Clinical trial NCT03076164
Conditions: Lung Adenocarcinoma Lung Cancer Lung Cancer Metastatic Lung Cancer Stage IV Recurrent Lung Adenocarcinoma Recurrent Lung Cancer
Keywords: erlotinib trametinib 15-098
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2017-03-01; Completion date: 2020-12-18
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine the safety, tolerability and overall response rate of trametinib when given in combination with erlotinib in patients with Stage IV or recurrent lung adenocarcinoma that cannot be treated with curative intent.

Detailed description:

Arms: arm 1: Phase 1: Accrue 6 patients on Trametinib 1.5mg + Erlotinib 75mg by mouth once daily Phase 2: Accrue 24 patients (including 6 patients treated during Phase 1) on Trametinib 1.5mg + Erlotinib 75mg by mouth once daily or Trametinib 1.0mg + Erlotinib 100mg by mouth once daily.
Interventions: intervention 1: Trametinib intervention 2: Erlotinib
Intervention descriptions: intervention 1: Trametinib 1.5mg once daily by mouth intervention 2: Erlotinib 75mg once daily by mouth

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
Page 1 of 43 
 
 
 
 
 
A Phase 1/2 Trial of Trametinib and Erlotinib in Patients with EGFR-Mutant Lung 
Adenocarcinomas and Acquired Resistance to Erlotinib 
 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC  PROTOCOL 
 
 
Principal Investigator/Department: 
Helena Yu, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Gregory Riely, MD, PhD 
Medicine 
Investigator(s)/Department: 
Jamie Chaft, MD 
Alexander Drilon, MD 
Matthew Hellmann, MD 
Mark G. Kris, MD 
Piro Lito, MD, PhD 
Paul K. Paik, MD 
Charles Rudin, MD, PhD 
Marjorie G. Zauderer, MD 
Bob Li, MD 
Stephen Veach, MD 
Robert Daly, MD 
Kathryn Arbour, MD 
Wei-Chu Victoria Lai, MD 
Michael Offin, MD 
Andrew Chow, MD, PhD 
Adam Schoenfeld, MD 
Linda Ahn, NP 
Alison Massey, NP 
Elizabeth Panora, NP 
Leticia Smith, APN 
Christine Anderson, NP 
Christina Larsen, NP 
Erica Stumpf, MSc 
Andrew Plodkowski, MD 
Etay Ziv, MD, PhD 
Jasmine Francis, MD 
Julia Canestraro, OD 
Natasha Rekhtman, MD 
Glenn Heller, MD 
Han Xiao, MD 
Sree Chalasani, MD 
Afsheen Iqbal, MD 
Elizabeth Quigley, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Radiology 
Radiology 
Surgery 
Surgery/Opthalmic 
Oncology 
Pathology 
Epidemiology  and Biostatistics 
Medicine 
Medicine 
Medicine 
Dermatology 


Page 2 of 43 
 
 
 
 
 
 
 
 
 
 
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Memorial Sloan Kettering Cancer 
Center IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-
2020 
Avni Desai, MD 
Medi
John Fiore, MD 
Medi
Juliana Eng, MD 
Medi
Jia Li, MD 
Medi
Kenneth Ng, MD 
Medi
Arlyn Apollo, MD 
Medi
Zoe Goldberg, MD 
Medi
Tiffany Troso-Sandoval, MD 
Medi
Pamela Drullinsky, MD 
Medi
Oscar Lahoud, MD 
Medi
Serena Wong, MD 
Medi
Azadeh Namakydoust, MD 
Medi
Colette Owens, MD 
Medi
Loren Michel, MD 
Medi
Marina Shcherba, DO 
Medi
Curtis Chong, MD 
Medi
Louise Ligresti, MD 
Medi
Ping Gu, MD 
Medi
Daniel Danila, MD 
Medi
Isabel Preeshagul, MD 
Medi
Rui Wang, MD 
Medi
Anuja Kriplani, MD 
Medi
James Fetten, MD 
Medi
Geri Arnell, RN 
Nurs
Janet Cogswell, RN 
Nurs
Irene Kelly, RN 
Nurs
Raylene Langish, RN 
Nurs
Nicole Heinz, RN 
Nurs
Gloria Wasilewski, RN 
Nurs
Sherie Mar-Chaim, RN 
Nurs
Megan Stasi, RN 
Nurs
Ofer Maimran, RN 
Nurs
Jessica Marchisotto, RN 
Nurs
Karen Flynn, APN 
Nurs
Joanne Wells, APN 
Nurs
Consenting  Professional(s)/Department: 
Jamie Chaft, MD 
Medi
Alexander Drilon, MD 
Medi
Matthew Hellmann, MD 
Medi
Mark G. Kris, MD 
Medi
Piro Lito, MD, PhD 
Medi
Paul K. Paik, MD 
Medi
Gregory J. Riely, MD, PhD 
Medi
Charles Rudin, MD, PhD 
Medi
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Page 3 of 43 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
 
 
 
 
Helena Yu, MD 
Medicine 
Marjorie G. Zauderer, MD 
Medicine 
Bob Li, MD 
Medicine 
Stephen Veach, MD 
Medicine 
Robert Daly, MD 
Medicine 
Kathryn Arbour, MD 
Medicine 
Wei-Chu Victoria Lai, MD 
Medicine 
Michael Offin, MD 
Medicine 
Han Xiao, MD 
Medicine 
Sree Chalasani, MD 
Medicine 
Afsheen Iqbal, MD 
Medicine 
Avni Desai, MD 
Medicine 
John Fiore, MD 
Medicine 
Juliana Eng, MD 
Medicine 
Jia Li, MD 
Medicine 
Kenneth Ng, MD 
Medicine 
Arlyn Apollo, MD 
Medicine 
Zoe Goldberg, MD 
Medicine 
Tiffany Troso-Sandoval, MD 
Medicine 
Pamela Drullinsky, MD 
Medicine 
Oscar Lahoud, MD 
Medicine 
Serena Wong, MD 
Medicine 
Azadeh Namakydoust, MD 
Medicine 
Colette Owens, MD 
Medicine 
Loren Michel, MD 
Medicine 
Marina Shcherba, DO 
Medicine 
Curtis Chong, MD, PhD 
Medicine 
Louise Ligresti, MD 
Medicine 
Ping Gu, MD 
Medicine 
Daniel Danila, MD 
Medicine 
Isabel Preeshagul, MD 
Medicine 
Rui Wang, MD 
Medicine 
Anuja Kriplani, MD 
Medicine 
James Fetten, MD 
Medicine 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
OneMSK  Sites 
Basking Ridge 
All Protocol Activites 
Commack 
All Protocol Activites 
Westchester 
All Protocol Activites 


Page 4 of 43 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
 
 
 
 
Monmouth 
All Protocol Activites 
Manhattan 
All Protocol Activites 
Bergen 
All Protocol Activites 
Nassau 
All Protocol Activites 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
Page 5 of 43 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ....................................................................... 6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................ 8 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 9 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 11 
4.1 
Design................................................................................................................................. 11 
4.2 
Intervention .............................................................................................................................. 12 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 13 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................... 14 
6.1 
Subject Inclusion Criteria ..................................................................................................... 14 
6.2 
Subject Exclusion Criteria ................................................................................................... 15 
7.0 
RECRUITMENT PLAN .................................................................................................................... 15 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 16 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................ 16 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION .................................................... 18 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 20 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 32 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 34 
14.0 
BIOSTATISTICS ............................................................................................................... 34 
15.0   RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 36 
15.1 
Research Participant Registration ....................................................................................... 36 
15.2 
Randomization .................................................................................................................... 36 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 36 
16.1 
Quality Assurance............................................................................................................... 37 
16.2 
Data and Safety Monitoring .................................................................................................... 37 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 38 
17.1 
Privacy ................................................................................................................................ 39 
17.2 
Serious Adverse Event (SAE) Reporting ...........................Error! Bookmark not defined. 
17.2.1 ............................................................................................................................................... 40 
18.0 
INFORMED CONSENT PROCEDURES................................................................................... 41 
19.0 
REFERENCES ....................................................................................................................... 42 
20.0 
APPENDICES ................................................................................................................... 43 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
Page 6 of 43 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
 
 
Study Title: A Phase 1/2 Trial of Trametinib and Erlotinib in Patients with EGFR-Mutant Lung 
Adenocarcinomas and Acquired Resistance to Erlotinib 
Study 
Objectives: 
Phase 1: Safety Run In 
Primary Objective: Determine the safety and tolerability of erlotinib 75mg by mouth 
once daily with trametinib 1.5mg by mouth once daily for patients with acquired 
resistance to erlotinib 
Phase 2: 
Primary Objective: Assess overall response rate (CR+PR) of trametinib when given in 
combination with erlotinib for patients with EGFR-mutant lung cancers and acquired 
resistance to erlotinib 
Secondary Objectives: 1) Measure progression-free survival and overall survival 
among patients treated with trametinib and erlotinib 2) further define the toxicity profile 
of the combination 
Correlative Studies: 
Objectives: 1) Confirm BIM induction with MEK inhibition by assessing BIM protein 
expression by IHC on serial biopsies 2) Identify changes in protein expression related 
to apoptosis, EMT and NF1 expression  3) Perform transcriptome analysis (using RNA- 
seq) on tumor tissue from serial biopsies. 4) Perform next-generation sequencing 
based mutation testing to identify genetic alterations on tumor tissue from serial 
biopsies 5) Assess EGFR T790M status on all patients on study. 
Patient 
Population: 
Patients with locally advanced or metastatic lung adenocarcinomas with a confirmed 
EGFR mutation who have developed acquired resistance to EGFR tyrosine kinase 
inhibitor therapy 
Number of 
patients: 
Phase 1: Maximum of 6 patients 
Phase 2: Maximum of 24 patients (including up to 6 patients from Phase 1) 
Inclusion 
Criteria: 
All patients must have: 
• Pathologic evidence of stage IV or recurrent lung adenocarcinoma that cannot be 
treated with curative intent 
• Somatic activating mutation in EGFR 
• Radiographic progression during treatment with erlotinib. Prior chemotherapy 
regimens are permitted. 
• Measurable (RECIST 1.1) indicator lesion not previously irradiated 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
Page 7 of 43 
 
 
 
