Clinical trial NCT03292133
Conditions: Lung Cancer
Keywords: Lung Cancer
Sponsor: Massachusetts General Hospital
Start date: 2017-10-31; Completion date: 2025-03-04
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is studying a combination of drugs as a possible treatment for EGFR mutation-positive lung cancer.

The drugs involved in this study are:

* EGF816
* Gefitinib

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease or patient population. "Investigational" means that the drug or drugs are being studied and have not been approved together for patients.

The FDA (the U.S. Food and Drug Administration) has approved gefitinib as a treatment option for EGFR mutation-positive lung cancer.

The FDA has not approved EGF816 as a treatment for any disease at this time.

In this research study, the investigators are studying the safety and efficacy of the combination of the study drugs EGF816 and gefitinib.

Both EGF816 and gefitinib are inhibitors which target a specific mutation in cancer and may stop tumors growing and multiplying.

Arms: arm 1: * All patients will receive gefitinib orally once daily
* EGF816 will be administered orally once daily
* Participant will be requested to maintain a medication diary of each dose of medication
Interventions: intervention 1: EGF816 intervention 2: Gefitinib
Intervention descriptions: intervention 1: EGF816 is an inhibitor which target a specific mutation in cancer and may stop tumors growing and multiplying intervention 2: Gefitinib is an inhibitor which target a specific mutation in cancer and may stop tumors growing and multiplying

Protocol documents:
Prot_SAP_000.pdf: 
Page 1
NCI Protocol #: N/A
DF/HCC Protocol #: 17-291
TITLE: A Phase 2 Study of EGF816 and gefitinib in TKI-naïve EGFR-mutant Non-Small Cell 
Lung Cancer
Coordinating Center:
Massachusetts General Hospital
*Principal Investigator (PI):
Zofia Piotrowska, MD
MGH Cancer Center
zpiotrowska@partners.org
Other Investigators:
Lecia Sequist, MD
MGH Cancer Center
lvsequist@partners.org
Statistician:
Alona Muzikansky
Massachusetts General Hospital
AMUZIKANSKY@mgh.harvard.edu
NCI-Supplied Agent(s):  EGF816, Novartis Pharmaceuticals
Other Agent(s):  Gefitinib, commercial
IND #:  [Enter the # of the IND under which this study will be performed. Enter “TBD” if an
IND # is not yet available.]
IND Sponsor: Zofia Piotrowska, MD
Protocol Type / Version # / Version Date:
January 10th, 2019


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SCHEMA
|______11 Patients Total in First Stage______|
Initial 
safety run-
in cohort:  
6 patients
5 additional 
patients (11 pts 
total) in first 
stage
# Patients 
progression
-free at 9 
months
Stop
< 7
> 7
25 additional 
patients 
enrolled in 
second stage
No unexpected grade 
3/4 toxicities seen


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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................2
1.
OBJECTIVES......................................................................................................................5
1.1
Study Design............................................................................................................5
1.2
Primary Objectives...................................................................................................5
1.3
Secondary Objectives...............................................................................................5
1.4
Exploratory Objectives ............................................................................................5
2.
BACKGROUND .................................................................................................................5
2.1
Study Disease(s).......................................................................................................5
2.2
EGF816....................................................................................................................7
2.3
Gefitinib.................................................................................................................10
2.4
Rationale for the combination of EGF816 and gefitinib .......................................11
2.5
Correlative Studies Background ............................................................................12
3.
PARTICIPANT SELECTION...........................................................................................13
3.1
Eligibility Criteria..................................................................................................13
3.2
Exclusion Criteria ..................................................................................................15
3.3
Inclusion of Women and Minorities ......................................................................18
4.
REGISTRATION PROCEDURES ...................................................................................18
4.1
General Guidelines for DF/HCC Institutions ........................................................18
4.2
Registration Process for DF/HCC Institutions.......................................................18
5.
TREATMENT PLAN........................................................................................................18
5.1
Treatment Regimen................................................................................................18
5.2
Pre-Treatment Criteria ...........................................................................................19
5.3
Agent Administration.............................................................................................21
5.4
General Concomitant Medication and Supportive Care Guidelines......................23
5.5
Criteria for Taking a Participant Off Protocol Therapy.........................................24
5.6
Duration of Follow Up...........................................................................................25
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................25
6.1
Conditions requiring dose modification: ...............................................................26
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................41
7.1
Adverse Event Characteristics...............................................................................41
7.2
Expedited Adverse Event Reporting......................................................................42
7.3
Expedited Reporting to the Food and Drug Administration (FDA) ......................43
7.4
Expedited Reporting to Hospital Risk Management .............................................44
7.5
Routine Adverse Event Reporting .........................................................................44
8.
PHARMACEUTICAL agent INFORMATION................................................................44
8.1
EGF816..................................................................................................................44


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8.2
Gefitinib.................................................................................................................45
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................45
9.1
Tumor biopsies.......................................................................................................45
9.2
Longitudinal circulating tumor DNA analyses......................................................47
9.3
Pharmacokinetic studies: .......................................................................................47
10.
STUDY CALENDAR .......................................................................................................49
11.
MEASUREMENT OF EFFECT........................................................................................51
11.1
Antitumor Effect – Solid Tumors ..........................................................................51
11.2
Response Criteria...................................................................................................53
12.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................57
12.1
Data Reporting.......................................................................................................57
12.2
Data Safety Monitoring..........................................................................................57
13.
STATISTICAL CONSIDERATIONS...............................................................................57
13.1
Study Design/Endpoints.........................................................................................57
13.2
Sample Size, Accrual Rate and Study Duration ....................................................58
13.3
Patient Disposition.................................................................................................58
A detailed description of patient disposition will be provided. It will include:.................58
13.4
Patient Characteristics............................................................................................58
Patient characteristics will include a summary of the following:......................................58
13.5
Interim Monitoring Plan- N/A ...............................................................................58
13.6
Analysis of Primary Endpoints..............................................................................58
13.7
Analysis of Secondary Endpoints..........................................................................59
14.
PUBLICATION PLAN .....................................................................................................60
REFERENCES ..............................................................................................................................61
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................63
APPENDIX B
INFORMATION ON USE OF CONCOMITANT MEDICATIONS.......64
APPENDIX C  Plasma isolation PROTOCOL for ctDNA analysis..............................................66
APPENDIX D SOP  For Tumor Biopsy Sample Collection …....................................................67


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1.
OBJECTIVES
1.1
Study Design
This is a single arm, open-label phase II study evaluating the safety and efficacy of the combination 
of the third-generation EGFR inhibitor EGF816 with the first-generation EGFR inhibitor gefitinib 
in the treatment of TKI-naïve EGFR-mutant non-small cell lung cancer. The study will have a 
Simon two-stage design with eleven patients enrolled in the first stage and a plan to enroll a total 
of 36 patients (25 patients in the second stage) if at least seven patients remain progression-free at 
nine months in the first stage. The first six patients enrolled in the study will constitute a safety 
run-in evaluating the safety of the combination of EGF816 at the recommended phase II dose of 
150mg QD and gefitinib at a standard dose of 250mg QD. If unexpected toxicities are observed 
among the first six patients, expansion cohorts will be added to explore different doses and/or 
schedules of the combination.
1.2
Primary Objectives
The primary objective of the study is to evaluate the efficacy of EGF816 in combination with
gefitinib in the treatment of TKI-naïve EGFR-mutant NSCLC. Efficacy will be measured as 
proportion that are progression-free at 39 weeks. 
1.3
Secondary Objectives
The secondary objectives of the study will include:
To describe the median progression free and overall survival of patients treated with 
EGF816 and gefitinib.
To evaluate the safety and tolerability of the EGF816/gefitinib combination.
1.4
Exploratory Objectives
To characterize the pharmacokinetic interactions between gefitinib and EGF816.
To evaluate resistance mechanisms to EGF816 and gefitinib.
To characterize the molecular response to treatment in on-treatment tumor biopsies and in 
circulating tumor DNA.
2.
BACKGROUND
2.1
Study Disease(s)
Non small cell lung cancer (NSCLC) is a heterogeneous entity which affects over 220,000 people 
in the US each year, and is the leading cause of cancer-related mortality in the world2. Over half 
of NSCLC patients have advanced or metastatic disease at presentation. Unfortunately, metastatic 
disease is not curable, and current chemotherapy offers only modest improvements in survival. 
Recently, genetic alterations leading to an “oncogene-addicted” biology have been shown to occur 


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in a subset of NSCLC patients and confer sensitivity to specific tyrosine kinase inhibitors (TKI’s.)3
These biologically targeted agents have had a significant impact on the survival of patients 
carrying such genetic alterations, but their efficacy is limited and the discovery of novel ways to 
prolong the disease course remains a top research priority.
The epidermal growth factor receptor (EGFR) receptor signaling pathway plays a central role in 
the neoplastic transformation of NSCLC and promotes cancer cell survival, metastasis and 
angiogenesis4. Somatic mutations in the EGFR gene in NSCLC tumors have been well-described. 
EGFR mutations are present in about 10% of unselected US patients with NSCLC, but in up to 
50% of never-smoking NSCLC patients5. Although a variety of mutations within EGFR have been 
described, the most common of these mutations include exon 19 deletion and the L858R mutation 
in exon 21, both of which sensitize NSCLC tumors to treatment with EGFR TKIs such as gefitinib 
and erlotinib.  Erlotinib and gefitinib have now been shown to improve both response rates and 
progression-free survival in patients with EGFR-mutant NSCLC in multiple randomized trials6-8.
Although remarkable response rates are seen in patients with EGFR mutations that are treated with 
EGFR TKIs (~ 80%), the responses are of limited duration because eventually patients develop 
“acquired resistance”. Several resistance mechanisms have been identified, the most common 
being a secondary mutation at the threonine gatekeeper residue at position 790, T790M, which 
develops in up to 50% of NSCLC patients harboring a primary EGFR mutation treated with first 
generation EGFR TKIs9,10.
Third generation EGFR inhibitors targeting T790M and activating EGFR mutations with relative 
sparing of wild-type EGFR have now been developed. One such drug, osimertinib, received FDA 
approval based on objective response rate of ~60% among patients with T790M-mediated acquired 
resistance to initial EGFR inhibitor11. Several other third-generation EGFR inhibitors, including 
EGF816, are in clinical development and have shown equally promising activity. Unfortunately, 
the activity of these new drugs is also limited by the eventual development of acquired resistance, 
with current PFS estimates of about 9-13 months on osimertinib and other third-generation EGFR 
inhibitors11,12.
Recent reports show that resistance to osimertinib, olmutinib and rociletinib can be mediated by 
the development of a new tertiary resistance mutation, C797S13-15, which occurs at the site of 
covalent binding of all irreversible EGFR inhibitors, and has previously been identified as a 
putative resistance mechanism to this class of drugs in in vitro models16. Other resistance 
mechanisms, including MET amplification, Her2 amplification, BRAF mutations and SCLC 
transformation have also been identified in individual cases treated with third-generation EGFR 
inhibitors17-19, and there is growing evidence that resistance to these novel agents may develop in 
the setting of increasing molecular heterogeneity and that multiple resistance mechanisms can co-
exist in cancers progressing on third-generation EGFR TKIs15.
Since cancers treated with sequential single-agent EGFR inhibitors have repeatedly demonstrated 
the ability to overcome such drugs through eventual development of resistance mechanisms 
including T790M and C797S, we hypothesize that using combinations of a first- and third-
generation EGFR inhibitor in the first-line setting may delay the development of acquired 
resistance as neither resistance mutation alone would be sufficient to overcome the combination. 


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2.2
EGF816
2.2.1
Overview and non-clinical experience
EGF816 is a targeted covalent epidermal growth factor receptor (EGFR) inhibitor that selectively 
inhibits activating and resistance mutants (L858R, Exon 19 deletion mutation(s) of EGFR 
(ex19del), and T790M) while sparing wild type (WT) EGFR. First and second generation 
inhibitors of EGFR, which target activating mutations as well as WT EGFR, have been validated 
as therapeutic agents in specific scenarios; however, the narrow therapeutic window of these 
EGFR inhibitors, by inhibiting both mutant EGFR within the tumor and WT EGFR within normal 
tissues, significantly limits the maximum potential of this class of drugs. By sparing WT EGFR, 
while inhibiting mutant EGFR, EGF816 has the potential to improve upon the first and second 
generation EGFR inhibitors. Additionally, by inhibiting EGFR T790M, EGF816 offers a 
therapeutic option for patients harboring that mutation. EGF816 demonstrated efficacy in several 
EGFR-mutant non-small cell lung cancer (NSCLC) cell lines and xenograft models, including in 
vivo tumor regression in the H1975 model, which harbors EGFR L858R/T790M. In in vivo
models, EGF816 also demonstrated a pharmacokinetic (PK)-tumor pharmacodynamic (PD) 
relationship, with PD outlasting PK, consistent with the irreversible binding of EGF816 to EGFR. 
Dose-dependent anti-tumor efficacy was observed in several xenograft models, and EGF816 was 
well tolerated with no body weight loss observed at efficacious doses.
In preclinical toxicology studies conducted in rats and dogs, EGF816 was overall well tolerated at 
plasma concentrations that resulted in anti-tumor activity in rodent efficacy models. One of the 
off-targets of EGF816 is Tyrosine kinase expressed in hepatocellular carcinoma (TEC) family 
kinases. The results of a T-cell Dependent Antigen Response (TDAR) assay in rats indicated a 
trend for a dose-response effect of EGF816 on inhibiting the generation of antigen-specific 
antibodies to a foreign antigen; this effect was reversible following withdrawal of EGF816. In the 
first-in-human study of EGF816 in patients with EGFR-T790M NSCLC, preliminary PK data 
demonstrated that the EGF816 exposure increased largely in proportion to dose 75 mg to 350 mg, 
quaque die/ daily (q.d.) and the terminal half-life (T1/2) ranged from 13 hours (h) to 18h EGF816 
appears to be efficacious at doses of 75 mg q.d. and above, and preliminary exposure-response 
analyses showed a flat relationship between EGF816 steady state trough concentration and overall 
response rate (RR). Preliminary population PK analysis indicated similar exposures from the 
matched doses in capsule and tablet formulations.
2.2.2
Clinical Experience
CEGF816X2101 is the first-in-human Phase I/II study of single-agent oral EGF816, and is 
currently ongoing. As of the data cut-off date (18-Dec-2015), 148 patients have been treated 
with EGF816 capsules or tablets at seven dose levels: 75 mg q.d. (N=7), 100 mg q.d. (N=29), 
150 mg q.d. (N=64), 200 mg q.d. (N=8), 225 mg q.d. (N=24), 300 mg q.d. (N=5) and 350 mg 
q.d. (N=11). Eighty-four patients (56.8%) were still receiving treatment and 64 patients 
(43.2%) had discontinued treatment. Of these 64 patients, 53 (35.8%) discontinued treatment 
due to progressive disease, three (2.0%) discontinued treatment due to AEs, and 3 (2.0%) 
discontinued treatment due to death. Of the three patients who discontinued treatment due to 


