Clinical trial NCT02147990
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
Sponsor: Clovis Oncology, Inc.
Start date: 2014-06-16; Completion date: 2019-08-27
Enrollment: 318 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety and anti-tumor effect of rociletinib. The trial is open-ended, which means patients will continue to take rociletinib until the study doctor determines it is no longer beneficial for them.

Detailed description:
This is a Phase 2, single arm, open-label, dual cohort, multicenter study evaluating the safety and efficacy of rociletinib administered orally to patients with previously treated mutant EGFR NSCLC.

Patients will be enrolled into 2 cohorts. Cohort A will enroll approximately 125 eligible patients who are centrally confirmed T790M-positive. Cohort B will be a continuation of the study and will enroll up to approximately 100 eligible patients who will be either centrally confirmed T790M-positive or T790M-negative.

All patients (for Cohort A and B) should have experienced disease progression while on treatment with the first single-agent EGFR-directed TKI (EGFR-TKI) for advanced/metastatic NSCLC. One line of chemotherapy prior to the EGFR-TKI treatment is permissible.

The study (Cohorts A and B) will consist of a screening phase to establish study eligibility and document baseline measurements, an open-label treatment phase, in which the patient will receive rociletinib to ascertain safety and efficacy until disease progression as defined by RECIST Version 1.1, clinical tumor progression, or unacceptable toxicity as assessed by the investigator. For patients with clinical progression, radiographic assessment should be performed to document evidence of radiographic progression.

Arms: arm 1: Starting dose of 625mg rociletinib, taken orally twice daily, with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Tablets should be swallowed whole. Treatment with rociletinib is continuous and each cycle will comprise of 28 days. arm 2: Starting dose of 500mg rociletinib, taken orally twice daily, with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Tablets should be swallowed whole. Treatment with rociletinib is continuous and each cycle will comprise of 28 days. arm 3: Starting dose of 500mg rociletinib, taken twice daily, with 8 oz (240 mL) of water and with a meal or within 30 minutes after a meal. Tablets should be swallowed whole. Treatment with rociletinib is continuous and each cycle will comprise of 28 days.
Interventions: intervention 1: Rociletinib
Intervention descriptions: intervention 1: Rociletinib will be administered to patients orally

Protocol documents:
Prot_000.pdf: 
CO-1686-019 
 
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TIGER-2: A Phase 2, Open-label, Multicenter, Safety and Efficacy Study of 
Oral CO-1686 as 2nd Line EGFR-directed TKI in Patients with Mutant EGFR 
Non-small Cell Lung Cancer (NSCLC) 
Protocol Number: 
CO-1686-019 
Investigational Product: 
CO-1686 
IND Number: 
EUDRA CT Number 
Development Phase: 
Phase 2 
Indication Studied: 
Locally advanced or metastatic NSCLC with mutant 
epidermal growth factor receptor (EGFR) 
Sponsor Name and Address: 
Clovis Oncology, Inc. 
 
 
Responsible Medical Officer: 
 
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 Harmonization 
(ICH) Good Clinical Practices (GCP) Guidelines. Essential 
study documents will be archived in accordance with 
applicable regulations. 
 
 
 
 
Amendment 5:Date  
 
 
16 August 2016 
Version: 
6.0 
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 


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by them. These restrictions on disclosure will apply equally to all future information supplied to 
you which is indicated as privileged or confidential. 


CO·l6IJ6.019 
Clinical l'mlacol 
Protocol: 
Protocol Approval Signature Page 
C0-1686-019 
Clovii; Oncology 
Amd ·S (Vcr1i1111 6.0) 16 Au; 2016 
Title: 
TIGER-2: A Phase 2, Open-label, MuJticenter, Safety and Efficacy Study of 
Oral C0-1686 as 2nd Line EGFR-dirccted TKJ in Patients with Mutant 
EGFR Non-small Cell Lung Cancer (NSCLC) 
Dare: 
16 August2016 
Version: 
6.0 
Confldendat 
Page3 


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Protocol Acceptance Form 
Protocol: 
CO-1686-019 
Title: 
TIGER-2: A Phase 2, Open-label, Multicenter, Safety and Efficacy Study 
of Oral CO-1686 as 2nd Line EGFR-directed TKI in Patients with Mutant 
EGFR Non-small Cell Lung Cancer (NSCLC) 
Date: 
16 August 2016 
Version: 
6.0 
 
 
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 
LIST OF IN-TEXT TABLES ..........................................................................................................9 
LIST OF IN-TEXT FIGURES.......................................................................................................10 
1 
SYNOPSIS ..........................................................................................................................11 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .....................................23 
3 
INTRODUCTION ...............................................................................................................26 
3.1 
CO-1686 Clinical Development Program Update .......................................................26 
3.1.1 
Extension Phase .................................................................................................26 
3.2 
Mutant EGFR Non-small Cell Lung Cancer ...............................................................26 
3.3 
Nonclinical Overview ..................................................................................................28 
3.4 
Clinical Experience with CO-1686 ..............................................................................30 
3.4.1 
Safety .................................................................................................................31 
3.4.1.1 
Study CO-1686-008 - Ongoing Phase 1/2 Study .....................................31 
3.4.2 
Activity of CO-1686 ..........................................................................................36 
3.4.3 
Pharmacokinetics of CO-1686 HBr ...................................................................37 
3.5 
Rationale for Study ......................................................................................................38 
4 
STUDY OBJECTIVES AND ENDPOINTS ......................................................................40 
4.1 
Objectives ....................................................................................................................40 
4.1.1 
Primary Objective ..............................................................................................40 
4.1.2 
Secondary Objectives .........................................................................................40 
4.1.3 
Exploratory Objectives ......................................................................................40 
4.2 
Endpoints .....................................................................................................................40 
4.2.1 
Primary Endpoint ...............................................................................................40 
4.2.2 
Secondary Endpoints .........................................................................................40 
4.2.3 
Exploratory Endpoints .......................................................................................41 
5 
STUDY DESIGN ................................................................................................................42 
5.1 
Overall Study Design and Plan ....................................................................................42 
5.1.1 
Screening Period ................................................................................................42 
5.1.2 
Treatment Period ................................................................................................42 
5.1.3 
End-of-treatment ................................................................................................43 
5.1.4 
Two Monthly Follow-up ....................................................................................43 
5.1.5 
Extension Phase .................................................................................................44 
5.2 
Study Schema...............................................................................................................44 
6 
STUDY POPULATION......................................................................................................46 
6.1 
Number of Patients and Sites .......................................................................................46 
6.2 
Inclusion Criteria .........................................................................................................46 
6.3 
Exclusion Criteria ........................................................................................................47 
6.4 
Patients or Partners of Patients of Reproductive Potential ..........................................49 


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6.5 
Waivers of Inclusion/Exclusion Criteria ......................................................................49 
7 
DESCRIPTION OF STUDY TREATMENTS AND DOSE MODIFICATIONS .............50 
7.1 
Description of Investigational Product ........................................................................50 
7.2 
Method of Assigning Patients to Treatment Groups ....................................................50 
7.3 
Preparation and Administration of Protocol-specified Treatment ...............................50 
7.4 
Dose Modifications of Protocol-specified Treatment ..................................................50 
7.5 
Accountability of Protocol-specified Treatment ..........................................................54 
7.6 
Blinding/Masking of Treatment ...................................................................................55 
7.7 
Treatment Compliance .................................................................................................55 
8 
PRIOR AND CONCOMITANT THERAPIES ..................................................................56 
8.1 
Anticancer or Experimental Therapy ...........................................................................56 
8.2 
Hematopoietic Growth Factors and Blood Products ...................................................56 
8.3 
CYP450 Isozyme Inhibitors and Inducers ...................................................................56 
8.4 
P-gp Substrates, Inhibitors and Inducers .....................................................................57 
8.5 
Other Concomitant Medications ..................................................................................57 
9 
STUDY PROCEDURES .....................................................................................................58 
9.1 
Screening Period ..........................................................................................................63 
9.2 
Treatment Period ..........................................................................................................64 
9.2.1 
Cycle 1 Day 1 (C1D1) .......................................................................................65 
9.2.2 
Cycle 1 Day 4 (± 1 Day) ....................................................................................65 
9.2.3 
Cycle 1 Day 8 (± 1 Day) ....................................................................................65 
9.2.4 
Cycle 1 Day 15 (± 1 Day) ..................................................................................66 
9.2.5 
Cycle 2 Day 15 (± 1 Day) ..................................................................................66 
9.2.6 
Cycle 2 (Day 1, Occurring 28 ± 3 Days After C1D1) and Cycle 3+ (Day 1, 
Every 28 ± 3 Days Thereafter, Counting from C1D1) ......................................66 
9.3 
End-of-Treatment Visit ................................................................................................67 
9.4 
Two Monthly Follow-up ..............................................................................................67 
9.5 
Methods of Data Collection .........................................................................................68 
9.5.1 
Safety Evaluations .............................................................................................68 
9.5.1.1 
Adverse Event Assessment ......................................................................68 
9.5.1.2 
Clinical Laboratory Investigations ...........................................................68 
9.5.1.3 
Vital Signs ................................................................................................69 
9.5.1.4 
12-lead Electrocardiograms .....................................................................69 
9.5.1.5 
Body Weight and Height .........................................................................69 
9.5.1.6 
Physical Examinations .............................................................................69 
9.5.1.7 
ECOG Performance Status ......................................................................70 
9.5.2 
Efficacy Evaluations ..........................................................................................70 
9.5.2.1 
Tumor Assessments .................................................................................70 
9.5.3 
Pharmacokinetic Evaluations .............................................................................71 
9.5.4 
Biomarker Assessments .....................................................................................71 


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9.5.5 
Quality of Life Assessments ..............................................................................72 
9.5.6 
Patient Diary ......................................................................................................72 
10 
ADVERSE EVENT MANAGEMENT...............................................................................73 
10.1 
Definition of an Adverse Event ...................................................................................73 
10.2 
Definition of a Serious Adverse Event ........................................................................73 
10.3 
Events or Outcomes Not Qualifying as Serious Adverse Events ................................74 
10.4 
Clinical Laboratory Assessments as Adverse Events and Serious Adverse Events ....74 
10.5 
Pregnancy or Drug Exposure during Pregnancy ..........................................................74 
10.6 
Recording of Adverse Events and Serious Adverse Events ........................................75 
10.6.1 
Intensity of Adverse Events ...............................................................................75 
10.6.2 
Causal Relationship of Adverse Events to Investigational Medicinal 
Products..............................................................................................................75 
10.6.3 
Outcome and Action Taken ...............................................................................76 
10.7 
Follow-up of Adverse Events and Serious Adverse Events ........................................77 
10.8 
Regulatory Aspects of Serious Adverse Event Reporting ...........................................77 
11 
STATISTICAL METHODS ...............................................................................................78 
11.1 
Analysis Populations ....................................................................................................78 
11.2 
Statistical Methods .......................................................................................................78 
11.2.1 
General Considerations ......................................................................................78 
11.2.2 
Patient Disposition .............................................................................................78 
11.2.3 
Baseline Characteristics .....................................................................................78 
11.2.4 
Efficacy Analyses ..............................................................................................78 
11.2.4.1 
Primary Endpoint .....................................................................................79 
11.2.4.2 
Secondary Efficacy Endpoints .................................................................79 
11.2.4.3 
Exploratory Endpoints .............................................................................81 
11.2.5 
Safety Analyses ..................................................................................................81 
11.2.5.1 
Extent of Exposure ...................................................................................81 
11.2.5.2 
Adverse Events ........................................................................................81 
11.2.5.3 
Clinical Laboratory Evaluations ..............................................................82 
11.2.5.4 
Vital Sign Measurements .........................................................................83 
11.2.5.5 
12-lead Electrocardiograms .....................................................................83 
11.2.5.6 
Other Safety Measurements .....................................................................83 
11.2.6 
Exploratory Endpoints−Pharmacodynamic Analysis ........................................83 
11.3 
Sample Size Considerations .........................................................................................84 
12 
PATIENT DISPOSITION ...................................................................................................85 
12.1 
Patient Discontinuations ..............................................................................................85 
13 
STUDY ADMINISTRATION ............................................................................................86 
13.1 
Regulatory and Ethical Considerations ........................................................................86 
13.1.1 
Regulatory Authority Approvals........................................................................86 
13.1.2 
Independent Ethics Committee/Institutional Review Board ..............................86 


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13.2 
Confidentiality of Information .....................................................................................87 
13.3 
Patient Informed Consent ............................................................................................87 
13.4 
Study Monitoring .........................................................................................................88 
13.5 
Case Report Form ........................................................................................................88 
13.6 
Study Termination and Site Closure ............................................................................89 
13.7 
Modification of the Study Protocol..............................................................................89 
13.8 
Retention of Study Documents ....................................................................................89 
13.9 
Clinical Study Report ...................................................................................................90 
13.10 Study Publication .........................................................................................................90 
13.11 Quality Assurance Audits ............................................................................................90 
14 
REFERENCES ....................................................................................................................91 
15 
APPENDICES .....................................................................................................................94 
 


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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 ...............................................................................................33 
Table 3-2: 
Treatment-related Adverse Events Reported in at Least 5% of 
Patients in Study CO-1686-008 .............................................................................35 
Table 3-3: 
Best Response, Objective Response, and Disease Control Rate in 
T790M-positive Patients ........................................................................................37 
Table 9-1: 
Schedule of Assessments .......................................................................................59 
Table 11-1: 
Confidence Intervals for Observed Response Rates ..............................................84 
 


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LIST OF IN-TEXT FIGURES 
Figure 3-1: 
CO-1686 Generates Complete Responses in L858R/T790M 
Transgenic Model ..................................................................................................29 
Figure 3-2: 
Target Lesion Response in Centrally Confirmed T790M-positive 
Patients ...................................................................................................................36 
Figure 3-3: 
Individual CO-1686 AUC0-24 on Day 1 Following 500 mg to 
1000 mg CO-1686 HBr BID ..................................................................................38 
Figure 5-1: 
Study Schema.........................................................................................................45 
Figure 7-1: 
Guidelines for Management of Hyperglycemia .....................................................54 
 


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1 
 SYNOPSIS 
Protocol Number 
CO-1686-019 
Title 
TIGER-2: A Phase 2, Open-label, Multicenter, Safety and Efficacy Study of 
Oral CO-1686 as 2nd Line EGFR-directed TKI in Patients with Mutant EGFR 
Non-small Cell Lung Cancer (NSCLC) 
Phase 
Phase 2  
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 (Amendment 5) 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, Amendment 5 (Appendix C) 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 patients’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, 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. 
CO-1686 is a novel, potent, small molecule irreversible tyrosine kinase 
inhibitor (TKI) that selectively targets mutant forms of the epidermal growth 
factor receptor (EGFR) while sparing wild-type (WT) 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 Patients with the most common EGFR activating 
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 


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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 9-14 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 disease is 
fatal, with a median overall survival (OS) of less than 2 years.10  
Nonclinical data demonstrate that CO-1686 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 
CO-1686 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 CO-1686 500 mg BID dose, additional patients 
will be enrolled at a starting dose of 500 mg BID in this study (Cohort B). 
Response Evaluation Criteria In Solid Tumors (RECIST)11 responses have 
been observed across the range of doses studied in Phase 1 with CO-1686, and 
the current objective response rate (ORR) in patients with T790M-positive 
NSCLC is > 60%. The most common toxicity observed is hyperglycemia, 
occurring in approximately 30% of patients, which can usually be readily 
managed with PO anti-hyperglycemic therapy. Adverse events (AEs) typical 
of WT-EGFR inhibition (the combination of rash and chronic diarrhea) have 
not been observed with CO-1686 
The goals of protocol CO-1686-019 are to evaluate the antitumor efficacy, 
safety and population pharmacokinetic (POPPK)/pharmacodynamic 
relationships of PO single-agent CO-1686, when administered at the 
therapeutically active doses of 625 mg BID and 500 mg BID to patients with 
EGFR-mutated, advanced/metastatic NSCLC after failure of 1 previous 
EGFR-directed TKI.  
CO-1686  was 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.  
Planned Number of 
Patients 
The total enrollment planned for this study is approximately 225 patients. The 
patients will be enrolled into 2 cohorts: 
Cohort A: Approximately 125 patients with centrally confirmed 
T790M-positive NSCLC will be enrolled. These patients will be treated at a 
dose of 625 mg BID. 


