MATCH Treatment Subprotocol C2: Crizotinib in Patients With Tumors With MET Exon 14 Deletion
Phase: PHASE2
Conditions: Advanced Lymphoma, Advanced Malignant Solid Neoplasm, Refractory Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Multiple Myeloma
Sponsor: National Cancer Institute (NCI)

 
i 
28 State Street, Suite 1100, Boston, MA 02109 
p: 857.504.2900 
f: 617. 589.0914 
ecog-acrin.org 
 
 
August 19, 2020 
 
Martha Kruhm, MS RAC 
Head, Protocol and Information Office 
Quality Assurance Section 
CTEP, DCT, NCI  
6130 Executive Blvd, EPN Room 7000 
Bethesda, MD   20892 
Dear Ms. Kruhm: 
 
Enclosed is Addendum #25 to EAY131-C2, Crizotinib in Patients with Tumors with MET Exon 
14 Deletion 
 
This addendum is in response to Dr. Tali Johnson’s Amendment Request for updates to specific 
protocol language for Crizotinib dated June 5, 2020. 
 
Please replace your current copy of the protocol and Informed Consent document with these 
updated versions. We recommend that each institution maintain a file containing the original 
protocol, Informed Consent, and all subsequent revisions/versions. 
IRB Review Requirements: 
This addendum has been reviewed and approved by the Central IRB, which is the sole 
IRB of record for this study. Local IRB review and approval is unnecessary. 
Implementation of this addendum must occur on the activation date. Sites are not 
permitted to conduct the study utilizing outdated versions of any MATCH protocol documents 
after the activation date of this addendum. 
The following revisions to EAY131-C2 protocol have been made in this addendum: 
 
Section 
Change 
1. 
Cover Page 
Updated Version Date and addendum number. 
2. 
Appendix III 
Updated patient drug information template format.  
The following revisions to EAY131-C2 Informed Consent Document have been made in this 
addendum: 
 
Section 
Change 
1. 
Page 1 
Updated Version Date. 
If you have any questions regarding this addendum, please contact aagu@ecog-acrin.org or 
857-504-2900. 

ii 
We request review and approval of this addendum to EAY131-C2 so ECOG-ACRIN may 
activate it promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Senior Director of Protocol Development 
 
 

 
EAY131-C2 
1 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol C2: Crizotinib in Patients 
with Tumors with MET Exon 14 Deletion 
CRIZOTINIB TREATMENT SUBPROTOCOL  
CHAIR: 
 
David S. Hong, MD 
CRIZOTINIB TRANSLATIONAL  
CHAIR:  
 
Daniel Catenacci, MD 
Version Date:  August 19, 2020 
NOTE: This subprotocol (EAY131-C2) should 
be used in conjunction with the MATCH 
Master Protocol (EAY131) 
NOTE: As of 11/17, all protocol changes will be 
noted by addendum number. 
 
SUBPROTOCOL ACTIVATION DATE 
 
May 31, 2016 (Incorporated in Addendum #3) 
 
Addendum #5 – 12/16 
Addendum #7 – 3/17 
Addendum #11 – 8/17 
Addendum #13 
Addendum #16 
 
 
Addendum #18 
 
 
Addendum #19 
 
 
Addendum #24 
 
 
Addendum #25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Agent 
IND# 
NSC# 
Supply 
Crizotinib 
IND Sponsor:  DCTD, NCI IND#: 
 
749005 
NCI Supplied 
 
Rev. Add13 
Rev. Add19 

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Table of Contents 
Molecular Analysis for Therapy Choice (MATCH) ...................................................... i 
MATCH Treatment Subprotocol C2: Crizotinib in Patients with Tumors with MET 
Exon 14 Deletion ................................................................................................. 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 4 
1. Introduction ........................................................................................................ 5 
1.1 Crizotinib ................................................................................................... 5 
1.2 Supporting Preliminary Data ..................................................................... 7 
1.3 MET exon 14 Skipping Criteria .................................................................. 9 
2. Selection of Patients ......................................................................................... 10 
2.1 Registration to Treatment ....................................................................... 10 
3. Crizotinib Treatment Plan ................................................................................. 12 
3.1 Administration Schedule ......................................................................... 12 
3.2 Adverse Event Reporting Requirements ................................................. 12 
3.3 Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Crizotinib (PF-02341066, NSC 749005) ................................................... 15 
3.4 Dose Modifications ................................................................................. 19 
3.5 Supportive Care ....................................................................................... 21 
3.6 Duration of Agent-specific treatment ..................................................... 23 
3.7 Duration of Follow-Up ............................................................................. 23 
4. Study Parameters .............................................................................................. 24 
4.1 Therapeutic Parameters for Crizotinib Treatment ................................. 24 
5. Drug Formulation and Procurement ................................................................. 26 
5.1 Crizotinib (NSC #749005) ........................................................................ 27 
6. Translational Studies ......................................................................................... 28 
7. References ........................................................................................................ 28 
Appendix I  Patient Pill Calendar ............................................................................. 31 
Appendix II  CYP3A4 Inducers and Inhibitors .......................................................... 33 
Appendix III  PATIENT CLINICAL TRIAL WALLET CARD ............................................. 34 
Appendix IV  Medications That May Cause QTc Prolongation ................................ 35 
Appendix V  Actionable Mutations for Sub-Protocol EAY131-C2 ............................ 37 
Appendix VI  CS-MATCH-0008  Confirmation of low-level MET exon 14 skipping 
(Arm C2) ............................................................................................................ 38 
 
 
 
Rev. 3/17 

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TREATMENT SUBPROTOCOL CHAIR 
David S. Hong, MD 
University of Texas M.D. Anderson Cancer Center 
1515 Holcombe Blvd 
Houston TX 77030 
Phone: 713-563-5844 
Fax: 713-563-0566 
Email: dshong@mdanderson.org 
 
TRANSLATIONAL CHAIR 
Daniel Catenacci, MD 
Univeristy of Chicago 
900 E 57th St, Suite 7128 
Chicago, IL 60637 
Phone: 773-702-7596  
Fax: 773-702-9268 
Email: dcatenac@bsd.uchicago.edu 
 
 
 
 
 

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Schema 
Long-Term Follow-Up
Crizotinib 250 mg PO BID
Until progression or 
unacceptable toxicity
Cycle = 28 days
Accrual Goal: 35
 
 

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1. 
Introduction 
1.1 
Crizotinib  
1.1.1 
Background 
Deregulated signaling by the epithelial cell receptor tyrosine kinase 
(RTK), MET, appears critical to the growth, invasion, and metastasis 
of many solid tumors. Under physiological conditions, MET and its 
ligand, hepatocyte growth factor (HGF), regulate pathways essential 
for embryogenesis, liver regeneration and wound healing. HGF 
initiates these pathways by inducing MET dimerization and 
autophosphorylation which activates signaling cascades that promote 
cell proliferation, migration, matrix invasion and branching 
morphogenesis (Birchmeier et al., 2003; Comoglio et al., 2008; Naran 
et al., 2009) HGF can also drive aberrant MET signaling in cancer 
through autocrine loops(Catenacci et al., 2011); however, MET 
activation also occurs independently of HGF via gene amplification 
and consequent MET over-expression (Smolen et al., 2006) as well 
as, more rarely, mutation and/or cross-talk with RTKs and other 
receptors. 
MET exon 14 skipping can result in decreased ubiquitination and 
delayed downregulation of the receptor after ligand stimulation (Chi et 
al. 2011). Crizotinib is an oral small-molecule inhibitor of ALK, MET, 
and ROS1 receptor tyrosine kinases. It was first discovered through a 
screen of inhibitors of MET, the receptor for HGF. Crizotinib has 
demonstrated preclinical and early clinical activity in cancers identified 
by MET gene amplification and exon 14 deletion (Paik et al. 2015). 
There has been early activity as monotherapy in cell lines and early 
case reports of  lung cancer and other cancers harboring exon 14 
deletion(Chi et al. 2011; Gandhi et al. 2012; Kwak et al. 2010; 
Sampson et al. 2011; Sen et al. 2011). Multiple types of tumors have 
been found to have MET exon 14 deletion with prevalence overall of 
0.6%  in more than 38,000 tumors tested by Foundation Medicine., 
and up to 3% of NSCLC and 0.4% of cancers of unknown primary 
(Gandhi et al. 2012). Recently, 14 of 230 patients were found to have 
MET exon 14 deletions (3 gastric cancer, 4 colon cancer, 5 non-small 
cell lung cancer, and one adenocarcinoma of unknown primary) 
(Shaw et al. 2012), which were associated with MET overexpression 
but rarely with MET amplification. 
However, the story of MET in all cancers is not entirely clear. For 
example onartuzumab, an antibody that targets the MET receptor, 
combined with erlotinib, showed improved progression free and 
overall survival in the MET positive (assessed by IHC)  lung cancer 
population in a phase II trial, but failed to show a difference in 
progression free or overall survival in a large randomized phase 3 trial 
of onartuzumab in combination to erlotinib compared to erlotinib alone 
in non-small lung cancer (median 2.7 versus 2.6 months, P=0.92). 
Moreover the overall survival trended in favor of erlotinib alone (9.1 
months vs 6.8 on the combination m p=0.07). (Spigel et al, ASCO 
2014). 