 
• Karnofsky performance status (KPS) ≥ 70% 
• Age >18 years old 
• Adequate organ function: 
- AST, ALT ≤ 2.5 x ULN 
- Total bilirubin ≤ 1.5 x ULN 
- Albumin≥2.5g/dL 
- Creatinine < 1.5 x ULN OR calculated creatinine clearance ≥50mL/min 
- Absolute neutrophil count (ANC) ≥ 1,200 cells/mm3 
- Hemoglobin≥9.0  g/dL 
- Platelets ≥100,000/mm3 
Exclusion 
Criteria: 
Patients are to be excluded from the study if they meet any of the following criteria: 
• Patients with symptomatic brain metastasis requiring escalating doses of steroids 
• Patients with grade 2 or greater diarrhea prior to study initiation despite maximal 
medical management due to medications or a medical condition such as 
Crohn’s disease or malabsorption 
• Pregnant or lactating women 
• Any type of systemic therapy (chemotherapy or experimental drugs) within 2 
weeks of starting treatment on protocol except for a EGFR TKI 
• Patients who have received prior treatment with MEK inhibitor 
• Any major surgery or extensive radiotherapy within 21 days of starting treatment 
on protocol. 
• A history of clinically significant interstitial lung disease or pneumonitis 
• Clinically significant cardiac disease including unstable angina, acute myocardial 
infarction within 6 months from Day 1 of study administration, New York Heart 
Association Class III or IV congestive heart failure, or symptomatic uncontrolled 
Arrythmias, prolonged corrected QT interval >480msec, treatment refractory 
hypertension, presence of a cardiac defibrillator 
• History of central serous retinopathy or retinal vein occlusion 
• Patients with baseline risk factors for central serous retinopathy or retinal vein 
occlusion such as evidence of new optic disc cupping, evidence of new visual 
field defects, and intraocular pressure >21 mmHg are excluded from the trial 
• History of prior malignancy within 3 years. Patients who are considered NED from 
a malignancy may be considered on a case by case basis. 
• 
Have a known immediate or delayed hypersensitivity reaction to drugs 
chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO). 
• Any other condition that, in the opinion of the investigator, may compromise the 
safety, compliance of the patient, or would preclude the patient from successful 
completion of the study 
Study drug: Erlotinib and Trametinib 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
Page 8 of 43 
 
 
 
 
Study 
Design: 
 
Phase 1: Safety Run In 
 
This portion of the study will assess whether a dose of trametinib 1.5mg by mouth once 
daily and erlotinib 75mg by mouth once daily is a tolerable and safe dose. Six patients 
will be enrolled at this dose level and assessed for dose limiting toxicities (DLTs) for 1 
full cycle (28 days). Toxicity will be graded according to NCI CTCAE version 4.0. If more 
than one patient develops a DLT, we will move on to the phase 2 portion of the study 
and the dose level -1 will be used. If no <1 DLT is detected, we will move on to the 
phase 2 portion of the study at dose level 0. 
 
Dose levels 
Trametinib Dose 
Erlotinib Dose 
Dose Level 0 
1.5mg PO qdaily 
75mg PO qdaily 
Dose Level -1 
1 mg PO qdaily 
100mg PO qdaily 
 
 
Phase 2: 
 
Once the phase 1 run-in portion of the study has been completed, patients will be 
enrolled in the phase 2 portion of the single-arm, two-stage, open-label study of 
trametinib and erlotinib in the treatment of patients with EGFR-mutant lung cancers with 
acquired resistance to erlotinib.  After screening and registration, patients will be treated 
with the combination of trametinib and erlotinib. Response to therapy will be assessed 
by interval imaging every 8 weeks (every 2 cycles) with CT scan of the chest and 
imaging of any other target lesion with response evaluated by RECIST 1.1. A maximum 
of 24 patients will be enrolled during this portion of the study. 
Correlative studies: 
 
Biopsies will be required within 30 days of start of study treatment and at the time of 
progression. At prespecified time points and after additional informed consent, patients 
will have image-guided core needle biopsies with 3-4 cores obtained. At least 2 cores 
will be immediately frozen in liquid nitrogen and sent to Dr. Rudin’s lab. The remaining 
cores will be fixed in formalin and sent to Surgical Pathology. We will use our genomics 
core facility for all DNA and RNA extraction and analysis. IHC will be performed to look 
at expression of specific proteins of interest including:  BIM, TGFB2, vimentin, e- 
cadherin, n-cadherin and neurofibromin. Transcriptome sequencing (RNA-Seq) will be 
utilized to look at changes in gene expression at various time points of treatment and to 
identify potential biomarkers of response to combination therapy.  IMPACT,  our next- 
generation sequencing based mutation platform that assesses for genetic alterations in 
340 cancer-related genes, will be used for molecular analysis. 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Hypothesis: The combination of erlotinib and trametinib is an effective treatment in 
patients with EGFR mutant lung cancers with acquired resistance to erlotinib 
monotherapy. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
Page 9 of 43 
 
 
 
 
Phase 1 Trial: 
 
A. Primary Objective: Determine the safety and tolerability of erlotinib 75mg by 
mouth once daily with trametinib 1.5mg by mouth once daily 
 
Phase 2 Trial: 
 
A. Primary Objectives: Assess overall response rate (CR+PR) of trametinib when 
given in combination with erlotinib in patients with acquired resistance to erlotinib 
at 8 weeks (2 cycles) 
 
B. Secondary Objective: Measure progression free survival and overall survival 
among patients treated with trametinib and erlotinib and further define the toxicity 
profile of the combination 
 
Correlative Studies: 
 
A. Primary Objective: 1) Determine whether trametinib leads to upregulation of BIM 
in patients with acquired resistance 2) Identify changes in protein expression 
related to apoptosis, EMT and NF1 expression 3) Perform  transcriptome 
analysis (using RNA-seq) on tumor tissue from serial biopsies. 4) Perform next- 
generation sequencing based mutation platform testing to identify genetic 
alterations on tumor tissue from serial biopsies 
. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 EGFR-mutant lung adenocarcinoma and acquired resistance to EGFR tyrosine Kinase 
Inhibitors 
Twenty percent of patients with metastatic lung adenocarcinoma have somatic activating 
mutations in the epidermal growth factor receptor (EGFR). Patients with these oncogene-addicted 
lung adenocarcinomas have a 70% response rate to EGFR-TKI therapy (erlotinib, afatinib, or 
gefitinib) and a median progression-free survival of 12 months.4 All of these patients will develop 
resistance to EGFR TKI therapy and clinical progression. A mechanism of resistance can be 
identified 82% of the time, with acquisition of EGFR T790M seen most frequently.5  There are 
several EGFR T790M targeting EGFR inhibitors 
currently in clinical development. CO-1686, which 
targets mutant EGFR including T790M, has a reported 
overall response rate of 58% in 40 patients with centrally 
confirmed EGFR T790M tumors.6 AZD9291, another 
mutant specific EGFR TKI, has a reported response rate 
of 64% in 107 patients with EGFR T790M mutant 
tumors.7 At this time however, there are currently no 
approved drugs available for patients with acquired 
resistance to EGFR TKIs. Therapeutic options are 
especially limited for patients without acquired EGFR 
T790M present in their tumors. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
Page 10 of 43 
 
 
 
Role of BIM and apoptosis 
 
Expression of the apoptotic protein BIM is required for 
apoptosis triggered by EGFR tyrosine kinase inhibitors 
(TKIs).2,8-10  (Figure 1) Treatment with EGFR TKIs 
induces rapid and sustained increases in the level of 
BIM, and knockdown of BIM nearly eliminates EGFR 
TKI-induced cell killing in EGFR-mutant cell lines.8 
Levels of pre- treatment (and post-treatment) BIM 
predict response to EGFR TKI therapy with an 
association of both response rate and progression-free 
survival on EGFR TKI with BIM expression. 2  Similar 
results were seen when analyzing BIM mRNA 
expression of patients with EGFR-mutant lung cancers 
treated in the EURTAC trial.11  Progression-free survival 
on erlotinib and overall survival were shorter in those with 
low BIM expression.11 
The importance of BIM was again demonstrated in patients with a BIM deletion polymorphism that 
results in an isoform of BIM without the crucial BH3 domain that is required for BIM’s apoptotic 
function.1    The presence of this polymorphism was predictive of a shorter progression free  
survival with erlotinib re-emphasizing the importance of BIM expression to response to TKI 
therapy.1  (Figure 2) 
Inhibition of the MEK/ERK pathway is critical for BIM upregulation required for TKI-induced 
apoptosis.  MEK inhibition is sufficient to induce rapid BIM induction by preventing 
dephosphorylation resulting in BIM accumulation.10  In EGFR T790M containing cell lines, there is 
increased phosphorylated ERK in the presence of an EGFR TKI that was attenuated with the 
addition of a MEK inhibitor.9  In sensitive EGFR mutant cell lines, the addition of a MEK inhibitor to 
an EGFR inhibitor may not be additive, but in the resistance setting there is more limited BIM 
induction and the additive effect of a MEK inhibitor may be more apparent. Song and colleagues 
evaluated dual MEK and EGFR inhibition which resulted in apoptosis in EGFR resistant, EGFR 
T790M containing cell lines (H1975) with decreased phospho-ERK and increased BIM 
expression.12    Induction of BIM through MEK inhibition has the potential to re-sensitize patients to 
EGFR TKI irrespective of EGFR T790M status making this a potential treatment strategy in all 
patients with acquired resistance to EGFR TKI therapy. 
Additional support for MEK inhibition in EGFR-mutant lung cancers 
 
In addition to acquisition of EGFR T790M, there are multiple other mechanisms of acquired 
resistance to EGFR TKI therapy. Histologic transformation including epithelial-mesenchymal 
transition (EMT) is a mechanism of resistance identified in tumor samples in patients treated with 
EGFR TKI.13    ERK/MAPK pathway activation is required for TGF-B2 induced EMT.14  Inhibition of 
MEK was able to prevent EMT and augment sensitivity to gefitinib in cell lines resistant to EGFR 
TKI therapy.15 
Figure 1: basal BIM RNA levels correlate with 
apoptosis2 
Figure 2: Figure 2: BIM polymorphismpredicts PFS w / 
EGFR TKI1 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
Page 11 of 43 
 
 
 
Another mechanism of resistance to EGFR 
TKI identified is decreased expression of 
neurofibromin that results in incomplete 
inhibition of RAS/ERK signaling in the 
presence of erlotinib.3  Low NF1 expression 
was associated with both primary and 
secondary resistance to EGFR TKIs. 
Treatment of neurofibromin deficient lung 
cancers with a trametinib and erlotinib 
restored sensitivity to erlotinib. (Figure 3). 
Preliminary data and Rationale for Dose 
Selection: 
Trametinib is approved for the treatment of 
BRAF-mutant melanomas at a dose of 2mg 
orally daily. A phase 1 study of trametinib 
and erlotinib was conducted in patients with 
solid tumors (NCT01192165).   Twenty-two 
patients were treated and 3 dose-limiting 
toxicities were seen: 1 DLT of diarrhea at 
the dose of trametinib 1mg with erlotinib 100mg and 2 DLTs of diarrhea and mucositis with 
trametinib 1.5mg with erlotinib 100mg. Most common side effects (>30% of all patients), any 
grade, were diarrhea, rash, fatigue, nausea, vomiting, anorexia, hypokalemia and anemia. The 
maximum tolerated dose level of the combination was determined to be trametinib 1mg daily and 
erlotinib 100mg daily. No partial or complete responses were seen in this unselected population. 
Prophylactic antidiarrheals were not utilized on protocol. 
We hypothesize that effective MEK inhibition with trametinib will circumvent acquired resistance to 
erlotinib therapy. We would therefore like to first conduct a phase 1 safety run in with a higher 
dose of MEK inhibitor (trametinib 1.5mg once daily) with a reduced dose of erlotinib at 75mg once 
daily. This dose had not been tested during the previous phase 1 study described above. It is our 
hypothesis that a lower dose (75mg) of erlotinib would allow us to maximize the dose of trametinib 
given. We will also utilize prophylactic anti-diarrheal medications to minimize toxicities. Six  
patients will be accrued to this portion of the study. If zero to one patient experiences a toxicity 
with these doses, we will move to the phase 2 portion of the study. If two or more patients develop 
a DLT at this higher dose of trametinib, we will use trametinib 1mg daily with erlotinib 100mg daily 
during the phase 2 portion of the study. 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a phase 1 safety run-in/phase 2 single arm, open labeled, single institution study of 
erlotinib and trametinib in patients with EGFR mutant lung cancer and acquired resistance to 
erlotinib therapy 
Figure 3: Treatment of murine E-resistant tumors w ith erlotinib 
MEK and E+MEK3: Waterfall plot showing tumor response of the f inal 
4 w eeks of combined treatment w ith EGFR and MEK inhibitors (red 
bars), the EGFR inhibitor alone (blue bars) or MEK inhibitor alone 
(grey). Each bar represents one individual tumor, w ith data expressed 
relative to the tumor volume measured prior to the 4-w eeks treatment 
round, show ing progressive disease (PD), stable disease (SD), partial 
response (PR) or complete response (CR). Tumor mRNA w as 
sequenced for the presence of EGFR-T790M and analysed for Met 
expression; T790M-positive tumors are marked w ith an T, and tumors 
show ing a >4-fold Met expression are marked w ith an M. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
Page 12 of 43 
 
