Clinical trial NCT02954523
Conditions: EGFR Gene Mutation Nonsmall Cell Lung Cancer
Keywords: NSCLC Non-small cell Lung Cancer Dasatinib Osimertinib AZD9291 EGFR Mutations Epidermal growth factor receptor (EGFR)
Sponsor: Chul Kim
Start date: 2016-10-01; Completion date: 2023-03-03
Enrollment: 10 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a study for patients with advanced non-small cell lung cancer with changes to their cancer cells called EGFR mutations. Mutated EGFR is important in the growth of cancer cells. Medical studies have shown that patients with EGFR mutation-positive lung cancer gain more benefit from targeted therapy drugs such as EGFR inhibitors than with standard chemotherapy. However, a significant proportion of patients carrying these sensitizing mutations do not respond well to the first-generation EGFR-TKIs (erlotinib and gefitinib), indicating the existence of intrinsic resistance mechanisms. Moreover, despite initial response to EGFR-TKIs, acquired resistance is inevitable in all patients.

The investigators have recently shown that Cripto-1 overexpression in EGFR mutant NSCLC contributes to the intrinsic resistance to EGFR-TKIs through activation of the SRC oncogene. They have also shown that a combination of an EGFR-TKI (both erlotinib and osimertinib) and a Src inhibitor are synergistic in Cripto-1 overexpressing tumors in the laboratory.

This study will be testing a combination of two drugs, dasatinib and osimertinib, to overcome resistance to EGFR-TKIs. Osimertinib (AZD9291) is a third-generation EGFR-TKI, which selectively blocks the activity of EGFR mutants, but spares that of wild type. The advantage of using osimertinib is that it inhibits not only the sensitizing EGFR mutations, but also the T790M mutant, which is the most common mechanism of acquired resistance. Dasatinib is a potent, orally available ABL1/SRC TKI, approved for the treatment of chronic myeloid leukemia (CML) in first-line and in patients with imatinib-resistant disease or intolerant, and is being actively studied in patients with advanced solid tumors.

The first part of the study will involve finding the highest dose of dasatinib that can be given with osimertinib without causing severe side effects, finding out the side effects seen by giving dasatinib at different dose levels with osimertinib, and measuring the levels of dasatinib and osimertinib in blood at different dose levels. The second part will determine the effects of the combination of dasatinib and osimertinib and determine if the amount of Cripto-1 protein in your tumor or blood makes you more likely to have a good response to the combination of dasatinib and osimertinib.

Detailed description:
The treatment of patients with advanced non-small cell lung cancer is unsatisfactory. The median survival is approximately 12 months with standard chemotherapy. Epidermal growth factor receptor (EGFR) mutations are one of the most frequent genetic abnormalities observed in non-small cell lung cancer (NSCLC), especially in adenocarcinoma subtype. The most predominant EGFR mutations are in-frame deletions in exon-19 and L858R missense mutation, and patients carrying these mutations are mostly sensitive to the EGFR-targeted tyrosine kinase inhibitors (TKIs). However, a significant proportion of patients carrying these sensitizing mutations do not respond well to the first generation EGFR-TKIs (erlotinib and gefitinib), indicating the existence of intrinsic resistance mechanisms. Moreover, despite initial response to EGFR-TKIs, acquired resistance is inevitable in all patients. Novel treatment strategies need to be developed to overcome resistance to EGFR-TKIs. The investigators have recently shown that Cripto-1 overexpression in EGFR mutant NSCLC contributes to the intrinsic resistance to EGFR-TKIs through SRC activation. They have also shown that a combination of an EGFR-TKI (both erlotinib and AZD9291) and a Src inhibitor are synergistic in vitro and in vivo in Cripto-1 overexpressing tumors. AZD9291 is a third-generation EGFR-TKI, which selectively blocks the activity of EGFR mutants but spares that of wild type. The advantage of using AZD9291 is that it inhibits not only the mutants of exon-19 deletion and L858R, but also the T790M mutant, which is the most common mechanism of acquired resistance. Dasatinib is a potent, orally available ABL1/SRC TKI, approved for the treatment of chronic myeloid leukemia (CML) in first-line and in patients with imatinib-resistant disease or intolerant, and is being actively studied in patients with advanced solid tumors.

This is an open-label, non-randomized, prospective phase I/II trial. The phase I portion will follow a standard 3+3 design for the phase I portion and one-sample group sequential multiple testing procedure for the phase II portion.

Arms: arm 1: Osimertinib (AZD9291) will be given at a 80mg/day dose taken orally across all levels of the dose escalation schedule.

Dasatinib is taken orally and will be given at up to 4 dose levels. Level 1 (the starting dose - 50 mg twice daily).

Dose escalation will only include 2 dose levels (Levels 1 and 2); in addition there will be 2 dose levels below the starting dose level if dose reductions are necessary (Levels -1 and -2).

There is no limit to the number of cycles a patient can receive. arm 2: Osimertinib (AZD9291) will be given at a 80mg/day dose taken orally across all levels of the dose escalation schedule.

Dasatinib is taken orally and will be given at up to 4 dose levels. Level 2 (70 mg twice daily).

Dose escalation will only include 2 dose levels (Levels 1 and 2); in addition there will be 2 dose levels below the starting dose level if dose reductions are necessary (Levels -1 and -2).

There is no limit to the number of cycles a patient can receive. arm 3: Osimertinib (AZD9291) will be given at a 80mg/day dose taken orally across all levels of the dose escalation schedule.

Dasatinib is taken orally and will be given at up to 4 dose levels. Level -1 (70 mg once daily).

Dose escalation will only include 2 dose levels (Levels 1 and 2); in addition there will be 2 dose levels below the starting dose level if dose reductions are necessary (Levels -1 and -2).

There is no limit to the number of cycles a patient can receive. arm 4: Osimertinib (AZD9291) will be given at a 80mg/day dose taken orally across all levels of the dose escalation schedule.d

Dasatinib is taken orally and will be given at up to 4 dose levels. Level -2 (50 mg once daily).

Dose escalation will only include 2 dose levels (Levels 1 and 2); in addition there will be 2 dose levels below the starting dose level if dose reductions are necessary (Levels -1 and -2).

There is no limit to the number of cycles a patient can receive. arm 5: The phase II portion of the study will use the maximum tolerated dose of dasatinib determined in the phase I portion. Osimertinib (AZD9291) will be given at the same 80mg dose as the phase I portion. There is no limit to the number of cycles a patient can receive.
Interventions: intervention 1: Dasatinib intervention 2: Osimertinib
Intervention descriptions: intervention 1: oral every day intervention 2: oral every day

Protocol documents:
Prot_SAP_000.pdf: 
 
TITLE: Phase I/II study of Dasatinib and Osimertinib in patients with advanced non-small cell 
lung cancer with EGFR mutations  
 
NCT02954523 
 
Version: 
 January 26, 2022 
 
 
 
 


Georgetown Lombardi Comprehensive Cancer Center 
 
 
CONFIDENTIAL 
This material is the property of Georgetown University.  Do not disclose or use except as authorized in writing by the study sponsor. 
 
TITLE: Phase I/II study of Dasatinib and Osimertinib in patients with advanced non-small cell 
lung cancer with EGFR mutations  
 
Principal Investigator:  
Chul Kim, M.D. M.P.H.,  
Georgetown Lombardi Comprehensive Cancer Center 
3970 Reservoir Road NW Washington DC 20007 
Phone: 202-444-1285; E-mail: Chul.Kim@gunet.georgetown.edu  
 
Sub-Investigator(s): 
 
Stephen Liu, M.D., Georgetown Lombardi Comprehensive Cancer Center 
Joshua Reuss, MD, Georgetown Lombardi Comprehensive Cancer Center 
Jillian Thompson, NP, Georgetown Lombardi Comprehensive Cancer Center 
 
Biostatistician: 
 
Ming T. Tan, Ph.D. 
Department of Biostatistics, Bioinformatics, and Biomathematics 
Georgetown University, Basic Science 255 
Phone: 202-687-0197; E-mail: mtt34@georgetown.edu 
 
Pathologist: 
Bhaskar Kallakury, M.D. 
Department of Pathology 
Georgetown University 
Phone: 202) 687-3444; E-mail: KALLAKUB@gunet.georgetown.edu 
 
Study Drugs: 
 
Osimertinib, Dasatinib (Sprycel) 
 
Funding Source:   AstraZeneca for Osimertinib, Bristol-Myers Squibb for Dasatinib 
 
 
Version: 
 January 26, 2022 
 
 
 
 
 


Georgetown Lombardi Comprehensive Cancer Center 
 
 
CONFIDENTIAL 
This material is the property of Georgetown University.  Do not disclose or use except as authorized in writing by the study sponsor. 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
Principal Investigator (PI) Name:_______________________ 
 
PI Signature: ___________________ 
 
Date:____________________ 
 


 
i 
TABLE OF CONTENTS 
1.0 PRÉCIS ........................................................................................ 1 
2.0 BACKGROUND AND RATIONALE ...............................................5 
2.1 
N0n-small cell lung cancer (NSCLC) .....................................................................5 
2.2 
Osimertinib ...........................................................................................................11 
2.3 
Dasatinib ...............................................................................................................16 
2.4 
Rationale for the combination of EGFR-TKI and SRC inhibitor .........................18 
3.0 STUDY HYPOTHESIS AND OBJECTIVES .................................. 21 
3.1 
Hypothesis .............................................................................................................21 
3.2 
Primary Objectives ................................................................................................21 
3.3 
Secondary Objectives ............................................................................................21 
3.4 
Exploratory Objectives and Correlative Studies ...................................................22 
4.0 PATIENT ELIGIBILITY ............................................................. 24 
4.1 
Inclusion Criteria ..................................................................................................24 
4.2 
Exclusion Criteria .................................................................................................25 
5.0 TREATMENT PLAN .................................................................. 28 
5.1 
Treatment Dosage and Administration .................................................................28 
5.2 
General Management of Toxicities .......................................................................30 
5.3 
Concomitant Medications/Treatments ..................................................................36 
5.4 
Off-treatment criteria ............................................................................................36 
5.5 
Off-study criteria ...................................................................................................37 
5.6 
Duration of Follow-Up .........................................................................................37 
6.0 STUDY PROCEDURES .............................................................. 38 


 
ii 
6.1 
Screening/Baseline Procedures .............................................................................38 
6.2 
Procedures During Treatment ...............................................................................39 
7.0 Measurement of Effect .............................................................. 40 
7.1 
Antitumor Effect- Solid Tumors ...........................................................................40 
8.0 ADVERSE EVENTS ................................................................... 49 
8.1 
Definitions .............................................................................................................49 
8.2 
Adverse Event Monitoring ....................................................................................53 
8.3 
Reporting Requirements for Adverse Events........................................................54 
8.4 
Reporting of Serious Adverse Events (SAEs) to Astra Zeneca ............................55 
8.5 
Reporting of Serious Adverse Events (SAEs) to Bristol-Myers Squibb ..............57 
9.0 DRUG INFORMATION ............................................................... 61 
9.1 
Osimertinib ....................................................... 61Error! Bookmark not defined. 
9.2 
Dasatinib ...............................................................................................................63 
9.3 
Unused Study Drug and Destruction ....................................................................65 
10.0  CORRELATIVES/SPECIAL STUDIES ........................................ 65 
10.1 Pharmacokinetics ..................................................................................................65 
10.2 Pathology Correlative Studies ...............................................................................66 
10.3 Serum Correlative Studies ....................................................................................69 
10.4 FDG-PET ..............................................................................................................70 
10.5 Specimen Banking ................................................................................................70 
11.0  STATISTICAL CONSIDERATIONS ............................................ 71 
11.1 Study Design/Study Endpoints .............................................................................71 
11.2 Sample Size and Accrual ......................................................................................71 
11.3 Data Analyses Plans ..............................................................................................73 


 
iii 
12.0 STUDY MANAGEMENT ............................................................ 74 
12.1 Institutional Review Board (IRB) Approval and Consent ....................................74 
12.2 Required Documentation ......................................................................................75 
12.3 Registration Procedures ........................................................................................76 
12.4 Data Management and Monitoring/Auditing ........................................................76 
12.5 Adherence to the Protocol .....................................................................................78 
12.6 Amendments to the Protocol .................................................................................79 
12.7 Record Retention ..................................................................................................80 
12.8 Obligations of Investigators ..................................................................................80 


 
1 
1.0 
PRÉCIS 
 
Background 
 
The treatment of patients with advanced non-small cell lung cancer is unsatisfactory. 
The median survival is approximately 12 months with standard chemotherapy.  
 
Epidermal growth factor receptor (EGFR) mutation is one of the most frequent genetic 
abnormalities observed in non-small cell lung cancer (NSCLC), especially in 
adenocarcinoma subtype. The most predominant EGFR mutations are in-frame 
deletions in exon-19 and L858R missense mutation, and patients carrying these 
mutations are mostly sensitive to the EGFR-targeted tyrosine kinase inhibitors (TKIs). 
However, a significant proportion of patients carrying these sensitizing mutations do not 
respond well to the first generation EGFR-TKIs (erlotinib and gefitinib), indicating the 
existence of intrinsic resistance mechanism. Moreover, despite initial response to EGFR-
TKIs, acquired resistance is inevitable in all patients. 
 
Novel treatment strategies need to be developed to overcome resistance to EGFR-TKIs. 
 
We have recently shown that Cripto-1 overexpression in EGFR mutant NSCLC 
contributes to the intrinsic resistance to EGFR-TKIs through SRC activation. We have 
also shown that a combination of an EGFR-TKI (both erlotinib and osimertinib) and a 
Src inhibitor are synergistic in vitro and in vivo in Cripto-1 overexpressing tumors. 
 
Osimertinib is a third-generation EGFR-TKI, which selectively blocks the activity of 
EGFR mutants but spares that of wild type. The advantage of using osimertinib is that it 
inhibits not only the mutants of exon-19 deletion and L858R, but also the T790M 
mutant, which is the most common mechanism of acquired resistance. 


 
2 
 
Dasatinib is a potent, orally available ABL1/SRC-TKI, approved for the treatment of 
chronic myeloid leukemia (CML) in first-line and in patients with imatinib-resistant 
disease or intolerant, and being actively studied in patients with advanced solid tumors. 
 
Primary objectives 
 
In the phase I portion of the study, the primary objective will be to determine a safe and 
tolerable phase II dose of osimertinib and dasatinib in patients with EGFR mutant non-
small cell lung cancer naïve to EGFR-TKI treatment.  
 
In the phase II portion of the study, the primary objective will be to determine the rate of 
non-response to the combination of osimertinib and dasatinib, in patients stratified by 
Cripto-1 expression in their tumor.  
 
Secondary objectives 
 
In the phase I portion of the study, the secondary objective will be to describe the 
pharmacokinetics associated with osimertinib when administered with dasatinib. 
 
In the phase II portion of the study, the secondary objective will be to determine the 
median progression free survival (PFS), overall survival (OS), duration of response, and 
safety and tolerability of this combination regimen. 
 
Eligibility 
 
Patients must have cytologically or histologically confirmed advanced non-small cell 
carcinoma of the lung. 
 