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Likewise, in the Phase III Multinational, Randomized, Double-Blind, 
Placebo-Controlled Study of Tivantinib (ARQ 197) Plus Erlotinib 
Versus Erlotinib Alone in Previously Treated Patients With Locally 
Advanced or Metastatic Nonsquamous Non–Small-Cell Lung Cancer 
Scagliotti et al (2015) reported that the study was ended early for 
futility and did not improve overall survival. However, in a preplanned 
subgroup exploratory analysis, of 211 patients with high MET 
expression by IHC,  the combination of erlotinib and tivantinib had 
improved median overall survival (9.3 vs 5.9 months). 
The reasons for failure of these trials in NSCLC is not fully 
understood, but may be due to differences in how MET activation, 
amplification or overexpression were measured.  Others have shown 
that MET maybe a valid target in MET amplified NSCLC. For 
example, D. Ross Camidge showed that durable responses were 
seen in MET high amplified NSCLC patients treated with criztoinib (D. 
Ross Camidge et al, ASCO 2014). In addition, activation of the MET 
signaling pathway by  molecular variants that result in MET exon 14 
skipping may also be a valid target. Tumors harboring such changes 
have responded to crizotinib (Paik et al, 2015). 
Crizotinib is an inhibitor of the MET, ALK, and ROS1 receptor tyrosine 
kinases that was recently approved by the Food and Drug 
Administration for treatment of ALK-positive non-small cell lung 
cancer (NSCLC) because of a striking response rate in those tested 
positive for ALK rearrangement. ALK rearrangement can also be 
found in a subset of patients with sarcoma, breast cancer, and 
lymphoma, but their response to this agent is as of yet unknown. 
Recently, Crizotinib also was FDA approved to treat ROS1 positive 
tumors because it was shown to be highly active in the treatment of 
lung cancer harboring ROS1 gene rearrangement (Shaw, et al., 2012 
and its activity as a MET inhibitor in tumors with MET amplification is 
considerable(Tanizaki, et al, 2011; Ou et al., 2011). Despite a proven 
efficacy in these genetic subsets of cancers, acquired or intrinsic 
resistance is common and leads to tumor progression, highlighting the 
need to combine this drug with other agents. 
Crizotinib is an oral small-molecule inhibitor of ALK, MET, and ROS1 
receptor tyrosine kinases. It was first discovered through a screen of 
inhibitors of MET, the receptor for HGF. The kinase selectivity of 
crizotinib was evaluated against a panel of more than 120 human 
kinases; crizotinib inhibited autophosphorylation of both MET and ALK 
with high potency and specificity (Cui et al, 2011). 
Crizotinib demonstrated concentration-dependent inhibition of ALK 
and MET phosphorylation in cell-based assays using tumor cell lines 
and demonstrated antitumor activity in mice bearing tumor xenografts 
that expressed EML4- or NPM-ALK fusion proteins or MET. 
The IC50 of crizotinib in blocking MET phosphorylation and MET 
dependent cell growth and invasion in a variety of cell lines is 5-20 nM 
(Cui et al, 2011). Crizotinib blocks cell proliferation and enhances 
apoptosis in NSCLC lines carrying an EML4-ALK fusion in the range 
of 250-340 nM. Based upon clinical pharmacokinetic data, more than 

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70% of ALK inhibition is projected at the FDA-approved dose of 250 
mg twice a day and, thus, a highly MET inhibition is also expected at 
this dose (Gandhi et al., 2012). 
1.2 
Supporting Preliminary Data  
1.2.1 
Crizotinib Preclinical Pharmacology and Efficacy 
In the preclinical setting, crizotinib blocks MET activation across 
multiple tumor types. Data were generated in gastric and breast 
carcinoma cells, prostate, squamous head and neck cancer, 
osteosarcoma, ovarian cancer and renal cancer (Zou et al., 2007). 
Convincing pre-clinical evidence for induction of apoptosis by 
crizotinib in gastric cancer cells with MET amplification has been 
published (Sampson et al, 2011). Crizotinib also showed in the lab to 
induce cell death in head and neck cancer when combined with 
dasatinib in cells that were previously resistant to this drug (Sen et al, 
2011). 
1.2.2 
Summary of Clinical Experience 
Crizotinib is approved for use in patients with advanced NSCLC who 
have evidence of anaplastic lymphoma kinase (ALK)-positive tumor 
as detected by the FDA approved test for the EML4-ALK gene fusion. 
This alteration is observed in about 5% of patients with NSCLC. The 
response rates seen in early-phase studies in ALK-positive NSCLC 
led to the accelerated FDA approval of crizotinib in this setting (Kwak 
et al., 2010). In addition to ALK inhibition in NSCLC, there is clinical 
evidence of efficacy of crizotinib in NSCLC harboring ROS1 
rearrangements and in inflammatory myofibroblastic tumor (IMT) and 
anaplastic large-cell lymphoma (ALCL) with ALK aberrations. 
Moreover, crizotinib has shown clinical efficacy in MET amplified 
NSCLC, esophagogastric adenocarcinoma and glioblastoma. 
In a patient with advanced NSCLC whose tumor was identified as 
harboring de-novo MET amplification but no ALK rearrangement by 
FISH (Ou et al., 2011), treatment with crizotinib resulted in rapid tumor 
shrinkage and partial response. This validated MET amplification as a 
molecular driver that could be therapeutically targeted with MET 
inhibitors. Lennerz et al. reported 2 cases of MET-amplified 
esophagogastric cancers which exhibited tumor shrinkage in 
response to crizotinib, again supporting a role for MET inhibitor 
therapy in MET-amplified tumors  (Lennerz et al, 2011). Furthermore, 
a case report of a patient with a -MET amplified glioblastoma 
described a rapid clinical improvement and a 40% reduction in the 
central lesion while receiving crizotinib (Chi et al, 2011). Progression 
was detected after 6 months of crizotinib initiation. Paik et al (Paik PK 
et al. Cancer Discov 2015; 5(8): 842-9) have reported responses to 
crizotinib in NSCLC patients whose tumors manifest changes that 
result in MET exon 14 skipping. 

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Pharmacokinetics 
Absorption  
The Phase I trial of crizotinib showed that patients treated at the 
recommended phase 2 dose (RP2D) were noted to achieve a Cmax 
of the drug at a median Tmax of 4 hours with a terminal half-life of 42 
hours following a single oral dose. Steady-state levels were reached 
within 15 days, with a non-linear pharmacokinetics as reflected by 
decreases in CL/F observed with multiple doses. Steady state 
systemic exposure (Cmin and AUC) appeared to increase in a greater 
than dose proportional manner over the dose range of 200-300 mg 
twice daily.  
The mean absolute bioavailability of crizotinib was 43% (range: 32% 
to 66%) following the administration of a single 250 mg oral dose. A 
high-fat meal reduced crizotinib AUC and Cmax by approximately 
14%. A mouse model showed that the EC50 for ALK inhibition 
approximately corresponded to the EC50 for tumor growth inhibition, 
suggesting that >50% of ALK inhibition would be required for tumor 
killing of >50%. Based in a non clinical mouse xenograft model more 
than 70% of ALK inhibition is projected in lung cancer patients taking 
the usual dose of crizotinib, 250 mg twice daily. 
Distribution 
The geometric mean volume of distribution (Vss) of crizotinib was 
1,772 L following intravenous administration of a 50 mg dose, 
indicating extensive distribution into tissues from the plasma. Binding 
of crizotinib to human plasma proteins in vitro is 91% and is 
independent of drug concentration. In vitro studies suggested that 
crizotinib is a substrate for P-glycoprotein (P-gp). The blood-to-plasma 
concentration ratio is approximately 1.  
Metabolism 
In vitro studies demonstrated that crizotinib is predominantly 
metabolized by CYP3A4/5(package insert). Additional information is 
found in Section 5.1.8. The primary metabolic pathways in humans 
were oxidation of the piperidine ring to crizotinib lactam and O-
dealkylation, with subsequent Phase 2 conjugation of O-dealkylated 
metabolites. In vitro studies in human liver microsomes demonstrated 
that crizotinib is a time-dependent inhibitor of CYP3A. 
Elimination 
Following single doses of crizotinib, the mean apparent plasma 
terminal half-life of crizotinib was 42 hours in patients. Following the 
administration of a single 250 mg radiolabeled crizotinib dose to 
healthy subjects, 63% and 22% of the administered dose was 
recovered in feces and urine, respectively. Unchanged crizotinib 
represented approximately 53% and 2.3% of the administered dose in 
feces and urine, respectively. 
The  mean apparent clearance (CL/F) of crizotinib was lower at 
steady state (60 L/hr) after 250 mg twice daily than that after a single 

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250 mg oral dose (100 L/hr), which was likely due to autoinhibition of 
CYP3A by crizotinib after multiple dosing. 
1.3 
MET exon 14 Skipping Criteria 
Patient’s RNA from tumor will be sequenced and if patient has MET exon 14 
deletion and meets other eligibility requirements, the patient will be entered; 
Tumor measurements every other cycle. This is part of a multi-arm trial with no 
randomization. Selection to each arm is based on genetic screening. All patients 
on this arm will be treated with crizotinib at 250 mg twice daily approximately 12 
hours apart. Cycles will be 28 days. 
The primary endpoint is objective response (OR), defined as a complete or 
partial response, which is defined consistent with RECIST version 1.1 criteria for 
solid tumors and the Cheson (2014) criteria for lymphoma patients. After 
completing participation in a given treatment sub-study, patients may enroll on 
additional sub-studies if they have another actionable mutation and meet the 
eligibility requirements. Such patients will be counted toward the accrual, and 
their data will be included in the primary analysis, for any sub-studies in which 
they participated and were confirmed eligible. Patients who are determined to be 
ineligible for an arm on which they are initially enrolled, or who do not start 
treatment on that arm, will be excluded from the primary analysis for the arm. 

