Conditions: Oligometastatic Lung Adenocarcinoma
Keywords: Sensitizing EGFR Mutations Erlotinib Surgery Radiation Therapy 15-067
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
This study will test if local therapies in addition to erlotinib can improve responses and delay the time until new treatment is required. This study will also collect blood samples for research blood tests.

Detailed description:

Arms:
arm 1: Patients will be placed on EGFR-TKI for their metastatic EGFR-mutant stage IV oligometastatic disease. All patients will undergo induction TKI for 12 weeks. At the conclusion of 12 weeks on erlotinib, patients without disease progression \[partial response (PR) or stable disease (SD)\] will undergo definitive local treatment to all remaining sites of disease. After local therapy, erlotinib will be resumed until progression of disease (POD) by RECIST criteria. All assessments completed during the 12 week TKI induction phase are to be performed per protocol with a ± 7 day window.

Interventions: intervention 1: Erlotinib intervention 2: Local Therapies
Intervention descriptions: intervention 1: None intervention 2: Definitive local therapies include surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB #: 15-067 A(8) 
Approved: 19-APR-2017 
Page  1 of 33 
 
 
 
 
 
Pilot Study of Local Therapies for Oligometastatic Non-Small Cell Lung Cancer harboring 
Sensitizing EGFR Mutations 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Helena Yu MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Abraham Wu MD 
James Huang MD 
Steven Solomon, MD 
Radiation Oncology 
Surgery 
Radiology 
Investigator(s)/Department: 
Jamie Chaft, MD 
Alexander Drilon, MD 
Mark Kris, MD 
Paul Paik, MD 
Charles Rudin, MD, PhD 
Stephen Veach, MD 
Marjorie Zauderer, MD 
Matthew Hellmann, MD 
Gregory Riely, MD 
Bob Li, MD 
Robert Daly, MD 
Piro Lito, MD PhD 
Leslie Tyson, NP 
Karen Lee, NP 
Linda Ahn, NP 
Elizabeth Panora, NP 
Alison Massey, NP 
Maureen Kennedy, RN 
Afsheen Iqbal, MD 
Han Xiao, MD 
Sree Chalasani, MD 
Leticia Smith, APN 
Janet Cogswell, CRN 
John Fiore, MD 
Juliana Eng, MD 
Jahan Aghalar, MD 
Avni Desai, MD 
Stuart Lichtman, MD 
Jia Li, MD 
Wanqing Iris Zhi, MD PhD 
Lori Gofter, CRN 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Nurisng 
Nursing 
Nursing 
Nursing 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Medicine 
Medicine 
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Medicine 
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Nursing 


Memorial Sloan Kettering Cancer Center 
IRB #: 15-067 A(8) 
Approved: 19-APR-2017 
Page  2 of 33 
 
 
 
 
Kenneth Ng, MD Aryln 
Apollo, MD Pamela 
Drullinsky, MD Zoe 
Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Erin Scansarole, CRN 
Krysti Corrado, CRN 
 
Alice Zervoudakis, MD 
Parisa Momtaz, MD 
Daniel McFarland, DO 
Gloria Wasilewski, CRN 
 
Jason Konner, MD 
Serena Wong, MD 
Jacqueline Bromberg, MD PhD 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Loren Michel, MD 
Marina Shcherba, DO 
Kaitlin Woo, MS 
Viviane Tabar, MD 
Peter Kingham MD 
Vivian Strong MD 
Prasad Adusumilli, MD 
Manjit Bains, MD 
Robert Downey, MD 
David Jones, MD 
Bernard Park, MD 
Valerie Rusch, MD 
Matt Bott, MD 
Daniela Molena, MD 
James Huang, MD 
Matthew Bott, MD 
James Isbell, MD 
 
Andreas Rimner, MD 
Timothy Chan, MD PhD 
Kathryn Beal, MD 
Yoshiya Yamada, MD 
Sean McBride, MD 
Adam Schmitt, MD 
Medicine 
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Medicine 
Nursing 
Nursing 
 
Medicine 
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Medicine 
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Biostatistics 
Neurosurgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
Surgery 
 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Onoclogy 


Memorial Sloan Kettering Cancer Center 
IRB #: 15-067 A(8) 
Approved: 19-APR-2017 
Page  3 of 33 
 
 
 
Karen Borofsky, MD 
Karen Schupak, MD 
Preeti Parhar, MD 
Melissa Zinovoy, MD 
Daphna Gelblum, MD 
Marsha Reyngold, MD PhD 
Jillian Tsai, MD PhD 
Richard Gewanter, MD 
Pinaki Dutta, MD PhD 
Borys Mychalczak, MD 
Boris Mueller, MD 
Annemarie Sheperd, MD 
Carla Hajj, MD 
John Cuaron, MD 
James Lee, MD 
Lior Braunstein, MD 
Nancy Lee, MD 
Beryl McCormick, MD 
Sara Hayes, MD 
Andrew Plodkowski, MD 
Etay Ziv, MD 
Joseph Erinjeri, MD, PhD 
William Alago, Jr., MD 
Marc Ladanyi MD 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiology 
Radiology 
Radiology 
Radiology 
Radiology 
Pathology 
Consenting Professional(s)/Department: Helena Yu, MD 
Jamie Chaft, MD 
Alexander Drilon, MD 
Mark Kris, MD 
Paul Paik, MD 
Charles Rudin, MD, PhD 
Stephen Veach, MD 
Marjorie Zauderer, MD 
Matthew Hellmann, MD 
Gregory Riely, MD 
Bob Li, MD 
Robert Daly, MD 
Piro Lito, MD PhD 
Han Xiao, MD 
Afsheen Iqbal, MD 
Sree Chalasani, MD 
Medicine 
Medicine 
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Medicine 
Medicine 
Medicine 
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Memorial Sloan Kettering Cancer Center 
IRB #: 15-067 A(8) 
Approved: 19-APR-2017 
Page  4 of 33 
 
 
 
John Fiore, MD 
Juliana Eng, MD 
Jahan Aghalar, MD 
Avni Desai, MD 
Juliana Eng, MD 
Stuart Lichtman, MD 
Wanqing Iris Zhi, MD PhD 
 
Kenneth Ng, MD Arlyn 
Apollo, MD Pamela 
Drullinsky, MD Zoe 
Goldberg, MD 
Tiffany Troso-Sandoval, MD 
 
Parisa Momtaz, MD 
Daniel McFarland, DO 
Alice Zervoudakis, MD 
 
Jason Konner, MD 
Serena Wong, MD 
Jacqueline Bromberg, MD PhD 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Loren Michel, MD 
Marina Shcherba, DO 
 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
 
