Clinical trial NCT02155465
Conditions: Lung Cancer
Keywords: Ruxolitinib Erlotinib EGFR-mutant 14-043
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2014-06-01; Completion date: 2017-10-01
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase 2 study. The goal of this study is to find out what effects, good and/or bad, taking erlotinib and ruxolitinib has on the patients and on lung cancer. Erlotinib and ruxolitinib are FDA approved for other indications, but the use of erlotinib and ruxolitinib together has not been studied before and is not FDA-approved.

Detailed description:

Arms: arm 1: Phase I The study will follow a standard 3+3 dose escalation trial design. Three to six patients will need to be enrolled at each dose level and assessed for DLT for 1 full cycle (21 days) before a dose escalation decision is made.

Phase II Once the MTD has been determined, patients will be enrolled in the phase 2 portion of the single-arm, two-stage, open-label study to determine efficacy of erlotinib and ruxolitinib. Patients will receive erlotinib and ruxolitinib at the MTD established in the phase I portion. The patient take their previous dose of erlotinib if it is less than 150mg daily.
Interventions: intervention 1: Ruxolitinib intervention 2: Erlotinib
Intervention descriptions: intervention 1: Ruxolitinib 10mg PO BID

Ruxolitinib 15mg PO BID

Ruxolitinib 20mg PO BID intervention 2: Erlotinib 150mg PO QD

Protocol documents:
Prot_SAP_000.pdf: 
MEMORIAL SLOAN-KETTERING CANCER CENTER 
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Amended: 04/14/15 
Page  1 of 33 
 
 
 
A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients with EGFR-mutant Lung 
Adenocarcinoma with Acquired Resistance to Erlotinib 
 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
Principal Investigator/Department: 
Helena Yu, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Gregory Riely, MD, PhD 
Jacqueline Bromberg, MD, PhD 
Medicine 
Medicine 
Investigator(s)/Department: 
Jamie Chaft, MD 
Alexander Drilon, MD 
Mark Kris, MD 
Lee Krug, MD 
Paul Paik, MD 
M. Catherine Pietanza, MD 
Charles Rudin, MD, PhD 
Stephen Veach, MD 
Marjorie Zauderer, MD 
Matthew Hellman, MD 
Piro Lito, MD 
Camelia Sima MD, MS 
Michelle Ginsberg, MD 
Leslie Tyson, NP 
Melanie Albano, NP 
Rachael Pollina, NP 
Linda Ahn, NP 
Sarah Lee, NP 
Ephraim Casper, MD 
Han Xiao, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Sree Chalasani, MD 
Asma Latif, MD 
Afsheen Iqbal, MD 
Stefan Berger, MD 
Avni Desai, MD 
Julie Fasano, MD 
John Fiore, MD 
Steven Sugarman, MD 
Stuart Lichtman, MD 
Marisa Siebel, MD 
Kenneth Ng, MD 
Arlyn Apollo, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Biostatistics 
Radiology 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Medicine-All Network sites 
Medicine-Basking Ridge 
Medicine-Basking Ridge 
Medicine-Basking Ridge 
Medicine-Basking Ridge 
Medicine-Basking Ridge 
Medicine-Basking Ridge 
Medicine-Commack 
Medicine-Commack 
Medicine-Commack 
Medicine-Commack 
Medicine-Commack 
Medicine-Commack 
Medicine-Commack 
Medicine- Rockville Centre 
Medicine- Rockville Centre 
Medicine- Rockville Centre 
Medicine- Rockville Centre 


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Pamela Drullinsky, MD 
Philip Caron, MD 
Stephanie Smith-Marrone, MD 
Carolyn Wasserheit-Lieblich, MD 
Nancy Mills, MD 
Michelle Boyar, MD 
Michael Fanucchi, MD 
Chau Dang, MD Diana 
Lake, MD Richard 
Bambury, MD 
Elizabeth Won, MD 
Karen Cadoo, MD 
Hani Hassoun, MD 
Andrew Zelenetz, MD 
Kenneth Ng, MD 
Martin Tallman, MD 
Medicine- Rockville Centre 
Medicine- Sleepy Hollow 
Medicine- Sleepy Hollow 
Medicine- Sleepy Hollow 
Medicine- Sleepy Hollow 
Medicine- Sleepy Hollow 
Medicine- Sleepy Hollow 
Medicine – West Harrison 
Medicine – West Harrison 
Medicine – West Harrison 
Medicine – West Harrison 
Medicine – West Harrison 
Medicine – West Harrison 
Medicine – West Harrison 
Medicine – West Harrison 
Medicine – West Harrison 
Consenting Professional(s)/Department: Helena Yu, MD 
Gregory Riely, MD, PhD 
Jamie Chaft, MD 
Alexander Drilon, MD 
Mark Kris, MD 
Lee Krug, MD 
Paul Paik, MD 
M. Catherine Pietanza, MD 
Charles Rudin, MD, PhD 
Stephen Veach, MD 
Marjorie Zauderer, MD 
Matthew Hellmann, MD 
Piro Lito, MD 
Ephraim Casper, MD 
Han Xiao, MD 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Sree Chalasani, MD 
Asma Latif, MD 
Afsheen Iqbal, MD 
Stefan Berger, MD 
Avni Desai, MD 
Julie Fasano, MD 
John Fiore, MD 
Steven Sugarman, MD 
Stuart Lichtman, MD 
Marisa Siebel, MD 
Kenneth Ng, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine-All Network sites 
Medicine-Basking Ridge 
Medicine-Basking Ridge 
Medicine-Basking Ridge 
Medicine-Basking Ridge 
Medicine-Basking Ridge 
Medicine-Basking Ridge 
Medicine-Commack 
Medicine-Commack 
Medicine-Commack 
Medicine-Commack 
Medicine-Commack 
Medicine-Commack 
Medicine-Commack 
Medicine- Rockville Centre 
Medicine- Rockville Centre 
 


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Arlyn Apollo, MD 
Zoe Goldberg, MD 
Tiffany Troso-Sandoval, MD 
Pamela Drullinsky, MD 
 
Philip Caron, MD 
Stephanie Smith-Marrone, MD 
Carolyn Wasserheit-Lieblich, MD 
Nancy Mills, MD 
Michelle Boyar, MD 
Michael Fanucchi, MD 
 
Chau Dang, MD Diana 
Lake, MD Richard 
Bambury, MD 
Elizabeth Won, MD 
Karen Cadoo, MD 
Hani Hassoun, MD 
Andrew Zelenetz, MD 
Kenneth Ng, MD 
Martin Tallman, MD 
Medicine- Rockville Centre 
Medicine- Rockville Centre 
Medicine- Rockville Centre 
 
Medicine- Sleepy Hollow 
Medicine- Sleepy Hollow 
Medicine- Sleepy Hollow 
Medicine- Sleepy Hollow 
Medicine- Sleepy Hollow 
Medicine- Sleepy Hollow 
 
 
Medicine – West Harrison 
Medicine – West Harrison 
Medicine – West Harrison 
Medicine – West Harrison 
Medicine – West Harrison 
Medicine – West Harrison 
Medicine – West Harrison 
Medicine – West Harrison 
Medicine – West Harrison 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


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MEMORIAL SLOAN-KETTERING CANCER CENTER 
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Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ......................................................................... 5 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 7 
 
3.0 
BACKGROUND AND RATIONALE ....................................................................................... 8 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION.............................................................. 10 
 
4.1 
Design............................................................................................................................... 10 
 
4.2 
Intervention ....................................................................................................................... 10 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................. 12 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................. 13 
 
6.1 
Subject Inclusion Criteria................................................................................................... 13 
 
6.2 
Subject Exclusion Criteria ................................................................................................. 14 
 
7.0 
RECRUITMENT PLAN ......................................................................................................... 15 
 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 15 
 
9.0 
TREATMENT/INTERVENTION PLAN.................................................................................. 15 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 18 
 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................. 199 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 23 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 24 
 
14.0 BIOSTATISTICS .................................................................................................................. 25 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES... 27 
 
15.1 Research Participant Registration ..................................................................................... 27 
 
15.2 Randomization .................................................................................................................. 27 
 
16.0 DATA MANAGEMENT ISSUES ........................................................................................... 27 
 
16.1 Quality Assurance ............................................................................................................. 27 
 
16.2 Data and Safety Monitoring ............................................................................................... 28 
 
17.0 PROTECTION OF HUMAN SUBJECTS .............................................................................. 28 
 
17.1 Privacy .............................................................................................................................. 30 
 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................... 30 
 
17.2.1 .......................................................................................... Error! Bookmark not defined. 
 