 
 
 
 
 
Dose levels 
Trametinib Dose 
Erlotinib Dose 
Dose Level 0 
1.5mg PO qdaily 
75mg PO qdaily 
Dose Level -1 
1 mg PO qdaily 
100mg PO qdaily 
 
 
4.3 
Intervention 
 
Phase 1: Safety Run in 
 
This portion of the study will assess whether a dose of trametinib 1.5mg by mouth once daily and 
erlotinib 75mg by mouth once daily is a safe dose. Up to six patients will need to be enrolled at 
this dose level and assessed for dose limiting toxicities (DLTs) for 1 full cycle (28 days). Toxicity 
will be graded according to NCI CTCAE version 4.0. If more than one patient develops a DLT, we 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
Page 13 of 43 
 
 
 
will move on to the phase 2 portion of the study and the dose level -1 will be used. Dose level -1 
was already deemed safe in a previous phase 1 study (NCT01192165). If < 1 DLT is detected, we 
will move on to the phase 2 portion of the study at dose level 0. Two to six patients will be enrolled 
in the phase 1 portion. 
 
Dose levels 
Trametinib Dose 
Erlotinib Dose 
Dose Level 0 
1.5mg PO qdaily 
75mg PO qdaily 
Dose Level -1 
1 mg PO qdaily 
100mg PO qdaily 
 
 
Phase 2: 
 
Once the run-in phase 1 portion of the study has been completed, patients will be enrolled in the 
phase 2 portion of the single-arm, two-stage, open-label study of trametinib and erlotinib in the 
treatment of patients with EGFR-mutant lung cancers with acquired resistance to erlotinib.  After 
screening and registration, patients will be treated with the combination of trametinib and erlotinib. 
Response to therapy will be assessed by interval imaging every 8 weeks (every 2 cycles) with CT 
scan of the chest and imaging of any other target lesion with response evaluated by RECIST 1.1. 
A maximum of 24 patients will be enrolled in the phase 2 study. Dosing for the phase 2 portion of 
the study will depend on the results from the run In Phase 1 Portion. If 0-1 DLTs occur, and dose 
level 0 is used in the phase 2 portion, the patients treated in the phase 1 portion at dose level 0 
will be included in the phase 2 portion. 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Trametinib 
 
Drug: Trametinib () 
 
Classification: MEK inhibitor 
 
Composition, Formulation, and storage: all study medication will be stored and inventoried in 
accordance with applicable state and federal regulations. 
Chemical Name:  Acetamide, N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl- 
2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)-dimethylsulfoxide 
Description: Trametinib dimethyl sulfoxide is a white to almost white powder 
 
Trametinib Tablets: Novartis will provide each investigator with adequate supplies of trametinib 
which will be supplied at 0.5 mg and 1mg (as free base) tablets. Tablets are packaged in high 
density polyethylene bottles with child resistant closures including an induction seal liner. The 
enclosed paperboard carton is required for additional light protection. 
• 
0.5mg tablets are white or yellow, modified oval, biconvex and film-coated. 
• 
1mg tablets are white, round, biconvex,  film-coated tablets 
Schedule, route of administration, and dosing: Subjects will receive trametinib 1.5mg by mouth 
once daily or 1mg by mouth once daily depending on the results of the phase 1 Run In. In all 
subjects dose reductions and delays to manage toxicity are allowed under the guidelines in 
Section 11. Take by mouth on an empty stomach, either one hour before or two hours after a 
meal 


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Stability and Storage: Store tablets at 2C-25C in the original bottle. Bottles should be stored in the 
manufacturer’s package carton for light protection. Protect from moisture. Shelf life studies of 
trametinib dimethyl sulfoxide are ongoing. 
Compliance: Drug accountability and subject compliance will be assessed with drug dispensing 
and return records. 
Study Drug Accountability: The investigator will maintain accurate records of receipt of all 
trametinib, including dates of receipt. In addition, accurate records will be kept regarding when 
and how much study treatment is dispensed and used by each subject in the study. Reasons for 
deviation from the expected dispensing regimen must also be recorded. At completion of the 
study, to satisfy regulatory requirements regarding drug accountability, all unused trametinib will 
be reconciled and destroyed in accordance with applicable state and federal regulations. 
Inactive Ingredients: Tablet Core: colloidal silicon dioxide, croscarmellose sodium, hypromellose, 
magnesium stearate (vegetable source), mannitol, microcrystalline cellulose, sodium lauryl 
sulfate. Coating: hypromellose, iron oxide red (2-mg tablets), iron oxide yellow (0.5-mg tablets), 
polyethylene glycol, polysorbate 80 (2-mg tablets), titanium dioxide. 
Additional  information regarding trametinib can be found in the Trametinib® Package Insert. 
5.2 Erlotinib 
 
Drug: Erlotinib (Tarceva) 
Classification: quinazolinamine that inhibits the intracellular phosphorylation of tyrosine kinase 
associated with the epidermal growth factor receptor 
 
Chemical Name:  N-(3-ethynylphenyl)-6,7-bis(2-m ethoxyethoxy)4-quinazolinamine 
 
Erlotinib Tablets: Erlotinib will be commercially supplied. 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
All patients must have: 
 
• 
Pathologic evidence of advanced stage IV or recurrent lung adenocarcinoma reviewed at 
MSKCC 
• 
Somatic activating mutation in EGFR  Radiographic progression during treatment with 
erlotinib or any other EGFR TKI therapies. 
• 
Any number of prior chemotherapy regimens is permitted. 
• 
Measurable (RECIST 1.1) indicator lesion not previously irradiated 
• 
KPS ≥ 70% 
• 
Age >18 years old 
• 
Must have undergone biopsy after development of acquired resistance to erlotinib with 
available archived tissue (equivalent of > 10 unstained slides) 
• 
Left ventricular Ejection Fraction ≥ the lower limit of normal by ECHO or MUGA 
• 
Adequate organ function: 
− 
- AST, ALT ≤ 2.5 x ULN 


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− 
- Total bilirubin ≤ 1.5 x ULN 
− 
-Albumin≥2.6g/dL - Creatinine < 1.5 x ULN OR calculated creatinine clearance 
≥50mL/min 
− 
- Absolute neutrophil count (ANC) ≥ 1,200 cells/mm3 
− 
- Hemoglobin≥9.0 g/dL 
− 
- Platelets ≥100,000/mm3 
 
6.3 
Subject Exclusion Criteria 
 
Patients are to be excluded from the study if they meet any of the following criteria: 
 
• Patients with symptomatic brain metastasis requiring escalating doses of steroids 
• Patients with grade 2 or greater diarrhea prior to study initiation despite maximal medical 
management due to medications or a medical condition such as Crohn’s disease or 
malabsorption 
• Pregnant or lactating women 
• Any type of systemic therapy (chemotherapy or experimental drugs) within 2 weeks of 
starting treatment on protocol except for a EGFR TKI 
• Patients who have received prior treatment with a MEK inhibitor 
• Any major surgery or extensive radiotherapy within 21 days of starting treatment on 
protocol. 
• A history of clinically significant interstitial lung disease or pneumonitis 
• Clinically significant cardiac disease including unstable angina, acute myocardial infarction 
within 6 months from Day 1 of study administration, New York Heart Association Class III 
or IV congestive heart failure, or symptomatic uncontrolled Arrythmias, prolonged 
corrected QT interval >480msec, treatment refractory hypertension, presence of a cardiac 
defibrillator 
• History of central serous retinopathy or retinal vein occlusion 
• Patients with baseline risk factors for central serous retinopathy or retinal vein occlusion 
such as evidence of new optic disc cupping, evidence of new visual field defects, and 
intraocular pressure >21 mmHg are excluded from the trial 
• History of prior malignancy within 3 years. Patients who are considered NED from a 
malignancy may be considered on a case by case basis. 
• 
Have a known immediate or delayed hypersensitivity reaction to drugs chemically related 
to study drug, or excipients or to dimethyl sulfoxide (DMSO). 
• Any other condition that, in the opinion of the investigator, may compromise the safety, 
compliance of the patient, or would preclude the patient from successful completion of the 
study 
7.1 
RECRUITMENT PLAN 
 
A member of the patient’s treatment team, the protocol investigator, or research team at 
Memorial Sloan Kettering Cancer Center will identify potential research participants. If the 
investigator is a part of the treatment team, s/he will screen the patient as to eligibility, and 
will discuss the study and the possibility of enrollment in the research study with the 
patient. The preliminary screen of eligibility will be confirmation for the diagnosis of the 
following: 


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• Patients with EGFR mutant lung cancers with progression of disease on Erlotinib 
therapy 
Potential subjects that meet these basic criteria will be referred by their treatment 
physician to the investigator, co-investigators, or research staff of the study. Minority and 
women are well represented in the thoracic oncology clinics, and we expect that they will 
be well represented in the trial accrual. The principal investigator, Dr. Helena Yu, will be 
available to all patients for further questions and information through a contact number 
which will be provided on the consent form itself. 
8.1 
PRETREATMENT EVALUATION 
 
Study eligibility is based on meeting all of the study inclusion criteria and none of the exclusion 
criteria at screening and on Study Day 1 before study treatment administration. The following 
assessments will be conducted prior to subjects receiving their first dose of trametinib on this 
protocol. All aspects of the screening evaluation should be completed within 4 weeks of starting 
treatment: 
• 
Documented presence of a somatic activating EGFR mutation 
• 
Full medical history and physical examination 
• 
Baseline tumor assessment of the CT scan of the chest (and other additional studies 
based on the patient’s sites of disease). Tumor burden must be measurable using 
RECIST 1.1. 
• 
Complete vital signs (pulse, blood pressure, temperature, respiratory rate) as well as 
weight and height 
• 
12 lead electrocardiogram (ECG) and echocardiogram within 1 month of study initiation 
• 
Performance status 
• 
Serum pregnancy test for women with child bearing potential 
• 
Complete blood count with differential 
• 
Comprehensive metabolic panel (glucose, blood urea nitrogen, creatinine, sodium, 
potassium, chloride, bicarbonate, calcium, total protein, albumin, serum bilirubin, alkaline 
phosphatase, ALT, AST) 
• 
Ophthalmology Exam (See Section 10 for more details) 
• 
Archival Tumor Tissue 
9.0 
TREATMENT/INTERVENTION PLAN 
 
Erlotinib will be commercially obtained. Investigators should reference the current approved 
prescribing information. A pill diary will be used to track adherence. Erlotinib is administered daily, 
at approximately the same time of day every day. Erlotinib should be taken on an empty stomach 
(at least 1 hour before, or 2 hours after the ingestion of food). If vomiting occurs during the course 
of treatment, patients should not take an additional dose of erlotinib that day. The patient should 
resume treatment with the next scheduled dose. If more than 12 hours have elapsed, that day’s 
dose should be omitted, and the patients should continue treatment with the next scheduled dose. 
A pill diary will be used to record adherence. 
9.1.2 Therapeutic Agent-Trametinib 
 
Trametinib will be supplied for the purposes of this trial by Novartis. Trametinib is given once daily 
and can be taken with or without food at approximately the same time of the day each day. A pill 
diary will be used to record adherence. 