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2. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met, along with the eligibility in 
the main screening study, in order for a patient to be considered eligible for this study. 
Use the checklist to confirm a patient’s eligibility. For each patient, this checklist must be 
photocopied, completed and maintained in the patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
All CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies deviations.htm). 
Therefore, all eligibility criteria listed in Section 2 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 2 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit. All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.Execofficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
NOTE: 
All patients must have signed a relevant treatment consent form 
2.1 
Registration to Treatment  
2.1.1 
Patient must fulfill all eligibility criteria outlined in Section 3.1 of 
MATCH Master protocol (excluding Section 3.1.6) at the time of 
registration to treatment step (Step 1, 3, 5, 7). 
2.1.2 
Patient must have MET exon 14 skipping as defined via the MATCH 
Master Protocol and described in Appendix V or other mutations that 
disrupt exon 14 that are approved as a dynamic aMOI. See Appendix 
V for information on the mutations and corresponding Levels of 
Evidence. 
2.1.3 
Patients must have an electrocardigram (ECG) within 8 weeks prior to 
treatment assignment and must not have clinically important 
abnormalities in rhythm, conduction or morphology of resting ECG, 
including complete left bundle branch block, third degree heart block. 
Date of ECG:  _______________ 
2.1.4 
Patients must not have known hypersensitivity to crizotinib or 
compounds of similar chemical or biologic composition. 
Date:  _______________ 
_____
_____
_____
_____
Rev. Add13 
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2.1.5 
Patient must not have had any of the following prior therapies: AMG 
337, BMS 777607, Cabozantinib (XL184), Crizotinib (PF02341066), 
EMD1214063, Foretinib (GSK1363089) (XL880), Golvatinib (E7050), 
IncB28060 (INC280), JNJ 8877605, MGCD265, MK2461, 
MSC2156119J, PF 04217903, SGX523, Tivantinib (ARQ197) or any 
other novel MET TKI with any MET inhibitory activity IC50 < 1 uM. 
Prior anti-HGF or anti-MET antibodies are acceptable. 
2.1.6 
Patients must not have a history of extensive disseminated/bilateral or 
known presence of Grade 3 or 4 interstitial fibrosis or interstitial lung 
disease, including a history of pneumonitis, hypersensitivity 
pneumonitis, interstitial pneumonia, interstitial lung disease, 
obliterative bronchiolitis, and pulmonary fibrosis, but not history of 
prior radiation pneumonitis. 
2.1.7 
Patients must not have had myocardial infarction, severe/unstable 
angina, coronary/peripheral artery bypass graft, congestive heart 
failure, or cerebrovascular accident including transient ischemic attack 
within 3 months prior to start of study treatment * Clinically significant 
GI abnormalities that may alter absorption (e.g., malabsorption 
syndrome, major resection of stomach or small bowel). 
2.1.8 
Patients using drugs or foods that are known strong CYP3A4 
inhibitors or inducers will be excluded. Patients must not require 
concurrent use of CYP3A substrates with narrow therapeutic indices.  
Please see Appendix II. 
2.1.9 
Patients must not have had major surgery or tumor embolization 
within 4 weeks and minor surgery within 2 weeks prior to the initiation 
of the study drug. 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 
_____
_____
_____
_____ 
_____

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3. 
Crizotinib Treatment Plan 
3.1 
Administration Schedule 
Study Drug: Crizotinib 
Crizotinib capsules, 250 mg, will be administered orally twice daily on a 
continuous daily dosing schedule. Crizotinib should be taken approximately 12 
hours apart and without regard to meals. Cycles are defined in 28-day periods to 
facilitate scheduling of visits and assessments. 
Patients should be instructed that if they vomit after taking a dose, then they 
must not “make it up” with an extra dose, but instead, resume subsequent doses 
as prescribed. Capsules should not be crushed. Any missed dose may be taken 
up to 6 hours prior to the next schedule dose, otherwise it should be skipped and 
dosing resumed with subsequent doses. 
3.2 
Adverse Event Reporting Requirements 
The Adverse Event Reporting Requirements for all EAY131 subprotocols are 
outlined in the MATCH MASTER protocol. Please refer to those guidelines when 
determining if an event qualifies as a Serious Adverse Event (SAE) and requires 
expedited reporting via CTEP’s Adverse Event Reporting System (CTEP-AERS).  
In addition, the following section outlines agent specific requirements and must 
be followed to ensure all reporting requirements are met. 
3.2.1 
Additional adverse event reporting instructions, requirements and 
instructions for protocol EAY131 – Subprotocol C2 
Additional Instructions 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, 
or birth defect events via CTEP-AERS, please contact the AEMD 
Help Desk at aemd@tech-res.com or 301-897-7497. This will 
need to be discussed on a case-by-case basis. 
 
EAY131-C2 specific expedited reporting requirements: 
• 
Pregnancies: Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless 
of age or disease state) occurring while the subject is on 
crizotinib, or within 28 days of the subject’s last dose of 
crizotinib, are considered immediately reportable events. The 
pregnancy, suspected pregnancy, or positive/ inconclusive 
pregnancy test must be reported via CTEP-AERS within 24 
hours of the Investigator’s knowledge. Please refer to Appendix 
VIII in MATCH screening protocol for detailed instructions on 
how to report the occurrence of a pregnancy as well as the 
outcome of all pregnancies. 
 
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EAY131-C2 specific expedited reporting exceptions: 
For study Subprotocol C2, the adverse events listed below do not 
require expedited reporting via CTEP-AERS: 
• 
If an AE meets the reporting requirements of the protocol, and 
it is listed on the SPEER, it should ONLY be reported via 
CTEP-AERS if the grade being reported exceeds the grade 
listed in the parentheses next to the event. 
3.2.2 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
• 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. 
Complete a Second Primary Form in Medidata Rave within 
14 days. 
2. 
Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. 
If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-
ACRIN via Medidata Rave. 
• 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. 
Complete a Second Primary Form in Medidata Rave within 
14 days 
2. 
Report the diagnosis via CTEP-AERS at 
http://ctep.cancer.gov  
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
3. 
Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming 
the diagnosis. 
4. 
If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-
ACRIN via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 

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NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form. 

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INFECTIONS AND INFESTATIONS - Abdominal infection; Infections and infestations - Other 
(peridiverticular abscess); Kidney infection; Lung infection; Sepsis; Skin infection; Urinary tract 
infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Injury, poisoning and 
procedural complications - Other (traumatic lung injury); Spinal fracture; Wound complication 
INVESTIGATIONS - Blood lactate dehydrogenase increased; CPK increased; GGT increased; 
Investigations - Other (monocyte count increased); Investigations - Other (platelet count 
increased); Platelet count decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hyperkalemia; 
Hypermagnesemia; Hypertriglyceridemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; 
Hyponatremia; Hypophosphatemia; Metabolism and nutrition disorders - Other 
(hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; 
Musculoskeletal and connective tissue disorder - Other (myopathy); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Treatment related secondary malignancy; Tumor hemorrhage 
NERVOUS SYSTEM DISORDERS - Intracranial hemorrhage; Ischemia cerebrovascular; 
Pyramidal tract syndrome; Seizure; Stroke 
PREGNANCY, PUERPERIUM AND PERINATAL CONDITIONS - Pregnancy loss 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Euphoria 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Renal calculi; Urinary 
retention 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Dyspnea; Pleural effusion; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (pneumomediastinum); Respiratory, thoracic and mediastinal 
disorders - Other (respiratory distress) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Skin and subcutaneous tissue disorders 
- Other (drug eruption) 
VASCULAR DISORDERS - Hematoma; Hypotension; Phlebitis; Thromboembolic event; 
Vasculitis 
NOTE: 
Crizotinib (PF-02341066) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, 
or the combination may result in events never previously associated with either 
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3.4 
Dose Modifications  
All toxicity grades below are described using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
All appropriate treatment areas should have access to a copy of the CTCAE 
version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website (http://ctep.cancer.gov). 
Patients will be monitored closely for toxicity and the dose of crizotinib may be 
adjusted as indicated in Table 3.5.  Intrapatient dose reduction by 1, and if 
needed, 2 dose level(s) will be allowed depending on the type and severity of 
toxicity encountered. 
Dose Level 
Crizotinib Dose 
1 
250mg BID 
-1 
200mg BID 
-2 
250mg Daily 
Patients requiring more than 2 dose reductions due to treatment-toxicity will be 
removed from treatment. Patients requiring treatment to be held for >4 weeks will 
be taken off treatment.  
Table 3.5 
Crizotinib Dose Modifications for Treatment-Related Toxicity 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Non- hematologic General 
(except as noted below), 
eg, neuropathy, edema 
(including peripheral 
edema and localized 
edema), fatigue, and skin 
rash (including 
erythematous, macular, 
papular, and pruritic rash) 
Continue 
at the 
same 
dose 
level. 
Continue at 
the same 
dose level. 
Withhold dose until toxicity is 
Grade ≤ 1, or has returned to 
baseline, then resume 
treatment at the same dose 
level or reduce the dose by 1 
level at the discretion of the 
investigator.* 
Withhold dose 
until toxicity is 
Grade ≤ 1, or has 
returned to 
baseline, then 
reduce the dose 
by 1 level and 
resume treatment, 
or discontinue at 
the discretion of 
the investigator*. 
Grade 3 or 4 alanine 
aminotransferase (ALT) or 
aspartate 
aminotransferase (AST) 
elevation with Grade ≤1 
total bilirubin 
Continue 
at the 
same 
dose 
level. 
Continue at 
the same 
dose level. 
Obtain 
repeat ALT 
and total 
bilirubin 
when 
symptomatic 
or within 7 
days. 
Withhold until recovery to 
Grade ≤1 or baseline, then 
resume at 200 mg twice 
daily. In case of recurrence, 
withhold until recovery to 
Grade ≤1, then resume at 
250 mg once daily. 
Permanently discontinue in 
case of further Grade 3 or 4 
recurrence. 
See Grade 3. 