Presence of sensitizing EGFR mutations (with or without T790M) 
 
No previous treatment with EGFR-TKIs 


 
3 
 
Adequate organ and bone marrow function 
 
ECOG performance status of 0-2 
 
Design 
 
Open-label, non-randomized, prospective phase I/II trial 
 
Following a standard 3+3 design for the phase I portion 
 
One-sample group sequential multiple testing procedure for the phase II portion 
 
 
 


 
4 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
MTD: Maximum tolerated dose 
RP2D: Recommended phase II dose 
 
Phase	1	
Pa ents	with	advanced	NSCLC	
with	EGFR	muta ons		
Phase	2	
Pa ents	with	advanced	NSCLC	
with	EGFR	muta ons	
Dose	escala on		
un l	MTD	and/or	RP2D	
MTD	and/or	RaP2D	
D0												D28											D56											Progression		
Screening	Registra on	
Screening	
Registra on	
FDG	PET																	x																																				x	
Blood	Cripto-1						x																																																					x																						x								
Tumor	Biopsy							x	(op onal)																																																											x	


 
5 
2.0 
BACKGROUND AND RATIONALE 
2.1 
N0n-small cell lung cancer (NSCLC) 
2.1.1 
Overview of NSCLC 
Lung cancer remains the leading cause of cancer deaths among both men and women in 
the United States. In 2014, 159,260 patients died of lung cancer in the United States, 
making up 27% of all cancer deaths[1]. The 5-year survival rate for lung cancer (17%) is 
lower than most of other common solid tumors, such as colon cancer (65%) and breast 
cancer (89%)[1]. Non-small cell lung cancer (NSCLC) is the most common type of lung 
cancer, comprising 86% of all lung cancer cases[2]. Of these patients, more than 55% will 
present with advanced disease[1], not amenable to curative treatment. Of the remaining 
45% that are treated with curative intent, only 20-30% are radically resectable. 
Platinum-based doublet chemotherapy regimens are the standard of care for patients 
with advanced NSCLC and good performance status[3], who do not have targetable 
driver mutations. The treatment with platinum-based doublet chemotherapy is 
unsatisfactory, with objective response rates generally in the range of 20-30%[4, 5], and 
the median survival in the range of approximately 10-12 months[6]. Adding a third 
chemotherapy drug to the platinum-doublet has not improved overall survival[7]. Non-
platinum-based regimens have been evaluated in several trials, but objective response 
rates were lower compared to platinum-containing regimens[8], and progression-free 
survival (PFS) was inferior[9]. 


 
6 
2.1.2 
Targeted therapy for advanced NSCLC 
The last decade has seen major advances in the understanding of the genetics and 
molecular pathogenesis of lung cancer, which led to the advent of targeted therapies. 
EGFR mutation is one of the most frequent genetic abnormalities observed in NSCLC, 
especially in adenocarcinoma subtype[10]. The most predominant EGFR mutations 
(over 90%) are in-frame deletions in exon 19 and L858R missense mutation[10], and the 
majority of patients with these mutations have tumors that are sensitive to the EGFR-
targeted tyrosine kinase inhibitors. Erlotinib is an orally active reversible epidermal 
growth factor receptor tyrosine kinase inhibitor, which has demonstrated marked 
clinical efficacy over standard chemotherapy in EGFR mutation-positive advanced 
NSCLC[11]. Two randomized trials, which compared erlotinib with standard 
chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive 
NSCLC, demonstrated objective response rates of 58-83% for erlotinib, and 15-36% for 
chemotherapy[4, 5]. Median progression-free survival was also significantly longer in 
erlotinib-treated patients (9.7-13.1 months) than in those treated with chemotherapy 
(4.6-5.2 months). Erlotinib received approval for the treatment of patients with locally 
advanced or metastatic NSCLC after failure of one or two chemotherapy regimens by the 
U.S. Food and Drug Administration (FDA) in 2004[12]. In 2013, the indication for 
erlotinib was expanded to include first-line treatment of metastatic NSCLC harboring 
EGFR mutations[13]. Erlotinib is well tolerated with most adverse events being grade 1 
or 2[14, 15]. The most common side effects of erlotinib are skin rash, diarrhea, and 
fatigue, which were primarily grade 1 or 2 in severity[4]. 


 
7 
2.1.3 
Intrinsic and acquired resistance to EGFR-TKIs 
Despite remarkable clinical responses to EGFR-TKIs, approximately 10% of patients 
with EGFR mutation-positive NSCLC are refractory to EGFR-TKIs (progression on 
treatment) [16], and up to 40% of patients harbouring EGFR sensitizing mutations do 
not attain a major response (stable disease of short duration) to the first generation 
EGFR-TKIs (erlotinib and gefitinib), indicating the existence of intrinsic resistance 
mechanisms. Furthermore, acquired resistance is inevitable in all patients. Patients 
develop resistance to EGFR-TKIs in 10-13 months after initiation of EGFR-TKIs[4, 5]. 
Known acquired mechanisms of resistance to EGFR-TKIs include EGFR T790M 
mutation (50-60%), and much less frequently mutations in PIK3CA gene, MET gene 
amplification resulting in ERBB3 signaling, and small cell lung cancer 
transformation[17-19]. On the contrary, the mechanisms of intrinsic resistance to EGFR-
TKIs are relatively unidentified. KRAS mutation, MET amplification, and high-level 
hepatocyte growth factor (HGF) expression have been implicated in the molecular 
pathogenesis of intrinsic resistance to EGFR-TKIs[16, 20]. 
2.1.4 
Role of Cripto-1 in the molecular pathogenesis of resistance to EGFR-
TKI 
Cripto-1, a member of EGFR-CFC protein family, is also known as teratocarcinoma-
derived growth factor-1 (TDGF-1)[21]. Cripto-1 activates phosphatidylinositol 3’-kinase 
(PI3K)/AKT/glycogen synthase kinase 3 (GSK-3) and mitogen-activated protein 
kinase (MAPK) signaling pathways, and functions as a survival factor[22, 23]. High 
levels of expression of Cripto-1 have been found in a number of human carcinomas 


 
8 
including colorectal, breast, ovarian, and gastric cancers[21]. Overexpression of Cripto-1 
was associated with worse prognosis in breast and gastric cancer[24, 25]. 
We discovered that the expression of Cripto-1 is significantly higher in the EGFR-
mutated NSCLC tumors from EGFR-TKI-non-responders than in those from 
responders[26]. We have also demonstrated that Cripto-1 expression contributes to 
EGFR-TKI (1st generation erlotinib, 2nd generation dacomitinib [26], and 3rd generation 
osimertinib and CO-1681 inhibitors [unpublished observation]) resistance in lung 
adenocarcinoma cells in vitro (Figure 1A and 1B) and in a mouse xenograft tumor model 
(Figure 1C) [26]. Both in Cripto-1 transfected lung adenocarcinoma cell lines and 
primary lung adenocarcinoma cells bearing EGFR sensitizing mutations, high Cripto-1 
expression correlates with increased levels of SRC phosphorylation (Figure 1B) [26]. 
Moreover, Cripto-1 was clearly detectable in the medium of Cripto-1 transfected but not 
mock control lung adenocarcinoma cells (Figure 1D) and the shed Cripto-1 augmented 
SRC phosphorylation (Figure 1E), suggesting that the shed Cripto-1 may activate SRC 
signaling. Immunohistochemistry analysis revealed that high Cripto-1 expression 
correlates with intrinsic erlotinib and gefitinib resistance in EGFR mutant lung 
adenocarcinoma patients (Figure 2A; p = 0.0001). High Cripto-1 expression also 
correlates with worse prognosis in patients with stage I NSCLC (Figure 2B, unpublished 
observation). The siRNA-mediated depletion of SRC kinase, a downstream effector of 
Cripto-1, or inhibition with AZD0530, a small molecule Src inhibitor, overcome Cripto-1-
induced EGFR-TKI resistance in vitro and in xenograft tumors (Figure 2C and 2D) [26]. 
These findings suggest that 1) Cripto-1 could serve as a surrogate marker to predict 
EGFR-TKI response and 2) targeting the Cripto-1 pathway may be an effective strategy 
to combat EGFR-TKI resistance including resistance to the 3rd generation of EGFR 


 
9 
inhibitors (osimertinib and CO-1686) in Cripto-1 positive EGFR mutant lung 
adenocarcinoma. These data suggests that Cripto-1 may be an important contributor to 
the innate resistance to EGFR-TKIs, and provides a good rationale for targeting both 
EGFR and Cripto1-SRC pathways to overcome such resistance. Preliminary studies 
demonstrated an even stronger synergistic antitumor effect when using a third 
generation EGFR inhibitor (e.g. osimertinib) with a SRC inhibitor. We have generated 
multiple EGFR-mutated NSCLC cell lines stably expressing Cripto1, along with their 
mock controls. Using these model systems, we have acquired data showing that 
osimertinib (from a commercial source) can synergize with dasatinib, a SRC inhibitor, to 
inhibit in vitro tumor cell proliferation (Figure 3). 
 
Fig 1. A. Exogenous expression of Cripto-1 renders EGFR mutant HCC827 lung adenocarcinoma cells 
resistant to erlotinib, Osimertinib and CO-1686 in vitro. CellTiter Glo assays were performed 72 hours 


 
10 
after erlotinib treatment. Data represent the mean ± SD of triplicate measurements relative to untreated 
cells. P value was calculated using paired 2-tailed t test. IC50s are shown in parentheses. B. Progressive 
loss of Cripto-1 expression in primary cells (MP41), derived from an intrinsic erlotinib resistant lung 
adenocarcinoma patient carrying EGFR L858R mutation, correlates with increasing sensitivity to 
erlotinib. Note that the progressive loss of Cripto-1 expression is accompanied by concomitant reduction 
of total SRC and phospho-SRC. C. Cripto-1 renders EGFR mutant lung adenocarcinoma HCC827 
xenografts resistant to erlotinib in immunocompromised mice. D. Shedding of Cripto-1. Cripto-1 
western blot of concentrated cell culture media of Cripto-1- and mock-transfected HCC827 lung 
adenocarcinoma cells. E. Conditioned medium of Cripto-1-transfected HCC827 cells induced SRC 
phosphorylation of Cripto-1 negative HCC827 and H4006 cells. w/ CM or w/o CM, with or without 
conditioned medium treatment. 
 
Fig 2. A. High Cripto-1 expression (determined by immunohistochemistry) correlates with intrinsic 
erlotinib and gefitinib resistance in EGFR mutant NSCLC patients (n=85; p=0.0001). B. Cripto-1 
expression correlates with worse prognosis in stage I NSCLC. Recurrence–free survival was analyzed in 
106 radically resected stage I NSCLC patients according to levels of Cripto-1 expression by 
immunohistochemistry. C. Inhibition of SRC by siRNA-mediated knockdown reinstates erlotinib 


 
11 
sensitivity of Cripto-1-transfected EGFR mutant HCC827 cells. D. AZD0530 sensitizes EGFR mutant 
HCC827Cripto-1 xenografts to erlotinib in immunocompromised mice. 
 
 
Fig 3. The effect of osimertinib on the Cripto-1 expressing/EGFR-mutated NSCLC cells with/without 
Dasatinib combination. A) Ectopic Cripto-1 expression drastically desensitizes EGFR-mutated NSCLC 
tumor cells to osimertinib treatment, as determined by the CellTiter-Glo Luminescent Cell Viability 
Assay. IC50 for each cell line is shown in the parenthesis. B) Dasatinib resensitizes Cripto-1 expressing 
cells (HCC827-Cripto1 and HCC4006-Cripto1) to  osimertinib, and the combination results in a 
synergistic inhibitory effect in vitro. 
2.2 
Osimertinib 
2.2.1 
Non-clinical studies of  osimertinib 
Osimertinib is a potent, selective, orally active, irreversible inhibitor that targets both 
sensitizing and T790M EGFR mutations[27]. In EGFR recombinant enzyme assays 


 
12 
(Millipore),  osimertinib had approximately 200 times greater potency against 
L858R/T790M than wild-type EGFR, suggesting its wide selectivity margin. Compared 
to both first (erlotinib and gefitinib) and second generation (afatinib and dacomitinib) 
EGFR-TKIs,  osimertinib demonstrated comparable potency in inhibiting EGFR 
phosphorylation in EGFR cell lines harboring activating EGFR mutations (PC-9, H3255, 
H1650). Importantly,  osimertinib was much more potent in inhibiting EGFR 
phosphorylation in EGFR cell lines (H1975, PC-9VanR) carrying T790M mutation with 
mean IC50 less than 15 nmol/L.  
 
Osimertinib showed d0se-dependent tumor regression in both PC-9 (ex19del) and 
H1975 (L858R/T790M) tumor xenograft models[27]. In both models, tumor shrinkage 
was observed at doses as low as 2.5 mg/kg/day after 14-day treatment. The response to  
osimertinib was shown to be durable in tumor xenograft models. In PC-9 xenografts, 
there was a complete response following 40 daily doses of 5 mg/kg/day  osimertinib, 
which lasted more than 200 days. By comparison, gefitinib at 6.25 mg/kg/day resulted 
in less tumor regression, and tumors began to regrow after nearly 90 days in the same 
xenograft model. The activity of  osimertinib was further examined in in vivo transgenic 
mouse models. Tumors harboring EGFRL858R were sensitive to afatinib and  osimertinib, 
but tumors carrying EGFRL858R+T790M were only sensitive to osimertinib.  
 
Osimertinib is metabolized into at least two metabolite species, AZD5104 and 
AZ7550[27]. Biochemical assays showed that AZD7550 had a similar potency and 
selectivity profile to osimertinib, whereas AZD5104 exhibited significantly greater 
potency than osimertinib across mutant and wild-type EGFR assays, and thus displayed 
a smaller margin of selectivity against wild-type EGFR compared to EGFRm/T790M and 
EGFRm in vitro. Osimertinib has good bioavailability, and wide tissue distribution. 


 
13 
When tumor tissues from H1975 xenografts were harvested 1, 6, 16, 24, and 30 hours 
after a single dose of  osimertinib (5mg/kg), both phospho-EGFR and downstream 
signaling pathway were inhibited after 6 hours. Although  osimertinib had a half-life of 
approximately 3 hours after oral dosing in the mouse model, phospho-EGFR staining 
remained reduced even after the 30-hour time point, which was consistent with the fact 
that  osimertinib is an irreversible inhibitor of EGFR.  Osimertinib was well tolerated in 
the animals. There was minimal weight loss, which was defined as less than 5% loss of 
baseline body weight, even after administration for 200 days. 
2.2.2 
Clinical studies of osimertinib 
The mesylate salt of  osimertinib has been evaluated in a phase I dose-escalation clinical 
trial in patients with advanced EFGR-mutant NSCLC who progressed after treatment 
with EGFR-TKIs[28]. The study included dose-escalation and dose expansion cohorts. 
Patients in the dose-escalation cohort received a single oral dose of  osimertinib, which 
was followed by a period of pharmacokinetic evaluation. After 7 days, the patients 
received the same dose of  osimertinib in an oral form for the remainder of the study. 
Additional pharmacokinetic assessment was performed while patients were receiving 
daily continuous dosing. The first dose level was 20 mg daily. If there was evidence of 
clinical activity in a dose-escalation group, a dose-expansion cohort could be opened. In 
the dose-escalation cohorts, daily dosing of  osimertinib was initiated immediately. 
 
A total of 253 patients from 33 sites were enrolled in the study[28]. 31 patients were 
treated in dose-escalation cohorts, and 222 patients were enrolled to dose-expansion 
cohorts. The dose range of  osimertinib used in the dose-escalation cohorts was from 20 
mg to 240 mg.  The first dose level of 20 mg was selected based on the preclinical data. 


 
14 
The most common side effects included diarrhea, rash, nausea, and anorexia. Most of the 
adverse effects were grade 1 or 2. There was an increased incidence of adverse effects, 
most notably at the 160 mg and 240 mg dose levels. There were 6 cases of potential 
pneumonitis-like events. All 6 patients discontinued osimertinib at the time of the event, 
and received steroid treatment with subsequent resolution or improvement of 
symptoms. There were 6 patients who developed hyperglycemia, and 11 patients who had 
prolongation of QTc (corrected QT) interval; none of these events led to discontinuation 
or reduction of osimertinib. Fatal adverse events were observed in 7 patients, and it was 
reported that one case (pneumonia) was possibly drug-related. Pharmacokinetic 
analyses showed that osimertinib had a median time to reach the maximum observed 
concentration (Cmax) of 6 hours, and a mean half-life of 55 hours. Based on this 
information, it was estimated that steady-state concentrations would be reached within 
22 days of daily dosing. 
 