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9.2 Treatment Arms 
 
All patients will receive trametinib and erlotinib in this single-arm study. 
 
9.3 Study design 
 
Phase 1 (safety run-in): This portion of the study will assess whether a dose of trametinib 1.5mg 
by mouth once daily and erlotinib 75mg by mouth once daily is a safe dose. Six patients will need 
to be enrolled at this dose level and assessed for dose limiting toxicities (DLTs) for 1 full cycle (28 
days). Toxicity will be graded according to NCI CTCAE version 4.0. If more than one patient 
develops a DLT, we will move on to the phase 2 portion of the study and the dose level -1 will be 
used. Dose level -1 of trametinib 1mg daily and erlotinib 100mg daily was already established to 
be safe and tolerable in a previous phase 1 study. If <1 DLTs are detected, we will move on to the 
phase 2 portion of the study at dose level 0. 
 
Dose levels 
Trametinib Dose 
Erlotinib Dose 
Dose Level 0 
1.5mg PO qdaily 
75mg PO qdaily 
Dose Level -1 
1 mg PO qdaily 
100mg PO qdaily 
 
 
Phase 2: All patients will receive erlotinib and trametinib at the dose level defined during the 
phase 1 portion of the study. Patients will be monitored for response by CT every 2 cycles (8 
weeks). The first 8 week response will be considered the primary objective outcome for this 
portion of the study. The schedule of evaluations and interventions is described in Section 10.0. 
9.4 Dose Limiting Toxicities: 
 
The NCI Common Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE) will be used 
to grade toxicities during the trial. Dose limiting toxicities (DLTs) are defined as any of the  
following events occurring during the first cycles of treatment (i.e. 4 weeks) that are, in the opinion 
of the treatment physician, possibly, probably, or definitely related to the investigational regimen: 
• 
Death related to the investigational regimen 
• 
Hematologic toxicities including: 
o Grade=4 neutropenia lasting >5 days 
o Grade=4 thrombocytopenia (<25,000/mm3) 
o Grade≥ thrombocytopenia with evidence of clinically significant bleeding 
o Grade=4 anemia 
• 
Non-hematologic toxicities include: 
o Grade ≥ 3 AST, ALT, alkaline phosphatase or total bilirubin 
o Grade  ≥ 3 diarrhea, nausea, vomiting that lasts >72 hours despite optimal 
maximum supportive care 
o Grade 4 diarrhea, nausea, vomiting 
o Any other non-hematologic grade  ≥3  major organ toxicity 
o central serous retinopathy or retinal vein occlusion 
9.5 Correlative Studies: Biopsies will be required prior to start of study treatment and at the time 
of progression. At prespecified time points, and after additional informed consent, patients will 


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Administrative Update 3 : 18-Jun-2020 
Page 18 of 43 
 
 
 
have image-guided core needle biopsies with 3-4 cores obtained. At least 2 cores will be 
immediately frozen in liquid nitrogen and sent to Dr. Rudin’s lab. 
 
 
The remaining cores will be fixed in formalin and sent to Surgical Pathology. Blood will also be 
used for IMPACT  testing for next-generation sequencing based testing if not obtained previously. 
DNA/RNA will be extracted from one flash-frozen core using an AllPrep® DNA/RNA mini kit 
(Qiagen). RNA quality will be assessed at the MSKCC integrative genomics (iGO) core facility 
using an Agilent Bioanalyzer 2100 platform. We will perform RNA-seq on all patients with 
sufficient tissue from the phase 2 cohort, to quantify changes in gene expression at various time 
points of treatment and to identify potential biomarkers of response to combination therapy. 
Extracted RNA (5ug) will be submitted to Genewiz for single-end 75bp reads on a HiSeq 2500 
instrument. RNA samples that are limiting in quality/amount will be amplified using the Ovation® 
RNA-seq System V2 kit (NuGen) and submitted for RNA-seq as cDNA. We expect RNA yields 
from core biopsies to be limiting, thus we will not perform rRNA depletion prior to submission of 
samples. Analysis of RNA-seq data will be performed at the MSKCC Bioinformatics core facility. 
Remaining RNA will be frozen at -80C for validation of genes of interest highlight by RNA-seq 
data. Validation will be performed using either RT-PCR or through the construction of a custom 
nanostring nCounter panel that includes genes of interest. One fixed core will be used for 
immunohistochemistry to determine protein expression for transcripts of interest, including:  BIM, 
cleaved caspase 3, TGFB2, vimentin, e-cadherin, n-cadherin and neurofibromin. MSK-IMPACT, 
our next-generation sequencing based mutation platform that assesses for genetic alterations in 
340 cancer-related genes will be used for molecular analysis. 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
Tables 10.1 outlines the schedule of assessments applied to patients. If the subject is unable to 
have a study assessment taken within the defined time window due to an event outside of his or 
her control (e.g. clinic closure, personal emergency, inclement weather, vacation) the assessment 
should be performed as close as possible to the required schedule. More frequent assessments 
should be obtained if clinically indicated. Subjects will return to the study site within 30 days after 
their last dose of trametinib and erlotinib to complete end of study assessments outlined below. 
Additional follow up will occur for subjects with AEs related to study treatment that are ongoing at 
the time of this visit and for subjects with SAEs related to study treatment that occur after the time 
of this visit. 


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Table 10.1: Study Calendar 
1 cycle=28 days 
Screening 
Cycle  1 
Cycle 
2 
Cycle 
3+ 
At 
progression/off 
study 
Within 4 
weeks 
unless 
otherwise 
noted 
C1D1 
C1D7 
C1D8 
C1 
D15 
C2D1 
C3+D1 
Informed Consent 
X 
Medical History 
X 
X 
X 
X 
X 
X 
X 
Concurrent Medication 
Reconciliation 
X 
X 
X 
X 
X 
X 
X 
Physical 
Exam/Performance 
status 1 
X 
X 
X 
X 
X 
X 
OphthalmologyExam 2 
X 
X 
Vital Signs and 
Weight1 
X 
X 
X 
X 
X 
X 
Complete Blood Count 
w/ differential1 
X 
X 
X 
X 
X 
X 
Comprehensive 
Metabolic Panel 
(CMP)1,3 
X 
X 
X 
X 
X 
X 
12 lead EKG4 
X 
X 
X 
X 
Echocardiogram5 
X 
X5 
Adverse Events 
Evaluation1 
X 
X 
X 
X 
X 
X 
X 
Radiologic Tumor 
Assessments6 
X 
X 
X 
MRI brain/disease 
assessment 
X 
B-HCG7 
X 
Tumor Tissue8 
X 
X 
IMPACT Bloods 9 
x 
 
 
1Study Assessments (physical exams, vitals, weight, CBC, CMP, adverse  events  evaluation)  will be 
repeated C1D1,  C1D8, C1D15  (first cycle), then monthly subsequently. C1 assessments have  a window of 
+/- 3 days, C2 onward  assessments have  a window of +/- 2 weeks. 
2Baseline Opthalmic exam will include visual  acuity, visual  field examination, tonometry,  slit lamp 
biomicroscopy of the anterior segment (with special attention to inflammation) and the posterior segment, 
and indirect funduscopic  examination with special attention to possible retinal abnormalities .  Exams are 
required  at screening,  month 1 +/- 2 week, and month 6 +/- 4 weeks. Additional ophthalmic exams will be 
performed  if symptomatically warranted. 
3CMP includes glucose, blood urea nitrogen,  creatinine, sodium, potassium, chloride,  bicarbonate,  calcium, 
total protein, albumin, serum bilirubin, alkaline phosphatase,  ALT, AST 
4A single 12 lead ECG should be performed  at screening and day 1 of every  cycle +/- 2 weeks. 
5Echocardiogram  should be performed  at screening and every  three cycles +/- 2 weeks 
6Response to therapy  will be assessed by interval  imaging studies every  2 cycles (8 weeks)+/- 2 weeks with 
response evaluated  using RECIST version  1.1. Radiologic  imaging will include a CT chest +/ - 
abdomen/pelvis  depending  on sties of disease with or without contrast.  If an appropriate  imaging study is 
performed  early for any reason (i.e. hospitalization), it can be used for disease assessment. CT scans  
should be completed if the patient comes off study for any reason other than progression.  If a CT scan was 
completed within the last 8 weeks, it will not need to be repeated. 


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7 B-HCG testing (serum or urine) should be performed  only in women of child bearing potential. 
8Tumor biopsy will be performed  within 3 months of study initiation (unless archived  tissue is available  from 
a biopsy obtained after progression on erlotinib)and  at time 
of progression +/- 4 weeks.  Both patients on the phase 1 and phase 2 portion of the study will have 
biopsies  performed. 
9IMPACT bloods will be drawn at screening for next-generation  sequencing based testing. 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
Adverse events occurring in patients treated with trametinib and erlotinib may be 1) overlapping 
toxicities seen in both agents (i.e. rash, diarrhea, and pneumonitis); 2) toxicities typically 
associated with trametinib (i.e. visual disturbance, QTc prolongations) or 3) toxicities typically 
associated with erlotinib. However, toxicities with individual agents may be potentiated in the 
combination or unanticipated AEs may occur.  The dose modifications may involve one or both 
agents, and should be based on the nature, severity, and attributions of the AEs. General 
guidelines are provided below. For safety and adverse event reporting, see Section 17.0. 
 
While AEs may be thought to be related to individual agents for purposes of dose modifications, 
all toxicities will be considered related to combination therapy for description of AE profile. 
 