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Cohort B: Approximately 100 patients will be enrolled in order to include 
approximately 40 response evaluable, centrally confirmed T790M-negative 
patients. All Cohort B patients will be treated at a dose of 500 mg BID. 
Planned Number of 
Sites 
Approximately 90 investigative sites in the United States (US), Europe, Asia 
and Australia. 
Study Objectives 
Primary Objective 
• 
To evaluate the antitumor efficacy of PO single-agent CO-1686, as 
measured by ORR, when administered to patients with EGFR-mutated, 
centrally confirmed T790M-positive and T790M-negative advanced 
NSCLC after tumor progression on 1 previous EGFR-directed TKI  
Secondary Objectives 
• 
To assess clinical efficacy in patients with centrally confirmed 
T790M-positive NSCLC: disease control rate (DCR), duration of response 
(DR), PFS, and OS following CO-1686 treatment  
• 
To assess quality of life (QoL) by patient-reported outcomes (PRO) 
following CO-1686 treatment 
• 
To evaluate the safety and tolerability of CO-1686 
• 
To determine the pharmacokinetics (PK) of CO-1686 using POPPK 
methods and explore correlations between PK, exposure, response, and/or 
safety findings 
Exploratory Objectives 
• 
To evaluate clinical benefit of continued CO-1686 treatment following 
disease progression 
• 
To evaluate concordance of mutant EGFR detection between tissue and 
plasma and assess CO-1686 mediated alterations in mutant EGFR levels 
over time using circulating tumor deoxyribonucleic acid (ctDNA) 
obtained from plasma 
• 
To explore tissue and blood-based biomarkers that may be predictive of 
response or primary resistance to CO-1686 and investigate mechanisms of 
acquired resistance in the tissue and blood of patients who experience 
clinical progression during treatment with CO-1686 
Study Endpoints 
Primary Endpoints 
• 
ORR according to RECIST Version 1.1. For Cohort A, ORR will undergo 
independent radiology review (IRR) and in Cohort B, scans will be 
assessed by IRR if needed as a supporting analysis. 
Secondary Endpoints 
• 
DR, DCR and PFS according to RECIST Version 1.1 as determined by 
IRR  
• 
ORR, DR, DCR and PFS according to RECIST Version 1.1 as determined 
by investigator assessment 
• 
OS 
• 
Change from baseline in PROs using the European Organization for 
Research and Treatment of Cancer Core Quality of Life Questionnaire 
(EORTC QLQ-C30), EORTC Quality of Life Questionnaire Lung Cancer 


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module (EORTC QLQ-LC13), and the Dermatology Life Quality Index 
(DLQI)12,13  
• 
Treatment-emergent AEs, laboratory abnormalities, and electrocardiogram 
(ECG) abnormalities 
• 
Plasma PK parameters for CO-1686 based on sparse sampling 
Exploratory Endpoints 
• 
Time-to-treatment failure  
• 
Extra-cranial PFS 
• 
Change from baseline in mutant EGFR levels in ctDNA obtained from 
plasma  
• 
Positive and negative percent agreement between blood and tissue results 
for T790M  
• 
Identify biomarkers associated with response or resistance to CO-1686 
Study Design 
 
This is a Phase 2, single arm, open-label, dual cohort, multicenter study 
evaluating the safety and efficacy of CO-1686 administered PO BID to 
patients with previously-treated mutant EGFR NSCLC. 
Patients will be enrolled into 2 cohorts. Cohort A will enroll approximately 
125 eligible patients who are centrally confirmed T790M-positive and will be 
treated at 625 mg BID. Cohort B will be a continuation of the study and will 
enroll up to approximately 100 eligible patients who will be either centrally 
confirmed T790M-positive or T790M-negative. All patients in Cohort B will 
be treated at a starting dose of 500 mg BID. The priority for study enrollment 
will be for all T790M-positive patients to be enrolled into Cohort A first. 
Once Cohort A is complete, eligible T790M-positive patients will then be 
enrolled into Cohort B. All eligible T790M-negative patients will be enrolled 
into Cohort B. 
All patients (for Cohort A and B) should have experienced disease progression 
while on treatment with the first single-agent EGFR-directed TKI 
(EGFR-TKI) for advanced/metastatic NSCLC. One line of chemotherapy 
prior to the EGFR-TKI treatment is permissible. 
The study (Cohorts A and B) will consist of a Screening Phase to establish 
study eligibility and document baseline measurements; an open-label 
Treatment Phase, in which the patient will receive CO-1686 to ascertain 
efficacy and safety until disease progression as defined by RECIST 
Version 1.1, clinical tumor progression, or unacceptable toxicity as assessed 
by the investigator. For patients with clinical progression, radiographic 
assessment should be performed to document evidence of radiographic 
progression. 
Patients may opt to continue to receive treatment with CO-1686 following 
radiographic progression, as outlined in the National Comprehensive Cancer 
Network (NCCN) guidelines for treatment of NSCLC with EGFR-TKIs,14 if 
the patient provides additional consent, the investigator believes it is in the 
best interest of the patient, and the sponsor approves. In general, eligible 
patients may include those with asymptomatic systemic progression or locally 
symptomatic progression, such as brain metastases amenable to local 


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treatment, with concomitant asymptomatic systemic progression or continued 
systemic disease control. 
Each 28-day period of treatment will represent 1 cycle, with dosing initiated 
on Cycle 1 Day 1 (C1D1).  
Dosing will be delayed or reduced according to protocol-specified toxicity 
criteria. As mentioned above, patients who provide additional consent may 
continue to receive treatment with CO-1686 post-progression if, in the opinion 
of the investigator and approved by the sponsor, the patient is still benefitting.  
Sparse blood sampling for population PK analyses will be conducted in all 
patients treated with CO-1686. Serial blood sampling for longitudinal 
quantitative assessment of ctDNA will be conducted. A central laboratory will 
confirm presence or absence of the T790M mutation in formalin-fixed 
paraffin-embedded (FFPE) tumor tissue prior to study enrollment. Following 
disease progression on CO-1686, 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 CO-1686 is administered 
through 28 days after the last dose. Study procedure-related AEs that occur 
after signing of the Informed Consent Form (ICF) and before administration 
of CO-1686 will also be captured. All patients will be followed at 
approximately 2 monthly intervals to determine disease progression (if patient 
discontinues treatment before progression), survival status and subsequent 
NSCLC therapy until death or sponsor decision, whichever comes first. After 
discontinuation of protocol-specified treatment, subsequent anticancer therapy 
use will be recorded. 
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 (Amendment 5) 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, Amendment 5 (Appendix C) 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 patients’s treating physician will not affect the monitoring 
and associated treatment guidelines for these adverse events. 


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For patients who wish to continue rociletinib treatment post progression, 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. 
Study Population 
 
Except where specified, inclusion and exclusion criteria are applicable to 
both Cohorts A and B of the study. 
Inclusion Criteria 
All patients must meet all of the following inclusion criteria: 
1. Histologically or cytologically confirmed metastatic or unresectable 
locally advanced NSCLC 
2. Documented evidence of a tumor with 1 or more EGFR mutations 
excluding exon 20 insertion 
• 
Disease progression confirmed by radiologic assessment 
while receiving treatment with the first single agent 
EGFR-TKI (eg, erlotinib, gefitinib, afatinib, or dacomitinib) 
o EGFR-TKI treatment discontinued ≤ 30 days prior to 
planned initiation of CO-1686 (the washout period for an 
EGFR inhibitor is a minimum of 3 days) 
o No intervening treatment between cessation of 
single-agent EGFR-TKI and planned initiation of 
CO-1686 
o Previous treatment with ≤ 1 prior chemotherapy 
(excluding prior neo-adjuvant or adjuvant chemotherapy 
or chemoradiotherapy with curative intent)  
o Any toxicity related to prior EGFR inhibitor treatment 
must have resolved to Grade 1 or less 
• 
Central laboratory confirmation of the presence of the T790M 
mutation in tumor tissue in Cohort A and the presence or 
absence of the T790M mutation in tumor tissue in Cohort B. 
Centrally indeterminate, unknown or invalid specimens are 
not acceptable. Biopsy material obtained from either primary 
or metastatic tumor tissue must have been obtained (and sent 
to the central laboratory) within 60 days prior to dosing study 
drug but following disease progression on the first 
EGFR-TKI. 
3. Measureable disease according to RECIST Version 1.1 
4. Life expectancy of at least 3 months 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 
0 to 1 
6. Age ≥ 18 years (in certain territories, the minimum age requirement 
may be higher, eg age ≥ 20 years in Japan and Taiwan) 
7. Adequate hematological and biological function, confirmed by the 
following laboratory values: 
 


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• 
Bone Marrow Function 
o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
o Platelets > 100.0 × 109/L  
o Hemoglobin ≥ 9 g/dL (or 5.6 mmol/L) 
• 
Hepatic Function 
o Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 3 × upper limit of normal 
(ULN); if liver metastases, ≤ 5 × ULN  
o Bilirubin ≤ 2 × ULN 
• 
Renal Function  
o Serum creatinine ≤ 1.5 × ULN 
• 
Electrolytes 
o Potassium and magnesium within normal range. Patients 
may receive supplements to meet this requirement 
8. Written consent on an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC)-approved ICF prior to any study-specific 
evaluation 
Exclusion Criteria 
Any of the following criteria will exclude patients from study participation: 
1. Documented evidence of an exon 20 insertion activating mutation in 
the EGFR gene 
2. Active second malignancy; i.e. patient known to have potentially fatal 
cancer present for which he/she 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 
3. Known pre-existing interstitial lung disease 
4. Cohort A only: 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 4 weeks prior to the start of study treatment). Cohort B 
only: Patients with CNS metastases or leptomeningeal carcinomatosis 
are excluded. 
5. Treatment with prohibited medications (eg, concurrent anticancer 
therapy including other chemotherapy, radiation, hormonal treatment 
[except corticosteroids and megesterol acetate], or immunotherapy) 
≤ 14 days prior to treatment with CO-1686 
6. Patients who are currently receiving treatment with any medications 
that have the potential to prolong the QT interval and the treatment 
cannot be either discontinued or switched to a different medication 
before starting CO-1686 
• 
see http://crediblemeds.org/ for a list of QT-prolonging 
medications (includes all medication under categories of 
Known, Possible and Conditional risk of Torsades de Pointes) 


