MATCH Treatment Subprotocol G: Phase II Study of Crizotinib in Patients With ROS1 Translocations (Other Than Patients With Non-Small Cell Lung Cancer)
Phase: PHASE2
Conditions: Advanced Lymphoma, Advanced Malignant Solid Neoplasm, Hematopoietic and Lymphoid Cell 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
January 25, 2019
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 Dr. John J. Wright:
Enclosed is Addendum #18 to EAY131-G, Molecular Analysis for Therapy Choice (MATCH): 
MATCH Treatment Subprotocol F: Phase II Study of Crizotinib in Patients with ROS1 
Translocations (Other Than Patients with Non-Small Cell Lung Cancer).
This addendum is in response to Dr. John J. Wright’s January 22, 2019 Request for Rapid 
Amendment for Crizotinib.
The following revisions to EAY131-G protocol have been made in this addendum:
Section
Change
1.
Cover Page
Updated Version Date.
2.
3.3
Updated the Crizotinib CAEPR list with Version 2.3, October 30, 2018.
The following revisions to EAY131-G Informed Consent Document have been made in this 
addendum:
Section
Change
1.
Page 1
Updated Version Date.
2.
What possible risks 
can I expect from 
taking part in this 
study?
Updated the Crizotinib risk list with Version Date October 30, 2018.
If you have any questions regarding this addendum, please contact aagu@ecog-acrin.org or 
857-504-2900.
We request review and approval of this addendum to EAY131-G so ECOG-ACRIN may activate 
it promptly.
Thank you.

ii 
Sincerely, 
Pamela Cogliano 
Senior Director of Protocol Development 
Enclosure 
CC: David S. Hong, MD  
Anna F. Farago, MD, PhD  
Alice Chen, MD 
Keith Thomas Flaherty, MD 
Barbara A. Conley, MD 
Peter O’Dwyer, MD 
Mickey Williams, PhD 
Stanley Hamilton, MD 
Lisa McShane, PhD  
Larry Rubinstein, PhD 
Robert Gray, PhD 
Shuli Li, PhD 
Lalitha Shankar, MD, PhD 
Susanna Lee, MD, PhD 
Constantine Gastonis, PhD 
Paolo Caimi, MD 
Shaji Kumar, MD 
Carlos Arteaga, MD 
Edith Mitchell, MD 
John J. Wright, MD 
Angela Chen 
Daniel Reeve 
Lyndsay Harris, MD 
James Tricoli, PhD 
Bruce Giantonio, MD 
Donna Marinucci 
Kerry Higgins 
Gayle Ipock 
Jean MacDonald 
Carol Chami, RN 
Julianne Human 
Kelly Redmond 
Becky Fillingham 
Jeffrey Zhang 
Kevin Pollard 
Amy Li 
Abuchi Agu 
Michael T. Balco 
Lauren Lambert 
Cayden Maican 
Margaret Cavenagh 
Ben Kim 
Alexandra Sachs 
Russell McDaniel 
Jennifer VanCamp  
 
 

EAY131-G 
1 
Molecular Analysis for Therapy 
Choice (MATCH) 
MATCH Treatment Subprotocol G: Phase II Study of 
Crizotinib in Patients with ROS1 Translocations (Other 
Than Patients with Non-Small Cell Lung Cancer) 
TREATMENT SUBPROTOCOL CHAIR: 
Aaron Mansfield, MD 
TREATMENT SUBPROTOCOL CO-CHAIR: 
Christopher Lieu, MD 
TRANSLATIONAL CHAIR: 
Patrick Forde, MD, MBBCh 
Version Date:  January 25, 2019 
NCI Update Date:  August 12, 2015 
NOTE: This subprotocol (EAY131-G) should 
be used in conjunction with the 
MATCH Master Protocol (EAY131). 
SUBPROTOCOL ACTIVATION DATE 
August 12, 2015 
SUBPROTOCOL PRE-ACTIVATION DATE 
NOTE: As of 11/17, all protocol changes will 
be noted by addendum number. 
please reference the activation memo 
for the addendum activation date. 
May 29, 2015 
Update #1 – Incorporated Prior to Activation 
Addendum #1 – 8/15 
Update #2 – 8/15 
Addendum #2 – 2/16 
Addendum #3 – 5/16 
Addendum #5 – 12/16 
Addendum #7 – 3/17 
Addendum #11 – 8/17 
Addendum #13 
Addendum #18 
Agent 
IND# 
NSC# 
Supply 
Crizotinib 
 
749005 
NCI Supplied 
Rev. 8/15 
Rev. Add13 

ECOG-ACRIN 
EAY131-G 
Cancer Research Group 
Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
2 
Table of Contents 
Molecular Analysis for Therapy Choice (MATCH) ...................................................... i 
MATCH Treatment Subprotocol G: Phase II Study of Crizotinib in Patients with 
ROS1 Translocations (Other Than Patients with Non-Small Cell Lung Cancer) .. 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 4 
1. Introduction ........................................................................................................ 5 
1.1 Crizotinib ................................................................................................... 5 
1.2 Supporting Preliminary Data ..................................................................... 7 
2. Selection of Patients ........................................................................................... 9 
2.1 Eligibility Criteria ....................................................................................... 9 
3. Criztonib Treatment Plan .................................................................................. 11 
3.1 Administration Schedule ......................................................................... 11 
3.2 Adverse Event Reporting Requirements ................................................. 11 
3.3 Comprehensive Adverse Events and Potential Risks List (CAEPR) for 
Crizotinib (PF-02341066, NSC 749005) ................................................... 14 
3.4 Dose Modifications ................................................................................. 19 
3.5 Supportive Care ....................................................................................... 22 
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 ......................................................................................... 29 
7. References ........................................................................................................ 29 
Appendix I  Pill Calendar .......................................................................................... 31 
Appendix II  CYP3A4 Inducers and Inhibitors .......................................................... 33 
Appendix III  Information On Possible Drug Interactions ........................................ 34 
Appendix IV  Actionable Mutations for Sub-Protocol EAY131-G ............................ 37 
Appendix V  Medications That May Cause QTc Prolongation ................................. 39 
 