11.1 Management of Erlotinib-Related Toxicities: 
 
Toxicities with erlotinib that are likely (>20%) include: 
• 
Fatigue 
• 
Rash 
• 
Diarrhea 
• 
Decreased appetite 
• 
Nausea/Vomiting 
 
 
Toxicities with erlotinib that are less likely (<20%) include: 
• 
Cough 
• 
Shortness of breath 
• 
Mucositis 
• 
Abdominal Pain 
• 
Changes in hair or nails 
• 
Liver Toxicity 
 
Side effects of erlotinib that are rare, but serious include: 
• 
Pneumonitis 
• 
Acute renal failure 
• 
Stevens Johnson Syndrome 
• 
Liver failure 
• 
Conjunctivitis 
• 
GI bleeding/perforation 
 
The table below outlines the dose levels to be used for any necessary erlotinib dose 
modification: 
 
If Dose level 0 of erlotinib (75mg daily) in the Phase 1 run-in is used for the phase 2 study: 


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Dose Reduction Erlotinib Dose/Schedule 
0 
75mg QD 
1 
50mg QD 
2 
25mg QD 
 
 
 
If dose level -1 of erlotinib (100mg daily) in the Phase 1 run-in is used for the phase 2 study: 
 
Dose Reduction Erlotinib Dose/Schedule 
0 
100mg QD 
1 
75mg QD 
2 
50mg QD 
 
 
A maximum of two erlotinib dose level reductions are allowed.  If a third dose level reduction is 
required, study treatment will be permanently discontinued. 
 
Erlotinib Dose Modification for Toxicities Not Specified in Subsequent Sections 
Erlotinib  Treatment Modification for  Clinically Significant Toxicities Deemed Related to Erlotinib 
(This section is not for specific AEs such as rash, pneumonitis, or diarrhea.   Refer to other sections for 
these specific AEs). 
CTCAE  v4 
Grade 
Dose  Modification 
Management Guideline 
Grade 1 
Continue erlotinib at current  dose level. 
Monitor as clinically indicated. 
Provide  supportive  care 
according  to institutional 
standards 
Grade 2 
• Consider interrupting  treatment until resolution to 
grade 1 or baseline. 
• Upon resolution, restart treatment at current dose 
level. 
Grade 3 
• Interrupt treatment until resolution to grade ≤2 Upon 
resolution to grade ≤2, restart with one level of dose 
reduction 
• If the Grade 3 toxicity recurs, interrupt erlotinib; When 
toxicity resolves to grade ≤2, restart erlotinib reduced 
by another dose  level 
Grade 4 
Erlotinib should be discontinued if treatment  delay is >21 days due to toxicities.  If the investigator 
concludes that continued erlotinib will benefit  a patient, the study PI may be consulted for the possibility of 
resuming erlotinib provided  that toxicities have resolved  to grade ≤2. 
 
11.2 Management of Trametinib-Related T oxicities: 
 
Toxicities with trametinib that are likely (>20%) include: 
• Fatigue 
• 
Rash 
• 
Diarrhea 
• 
Nausea/Vomiting 
• 
Leg or arm swelling 
• 
Constipation 
• 
Decreased appetite 
• 
Decreased red block cell count leading to fatigue 


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Toxicities with trametinib that are less likely (<20%) include: 
• 
dehydration 
• 
Cough 
• 
Shortness of breath 
• 
Itching 
• 
Abdominal pain 
• 
Dry skin 
• 
Fever/chills 
• 
Dizziness 
• 
Pain in the bones 
• 
Difficulty sleeping 
• 
Dry mouth 
• 
Headache 
• 
Increases in blood pressure 
• 
Loss of hair 
• 
Headaches 
• 
Blurry vision 
• 
Changes or infection in fingernails 
 
Side effects of trametinib that are rare, but serious include: 
• 
Changes in the eye that can cause blindness or serious vision problems 
(Chorioretinopathy or central serous retinopathy (CSR), retinal vein occlusion (RVO), 
Retinal Detachment) 
• 
Impaired heart function (decreased in cardiac ejection fraction) 
• 
Liver failure or abnormalities in the liver function blood tests 
• 
Pneumonitis 
• 
Infections in the lung or urinary tract 
 
Trametinib Dose Modifications 
The tables below outlines the dose levels to be used for any necessary trametinib dose 
modification: 
 
If Dose level 0 of trametinib (1.5mg daily) in the Phase 1 run-in is used for the phase 2 study: 
 
Dose Reduction Trametinib Dose/Schedule 
0 
1.5mg QD 
1 
1mg QD 
2 
0.5mg QD 
 
 
If dose level -1 of trametinib (1 mg daily) in the Phase 1 run-in is used for the phase 2 study: 
 
Dose Level Trametinib Dose/Schedule 
0 
1mg QD 
1 
0.5mg QD 
2 
0.25mg QD 


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A maximum of two trametinib dose level reductions are allowed.  If a third dose level reduction is 
required, treatment will be permanently discontinued. 
 
 
 
Trametinib Dose Modification for Toxicities Not Specified in Subsequent Sections 
 
Trametinib Treatment Modification for  Clinically Significant Toxicities Deemed Related to 
Trametinib 
(This section is not for specific AEs such as rash, pneumonitis, diarrhea,  liver chemistry, QTc 
prolongation,  or visual changes.   Refer to other sections for these specific AEs). 
CTCAE  v4 
Grade 
Dose  Modification 
Management Guideline 
Grade 1 
Continue trametinib at current dose level. 
Monitor as clinically indicated. 
Provide  supportive  care 
according  to institutional 
standards 
Grade 2 
• Consider interrupting  treatment until resolution to 
grade 1 or baseline. 
• Upon resolution, restart treatment at current dose 
level. 
Grade 3 
• Interrupt  trametinib  if clinically indicated 
• When toxicity resolves to Grade 1 or baseline, restart 
trametinib reduced by one dose level. 
• If the Grade 3 toxicity recurs, interrupt  trametinib; 
When toxicity resolves to grade ≤1, restart trametinib 
reduced by another dose  level 
Grade 4 
• 
Interrupt  treatment until resolution to grade ≤1 
Upon resolution to grade ≤1, restart with one 
level of dose reduction. 
• 
It toxicity does not resolve  to ≤1 or baseline, 
permanently  discontinue trametinib. 
Trametinib  should be discontinued if treatment delay is >21 days due to toxicities.  If the investigator 
concludes that continued trametinib will benefit  a patient, the study PI and GSK medical monitor may be 
consulted for the possibility of resuming trametinib, provided  that toxicities have  resolved  to grade ≤1. 
 
11.3 
Specific Dose Modifications 
 
11.3.1 Rash 
 
Rash is a frequent AE observed in patients receiving trametinib and erlotinib (package insert). 
Recommendations for supportive care and guidelines for dose modifications for rash are based 
on experience with other MEK inhibitors and EGFR inhibitors.16,17  Patients should be informed  
that skin toxicity is expected during treatment with erlotinib and trametinib. Skin toxicity can take 
the form of dry skin, rash, acneiform eruption, and hair/nail changes. Prophylactic treatment of the 
skin with the recommendations below may prevent or reduce skin toxicity. 
 
Patients with significant skin toxicity will be referred to dermatology for management. 
Recommended treatments may include topical therapy such as hydrocortisone cream or 
clindamycin gel. If needed, oral minocycline or oral doxycycline may be combined with topical 
therapy. For more severe cases, oral corticosteroids may be administered. Patients who fail to 
respond to these measures may have erlotinib and or trametinib interrupted, dose reduced, or 
discontinued. 


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Guidelines for Supportive  Care of Rash 
Type of Care 
Recommendations 
Prevention/Prophylaxisa 
• Avoid unnecessary exposure to sunlight. 
• Apply broad-spectrum sunscreen (containing titanium dioxide or 
zinc oxide) with a skin protection factor (SPF) ≥15 at least twice 
daily. 
• Use thick, alcohol-free  emollient cream (e.g., glycerine and 
cetomacrogol cream) on dry areas of the body at least twice daily. 
• Topical steroids and antibiotics should be applied at least twice 
daily, starting on Day 1 of study treatment, to affected  body areas 
such as face, chest, and upper back. 
• Consider mild-strength topical steroid (hydrocortisone  1% cream) or 
topical antibiotic (e.g., clindamycin) or oral antibiotics (e.g., 
doxycycline 100 mg BID, minocycline 100 mg BID). 
Symptomatic  Careb 
• Pruritic lesions:  Cool compresses and oral antihistamine therapies. 
• Fissuring lesions:  Monsel’s solution, silver nitrate, or zinc oxide 
cream. 
• Desquamation:   Thick emollients and mild soap. 
• Paronychia:   Antiseptic bath, local potent corticosteroids in addition 
to antibiotics; if no improvement,  consult dermatologist  or surgeon. 
• Infected lesions:  Appropriate bacterial/fungal   culture-driven 
systemic or topical antibiotics. 
a Rash prophylaxis  is recommended  for the first 6 weeks of study treatment. 
b Patients who develop  rash/skin toxicities should be seen by a qualified  dermatologist and should 
receive  evaluation  for  symptomatic/supportive  care management. 
 
 
 
Trametinib/Erlotinib Dose  Modification Guidelines and Management for Rash 
Rash  Severity 
Management Guideline 
Dose  Modification 
Grade 1 
• Initiate prophylactic and 
symptomatic  treatment 
measures.1 
Continue trametinib and erlotinib at same dose 
level. 


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Trame tinib/Erlotinib Dose  Modification Guidelines and Management for Rash 
Rash  Severity 
Management Guideline 
Dose  Modification 
Grade 2 
Initiate prophylactic and 
symptomatic  treatment 
measures.1 
Continue at same dose level.  If rash persists or 
worsens over  14 days consider dose reduction of 
trametinib and/or erlotinib by one dose level at 
discretion of investigator. 
Grade 3 
Suggest withholding erlotinib  and/or trametinib 
until toxicity is grade ≤2. If rash persists or 
worsens over  14 days, consider dose reduction at 
discretion of investigator.2 
Grade 4 
Withhold trametinib and/or erlotinib until toxicity is 
grade ≤2. Restart with trametinib and or erlotinib 
reduced by one dose level.2  If No recovery  to ≤ 
grade 2 within 4 weeks, permanently  discontinue 
trametinib and/or  erlotinib. 
1. Rash prophylaxis  is recommended  for the first 6 weeks of study treatment. See above  table. 
2. Trametinib may be escalated to previous  dose level if no rash is evident  4 weeks after restarting 
study treatment. 
 
 
 
11.3.2 Diarrhea 
 
Episodes of diarrhea have occurred in patients receiving trametinib and erlotinib (package insert). 
Other frequent causes of diarrhea may include concomitant medications (e.g., stool softeners, 
laxatives, antacids, etc.), infections by C. difficile or other pathogens, or partial bowel obstruction. 
Those conditions should be excluded. 
 
Guidelines regarding management and dose modification for diarrhea considered related to 
trametinib and/or erlotinib are provided in the table below. 