Medicine 
Medicine 
Medicine 
 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
OneMSK Sites 
Manhattan 
Monmouth 
Westchester 
Basking Ridge 
Rockville Centre 
Commack 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB #: 15-067 A(8) 
Approved: 19-AP R-2017 
Page  5 of 33 
 
 
Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 6 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 7 
 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 8 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION.......................................................... 11 
 
4.1 
Design........................................................................................................................... 11 
 
4.2 
Intervention ................................................................................................................... 11 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ......................................................................... 11 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ......................................................................... 13 
 
6.1 
Subject Inclusion Criteria............................................................................................... 13 
 
6.2 
Subject Exclusion Criteria ............................................................................................. 14 
 
7.0 
RECRUITMENT PLAN ..................................................................................................... 14 
 
8.0 
PRETREATMENT EVALUATION .................................................................................... 15 
 
9.0 
TREATMENT/INTERVENTION PLAN.............................................................................. 15 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ................................................. 17 
 
11.0 TOXICITIES/SIDE EFFECTS ........................................................................................... 18 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..................... 22 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ..................................................................... 23 
 
14.0 BIOSTATISTICS .............................................................................................................. 24 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES25 
 
15.1 Research Participant Registration ................................................................................. 25 
 
15.2 Randomization .............................................................................................................. 25 
 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 25 
 
16.1 Quality Assurance ......................................................................................................... 25 
 
16.2 Data and Safety Monitoring ........................................................................................... 26 
 
17.0 PROTECTION OF HUMAN SUBJECTS .......................................................................... 26 
 
17.1 Privacy .......................................................................................................................... 28 
 
17.2 Serious Adverse Event (SAE) Reporting ....................................................................... 28 
 
17.2.1 ................................................................................................................................... 29 
 
18.0 INFORMED CONSENT PROCEDURES .......................................................................... 29 
 
19.0 REFERENCES ................................................................................................................. 30 
 
20.0 APPENDICES .................................................................................................................. 33 


Memorial Sloan Kettering Cancer Center 
IRB #: 15-067 A(8) 
Approved: 19-AP R-2017 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Title: 
Local Therapies for Oligometastatic Non-Small Cell Lung Cancer 
(NSCLC) harboring Sensitizing EGFR Mutations 
Objectives: 
Primary objective: 
 
To assess the safety and tolerability of local treatment of 
oligometastatic disease combined with tyrosine kinase 
inhibitor (TKI) therapy 

 
To determine the feasibility of accruing eligible patients to 
undergo the proposed treatment plan 
 
To collect preliminary data on the efficacy of the proposed 
treatment strategy: 
o Time to progression 
o Time to death 
o Local control at site of local therapy 
o Time on EGFR TKI before a new systemic therapy is 
required 
Correlative objectives: 
 
To compare the molecular alterations in the primary lung 
versus metastatic sites by performing next-generation 
sequencing (IMPACT) on archived pre-treatment and 
resected specimens. 
 
To evaluate cell free plasma DNA (cfDNA) as a tumor 
biomarker for recurrent disease. 
Patient Population: 
Patients with newly diagnosed, untreated stage IV oligometastatic 
(≤5 lesions of disease) lung adenocarcinomas harboring sensitizing 
EGFR mutations: 
 
all sites of disease (including CNS) must be amenable to 
definitive treatment with a local therapy (as per surgery, 
interventional radiology and radiation oncology) 
 
all hilar and mediastinal nodal disease to be considered as 
part of the primary disease and not a metastatic site 
Design: 
Single-arm, prospective trial:  5 patients will be enrolled at our 
institution to demonstrate feasibility of both enrolling patients and 
having them complete all local therapies in a 2 year time frame. 
Treatment Plan: 
Patients will be placed on EGFR-TKI for their metastatic EGFR- 
mutant stage IV oligometastatic disease.  All patients will undergo 
induction TKI for 12 weeks.  At the conclusion of 12 weeks on 
erlotinib, patients without disease progression [partial response 
(PR) or stable disease (SD)] will undergo definitive local treatment 
to all remaining sites of disease.  After local therapy, erlotinib will be 
resumed until progression of disease (POD) by RECIST criteria. 


Memorial Sloan Kettering Cancer Center 
IRB #: 15-067 A(8) 
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Patients who achieve a complete response (CR) at a site of 
disease, will have the option to forgo local therapy at that site and 
just continue EGFR TKI. Patients with progressive disease after 12 
weeks of erlotinib will be taken off study. 
 
Definitive local therapies include surgical resection, 
stereotactic radiosurgery, ablation and conventional 
radiation therapy 
 
After induction TKI (12 weeks), local therapies will be 
completed sequentially. The expectation is that all local 
therapies will be completed within 8 months of patient 
enrollment. 
 
The treating MD will confirm if the patients TKI should be 
held for 2 days before and restarted within 14 days after 
each local therapy and otherwise continued. If the treating 
MD feels that it will be ok for the patient to continue 
erlotinib during local treatment, this will be allowed per 
protocol. 
 
If initially symptomatic, a patient may receive a definitive 
local therapy prior to completion of induction TKI at the 
discretion of the treating physician. 
 
Patients who have POD at any time will be taken off study 
and continue conventional systemic treatment and/or local 
therapies for palliative purposes as per their primary 
medical oncologist. 
Number of Patients: 5 patients for feasibility 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1 Primary objective: 
 
 
This is a single-arm, single institution trial evaluating a multimodality treatment plan 
consisting of local therapies and continued erlotinib in patients with stage IV oligometastatic 
lung adenocarcinoma harboring sensitizing EGFR mutations 
 
To assess the safety and tolerability of local treatment of oligometastatic disease combined 
with TKI therapy 
 
To determine the feasibility of accruing eligible patients to undergo the proposed treatment 
plan 
 
To collect preliminary data on the efficacy of the proposed treatment strategy: 
o Time to progression 
o Time to death 
o Local control at site of local therapy 
o Time on EGFR TKI before a new systemic therapy is required 


Memorial Sloan Kettering Cancer Center 
IRB #: 15-067 A(8) 
Approved: 19-AP R-2017 
Page  8 of 33 
 
 
2.3 Correlative objectives: 
 
Correlative objectives: 
 
 
To compare the molecular alterations in the primary lung versus metastatic sites by 
performing next-generation sequencing (IMPACT) on archived pre-treatment and resected 
specimens. 
 
To evaluate cell free plasma DNA (cfDNA) as a tumor biomarker for recurrent disease. 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
Lung Cancer 
Lung cancer is the most common cancer worldwide, and in the United States, there 
will be an estimated 224,000 new cases of lung cancer and 159,000 deaths in 2014.1   Half of 
all patients with stage IB – IIIA non-small-cell lung cancers (NSCLCs) who undergo curative 
therapy with surgery and peri-operative chemotherapy die within five years of their initial 
diagnosis.2   The majority of patients with NSCLC present with metastatic (stage IV) disease. 
The 5-year survival rate for patients with stage IV NSCLC is <5%.  However, a subset of 
patients with stage IV NSCLC present with oligometastatic disease, and appear to have a 
more favorable prognosis. 
 