Among 239 evaluable patients, 123 (51%) had a confirmed complete response (1 
patient) or partial response (122 patients)[28]. 78 (33%) had stable disease, 34 (14%) 
had progressive disease, and 4 (2%) were unevaluable for response. The response rate 
was comparable at each dose level. EGFR T790M was detected in tumors from 138 of the 
222 patients  (62%). Of the 138 patients, 127 patients were evaluable for response. The 
objective response rate was seen in 78 of the 127 patients (61%) in patients with EGFR 
T790M. The objective response rate in patients without EGFR T790M was 21% (13 of the 
61 patients). Of the 105 patients in the dose-expansion cohorts who had a confirmed 
response, 85% had responses lasting equal to or longer than 6 months, and the median 
progression free survival was 8.2 months. Based on the safety and efficacy data from the 


 
15 
phase I study, the recommended first dose level of osimertinib for phase II and III 
studies (NCT02094261, NCT02296125) was 80 mg daily. 
 
The preliminary data of osimertinib as first-line therapy for patients with advanced 
NSCLC with EGFR mutations who were naïve to EGFR-TKI treatment were presented at 
the 51th annual meeting of the American Society of Clinical Oncology (ASCO)[29]. In this 
trial, a total of 60 patients were treated with osimertinib at doses of 80 mg daily (n=30) 
and 160 mg daily (n=30). At the time of data analysis, the median duration of follow-up 
was 9.6 months. osimertinib was well tolerated with most adverse events being grade 1 
or 2. Most common adverse events were rash, diarrhea, dry skin, stomatitis, paronychia, 
decreased appetite, and fatigue. The incidences of hyperglycemia, QT prolongation, and 
interstitial lung disease (ILD)-like events were 5%, 7%, and 5%, respectively. Dose 
reduction due to adverse events occurred in 10% of patients treated with 80 mg daily and 
43% of those treated with 160 mg daily. 3 (10%) patients treated with 80 mg daily and 1 
(3%) patient treated with 160 mg daily discontinued osimertinib due to adverse events. 
The objective response rate in patients treated with 80 mg daily was 63% with all 
responses being partial response. In the group receiving 160 mg daily, 83% had objective 
responses with 1 (3%) complete response and 24 (80%) partial responses. The 
percentages of patients remaining progression-free at 9 months were 83% in patients 
receiving 80 mg daily and 78% in those receiving 160 mg daily. 
 
In 2015, osimertinib was approved by the FDA for the treatment of patients with 
metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved 
test, who have progressed on or after EGFR-TKI therapy. 


 
16 
2.3 
Dasatinib 
2.3.1 
Non-clinical studies of dasatinib (from the Dasatinib Investigator’s 
Brochure, Version 15, June 2015)  
Detailed information on all nonclinical studies performed to date can be found in the 
Investigator’s Brochure (IB). A brief summary of preclinical studies is as follows. 
Dasatinib is an orally bioavailable synthetic small molecule inhibitor of the SRC-family 
protein-tyrosine kinases, and it also inhibits c-KIT and PDGFR-ß. Dasatinib binds to and 
inhibits the growth-promoting activities of these kinases. Apparently because of its less 
stringent binding affinity for the BCR-ABL kinase, dasatinib has been shown to 
overcome the resistance to imatinib of CML cells harboring BCR-ABL kinase domain 
point mutations, although not the T315I gatekeeper mutation [30]. Dasatinib induces 
apoptosis in lung cancer cells which are dependent on the EGFR mutation status: EGFR 
mutant cells are much more sensitive to dasatinib (IC50 of 100 to 250 nmol/L) than the 
wild type EGFR cells (IC50 >10mol/L)[31]. Apoptosis induced by dasatinib was 
associated with down-regulation of Akt and STAT3[31]. Preclinical pharmacokinetics of 
dasatinib have been examined in mice, rats, dogs, and monkeys.  Dasatinib underwent 
metabolism via various mechanisms including hydroxylation, N-oxidation, N-
dealkylation, glucuronidation and sulfation. No unique metabolites were found in 
humans. Dasatinib was mainly excreted in feces with a small portion found in urine. 
With respect to toxicology, there were no toxicities that would hinder the administration 
of dasatinib to humans.  


 
17 
2.3.2 
Clinical studies of dasatinib (from the Dasatinib Investigator’s 
Brochure, Version 15, June 2015) 
Dasatinib is a second-generation BCR-ABL1 inhibitor, approved for the treatment of 
patients with newly diagnosed CML or intolerant, and in imatinib-resistant disease. The 
absorption of dasatinib is rapid. The median time to reach Cmax is 0.45 to 3.2 hours. 
Dasatinib has wide distribution to the extravascular space and is metabolized by 
cytochrome P450 3A4 in humans. The mean half-life of dasatinib ranges from 3 to 5 
hours, and is not affected by dose administration interval. Adverse effects described in 
patients treated with dasatinib include myelosuppression, fluid retention, pleural 
effusion, gastrointestinal disorders, fatigue, headache, musculoskeletal disorders, rash, 
infection and less frequently pulmonary hypertension[30]. 
 
The efficacy of single-agent dasatinib has been studied in several phase II trials in 
patients with advanced NSCLC. In a phase II study of patients with unselected advanced 
NSCLC, a total of 34 patients received dasatinib as first-line treatment[32]. The first 22 
patients were treated with 100 mg twice a day. Due to pleural effusion and fatigue, the 
remainder of the patients received 100 mg in the morning and 50 mg in the evening. Out 
of 34 patients treated, there was only one responder and that was wild-type EGFR. This 
patient obtained a complete metabolic response by FDG-PET (2-deoxy-2-(18F)fluoro-D-
glucose positron emission tomography) scanning, despite treatment being stopped after 
only 12 weeks due to malaise. Response continued without treatment for over 28 
months. The incidence of grade 2-3 pleural effusion and fatigue was 44% and 27%, 
respectively. Another phase II study gave dasatinib at 70 mg twice a day in patients with 
EGFR mutant adenocarcinoma who progressed on an EGFR-TKI (acquired resistance). 
After a protocol amendment, patients were kept on the EGFR-TKI to which dasatinib 


 
18 
was added at 100 mg once daily. There were no responses out of a total of 21 patients 
treated (9 under the original design and 12 after amendment)[33]. Pleural effusions were 
a significant side effect with four patients requiring chest tube placement. A phase II 
study by Brunner et al. in patients with squamous cell carcinoma of the lung was halted 
after 5 patients were enrolled due to excessive toxicity[34].  
 
These data indicate that dasatinib has substantial toxicity in NSCLC patients at high 
doses and that in unselected patients activity as a single agent is modest. 
2.4 
Rationale for the combination of EGFR-TKI and SRC inhibitor 
SRC is the prototypic member of a family of proto-oncogenic tyrosine kinases collectively 
known as SFKs (Src Family of Kinases), which includes Fyn, Yes, Fgr, Hck, Lck and 
Lyn[35]. SRC has multiple regulatory functions and has been implicated in pathways 
regulating bone metabolism, proliferation, angiogenesis, invasion and metastasis[36]. 
SRC is involved in signaling from many receptor tyrosine kinases, including EGFR, 
PDGFR, HGFR and others. High expression and activity of SRC has been correlated with 
advanced malignancy and poor prognosis in a variety of human cancers[37]. Expression 
of SRC in lung cancer has been found to be high in over 50% of lung cancers of different 
histologies[38]. 
 
Several SRC inhibitors have been developed for the treatment of cancer, but activity 
has been modest so far. Saracatinib (AZD0530), a potent oral inhibitor of the SRC family 
at nanomolar concentrations, has been tested in a phase II study in patients with 
advanced NSCLC who had progressed after one line of chemotherapy with or without an 
EGFR inhibitor [39]. Of the 37 patients who were included, 2 patients experienced a 
partial response, one had a tumor with an EGFR exon 19del mutation and the other was 


 
19 
wild type for EGFR and K-Ras. The development of Saracatinib (a relatively selective 
SRC inhibitor) in cancer has however been halted by AstraZeneca. 
 
The concept of combining TKIs against EGFR and SRC has recently been tested in 
advanced NSCLC, with the combination of erlotinib and dasatinib. In a phase I/II study 
in advanced pretreated NSCLC patients, erlotinib was given alone for a week, followed by 
co-administration of dasatinib[40]. The dose-escalation cohorts consisted of cohort 1 
(dasatinib 50 mg twice daily and erlotinib 100 mg once daily), cohort 2 (dasatinib 50 mg 
twice daily and erlotinib 150mg once daily), cohort 3, dasatinib 70mg twice daily and 
erlotinib 150 mg once daily), and cohort 4 (dasatinib 140 mg once daily and erlotinib 150 
mg once daily). Erlotinib at a dose of 150 mg daily and dasatinib at 70 mg twice daily 
were the maximum tolerated dose (MTD) and recommended doses for phase II testing. 
The most common side effects were GI toxicities such as diarrhea (88%), anorexia (71%), 
and nausea (79%). Only two patients had grade 3 diarrhea. Acneiform rash was a 
frequent adverse effect, but only two events were grade 3. Regarding hematologic 
toxicity, 53% had anemia (two events of grade 3), 29% had thrombocytopenia (one event 
of grade 3), and 65% had lymphopenia (6 events of grade 3). 35% of patients had pleural 
effusions, but all were grade 2 or less and no patient required thoracentesis or 
pleurodesis to treat drug-related effusions. Lastly, 74% had fatigue, but there were no 
grade 3 episodes. The steady-state pharmacokinetics of erlotinib were not affected by 
dasatinib. Of 34 patients included in the study, 2 experienced a partial response, one 
short lasting in a patient with an EGFR mutation and another response of over a 14-
month duration in a patient with wild-type EGFR squamous cell carcinoma. This tumor 
was later found to bear a DDR2 kinase domain mutation. Dasatinib is known to be able 
to inhibit DDR2 to some extent[41]. Interestingly, a phase I/II study of the same 


 
20 
combination in untreated patients with advanced solid tumors (phase I) and advanced 
NSCLC (phase II) demonstrated 5 partial responses out of 35 patients (14%), all of whom 
had advanced NSCLC with activating EGFR mutations[42]. In this study, the MTD was 
erlotinib 150 mg daily and dasatinib 70 mg daily based on the phase I proportion of the 
study. 
 
These clinical studies indicate that SRC inhibitors have a low level of activity as single 
agents in unselected NSCLC patients and the combination of a SRC inhibitor and an 
EGFR inhibitor might be potentially of interest, but the selection of patients is 
important. The clinical experience with the combination of erlotinib and dasatinib 
suggests that EGFR mutant lung cancer is where the activity is most expected. Together, 
preclinical data[31], the clinical experience with the combination of erlotinib and 
dasatinib[40], and our finding of important synergy between the SRC inhibitor dasatinib 
and osimertinib in reverting intrinsic EGFR resistance due to Cripto-1 overexpression in 
EGFR mutant adenocarcinoma[26], leads us to hypothesize that selecting patients with 
EGFR mutant adenocarcinoma of the lung will be crucial in order to have activity of this 
combination. This study proposes to explore the feasibility and benefit of combining 
osimertinib with a SRC inhibitor (dasatinib) for treating Cripto-1-positive EGFR-
mutated NSCLC patients. The advantage of using osimertinib is that it not only inhibits 
the exon 19 deletion and L858R mutants, but also the T790M mutant. In addition, 
osimertinib appears overall to be better tolerated than erlotinib. 
 
 
 


 
21 
3.0 
STUDY HYPOTHESIS AND OBJECTIVES 
3.1 
Hypothesis 
The combination of osimertinib with dasatinib is feasible and will decrease the rate of 
non-response in EGFR-mutant NSCLC patients who have not received an EGFR-TKI 
before. In particular, and more precisely, the combination of osimertinib and dasatinib 
will reduce the proportion of patients who progress or have stable disease lasting 4 
months or less (intrinsic resistance). Secondary endpoints will be time to progression, 
overall survival, and tolerability of the combination. 
3.2 
Primary Objectives  
3.2.1 
The primary objective of the phase I portion is to determine the maximum 
tolerated dose and recommended phase II doses of osimertinib when given in 
combination with dasatinib in patients with advanced NSCLC with EGFR 
mutations. 
3.2.2 
The primary objective of the phase II portion is to determine the rate of non-
response (progressive disease or stable disease lasting 4 months or less) to the 
combination of osimertinib and dasatinib in patients with EGFR mutations 
(including T790M), who have not received an EGFR-TKI before, stratified by 
Cripto-1 expression in their tumor. 
3.3 
Secondary Objectives  
3.3.1 
To characterize the safety profile for the combination of osimertinib and 
dasatinib  


 
22 
3.3.2 
To describe the pharmacokinetics associated with osimertinib when administered 
with dasatinib.  
3.3.3 
To determine progression-free survival, overall survival, and duration of response 
after treatment with the combination of osimertinib and dasatinib. 
3.4 
Exploratory Objectives and Correlative Studies 
Because the data of the correlation of Cripto-1 expression with intrinsic resistance to 
EGFR-TKI are retrospective[26], a prospective study will be needed to confirm these 
findings. Ideally, only patients with high Cripto-1 expression in their tumors would be 
the subject of this study. This, however, would require a validated and Clinical 
Laboratory Improvement Amendments (CLIA)-certified test to be able to prospectively 
allocate patients to treatment. We will therefore treat all patients with the combination 
of osimertinib and dasatinib, and then stratify patients based on Cripto-1 expression 
assessed post-treatment. Because the overall response rate and non-responder rate to 
osimertinib is similar to erlotinib, and all patients treated with single agent osimertinib 
are expected to develop resistance, a combination approach to all patients with EGFR 
mutations is reasonable. We will also evaluate the relationship between Cripto-1 levels 
and patients’ response to drug treatment. 
 
Cripto-1 expression will be assessed in all patients on tumor samples, obtained before 
treatment with osimertinib and dasatinib, using an immunohistochemistry method that 
has been developed in our previous study[26]. Based on our own research[26] and prior 
studies[43], Cripto-1 expression is expected to be present in the majority of samples, but 
high expression (score 2-3) will be present in less than 50% of the positive cases[26]. We 
will correlate the Cripto-1 expression in the baseline sample with response to treatment. 


 
23 
In addition, whenever feasible, fresh tumor biopsies will be obtained before starting 
treatment and at progression. These biopsies will be analyzed for Cripto-1 expression by 
RT-PCR and/or immunohistochemistry as described in our recent publication[26], 
before treatment and at progression. Briefly, quantitative RT-PCR will be performed 
using Cripto-1 primers described in our previous studies[26], the specificity of which has 
already been and will be revalidated in Cripto-1-positive/Cripto-3-negative (H727) and 
Cripto-3 positive/Cripto-1 negative cells as described in our previous study[26]. If 
sufficient biopsy material is available, we will determine the phosphorylation status of 
SRC by western blot using the anti-phospho-SRC Tyr416 (Cell Signaling) antibody 
described in our paper[26], in parallel with Cripto-1 expression study. 
 
 In collaboration with Dr. David S. Salomon at the National Cancer Institute (NCI) in 
Bethesda, Maryland, levels of plasma Cripto-1 will be assessed using a validated ELISA 
with a rabbit monoclonal antibody against the NH2-terminus of human Cripto-1 that can 
measure as little as 1 ng of Cripto-1 in plasma and serum and that can detect both free 
Cripto-1 or Cripto-1 bound to known protein partners such as GRP78, Alk4 or Nodal. The 
Cripto-1 ELISA assay is specific for Cripto-1 and is linear from 1 ng to 100 ng of Cripto-1. 
ELISA assays will be performed on plasma or serum samples from patients before 
treatment, after 8 weeks and at the time of progression. The shed Cripto-1 levels in blood 
of patients will not be a direct evidence of inhibition of the intrinsic EGFR resistance, 
because the study will use a combination of EGFR and SRC-TKIs, but it will potentially 
be a valuable marker of efficacy and a way to monitor treatment effect. 
In addition, we will investigate whether the PK of osimertinib is influenced by 
dasatinib. Finally, we will assess whether FDG-PET performed at day 28 will predict 
responses to osimertinib and dasatinib, compared to baseline FDG-PET. 