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7. Prior treatment with CO-1686, or other drugs that target 
T790M-positive mutant EGFR with sparing of wild type EGFR eg, 
AZD9291, HM61713, TAS-121 
8. Any of the following cardiac abnormalities or history: 
• 
Clinically significant abnormal 12-lead ECG, QT interval 
corrected using Fridericia’s method (QTCF) > 450 msec 
• 
Inability to measure QT interval on ECG 
• 
Personal or family history of long QT syndrome 
• 
Implantable pacemaker or implantable cardioverter 
defibrillator 
• 
Resting bradycardia < 55 beats/min 
9. Nonstudy-related surgical procedures ≤ 7 days prior to administration 
of CO-1686. 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 12 weeks after the last dose of 
CO-1686 
12. Presence of any serious or unstable concomitant systemic disorder 
incompatible with the clinical study (eg, substance abuse, 
uncontrolled intercurrent illness including active infection, arterial 
thrombosis, and symptomatic pulmonary embolism) 
13. Any other reason the investigator considers the patient should not 
participate in the study 
Study Treatment 
CO-1686 will be administered to patients as PO tablets at a dose of 
625 mg BID (Cohort A) or 500 mg BID (Cohort B). Patients will be instructed 
to take each dose of CO-1686 with a meal or within 30 minutes after a meal.  
Dose-Modification 
Criteria 
No dose escalation beyond the starting dose is allowed in either cohort. Dose 
reduction steps are allowed for each patient, with the overall number of dose 
reduction steps at the investigator’s discretion. Dose reduction should be in 
increments of 125 mg BID with up to 2 dose reduction steps permitted. Any 
need for further dose reduction, or dose adjustment to a 3 times daily (TID) 
regimen should be discussed with the sponsor before implementing. 
For Grade 3 or 4 hematologic and non-hematologic toxicities (except for 
nausea/vomiting, alopecia, QT interval corrected for heart rate [QTc] 
prolongation and hyperglycemia), the dose should be initially reduced by 
125 mg BID (to 500 mg BID, if the starting dose was 625 mg BID; or to 
375 mg BID, if the starting dose was 500 mg BID). Re-escalation of dose after 
resolution of AEs must be discussed with, and approved by, the sponsor.  
ECGs will be measured throughout the study as described in the protocol. If 
QTC prolongation of National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE v4.03)15 Grade 3 is observed, CO-1686 
will be held until the event has improved to Grade 1. CO-1686 can then be 
re-started at a reduced dose after sponsor approval. If CTCAE Grade 3 or 
above QTC prolongation recurs, then CO-1686 will be discontinued unless 
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QTC prolongation changes of CTCAE Grade 4 are observed at any time, 
CO-1686 will be discontinued permanently. 
If a patient experiences hyperglycemia, dose management should be as 
outlined in Section 7.4 of the protocol.  
Concomitant 
Medications 
Supportive care (eg, antiemetics, analgesics for pain control) may be used at 
the investigator’s discretion and in accordance with institutional procedures.  
Withdrawal Criteria 
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 
• 
Progression of patient’s underlying disease, except as described 
Section 5.1.2 of the protocol 
• 
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 
After stopping protocol-specified treatment, all patients will remain in the 
study and will be followed for safety (through 28 days after last dose), disease 
progression (if patient discontinues treatment before progression), survival 
status, and subsequent therapy assessment (approximately every 2 months 
until death or sponsor decision).  
Efficacy 
Assessments 
Efficacy measures will include tumor assessments, preferably by computed 
tomography (CT) scans of the chest and abdomen with appropriate slice 
thickness per RECIST Version 1.1; other studies (magnetic resonance imaging 
[MRI] and X-ray) may be performed if required. Pelvic imaging should be 
performed if clinically indicated eg, prior or existing site of metastasis or 
symptomatic. Brain imaging (CT/MRI) is required at baseline. In Cohort A, 
patients with brain lesions at baseline will require repeat brain imaging as part 
of the follow-up tumor assessments. In Cohort B, patients with evidence of 
brain lesions at Screening are not eligible for the study. Tumor assessments 
will be performed at Screening and every 8 ± 1 weeks thereafter (Day 1 of 
Cycles 3, 5, 7 etc. ± 1 week), including at the End-of-Treatment Visit. Tumor 
scan at end-of-treatment 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, 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. If a patient discontinues treatment before 
progression, then scans should continue until progression according to the 
protocol schedule. Exceptions to this requirement may be acceptable based on 
local institutional or regulatory requests and must be approved in advance by 
the sponsor. Tumor scans will be assessed by IRR for the primary endpoint 
evaluation in Cohort A. In Cohort B, scans will be assessed by IRR if needed 
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Safety Assessments 
Safety assessments will include:  
• 
AEs  
• 
Hematology, including reticulocyte count, clinical chemistry including 
hemoglobin A1c (HbA1c), and urinalysis 
• 
12-lead ECGs  
• 
Physical examination 
• 
Vital signs and body weight 
• 
Concomitant medications/procedures 
• 
ECOG performance status 
Where applicable, AEs will be classified according to the NCI CTCAE 
Version 4.03.15  
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 dosing. 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.  
When 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 on CO-1686, 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 deoxyribonucleic acid 
(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. 
Blood will be collected for detection and quantification of mutant EGFR from 
plasma. Blood may also be used to test for biomarkers of response or 
resistance to EGFR-targeted therapy.  
All patients (Cohorts A and B) will have blood collected during Screening 
(within 60 days prior to dosing), at Day 1 of each cycle, and at progression. 
Blood collected at these time points may also be used to test for biomarkers of 
response or resistance to EGFR-targeted therapy. 
Patient Reported 
Outcome 
Assessments 
PRO will be measured using the EORTC QLQ-C30 and LC13 and the 
DLQI,12,13 which will be administered at Screening, prior to dosing on C1D1, 
then every 8 ± 1 weeks for 6 months (Day 1 of Cycles 3, 5, 7, ± 1 week). After 
Cycle 7, questionnaires will be collected every 12 ± 1weeks (Day 1 of Cycles 
10, 13, 16, etc, ± 1 week) and at end-of-treatment.  


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Statistical 
Procedures 
Analysis Populations 
• 
Tumor evaluable population−all patients who received at least 1 dose of 
CO-1686, have at least 1 measureable tumor lesion at baseline and have at 
least 1 post-baseline tumor assessment as assessed by IRR (Cohort A) or 
investigator assessment (Cohort B) 
• 
Safety population−all patients who have received at least 1 dose of 
CO-1686 
Sample Size Justification 
Cohort A: Approximately 125 patients will be enrolled. The ORR will be 
presented with 95% confidence intervals (CIs). The following table provides 
the 95% CIs for observed response rates of 30%, 40%, and 50% assuming a 
total of 125 patients. 
 
Confidence Intervals for Observed Response Rates 
Number of Patients 
ORR (%) [95% CI] 
125 
30 [22, 39] 
125 
40 [31, 49] 
125 
50 [41, 59] 
 
Cohort B: Approximately 100 patients will be enrolled with the aim to 
include approximately 40 response evaluable, centrally confirmed 
T790M-negative NSCLC patients. To be response evaluable, patients should 
have received at least one cycle of therapy, and have had their disease 
re-evaluated by radiological assessment.  
An exact binomial test with a nominal 0.10 2-sided significance level will 
have approximately 90% power to detect the difference between a null 
hypothesis response rate of 20% and a clinically meaningful response rate of 
40% when the sample size is 40. 
Efficacy Analysis 
The ORR in both centrally confirmed T790M-positive and centrally 
confirmed T790M-negative patients will be summarized separately with 
frequencies and percentages. The DR for complete response (CR) and partial 
response (PR) for both centrally confirmed T790M-positive and centrally 
confirmed T790M-negative patients will be summarized separately with 
descriptive statistics (N, mean, standard deviation, median, minimum, and 
maximum) as well as categorically. 
DCR is defined as the percentage of patients who have achieved CR, PR, and 
stable disease (SD). Kaplan-Meier methodology will be used to summarize 
PFS and OS. 
Safety Analyses 
Data from all patients who receive 1 or more doses of CO-1686 will be 
included in the safety analyses. AEs, clinical laboratory information, vital 
signs, ECOG performance status and concomitant medications/procedures 
will be tabulated and summarized.  
Population PK  
Sparse blood sampling for POPPK analyses will be conducted in all patients 
treated with CO-1686. A specific POPPK data analysis plan will be developed 


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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. 
 


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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AAG 
alpha-1 acid glycoprotein 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC0−24 
area under the curve from time zero to 24 hours 
β-hCG 
β subunit of hCG gonadotropin 
BID 
twice daily 
BUN 
blood urea nitrogen 
C1D1 
Cycle 1 Day 1 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CO-1686 free base 
free base form of CO-1686 
CO-1686 HBr 
hydrobromide salt formulation CO-1686 
Cmax 
maximum concentration 
CNS 
central nervous system 
CR 
complete response  
CRO 
contract research organization  
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
CTCAE 
Common Terminology Criteria for Adverse Events (Version 4.03) 
CYP 
cytochrome P450 
DCR 
disease control rate 
DLQI 
Dermatology Life Quality Index  
DLT 
dose-limiting toxicity  
DNA 
deoxyribonucleic acid 
DR 
duration of response 
EC 
European Commission 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
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 


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EOT 
end-of-treatment 
EURTAC 
EURopean TArceva® (erlotinib) versus Chemotherapy study 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
FG 
fasting plasma or serum glucose 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GRAS 
generally regarded as safe 
HbA1c 
hemoglobin A1c 
HBr 
hydrobromide 
HIPAA 
Health Information Portability and Accountability Act  
HR 
hazard ratio 
ICH 
International Conference on Harmonization 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
INR 
international normalized ratio 
iPASS 
Iressa™ Pan-ASia Study 
IRB 
Institutional Review Board  
IRR 
Independent Radiology Review 
MedDRA 
Medical Dictionary for Regulatory Activities 
MET 
MET proto-oncogene 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
not evaluable 
NSAID 
nonsteroidal anti-inflammatory drug 
NSCLC 
non-small cell lung cancer 
OS 
overall survival 
ORR 
objective response rate 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PIK3CA 
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha 
PK 
pharmacokinetic(s) 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PO 
Orally 


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POPPK 
population pharmacokinetics 
PR 
partial response 
PRO 
patient-reported outcomes 
PT 
preferred term 
QD 
once daily 
QoL 
quality of life 
QTc 
QT interval corrected for heart rate 
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 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
T1/2 
elimination half-life 
T790M 
EGFR mutation in exon 20, gatekeeper mutation 
TID 
three times daily 
TKI 
tyrosine kinase inhibitor 
Tmax 
time to maximum concentration 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
WT 
wild-type 


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3 
INTRODUCTION 
3.1 
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.   
3.1.1 
Extension Phase 
The purpose of this protocol amendment (Amendment 5) 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, Amendment 5 (Appendix C) also introduces the availability of NAT2 testing for 
patients, an indirect indicator of the likelihood of developing hyperglycemia 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, it is imporatant 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. 
3.2 
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 
have been a result of molecular characterization of NSCLC and development of molecularly 


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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 NSCLC. 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.23 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.3,8,9,23 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.23  
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.24 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 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, CO-1686 was expected to  provide improved activity by inhibiting a 
key resistance pathway. Furthermore, as CO-1686 has only minimal activity against WT EGFR, 
patients receiving CO-1686 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. 
3.3 
Nonclinical Overview 
CO-1686 is a novel, potent, small molecule irreversible TKI that selectively targets mutant forms 
of the EGFR. Clovis Oncology, Inc. (Clovis), was  developing CO-1686 as a therapeutic agent to 
be administered orally (PO) to patients with mutant EGFR NSCLC. CO-1686 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.  
CO-1686 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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Pharmacology 
CO-1686 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 CO-1686 was 
evaluated against common and rare lung-cancer associated EGFR mutants. CO-1686 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 CO-1686 shows potent activity in the NCI-H1975 
(EGFRL858R/T790M) and primary LUM1868 (EGFRL858R/T790M) subcutaneous xenograft models.25 
In addition, the efficacy of CO-1686 was examined in an EGFRL858R/T790M transgenic model and 
compared with that of afatinib. Complete responses (CRs) were observed in all mice treated with 
CO-1686, with very limited activity in the afatinib group (Figure 3-1). 
Figure 3-1: CO-1686 Generates Complete Responses in L858R/T790M 
Transgenic Model 
 
Metabolism 
In liver microsomes CO-1686 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 CO-1686 metabolism, 
implying a low potential for ethnic sensitivity variability in humans. CO-1686 is a substrate and 
an inhibitor of P-glycoprotein (P-gp) and caution should be exercised when CO-1686 is 
co-administered with P-gp inhibitors and inducers (see Section 8.4 for further information). 
Caution should also be exercised in patients receiving PO CO-1686 and requiring concomitant 
medication with warfarin (Coumadin), nonsteroidal anti-inflammatory drugs (NSAIDs), or 
clopidogrel, as CO-1686 moderately inhibited CYP2C8, CYP2C9 and CYP2C19 activities 
in vitro. Please 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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Safety Pharmacology and Toxicology 
Safety pharmacology and toxicology studies were performed in rats and dogs with 
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 CO-1686 HBr 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 four tissues which was reversible and 
principally occurred in the high dose group. Only minor effects were observed with 
CO-1686 HBr on hematopoietic tissue.  
Primary indices of toxicity in the dog included dose-related clinical signs which included 
abnormal feces (liquid and/or non-formed feces), vomiting, and redness of gingival 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 CO-1686-related cardiac safety or neurobehavioral findings from the Good Laboratory 
Practices (GLP) repeat-dose toxicity studies. CO-1686 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.  
3.4 
Clinical Experience with CO-1686 
Five studies are currently ongoing in patients with advanced NSCLC (CO-1686-008, 
CO-1686-018, CO-1686-019, CO-1686-022, CO-1686-020).  
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. 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 
− 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, seemless phase 2/3 study 
evaluating the safety and efficacy of CO-1686 versus erlotinib in a first line setting in 
patients with advanced/metastatic NSCLC whose tumors have EGFR activating 
mutations  
− CO-1686-020 (TIGER-3) is a randomized study evaluating the safety and efficacy of 
CO-1686 versus single agent chemotherapy in previously treated patients with mutant 
EGFR NSCLC 
3.4.1 
Safety  
Please refer to the current version of Investigator’s Brochure for the most up-to-date safety 
information. 
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 4 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 4 June 2014. 
3.4.1.1 
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 4 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. 


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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 
SOC 
PT 
< 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; PT, preferred term; SAE, serious adverse event; SOC, system organ class. 


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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 the 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 QT interval corrected for heart rate (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.  
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 
SOC 
PT 
< 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: TEAE, treatment-emergent adverse event; BID, twice daily; FB, CO-1686 free base; HBr, CO-1686 hydrobromide; N, number of patients; PT, 
preferred term; SOC, system organ class.


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3.4.2 
Activity of CO-1686  
Please refer to the current version of Investigator’s Brochure for the most up-to-date efficacy 
information. 
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-positive 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-positive 
Patients 
 
Abbreviations: BID, twice daily; FB, CO-1686 free base; HBr, CO-1686 hydrobromide; 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-positive 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%) 
Data shown are for patients with measurable disease at baseline. 
Abbreviations: BID, twice daily; CR, complete response; FB, CO-1686 free base; HBr, CO-1686 hydrobromide; N, 
number of patients; PR, partial response; SD, stable disease; PD, progressive disease. 
 