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Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 2, 3 or 4 ALT or 
AST elevation with 
concurrent Grade 2, 3 or 4 
total bilirubin elevation (in 
the absence of cholestasis 
or hemolysis) 
Continue 
at the 
same 
dose 
level. 
Obtain 
repeat 
ALT and 
total 
bilirubin 
within 48 
hours. 
Discontinue 
treatment 
and do not 
retreat 
Discontinue treatment and do 
not retreat 
Discontinue 
treatment and do 
not retreat 
Left ventricular systolic 
dysfunction 
Continue 
at the 
same 
dose level 
Continue at 
the same 
dose level 
Discontinue treatment and do 
not retreat 
Discontinue 
treatment and do 
not retreat 
Prolonged QTc  
Continue 
at the 
same 
dose level 
Assess 
electrolytes 
and 
concomitant 
medications. 
Correct any 
electrolyte 
or 
magnesium 
abnormalitie
s 
Withhold until recovery to 
Grade ≤1, then resume at 
200 mg twice daily In case of 
recurrence, withhold until 
recovery to Grade ≤1, then 
resume at 250 mg once daily. 
Permanently discontinue in 
case of further Grade 3 or 4 
recurrence 
Discontinue 
treatment and do 
not retreat 
Pneumonitis (in absence 
of disease progression, 
pulmonary embolism, 
positive cultures or 
radiation effect) 
Discontin
ue 
treatment 
and do 
not retreat 
Discontinue 
treatment 
and do not 
retreat 
Discontinue treatment and do 
not retreat 
Discontinue 
treatment and do 
not retreat 
Visual disturbance 
Continue 
at the 
same 
dose 
level. 
Repeat 
ophthalm
ologic 
examinati
on+ 
Continue at 
the same 
dose level. 
Repeat 
ophthalmolo
gic 
examination
+ 
Interrupt crizotinib until 
recovery. Repeat 
ophthalmologic 
examination+. 
Resume treatment by 
reducing by one dose level. 
Discontinue 
treatment and do 
not retreat. 
Repeat 
ophthalmologic 
examination+. 
Hematologic (excluding 
lymphopenia**) 
Continue 
at the 
same 
dose 
level. 
Continue at 
the same 
dose level. 
Withhold dose until toxicity is 
Grade ≤ 2, or has returned to 
baseline, then resume 
treatment at the same dose 
level or reduce by 1 level 
after discussion with the 
study chair**/***. 
Withhold dose 
until toxicity is 
Grade ≤ 2, or has 
returned to 
baseline, then 
reduce the dose 
by 1 level and 
resume 
treatment**. 
Hypophosphatemia or 
hyperuricemia* 
Continue 
at the 
same 
dose level 
Continue at 
the same 
dose level 
Continue at the same dose 
level at investigator discretion 
Discontinue 
treatment until 
resolution to 
grade 3 or lower 

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* Patients who develop Grade 3 hyperuricemia or Grade 3 hypophosphatemia without clinical symptoms 
may continue study treatment without interruption at the discretion of the investigator. Nausea, 
vomiting or diarrhea must persist at Grade 3 or 4 despite maximal medical therapy, to require dose 
modification. 
** Patients who develop Grade 3 or 4 lymphopenia without other dose-limiting events (eg, opportunistic 
infection) may continue study treatment without interruption. 
*** Patients entering with platelet counts > 30,000 (to < 50,000/µL) will be monitored for drug related 
decreases at which point dose modifications will be discussed with the Sponsor 
§ Patients entering with ALT and/or AST ≥ 5 x ULN (ie, Grade ≥ 3) due to underlying malignancy will be 
monitored for potential drug related increases at which point dose modifications will be discussed with 
the Sponsor (Note: this option does not apply for France). 
+ Ophthalmologic examination includes visual acuity and slit lamp and should be performed by an 
ophthalmologist. 
3.4.1 
Missed Doses 
A missed dose will not be made up. In the event that a subject 
requires an unscheduled interruption of crizotinib under conditions 
other than those associated with toxicity, the case will be reviewed by 
the Study Chair to determine whether such a subject will be allowed to 
resume crizotinib treatment.  
3.5 
Supportive Care  
Throughout the duration of the study, all herbal supplements, vitamins, and 
nutritional supplements taken must be reviewed and approved by the Investigator 
prior to administration. 
3.5.1 
Nausea and emesis: For nausea and vomiting, treat with standard 
anti-emetics such as prochloroperazine or ondansetron. Patients 
should be counseled that taking the medication with food may reduce 
nausea. The use of prophylactic antiemetics should be considered. 
Given the potential for ondansetron to increase QTc prolongation, 
review baseline QTc EKG prior to initiation of ondansetron and 
consider follow up EKGs on treatment. 
3.5.2 
Diarrhea: For grade 1 diarrhea, symptomatic care such as loperamide 
(Imodium) or no intervention at investigator judgment. For grade 2 
diarrhea, loperamide (4 mg at first onset, then 2 mg every 2-4 hrs until 
symptom free for 12 hours). See Table 3.5.for instructions on dose 
modifications.  

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3.5.3 
Bradycardia:   
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Bradycardia 
(heart rate 
less than 60 
beats per 
minute) 
Continue 
at the 
same 
dose 
level. 
Withhold until recovery to Grade ≤ 1 
or to heart rate ≥ 60. 
Evaluate concomitant medications 
known to cause bradycardia, as well 
as anti-hypertensive medications. 
If contributing concomitant 
medication is identified and 
discontinued, or its dose is adjusted, 
resume at previous dose upon 
recovery to Grade ≤ 1 or to heart 
rate ≥ 60. 
If no contributing concomitant 
medication is identified, or if 
contributing concomitant medications 
are not discontinued or dose 
modified, resume at reduced dose 
upon recovery to Grade ≤ 1 or to 
heart rate ≥60. 
Same as for 
Grade 2 
bradycardia. 
Permanently 
discontinue if no 
contributing 
concomitant 
medication is 
identified. 
If contributing 
concomitant 
medication is 
identified and 
discontinued, or its 
dose is adjusted, 
resume at 250 mg 
once daily upon 
recovery to Grade  
≤ 1 or to heart rate  
≥ 60, with frequent 
monitoring. 
Permanently 
discontinue for 
recurrence. 
3.5.4 
Pneumonitis/pneumonia: Investigators must evaluate thoroughly 
patients who demonstrate potential signs or symptoms of pneumonitis 
or pneumonia. If a patient has a potential diagnosis of pneumonitis or 
drug-related lung injury, the following evaluations/procedures should 
be considered to assist or exclude the diagnosis of pneumonitis: 
• 
Evaluate for pneumonia: Pneumonia would be supported by 
clinical symptoms/signs of infection, including fever, leukocytosis, 
productive cough, characteristic radiologic findings, and most 
importantly, documentation of microbiology studies (sputum 
gram/stain and culture, blood cultures). Pneumonia should be 
treated with the appropriate antibiotics and supportive care. Many 
of these symptoms/signs may be seen in pneumonitis, but in this 
case, all microbiological studies would be negative (including 
possibly bronchoscopy for specimens). 
• 
Sputum gram stain and culture (induced sputum if needed), to 
evaluate for bacterial, viral, fungal, protozoal, and mycobacterial 
infections 
• 
Blood cultures if febrile 
• 
Thoracentesis if pleural fluid is present (examined for the same 
pathogens as in 3.6.4.1) 
• 
Bronchoscopy with bronchoalveolar lavage (BAL) if appropriate.  
BAL fluid should be sent for culture and cytology 
• 
Lung biopsy if appropriate and necessary to distinguish between 
pneumonia and pneumonitis 
• 
BNP levels to evaluate for heart failure 

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• 
If clinically appropriate, particularly if pneumonia can be ruled out, 
high dose corticosteroid treatment should be initiated. Should the 
event be fatal, an autopsy is recommended to confirm/exclude the 
diagnosis.  
3.5.5 
Renal cysts: Complex renal cysts have been reported in some 
patients treated with crizotinib. These cysts may be symptomatic or 
asymptomatic, and typically develop between 2 and 6 months after 
starting crizotinib. The precise nature and significance of these cysts 
is unclear. However, complex renal cysts can be associated with renal 
malignancy, so consultation with a urologist is recommended. 
Urinalysis should be performed if renal cysts are detected, and 
followed on Day 1 of each cycle thereafter. Urine reflex microscopy is 
required if the urinalysis demonstrates blood or protein. 
3.5.6 
Hypogonadism: For males reporting symptoms of hypogonadism 
(fatigue, sexual dysfunction, decreased libido, mood or sleep disorder, 
gynecomastia), a panel of blood tests should be drawn, including total 
testosterone, free testosterone, and sex-hormone binding globulin 
(SHBG). If free testosterone is low, consultation with endocrinology is 
recommended for possible testosterone supplementation. 
3.6 
Duration of Agent-specific treatment  
In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies: 
• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
MATCH Forms Packet. 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity. 
• 
Non-protocol therapies are administered. 
• 
Disease progression 
3.7 
Duration of Follow-Up  
Refer to the MATCH Master Protocol for specifics on the duration of follow-up. 
 