 
 

ECOG-ACRIN 
EAY131-G 
Cancer Research Group 
Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
3 
TREATMENT SUBPROTOCOL CHAIR 
Aaron Mansfield, MD 
Mayo Clinic 
200 First St SW 
Rochester, MN 55905 
Phone: 507 293-0569  
Fax: 507 284-1803 
E-mail: mansfield.aaron@mayo.edu 
 
TREATMENT SUBPROTOCOL CO-CHAIR  
Christopher Lieu, MD 
12801 E. 17th Ave, MS 8117 
Aurora, CO 80045 
Phone: 303-724-6390   
Fax: 303-724-3889 
E-mail: christopher.lieu@ucdenver.edu 
 
TRANSLATIONAL CHAIR 
Patrick Forde, MD 
Johns Hopkins University 
1650 Orleans Street,  
CRB1 Rm G92 
Baltimore, MD 21287 
Phone: 410-955-3974  
Fax: 410-614-9334 
E-mail: pforde1@jhmi.edu 
 
 
 
 
 

ECOG-ACRIN 
EAY131-G 
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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
4 
Schema 
 
 
Long-Term Follow-Up
Crizotinib 250 mg PO BID
Until progression or 
unacceptable toxicity
Cycle = 28 days
Accrual Goal: 35

ECOG-ACRIN 
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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
5 
1. 
Introduction 
1.1 
Crizotinib 
Crizotinib is an ATP-competitive small-molecule oral inhibitor of the anaplastic 
lymphoma kinase, c-MET/hepatocyte growth factor receptor (HGFR), Recepteur 
d’Origine Nantais (RON), and ROS receptor tyrosine kinases and their oncogenic 
variants (e.g., c-MET/HGFR mutations and ALK or ROS1 fusion proteins).  The 
rationale for use of this mechanism to treat cancer is supported by an emerging 
paradigm in oncology that robust clinical efficacy can be obtained with well-
tolerated inhibitors directed toward oncogenic tyrosine kinases that are 
genetically altered through activating mutations, gene translocations, or gene 
amplification.  
Clinical Experience with Crizotinib 
Crizotinib has been tested in numerous phase I, II and III studies in patients with 
advanced solid tumors. More than 1511 advanced NSCLC patients have 
received crizotinib on clinical trials at the dosage of 250mg BID that is approved 
for advanced ALK-rearranged NSCLC. In the first report of crizotinib for ALK-
rearranged NSCLC there was an overall response rate of 57% and a 6-month 
progression free survival of 72% amongst 82 treated patients.1 An update of this 
phase 1 trial which included a total of 149 patients reported an overall response 
rate of 60.8% and a median duration of response of 49.1 weeks.2 In a separate 
trial that compared crizotinib in 173 patients to chemotherapy in 174 patients, all 
with metastatic ALK-rearranged NSCLC, there was a response rate of 65% in the 
criztonib group compared to 20% in the chemotherapy group. Additionally, 
median progression free survival was 7.7 months in the crizotinib group 
compared to 3.0 months in the chemotherapy group.3 There are few data 
available on the effects of crizotinib for patients with ROS1-rearranged metastatic 
NSCLC. The largest study that has been published included 50 patients and 
demonstrated a 72% response rate and median progression free survival of 19.2 
months.4  ROS1 rearrangements have been identified in other malignancies. 
There were three patients out of 33 with inflammatory myofibroblastic tumors that 
harbored a ROS1 rearrangement. The one patient in this study for whom 
treatment data were available obtained an objective response with crizotinib.5 
Pharmacokinetics & Metabolism 
After a single crizotinib dose of 250 mg, Cmax (peak plasma concentration) was 
achieved at a median of 4 h, and was associated with a geometric mean terminal 
half life at steady state of 42 hours.1-2, 6-7  Age, gender, race, or body weight do 
not appear to affect crizotinib pharmacokinetics.  At the licensed dose of 250 mg 
BID PO, crizotinib reaches steady state within 15 days.  Crizotinib exhibits non-
linear PK with reductions noted in CL/F with multiple dosing compared with single 
dosing. This may be due to auto-inhibition of CYP3A.  Crizotinib PK in ALK-
positive NSCLC patients was similar to that seen in patients with other tumor 
types. The concentration-time profiles and PK parameters of crizotinib in Chinese 
patients were similar to those observed in Asian (mainly Korean and Japanese) 
and non-Asian patients. 