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AE, one patient at the 350 mg q.d. reported Grade 3 maculopapular rash, one patient at the 
150 mg daily dose reported Grade 3 interstitial lung disease, and one patient at the 300 mg 
daily dose reported Grade 3 pulmonary oedema. Of the three patients who discontinued 
treatment due to death, one patient died due to sepsis (considered not related to study 
treatment), one patient died due to hepatitis B virus (HBV) reactivation (considered related 
to study treatment), and one patient died due to pneumonia (considered not related to study 
treatment).
As of 18-Dec-2015, dose-limiting toxicities (DLT) were reported in five patients: one patient at 
the dose level of 150 mg capsule reported Grade 3 maculopapular rash that resulted in temporary 
treatment interruption, one patient at the dose level of 225 mg capsule reported Grade 3 
maculopapular rash that resulted in temporary treatment interruption, one patient at the dose level 
of 350 mg capsule reported Grade 3 acute kidney failure and Grade 3 maculopapular rash that 
resulted in temporary treatment interruption, one patient at the dose level of 350 mg capsule 
reported Grade 3 maculopapular rash that resulted in permanent discontinuation of treatment, and 
one patient at the dose level of 350 mg capsule reported. Grade 3 enteritis and Grade 3 dehydration 
that resulted in temporary treatment interruption.
As of the data cutoff date of 18-Dec-2015, 142 patients (95.9%) who were treated with EGF816 
capsules or tablets experienced at least one AE of any grade, regardless of relationship to the study 
drug. The most frequent AEs (all CTCAE grades, >10% of patients) regardless of study drug 
relationship at the seven dose levels specified below were rash (group term) (56.1%), diarrhea 
(41.9%), maculopapular rash , pruritus (36.5%), fatigue (27.0%), stomatitis (27.0%), dry skin 
(24.3%), nausea (23.6%), cough (20.9%), decreased appetite (20.3%), vomiting (14.9%), 
constipation (14.2%), headache (12.8%), anemia (12.2%), paronychia (11.5%), pyrexia (11.5%), 
dyspnea (10.8%), edema peripheral (10.8%), back pain (10.1%), and upper respiratory tract 
infection (10.1%)
One-hundred thirty-four (90.5%) patients experienced AEs of any grade that were suspected to be 
related to EGF816. The most frequent (>10% of patients) AEs of any CTCAE grade suspected to 
be related to EGF816 were rash (group term) (52%), diarrhea (36.5%), pruritus (33.8%), dry skin 
(24.3%), stomatitis (24.3%), fatigue (16.2%), nausea (15.5%), decreased appetite (12.2%), and 
vomiting (10.1%)
Seventy (47.3%) patients who were treated with EGF816 capsules or tablets at the dose levels 
specified below experienced Grade 3 or Grade 4 AEs regardless of relationship to the study drug. 
pneumonia (5.4%), diarrhea (4.7%), fatigue (2.7%), dyspnea (2.7%), urticaria (2.7%),hypertension 
(2.7%), stomatitis (2.0%), decreased appetite (2.0%), hyperuricemia (2.0%), and seizure (2.0%) .
Forty-four patients (29.7%) experienced Grade 3/4 AEs that were suspected to be related to 
urticaria (2.7%), diarrhea (2.0%), fatigue (2.0%), stomatitis (2.0%), HBV (1.4%), and increased 
lipase (1.4%).
As of the data cutoff date (18-Dec-2015), SAEs, regardless of study drug relationship, were 


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reported in 48 patients (32.4%) who received at least one dose of single agent EGF816 capsules 
or tablets (at seven dose levels: 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, 300 mg and 350 mg) 
(Table 5-9). Of these 48 patients, 15 experienced SAEs that were suspected to be related to study 
drug or study procedures: one patient at the 350 mg capsule daily dose was reported to have Grade 
3 acute kidney injury that resulted in temporary drug interruption, one patient at the 350 mg capsule 
daily dose was reported to have Grade 3 dehydration and enteritis that resulted in temporary drug 
interruption, one patient at the 225 mg capsule daily dose was reported to have Grade 3 hepatitis 
B reactivation and Grade 3 hepatic failure that resulted in permanent treatment discontinuation and 
death, one patient at the 225 mg capsule daily dose was reported to have Grade 3 purpura that 
resulted in temporary drug interruption, one patient at the 225 mg capsule daily dose was reported 
to have Grade 3 hepatitis B reactivation that resulted in temporary drug interruption, one patient 
at the 225 mg capsule daily dose was reported to have Grade 3 maculopapular rash that resulted in 
temporary drug interruption, one patient at the 225 mg capsule daily dose was reported to have 
Grade 3 diarrhea that resulted in temporary drug interruption, two patients at the 150 mg capsule 
daily dose reported Grade 2 dyspnea that resulted in no action taken with study drug, one patient 
at the 150 mg capsule daily dose was reported to have Grade 1 acute renal failure that resulted in 
temporary drug interruption, one patient at the 150 mg capsule daily dose reported Grade 2 diarrhea 
that resulted in temporary drug interruption, one patient at the 150 mg capsule daily dose was 
reported to have Grade 3 interstitial lung disease that resulted in temporary drug interruption, one 
patient at the 150 mg capsule daily dose was reported to have Grade 3 pneumothorax that was 
related to a study-associated procedure that occurred after the patient had discontinued study drug, 
one patient at the 150 mg tablet daily dose was reported to have Grade 3 diarrhea that resulted in 
temporary drug interruption, and one patient at the 150 mg tablet daily dose was reported to have 
Grade 3 upper gastrointestinal hemorrhage that resulted in temporary drug interruption and was 
reported to have Grade 3 anemia (the SAEs of gastrointestinal hemorrhage and anemia were 
updated to not suspected related to study treatment in the safety database, but have not been 
updated in the clinical database).
As of 18-Dec-2015, the outcome of SAEs suspected to be related to study treatment was recovered 
or recovering in 12 of 15 patients. One patient died due to hepatic failure secondary to HBV 
reactivation, one patient was reported as not recovered from Grade 3 maculopapular rash, and one 
patient was reported as not recovered from Grade 3 anemia. 
As of 18-Dec-2015, 2 SAEs of HBV reactivation have been reported in 2 patients participating in 
the CEGF816X2101 study. One case had a fatal outcome, and the second case (Patient 9001-012) 
was considered medically significant. The fatal case involved a patient who received EGF816 at 
225 mg q.d., had a history of HBV infection and was not on antiviral treatment at study entry. The 
patient developed HBV reactivation during the study and died due to hepatic failure despite 
initiation of antiviral treatment after HBV reactivation had been confirmed. The second patient 
also received EGF816 at 225 mg q.d., had a history of HBV and was not on antiviral treatment at 
the time of joining the study, HBV reactivation was detected after the patient had been on study 
for approximately 10 weeks. Antiviral treatment was immediately initiated, EGF816 was 
interrupted and the HBV infection was brought under control. The patient later resumed EGF816 
at the same dose of 225 mg q.d. while continuing on antiviral medication. The viral reactivation in 
these two patients was likely due to immunosuppression related to EGF816. Reactivation of HBV 
and hepatitis C virus (HCV) has been reported with anticancer therapies that suppress the immune 


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system.
The preliminary efficacy results showed an overall response rate (ORR) of 59.5% by Investigator 
assessment in 25 (11 confirmed and 14 awaiting confirmation) out of 42 evaluable patients
treated at all dose levels. Note: evaluable patients include those who were ongoing and had at
least one post-baseline tumor assessment or who discontinued study treatment as of the data cut-
off date. The antitumor activity of EGF816 is in line with the antitumor activity observed
with other 3rd-generation EGFR TKIs including AZD9291and CO-1686. To minimize the risk 
to all trial subjects and to manage the potential risk of severe liver toxicity associated with hepatitis 
reactivation, Novartis has amended the protocols for all clinical trials involving EGF816 to provide 
guidance for patients with evidence of current or prior hepatitis B or hepatitis C infection.
Please refer to the current Investigator’s Brochure for more details.
2.3
Gefitinib
Gefitinib is an oral first-generation EGFR inhibitor which reversibly inhibits the kinase activity of 
wild-type and certain activating mutations of EGFR, preventing autophosphorylation of tyrosine 
residues associated with the receptor, thereby inhibiting further downstream signaling and 
blocking EGFR-dependent proliferation. Gefitinib’s binding affinity for EGFR exon 19 deletion 
or exon 21 point mutation L858R mutations is higher than its affinity for the wild-type EGFR. 
Gefitinib also inhibits IGF and PDGF-mediated signaling at clinically relevant concentrations; 
inhibition of other tyrosine kinase receptors has not been fully characterized. 
Gefitinib is approved for the first-line treatment of EGFR-mutant NSCLC in the United States, 
Europe and Asia. The IPASS study was a randomized, multicenter, open-label trial conducted in 
patients with metastatic adenocarcinoma histology NSCLC receiving first-line treatment8. Patients 
were randomized (1:1) to receive gefitinib 250 mg orally once daily or up to 6 cycles of 
carboplatin/paclitaxel. The efficacy outcomes included progression-free survival (PFS) and 
objective response rate (ORR) as assessed by BICR. 
The subset population consisted of 186 of 1217 patients (15%) determined to be EGFR positive 
and had radiographic scans available for a retrospective assessment by BICR. In this subset, there 
were 88 gefitinib-treated patients and 98 carboplatin/paclitaxel-treated patients. Demographic and 
baseline characteristics of this subset were a median age of 59 years, age 75 years or older (7%), 
age less than 65 (70%), Asian (100%), female (83%), never smokers (96%), adenocarcinoma 
histology (100%), and PS 0-1 (94%). 
The median duration of treatment for gefitinib-treated patients was 9.8 months. The hazard ratio 
for PFS favored the gefitinib-treated patients [HR of 0.54 (95% CI: 0.38, 0.79)] with a median PFS 
of 10.9 months for the gefitinib-treated patients and 7.4 months for the carboplatin/paclitaxel-
treated patients as assessed by BICR. In addition, the objective response rate was 67% (95% CI: 
56, 77) for gefitinib-treated patients and 41% (95% CI: 31, 51) for carboplatin/paclitaxel-treated 
patients based on BICR assessment. The median duration of response was 9.6 months for gefitinib-
treated patients and 5.5 months for carboplatin/paclitaxel-treated patients. 


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Gefitinib is generally well-tolerated, with common side effects including rash and diarrhea. Rare 
but serious side effects including interstitial lung disease, hepatotoxicity and ocular disorders 
including keratitis can be seen. 
Please see the gefitinib package insert and latest version of the investigator’s brochure for further 
details.
2.4
Rationale for the combination of EGF816 and gefitinib
It is well-known that resistance to first 
generation EGFR inhibitors is mediated 
in 
a 
majority 
of 
cases 
by 
the 
development of a secondary mutation in 
EGFR 
exon 
20, 
T790M. 
The 
development of T790M restores the 
receptor’s affinity for ATP and prevents 
first-generation 
EGFR 
TKIs 
from 
effectively inhibiting EGFR20. T790M 
can be successfully overcome with third-
generation EGFR inhibitors, which bind 
covalently to EGFR and have activity 
against both T790M and the original founder EGFR mutations11,12. We have now seen that 
resistance to third-generation EGFR TKIs is frequently mediated by the development of a tertiary 
resistance mutation in EGFR, C797S, which occurs at the site of covalent binding of all irreversible 
EGFR inhibitors14-16,21. Indeed, using in vitro models, C797S renders cancers resistant to all tested 
third-generation EGFR inhibitors1. Interestingly, cell lines bearing C797S alone, in the absence of 
T790M, retain sensitivity to first-generation EGFR inhibitors (erlotinib and gefitinib) which do 
not rely on C797 to engage in the drug pocket.
In vitro models suggest that the genetic context of the C797S mutation is important to its 
therapeutic implications. C797S which arises on the same allele (in cis configuration) with T790M 
renders the cells resistant to all currently available EGFR inhibitors; none are able to overcome 
the combination of both resistance mutations on the same DNA strand1,22. However, in cell line 
models where T790M and C797S are on different alleles (in a trans configuration) retain 
sensitivity to combination of a first-generation and a third-generation EGFR inhibitor. This data 
suggests that upfront use of a combination of a 1st and 3rd generation EGFR inhibitor could not 
be overcome by development of either resistance mutation alone. Resistance to the combination 
would require the simultaneous development of C797S and T790M in a cis configuration, an event 
which is statistically unlikely.  Thus, we hypothesize that the combination of a first and third-
Figure 1. A WZ4002-resistant patient-derived cell line (121 Res) 
acquires a C797S mutation and maintains EGFR activity in the 
presence of TKI, while the parental (121 pt) cell line is sensitive 
to WZ40021.


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generation EGFR inhibitor 
given together in the first-line 
setting may have the potential 
to induce highly 
durable 
remissions, 
as 
the 
development 
of 
both 
mutations 
in 
a 
cis 
configuration 
would 
be 
required to drive resistance. 
We therefore propose a phase 
II trial to test the efficacy and 
safety 
of 
EGF816 
in 
combination with gefitinib for 
the first-line treatment of 
EGFR-mutant NSCLC
2.5
Correlative Studies Background
2.5.1
Pre-treatment, on-treatment and resistant tumor biopsies 
Mandatory tumor biopsies will be required at the start of treatment and at the time of disease 
progression. These samples will be analyzed via next-generation sequencing at Novartis to 
characterize mechanisms of resistance to the EGF816/gefitinib combination. 
In addition, an on-treatment biopsy will be obtained after about 2-3 weeks of treatment. These 
samples will allow for characterization of the response to treatment. Biopsies will be submitted for 
single-cell sorting and transcriptional profiling to study the direct effect of the TKI combination 
on tumor cells, and to identify potential early signs of eventual resistance to the combination. These 
exploratory analyses will be performed at Massachusetts General Hospital and at Novartis 
Pharmaceuticals.
2.5.2
Plasma-based circulating tumor DNA (ctDNA) analysis
The characterization of circulating tumor DNA (ctDNA) in patient plasma samples is now widely 
utilized on both a research and clinical basis. ctDNA has several advantages over tissue-based 
testing, and can serve as an key complement to traditional tumor biopsies. Tumor DNA is shed by 
cancer cells into the plasma from multiple disease sites; as our understanding of the intra and 
intertumoral heterogeneity which can exist within an individual patient grows, there is growing 
evidence that ctDNA can more fully capture the heterogeneity of disease present within the 
patient23,24. In addition, ctDNA allows for easier sampling and facilitates longitudinal analyses 
Figure 2. EGFR C797S located in cis or trans with T790M alters drug sensitivity1.