Local Therapies in Oligometastatic Disease 
The limited extent of metastases in the oligometastatic state raises the possibility of 
definitively treating all site of disease. Oligometastatic disease may represent a separate 
intermediate disease state where cancers have gained additional genetic alterations that 
result in metastasis, but have not yet acquired the capability for widespread metastases. 
Local therapies such as radiation, radiofrequency ablation, and metastatectomy are routinely 
performed in other cancers such as renal cell carcinoma, sarcoma, and colorectal cancer for 
oligometastatic disease with excellent disease free survival in a subset of cases. 
Oligometastatic disease is typically defined as fewer than 5 discrete sites of disease3-5 
although this can vary with different tumor types. The goal of treating oligometastatic 
disease with local therapies is to render the patient free of disease if the primary tumor is 
otherwise controlled. 
 
Local Therapies in Oligometastatic Lung Cancer 
While local therapies in metastatic lung cancer are typically reserved for palliative 
purposes, some studies suggest patients with oligometastatic disease treated with local 
therapies might have improved outcomes.6-9   Patients who undergo surgical resection and/or 
radiation therapy of a solitary brain metastasis have a median survival of approximately 40 
weeks10, and the 5-year survival rates range from 10-20%.11   Follow-up whole brain radiation 
and/or SRS12-1415,16 are additional treatment options.  In patients undergoing resection of 
brain metastases from NSCLC, complete resection of the primary lung disease prolongs 
survival.11   Local treatment for brain metastases is currently considered standard of care.  In 
patients with an isolated adrenal metastasis (up to 33% patients) and an otherwise curable 
lung cancer, local therapy of the adrenal lesion can result in long-term survival in up to 25% 
patients.17-19. There is some thought that ipisilateral adrenal metastases actually represent 
locoregional spread though retroperitoneal lymphatic channels.  Guidelines now recommend 
that in patients with a distant metastasis in a solitary site, such as a brain or adrenal lesion, 
metastastectomy should be considered in addition to systemic therapy20 


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IRB #: 15-067 A(8) 
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A recent study by Parikh and colleagues prospectively enrolled 186 patients with 
oligometastatic non-small cell lung cancer, defined as 5 or fewer distant metastatic lesions at 
diagnosis, and evaluated patient and disease characteristics associated with improved 
survival.  The number of metastatic lesions and radiologic size of the primary tumor were not 
associated with overall survival.  Eastern Cooperate Oncology Group performance status ≥2 
(hazard ratio [HR] 2.43), nodal status N2-3 (HR 2.16), squamous pathology, and metastases 
to multiple organs (HR 2.11) were associated with a greater hazard of death (all P<0.01). 
Importantly, patients who received aggressive local treatment to either the primary tumor 
only (HR 0.64; 95%CI 0.33-1.24; P=0.19) or to both primary tumor and metastatic sites (HR 
0.59; 95%CI 0.37-0.95; P=0.03) had improved survival (19 months [95%CI 13-34 months] vs 
16 months [95%CI 13-19 months]) compared to patients who received either aggressive 
treatment to the metastatic sites only or no aggressive treatment.21 
 
Rationale for Local Therapies in EGFR-mutant Metastatic Lung Cancer 
Sensitizing EGFR mutations are found in approximately 10% of Caucasian patients 
with NSCLC and up to 50% Asian patients. The majority of patients with tumors harboring 
sensitizing EGFR mutations will respond to EGFR TKIs (>70% response rate) with a median 
progression-free survival of 12 months.22-27   Patients with EGFR-mutant lung cancer have a 
unique biology and are clinically characterized not only by improved outcomes with EGFR- 
TKIs, but also by better results from chemotherapy and surgery compared to their EGFR- 
wild-type counterparts.22,28   Prospective studies evaluating EGFR TKIs, including gefitinib, 
erlotinib, and afatinib, all show a superior radiographic response rate and progression-free 
survival with TKI compared to standard cytotoxic chemotherapy.22-26   Even with the 
development of acquired resistance to TKIs, patients with EGFR-mutant lung cancers have a 
median survival of 16 months29 compared to 12 months from initial diagnosis of stage IV 
disease in unselected patients.30 
One of the favorable prognostic factors generally used in the selection of patients for 
metastasectomy includes prolonged progression-free survival, representing patients with 
slower growing disease.31-33   Given their relatively indolent clinical course, patients harboring 
sensitizing EGFR mutations are more likely to benefit from local treatment for oligometastatic 
disease sites and thus present a unique opportunity to achieve increased long-term survival. 
Not only do EGFR-mutated patients have a superior prognosis with longer overall survival, 
but 60% of patients with metastatic EGFR-mutated NSCLC treated with EGFR-TKIs first 
develop disease progression in their initial sites of disease, lending credence to the concept 
that upfront local therapy to all sites may prolong progression-free survival. (unpublished 
data). 
In a published report, we identified 18 patients who received elective non-central 
nervous system local therapy (surgical resection, radiofrequency ablation, or radiation), in 
conjunction with continued EGFR-TKIs.34   Local therapy was well tolerated with 85% of 
patients restarting TKI therapy within 1 month. The median time to progression after local 
therapy was 10 months (95%CI 2-27 months), and medial overall survival from local therapy 
was 41 months (95%CI 26-not reached). The median time until a subsequent change in 
systemic therapy was 22 months (95%CI 6-30 months). 
Another retrospective analysis by Weickhardt and colleagues described 25 patients, 
with either an EGFR mutation or an ALK rearrangement, who received a local therapy 
(stereotactic body radiation therapy in most cases) to oligoprogressive metastases after 
targeted therapy.  After local therapy, the median progression-free survival was 6.2 months 
with 19 of 25 patients progressing again.35 


Memorial Sloan Kettering Cancer Center 
IRB #: 15-067 A(8) 
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Page  10 of 33 
 
 
These remarkable outcomes are likely a reflection of a multitude of factors including 
the natural history of this patient population, continued benefits of TKI therapy even after 
progression, and the potential benefits of local therapy.  Prospective evaluation of local 
therapy as part of a standard treatment paradigm is warranted to better define the patient 
population and treatment parameters that could result in improved outcomes, possibly even 
prolonged disease-free survival. 
For locally advanced disease we often give induction chemotherapy prior to surgical 
resection for a number of reasons including 1) easier tolerability 2) to eliminate 
micrometastatic disease 3) to achieve a pathologic response and 4) to improve surgical 
outcomes. This approach has led to an improved median disease-free survival (27 vs 13 
months) and median overall survival (37 vs 26 months) compared to surgery alone.36   We 
hope to apply this concept to patients with EGFR-mutant oligometastatic stage IV disease 
using TKI therapy as induction therapy to improve survival outcomes. 
 