In a recent interim analysis of patients receiving the therapeutically active doses of 500 mg BID 
and 625 mg BID, a response rate of 36% was achieved in a small subset (n = 11) of evaluable 
T790M-negative patients, with at least a Cycle 2 scan measurement (Soria 2014). These data 
demonstrate a signal of activity 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-positive cells falling out with the 
sensitivity limit of the assay.  
The data support the inclusion of T790M-negative patients in clinical studies, to characterize the 
signal further. 
3.4.3 
Pharmacokinetics of CO-1686 HBr 
Study CO-1686-016 
In healthy volunteers (study CO-1686-016), maximum concentration (Cmax), and area under the 
curve from time zero to 24 hours (AUC0–24) of CO-1686 increased with ascending single doses of 
CO-1686 HBr (50 mg to 1000 mg), with CO-1686 plasma levels increasing in a less than dose 
proportional manner above 125 mg.  
The single-dose PK of CO-1686 HBr was compared in the fasted and fed state, and it was 
concluded that a high-fat meal increased the plasma drug concentrations from 3-12 hours 
postdose with a mean increase of 172% at C12h (–22% to +400%) and a mean increase of 77% in 


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AUC0–24 (+10% to 146%) with no change in elimination half-life (T1/2); a slight mean increase of 
12% in Cmax was observed and a delayed time to Cmax (Tmax) was seen in a majority of subjects.  
Six healthy subjects were dosed, in the fed state, with 500 mg BID CO-1686 HBr for 4 days. 
PK profiles of CO-1686 following morning and evening dosings were similar, with low 
intra subject variability (Day 1 and Day 4 comparison). There was no accumulation of CO-1686. 
Study CO-1686-008 
In the patient study (CO-1686-008), PK data following CO-1686 HBr salt administration were 
available from a total of 44 patients (4 started at 500 mg BID, 10 switched from CO-1686 free 
base to 500 mg BID CO-1686 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 2 to 3.25 hrs. and T1/2 ranged from 1.7 – 4.7 hours. 
Following CO-1686 HBr administration, exposure (measured as Cmax and AUC0-24) increased 
dose-proportionally from 500 mg to 1000 mg BID (Figure 3-3). 
Figure 3-3: Individual CO-1686 AUC0-24 on Day 1 Following 500 mg to 1000 mg 
CO-1686 HBr BID 
5 0 0
7 5 0
1 0 0 0
0
1 2 5 0 0
2 5 0 0 0
3 7 5 0 0
5 0 0 0 0
6 2 5 0 0
8 0 0 0 0
1 2 0 0 0 0
H B r D o s e  v s  A U C
B ID  D o s e  (m g )
625
C O -1 6 8 6  A U C 0 -2 4 (n g .h /m L )
 
3.5 
Rationale for Study  
There are limited treatment options for mutant EGFR NSCLC patients who have failed treatment 
with first generation TKIs and have acquired resistance through the T790M mutation. Currently 
there are no targeted therapies for these patients, who are usually treated with cytotoxic 
chemotherapy that has limited efficacy, but 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 
both T790M-positive and T790M-negative populations, rociletinib may provide a tolerable and 
effective therapy for a patient population with few alternative treatment options. 


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In this study, the safety and efficacy of CO-1686 will be investigated in patients with mutant 
EGFR NSCLC who have progressed on their first single-agent EGFR-directed TKI and have a 
T790M-positive tumor (Cohort A).  
An additional secondary goal will be to determine the effectiveness of CO-1686 in patients who 
test negative with respect to the T790M mutation, given initial findings suggestive of a clinical 
benefit of CO-1686 in this group of patients (Cohort B). 
The therapeutically active doses of 625 mg BID and 500 mg BID will be investigated. 
Continuation of the ongoing Phase 2 program will obtain additional data at 500 mg BID to 
further describe the risk/benefit profile of CO-1686 across the therapeutic dose range. 


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4 
STUDY OBJECTIVES AND ENDPOINTS 
4.1 
Objectives 
4.1.1 
Primary Objective 
• To evaluate the antitumor efficacy of PO single-agent CO-1686, as measured by ORR, when 
administered to patients with EGFR-mutated, centrally confirmed T790M-positive and 
T790M-negative advanced NSCLC after tumor progression on 1 previous EGFR-directed 
TKI  
4.1.2 
Secondary Objectives 
• To assess clinical efficacy in patients with centrally confirmed T790M-positive NSCLC: 
DCR, DR, PFS, and OS following CO-1686 treatment 
• To assess quality of life (QoL) by patient-reported outcomes (PRO) following 
CO-1686 treatment 
• To evaluate the safety and tolerability of CO-1686 
• To determine the PK of CO-1686 using population PK (POPPK) methods and explore 
correlations between PK, exposure, response, and/or safety findings 
4.1.3 
Exploratory Objectives 
• To evaluate clinical benefit of continued CO-1686 treatment following disease progression 
• To evaluate concordance of mutant EGFR detection between tissue and plasma and assess 
CO-1686 mediated alterations in mutant EGFR levels over time using circulating tumor 
deoxyribonucleic acid (ctDNA) obtained from plasma 
• To explore tissue and blood-based biomarkers that may be predictive of response or primary 
resistance to CO-1686 and investigate mechanisms of acquired resistance in the tissue and 
blood of patients who experience clinical progression during treatment with CO-1686 
4.2 
Endpoints 
4.2.1 
Primary Endpoint 
• ORR according to RECIST Version 1.1.11 For Cohort A, ORR will undergo independent 
radiology review (IRR) and in Cohort B, scans will be assessed by IRR if needed as a 
supporting analysis. 
4.2.2 
Secondary Endpoints 
• DR, DCR and PFS according to RECIST Version 1.1 as determined by IRR  
• ORR, DR, DCR and PFS according to RECIST Version 1.1 as determined by investigator 
assessment 
• OS 


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• Change from baseline in PRO using the European Organization for Research and Treatment 
of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30), EORTC Quality of Life 
Questionnaire Lung Cancer module (EORTC QLQ-LC13), and the Dermatology Life 
Quality Index (DLQI)12,13 
• Treatment-emergent AEs, laboratory abnormalities and ECG abnormalities 
• Plasma PK parameters for CO-1686 based on sparse sampling 
4.2.3 
Exploratory Endpoints 
• Time-to-treatment failure  
• Extra-cranial PFS 
• Change from baseline in mutant EGFR levels in ctDNA obtained from plasma  
• Positive and negative percent agreement between blood and tissue results for T790M  
• Identify biomarkers associated with response or resistance to CO-1686 


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5 
STUDY DESIGN 
5.1 
Overall Study Design and Plan 
This is a Phase 2, single arm, open-label, dual cohort, multicenter study evaluating the safety and 
efficacy of CO-1686 administered PO BID to patients with previously-treated mutant EGFR 
NSCLC. 
Patients will be enrolled into 2 cohorts. Cohort A will enroll approximately 125 eligible patients 
who are centrally confirmed T790M-positive and will be treated at 625 mg BID. Cohort B will 
be a continuation of the study and will enroll up to approximately 100 eligible patients who will 
be either centrally confirmed T790M-positive or T790M-negative. All patients in Cohort B will 
be treated at a starting dose of 500 mg BID. The priority for study enrollment will be for all 
T790M-positive patients to be enrolled into Cohort A first. Once Cohort A is complete, eligible 
T790M-positive patients will then be enrolled into Cohort B. All eligible T790M-negative 
patients will be enrolled into Cohort B. 
All patients (for Cohort A and B) should have experienced disease progression while on 
treatment with the first single-agent EGFR-directed TKI (EGFR-TKI) therapy for 
advanced/metastatic NSCLC, and have had no intervening chemotherapy between EGFR-TKI 
and planned treatment with CO-1686. One line of chemotherapy prior to any EGFR-TKI 
treatment is permissible. The central laboratory will confirm that the patient’s tumor harbors or 
does not harbor the T790M mutation using biopsy material obtained from either primary or 
metastatic tumor tissue within 60 days prior to dosing with study drug but after progression on 
EGFR-directed therapy. 
5.1.1 
Screening Period 
Patients will undergo Screening assessments within 28 days before receiving the first dose of 
CO-1686. Patients will be monitored for AEs from the time the first dose of CO-1686 is 
administered through 28 days after the last dose. Study procedure-related AEs that occur after 
signing of the Informed Consent Form (ICF) and before administration of CO-1686 will also be 
collected. If a biopsy was performed within 60 days prior to Cycle 1 Day 1 (C1D1), and no 
intervening treatment was given, a repeat biopsy is not required if adequate tumor tissue can be 
provided to the sponsor during the Screening period.  
5.1.2 
Treatment Period 
CO-1686 will be administered to patients BID (see Section 7.3). Patients will take CO-1686 with 
a meal or within 30 minutes after a meal. Treatment with CO-1686 is continuous, except where 
delayed or reduced according to protocol-specified toxicity criteria (Section 7.4). Each 28-day 
period of treatment will represent 1 cycle, with dosing initiated on C1D1. No dose escalation 
beyond the starting dose is allowed in either cohort. The counting of all 28-day cycles should 
start from C1D1. 


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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 CO-1686. 
Serial blood sampling for longitudinal quantitative assessment of ctDNA will be conducted.  
Tumor scans will be acquired by the investigative site and evaluated locally for patient treatment 
decisions; however, copies of all tumor scans will be sent to a central radiological vendor. In 
Cohort A, scans will be assessed by IRR for the primary endpoint evaluation. In Cohort B, scans 
will be assessed by IRR if needed as a supporting analysis. Protocol-specified treatment will 
continue until there is RECIST version 1.1 or clinical tumor progression or unacceptable toxicity 
as assessed by the investigator. Following disease progression on CO-1686 and discontinuation 
of protocol-specified treatment, patients who provide additional consent will undergo tumor 
biopsy before subsequent-line therapy is initiated. After discontinuation of protocol-specified 
treatment, subsequent anticancer therapy will be recorded. 
Patients may opt to continue to receive treatment with CO-1686 following radiographic 
progression, as outlined in the National Comprehensive Cancer Network (NCCN) guidelines for 
treatment of NSCLC with EGFR-TKIs,14 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 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 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.  
5.1.3 
End-of-treatment  
All patients should return to the clinic for end-of-treatment assessments 28 (± 7) days after the 
last dose of PO CO-1686 has been administered.  
The trial will be completed when all enrolled patients have discontinued treatment in this 
protocol and completed the End-of-Treatment follow-up Visit. 
5.1.4 
Two Monthly Follow-up 
After the End-of-Treatment Visit, all patients will be followed at approximately 2 monthly 
intervals to monitor disease progression (if patient discontinues treatment before progression), 
survival status, and subsequent NSCLC cancer therapy until death or sponsor decision, 
whichever comes first. After discontinuation of protocol-specified treatment, subsequent 
anticancer therapy use will be recorded. 


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5.1.5 
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, it is imporatant that a 
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 
 


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6 
STUDY POPULATION 
6.1 
Number of Patients and Sites 
The total enrollment planned for this study is approximately 225 patients. Patients will be 
enrolled into 2 cohorts: 
Cohort A: Approximately 125 patients with centrally confirmed T790M-positive NSCLC will 
be enrolled. These patients will be treated at a dose of 625 mg BID. 
Cohort B: Approximately 100 patients will be enrolled in order to include approximately 
40 response evaluable, centrally confirmed T790M-negative patients. All Cohort B patients will 
be treated at a dose of 500 mg BID. 
The priority for study inclusion will be for all T790M-positive patients to be enrolled into 
Cohort A first. Once this cohort is complete, eligible T790M-positive patients will then be 
enrolled into Cohort B. All eligible T790M-negative patients will be enrolled into Cohort B.  
There will be approximately 90 investigative sites in the United States (US), Europe, Asia, and 
Australia. 
6.2 
Inclusion Criteria 
All patients must meet all of the following inclusion criteria (both Cohort A and B, except where 
otherwise specified): 
1. Histologically or cytologically confirmed metastatic or unresectable locally advanced, 
NSCLC 
2. Documented evidence of a tumor with 1 or more EGFR mutations excluding exon 
20 insertion 
• Disease progression confirmed by radiologic assessment while receiving treatment 
with the first single-agent EGFR-TKI (eg, erlotinib, gefitinib, afatinib, or 
dacomitinib) 
o EGFR-TKI treatment discontinued ≤ 30 days prior to planned initiation of 
CO-1686 (the washout period for an EGFR inhibitor is a minimum of 3 days) 
o No intervening treatment between cessation of single-agent EGFR-TKI and 
planned initiation of CO-1686 
o Previous treatment with ≤ 1 prior chemotherapy (excluding prior neo-adjuvant or 
adjuvant chemotherapy or chemoradiotherapy with curative intent)  
o Any toxicity related to prior EGFR inhibitor treatment must have resolved to 
Grade 1 or less 
• Central laboratory confirmation of the presence of the T790M mutation in tumor 
tissue in Cohort A and the presence or absence of the T790M mutation in tumor 


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tissue in Cohort B. Centrally indeterminate, unknown or invalid specimens are not 
acceptable. Biopsy material obtained from either primary or metastatic tumor tissue 
must have been obtained (and sent to the central laboratory) within 60 days prior to 
dosing study drug but following disease progression on the first EGFR-TKI.  
3. Measureable disease according to RECIST Version 1.1 
4. Life expectancy of at least 3 months 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 
6. Age ≥ 18 years (in certain territories, the minimum age requirement may be higher eg, age 
≥ 20 years in Japan and Taiwan) 
7. Adequate hematological and biological function, confirmed by the following laboratory 
values: 
• Bone Marrow Function 
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
- Platelets > 100.0 × 109/L  
- Hemoglobin ≥ 9 g/dL (or 5.6 mmol/L) 
• Hepatic Function 
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤ 3 × upper limit of normal (ULN); if liver metastases, ≤ 5 × ULN  
- Bilirubin ≤ 2 × ULN 
• Renal Function  
- Serum creatinine ≤ 1.5 × ULN 
• Electrolytes 
- 
Potassium and magnesium within normal range. Patients may receive 
supplements to meet this requirement 
8. Written consent on an Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)-approved ICF prior to any study-specific evaluation 
6.3 
Exclusion Criteria 
Any of the following criteria will exclude patients from study participation (both Cohort A 
and B, except where otherwise specified): 
1. Documented evidence of an exon 20 insertion activating mutation in the EGFR gene 


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2. Active second malignancy, i.e. patient known to have potentially fatal cancer present for 
which he/she 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 
3. Known pre-existing interstitial lung disease 
4. Cohort A only: 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 4 weeks prior to the start of study treatment). Cohort B only: 
Patients with CNS metastases or leptomeningeal carcinomatosis are excluded. 
5. Treatment with prohibited medications (eg, concurrent anticancer therapy including other 
chemotherapy, radiation, hormonal treatment [except corticosteroids and megesterol acetate], 
or immunotherapy) ≤ 14 days prior to treatment with CO-1686 
6. Patients who are currently receiving treatment with any medications that have the potential to 
prolong the QT interval and the treatment cannot be either discontinued or switched to a 
different medication before starting CO-1686 
• see http://crediblemeds.org/ for a list of QT-prolonging medications (includes all 
medication under categories of Known, Possible and Conditional risk of Torsades de 
Pointes) 
7. Prior treatment with CO-1686, or other drugs that target T790M-positive mutant EGFR with 
sparing of WT-EGFR eg, AZD9291, HM61713, TAS-121 
8. Any of the following cardiac abnormalities or history: 
• Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia’s 
method (QTCF) > 450 msec 
• Inability to measure QT interval on ECG 
• Personal or family history of long QT syndrome 
• Implantable pacemaker or implantable cardioverter defibrillator 
• Resting bradycardia < 55 beats/min 
9. Nonstudy-related surgical procedures ≤ 7 days prior to administration of CO-1686. 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 12 weeks after the last dose of CO-1686 