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over time. We and others have demonstrated that longitudinal plasma assessments can be used to 
track response to treatment and that emerging resistance can be detected on the molecular level in 
the ctDNA prior to the development of radiographic disease progression14,18.
In this study, longitudinal plasma samples will be obtained at the start of treatment, on D3, D8 and 
D15 of cycle 1,and at the start of each cycle and at the time of progression. Samples will be 
analyzed by ddPCR and next-generation sequencing to quantify molecular response to treatment, 
detect early signs of emerging resistant clones and to more fully characterize resistance 
mechanisms via NGS at the time of progression. 
3.
PARTICIPANT SELECTION
3.1
Eligibility Criteria 
Patients may be entered in the study only if they meet all of the following criteria:
3.1.1
Participants must have a pathologically-confirmed diagnosis of non-small cell 
lung cancer (NSCLC).
3.1.2
Participants must have advanced disease - either stage IV disease, stage IIIB 
disease not amenable to definitive multi-modality therapy, or recurrent disease 
after a prior diagnosis of stage I-III disease. All staging is via the American Joint 
Committee on Cancer (AJCC)/IASLC 7th edition proposed staging criteria (see 
appendix 2)
3.1.3
An EGFR sensitizing mutation must be detected in tumor tissue. Specifically, 
patients harboring the most common mutations, deletions in exon 19 or the 
L858R mutation in exon 21 are eligible. Other EGFR sensitizing mutations may 
be eligible after discussion with the principal investigator. Patients may be 
enrolled in the study based on an activating EGFR mutation detected by a CLIA-
certified tissue or plasma-based assay, but will be required to undergo a 
mandatory tumor biopsy during study screening. 
3.1.4
Participants must have measurable disease, per RECIST 1.1.  See Section 11 for 
the evaluation of measurable disease.
3.1.5
Patients in the six patient safety run-in cohort may have had a prior EGFR TKI in 
the metastatic setting (to allow for patients who started initial therapy at an outside 
hospital), but treatment duration must have been less than three months. After the 
initial six-patient safety run-in, no prior EGFR TKI therapy in the metastatic setting 
is allowed. An EGFR TKI given in the adjuvant setting (i.e. with no measurable 
disease at the time of administration) is allowable provided the subject has been off 
of EGFR TKI therapy for at least six months at the time of enrollment.


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3.1.6
Patients may have had no more than one prior line of chemotherapy or 
immunotherapy in the metastatic setting. At least  14 days must have elapsed from 
the last chemo/immunotherapy administration until the start of protocol treatment, 
and patients must have recovered from the side effects of any of these agents.
3.1.7
Patients must be screened for HBV. Patients who are either HBsAg positive or 
HBV-DNA positive must be willing and able to take antiviral therapy 1-2 weeks
prior to 1st dose of study treatment and continue on antiviral therapy for at least 4
weeks after the last dose of EGF816. Additional management of the patients would 
be provided by a physician with expertise in management of HBV, if needed. 
Patients must have negative hepatitis C antibody (HCV-Ab) or positive HCV-
Ab but undetectable level of HCV-RNA. Note: patients with detectable HCV-RNA 
are not eligible for the study.
3.1.8
Patients must receive insurance approval for or be willing to pay for commercial 
gefitinib.
3.1.9
Age > 18 years.
3.1.10
3.1.11 Life expectancy of greater than 12 weeks.
3.1.12 Participants must have normal organ and marrow function as defined below:
Total bilirubin <1.5 x upper limit of normal (ULN) *For patients with Gilbert’s
syndrome total bilirubin <3.0 x ULN
known hepatic metastases AST and/or ALT > 5x ULN
3.1.13 The effects of EGF816 and gefitinib on the developing human fetus are unknown.  
For this reason, women of child-bearing potential and men must agree to use highly 
effective contraception during the study and for 3 months after stopping the study 
treatment. Highly effective contraception methods include:
Total abstinence (when this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptomthermal, postovulation methods) and withdrawal are not 
acceptable methods of contraception
Female sterilization (have had surgical bilateral oophorectomy with or 
without hysterectomy) or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up 
hormone level assessment


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Male Partner: male sterilization (at least 6 months prior to screening). 
For female subjects on the study the vasectomized male partner should 
be the sole partner for that subject.
Combination of any two of the following (a+b or a+c, or b+c):
o
A. Use of oral, injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that 
have comparable efficacy (failure rate <1%), for example 
hormone vaginal ring or transdermal hormone contraception.
o
B. Placement of an intrauterine device (IUD) or intrauterine 
system (IUS)
o
C. Barrier methods of contraception: Condom or Occlusive cap 
(diaphragm 
or 
cervical/vault 
caps) 
with 
spermicidal 
foam/gel/film/cream/vaginal suppository.
o
D. In case of use of oral contraception women should have been 
stable on the same pill for a minimum of 30 days before taking 
study treatment. 
Women are considered post-menopausal and not of childbearing 
potential if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g. age appropriate, 
history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up 
hormone level assessment is she considered not of childbearing 
potential.
Sexually active males must agree to use a condom during intercourse 
while taking drug and for 3 months after stopping treatment; men should 
not father a child in this period. A condom is required to be used also 
by vasectomized men in order to prevent delivery of the drug via 
seminal fluid.
3.1.14 Ability to understand and the willingness to sign a written informed consent 
document. Written informed consent must be obtained prior to any screening 
procedures.
3.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria will not be eligible to enter in the study:
3.2.1
Participants with clinically active or symptomatic interstitial lung disease or 
interstitial pneumonitis (i.e., affecting activities of daily living or requiring 
therapeutic intervention) and patients with history of clinically significant 
interstitial lung disease or radiation pneumonitis.


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3.2.2
Patients with clinically symptomatic brain metastases or leptomeningeal disease. 
Patients may be on a stable dose of corticosteroids to control brain metastases if 
they have been on a stable dose for two weeks prior to study treatment and are 
clinically asymptomatic.
3.2.3
Patients who have had radiation to the lung fields within four weeks of starting 
treatment. For patients receiving palliative radiation to thoracic vertebrae, ribs or 
other sites where the radiation field includes the lungs,  radiation must be 
completed at least two weeks before starting treatment. For all palliative radiation 
to all other sites, at least  7 days must have elapsed prior to starting to treatment. 
At least six months must have elapsed from radiation given with curative intent.
3.2.4
Patients who have had major surgery (e.g., intra-thoracic, intra-abdominal or 
intra-pelvic) within 2 weeks prior to starting study drug or who have not 
recovered from side effects of such procedure. Video-assisted thoracic surgery 
(VATS) and mediastinoscopy will not be counted as major surgery and patients 
.
3.2.5
Patients unable or unwilling to undergo a biopsy for research during the screening 
period, 2-3 weeks into the course of therapy and at the time of progression.
3.2.6
Patients with a second, clinically active, cancer. Patients with second cancers 
which have been treated with curative intent and/or are currently inactive are 
allowed.
3.2.7
Patients who have undergone a bone marrow or solid organ transplant.
3.2.8
Known history of human immunodeficiency virus (HIV) seropositivity (HIV 
testing is not mandatory).
3.2.9
Participants who are receiving any other investigational agents. Patients 
previously treated with investigational agents must complete a washout period of 
at least one week or five half-lives, whichever is longer, before starting treatment.
3.2.10 Patients receiving concomitant immunosuppressive agents or chronic 
corticosteroid use, except those on steroid to control brain metastases, those on 
topical or inhaled steroids, or steroids given via local injection.


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3.2.11 Patients with clinically significant, uncontrolled cardiovascular disease, such as:
o
Unstable angina within 6 months prior to screening
o
Myocardial infarction within 6 months prior to screening
o
Patients with a history of documented congestive heart failure (New York 
Heart Association functional classification III-IV)
o
Peripheral vascular disease
o
Patients with uncontrolled hypertension defined as a Systolic Blood Pressure 
Hg, 
with or without anti-hypertensive medication. Initiation or adjustment of 
antihypertensive medication(s) is allowed prior to screening
o
Ventricular arrhythmias
o
Supraventricular and nodal arrhythmias not controlled with medication
o
Other cardiac arrhythmia not controlled with medication
o
(female patients) using Fridericia correction (QTcF) on the screening ECG 
o
Patients with history of congenital long QT syndrome or history of torsade de 
pointes
3.2.12 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to EGF816 or gefitinib.
3.2.13 Participants receiving any medications or substances that are strong inhibitors or 
inducers of CYP3A4 are ineligible.  Because the lists of these agents are 
constantly changing, it is important to regularly consult a frequently-updated list 
such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference 
texts such as the Physicians’ Desk Reference may also provide this information.  
As part of the enrollment/informed consent procedures, the patient will be 
counseled on the risk of interactions with other agents, and what to do if new 
medications need to be prescribed or if the patient is considering a new over-the-
counter medicine or herbal product.
3.2.14 Unable or unwilling to swallow tablets or capsules.
3.2.15 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements
3.2.16 Pregnant women are excluded from this study because the effects of EGF816 and 
gefitinib on a developing fetus are unknown. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the 
mother with EGF816 or gefitinib, breastfeeding should be discontinued if the 
mother is treated with EGF816 and gefitinib.


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3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
4.
REGISTRATION PROCEDURES
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS)
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.
4.2
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.  
5.
TREATMENT PLAN
5.1
Treatment Regimen
All patients will receive combination therapy with EGF816 and gefitinib in an open-label fashion. 
A treatment cycle will be defined as 28 days. After completing 1 year of study treatment, visits 
will occur every 6 weeks. 
The first six patients enrolled in the study will constitute a safety run-in; if severe unexpected 
toxicities are observed during cycle 1 among these six patients, further expansion cohorts at lower 
dose levels will be explored. Severe unexpected toxicities will be defined as any grade  3or higher 
adverse event assessed to be treatment-related by the treating physician occurring in > 1/6 patients 
during the safety run-in. Rash will be excluded as grade 3 rash during the 1st cycle has occured 
with each drug individually and is typically responsive to dose hold. If >1 patient has a grade 3 or 
higher treatment-related adverse event during cycle 1 of treatment, we will de-escalate treatment 
to gefitinib 250 mg QD and EGF816 100 mg QD.


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EGF816 will be supplied by Novartis to the investigational drug pharmacy at all participating sites. 
Gefitinib will be supplied directly to the patient through prescription as a commercial product. As 
stated in the eligibility criteria, only patients with insurance approval to obtain gefitinib or who 
agree to self-pay for gefitinib will be able to participate in this study. Upon signing of the study 
ICF and confirmation of eligibility, participants will be prescribed a 30-day (one 28-day cycle; 
with two additional pills in case of lost, dropped pills) supply of gefitinib. C1D1 will begin only 
once the supply of gefitinib is in the patient’s possession.
All patients will receive gefitinib 250 mg orally once daily and EGF816 100 mg orally once daily 
without interruption, unless an interruption is required to manage treatment-related toxicity (as 
outlined in Tables 6-1 and 6-2). Patients will be monitored at the start of each 28-day treatment 
cycle. Treatment will be administered on an outpatient basis. The participant will be requested to 
maintain a medication diary of each dose of medication.  The medication diary will be returned to 
clinic staff at the end of each cycle.
Reported adverse events and potential risks are described in Section 7.  Appropriate dose 
modifications are described in Section 6.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the participant's 
malignancy.
5.2
Pre-Treatment Criteria
Prior to any study related testing, patients will sign the informed consent form and undergo medical 
evaluation to establish their baseline condition and determine eligibility. Imaging and all other 
studies will be obtained within 28 days of enrollment for the purpose of baseline assessment:
Complete medical history and physical examination including:
Complete medical history
Documentation of disease status
Documentation of prior systemic therapies for advanced disease treatment
Documentation of current medications and all medications used within 30 days prior to 
enrollment.
Complete physical examination, including vital signs (pulse, blood pressure, weight, and 
height) and assessment of ECOG performance status (See Appendix A)
Pre-existing conditions will be assessed and evaluated according to the NCI CTCAE v4.0 
to establish the patient’s baseline condition
The following screening laboratory tests will be performed within 28 days prior to Day 1 of 
treatment:
CBC with differential
Chemistries: sodium, potassium, calcium, magnesium, glucose, creatinine, total bilirubin 
alkaline phosphatase [ALP], aspartate transaminase [AST], alanine transaminase [ALT], 
urea or blood urea nitrogen [BUN], total protein, albumin


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Urinalysis
Urine or serum pregnancy test (for premenopausal women)
ECG
Disease-specific testing:
Baseline CT scans of the chest, abdomen and pelvis and baseline imaging of the brain by 
MRI (or CT with contrast if MRI is contraindicated.) Repeat tumor assessments (CT chest, 
abdomen and pelvis) will be performed every 8 weeks thereafter to assess response and 
disease progression. Brain imaging (MRI, or CT with contrast in patients with 
contraindications to MRI) should be obtained every 8 weeks for patients with known brain 
metastases at the start of treatment. For patients without known history of brain metastases, 
CNS imaging should be obtained if clinically indicated based on symptoms.
Mandatory pre-treatment tumor biopsy will be obtained within 28 days of Cycle 1, Day 1. 
Processing of tumor biopsy specimens will be performed as outlined in section 8.3.1.1
5.2.1
Cycle 1, Day 1
Patients who have signed the informed consent form, completed the screening 
process, and met the criteria for enrollment will be entered into the trial and 
assigned an identification number. In addition the following will be performed:
Certification that patient meets all inclusion and exclusion criteria and is 
able to comply with all requirements of the clinical trial
Review concomitant medications since screening
Perform physical examination with vital signs and ECOG performance 
status
Blood investigations – to be done if screening labs were done more than 7 
days prior to day 1. 
Blood investigations performed on C1D1 must be reviewed before starting
treatment to ensure that there are no clinically significant abnormalities.  
However, C1D1 laboratory studies do not have to re-meet eligibility 
criteria to begin treatment. 
Blood for correlative ctDNA analyses