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Management and Trametinib /Erlotinib Dose  Modification  Guidelines for Diarrhea 
CTCAE  Grade 
Adverse  Event Management 
Action and Dose  Modification 
Grade 1 or 2 
• Diet:  Stop all lactose containing 
products; eat small meals, 
BRAT-diet  (banana,  rice, 
apples,  toast) recommended. 
• Hydration:   8-10 large glasses 
of clear liquids per day (e.g., 
Gatorade or broth). 
• Loperamide1:   Initially 4 mg, 
followed  by 2 mg every  4 hours 
or after every  unformed  stool; 
maximum 16 mg/day.  Continue 
until diarrhea-free  for 12 hours. 
• Lomotil1: 2.5-5mg of 
diphenoxylate up to 4x a day; 
maximum 20mg/daily. Continue 
until diarrhea-free  for 12 hours. 
• Diarrhea  >24 hours: 
Loperamide  2 mg every  2 
hours; maximum 16 mg/day. 
Consider adding oral antibiotics. 
• Continue  trametinib and 
erlotinib at same dose. Initiate 
adverse  event  management 
Grade 3 diarrhea 
• Clinical evaluation  mandatory. 
• Loperamide1:   Initially 4 mg, 
followed  by 2 mg every  4 hours 
or after every  unformed  stool; 
maximum 16 mg/day.  Continue 
until diarrhea-free  for 12 hours. 
• Lomotil1: 2.5-5mg of 
diphenoxylate up to 4x a day; 
maximum 20mg/daily. Continue 
until diarrhea-free  for 12 hours. 
• Oral antibiotics and second-line 
therapies  if clinically indicated 
• Hydration:   Intravenous   fluids if 
clinically indicated. 
• Antibiotics (oral or intravenous) 
if clinically indicated. 
• Intervention  should be 
continued until the subject is 
diarrhea-free  for ≥24 hours. 
• Intervention  may require 
hospitalization for  subjects at 
risk of life-threatening 
complications. 
• Interrupt  trametinib and or 
erlotinib until diarrhea resolves 
to ≤ grade 2. 
• Restart treatment at same dose 
or with a dose reduction at 
discretion of investigator.2 
Grade 4 
• Withhold trametinib and erlotinib 
until toxicity is grade <=2. 
Initiate adverse  event 
management.  Discontinue 
permanently  or restart with a 
dose reduction at the discretion 
of the investigator.2 
1. Loperamide  and Lomotil should be made available  prior to start of study treatment so loperamide 
administration can begin at the first signs of diarrhea. 
2. Escalation of trametinib to previous dose level is allowed after consultation with the medical monitor 
and in the absence of another episode of complicated or severe diarrhea in the 4 weeks subsequent  to 
dose reduction. 
 
 
11.3.3 Pneumonitis 


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Pneumonitis has been observed in patients receiving trametinib and erlotinib.  To reduce the risk 
of pneumonitis, patients will be monitored closely for symptoms and evaluated with imaging and 
functional tests.  Dose modification and supportive care guidelines for pneumonitis are described 
in the tables below. 
 
CTCAE  Grade 
Adverse  Event 
Management 
Action and Dose  Modification 
Grade 1 
• CT scan (high-resolution 
with lung windows) 
recommended 
• Clinical evaluation and 
laboratory work-up for 
infection 
• Monitoring  of oxygenation 
via  pulse-oximetry 
recommended 
• Consultation  of 
pulmonologist 
recommended 
• Continue trametinib/erlotinib  at current dose 
if clinically indicated. 
Grade 2 
• CT scan (high-resolution 
with lung windows) 
• Clinical evaluation and 
laboratory work-up for 
infection 
• Consult  pulmonologist 
• Pulmonary function  tests 
–if < normal, repeat  every 
8 weeks until ≥ normal 
• Bronchoscopy with biopsy 
and/or  BAL recommended 
• Symptomatic  therapy 
including corticosteroids if 
clinically indicated 
• Interrupt  trametinib/erlotinib  until recovery 
to grade ≤1 
• Consider restarting with   trametinib/erlotinib 
reduced by one dose level 
• Escalation to previous  dose level  after 4 
weeks and consultation with medical 
monitor possible 
• If no recovery  to grade ≤1 within 4 weeks, 
permanently  discontinue study treatment 
Grade 3 
• CT scan (high-resolution 
with lung windows) 
• Clinical evaluation and 
laboratory work-up for 
infection 
• Consult  pulmonologist 
• Pulmonary function  tests- 
if < normal, repeat every 8 
weeks until ≥ normal 
• Bronchoscopy with biopsy 
and/or BAL if possible 
• Symptomatic  therapy 
including  corticosteroids 
as clinically indicated 
• Interrupt  trametinib/erlotinib  until recovery 
to grade ≤1 
• After consultation with medical monitor, 
study treatment may be restarted reduced 
by one dose level 
• If no recovery  to grade ≤1 within 4 weeks, 
permanently  discontinue study treatment 
Grade 4 
• Same as grade 3 
• Permanently  discontinue trametinib/erlotinib 
 
 
 
11.3.4 Reduced Left Ventricular Ejection Fraction 
Decreases of the left ventricular ejection fraction (LVEF) have been observed in patients receiving 
trametinib.  Therefore, ECHOs must be performed in regular intervals outlined in the Study 


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Calendar.  The same procedure (either ECHO or MUGA,  although ECHO is preferred) should be 
performed at baseline and at follow-up visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trametinib Dose  Modification Guidelines and Stopping Criteria for LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE  grade 
Action and Dose 
Modification 
Asymptomatic 
Absolute decrease of >10% in 
LVEF compared to baseline and 
ejection fraction below the 
institution’s LLN. 
• Interrupt  trametinib and repeat 
ECHO within 2 weeks.a 
• If the LVEF recovers within 4 
weeks (defined as LVEF ≥LLN 
and absolute decrease ≤10% 
compared  to baseline): 
− Consult with the trametinib 
medical monitor and PI and 
request approval  for restart. 
− Restart treatment with 
trametinib at reduced dose by 
one dose levelb 
− Repeat ECHO 2, 4, and 12 
weeks after re-start; continue 
in intervals  of 12 weeks 
thereafter. 
• If LVEF does not recover  within 
4 weeks: 
− Consult with cardiologist. 
− Permanently  discontinue 
trametinib. 
− Report  as SAE 
− Repeat ECHO after 2, 4, 8, 
12, and 16 weeks or until 
resolution. 


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Trametinib Dose  Modifica tion Guidelines and Stopping Cr iteria for LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE  grade 
Action and Dose 
Modification 
Symptomaticb 
• Grade 3:  resting LVEF 39-20% 
or >20% absolute reduction 
from baseline 
• Grade 4:  Resting LVEF ≤20%. 
• Permanently discontinue 
trametinib. 
• Report as SAE. 
• Consult  with cardiologist. 
• Repeat ECHO after 2, 4, 8, 12, 
and 16 weeks or until resolution. 
a If ECHO does not show LVEF recovery  after 2 weeks, repeat  ECHO 2 weeks later. 
b Escalation of trametinib to previous  dose level  can be considered if LVEF remains stable for 4 weeks 
after restarting of trametinib.  Approval  from GSK Medical Monitor is required. 
CSymptoms may include:  dyspnea, orthopnea,  and other signs and symptoms of pulmonary  congestion 
and edema. 
 
 
 
 
 
 
 
 
 
 
 
 
11.3.5 QTc Prolongation 
QTc prolongation has been observed in patients receiving trametinib.  Therefore, 12 lead EKGs 
must be performed in regular intervals outlined in the Study Calendar. 
 
Trametinib Withholding and Stopping Criteria for QTc Prolongation 
Prolongation* 
Action and Dose  Modification 
• QTcB ≥501 msec, or 
• Uncorrected QT >600 msec, or 
• QTcB >530 msec for subjects 
with bundle branch block 
• Interrupt  study treatment until QTcB prolongation  resolves  to grade 
1 or baseline. 
• Test electrolytes (K, Ca, Phos, Mg). If abnormal,  replete to normal 
limits. 
• Review  concomitant medication usage for a prolonged  QTc 
• If the QTc prolongation  resolves  to grade 1 or baseline, trametinib 
may be resumed at current dose level 
• If the event does not resolve, permanently discontinue  study 
treatment. 
• If the event recurs, permanently discontinue  study  treatment. 


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Trametinib Withholding and Stopping Criteria for QTc Prolongation 
Prolongation* 
Action and Dose  Modification 
Abbreviations:   msec = milliseconds; QTcB = QT interval  on electrocardiogram  corrected using the 
Bazett’s formula 
* Based on average  QTc value of triplicate ECGs.  For example, if an ECG demonstrates  a prolonged 
QT interval,  obtain two or more ECGs over  a brief period, and then use the averaged  QTc values  of the 
three ECGs to determine if study treatments should be interrupted or discontinued. 
 
11.3.6 Visual Changes 
 
Episodes of visual changes have been observed in patients receiving trametinib.  The causal 
relationship between a change in vision and the study treatment should be carefully explored and 
an ophthalmologist should be consulted.  Patients are required to have a standard ophthalmic 
exam performed by an ophthalmologist at baseline and as clinically warranted.  The exam will 
include indirect funduscopic examination, visual acuity (corrected), visual field examination, 
tonometry, and direct funduscopy.  Special attention should be given to retinal (e.g., CSR) or 
retinal vein abnormalities (e.g., RVO). 
 
Guidelines regarding event management and dose reduction for visual changes considered to be 
related to study treatment are provided in the table below. 
 
Management and Trametinib Dose  Modification for Visual Changes 
Event 
CTCAE  Grade 
Management Guideline 
Dose  Modification 
Any grade of CRS or RVO should be reported as SAE 
Grade 1 
Asymptomatic or symptomatic but 
not limiting ADL; intervention  not 
indicated. 
• Consult ophthalmologist  within 7 
days of onset. 
• Exclude CSR or RVO. 
• Consult retinal specialist if 
available  in case of CSR or 
RVO. 
• Continue follow up 
examination(s)  (by retinal 
specialist if available)  for CSR 
and RVO. 
• Continue trametinib at the same 
dose level  until ophthalmologic 
examination  can be conducted.* 
• If ophthalmologic  examination 
cannot be performed  within 7 
days of onset, interrupt 
trametinib until CSR and RVO 
can be excluded and symptoms 
resolve. 
• If CSR and RVO excluded 
restart trametinib at same dose 
level. 
• If CSR:  Interrupt  trametinib until 
symptoms resolve  and exam 
(by retinal specialist if available) 
shows resolution.  May restart 
trametinib with one dose level 
reduction. 
• If RVO:  Permanently 
discontinue  trametinib. 