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4. 
Study Parameters 
4.1 
Therapeutic Parameters for Crizotinib Treatment  
NOTE: 
In addition to the study parameters listed in the MATCH Master Protocol, the below parameters must also be 
performed for patients receiving crizotinib treatment. 
NOTE: 
All assessments required prior to registration to treatment should be done ≤ 4 weeks prior to registration to 
Steps 1, 3, 5, 7, excluding the radiologic evaluation and electrocardiogram (ECG). 
Test/Assessment 
Prior to Registration 
to Treatment 
Treatment 
End of 
Treatment 
Follow UpF 
Every Cycle, prior to 
treatment 
Every 2 Cycles 
H&P, Weight, Vital signsA 
X 
XJ 
 
 
X 
Performance status 
X 
XJ 
 
 
X 
CBC w/diff, pltsB 
X 
XJ 
 
 
X 
Serum chemistryB 
X 
XJ 
 
 
X 
Radiologic evaluationD 
X 
 
XD 
 
XF 
β-HCGC 
X 
 
 
 
 
Toxicity AssessmentG 
 
X 
 
X 
XF 
Pill Count/DiaryH 
 
X 
 
X 
 
ECGK 
X 
XI 
 
 
 
Tumor biopsy and blood sample for MATCH 
Master protocolE 
 
 
X 
X 
 
A. History and physical, including vital signs and weight at the start of each cycle (up to 3 days before start of new cycle). Particular attention should 
be given to any signs of pulmonary fibrosis (shortness of breath, cough); these symptoms should be pursued with appropriate tests. Patients 
should be instructed to notify their provider if they have increased shortness of breath or cough. 
B. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, creatinine, glucose, phosphorus, potassium,  SGOT[AST], SGPT[ALT], 
sodium, magnesium and serum tumor markers (including LDH, PSA if appropriate). For eligibility purposes, participants with creatinine levels 
above institutional normal, Cockcroft-Gault will be used to calculate creatinine clearance. CBC w/diff, platelets and serum chemistries should be 
performed on cycle 1, day 1 (or up to 7 days prior), and at the start of each subsequent cycle (up to 3 days before start of new cycle). CBC with 
differential will be performed more frequently in patients with grade 4 neutropenia or thrombocytopenia until resolution to ≤ grade 3. CBC and 
serum chemistries are only required in follow-up until values return to pre-treatment levels or until progressive disease. 
C. Blood pregnancy test (women of childbearing potential) required prior to beginning treatment. 
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D. Disease measurements are repeated every 2 cycles for the first 26 cycles, and every 3 cycles thereafter until PD or start of another MATCH 
treatment step. The baseline evaluation should be performed as closely as possible to the beginning of treatment and never more than 6 weeks 
before registration to treatment step. For multiple myeloma patients, please refer to Section 6.4 of the MATCH Master Protocol for additional 
information on myeloma response criteria and the required disease assessments. Documentation (radiologic) must be provided for patients 
removed from study for progressive disease. 
E. Additional blood specimens and/or biopsies are to be submitted from consenting patients per Section 9.3.2 of the MATCH Master Protocol. Submit 
at the following time points, as applicable: 
• 
Blood specimens are to be submitted at the end of Cycle 2 (prior to start of Cycle 3 treatment). If patient progresses or treatment is 
discontinued prior to Cycle 3, collect the blood at that time instead.  On-treatment kits for blood sample collections will be automatically 
shipped to sites upon registration to the treatment step. 
• 
Screening biopsies for additional aMOI assessments after registration to appropriate screening step, if applicable (Step 2 or Step 4). 
• 
At end of all MATCH study treatments, blood specimens and/or research biopsy after consent and registration to Step 8 
Please refer to Section 4 of the MATCH Master Protocol to determine whether the patient proceeds to the next screening step or to follow-up (with 
a potential end of treatment biopsy for research purposes on Step 8). Samples are to be submitted as outlined in Section 9 of the MATCH Master 
Protocol. To order Step 2/4 Screening or Step 8 kits, complete the EAY131 Collection and Shipping Kit Order Form (See Appendix XII of the 
MATCH Master Protocol) and fax to 713-563-6506. 
F. Every 3 months if patient is < 2 years from study entry, and every 6 months for year 3. Toxicity assessments and radiologic evaluations are not 
required to be done during Follow Up if progression has been previously reported; however if an adverse event occurs post treatment that meets 
the SAE reporting requirements, it still must be reported via CTEP-AERS, even if progression has occurred. 
G. Site personnel should evaluate for toxicity and discuss treatment compliance with the patient in order to ensure the medication is taken correctly; 
this evaluation may be conducted by telephone or in person. The Toxicity Assessment is not required prior to Cycle 1, but is required every 
subsequent cycle. 
H. The pill calendar will be collected at the end of every cycle. The Pill Count/Diary is not required prior to Cycle 1, but is required every subsequent 
cycle. 
I. As clinically indicated. 
J. For Cycle 1, if the following tests/assessments occurred within 7 days of Day 1, they do not need to be repeated at this timepoint: H&P, Weight, 
Vital Signs; Performance Status; CBC w/diff, plts; Serum chemistry; Concomitant Medications. 
K. Within 8 weeks of treatment assignment. 
 
 

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5. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. 
Availability 
NO STARTER SUPPLIES MAY BE ORDERED. Subjects must be enrolled and 
assigned to the treatment arm prior to submitting the clinical drug request to PMB. 
Drug Ordering: NCI supplied agents may be requested by eligible participating 
Investigators (or their authorized designee) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that drug be shipped 
directly to the institution where the patient is to be treated. PMB does not permit the 
transfer of agents between institutions (unless prior approval from PMB is obtained – 
see general information) The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents. The eligible participating 
investigators at each participating institution must be registered with CTEP, DCTD 
through an annual submission of FDA Form 1572 (Statement of Investigator), NCI 
Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are 
several participating investigators at one institution, CTEP-supplied investigational 
agents for the study should be ordered under the name of one lead investigator at that 
institution.  
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application (https://ctepcore.nci.nih.gov/OAOP). Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam/) and the maintenance of an “active” account status, a 
“current” password, and an active person registration status. 
NCI Supplied Agent(s) – General Information 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time. 
Drug Returns: All undispensed drug supplies should be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed bottles remaining when PMB sends a stock 
recovery letter), investigators should return the study drug to the PMB using the NCI 
Return Agent Form available on the NCI home page (http://ctep.cancer.gov).  
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of 
agent received from the PMB using the NCI Investigational Agent Accountability Record 
Form for Oral Agents available on the NCI home page (http://ctep.cancer.gov). Maintain 
separate NCI Investigational Agent Accountability Records for each agent, strength, 
formulation and ordering investigator. 
Investigator Brochure Availability: The current versions of the IBs for PMB-supplied 
agents will be accessible to site investigators and research staff through the PMB Online 
Agent Order Processing (OAOP) application. Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status, a “current” password, and active person 
registration status. Questions about IB access may be directed to the PMB IB 
coordinator at IBCoordinator@mail.nih.gov. 
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5.1 
Crizotinib (NSC #749005) 
5.1.1 
Other Names  
Xalkori®, PF-02341066 
5.1.2 
Classification  
MET inhibitor 
5.1.3 
Mode of Action  
Crizotinib is a selective ATP-competitive small –molecule inhibitor of 
anaplastic lymphoma kinase (ALK), MET/hepatocyte growth factor 
receptor (HGFR) and Recepteur d’Origine Nantais (RON), and ROS1 
receptor tyrosine kinases and their oncogenic variants. Translocations 
of these genes can result in expression of oncogenic fusion proteins 
that contribute to increased cell proliferation and survival. Antitumor 
efficacy of crizotinib is correlated to pharmacodynamic inhibition of 
phosphorylation of ALK fusion variants or MET/HGFR in tumors in 
vivo. 
5.1.4 
Storage and Stability  
Storage: Store at room temperature 20° to 25° C (68° to 77° F). 
Stability:  Shelf life is consistent with commercially-labeled product. 
5.1.5 
Dose Specifics  
Crizotinib capsules, 250 mg, will be administered orally twice daily on 
a continuous daily dosing schedule. 
See Section 3.4 for dose modifications. 
5.1.6 
Preparation  
Pfizer supplies and PMB, CTEP, DCTD distributes commercially-
labeled crizotinib as 200 mg (size 1, white opaque body and pink 
opaque cap, with “Pfizer” on the cap and “CRZ 200” on the body) and 
250 mg (size 0, pink opaque body and cap, with “Pfizer” on the cap 
and “CRZ 250 on the body) hard gelatin capsules. Each bottle 
contains 60 capsules. 
Excipients include colloidal silicon dioxide, microcrystalline cellulose, 
anhydrous dibasic calcium phosphate, sodium starch glycolate, 
magnesium stearate, and hard gelatin capsule shells as inactive 
ingredients. 
The pink opaque capsule shell components contain gelatin, titanium 
dioxide, and red iron oxide. The white opaque capsule shell 
components contain gelatin, and titanium dioxide. The printing ink 
contains shellac, propylene glycol, strong ammonia solution, 
potassium hydroxide, and black iron oxide. 
5.1.7 
Route of Administration  
Oral. Take with or without food. 