 
24 
4.0 
PATIENT ELIGIBILITY 
4.1 
Inclusion Criteria  
4.1.1 
Patients must have cytologically or histologically confirmed advanced NSCLC. 
Patients with mixed histology containing a small cell lung cancer component are 
not eligible. 
4.1.2 
Patients must have adequate archival material from a previous biopsy to 
determine EGFR mutation status and Cripto-1 expression, or undergo a biopsy of 
fresh tissue of the primary cancer or a metastatic site in order to make these 
determinations, if archival material is not available. 
4.1.3 
Presence of sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, 
G719X, and L861Q). Patients with the T790M mutation will also be eligible. 
4.1.4 
No prior treatment with an EGFR TKI for the advanced NSCLC. 
4.1.5 
ECOG performance status of 0-2. 
4.1.6 
Patients must have measurable disease by RECIST criteria, defined as at least one 
lesion that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >20 mm with conventional techniques or as >10 mm 
with spiral CT scan. See Section 7.1.2 for the evaluation of measurable disease. 
4.1.7 
Prior systemic treatment is allowed, but toxicities of prior therapy must be 
resolved to grade 1 or less as per Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. 


 
25 
4.1.8 
Adequate organ and bone marrow function (hemoglobin > 9 g/dL; absolute 
neutrophil count > 1.5 x 109/L; platelet counts > 100 x 109/L; serum bilirubin < 2 
x ULN; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 
2.5 x ULN or < 5 x ULN if liver metastases; calculated creatinine clearance > 50 
mL/min or normal creatinine (as defined as serum creatinine not exceeding the 
upper normal limit as defined by the performing laboratory)). 
4.1.9 
No uncontrolled arrhythmia; no myocardial infarction in the last 6 months. 
4.1.10 Life expectancy of at least 12 weeks. 
4.1.11 Age > 18 years.  
4.1.12 Ability to understand and willingness to sign a written informed consent 
document. 
4.2 
Exclusion Criteria 
4.2.1 
Patients who have had immunotherapy or chemotherapy during the previous 4 
weeks (6 weeks for nitrosoureas or mitomycin) before treatment, or those who 
have ongoing toxic manifestations of previous treatments, with the exception of 
alopecia, of grade higher than 1. Patients who have had whole brain radiation 
therapy (WBRT) during the previous 2 weeks before treatment (no washout 
period is required for patients who have received stereotactic body radiation 
therapy). 
4.2.2 
Major thoracic or abdominal surgery from which the patient has not sufficiently 
recovered yet. 


 
26 
4.2.3 
Untreated and uncontrolled second tumor in the past 2 years. 
4.2.4 
Logistical or psychological hindrance to participation in clinical research. 
4.2.5 
Patients with untreated symptomatic brain metastases may be eligible if 
symptoms do not require urgent surgery or radiation, and no steroids are 
necessary. 
4.2.6 
Patients with evidence of interstitial lung disease (bilateral, diffuse, parenchymal 
lung disease).  
4.2.7 
Pleural or pericardial effusions of any grade at study entry. Subjects previously 
diagnosed with pleural/pericardial effusion of any grade resolved at the time of 
study entry are allowed. 
4.2.8 
Ability to become pregnant (or already pregnant or lactating). Women and men 
who want to participate have to agree to use two highly effective forms of 
contraceptive prior to study entry, for the duration of study participation, and for 
30 days following completion of therapy, to be eligible. Women of childbearing 
potential (WOCBP) must have a negative serum or urine pregnancy test 
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior 
to the start of study drug. 
4.2.9 
At high medical risk because of non-malignant systemic disease including 
uncontrolled infection. 
4.2.10 Known to be serologically positive for hepatitis B, hepatitis C or HIV. 


 
27 
4.2.11 Uncontrolled or significant cardiovascular disease, including any of the following: 
o QTc interval > 480 msec (mean value and manually verified) at 3 or more time 
points within a 24 hour period if necessary.  
o Diagnosed or expected congenital long QT syndrome.  
o Concurrent congestive heart failure, prior history of class III/IV cardiac disease 
(New York Heart Association).  
o Left ventricular ejection fraction < 50% 
o Prior history of cardiac ischemia or cardiac arrhythmia within the last 6 months. 
Coronary angioplasty or stenting in the previous 12 months.  
o Any history of second or third degree heart block (may be eligible if the subject 
currently has a pacemaker).  
o Uncontrolled hypertension defined as inability to maintain blood pressure below 
the limit of 140/90 mmHg. 
o Known pulmonary hypertension. 
4.2.12 History of significant bleeding disorder unrelated to CML, including: 
o Diagnosed congenital bleeding disorders (e.g. von Willebrand’s disease)  
o Diagnosed acquired bleeding disorder within one year (e.g. acquired anti-factor 
VII antibodies) 


 
28 
4.2.13 Any other medical condition that in the Investigator’s opinion would not make 
the patient a good candidate for the study. 
5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
5.1.1 
Phase I  
5.1.1.1 
Dose Limiting Toxicity (DLT) 
The dose limiting toxicity (DLT) period consists of one cycle, 28 days. Dose-limiting 
toxicity is defined as adverse events occurring during the first cycle of therapy and 
related to the study drugs (attributions: possible, probable, and definite) while fulfilling 
one of the following criteria as per CTCAE version 4.03: 
o Any grade 3 or 4 toxicity except for grade 3 diarrhea, nausea, or vomiting 
if it can be controlled with supportive therapy 
o Persistent (>21 days) non-hematologic grade 2 adverse events despite 
optimal medical management and treatment delay > 21 days 
5.1.1.2 
Dose Escalation and Treatment Duration 
Treatment will be administered on an outpatient basis. A standard dose-escalation phase 
I design will be used. Selection of the starting dose of osimertinib in combination with 
dasatinib is based on the results from previous clinical studies. Since osimertinib is the 
known active drug for EGFR-mutant NSCLC, the dose of osimertinib will be the 
recommended phase II dose of 80 mg/day. Dose escalation will only include 2 dose 
levels; in addition there will be 2 dose levels below the starting dose level if dose 


 
29 
reductions are necessary.  A typical targeted DLT level is 30%, thus we will utilize the 
classical 3+3 design. So three subjects will be enrolled at each dose level in the absence 
of DLT. If 0 of 3 have DLT at DL2 (see Table 1), a total of 6 patients will be enrolled at 
DL2. If 1 of 3 patients experiences a DLT at a given dose level, that dose level will be 
expanded to a maximum of 6 patients. If 2 patients in a dose level of 3 or 6 patients 
experiences DLT, then the MTD will have been exceeded and the next lower dose level 
will be expanded to 6 patients, if needed. MTD will be the highest dose at which 0-1 of 6 
patients experience a DLT. If a patient does not complete cycle 1 for any reason other 
than DLT, the patient will not be evaluable for DLT and will be replaced at that dose 
level. Patients who develop a DLT will be de-escalated by one dose level (DL). There is no 
limit to the number of cycles a patient can receive. 
Table 1. Dose-escalation schedule 
Dose-Escalation Schedule 
Dose Level 
(DL) 
Osimertinib 
dose  
(Oral) 
Dasatinib  
(Oral) 
Level -2 
80 mg 
50 mg once daily 
Level -1 
80 mg 
70 mg once daily 
Level 1 
(starting doses) 
80 mg 
50 mg twice daily 
Level 2 
80 mg 
70 mg twice daily 
5.1.1.3 
Patient Replacement 
Three patients within a dose level must be observed for one cycle (28 days) before 
accrual to the next higher dose level may begin. If a patient is withdrawn from the study 
prior to completing 28 days of therapy without experiencing a DLT prior to withdrawal, 
an additional patient may be added to that dose level. 


 
30 
5.1.2 
Phase II 
Determination of the recommended phase II dose will be based on the MTD, tolerability, 
and toxicities beyond cycle 1.  Courses are defined as 28 days of dosing. There is no limit 
to the number of cycles a patient can receive. 
5.2 
General Management of Toxicities 
Any patient who receives treatment on this protocol will be evaluable for toxicity. 
Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse 
Events (CTCAE), version 4.03. Dose adjustments should be made according to the 
system showing the greatest degree of toxicity. Once a patient has a dose reduction due 
to toxicity, the dose will not be re-escalated. General guidelines for the management of 
toxicities are described in Table 2 and Table 3. In the case of toxicity, supportive 
treatment should be used (e.g. anti-emetics, anti-diarrheals). 
5.2.1 
Hematologic Toxicities 
Since osimertinib is associated with hematologic toxicity to a lesser extent than dasatinib 
and it is the known active drug for EGFR-mutant NSCLC, dasatinib will be dose modified 
first as described in Table 2. Osimertinib will be dose reduced as per Table 4 if 
hematologic toxicity is refractory to discontinuation of dasatinib, meaning that the 
hematologic toxicity recurs or persists even after discontinuation of dasatinib. 
 
Table 2. General Recommendations for Dose Modification and Management 
of Hematological Toxicities 
Adverse Event or Observation 
Dose Modification at a given dose level 
ANC*  750/mm3 
AND  
Maintain dose 


 
31 
Platelets  75,000/mm3 
AND 
Hemoglobin  8 g/dL 
ANC 500-750/mm3 
OR 
Platelets 50,000-75,000/mm3 
OR 
Hemoglobin 6-8 g/dL 
1. Hold dasatinib until ANC  750/mm3, platelets ≥ 
75,000/mm3, and hemoglobin  8 mg/dL. Initiate 
appropriate medical therapy**. 
2. Resume treatment at the original starting dose.  
3. On second occurrence, repeat step 1. 
4. On third occurrence, reduce one dose level and 
resume treatment. 
ANC < 500/mm3 
OR 
Platelets <50,000/mm3 
OR 
Hemoglobin < 6 g/dL 
OR 
Anemia with life-threatening 
consequences*** 
  1. Hold dasatinib until ANC  750/mm3, platelets ≥ 
75,000/mm3, and hemoglobin  8 mg/dL. Initiate 
appropriate medical therapy. 
  2. Study drug(s) may be restarted at one DL lower.   
  3. On second occurrence, discontinue dasatinib.   
*ANC: Absolute neutrophil count 
** Growth factors to prevent neutropenia will not be administered prophylactically, but 
can be used during a drug hold to assist the recovery. Thrombocytopenia will be treated 
conservatively. In the absence of bleeding, or a necessary invasive procedure, platelet 
transfusions should be given for a platelet count ≤ 10,000/mm3. If invasive procedure(s) 
is (are) planned, or the patient develops bleeding, platelet transfusions should be 
administered in accordance with the standard of practice, usually maintaining a platelet 
count above 50,000/mm3. Red blood cell transfusion and is recommended if the 
hemoglobin falls below 8 g/dL or the patient is symptomatic.  
*** Rare reports of aplastic anaemia have been reported in association with osimertinib 
treatment. Some cases had a fatal outcome. Before initiating treatment, patients should 
be advised of signs and symptoms of aplastic anemia including but not limited to 


 
32 
persistent fever, bruising, bleeding, and/or pallor. If signs and symptoms suggestive 
of aplastic anemia develop, close patient monitoring and drug interruption or 
discontinuation of osimertinib should be considered. Osimertinib should be 
discontinued in patients with confirmed aplastic anemia.  
 
5.2.2 
Non-hematologic Toxicities 
For non-hematologic toxicities, dose reductions will be allowed, with the aim of 
maintaining a full dose of osimertinib and reducing primarily dasatinib unless the 
toxicity is clearly associated with osimertinib (see Table 3). If dose reduction of 
osimertinib is indicated, osimertinib will be dose reduced as per Table 4. 
 
Table 3. General Recommendations for Dose Modification and Management 
of Non-Hematological Toxicities 
Event 
AE Grade or 
Observation 
Dose Modification 
Dermatology/Ski
n 
Grade 1 or 2 
Maintain dose. 
Grade 3 or 4  
OR 
Intolerable Grade 2 
1. Hold the drug(s) causing the toxicity until ≤ 
tolerable grade 2. 
2. Study drug(s) may be restarted at one DL lower. 
3. On second occurrence, repeat step 1. 
Recurrent Grade 3 
after 2 dose reductions 
Discontinue the drug(s) causing the toxicity. 
Grade 4 
Discontinue the drug(s) causing the toxicity. 
Diarrhea 
Grade 1 or 2 
Maintain dose. Supportive treatment with anti-
diarrheal treatment (e.g. Loperamide 4 mg at first 
onset, followed by 2 mg every 2-4 hours until 
diarrhea free for 12 hours). 
Grade 3 or 4 
Hold the drug(s) causing the toxicity until ≤ 


 
33 
tolerable grade 2. Reduce one dose level and 
resume treatment. 
Recurrent Grade 3 or 4 Hold the drug(s) causing the toxicity until ≤ 
tolerable grade 2. Reduce one additional dose 
level and resume treatment. 
Recurrent Grade 3 or 4 
after 2 dose reductions 
Discontinue the drug(s) causing the toxicity. 
Liver Function 
(serum bilirubin, 
AST/ALT) 
Grade 1 or 2 
Maintain dose. 
Grade 3 or 4 
Hold the drug(s) causing the toxicity until grade 2, 
then reduce one dose level and resume treatment. 
Recurrent Grade 3 or 4 Hold the drug(s) causing the toxicity until ≤ grade 
2. Reduce one additional dose level and resume 
treatment. 
Recurrent Grade 3 or 4 
after 2 dose reductions 
Discontinue the drug(s) causing the toxicity. 
Pulmonary 
Toxicities* 
ILD/Pneumonitis 
Permanently discontinue osimertinib 
Cardiac** 
QTc interval greater 
than 500 msec on at 
least 2 separate ECGs 
Withhold osimertinib until QTc interval is less 
than 481 msec or recovery to baseline if baseline 
QTc is greater than or equal to 481 mseca within 3 
weeks of withholding osimertinib, then restart at a 
reduced dose (40 mg) or at 80 mg (at the 
discretion of the investigator).  
QTc interval 
prolongation with 
signs/symptoms of 
serious arrhythmia 
Permanently discontinue osimertinib 
Other non-
hematologic 
toxicity*** 
(Please see the 
footnotes for 
further guidance 
on keratitis, and 
Grade 1 or 2 
Maintain dose. 
Any grade 2 of concern 
Hold the drug(s) causing the toxicity until grade 1, 
then reduce one dose level and resume treatment. 
Grade 3 or 4 
Hold the drug(s) causing the toxicity until grade 2, 
then reduce one dose level and resume treatment. 
Recurrent Grade 3 or 4 Hold the drug(s) causing the toxicity until grade 2. 
Reduce one additional dose level and resume 


 
34 
erythema 
multiforme/Stev
ens-Johnson 
syndrome) 
treatment. 
Recurrent Grade 3 or 4 
after 2 dose reductions 
Discontinue the drug(s) causing the toxicity. 
* Pleural effusion: Dasatinib is associated with fluid retention including pleural effusion. 
Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry 
cough should be evaluated by chest imaging. Grade 3 or 4 pleural effusion may require 
thoracentesis and oxygen therapy. Fluid retention events are typically managed by 
supportive care measures that include diuretics and short courses of steroids. 
*ILD/Pneumonitis-like toxicity: If new or worsening pulmonary symptoms (e.g., 
dyspnea) or radiological abnormality suggestive of interstitial lung disease/pneumonitis 
is observed, an interruption in study treatment dosing is recommended, and the Sponsor 
study team should be informed. It is strongly recommended to perform a full diagnostic 
workup, to exclude alternative causes such as lymphangitic carcinomatosis, infection, 
allergy, cardiogenic oedema or pulmonary hemorrhage. The results of full diagnostic 
workup (including high-resolution computed tomography (HRCT), blood and sputum 
culture, hematological parameters) will be captured by eCRF. In the presence of 
confirmatory HRCT scans where other causes of respiratory symptoms have been 
excluded, a diagnosis of interstitial lung disease should be considered and study 
treatment permanently discontinued.  
**Cardiac toxicity 
 
Based on the available clinical trial data, a causal relationship between effects on 
changes in cardiac contractility and osimertinib has not been established. In 
patients with cardiac risk factors and those with conditions that can affect LVEF, 
cardiac monitoring, including an assessment of LVEF at baseline and during 


 
35 
treatment, should be considered. In patients who develop relevant cardiac 
signs/symptoms during treatment, cardiac monitoring including LVEF 
assessment should be considered.  
 