ECOG-ACRIN 
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NCI Update Date: August 12, 2015 
6 
After oral dosing, crizotinib is absorbed with peak plasma concentration occurring 
between 4-6 hours under fasted condition. The presence of food did not result in 
clinically meaningful changes in crizotinib PK therefore crizotinib may be taken 
with or without food. 
Crizotinib is highly bound to plasma proteins and is predominantly metabolized 
by CYP3A. Approximately 53.5% of orally administered crizotinib is excreted 
unchanged in feces.  
Safety, Adverse Events and Efficacy of Crizotinib 
Crizotinib has primarily been utilized in the setting of patients with ALK 
rearrangements. In the expanded cohort phase I trial, most subjects tolerated 
crizotinib well with grade 1 nausea (52%) and diarrhea (46%) being the most 
common side effects.1,2 Additionally, 41% of subjects experienced grade 1 visual 
disturbances most commonly described as trails of light following moving objects. 
There was one grade 4 elevation in alanine aminotransferase, and one grade 3 
episode of pneumonitis. In this trial there was an overall response rate of 57% 
and a 6-month progression free survival of 72%. Follow up data from this study 
were reported in 2012 and adverse events are detailed in Table 1. In a phase III 
study comparing crizotinib to chemotherapy for patients with NSCLC and ALK 
rearrangements, 172 patients tolerated criztonib relatively well.3 The most 
common grade 3 or 4 event was elevated aminotransferase levels (16%). Less 
common grade 3 or 4 events included nausea (1%), vomiting (1%), constipation 
(2%), fatigue (2%), dizziness (1%) and dyspnea (4%).  The most common 
adverse events (all grades) were visual disturbances (60%) and diarrhea (60%).  
In this trial, the patients who received crizotinib had a 65% response rate and a 
median progression free survival of 7.7 months.  Similarly, in a phase I clinical 
trial for 50 patients with NSCLC and ROS1 rearrangements, crizotinib was well 
tolerated.4 There was a similar side effect profile. No grade 4 or 5 events were 
observed. Grade 3 vomiting or elevated aspartate aminotransferase was seen in 
one patient each, elevated alanine aminotransferase in two patients, and 
hypophosphatemia or neutropenia in five patients each. The most common side 
effect again was grade 1 visual disturbances (82%). There was a 72% response 
rate and median progression free survival of 19.2 months observed in this clinical 
trial. Less common adverse events have been described with crizotinib use 
including hypogonadism and decreased testosterone levels in males.8 

ECOG-ACRIN 
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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
7 
Adverse Events 
Study & Population 
Selected Adverse Events 
All Grades 
Grade 3 & 4 
Kwak et al. NEJM 2010, 
Camidge et.al Lancet 
Oncol 20121, 2 
Phase I ALK-rearranged 
NSCLC 
N=149 
Any Adverse Event 
 
Visual Effects 
Nausea 
Diarrhea 
Vomiting 
Peripheral edema 
Constipation 
Reduced appetite 
Fatigue 
Increased ALT 
Increased AST 
Pnemonitis 
97% 
 
64% 
56% 
50% 
39% 
30% 
28% 
16% 
16% 
12% 
10% 
< 1% 
24% 
 
0% 
< 1% 
0% 
< 1% 
0% 
< 1% 
0% 
1% 
4% 
3% 
< 1% 
Shaw et al. 
NEJM 20135 
Phase III 2nd line ALK-
rearranged NSCLC 
N=172 
Visual Effects 
Diarrhea 
Nausea 
Constipation 
Elevated ALT/AST 
60% 
60% 
55% 
42% 
38% 
0% 
0% 
1% 
2% 
16% 
1.2 
Supporting Preliminary Data 
Preclinical Data 
Crizotinib has been studied in a variety of in vitro and in vivo model systems to 
determine potency for inhibition of ALK, c-MET/HGFR, RON, or ROS1 RTK 
activity, kinase selectivity, antitumor efficacy, PK/PD relationships, and 
mechanism of action.  Crizotinib demonstrated potent concentration-dependent 
inhibition of the kinase activity of ALK, c-MET/HGFR, RON, and ROS1 in 
biochemical assays and inhibited phosphorylation and kinase dependent function 
in cell-based assays.  Crizotinib demonstrated potent and selective growth 
inhibitory activity and induced apoptosis in tumor cells lines exhibiting ALK fusion 
variants (EML4-ALK) or NPM-ALK), ROS1 fusion variants, or exhibiting 
amplification of the ALK or c-MET/HGFR gene locus.  In vivo, crizotinib 
demonstrated potent and selective growth inhibitory activity and induced 
apoptosis in tumor cell lines exhibiting ALK fusion variants (EML4-ALK or NPM-
ALK), ROS1 fusion variants, or exhibiting amplification of the ALK or c-
MET/HGFR gene locus.  In vivo, crizotinib demonstrated antitumor efficacy, 
including marked cytoreductive antitumor activity, in mice bearing tumor 
xenografts that expressed ALK fusion variants or activated c-MET/HGFR.  The 
anti-tumor efficacy of crizotinib was dose-dependent and correlated to 
pharmacodynamic inhibition of phosphorylation of ALK fusion variants (EML4-
ALK or NPM-ALK) or c-MET/HGFR in tumors in vivo.  The collective rationale for 
investigation of crizotinib in clinical studies is built on genetic alteration of its 
molecular targets, its predicted ability to target multiple processes that are 
common to cancer progression, and preclinical efficacy data. 