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5.1.8 
Potential drug-interactions 
Crizotinib is primarily metabolized by CYP 3A4/5 with minor 
contributions from CYP2C8, CYP2C19, and CYP2D6. Avoid 
concomitant use of strong CYP3A inhibitors and inducers. Use of 
potent CYP3A inducers should be avoided for at least 12 days prior to 
the first dose of crizotinib. Use of strong CYP3A inhibitors should be 
avoided for at least 7 days prior to the first dose of crizotinib. Exercise 
caution with concomitant use of moderate CYP3A inhibitors. Crizotinib 
moderately inhibits CYP3A4 in a time-dependent fashion. Use caution 
with patients who receive CYP3A4 substrates with a narrow 
therapeutic index. 
Crizotinib is an inhibitor of CYP2B6 in vitro. Use caution with co-
administered drugs that are predominantly metabolized by CYP2B6. 
Studies demonstrate that crizotinib is a substrate of P-gp and a weak 
BCRP inhibitor, however the potential to cause drug-drug interactions 
at therapeutic doses is low. Crizotinib inhibited P-gp, OCT1, and 
OCT2 in vitro at clinically relevant concentrations. Use caution with 
co-administration of P-gp, OCT1, and OCT2 substrates. 
5.1.9 
Side Effects  
See Section 3.3 for side effects. 
6. 
Translational Studies 
Please refer to the MATCH Master Protocol for information on the Translational Studies. 
7. 
References 
1. Birchmeier, C., Birchmeier, W., Gherardi, E., and Vande Woude, G.F. (2003). Met, 
metastasis, motility and more. Nature reviews Molecular cell biology 4, 915-925.  
2. Camidge D.R., Ou S.I., Shapiro G, Otterson G.A., et al. Efficacy and safety of 
crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer 
(NSCLC). J Clin Oncol 32:5s, 2014 (suppl; abstr 8001) 
3. Cappuzzo, F., Janne, P.A., Skokan, M., Finocchiaro, G., Rossi, E., Ligorio, C., 
Zucali, P.A., Terracciano, L., Toschi, L., Roncalli, M., et al. (2009). MET increased 
gene copy number and primary resistance to gefitinib therapy in non-small-cell lung 
cancer patients. Annals of oncology : official journal of the European Society for 
Medical Oncology / ESMO 20, 298-304. 
4. Catenacci, D.V., Henderson, L., Xiao, S.Y., Patel, P., Yauch, R.L., Hegde, P., Zha, 
J., Pandita, A., Peterson, A., and Salgia, R. (2011). Durable complete response of 
metastatic gastric cancer with anti-Met therapy followed by resistance at recurrence. 
Cancer discovery 1, 573-579. 
5. Catenacci, D.V., Liao, W.L., Thyparambil, S., Henderson, L., Xu, P., Zhao, L., 
Rambo, B., Hart, J., Xiao, S.Y., Bengali, K., et al. (2014). Absolute quantitation of 
Met using mass spectrometry for clinical application: assay precision, stability, and 
correlation with MET gene amplification in FFPE tumor tissue. PloS one 9, e100586. 
6. Chi AS, Batchelor TT, Kwak EL, et al. Rapid radiographic and clinical improvement 
after treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-
epithelial transition inhibitor. J Clin Oncol 2011;30:e30-3. 
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7. Comoglio, P.M., Giordano, S., and Trusolino, L. (2008). Drug development of MET 
inhibitors: targeting oncogene addiction and expedience. Nature reviews Drug 
discovery 7, 504-516. 
8. Cui JJ, Tran-Dube M, Shen H, et al. Structure based drug design of crizotinib (PF-
02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition 
factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem 
2011;54:6342-63. 
9. Engelman, J.A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J.O., 
Lindeman, N., Gale, C.M., Zhao, X., Christensen, J., et al. (2007). MET amplification 
leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 
316, 1039-1043. 
10. Gandhi L, Janne PA. Crizotinib for ALK-Rearranged Non-Small Cell Lung Cancer: A 
New Targeted Therapy for a New Target. Clin Cancer Res 2012. 
11. Graziano, F., Galluccio, N., Lorenzini, P., Ruzzo, A., Canestrari, E., D'Emidio, S., 
Catalano, V., Sisti, V., Ligorio, C., Andreoni, F., et al. (2011). Genetic activation of 
the MET pathway and prognosis of patients with high-risk, radically resected gastric 
cancer. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 29, 4789-4795. 
12. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in 
non-small-cell lung cancer. N Engl J Med 2010;363:1693-703. 
13. Lennerz, J.K., Kwak, E.L., Ackerman, A., Michael, M., Fox, S.B., Bergethon, K., 
Lauwers, G.Y., Christensen, J.G., Wilner, K.D., Haber, D.A., et al. (2011). MET 
amplification identifies a small and aggressive subgroup of esophagogastric 
adenocarcinoma with evidence of responsiveness to crizotinib. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 29, 4803-
4810. 
14. Naran, S., Zhang, X., and Hughes, S.J. (2009). Inhibition of HGF/MET as therapy for 
malignancy. Expert opinion on therapeutic targets 13, 569-581.  
15. Ou SH, Kwak EL, Siwak-Tapp C, et al. Activity of crizotinib (PF02341066), a dual 
mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) 
inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. J 
Thorac Oncol 2011;6:942-6. 
16. Paik PK,  Drilon A, Fan PD, et al. Response to met inhibitors in patients with stage IV 
lung adenocarcinoma harboring MET mutations causing exon 14 skipping. Cancer 
Discov 2015; 5(8) 642-9. 
17. Sampson ER, Martin BA, Morris AE, et al. The orally bioavailable met inhibitor PF-
2341066 inhibits osteosarcoma growth and osteolysis/matrix production in a 
xenograft model. J Bone Miner Res 2011;26:1283-94. 
18. Scagliotti G, von Pawel J, Novello S, Ramlau R, Favaretto A, Barlesi F, Akerley W, 
Orlov S, Santoro A, Spigel D, Hirsh V, Shepherd FA, Sequist LV, Sandler A, Ross 
JS, Wang Q, von Roemeling R, Shuster D, Schwartz B. Phase III Multinational, 
Randomized, Double-Blind, Placebo-Controlled Study of Tivantinib (ARQ 197) Plus 
Erlotinib Versus Erlotinib Alone in Previously Treated Patients With Locally 
Advanced or Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 
2015 Aug 20;33(24):2667-74. 
19. Sen B, Peng S, Saigal B, Williams MD, Johnson FM. Distinct interactions between c-
Src and c-Met in mediating resistance to c-Src inhibition in head and neck cancer. 
Clin Cancer Res 2011;17:514-24. 

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20. Shaw ATC, D.R.; Engelman, G.A. Clinical activity of crizotinib in advanced non-small 
cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. In: 2012 ASCO 
Annual Meeting. Chicago, IL: Journal of Clinical Oncology 2012:Abstr 7508. 
21. Smolen, G.A., Sordella, R., Muir, B., Mohapatra, G., Barmettler, A., Archibald, H., 
Kim, W.J., Okimoto, R.A., Bell, D.W., Sgroi, D.C., et al. (2006). Amplification of MET 
may identify a subset of cancers with extreme sensitivity to the selective tyrosine 
kinase inhibitor PHA-665752. Proceedings of the National Academy of Sciences of 
the United States of America 103, 2316-2321. 
22. Spigel DR, Edelman MJ, O'Byrne K et al;.Onartuzumab plus erlotinib versus erlotinib 
in previously treated stage IIIb or IV NSCLC: Results from the pivotal phase III 
randomized, multicenter, placebo-controlled METLung (OAM4971g) global trial. J 
Clin Oncol 32:5s, 2014 (suppl; abstr 8000) 
23. Tanizaki J, Okamoto I, Okamoto K, et al. MET tyrosine kinase inhibitor crizotinib (PF-
02341066) shows differential antitumor effects in non-small cell lung cancer 
according to MET alterations. J Thorac Oncol 2011;6:1624-31. 
24. Zou HY, Li Q, Lee JH, et al. An orally available small-molecule inhibitor of c-Met, PF-
2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and 
antiangiogenic mechanisms. Cancer Res 2007;67:4408-17. 
 

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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol C2: Crizotinib/MET Exon 14 Skipping 
Appendix I 
 
Patient Pill Calendar 
Storage: Store at Room Temperature 
Pill Calendar Directions 
1. Take your scheduled dose of each capsule. If you take your capsules twice a day, 
the capsules must be taken 12 hours apart. 
2. Any missed dose may be taken up to 6 hours prior to the next scheduled dose, 
otherwise it should be skipped and dosing resumed with subsequent doses. 
3. Please bring the empty bottle or any leftover capsules and your pill calendar to your 
next clinic visit. 
4. Swallow capsules whole and do not take if the capsules are broken. 
5. Take with or without food. Taking with food may decrease nausea. 
6. If you vomit after a study dose, another dose should not be taken; instead, wait and 
resume drug dosing at your next scheduled dose. 
 