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Management and Trametinib Dose  Modification for Visual Changes 
Event 
CTCAE Grade
Management Guideline 
Dose  Modification 
Any grade of CRS or RVO should be reported as SAE 
Grade 2 and 3 
Grade 2 defined as: 
Symptomatic with moderate 
decrease in visual acuity (20/40 
or better; limiting instrumental 
ADL; local or non-invasi ve 
intervention  indicated.) 
Grade 3 defined as:  
Symptomatic with marked 
decrease in visual acuity or 
marked visual  field defect (worse 
than 20/40 but better than 
20/200);  severe pain or medically 
significant; operative  intervention 
indicated. 
• Consult  ophthalmologist 
immediately. 
• Exclude CSR and RVO. 
• Consult retinal specialist in case 
of RVO or CSR for follow-up 
exam. 
• Continue follow up 
examination(s)  (by retinal 
specialist if available)  for CSR 
and RVO 
• Interrupt  trametinib until signs 
and symptoms have  resolved  to 
baseline. 
• If CSR and RVO excluded and 
symptoms resolved  to baseline, 
restart trametinib reduced by 
one dose level. 
• If CSR:  Interrupt  trametinib until 
symptoms resolve  and exam 
(by retinal specialist if available) 
shows resolution.  If CSR 
resolves  restart trametinib 
reduced by one dose level. 
• If RVO:  Permanently 
discontinue  study  treatment. 
Grade 4 
Sight-threatening  consequences; 
urgent  intervention  indicated; 
blindness (20/200 or worse). 
• Consult  ophthalmologist 
immediately. 
• Exclude CSR and RVO. 
• Continue follow up 
examination(s)  (by retinal 
specialist if available)  for CSR 
and RVO. 
Permanently discontinue 
trametinib. 
Abbreviations:   CSR = central serous retinopathy; RVO = retinal vein  occlusion; SAE = serious adverse 
event 
* If visual  changes are clearly unrelated  to study treatment (e.g., allergic conjunctivitis),  monitor closely 
but ophthalmic examination is not required. 
* If ocular toxicities do not resolve within 21 days, permanently  discontinue trametinib. 
 
 
 
 
 
 
11.3.7 Hypertension 


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Management and Dose Modification Guidelines for Hypertension 
 
Hypertension 
Action and Dose  Modification 
(Scenario  A) 
• 
Asymptomatic and persistenta  SBP of ≥140 and 
<160 mmHg, or DBP ≥90 and <100 mmHg, 
or 
• 
Clinically significant increase in DBP of 20 
mmHg (but DBP still <100 mmHg). 
• 
Continue trametinib at the current dose 
• 
Adjust current or initiate new 
antihypertensive   medication 
• 
Titrate  antihypertensive  medication(s) 
during the next 2 weeks as indicated to 
achieve  well-controlledb   BP 
• 
If BP is not well controlled within 2 weeks, 
consider referral  to a specialist and go to 
scenario (B). 
(Scenario  B) 
• 
Asymptomatic SBP ≥160 mmHg, or DBP 
≥100 mmHg, 
or 
• 
Failure to achieve  well-controlled  BP within 2 
weeks in Scenario A 
• 
Interrupt  trametinib  if clinically indicated 
• 
Adjust current or initiate new 
antihypertensive   medication(s) 
• 
Titrate  antihypertensive  medication(s) 
during the next 2 weeks to achieve  well- 
controlled  BP 
• 
Once BP is well controlledb, restart 
trametinib reduced by one dose levelc 
(Scenario  C) 
• 
Symptomaticd   hypertension 
or 
• 
Persistent SBP ≥160 mmHg, or DBP 
≥100 mmHg, despite antihypertensive 
medication and dose reduction of trametinib 
• 
Interrupt  trametinib 
• 
Adjust current or initiate new 
antihypertensive   medication(s) 
• 
Titrate  antihypertensive  medication  during 
the next 2 weeks to achieve well-controlled 
BP 
• 
Referral  to a specialist for further  evaluation 
and follow-up  is recommended 
• 
Once BP is well controlled, restart 
trametinib reduced by one dose levelc 
(Scenario  D) 
• 
Refractory  hypertension unresponsive  to above 
interventions,  or having  hypertensive  crisis. 
• 
Permanently discontinue  trametinib 
• 
Continue follow-up  per protocol. 
Abbreviations:   BP = blood pressure;  DBP = diastolic blood pressure;  mmHg = millimetres mercury; SBP 
= systolic blood pressure; 
a. 
Hypertension detected in two separate readings  during up to three consecutive visits 
b. 
Well-controlled blood pressure defined as SBP ≤140 mm Hg and DBP ≤90 mm Hg in two separate 
readings  during up to three consecutive visits. 
c. 
Escalation of trametinib to previous  dose level can be considered if BPs remain well-controlled  for 4 
weeks after restarting of trametinib.   Approval  from GSK Medical Monitor is required. 
d. 
Symptomatic hypertension defined as hypertension aggravated   by symptoms (e.g., headache,  light - 
headedness,  vertigo,  tinnitus, episodes of fainting) that resolve  after the blood pressure  is controlled 
within the normal  range. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 


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The same method of assessment (i.e. CT or MRI) and the same technique (i.e. with or without 
contrast) should be used to characterize each identified and reported lesion at baseline and every 
two cycles (+/- 1 week). A designated radiologist at MSKCC will interpret the study CTs or MRIs 
according to RECIST 1.1 criteria. The same radiologist/physician should perform the evaluation 
for the entire duration of the study. 
Tumor response will be assessed using RECIST 1.1. Confirmation of response will not need to be 
required. A CT scan of the chest +/- abdomen/pelvis will be performed to demonstrate all known 
areas of measurable disease. The baseline study will occur no more than 4 weeks prior to first 
study drug administration. A CT scan with contrast will be the preferred method and modality of 
imaging. A CT scan without contrast or MRI can be used in patients with contraindications to 
radiographic contrast media used in CT scans. All patients must have at least one measurable 
disease lesion by CT or MRI. 
All measurable lesions, up to a maximum of 5 lesions 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, should be representative of all involved organs, and 
should lend themselves to reproducible repeat measurements. All other lesions (or sites of 
disease) should be identified as non-target lesions and should also be recorded at baseline. 
Definitions of response in target and non-target lesions are described in table 12.1. Table 12.2 
provides overall responses for all possible combination of tumor responses in target and non- 
target lesions. 
 
Table 12.1 Evaluations of Target Lesions 
Complete response (CR): 
Disappearance of all target lesions 
Partial Response (PR): 
At least a 30% decrease in the sumo of the 
diameters of the target lesions 
Progressive Disease (PD): 
At least a 20% increase in the sum of the 
diameters of the target lesions or the 
appearance of one ore more new lesions 
Stable Disease (SD): 
Neither sufficient shrinkage or qualify to PR 
nor sufficient increase to qualify for PD 
 
Table 12.2 Evaluations of Non-Target Lesions 
Complete response (CR): 
Disappearance of all non-target lesions 
Incomplete response/stable disease (SD): 
Persistence of one or more non-target 
lesions 
Progressive Disease (PD): 
Appearance of one or more new lesions 
and/or unequivocal progression of existing 
non-target lesion 
 
 
 
 
 
 
 
 
 
 
Table 12.3 Best Overall Response 


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Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Incomplete/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
Evaluation of Best Overall Response: The best overall response is the best response recorded 
from the start of treatment until disease progression, as defined in Table 12.3. 
Evaluation of Toxicity: All patients who receive at least one dose of treatment with erlotinib and 
trametinib will be evaluable for toxicity. 
Progression Free Survival (PFS): Duration of time from first treatment to time of progression or 
death, whichever occurs first. 
Overall Survival (OS): Duration of time from first treatment to time of death. 
 
 
13.0 
CRITERIAFOR REMOVAL FROM STUDY 
 
Patients may withdraw from the study at any time. Other reasons for study discontinuation include 
but are not limited to: 
• 
Change in patient eligibility 
• 
Non-compliance with the defined treatment plan 
• 
Protocol violation 
• 
Investigator’s decision based on patient’s best interest 
• 
Withdrawal of consent 
• 
Severe, unexpected toxicities/side effects 
• 
Lost to follow up 
• 
Death 
• 
Progression of disease (defined by RECIST 1.1) 
 
For the Phase 1 portion of the study, patients who withdraw from the study for reasons other than 
DLT without completing a full treatment cycle will be replaced. 
14.0 
BIOSTATISTICS 
Phase 1: Safety Run In 
Primary Objective: To determine the safety and tolerability of the combination of erlotinib 75mg 
by mouth once daily with trametinib 1.5mg by mouth once daily in patients with EGFR mutant lung 
cancer and acquired resistance to EGFR tyrosine kinase inhibitors. 
Endpoints: Identify any dose limiting toxicities of the combination. A dose limiting toxicity is a binary 


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outcome where a patient either experiences a DLT or not. DLT is defined as any of the toxicities 
described in Section 9 that occurs within one cycle after initiation of treatment with erlotinib and 
trametinib. 
Method: Up to six patients will be enrolled at dose level 0 (trametinib 1.5mg by mouth once daily 
and erlotinib 75mg by mouth once daily) and assessed for dose limiting toxicities (DLTs) for 1 full 
cycle (28 days). Toxicity will be graded according to NCI CTCAE version 4.0. If more than one 
patient develops a DLT, we will move on to the phase 2 portion of the study and the dose level -1 
will be used. If <1 DLTs are detected, we will move on to the phase 2 portion of the study at dose 
level 0. 
If 0-1 DLTs occur, and dose level 0 is used in the phase 2, the  patients accrued during the phase 
1 portion of the study will be followed for response assessment and included in the phase 2 portion 
of the study. Given an expected accrual rate of 2 patients per month, the accrual to the phase 1 
portion of the study will be completed in about 3 months. Two to six patients will be enrolled in the 
phase 1 portion of the study. 
 
Dose levels 
Trametinib Dose 
Erlotinib Dose 
Dose Level 0 
1.5mg PO qdaily 
75mg PO qdaily 
Dose Level -1 
1 mg PO qdaily 
100mg PO qdaily 
 
Phase 2: 
 
Primary Objective:To determine the ORR of the combination of erlotinib and trametinib in patients 
with EGFR mutant lung cancer and acquired resistance to EGFR tyrosine kinase inhibitors 
 
Secondary Objective: To determine the progression free survival and overall survival and further 
assess the toxicity of trametinib and erlotinib 
Methods: A Simon optimal two-stage trial design will be utilized to assess the primary endpoint of 
response rate (RECIST 1.1 CR+PR). This study will test the null hypothesis of 5% response rate 
against the alternative hypothesis of 25% response rate for patients with acquired resistance. A 
null hypothesis of 5% was chosen because all eligible patients have demonstrated progression and 
lack of response to erlotinib. The most effective treatment for both EGFR T790M positive and 
negative patients is afatinib and cetuximab which has a response rate of 29% but results in 
significant adverse events18. Subsequently, an alternative hypothesis of 25% was chosen for this 
study. The design chosen has a 10% type I error (falsely accepting a non-promising therapy), 10% 
type II error (falsely rejecting a promising therapy), for 90% power.  In the first stage of this design, 
9 patients will be treated. If 0 responses are seen in the first 9 patients, the trial will be stopped and 
declared negative. If at least 1 response is observed, than an additional 15 patients will be accrued 
to the second stage. At the end of the study, if 3 or more patients have a response out of a total of 
24 patients enrolled, the combination of trametinib and erlotinib will be considered worthy of further 
investigation. Overall survival and time to progression will be estimated using the Kaplan-Meier 
method, with the follow-up starting at the initiation of therapy. Patients will be censored at the time 
of the last on-study evaluation if they do not experience the event of interest. Safety and tolerability 
will be summarized using descriptive statistics. The toxicities and the adverse events will be 
assessed for each patient according to the NCI CTCAE version 4.0 criteria. All correlative aims are 
exploratory and will be hypothesis-generating only. 


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Given an expected accrual rate of 2 patients per month, the accrual to the phase 2 portion of the 
study will be completed in about 6-12 months. 
Correlatives: For the correlative studies, the analysis is primarily exploratory and hypothesis 
generating. Correlative studies will be performed on all patients participating in both the phase 1 
and 2 portions of this clinical trial. 
 
