occurs prior to the 
first dose of study drug should be recorded on the Medical History eCRF. In order to avoid 
vague, ambiguous, or colloquial expressions, the AE should be recorded in standard medical 
terminology rather than the patient’s own words. Whenever possible, the investigator should 
combine signs and symptoms that constitute a single disease entity or syndrome. For example, 
fever, headache, and nasal discharge may be reported as coryza, if that is a reasonable diagnosis. 
The existence of an AE may be concluded from a spontaneous report from the patient; from the 
physical examination; or from special tests such as the ECG, laboratory assessments, or other 
study-specified procedure (source of AE). 
Each AE is to be evaluated for duration, severity, seriousness, and causal relationship to the 
investigational drug. The action taken and the outcome must also be recorded. 
SAEs that occur during the study or within 28 days after receiving the last dose of study 
treatment, and all AESIs, whether or not related to study drug, must be immediately reported to 
the sponsor/designated safety contact within 24 hours of knowledge of the event (Section 10.9). 
After the 28-day specified window, only SAEs considered to be treatment-related should be 
reported. This should be done by faxing or emailing the completed SAE/AESI report to the 
Sponsor/designee contact provided on the SAE/AESI report form. Information on the follow-up 
of AEs, SAEs, and AESIs is provided in Section 10.8. SAEs that are not considered 
treatment-related should be reported per local institutional or regulatory policy and practices, 
using the SAE form until alternative therapy has started. 


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10.7.1 
Intensity of Adverse Events 
The severity of the AE will be graded according to the NCI CTCAE Version 4.03 grading 
scale.14 For AEs not covered by NCI CTCAE, the severity will be characterized as mild, 
moderate, severe, or life-threatening according to the following definitions: 
• Mild events are usually transient and do not interfere with the patient’s daily activities 
• Moderate events introduce a low level of inconvenience or concern to the patient and may 
interfere with daily activities 
• Severe events interrupt the patient’s usual daily activities and hospitalization (or prolongation 
of hospitalization) may be required 
• Life-threatening events require urgent intervention to prevent death 
10.7.2 
Causal Relationship of Adverse Events to Investigational Medicinal Products 
Medical judgment should be used to determine the cause of the AE considering all relevant 
factors such as, but not limited to, the underlying study indication, coexisting disease, 
concomitant medication, relevant history, pattern of the AE, temporal relationship to the study 
medication, dechallenge or rechallenge. 
Not Related  
• An AE that is clearly due to extraneous causes (eg, concurrent disease, concomitant 
medications, disease under study, etc.) 
• It does not follow a reasonable temporal sequence from administration of study drug 
• It does not follow a known pattern of response to study drug 
• It does not reappear or worsen when study drug is restarted 
• An alternative explanation is likely but not clearly identifiable 
Related  
• An AE that is difficult to assign to alternative causes 
• It follows a strong or reasonable temporal sequence from administration of study drug 
• It could not be reasonably explained by the patient’s clinical state, concurrent disease, or 
other concomitant therapy administered to the patient 
• It follows a known response pattern to study drug 
• It is confirmed with a positive rechallenge or supporting laboratory data 


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10.7.3 
Outcome and Action Taken 
The investigator will record the action taken and outcome for each AE according to the 
following criteria: 
Action Taken with Study Drug 
• None 
• Dose reduced/delayed 
• Drug temporarily interrupted 
• Drug permanently discontinued 
• Other (specify) 
Outcome 
• Recovered 
• Recovered with sequelae 
• Improved 
• Ongoing 
• Death 
• Lost to follow-up 
10.8 Follow-up of Adverse Events, Serious Adverse Events, and Adverse 
Events of Special Interest 
All AEs (including SAEs and AESIs) occurring during the study are to be followed up in 
accordance with good medical practice until resolved; judged no longer clinically significant; or, 
if a chronic condition, until fully characterized until 28 days after the last dose of study 
treatment. All SAEs and AESIs must be followed until resolution or stabilization. 
10.9 Regulatory Aspects of Serious Adverse Event Reporting and Adverse 
Events of Special Interest 
All SAEs, AESIs, and pregnancy, regardless of relationship to study drug, must be reported to 
the sponsor/designated safety contact within 24 hours of knowledge of the event, according to 
the procedures below. It is important that the Investigator provides an assessment of relationship 
of the SAE to study treatment at the time of the initial report. The Clinical Trial Serious Adverse 
Event/ Adverse Event of Special Interest (SAE/AESI) Report Form must be used for reporting 
SAEs.  
While not considered an SAE, pregnancy occurring in a female patient or in the female partner 
of a male patient must also be reported to the sponsor/designated safety contact as soon as the 
event is known by the clinical site. If the pregnancy occurs in a female patient, study drug should 


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be stopped immediately. Notification to the sponsor/designated safety contact should take place 
via facsimile or email utilizing the Pregnancy Report Form.  
Further details on SAE/pregnancy reporting can be found in the Investigator’s File.  
Clovis or its designee is responsible for submitting reports of AEs associated with the use of the 
drug that are both serious and unexpected to the U.S. Food and Drug Administration (FDA), 
according to 21 Code of Federal Regulations (CFR) 312.32; to the Japanese Pharmaceuticals and 
Medical Devices Agency (PMDA); to the European regulatory authorities according to the 
European Commission Clinical Trials Directive (2001/20/EC); and to other regulatory 
authorities, according to national law and/or local regulations. All investigators participating in 
ongoing clinical studies with the study medication will receive copies of these reports for prompt 
submission to their IRB or IEC. In accordance with the European Commission Clinical Trials 
Directive (2001/20/EC), Clovis or its designee will notify the relevant ethics committees in 
concerned member states of applicable suspected unexpected serious adverse reactions 
(SUSARs) as individual notifications or through periodic line listings. 
Clovis or its designee will submit all safety updates and periodic reports to the regulatory 
authorities as required by applicable regulatory requirements.  


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11 STATISTICAL METHODS  
11.1 Analysis Populations 
The following analysis populations are defined for the study: 
• Intent-to-treat (ITT) population: all randomized patients 
• Safety population: all patients who have received at least 1 dose of rociletinib or single-
agent cytotoxic chemotherapy 
11.2 Statistical Methods 
11.2.1 
General Considerations 
Quantitative variables will be summarized using descriptive statistics (N, mean, standard 
deviation, median, minimum, and maximum) and/or frequency and percentages for medically 
relevant categories. Categorical variables will be presented using frequencies and percentages.  
Kaplan-Meier methodology will be used to summarize time to event variables.  
All data will be used to their maximum possible extent but without any imputations for missing 
data. 
All statistical analyses will be conducted with the statistical analysis software (SAS®) System. 
11.2.2 
Patient Disposition  
The frequency and percentage of patients in each analysis population and stratification subgroups 
will be presented. The primary reason for discontinuation of study treatment will be summarized.  
11.2.3 
Baseline Characteristics  
Baseline characteristics and demographic data will be summarized for the safety population. 
11.2.4 
Efficacy Analyses  
The efficacy endpoints will be evaluated using RECIST Version 1.1.11  
The primary and key secondary endpoints will be tested among the centrally confirmed T790M+ 
and all randomized patients, using an ordered step-down multiple comparisons procedure. 
InvPFS in the T790M+ subgroup will be tested first at a one-sided 0.025 significance level. If 
invPFS in the T790M+ subgroup is statistically significant then invPFS in all randomized 
patients will be tested at a one-sided 0.025 significance level. The remaining key secondary 
efficacy analyses will also be tested using this step-down approach in the order presented below. 
Once statistical significance is not achieved for one test, the statistical significance will not be 
declared for all subsequent analyses in the ordered step-down procedure.  


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11.2.4.1 
Primary Endpoint: Progression-free Survival 
The primary endpoint of the study is PFS according to RECIST Version 1.1 as determined by 
investigator assessment.  
PFS will be calculated as 1+ the number of days from the date of randomization to documented 
radiographic progression as determined by the investigator, or death due to any cause, whichever 
occurs first. Patients without a documented event of radiographic progression will be censored 
on the date of their last adequate tumor assessment (ie, radiological assessment) or date of 
randomization if no tumor assessments have been performed. For patients who continue 
treatment post-progression, the first date of progression will be used for the analysis of PFS.  
Kaplan-Meier methodology will be used to summarize PFS. The stratified and unstratified 
log-rank tests and the HR will be used for comparing the PFS distributions among the rociletinib 
and single-agent cytotoxic chemotherapy treated patients. The stratification factors of brain 
metastases and territory will be used for analysis.  
A PFS sensitivity analysis based on an Independent Radiographic Review (IRR, irrPFS) will be 
performed. The irrPFS is defined as the time from randomization to disease progression 
according to RECIST v1.1 as assessed by IRR, or death due to any cause, whichever occurs first. 
11.2.4.2 
Secondary Efficacy Endpoints 
OBJECTIVE RESPONSE RATE 
The ORR is the best overall response recorded from randomization until disease progression or 
recurrence as assessed by the investigator.  
The ORR will be summarized with frequencies and percentages. The frequency and percentages 
of patients with a best overall response of CR, PR, stable disease (SD), or progressive disease 
(PD) will be summarized. 
DURATION OF RESPONSE 
The DR for CR and PR will be measured from the date that any of these best responses is first 
recorded until the first date that PD is objectively documented. DR will be summarized using 
descriptive statistics (N, mean, standard deviation, median, minimum, and maximum) as well as 
categorically. For patients who continue treatment post-progression, the first date of progression 
will be used for the analysis.  
OVERALL SURVIVAL 
OS will be calculated as 1+ the number of days from randomization to death due to any cause. 
Patients without a documented date of death will be censored on the date the patient was last 
known to be alive. 