Osimertinib will be withheld if ejection fraction decreases by 10% from 
pretreatment values and is less than 50%. For symptomatic congestive heart 
failure or persistent, asymptomatic LV dysfunction that does not resolve within 4 
weeks, osimertinib will be permanently discontinued.  
 
In light of the potential for QT changes associated with osimertinib, electrolyte 
abnormalities (hypokalaemia, hypomagnesaemia, hypocalcaemia) must be 
correct to be within normal ranges prior to first dose and electrolyte levels 
monitored during study treatment. Patients with QTcF prolongation to >500 
msec should have study treatment interrupted and regular ECGs performed until 
resolution to <481 msec or recovery to baseline if baseline QTcF is >481 msec 
and then restarted at a reduced dose of 40 mg, or 80mg at the discretion of the 
investigator. If the toxicity does not resolve to ≤ grade 1 within 21 days of 
withholding osimertinib the patient will be permanently withdrawn from study 
treatment. If QTc interval prolongation with signs/symptoms of serious 
arrhythmia occurs, osimertinib will be permanently discontinued.  
***Keratitis: Patients presenting with signs and symptoms suggestive of keratitis such as 
acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye 
pain and/or red eye should be referred promptly to an ophthalmology specialist.  
***Erythema multiforme (EM) and Stevens-Johnson syndrome (SJS): Case reports of 
Erythema multiforme (EM) and Stevens-Johnson syndrome (SJS) have been 


 
36 
uncommonly and rarely reported, respectively, in association with osimertinib 
treatment. Before initiating treatment, patients should be advised of signs and symptoms 
of EM and SJS. If signs and symptoms suggestive of EM develop, close patient 
monitoring and drug interruption or discontinuation of osimertinib should be 
considered. If signs and symptoms suggestive of SJS appear, osimertinib should be 
interrupted or discontinued immediately.  
 
Table 4. Osimertinib Dose Level Reductions 
Dose Level 
(DL) 
Osimertinib dose  
(Oral) 
Starting Dose 
80 mg once daily 
First dose reduction 
40 mg daily 
 
5.3 
Concomitant Medications/Treatments 
Treatment with other anticancer therapy or any other investigational agent is prohibited 
from 30 days prior to the first dose of Osimertinib and dasatinib, and throughout the 
study. 
5.4 
Off-treatment criteria 
In the absence of treatment delays due to adverse events, treatment may continue until 
one of the following criteria applies: 
o Disease progression* 
o Intercurrent illness that prevents further administration of treatment 
o Unacceptable adverse event(s) 


 
37 
o Any severe (grade 3 or 4) toxicity that has not resolved to 
NCI/CTEP grade 1 toxicity by three weeks or by medical judgment 
of the PI or one of the associate investigators discontinuation is 
considered to be in the best interest for the patient.  
o For osimertinib, interstitial lung disease/pneumonitis and QTc 
elevation with signs or symptoms of serious arrhythmia are 
unacceptable adverse events.  
o Patient decides to withdraw from the study, OR 
o General or specific changes in the patient’s condition render the patient unfit for 
further treatment in the judgment of the investigator. 
o Patient is non-compliant with the protocol guidelines 
 
* Patients are allowed to stay on treatment beyond progression if the investigator thinks 
that the patient is still benefiting from the treatment. 
5.5 
Off-study criteria 
o Death 
o Patient refuses follow-up or decides to withdraw consent from the study 
5.6 
Duration of Follow-Up 
Patients will remain on the study and be followed for adverse events after removal from 
treatment for minimum of 4 weeks after the final dose of osimertinib and/or dasatinib. 
Patients who were removed from treatment for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. Patients will be followed 
for progression of the disease and survival. 


 
38 
 
6.0 
STUDY PROCEDURES 
6.1 Screening/Baseline Procedures 
Subjects who meet all eligibility criteria will be enrolled in the study. Assessments 
performed exclusively to determine eligibility for this study will be done after obtaining 
informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done 
before informed consent was obtained. All screening procedures must be performed 
within 4 weeks prior to starting study drugs unless otherwise stated. The screening 
procedures include: 
o Complete history and physical examination including vital signs, height, weight 
and ECOG performance score (see appendix A). 
o Baseline imaging studies: Patients should have a baseline radiographical 
evaluation with whole-body FDG-PET scan and contrast-enhanced computed 
tomography (CT) scan of the chest/abdomen/pelvis. Baseline brain imaging will 
also be obtained via either MRI or CT of the brain with contrast. Outside imaging 
studies will be accepted at the discretion of the PI. 
o A baseline chest x-ray (optional if chest CT is performed) 
o Electrocardiogram (EKG) 
o Echocardiogram or multigated acquisition (MUGA) scan to assess left ventricular 
ejection fraction 
o Laboratory evaluation (baseline tests to be obtained within one week prior to 
starting treatment unless otherwise noted) 


 
39 
o Hematological Profile: Complete blood count (CBC) with differential and 
platelet count, prothrombin time/international normalized ratio 
(PT/INR), activated partial thromboplastin time (aPTT). 
o Biochemical Profile: Sodium, potassium, calcium, phosphorous, 
magnesium, blood urea nitrogen (BUN), creatinine, glucose, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase, lactic acid dehydrogenase (LDH), bilirubin, albumin.  
o Baseline glomerular filtration rate (GFR) calculation. 
o Serum or urine beta-hCG for female patients of childbearing age within 24 
hours prior to the start of study drug. 
o Plasma or serum Cripto-1 
6.2 
Procedures During Treatment 
Patients will be followed every two weeks for the first 4 weeks and the following will be 
done.  
Prior to Each Treatment Cycle: 
o History and physical exam 
o Laboratory evaluation: Hematologic and biochemical profile 
o EKG 
 


 
40 
Once treatment tolerance has been established, patients will be seen every 4 weeks, or 
more frequently if medically indicated. 
o Tumor imaging will be performed every 2 cycles (within a week of starting the 
next cycle). Scans may be extended to every 3 cycles at the discretion of the 
investigator, if the subject has remained stable on treatment.  
o Echocardiogram or multigated acquisition (MUGA) scan will be performed as 
clinically indicated. 
o FDG-PET will be repeated 4 weeks (cycle 1 day 28 ± 2 days) after initiation of 
study drugs in order to assess the metabolic response. 
o Plasma or serum for detection of shed Cripto-1 will be obtained at 8 weeks and at 
tumor progression. 
o In consenting patients, a fresh tumor biopsy will be obtained at disease 
progression to assess Cripto-1 expression by RT-PCR and/or 
immunohistochemistry. 
 
After 30 days from treatment termination, the following will be obtained: 
o History and physical exam 
o Laboratory evaluation: Hematologic and biochemical profile 
o EKG 
7.0 
Measurement of Effect 
7.1 Antitumor Effect- Solid Tumors 
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 


 
41 
[44]. Changes in only 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 version 1.1 criteria. 
7.1.1 
Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their 
first treatment with osimertinib and dasatinib. 
 
Evaluable for objective response: Only those patients who have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response.  These patients will have their response classified according to the definitions 
stated below.  (Note:  Patients who exhibit objective disease progression prior to the end 
of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response: Patients 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 reevaluated will be considered 
evaluable for non-target disease. The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions. 
7.1.2 
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, as >10 mm with CT scan, or 10 mm with calipers by clinical exam. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 


 
42 
 
Note: Tumor lesions that are located in a previously irradiated area might or might not 
be considered measurable at the discretion of the PI.  
 
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 
(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/pulmonis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all non-
measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor nonmeasurable) 
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 patient, these are preferred for selection as target 
lesions. 


 
43 
 
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, and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically).  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 6 target lesions should be identified as non-target lesions 
and should also be recorded at baseline.  Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow-up.  
7.1.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 28 days before the beginning of the 
treatment. 
 


 
44 
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. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm 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. 
 
Conventional CT and MRI: CT and MRI - CT and MRI are the best currently available 
and reproducible methods to measure target lesions selected for response assessment. 
For this study helical Multidetector CT will be performed with cuts of 5 mm in slice 
thickness for chest, abdomen and pelvis lesions and 2-3 mm thickness for head and neck 
lesions. 
 
Cytology, Histology: These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases. 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 


 
45 
FDG-PET: New lesions on the basis of FDG-PET imaging can be identified according to 
the following algorithm. Negative FDG-PET at baseline, with a positive FDG-PET at 
follow-up may be a sign of progressive disease. If the positive FDG-PET at follow-up 
corresponds to a new site of disease confirmed by CT, this is progressive disease (PD). If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site. If so, the date of PD will be the date of the initial abnormal FDG-
PET scan. If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD.  
 
Note: A positive FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
7.1.4 
Response Criteria 
7.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, determined by two 
separate observations conducted not less than 4 weeks apart. There can be no 
appearance of new lesions. Any pathological lymph nodes must have reduction in short 
axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of target lesions, taking as 
reference the baseline sum diameters. There can be no appearance of new lesions. 
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 


 
46 
that is the smallest on study). The appearance of one or more new lesions is also 
considered progression). 
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. 
7.1.4.2 
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) 
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). 
7.1.4.3 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 


 
47 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
Table 3. Evaluation of patients with measureable 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:  
Patients 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. 
 
Table 4. Evaluation of patients with non-measureable disease 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 


 
48 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated  
No 
Not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
7.1.5 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
 
 
Duration of stable disease:  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.  
7.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment 
to time of progression or death, whichever occurs first. 
7.1.7 
Overall Survival 
Overall survival is defined as the duration of time from start of treatment to death from 
any cause. 


 
49 
 
8.0 
ADVERSE EVENTS 
8.1 Definitions 
8.1.1 
Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving study 
treatment and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an 
experimental intervention, whether or not related to the intervention.  For this study, 
AEs will include events reported by the patient, as well as clinically significant abnormal 
findings on physical examination or laboratory evaluation. A new illness, symptom, sign 
or clinically significant laboratory abnormality or worsening of a pre-existing condition 
or abnormality is considered an AE. All AEs must be recorded on the AE case report 
form. 
AEs should be reported up to 30 days following the last dose of study drug. All 
AEs, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until satisfactory resolution. AEs should be 
reported up to 30 days following the last dose of study drug. 
An abnormal laboratory value will be considered an AE if the laboratory 
abnormality is characterized by any of the following: 
o Results in discontinuation from the study 
o Is associated with clinical signs or symptoms 
o Requires treatment or any other therapeutic intervention 


 
50 
o Is associated with death or another serious adverse event, including 
hospitalization. 
o Is judged by the Investigator to be of significant clinical impact 
o If any abnormal laboratory result is considered clinically significant, the 
investigator will provide details about the action taken with respect to the test 
drug and about the patient’s outcome. 
8.1.2 
Suspected Adverse Reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. The term ‘reasonable possibility’ 
means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about 
causality than adverse reaction, which means any adverse event caused by a drug. 
8.1.3 
Unexpected Adverse Reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has 
been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application. "Unexpected”, also refers to adverse events or 
suspected adverse reactions that are mentioned in the investigator brochure as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, 
but are not specifically mentioned as occurring with the particular drug under 
investigation. 


 
51 
8.1.4 
Serious Adverse Events  
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor*, it results in any of the following:  
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization, excluding 
hospitalizations done to facilitate research studies or for non-medical reasons (to 
facilitate completion of protocol-directed requirements, i.e. biopsy, imaging, 
desensitization for platinum) 
o Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
o A congenital anomaly/birth defect 
o Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the patient 
or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition 
o Potential drug induced liver injury (DILI)** 
o Suspected transmission of an infectious agent (e.g. pathogenic or nonpathogenic) 
via the study drug is a serious adverse event. 
o Adverse Events (AEs) for new malignant tumors (i.e., it is not the tumor for which 
entry into the study is a criterion and that is being treated by the IP under study and 
is not the development of new or progression of existing metastasis to the tumor 
under study) reported during a study should generally be assessed as Serious AEs. 


 
52 
If no other seriousness criteria apply, the ‘Important Medical Event’ criterion 
should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumor event should be 
assessed and reported as a Non-Serious AE. For example, if the tumor is included 
as medical history, and progression occurs during the study, but the progression 
does not change treatment and/or prognosis of the malignant tumor, the AE may 
not fulfill the attributes for being assessed as Serious, although reporting of the 
progression of the malignant tumor as an AE is valid and should occur. Also, some 
types of malignant tumors, which do not spread remotely after a routine treatment 
that does not require hospitalization, may be assessed as Non-Serious; examples 
include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via 
cone biopsy 
 
*Dr. Chul Kim is the sponsor of this trial. 
**Potential Drug Induced Liver Injury 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event. All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as potential drug induced liver 
injury is defined as: 
1) ALT or AST elevation > 3 times upper limit of normal (ULN) 
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 


 
53 
3) No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
8.1.5 
Severity of Adverse Events 
All non-hematologic adverse events will be graded according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. The CTCAE v4 is 
available at http://ctep.cancer.gov/reporting/ctc.html 
Attribution categories are as follows: 
o Definite – The AE is clearly related to the study treatment. 
o Probable – The AE is likely related to the study treatment. 
o Possible – The AE may be related to the study treatment. 
o Unrelated – The AE is clearly NOT related to the study treatment. 
8.2 Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of Subjects enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial.  Additionally, certain adverse events must be 
reported in an expedited manner to allow for optimal monitoring of patient safety and 
care.  
 
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be monitored until:  
o The adverse event resolves or the symptoms or signs that constitute the adverse 


 
54 
event return to baseline;  
o Any abnormal laboratory values have returned to baseline;  
o There is a satisfactory explanation other than the study drug for the changes 
observed; or 
o Death. 
8.3 Reporting Requirements for Adverse Events 
8.3.1 
Expedited Reporting 
o The Principal Investigator must be notified within 24 hours of learning of any serious 
adverse events, regardless of attribution, occurring during the study or within 30 
days of the last administration of the study drug.  The Sponsor-Investigator can be 
contacted at Chul Kim, MD, E-mail: Chul.Kim@gunet.georgetown.edu, phone: 202-
444-2223 with CC to LCCC-Multicenter-IITs@georgetown.edu. 
o The institutional officials must be notified within 10 business days of “any 
unanticipated problems involving risk to subjects or others” (UPR). UPRs are defined 
as any problem or event that is considered: 1) serious, 2) unexpected, and 3) at least 
possibly related to study participation. 
o The FDA should be notified within 7 business days of any unexpected fatal or life-
threatening adverse event with possible relationship to study drug, and 15 business 
days of any event that is considered: 1) serious, 2) unexpected, and 3) at least 
possibly related to study participation. 


 
55 
8.3.2 
Routine Reporting 
o All other adverse events- such as those that are expected, or are unlikely or definitely 
not related to the study participation- are to be reported annually as part of regular 
data submission. 
8.4 Reporting of Serious Adverse Events (SAEs) to Astra Zeneca (AZ) 
Investigators and other site personnel must inform the FDA, via a MedWatch/AdEERs 
form, of any serious or unexpected adverse events that occur in accordance with the 
reporting obligations of 21 CFR 312.32, and will concurrently forward all such reports to 
AZ.  A copy of the MedWatch/AdEERs report must be faxed to AstraZeneca at the time 
the event is reported to the FDA.  It is the responsibility of the investigator to compile all 
necessary information and ensure that the FDA receives a report according to the FDA 
reporting requirement timelines and to ensure that these reports are also submitted to 
AstraZeneca at the same time. 
 