18.0 INFORMED CONSENT PROCEDURES .............................................................................. 31 
 
19.0 REFERENCES ..................................................................................................................... 32 
 
20.0 APPENDICES .................................................................................................................... 333 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
Study title: 
A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients with 
EGFR-mutant Lung Adenocarcinoma with Acquired Resistance to 
Erlotinib 
Study objectives: 
Phase I trial: 
Primary Objective:  Determine the maximum tolerated dose 
(MTD) of ruxolitinib when given in combination with erlotinib for 
patients with acquired resistance to erlotinib. 
Secondary Objective: Establish the toxicity profile of ruxolitinib 
and erlotinib when administered in combination. 
Phase 2 trial: 
Primary Objective:  Assess overall response rate (CR+PR) of 
ruxolitinib when given in combination with erlotinib for patients 
with acquired resistance to erlotinib. 
Secondary Objectives: 
Measure progression-free survival and overall survival among 
patients treated with ruxolitinib and erlotinib, and further define 
the toxicity profile of the combination. 
Correlative studies: 
Primary Objective: Understand the role of the JAK/STAT pathway 
in the development of acquired resistance, utilize exosomes to 
analyze protein expression in tumors, and analyze the role of JAK 
inhibition on immune function. 
Study endpoints: 
Phase I trial: 
Primary Endpoint: Identify any dose limiting toxicities, and 
establish the maximum tolerated doses for the combination of 
erlotinib and ruxolitinib 
Phase 2 trial: 
Primary Endpoint: Overall response rate (CR+PR) of ruxolitinib 
when given in combination with erlotinib 
Secondary Endpoints: 
Progression-free survival and overall survival among patients 
treated with ruxolitinib and erlotinib 
Patient population: 
Patients with locally advanced or metastatic (stage IIIB or IV) 
non-small cell lung cancer with a confirmed EGFR mutation who 
have developed acquired resistance to EGFR tyrosine kinase 
inhibitor therapy 
Number of patients: 
Phase 1:  2-18 
Phase 2: 16-25 (including 6 patients from Phase I) 
Inclusion criteria: 
All patients must have: 
-Pathologic evidence of advanced (non-operable or metastatic) 
biopsy-proven stage IV or recurrent lung cancer reviewed at 
MSKCC. 
-a documented somatic activating mutation in EGFR (including 
but not limited to Exon 19 deletion or L858R) 
-Radiographic progression during treatment with erlotinib. Prior 
chemotherapy regimens are permitted. 
-Measurable (RECIST 1.1) indicator lesion not previously 
irradiated 


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-Must have undergone biopsy after development of acquired 
resistance to erlotinib.  Slides from an outside institution may be 
used. 
-KPS ≥ 70% 
-Age>18 years old 
-Patients must have adequate organ function: 
o AST, ALT, Alk phos ≤ 3.0 x ULN 
o Total bilirubin ≤ 2.0 x ULN 
o Creatinine <2.0 X upper limit of normal and/or a 
creatinine clearance ≥ 60ml/min 
o Absolute neutrophil count (ANC) ≥1,000 cells/mm³. 
o Platelet count ≥100,000/mm³ 
o Hemoglobin ≥9.0g/dL. 
Exclusion Criteria: 
Patients are to be excluded from the study if they meet any of the 
following criteria: 
-Concurrent therapy with a potent CYP3A4 inducer or 
inhibitor.  Subjects may enter screening when therapy with the 
potent inhibitor or inducer is completed and may begin study 
treatment after 1 week or 5 half-lives, whichever is longer 
-Patients with symptomatic brain metastasis requiring escalating 
doses of steroids. 
-Any type of systemic therapy (chemotherapy or experimental 
drugs) within 3 weeks of starting treatment on protocol except for 
erlotinib or any other EGFR TKI. 
-Any radiation within 2 weeks prior to starting treatment on 
protocol 
-Patients with ≥ grade 2 or greater diarrhea despite maximal 
medical management due to medications or a medical condition 
such as Crohn’s disease, malabsorption. 
-Inadequate recovery from any toxicities related to prior treatment 
(to Grade 1 or baseline). 
-Pregnant or lactating women 
-Patients who have received prior treatment with JAK inhibitor 
-Previously or current malignancies at other sites within the last 2 
years, with the exception of adequately treated in situ carcinoma 
of the cervix, basal or squamous cell carcinoma of the skin, or 
prostate cancer that does not require active treatment per 
National Comprehensive Cancer Network (NCCN) guidelines, 
superficial bladder cancer or other noninvasice indolent or stage 
1 malignancy without sponsor approval. 
-Clinically significant cardiac disease including unstable angina, 
acute myocardial infarction within 6 months from Day 1 of study 
drug administration, New York Heart Association Class III or IV 
congestive heart failure, or symptomatic arrythmias requiring 
therapy, 
-Chronic or current active infections requiring systemic antibiotics, 
antifungals or antiviral therapy. 
-Known human immunodeficiency virus infection, or hepatitis B 
virus (HBV) viremia or hepatitis C virus (HCV) viremia. Screening 
for the study does not require assessment for these infections if 
not already known 
-Any other condition that, in the opinion of the Investigator, may 
 


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Dose Escalation Schedule 
Dose 
Level 
Ruxolitinib 
dose 
Erlotinib daily 
Level 1 
10 mg PO bid 
150 mg PO daily 
Level 2 
15 mg PO bid 
150 mg PO daily 
Level 3 
20 mg PO bid 
150 mg PO daily 
compromise the safety, compliance of the patient, or would 
preclude the patient from successful completion of the study. 
Study drug: 
Erlotinib and ruxolitinib 
Study design: 
Phase 1: 
The study will follow a standard 3+3 dose escalation trial design. 
Three to six patients will need to be enrolled at each dose level 
and assessed for DLT for 1 full cycle (21 days) before a dose 
escalation decision is made. No intra-patient dose escalation will 
be performed. Toxicity will be graded according to NCI CTCAE, 
version 4.0. 
A minimum of 6 evaluable patients must be treated at the dose 
declared to be the MTD. An estimated 2-18 patients will be 
necessary to establish the MTD. 
Phase 2: 
Once the MTD has been determined, patients will be enrolled in 
the phase 2 portion of the single-arm, two-stage, open-label study 
to determine efficacy of erlotinib and ruxolitinib. Patients will 
receive erlotinib and ruxolitinib at the MTD established in the 
phase I portion. The patient take their previous dose of erlotinib if 
it is less than 150mg daily. Response to therapy will be assessed 
by interval imaging every 6 weeks with high resolution CT scan 
with response evaluated per RECIST 1.1. A minimum of 10 and a 
maximum of 19 patients will be enrolled in the phase 2 study. 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Hypothesis: The combination of erlotinib and ruxolitinib is an effective treatment in patients with 
EGFR-mutant lung cancers with acquired resistance to erlotinib monotherapy. 
 
1.   Phase I trial: 
A.  Primary Objective: 
Determine the maximally tolerated dose (MTD) of ruxolitinib when given in 
combination with erlotinib for patients with acquired resistance to erlotinib. 
B.  Secondary Objective: 
Establish the toxicity profile of ruxolitinib and erlotinib when administered in 
combination. 
2.   Phase II trial: 


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A.  Primary Objective: 
Assess overall response rate (CR+PR) of ruxolitinib when given in combination with 
erlotinib for patients with acquired resistance to erlotinib at 6 weeks (2 cycles). 
 
B.  Secondary Objectives: 
Measure progression-free survival and overall survival among patients treated with 
ruxolitinib and erlotinib, and further define the toxicity profile of the combination. 
3.   Correlative studies: 
Primary objective: Understand the role of the JAK/STAT pathway in the development 
of acquired resistance, utilize exosomes to analyze protein expression in tumors, and 
analyze the role of JAK inhibition on immune function. 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 EGFR-mutant lung adenocarcinoma and acquired resistance to EGFR tyrosine kinase inhibitors 
Approximately 20% of patients with lung adenocarcinomas will harbor a mutation in the epidermal 
growth factor receptor (EGFR) gene found within their tumors. EGFR-mutant lung cancer is highly 
responsive to the first-generation EGFR tyrosine kinase inhibitors, gefitinib and erlotinib, with 
superior progression free survival when compared to cytotoxic chemotherapy[1-3] and is now 
recommended as first-line therapy for patients with EGFR-mutant lung cancer. The majority of 
EGFR-mutant patients respond to EGFR TKI’s (>70% response rate) for an average of 10-16 
months, but then develop acquired resistance to EGFR TKI therapy with subsequent disease 
progression[1, 3, 4]. There are several known mechanisms of resistance, with the most common 
being the development of second-site mutations within the EGFR kinase domain[5]. There is 
significant research effort being directed at new second generation EGFR TKI’s and combination 
therapies to treat patients in the acquired resistance setting[6-9]; there are currently no approved 
drugs for use in the acquired resistance setting. 
 
3.2 Rationale for continuing erlotinib in Acquired Resistance 
Cessation of EGFR TKI therapy upon acquired resistance results in symptom exacerbation and 
acceleration of disease progression in 20% of patients [10].  Symptoms and radiographic studies 
improve when these patients restart erlotinib [11], indicating that tumors remain at least in part 
reliant on signaling through EGFR.  As standard practice, we continue EGFR-TKI therapy in all 
patients with acquired resistance, in addition to initiating second-line therapies in combination; we 
hypothesize that EGFR-driven tumors with acquired resistance remain dependent on EGFR 
signaling, even after the development of radiographic progression.  Current standard of care therapy 
at AR includes co-administration of erlotinib and cytotoxic chemotherapy. 
 
3.3 Rationale for combining JAK1/2 inhibition by ruxolitinib with erlotinib 
Activation of the EGFR is known to result in downstream pathway activation of the ERK, AKT and 
JAK/STAT pathways. Several groups have recently demonstrated that JAK signaling is involved in 
resistance to EGFR TKIs, and have proposed JAK inhibition as a potential therapeutic strategy in 
the setting of acquired resistance[12, 13]. 
 
Work done by Dr. Jacqueline Bromberg and colleagues has established a critical role for JAK/STAT 
pathway signaling in EGFR-mutant lung adenocarcinoma[14].  Unpublished data from Dr 


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Bromberg’s lab shows that the JAK1/2 inhibitor ruxolitinib synergizes with erlotinib in TKI-sensitive 
lines in vitro [15].  JAK inhibition also restores sensitivity to erlotinib in TKI-resistant lines, including 
those harboring EGFR T790M.  Furthermore, EGFR TKI resistance was reversed with a JAK 
inhibitor in a xenograft model of EGFR-mutant lung adenocarcinoma. In a transgenic mouse model 
of EGFR L858R/T790M mutant TKI-resistant lung adenocarcinoma, time to death is significantly 
prolonged by co-treatment with a JAK inhibitor and erlotinib. Inhibition of the JAK2 feedback loop is 
thought to increase sensitivity to erlotinib in sensitive lines and restore sensitivity in resistant lines. 
JAK2 inhibitors decrease EGFR recycling, resulting in increased wild-type (WT) EGFR expression. 
This WT EGFR is thought to heterodimerize with mutant EGFR, forming a complex successfully 
inhibited by erlotinib [15]. 
 
Cho and colleagues separately demonstrated that JAK inhibition with ruxolitinib also increases 
sensitivity to afatinib in both resistant cell lines (H1975, PC9-GR) and xenograft models[12]. The 
mechanism of re-sensitization is not fully elucidated but may involve inhibition of EGFR TKI induced 
STAT3 activation. These pre-clinical findings support the study of combination JAK and EGFR 
inhibition in EGFR-mutant lung cancers that are resistant to EGFR TKI. 
 
3.5 Ruxolitinib: Studies to Date 
The JAK1 and -2 inhibitor ruxolitinib is FDA-approved at a dose of 20mg by mouth twice daily for the 
treatment of myelofibrosis, based on a randomized Phase III trial in which it decreased 
splenomegaly (primary endpoint), and improved symptom burden and overall survival (secondary 
endpoints) [16]. It is generally well-tolerated with a side effect profile (primarily grade 1 or 2 
ecchymosis, dizziness and headache) that does not overlap with that of erlotinib (rash, diarrhea). 
The dose-limiting toxicity of ruxolitinib is myelosuppression; however, this adverse effect was 
described in patients with hematologic malignancies and therefore may be less problematic in 
patients with lung adenocarcinoma. Ruxolitinib has also been studied in a Phase 2 trial of patients 
with relapsed/refractory AML, in which it was administered at a dose of 25mg by mouth twice daily, 
yielding a response rate of 60 percent [17]. 
 
3.6 Selection of Doses 
Patients in the proposed trial will receive treatment with both ruxolitinib, the JAK1/2 inhibitor, and 
erlotinib.  Subjects will be given erlotinib at 150mg PO daily which is the FDA approved dose. After 
cycle 1, should there be toxicity related to the erlotinib dose, dose reductions will be allowed after 
completion of cycle 1. Retrospective strongly suggests that lower doses of EGFR TKIs may as 
effective as the FDA-approved standard doses with significantly less toxicity[18, 19].The doses of 
ruxolitinib to be tested will be 10mg PO BID, which was the lowest dose studied in the Phase 1/2 
study of ruxolitinib [20]; 15mg POD BID and 20mg PO bid.. FDA approved doses are 5-25mg BID 
depending on concurrent medications or comorbidities and the specific indication for ruxolitinib. For 
myelofibrosis the initial doses is 20mg twice daily for patients with normal platelet counts 
(>200,000mm3) 
 
3.7 Summary 
There are currently no FDA approved treatments in the acquired resistance setting. However, there 
are currently several mutant-specific EGFR TKIs in clinical development with promising early phase 
results. In this background, we choose a null hypothesis of 10% as the bar from which we are 
measuring efficacy of this combination. We hypothesize that JAK inhibition in combination with 


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EGFR inhibition will lead to tumor shrinkage in patients with AR to erlotinib. To test this hypothesis, 
we propose a Phase 1 trial to determine the safest dose of the combination of erlotinib with 
ruxolitinib followed by a Phase 2 trial to determine the efficacy of this combination for the treatment 
of EGFR-mutant lung adenocarcinoma with AR to erlotinib.  Proposed correlative studies include 
assessment of pathway activation both by conventional immunohistochemical staining of biopsy 
slides, and by isolation and analysis of tumor exosomes, vesicles extruded from tumors that reflect 
tumor characteristics in their make-up [21, 22]. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This phase 1/2 study is a single-arm, open lab, single institution study of erlotinib and ruxolitinib in 
patients with EGFR-mutant lung cancer and acquired resistance to erlotinib therapy 
 
 
 
 
Phase I trial (3+3 dose escalation) 
Planned accrual: up to 18 patients (2-18 patients) 
 
-Stage III/IV NSCLC 
-EGFR+ 
-Acquired resistance 
to EGFR TKI therapy 
-Biopsy at time of 
acquired resistance 
 
Determine MTD: Erlotinib + Ruxolitinib 
Dose level 1: Erlotinib 150mg PO QD + Ruxolitinib 10mg PO BID 
Dose level 2: Erlotinib 150mg PO QD  + Ruxolitinib 15mg PO BID 
Dose level 3: Erlotinib 150mg PO QD + Ruxolitinib 20mg PO BID 
 
 
 
Phase 2 trial 
Planned accrual: up to 19 patients (10-19 patients). In addition, 6 patients treated at MTD in Phase I 
will be included in Phase II, for a total of 16-25 patients evaluated. 
 
 
-Stage III/IV NSCLC 
-EGFR+ 
-Acquired resistance 
to EGFR TKI therapy 
-Biopsy at time of 
acquired resistance 
 
 
Treat at MTD with Erlotinib+ Ruxolitinib 
 
 
4.2 
Intervention 
 
Phase 1 trial: 
We propose a conventional dose-escalation study in which oral ruxolitinib will be administered along 
with erlotinib 150mg PO daily.  The patient must have been on that dose of erlotinib for at least one 
month prior to initiating treatment on study. Erlotinib is taken orally once daily. We anticipate 
minimal overlapping toxicities and predict 3 dose levels (50%, 75%, and 100% of the FDA-approved 
dose of ruxolitinib of 20mg BID for myelofibrosis with a normal platelet count of >200,000/mmᶾ) will 
be required. Ruxolitinib is given orally twice daily at a given dose level in a cohort. 
 
Dose Escalation Schedule 
Dose 
Ruxolitinib dose 
Erlotinib daily 


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Level 
Level 1 
10 mg PO bid 
150 mg PO daily 
Level 2 
15 mg PO bid 
150 mg PO daily 
Level 3 
20 mg PO bid 
150 mg PO daily 
 
 
Three patients will be treated per cohort, starting at dose level 1.  All 3 patients in a given cohort 
must complete 1 cycle (3 weeks) of therapy without dose-limiting toxicity (DLT) prior to enrollment at 
the next dose level. No intra-patient dose escalation will be performed.  If one patient of the 3- 
patient-cohort has a DLT, than that dose level will be expanded to 6 patients.  Escalation will 
continue only if no additional DLTs are observed. 
 
If two or more patients experience a DLT, the previous dose will be declared the MTD. 
If only 
three patients were treated at the dose under consideration as the MTD, an additional three patients 
will be treated at that level to confirm no added DLTs are observed. A minimum of 6 evaluable 
patients must be treated at the dose declared to be the MTD. Each cohort will consist of newly 
enrolled patients. All adverse events will be graded according to the NCI CTCAE version 4.0. 
Response to therapy will be assessed by interval imaging every 2 cycles (6 weeks) with high 
resolution CT scan with response evaluated per RECIST 1.1. An estimated 2-18 patients will be 
necessary to establish the MTD. Actual accrual will depend on the number of DLT’s observed. 
 
Phase II trial: 
Once the MTD has been determined, patients will be enrolled in the phase 2 portion of the single- 
arm, two-stage, open-label study to determine efficacy of erlotinib and ruxolitinib. Patients will 
receive erlotinib and ruxolitinib at the MTD established in the phase 1 portion. The patient may take 
their previous dose of erlotinib if this is less than 150mg daily.  Response to therapy will be 
assessed by interval imaging every 6 weeks with high resolution CT scan with response evaluated 
per RECIST 1.1. The first 6 week response will be considered as the primary objective outcome in 
the phase 2 portion. Safety and efficacy will be assessed throughout the treatment period. In the 
event of disease progression or unacceptable toxicity, the patient will be removed from the study. All 
patients will be followed for adverse events for 30 days following the last dose of study medication. 
 
Correlative studies: 
A. Each study participant is required to have undergone a biopsy at the time of acquired resistance 
to EGFR TKI monotherapy. EGFR T790M status will be determined at acquired resistance, as well 
as assessment for MET amplification or any additional acquired mutations as is standard of care on 
these acquired resistance biopsy samples. These are performed in our Diagnostic Molecular 
Pathology Laboratory using standard CLIA approved assays for mutational analysis and 
amplification.  Immunohistochemical stains for pEGFR, pSTAT3, pERK, pAKT, Her2 and Her3 will 
be done on archived biopsy tissue.These are routinely performed in the Molecular Cytology Core 
Facility and in our Diagnostic Molecular Pathology Laboratory at MSKCC.  Scoring of IHC will be 
performed by Dr. Maria Arcila (Director of the Diagnostic Molecular Pathology Lab) using standard 
IHC-H score criteria with assessment of staining intensity (0-3) x by the percentage of positive cells 
for each intensity for a final IHC-score. 
 
B. We and others have determined that patients with EGFR mutant NSCLC secrete microvesicles 
(exosomes) which express the mutant forms of EGFR and other signaling molecules[23, 24]. We 
(Bromberg lab) routinely isolate exosomes from patient plasma, murine plasma and conditioned 


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media.  For patient plasma, we isolate exosomes using a well established protocol (see our 
published manuscript [22]). Whole blood is collected in heparin containing tubes (green top), placed 
on ice and delivered to our laboratory or picked up by my technician or assistant. The MRN and 
patient features are entered onto a secure server and the sample is given a new numeric identifier. 
Here we follow a standard protocol for isolation of exosomes [22]. The blood is sequentially 
centrifuged (300x g for 10 minutes at 4 °C to pellet the cells, 16,500x g for 20 minutes at 4 °C to 
further remove cells and cell debris, filtered through a .0.2 μm filter to remove particles larger than 
200 nm and finally at 100,000x g for 70 minutes 4 °C to pellet the exosomes). The total number of 
exosomes is quantified using NanoSite and protein concentration is determined using a Bradford 
assay.  Equal numbers of exosomes (using a spectrophotometer based analysis: NanoSite) or equal 
protein concentrations (5 ug) of exosomes are analyzed by western blot analysis and probed for 
pEGFR, EGFR, HER2, HER3 pStat3, pAKT, pS6, pERK signaling proteins and Tubulin, Alix and 
Tsg101 (as loading controls and canonical exosome proteins).  Semi-quantitative analyses is 
performed using ImageJ software of chemiluminescent signals. 
 
 
Significnatly, treatment of tumour bearing mice with a JAK2 inhibitor leads to the release of 
exosomes in the circulation expressing elevated levels of EGFR/pEGFR. This was determined 
using western blot analyses as described above. Conversely, erlotinib (TKI) treatment of EGFR 
mutant tumours leads to increased pStat3 levels both in tumor and in circulating exosomes. We 
therefore hypothesize that the protein/phosphor-protein profile of exosomes will recapitulate the 
phosphor-signaling cross-talk occurring in tumors. We therefore propose analyzing circulating 
exosomes prior and during treatment of patients.  10 to 15 milliliters of peripheral blood will be 
obtained at pre-determined intervals during the study. Timepoints include start of study treatment 
(C1D1), C1D8, followed by every 2 cycles, corresponding to when a radiographic assessment on 
protocol will be reviewed (C3D1, C5D1, C7D1, etc). The samples will be obtained in order to assess 
circulating exosomes for the presence of EGFR T790M (using primers specific to this gate-keeper 
isoform and detected by QPCR-which have been established in the lab), , pEGFR, pSTAT3, pERK, 
pAKT, Her2 and Her3 using semi-quantitative western blot analysis as described above. We 
hypothesize that exosome total EGFR protein levels will be elevated while pEGFR, pERK and 
pStat3 levels will be reduced in the exosome samples from patients on Ruxolitinib and Erlotinib as 
compared to Erlotinib alone. 
 
 
C. The recent clinical success of immunomodulatory molecules for the treatment of NSCLC has re- 
focused our attention on the potential role of immunesuppressive myeloid and t-cells with targeted 
therapies. We and others have recently shown that JAK inhibitors potently suppress the function 
and abundance of myeloid derived suppressive cells and increase CD4 and CD8 cells in pre-clinical 
models[25]. We therefore propose examining the levels of CD33+ MDSCs, CD4 and CD8 cells in 
these patients at pre-determined intervals as described above. The same blood samples used for 
exosomes will be processed for the analysis of immune cells by FACS analysis using established 
approaches previously used in the Bromberg lab. The cell pellet obtained following initial 300xg 
centrifugation is purified using density gradient purification (Ficoll) and then analyzed by FACS using 
antibodies specific to myeloid, and T-cell populations. We hypothesize that a reduction of CD33+ 
myeloid cells and an increase in CD4 and CD8 T-cells will be observed in those patients receiving 
Ruxolitinib. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Ruxolitinib 


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Ruxolitinib is a potent and selective inhibitor of JAK1 (IC50=3.3+/-1.2nM) and JAK2 (IC50=2.8+/- 
1.2nM) with modest selectivity against TYK2 (IC50=19+/-3.2nM) and JAK3 (IC50=428+/-243nM), 
respectively.  It is inactive against 28 additional kinases when tested at 200nM.  Ruxolitinib has high 
solubility and permeability (i.e. it is designated as a Class I molecule in the Biopharmaceutical 
Classification System) and exhibits moderate to high clearance, volume of distribution and oral 
bioavailability in preclinical species.  After oral administration, ruxolitinib is absorbed rapidly, with 
maximal plasma concentrations (Cmax) achieve within 1-2 hrs post-dose. The half-life is about 3 
hours in humans; ruxolitinib plus metabolites have a half life of approximately 6 hours. Time to peak 
is 1-2 hours. It is predominantly metabolized by CYP3A4, and is excreted in the urine (74%) and 
feces (22%) with parent drug accounting for less than one percent of each.  It is primarily protein- 
bound (97%). 
 
Ruxolitinib is a white to almost white powder. Ruxolitinib has been shown to be stable for up to six 
months at 40ºC and up to 24 months at 25ºC. The 5mg (free base equivalent) is packaged in HDPE 
bottles.  Ruxolitinib is provided as 5mg strength tablets. The tablet formulations contain the active 
ingredient and may include the following commonly used excipients: microcrystalline cellulose, 
lactose, stearic acid, magnesium stearate, colloidal silicone dioxide, sodium starch glycolate, 
Povidone and hydroxyl propyl cellulose. 
 
Ruxolitinib was approved by the FDA with the trade name Jakafi, for the treatment of patients with 
intermediate or high-risk myelofibrosis.  Incyte will provide ruxolitinib for this trial.  Because the 
proposed trial addresses an unapproved indication, MSKCC will hold the IND and will cross-file with 
Incyte’s IND. 
 
5.2 Erlotinib 
Erlotinib hydrochloride is a quinazolinamine that inhibits the intracellular phosphorylation of tyrosine 
kinase associated with the epidermal growth factor receptor (EGFR). The approved dose for 
maintenance therapy in non-small-cell lung cancer is 150mg daily.  It is very slightly soluble in water. 
It is a major substrate of CYP3A4, and minor substrate of CYP1A2.  Erlotinib bioavailability is 
significantly increased upon co-administration of food, so recommended dosing is on an empty 
stomach at least 1 hour before or 2 hours after eating.  Half-life in humans is 24-36 hours, with time 
to peak of 1-7 hours. It is excreted in the feces (1% as unchanged drug) and urine (8%).  92 to 95% 
of the drug is bound to albumin and α1-acid glycoprotein. 
 
Erlotinib is supplied as 25mg, 100mg and 150mg round biconvex tablets. Erlotinib is stable when 
stored at 25ºC. Erlotinib hydrochloride is available at 25mg, 100mg and 150mg tablets that also 
include the following inactive ingredients: lactose monohydrate, hypromellose, hydroxypropyl 
cellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl 
sulfate and titanium dioxide. The 25mg dose also includes trace color additives, including FD&C 
Yellow#6. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
All patients must have or be: 


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• 
Pathologic evidence of advanced (non-operable or metastatic) biopsy-proven stage IV or 
recurrent lung cancer reviewed at MSKCC. 
• 
a documented somatic activating mutation in EGFR (including but not limited to Exon 19 
deletion or L858R) 
• 
Radiographic progression during treatment with erlotinib. Prior chemotherapy regimens are 
permitted. 
• 
Received erlotinib or other EGFR TKI treatment for at least 2 weeks prior to enrollment 
• 
Measurable (RECIST 1.1) indicator lesion not previously irradiated 
• 
Must have undergone biopsy after development of acquired resistance to erlotinib (which is 
performed as standard of care) with adequate tissue to determine EGFR T790M and tumor 
histology.  Slides from an outside institution may be used. 
• 
KPS ≥ 70% 
• 
Age>18 years old 
• 
Patients must have adequate organ function: 
o AST, ALT, Alk phos ≤ 3.0 x ULN 
o Total bilirubin ≤ 2.0 x ULN 
o Creatinine <2.0 X upper limit of normal and/or a creatinine clearance ≥ 60ml/min 
o Absolute neutrophil count (ANC) ≥1,000 cells/mm³. 
o Platelet count >100,000/mm³ 
o Hemoglobin >9.0g/dL. 
 
6.2 
Subject Exclusion Criteria 
 
Patients are to be excluded from the study if they meet any of the following criteria: 
 
• Concurrent therapy with a potent CYP3A4 inducer or inhibitor.  Subjects may enter screening 
when therapy with the potent inhibitor or inducer is completed and may begin study treatment 
after 1 week or 5 half-lives, whichever is longer. 
 
• Patients with symptomatic brain metastasis requiring escalating doses of steroids. 
• 
Any type of systemic therapy (chemotherapy or experimental drugs) within 3 weeks of 
starting treatment on protocol except for erlotinib or other EGFR TKI. 
• 
Any radiation within 2 weeks prior to starting treatment on protocol 
• 
Patients with ≥ grade 2 or greater diarrhea despite maximal medical management due to 
medications or a medical condition such as Crohn’s disease, malabsorption. 
• 
Inadequate recovery from any toxicities related to prior treatment (to Grade 1 or baseline). 
• 
Pregnant or lactating women 
• 
Patients who have received prior treatment with JAK inhibitor 
• 
Previously or current malignancies at other sites within the last 2 years, with the exception of 
adequately treated in situ carcinoma of the cervix, basal or squamous cell carcinoma of the 
skin, prostate cancer that does not require active treatment per National Comprehensive 
Cancer Network (NCCN) guidelines, superficial bladder cancer or other noninvasice indolent 
or stage 1 malignancy without sponsor approval 
• 
Clinically significant cardiac disease including unstable angina, acute myocardial infarction 
within 6 months from Day 1 of study drug administration, New York Heart Association Class 
III or IV congestive heart failure, or symptomatic arrythmias requiring therapy, 


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• 
Chronic or current active infections requiring systemic antibiotics, antifungals or antiviral 
therapy. 
• 
Known human immunodeficiency virus infection, or hepatitis B virus (HBV) viremia or 
hepatitis C virus (HCV) viremia. Screening for the study does not require assessment for 
these infections if not already known.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. 
 
 
 
 
7.0 
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. All recruited patients will 
be under the care of attending medical oncologists of the MSKCC Thoracic Oncology Service. 
 
There will be no direct advertising for this study and participants will not be reimbursed for 
participation.  Patients will be accrued to this study without regard for gender or minority status. The 
study will be available to the public and the details of the inclusion criteria, exclusion criteria and 
study design will be posted at www.clinicaltrials.gov. 
 
8.0 
PRETREATMENT EVALUATION 
 
The following tests must be completed within 28 days of started treatment on study unless otherwise 
noted. 
• 
Documented presence of the EGFR mutation within the patient’s tumor (no time window) 
• 
Biopsy of lesion at acquired resistance must have been performed  (no time window) 
• 
Full medical history 
• 
Baseline tumor assessment with CT scan of the chest (and abdomen and pelvis if 
appropriate based on the patient’s sites of disease), or other comparable radiologic study 
(PET scan or MRI) as medically appropriate. Tumor burden assessed by RECIST 1.1 
• 
Physical examination, complete vital signs (pulse, blood pressure, temperature, respiratory 
rate) as well as weight and height 
• 
12-lead electrocardiogram (ECG) within 3 months 
• 
Performance status by KPS or ECOG 
• 
Serum or urine pregnancy test (for premenopausal 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) 
• 
C-Reactive Protein (High Sensitivity) 
• 
Routine urinalysis 
• 
12-lead electrocardiogram (ECG) within 90 days 
 
9.0 
TREATMENT/INTERVENTION PLAN 


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We propose a conventional dose-escalation study in which oral ruxolitinib will be administered along 
with the patient’s prior stable dose of erlotinib.  Erlotinib is taken orally once daily.  We anticipate 
minimal overlapping toxicities and predict 3 dose levels (50%, 75%, and 100% of the FDA-approved 
dose of ruxolitinib) will be required. Ruxolitinib is given orally twice daily at the given dose level in a 
cohort. 
 
9.1 Therapeutic Agents 
 
9.1.1 Therapeutic Agent - Erlotinib 
Erlotinib will be commercially obtained. Investigators should reference the current approved 
prescribing information. The FDA approved dose for non-small cell lung cancer is 150mg orally once 
daily and will be used in the phase 1, dose-finding portion of the study.  The medications will be 
dispensed at the beginning of each treatment cycle and 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. They should resume treatment with the next scheduled dose. If the patient forgets to take 
his/her daily dose, he/she should take erlotinib within 12 hours after the missed dose. If more that 12 
hours have elapsed, that day’s dose should be omitted, and the patients should continue treatment 
with the next scheduled dose. 
 
9.1.2 Therapeutic Agent – Ruxolitinib 
The experimental agent being evaluated is ruxolitinib. It will be supplied for the purposes of this trial 
by Incyte Corporation. Study drug will be handled by designated persons only, and handled per 
according to the specific care instructions. Ruxolitinib is given orally twice daily and can be taken 
with or without food at approximately the same time of the day each day. The medications will be 
dispensed at the beginning of each treatment cycle and a pill diary will be used to track adherence. 
When a dose is missed, patients should not take an additional dose, but should take the next usual 
prescribed dose. 
 
9.2 Treatment arms 
All patients will receive ruxolitinib and erlotinib in this single-arm study. 
 
 
9.3 Phase 1 Study 
The study will follow a standard 3+3 dose escalation trial design. Three to six patients will need to be 
enrolled at each dose level and assessed for DLT for 1 full cycle (21 days) before a dose escalation 
decision is made. No intra-patient dose escalation will be performed. Toxicity will be graded 
according to NCI CTCAE, version 4.0. Response to therapy will be assessed by interval imaging 
every 2 cycles with response evaluated per RECIST 1.1. 
 
Table 1: Cohort dose levels of Erlotinib and Ruxolitinib 
 
Dose Escalation Schedule 
Dose 
Level 
Ruxolitinib dose 
Erlotinib daily 
Level 1 
10 mg PO bid 
150 mg PO daily 
Level 2 
15 mg PO bid 
150 mg PO daily 


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Level 3 
20 mg PO bid 
150 mg PO daily 
 
 
The phase 1 portion will accrue cohorts of 3-6 patients (maximum enrollment 18 patients). All 
patients will receive erlotinib at 150mg orally daily along with doses of ruxolitinib orally twice daily. 
Patients in dose level 1 will receive erlotinib 150mg orally daily and ruxolitinib 10mg orally twice 
daily. In dose level 2, patients will receive erlotinib 150mg orally daily and ruxolitinib 15mg orally 
twice daily. In dose level 3, patients will receive erlotinib 150mg orally daily and ruxolitinib 20mg 
orally twice daily. 
 
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 (DLT’s) are defined as any of the following 
events occurring during the first cycle of treatment (i.e. 3 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 ≥ 3 thrombocytopenia with evidence of clinically significant bleeding 
o Grade = 4 anemia 
• 
Non-hematologic toxicities including: 
o Grade ≥ 3 AST, ALT, alkaline phosphatase or total bilirubin 
o Grade ≥ 3 diarrhea, nausea, vomiting that lasts > 72 yrs despite optimal maximal 
supportive care 
o Grade = 4 diarrhea, nausea or vomiting 
o Any other non-hematologic grade ≥ 3 major organ toxicity 
 
Patients in each cohort must complete the first 3 weeks of study therapy prior to enrollment of 
subsequent cohorts. If no DLT is seen in the first 3 patients at a dose level (i.e. dose level 1), the 
following 3 patients will be enrolled at the next dose level (i.e. dose level 2). If 1 DLT is observed in 
the first cohort, the next 3 patient cohort will be enrolled at the same dose level to expand the cohort 
at that dose level to 6 patients. If no further DLTs are identified in the expanded cohort (i.e. 0-1 DLT 
for 6 patients at the same dose level), then the following 3 patient cohort will be enrolled at the next 
dose level. If 2 DLTs are observed in any observed 3 patient cohort, the next 3 patient cohort will be 
enrolled at the immediately previous lower dose level to expand the number of patients at that level 
to 6 patients and no further dose escalation will occur. 
 
The MTD will be defined as the highest dose where not more than 1 of 6 patients develops a DLT. 
Dose levels are outlined in Table 1 above. Dose escalation will proceed within each cohort 
according to the schema in Table 2 below. 
 
Table 2 Dose Escalation Schema 
 
# of pts with DLT at a given dose level 
Escalation decision rule 
0 of 3 
Enter next cohort (3 pts) at next dose level 
1 of 3 
Enter next cohort (3 pts) at same dose level 
• 
If 0 of 3 experience DLT, proceed to next 


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dose level 
• 
If 1 or more experience DLT, dose 
escalation stopped. 3 additional pts will 
be entered at next lowest dose level if 
only 3 patients were treated previously at 
that dose level 
≥2 of 3 
Dose escalation stopped. 3 additional pts will be 
entered at next lowest dose level if only 3 patients 
were treated previously at that dose level 
≤1 of 6 at highest dose level 
Recommended phase 2 dose. 6 patients must be 
entered at the recommended phase II dose prior 
to proceeding to the phase 2 study. 
 
 
Patients who do not complete 21 days of treatment for reasons other than experiencing a DLT will 
be replaced. For the purposes of dose-escalation decisions, only DLTs occurring during the first 
cycle (21 days) will be considered. 
 
9.5 Phase 2 Study 
All patients will receive oral ruxolitinib and erlotinib at the MTD established during the phase 1 
portion. The patient take their previous dose of erlotinib if it is less than 150mg daily. Dose 
modifications due to toxicity are described further in Section 11.0. Patients will be monitored for 
response by CT every 2 cycles (6 weeks). The first 6 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 
 
9.6 Correlative Studies 
All patients are required to have a repeat biopsy at the time of acquired resistance to erlotinib 
therapy. Correlative studies will be performed on all patients participating in both the phase I and 
phase II portions of this clinical trial. Archival tissue from these biopsies will be obtained if available. 
Mechanisms of acquired resistance will be assessed for including EGFR T790M, MET amplification, 
HER2 amplification and additional secondary point mutations. 
 
Samples will undergo immunohistochemical staining for pEGFR, pSTAT3, pERK, pAKT, Her2 and 
Her3 in the Molecular Cytology Core Facility and in our Diagnostic Molecular Pathology Laboratory 
at MSKCC . In addition, peripheral blood will be drawn at regular intervals to analyze exosomes for 
the presence of EGFR T790M as well as the same markers stained for by immunohistochemistry. 
Two tubes (10-15 ml) is required, and the research blood will be drawn at C1D1, C1D15, and then 
every two cycles ongoing (C3D1, C5D1, etc). 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
Study drug administration: 
Table 3: Calendar of Ruxolitinib and Erlotinib dosing 
 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Week 1 
AM: Rux, 
Erlotinib* 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
PM: Rux 
PM: Rux 
PM: Rux 
PM: Rux 
PM: Rux 
PM: Rux 
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Week 2 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
PM: Rux 
PM: Rux 
PM: Rux 
PM: Rux 
PM: Rux 
PM: Rux 
PM: Rux 
Week 3 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
AM: Rux, 
Erlotinib 
PM: Rux 
PM: Rux 
PM: Rux 
PM: Rux 
PM: Rux 
PM: Rux 
PM: Rux 
*Can take erlotinib either in AM or PM, but should be consistent through the duration of the study 
Evaluations will occur at each clinic visit, which will be weekly for cycle 1, and then on day 1 of each 
subsequent 21 day cycle. The evaluations are further defined in the study calendar (Table 4).Study 
Calendar: 
 
Table 4: 
 
Study Assessments 
Screening 
Cycle 1 
Cycle 
2+ 
At Progression/ 
Off study 
Day 
Within 4 
weeks 
C1 
D1 
C1 
D8 
C1 
D15 
C2+ 
D1 
Informed consent 
X 
Medical history 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
Adverse Events 
X 
X6 
X 
X 
X 
12-lead EKG 
X 
Tumor Assessment¹ 
X 
X 
X 
Pregnancy test 
X 
CBC² 
X 
X 
X 
X 
X 
CMP³ 
X 
X 
X 
X 
X 
Research blood tests⁴ 
X 
X 
X 
C-Reactive Protein 5 
X 
X 
X 
X5 
 
1. CT C (+/- abdomen/pelvis depending on sites of disease) w ith or w ithout contrast or other comparable radiologic study 
(PET scan or MRI). Will be done at screening, every 6 w eeks(+/- 2 w eeks) and at progression or w hen patient comes off 
study. 
2. CBC- complete blood count w ith differential 
3. CMP-comprehensive metabolic panel (glucose, blood urea nitrogen, creatinine, sodium, potassium, chloride, 
bicarbonate, calcium, total protein, albumin, serum bilirubin, alkaline phosphatase, ALT, AST) 
4. Research blood tests- exosome analysis, refer to section 9.6 for full details. 
5. C-Reactive Protein (high sensitivity)- To be draw n at Screening, C1D1, and then every tw o cycles ongoing (C3D1, 
C5D1, etc).6. Adverse events on C1D8 w ill be done via a nurses phone call. 
 
All medical histories, physical exam, vital signs and adverse event documentation can occur within 
+/- 7 days. The off study visit should occur within 4 weeks of completing therapy on study. All blood 
draws including CBC, CMP and research bloods can occur within +/- 7 days. Tumor assessments 
have a window of +/- 2 week. If an appropriate imaging study is done for an unrelated reason, it can 
be used for disease assessment if it falls within the appropriate time frame. 
 
 
 
 
 
 
 
11.0 TOXICITIES/SIDE EFFECTS 


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Toxicity grading will be performed in accordance with NCI CTCAE, version 4.0. Dose-limiting 
toxicities will be identified as described in Section 9.4. After the MTD of the erlotinib and ruxolitinib 
combination is established, if toxicities are encountered, adjustments will be made to either erlotinib, 
ruxolitinib or both based on the investigator’s discretion. He/She will base the decision on the 
presumed attribution of the adverse event. For safety and adverse event reporting, see section 17.0 
 
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 
• 
Mouth sores (mucositis) 
• 
Abdominal pain 
• 
Conjunctivitis (inflammation of the eye) 
• 
Liver toxicity (elevated liver function studies) 
 
Side effects of erlotinib 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) 
 
Erlotinib dose modifications will are to be made according to the criteria outline in Table 5 
 
Table 5: 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, or w ith a 
suggested dose 
reduction of 25mg 
daily, at the 
discretion of the 
investigator 
Withhold dose until 
toxicity is grade ≤ 1, 
then resume 
treatment at same 
dose, or w ith a 
suggested dose 
reduction of 25mg 
daily, at the 
discretion of the 
investigator 
Pneumonitis (in the 
absence of other 
causes of pulmonary 
infiltrates/dysfunction) 
Withhold until at 
baseline. Can 
resume trtmt at 
discretion of 
investigator. If recurs, 
discontinue 
permanently. 
Withhold until at 
baseline. Can 
resume trtmt 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 anti- 
Continue at same  
dose level. Initiate  
therapy w ith anti- 
Initiate therapy w ith 
anti-diarrheal 
medications. Suggest 
Initiate therapy w ith 
anti-diarrheal 
medications. 


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diarrheal 
medications. 
diarrheal 
medications. 
withholding erlotinib 
until toxicity is grade 
≤ 2. Resume trmt at 
same dose or w ith a 
dose reduction at the 
discretion of 
investigator. 
Withhold until toxicity 
is grade ≤ 2. Resume 
trmt at same dose or 
with a dose reduction 
at the discretion of 
investigator. 
Rash 
Continue at same 
dose level. Initiate 
supportive symptom 
management. 
Continue at same 
dose level. Initiate 
supportive symptom 
management. If rash 
persists or w orsens 
over 14 days, 
consider dose 
reduction at 
discretion of 
investigator. 
Suggest w ithholding 
erlotinib until toxicity 
is grade ≤ 2. Initiate 
supportive symptom 
management. If rash 
persists or w orsens 
over 14 days, 
consider dose 
reduction at 
discretion of 
investigator. 
Withhold until toxicity 
is grade ≤ 2. Initiate 
supportive symptom 
management. 
Discontinue 
permanently or 
restart w ith a dose 
reduction at the 
discretion of 
investigator. 
 
 
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. 
 
11.4 Management of Ruxolitinib related toxicities 
 
Toxicities with ruxolitinib that are likely (>20%) include: 
• 
Anemia (low red blood cells) that may cause you to feel fatigued or short of breath 
• 
Low platelet count may lead to bleeding and/or bruising 
 
Toxicities with ruxolitinib that are less likely (<20%) include: 
• 
Diarrhea 
• 
Fatigue 
• 
Weight gain 


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• 
Nausea 
• 
Fevers 
• 
Shortness of breath 
• 
Dizziness 
• 
Headache 
• 
Swelling of the arms and legs 
• 
Bruising 
• 
Increased in certain proteins in the blood that may indicate mild liver damage 
• 
Mild increases in cholesterol levels 
• 
Increased blood pressure 
• 
Urinary tract infections 
• 
Certain viral skin infections (called herpes zoster) 
• 
Low white blood cell count that could increase the risk of infection 
• 
Bruising 
• 
Gas 
 
Side effects of ruxolitinib  that are rare, but serious include: 
• 
Tuberculosis 
• 
Progressive multifocal leukoencephalopathy (PML), an inflammation of the brain 
 
 
 
Tuberculosis has occurred in a small number of patients with a blood disorder called myelofibrosis 
treated with ruxolitinib. It is unclear whether this was related to the drug but other patient factors. 
One patient with myelofibrosis taking ruxoltiinib developed PML. It is unclear whether this was 
related to the drug or other patient factors. 
 
 
 
Table 6 Criteria for dose modifications of Ruxolitinib 
 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hematologic toxicities 
including anemia, 
thrombocytopenia, 
leukopenia and 
neutropenia 
Continue at same 
dose level 
Optional dose 
reduction of 
ruxolitinib by 5mg 
BID 
Withhold dose until 
toxicity is grade ≤ 2, 
then can resume 
treatment at the 
discretion of the 
investigator w ith a 
dose reduction of 
ruxolitinib by 5mg 
BID. 
Withhold dose until 
toxicity is grade ≤ 2, 
then can resume 
treatment at the 
discretion of the 
investigator w ith a 
dose reduction of 
ruxolitinib by 5mg 
BID. 
Non-hematologic, 
general 
Continue at same 
dose level 
Optional dose 
reduction of 
ruxolitinib by 5mg 
BID 
Withhold dose until 
toxicity is grade ≤ 2, 
then can resume 
treatment at the 
discretion of the 
investigator w ith a 
dose reduction of 
ruxolitinib by 5mg 
BID. 
Withhold dose until 
toxicity is grade ≤ 2, 
then can resume 
treatment at the 
discretion of the 
investigator w ith a 
dose reduction of 
ruxolitinib by 5mg 
BID. 


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If treatment is held for longer than 4 weeks, discontinuation of study treatment should be considered. 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
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, after 2 
cycles (+/- 2 weeks), and every two cycles (+/- 2 weeks).  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. A CT scan of the chest or CT 
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 as well. Definitions of 
response in target and non-target lesions are described in Table 7 and 8 below. Table 9 provides 
overall responses for all possible combinations of tumor responses in target and nontarget lesions. 
 
 
 
Table 7: Evaluation of target lesions 
Complete Response (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 8: Evaluation 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  lesion and/or 
unequivocal progression of existing non-target lesion 
 
 
Table 9: 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 


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Discontinuation of treatment 
Early death is defined as having no repeat tumor assessments following initiation of study therapy 
resulting from death of the patient due to disease or treatment. Patients with global deterioration of 
health status requiring discontinuation of treatment without objective evidence of disease 
progression will be recorded as ‘symptomatic deterioration’. Every effort will be made to document 
objective progression even after discontinuation of treatment. 
 
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 9. 
 
Other definitions 
Evaluable for toxicity: All patients who receive at least one dose of treatment with erlotinib and 
ruxolitinib will be evaluable for toxicity. However, patients who are replaced during the first cycle of 
treatment in the dose escalation phase for any reason other than DLT will not be included in the 
assessment of MTD. 
Evaluable for objective response: All patients at MTD will be included in the intent-to-treat analysis of 
efficacy. 
Progression free survival (PFS) is defined as the duration of time from first treatment to time of 
progression or death, whichever occurs first. 
Overall survival (OS) is defined as the duration of time from first treatment to time of death. 
 
 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
Patients may withdraw from the study at any time. Patients who are treated at the MTD 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 in Table 4 will be performed at that time. 
 
Patients will be withdrawn from the study should they experience any of the following: 
• 
Dose limiting toxicity 
• 
Disease progression (defined by RECIST 1.1) 
 
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 
 
For the Phase I portion of the study, patients who withdraw from the study for reasons other than 
DLT without completing a full treatment cycle will be replaced. 


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14.0 
BIOSTATISTICS 
 
Phase 1 
Primary objective: to determine the safety, tolerability, and maximum tolerated dose (MTD) of the 
combination of erlotinib and ruxolitinib in patients with EGFR-mutant lung cancer and acquired 
resistance to EGFR tyrosine kinase inhibitors. 
 
Endpoints: identify any dose limiting toxicities (DLTs), and establish the MTD for the combination. 
The MTD will be defined as the dose that does not exceed an acceptable threshold of toxicity. Dose 
limiting toxicity is a binary outcome where a patient either experiences a DLT or not. DLT is defined 
as any of the toxicities described in Section 9.4 that occurs within one cycle after initiation of 
treatment with erlotinib and ruxolitinib. 
 
Methods: A standard 3+3 design will be used to find the maximum tolerated dose (MTD). There will 
be three set dose levels, using the approved dose of ruxolitinib, with 50%, 75% and 100% of the 
FDA approved ruxolitinib dose of 20mg PO BID for patients with myelofibrosis with platelets >200,000mm3. 
 
Dose Escalation Schedule 
Dose 
Level 
Ruxolitinib dose 
Erlotinib daily 
Level 1 
10 mg PO bid 
150 mg PO daily 
Level 2 
15 mg PO bid 
150 mg PO daily 
Level 3 
20 mg PO bid 
150 mg PO daily 
The dose escalation scheme is as follows: 
 
1.  If none of the initial three patients at a given dose level experience DLT, the next dose level 
will be studied. 
2.  If one of the initial three patients at a given dose level experiences DLT, three additional 
patients will be treated at the same dose level. Escalation will continue only if there has been 
no additional DLT observed. 
3.  If two or more patients experience DLT at a given dose, the previous dose will be declared 
the MTD. Should two or more patients experience the DLT at dose level 1, the study will be 
halted, and alternative combination dosing will be considered. 
4.  If only three patients were treated at a dose under consideration as the MTD, an additional 
three patients will be treated at that level to confirm previous results. 
 
Thus, the maximum number of patients that will be enrolled in the phase I portion is 18 (6 at each 
dose level). The probability of escalation given different true rates of dose-limiting toxicity is given 
below 
 
Toxicity rate 
0.10 
0.20 
0.30 
0.40 
. 0.50 
. Probability of escalation 
. 91% 
. 71% 
. 49% 
. 31% 
. 17% 
 
 
The MTD will be the phase 2 recommended dose.  However, if the MTD is not exceeded at dose 
level 3, then dose level 3 will be the phase 2 recommended dose. At the completion of the phase 1 
portion, 6 patients will have been treated at the MTD. These patients will be followed for response 
assessment and included in the phase 2 portion of the study. A minimum of 2 and a maximum of 18 
patients will be enrolled in this phase. Given an expected accrual rate of 2 patients per month, the 
phase 1 portion of the study will be completed in within 9 months or less. 


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Phase II 
Primary objective:  to determine the efficacy of the combination of erlotinib and ruxolitinib in patients 
with EGFR-mutant lung cancer and acquired resistance to EGFR tyrosine kinase inhibitors. 
 
Secondary objective: to determine overall survival and response rate and further assess the toxicity 
of the combination at the MTD. 
 
Methods: A Simon minimax two-stage trial design will be utilized to assess the primary endpoint of 
response rate (RECIST 1.1 CR+PR) at 6 weeks (2 cycles). This study will test the null hypothesis of 
10% response rate against the alternative hypothesis of 30% response rate for patients with 
acquired resistance. 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, 16 patients will be treated.  Patients included in the phase 1 trial that were treated at 
the recommended phase 2 dose will be included toward accrual to the phase 2 portion. If 0-1 
responses are seen in the first 16 patients, the trial will be stopped and declared negative.  If 2 or 
more patients have a response, than an additional 9 patients will be accrued to the second stage. At 
the end of the study, if 5 or more patients have a response out of a total of 25 patients enrolled, the 
combination of ruxolitinib 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 don’t experience the event of interest. Disease control rate will be calculated 
by the sum of partial responses, complete responses and stable disease. 
Safety and tolerability will be summarized using descriptive statistics. The toxicities and the adverse 
events will be assessed for each patients according to NCI CTCAE version 4.0 criteria. The serious 
toxicities will be described separately. The safety population will comprise of all the patients who 
receive at least one dose of MTD treatment. 
 
A minimum of 10 and a maximum of 19 patients will be enrolled in this phase, in addition to the 6 
patients carried over from the Phase I MTD level. 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. 
 
Correlative Studies 
 
Objectives: Exploratory objectives include analyzing biopsies obtained at the time of development of 
acquired resistance to EGFR TKIs to identify the mechanism of resistance in each sample. In 
addition, peripheral blood will be collected to obtain exosomes for further study. Within tumor 
exosomes, we will assess for the presence of EGFR T790M and also do immunohistochemical 
stains to quantitate protein expression. 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 I and phase II portions of this clinical trial. 
 
Methods:  EGFR T790M status will be determined for the biopsy samples obtained at the time of 
acquired resistance to EGFR TKI monotherapy. The proportion of patients with T790M mutation will 
be calculated, along with the exact 95% confidence interval. The expression of proteins such as 
phospho-EGFR, phospho-sTAT3, phospo-ERK, phospho-AKT, Her2 and Her3 will be quantified by 
using immunohistochemical (IHC) in these biopsy tissues and reported as a proportion of patients 
with each IHC score. 
 
Small amount of peripheral blood will be collected at pre-determined time points such as C1D1 (pre- 
treatment), C1D8 (one week into the first treatment cycle), and then every 2 cycles, corresponding to 
when a radiographic  assessment on protocol will be reviewed, for obtaining exosomes. The status 
of phospho-EGFR, phospho-sTAT3, phospo-ERK, phospho-AKT, Her2 and Her3 in the exosomes 


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will be quantified using IHC. Results are expressed as scores (1+, 2+ etc) or counts and will be 
summarized at each time points using descriptive statistics (mean±std). Graphical methods will be 
used to evaluate the way protein expression changes during the course of treatment. Immune cells 
(CD33+ MDSCs, CD4 and CD8 cells) will be serially quantified by FACS analysis at C1D1, C1D8 
and then every 2 cycles, and summarized at each time point using descriptive statistics (mean±std) 
and graphical methods. 
 
With the exception of T790 determination in biopsy tissue, the correlative analyses will be 
exploratory and hypothesis generating. 
 
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 
 
Both Phase 1 and 2 of this trial are single arm studies.  As such, no randomization will occur. 
 
16.0 
DATA MANAGEMENT ISSUES 
 
This trial will be conducted in accordance with the Memorial Sloan-Kettering Cancer Center’s Data 
Safety and Monitoring Plan. 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. 
 
The immunohistochemical and exosome results will not be reported in the EMR; rather, these 
studies will be conducted and their results stored by Dr Jacqueline Bromberg and her lab on 
password-protected computers.  Patients will have a unique study identifier, and all PHI will be 
removed linking the samples in the laboratory to patients. 
 
16.1 
Quality Assurance 


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There will be weekly teleconferences attended by the Principal Investigators and research study 
personnel. The clinical status of enrolled patients will be reviewed during the meeting with specific 
attention to study-related toxicity. 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. 
 
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%20Quality%20A 
ssurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Plan.pdf 
 
 
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 
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 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 and serial 
cardiac monitoring. Specific guidelines for symptom management are in place to protect the study 
participant. 


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Human Subjects Involvement and Characteristics: All patients at MSKCC who meet the inclusion 
criteria will be eligible. 3-18 patients will be enrolled unto the phase 1 portion, and and addition 3-19 
patients will be enrolled onto the Phase 2 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 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 combination of ruxolitinib and erlotinib has the potential to be effective and induce 
tumor responses 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, ruxolitinib. The research studies will be covered with separate research funding and 
no charges associated with research will be billed to the patient.  CLIA-certified mutation testing (i.e. 
EGFR mutation by fragment analysis, Sequenom or standard sequencing) will be billed to the 
patient/patient’s insurance. 
 
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 (eg. qualified monitors from MSKCC) and external personnel (e.g. qualified monitors from 
Astellas (the manufacturer of erlotinib), its authorized agents, 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 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. 


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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 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar days. The 
IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted electronically to the 
SAE Office at  sae@mskcc.org. The report should contain the following information: 
 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
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 
• 
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 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office. 
 
17.2.1 Adverse Even Reporting to Incyte Corporation 
 
All Serious Adverse Events (“SAE”) required to be reported pursuant to the Protocol shall be proved 
to Incyte and its representatives by Institution or Principal Investigator within 24 hours of learning of 
the event as well as provide any additional reports agreed upon by the Institution or Principal 
Investigator and Incytes contact below. SAE Reports will be sent to the email address provided 


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below. By sending to this email address, the Incyte Pharmacovigilance group and the Incyte clinical 
operations project manager will receive copies of the reports. This process will be tested and 
established before the first patient is enrolled in the trial. The Institution or Principal Investigator will 
have the primary responsibility of reporting adverse events (“AE”) to regulatory authorities. 
 
Copies of IND Safety reports submitted to the FDA by the institution under the Institution’s IND will 
be shared with the contact below so that these reports can be evaluated and included in investigator 
brochures or Incyte IND safety submissions as required to ensure safety of other patients who are 
receiving the product from Incyte for sponsored trials. 
Incyte Corporation: IncytePhVOps@incyte.com or email transmission of individual SAE reports; 
Safety Contact: 
Kathy Lenard Roberts, Exec. Dir, Incyte Pharmacovigilance 
Phone: 302-498-6727 
Fax: 302-425-2780 
Robert Livingston, MD, Exec. Director, Incyte Pharmacovigilance 
Phone: 302-498-7098 
Fax: 302425-2780 
 
Principal Investigator shall provide Incyte or its contacts above with copies of IND safety reports 
every 6 months in the format of a line listing with details regarding the reports that were submitted to 
the FDA. Individual submissions will be provided to Incyte upon request. 
 
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. 
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. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-043 A(3) 
Amended: 04/14/15 
Page  32 of 33 
 
 
 
19.0 
REFERENCES 
 
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lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an 
open label, randomised phase 3 trial. Lancet Oncol, 2010. 11(2): p. 121-8. 
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Maemondo, M., et al., Gefitinib or chemotherapy for non-small-cell lung cancer with mutated 
EGFR. N Engl J Med, 2010. 362(25): p. 2380-8. 
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resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second 
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Riely, G.J., et al., Prospective assessment of discontinuation and reinitiation of erlotinib or 
gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of 
everolimus. Clin Cancer Res, 2007. 13(17): p. 5150-5. 
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Kim, S.M., et al., Activation of IL-6R/JAK1/STAT3 signaling induces De Novo resistance to 
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Harada, D., et al., JAK2-related pathway induces acquired erlotinib resistance in lung cancer 
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Gao, S.P., et al., Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 
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Gao SP, M.N., Bournazou I, et al, Negative feedback regulation of EGFR by JAK2 in 
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Eghtedar, A., et al., Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with 
refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. 
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MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-043 A(3) 
Amended: 04/14/15 
Page  33 of 33 
 
 
18. 
Yeo, W.L., et al., Erlotinib at a dose of 25 mg daily for non-small cell lung cancers with EGFR 
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Satoh, H., et al., Low-dose gefitinib treatment for patients with advanced non-small cell lung 
cancer harboring sensitive epidermal growth factor receptor mutations. J Thorac Oncol, 
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Verstovsek, S., et al., Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in 
myelofibrosis. N Engl J Med, 2010. 363(12): p. 1117-27. 
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Sanderson, M.P., et al., Generation of novel, secreted epidermal growth factor receptor 
(EGFR/ErbB1) isoforms via metalloprotease-dependent ectodomain shedding and exosome 
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20.0 
APPENDICES 
 
N/A