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POPULATION PK ANALYSES  
Sparse blood sampling for POPPK analyses will be conducted in all patients treated with 
rociletinib. A specific POPPK data analysis plan will be developed and will outline the detailed 
approach to data handling, model development and diagnostics, individual model parameter 
estimation, exploration of covariate effects, and final model evaluation techniques. 
11.2.4.3 
Exploratory Endpoints 
DISEASE CONTROL RATE 
The DCR is defined as the percentage of patients who have achieved a CR, PR, or SD lasting at 
least 12 weeks. The frequency and percentages of patients with a best overall response of CR, 
PR, or SD lasting at least 12 weeks, SD lasting less than 12 weeks, or PD will be summarized. 
TIME-TO-TREATMENT FAILURE 
The time-to-treatment failure will be computed as 1+ the number of days from the first dose of 
study drug to the last dose of study drug and will be presented with summary statistics. 
OS, ORR, PFS, DR, AND DCR IN PATIENTS WHO CROSS OVER TO RECEIVE ROCILETINIB 
OS, ORR, PFS, DR, and DCR in patients who cross over from single-agent cytotoxic 
chemotherapy to receive rociletinib will be summarized descriptively. 
CHANGE FROM BASELINE IN PROS USING THE EORTC QLQ-C30, EORTC QLQ-LC13 AND THE 
EQ-5D PREFERENCE-BASED HEALTH INSTRUMENT 
QoL will be measured using the PROs of the EORTC QLQ-C30, EORTC QLQ-LC1312 and 
EQ-5D.13  
The EORTC questionnaires will be scored using the published scoring algorithms provided by 
the EORTC. For each item or scale, a linear transformation will be applied to standardize the raw 
score to a range from 0 to 100. A high scale score represents a higher response level. Thus, a 
high score for a functional scale represents a high/healthy level of functioning, a high score for 
the global health status/QoL represents a high QoL, but a high score for a symptom 
scale/item represents a high level of symptomatology/problems. 
The baseline QoL measurement will be defined as the last value prior to or on the day of the first 
dose of study treatment. The on-treatment period will be defined as the day after the first dose of 
study treatment to 28 days after the last dose of study treatment. QoL measurements collected 
during the on-treatment period will be included in the summary tables. 
Evaluation of Symptoms 
An improvement in symptoms will be defined as a ≥ 10 point decrease from baseline. A 
worsening in symptoms will be defined as a ≥ 10 point increase from baseline. Patients with 
neither an increase nor a decrease will be considered stable. The frequency and percentage of 
patients categorized as an increase, stable, or decrease will be presented. 


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Time to Deterioration 
The time to a worsening in symptoms will be computed as 1+ the number of days from the date 
of randomization to the first instance of a ≥ 10 point increase from baseline in symptoms.  
Longitudinal Analysis 
The summary of QoL data will include descriptive statistics (N, mean, standard deviation, 
minimum, median, and maximum) of the mean and/or percent change from baseline during the 
on-treatment period. Summaries using descriptive statistics of the change from baseline to each 
scheduled visit during the on-treatment period will be presented. Graphical presentations may be 
used to present the mean changes over time. 
EQ-5D HEALTH STATUS 
Analyses of changes and/or percent changes from baseline will be analyzed for each scheduled 
post-baseline visit and for the final visit for the EQ-5D instrument and the EQ-VAS. If more than 
one measurement exists for a patient on a particular day, then an arithmetic average will be 
calculated. This average will be considered to be that patient’s measurement for that day. 
Post-baseline measurements more than 28 days after the last dose of protocol-specified treatment 
will not be included. Patients that do not have both a baseline measurement and at least one 
post-baseline measurement will not be included. 
At a given visit, the change and/or percent change from baseline will be compared between the 
randomized treatment groups using an analysis of covariance (ANCOVA), with the treatment as 
a categorical factor and baseline measurement for the parameter as a continuous covariate. 
CHANGE FROM BASELINE IN MUTANT EGFR LEVELS IN CTDNA 
The change from baseline in tissue and blood biomarkers associated with the EGFR signaling 
pathway will be summarized with descriptive statistics, and the t-test will be used to compare the 
mean changes between rociletinib and the comparator at each scheduled visit. Both the time from 
randomization to the first observed increase in plasma mutant EGFR levels and the time from 
first observed increase in plasma mutant EGFR levels to disease progression will be compared 
between arms and summarized using Kaplan-Meier methodology.  
COMPARISON OF BLOOD AND TISSUE RESULTS FOR T790M 
The relationship between T790M detected in tumor compared with that detected in blood will be 
explored. This will involve determining the sensitivity, specificity, and positive and negative 
predictive values of blood with respect to tumor assuming that EGFR mutational status in tumor 
is a true reflection of tumor biology. Additionally, an analysis of clinical endpoints based on the 
results of EGFR mutation plasma test may be performed. 
Analyses may be performed on a subset of patients if it becomes clear that the analysis will have 
limited scientific value in some patients (eg, because of a very low titer of ctDNA), or if there are 
not enough serially collected samples to allow for adequate biomarker evaluation. 


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BIOMARKERS ASSOCIATED WITH RESPONSE OR RESISTANCE TO ROCILETINIB 
Blood may be tested for biomarkers of response or resistance to EGFR-targeted therapy. 
Analysis may be performed on a subset of patients if it becomes clear that the analysis will have 
limited scientific value in some or if there are not enough serially collected samples from 
individual patients to allow for adequate biomarker evaluation. 
11.2.5 
Safety Analyses  
The safety analyses will be performed using the safety population (all patients who have received 
at least 1 dose of rociletinib or single-agent cytotoxic chemotherapy).  
11.2.5.1 
Extent of Exposure 
The number of cycles of treatment will be summarized by treatment group. 
11.2.5.2 
Adverse Events 
AE coding will be performed using MedDRA. The severity of the toxicities will be graded 
according to the NCI CTCAE whenever possible. Treatment-emergent AEs are defined as AEs 
with an onset date on or after the date of first dose of study treatment until the date of the last 
dose plus 28 days. AEs will be considered treatment-emergent if all or part of the date of onset of 
the AE is missing and it cannot be determined if the AE meets the definition for 
treatment-emergent. 
The number and percentage of patients who experienced treatment-emergent AEs for each SOC 
and PT will be presented by treatment group. Multiple instances of the treatment-emergent AEs 
in each SOC and multiple occurrences of the same PT are counted only once per patient. The 
number and percentage of patients with at least one treatment-emergent AE will also be 
summarized by treatment group.  
Separate tables will present the following by treatment group and study phase: 
• All treatment-emergent AEs 
• Treatment-emergent AEs by CTCAE grade 
• Grade 3 or greater treatment-emergent AEs 
• Treatment-related, treatment-emergent AEs 
• Serious treatment-emergent AEs 
• Treatment-emergent AEs with an outcome of death 
• Treatment-emergent AEs leading to discontinuation of study treatment 
• Treatment-emergent AEs resulting in interruption, reduction, or delay of study treatment 
The incidence of treatment-emergent AEs will be summarized by relationship to treatment using 
“treatment-related” and “not treatment-related” categories. If a patient experiences multiple 
occurrences of the same AE with different relationship categories, the patient will be counted 
once as a relationship category of treatment-related.  


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If a patient experiences multiple occurrences of the same AE with different intensity toxicity 
grades, the patient will be counted once for the maximum (most severe) toxicity grade. AEs with 
a missing intensity will be presented in the summary table with a toxicity grade of “Missing”. 
For each toxicity grade, the number and percentage of patients with at least 1 treatment-emergent 
AE of the given grade will be summarized.  
Non-treatment-emergent AEs (pre- and post-treatment) will be presented in the data listings.  
11.2.5.3 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations include the continuous variables for hematology, serum 
chemistry, and urinalysis. Laboratory values will be presented in Systeme International units. 
The baseline laboratory value will be defined as the last value prior to or on the day of the first 
dose of study treatment. The on-treatment period will be defined as the day after the first dose of 
study treatment to 28 days after the last dose of study treatment. Laboratory values collected 
during the on-treatment period will be included in the summary tables.  
The summary of laboratory data will include descriptive statistics (N, mean, standard deviation, 
minimum, median, and maximum) of the maximum, minimum, and last value during the 
treatment period by treatment group. Summaries using descriptive statistics of the change from 
baseline to the maximum, minimum, and last value during the on-treatment period will also be 
given by treatment group. Separate listings will be produced for clinically significant laboratory 
abnormalities (ie, those that meet Grade 3 or 4 criteria according to CTCAE) by treatment group.  
11.2.5.4 
Vital Signs Measurements 
The baseline vital signs measurement will be defined as the last value prior to or on the day of 
the first dose of study treatment. The on-treatment period will be defined as the day after the first 
dose to 28 days after the last dose of study treatment. Vital signs measurements collected during 
the on-treatment period will be included in the summary tables. The vital signs measurements 
collected after the on-treatment period will only be presented in the data listings.  
The summary of vital signs data will include descriptive statistics (N, mean, standard deviation, 
minimum, median, and maximum) of the maximum, minimum, and last value during the 
on-treatment period by treatment group. Summaries using descriptive statistics of the change 
from baseline to the maximum, minimum, and last value during the on-treatment period will also 
be given by treatment group.  
11.2.5.5 
12-lead Electrocardiograms  
ECG intervals will be stratified into categories indicative of potential clinical significance. Each 
patient’s maximum QT and QTC intervals from the pre-treatment visit and treatment period visits 
will be classified as  450 msec, > 450 to  480 msec, > 480 to  500 msec, and > 500 msec. For 
each patient’s maximum change from the pre-treatment ECG visit for QT and QTC, intervals will 
be classified into < 30 msec,  30 to < 60 msec, and  60 msec. The number and percentage of 
patients in each classified category will be presented by treatment group. Additional endpoints 
will include abnormal T waves and U waves and other ECG intervals and diagnostic parameters.  