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5.2.2
Subsequent Cycles 
The following studies will be obtained at the start of each new treatment cycle:
Complete medical history
Complete physical examination, including vital signs (pulse, blood 
pressure, weight, and height) and assessment of ECOG performance status 
(See Appendix A)
Documentation of all current medications
Laboratory studies including:
o
CBC with differential
o
Chemistries: sodium, potassium, calcium, magnesium, glucose, 
creatinine, total bilirubin alkaline phosphatase [ALP], aspartate 
transaminase [AST], alanine transaminase [ALT], urea or blood 
urea nitrogen [BUN], total protein, albumin
Blood for correlative ctDNA analyses will be collected at baseline, on C1D3, C1D8, 
C1D15 and at the start of each new cycle. 
Before beginning each cycle, any treatment related toxicities requiring treatment 
delay must have resolved to grade 1 or pre-therapy baseline. If toxicities have not 
resolved to grade 1 on the scheduled day of retreatment, treatment may be delayed for 
up to 28 days from the time of the last daily dose of EGF816 and gefitinib. 
For patients who require drug holds to manage toxicities, the cycle day count should 
continue during the hold and the dosing and assessment schedule should not change. 
5.3
Agent Administration
5.3.1
EGF816
Investigational Product: EGF816
Pharmaceutical Form: Tablets
Source: Novartis
Procurement: Provided via sponsor, dispensed from research pharmacy.
Unit Strength: 150mg tablets
Daily Dose: 100 mg once daily
Duration of Use: Continuous daily dosing without interruption
Administration Route: Oral (swallowed)
Schedule: Once daily, with or without food
Missed Doses/Vomited Doses:  If a patient inadvertently does not take the EGF816 dose 
at their usual time, he or she may take the dose up to 6 hours later; in other words, they 
may continue as long as it is at least 6 hours before the next dose of gefitinib is due to be 
taken. The daily treatment schedule will be resumed the next day with the patient taking 
the scheduled dose at the usual time. If an entire daily dose is skipped, the patient should 


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resume treatment the following day with their regular dose. No “make-up dose” or 
increased dosing should occur. If a dose is vomited within 1 hour of administration, 
medications to control nausea and vomiting should be used, and the dose can be repeated. 
Patients should report all vomited, missed or delayed doses to the study staff and will be 
provided with a medication diary which should be turned in at every visit (see appendix 5.)
Tablets should be swallowed whole and not chewed or opened.  Patients should be 
instructed to take their dose of each drug at approximately the same time of day. Drugs 
should be separated by approximately 12 hours (e.g, gefitinib taken in the morning 
and EGF816 in the evening.) The time of drug administration should be recorded by the 
patient in the study-provided drug diary.  On days when blood for PK samples need to be 
collected in clinic, the patient should hold their morning gefitinib until arrival, and take the 
dose in the clinic after clearance to do so from the care team.
Grapefruit or grapefruit juice, seville orange (and juice), pummelos, star citrus fruits and 
hybrids of these mentioned fruits should be avoided during study treatment.
5.3.2
Gefitinib
Commercial Product: Gefitinib
Pharmaceutical Form: Tablets
Source: Commercial pharmacy
Procurement: Obtained directly from commercial pharmacy, delivered to patient.
Unit Strength: 250 mg tablets
Daily Dose: 250 mg once daily
Duration of Use: Continuous daily dosing without interruption
Administration Route: Oral (swallowed)
Schedule: Once daily, with or without food
If a patient inadvertently does not take the gefitinib dose at their usual time, he or she may 
take the dose up to 6 hours later, in other words, they may continue  as long as it is at least 
6 hours before the next dose of EGF816 is due to be taken. The daily treatment schedule 
will be resumed the next day with the patient taking the scheduled dose at the usual time. 
If an entire daily dose is skipped, the patient should resume treatment the following day 
with their regular dose. No “make-up dose” or increased dosing should occur. If a dose is 
vomited within 1 hour of administration, medications to control nausea and vomiting 
should be used, and the dose can be repeated.  Patients should report all vomited, missed 
or delayed doses to the study staff and will be provided with a medication diary which 
should be turned in at every visit (see appendix 5.)
Tablets should be swallowed whole and not chewed or opened. However, gefitinib may be 
dissolved in 4-8 oz of water if patients have difficulty swallowing the tablets. Drugs should 
be separated by 12 hours (e.g, gefitnib taken in the morning and EGF816 in the 
evening.) Patients should be instructed to take their dose of each drug consistently at 
approximately the same time each day. Time of drug administration should be recorded by 


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the patient in the study-provided drug diary.  On days when blood for PK samples need to 
be collected, the patient should take the dose in the clinic.
5.4
General Concomitant Medication and Supportive Care Guidelines
Information about concomitant medications will be collected as part of this study. This will be 
collected during screening, at the start of each cycle, and at the time of study discontinuation. 
Patients are allowed to receive full supportive care therapies concomitantly during the study. No 
other chemotherapy, immunotherapy, hormonal cancer therapy or experimental medications will 
be permitted while the patients are receiving study therapy.
5.4.1
Permitted Concomitant Therapy
In general, concomitant medications and therapies deemed necessary for the supportive care (e.g., 
such as anti-emetics, anti-diarrhea) and safety of the patient are allowed. Anticoagulation treatment 
is also allowed if INR has been established within the therapeutic range prior to study entry. PT 
investigational site about any new medications he/she takes after the start of the study treatment. 
All medications (other than study treatment) and significant non-drug therapies (including physical 
therapy, herbal/natural medications and blood transfusions) administered within 28 days prior to 
the administration of study treatment and during the study must be listed on the Prior and 
Concomitant Medications or the Surgical and Medical procedures eCRF.
Patients who develop a solitary site of disease progression may undergo locally ablative therapy 
(LAT; including radiotherapy, ablation or surgical resection) to the site of progression and remain 
on study. Note that if the solitary site of progression is within a target lesion, the tumor response 
will be categorized as progression at the time LAT begins. EGF816 and gefitinib should be held 
for at least 5 days prior to LAT. EGF816 and gefitinib may be resumed >3 days after completing 
anti-neoplastic therapy will be allowed.
5.4.2
Permitted Concomitant Therapy Requiring Caution and/or Action
Based on the in vitro studies, both EGF816 and gefitinib are metabolized by CYP3A4. Moderate 
inhibitors and inducers of CYP3A4 should be used with caution and strong inhibitors and strong 
inducers of CYP3A4 should not be used concomitantly with either drug. Grapefruit juice is a 
CYP3A4 inhibitor, therefore, consumption of grapefruit or grapefruit juice should be avoided 
during study treatment.
EGF816 is a P-gp substrate. Co-administration of EGF816 with P-gp inhibitors may increase 
systemic exposure and/or alter tissue uptake of EGF816. EGF816 is a moderate inhibitor of BCRP 
with EGF816. EGF816 is an inhibitor of the human multidrug and toxin extrusion transporter 1 
and 2-K (MATE1 and MATE2-
EGF816 has potential to increase the exposure of co-medications whose clearance is significantly 


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mediated by MATE. In the absence of data confirming whether such an interaction occurs in 
patients, caution should be exercised when potent P-gp inhibitors and MATE or BCRP substrates 
are concurrently used. The patient and the Investigator should be aware of potential signs of 
overdose of the concomitant medication. In the event of suspected toxicity, administration of either 
EGF816 or concomitant drugs should be discontinued according to Investigator judgment. Refer 
to Appendix B, Table 13-1, for permitted medications that require caution and Appendix B, Table 
13-2 for a list of prohibited medications.
Live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, 
varicella, and TY21a typhoid vaccines) should not be administered while a patient is dosed with 
EGF816 and for 30 days after the last dose of EGF86. Refer to Appendix B, Table 13-1, for 
permitted medications that require caution and Appendix B, Table 13-2 for a list of prohibited 
medications. If a patient must use a drug in Appendix B, Table 13-2, the patient must be 
discontinued from the study.
Drugs that elevate gastric pH (e.g., proton pump inhibitors, histamine H2-receptor antagonists, and 
antacids) may reduce plasma concentrations of gefitinib. Avoid concomitant use of gefitinib with 
proton pump inhibitors, if possible. If treatment with a proton-pump inhibitor is required, take 
gefitinib 12 hours after the last dose or 12 hours before the next dose of the proton-pump inhibitor. 
Take gefitinib 6 hours after or 6 hours before an H2-receptor antagonist or antacid.
5.5
Criteria for Taking a Participant Off Protocol Therapy
The duration of treatment will depend on response and tolerance. In the absence of treatment delays 
due to adverse events, EGF816 and gefitinib may be continued until there is disease progression 
by RECIST 1.1. Patients may continue treatment beyond disease progression determined by 
RECIST if they are deemed to be deriving ongoing clinical benefit from treatment by the treating 
investigator.
Participants will also be removed from the study if any of the following criteria apply:
Clinically significant disease progression
Intercurrent illness that prevents further administration of treatment
Unacceptable adverse event(s)
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements
Participant decides to withdraw from the protocol therapy
General or specific changes in the participant's condition render the participant
unacceptable for further treatment in the judgment of the treating investigator
Lost to follow-up
Withdrawal of consent for data submission
Death


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Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
An ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the DF/HCC website at 
http://www.dfhcc.harvard.edu/research/clinical-research-support/document-library-forms-sops-
etc/.
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Zofia Piotrowska at 617-724-4000.
5.6
Duration of Follow Up
Participants will be followed for 30 days (+/- 7) after removal from study for adverse event 
assessment, or until all AEs present at end of treatment have resolved or stabilized. Patients will 
then be monitored every 3 months until death for survival follow up.
6.
DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP website
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
Dose delays and modifications will be made as indicated in the following table(s). The descriptions 
and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A copy of the 
CTCAE 
version 
4.0 
can 
be 
downloaded 
from 
the 
CTEP 
website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
EGF816 and gefitinib are both EGFR tyrosine kinase inhibitors and have both overlapping and 
distinct toxicities. Guidelines for the management of potentially drug-related toxicities, including 
dose interruptions and dose reductions of each drug, are provided in section 6.1. 
When possible, toxicities should be managed with appropriate medical treatment (including anti-
emetics, anti-diarrheals, etc.) Other contributing factors, including concomitant medications which 
may be contributing to the toxicity, should be identified and discontinued or dose reduced if 
appropriate. The following sections provide guidelines for dose modification and dose interruption 
(i.e., interruption and re-initiation criteria for EGF816 and gefitinib treatment). All dose 
modifications should be based on the worst preceding toxicity (CTCAE version 4.0). If, due to 
study drug related toxicity, a patient requires a dose interruption of >28 days from the intended 
day of the next scheduled dose, then the patient must be discontinued from the study treatment.


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Each patient is allowed no more than two dose reductions of each study drug. In addition, a patient 
must discontinue treatment with EGF816 and gefitinib if, after treatment is resumed at a lower 
dose, the toxicity recurs with the same or worse severity.
Exceptions can be made on a case by case basis after discussion with the Principal Investigator. In 
exceptional cases, after discussion with the PI, patients may be allowed to continue treatment or 
resume treatment with only one of the investigational drugs. All interruptions or modifications 
must be recorded on the Dosage Administration Record CRF. 
In case of study treatment interruption, visit schedule should still be followed and assessments 
performed as per Table 10-1 (study calendar.)
6.1
Conditions requiring dose modification:
The dose modification levels for EGF816 are as follows:
Table 6-1: EGF816 dose reduction
Dose Level
EGF816 Dose
0
100 mg once daily
-1
75 mg once daily
-2
50 mg once daily
The dose modification levels for gefitinib are as follows:
Table 6-2: Gefitinib dose reduction
Dose Level
Gefitinib Dose
0
250 mg once daily
-1
250 mg every other day
General guidelines for dose of modifications of EGF816 and gefitinib for all toxicities that are at 
least possibly related to study drug are listed in table 6-3. Please see sections 6.1.1-6.1.6 for 
detailed guidelines for management of specific toxicities including pneumonitis/interstitial lung 
disease, liver function abnormalities, diarrhea, rash and cardiac toxicities. Modifications to these 
recommended guidelines may be made individual cases based on the clinical judgment of the 
treating investigator.
Table 6-3: Criteria for interruption, re-initiation and dose-reduction of study treatment
Recommended Dose Modifications
Worst toxicity
CTCAE Grade
Action
Grade 1
Maintain dose level of both drugs
Grade 2
Maintain dose level of both drugs
Grade 3
Omit both EGF816 and gefitinib until resolved to 


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1 or less, reintroduce drugs one at a time with one 
dose-level reduction in each drug. EGF816 should 
be reintroduced firsta and the patient should then 
be monitored closely for  recurrence of the AE for 
at least 7 days; if there is no recurrence of > grade
1 AE, gefitinib can then be reintroduced.
Grade 4
Permanently discontinue treatment.
A. The order of drug reintroduction can be changed in clinical circumstances where the 
treating investigator feels it would be indicated to reintroduce gefitinib first.
6.1.1
Management of Pneumonitis/Interstitial Lung Disease
CTCAE Grade
Required 
investigations
Management of
pneumonitis
Action 
and 
dose 
modification
Grade 1
Asymptomatic, 
radiographic 
findings only
CT Chest; repeat 
at least every 2 
cycles until 
radiographic 
abnormalities 
resolve. 
No specific therapy 
required.
Continue both drugs with 
close monitoring for the 
development of symptoms.
Grade 2
Symptomatic, 
not interfering 
with activities of 
daily living 
(ADLs)
CT Chest
Consider PFTsa
Repeat scan at 
least every other 
cycle until 
radiographic 
abnormalities 
resolve. 
Consider 
bronchoscopy 
with biopsy and 
/or 
bronchoalveolar 
lavage (BAL)c.
Symptomatic only.
Consider 
corticosteroidsb if 
symptoms are 
clinically significant.
Interrupt both drugs until 
gefitinib and EGF816 by 1 
dose level and reintroduce 
one at a time as above. If 
symptoms fail to resolve 
within 7 days or recur after 
resumption of study drug at 
decreased dose, permanently 
discontinue both study drugs.
Grade 3
Symptomatic, 
interfering with 
ADL; O2 
indicated
CT Chest and 
Pulmonary 
Function Testing 
(PFTs)
Repeat scan at 
least every cycle 
until 
radiographic 
Short course of 
corticosteroidsb to be 
considered if 
infective origin is 
ruled out.
Permanently discontinue both 
study drugs.