ECOG-ACRIN 
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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
8 
Rationale for Crizotinib in ROS1-translocated Tumors 
Several lines of evidence suggest that ROS1 may represent another therapeutic 
target of crizotinib. ROS1 encodes a transmembrane protein with an extracellular 
domain that is partially analogous to fibronectin.8 Although the function of wild 
type ROS1 is poorly understood, it is speculated that ROS1 might translate 
adhesion events to intracellular signaling because of the structural similarities to 
cell adhesion molecules. The kinase domains of ALK and ROS1 share 77% 
amino acid identity within the ATP-binding sites, and due to this homology, 
crizotinib binds with high-affinity to both ALK and ROS1.8  In cell-based assays 
for inhibition of autophosphorylation of different kinase targets, both ALK and 
ROS1 are sensitive to crizotinib, with a half-maximal inhibitory concentration of 
40 to 60nM.8  Preclinical studies have shown that crizotinib potently inhibits 
ROS1 signaling and cell viability in cell lines expressing ROS1 fusions.9-12  
The ROS1 proto-oncogene has been identified to be translocated in non-small 
cell lung cancers and is predicted to exhibit the properties of an “oncogenic 
driver”.  In published studies, the frequency of ROS1-positive NSCLC has been 
examined in 2 studies ranging from 1.7% (18/107) to 2.6% (17/656).10,13 Patients 
with adenocarcinoma of lung have demonstrated remarkable responses to 
crizotinib when their tumor has a ROS1 translocation.   An expansion cohort of 
50 response-evaluable advanced ROS1-positive NSCLC patients with crizotinib 
250 mg BID (NCT00585195) was recently reported, including an ORR of  72% 
(95% CI: 58–84), with 3 complete responses and 33 partial responses.6 The 
median duration of response was 17.6 months (95% CI, 14.5 to not reached), 
with 25 patients (50%) still in follow-up for progression.  Among 30 tumors that 
were tested, 7 ROS1 fusion partners: 5 known and 2 novel partner genes were 
identified.6 The most common ROS1 fusion partner was the gene encoding 
CD74.  Other partner genes included SDC4, EZR, SLC34A2, TPM3, LIMA1, and 
MSN. 
It is anticipated that the frequency of ROS1 translocations across all tumors is 
relatively rare.  However, there have been reports of ROS rearrangements in 
cancers such as CMML (70%), gastric cancer (5), glioblastoma (incidence 
unknown), NSCLC (1-2%), cholangiocarcinoma (9%), ovarian cancer (0.5%), 
colorectal cancer (1%), inflammatory myofibroblastic tumor, angiosarcoma and 
epithelial hemangioendothelioma.14-17  Additional ROS1 fusion partner genes 
identified in these malignancies included CCDC6, CEP85L, FIG (aka GOPC), 
KDELR2, KIF5B, LRIG3, TFG, and YWHAE. The dramatic responses and 
duration of benefit for patients with ROS1 translocations in non-small cell lung 
cancer argue that, though infrequent, ROS translocations may be a substantial 
“driver” mutation, and thus, across cancers, and with crizotinib treatment, there 
may be a response/longer progression-free survival time in any tumor harboring 
a ROS translocation.   
 

ECOG-ACRIN 
EAY131-G 
Cancer Research Group 
Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
9 
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: 
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 the relevant treatment consent form. 
2.1 
Eligibility Criteria 
2.1.1 
Patients must be positive for translocation or inversion events 
involving the ROS1 gene via the MATCH Master Protocol and 
described in Appendix IV. See Appendix IV for information on the 
ROS1 translocations and inversions and corresponding LOEs. 
2.1.2 
Patients must not have NSCLC with ROS1 rearrangements. 
2.1.3 
Patients with a history of interstitial lung disease or pneumonitis are 
excluded. 
2.1.4 
Patient must fulfill all eligibility criteria outlined in Section 3.1 of the 
MATCH Master Protocol (excluding Section 3.1.6) at the time of 
registration to treatment step (Step 1, 3, 5, 7). 
2.1.5 
Patients must have an electrocardiogram (ECG) within 8 weeks prior 
to treatment assignment and must have no clinically important 
abnormalities in rhythm, conduction or morphology of resting ECG 
(e.g. complete left bundle branch block, third degree heart block). 
Date of ECG:  _______________ 
2.1.6 
Patients must not have known hypersensitivity to crizotinib or 
compounds of similar chemical or biologic composition. 
Rev. 8/15 
Rev. 8/15 
Rev. 8/15 
Rev. 2/16 
Rev. 2/16 
Rev. Add13 

ECOG-ACRIN 
EAY131-G 
Cancer Research Group 
Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
10 
2.1.7 
Patients using drugs or foods that are known potent CYP3A4 
inhibitors or inducers will be excluded (See Appendix II) 
2.1.8 
Patients must not have had prior therapy with any ROS1 inhibitor 
including crizotinib, ceritinib, foretinib, cabozantinib, AP26113, 
ASP3026, WZ-5-126, TAE684, KIST301072, KIST301080, AZD1480, 
PF-06463922, RXDX-101 and PF-3922 
 
 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 

ECOG-ACRIN 
EAY131-G 
Cancer Research Group 
Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
11 
3. 
Criztonib 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, ie, no break in dosing.  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.  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.   
3.2 
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 G  
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- Subprotocol G 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 Master protocol for detailed instructions on how 
to report the occurrence of a pregnancy as well as the outcome 
of all pregnancies. 
 

ECOG-ACRIN 
EAY131-G 
Cancer Research Group 
Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
12 
EAY131 – Subprotocol G specific expedited reporting 
exceptions: 
For subprotocol G, 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. 

ECOG-ACRIN 
EAY131-G 
Cancer Research Group 
Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
13 
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. 
 

ECOG-ACRIN 
EAY131-G 
Cancer Research Group 
Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
14 
3.3 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for Crizotinib 
(PF-02341066, NSC 749005) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below). Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 2058 patients. 
Below is the CAEPR for Crizotinib (PF-02341066). 
NOTE: 
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 in the SPEER. 
Version 2.3, October 30, 20181 
Adverse Events with Possible  
 Relationship to Crizotinib (PF-02341066) 
 (CTCAE 5.0 Term) 
[n= 2058] 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)   
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
 
Febrile neutropenia 
  
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
 
Sinus bradycardia 
 
  
ENDOCRINE DISORDERS 
  
 
 
Testosterone deficiency   
EYE DISORDERS 
  
Eye disorders - Other 
(vision disorders)2 
 
 
 Eye disorders - Other 
(vision disorders)2  
(Gr 2) 
Periorbital edema 
 
 
 Periorbital edema (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
 
Colonic perforation 
  
Constipation 
 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dyspepsia 
 
  
 
 
Esophageal ulcer 
  
 
 