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Descriptive statistics will be used to summarize other ECG parameters of PR, QRS, QT, and RR 
interval, and the corresponding changes from pre-treatment ECG visit at each time point. Plots of 
the mean QT/QTC over time will be provided.  
11.2.5.6 
Other Safety Measurements 
Body weight and ECOG performance status will be summarized with descriptive statistics (N, 
mean, standard deviation, minimum, median, and maximum). Concomitant 
medications/procedures will be tabulated and summarized. 
11.3 Sample Size Considerations 
Up to 600 patients will be randomized in a 1:1 ratio to receive treatment with rociletinib or 
single-agent cytotoxic chemotherapy.  
The primary objective of this study is to estimate the difference in PFS between rociletinib and 
single-agent cytotoxic chemotherapy. The median PFS for cytotoxic chemotherapy in this patient 
population is expected to be approximately 4 months15 while the median PFS in all rociletinib 
patients (both T790M+ and negative) is expected to be at least 6 months. 
A step-down procedure will be used where PFS will first be evaluated in the T790M+ subgroup 
followed by all randomized patients.  
The total sample size for the study is based on the minimum anticipated treatment effect of 
4 months versus 6 months median PFS in all patients. A total of 600 patients should result in 
about 400 events of progression which provides 90% power to detect a HR of 0.70 at a one-sided 
0.025 significance level.  
The targeted number of T790M+ patients in this study is between 250 and 275 patients. A 
sample size of 250 T790M+ patients should result in about 170 events of progression which 
provides 90% power to detect a HR of 0.60 at a one-sided 0.025 significance level.  
In the event that the frequency of T790M+ patients in this trial is lower than expected, 
enrollment will continue until 250 T790M+ patients have been enrolled.  
11.4 Interim Analysis 
A data monitoring committee consisting of both Clovis personnel and the primary study 
investigators will meet no less than twice a year to review the safety and efficacy data to ensure 
that a favorable risk/benefit ratio is maintained throughout the study.  
No formal stopping rules for efficacy will be implemented. 


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12 PATIENT DISPOSITION 
12.1 Patient Discontinuations 
To the extent possible, end-of-treatment procedures should be carried out on all patients who 
receive rociletinib or single-agent cytotoxic chemotherapy. The End-of-Treatment Visit should 
occur 28 (± 7) days following the last dose of study treatment. After stopping protocol-specified 
treatment, all patients will remain in the study and will be followed for safety (until 28 days after 
last dose for all AEs or until resolution for study treatment related SAEs) and for survival status 
and subsequent therapy assessment (approximately every 2 months from the End-of-Treatment 
Visit until death or sponsor decision, whichever comes first). Patients who discontinue treatment 
prior to progression should continue to have scans every 6 ± 1 weeks until progression. 
A patient must be discontinued from protocol-prescribed therapy if any of the following apply: 
• Consent withdrawal at the patient’s own request or at the request of their legally authorized 
representative 
• Radiographic progression of patient’s underlying disease per RECIST Version 1.1, except as 
described in Section 5.1.3. If clinical progression is diagnosed then confirmation with a CT 
scan will be required before patient withdrawal. 
• Any event, adverse or otherwise, that, in the opinion of the investigator, would pose an 
unacceptable safety risk to the patient 
• An intercurrent illness that, in the opinion of the investigator, would affect assessments of the 
clinical status to a significant degree  
• A positive pregnancy test at any time during the study 
• Noncompliance as described in Section 7.7 
• Investigator decision 
In addition, the sponsor may discontinue the trial early for any of the reasons noted in 
Section 13.6. 
The sponsor (or designee) should be notified of all study terminations as soon as possible. The 
date and reason for cessation of study treatment must be documented in the eCRF and source 
documents. 


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13 STUDY ADMINISTRATION 
13.1 Regulatory and Ethical Considerations 
This study will be conducted in compliance with the protocol; Good Clinical Practices (GCPs) 
including International Conference on Harmonization (ICH) Technical Requirements for 
Registration of Pharmaceuticals for Human Use Guidelines; FDA regulatory requirements; and 
in accordance with the ethical principles of the Declaration of Helsinki.  
13.1.1 
Regulatory Authority Approvals 
The sponsor or designee will submit the study protocol plus all relevant study documents to 
concerned regulatory agencies for approval before the study start. No patient will be admitted to 
the study until appropriate regulatory approval of the study protocol has been received. 
Each investigator must complete a Form FDA 1572 or equivalent and provide the completed 
form according to written instructions to the sponsor (or designee). Each investigator must 
submit to the sponsor (or designee) financial disclosure information according to national law 
and/or local regulations. 
US-generated data will be handled in accordance with the Health Information Portability and 
Accountability Act (HIPAA). The trial will be registered at www.clinicaltrials.gov using the 
Protocol Registration System. 
13.1.2 
Independent Ethics Committee/Institutional Review Board 
This protocol and any material to be provided to the patient (such as advertisements, patient 
information sheets, or descriptions of the study used to obtain informed consent) will be 
submitted by the investigator to an IEC/IRB. This also applies to protocol amendments.  
Clovis will supply relevant data for the investigator to submit the study protocol and additional 
study documents to the IEC/IRB. The principal investigator will submit the study protocol for 
review and approval by an IEC/IRB, according to national law and/or local regulations, and will 
provide the IEC/IRB with all appropriate materials.  
Verification of the IEC’s/IRB’s unconditional approval of the study protocol and the written ICF 
will be transmitted to Clovis. This approval must refer to the study by exact study protocol title 
and number, identify the documents reviewed, and state the date of the review. 
No patient will be admitted to the study until appropriate IEC/IRB approval of the study protocol 
has been received, the investigator has obtained the signed and dated ICF, and the sponsor is 
notified.  
The principal investigator will submit appropriate reports on the progress of the study to the 
IEC/IRB at least annually in accordance with applicable national law and/or local regulations 
and in agreement with the policy established by the IEC/IRB and sponsor.  


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The IEC/IRB must be informed by the principal investigator of all subsequent study protocol 
amendments and of SAEs or SUSARs occurring during the study that are likely to affect the 
safety of the patients or the conduct of the study. 
13.2 Confidentiality of Information 
The investigator must assure that patients’ anonymity is strictly maintained and that their 
identities are protected from unauthorized parties. Only patient initials and an identification code 
(ie, not names) should be recorded on any form submitted to the sponsor and the IEC/IRB. The 
investigator must keep logs on screened and enrolled patients. In addition, the investigator must 
have a list where the identity of all treated patients can be found. 
The investigator agrees that all information received from Clovis, including, but not limited to, 
the Investigator’s Brochure, this protocol, eCRFs, the protocol-specified treatment, and any other 
study information, remain the sole and exclusive property of the sponsor during the conduct of 
the study and thereafter. This information is not to be disclosed to any third party (except 
employees or agents directly involved in the conduct of the study or as required by law) without 
prior written consent from the sponsor. The investigator further agrees to take all reasonable 
precautions to prevent the disclosure by any employee or agent of the study center to any third 
party or otherwise into the public domain. 
13.3 Patient Informed Consent 
All information about the clinical study, including the patient information and the ICF, is 
prepared and used for the protection of the human rights of the patient according to ICH GCP 
guidelines and the Declaration of Helsinki. 
It is the responsibility of the investigator to obtain signed ICFs from each patient participating in 
this study after adequate explanation of the aims, methods, objectives, and potential hazards of 
the study and before undertaking any study-related procedures.  
The ICF, prepared by the Investigator with the assistance of the sponsor, must be approved along 
with the study protocol by the IEC/IRB and be acceptable to the sponsor. 
The patient must be provided with the patient information and ICF consistent with the study 
protocol version used and approved by the relevant IEC/IRB. The ICF must be in a language 
fully comprehensible to the prospective patient. Patients (and/or relatives, guardians, or legal 
representatives, if necessary) must be given sufficient time and opportunity to inquire about the 
details of the study and to discuss and decide on their participation in the study with the 
investigator concerned. The patient and the person explaining about the study and with whom 
they discuss the informed consent will sign and date the ICF. A copy of the signed ICF will be 
retained by the patient and the original will be filed in the Investigator File unless otherwise 
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13.4 Study Monitoring 
A monitor will contact and visit the investigator at the study center before the entry of the first 
patient as necessary during the study until after the last patient has completed. A monitor will 
also perform a study closure visit.  
In accordance with ICH GCP guidelines, the investigator must ensure provision of sufficient 
time, reasonable space, and adequate qualified personnel for the monitoring visits. The visits are 
for the purpose of verifying adherence to the study protocol and the completeness, consistency, 
and accuracy of data entered on the eCRF and other documents.  
The investigator will make all source data (ie, the various study records, the eCRFs, laboratory 
test reports, other patient records, drug accountability forms, and other pertinent data) available 
for the monitor and allow access to them throughout the entire study period. Monitoring is done 
by comparing the relevant site records of the patients with the entries on the eCRF (ie, source 
data verification). It is the monitor’s responsibility to verify the adherence to the study protocol 
and the completeness, consistency, and accuracy of the data recorded on the eCRFs.  
Drug accountability will be performed as described in Section 7.5. The Investigator Site File will 
be reviewed to ensure all regulatory documents (eg, IRB/IEC approvals, approved ICFs, SAE 
reporting to IRB/IEC, etc.) are present.  
By agreeing to participate in the study, the investigator agrees to cooperate with the monitor to 
ensure that any problems detected in the course of the monitoring visits are resolved. Contact 
information for the study monitor is located in the Investigator File. Representatives from Clovis 
may also contact and visit the investigators and monitor data during the study.  
13.5 Case Report Form 
The data will be collected using an electronic data capture (EDC) system by remote data entry on 
eCRFs. Sites will receive training on the EDC system. All users will be supplied with unique 
login credentials. 
Before study start, the investigator will prepare a list showing the signature and handwritten 
initials of all individuals authorized to make or change entries on eCRFs. This “study center 
personnel and delegation list” must be kept current throughout the study. 
For each patient enrolled, an eCRF must be completed and reviewed by the principal investigator 
or co-investigator within a reasonable time period (< 2 weeks) after data collection. This also 
applies to records for those patients who fail to complete the study. If a patient withdraws from 
the study, the reason must be noted on the eCRF. If a patient is withdrawn from the study 
because of a treatment-limiting AE, thorough efforts should be made to clearly document the 
outcome. 
All laboratory data and investigator observations on the results and any other clinically 
significant test results must be documented on eCRFs. 