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abnormalities 
resolve. 
Bronchoscopy 
with 
biopsy 
and/or BALc is 
recommended.
Grade 4
Life threatening; 
ventilator 
support indicated
CT Chest and 
required PFTs, if 
possible 
(including 
spirometry, 
DLCO, and room 
air O2 saturation 
at rest.)
Repeat scan at 
least every cycle 
until return to 
within normal 
limits. 
Bronchoscopy 
with biopsy and / 
or BALc is 
recommended, if 
possible.
Short course of 
corticosteroidsb to be 
considered if 
infective origin is 
ruled out.
Permanently discontinue 
both study drugs.
A PFT (Pulmonary function tests) to include: diffusing capacity corrected for hemoglobin (DLCO); spirometry;
resting oxygen saturation. Guideline for significant deterioration in lung function: Decrease in spirometry and/or DLCO of 
B Duration and dose of course of corticosteroids will vary according to circumstances but should be as limited as possible. 
C If bronchoscopy is performed, bronchoalveolar lavage (BAL) should be done where possible to exclude alveolar 
hemorrhage, opportunistic infections, cell count + determination lymphocyte CD4/8 count where possible.
6.1.2
Management of liver function abnormalities (bilirubin, AST, ALT)
Table 6-4: Guidelines for management of abnormal LFTs:
Investigations (Hepatic)a
Total Bilirubin (for patients with Gilbert Syndrome these dose modifications apply to changes in 
direct [conjugated] bilirubin only)
Maintain dose level with liver function test 
(LFTs) monitored as per protocol
the original dose level with close LFT 
monitoring. Resume gefitinib at the original dose 
level if LFTs remain < grade 1 after 7 days of 
EGF816.
If resolved in >7 days, then resume drugs one at a 


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time (as above) with one level dose reduction in 
each drug. 
level dose reduction and close LFT monitoring. 
Resume gefitinib with one level dose reduction if 
LFTs remain < grade 1 after 7 days of EGF816.
If resolved in 7 days discontinue patient from 
study treatment. 
The patient should be monitored weekly 
(including LFTsb), or more frequently if clinically 
indicated, until total bilirubin has resolved to 
baseline or stabilized over 4 weeks.
Grade 4 (>10.0 x ULN)
Permanently discontinue study treatment.
The patient should be monitored weekly 
(including LFTs), or more frequently if clinically 
indicated, until total bilirubin has resolved to 
baseline or stabilized over 4 weeks.
AST or ALT
Maintain dose level with LFTs monitored per 
protocol
without total bilirubin elevation to >2.0
x ULN
Maintain dose level with LFTs monitored per 
protocol
without total bilirubin elevation to >2.0
x ULN
baseline), then resume EGF816 with one level 
dose reduction and close LFT monitoring. 
Resume gefitinib with one level dose reduction if 
LFTs remain < grade 1 after 7 days of EGF816.
Permanently discontinue
Grade 3 elevation recurs.
If AST or ALT > 5 x ULN in patients with 
ALT > 8 x  ULN in patients with baseline AST or 
immediate 
testing for viral hepatitis infection or 
reactivation should be performed, see Section 
6.1.3. Patients who have HBV-DNA monitoring 
during the study should be re-tested immediately.
Grade 4 (>20.0 x ULN) without total
bilirubin elevation to >2.0 x ULN
ade 1 (or to 
baseline), then resume EGF816 with one level 
dose reduction and close LFT monitoring. 
Resume gefitinib with one level dose reduction if 


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LFTs remain < grade 1 after 7 days of EGF816. 
However, permanently discontinue study 
treatment if the elevation of Grade 4 recurs.
If AST or ALT>20.0 x ULN immediate testing 
for viral hepatitis infection or reactivation 
should be performed, see Section 6.1.3. Patients 
who have HBV-DNA monitoring during the 
study should be retested immediately.
Combinedb elevation of AST or ALT and concurrent total bilirubinc
For patients with normal baseline ALT or AST 
or total bilirubin value:  AST or ALT >3.0 x 
ULN combined with total bilirubin >2.0 x 
ULN without evidence of cholestasisd
OR
For patients with elevated baseline AST or 
ALT or total bilirubin value:  
[AST or ALT>2x baseline AND > 3.0xULN] 
OR [AST or ALT > 8.0 x ULN], whichever is 
lower, combined with [total bilirubin >2x 
baseline AND >2.0xULN]
Discontinue study treatment permanently in the 
absence of signs of cholestasis, hemolysis, and if 
alternative causes of the liver injury have been 
excluded (e.g., concomitant use of hepatotoxic 
drug(s), alcoholic hepatitis, viral hepatitis etc.)
Repeat LFTs as soon as possible, preferably 
within 48 hours from awareness of the abnormal 
results, then with weekly monitoring of LFTsb), 
or more frequently if clinically indicated, until 
AST, ALT, or bilirubin have resolved to baseline 
or stabilized over 4 weeks. Testing for viral 
hepatitis infection or reactivation should be 
performed, see Section 6.1.3 and Table 6-5.
a. If Grade 3 or 4 hyper-bilirubinemia is due to the indirect (non-conjugated) component only, and hemolysis as the 
etiology has been ruled out as per institutional guidelines (e.g., Review of peripheral blood smear and haptoglobin 
b. “Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold
c. If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative 
action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is needed for 
one parameter and discontinue treatment is required for another parameter). After all elevations resolve to the 
defined thresholds that allow treatment re-initiation, re-start the treatment either at the same dose or at one dose 
lower if meeting a criterion for dose reduction
d. “Cholestasis” defined as: ALP elevation (>2xULN and R value< 2) in patients without bone metastasis, or 
elevation of ALP liver fraction in patients with bone metastasis
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It denotes 
the relative pattern of ALT and/or ALP elevation is due to cholestatic or hepatocellular liver injury
6.1.3
HBV screening tests, on study monitoring, and management of HBV reactivation:
1. All patients must be screened with HBV serologic markers: HBsAg, HBsAb, and HBcAb.  


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2. If HBsAg and/or HBcAb are positive, test for HBV-DNA. 
3. Refer to Table 6-5 for actions to be taken based on screening HBV results.
4. If a patient is HBsAg positive or HBV-DNA positive BUT is not on antiviral therapy: 
a.
Consult a physician with expertise in managing HBV
b. Initiate antiviral therapy with entecavir 0.5mg QD 1-2 weeks prior to first dose of EGF816 
treatment. 
c.
If a patient cannot take entecavir, contact the principal investigator to select an appropriate 
antiviral therapy.
d. If antiviral therapy cannot be given, the patient is not eligible for the study.
e.
During the study, monitor HBV-DNA every 12 weeks (or more frequently if clinically 
indicated). (Refer to Table 6-6 if there is evidence of viral reactivation on study)
f.
Antiviral therapy should continue for at least 4 weeks after the last dose of EGF816.
5. Patients who are HBsAg positive or HBV-DNA positive at screening and already have been 
receiving antiviral therapy are eligible provided the patient remains on antiviral treatment.  
a.
Identify a consulting physician with expertise in managing HBV who can provide 
treatment guidance, if required, while the patient is on study.
b. HBV-DNA should be monitored every 12 weeks (or more frequently if clinically 
indicated).
c.
Antiviral therapy should continue for at least 4 weeks after the last dose of EGF816. 
6. Refer to Table 6-6 for guidelines of management for HBV reactivation. 
Table 6-5: Actions to be taken based on hepatitis B results screening
Test
Result
Result
Result
Result
Result
HBV-DNA
+
+ or -
-
-
-
HBsAg
+ or -
+
-
-
-
HBsAb
+ or -
+ or -
+
and no 
prior HBV 
vaccination
-
or + with 
prior HBV 
vaccination
-
or + with 
prior HBV 
vaccination
HBcAb
+ or -
+ or -
+ or -
+
-


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Test
Result
Result
Result
Result
Result
Required 
actions
* Consult a physician with expertise 
in managing HBV. 
After the consultation, antiviral 
therapy should be started 1-2 weeks 
prior to 1st dose of EGF816 treatment.
Recommended antiviral therapy is 
entecavir 0.5mg QD. Contact the 
study PI if a patient cannot take 
entecavir.
Monitor HBV-DNA every 12 weeks 
(or more frequently if clinically 
indicated).
Antiviral therapy should continue for 
at least 4 weeks after the last dose of 
EGF816.
No antiviral therapy.
.
Monitor HBV-DNA 
every 4 weeks.
No 
antiviral 
therapy.
HBV-DNA
screening 
not 
required 
unless 
HBsAg 
and/or 
HBcAb are 
positive 
Table 6-6 Guidelines for management of HBV reactivation


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HBV reactivation (with or without clinical signs and symptoms)*
Screening test 
results
Monitoring test 
results that define 
HBV reactivation
Actions to be taken
Positive HBV-
DNA
OR
Positive HBsAg
Increase of 1 log in 
HBV-DNA relative 
to screening HBV-
DNA value 
OR
New appearance of 
measurable HBV-
DNA
Interrupt EGF816 and gefitinib treatment. Assess 
patient compliance with antiviral therapy. Consult a 
physician with expertise in managing HBV and 
consider changing antiviral therapy.
While patient is on antiviral therapy, continue 
interruption of EGF816 administration until 
resolution to:
-DNA levels and
1) if ALT elevation was observed
gefitinib should be re-started, one at a time, at the 
same dose level unless dose reduction/interruption 
is indicated due to any other reason. Resume 
EGF816 first with close LFT monitoring. Resume 
gefitinib if LFTs remain < grade 1 after at least 7 
days of EGF816. Antiviral therapy should continue 
for at least 4 weeks after the last dose of EGF816.
If resolution occurs > 21 days, contact study PI for 
approval of restarting of EGF816.
If restarting of EGF816 and gefitinib is 
approved: follow the same guidelines as 
above.
If restarting of EGF816 and gefitinib is 
NOT approved: discontinue study 
treatment. Continue antiviral therapy for at 
least 4 weeks after the last dose of EGF816
Monitor HBV-DNA every 12 weeks (or 
more frequently if clinically indicated).


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HBV reactivation (with or without clinical signs and symptoms)*
Screening test 
results
Monitoring test 
results that define 
HBV reactivation
Actions to be taken
Negative HBV-
DNA
AND
Negative HBsAg
New appearance of 
measurable HBV-
DNA
Interrupt EGF816 and gefitinib treatment. Consult 
a physician with expertise in managing HBV. After 
the consultation, start antiviral therapy.
While patient is on antiviral therapy, continue 
interruption of EGF816 and gefitinib 
administration until resolution to:
-DNA levels and
1) if ALT elevation was observed
EGF816 and gefitinib should be re-started 
at the same dose level unless dose 
reduction/interruption is indicated due to 
any other reason. Reintroduce EGF816 first; 
if LFT remains < grade 1 after at least 7
days on EGF816, resume gefitinib.
Antiviral therapy should continue for at 
least 4 weeks after the last dose of EGF816.
If resolution occurs > 21 days Contact study 
PI for approval of restarting of EGF816.
If restarting of EGF816 and gefitinib is approved: 
follow the same guidelines as above. 
If restarting of EGF816 and gefitinib is NOT 
approved: discontinue EGF816 treatment. Continue 
antiviral therapy for at least 4 weeks after the last 
dose of EGF816.
Monitor HBV-DNA every 12 weeks (or more 
frequently if clinically indicated).
* All reactivations of HBV are to be recorded as serious adverse event (SAE). Date of viral reactivation is the 
date on which the defined lab results for reactivation were met (e.g. for a patient who was HBV-DNA positive on 
01-JAN-15 and whose ALT reached > 5 × ULN on 01-APR-15, the date of viral reactivation is 01-APR-15).
HCV screening tests, on study monitoring, and management of HCV reactivation 
1. Screen all new patients for HCV-Ab. If HCV-Ab is detected then check HCV-RNA.
2. Only patients with negative HCV-Ab or with positive HCV-Ab but undetectable level of 
HCV-RNA are eligible to be enrolled in the study (assuming all other eligibility criteria are 
met). Patients with detectable HCV-RNA are not eligible to be enrolled in the study.


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3. Patients with known history of HCV infection and undetectable HCV-RNA at screening should 
be monitored every 8 weeks (or more frequently if clinically indicated) with HCV RNA-PCR 
for HCV reactivation.
4. Refer to Table 6-7 for definition of HCV reactivation and the management guidelines.
Table 6-7 Guidelines for management of HCV reactivation
HCV reactivation (with or without clinical signs and symptoms)1
Screening test 
results
Monitoring test 
results that define 
HCV reactivation
Action to be taken
Knowledge of past 
hepatitis C 
infection with no 
detectable HCV-
RNA
New appearance of 
detectable HCV-RNA
Interrupt EGF816 and gefitinib treatment. 
Consult a physician with expertise in managing 
HCV. After the consultation, start antiviral 
therapy.
While patient is on antiviral therapy, continue 
interruption of EGF816 and gefitinib 
administration until resolution to:
no detectable HCV-RNA and
grade 1) if ALT elevation was observed.
should be re-started at the same dose level 
unless dose reduction/interruption is indicated 
due to any other reason. Reintroduce EGF816 
first; if LFT remains < grade 1 after at least 7 
days on EGF816, resume gefitinib.
If resolution occurs > 21 days Contact study PI 
for approval of restarting of EGF816.
If restarting of EGF816 and gefitinib is 
approved: follow the same guidelines as 
above. 
If restarting of EGF816 and gefitinib is 
NOT approved: permanently 
discontinue the patient from EGF816 
treatment
Monitor HCV-RNA every 8 weeks (or more 
frequently if clinically indicated)


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1 All reactivations of HCV are to be recorded as serious adverse event (SAE). Date of viral reactivation is the date on which 
the defined lab results for reactivation were met (e.g., for a patient whose HCV-RNA was detectable on 01-JAN-15 and ALT 
reached > 5 x ULN on 22-JAN-15, the date of viral reactivation is 22-JAN-15).
On study monitoring of liver function test (LFT) for all patients
LFTs should be monitored for all patients as per protocol, or more frequently if clinically indicated.
ALT > 8 x ULN in patients with baseline ALT > 3 x 
immediately
1. Perform test(s) for viral hepatitis infection or reactivation: all patients should be screened with 
viral hepatitis panel (HAV-Ab-IgM, HBsAg, HBcAb-IgM, and HCV-Ab).  In addition:
a.
Patients who have HBV-DNA monitoring during the study should be re-tested for HBV-
DNA immediately; refer to Table 6-6 for definition and management of HBV reactivation.
b. Patients who have HCV-RNA monitoring during the study should be re-tested for HCV-
RNA immediately; refer to Table 6-7 for definition and management of HCV reactivation.
2. If any of the above tests indicate:
a.
HBV reactivation: refer to Table 6-6 for management guidelines.
b. HCV reactivation: refer to Table 6-7 for management guidelines.
c.
New viral infection: immediately interrupt EGF816 and gefitinib dosing, consult a 
physician with expertise in managing viral hepatitis and contact study PI for further 
discussion.
3. Perform other relevant tests/procedures as clinically indicated.
4. Follow the dosing modification for ALT elevation according to guidelines in Table 6-4.
6.1.4
Management of diarrhea
Table 6-8: Guidelines for management of diarrhea
Diarrheaa
Grade 1
Maintain dose level but adjust anti-diarrheal treatment
Grade 2 (despite maximal 
antidiarrheal medication)
reintroduce EGF816 same dose level; if diarrhea remains < grade 
1 after at least a week on EGF816, resume gefitinib.
and reintroduce one at a time as above. 
Grade 3 (despite maximal 
antidiarrheal medication)
Omit both drugs un
EGF816 and gefitinib by 1 dose level and reintroduce one at a 
time (as above) if diarrhea is grade < 1 after at least one week on 
EGF816.
Grade 4 (despite maximal 
antidiarrheal medication)
EGF816 and gefitinib by 1 dose level and reintroduce one at a 