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Patient Pill Calendar 
This is a calendar on which you are to record the time and number of capsules you take each 
day. You should take your scheduled dose of each capsule. Note the times and the number 
of capsules that you take each day. If you develop any side effects, please record them and 
anything you would like to tell the doctor in the space provided. Bring any unused capsules and 
your completed pill calendar to your doctor’s visits. 
Crizotinib 
DAY  
Date 
Time capsules 
taken 
Number of 
capsules taken 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you 
think would be of interest.) 
AM 
PM 
Month 
Day 
Year 
AM 
PM 
1 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
Patient Signature: __________________________________ Date: _____________ 

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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol C2: Crizotinib/MET Exon 14 Skipping 
Appendix II 
 
CYP3A4 Inducers and Inhibitors 
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as Facts and Comparisons or Lexicomp; medical 
reference texts such as the Physicians’ Desk Reference may also provide this 
information. The Principal Investigator should be alerted if the subject is taking any agent 
on these lists. 
 
List of CYP3A4 Inducing Agents: 
Carbamazepine 
Phenytoin 
Dexamethasone 
Primidone 
Ethosuximide 
Progesterone 
Glucocorticoids 
Rifabutin 
Griseofulvin 
Rifampin 
Modafinil 
Rifapentine 
Naficillin 
Rofecoxib 
Nelfinavir 
St. John’s Wort 
Nevirapine 
Sulfadimidine 
Oxcarbazepine 
Sulfinpyrazone 
Phenobarbitol 
Tipranavir 
Phenylbutazone 
Troglitazone 
List of CYP3A4 Inhibitors: 
Amiodarone 
 
Mifepristone 
Cimetidine 
 
Nefazodone 
Ciprofloxacin 
 
Nelfinavir 
Clarithromycin 
 
Norfloxacin 
Delavirdine 
 
Norfluoxetine 
Diethyl-dithiocarbamate 
 
Ritonavir 
Diltiazem 
 
Roxithromycin 
Erythromycin 
 
Saquinavir 
Fluconazole 
 
Troleandomycin 
Fluvoxamine 
 
Voriconazole 
Gestodene 
 
Warfarin 
Grapefruit or Grapefruit juice 
 
Amprenavir 
Indanvir 
 
Atazanavir 
Itraconazole 
 
Miconazole 
Ketoconazole 
 
Telithromycin 
Mibefradil 
 
Verapamil 
 
 

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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol C2: Crizotinib/MET Exon 14 Skipping 
Appendix IV 
 
Medications That May Cause QTc Prolongation 
Drugs that are generally 
accepted to have a risk of 
causing Torsades de 
Pointes 
Drugs that in some reports have 
been associated with Torsades 
de Pointes and/or QTc 
prolongation but at this time lack 
substantial evidence for causing 
Torsades de Pointes 
Drugs that, in some reports, have been weakly 
associated with Torsades de Pointes and/or QTc 
prolongation but that are unlikely to be a risk for 
Torsades de Pointes when used in usual 
recommended dosages and in subjects without 
other risk factors (e.g., concomitant QTc prolonging 
drugs, bradycardia, electrolyte disturbances, 
congenital long QTc syndrome, concomitant drugs 
that inhibit metabolism) 
Generic/Brand Name 
Generic/Brand Name 
Generic/Brand Name 
Amiodarone /Cordarone® 
Alfuzosin /Uroxatral® 
Amitriptyline /Elavil® 
Amiodarone /Pacerone® 
Amantadine /Symmetrel® 
Ciprofloxacin /Cipro® 
Arsenic trioxide 
/Trisenox® 
Atazanavir /Reyataz® 
Citalopram /Celexa® 
Astemizole /Hismanal® 
Azithromycin /Zithromax® 
Clomipramine /Anafranil® 
Bepridil /Vascor® 
Chloral hydrate /Noctec® 
Desipramine /Pertofrane® 
Chloroquine /Aralen® 
Clozapine /Clozaril® 
Diphenhydramine /Benadryl® 
Chlorpromazine 
/Thorazine® 
Dolasetron /Anzemet® 
Diphenhydramine /Nytol® 
Cisapride /Propulsid® 
Dronedarone /Multaq® 
Doxepin /Sinequan® 
Clarithromycin /Biaxin® 
Felbamate /Felbatrol® 
Fluconazole /Diflucan® 
Disopyramide /Norpace® 
Flecainide /Tambocor® 
Fluoxetine /Sarafem® 
Dofetilide /Tikosyn® 
Foscarnet /Foscavir® 
Fluoxetine /Prozac® 
Domperidone /Motilium® 
Fosphenytoin /Cerebyx® 
Galantamine /Reminyl® 
Droperidol /Inapsine® 
Gatifloxacin /Tequin® 
Imipramine /Norfranil® 
Erythromycin /Erythrocin® 
Gemifloxacin /Factive® 
Itraconazole /Sporanox® 
Erythromycin /E.E.S.® 
Granisetron /Kytril® 
Ketoconazole /Nizoral® 
Halofantrine /Halfan® 
Indapamide /Lozol® 
Mexiletine /Mexitil® 
Haloperidol /Haldol® 
Isradipine /Dynacirc® 
Nortriptyline /Pamelor® 
Ibutilide /Corvert® 
Lapatinib /Tykerb® 
Paroxetine /Paxil® 
Levomethadyl /Orlaam® 
Lapatinib /Tyverb® 
Protriptyline /Vivactil® 
Mesoridazine /Serentil® 
Levofloxacin /Levaquin® 
Sertraline /Zoloft® 
Methadone /Dolophine® 
Lithium /Lithobid® 
Solifenacin /VESIcare® 
Methadone /Methadose® 
Lithium /Eskalith® 
Trimethoprim-Sulfa /Sulfa® 
Pentamidine /Pentam® 
Moexipril/HCTZ /Uniretic® 
Trimethoprim-Sulfa /Bactrim® 
Pentamidine /NebuPent® 
Moxifloxacin /Avelox® 
Trimipramine /Surmontil® 
Pimozide /Orap® 
Nicardipine /Cardene® 
  
Probucol /Lorelco® 
Nilotinib /Tasigna® 
  
Procainamide /Pronestyl® 
Octreotide /Sandostatin® 
  

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Drugs that are generally 
accepted to have a risk of 
causing Torsades de 
Pointes 
Drugs that in some reports have 
been associated with Torsades 
de Pointes and/or QTc 
prolongation but at this time lack 
substantial evidence for causing 
Torsades de Pointes 
Drugs that, in some reports, have been weakly 
associated with Torsades de Pointes and/or QTc 
prolongation but that are unlikely to be a risk for 
Torsades de Pointes when used in usual 
recommended dosages and in subjects without 
other risk factors (e.g., concomitant QTc prolonging 
drugs, bradycardia, electrolyte disturbances, 
congenital long QTc syndrome, concomitant drugs 
that inhibit metabolism) 
Generic/Brand Name 
Generic/Brand Name 
Generic/Brand Name 
Procainamide /Procan® 
Ofloxacin /Floxin® 
  
Quinidine /Cardioquin® 
Ondansetron /Zofran® 
  
Quinidine /Quinaglute® 
Oxytocin /Pitocin® 
  
Sotalol /Betapace® 
Paliperidone /Invega® 
  
Sparfloxacin /Zagam® 
Perflutren lipid microspheres 
/Definity® 
  
Terfenadine /Seldane® 
Quetiapine /Seroquel® 
  
Thioridazine /Mellaril® 
Ranolazine /Ranexa® 
  
  
Risperidone /Risperdal® 
  
  
Roxithromycin* /Rulide® 
  
  
Sertindole /Serlect® 
  
  
Sertindole /Serdolect® 
  
  
Sunitinib /Sutent® 
  
  
Tacrolimus /Prograf® 
  
  
Tamoxifen /Nolvadex® 
  
  
Telithromycin /Ketek® 
  
  
Tizanidine /Zanaflex® 
  
  
Vardenafil /Levitra® 
  
  
Venlafaxine /Effexor® 
  
  
Voriconazole /VFend® 
  
  
Ziprasidone /Geodon® 
  
 

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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol C2: Crizotinib/MET Exon 14 Skipping 
Appendix V 
 
Actionable Mutations for Sub-Protocol EAY131-C2 
 
Gene Name 
Variant ID 
Variant 
Type 
Level of Evidence 
Code 
Variant Description 
MET 
MET-MET.M13M15 
Fusion 
2 
MET Exon 14 
skipping 

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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol C2: Crizotinib/MET Exon 14 Skipping 
Appendix VI 
 
CS-MATCH-0008  
Confirmation of low-level MET exon 14 skipping (Arm C2) 
Principal Investigators: 
PRINCIPAL INVESTIGATORS 
Stanley Hamilton, MD 
John A. Iafrate, MD PhD 
Shahanawaz Jiwani, MD, PhD 
BIOSTATISTICS 
Laura Yee 
SUB-PROTOCOL PRINCIPAL INVESTIGATORS 
David S. Hong, MD 
Daniel Catenacci, MD 
 