 
Method: EGFR T790M status will be determined for the biopsy samples obtained at the time of 
acquired resistance to EGFR TKI monotherapy. The portion of patients with T790M mutation will 
be calculated along with the exact 95% confidence interval. The expression of proteins such as 
BIM, TGFB2, vimentin, e-cadherin, n-cadherin, and neurofibromin will be quantified using 
immunohistochemical (IHC) staining in the biopsy tissue obtained and reported as a proportion of 
patients with each IHC score. Results will be summarized at each time point using descriptive 
statistics (mean +/- std). Graphical methods will be used to evaluate the way protein expression 
changes during the course of treatment. 
15.1 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the 
PPR Electronic Registration System (http://ppr/).  The completed signature page of the 
written consent/RA or verbal script/RA, a completed Eligibility Checklist and other relevant 
documents must be uploaded via the PPR Electronic Registration System. 
15.3 
Randomization 
 
There will be no randomization in this phase 2 study. 
 
16.1 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. The data collected for this study will be entered into a secure 
database (Clinical Research Database CRDB). Source documentation will be available to 
support the computerized patient record. The principal investigator will maintain ultimate 
responsibility for the clinical trial. 


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16.2 
Quality Assurance 
Weekly meetings will occur to monitor patient accrual and completeness of registration data. 
Routine data quality reports will be generated to assess missing data and inconsistencies. 
Accrual rates and extent and accuracy of evaluations and follow up will be monitored 
periodically throughout the study period and potential problem will be brought to the 
attention of the study team for discussion and action. Random sample data quality and 
protocol compliance audits will be conducted by the study team, at a minimum of two times 
a year, and more frequently if indicated. 
 
 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at:  
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The  DSM  Plans  at  MSKCC 
were established and are monitored by the Office of Clinical Research. The MSKCC Data 
and 
Safety 
Monitoring 
Plans 
can 
be 
found 
on 
the 
MSKCC 
Intranet 
at:  
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms bywhich clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) 
for Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase 
III clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 


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Approval date: 12-Jul-2019 
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17.1 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits, and objectives of the study will be 
reviewed with the participant, including a discussion of the possible toxicities and side  
effects. Alternative,  non-protocol, treatment options will be discussed with the patient. It will 
be reviewed that participation in this clinical trial is voluntary and that the patient may 
withdraw consent at any time. The study is designed with careful safety monitoring for toxicity 
including physician visits. Specific guidelines for symptom management are in place to 
protect the study participants. 
Human Subjects Involvement and Characteristics: All patients at MSKCC who meet the 
inclusion criteria will be eligible to enroll. Patients eligible will be 18 years of age or older with 
a KPS of 70% or greater. Both men and women and members of all ethnic groups will be 
eligible for this trial. Pregnant and breast feeding women are excluded from this study. This 
protocol does not include children because the number of children is expected to be limited 
for the patient population expected to be accrued onto this study. Also the majority of  
children are already accessed by a nationwide pediatric cancer research network. This 
statement is based on exclusion 4b of the NIH policy and guidelines on the Inclusion of 
Children as Participants in Research Involving Human Subjects. 
Consent process: All patients at MSKCC who meet the inclusion criteria will be eligible. 
Participation in the trial is voluntary. All patients will be required to sign a statement of 
informed consent, which must conform to IRB guidelines. The informed consent procedure is 
described in Section 18.0. 
Possible Toxicities: There are risks associated with treatment as described in Section 11.0. 
 
Benefits: The combination of trametinib and erlotinib has the potential to be effective and 
induce tumor response in patients with EGFR mutant lung cancer and acquired resistance to 
erlotinib. 
Costs: Patients will be charged (insurance billed) for physician visits, erlotinib, routine 
laboratory tests, and radiologic studies required for monitoring their condition. The patients 
will not be billed for the study drug, trametinib. The research studies will be covered with 
separate research funding and no charges associated with research will be billed to the 
patient. Repeat biopsy on progression of disease on study will not be charged to the patient. 
Alternatives: The alternative to this trial would be treatment with chemotherapy with or 
without continuation of erlotinib or participation in an alternative clinical trial. 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research and 
hospital records are confidential. Patients’ names and any other identifying information will 
not be used in reports or publications resulting from this study. Other authorized agencies 
and appropriate internal personnel (e.g. qualified monitors from MSKCC) and external 
personnel (e.g. qualified monitors from Novartis(the manufacturer of trametinib), its 
authorized agents, the FDA, and/or other governmental agencies) may review patient 
records as required. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
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Patient Safety: Patients are monitored by physicians and oncology nurses who are very 
familiar with clinical trials. In the case of an adverse reaction, immediate medical attention is 
available. In the evenings and weekends, we have a 24 hour urgent care facility for 
outpatients. The PI or co-PI will also be available at all times to organize any necessary 
intervention. 
Monitoring of data to ensure safety: The study is to be monitored by the institutional IRB. 
This incorporates an independent data and safety monitoring board established by 
arrangement with the National Cancer Institute. The analysis of safety will include all 
patients. Adverse events, including all toxic effects of treatment, will be tabulated individually 
and summarized by severity and causality. 
17.2 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or participant and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
 
SAE reporting is required as soon as the participant starts investigational treatment/intervention. 
SAE reporting is required for 30-days after the participant’s last investigational 
treatment/intervention. Any event that occur after the 30-day period that is unexpected and at least 
possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention and is 
related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per IRB 
SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted within 5 
calendar days of the event. All other SAEs must be submitted within 30 calendar days of the event. 
 
The report should contain the following information: 
• The date the adverse event occurred 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
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Administrative Update 3 : 18-Jun-2020 
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• The adverse event 
• The grade of the event 
• Relationship of the adverse event to the treatment(s) 
• If the AE was expected 
• Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
• If an amendment will need to be made to the protocol and/or consent form 
• If the SAE is an Unanticipated Problem 
 
For IND/IDE protocols: 
The SAE report should be completed as per above instructions. If appropriate, the report will 
be forwarded to the FDA by the IND Office 
 
 
17.2.1  Adverse Event Reporting to  Novartis 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided the main informed consent and until at least 30 days after the patient 
has stopped study treatment must be reported to Novartis within 24 hours of learning of its 
occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to 
each specific study treatment (if there is more than one study treatment), complete the SAE 
Report Form in English, and send the completed, signed form by fax within 24 hours to the 
oncology Novartis Drug Safety and Epidemiology (DS&E) department - Fax: (877-778-9739). 
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with 
the case report form documentation at the study site. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
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If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
Pregnancies 
 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported on the SAE Report Form. 
Warnings and precautions 
 
Additional safety information collected between IB updates will be communicated in the form 
of Investigator Notifications. This information will be included in the patient informed consent 
and should be discussed with the patient during the study as needed 
18.1 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain  
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
Page 42 of 43 
 
 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
19.0 
REFERENCES 
 
1. 
Ng KP, Hillmer AM, Chuah CT, et al. A common BIM deletion polymorphism mediates 
intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nature 
medicine 2012;18:521-8. 
2. 
Faber AC, Corcoran RB, Ebi H, et al. BIM expression in treatment-naive cancers 
predicts responsiveness to kinase inhibitors. Cancer discovery 2011;1:352-65. 
3. 
de Bruin EC, Cowell C, Warne PH, et al. Reduced NF1 Expression Confers 
Resistance to EGFR Inhibition  in Lung Cancer. Cancer discovery 2014;4:606-19. 
4. 
Janne PA, Wang X, Socinski MA, et al. Randomized Phase II Trial of Erlotinib Alone 
or With Carboplatin and Paclitaxel in Patients Who Were Never or Light Former Smokers 
With Advanced Lung Adenocarcinoma: CALGB 30406 Trial. Journal of clinical oncology 
2012; 30(17):2063-9. 
5. 
Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of 
acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. 
Clinical cancer research 2013;19:2240-7. 
6. 
Sequist LV, Soria J-C, Gadgeel SM, Wakelee HA, Camidge DR, et al. First in human 
evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations 
of EGFR (activating and T790M). JCO 32:5s,2014 (suppl; abstr 8010). 
7. 
Janne PA, Pamaligam SS, Yang JC; et al. Clinival activity of the mutatn-selective 
EGFR inhibitor AZD9291 in patients with EGFR inhibitor resistant non-small cell lung cancer. 
JCO 32:5s, 2014 (suppl: abstr 8009). 
8. 
Gong Y, Somwar R, Politi K, et al. Induction of BIM is essential for apoptosis triggered 
by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS 
medicine 2007;4:e294. 
9. 
Costa DB, Halmos B, Kumar A, et al. BIM mediates EGFR tyrosine kinase inhibitor- 
induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS medicine 
2007;4:1669-79;  discussion 80. 
10. 
Cragg MS, Kuroda J, Puthalakath H, Huang DC, Strasser A. Gefitinib-induced killing 
of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 
mimetics. PLoS medicine 2007;4:1681-89;  discussion 90. 
11. 
Costa C, Molina MA, Drozdowskyj A, et al. The impact of EGFR T790M mutations  
and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with 
erlotinib or chemotherapy in the randomized phase III  EURTAC trial. Clinical cancer research 
2014;20:2001-10. 
12. 
Song JY, Kim CS, Lee JH, et al. Dual inhibition of MEK1/2 and EGFR synergistically 
induces caspase-3-dependent apoptosis in EGFR inhibitor-resistant lung cancer cells via 
BIM upregulation. Investigational  new drugs 2013;31:1458-65. 
13. 
Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological 
evolution of lung cancers acquiring resistance to EGFR inhibitors. Science translational 
medicine 2011;3:75ra26. 
14. 
Grande M, Franzen A, Karlsson JO, Ericson LE, Heldin NE, Nilsson M. Transforming 
growth factor-beta and epidermal growth factor synergistically stimulate epithelial to 


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IRB Number: 15-098 A(8) 
Approval date: 12-Jul-2019 
Administrative Update 3 : 18-Jun-2020 
Page 43 of 43 
 
 
 
mesenchymal transition (EMT) through a MEK-dependent mechanism in primary cultured pig 
thyrocytes. Journal of cell science 2002;115:4227-36. 
15. 
Buonato JM, Lazzara MJ. ERK1/2 blockade prevents epithelial-mesenchymal 
transition in lung cancer cells and promotes their sensitivity to EGFR inhibition. Cancer 
research 2014;74:309-19. 
16. 
Balagula, Y., K. Barth Huston, K.J. Busam, et al.  (2010).  Dermatologic side effects 
associated with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886).   Invest New 
Drugs.  29:1114-1121. 
17. 
Lacouture, M.E., M.J. Anadkat, R.J. Bensadoun, et al.  (2011).  Clinical practice 
guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic 
toxicities.  Support Care Cancer.  19:1079-1095. 
18. Janjigian YY, Smit EF, Groen HJ, et al. (2014). Dual inhibition of EGFR with afatinib and 
cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M 
mutations. Cancer Discovery 9:1036-45. 
 
 
20.0 
APPENDICES 
 
Pill diary