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time (as above) if diarrhea is grade < 1 after at least one week on 
EGF816.
a. Antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea.
Grade 1-2 diarrhea should be managed with Loperamide (4mg at first onset, followed by 2mg every 
2-4 hours until diarrhea free for 12 hours with maximum daily dose of 16 mg per 24 hours.) If 
loperamide is ineffective, consider adding Lomotil (5 mg, four times a day), or tincture of opium 
(15-20 drops orally every 4 hours) or octreotide (150 to 300 mcg SQ twice daily).
6.1.5
Management of rash
Both EGF816 and gefitinib are known to cause rash, but the rash typically associated with each 
drug is distinct. Gefitinib-associated rash is generally an acneiform, papular rash while that 
associated with EGF816 is more commonly maculopapular, pruritic and without true acneiform 
lesions. The management of each type of rash is different, and both are outlined below.
Table 6-9: Guidelines for prevention and symptomatic care of rash/skin toxicities
Type of care
Action
Prevention/Prophylaxis
Starting from Day 1 for all
patients
Avoid unnecessary exposure to sunlight
Apply broad-
daily
Use thick, alcohol-free emollient cream (e.g. glycerin and 
cetomacrogol cream) on dry areas of the body at least twice 
daily
Symptomatic lesions
Pruritic lesions: cool compresses and oral antihistamine 
therapies
Desquamation: thick, alcohol-free emollient cream and mild 
soap
Paronychia: antiseptic bath and topical antibiotics; if no 
improvement,
consult dermatologist
Infected lesions: appropriate topical or systemic antibiotics
Patients who develop rash/skin toxicities should be evaluated by a qualified physician and 
receive symptomatic and supportive care management.
Table 6-10. Guidelines for management of maculopapular rash
CTCAE Grade
Adverse Event Management
Action 
and 
Dose 
Modification
Grade 1
Initiate appropriate 
symptomatic care (Refer to 
Table 6-9)
Use mild-strength topical 
steroid (e.g. 1% 
hydrocortisone cream) on 
Continue both study drugs at 
same dose level


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affected areas 
Re-assess after 1 week
Grade 2
Initiate appropriate 
symptomatic care (Refer to 
Table 6-9)
Use moderate-strength topical 
steroid (e.g. 2.5% 
hydrocortisone cream or 0.5% 
fluticasone cream) on affected 
areas PLUS low-dose oral 
steroid (e.g. 5mg-10mg PO 
QD for 1 week) with taper
Re-assess after 1 week
Continue both study drugs at 
same dose level
If no recovery or worsened 
within 1 week, interrupt 
EGF816 and gefitinib until 
1, restart EGF816 at one level 
reduced from the previous 
dose level3. Drugs should be 
reintroduced one at a time; if 
no recurrent rash occurs with 
introduction of EGF816, 
gefitinib can be resumed at 
the original dose level.
Grade > 3
Initiate 
appropriate 
symptomatic care (Refer to 
Table 6-9)
Use moderate-strength topical 
steroid on affected areas PLUS 
mid-dose oral steroid (e.g. 20-
40mg PO QD for 1 week) with 
taper over 1-2 weeks or IV 
steroid 
(e.g. 
methylprednisolone 20-30mg 
IV BID for 3 days) if clinically 
indicated
Consult dermatologist
Interrupt both study drugs 
1, restart EGF816 at one level 
reduced from the previous 
dose level. Drugs should be 
reintroduced one at a time; 
EGF816 should be resumed 
first and, if no recurrent rash 
occurs within a week, 
gefitinib can be resumed at 
original dose level.
Oral antihistamine therapies 
(e.g.
levocetirizine 5mg QD, 
desloratadine 5mg QD, or 
fexofenadine 180 mg QD) 
should be given concurrently 
with study drugs for 4 weeks 
when restarting treatment.
within 3 weeks, permanently 
discontinue EGF816. 
Gefitinib can be continued.
Patients who develop more 
rash will be permanently 
discontinued from EGF816.
1. Maculopapular rash includes macular rash, papular rash, and maculopapular rash.


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2. For all grades of maculopapular rash, consider skin biopsy for pathologic evaluation.
Table 6-11. Guidelines for management and dose modification of other rashes including 
acneiform rash.
Adverse 
Event 
Management
Adverse 
Event 
Management
Grade 1
Monitor for change in 
severity and consider 
symptomatic and/or topical 
treatment (Refer to Table 6-
9)
Re-assess after 2 weeks
Continue study drug at same 
dose level
Grade 2
Initiate appropriate 
symptomatic care (Refer to 
Table 6-9)
Depending on the type of 
rash, a variety of agents can 
be used including mild to 
moderate strength steroid 
creams, topical or systemic 
antibiotics, topical or 
systemic antihistamines, and 
retinoid creams.
Re-assess after 2 weeks
Continue study drugs at same 
dose level
If no recovery or worsened 
within 2 weeks, interrupt 
both study drugs until rash 
Grade 1, then restart gefitinib 
at one reduced dose level and 
continue same EGF816 dose.
Grade 3 
Initiate appropriate 
symptomatic care (Refer to 
Table 6-9)
Depending on the type of 
rash, a variety of agents can 
be used including mild to 
moderate strength steroid 
creams, low-dose oral 
steroids, topical or systemic 
antibiotics, topical or 
systemic antihistamines, and 
retinoid creams.
Consult dermatologist
Interrupt both study drugs 
1.
Grade 2, restart gefitinib at 
one reduced dose level. If no 
rash > grade 1 recurs after at 
least 7 days on gefitinib, 
EGF816 can be then be 
resumed at the original dose 
level. If rash > grade 1 recurs 
within 1 week, interrupt both 
drugs again until rash 
resume gefitinib at the 
reduced dose level, monitor 
for recurrence and then 
resume EGF816 reduced by 
one dose level.


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within 3 weeks, permanently 
discontinue study drugs.
Patients who develop more 
rash will be permanently 
discontinued from study 
treatment
6.1.6
Management of Cardiac Toxicities
Cardiac Investigations
Electrocardiogram QT corrected (QTc) interval prolonged
Grade 1 (QTc 450-480 ms)
Maintain dose level.
Grade 2 (QTc 481-500 ms)
Maintain dose level.
on at least two 
separate ECGs)
Omit EGF816 and gefitinib until QTc is less than 
481 ms and then decrease EGF816 by one dose 
level; monitor QTc after 48 hours and 1 week on 
EGF816, if it remains < grade 1 after 7 days of 
EGF816, resume gefitinib with one level dose-
reduction and continue to monitor QTc closely.
- Perform an analysis of serum potassium and, if 
below lower limit of normal, correct with 
supplements to within normal limits.- Repeat 
ECG in 24 hours, or less, as clinically indicated; 
continue monitoring as clinically indicated until 
QTc <481 ms
- Repeat ECGs 7 days after dose resumption for 
all patients who had therapy interrupted due to 
Bradycardia
Grade 1 or 2
Omit EGF816 until recovery to asymptomatic 
bradycardia or to a heart 
gefitinib.
Evaluate concomitant medications known to 
cause bradycardia and adjust the dose of EGF816
Grade 3 or
Grade 4 (in patients taking a concomitant 
medication also known to cause bradycardia or 
a medication known to cause hypotension)
Omit EGF816 and gefitinib until recovery to 
bpm
If grade with a concomitant medication-- if the 
concomitant medication can be adjusted or 
discontinued, resume EGF816 with a decrease by 
one dose level with frequent monitoring, if no 
recurrent bradycardia after 7 days on treatment, 
resume gefitinib.


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Grade 4 (in patients who are not taking a 
concomitant medication also known to cause 
bradycardia or known to cause hypotension)
Permanently discontinue EGF816. If bradycardia 
resolved, continue gefitinib.
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting.
7.1
Adverse Event Characteristics
Expected Adverse Events
Adverse events can be 'Expected' or 'Unexpected’. Expected adverse events are those that have 
been previously identified as resulting from administration of the agent. For the purposes of this 
study, an adverse event is considered expected when it appears in the Investigator’s Brochure 
Unexpected Adverse Events
For the purposes of this study, an adverse event is considered unexpected when it varies in 
nature, intensity or frequency from information provided in the Investigator’s Brochure.
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
For expedited reporting purposes only:  
-
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions.
Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.


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-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
7.2
Expedited Adverse Event Reporting
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of 
causality that: 
Results in death
Is life-threatening. Life-threatening means that the person was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form.
Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour 
hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered SAEs if the illness or disease 
existed before the person was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (e.g., surgery performed earlier than planned).
Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions.
Is a congenital anomaly or birth defect; or
Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
Events not considered to be serious adverse events are hospitalizations for:
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures
Abnormal lab values that do not require treatment
treatment planned before signing informed consent for a pre-existing condition that did not 
worsen 
emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission
respite care
7.2.1
Investigators must report to the Overall PI any serious adverse event (SAE) that 
occurs after the initial dose of study treatment, during treatment, or within 30 days 
of the last dose of treatment on the local institutional SAE form. 
7.2.2
DF/HCC Expedited Reporting Guidelines
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 


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Human Research Studies (OHRS) per the DFCI IRB reporting policy.
7.2.3
Reporting to Novartis
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the patient 
has provided the main informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department - Fax: (877-778-9739).
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with the 
case report form documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. Each re-occurrence, complication, or progression 
of the original event should be reported as a follow-up to that event regardless of when it occurs. 
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, whether the blind was broken or not, and whether the patient continued or 
withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Drug Safety and Epidemiology (DS&E) department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to issue an 
Investigator Notification (IN), to inform all investigators involved in any study with the same 
drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries.
7.3
Expedited Reporting to the Food and Drug Administration (FDA)


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The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.
7.4
Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy. 
7.5
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms. AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
8. PHARMACEUTICAL AGENT INFORMATION
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.1.
8.1
EGF816
The investigator or responsible site personnel must instruct the patient or caregiver to take 
EGF816 as per protocol. EGF816 will be dispensed to the patient by authorized site personnel 
only. Dose strength and treatment schedule are described in Table 6-1 and 6-2 and sections 5.3.1 
and 5.3.2. All dosages prescribed to the patient and all dose changes during the study must be 
recorded on the Dosage Administration Record CRF. Study treatment including instructions for 
administration is dispensed by study personnel. Patients will be provided with adequate supply of 
EGF816.
8.1.1
EGF816 packaging and labeling
The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label. Responsible site personnel will identify the study treatment package(s) to 
dispense to the patient by using the IRT and obtaining the medication number(s). Site personnel 
will add the patient number on the label. All information on labels will be included in the 
pharmacy reversibility record. Medication labels will be in compliance with the US legal 
requirements. They will include storage conditions for the drug and the medication number but 
no information about the patient.
8.1.2
EGF816 Supply and storage


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EGF816 must be received by designated personnel at the study site, handled and stored safely 
and properly, and kept in a secured location to which only the investigator and designated site 
personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels and in the Investigator’s Brochure.
8.1.3
EGF816 Compliance and Accountability
8.1.3.1
EGF816 Compliance
Compliance will be assessed by the investigator and/or study personnel at each 
patient visit and information provided by the patient and/or caregiver will be captured 
in the Drug Accountability Form. This information must be captured in the source 
document at each patient visit.
8.1.3.2
EGF816 Accountability
The investigator or designee must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability log. Drug accountability will be 
noted by the field monitor during site visits and at the completion of the study. Patients 
will be asked to return all unused study treatment and packaging on a regular basis, at 
the end of the study or at the time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator 
will return all used and unused study treatment, packaging, drug labels, and a copy of 
the completed drug accountability log to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site.
8.1.4
EGF816 Disposal and Destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or third 
party, as appropriate. . IP returned by participants and expired medications will be destroyed at 
the investigational site.
8.2
Gefitinib
Gefitinib will be obtained by each patient through a commercial pharmacy. Patients will be 
required to bring gefitinib supply in at the start of each treatment cycle for verification by study 
staff.
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1
Tumor biopsies


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9.1.1
Pre-treatment biopsy:
Patients will undergo a mandatory fresh core needle or excisional pre-treatment 
biopsy within 28 days of starting treatment. The site of biopsy will be selected by the 
treating investigator; cytology specimens and FNA specimens will not be accepted. 
Cell blocks made from pleural or pericardial fluid are acceptable.At least six cores 
will be obtained; one fresh sample for single-cell sorting and RNA sequencing, one 
each for patient-derived cell line and patient-derived xenograft establishment, one 
core snapfrozen and one core fixed in formalin and embedded in paraffin for 
subsequent DNA and protein-based studies. An FNA or core sample will be sent for 
clinical testing to confirm non-small cell histology.  Any additional cores will be 
transported to the MGH Center for Cancer Research at the Charlestown Navy Yard 
campus.
Although the results of local testing will be used to confirm EGFR mutation status for 
study screening and registration, all samples will be analyzed centrally post-hoc by 
NGS for confirmation of pre-treatment EGFR status.
9.1.2
On-treatment biopsy
A mandatory on-treatment core needle or excisional biopsy will be obtained between 
D15 and 21 of cycle 1. The site of biopsy will be selected by the treating investigator,
preferably the same site as the pre-treatment biopsy, however if this is not possible, a 
biopsy of a different site is allowed; cytology specimens and FNA specimens will not 
be accepted. Cell blocks made from pleural or pericardial fluid are acceptable. At 
least four cores will be obtained. One fresh core will be saved in media for single-cell 
sorting and RNA analysis, one snapfrozen and two cores fixed in formalin and 
embedded in paraffin for subsequent DNA and protein-based studies. Any additional 
cores will be sent to the MGH Center for Cancer Research at the Charlestown Navy 
Yard campus.
9.1.3
Post-progression tumor biopsy
A post-treatment core needle or excisional biopsy will be obtained at the time of 
disease progression. The exact timing of this biopsy will be at the discretion of the 
treating investigator, but must occur at or after the patient reaches PD by RECIST. 
The site of biopsy will be selected by the treating investigator; cytology specimens
and FNA specimens will not be accepted. Cell blocks made from pleural or 
pericardial fluid are acceptable. At least six cores will be obtained; one fresh sample 
for single-cell sorting and RNA sequencing, one each for patient-derived cell line and 
patient-derived xenograft establishment, one core snapfrozen and one core fixed in 
formalin and embedded in paraffin for subsequent DNA and protein-based studies. 
An FNA or core sample will be sent for clinical testing to confirm non-small cell 
histology.  Any additional cores will be transported to the MGH Center for Cancer 
Research at the Charlestown Navy Yard campus.