* A cover page should accompany the MedWatch/AdEERs form indicating the 
following: 
 
Investigator Sponsored Study (ISS) 
 
The investigator IND number assigned by the FDA 
 
The investigator’s name and address 
 
The trial name/title and AstraZeneca ISS reference number 


 
56 
* Investigative site must also indicate, either in the SAE report or the cover page, 
the causality of events in relation to all study medications and if the SAE 
is related to disease progression, as determined by the principal 
investigator. 
* Send SAE report and accompanying cover page by way of email to 
AstraZeneca’s designated mailbox 
AEMailboxClinicalTrialTCS@astrazeneca.com (email is preferred 
method) 
or 
* Send SAE report and accompanying cover page by way of fax to 
AstraZeneca’s designated fax line: 1-888-984-7229  
 
If a non-serious AE becomes serious, this and other relevant follow-up information 
must also be provided to AstraZeneca and the FDA. 
Serious adverse events that do not require expedited reporting to the FDA need to be 
reported to AstraZeneca preferably using the MedDRA coding language for serious 
adverse events.  This information should be reported on a monthly basis and under no 
circumstance less frequently than quarterly. 
In the case of blinded trials, AstraZeneca will request that the Sponsor either provide 
a copy of the randomization code/ code break information or unblind those SAEs 
which require expedited reporting. 
All SAEs have to be reported to AstraZeneca, whether or not considered causally 
related to the investigational product.  All SAEs will be documented.  The investigator 


 
57 
is responsible for informing the IRB and/or the Regulatory Authority of the SAE as 
per local requirements. 
Non-serious adverse events and SAEs will be collected from the time consent is given, 
throughout the treatment period and up to and including the 30 day follow-up 
period.  After withdrawal from treatment, subjects must be followed-up for all 
existing and new AEs for 30 calendar days after the last dose of trial drug and/or 
until event resolution.  All new AEs occurring during that period must be recorded (if 
SAEs, then they must be reported to the FDA and AstraZeneca).  All study-related 
toxicities/ SAEs must be followed until resolution, unless in the Investigator’s 
opinion, the condition is unlikely to resolve due to the patient’s underlying disease. 
8.5 Reporting of Serious Adverse Events (SAEs) to Bristol-Myers 
Squibb (BMS) 
8.5.1 
Serious Adverse Event Collection and Reporting 
See Appendix B for mandatory adverse event reporting information. All serious adverse 
events must be reported to BMS Worldwide Safety. 
8.5.2 
Special Warnings and Precautions for Use 
8.5.2.1 
Reproductive status 
o Women of childbearing potential (WOCBP) must have a negative serum or 
urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of 
HCG) within 24 hours prior to the start of study drug. 
o Women must not be breastfeeding. 


 
58 
o WOCBP must agree to follow instructions for method(s) of contraception for 
the duration of treatment with study drug, plus 30 days (duration of 
ovulatory cycle) for a total of 30 days post-treatment completion. 
o Men who are sexually active with WOCBP must agree to follow instructions 
for method(s) of contraception for the duration of treatment with study drug 
plus 90 days (duration of sperm turnover) for a total of 90 days post-
treatment completion. 
o Azoospermic males and WOCBP, who are not heterosexually active, are 
exempt from contraceptive requirements.  However, WOCBP must still under 
pregnancy testing as described in this section. 
o Investigators shall counsel WOCBP and male subjects who are sexually active 
with WOCBP on the importance of pregnancy prevention and the 
implications of unexpected pregnancy. Investigators shall advise WOCBP and 
male subjects who are sexually active with WOCBP on the use of highly 
effective contraception.  Highly effective methods of contraception have a 
failure rate of <1% when used consistently and correctly. 
o At a minimum, subjects must agree to the use of two methods of 
contraception, with one method being highly effective and the other method 
being either highly effective or less effective as listed below. 
8.5.2.2 
Highly effective methods of contraception 
o Male condoms with spermicide 


 
59 
o Hormonal methods of contraception including combined oral contraceptive 
pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such 
as Mirena by WOCBP subject or male subject’s WOCBP partner (previous 
language flexible as appropriate per Directive as based on current knowledge 
of effects of study drug(s) on hormone exposures and as agreed upon by MST 
Lead and Medical Monitor in consultation with the compound Lead Clinical 
Pharmacologist.). Female partners of male subjects participating in the study 
may use hormone based contraceptives as one of the acceptable methods of 
contraception since they will not be receiving study drug  
o IUDs, such as ParaGard 
o Vasectomy 
o Complete Abstinence* 
Note: *Complete abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study drugs. Female 
subjects must continue to have pregnancy tests. Acceptable alternate methods of highly 
effective contraception must be discussed in the event that the subject chooses to forego 
complete abstinence. 
8.5.2.3 
Less effective methods of contraception 
o Diaphragm with spermicide 
o Cervical cap with spermicide 
o Vaginal sponge 
o Male Condom without spermicide  


 
60 
o Progestin only pills by WOCBP subject or male subject’s WOCBP partner 
(inclusion flexible as appropriate per Directive as based on current knowledge 
of effects of study drug (s) on hormone exposures and as agreed upon by MST 
Lead and Medical Monitor in consultation with the compound Lead Clinical 
Pharmacologist) 
o Female Condom (A male and female condom must not be used together) 
8.5.2.4 
Prohibited and/or Restricted Treatments 
Medications associated with QT interval prolongation that are prohibited on this study 
include: 
o Quinidine, procainamide, disopyramide 
o Amiodarone, sotalol, ibutilide, dofetilide 
o Erythromycins, clarithromycin 
o Chlorpromazine, haloperidol, mesoridazine, thiordazine, pimozide 
o Cispride, bepridil, droperidol, methadone, arsenic, chlorquine, domperidone, 
halofantrine, levomethadyl, penamidine, sparfloxacin, lidoflazine. 
8.5.2.5 
Other Restrictions and Precautions 
o Caution should be exercised if subjects are required to take medications that 
inhibit platelet function or anticoagulants. Antiplatelet agents or 
anticoagulants should be avoided in the setting of Grade 3 or 4 
thrombocytopenia. 
o Ideally, subjects should not be taking other medications known to prolong the 
QT interval. However, should the investigator believe that therapy with a 


 
61 
potentially QT prolonging medication is vital to an individual subject’s care, 
then additional ECG(s) should be done at the investigator’s discretion to 
ensure the subject’s safety. 
o Dasatinib is a substrate and an inhibitor of cytochrome P450 (CYP) 3A4. 
Caution is warranted when administering dasatinib to subjects taking drugs 
that are highly dependent CYP3A4 for metabolism and have a narrow 
therapeutic index.  Systemic exposures to these medications could be 
increased while receiving dasatinib. 
o Additionally, strong to moderate CYP3A4 inhibitors (e.g. ketoconazole, 
itraconazole, erythromycin, clarithromycin, atazanavir, indinavir, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) may significantly 
increase concentrations of dasatinib and should be used with caution when 
administered concurrently with dasatinib. 
o Strong to moderate CYP3A4 inducers (e.g. rifampicin) may decrease the 
concentration of dasatinib and should be used with caution when 
administered concurrently with dasatinib. 
9.0 
DRUG INFORMATION 
9.1 
Osimertinib 
o Classification and Mode of action: Osimertinib is a third-generation, 
selective, irreversible inhibitor that targets both sensitizing and EGFR T790M 
mutations. 
o Storage: The product should be stored in the pack provided and used 


 
62 
according to the instructions on the label. 
o Protocol dose: Whole tablets should be administered and swallowed whole 
with a glass of water during the morning at the same time each day. The dose 
for this study starts 80 mg orally once daily. 
o Route of administration for this study: oral 
o Incompatibilities: Not applicable 
o Availability: Provided by sponsor 
o Side effects: 
 
Based on the phase I study by Janne et al., most of the adverse effects 
were grade 1 or 2[28]. The incidences of grade 3-5 diarrhea, rash, 
nausea, and anorexia were 2%, 1%, 1%, and 2%, respectively. There 
were 6 cases of potential pneumonitis-like events. There were 6 
patients who developed hyperglycemia, and 11 patients who had 
prolongation of QTc (corrected QT) interval; none of these events led 
to discontinuation or reduction of osimertinib. 
 
Please refer to the IB for further details about the side effect profile of 
osimertinib. 
9.1.1 
Drug accountability  
The investigator, or a responsible party designated by the investigator, must maintain 
careful record of the inventory and disposition of all agents received from AstraZeneca. A 
member of the research team will be documenting pill counts at each visit and patients 
will be required to bring their bottles to every visit and return any unused pills when they 
go off-study. Patients going off-study must return unused pills to the research team. 


 
63 
9.2 
Dasatinib 
o Other names for the drug(s): SPRYCEL, BMS-354825 
o Classification and mode of action: a potent, broad-spectrum adenosine 
triphosphate (ATP) competitive inhibitor of multiple critical oncogenic 
tyrosine kinases and kinase families, including BCR-ABL, SRC, c-KIT, 
platelet-derived growth factor (PDGF) receptor, and ephrin receptor kinases 
o Storage and stability:  
 
SPRYCEL (20, 50, 80, 100, and 140 mg) or dasatinib film-coated 
tablets (5, 20, and 50 mg) should be stored at 15° to 25°C (59° to 
77°F). 
 
Dasatinib for oral suspension may be stored at 15° to 30°C (59° to 
86°F). 
o Protocol dose: Whole tablets should be administered and swallowed whole 
with a glass of water during the morning and evening at the same time each 
day. The dose for this study starts 50 mg orally twice daily, with the potential 
for higher doses with higher dose levels or lower dose levels.  
o Route of administration for this study: Per oral 
o Incompatibilities: Not applicable 
o Availability: Provided by sponsor 
o Side effects: Refer to the agent’s package insert for a comprehensive list of 
adverse events. 
 
In a phase II study of dasatinib in patients with advanced NSCLC[32], 
the most common grade 3 toxicity was dyspnea (44%) caused by 
underlying disease, chronic obstructive pulmonary disease, and/or 


 
64 
pleural effusion. The incidences of grade 2 and 3 pleural effusion were 
26% and 18%, respectively. Grade 2 nausea occurred in 6% of the 
patients. There was no grade 3 nausea. 6% of the patients developed 
grade 2 or 3 rash. Lymphopenia was the most common hematologic 
adverse effect (grade 2 in 15% of the patients, grade 3 in 3% of the 
patients). 6% of the patients had grade 2 or 3 anemia. There was no 
thrombocytopenia or neutropenia. Significant laboratory 
abnormalities were infrequent. The most common non-hematologic 
adverse effect was elevated AST/ALT (grade 2 in 6% of the patients). 
 
PRODUCT INFORMATION TABLE 
 
9.2.1 
Drug accountability  
The investigator, or a responsible party designated by the investigator, must maintain 
careful record of the inventory and disposition of all agents received from Bristol-Myers 
Product Description 
Product 
Description 
and Dosage 
Form 
Potency 
Primary 
Packaging 
(Volume)/ 
Label Type 
Secondary 
Packaging 
(Qty)/Label 
Type 
Appearance 
Storage Conditions 
(per label) 
Dasatinib 
20mg, 
50mg 
Various 
packaging 
configurations 
Open label 
Not 
applicable 
White to off-
white, biconvex, 
film-coated 
tablets 
Refer to label on 
container or 
package 
insert/summary of 
product 
characteristics 


 
65 
Squibb. A member of the research team will be documenting pill counts at each visit and 
patients will be required to bring their bottles to every visit and return any unused pills 
when they go off-study. Patients going off-study must return unused pills to the research 
team. 
9.3 
Unused Study Drug and Destruction 
A copy of the standard institutional procedure for destroying investigational drugs will 
be provided to the Sponsor or designee upon request. Unused study drug not destroyed 
at the site must be returned to the Sponsor or designee at the end of the study or upon 
expiration. 
10.0 CORRELATIVES/SPECIAL STUDIES  
10.1 Pharmacokinetics 
During the phase I portion of the study, pharmacokinetics for osimertinib will be 
assessed.  
10.1.1 Timeline 
 
Blood samples will be collected at the following times. 
o Baseline Pre-dose Day 1 
o Post-dose Day 1: 2 hours; Post-dose Day 1: 4 hours Post-dose Day 1: 6 hours 
o Pre-dose Day 1, Cycle 2; Post-dose Day 1, Cycle 2: 4 hours 
o Pre-dose Day 1, cycle 3, and then every cycle pre-dose  


 
66 
10.1.2 Procedure 
o Samples will be analyzed using an ultra high-performance liquid chromatography 
(HPLC), validated for processing human samples. 
o The samples are to be drawn, immediately placed on wet ice, refrigerated, and 
serum and plasma will be separated, aliquoted and stored at -20 C until 
shipment.  
o The sample label should contain the following information: Cycle number, Day 
number, time after dosing, and exact draw date and time. 
o Blood samples (7ml green top [heparin] tube) for osimertinib measurement by 
HPLC will be drawn according to the above timeline. [Osimertinib will be 
assessed by Covance Laboratories.  Details for shipment will be provided as part 
of a Laboratory Manual.] 
o Blood samples (7ml green top [heparin] tube) for dasatinib measurement by 
HPLC will be drawn according to the above timeline.  
10.2 Pathology Correlative Studies  
Acknowledging the difficulties in obtaining fresh tumor samples in NSCLC due to the 
location of tumors being mostly within the thorax, utilization of existing tumor biopsy 
samples (mainly from the initial diagnosis, and/or surgery) will be allowed. If the 
patient’s tumor tissue is unavailable, then the patient will be evaluated for repeat biopsy 
prior to enrollment in the study. If the patient refuses or the patient’s tumor is located in 
a position that places the patient at increased risk, then the patient may not be eligible 
for the study. 


 
67 
10.2.1 Timing* 
Tumor biopsies will be performed at the following times. 
o Prior to treatment on C1D1 
o Mandatory if there is no archival material that can be used to determine 
EGFR mutation status and Cripto-1 expression in order to be eligible for 
the study 
o When archival tumor material is available, a fresh tumor biopsy is 
optional. 
o Optional – at the time of progression 
*Biopsies may be not performed on the specific dates and times due to the following 
reasons, including but not limited to, delayed recovery of hematologic toxicities, delayed 
clinic schedule, or national holidays. 
10.2.2 Tissue sampling and Handling  
A block of archival tumor material will be requested from each patient. If no archival 
material is available, fresh material will be obtained. A resection sample or blocks of 
tissue from the original resection are requested. Where a block cannot be released by the 
governing pathology department, 5 x 6μm re-cuts on charged slides will be requested. 
Samples from participating institutions will be shipped as described below. 
o Archival material will be sent from outside institution to the Georgetown 
University Medical Center via FedEx at room temperature. Testing will be 
performed at: 
Bhaskar Kallarury, M.D.  
Department of Pathology 


 
68 
Lombardi Comprehensive Cancer Center 
Georgetown University 
3970 Reservoir Road NW Washington DC 20007 
o If a fresh tumor biopsy is obtained, the biopsy samples are to be immediately 
embedded, frozen, and stored in Dr. Giaccone’s lab at -80C on site. 
Giuseppe Giaccone, M.D., Ph.D. 
Department of Oncology 
Lombardi Comprehensive Cancer Center 
Georgetown University 
3970 Reservoir Road NW Washington DC 20007 
 
o Each patient sample set will be assigned a unique patient identifier. The protocol 
scientific investigator(s) handling the samples will be blinded as to the patient 
identification, patient data and outcome. 
10.2.3 Studies 
o Cripto-1 expression on tumor samples obtained before treated with Osimertinib 
and dasatinib using an immunohistochemistry method that has been 
developed[26]. 
o The formalin-fixed, paraffin-embedded (FFPE) tumor specimen will first 
be H&E-stained and evaluated by a pathologist to ensure the tumor 
content. FFPE slides will undergo antigen retrieval (Dako Target Retrieval 
Solution) followed by staining with human rabbit anti-Cripto-1 antibody 


 
69 
(Rockland) at 1:2500 dilution. Samples will be scored by a pathologist 
according to overall intensity of the staining using a 0-3 scoring system. 
o Whenever feasible, fresh tumor biopsies will be obtained before starting 
treatment and at progression. These biopsies will be analyzed for Cripto-1 
expression by RT-PCR and/or immunohistochemistry. Quantitative RT-PCR will 
be performed using Cripto-1 primers as described in our previous study[26]. 
o If sufficient biopsy material is available, we will determine the phosphorylation 
status of SRC by western blot using the anti-phospho-SRC Tyr416 (Cell 
Signaling) antibody as previously described[26], in parallel with Cripto-1 
expression study. 
o EGFR mutational analysis will be performed on pretreatment tumor samples at 
Dr. Giaccone’s lab. 
10.3 Serum Correlative Studies  
10.3.1 Timing 
Subjects consented to participate will provide blood samples at the following time points. 
o Baseline Pre-dose Day 1 
o Pre-dose Day 1, Cycle 3 
o At the time of disease progression 
10.3.2 Tissue sampling and Handling 
Each patient sample set will be assigned a unique patient identifier. Blood samples 
needed for the measurement of plasma Cripto-1 levels will be sent to Dr. Giuseppe 
Giaccone’s lab. Details on shipment will be provided in a Laboratory Manual. 