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I. 
Introduction 
MET exon 14 skipping (METex14), which results in decreased ubiquitination and 
delayed downregulation of the MET receptor after ligand stimulation (Chi et al. 2011), 
has recently been described as a potential driver alteration in lung cancer. The 
subprotocol C2 of EAY131 assigns eligible patients whose tumors had METex14 for 
treatment with crizotinib, an oral small-molecule inhibitor of MET,ALK, and ROS1 
receptor tyrosine kinases. All patients were considered eligible for treatment with 
crizotinib per EAY131-C2 clinical protocol. 
Somatic mutations identified in DNA affecting splice sites have been shown to promote 
RNA­ splicing based skipping events. METex 14 skipping events pose a diagnostic 
challenge. Recently emerging data coming from Dr. lafrate's laboratory and other 
authors , strongly suggest that DNA splice site allelic variants are associated with MET 
expression resulting in a high level of METex14 skipped RNA molecules. At present, 
there is no such evidence that low-level METex14 RNA read counts correlate with DNA 
mutations or with treatment response.And there is very little data on tumors possessing 
such variants in tissues other than lung.These low level METex14 skipping events may 
be spurious artifacts of inaccurate splicing and may be present in many histologies; 
however, the events may not be drivers of the tumor biology. Patients with low levels of 
METex14 skipping RNA may not benefit from MET inhibitor therapy. In comparison, we 
believe high RNA read cases will possess the DNA alteration. Our study will compare 
the intronic MET DNA mutations in the tumor with that of METex14 skipping RNA 
events. 
Within the EAY131 trial, all cases with identifiable METex14 RNA reads are considered 
positive and all non-detected cases are negative.This proposed effort is an attempt to 
verify the existence of underlying DNA mutations by use of an orthogonal clinical assay 
and correlate the DNA data with the level of RNA reads. Cases without METex14 
skipping reported by the NCI-MATCH Assay (RNA reads) are not included in this 
proposed study. 
The METex14 skipping event in the NCI-MATCH assay is analyzed by the messenger 
RNA panel, where a fusion product from METEx13 and METex15 is identified. This 
fusion product skips the full length of the Exon 14 of the MET gene. The validation of the 
NCI-MATCH assay was performed on RNA material collected from the samples which 
were confirmed to have a METex14 skipping event using a DNA based intronic 
orthogonal assay. 
During the early phase of NCI-MATCH assay development for the clinical study, it was 
determined that a 1,000-count RNA read depth for METex14 skipping would be used as 
lower limit threshold to enroll patients in EAY131-C2. The 1,000-count RNA read depth 
was established, following the discussion with an industry expert and input from 
pharmaceutical industry colleagues. At the time of the development of NCI-MATCH 
assay, there was lack of data defining the correlation between the low and high level of 
METex14 skipping RNA counts. In our correlative study, it was noted that there is a 
dichotomy of the data that exists a) high METex14 skipping RNA reads are usually 
>100,000 and b) low METex14 skipping RNA reads at <6,000. In our data set, we have 
not seen any case which is in between 6,000-100,000 RNA reads for METex14 skipping, 
so this cut-point was chosen. However, in patients screened for MATCH, 16 patients had 
METex14 less than 5,500 read counts, twelve of which were enrolled in EAY131-C2 and 
received treatment with crizotinib. 

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We hypothesize that low-level RNA read counts for intragenic events like METex14 will 
not predict response and should likely be considered separately from high read count 
cases. The study, if successful, should guide the definition of a threshold for METex 14 
skipping RNA reads that correlate with that of DNA splice site allelic variants. In our NCI-
MATCH clinical study we identified 16 patients with low level METex14 skipping RNA 
reads, which as per our clinical protocol where put on treatment arm along with patients 
having high level METex14 RNA reads. This study, when complimented with unblinded 
patient response data, will help guide future studies with where METex14 skipping is 
used as a treatment selection biomarker. 
II. 
Objective 
To confirm METex14 skipping at the DNA level for patients on EAY131-C2 
III. 
Methodology 
Dr. John Iafrate at MGH will be leading the DNA-based METex14 skipping work. Dr. 
Iafrate heads the NCI MATCH sequencing lab at MGH and the assay would be 
performed in his lab. 
NGS SNaPshot v2 is a customized gene primer panel utilizing a commercially-available 
library preparation kit (VariantPlex Solid Tumor kit from ArcherDx , Inc.) applying AMP 
(anchored multiplex PCR) with next-generation sequencing for the detection of single 
nucleotide variants and insertions/deletions in 104 known cancer genes. The test utilizes 
TNA (total nucleic acid) which contains genomic DNA derived from formalin-fixed , 
paraffin­ embedded tissue and fresh specimens (blood, bone marrow aspirates, 
pancreatic cyst fluid). The lllumina NextSeq is used for sequencing. The assay has been 
clinically-validated as a CLIA test and shows reproducible sequencing coverage over 
required targets. The SNaPshot assay has been validated to detect SNVs, CNVs, and 
small insertions and deletions {< 50 bp). MET exon 14 skipping is typically caused by 
splice or splice region variants that fall within the scope of SNV and indel detection of the 
SNaPshot assay. MGH's internal data has shown mutual exclusivity between legit MET 
exon 14 skipping and other known RAS driver variants. The DNA-based SNaPshot 
assay has not been used to validate RNA-based assays. It is routinely used clinically at 
MGH to orthogonally corroborate MET exon 14 skipping events from the Solid Fusion 
Assay (SFA). Reagent QC and proficiency testing is routinely performed. A negative 
template control sample (nuclease-free water) is included in every clinical testing batch 
to control for contamination. 
No patient identifiers will be provided to investigators with the samples. The trial-specific 
patient ID will be replaced with a unique randomized number and specimens will be 
labeled with a barcode not related to any PHI. The following entities have access to the 
key:  the ECOG-ACRIN biobank, the ECOG-ACRIN Operations Office, and the MATCH 
statisticians. 
IV. 
Statistical Considerations 
A. Case Selection 
NCI-MATCH is histology agnostic signal finding study, and in this arm the MET 
inhibitor (Crizotinib) is provided to patients with METex14skip event regardless of the 
histology being evaluated. This study will not be heavily influenced by the different 
histologies present in our small group of patients. 
Requirements for biospecimens to be analyzed are: 
• 
The MATCH-assay screening assessment determined the patient was a potential 
candidate for MATCH-C2. It is not required that the patient be enrolled on the 
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treatment arm. Biospecimens from patients referred to EAY131 by a designated 
Outside Laboratory are not included in this project. 
• 
Patient consented to allow their specimens to be used for future research. 
• 
The MATCH-assay screening assessment found a potential METex14 MOI such 
that the patient was not a candidate for MATCH-C2 and the patient was not 
registered to any treatment arm. 
• 
Adequate residual nucleic acid or tissue to generate nucleic acids exist. 
There are no proposed additional inclusion/exclusion criteria. 
B. Analysis Plan 
The primary hypothesis is to determine the proportion of patients that have a DNA-
based MET exon 14 skipping among patients determined to have RNA-based MET 
exon 14 skipping.This will be assessed in the MATCH C2 arm which has 21 patients 
in total, all of whom were enrolled in the arm due to RNA-based MET exon 14 
skipping (all "RNA +"). Therefore, the primary analysis will describe the positive 
percent agreement (PPA) of DNA-based MET exon 14 skipping (denoted by "DNA 
+") compared to RNA-based MET exon 14 skipping ("RNA +"), which is defined as 
follows: 
 
RNA + 
DNA + 
b 
DNA - 
d 
 
b+d = 21 
 
PPA = 
100 x (# DNA and RNA-based MET exon 14 skipping) 
(# RNA-based MET exon 14 skipping) 
= 
100 X b 
(b+d) 
Table 1 describes confidence interval widths for a range of possible observed PPAs 
(14%, 29%, 43%). The confidence intervals assume a confidence level of 95%, two-
sided intervals, and use the exact (Clopper-Pearson) method. With an observed PPA 
of 29% (6/21), we would be 95% confident that the true PPA is between 11% and 
52%. 
Table 1- Confidence intervals for various levels of positive agreement. Exact 
(Clopper-Pearson) two-sided intervals and 95% confidence. 
Total RNA 
Agree 
(b) 
Positive 
(b+d) 
Observed 
PPA% 
Lower 
Upper 
3 
21 
14 
3 
36 
6 
21 
29 
11 
52 
9 
21 
43 
22 
66 
We further hypothesize that DNA-reads will be highly discordant in samples with low-
level RNA reads (RNA gene count < 6,000), as compared to samples with high-level 
RNA reads (RNA gene count >=6,000). Therefore, we also will calculate PPA 
separately for low-level and high-level gene counts. We recognize that there will not 
be adequate power for this analysis, so it is deemed exploratory. 
Additional descriptive analyses of continuous measurements will be completed in an 
exploratory fashion to visualize the relationship between RNA-based gene counts 

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and DNA-based variant allele frequencies. In particular,we plan to include plots (e.g. 
scatter plots, Bland-Altman plots) to explore this relationship. 
The proposed study objectives are not related to therapy response since the data are 
not currently available. At this time, we  do  not plan  to address  the relationship  of  
METex14  skipping mRNA abundance to therapy response. Long term, it will be 
important to correlate the data with the therapy response in low level METex14 
skipping RNA reads. To date, no therapy response data exist in a patient population 
with low level of METex14 skipping events Our study is important for patient 
selection for MET inhibitor therapies to define the RNA threshold for METex14 
skipping event and to indicate whether DNA and/or RNA based biomarker analysis is 
best for selection to MET inhibitor trials. Once the clinical outcome data is available 
we will correlate the data. 
V. 
References 
1. Jenkins RW, Oxnard GR, Elkin S, et al. Response to crizotinib in a patient with lung 
adenocarcinoma harboring a MET splice site mutation. Clin Lung Cancer 
2015;16:e101-4. 
2. Chi AS, Batchelor TT, Kwak EL, et al. Rapid radiographic and clinical improvement 
after treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-
epithelial transition inhibitor. J Clin Oncol 2011;30:e30-3.