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9.1.4
Analysis of pre-treatment, on-treatment and post-treatment tumor biopsies
Pre-treatment and progression biopsies will be used to establish patient-derived cell lines as has been 
previously described (Crystal, et al, Science 2015.) Next-generation sequencing will be performed at 
Novartis. Because the scientific assays used to interrogate tumor specimens are constantly evolving, 
additional tumor samples may be used for research purposes in exploratory studies. These studies may 
include DNA sequencing (including gene-specific, whole exome, and whole genome sequencing), 
RNA sequencing (including RT-PCR, Q-PCR, and whole transcriptome sequencing), DNA 
methylation studies (including CHIP-sequencing), and proteomics assays. Live tissue may also be 
cultured in vitro and/or implanted into immunodeficient mice to generate xenograft models. Any 
exploratory research studies will be performed at the MGH Center for Cancer Research at the 
Charlestown Navy Yard Campus or at the Novartis Institute for Biomedical Research. 
9.2
Longitudinal circulating tumor DNA analyses
Blood samples will be collected for circulating tumor DNA analyses at screening, C1D1, C1D3 
(as close to 48 hours after the first dose as possible), C1D8, C1D15 and on the first day of each 
subsequent cycle (every 28 days) until the end of treatment. Two Streck tubes (a total of 20 cc of 
blood) will be collected at each time point. Samples will be sent to the Charlestown Navy Yard 
via US Ground courier for isolation of plasma within 8 hours of sample collection. Plasma will 
be isolated from each tube according to the protocol in Appendix C. Plasma will be stored frozen 
at -80 degrees until ctDNA extraction. The remaining whole blood will be used to extract 
peripheral blood mononuclear cells for germline analyses. 
Next-generation sequencing will be used to analyze pre-treatment ctDNA sample and the one 
obtained at progression to identify mechanisms of resistance to the EGF816/gefitinib 
combination. The intervening samples will then be studied via ddPCR or next-generation 
sequencing to further characterize dynamic molecular changes occurring in ctDNA over time. 
Because the scientific assays used to interrogate ctDNA specimens are constantly evolving, 
additional samples may be used for research purposes in exploratory studies.
Please Note: 
Sam Bilton (sbilton@mgh.harvard.edu) should be alerted 24hrs prior to each sample being 
drawn if possible (or as soon as it is determined that a sample will be drawn).
561-901-5369
Samples Shipped To:
MGH Charlestown Navy Yard Facility
Hata Laboratory
149 13th Street, Room 7316
Charlestown, MA 02129
9.3
Pharmacokinetic studies:
A pre-EGF816 dose blood sample will be obtained at baseline on C1D1 and on C1D15 for 
pharmacokinetic analysis to establish steady state levels of EGF816 and gefitinib.  For each 
timepoint, at least two 2mL of blood will be collected in a properly labelled plastic lavender top 
K2-EDTA-tube. Immediately after each tube of blood is drawn, it should be inverted gently 


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several times to ensure the mixing of tube contents. Avoid prolonged sample contact with the 
rubber stopper. Place the tube upright in a test tube rack surrounded by ice until centrifugation. 
Within 30 minutes, centrifuge the sample at between 3-5 degrees Celsius for 10 minutes at 
approximately 2000g (or centrifuge the sample at room temperature if tubes placed on ice 
quickly after processing). Immediately after centrifugation, aliquot the collected plasma into two 
uniquely labeled tubes (PK plasma A and B). The tubes will be frozen immediately over solid 
carbon dioxide (dry ice) then kept frozen at -70 degrees Celsius or colder pending analysis, 
which will be performed in collaboration with WuXi AppTec.
Samples will be shipped frozen at -70 to: 
Li Li
288 Fute Zhong Road,
Waigaoqiao Free Trade Zone
Shanghai 200131
China
Tel: 86 21 50464116
E-mail: li_li_003152@wuxiapptec.com


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10. STUDY CALENDAR
Baseline evaluations are to be conducted within 28 days prior to start of protocol therapy.  Scans 
must be done <4 weeks prior to the start of therapy.  In the event that the participant’s condition 
is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of 
the next cycle of therapy.
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted.
Table 10-1 Study Calendar
Pre-
Study
C1D1
C1D3
C1D8
C1D15
C2D1 and 
D1 of all 
subsequen
t cyclesn
Disease 
Progression
Off Studyk
EGF816
X------------------------------------------------
Xa
Gefitinib
X------------------------------------------------
Xa
Informed consent*
X
Medical history
X
X
X
X
X
X
Concurrent meds
X
X
X
X
X
X
X
Physical exam 
(including VS, weight)
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
CBC w/diff
X
Xl
X
X
X
X
X
Serum chemistryb
X
X
X
X
X
X
X
Hepatitis serologiesc
X
Urinalysisd
X
ECG
X
Xm
Xm
PK Sampling
Xj
Xj
Adverse event 
evaluation
X
X
X
X
X
Radiologic evaluation 
(CT C/A/P, +/- brain 
imaging) e
X
X
B-HCG (serum or 
urine)
X
X
X
Tumor biopsy
Xf
Xg
Xh
Plasma for ctDNA 
analysis
X
X
Xi
X
X
X
X
X


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* Re-consent is required if treatment starts more than 28 days after the original consent.
a.
Treatment with EGF816 and gefitinib can be continued beyond progression at the discretion of the treating 
investigator (see section 5.5)
b.
Sodium, potassium, calcium, magnesium, glucose, creatinine, total bilirubin, alkaline phosphatase [ALP], 
aspartate transaminase [AST], alanine transaminase [ALT], blood urea nitrogen [BUN], total protein, 
albumin and lactic dehydrogenase [LDH]. If screening chemistry is drawn > 7 days before C1D1, chemistry 
should be redrawn on C1D1. These do not need to re-meet eligibility.
c.
Screening labs should include HBsAg, HBsAb, HCV-Ab, and HBcAb. Check HBV-DNA if HBsAg and/or 
HBcAb are positive (see section 6.1.3). In addition, HBV DNA and/or HCV RNA monitoring will be required 
for some patients based on initial screening (see section 6.1.3)
d.
Urinalysis should be performed at baseline and then only if clinically indicated.
e.
Radiologic evaluation (CT chest, abdomen and pelvis) should be performed every 8 weeks of treatment. After 
completing 1 year of treatment, radiologic evaluations should be performed every 12 weeks. Brain imaging 
(MRI, or CT with contrast in patients with contraindications to MRI) should be obtained every 8 weeks for 
patients with known brain metastases at the start of treatment. For patients without known baseline brain 
metastases, CNS imaging should be obtained if clinically indicated based on symptoms.
f.
Pre-treatment core needle or excisional should be done within 28 days of start of treatment
g.
On-treatment biopsy should be performed between D15 and D21 of cycle 1. On the day of the on-treatment 
biopsy, patients should take both study drugs. Their morning gefitinib dose can be taken with sips of water.
h.
Post-treatment core needle biopsy should be obtained at the time of disease progression. The exact timing of 
this biopsy will be at the discretion of the treating investigator, but must occur at or after the patient reaches 
PD by RECIST.
i.
Cycle 1, Day 3 ctDNA blood draw should be performed as close to 48 hours after first dose as possible.
j.
Pre-dose steady state levels of EGF816 and gefitinib will obtained on C1D1 and C1D15.
k.
The duration of EGF816 and gefitinib administration will be determined as specified in section 5.5. Follow 
up for survival will be performed by telephone contact or clinic visits every 3 months (+/-1 month) after exit 
visit until the participant is deceased or lost to follow up.
l.
If screening CBC with differental is done > 7 days from C1D1, CBC with differental should be repeated on 
C1D1. These do not have to remeet eligibility.
m. ECGs at each cycle visit should be captured pre-dose
n.
After completing 1 year of treatment, visits should be performed every 6 weeks.


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11. MEASUREMENT OF EFFECT
11.1
Antitumor Effect – Solid Tumors
For the purposes of this study, participants should be re-evaluated for response 8 weeks. After 
completing one year of treatment, re-evaluation should occur every 12 weeks. In addition to a 
baseline scan, confirmatory scans should also be obtained 4 (not less than 4) weeks following 
initial documentation of objective response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria.
11.1.1 Definitions
Evaluable for Target Disease response. Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.)
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions. 
11.1.2 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as 
20 mm by
chest x-ray or 10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.
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 no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 


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(longest diameter <10 mm or pathological lymph nodes with 10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered
non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since 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 non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions.
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
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), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up. 
11.1.3 Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler, calipers,
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 


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Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable. 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible.
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.  
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later data and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT is advised. 
11.2
Response Criteria


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11.2.1 Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters 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.  (Note:  
the appearance of one or more new lesions is also considered progressions).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
11.2.2 Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis).
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.    
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator).
11.2.3 Evaluation of New Lesions
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 


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flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered.
11.2.4 Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria.
For Participants with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks Confirmation**
CR
Non-CR/Non-
PD
No
PR
>4 wks Confirmation**
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4
wks from baseline**
PD
Any
Yes or No
PD
no prior SD, PR or CR
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**
Only for non-randomized trials with response as primary endpoint.
***
In exceptional circumstances, unequivocal progression in non-target lesions may be
accepted as disease progression.
Note: Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment.
For Participants with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response


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CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised
11.2.5 Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or
death due to any cause. Participants without events reported are censored at the last 
disease evaluation).
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation.
Duration of stable disease:  Stable disease 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, including the baseline measurements. 
11.2.6 Progression-Free Survival
Progression-Free Survival (PFS) is defined as the time from randomization (or 
registration) to the earlier of progression or death due to any cause. Participants alive 
without disease progression are censored at date of last disease evaluation.
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive.
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation.
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported.


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12. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements).
12.1
Data Reporting
12.1.1 Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study.
12.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality in accordance with DF/HCC SOPs.
12.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team.
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. 
13. STATISTICAL CONSIDERATIONS
13.1
Study Design/Endpoints
This is a phase II study designed to evaluate the efficacy of the combination of EGF816 and 
gefitinib in the first-line treatment of EGFR-mutant non-small cell lung cancer. The primary end-
point is proportion of patients free from progression at 9 months. The study is designed as a 
Simon two-stage study. The null hypothesis is that EGF816 does not add any benefit to gefitinib 
monotherapy, with the assumption that the median PFS for gefitinib monotherapy is 9 mo, in 
other words 50% of patients will be free from progression at 9 months. The study is designed to 
have 80% power at the 0.05 significance level to show that the combination regimen of gefitinib 
plus EGF816 increases the proportion of progression-free patients at 9 months to 73% using a 


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one-sided binomial test. The total study size is 36 patients. 11 patients will be enrolled in the first 
stage of the study, with a planned second stage of 25 patients if at least 7 patients in the first-
stage are progression-free at nine month.  The rejection criteria for the null would be having 23 
patients who are progression-free by 9 months. Based on our prior experience with first-line 
treatment of pateints with EGFR mutant NSCLC, we do not expect any patients to be lost to 
follow-up or unevaluable prior to the 9 month timepoint.
13.2
Sample Size, Accrual Rate and Study Duration
As stated above, 11 patients will be enrolled in the first stage of the study, with a planned second 
stage of 25 patients if at least 7 patients in the first-stage are progression-free at nine months. The 
null will be rejected and the study deemed positive if at least  23 total patients  are progression-
free at 9 months. 
We expect to accrue approximately 10-15 patients/year, therefore assuming the study advances 
to the second stage and that there may be a brief pause in enrollment between the first and 
second stage (to allow for patients to reach the 9 month endpoint), will complete accrual for the 
study within 3 years. Final data for the primary endpoint will be mature within 4 years. 
13.3
Patient Disposition
A detailed description of patient disposition will be provided. It will include:
A definition of patient enrollment
A summary of data regarding patient discontinuation of study treatment
A summary of data regarding patient inclusion and exclusion in efficacy and 
safety analyses
13.4
Patient Characteristics
Patient characteristics will include a summary of the following:
Patient demographics
Baseline disease characteristics
Baseline tumor molecular characteristics
Significant medical history and co-morbidities
Concomitant therapies
Other characteristics as appropriate
13.5
Interim Monitoring Plan- N/A
13.6
Analysis of Primary Endpoints
The primary end-point is proportion of patients free from objective disease progression or death 
at 9 months. Progression will be defined by RECIST 1.1


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13.7
Analysis of Secondary Endpoints
Response rate will be assessed as per RECIST, see Section 9.1. Results will be reported with 95% 
confidence intervals. All patients will be evaluable for response rate. Progression-Free Survival 
(PFS) will be defined as the duration of time from start of treatment to time of objective disease 
progression or death. Overall survival (OS) will be defined as the duration of time from start of 
treatment until death. Analysis will be performed using the Kaplan-Meier method. All patients will 
be evaluable for survival endpoints.
A summary of the adverse events, grading according to CTCAE and their attributed relatedness 
to treatment will be provided as a measure of patient safety and tolerability. All patients will be 
included in the safety analyses.
The first six patients in the study will constitute a safety cohort as outlined in section 5.1. If >1
patient has a grade 3 or higher treatment-related adverse event during cycle 1 of treatment, the 
dose will be de-escalated as outlined. Six additional patients will be treated at the lower dose to 
establish safety prior to proceeding to open enrolment of the remainder of the trial.  The 
probability of stopping at the initial dose in order to dose de-escalate and the probability of 
stopping the trial after the safety run in at the lower dose based on assumptions about  the 
associated underlying toxicity rates are as follows: 
True toxicity rate
Probability of reducing the 
starting dose
Probability of stopping the 
trial
0.05
0.265
0.033
0.1
0.468
0.114
0.2
0.738
0.345
0.3
0.883
0.580
0.4
0.954
0.767
0.5
0.985
0.890
 
Biopsies from pre, post and on-treatment will be obtained to facilitate comparative analysis by 
next-generation sequencing, single-cell RNA sequencing, transcriptional profiling and an 
evaluation of the emergent resistance mechanisms at the time of progression. Analyses for these 
outcomes may include the Cox proportional Hazard models for the examination of the 
relationship between changes in sequencing parameters and time to progression, Sign-Rank test 
to compare pre and post measurements of gene expression for genes of interest and other 
correlation tests such as linear regression to examine relationship between relevant outcomes.
The feasibility of single-cell sorting and transcriptional analysis of on-treatment biopsies will be 
assessed based on the rate of interpretable results. The lower-bound of the 95% CI will be 
provided for this rate and will serve as an indication of the ability to use such methods in an 
expanded setting.


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The results of longitudinal ctDNA analysis before, during and after treatment are exploratory and 
will be evaluated in a descriptive manner.
14. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.