Esophagitis 
  
Rev. 5/16 
Rev. 8/17 
Rev. Add18 

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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
15 
Adverse Events with Possible  
 Relationship to Crizotinib (PF-02341066) 
 (CTCAE 5.0 Term) 
[n= 2058] 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)   
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Edema face 
 
 
 Edema face (Gr 2) 
Edema limbs 
 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
Generalized edema 
 
 
 Generalized edema  
(Gr 2) 
Localized edema 
 
 
 Localized edema (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
 
 
Hepatobiliary disorders - 
Other (hepatotoxicity) 
  
INFECTIONS AND INFESTATIONS 
  
 
Upper respiratory infection  
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine 
aminotransferase 
increased (Gr 2) 
 
Alkaline phosphatase 
increased 
 
  
 
Aspartate 
aminotransferase 
increased 
 
 Aspartate 
aminotransferase 
increased (Gr 2) 
 
 
Blood bilirubin increased   
 
Creatinine increased 
 
  
 
 
Electrocardiogram QT 
corrected interval 
prolonged 
  
 
Lymphocyte count 
decreased 
 
  
Neutrophil count 
decreased 
 
 
 Neutrophil count 
decreased (Gr 2) 
 
White blood cell 
decreased 
 
 White blood cell 
decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Muscle cramp 
 
  

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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
16 
Adverse Events with Possible  
 Relationship to Crizotinib (PF-02341066) 
 (CTCAE 5.0 Term) 
[n= 2058] 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER)   
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
  
 
Nervous system disorders 
- Other (neuropathy)3 
 
 Nervous system 
disorders - Other 
(neuropathy)3 (Gr 2) 
 
 
Syncope 
  
RENAL AND URINARY DISORDERS 
  
 
 
Renal and urinary 
disorders - Other (renal 
cyst) 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash4 
 
  
1 This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2 Vision disorders may include the following: Chromatopsia, Diplopia, Halo vision, Photophobia, 
Photopsia, Vision blurred, Visual acuity reduced, Visual brightness, Visual impairment, Vitreous floaters, 
and Visual perseveration. 
3 Neuropathy may include the following: Acute polyneuropathy, Amyotrophy, Areflexia, Autoimmune 
neuropathy, Autonomic failure syndrome, Autonomic neuropathy, Axonal neuropathy, Biopsy peripheral 
nerve abnormal, Burning feet syndrome, Burning sensation, Decreased vibratory sense, Demyelinating 
polyneuropathy, Dysesthesia, Electromyogram abnormal, Formication, Gait disturbance, Genital 
hypoesthesia, Guillain-Barre syndrome, Hyperesthesia, Hypoesthesia, Hyporeflexia, Hypotonia, 
Ischemic neuropathy, Loss of proprioception, Miller Fisher syndrome, Mononeuritis, Mononeuropathy, 
Mononeuropathy multiplex, Motor dysfunction, Multifocal motor neuropathy, Muscle atrophy, Muscular 
weakness, Myelopathy, Nerve conduction studies abnormal, Nerve degeneration, Neuralgia, Neuritis, 
Neuromuscular toxicity, Neuromyopathy, Neuropathy peripheral, Neuropathy vitamin B6 deficiency, 
Neurotoxicity, Paresthesia, Peripheral motor neuropathy, Peripheral nerve lesion, Peripheral nerve 
palsy, Peripheral nervous system function test abnormal, Peripheral sensorimotor neuropathy, 
Peripheral sensory neuropathy, Peroneal muscular atrophy, Peroneal nerve palsy, Phrenic nerve 
paralysis, Polyneuropathy, Polyneuropathy chronic, Polyneuropathy idiopathic progressive, Radiation 
neuropathy, Sensorimotor disorder, Sensory disturbance, Sensory loss, Skin burning sensation, 
Temperature perception test decreased, Tinel’s sign, Toxic neuropathy, and Ulnar neuritis. 
4 Treatment-related rash may include erythematous rash, rash maculo-papular, and pruritus. 

ECOG-ACRIN 
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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
17 
Adverse events reported on crizotinib (PF-02341066) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that crizotinib 
(PF-02341066) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - 
Other (basophilia); Disseminated intravascular coagulation; Eosinophilia; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Myocarditis; 
Pericardial effusion; Supraventricular tachycardia 
EYE DISORDERS - Cataract; Optic nerve disorder; Papilledema 
GASTROINTESTINAL DISORDERS - Colitis; Dysphagia; Gastric ulcer; Gastroesophageal 
reflux disease; Gastrointestinal disorders - Other (gastrointestinal amyloidosis); Ileus 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Fever; General 
disorders and administration site conditions - Other (failure to thrive); Malaise; Non-cardiac 
chest pain 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (cholestasis); Hepatobiliary 
disorders - Other (hepatitis) 
IMMUNE SYSTEM DISORDERS - Autoimmune disorder 
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) 

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NCI Update Date: August 12, 2015 
18 
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 
agent. 

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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
19 
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. 

ECOG-ACRIN 
EAY131-G 
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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
20 
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*. 
ALT elevation with total bilirubin < 2 
X ULN (in the absence of 
cholestasis or hemolysis) § 
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 dose until toxicity is grade  
1, or has returned to baseline, then 
resume treatment by reducing the 
dose by one dose level. If Grade 3 
ALT elevation recurs reduce further 
(at most by 2 dose levels from initial 
dose level). If recurrence at dose 
level -2, discontinue permanently. If 
Grade 3 ALT elevation does not 
recur after at least 4 weeks, the 
dose may be escalated by single 
dose level increments up to the 
initial dose level. 
See Grade 3. 
ALT elevation concurrent with total 
bilirubin elevation ≥ 2 X ULN (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 

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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
21 
Prolonged QTc  
Continue at the same dose 
level 
Assess 
electrolytes and 
concomitant 
medications. 
Correct any 
electrolyte or 
magnesium 
abnormalities 
Interrupt crizotinib until recovery to 
baseline. Assess and correct 
electrolytes and concomitant 
medications. 
Resume treatment by reducing the 
dose by one dose level, unless an 
alternative cause for QTc 
prolongation is found and corrected, 
resume at the same dose level. 
Discontinue treatment and 
do not retreat 
Pneumonitis (in absence of disease 
progression, pulmonary embolism, 
positive cultures or radiation effect) 
Discontinue 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 ophthalmologic 
examination+ 
Continue at the 
same dose 
level. Repeat 
ophthalmologic 
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 
* 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. 