Correlative Studies 
 
Intratumor heterogeneity 
Large-scale sequencing platforms have revealed extensive genetic heterogeneity 
between individual tumors that can contribute to treatment failure and drug resistance. 
Specifically, studies comparing mutational profiles of primary tumors and associated 
metastatic lesions or local recurrences have provided evidence of intratumor 
heterogeneity.37-40   Intratumor heterogeneity within primary tumors and associated metastatic 
sites has not been systematically characterized by next-generation sequencing in lung 
cancer. 
This study affords an opportunity to investigate intratumor heterogeneity by 
comparing mutation profiles on matched primary and metastatic resected tissue specimens. 
We will use a next generation sequencing based genotyping assay (MSK IMPACT) that 
performs massively parallel sequencing of all exons corresponding to 341 cancer genes. 
The sequencing data will be analyzed for base mutations, insertions, deletions, copy number 
alterations and genomic rearrangements in all target genes. 
 
Cell-free plasma DNA as a biomarker for recurrence 
Studies suggest that highly sensitive genotyping assays can detect mutations in cell- 
free plasma DNA (cfDNA) from patients with cancer, potentially providing a non-invasive 
method to identify and track intratumoral genetic alterations. 
 
Several studies have demonstrated a prognostic value of the total level of tumor 
cfDNA, with high levels being associated with shorter survival.41,42   Quantitative changes in 
tumor cfDNA during a patient’s treatment course may be used as a marker to monitor 
response to therapy.43   Quantification of cfDNA could be used as a tumor marker that tracks 
with response to therapy, but also as a biomarker whose presence could predict recurrent 
disease prior to radiographic or clinical recurrence. To investigate this, we will obtain serial 
assessments of cfDNA during routine venipunctures as per protocol to capture changes in 
cfDNA during treatment. 


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4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This is a single-arm, single institution trial evaluating a treatment plan consisting of local 
therapies and continued erlotinib in patients with stage IV oligometastatic lung 
adenocarcinoma harboring sensitizing EGFR mutations.  At least five patients will be enrolled 
at our institution to demonstrate feasibility  of accrual and successful completion of treatment 
over a 2 year time period. After demonstrating feasibility of this approach, a multicenter 
efficacy study will be planned. Patients will be enrolled at the start of TKI for their untreated 
EGFR-mutant stage IV oligometastatic disease. All patients will receive “induction” TKI for 
12 weeks.  Patients who respond (PR/SD) will undergo definitive local treatment to all 
remaining measurable sites of disease.  After local therapy, TKI will be resumed until 
progression of disease (POD) by RECIST criteria.  Patients who achieve a complete 
response (CR) will not be mandated to have local therapy performed, and TKI will be 
continued. Patients with progressive disease during these 12 weeks such that complete local 
therapy is no longer possible will be removed from the study. 
 
The start of the timeline of prtocol assessments begins when the patient starts erlotinib, 
regardless if that was before or after registration on the study. Patients would be required to 
follow the schedule of assessments from the timepoint at which they were registered on 
study. Retroactive pill compliance will not ned to be completed for these patients. Patient 
dosing compliance will only be required once the patient is registered to the protocol. 
 
4.2 
Intervention 
 
All patients will receive erlotinib 150mg daily as induction therapy, with dose reductions 
allowed based on patient’s symptoms. If patients have a PR or SD, definitive local therapies 
will be performed on all remaining measurable sites of disease.  Definitive local therapies 
include surgical resection, stereotactic radiosurgery, radiofrequency ablation and 
conventional radiation therapy and will be determined by respective departments (surgery, 
interventional radiology and radiation oncology). Specifically, whole brain radiation therapy 
(WBRT)  and hepatic artery embolization will not be included as definitive local treatment 
options.  Per the discretion of the treating MD, a patients erlotinib may be held for 2 days 
before and up to 14 days after each local treatment, but otherwise will be continued for the 
duration of the trial until progression of disease. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 
Erlotinib 
 
Commercially available erlotinib will be obtained. All tablets are round, white, film-coated and 
bi-convex with no imprint. Erlotinib should be stored at room temperature, not above 25°C 
(77°F). Additional information regarding erlotinib can be found in the Tarveva® Package 
Insert. 


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5.2 
Surgery 
 
Resectability of the primary lung lesion will be assessed by a thoracic surgeon, and resection 
of metastases will be evaluated by the appropriate surgical service, i.e. neurosurgery for 
CNS lesions, surgical oncology for adrenal lesions, thoracic surgery for lung or intrathoracic 
lesions, etc.  A complete resection should be deemed achievable in order to consider 
surgical resection of a site of disease, and the appropriate extent of resection (anatomic, 
limited resection, etc.) will be at the discretion of the surgeon, so long as ideally an R0 
resection of the lesion can be obtained (with the exception of bone, where an R0 resection is 
difficult to confirm).  Either minimally invasive or open approaches may be utilized at the 
discretion of the surgeon.  Resection of the lung primary should entail an anatomic resection 
if possible. 
 
5.3 
Radiation Therapy 
 
The optimal radiotherapeutic dose and technique will be determined by the radiation 
oncologist. Stereotactic body radiation therapy (SBRT) is the preferred technique wherever 
technically feasible. However, conventionally fractionated radiation therapy will also be 
acceptable for lesions or sites deemed suboptimal for SBRT. The minimum biologically 
effective dose (BED) to all sites treated with RT is 48Gy10. 
 
5.3.1 SBRT 
 
In general, SBRT should be recommended, prescribed and delivered according to prevailing 
institutional standards for that anatomic site. In the lung, SBRT should be utilized if there is 
no evidence of intrathoracic nodal metastasis. Preferred regimens include 50Gy in five 
fractions, 48Gy in four fractions, or 54Gy in three fractions, in order to achieve a BED of at 
least 100Gy10, but lower-BED regimens may be chosen in cases of large tumor volume or 
proximity to critical structures such as the esophagus. 
 
Brain metastases must be amenable to treatment with stereotactic radiosurgery (SRS) or to 
hypofractionated stereotactic radiotherapy. For SRS, treatment regimens will typically entail a 
dose of 16-22Gy in a single fraction. For tumors too large for SRS, hypofractionated 
stereotactic radiotherapy to a dose of 30Gy in 5 fractions is acceptable. 
 
For other disease sites, recommended SBRT regimens include 50Gy in five fractions 
(particularly for liver metastases), 24Gy in one fraction (primarily for bony metastases), and 
27Gy in 3 fractions. The minimum acceptable SBRT regimen is 30Gy in 5 fractions, 
corresponding to a BED of 48Gy10. 
 