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12. Presence of any serious or unstable concomitant systemic disorder incompatible with the 
clinical study (eg, substance abuse, uncontrolled intercurrent illness including active 
infection, arterial thrombosis, and symptomatic pulmonary embolism) 
13. Any other reason the investigator considers the patient should not participate in the study 
6.4 
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 test result within 3 days prior to 
administration of the first dose of CO-1686. If the serum pregnancy results are not available on 
C1D1, a urine pregnancy test can be performed on C1D1 to confirm that the patient is not 
pregnant prior to 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. 
Patients of reproductive potential (males and females) must practice double-barrier methods of 
contraception during treatment and for 12 weeks following the last dose of CO-1686. Adequate 
contraception is defined as double-barrier protection (i.e., condom plus spermicide in 
combination with either a diaphragm, cervical/vault cap, or intrauterine device). Birth control 
pills, birth control patches and/or injections of hormones to prevent pregnancy are not considered 
an adequate method of preventing pregnancy, and double-barrier protection is required while on 
study and for 12 weeks after last dose.  
Patients will be instructed to notify the investigator if pregnancy is discovered either during or 
within 12 weeks of completing treatment with CO-1686. This also applies to male patients 
whose partners become pregnant while the patient is on study or within the 12-week period after 
last dose of study drug. 
6.5 
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 Investigational Product  
CO-1686 is provided as yellow, film-coated tablets for PO administration in 2 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: 125 mg strength is a round tablet and 250 mg 
strength tablet 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. 
CO-1686 tablets should be stored in their original packaging at 15-30 °C (59-86 °F). 
Child-resistant bottles containing CO-1686 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 gross visual defects such as chips. Defective 
tablets should be returned to the study site. 
7.2 
Method of Assigning Patients to Treatment Groups 
All patients enrolled in the study will receive PO CO-1686. 
7.3 
Preparation and Administration of Protocol-specified Treatment 
CO-1686 will be administered at a dose of 625 mg BID (Cohort A) or 500 mg BID (Cohort B). 
Patients should take CO-1686 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.  
If a patient misses a dose (i.e., does not take it within 6 hours of the scheduled time), he or she 
should resume taking CO-1686 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 PO 
CO-1686 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 on a patient diary, and will be instructed to bring their CO-1686 tablets and patient diary to 
the next scheduled visit for reconciliation by site personnel. 
7.4 
Dose Modifications of Protocol-specified Treatment 
No dose escalation beyond the starting dose is allowed in either cohort. 
Dose reduction steps are allowed for each patient, with the overall number of dose reduction 
steps at the investigator’s discretion. Dose reduction should be in increments of 125 mg BID 


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with up to 2 dose reduction steps permitted in both cohorts. Any need for further dose reduction, 
or adjustment from a twice to 3 times daily (TID) dosing regimen should be discussed with the 
sponsor before implementing. If a TID regimen is used, the total daily dose should not exceed 
1,125 mg (i.e. not more than 375 mg TID). 
For Grade 3 or 4 hematologic and non-hematologic toxicities (except for nausea/vomiting, 
alopecia, QTc prolongation and hyperglycemia), the dose should be initially reduced by 
125 mg BID (to 500 mg BID, if the starting dose was 625 mg BID; or to 375 mg BID, if the 
starting dose was 500 mg BID). Re-escalation of dose after resolution of AEs must be discussed 
with, and approved by the sponsor. 
Once the dose has been reduced, treatment continues at that dose level until the next visit; no 
dose escalation is possible between visits. If a patient continues to experience toxicity, or if 
dosing with CO-1686 is interrupted for > 14 consecutive days due to toxicity, treatment should 
be discontinued unless otherwise agreed between the investigator and the sponsor before 
reintroduction of study drug. 
Management of prolonged QTcF 
ECGs will be measured throughout the study as described in the protocol. Readings for QTcF 
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 CO-1686 treatment, if necessary using 
supplementation. If QTC prolongation of National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE)15 version 4.03 Grade 3 are observed, CO-1686 will be 
held until the event has improved to Grade 1. CO-1686 can then be re-started at a reduced dose 
upon approval by sponsor. If CTCAE Grade 3 or above QTC prolongation recurs, then CO-1686 
will be discontinued unless agreed with the sponsor that additional dose reduction can be 
evaluated. If QTC prolongation changes of CTCAE Grade 4 are observed at any time, CO-1686 
will be discontinued permanently. 
Management of hyperglycemia 
CO-1686 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 CO-1686 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 and 
vomiting, and 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 CO-1686-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 


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used most frequently in CO-1686 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 
CO-1686 therapy is initiated may prevent the development of CO-1686-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 the 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 the 
maximum approved dose of the anti-hyperglycemic agent should not be exceeded. 
1. Additional monitoring outside of per protocol schedule (Table 9-1) is not needed if 
fasting glucose is less than 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 once daily (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 a 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 testing before their next scheduled clinic visit, they 
should call their health care professional (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 (See Figure 7-1). 
 
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 the treating physician. 
 


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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 CO-1686 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, 
CO-1686 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 toxicity associated with metformin use, the extended release form and taking 
medication at bedtime are recommended to improve tolerability.26 Additional recommendations 
to avoid gastrointestinal 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, 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. 
End-of-treatment  
When CO-1686 is discontinued, need and use of anti-diabetic medications should be reassessed 
and patient treated appropriately. 


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Figure 7-1: Guidelines for Management of Hyperglycemia 
 
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. 
 
7.5 
Accountability of Protocol-specified Treatment 
Study personnel will maintain accurate records of CO-1686 shipments/receipts, administration, 
and drug reconciliation. The study site is responsible for the return or destruction of CO-1686 as 
required. A drug management system will manage CO-1686 inventory at all sites. The system 
will be required to manage study treatment requests and shipments. 
Any CO-1686 accidentally or deliberately destroyed must be accounted for. All bottles must be 
accounted for prior to their destruction at the study center. Unused bottles 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 CO-1686 
shipped, destroyed, and returned must be reconciled.  
Asymptomatic
Symptoms
FG > 250
FG < 125
No action
Test Fasting Glucose (FG) 
b
Hold rociletinib, 
manage
hypeglycemia, 
then resume at 
reduced dose
125 ≤ FG ≤ 160
160 < FG ≤ 250c
x2
Finger stick or 
urine dipstick
at home 
QD for 2 weeks
Startmetformin/ 
anti-hyperglycemic 
agent
FG ≤ 160; or 
random≤ 200; 
or urine 
negative
FG > 160 x2; or 
random > 200 x2;
or urine positive 
at any timec
Instruct 
patient to 
call HCP


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7.6 
Blinding/Masking of Treatment 
This is an open-label study; the investigational product will not be blinded or masked. All 
patients enrolled will receive PO CO-1686. 
7.7 
Treatment Compliance 
Documentation of dosing will be recorded in a study specific patient diary 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. Dosing noncompliance is defined as a patient missing > 14 days 
of medication in a 28-day visit window for 2 consecutive visits. Patients meeting noncompliance 
criteria will be required to discontinue study treatment. 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 PO CO-1686 taken at home in the patient diary and to bring the patient diary and 
all unused tablets with them to scheduled clinic visits. A compliance check and tablet count will 
be performed by study personnel. Study site personnel will record compliance information on the 
eCRF and retain the patient diary in the patient’s medical record.  


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8 
PRIOR AND CONCOMITANT THERAPIES 
Medications known to produce QT prolongation should be avoided during the study. 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 
CO-1686 therapy, then additional ECGs should be performed 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 and be documented accordingly. 
All procedures performed and medications used during the study must be documented on the 
eCRF.  
8.1 
Anticancer or Experimental Therapy 
No other anti-cancer therapies (including chemotherapy, 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 per RECIST 
Version 1.1. Treatment should be held 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 5.1.2 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  
In vitro studies suggested the potential involvement of CYP2C8 in CO-1686 metabolism and 
thus, clinically, there is potential for CO-1686 plasma concentrations to be increased in the 
presence of co-administered potent inhibitors of CYP2C8. CYP2D6 appears to play a minor role, 
but its involvement in CO-1686 metabolism cannot be fully ruled out. Therefore, caution should 
be exercised with strong inhibitors of CYP2C8 and CYP2D6. For example, CYP2C8 inhibitors 
such as gemfibrozil, trimethoprim, glitazones, montelukast, and quercetin and 
CYP2D6 inhibitors such as bupropion, fluoxetine, paroxetine, and quinidine should be avoided. 
Selection of an alternative concomitant medication with no or minimal enzyme inhibition 
potential is recommended. 


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Inducers of CYP2C8 and CYP2D6 have the potential to decrease CO-1686 exposure. Therefore, 
caution should be exercised with rifampin, an inducer of CYP2C8. No inducers of CYP2D6 have 
been identified.  
With regards to strong inhibitors or inducers of CYP2C8 and CYP2D6, selection of an 
alternative concomitant medication with no or minimal enzyme inhibition potential is 
recommended. 
Caution should be exercised in patients receiving PO CO-1686 and requiring concomitant 
medication with warfarin (Coumadin), NSAIDs, or clopidogrel, as CO-1686 moderately 
inhibited CYP2C8, CYP2C9 and CYP2C19 activities in vitro.  
8.4 
P-gp Substrates, Inhibitors and Inducers 
Because CO-1686 is a P-gp inhibitor in vitro, caution should be exercised in patients receiving 
PO CO-1686 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. 
CO-1686 is a P-gp substrate and thus, P-gp inhibitors have the potential to increase 
CO-1686 exposure. As such, caution should be exercised in patients receiving CO-1686 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 CO-1686 exposure. Caution should be 
exercised in patients receiving CO-1686 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 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.  
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. 
Because CO-1686 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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9 
STUDY PROCEDURES 
Table 9-1 summarizes the procedures and assessments to be performed for all patients. All 
procedures and assessments will be performed for patients in both Cohorts A and B of the study, 
except where otherwise specified. 
All procedures and assessments are to be completed at the scheduled time point and cycles 
should be counted forward from C1D1 of PO CO-1686 treatment unless otherwise indicated. 


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Table 9-1: 
Schedule of Assessments 
 
Before Any 
Study 
Assessments 
Screening 
Treatment Period 
(Daily Dosing)a 
Post-treatment 
Procedureb 
 
Day −28 
to Day 
−1 
Cycle 1 
Day 1 
(C1D1) 
Cycle 1 
Day 4 ± 
1 Day 
Cycle 1 
Day 8 ± 
1 Day 
Cycle 1 
Day 15 
± 1 Day 
Cycle 2 
Day 1 
(28 ± 3 
Days After 
C1D1) 
Cycle 2 
Day 15 
± 1 Day 
Cycle 3 
+ 
Day 1 
Every 
28 ± 3 
Days 
End-of-treatment 
(EOT) 28 ± 7 
Days After Last 
Dose 
Follow-up 
 
Every 8 ± 
1 Weeks 
After 
EOT 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical/oncology history 
 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
including weight  
 
X 
(including 
height) 
X 
 
 
 
X 
 
X 
X 
 
ECOG performance status 
 
X 
X 
 
 
 
X 
 
X 
X 
 
Vital signsc  
 
X  
X 
 
 
 
X 
 
X 
X 
 
Prior/concomitant 
medications and 
procedures including 
prior treatment for 
NSCLC 
 
X 
X 
 
 
 
X 
 
X 
X 
 
Contraceptive counselingd 
 
X 
 
 
 
 
 
 
 
X 
 
Serum pregnancy teste 
 
X 
 
 
 
 
 
 
 
X 
 
Hematology, including 
reticulocytesf 
 
X 
X 
 
 
 
X 
 
X 
X 
 
Fasting serum chemistryg 
 
X 
X 
 
 
 
X 
 
X 
X 
 
Fasting glucose 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysish 
 
X 
 
 
 
 
 
 
 
 
 
Tumor assessments and 
scans, including brain 
imaging at Screeningi 
 
X 
 
 
 
 
 
 
X (every 
8 ±1 
weeks 
from 
C3D1, 
etc ) 
X 
X 
 


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Table 9-1: 
Schedule of Assessments (Cont.) 
 
Before Any 
Study 
Assessments 
Screening 
Treatment Period 
(Daily Dosing)a 
Post-treatment 
Procedureb 
 
Day −28 
to Day 
−1 
Cycle 1 
Day 1 
(C1D1) 
Cycle 1 
Day 4 ± 
1 Day 
Cycle 1 
Day 8 ± 
1 Day 
Cycle 1 
Day 15 
± 1 Day 
Cycle 2 
Day 1 
(28 ± 3 
Days After 
C1D1) 
Cycle 2 
Day 15 
± 1 Day 
Cycle 3 
+ 
Day 1 
Every 
28 ± 3 
Days 
End-of-treatment 
(EOT) 28 ± 7 
Days After Last 
Dose 
Follow-up 
 
Every 8 ± 
1 Weeks 
After 
EOT 
Tumor/metastasis biopsy 
for T790M assessment at 
central laboratoryj 
 
X; up to 
60 days 
prior to 
C1D1  
 
 
 
 
 
 
 
X (optional 
consent required) 
 
Blood for 
biomarker/EGFR 
mutational testing and 
exploratory researchk 
 
X; up to 
60 days 
prior to 
C1D1 
X 
 
 
 
X 
 
X 
X 
 
Blood for CYP evaluation 
(optional consent 
required)l 
 
 
X 
 
 
 
 
 
 
 
 
Adverse eventsm 
 
X 
X 
 
 
X 
X 
 
X 
X 
 
CO-1686 
dispensing/administration 
 
 
X 
 
 
 
X 
 
X 
 
 
Patient diaryn  
 
 
 
 
 
 
X 
 
X 
X 
 
Triplicate ECG 
assessmento 
 
X 
X 
 
 
X 
X 
 
X 
X 
 
Blood for sparse PK 
sampling and AAG serum 
levels  
(Central Lab) 
 
 
 
 
 
 
X 
(Cycle 2 
to 7 
inclusive 
only) 
 
X  
(Cycle 2 
to 7 
inclusive 
only) 
 
 
Quality of life  
questionnairesp 
 
X 
X 
 
 
 
 
 
X (Every 8 
±1 weeks 
from C3D1,
etc; Every 
12 ±1 
weeks from 
C10D1, etc)
X 
 


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Table 9-1: 
Schedule of Assessments (Cont.) 
 