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Full information regarding EDC and completing eCRFs is included in the Investigator File. All 
questions or comments related to electronic capture should be directed to the assigned monitor. 
13.6 Study Termination and Site Closure 
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures. In terminating the study, 
Clovis and the investigator will assure that adequate consideration is given to the protection of 
the patients’ interests. 
Clovis reserves the right to discontinue the study at any time for medical or administrative 
reasons. When feasible, a 30-day written notification will be given. 
The entire study will be stopped if: 
• The protocol-specified treatment is considered too toxic to continue the study 
• Evidence has emerged that, in the opinion of the sponsor or the investigator(s), makes the 
continuation of the study unnecessary or unethical 
• The stated objectives of the study are achieved 
• The sponsor discontinues the development of oral rociletinib 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded on the eCRF. All reasons for discontinuation of 
treatment must be documented. In terminating the study, the investigator will ensure that 
adequate consideration is given to the protection of the patients’ interests. 
13.7 Modification of the Study Protocol 
Protocol amendments, except when necessary to eliminate an immediate hazard to patients, must 
be made only with the prior approval of Clovis. Agreement from the investigator must be 
obtained for all protocol amendments and amendments to the informed consent document. The 
IEC/IRB must be informed of all amendments and give approval before their implementation. 
The sponsor will submit any study protocol amendments to the concerned regulatory authorities 
for approval and keep the investigator(s) updated as detailed in the ICH GCP guidelines. 
13.8 Retention of Study Documents 
The study site will maintain a study file, which should contain, at minimum, the Investigator’s 
Brochure, the protocol and any amendments, drug accountability records, correspondence with 
the IEC/IRB and Clovis, and other study-related documents. 
The investigator agrees to keep records and those documents that include (but are not limited to) 
the identification of all participating patients, medical records, study-specific source documents, 
source worksheets, all original signed and dated ICFs, copies of all eCRFs, query responses, and 
detailed records of drug disposition to enable evaluations or audits from regulatory authorities 
and Clovis or its designees. 


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The investigator shall retain records required to be maintained for a period of 5 years following 
the date a marketing application in an ICH region is approved for the drug for the indication for 
which it is being investigated or, if no application is to be filed or if the application is not 
approved for such indication, until at least 5 years after the investigation is discontinued. 
However, these documents should be retained for a longer period if required by the applicable 
regulatory requirement(s) or if needed by Clovis. In addition, the investigator must make 
provision for the patients’ medical records to be kept for the same period of time. 
No data should be destroyed without the agreement of Clovis. Should the investigator wish to 
assign the study records to another party or move them to another location, Clovis must be 
notified in writing of the new responsible person and/or the new location. Clovis will inform the 
Investigator, in writing, when the trial-related records are no longer needed. 
Patients’ medical records and other original data will be archived in accordance with the 
archiving regulations or facilities of the investigational site. 
13.9 Clinical Study Report 
A clinical study report will be prepared under the responsibility and supervision of Clovis and 
signed by the sponsor’s chief medical officer, thereby indicating their agreement with the 
analyses, results, and conclusions of the clinical study report.  
13.10  Study Publication 
All data generated from this study are the property of Clovis and shall be held in strict 
confidence along with all information furnished by Clovis. Independent analysis and/or 
publication of these data by the investigator(s) or any member of their staff are not permitted 
without the prior written consent of Clovis. Written permission to the investigator will be 
contingent on the review by Clovis of the statistical analysis and manuscript, and will provide for 
nondisclosure of Clovis confidential or proprietary information. In all cases, the parties agree to 
submit all manuscripts or abstracts to all other parties 30 days before submission. This will 
enable all parties to protect proprietary information and to provide comments based on 
information that may not yet be available to other parties. 
13.11 Quality Assurance Audits 
An audit visit to clinical centers may be conducted by a quality control auditor appointed by 
Clovis. The purpose of an audit, which is independent of and separate from routine monitoring or 
quality control functions, is to evaluate trial conduct and compliance with the protocol, standard 
operating procedures (SOPs), ICH GCPs, and the applicable regulatory requirements. The 
investigator and the sponsor may also be subject to an inspection by FDA, European Regulatory 
authorities, or other applicable regulatory authorities at any time. The auditor and regulatory 
authorities will require authority from the investigator to have direct access to the patients’ 
medical records. It is important that the investigator(s) and their staff cooperate with the auditor 
or regulatory authorities during this audit or inspection.  


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carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-57. 
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growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958-67. 
4. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III study of 
afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with 
EGFR mutations. J Clin Oncol. 2013;31(27):3327-34. 
5. Herbst RS, LoRusso PM, Purdom M, Ward D. Dermatologic side effects associated with 
gefitinib therapy: clinical experience and management. Clin Lung Cancer. 2003;4(6):366-9. 
6. Perez-Soler R, Saltz L. Cutaneous Adverse Effects With HER1/EGFR-Targeted Agents: Is 
There a Silver Lining? J Clin Oncol. 2005;23(22):5235-46. 
7. Sridhar SS, Seymour L, Shepherd FA. Inhibitors of epidermal-growth-factor receptors: a 
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8. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. Acquired resistance 
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9. Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations 
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10. Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor 
specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with 
EGFR-mutant lung cancers. Clin Cancer Res. 2013;19(8):2240-7. 
11. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45(2):228-47. 
12. Aaronson NK, Ahmedzai S, Bullinger M, et al. For the EORTC Study Group on Quality of 
Life. The EORTC Core Quality of Life Questionnaire:  Interim results of an international 
field study. In: Osoba D, editor. Effect of Cancer on Quality of Life. Boca Raton: CRC Press 
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13. Hurst NP, Jobanputra P, Hunter M, Lambert M, Lochhead A, Brown H. Validity of Euroqol--
a generic health status instrument--in patients with rheumatoid arthritis. Economic and 
Health Outcomes Research Group. Br J Rheumatol. 1994;33(7):655-62. 
14. National Cancer Institute. Common Terminology Criteria for Adverse Events, Version 4.03. 
14 June 2010 [accessed 19 November 2014]; Available from: 
http://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. 
15. Carnio S, Novello S, Mele T, Levra MG, Scagliotti GV. Extending survival of stage IV non-
small cell lung cancer. Seminars in Oncology. 2014;41(1):69-92. 
16. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 
v1.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 11 [Internet]. Lyon, 
France: IARC;2013 [accessed 29 August 2014]; Available from: http://globocan.iarc.fr. 


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17. Yang P, Allen MS, Aubry MC, Wampfler JA, Marks RS, Edell ES, et al. Clinical features of 
5,628 primary lung cancer patients: experience at Mayo Clinic from 1997 to 2003. Chest. 
2005;128(1):452-62. 
18. Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, et al. SEER Cancer 
Statistics Review - Lung and Bronchus Cancer, 1975-2002. Bethesda, MD: National Cancer 
Institute; Available from: http://seer.cancer.gov/csr/1975_2002/, based on November 2004 
SEER data submission, posted to the SEER web site 2005. 
19. Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, et al. Crizotinib versus 
chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385-94. 
20. Camidge DR, Bang YJ, Kwak EL, Iafrate AJ, Varella-Garcia M, Fox SB, et al. Activity and 
safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results 
from a phase 1 study. Lancet Oncol. 2012;13(10):1011-9. 
21. Malik SM, Maher VE, Bijwaard KE, Becker RL, Zhang L, Tang SW, et al. U.S. Food and 
Drug Administration approval: crizotinib for treatment of advanced or metastatic non-small 
cell lung cancer that is anaplastic lymphoma kinase positive. Clin Cancer Res. 
2014;20(8):2029-34. 
22. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, et al. 
Biomarker analyses and final overall survival results from a phase III, randomized, open-
label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients 
with advanced non-small-cell lung cancer in Asia (IPASS) (Data Supplement). J Clin Oncol. 
2011;29(21):2866-74. 
23. Rosell R, Gervais R, Vergnenegre A, Massuti B, Felip E, Cardenal F, et al. Erlotinib versus 
chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with 
epidermal growth factor receptor (EGFR) mutations: Interim results of the European 
Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial. J Clin Oncol. 
2011;29(suppl; abstr 7503). 
24. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. 
Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR 
Inhibitors. Sci Transl Med. 2011;3(75):75ra26-75ra26. 
25. Sequist LV, Besse B, Lynch TJ, Miller VA, Wong KK, Gitlitz B, et al. Neratinib, an 
irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients 
with advanced non-small-cell lung cancer. J Clin Oncol. 2010;28(18):3076-83. 
26. Walter AO, Sjin RT, Haringsma HJ, Ohashi K, Sun J, Lee K, et al. Discovery of a mutant-
selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. 
Cancer Discov. 2013;3(12):1404-15. 
27. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, 
Lung Cancer Screening. Fort Washington: National Comprehensive Cancer Network. 
Review: Cancer Res Treat. 2013;45(2):79-85. 
28. Jabbour S, Ziring B. Advantages of extended-release metformin in patients with type 2 
diabetes mellitus. Postgrad Med. 2011;123(1):15-23. 
29. McDonagh EM, Boukouvala S, Aklillu E, Hein DW, Altman RB, Klein TE. PharmGKB 
summary: very important pharmacogene information for N-acetyltransferase 2. 
Pharmacogenet Genomics. 2014;24(8):409-25. 
 


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15 APPENDICES 
Appendix A. Response Evaluation Criteria in Solid Tumors 
Appendix B. Eastern Cooperative Oncology Group Performance Status Scale 
Appendix C. Study CO-1686-020 Extension Phase 
 
Appendix A 
Response Evaluation Criteria in Solid Tumors 
The RECIST guidelines (Version 1.1) are described in Eisenhauer (2009)11 and at 
http://www.eortc.be/Recist/Default.htm. A short summary is given below. 
Measurable Disease: 
Tumor lesions: measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter [LD] to be recorded) with the following: 
1. A minimum size of 10 mm by CT scan (CT scan thickness no greater than 5 mm) 
2. A minimum size of 10 mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable) 
3. A minimum size of 20 mm by chest X-ray 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph node 
must be  15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be not greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed.  
Nonmeasurable Disease: 
All other lesions (or sites of disease), including small lesions (LD < 10 mm or pathological 
lymph nodes with  10 to < 15 mm short axis), as well as truly nonmeasurable lesions, are 
considered nonmeasurable disease. Lesions considered truly nonmeasurable include 
leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast disease, 
lymphangitic involvement of skin and lung, and abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques.  
Bone Lesions 
Bone lesions, cystic lesion, and lesions previously treated with local therapy require particular 
comment. Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions. However, these techniques can 
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Lytic bone lesions or mixed lytic–blastic lesions with identifiable soft tissue components that can 
be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
Blastic bone lesions are nonmeasurable. 
Cystic Lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor nonmeasurable) because they are, by definition, 
simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions if 
they meet the definition of measurability described above. However, if noncystic lesions are 
present in the same patient, these are preferred as target lesions. 
Lesions with Prior Local Treatment 
Tumor lesions situated in a previous irradiated area or in an area subjected to other locoregional 
therapy are usually not considered measurable unless there has been demonstrated progression in 
the lesion. 
Target Lesions 
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
LD) and their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). A sum of the 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 
RECIST criteria require unequivocal quantification of the changes in tumor size for adequate 
interpretation of the sum of target lesions. Consequently, when the boundaries of the primary are 
difficult to delineate, this tumor should not be considered a target lesion. 
Guidelines for Evaluation of Measurable Disease 
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 
anti-tumor effect of a treatment. 


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Evaluation of Target Lesions 
Complete Response 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
< 10 mm. 
Partial Response 
At least a 30% decrease in the sum of the LD of target lesions, taking as 
reference the baseline sum LD. 
Stable Disease 
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. 
Progressive Disease 
At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, 
the sum must also demonstrate an absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered 
progression. 
 
Evaluation of Non-target Lesions 
Complete Response 
Disappearance of all non-target lesions and normalization of tumor 
marker level. 
Stable Disease/Incomplete 
Response 
Persistence of one or more non-target lesion(s) or/and maintenance of 
tumor marker level above the normal limits. 
Progressive Disease 
Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions. 
 
If tumor markers are initially above the institutional ULN, they must normalize for a patient to 
be considered a complete responder.  
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 PD the smallest measurements recorded 
since the treatment started). The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria.  
Time Point Response 
A response assessment will occur at the protocol-specified time points. The tables below provide 
a summary of the overall response status calculation at each time point for patients who have 
measureable and non-measureable disease (non-target disease only).  


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Time Point Response: Patients with Target (+/– Non-target) Disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not 
evaluated 
No 
PR 
SD 
Non-PD or not 
evaluated 
No 
SD 
Not Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
NE = Not evaluable 
 
Evaluation of Best Overall Response When Confirmation of CR and PR Required 
Overall Response  
First Time Point 
Overall Response 
Subsequent Time 
Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration 
met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration 
met, otherwise, NE 
NE 
NE 
NE 
a 
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria 
relative to baseline, makes this disease PD at that point (since disease must have reappeared after CR). Best response would 
depend on whether minimum duration for SD was met. However sometimes ‘CR’ may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR at the first time point. Under these 
circumstances, the original CR should be changed to PR and the best response is PR. 
 


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Missing Assessments and Not Evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response, which is most likely to occur in the case of PD; eg, if only 2 of 
3 baseline target lesions are assessed and result in a > 20% increase in the sum, then the patient 
would be assessed as a PD regardless of the missing lesion. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
symptomatic deterioration. Every effort should be made to document the objective progression, 
even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspiration/biopsy) prior to confirming the complete response 
status. 
Confirmatory Measurement/Duration of Response 
Confirmation 
CT scans are required every 6 ± 1 weeks. If an initial CR or PR is noted, confirmatory scans 
must be performed 4 ± 1 week later. In the case of SD, follow-up measurements must have met 
the SD criteria at least once after study entry at a minimum interval of no less than 4 ± 1 weeks.  
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded since the treatment 
started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
SD is measured from the start of the treatment until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the treatment started. 


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Appendix B 
Eastern Cooperative Oncology Group Performance Status Scale 
ECOG Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature (eg, light house work or 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. 
 
 


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Appendix C 
Study CO-1686-020 Extension Phase 
OBJECTIVE OF THE EXTENSION PHASE 
The purpose of the Extension Phase is to allow patients to continue on study but to avoid 
unnecessary collection of data that will no longer be analyzed or required for regulatory 
purposes, whilst maintaining an appropriate level of safety monitoring. 
In addition, this amendment also introduces the availability of NAT2 testing for patients, an 
indirect indicator of the likelihood of developing hyperglycaemia and QTc prolongation. The 
availability and disclosure of this information to the patients’ treating physician will not affect 
the monitoring and associated treatment guidelines for these adverse events. 
INTRODUCTION 
Additional information on efficacy/safety aspects 
The most current clinical and non-clinical updates, in particular those pertaining to efficacy and 
safety data, are provided in the current Investigator’s Brochure, in which integrated summaries 
of efficacy and safety data are presented. 
Additional information relating to Hyperglycemia and QTc prolongation 
The polymorphic enzyme NAT2 mediates the N-acetylation of M502 to form M544 and also 
plays a role in the elimination of M460. NAT2 genotype polymorphism was assessed for the 
group of patients who received rociletinib at 500 mg BID, 625 mg BID, 750 mg BID, and 1000 
mg BID and who gave additional informed consent for genomic testing. The NAT2 genotype 
polymorphism testing was performed using an assay based on polymerase chain reaction (PCR) 
followed by mass spectrometry to identify single nucleotide polymorphisms in NAT2. Based on 
NAT2 genotype results, patients were classified as having “low”, “intermediate”, and “rapid” 
acetylator phenotype.29 Acetylator status is currently available for 635 patients. Additional 
testing will be completed as additional samples are received. 
Adverse event and laboratory data based on NAT2 phenotype are summarized in Appendix C, 
Table 1, Appendix C, Table 2 , and Appendix C, Table 3. Analyses are presented by acetylator 
status for all doses combined, since the combined-dose findings were consistent with the findings 
within each dose group. 
Appendix C, Table 1 demonstrates that Grade 3 events are less common in patients who are 
classified as “rapid” acetylators. As expected, the relationship is most clear for hyperglycemia 
and QT-prolongation, while other AESIs appear to be less closely associated with acetylator 
status. Appendix C, Table 2 shows that hyperglycemia appears to be less frequent and less severe 
in rapid acetylators. Appendix C, Table 3 shows that QTcF prolongation on ECG appears to be 
less frequent and less severe in rapid acetylators. 
 


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Appendix C, Table 1: Grade 3 or Greater Treatment-emergent Adverse Events by 
Acetylator Status 
 
Overall 
(N = 635) 
Slow 
(n=300) 
Intermediate 
(n=259) 
Rapid 
(n=76) 
Overall 
243 (81%) 
194 (75%) 
48 (63%) 
Hyperglycemia (CT) 
131 (44%) 
66 (26%) 
13 (17%) 
QTc prolongation (CT) 
44 (15%) 
19 (7%) 
1 (1%) 
Malignant neoplasm progression 
39 (13%) 
39 (15%) 
8 (11%) 
Cataracts (CT) 
12 (4%) 
9 (4%) 
7 (9%) 
Pneumonitis (CT) 
3 (1%) 
4 (2%) 
0 
Diarrhea 
13 (4%) 
16 (6%) 
1 (1%) 
Abbreviation: CT=combined terms. 


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Appendix C, Table 2: Hyperglycemia Lab-shift by Acetylator Status 
Appendix C, Table 3: QTcF Changes on ECG by Acetylator Status 
For those patients ongoing on rociletinib trials, informed consent and testing for NAT2 
polymorphism status will be offered and the results will be shared with the treating 
physician. It will be up to the patient in consultation with the treating physician to decide 
continued participation in the trial in light of the acetylator status results or whether 
alternative treatment options should be sought.  
Regardless of acetylator status, monitoring should be the same for all patients receiving 
rociletinib whilst on treatment. 
 
 
 
Overall 
(N = 635) 
Slow 
(n = 300) 
Intermediate 
(n = 259) 
Rapid 
(n = 76) 
Subjects with any post-baseline 
glucose values > 250 mg/dL 
121 (40%) 
65 (25%) 
17 (22%) 
Subjects with 2 or more post-
baseline glucose values > 250 
mg/dL 
51 (17%) 
36 (14%) 
7 (9%) 
Subjects with any post-baseline 
glucose values > 500 mg/dL 
11 (4%) 
7 (3%) 
1 (1%) 
Subjects with 2 or more post-
baseline glucose values > 500 
mg/dL 
3 (1%) 
0 (0.0) 
0 (0.0) 
 
Overall 
(N = 635) 
Slow 
(n = 300) 
Intermediate 
(n = 259) 
Rapid 
(n = 76) 
QTcF Post-baseline ≥ 450 msec 
198 (66%) 
131 (51%) 
34 (45%) 
QTcF Post-baseline ≥ 481 msec 
92 (31%) 
44 (17%) 
7 (9%) 
QTcF Post-baseline ≥ 501 msec 
59 (31%) 
22 (9%) 
1 (1%) 
Two of more within 3 days ≥ 501 msec 
19 (6%) 
10 (4%) 
0 (0.0) 
QTcF Change from Baseline > 30 
msec 
246 (82%) 
171 (66%) 
47 (62%) 
QTcF Change from Baseline > 60 
msec 
141 (47%) 
57 (22%) 
9 (12%) 
Abbreviation: ECG=electrocardiogram. 


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STUDY DESIGN 
Treatment Regimen and Duration of Therapy 
All patients will sign an informed consent which explains the rationale for closing the 
rociletinib (CO-1686) clinical development program for NSCLC and the option for ongoing 
patients to continue receiving study treatment, should they decide to do so and/or if in the 
opinion of their treating physician they continue to receive clinical benefit.  
Patients may continue to receive rociletinib if the PI and patient deem it is appropriate for the 
patient though the availability and suitability of alternative treatment options should be 
considered by the treating physician and discussed with the patient. Rociletinib will be 
administered daily on a 21-day cycle. Dosing will be delayed or decreased according to 
protocol-specified toxicity criteria (Section 7.4). Each dose should continue to be taken with 
8 oz. (240 mL) of water and with a meal or within 30 minutes after a meal two times per day. 
Tablets should be swallowed whole.  
Treatment may continue until disease progression or intolerable toxicity. Please note, patients 
on rociletinib may opt to continue to receive treatment with rociletinib following 
radiographic progression as outlined in the NCCN guidelines for treatment of NSCLC with 
EGFR TKIs if patient provides additional consent, the investigator feels it is in the patient’s 
best interest and with sponsor approval. Similarly patients may opt to crossover to rociletinib 
following progression on single agent cytotoxic chemotherapy if eligibility criteria are met 
per Section 6.4. It is important that before deciding to continue treatment with rociletinib post 
progression in either of the two stated scenarios, additional treatment options are explored 
and discussed with the patient by the treating physician. In general, eligible patients may 
include those with asymptomatic systemic progression or locally symptomatic progression, 
such as brain metastases amenable to local treatment, with concomitant asymptomatic 
systemic progression or continued systemic disease control. This must be discussed with the 
sponsor and will be reviewed on a case-by-case basis.  
If a patient continues treatment post-progression, all Extension Phase study assessments 
should continue per protocol and data should be captured in the eCRF. The patient should be 
discontinued from treatment once it is clear that no further clinical benefit can be achieved. 
Both the hyperglycemia and QTc management guidelines (Section 7.4) should be followed 
during this extension phase and any modifications/deviations from these guidances should be 
discussed and agreed upon with the sponsor prior to implementation.  
Once study treatment has been discontinued and the End of Treatment visit has been 
completed, study participation will cease. Investigational centers will interpret tumor scans 
locally for the purpose of making treatment decisions and for final tumor response 
evaluation. The study will close once all patients have either completed participation, have 
transferred to a locally approved treatment access program (eg, a named patient program) in 
accordance with relevant local regulations or the sponsor decides to close the study. 
 
 


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PATIENT ELIGIBILITY AND WITHDRAWAL CRITERIA  
Eligibility and Number of Patients 
This amendment applies to patients who remain on either rociletinib or comparator 
chemotherapy on the CO-1686-020 study. No additional patients will be enrolled. 
Withdrawal Criteria 
The patient has the right to stop treatment or to withdraw from the study at any time. 
Patients will continue to receive treatment until one of the following cessation criteria 
applies: 
• Consent withdrawal at the patient’s own request or at the request of their legally 
authorized representative. 
• Progression of patient’s underlying disease. 
o Post-progression treatment is permitted, at the discretion of the Investigator and 
with the approval of the sponsor.  
• Intercurrent illness that prevents administration of treatment 
• Any event, adverse or otherwise, that, in the opinion of the investigator, would pose 
an unacceptable safety risk to the patient. 
• Major noncompliance that may affect patient safety (Reference Section 7.7). 
• Pregnancy. 
• Investigator decision. 
In addition, the sponsor may discontinue the trial early for any of the reasons noted in 
Section 13.6 of the protocol. 
The date and reason for cessation of treatment will be documented. Patients with ongoing 
SAEs will be followed until either resolution or stabilization has been determined.  
STUDY PROCEDURES 
Schedule of Assessments 
The procedures and assessments to be performed are outlined in the Schedule of Assessments 
presented in Appendix C, Table 4; Appendix C, Table 5; and Appendix C, Table 6. 
Procedures are synchronized with administration day of treatment unless indicated. The 
revised evaluations should commence immediately after the patient is consented, maintaining 
previous treatment cycle and day sequence. 
 
 


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Appendix C, Table 4: Schedule of Assessments for Patients Randomized to 
Rociletinib 
Procedure 
Prior to beginning 
Amendment 4 
Evaluations 
Day 1 of 
each cycle 
End-of-Treatment Visit  
(28 ± 7 days after last dose) 
Informed Consent 
X 
 
 
Physical Examination including vision check 
 
X 
X 
Vital Signsa and Weight 
 
X 
X 
Concomitant Medications and Procedures 
 
X 
X 
Contraceptive Counselingb 
 
 
X 
Pregnancy Testc 
 
 
X 
Local hematologyd 
 
X 
X 
Local fasting Serum Chemistrye 
 
X 
x 
Adverse events(including SAEs and AESI)f 
 
X 
X 
Rociletinib dispensing/ administration  
 
X 
 
Patient diaryg 
 
X 
X 
ECG Assessments using central ECG machineh 
 
X 
X 
Tumor Scansi 
To be done per institution standard of care or 6 ± 1 weeks during 
treatment ; scans are not required at the End of Treatment Visit 
PGx blood sample (Optional Sampling)j 
 
Xj  
 
a = Vital signs (blood pressure, pulse, and temperature) taken predose on drug administration days. 
b = Patients are to continue using effective contraception for 6 months after last dose of CO-1686 and report any 
pregnancies during this period. 
c = Serum ß-hCG to be evaluated by local lab will be performed only on women of childbearing potential. 
d = Hematology evaluation should include reticulocytes Includes hemoglobin, hematocrit, CBC, and differential (with 
ANC), and platelet count.Blood will be analyzed at a local laboratory and must be reviewed by the investigator before 
starting each new cycle of administration. Additional tests may be performed at the investigator’s discretion 
e = Glucose must be measured following an 8 hour fast (no food or liquid other than water). Hemoglobin A1c will be 
measured on Day 1 of every other cycle while the patient is on study. Samples should be analyzed by local laboratory.  
f = Patients will be monitored for AEs/SAEs/AESI from the time the first dose of CO-1686 is administered through 28 
days after the last dose.  
g= Patient diaries should be collected and reviewed for compliance at each visit. No diary will be dispensed at end of 
treatment. 
h=12-lead ECG (in triplicate, 10-sec tracings > 2 min apart) prior to dosing up to and including Cycle 12, at a minimum. 
For patients who are ongoing at this time and for whom QT has been < 470 ms (average of the triplicate value) 
throughout the study, ECG monitoring may be subsequently taken every 3rd cycle thereafter. ECGs will be performed 
and interpreted locally for patient care decisions; however, tracings should be submitted to the central lab for independent 
evaluation.  
i=Tumor scans will no longer be required to be submitted to a central reviewer; Disease progression to continue to be 
assessed locally by the Investigator. If a patient discontinues treatment before progression or is continuing treatment post 
progression (approval from Sponsor is required), then the decision to conduct additional scans and the frequency of those 
scans to monitor disease progression will be the responsibility of the treating physician 
j= Only one sample is needed and may be collected at any visit to enable NAT2 analysis. 
 
 
 


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Appendix C, Table 5: Schedule of Assessments for Patients Randomized to 
Single Agent Cytotoxic Chemotherapy 
Procedure 
Prior to beginning 
Amendment 4 
Evaluations 
Day 1 of 
each cycle 
Day 8 of 
each cycle 
Day 15 of 
each cycle 
End-of-Treatment 
Visit (28 ± 7 days 
after last dose) 
Informed Consent  
X 
 
 
 
 
Physical Examination 
including vision check 
 
X 
 
 
X 
Vital Signsa and 
Weight 
 
X 
 
 
X 
Concomitant 
Medications and 
Procedures 
 
X 
 
 
X 
Contraceptive 
Counselingb 
 
 
 
 
X 
Pregnancy Testc 
 
 
 
 
X 
Local hematology  
CBC and differentiald 
 
X 
X 
X 
X 
Local fasting Serum 
Chemistrye 
 
X 
 
 
x 
Adverse events 
(SAEs)f 
 
X 
X 
X 
X 
Chemotherapy 
administrationg 
 
X 
Xg 
Xg 
 
ECG Assessments 
using central ECG 
machinegh 
 
X 
 
 
X 
Tumor Scansi 
To be done per institution standard of care or every 6 ± 1 weeks during treatment; scans 
are not required at the End of Treatment Visit 
a = Vital signs (blood pressure, pulse, and temperature) taken predose on drug administration days. 
b = Patients are to continue using effective contraception for 6 months after last dose of chemotherapy and report any 
pregnancies during this period. 
c = Serum ß-hCG to be evaluated by local lab will be performed only on women of childbearing potential. 
d = Includes hemoglobin, hematocrit, CBC, and differential (with ANC), and platelet count. Blood will be analyzed at a 
local laboratory and must be reviewed by the investigator before starting each new cycle of administration. Additional 
tests may be performed at the investigator’s discretion 
e = Glucose must be measured following an 8 hour fast (no food or liquid other than water). Hemoglobin A1c will be 
measured on Day 1 of every other cycle while the patient is on study. Samples should be analyzed by local laboratory.  
f = Patients will be monitored for AEs/SAEs from the time the first dose of chemotherapy is administered through 28 
days after the last dose.  
g=All chemotherapy agents will be administered on Day 1 of each 21-day cycle. In addition, gemcitabine, docetaxel at 
the 35 mg/m2 dose, and paclitaxel will be administered on Day 8 of each 21-day cycle; and docetaxel at the 35 mg/m2 
dose and paclitaxel will also be administered on Day 15 of each 21-day cycle. This does not apply to pemetrexed and 
docetaxel at the 75 mg/m2 dose, which will only be administered on Day 1 of each 21-day cycle 
h=12-lead ECG (in triplicate, 10-sec tracings > 2 min apart) prior to dosing up to and including Cycle 12, at a minimum. 
For patients who are ongoing at this time and for whom QT has been < 470 ms (average of the triplicate value) 
throughout the study, ECG monitoring may be subsequently taken every 3rd cycle thereafter. ECGs will be performed 
and interpreted locally for patient care decisions; however, tracings should be submitted to the central lab for independent 
evaluation.  
i=Tumor scans will no longer be required to be submitted to a central reviewer; Disease progression to continue to be 
assessed locally by the Investigator. Frequency of the scans to monitor disease progression will be the responsibility of 
the treating physicians.  


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Appendix C, Table 6: Schedule of Assessments for Patients who Cross Over to Rociletinib after Chemotherapy 
 
Consent 
Screening 
Treatment Period (Daily dosing) 
Post-
treatment 
Period 
Procedurea 
Before 
Any 
Screening 
Procedures 
Day 
−35 to 
Day 
−1 
Day −14 
to Day −1 
XO-Cycle 1 Day 1 
(XO-C1D1)a, b 
XO-
Cycle 1 
Day 4 
± 1 Day 
XO-
Cycle 1 
Day 8  
± 1 Day 
XO-
Cycle 1 
Day 15 
± 1 Day 
XO-
Cycle 
2 
Day 1 
(21 ± 
3 days 
after 
C1D1) 
XO- 
Cycle 2 
Day 15 
± 1 day 
XO- 
Cycle 3+, 
Day 1 
(every 21 
± 3 days) 
End-of-
Treatment 
Visit 
(28 ± 7 days 
after last 
dose) 
Protocol Amendment 4 
Crossover informed 
Consent  
X 
 
 
 
 
 
 
 
 
 
 
Physical examination, 
including vision check 
 
 
X 
X 
 
 
 
X 
 
X 
X 
Vital signsc, height 
(screening only), weight, 
ECOG PS 
 
 
X 
(including 
height) 
X 
 
 
 
X 
 
X 
X 
Previous/concomitant 
medications and 
procedures 
 
X 
 
X 
 
 
 
X 
 
X 
X 
Contraceptive counselingd 
 
X 
 
 
 
 
 
 
 
 
X 
Local pregnancy teste 
 
 
X 
X 
 
 
 
 
 
 
X 
Local hematology, CBC 
and differentialf 
 
 
X 
X 
 
 
 
X 
 
X 
X 
Local fasting serum 
chemistryg 
 
 
X 
X 
Fasting 
glucose 
only 
Fasting 
glucose 
only 
Fasting 
glucose 
only 
X 
Fasting 
glucose 
only 
X 
X 
Tumor scansh 
 
X 
 
To be done per institution standard of care or every 6 ± 1 weeks during treatment, from 
XO-C1D1; End of Treatment scans are not required 
 
Adverse events (including 
SAEs and AESI)i 
 
X 
X 
X 
 
 
 
X 
 
X 
X 
Rociletinib 
dispensing/administration 
 
 
 
X 
 
 
 
X 
 
X 
 
Patient diaryj 
 
 
 
X 
 
 
 
X 
 
X 
X 


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ECGk 
 
X 
 
X 
 
 
X 
X 
 
X 
X 
PGx blood samplel 
(Optional ONE time 
Sampling) 
 
X 
X 
X 
 
 
 
X 
 
X 
 
a 
Unless specified, procedure is completed ± 1 day of scheduled time point and is synchronized with administration day of rociletinib (XO-C1D1). 
b 
Procedures required on XO-C1D1 may be omitted if completed  3 days earlier during the screening period. The EOT Visit may be performed earlier in patients 
requiring immediate treatment with another systemic anti-cancer therapy upon prior approval of the sponsor 
c 
Vital signs (blood pressure, pulse, and temperature, and ECOG PS) taken predose on XO-C1D1, and predose at every subsequent visit. All vital signs will be obtained 
after the patient has been resting for at least 5 minutes. Height is only required once at screening. 
d 
Fertile male patients and female patients of childbearing potential are to continue using effective contraception for 6 months after the last dose of rociletinib and report 
any pregnancies during this period. 
e 
Serum β-hCG (evaluated by local laboratories) will be performed only on women of childbearing potential  3 days before XO-C1D1. An additional urine pregnancy test 
must be performed locally and results obtained prior to dosing on XO-C1D1 to confirm that the patient is not pregnant before dosing. 
f 
Hematology evaluation should include reticulocytes ≤ 14 days before XO-C1D1. Blood will be analyzed at a local laboratory and must be reviewed by the investigator 
before start of each new cycle of rociletinib administration. Additional tests may be performed at the investigator’s discretion. 
g 
Fasting glucose required on XO-Cycle 1 Day 4 ± 1 day, XO-Cycle 1 Day 8 ± 1 day, XO-Cycle 1 Day 15 ± 1 day, and XO-Cycle 2 Day 15 ± 1 day and on Day 1 of each 
subsequent cycle Following an 8 hour fast (no food or liquid other than water). HbA1c will be measured ≤ 14 days before XO-C1D1 and on Day 1 of every other 
treatment cycle (XO-Cycles 3, 5, 7, etc.). Samples will be analyzed by a local laboratory.  
h 
Tumor scans obtained at progression on/after comparator arm treatment should be used as XO-screening scans. Other studies (MRI, X-ray) may be performed. Tumor 
scans will then be performed according the institutional standard of care or every 6 weeks ± 1 week from the time of crossover (Day 1 of XO-Cycles 3, 5, 7, etc.) until 
tumor progression. Disease progression to continue to be assessed locally by the Investigator. If a patient discontinues treatment before progression or is continuing 
treatment post progression (with approval from Sponsor), then the decision to conduct additional scans and the frequency of those scans to monitor disease progression 
will be the responsibility of the treating physician 
i 
Patients will be monitored for AEs/SAEs/AESIs from the time the first dose of CO-1686 is administered through 28 days after the last dose. 
j 
Patient diaries should be collected and reviewed for compliance at each visit. No diary will be dispensed at end of treatment. 
k 
12-lead ECG (in triplicate, 10-sec tracings > 2 min apart) prior to dosing up to and including Cycle 12, at a minimum. For patients who are ongoing at this time and for 
whom QT has been < 470 ms (average of the triplicate values) throughout the study, ECG monitoring may be subsequently taken every 3rd cycle thereafter. ECGs will 
be performed and interpreted locally for patient care decisions; however, tracings should be submitted to the central lab for independent evaluation. 
l 
Only one sample is needed and may be collected at any visit to enable NAT2 analysis.  
 


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Patients Randomized to Rociletinib 
Day 1 of Each Cycle (see also Appendix C, Table 4) 
Patients will be instructed to refrain from taking their dose of oral CO-1686 at home on the 
day of their clinic visit (Day 1 of the cycle) because the dose will be taken during the clinic 
visit. The following procedures will be completed: 
• Physical examination 
• Including a vision check as part of a standard physical exam 
• Weight 
• Vital signs (blood pressure, pulse, and temperature) 
• 12-lead ECG (in triplicate, 10-sec tracings > 2 min apart) prior to dosing, up to and 
including Cycle 12, at a minimum. For patients who are ongoing at this time and for 
whom QT has been < 470 ms (average of the triplicate values) throughout the study, ECG 
monitoring may be subsequently taken every 3rd cycle thereafter. ECGs will be 
performed and interpreted locally for patient care decisions; however, tracings should be 
submitted to the central lab for independent evaluation. ECGs can be collected at any 
time pre-dose on the day of the scheduled collection.  
• Local Fasting serum chemistry (including fasting glucose). HbA1c will be measured 
every other cycle (Day 1 of Cycle 3, 5, 7 etc). 
• Local Hematology (including reticulocyte count) 
• Concomitant medication and procedures  
• AE monitoring (until 28 days after last dose of protocol specified treatment; then only 
ongoing SAEs assessed as related to the study drug, and AESIs regardless of causality , 
are followed until resolution or stabilization) 
• Collection and review of patient diary and CO-1686 drug return. CO-1686 tablets will be 
dispensed to the patient; patient diary will be provided to the patient 
• Tumor assessments will be performed per institution standard of care or every 
6 ± 1 weeks after dosing until disease (tumor or clinical) progression. Disease 
progression to continue to be assessed locally by the Investigator. If a patient 
discontinues treatment before progression or is continuing treatment post progression 
(with approval from Sponsor), then the decision to conduct additional scans and the 
frequency of those scans to monitor disease progression will be the responsibility of the 
treating physician.  
• (Optional) PGx Blood Sample 
• Patient may consent for optional PGx sample collection if not previously collected 
already, and have the sample collected for NAT2 analysis 
• Sample should only be collected at a single visit 
 
 


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Patients Randomized to Single Agent Cytotoxic Chemotherapy 
Day 1 of Each Cycle (see also Appendix C, Table 5) 
• All chemotherapy agents will be administered to the patients at the clinic intravenously 
on Day 1 of each 21-day cycle: 
• Pemetrexed will be administered at 500 mg/m2 
• Gemcitabine will be administered at 1250 mg/m2 
• Docetaxel will be administered either at 75 mg/m2 (60 mg/m2 for patients residing 
in East-Asian territories) or at 35 mg/m2 
• Paclitaxel will be administered at 80 mg/m2 as a 1 hour infusion 
• Physical examination 
• Including a vision check as part of a standard physical exam 
• Weight 
• Vital signs (blood pressure, pulse, and temperature) 
• 12-lead ECG (in triplicate, 10-sec tracings > 2 min apart) prior to dosing, up to and 
including Cycle 12, at a minimum. For patients who are ongoing at this time and for 
whom QT has been < 470 ms (average of the triplicate values) throughout the study, ECG 
monitoring may be subsequently taken every 3rd cycle thereafter. ECGs will be 
performed and interpreted locally for patient care decisions; however, tracings should be 
submitted to the central lab for independent evaluation. ECGs can be collected at any 
time pre-dose on the day of the scheduled collection.  
• Local fasting serum chemistry (including fasting glucose). HbA1c will be measured 
every other cycle (Day 1 of Cycle 3, 5, 7 etc). 
• Local hematology (including reticulocyte count ) 
• Concomitant medication and procedures  
• AE monitoring (including SAEs) 
• Tumor assessments will be performed per institution standard of care or every 
6 ± 1 weeks after dosing until disease (tumor or clinical) progression. Disease 
progression to continue to be assessed locally by the Investigator and the frequency of 
those scans to monitor disease progression will be the responsibility of the treating 
physician.  
Cycle X Day 8 (± 1 Day) 
If selected as the comparator option, gemcitabine, docetaxel, and paclitaxel will be 
administered at the clinic intravenously on Day 8 of each 21-day cycle: 
• Gemcitabine will be administered at 1250 mg/m2 
• Docetaxel will be administered at 35 mg/m2 (in patients randomized to this docetaxel 
dosing regimen) 
• Paclitaxel will be administered at 80 mg/m2 as a 1 hour infusion 


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Please note, the other chemotherapy agents (pemetrexed and docetaxel 75 mg/m2 [60 mg/m2 
in Asian patients]) will not be administered on this day. 
In addition, the following procedures will be carried out for all patients randomized to 
receive single agent cytotoxic chemotherapy (pemetrexed, gemcitabine, docetaxel, or 
paclitaxel): 
• Hematology (CBC and differential ) 
• AE monitoring (including SAEs) 
Cycle X Day 15 (± 1 Day) 
If selected as the comparator option, docetaxel and paclitaxel will be administered at the 
clinic intravenously on Day 15 of each 21-day cycle: 
• Docetaxel will be administered at 35 mg/m2 (in patients randomized to this docetaxel 
dosing regimen) 
• Paclitaxel will be administered at 80 mg/m2 as a 1 hour infusion 
Please note, the other chemotherapy agents (pemetrexed, gemcitabine, and docetaxel 
75 mg/m2 [60 mg/m2 in patients residing in East-Asian territories]) will not be administered 
on this day. 
In addition, the following procedures will be carried out for all patients randomized to 
receive single-agent cytotoxic chemotherapy (pemetrexed, gemcitabine, docetaxel, or 
paclitaxel): 
• Hematology (CBC and differential) 
• AE monitoring (including SAEs) 
Patients who Cross Over to Rociletinib after Chemotherapy 
Screening Assessments (See also Appendix C, Table 6) 
The following baseline assessments will be established prior to the first dose of oral 
rociletinib and ≤ 35 days following radiographic progression on single-agent cytotoxic 
chemotherapy. Patients will be required to sign a cross over ICF before screening procedures 
begin. 
To be performed ≤ 35 days prior to XO-C1D1: 
• Informed Consent 
• Prior and concomitant medications and procedures 
• Contraceptive counseling 
• Study procedure-related AEs 


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• 12-lead ECG (in triplicate, 10-second tracings > 2 min apart) will be performed and 
interpreted locally for patient care decisions; however, tracings should be submitted to 
the central lab for independent evaluation. 
• Tumor scans will be performed per institution standard of care: scans used to determine 
radiographic progression on single agent cytotoxic chemotherapy will be used as 
baseline scans in cross over.  
To be performed ≤ 14 days prior to XO-C1D1: 
• Physical examination by body system 
• Including a vision check as part of a standard physical exam 
• Height and weight 
• Vital signs (blood pressure, pulse, and temperature) 
• Local hematology (including reticulocyte count)  
• Local fasting serum chemistry (including fasting glucose). HbA1c will be measured 
every other cycle (Day 1 of Cycle 3, 5, 7 etc). 
• Study procedure-related AEs 
To be performed ≤ 3 days prior to XO-C1D1: 
• Serum pregnancy test (by local laboratory)  3 days prior to randomization for women of 
childbearing potential 
Cross Over Cycle 1 Day 1 (XO-C1D1) 
Patients will be required to take their first dose of rociletinib at the clinic with 8 oz (240 mL) 
of water and with a meal or within 30 minutes after a meal. The following procedures will be 
carried out pre- and postdose. 
Predose Assessments 
Postdose Assessments 
Physical examination, including vision check 
Weight 
Vital signs (blood pressure, pulse, and temperature) 
Urine pregnancy test (with negative result) 
Concomitant medications and procedures 
Local hematology (including reticulocytes) 
Local fasting serum chemistry (includes glucose, 
HbA1c will be measured every other cycle (Day 1 
of Cycle 3, 5, 7 etc).  
Rociletinib tablets will be dispensed to the patient 
Patient diary dispensed 
12-lead ECG (in triplicate, 10-second tracings > 2 
minutes apart) will be performed and interpreted 
locally for patient care decisions; however, tracings 
should be submitted to the central lab for 
independent evaluation. ECGs can be collected at 
any time pre-dose on the day of the scheduled 
collection. 
AEs/SAEs/AESI experienced by the patient 
since dosing will be documented 
Concomitant medications administered since 
dosing will be recorded 
 


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Enough rociletinib tablets (and diary cards) will be dispensed to the patient for daily dosing 
until the next study clinic visit. 
Cross Over Cycle 1 Days 4, 8 and 15 (± 1 Day) 
The following procedures will be carried out: 
• Local Fasting glucose 
• (Day 15 only) 12-lead ECG (in triplicate, 10-sec tracings > 2 min apart). ECGs will be 
performed and interpreted locally for patient care decisions; however, tracings should be 
submitted to the central lab for independent evaluation. ECGs can be collected at any 
time pre-dose on the day of the scheduled collection 
 
Cross Over Cycle 2 Day 1 and every 21 ± 3 Days Thereafter 
The following procedures will be carried out at 21 ± 3 day intervals: 
• Physical examination 
• Including a vision check as part of a standard physical exam 
• Weight 
• Vital signs (blood pressure, pulse, and temperature) 
• 12-lead ECG (in triplicate, 10-sec tracings > 2 min apart) prior to dosing, up to and 
including Cycle 12, at a minimum. For patients who are ongoing at this time and for 
whom QT has been < 470 ms (average of the triplicate values) throughout the study, ECG 
monitoring may be subsequently taken every 3rd cycle thereafter. ECGs will be 
performed and interpreted locally for patient care decisions; however, tracings should be 
submitted to the central lab for independent evaluation. ECGs can be collected at any 
time pre-dose on the day of the scheduled collection 
• Local hematology (including reticulocyte count)  
• Local fasting serum chemistry (includes fasting glucose). HbA1c will be measured every 
other cycle (Day 1 of Cycles 3, 5, 7, etc.) after initiating rociletinib treatment. 
• Concomitant medication and procedures since last visit 
• AE monitoring (until 28 days after last dose of protocol specified treatment; then only 
ongoing SAEs assessed as related to the study drug, and AESIs regardless of causality , 
are followed until resolution or stabilization. 
• Collection and review of patient diary and CO-1686 drug return. CO-1686 tablets will be 
dispensed to the patient; patient diary will be provided to the patient 
• Tumor assessments will be performed per institution standard of care or every 
6 ± 1 weeks after dosing until disease (tumor or clinical) progression. Disease 
progression to continue to be assessed locally by the Investigator. If a patient 
discontinues treatment before progression or is continuing treatment post progression 
(with approval from Sponsor), then the decision to conduct additional scans and the 
frequency of those scans to monitor disease progression will be the responsibility of the 
treating physician.  


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Cross Over Cycle 2 Day 15 
The following procedures will be carried out: 
• Local Fasting glucose 
End of Treatment Visit (All Patients) 
The following procedures will be performed for all patients 28 days (±7 days) after the last 
dose of study treatment (initial study treatment or cross-over treatment, whichever comes 
last): 
• Physical examination  
• Including a vision check as part of a standard physical exam  
• Weight 
• Vital signs (blood pressure, pulse, and temperature) 
• Concomitant medications and procedures since last visit 
• 12-lead ECG (in triplicate, 10-sec tracings > 2 min apart) will be performed and 
interpreted locally for patient care decisions; however, tracings should be submitted to the 
central lab for independent evaluation. 
• Local Hematology (including reticulocyte count) 
• Local fasting serum chemistry (including fasting glucose) 
• Serum pregnancy test for women of childbearing potential 
• Contraceptive counseling (Both fertile male and female patients) 
• AE monitoring (until 28 days after last dose of study treatment; then only ongoing serious 
adverse events (SAEs) are followed until resolution or stabilization) 
• Collection and review of patient diary (patient randomized to rociletinib only)