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REFERENCES
1.
Niederst MJ, Hu H, Mulvey HE, et al. The Allelic Context of the C797S Mutation Acquired upon Treatment 
with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies. Clin Cancer 
Res. 2015;21(17):3924-3933.
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. http://www.seer.gov.
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Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to 
select targeted drugs. JAMA. 2014;311(19):1998-2006.
4.
Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. 
Nat Rev Cancer. 2007;7(3):169-181.
5.
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor 
underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129-
2139.
6.
Sequist LV, Martins RG, Spigel D, et al. First-line gefitinib in patients with advanced non-small-cell lung 
cancer harboring somatic EGFR mutations. J Clin Oncol. 2008;26(15):2442-2449.
7.
Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for 
European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a 
multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246.
8.
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N
Engl J Med. 2009;361(10):947-957.
9.
Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers 
acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.
10.
Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to 
EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19(8):2240-
2247.
11.
Jänne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N
Engl J Med. 2015;372(18):1689-1699.
12.
Sequist LV, Soria JC, Goldman JW, et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N Engl 
J Med. 2015;372(18):1700-1709.
13.
Song H-N, Ki SunYoo, Kwai HanCho, JinhyunLee, Ji YunLim, Sung HeeKim, Hae SuSun, Jong-MuLee, 
Se-HoonAhn, Jin Seok, Park K, Yoon-LaPark, WoongyangAhn, Myung-Ju. Acquired C797S Mutation upon 
Treatment with a T790M-Specific Third-Generation EGFR Inhibitor (HM61713) in Non–Small Cell Lung 
Cancer. Journal of Thoracic Oncology. 2015.
14.
Thress KS, Paweletz CP, Felip E, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in 
non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21(6):560-562.
15.
Chabon JJ, Simmons AD, Lovejoy AF, et al. Circulating tumour DNA profiling reveals heterogeneity of 
EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun. 2016;7:11815.
16.
Avizienyte E, Ward RA, Garner AP. Comparison of the EGFR resistance mutation profiles generated by 
EGFR-targeted tyrosine kinase inhibitors and the impact of drug combinations. Biochem J. 2008;415(2):197-
206.
17.
Planchard D, Loriot Y, André F, et al. EGFR-independent mechanisms of acquired resistance to AZD9291 
in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015;26(10):2073-2078.
18.
Piotrowska Z, Niederst MJ, Karlovich CA, et al. Heterogeneity Underlies the Emergence of EGFRT790 
Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR 
Inhibitor. Cancer Discov. 2015;5(7):713-722.
19.
Oxnard G, Thress K, Paweletz C, et al. Mechanisms of Acquired Resistance to AZD9291 in EGFR T790M 
Positive Lung Cancer. Journal of Thoracic Oncology. 2015;10(9 supplement 2):ORAL 17.07.
20.
Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is 
associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2(3):e73.
21.
Yu HA, Tian SK, Drilon AE, et al. Acquired Resistance of EGFR-Mutant Lung Cancer to a T790M-Specific 
EGFR Inhibitor: Emergence of a Third Mutation (C797S) in the EGFR Tyrosine Kinase Domain. JAMA 
Oncol. 2015;1(7):982-984.
22.
Ercan D, Choi HG, Yun CH, et al. EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR 
Inhibitors. Clin Cancer Res. 2015;21(17):3913-3923.
23.
Kwak EL, Ahronian LG, Siravegna G, et al. Molecular Heterogeneity and Receptor Coamplification Drive 


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Resistance to Targeted Therapy in MET-Amplified Esophagogastric Cancer. Cancer Discov. 
2015;5(12):1271-1281.
24.
Russo M, Siravegna G, Blaszkowsky LS, et al. Tumor heterogeneity and lesion-specific response to targeted 
therapy in colorectal cancer. Cancer Discov. 2015.


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APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
100
Normal, no complaints, no evidence 
of disease.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
80
Normal activity with effort; some 
signs or symptoms of disease.
70
Cares for self, unable to carry on 
normal activity or to do active work.
2
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
50
Requires considerable assistance and 
frequent medical care.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
40
Disabled, requires special care and 
assistance.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
20
Very sick, hospitalization indicated. 
Death not imminent.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


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APPENDIX B
INFORMATION ON USE OF CONCOMITANT MEDICATIONS
Table 13-1: Permitted Concomitant  Medications Requiring Caution.
Mechanism of Interaction
Drug Name
Moderate CYP3A4 inhibitor
Antibiotics: ciprofloxacin, erythromycin
Protease Inhibitors: amprenavir, atazanavir, 
darunavir, fosamprenavir
Antifungals: fluconazole
Antiviral: faldaprevir
Calcium Channel Blockers: diltiazem, verapamil
Other: aprepitant, casopitant, cimetidine, 
cyclosporine, dronedarone, lomitapide netupitant, 
schisandra sphenanthera,  tofisopam
Moderate CYP3A4 inducer
bosentan, efavirenz, etravirine, genistein, 
modafinil, nafcillin, [semagacestat], [talviraline], 
thioridazine, lersivirine
BCRP substrate
methotrexate, mitoxantrone, rosuvastatin, 
sulfasalazine
MATE substrate
Metformin, tenofovir
Potent P-gp inhibitor
quinidine, dronedarone, valspodar (PSC 833), 
elacridar (GF120918)
Source: Adapted from Oncology Clinical Pharmacology Drug-Drug Interaction Database (release date: 
Apr2015) which was compiled from the Indiana University School of Medicine’s “Clinically Relevant” 
Table and supplemented with the FDA Draft Guidance for Industry, Drug Interaction Studies – Study 
Design, Data Analysis,
and Implications for Dosing and Labeling (February 2012), and the University of Washington’s Drug 
Interaction Database. Please note that this list may not be exhaustive. For the latest information, 
please refer to the above mentioned database.
Drugs between brackets are not marketed in US.
Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-
administered with a known potent inhibitor.
Potent P-gp inhibitor, which results in AUC ratio>2-fold.
Table 12-3
Prohibited concomitant medications
Mechanism of 
interaction
Drug name
Strong CYP3A4 inhibitor
Antibiotics: clarithromycin, telithromycin, troleandomycin
Protease Inhibitors: indinavir, lopinavir, nelfinavir, ritonavir saquinavir, 
tipranavir
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole
Antivirals: boceprevir, telaprevir, danoprevir/ritonavir
Others: cobicistat, conivaptan, elvitegravir, mibefradil nefazodone, 
grapefruit or grapefruit juice, seville orange (and juice), pummelos, star 
citrus fruits, and hybrids of these mentioned fruits
Strong CYP3A4 inducer
avasimibe, carbamazepine, enzalutamide, mitotane, phenobarbital, 
phenytoin, rifabutin, rifampin, St. John's wort 
Live vaccines
e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, 
yellow fever, varicella, and TY21a typhoid vaccines


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NTI: narrow therapeutic index
Source: Adapted from Oncology Clinical Pharmacology Drug-Drug Interaction Database (release date: 
Apr2015) which was compiled from the Indiana University School of Medicine’s “Clinically Relevant” 
Table and supplemented with the FDA Draft Guidance for Industry, Drug Interaction Studies – Study 
Design, Data Analysis, and Implications for Dosing and Labeling (February 2012), and the University of 
Washington’s Drug Interaction Database. Please note that this list may not be exhaustive. For the 
latest information, please refer to the above mentioned database.


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APPENDIX C PLASMA ISOLATION PROTOCOL FOR CTDNA ANALYSIS
Preparation of plasma for the isolation of circulating DNA
Purpose
These instructions describe how to collect whole blood samples and prepare plasmafor the isolation of cell-free 
circulating tumor DNA.
Materials and Equipment
o
Two Streck tubes 
o Vacutainer needles or butterfly needles, 20G/21G (Becton Dickinson, # 367344/364815 or equivalent)
o 2 ml cryogenic vial, round bottom, self-standing (Corning, # 430659 or equivalent)
o 10 ml and 5 ml serological disposable pipettes (Corning, # 4487 or #4488 or equivalent)
o 15 ml polypropylene centrifuge tubes (Fisher, # 3208303 or equivalent)
o Freezer storage boxes for 2 ml cryogenic vials (Fisher, # 3468196 or equivalent)
o Centrifuge, capable of ~3000 g with a swing bucket rotor (e.g. Eppendorf, 5702; # 5702 000.019 or equivalent)
o Pipetting aid (e.g. Eppendorf, Easypet; #4421 000.013 or equivalent)
o Ultra-Low Temperature Freezer ( e.g. Thermo Electron, Revco Ultima PLUS; ULT1786-10 or equivalent)
Health and safety
In accordance with the site’s policies and guidelines, use personal protective equipment to prevent exposure to blood 
borne pathogens or other potentially infectious materials, and dispose of all clinical waste appropriately. Before 
starting to work under this protocol all staff should review the guidelines for working with blood borne pathogens and 
have been vaccinated.
Procedure
Blood Draw (in Clinic)
· Confirm subject’s ID and write subject’s name or subject ID and DOB on the sample sheet and EDTA tube.
· Prepare subject for blood draw.
· Obtain venous blood (~1 to 2 times10 ml) by any standard phlebotomy technique from a peripheral access point or 
from a central line by trained personnel into EDTA tubes.
For special instructions, see Streck tube product information.
· Gently invert tubes about 10 times immediately after collection.
· Record date and time of blood draw on samples sheet and Streck tube.
· Prepare sample for the transportation to the laboratory or processing side.
CRITICAL STEP
Time between blood collection and plasma/blood cell processing is recommended to be <4-5 h. Experiments have 
shown that extended storage at room temperature 
5 h can affect the detection of cell-free circulating tumor DNA in 
plasma. Plasma Processing (in Laboratory)
· Upon arrival in the laboratory, centrifuge Streck tubes at room temperature for 10 min at 1600 (±150) g.
If centrifuge uses rpm (revolutions per minute), see centrifuge instructions for the conversion.
Ensure that brake switch is off in order to prevent disruption of the cell layer.
· Record plasma processing start time at start of first centrifugation.
· After centrifugation remove tubes from centrifuge.
· Transfer supernatant of the two Streck tubes to one fresh 15 ml centrifuge tube without disturbing the cellular layer 
using a disposable 10 ml serological pipette or disposable bulb pipette.
CRITICAL STEP
Centrifugation separates plasma from leukocytes and erythrocytes as shown in the figure below (left). Leaving 
sufficient residual plasma in the tubes after the centrifugation and not disturbing the leukocyte layer (see image) when 
pipetting is a critical step in the sample preparation process (right). Be careful not to disturb leukocyte layer in the 
tubes.


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After transferring the plasma to a 15 ml centrifuge tube as described, discard Streck tube in biohazard trash.
· Centrifuge the plasma in the 15 ml centrifuge tube at room temperature for 10 min at 3000 (±150) g.
CRITICAL STEP
The 2nd centrifugation is intended to remove any residual intact blood cells carried over from the 1st centrifugation 
step. Tests have shown that speeds slower than 3000g do not completely remove blood cells from the supernatant. 
Centrifugation speeds higher than 3000 g are preferred.
· After centrifugation remove tubes from centrifuge.
· Transfer supernatant to a fresh 15 ml centrifuge tube without disturbing the cellular layer using a disposable 5 ml or 
10 ml serological pipette or disposable bulb pipette.
CRITICAL STEP
Leave a residual volume of about 0.3 ml (~7 mm) on the bottom of the 15 ml tube to avoid contaminating the plasma 
with cells (see image).
After transferring the plasma to a new 15 ml centrifuge tube as described, gently mix plasma and record total plasma 
volume (~8-10 ml plasma per 20 ml blood).
· Transfer 1 ml plasma aliquots with a pipette to 2 ml pre-labeled cryogenic vials.
Confirm that the sample tube ID matches the subject’s ID.
Suggested information on tube:
Plasma
Subject/patient ID or subject/patient name
DOB
Plasma collection date and time
Study or protocol code
Place plasma tubes into storage box and freeze plasma in freezer upright in storage box at -70°C or colder.
Short time storage at -20°C is possible.


NCI Protocol #:
DF/HCC Protocol #: 17-291
Protocol Version Date: January 10th, 2019
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Specimen Storage Instructions
· Once frozen, maintain samples continuously at -70°C or colder.
· When outside the freezer, such as when transferring to a different freezer in another location or preparing for 
shipment, boxes containing tubes should be covered with dry ice.
· Freezer or dry ice specimen storage container temperature must be checked and documented at least once each 
workday. Document any deviation from protocol.
· The freezer or dry ice storage box containing the specimens should either be locked or in a secure area accessible 
only to authorized site staff.
· A backup storage plan should be in place in the event of freezer failure.


NCI Protocol #:
DF/HCC Protocol #: 17-291
Protocol Version Date: January 10th, 2019
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APPENDIX D  SOP For Tumor Biopsy Sample Collection
Contacts:
Zosia Piotrowska, MD – pager 16423 (PI)
Aaron Hata, MD, PhD - 615 838-3607 (Primary lab collaborator)
Mandeep Banwait- pager 29830 (Research Assistant)
Sam Bilton - 561 901-5369 (Primary contact in Hata Lab)
For each biopsy, cores should be processed in the following order and stored as outlined:
1. Pre-Treatment Biopsy (within 28 days of treatment start)
1) Snapfrozen
2) Fresh- cell line/PDX (media)
3) Fresh- cell line/PDX (media)
4) Snapfrozen
5) Formalin
6) MGH path
7) Any extras- snapfrozen
Cores 1-4 (and any extra snapfrozen specimens) to be sent to Hata lab at CNY via courier.
Core 5 to be stored in research path by Marina Kem/Mari Mino-Kenudson
Clinical testing- Snapshot, MET and EGFR FISH
2. On-Treatment (C1D15-21)
1) Snapfrozen
2) Snapfrozen
3) Formalin
4) Formalin
5) Any extra- snapfrozen
Cores 1-2 (and any extra snapfrozen specimens) to be sent to Hata lab at CNY via courier.
Cores 3-4 to be stored in research path by Marina Kem/Mari Mino-Kenudson
Note- no MGH path/clinical sample submitted form on-treatment biopsy
3. Post-Progression (at/after RECIST progression)
1) Snapfrozen
2) Fresh- cell line/PDX
3) Fresh- cell line/PDX
4) Snapfrozen


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Protocol Version Date: January 10th, 2019
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5) Formalin
6) MGH path
7) Any extras- snapfrozen
Cores 1-4 (and any extra snapfrozen specimens) to be sent to Hata lab at CNY via courier.
Core 5 to be stored in research path by Marina Kem/Mari Mino-Kenudson
Clinical testing- Snapshot, MET and EGFR FISH on pre and post-treatment biopsies (none 
for on-treatment bx)