Before Any 
Study 
Assessments 
Screening 
Treatment Period 
(Daily Dosing)a 
Post-treatment 
Procedureb 
 
Day −28 
to Day 
−1 
Cycle 1 
Day 1 
(C1D1) 
Cycle 1 
Day 4 ± 
1 Day 
Cycle 1 
Day 8 ± 
1 Day 
Cycle 1 
Day 15 
± 1 Day 
Cycle 2 
Day 1 
(28 ± 3 
Days After 
C1D1) 
Cycle 2 
Day 15 
± 1 Day 
Cycle 3 
+ 
Day 1 
Every 
28 ± 3 
Days 
End-of-treatment 
(EOT) 28 ± 7 
Days After Last 
Dose 
Follow-up 
 
Every 8 ± 
1 Weeks 
After 
EOT 
Survival status 
 
 
 
 
 
 
 
 
 
X 
X 
Subsequent therapies for 
NSCLC 
 
 
 
 
 
 
 
 
 
X 
X 
AAG = alpha-1 acid glycoprotein; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST – aspartate aminotransferase; β-hCG = β subunit of hCG 
gonadotropin; BUN = blood urea nitrogen; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth 
factor receptor; EORTC QLQ-C30=European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire, Core 30; EORTC QLQ LC13 = European 
Organization for the Research and Treatment of Cancer Quality of Life Questionnaire, Lung Cancer 13; HbA1c = hemoglobin A1c; MRI = magnetic resonance imaging; PET = 
positron emission tomography; RECIST = Response Evaluation Criteria in Solid Tumors; WBC = white blood cells. 
a 
= 
 
CO-1686 will be administered BID at 625 mg BID (Cohort A) or 500 mg BID (Cohort B), with a meal or within 30 minutes after a meal. 
b 
= 
 
Unless specified, procedure is completed at the scheduled time point and is synchronized with administration day of CO-1686. 
c 
= 
 
Vital signs (after at least 5 min rest) taken predose on C1D1, and without reference to dose at every subsequent visit.  
d 
= 
 
Patients are to continue using effective contraception for 12 weeks after last dose of CO-1686 and report any pregnancies during this period. 
e 
= 
 
Serum ß-hCG (local labs) from women of childbearing potential within 3 days prior to C1D1. If the serum pregnancy test results are not available on C1D1, a urine 
pregnancy test can be performed on C1D1 to confirm that the patient is not pregnant prior to dosing. 
f 
= 
 
Central Lab: Includes hemoglobin, hematocrit, WBC and differential (with ANC), platelet count, and reticulocyte count ≤ 14 days prior to the first day of dosing. 
Blood will be sent for analysis at a central lab, but must also be analyzed by a local lab to inform treatment decisions. Local hematology results must be reviewed by 
the investigator prior to start of CO-1686 administration. Additional tests may be performed at the investigator’s discretion. 
g 
= 
 
Central Lab: Includes total protein, albumin, creatinine, BUN or urea, total bilirubin, alkaline phosphatase, ALT, AST, glucose, sodium, potassium, magnesium, 
chloride, calcium, phosphorus, total cholesterol, and HbA1c ≤ 28 days prior to first day of dosing. Samples analyzed by a central lab, but may also be performed 
locally to inform treatment decisions. Glucose must be measured following an 8 hour fast (no food or liquid other than water), and ‘fasting glucose only’ visits on 
C1D4, C1D8, C1D15, C2D15 will be performed at local labs only (not sent to central lab). HbA1c will be measured every other cycle (Day 1 of Cycle 3, 5, 7 etc). 
h 
= 
 
Includes dipstick for protein, glucose, blood, pH, and ketones. If findings are abnormal, a microscopic evaluation will be performed to assess abnormal findings. 


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Table 9-1: 
Schedule of Assessments (Cont.) 
 
Before Any 
Study 
Assessments 
Screening 
Treatment Period 
(Daily Dosing)a 
Post-treatment 
Procedureb 
 
Day −28 
to Day 
−1 
Cycle 1 
Day 1 
(C1D1) 
Cycle 1 
Day 4 ± 
1 Day 
Cycle 1 
Day 8 ± 
1 Day 
Cycle 1 
Day 15 
± 1 Day 
Cycle 2 
Day 1 
(28 ± 3 
Days After 
C1D1) 
Cycle 2 
Day 15 
± 1 Day 
Cycle 3 
+ 
Day 1 
Every 
28 ± 3 
Days 
End-of-treatment 
(EOT) 28 ± 7 
Days After Last 
Dose 
Follow-up 
 
Every 8 ± 
1 Weeks 
After 
EOT 
i 
= 
 
Tumor scans obtained within 28 days prior to C1D1, may be used as the baseline scans. Scans include the chest and abdomen (preferably CT scans) using the same 
methods throughout the study. Other studies (MRI, X-ray) performed if required. Pelvic imaging should be performed if clinically indicated eg, prior or existing site 
of metastasis or symptomatic. Brain imaging (CT/MRI) is required at baseline. For Cohort A only, patients with brain lesions at baseline will require repeat brain 
imaging as part of the follow-up tumor assessments (patients with brain lesions at Screening are not eligible for Cohort B). Tumor scans will be performed during 
Screening and every 8 ± 1 weeks thereafter (Day 1 of Cycles 3, 5, 7 ± 1 week etc), until tumor progression, and at the EOT Visit (scans do not need to be repeated at 
EOT if < 2 weeks since last scan or patient had disease progression on study. An MRI may be used in place of a CT at EOT if required per local authorities. For 
patients with clinical progression, radiographic assessment should be performed to document evidence of radiographic progression. If a patient discontinues 
treatment before progression, then scans should continue until progression according to the protocol schedule. Exceptions to this requirement may be acceptable 
based on local institutional or regulatory requests and must be approved in advance by the sponsor. Patients who continue treatment with CO-1686 post-progression 
should continue scans every 8 ± 1 weeks until they discontinue treatment. Scans will be evaluated locally for patient treatment, with copies sent to a central 
radiological lab for independent evaluation (Cohort A) or for storage for later evaluation (Cohort B). 
j 
= 
 
Central Lab: Biopsy tissue must be obtained within 60 days prior to C1D1 and following progression on the most recent therapy (extension of the 60-day window 
may only be allowed on a case by case basis, with sponsor approval). T790M assessment will be performed by a central lab to determine patient eligibility. At 
progression and/or EOT with CO-1686, an optional tumor biopsy will be performed with additional consent. All tissue processed locally as FFPE tissue.  
k 
= 
 
Central Lab: Blood sampling for biomarker/EGFR mutational testing and exploratory research will be collected at Screening (prior to biopsy, or at least 2 days 
AFTER the biopsy was performed); pre-dose on C1D1, then at Day 1 of every subsequent cycle (every 28 ± 3 day intervals), and at the EOT Visit. 
l 
= 
 
Central Lab: Blood for CYP evaluation to be collected pre-dose on C1D1 for patients who have signed optional consent 
m 
= 
 
Patients will be monitored for AEs from the time the first dose of CO-1686 is administered through 28 days after the last dose. Study procedure-related AEs that 
occur after signing of the ICF and before administration of CO-1686 will also be collected.  
n 
= 
 
Patient diaries should be collected and reviewed for compliance. 
o 
= 
 
Taken in triplicate (> 2 min apart) anytime during Screening, pre-dose on C1D1, then at Day 1 of every subsequent cycle (every 28 ± 3 day intervals), C1D15, and 
at EOT, any time after treatment is discontinued 
p 
= 
 
QoL Questionnaires (EORTC QLQ-C30, EORTC QLQ-L13, and the DLQI) will be collected at Screening, pre-dose on C1D1, then every 8 ± 1 weeks for the first 
6 months (Day 1 of Cycles 3, 5, 7 ± 1 week inclusive). After Cycle 7, questionnaires will be collected every 12 ± 1 weeks (Day 1 of Cycle 10, 13, 16 ± 1 week etc) 
and at EOT. 


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9.1 
Screening Period  
Following written informed consent, and unless otherwise specified, the following assessments 
should be performed during the 28-day period prior to the first dose (C1D1) of PO CO-1686 for 
Cohorts A and B, unless otherwise specified. If a biopsy was performed within 60 days prior to 
C1D1, and no intervening treatment was given, a repeat biopsy is not required if adequate tumor 
tissue can be provided to the sponsor during the Screening period.  
Assessments performed prior to patient signing informed consent are acceptable only if 
confirmed to have been standard of care. 
• 
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 
• 
Documented evidence of a tumor with an EGFR mutation known to be associated with 
CO-1686 drug sensitivity (exon 19 deletion, L858R, G719X, L861Q, and S768I) and 
documentation of the presence of the T790M mutation in EGFR for Cohort A and the 
presence or absence of the T790M mutation in EGFR for Cohort B determined by NSCLC 
tumor tissue by the central laboratory (centrally indeterminate, unknown or invalid 
specimens are not acceptable; results can be documented > 28 days from C1D1 as biopsy 
can have occurred within 60 days prior to C1D1) 
- Biopsy material obtained from either primary or metastatic tumor tissue must have been 
obtained (and sent to the central laboratory) within 60 days prior to dosing study drug 
and following disease progression on the first EGFR-TKI. Extension of the 60-day 
window may only allowed on a case by case basis with sponsor approval. 
- Biopsy of primary or metastatic lesions to provide formalin-fixed paraffin-embedded 
(FFPE) tumor tissue for EGFR mutational testing and companion diagnostic kit 
development. To ensure adequate viable tumor tissue is obtained, image-guided biopsies 
should be achieved with 18- to 20-gauge cutting needles to ideally 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 a biopsy was performed within 60 days prior to C1D1, and no intervening treatment 
was given, a repeat biopsy is not required if adequate tumor tissue can be provided to 
the sponsor during the Screening period 
• 
Physical examination by body system, height, and weight 
• 
ECOG performance status 
• 
Vital signs (blood pressure, pulse, and temperature) 
• 
Prior and concomitant medications and procedures (including prior treatment for NSCLC) 
• 
Contraceptive counseling 
• 
Serum pregnancy test (by local laboratory) within 3 days prior to the first day of dosing for 
women of childbearing potential. If the serum pregnancy test results are not available on 


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C1D1, a urine pregnancy test can be performed on C1D1 to confirm that the patient is not 
pregnant prior to dosing. Both values should be entered in the eCRF. 
• 
Hematology (hemoglobin, hematocrit, WBC and differential [with ANC], platelet count, and 
reticulocyte count) ≤ 14 days prior to the first day of dosing 
- Fasting serum chemistry (total protein, albumin, creatinine, blood urea nitrogen [BUN] 
or urea, total bilirubin, alkaline phosphatase, ALT, AST, glucose, sodium, potassium, 
magnesium, chloride, calcium, phosphorus, total cholesterol, and hemoglobin A1c 
[HbA1c])  
• 
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. 
• Tumor assessments of the chest and abdomen. Pelvic imaging should be performed if 
clinically indicated eg, prior or existing site of metastasis or symptomatic. Assessments 
should consist of clinical examination and appropriate imaging techniques (preferably 
computed tomography [CT] scans with appropriate slice thickness per RECIST Version 1.1); 
other studies (magnetic resonance imaging [MRI] and X-ray) may be performed if required. 
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.  
• 
Blood sampling for biomarker/EGFR mutational testing and exploratory research that may 
lead to development of a plasma-based EGFR test, or that may be used for the development 
of a plasma-based EGFR test. Matched blood sampling (up to 25 mL at baseline and time of 
progression and up to 12 mL the beginning of every cycle) should be collected prior to the 
biopsy procedure, if possible. If blood sample is not collected before the biopsy, allow at 
least a 2-day recovery period after the biopsy before blood collection for biomarker testing. 
Detailed sample handling instructions are provided in the Laboratory Manual.  
• 
AE monitoring (includes study procedure-related AEs that occur after signing of the ICF and 
before administration of CO-1686) 
• 
12-lead ECG (in triplicate, 10-sec tracings > 2 min apart) 
• 
QoL questionnaires (EORTC QLQ-C30, EORTC QLQ-LC13, and the DLQI) 
9.2 
Treatment Period  
Before enrolling a patient, all eligibility criteria must be satisfied.  
Patients will take CO-1686 625 mg BID (Cohort A) or 500 mg BID (Cohort B), as directed. PO 
CO-1686 should be taken with 8 oz (240 mL) of water and with a meal or within 30 minutes 
after a meal. Patients will record the dose and timing of administration of PO CO-1686 in their 
daily dosing patient diary.  
Unless otherwise specified, all patients in Cohorts A and B will undergo the following 
procedures and assessments. All procedures and assessments are to be completed at the 


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scheduled time point and the timing of all scans should be determined based on the date of C1D1 
of PO CO-1686 treatment. 
9.2.1 
Cycle 1 Day 1 (C1D1)  
Patients will be required to take their first dose at the clinic with 8 oz (240 mL) of water and with 
a meal or within 30 minutes after a meal.  
To be performed before dosing:  
• 
Physical examination 
• 
Weight 
• 
ECOG performance status 
• 
Vital signs (blood pressure, pulse, and temperature) 
• 
Concomitant medications and procedures 
• 
Fasting serum chemistry (including fasting glucose) 
• 
Hematology (including reticulocyte count) 
• 
Blood sampling for biomarker/EGFR mutational testing and exploratory research  
• 
Blood sampling for CYP testing (requires optional consent) 
• 
AE monitoring 
• 
CO-1686 tablets will be dispensed to the patient; patient diary will be provided to the patient 
• 
12-lead ECG (in triplicate, 10-sec tracings > 2 min apart) 5-10 minutes prior to dosing  
• 
QoL Questionnaires (EORTC QLQ-C30, EORTC QLQ-LC13, and the DLQI) 
To be performed after dosing: 
• 
AE assessment 
• 
Concomitant medications and procedures 
9.2.2 
Cycle 1 Day 4 (± 1 Day) 
The following procedures will be performed at C1D4 (± 1 day): 
• 
Fasting glucose (local laboratory) 
9.2.3 
Cycle 1 Day 8 (± 1 Day) 
The following procedures will be performed at C1D8 (± 1 day):  
• 
Fasting glucose (local laboratory) 


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9.2.4 
Cycle 1 Day 15 (± 1 Day) 
The following procedures will be performed at C1D15 (± 1 day): 
• 
Fasting glucose (local laboratory) 
• 
12-lead ECG (in triplicate, 10-sec tracings > 2 min apart) 
• 
AE assessment 
9.2.5 
Cycle 2 Day 15 (± 1 Day)  
• 
Fasting glucose (local laboratory) 
9.2.6 
Cycle 2 (Day 1, Occurring 28 ± 3 Days After C1D1) and Cycle 3+ (Day 1, 
Every 28 ± 3 Days Thereafter, Counting from C1D1) 
The following procedures will be performed at 28 ± 3 day intervals: 
• 
Physical examination 
• 
Weight 
• 
ECOG performance status 
• 
Vital signs (blood pressure, pulse, and temperature) 
• 
12-lead ECG (in triplicate, 10-sec tracings > 2 min apart) 
• 
Fasting serum chemistry (including fasting glucose). HbA1c will be measured every other 
cycle (Day 1 of Cycle 3, 5, 7 etc). 
• 
Hematology (including reticulocyte count). 
• 
Blood sampling for biomarker/EGFR mutational testing and exploratory research  
• 
Serum alpha-1 acid glycoprotein (AAG) samples and PK blood sample (Cycle 2 – 7 only; 
Section 9.5.3) 
• 
Concomitant medication and procedures since last visit 
• 
AE monitoring 
• 
Collection and review of patient diary and CO-1686 drug return 
• 
QoL questionnaires (EORTC QLQ-C30, EORTC QLQ-L13, and the DLQI) – at 8 ± 1 weeks 
for 6 months (Day 1 of Cycle 3, 5, 7, ±1 weeks inclusive). After Cycle 7, questionnaires will 
be collected every 12 ± 1 weeks (Day 1 of Cycle 10, 13, 16 etc ± 1 weeks) and at 
end-of-treatment  
• 
CO-1686 tablets will be dispensed to the patient; patient diary will be provided to the patient 
• 
Tumor assessments will be performed every 8 ± 1 weeks (Day 1 of Cycle 3, 5, 7 etc 
± 1 week) after dosing until tumor progression (see Section 9.5.2.1).  