With the exception of brain SRS which may be performed using a frame-based approach, all 
SBRT should be performed with on-board CT guidance at the time of each fraction. Where 
appropriate, motion management techniques should be applied as per prevailing institutional 
standards of care. Normal tissue constraints as per current institutional guidelines should be 
respected. 


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5.3.2 Conventionally fractionated radiotherapy 
 
Where SBRT is not deemed feasible due to the size or anatomic location, conventionally 
fractionated radiotherapy is acceptable. The recommended regimen is 45Gy in 15 fractions, 
with 40Gy in 10 fractions as an acceptable alternative. 30Gy in 10 fractions would not be 
acceptable, since this is not considered a definitive treatment dose and the BED of this 
regimen is <48Gy10. 3D-conformal radiation techniques, or intensity-modulated radiation 
therapy (IMRT) should be utilized, with the potential exception of small bony metastases in 
the extremities where no significant advantage from conformal techniques would be 
expected. In general, the PTV should be a minimum of a 1.0cm expansion from the GTV, 
with additional expansions to account for respiratory motion where appropriate. 
 
5.4 Radiofrequency ablation 
 
The optimal ablative therapy will be determined by the Interventional Radiologist.  A safe 
approach will be determined with the expectancy of completely (A0) ablating the targeted 
tumor. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
 
Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring 
sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 
insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of 
location, inclusive of the primary lesion): 
 
all sites of disease must be amenable to definitive treatment with a local therapy 
(surgical resection, stereotactic radiosurgery, ablation and conventional radiation 
therapy) as determined by  surgery, interventional radiology and radiation oncology 
 
all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal 
disease) are considered 1 discrete lesion. 
 
Each brain metastasis is included as a distinct lesion. 
 
Patients already started on erlotinib are eligible as long as their sites of disease are 
determined to be eligible for definitive local therapy by consensus of the principal 
investigators within 12 weeks of the patient first taking erlotinib. 
 
Lung adenocarcinoma histology confirmed at MSKCC. 
 
Available archived tissue to perform molecular analysis 
 
Patients without available archived tissue can have repeat biopsies to determine 
EGFR status as per standard clinical care guidelines 
 
Age 18 years or older 
 
Karnofsky Performance Status ≥ 70% 
 
Adequate bone marrow, liver and renal function, as specified below: 
 
Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L 
 
Hemoglobin ≥ 8 g/dL 
 
Platelets ≥ 100 x 109/L 
 
Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except for patients with 
documented Gilbert’s Syndrome) 


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 
AST and ALT ≤ 2.5 x ULN or ≤ 5 x ULN  if liver metastases are present 
 
Serum creatinine ≤ 1.5 x upper limit of normal or creatinine clearance ≥ 60ml/min for 
patients with creatinine levels above institutional normal. 
 
For women of child-bearing potential, negative pregnancy test within 14 days prior to 
starting treatment 
 
Men and women of childbearing age must be willing to use effective contraception while 
on treatment and for at least 3 months thereafter 
 
 
 
6.2 
Subject Exclusion Criteria 
 
 
Treatment with erlotinib prior to developing metastatic disease 
 
Patients with activating but not sensitizing mutations (exon 20 insertions, EGFR T790M) 
 
Malignant pleural effusion or pleural disease 
 
Leptomeningeal disease 
 
Any site of disease that is not amenable to definitively local therapy including surgery or 
radiation therapy 
 
Women who are breastfeeding or pregnant 
 
Concurrent malignancies other than non-melanoma skin cancer that require active 
ongoing treatment. 
 
Any medical co-morbidities that would preclude surgery or radiation therapy 
 
 
7.0 
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 of the diagnosis of advanced, oligometastatic NSCLC and confirmation of the 
presence of a sensitizing EGFR mutation within the patient’s tumor.  Potential subjects that meet 
these basic criteria will be referred by their treating physician to the investigator/research staff of the 
study. Minorities and women are well represented in the thoracic oncology clinics, and we expect 
that they will well represented in the trial accrual. The principal investigator, Helena Yu, MD , will be 
available to all patients for further questions and information through a contact number which will be 
provided on the consent form itself. 
 
During the initial conversation between the investigator/research staff and the patient, the patient 
may be asked to provide certain health information that is necessary to the recruitment and 
enrollment process. The investigator/research staff may also review portions of their medical records 
at MSKCC in order to further assess eligibility. They will use the information provided by the patient 
and/or medical record to confirm that the patient is eligible and to contact the patient regarding study 
enrollment. If the patient turns out to be ineligible for the research study, the research staff will 
destroy all information collected on the patients during the initial conversation and medical records 
review, except for any information that must be maintained for screening log purposes or processes, 
for example advertisements, payments to participants, reimbursement plans, etc. 


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8.0 
PRETREATMENT EVALUATION 
 
All aspects of the screening evaluation should be completed within four weeks of starting treatment 
unless otherwise noted. 
 
 
Documented presence of lung adenocarcinoma harboring a sensitizing EGFR mutation 
(L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) within the patient’s 
tumor. This may be done at any time prior to starting treatment. 
 
Medical history 
 
Baseline tumor assessment with PET/CT and Brain MRI (or CT head with contrast) to assess 
full extent of disease. Other comparable radiologic studies (MRI) can be used as medically 
appropriate. Radiographic assessments will be done by RECIST 1.1. 
 
Physical examination, complete vital signs (pulse, blood pressure, temperature, respiratory 
rate) as well as weight and height.  Height may be documented at any time prior to starting 
treatment. 
 
12-lead electrocardiogram (ECG) within 3 months prior to starting treatment 
 
Performance status by KPS or ECOG 
 
Serum pregnancy test 
 
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) 
 
Surgical, Interventional Radiology and/or Radiation Oncology consult to confirm all disease 
sites can be treated definitively with a local therapy (surgery or radiation therapy).  Patients 
can be enrolled and started on erlotinib prior to being seen by surgical and/or radiation 
oncology consults. The entire team will discuss each case to review the most appropriate 
local therapies, and the patient will be seen by the necessary services. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
This is a single-arm trial evaluating the feasibility of enrollment and successful completion of a 
treatment plan consisting of local therapies and continued TKI in patients with stage IV 
oligometastatic lung adenocarcinoma harboring sensitizing EGFR mutations.  Patients will be 
enrolled at the start of erlotinib for their untreated EGFR-mutant stage IV oligometastatic 
disease. All patients will start with “induction” erlotinib for 12 weeks. If patients have already 
started erlotinib, they are still eligible for this protocol as long as they can articulate a clear 
erlotinib start date, have baseline scans to review and enrollment and consultations by 
surgical oncology and/or radiation oncology are completed within 12 weeks of the patient first 
taking erlotinib. The start of the timeline of protocol assessments begins when the patient 
starts erlotinib, regardless if that was before or after registration on the study. Patients would 
be required to follow the schedule of assessments from the timepoint at which they were 
registered on the study.  Patients who respond (PR/SD) will undergo definitive local 
treatment to all remaining sites of disease with the goal of rendering the patient free of 
disease. Patients who achieve a complete response (CR) can continue TKI without any local 


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therapy. Patients with progression of disease and are no longer candidates for local 
therapies will be taken off study. Erlotinib will be resumed after local therapies until 
progression of disease (POD) by RECIST criteria. 
 