ECOG-ACRIN 
EAY131-G 
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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
22 
3.5 
Supportive Care  
All supportive measures consistent with optimal patient care will be given 
throughout the study.  
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 Section 3.4 for 
instructions on dose modifications.  
3.5.3 
Bradycardia:   
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). 
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. 
Rev. 8/15 

ECOG-ACRIN 
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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
23 
• 
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 (same 
pathogens as 3.6.4.1) 
• 
Lung biopsy if appropriate and necessary to distinguish between 
pneumonia and pneumonitis 
• 
BNP levels to evaluate for heart failure 
• 
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. 

ECOG-ACRIN 
EAY131-G 
Cancer Research Group 
Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
 
4. 
Study Parameters 
4.1 
Therapeutic Parameters for Crizotinib Treatment  
NOTE: 
In addition to the study parameters listed in the MATCH Master Protocol at Step 0, the below parameters 
must also be performed for patients on 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 
-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). 
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. 
D. Disease measurements are repeated every 2 cycles for 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 
Rev. 8/15, 2/16 
Rev. 2/16 
Rev. 2/16 
Rev. 5/16 
Rev. 12/16 
Rev. 2/16 
Rev. 3/17 

ECOG-ACRIN 
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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
 
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. 
Rev. 2/16 
Rev. Add13 

ECOG-ACRIN 
EAY131-G 
Cancer Research Group 
Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
26 
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 subprotocol 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 or email PMBAfterHours@mail.nih.gov 
anytime. 
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 
Rev. 8/15 
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Rev. 3/17 
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27 
registration status. Questions about IB access may be directed to the PMB IB 
coordinator at IBCoordinator@mail.nih.gov. 
5.1 
Crizotinib (NSC #749005) 
5.1.1 
Other Names  
Xalkori®, PF-02341066 
5.1.2 
Classification  
ALK inhibitor 
5.1.3 
Mode of Action  
Crizotinib is a selective ATP-competitive small –molecule inhibitor of 
anaplastic lymphoma kinase (ALK), c-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 c-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. 
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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NCI Update Date: August 12, 2015 
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5.1.8 
Incompatibilities  
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. 
 
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29 
6. 
Translational Studies 
Please refer to the MATCH Master Protocol for information on the Translational Studies. 
7. 
References 
1. 
Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic Lymphoma Kinase Inhibition in 
Non–Small-Cell Lung Cancer. New England Journal of Medicine 2010;363:1693-
703. 
2. 
Camidge DR, Bang Y-J, Kwak EL, et al. Activity and safety of crizotinib in patients 
with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. 
The Lancet Oncology 2012;13:1011-9. 
3. 
Shaw AT, Kim D-W, Nakagawa K, et al. Crizotinib versus Chemotherapy in 
Advanced ALK-Positive Lung Cancer. New England Journal of Medicine 
2013;368:2385-94. 
4. 
Shaw AT, Ou S-HI, Bang Y-J, et al. Crizotinib in ROS1-Rearranged Non–Small-Cell 
Lung Cancer. New England Journal of Medicine 2014;DOI: 
10.1056/NEJMoa1406766:null. 
5. 
Lovly CM, Gupta A, Lipson D, et al. Inflammatory myofibroblastic tumors harbor 
multiple potentially actionable kinase fusions. Cancer Discovery 2014;8:889-95. 
6. 
Li C, Alvey C, Bello A, Wilner K, Tan W. Pharmacokinetics (PK) of crizotinib (PF-
02341066) in patients with advanced non-small cell lung cancer (NSCLC) and other 
solid tumors. J Clin Oncol 2011;29. 
7. 
Kwak E, Camidge D, Clark J, et al. Clinical activity observed in a phase I dose 
escalation trial of an oral c-met and ALK inhibitor, PF-02341066. J Clin Oncol 
2009;27:(suppl; abstr 3509). 
8. 
Weickhardt AJ, Doebele RC, Purcell WT, et al. Symptomatic reduction in free 
testosterone levels secondary to crizotinib use in male cancer patients. Cancer 
2013;119:2383-90. 
9. 
Huber KVM, Salah E, Radic B, et al. Stereospecific targeting of MTH1 by (S)-
crizotinib as an anticancer strategy. Nature 2014;508:222-7. 
10. Shaw A, Camidge D, Engleman J, et al. Clinical activity of crizotinib in advanced 
non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. J Clin 
Oncol 2012. 
11. Bergethon K, Shaw AT, Ignatius Ou S-H, et al. ROS1 Rearrangements Define a 
Unique Molecular Class of Lung Cancers. Journal of Clinical Oncology 
2012;30:863-70. 
12. McDermott U, Iafrate AJ, Gray NS, et al. Genomic Alterations of Anaplastic 
Lymphoma Kinase May Sensitize Tumors to Anaplastic Lymphoma Kinase 
Inhibitors. Cancer Research 2008;68:3389-95. 
13. Yasuda H, Figueiredo-Pontes Ld, Kobayashi S, Costa D. Preclinical Rationale for 
Use of the Clinically Available Multitargeted Tyrosine Kinase Inhibitor Crizotinib in 
ROS1-Translocated Lung Cancer. Journal of Thoracic Oncology 2012;7:1086-90. 
14. Rimkunas V, Crosby K, Kelly M, et al. Frequencies of ALK and ROS in NSCLC 
FFPE tumor samples utilizing a highly specific immunohistochemistry-based assay 
and FISH analysis. J Clin Oncol 2010;28:suppl; abstr 10536. 

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15. Cilloni D, Carturan S, Bracco E, et al. Aberrant activation of ROS1 represents a new 
molecular defect in chronic myelomonocytic leukemia. Leukemia Research 
2013;37:520-30. 
16. Lee J, Lee SE, Kang SY, et al. Identification of ROS1 rearrangement in gastric 
adenocarcinoma. Cancer 2013;119:1627-35. 
17. Davies KD, Doebele RC. Molecular Pathways: ROS1 Fusion Proteins in Cancer. 
Clinical Cancer Research 2013;19:4040-5. 
18. Weickhardt A, Nguyen T, Paskulin D, et al. ALK and ROS1 gene rearrangements 
detected in colorectal cancer (CRC) by fluorescence in situ hybridization (FISH). J 
Clin Oncol 2013;31. 
 

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NCI Update Date: August 12, 2015 
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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol G: Criztonib 
Appendix I 
 
Pill Calendar 
Storage: Store at Room Temperature 
Pill Calendar Directions 
1. Take your scheduled dose of each capsule. 
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 (do not crush, dissolve, or open capsules). 
5. Take with or without food. Taking with food may decrease nausea. 
 
Rev. 12/16 
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NCI Update Date: August 12, 2015 
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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.) 
Month 
Day 
Year 
AM 
PM 
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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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol G: Criztonib 
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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Version Date: January 25, 2019 
 
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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol G: Criztonib 
Appendix III 
 
Information On Possible Drug Interactions 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental agents Crizotinib.  This clinical trial is sponsored by the National Cancer Institute. 
This form is addressed to the patient, but includes important information for others who care for 
this patient. 
Crizotinib interacts with many drugs that are processed by your liver.  Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study. It is 
also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study.  When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort. 
Many health care prescribers can write prescriptions. You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet. These 
are the things that you and they need to know: 
Crizotinib interacts with certain specific enzymes in your liver. 
• 
The enzymes in question are CYP 2B6 and 3A4 enzymes.  Crizotinib blood levels are 
affected (could be lower or higher) by some of these enzymes and taking crizotinib with 
some medicines can raise or lower the levels of crizotinib or other medicines you take (drug-
drug interaction). Crizotinib must be used very carefully with other medicines that need 
these liver enzymes to be effective or to be cleared from your system. 
• 
Other medicines may also affect the activity of the enzymes. 
• 
Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance of 
harmful side effects. 
• 
Crizotinib should not be taken with any other drugs that are strong inducers or 
inhibitors of CYP 3A4.  Prohibited medications include azole antifungals, some 
antiepileptic drugs, some antibiotics and some immunosuppressants as well as over 
the counter drugs such as St. John’s Wort.  Please check with the study investigator 
before prescribing or dispensing strong inhibitors/inducers of CYP 3A4. Grapefruit or 
grapefruit juice should also be avoided. 
• 
Crizotinib is considered an inhibitor of CYP 2B6 and 3A4, meaning that it can increase 
the levels of drugs that are substrates of CYP 2B6 or 3A4 with a narrow therapeurtic 
index. This can lead to harmful side effects of those medications. Avoid using or 
prescribing drugs that could be affected  including but not limited to alfentanil, 
cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus. 
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• 
Crizotinib inhibits the transport proteins P-glycoprotein, OCT1 or OCT2. Medications that 
are substrates for these transport proteins must be used with caution. 
• 
You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category. 
• 
Before you start the study, your study doctor will work with your regular prescriber to switch 
any prohibited medicines that are considered “strong inducers/inhibitors or substrates of 
CYP 2B6 or 3A4.” 
• 
Your prescribers should look at a frequently-updated drug reference to see if any medicine 
they want to prescribe is on a list of drugs to avoid. 
• 
Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list. Find the generic 
name and determine, with the pharmacist’s help, whether there could be an adverse 
interaction. 
• 
Be careful: 
• 
If you take acetaminophen regularly:  You should not take more than 3 grams (six 500 
mg pills, or nine 325 mg pills) a day if you are an adult or 2.4 grams (four 500 mg pills, or 
seven 325 mg pills) a day if you are older than 65 years of age.  Read labels carefully!  
Acetaminophen is an ingredient in many medicines for pain, flu, and cold. 
• 
If you take herbal medicine regularly:  You should not take St. John’s wort while you are 
taking crizotinib. 
• 
Avoid consumption of grapefruit, grapefruit juice, and Seville oranges. 
• 
Avoid antacids and tell your doctor if you are taking any medicine for heartburn 
symptoms. 
Other medicines can be a problem with your study drugs. 
• 
You should check with your doctor or pharmacist whenever you need to use an over-the-
counter medicine or herbal supplement. 
• 
Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you.   
Crizotinib may interact with other drugs which can cause side effects. For this reason, it is 
very important to tell your study doctors of any medicines you are taking before you enroll 
onto this clinical trial.  It is also very important to tell your doctors if you stop taking any 
regular medicines, or if you start taking a new medicine while you take part in this study.  
When you talk about your current medications with your doctors, include medicine you buy 
without a prescription (over-the-counter remedy), or any herbal supplements such as St. 
John’s Wort.  It is helpful to bring your medication bottles or an updated medication list with 
you. 
Your study doctor’s name is  
_____________________________________  
and he or she can be contacted at  
_____________________________________ 

ECOG-ACRIN 
EAY131-G 
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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
36 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG 
INTERACTIONS  
You are enrolled on a clinical trial using the 
experimental agent crizotinib.  This clinical trial is 
sponsored by the NCI.  Crizotinib interacts with drugs 
that are processed by your liver.  Because of this, it is 
very important to: 
➢ Tell your doctors if you stop taking regular medicine 
or if you start taking a new medicine. 
➢ Tell all of your prescribers (doctor, physicians’ 
assistant, nurse practitioner, pharmacist) that you 
are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever 
you need to use an over-the-counter medicine or 
herbal supplement. 
➢ Crizotinib interacts with specific liver enzymes 
called CYP 2B6 and 3A4, and must be used very 
carefully with other medicines that interact with 
these enzymes. 
➢ Before you start the study, your study doctor will work 
with your regular prescriber to switch any prohibited 
medicines that are considered “strong 
inducers/inhibitors or major substrates of CYP 2B6 or 
3A4 with a narrow therapeutic index” or will use 
caution when combining Crizotinib with medications 
that are substrates of the transporters P-glycoprotein, 
OCT1 or OCT2. 
➢ Avoid consumption of grapefruit, grapefruit juice or 
Seville oranges while taking crizotinib. 
➢ Before prescribing new medicines, your regular 
prescribers should check a frequently-updated drug 
resource for a list of drugs to avoid, or contact your 
study doctor. 
➢ Your study doctor’s name is  
 
_____________________________  
 
and can be contacted at  
 
_____________________________ 

ECOG-ACRIN 
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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
37 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol G: Criztonib 
Appendix IV 
 
Actionable Mutations for Sub-Protocol EAY131-G 
Other novel ROS1 fusions not listed in the below table but identified by one of the designated 
outside laboratories as described in the MATCH Master Protocol will also be considered 
actionable mutations (aMOIs) at Level of Evidence Code 3. Please refer to Section 1.4.2 of the 
MATCH Master Protocol for more information. 
Gene 
Variant ID 
Variant Description 
Level of Evidence 
ROS1 
TMEM106B-ROS1.T3R35 
Fusion 
1 
ROS1 
SDC4-ROS1.S4R34.COSF1280 
Fusion 
1 
ROS1 
SDC4-ROS1.S2R32.COSF1265 
Fusion 
1 
ROS1 
YWHAE-ROS1.Y4R36 
Fusion 
1 
ROS1 
MSN-ROS1.M9R34 
Fusion 
1 
ROS1 
CEP85L-ROS1.C8R36 
Fusion 
1 
ROS1 
CCDC6-ROS1.C5R35.1 
Fusion 
1 
ROS1 
KDELR2-ROS1.K5Rintron34 
Fusion 
1 
ROS1 
KDELR2-ROS1.K5R35 
Fusion 
1 
ROS1 
PWWP2A-ROS1.P1R36 
Fusion 
1 
ROS1 
SDC4-ROS1.S2R34 
Fusion 
1 
ROS1 
HLA_A-ROS1.H7R34 
Fusion 
1 
ROS1 
SLC34A2-
ROS1.S4R34.COSF1198 
Fusion 
1 
ROS1 
GOPC-ROS1.G8R35.COSF1139 
Fusion 
1 
ROS1 
EZR-ROS1.E10R35 
Fusion 
1 
ROS1 
SDC4-ROS1.S4R32.COSF1278 
Fusion 
1 
ROS1 
KIAA1598-ROS1.K11R36 
Fusion 
1 
ROS1 
CLIP1-ROS1.C19R36 
Fusion 
1 
ROS1 
CD74-ROS1.C6R34.COSF1200 
Fusion 
1 
ROS1 
PPFIBP1-ROS1.P9R35 
Fusion 
1 
ROS1 
LRIG3-ROS1.L16R35.COSF1269 
Fusion 
1 
ROS1 
TPM3-ROS1.T3R36 
Fusion 
1 
ROS1 
NFKB2-ROS1.N13R36 
Fusion 
1 
ROS1 
SLC34A2-
ROS1.S13R34.COSF1261 
Fusion 
1 
ROS1 
CD74-ROS1.C6R35.COSF1478 
Fusion 
1 
Rev. 5/16 
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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
38 
Gene 
Variant ID 
Variant Description 
Level of Evidence 
ROS1 
SLC34A2-ROS1.S13R36 
Fusion 
1 
ROS1 
ZCCHC8-ROS1.Z2R36 
Fusion 
1 
ROS1 
CD74-ROS1.C6R32.COSF1202 
Fusion 
1 
ROS1 
CD74-ROS1.C4R33.NGS 
Fusion 
1 
ROS1 
ERC1-ROS1.E11R36 
Fusion 
1 
ROS1 
SLC34A2-
ROS1.S13R32.COSF1259 
Fusion 
1 
ROS1 
TPM3-ROS1.T7R35.COSF1273 
Fusion 
1 
ROS1 
TFG-ROS1.T4R35 
Fusion 
1 
ROS1 
EZR-ROS1.E10R34.COSF1267 
Fusion 
1 
ROS1 
SLC34A2-
ROS1.S4R32.COSF1196 
Fusion 
1 
ROS1 
NCOR2-ROS1.N7R36 
Fusion 
1 
ROS1 
MYO5A-ROS1.M23R35 
Fusion 
1 
ROS1 
GOPC-ROS1.G4R36.COSF1188 
Fusion 
1 

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Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
39 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol G: Criztonib 
Appendix V 
 
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® 
  

ECOG-ACRIN 
EAY131-G 
Cancer Research Group 
Version Date: January 25, 2019 
 
NCI Update Date: August 12, 2015 
40 
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 /Pronestyl® 
Octreotide /Sandostatin® 
  
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®