 
70 
10.3.3 Studies 
o Levels of plasma Cripto-1 will also be assessed using a validated ELISA with a 
rabbit monoclonal antibody against the NH2-terminus of human Cripto-1 
10.4 
FDG-PET 
In order to assess whether FDG-PET performed at day 28, compared to baseline FDG-
PET, will predict responses to osimertinib and dasatinib, two FDG-PET scans will be 
obtained. 
10.4.1 Timing 
o Baseline FDG-PET scan to be obtained within 14 days prior to starting treatment  
o Cycle 1 Day 28 (±2 days) 
10.5 
Specimen Banking 
Patient samples collected for this study will be retained in the Dr. Giaccone’s lab. 
Specimens will be stored indefinitely or until they are used up. If future use is denied or 
withdrawn by the patient, best efforts will be made to stop any additional studies and to 
destroy the specimens. 
 
Dr. G. Giaccone will be responsible for reviewing and approving requests for clinical 
specimen from potential research collaborators outside of Georgetown University 
Medical Center. Collaborators will be required to complete an agreement (a Material 
Transfer Agreement or recharge agreement) that states specimens will only be released 
for use in disclosed research. 
 
The following information obtained from the subject's medical record may be 
provided to research collaborators when specimens are made available:   


 
71 
o Diagnosis  
o Collection time in relation to study treatment 
o Clinical outcome – if available 
o Demographic data 
11.0 STATISTICAL CONSIDERATIONS 
11.1 
Study Design/Study Endpoints 
This study is a dual-agent open-label phase I/II study of dasatinib and osimertinib. The 
phase I portion will follow a standard dose-escalation phase I design as described in 
section 5.1.1.2. The primary endpoint of the phase I part is to determine a safe and 
tolerable phase II dose of osimertinib and dasatinib based upon DLTs. Once the 
MTD/RP2D is determined, the study will accrue patients for the phase II portion. The 
endpoint of the phase II part is the reduction of the proportion of patients who progress 
or have stable disease lasting 4 months or less (intrinsic resistance).  
11.2 
Sample Size and Accrual 
The null hypothesis that the proportion of patients who progress or have stable disease 
lasting 4 months or less is at least 30% will be tested against a one-sided alternative. The 
null hypothesis is based on the fact that 37% of treatment-naïve patients treated with 
osimertinib at a dose level of 80 mg once daily had either stable disease or progressive 
disease as their best response. We would like to reject the null hypothesis with 85% 
power at a significance level of 5% when the true proportion of patients who progress or 
have stable disease ≤ 4 month is 10%. A two-stage (group sequential) design with a total 
of 28 patients will be used. This flexible multistage design (developed by the study 


 
72 
statistician and his colleagues), has operating properties similar to that of the Simon’s 
two-stage designs but offers flexibility in monitoring and interim analysis should the 
planned schedule be varied[45]. It allows an early assessment of statistical evidence for 
both efficacy and futility, and provides a discordance probability that an early trend 
could be reversed should the trial continue to enroll all 28 patients. At the first stage, 14 
patients will be entered. If 4 or less patients progress or have stable disease for ≤ 4 
months, then an additional 14 patients will be enrolled in the second stage; If 5 or more 
of the 14 patients in the first stage progress or have stable disease for ≤ 4 months, we will 
conclude that the therapy is not sufficiently active in this patient population. The 
protocol will be amended to reflect this conclusion. If no one among the first 14 patients 
progress or have stable disease for ≤ 4 months, we conclude there is already adequate 
statistical evidence that the therapy is active in this patient population and continue to 
enroll additional 14 patients to allow to be treated with this promising regimen. The 
chance for a reversal of the conclusion either for efficacy or for futility based on this 
decision rule is less than 2% (the discordance probability). At the completion of the 
second stage, if 4 or less among the 28 patients progress or have stable disease for ≤ 4 
months, we conclude that the therapy is active in this patient population, and otherwise 
it is not. 
     Progression-free survival  (PFS) is another very important endpoint in this study. 
Since there are relatively few successful Phase III trials in the disease studied here, we 
are only interested in detecting a large PFS time difference between the proposed 
treatment and historical control in this single arm early stage trial so as to increase the 
chance for Phase III success. The median PFS time is about 10 months based on current  
historical control data, and we are interested in an improvement of 10 months in median 


 
73 
PFS time to merit a treatment improvement that is considered promising. With 28 
patients determined from the primary outcome, we will have 83% power at a significance 
level of 0.05 to detect an improvement of 10 months in median PFS time from historical 
control.  This power calculation was based on uniform accrual over time in 18 months, 12 
months follow up, no loss to follow-up and exponentially distributed progression times.  
 
It is expected that at least 10% of the newly diagnosed patients with advanced NSCLC 
will potentially be eligible for this study. At Georgetown, approximately 150-200 new 
lung cancer cases are seen each year. The addition of Hackensack and the Military 
Hospital should allow to be accruing at a rate of 2-3 patients a month. This will allow 
accrual of 28 patients in approximately 18 months. 
11.3 
Data Analyses Plans 
The proportion of patients who progress or have stable disease lasting 4 months or less 
will be estimated as a binomial proportion with 95% exact confidence interval. The 
progression-free and overall survival functions will be estimated and plotted by the 
Kaplan–Meier method. In addition, the median progression-free and overall survival 
times will be reported along with the 95% confidence intervals. We will compare the 
levels of Cripto-1 shed into the blood stream of the patients enrolled in the phase I/II 
study of the combination of osimertinib and dasatinib, with an external cohort of 
patients treated with erlotinib alone by the nonparametric Wilcoxon rank-sum test. 
Comparisons of baseline plasma Cripto-1 levels and levels during treatment will be made 
using the Wilcoxon signed-rank test. Cripto-1 expression levels in plasma and tumor will 
be compared, and the relationship between Cripto-1 expression in plasmas/tumors and 
patients’ response to drug treatment will be determined with the Pearson’s correlation 


 
74 
coefficient and logistic regression, respectively. These tests will allow assessing whether 
changes in Cripto-1 in the blood might be a good surrogate for resistance to EGFR 
inhibition. The populations for analysis will include a safety population and a 
Pharmacokinetic population. 
- Safety population: All subjects who receive at least 1 dose of study medication. Only 
subjects with clear documentation that no study medication was received may be 
excluded from analysis. This population will be used for all summaries of safety data 
(AEs, concomitant medications, laboratory data). 
- Pharmacokinetic population: All subjects who have a PK profile. 
 
All statistical tests will be two-sided, and considered statistically significant when the p-
value is less than 0.05. All statistical analyses will be performed using SAS (Version 9.4; 
SAS Institute, Cary, NC). 
12.0 STUDY MANAGEMENT 
12.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the consent 
form and protocol. In obtaining and documenting informed consent, the investigator 
should comply with the applicable regulatory requirement(s), and should adhere to Good 
Clinical Practice (GCP) and to ethical principles that have their origin in the Declaration 
of Helsinki. 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 


 
75 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who conducted 
the informed consent discussion. 
12.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the Research office. 
o A copy of the official IRB approval letter for the protocol and informed consent 
o IRB membership list 
o CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study 
o Form FDA 1572 appropriately filled out and signed with appropriate 
documentation (NOTE: this is required if UNC holds the IND.  Otherwise, the 
affiliate Investigator’s signature on the protocol is sufficient to ensure 
compliance) 
o A copy of the IRB-approved consent form 
o CAP and CLIA Laboratory certification numbers and institution lab normal 
values 
o Executed clinical research contract 


 
76 
12.3 
Registration Procedures  
All patients must be registered with the Research Office before enrollment to study.  
Prior to registration, eligibility criteria must be confirmed with the Study Coordinator at 
each site. All patients must be registered with the Georgetown CMO (Clinical Research 
Management Office) before enrollment to study. Prior to registration, eligibility criteria 
must be confirmed by the Georgetown Multi-Site Study Coordinator. To register a 
patient, the following documents should be completed by the research nurse or data 
manager and faxed or emailed to the Coordinating center: 
Attn: Hilary Allen, fax 202-6872399, E-mail HKA10@georgetown.edu 
1) Subject Registration Form ? Eligibility Checklist 
2) All source documents for inclusion/exclusion criteria 
12.4 
Data Management and Monitoring/Auditing 
The Principle Investigator and the Co-Investigators will review the data including weekly 
safety monitoring.  The investigators shall meet on a weekly basis to review toxicities and 
follow up on results of patients enrolled on the study. 
 
Progress on the trial and the toxicities experienced will be reviewed by a Data and 
Safety Monitoring Board (DSMB) of three clinicians who are not investigators on the 
study.  The DSMB will review toxicity data on a monthly basis and will communicate any 
concerns about the trial to the DSMC Chair who will then schedule a meeting with the 
investigator to discuss the concerns and develop an action plan to address them   The 
monthly reports which are reviewed and signed off on by the DSMB will be forwarded to 
the Data and Safety Monitoring Committee (DSMC). The DSMC will meet quarterly to 


 
77 
review the progress and toxicity of the study.  Results of the DSMC meetings will be 
forwarded to the IRB. 
 
All Severe Adverse Events (SAEs) are required to be reported to the IRB.  Based on 
SAEs, the IRB retains the authority to close the study to further accrual pending more 
detailed reporting and/or modifications to further reduce risk and maximize the safety of 
participating patients. 
 
DSMC recommendations should be based not only on results for the trial being 
monitored as well as on data available to the DSMC from other studies.  It is the 
responsibility of the PI to ensure that the DSMC is kept apprised of non-confidential 
results from related studies that become available.  It is the responsibility of the DSMC to 
determine the extent to which this information is relevant to its decisions related to the 
specific trial being monitored. 
 
A written copy of the DSMC recommendations will be given to the trial PI and the 
IRB.  If the DSMC recommends a study change for patient safety or efficacy reasons, or 
that a study be closed early due to slow accrual, the trial PI must act to implement the 
change as expeditiously as possible.  In the unlikely event that the trial PI does not 
concur with the DSMC, then the Lombardi Cancer Center Director must be informed of 
the reason for the disagreement.  The trial PI, DSMC Chair, and the Lombardi Cancer 
Center Director will be responsible for reaching a mutually acceptable decision about the 
study. 
 
Confidentiality must be preserved during these discussions.  However, in some cases, 
relevant data may be shared with other selected trial investigators and staff to seek 
advice to assist in reaching a mutually acceptable decision. 


 
78 
 
If a recommendation is made to change a trial for reasons other than patient safety or 
efficacy the DSMC will provide an adequate rationale for its decision. 
12.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.   
12.5.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate 
an immediate hazard(s) to trial subjects without prior IRB approval. For any such 
emergency modification implemented, an IRB modification form must be completed 
within five (5) business days of making the change.   
12.5.2 Single Patient/Subject Exceptions 
Any request to enroll a single subject who does not meet all the eligibility criteria of this 
study requires the approval of the Principal Investigator and the IRB.  
12.5.3 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the Principal 
Investigator and the IRB.  According to the IRB, a protocol deviation is any unplanned 
variance from an IRB approved protocol that:  
o Is generally noted or recognized after it occurs 
o Has no substantive effect on the risks to research participants 
o Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected  


 
79 
o Did not result from willful or knowing misconduct on the part of the 
investigator(s). 
 
An unplanned protocol variance is considered a violation if the variance: 
o Has harmed or increased the risk of harm to one or more research participants. 
o Has damaged the scientific integrity of the data collected for the study. 
o Results from willful or knowing misconduct on the part of the investigator(s). 
o Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal Investigator, 
please follow the guidelines below: 
 
Protocol Deviations: Personnel will report to any sponsor or data and safety 
monitoring committee in accordance with their policies.  Deviations should be 
summarized and reported to the IRB at the time of continuing review. 
 
Protocol Violations: Violations should be reported by study personnel within one (1) 
week of the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems.   
12.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  It should also be noted that when an 


 
80 
amendment to the protocol substantially alters the study design or the potential risk to 
the patient, a revised consent form might be required. The written amendment, and if 
required the amended consent form, must be sent to the IRB for approval prior to 
implementation.   
12.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). Source documents include all recordings of 
observations or notations of clinical activities and all reports and records necessary for 
the evaluation and reconstruction of the clinical research study. Government agency 
regulations and directives require that all study documentation pertaining to the conduct 
of a clinical trial must be retained by the study investigator. In the case of a study with a 
drug seeking regulatory approval and marketing, these documents shall be retained for 
at least two years after the last approval of marketing application in an International 
Conference on Harmonization (ICH) region.  In all other cases, study documents should 
be kept on file until three years after the completion and final study report of this 
investigational study. 
12.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Principal Investigator is responsible for personally overseeing the 
treatment of all study patients.  The Principal Investigator must assure that all study site 


 
81 
personnel, including sub-investigators and other study staff members, adhere to the 
study protocol and all FDA/GCP/NCI regulations and guidelines regarding clinical trials 
both during and after study completion. The Principal Investigator at each institution or 
site will be responsible for assuring that all the required data will be collected and 
entered onto the Case Report Forms. Periodically, monitoring visits will be conducted 
and the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. At the completion of the study, all case report forms 
will be reviewed by the Principal Investigator and will require his/her final signature to 
verify the accuracy of the data. 
 