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9.3 
End-of-Treatment Visit 
The following procedures will be performed for all patients 28 days (± 7 days) after the last dose 
of PO CO-1686: 
• 
Physical examination 
• 
Weight 
• 
ECOG performance status 
• 
Vital signs (blood pressure, pulse, and temperature) 
• 
Concomitant medications and procedures since last visit 
• 
Contraceptive counseling 
• 
Serum pregnancy test for women of childbearing potential 
• 
Hematology (including reticulocyte count), 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 patient had disease progression on study. 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 PO CO-1686; then only ongoing SAEs will 
be followed until resolution or stabilization) 
• 
Collection and review of patient diary and CO-1686 drug return 
• 
12-lead ECG (in triplicate, 10-sec tracings > 2 min apart)  
• 
QoL questionnaires (EORTC QLQ-C30, EORTC QLQ-L13, and the DLQI) 
• 
Survival status 
• 
Subsequent therapies for NSCLC 
9.4 
Two Monthly Follow-up 
The following procedures will be performed every 8 weeks ± 7 days (unless otherwise specified) 
following the End-of-Treatment Visit:  
• 
Survival status - This may be performed during routine clinic visits or by telephone contact. 
• 
Subsequent therapies for NSCLC will be documented during routine clinic visits or by 
telephone contact. 


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• 
If a patient discontinues treatment before progression, then scans should continue until 
progression according to the protocol schedule of every 8 ± 1 weeks. Exceptions to this 
requirement may be acceptable based on local institutional or regulatory requests and must 
be approved in advance by the sponsor. 
9.5 
Methods of Data Collection 
9.5.1 
Safety Evaluations 
9.5.1.1 
Adverse Event 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 CO-1686 is administered through 28 days after the last dose. Study 
procedure-related AEs that occur after signing of the ICF and before administration of 
CO-1686 will also be collected. Any ongoing SAEs will be followed until resolution or 
stabilization. AEs and laboratory abnormalities will be graded according to the NCI CTCAE 
grading system (Version 4.03) and recorded on the eCRF. 
Complete details for monitoring AEs, including the definition of drug-related AEs, are provided 
in Section 10. 
9.5.1.2 
Clinical Laboratory Investigations 
Blood will be sent for analysis to a central laboratory for all cycles Day 1 visits, but must also be 
analyzed by a local laboratory to inform patient treatment decisions. Local hematology results 
must be reviewed by the investigator prior to start of CO-1686 administration. Additional tests 
may be performed at the investigators discretion. The panels of laboratory tests to be performed 
are shown below: 
Hematology: Hemoglobin, hematocrit, WBC and differential (with ANC), reticulocyte count, 
and platelet count per the schedule of evaluations at Screening, during treatment, and at the 
End-of-Treatment Visit. Hematology results must be reviewed by the investigator prior to the 
start of treatment with PO CO-1686. 
Patients known to require concomitant therapy with anticoagulant therapy such as warfarin 
should have international normalized ratio (INR) monitored at Screening and during the study. 
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 and every Cycle N D1 
thereafter and at the End-of-Treatment Visit, also if clinically indicated on study. Fasting glucose 
will be measured as part of clinical chemistry panel (see below) on all cycles Day 1 visits, and 
measured individually (local lab) C1D4, C1D8, C1D15, and C2D15. 
Clinical Chemistry: Total protein, albumin, creatinine, BUN or urea, total bilirubin, alkaline 
phosphatase, ALT, AST, total cholesterol, fasting glucose, sodium, potassium, magnesium, 
chloride, calcium, and phosphorus per the schedule of evaluations at Screening, during treatment, 
and at the End-of-Treatment Visit. Serum levels of AAG will be determined on PK sampling 


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days. HbA1c will be measured at Screening and Day 1 of every other cycle (Cycle 3, 5, 7 etc.) 
while the patient is on study. 
Urinalysis: Performed on freshly voided clean sample by dipstick for protein, glucose, blood, 
pH, and ketones per the schedule of evaluations. If dipstick findings are abnormal, then a 
microscopic evaluation will be performed to assess the abnormal findings. Urinalysis will be 
performed at Screening only. 
Serum ß-hCG Pregnancy Test (Local Lab): Performed on women of childbearing potential 
within 3 days before C1D1 and at the End-of-Treatment Visit. If the serum pregnancy test results 
are not available on C1D1, a urine pregnancy test can be performed on C1D1 to confirm that the 
patient is not pregnant prior to dosing. Both values should be entered in the eCRF. A negative 
result must be confirmed by a physician before the first dose of PO CO-1686 can be 
administered. 
Laboratory reports will be reviewed by the investigator or delegated physician who will then 
comment on out-of-range parameters and assess clinical significance. Clinically significant 
abnormalities and associated panel results, as well as results of any additional tests performed as 
follow-up to the abnormalities, will be documented on the eCRF as an AE. 
9.5.1.3 
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 performed at 
Screening and at Day 1 of each cycle including the End-of-Treatment Visit.  
9.5.1.4 
12-lead Electrocardiograms 
Triplicate serial 12-lead ECGs (10-sec ECG tracings collected in triplicate [> 2 min apart]) will 
be taken at Screening, C1D1, C1D15, C2D1, and every Cycle N D1, and at the End-of-Treatment 
Visit, and as clinically indicated. 
ECGs should be performed after the patient has been resting for at least 5 minutes. The 12-lead 
ECGs collected will be analyzed at a central ECG laboratory. Details on recording ECGs and 
preparation for central interpretation will be included in the Investigator’s File.  
9.5.1.5 
Body Weight and Height 
Height will be measured during the Screening visit only. Weight will be measured at Screening, 
at Day 1 of every cycle, and at the End-of-Treatment Visit (the patient should be in light indoor 
clothes).  
9.5.1.6 
Physical Examinations 
Physical examinations will include an assessment of all the major body systems. Complete 
physical examinations will be performed at Screening, at Day 1 of every cycle, and at the 
End-of-Treatment Visit.  


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9.5.1.7 
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. 
9.5.2 
Efficacy Evaluations 
9.5.2.1 
Tumor Assessments 
Tumor assessments will be performed at Screening, and every 8 ± 1 weeks thereafter (Day 1 of 
Cycle 3, 5, 7 etc ± 1 week) 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. 
For a patient who discontinues treatment before progression, scans should continue until 
progression according to the protocol schedule. Exceptions to this requirement may be 
acceptable based on local institutional or regulatory requests and must be approved in advance 
by the sponsor. Scans will be evaluated locally for patient treatment decisions. Scans will be sent 
to a central radiological laboratory for independent response evaluation. In Cohort B, scans will 
be held at the central radiological vendor for later evaluation, assessed by IRR, if needed as a 
supporting analysis. Tumor response will be interpreted using RECIST 
Version 1.1 (Appendix A).11  
Patients who continue treatment with CO-1686 post-progression should continue to be scanned 
according to the protocol until they discontinue from the study. 
Patients are required to have an end-of-treatment tumor scan using the same methodology used at 
Screening, unless: 
a) Patient has radiographic evidence of disease progression while on study 
or 
b) It has been < 2 weeks since last on-study scan  
In addition, an MRI may be used in place of CT at the end-of-treatment scan if required 
per local authorities.  
Tumor assessments should consist of clinical examination and appropriate imaging techniques 
(preferably CT scans of the chest and abdomen, with appropriate slice thickness per RECIST 
Version 1.1); other studies (MRI and X-ray) may be performed if required. Imaging of the pelvis 
is required if clinically indicated eg, prior site of metastasis or symptomatic. The same methods 
used to detect lesions at baseline are to be used to follow the same lesions throughout the clinical 
study.  


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Brain imaging is required at baseline. In Cohort A, patients with brain lesions at baseline will 
require repeat brain imaging as part of the follow-up tumor assessments. In Cohort B, patients 
with brain lesions at Screening are not eligible for the study. Patients without baseline brain 
lesions do not require brain imaging on study unless clinically indicated. 
9.5.3 
Pharmacokinetic Evaluations  
For all patients, 2 mL blood samples will be drawn for CO-1686 POPPK analysis at 28 ± 3 day 
intervals for the first 6 months (Day 1 of Cycles 2 to 7 inclusive). 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 CO-1686 levels and AAG 
measurement. Please refer to the laboratory manual for details on collection and processing of 
blood PK samples. 
9.5.4 
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 during the Screening period or within 60 days prior to dosing. 
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. 
When sufficient tissue is available from the baseline tumor biopsy, samples will be tested for 
other molecular alterations including histological markers, EGFR gene amplification, MET gene 
amplification, or PIK3CA mutations that may modulate response or resistance to EGFR-targeted 
therapy. 
Following disease progression on CO-1686, patients will undergo a tumor biopsy if they provide 
additional consent at that time. This tissue will be analyzed for molecular alterations that may 
confer resistance to EGFR inhibitors. Tissue preparation requirements are the same as listed 
above. 
Matched blood sampling (up to 25 mL at baseline and time of progression and up to 12 mL the 
beginning of every cycle) should be collected prior to the biopsy procedure, if possible. If blood 
sample is not collected before the biopsy, allow at least a 2-day recovery period after the biopsy 
before blood collection for biomarker testing. Blood samples will be processed locally for 
plasma and stored frozen for subsequent batch shipping to the sponsor’s lab.  
- If a biopsy was performed within 60 days prior to C1D1, and no intervening treatment 
was given, a repeat biopsy is not required if adequate tumor tissue can be provided to the 
sponsor during the Screening period. Matched blood sampling should occur during the 
Screening period following signing of ICF. 


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Sample handling instructions will be provided in a separate laboratory manual. 
For patients who provide additional consent, genomic DNA will be extracted from a blood 
sample from each patient (collected predose on C1D1) to detect genetic polymorphisms in 
CYP 450 isoenzymes in order to explore the correlation between potential polymorphisms 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.  
All patients (Cohorts A and B) will have blood collected during Screening, at Day 1 of each 
cycle, and at progression. Blood collected at these time points may also be used to test for 
biomarkers of response or resistance to EGFR-targeted therapy, including but not limited to 
EGFR mutational status, MET gene amplification, PIK3CA mutations, and alterations in other 
components of the EGFR signaling pathway. 
Please refer to the Laboratory Manual for details on collecting and processing of blood 
pharmacodynamics samples. 
9.5.5 
Quality of Life Assessments 
PRO will be measured using the EORTC QLQ-C30 and LC13 and the DLQI, which will be 
administered at Screening, predose on C1D1, then every 8 ± 1 weeks for 6 months (Day 1 of 
Cycle 3, 5, 7 ± 1 week inclusive). After Cycle 7, questionnaires will be collected every 
12 ± 1 weeks (Day 1 of Cycle 10, 13, 16 etc. ± 1 week) and at end-of-treatment.  
9.5.6 
Patient Diary  
Patient diaries will be provided to patients. Patients will use the diaries to note the date, time and 
dose of CO-1686 administration. 


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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 of CO-1686 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 PO 
CO-1686 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 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 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 
• 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 a 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 a 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 
10.4 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 lab 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 
• at the discretion of the investigator should the abnormality be deemed clinically significant 
10.5 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 10.8). 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. 


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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.  
10.6 Recording of Adverse Events and Serious Adverse Events 
Any AE from the time the first dose of CO-1686 is administered through 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 first dose of CO-1686 will also be captured on the AE eCRF. Any 
other AE that occurs prior to 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 of 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 CO-1686, 
whether or not related to CO-1686, must be immediately reported to the sponsor/designee SAE 
contact (Section 10.8). After the 28-day window, only SAEs that are considered 
treatment-related should be reported to the sponsor/designee within 24 hours of knowledge of the 
event. 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. 
10.6.1 
Intensity of Adverse Events 
The severity of the AE will be graded according to the NCI CTCAE Version 4.03 grading scale. 
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 
10.6.2 
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, 


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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 
10.6.3 
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 
• CO-1686 temporarily interrupted 
• CO-1686 permanently discontinued 
• Other (specify) 
Outcome 
• Recovered 
• Recovered with sequelae 
• Improved 
• Ongoing 


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• Death 
• Lost to follow-up 
10.7 Follow-up of Adverse Events and Serious Adverse Events 
All AEs 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 through 28 days after the last dose of CO-1686. All SAEs must be followed 
until resolution or stabilization. 
10.8 Regulatory Aspects of Serious Adverse Event Reporting 
All SAEs, regardless of relationship to study drug, must be reported to the sponsor/safety 
designee within 24 hours of knowledge of the event, according to the procedures below. It is 
important that the investigator provide an assessment of relationship of the SAE to study 
treatment at the time of the initial report. The Clinical Trial Serious Adverse Event 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/safety designee as soon as the event is 
known by the clinical site. If the pregnancy occurs in a female patient, study drug should be 
stopped immediately. Notification to the sponsor/safety designee 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 (EC) 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: 
Tumor Evaluable Population—all patients who received at least 1 dose of CO-1686, have at 
least 1 measureable tumor lesion at baseline, and have at least 1 post-baseline tumor assessment 
as determined by the IRR.  
Safety Population—all patients who have received at least 1 dose of CO-1686. 
11.2 Statistical Methods 
11.2.1 
General Considerations 
Data will be summarized by T790M status and by dose, but may also be pooled as appropriate. 
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 PFS and OS.  
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 will be presented. The 
primary reason for discontinuation of CO-1686 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 for the tumor evaluable 
population. Separate analyses will be performed for the assessments from the investigator and 
the independent reviewer.  
PFS and OS will also be presented for the safety population.  