 
 
 
Definitive local therapies include surgical resection, stereotactic radiosurgery, ablation 
and conventional radiation therapy 
 
After induction TKI (12 weeks), local therapies will be completed sequentially with the 
expectation that all local therapies will be completed within 8 months of patient 
enrollment. 
 
Per the discretion of the treating MD, a patients erlotinib may be held for 2 days before 
and restarted 2-14 days after each local therapy and otherwise continued in between 
therapies. 
 
No local therapy will be mandated to any original disease site that has completely 
regressed during induction erlotinib. Proceeding with local therapy in this situation is at 
the discretion of the treating physicians. 
 
For symptomatic purposes, a patient may receive a definitive local therapy prior to 
completion of induction erlotinib per treating physician. 
 
Patients who have POD during induction erlotinib will not receive local therapies unless 
otherwise necessary for palliative purposes. 
 
After induction TKI, patients will be monitored for POD and safety/tolerability with repeat 
imaging, physical exam, and laboratory tests every 8 weeks for 1 year.  These evaluations 
must be performed at MSKCC sites to ensure consistency of results and facilitate the 


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Baseline
a
 
Induction 
TKI 
Induction 
TKI 
Induction 
TKI 
Induction 
TKI 
Local 
Therapy 
(surgery 
and/or 
radiation) 
TKI only 
End of 
Study
h
 
W 
1 
W 
2 
W 
3 
W 
4 
W 
5 
W 
6 
W 
7 
W 
8 
W 
9 
W 
10 
W 
11 
W 
12 
W13 to 
W32 
W33 to 
end of 
study 
Erlotinib 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
a 
X 
Exam 
X 
X 
X 
X 
X 
X
e 
X
e 
X 
CBC 
X 
X 
X 
X 
X
e 
X
e 
X 
CMP 
X 
X 
X 
X 
X
e 
X
e 
X 
Pregnancy 
Test 
b
 
X 
PET
i
 
X 
CT 
X
c 
X
c 
X
c,e 
X
c,e 
X
c 
Brain MR or 
CT 
X 
ECG 
X 
Tissue 
analysis 
X 
X 
X 
Research 
Blood 
X 
X 
e 
X 
e 
X 
X 
Local therapy 
Consult and 
Procedures 
X 
X
f 
X
g 
collection of specimens for correlative analyses. After 1 year, the patient will be monitored in 
the same manner every 12 weeks until POD. 
 
In order to better understand feasibility, on a monthly basis, we will obtain a list of all patients 
with positive EGFR mutant test results by routine molecular testing. We will cross reference 
this list with patients that are seen by thoracic medical oncology and identify the subset that 
has stage IV disease. 
 
We will proceed with enrollment without accrual limitations until 5 patients have successfully 
completed all intended local therapies. To be deemed feasible, at least 5 patients will need to 
be enrolled, complete local therapy within two years of the study opening to accrual. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
10.1  Study Calendar 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Erlotinib may be held for 2 days before and up to14 after each local therapy, otherwise continued as 
tolerated in between local therapies 
b Serum pregnancy test is required prior to treatment for women of childbearing potential 
c CT chest and all other areas of disease as clinically indicated including repeat brain MRI/CT with 
contrast if brain metastases, with a +/- 14 day window. 
d Erlotinib may be held for 2 days before and 2-14 after each local therapy, otherwise continued as 
tolerated in between local therapies 
e To be completed every 8 weeks (± 2 weeks) etc until 1 year on study and then every 12 weeks 
thereafter indefinitely until POD 
f Surgical, radiation oncology and radiology procedures will be performed as planned during the 
screening period 
g standard follow up with surgery, radiation oncology and radiolology 


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h End of study visit to be performed within 30 days ± 7 days of treatment discontinuation 
i PET scan to be performed unless contra-indicated, and then a CT or MRI can be performed. 
j Week 1 
 
k All assessments completed during the 12 week TKI induction phase are to be performed per protocol 
with a ± 7 day window. 
 
10.2 Treatment Modifications 
 
For symptomatic purposes, a patient may receive a definitive local therapy prior to 
completion of induction TKI 
 
Erlotinib may be held for longer than 14 days after a local therapy if medically necessary. 
 
 
 
10.3 Correlatives 
 
10.3.1  MSK-IMPACT testing on primary and metastatic tumor specimens 
 
Next-generation sequencing (IMPACT) will be performed on all resected specimens 
to compare the molecular alterations in metastatic sites versus primary lung site. 
 
10.3.2  Cell free plasma DNA as biomarker for recurrent disease 
 
Plasma will be obtained at regular intervals including screening, week 12 of TKI 
induction, every 8 weeks until 1 year on study and then every 12 weeks thereafter. 
Five cc’s of peripheral blood will be drawn at a time of standard of care venipuncture, 
with plasma separated within 5 hours of collection.  Cell free DNA will be extracted 
and frozen at -80C until analyzed.  After samples are obtained, they will be sent to Dr. 
Marc Ladanyi’s laboratory for analysis. 
 
11.0 TOXICITIES/SIDE EFFECTS 
 
Local Therapy: 
 
Patients will be consented separately for each respective local therapy received. 
 
Toxicity grading will be performed in accordance with NCI CTCAE, version 4.0.  For safety and 
adverse event reporting, see section 17.0 
 
Erlotinib: 
 
Toxicities with erlotinib that are likely (>20%) include: 
 
Fatigue 
 
Rash 
 
Diarrhea 
 
Decreased appetite 
 
Nausea/Vomiting 


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Toxicities with erlotinib that are less likely (<20%) include: 
 
Cough 
 
Shortness of breath 
 
Infections 
 
Mouth sores (mucositis) 
 
Abdominal pain 
 
Conjunctivitis (inflammation of the eye) 
 
Gas, heartburn or upset stomach 
 
Hair loss or thinning 
 
Fever 
 
Fingernail/toenail changes and/or irritation of skin around nails 
 
Possible cracking of skin, especially of fingers and toes 
 
Increased body hair growth, or eyelash/eyebrow changes 
 
Dehydration, when you body does not have enough water/fluid as it should, caused by 
diarrhea and/or vomiting 
 
Side effects that are rare, but serious include: 
 
Pneumonitis (inflammation of the lung) 
 
Acute renal failure 
 
Stevens-Johnson syndrome (a severe skin rash) 
 
Liver failure 
 
GI bleeding/perforation (bleeding or a hole that develops in the intestine) 
 
Radiotherapy: 
 
Side effects from radiotherapy vary depending on dose, technique, and anatomic site. In general, 
side effects of radiotherapy that are common (>20%) include: 
 
 
Fatigue 
 
Dermatitis 
 
Decreased appetite 
 
Hair loss (only in the area of the radiation treatment) 
Toxicities from radiotherapy that are less common (<20%) include: 
 
Nausea/vomiting 
 
Diarrhea 
 
Pneumonitis 
 
Esophagitis 
 
Chest wall pain (when undergoing high-dose lung radiotherapy) 
 
Decreased bone density in the radiated area, which may lead to fracture 
 
Cough 
 
Side effects that are rare, but serious depend on the site being treated. These include: 
 
 
Brain: Seizures, radionecrosis, memory or other cognitive impairment 


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 
Lung: Respiratory failure leading to oxygen dependence or ventilator support, hemoptysis 
 
Liver: Liver failure 
 
Spine: Myelopathy 
 
Abdomen/pelvis: Bleeding or perforation of the stomach or intestines 
 
Surgery: 
 
Side effects from surgery vary considerably based on surgical site. Patients will be consented 
separately for any surgical procedure. Side effects or complications depend on site of surgery. 
Common risks and side effects related to surgery in general include: 
 
 
Bleeding 
 
Infection 
 
Postoperative pain 
 
Ablation: 
 
Side effects from ablation vary considerably based on ablation site. There is a risk of injury to nearby 
structures or organs. Other possible side effects include: 
 
 
Bleeding 
 
Infection 
 
Postoperative pain 
 
If an ablation is done in the lung, there is a risk of pneumothorax, or lung collapse. Sometimes a 
chest tube is required to a lung collapse. 


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11.1 Management of Erlotinib Related Toxicities 
 
Erlotinib dose modifications will are to be made according to the criteria outline in Table 11.1 for 
toxicities which are felt to be related to erlotinib. 
 
Table 11.1: Erlotinib Dose Modification Criteria 
 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Non-hematologic, 
general (except for 
what is noted below )* 
Continue at same 
dose level 
Continue at same 
dose level 
Withhold dose until 
toxicity is grade ≤ 1, 
then resume 
treatment at same 
dose level, or dose 
level -1, at the 
discretion of the 
investigator 
Withhold dose until 
toxicity is grade ≤ 1, 
then resume 
treatment at same 
dose level, or dose 
level -1, at the 
discretion of the 
investigator 
Pneumonitis (in the 
absence of other 
causes of pulmonary 
infiltrates/dysfunction) 
Withhold until at 
baseline. Can 
resume treatment at 
same dose at 
discretion of 
investigator. If 
recurs, discontinue 
permanently. 
Withhold until at 
baseline. Can 
resume treatment at 
same dose at 
discretion of 
investigator. If 
recurs, discontinue 
permanently. 
Discontinue 
treatment, do not 
retreat. 
Discontinue 
treatment, do not 
retreat. 
Diarrhea 
Continue at same 
dose level. Initiate 
therapy w ith 
loperamide. 
Continue at same 
dose level. Initiate 
therapy w ith 
loperamide. 
Initiate therapy w ith 
loperamide. 
Withhold until 
toxicity is grade ≤ 2. 
Resume treatment 
at same dose level 
or dose level -1 at 
discretion of 
investigator. 
Initiate therapy w ith 
loperamide. 
Withhold until 
toxicity is grade ≤ 2. 
Resume treatment 
at same dose level 
or dose level -1 at 
discretion of 
investigator. 
Rash 
Continue at same 
dose level. 
Supportive symptom 
management. 
Continue at same 
dose level. 
Supportive symptom 
management. If rash 
persists or w orsens 
over 14 days, 
reduce by 1 dose 
level. 
Reduce by 1 dose 
level. Supportive 
symptom 
management and 
initiate supportive 
symptom 
management. If rash 
persists of w orsens 
over 14 days, 
interrupt erlotinib 
until resolution to ≤ 
grade 2, and resume 
dose level -1 or -2 at 
discretion of 
investigator. 
Withhold until 
toxicity is grade ≤ 2. 
Initiate supportive 
symptom 
management. 
Discontinue 
permanently or 
restart at dose level 
-2 at discretion of 
investigator. 


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11.2 Anti-diarrheal Therapies 
 
Antidiarrheal medications may be introduced if symptoms occur. Previous erlotinib studies 
have shown that the frequency and severity of diarrhea rarely hindered administration of 
erlotinib and could be managed with loperamide. The recommended dose of loperamide is 
4mg at first onset, followed by 2mg every 2-4 hours until diarrhea-free for 12 hours. 
 
11.3 Anti-rash Therapies 
 
Rash or dermatosis can occur within the first several days of treatment with erlotinib in many 
patients and has been noted to diminish in severity despite continued treatment. Patients 
should be informed that skin toxicity is expected during treatment with erlotinib. Skin toxicity 
can take the form of dry skin, rash, acneiform eruption, and hair and nail changes. 
Prophylactic treatment of the skin may prevent or reduce skin toxicity. Patients will be 
encouraged to use an alcohol-free emollient cream or ointment to moisturize dry areas of the 
body twice a day after therapy with erlotinib is initiated. Patients will also be encouraged to 
use a titanium dioxide or zinc oxide based sunscreen product on sun exposed areas daily. 
Patients with any 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 interrupted, dose reduced or 
discontinued. 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1  Radiographic Response by RECIST 
 
A PET-CT and brain MRI or head CT with contrast will be performed at baseline to 
demonstrate all known areas of measurable disease. The baseline study will occur no more 
than 4 weeks prior to erlotinib administration. An alternative imaging test, including MRI or 
CT, can be used in patients with contraindications to the radiographic contrast media used.. 
All patients must have ≤ 5  discrete lesions of disease. 
 
Tumor response will be assessed using RECIST 1.1. The same method (CT scan 
recommended) and the same technique (i.e. with or without contrast) should be used to 
characterize each identified and reported lesion at baseline and serially as per protocol. If an 
appropriate imaging study is done early for any reason (i.e. hospitalization), it can be used 
for disease assessment. A designated radiologist/physician will be responsible for 
interpretation of the study imaging according to RECIST 1.1. 
 
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. Definitions of response in target and non-target lesions are described in Table 12.1 
and 12.2 below. Table 12.3 provides overall responses for all possible combinations of tumor 
responses in target and nontarget lesions. 


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Table 12.1: Evaluation of target lesions 
Complete Reponse (CR): 
Disappearance of all target lesions 
Partial response (PR) 
At least a 30% decrease in the sum of the diameters 
of the target lesions 
Progressive disease (PD): 
At least a 20% increase in the sum of the diameter of 
the target lesions or the appearance of one or more 
new  lesions 
Stable disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD 
 
 
Table 12.2: Evaluation of non-target lesions 
Complete Reponse (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  lesion and/or 
unequivocal progression of existing non-target lesion 
 
 
Table 12.3: Combinations of responses 
Target lesions 
Nontarget 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 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
Patients may withdraw from the study at any time. All patients who receive at least one dose of 
treatment with erlotinib will be evaluable for toxicity and outcomes. Patients who discontinue early 
should return within 30 days of the last dose of the study drugs for a follow up evaluation. Any 
assessments listed for the final visit as per the study calendar will be performed at that time. 
 
Patients will be withdrawn from the study therapy should they experience any of the following: 
 
Intolerable or persistent grade 3 or 4 toxicities with erlotinib 
 
Disease progression (defined by RECIST 1.1) to an extent that makes local therapy 
impossible per the respective treating physician.  Pathological confirmation is not required 
unless clinically indicated. 
 
Other reasons for study discontinuation include, but are not limited to: 
 
Change in patient eligibility 
 
Clinical deterioration or non-compliance with the defined treatment plan leading to inability to 
complete all local therapies or continue erlotinib 
 
Protocol violation 
 
Investigator’s decision based on patient’s best interest 
 
Withdrawal of consent 
 
Lost to follow-up 
 
Death 


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14.0 
BIOSTATISTICS 
 
14.1 Primary Objective 
 
The primary objective of this study will be to determine the feasibility of accrual and completion of 
the proposed treatment strategy of induction EGFR-directed tyrosine kinase inhibitor therapy 
followed by local therapies in a 2 year time frame in patients newly diagnosed with oligometastatic 
lung cancer. The treatment strategy will be deemed feasible if at least five patients are enrolled, 
respond to induction TKI therapy, and successfully complete all protocol-directed local therapy within 
2 years. At least five patients will need to complete local therapy within 2 years of the study being 
open to accrual for the primary endpoint to be met. We are choosing to initially perform a small 
feasibility study to ensure that we will be able to identify sufficient eligible subjects to proceed with 
further investigation of this study concept. We will proceed with enrollment without accrual limitations 
until 5 patients have successfully completed all intended local therapies. We will assess accrual after 
the study is open for 2 years. We will be noting the number of patients enrolled that are needed in 
order to have 5 patients successfully complete local therapy within the 2 year time. 
 
 
 
14.2 Secondary Objective 
 
We will collect information on the following efficacy measures and report them at the patient 
level 
 
- 
time to progression following enrollment 
- 
time to progression following completion of local therapy 
- 
time to death 
- 
local control at site of local therapy 
- 
time on TKI before a new systemic therapy is required 
 
Safety and Tolerability 
 
Toxicity grading will be performed in accordance with NCI CTCAE, version 4.0 during every 
clinical visit as per protocol.  Adverse events will be reported at the patient level. 
 
14.3 Correlative Objective 
 
The objectives below are exploratory in nature. We will perform the following statistical 
analyses, understanding that they are hypothesis-generating only. 
 
MSK-IMPACT testing on primary and metastatic tumor specimens 
 
MSK IMPACT testing will be performed on matched metastatic tumors and primary 
lung tumors. The molecular aberrations detected will be compared in a descriptive fashion. 
 
Cell free plasma DNA as biomarker for recurrent disease 
 
cfDNA will be measured during patients’ treatment course and plotted over time, both 
individually and as summary statistics (median, range). 


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15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
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. 
 
15.2 
Randomization 
 
This is a single-arm, non-randomized study. 
 
16.0 
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. 
 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals 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 problems 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 per year, more frequently if indicated. 


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16.2 
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://www.cancer.gov/clinicaltrials/patientsafety/dsm-guidelines/page1 
 
 
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://smskpsps9/dept/ocr/OCR%20Website%20Documents/Clinical%20Research%20Qualit 
y%20Assurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Plan.p 
df 
 
 
There are several different mechanisms by which 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 Data and Safety Monitoring Committee (DSMC) reports 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 or risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industry sponsored, NCI cooperative group, etc.) will be addressed and 
the monitoring procedures will be established at the time of protocol activation. 
 
17.0 
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 participant. 
 
Human Subjects Involvement and Characteristics: All patients at MSKCC who meet the inclusion 
criteria will be eligible. 5 patients will be enrolled in this study. 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 
are 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 


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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/Side-Effects: There are risks associated with treatment as described in Section 
11.0; however, patients screened for enrollment will be deemed appropriate for treatment 
independent of this study. 
 
Benefits: The addition of definitive local therapies has the potential to prolong progression free 
survival and improve the overall survival compared to standard treatment with erlotinib. Patients who 
progress on treatment can still receive standard, second-line systemic therapies and/or can 
participate in an alternative clinical trial. 
 
Costs:  Patients will be charged for physician visits, routine laboratory tests and radiologic studies 
required for monitoring their condition. The patient/patient’s insurance will be billed for erlotinib and 
all local therapies as a part of the patients standard treatment course. CLIA-certified mutation testing 
(i.e. EGFR mutation by fragment analysis, Sequenom or standard sequencing) will be billed to the 
patient/patient’s insurance.  Research bloods and any other mutation testing that is not required as 
part of the patient’s standard of care will not be billed to the patient/patient’s insurance. 
 
Alternatives: The alternative to this trial would be treatment with erlotinib monotherapy at the 
standard, FDA approved dose of 150mg orally daily, without local therapies. 
 
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), the FDA, and/or other governmental agencies) 
may review patient records as required. 
 
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: This study is to be monitored by the institutional IRB. This 
incorporates an independent data and safety monitoring committee 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 


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17.1 
Privacy 
 
MSKCC’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). 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
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 subject 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 signs consent.  SAE reporting is 
required for 30-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious 
Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org. All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org. All other reports should be sent to sae@mskcc.org. 
 
The report should contain the following information: 


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Fields populated from CRDB: 
 
 
Subject’s initials 
 
Medical record number 
 
Disease/histology (if applicable) 
 
Protocol number and title 
 
Data needing to be entered: 
 
 
The date the adverse event occurred 
 
The adverse event 
 
The grade of the event 
 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
 
If the AE was expected 
 
The severity of the AE 
 
The intervention 
 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject 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 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
17.2.1 
 
This protocol is not an Industry or Cooperative group protocol. 
 
18.0 
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. 


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5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
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. 
 
 
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20.0 
APPENDICES 
 
None