 
 


 
82 
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Houston, K.A., et al., Patterns in lung cancer incidence rates and trends by 
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Delbaldo, C., et al., Benefits of adding a drug to a single-agent or a 2-agent 
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Smit, E.F., et al., Three-arm randomized study of two cisplatin-based regimens 
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Pao, W., V.A. Miller, and M.G. Kris, 'Targeting' the epidermal growth factor 
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Shepherd, F.A., et al., Erlotinib in previously treated non-small-cell lung cancer. 
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Cohen, M.H., et al., FDA drug approval summary: erlotinib (Tarceva) tablets. 
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Khozin, S., et al., U.S. Food and Drug Administration approval summary: 
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Camidge, D.R., et al., Activity and safety of crizotinib in patients with ALK-
positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet 
Oncol, 2012. 13(10): p. 1011-9. 
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Perez-Soler, R., et al., Determinants of tumor response and survival with erlotinib 
in patients with non--small-cell lung cancer. J Clin Oncol, 2004. 22(16): p. 3238-
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Takeda, M., et al., De novo resistance to epidermal growth factor receptor-
tyrosine kinase inhibitors in EGFR mutation-positive patients with non-small cell 
lung cancer. J Thorac Oncol, 2010. 5(3): p. 399-400. 
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Bean, J., et al., MET amplification occurs with or without T790M mutations in 
EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc 
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Engelman, J.A., et al., MET amplification leads to gefitinib resistance in lung 
cancer by activating ERBB3 signaling. Science, 2007. 316(5827): p. 1039-43. 
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Sequist, L.V., et al., Genotypic and histological evolution of lung cancers 
acquiring resistance to EGFR inhibitors. Sci Transl Med, 2011. 3(75): p. 75ra26. 
20. 
Yano, S., et al., Hepatocyte growth factor expression in EGFR mutant lung 
cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a 
Japanese cohort. J Thorac Oncol, 2011. 6(12): p. 2011-7. 
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Ebert, A.D., et al., Cripto-1 induces phosphatidylinositol 3'-kinase-dependent 
phosphorylation of AKT and glycogen synthase kinase 3beta in human cervical 
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Kelber, J.A., et al., Blockade of Cripto binding to cell surface GRP78 inhibits 
oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways. Oncogene, 
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Gong, Y.P., et al., Overexpression of Cripto and its prognostic significance in 
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regulated E-cadherin with tumour progression and poor prognosis in gastric 
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EGFR-inhibitor resistance. J Clin Invest, 2014. 124(7): p. 3003-15. 
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Cross, D.A., et al., Osimertinib, an irreversible EGFR TKI, overcomes T790M-
mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov, 2014. 
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Janne, P.A., et al., Osimertinib in EGFR inhibitor-resistant non-small-cell lung 
cancer. N Engl J Med, 2015. 372(18): p. 1689-99. 
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Ramalingam, S.S., et al. Osimertinib, a mutant-selective EGFR inhibitor, as first-
line treatment for EGFR mutation-positive advanced non-small cell lung cancer 
(NSCLC): Results from a phase 1 expansion cohort. in ASCO Annual Meeting 
Proceedings. 2015. 
30. 
Hochhaus, A. and H. Kantarjian, The development of dasatinib as a treatment for 
chronic myeloid leukemia (CML): from initial studies to application in newly 
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31. 
Song, L., et al., Dasatinib (BMS-354825) selectively induces apoptosis in lung 
cancer cells dependent on epidermal growth factor receptor signaling for 
survival. Cancer Res, 2006. 66(11): p. 5542-8. 
32. 
Johnson, F.M., et al., Phase II study of dasatinib in patients with advanced non-
small-cell lung cancer. J Clin Oncol, 2010. 28(30): p. 4609-15. 
33. 
Johnson, M.L., et al., Phase II trial of dasatinib for patients with acquired 
resistance to treatment with the epidermal growth factor receptor tyrosine kinase 
inhibitors erlotinib or gefitinib. J Thorac Oncol, 2011. 6(6): p. 1128-31. 
34. 
Brunner, A.M., et al., Treatment-related toxicities in a phase II trial of dasatinib 
in patients with squamous cell carcinoma of the lung. J Thorac Oncol, 2013. 
8(11): p. 1434-7. 
35. 
Sen, B. and F.M. Johnson, Regulation of SRC family kinases in human cancers. J 
Signal Transduct, 2011. 2011: p. 865819. 
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Aleshin, A. and R.S. Finn, SRC: a century of science brought to the clinic. 
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Wheeler, D.L., M. Iida, and E.F. Dunn, The role of Src in solid tumors. 
Oncologist, 2009. 14(7): p. 667-78. 
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39. 
Laurie, S.A., et al., A phase II trial of saracatinib, an inhibitor of src kinases, in 
previously-treated advanced non-small-cell lung cancer: the princess margaret 
hospital phase II consortium. Clin Lung Cancer, 2014. 15(1): p. 52-7. 
40. 
Haura, E.B., et al., Phase I/II study of the Src inhibitor dasatinib in combination 
with erlotinib in advanced non-small-cell lung cancer. J Clin Oncol, 2010. 28(8): 
p. 1387-94. 
41. 
Hammerman, P.S., et al., Mutations in the DDR2 kinase gene identify a novel 
therapeutic target in squamous cell lung cancer. Cancer Discov, 2011. 1(1): p. 
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Gold, K.A., et al., A Phase I/II Study Combining Erlotinib and Dasatinib for Non-
Small Cell Lung Cancer. Oncologist, 2014. 
43. 
Fontanini, G., et al., Evaluation of epidermal growth factor-related growth factors 
and receptors and of neoangiogenesis in completely resected stage I-IIIA non-
small-cell lung cancer: amphiregulin and microvessel count are independent 
prognostic indicators of survival. Clin Cancer Res, 1998. 4(1): p. 241-9. 
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Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
45. 
  Tan M, and Xiong X. A Flexible Multi-Stage Design for Phase II Oncology Trials.          
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47. 
Osimertinib U.S. Prescribing Information (January 2022 edition). 
 


 
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Appendix A. ECOG Performance Status Score  


 
87 
Appendix B. Mandatory Adverse Event Reporting Information for Dasatinib 
o All Serious Adverse Events (SAEs) that occur following the subject’s written 
consent to participate in the study through 30 days of discontinuation of dosing 
must be reported to BMS Worldwide Safety. 
o If the BMS safety address is not included in the protocol document (e.g. 
multicenter studies where events are reported centrally), the procedure for safety 
reporting must be reviewed/approved by the BMS Protocol Manager.  Procedures 
for such reporting must be reviewed and approved by BMS prior to study 
activation. 
o The BMS SAE form should be used to report SAEs.  If the BMS form cannot be 
used, another acceptable form (i.e CIOMS or Medwatch) must be reviewed and 
approved by BMS.  The BMS protocol ID number must be included on whatever 
form is submitted by the Sponsor/Investigator. 
o Following the subject’s written consent to participate in the study, all SAEs, 
whether related or not related to study drug, are collected, including those 
thought to be associated with protocol-specified procedures. The investigator 
should report any SAE occurring after these time periods that is believed to be 
related to study drug or protocol-specified procedure. 
o In accordance with local regulations, BMS will notify investigators of all reported 
SAEs that are suspected (related to the investigational product) and unexpected 
(i.e., not previously described in the IB). In the European Union (EU), an event 
meeting these criteria is termed a Suspected, Unexpected Serious Adverse 


 
88 
Reaction (SUSAR). Investigator notification of these events will be in the form of 
an expedited safety report (ESR).  
o Other important findings which may be reported by the as an ESR include: 
increased frequency of a clinically significant expected SAE, an SAE considered 
associated with study procedures that could modify the conduct of the study, lack 
of efficacy that poses significant hazard to study subjects, clinically significant 
safety finding from a nonclinical (eg, animal) study, important safety 
recommendations from a study data monitoring committee, or sponsor decision 
to end or temporarily halt a clinical study for safety reasons. 
o Upon receiving an ESR from BMS, the investigator must review and retain the 
ESR with the IB. Where required by local regulations or when there is a central 
IRB/IEC for the study, the sponsor will submit the ESR to the appropriate 
IRB/IEC. The investigator and IRB/IEC will determine if the informed consent 
requires revision. The investigator should also comply with the IRB/IEC 
procedures for reporting any other safety information.  
o In addition, suspected serious adverse reactions (whether expected or 
unexpected) shall be reported by BMS to the relevant competent health 
authorities in all concerned countries according to local regulations (either as 
expedited and/or in aggregate reports). 
SAEs, whether related or not related to study drug, and pregnancies must be reported to 
BMS within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies 
on a Pregnancy Surveillance Form. 
SAE Email Address:  Worldwide.Safety@BMS.com 


 
89 
SAE Facsimile Number:  609-818-3804 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours to 
the BMS (or designee) using the same procedure used for transmitting the initial SAE 
report. 
All SAEs should be followed to resolution or stabilization. 
For studies conducted under an Investigator IND in the US include the following: 
For studies conducted under an Investigator IND in the US, any event that is both 
serious and unexpected must be reported to the Food and Drug Administration (FDA) as 
soon as possible and no later than 7 days (for a death or life-threatening event) or 15 days 
(for all other SAEs) after the investigator’s or institution’s initial receipt of the 
information. BMS will be provided with a simultaneous copy of all adverse events filed 
with the FDA.  
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 


 
90 
http://www.accessdata.fda.gov/scripts/medwatch/ 
o An SAE report should be completed for any event where doubt exists regarding 
its seriousness.  
o For studies with long-term follow-up periods in which safety data are being 
reported, include the timing of SAE collection in the protocol. 
o If the investigator believes that an SAE is not related to study drug, but is 
potentially related to the conditions of the study (such as withdrawal of previous 
therapy or a complication of a study procedure), the relationship should be 
specified in the narrative section of the SAE Report Form. 
o If only limited information is initially available, follow-up reports are required. 
(Note: Follow-up SAE reports should include the same investigator term(s) 
initially reported.) 
o If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 
hours to BMS using the same procedure used for transmitting the initial SAE 
report. All SAEs should be followed to resolution or stabilization.  All SAEs 
should be followed to resolution or stabilization. 
A nonserious adverse event is an AE not classified as serious.  
 
Nonserious Adverse Event Collection and Reporting 
The collection of nonserious AE information should begin at initiation of study drug. All 
nonserious adverse events (not only those deemed to be treatment-related) should be 
collected continuously during the treatment period and for a minimum of 100 days 


 
91 
following the last dose of study treatment. Nonserious AEs should be followed to 
resolution or stabilization, or reported as SAEs if they become serious. Follow-up is also 
required for nonserious AEs that cause interruption or discontinuation of study drug and 
for those present at the end of study treatment as appropriate.  
 
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and 
reported as such. The following laboratory abnormalities should be documented and 
reported appropriately: 
o Any laboratory test result that is clinically significant or meets the definition of an 
SAE 
o Any laboratory abnormality that required the subject to have study drug 
discontinued or interrupted 
o Any laboratory abnormality that required the subject to receive specific corrective 
therapy.  
 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a 
study subject is pregnant or may have been pregnant at the time of investigational 
product exposure, including during at least 6 half lives after product administration, the 
investigational product will be permanently discontinued in an appropriate manner (e.g. 
dose tapering if necessary for subject safety). The investigator must immediately notify 
Worldwide Safety @BMS of this event via the Pregnancy Surveillance Form in 


 
92 
accordance with SAE reporting procedures. Follow-up information regarding the course 
of the pregnancy, including perinatal and neonatal outcome and, where applicable, 
offspring information must be reported on the Pregnancy Surveillance Form [provided 
upon request from BMS]. Any pregnancy that occurs in a female partner of a male study 
participant should be reported to BMS. Information on this pregnancy will be collected 
on the Pregnancy Surveillance Form. 
 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE. 
 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not 
these procedures are required by the protocol, should also be recorded as a nonserious or 
serious AE, as appropriate, and reported accordingly. 
 


 
93 
Appendix C. Guidance Regarding Potential Interactions with Concomitant 
Medications 
The use of any natural/herbal products or other “folk remedies” should be discouraged, 
but use of these products, as well as use of all vitamins, nutritional supplements, and all 
other concomitant medications must be recorded in the electronic case report form 
(eCRF). 
 
1. Drugs Inducing CYP3A4 Metabolism That AstraZeneca Strongly 
Recommend Are Not Combined With Osimertinib 
Osimertinib is metabolised by CYP3A4 and CYP3A5 enzymes. A drug-drug interaction 
study of osimertinib evaluated in patients showed that there is potential for osimertinib 
being a victim when co-administered with strong inducers of CYP3A4 (osimertinib 
concentrations are decreased when co-dosed with rifampicin). 
 
The following potent inducers of CYP3A4 must not be used during this study for any 
patient receiving osimertinib. 
Drugs Inducing CYP3A4 
Contraindicated drugs 
Withdrawal period prior to 
osimertinib start 
Carbamazepine, phenobarbital, phenytoin, 
rifampicin, rifabutin, rifapentin 
St John’s Wort 
3 weeks 
Phenobarbitone 
5 weeks 
 
This list is not intended to be exhaustive, and a similar restriction will apply to other 
agents that are known to strongly modulate CYP3A4 activity.  Appropriate medical 
judgment is required.  Please contact AstraZeneca with any queries you have on this 
issue. 
 
2. Medicines Whose Exposures May be Affected by Osimertinib That 
AstraZeneca Considers May be Allowed With Caution 
Osimertinib may increase the concentration of sensitive BCRP and Pgp substrates 
(concentration of the sensitive BCRP substrate, rosuvastatin and sensitive Pgp substrate, 
fexofenadine, are increased). 


 
94 
Exposure, Pharmacological Action and Toxicity May be Increased by 
Osimertinib 
Warning of possible 
interaction 
Advice 
Rosuvastatin 
Drugs are permitted but caution should be exercised and 
patients monitored closely for possible drug interactions.  
Please refer to full prescribing information for all drugs 
prior to co-administration with osimertinib. 
Sulfasalazine 
Doxorubicin 
Daunorubicin 
Topotecan 
Dabigatran  
Aliskiren  
Digoxin  
 
 
3. Drugs That May Prolong QT Interval 
The drugs listed in this section are taken from information provided by The Arizona 
Center for Education and Research on Therapeutics website: 
https://www.crediblemeds.org/. The website categorizes drugs based on the risk of 
inducing Torsades de Pointes (TdP).  
During screening the drugs that patients are currently receiving (prescription and non-
prescription) should be checked against the ArizonaCert website. In addition, drugs 
intended for use following study treatment initiation should be checked against the 
website. 
3.1 Drugs with a known risk of Torsades de Pointes 
Drugs in this category are known to prolong the QT interval and are clearly associated 
with a known risk of TdP, even when taken as recommended 
 
3.1.1 Before commencing study treatment 
Drugs in the category of known risk of TdP must have been discontinued prior to the 
start of administration of study treatment in accordance with guidance provided in 
Table 3.  
 
3.1.2 During study treatment  
It is recommended that drugs in the category of known risk of TdP are not co-
administered with study treatment (osimertinib) and for a period of two weeks after 


 
95 
discontinuing study treatment, however if it is considered essential for patient 
management to co-administer these drugs with study treatment (osimertinib) close 
monitoring of ECGs and electrolytes is recommended. 
 
The list of drugs may not be exhaustive and is subject to change as new 
information becomes available. As such investigators are recommended to 
search the CredibleMeds® website (https://www.crediblemeds.org/) to 
provide the most up to date information.  
 
Table 3 Drugs with a known risk of TdPa  
Drug name  
Withdrawal period prior to study 
treatment start  
Aclarubicin, anagrelide, ciprofloxacin, 
clarithromycin, cocaine, droperidol, 
erythromycin, levofloxacin, ondansetron, 
papaverine hydrochloride, procainamide, 
sulpiride, sultopride, terfenadine 
terlipressin  
2 days  
Cilostazol, Cisapride, disopyramide, 
dofetilide, domperidone, flecainide, 
gatifloxacin, grepafloxacin, ibutilide, 
moxifloxacin, oxaliplatin, propofol, 
quinidine, roxithromycin, sevoflurane, 
sotalol, sparfloxacin, thioridazine  
7 days  
Azithromycin bepridil, citalopram, 
chlorpromazine, dronedarone, 
escitalopram, fluconazole, halofantrine, 
haloperidol, levomepromazine, 
levosulpiride, mesoridazine  
14 days  
Donepezil, terodiline  
3 weeks  
Levomethadyl, methadone, pimozide  
4 weeks  
Arsenic trioxideb, Ibogaine  
6 weeks  
Pentamidine  
8 weeks  
Astemizole, Probucol, vandetanib  
4 months  
Amiodarone, chloroquine  
1 year  
 
a. This list should be checked against the full and most current list presented in the 
CredibleMeds® website (https://www.crediblemeds.org/).  
b.  Estimated value as pharmacokinetics of arsenic trioxide has not been studied. 
 


 
96 
Other TdP risk Categories  
Patients receiving drugs that prolong QT interval or may increase the risk of TdP from 
other TdP risk categories can be enrolled, notwithstanding other exclusions and 
restrictions, if these drugs are considered essential for patient management and the 
patient has been stable on therapy. Close monitoring of ECGs and electrolytes is 
recommended.  
 
Patients with congenital long QT syndrome (CLQTS) are excluded from this 
study.  
 
Guidance regardless of TdP risk category  
Following study treatment initiation if it is considered essential for patient 
management to give drugs known to prolong QTc interval, regardless of TdP 
risk category, close monitoring of ECGs and electrolytes is recommended.