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11.2.4.1 
Primary Endpoint 
The primary endpoint of the study will be ORR according to RECIST Version 1.1. For Cohort A, 
ORR will undergo independent radiology review (IRR) and in Cohort B, scans will be assessed 
by IRR if needed as a supporting analysis. 
The ORR is the best overall response recorded from the start of the treatment until disease 
progression or recurrence.  
The frequency and percentages of patients with a best overall response of CR, PR, SD, or 
progressive disease (PD) will be summarized.  
11.2.4.2 
Secondary Efficacy Endpoints 
BEST OVERALL RESPONSE 
The frequency and percentages of best overall responses of CR, PR, SD, or PD will be 
summarized separately for T790M-positive and T790M-negative patients, and by dose.  
DURATION OF RESPONSE 
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 
separately for T790M-positive and T790M-negative patients, and by dose, 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.  
DISEASE CONTROL RATE 
DCR is defined as the percentage of patients who have achieved CR, PR, and SD lasting at least 
12 weeks.  
PROGRESSION-FREE SURVIVAL 
PFS will be calculated as 1+ the number of days from the first dose of study drug to documented 
radiographic progression 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 (i.e., radiologic assessment) or date of first dose of study drug 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.  
OVERALL SURVIVAL 
OS will be calculated as 1+ the number of days from the first dose of study drug 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 
CO-1686. 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. 
QUALITY OF LIFE  
QoL will be measured using the EORTC QLQ-C30, EORTC QLQ-LC13, and the DLQI.12,13  
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 CO-1686. The on-treatment period will be defined as the day after the first dose of 
CO-1686 to 28 days after the last dose of CO-1686. 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 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. 
Time to Deterioration 
The time to a worsening in symptoms will be computed as 1+ the number of days from the first 
dose of study drug to the first instance of a ≥ 10 point increase from baseline in symptoms.  
The time to deterioration will be summarized using Kaplan-Meier methodology. Patients without 
a 10 point increase will be censored on their last evaluation. 
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. 


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11.2.4.3 
Exploratory Endpoints  
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. 
 EXTRA-CRANIAL PFS 
In the subgroup of patients with brain metastases at baseline, extra-cranial PFS will be calculated 
as 1+ the number of days from the first dose of study drug to a 20% increase from nadir in the 
sum of the longest diameters of the extra-cranial target lesions.  
Patients without extra-cranial progression will be censored on the day of their last tumor 
assessment.  
CIRCULATING TUMOR DNA (CTDNA) 
The presence of both the activating mutation and T790M at baseline and subsequent time points 
will be presented both as copies/mL plasma and mutant allele percentages and summarized with 
descriptive statistics. 
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.  
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 CO-1686).  
11.2.5.1 
Extent of Exposure 
The following will be summarized:  
• Number of weeks of treatment initiated 
• Number of dose reductions, delays or interruptions 
The number of weeks of treatment initiated will be investigated by summarizing the number of 
weeks started by each patient. The number of patients with at least 1 dose reduction, delay or 
interruption will be summarized with frequencies and percentages.  
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 v4.03 whenever possible. Treatment-emergent AEs are defined as 


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AEs with an onset date on or after the date of first dose of CO-1686 until the date of the last 
CO-1686 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. 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 1treatment-emergent AE will also be summarized.  
Separate tables will present the following: 
• 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 PO CO-1686 
• Treatment-emergent AEs resulting in interruption or reduction or delay of CO-1686 
The incidence of treatment-emergent AEs will be summarized by relationship to PO 
CO-1686 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.  
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 (pretreatment 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 International System of Units. 
The baseline laboratory value will be defined as the last value prior to or on the day of the first 
dose of PO CO-1686. The on-treatment period will be defined as the day after the first dose of 
PO CO-1686 to 28 days after the last dose of CO-1686. Laboratory values collected during the 
on-treatment period will be included in the summary tables. The laboratory values collected after 
the on-treatment period will only be presented in the data listings. 


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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. 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. Separate 
listings will be produced for clinically significant laboratory abnormalities (i.e., those that meet 
Grade 3 or 4 criteria according to CTCAE). 
11.2.5.4 
Vital Sign Measurements 
The baseline vital sign measurement will be defined as the last value prior to or on the day of the 
first dose of CO-1686. The on-treatment period will be defined as the day after the first dose of 
CO-1686 to 28 days after the last dose of CO-1686. Vital sign measurements collected during the 
on-treatment period will be included in the summary tables. The vital sign measurements 
collected after the on-treatment period will only be presented in the data listings. 
The summary of vital sign 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. 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. 
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 pretreatment visit and treatment period visits 
will be classified as ≤ 450 msec, > 450 msec to ≤ 480 msec, > 480 msec to ≤ 500 msec, and 
> 500 msec. For each patient’s maximum change from the pretreatment ECG visit for QT and 
QTC, intervals will be classified into < 30 msec, ≥ 30 msec to < 60 msec, and ≥ 60 msec. The 
number and percentage of patients in each classified category will be presented. Additional 
endpoints will include abnormal T waves and U waves and other ECG intervals and diagnostic 
parameters. 
Descriptive statistics will be used to summarize other ECG parameters of PR, QRS, QT, and 
RR interval, and the corresponding changes from pretreatment ECG visit at each time point. 
Plots of the mean QT/QTC over time will be provided. 
11.2.5.6 
Other Safety Measurements 
Concomitant medications/procedures will be tabulated and summarized. 
11.2.6 
Exploratory Endpoints−Pharmacodynamic Analysis 
An exploratory pharmacodynamic endpoint is the detection and quantification of mutant EGFR 
ctDNA in blood collected at baseline and with every tumor assessment. The presence of both the 
activating mutation and T790M at baseline and subsequent time points will be presented both as 
copies/mL plasma and mutant allele percentages. In addition, the relationship between T790M 
detected in tumor compared with that detected in blood will be explored. This will involve 
determining the sensitivity, specificity, positive and negative predictive values with 95% CIs of 
blood with respect to tumor assuming that EGFR mutational status in tumor is a true reflection of 


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tumor biology. The ctDNA from blood collected at these time points may also be assessed to 
identify biomarkers of response or resistance to EGFR-targeted therapy. 
11.3 Sample Size Considerations 
Cohort A: Approximately 125 patients will be enrolled. The ORR will be presented with 95% 
CIs. Table 11-1 provides the 95% CIs for observed response rates of 30%, 40%, and 50% 
assuming a total of 125 patients. 
Table 11-1: Confidence Intervals for Observed Response Rates 
Number of Patients 
ORR (%) [95% CI] 
125 
30 [22, 39] 
125 
40 [31, 49] 
125 
50 [41, 59] 
 
Cohort B: Approximately 100 patients will be enrolled with the aim to include approximately 
40 response evaluable T790M-negative NSCLC patients. To be response evaluable, patients 
should have received at least one cycle of therapy, and have had their disease re-evaluated by 
radiological assessment. 
An exact binomial test with a nominal 0.10 2-sided significance level will have approximately 
90% power to detect the difference between a null hypothesis response rate of 20% and a 
clinically meaningful response rate of 40% when the sample size is 40. 


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12 PATIENT DISPOSITION 
12.1 Patient Discontinuations 
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 
• Progression of patient’s underlying disease, except as noted in Section 5.1.2 
• 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 and requires discontinuation of therapy 
• 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 PO CO-1686 must be documented in the eCRF and source 
documents. 
To the extent possible, end-of-treatment procedures should be performed on all patients who 
receive CO-1686. The End-of-Treatment Visit should occur 28 (± 7) days following the last dose 
of CO-1686. After stopping protocol-specified treatment, all patients will remain in the study and 
will be followed for safety (through 28 days after last dose; those with ongoing SAEs will be 
followed until either resolution or stabilization has been determined), for disease progression if 
the patient discontinues treatment prior to progression (every 8 ± 1 weeks until disease 
progression), and for survival status and subsequent NSCLC therapies (at approximately 
2-monthly intervals until death or sponsor decision). 


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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 prior to 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 
(i.e., 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 prior to 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 
agreed. 


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13.4 Study Monitoring 
A monitor will contact and visit the investigator at the study center prior to the entry of the first 
patient and 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 (i.e., 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 (i.e., 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.  
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. 
Prior to 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. 
Full information regarding EDC and completing eCRFs is included in the investigator files. All 
questions or comments related to electronic capture should be directed to the assigned monitor. 


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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 PO CO-1686 
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 prior to 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. 
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 


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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 prior to 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, 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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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). J Clin Oncol 
2011;29(21):2866-74. 
23. 
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. 
 


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24. 
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. 
25. 
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. 
26. 
Jabbour S, Ziring B. Advantages of extended-release metformin in patients with type 2 
diabetes mellitus. Postgrad Med 2011;123(1):15-23. 


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15 APPENDICES 
Appendix A. Response Evaluation Criteria in Solid Tumors Criteria 
Appendix B. Eastern Cooperative Oncology Group Performance Status Scale 
Appendix C. Study CO-1686-019  Extension Phase 
 


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Appendix A  
Response Evaluation Criteria in Solid Tumors Criteria 
 
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 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 n 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 (longest diameter < 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 exam 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, PET scan, or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
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. 


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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 
longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be 
calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference 
by which to characterize the objective tumor response.  
Nontarget 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 
antitumor 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 nontarget) 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 partial response 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 nontarget lesions and normalization of tumor 
marker level. 
Stable Disease/Incomplete 
Response 
Persistence of one or more nontarget 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 nontarget 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 
Nontarget 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 8± 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-1686-019  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, Amendment 5 also introduces the availability of NAT2 testing for patients, an 
indirect indicator of the likelihood of developing hyperglycemia and QTc prolongation.  The 
availability and disclosure of this information to the patients’s 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. 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 adverse events of special interest (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 
Abbreviation: CT=combined terms. 
 
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%) 


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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 
Abbreviation: ECG=electrocardiogram. 
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. 
STUDY DESIGN 
Treatment Regimen and Duration of Therapy 
All patients will sign an informed consent which explains the rationale for closing the CO-1686 
clinical development program for NSCLC and the option for ongoing patients to continue 
 
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%) 


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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 CO-1686 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.  CO-1686 will be 
administered daily on a 28-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 
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 TKIs if patient provides 
additional consent, the investigator feels it is in the patient’s best interest and with sponsor 
approval. It is important that before deciding to continue treatment with rociletinib post 
progression, 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 (e.g. a named patient program) in accordance with relevant 
local regulations or the sponsor decides to close the study. 
PATIENT ELIGIBILITY AND WITHDRAWAL CRITERIA  
Eligibility and Number of Patients 
This amendment applies to patients who remain on CO-1686 treatment in the CO-1686-019 
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: 


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• 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 Investigatory and with 
the approval of the sponsor.   
• Intercurrent illness that prevents administration of treatment (Reference Section 7.7) 
• 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. 
• 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.  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 – Extension Phase 
a = Vital signs (blood pressure, pulse, and temperature) taken predose on drug administration days. 
b = Patients are to continue using effective contraception for 12 weeks after last dose of CO-1686 and report any pregnancies 
during this period. 
c = Serum ß-hCG to be evaluated by local lab and performed only on women of childbearing potential. 
d = 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.  
e = Hematology evaluation should include reticulocytes. 
f = Patients will be monitored for AEs 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 QTc has been < 470 ms 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 laboratory 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 1 sample is needed and may be collected at any visit to enable NAT2 analysis. 
Day 1 of Each Cycle  
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 
o Including a vision check as part of a standard physical exam 
• Weight 
 
Prior to beginning 
Amendment 5 Evaluations 
Day 1 of 
each cycle 
End of Treatment 
(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 
Serum Pregnancy Testc 
 
 
X 
Fasting Serum Chemistryd 
 
X 
X 
Hematologye 
 
X 
X 
Adverse Eventsf 
 
X 
X 
Patient Diaryg 
 
X 
X 
CO-1686 Dispensing / Administration 
 
X 
 
ECG Assessments using central ECG machineh 
 
X 
X 
Tumor Scans i 
To be performed per institutional standard of care   or every 8 ± 1 weeks 
(every 2 cycles); scans are not required at the End of Treatment Visit 
Blood for CYP Evaluation  
 (Optional Sampling)j 
 
X 
 


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• Vital signs (blood pressure, pulse, and temperature) 
• 12-lead ECG (in triplicate, 10-sec tracings > 2 min apart) using central ECG machine 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 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.  
• Fasting serum chemistry (including fasting glucose).  HbA1c will be measured every other 
cycle (Day 1 of Cycle 3, 5, 7 etc). 
• Hematology (including reticulocyte count) 
• Concomitant medication and procedures  
• AE monitoring 
• Collection and review of patient diary and CO-1686 drug returnCO-1686 tablets will be 
dispensed to the patient; patient diary will be provided to the patient 
o Oral CO-1686 will be administered with a meal, or within 30 minutes after a meal. The 
patient must also drink at least 8 ounces (240 mL) of water when taking CO-1686. 
Tablets should be swallowed whole. 
• Tumor assessments will be performed per institution standard of care or every 8 ± 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) Blood for CYP Evaluation 
o Patient may consent for optional CYP sample collection if not previously collected 
already, and have the sample collected for NAT2 analysis 
o Sample should only be collected at a single visit 
End of Treatment Visit 
The following procedures will be performed for all patients 28 days (±7 days) after the last dose 
of oral CO-1686: 
• Physical examination  
o 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)  


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• Fasting serum chemistry (includes fasting glucose) . 
• Hematology (including reticulocyte count) 
• Serum pregnancy test for women of childbearing potential 
• AE monitoring (until 28 days after last dose of oral CO-1686; then only ongoing serious 
adverse events (SAEs) are followed until resolution or stabilization) 
• Collection and review of patient diary 
• Contraceptive counseling 
 
 

SAP_001.pdf: