MATCH Treatment Subprotocol F: Crizotinib in Patients With Tumors (Other Than Adenocarcinoma of Lung or ALCL) With ALK Rearrangements
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
March 11, 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 Ms. Kruhm:
Enclosed is Addendum #19 to EAY131-F, Crizotinib in Patients with Tumors (Other Than 
Adenocarcinoma of Lung or ALCL) with ALK Rearrangements.
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permitted to conduct the study utilizing outdated versions of any MATCH protocol documents 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-F protocol have been made in this addendum:
Section
Change
1.
Cover Page
Updated Version Date.
2.
Cover Page
In second note, removed second sentence, ”Please reference activation 
memo for the addendum activation date.”
The following revisions to EAY131-F 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.

 
ii 
We request review and approval of this addendum to EAY131-F so ECOG-ACRIN may activate 
it promptly.   
Thank you.  
Sincerely, 
Pamela Cogliano 
Senior Director, Protocol Development 
Enclosure 
CC: Erin Macrae, MD  
April Salama.MD  
Jong-In Park,  Ph.D  
Alice Chen, MD 
Keith Thomas Flaherty, MD 
Lyndsay N. Harris. MD 
Peter O’Dwyer, MD 
Mickey Williams, PhD 
James V. Tricoli, PhD 
Stanley Hamilton, MD 
Lisa McShane, PhD  
Larry Rubinstein, PhD 
Robert Gray, PhD 
Shuli Li, PhD 
Lalitha Shankar, MD 
Susanna Lee, MD, PhD 
Constantine Gastonis, PhD 
Paolo Caimi, MD 
Shaji Kumar, MD 
Carlos Arteaga, MD 
Edith Mitchell, MD 
John J. Wright, MD, PhD 
Bruce Giantonio, MD 
Donna Marinucci 
Kerry Higgins 
Gayle Ipock 
Jean MacDonald 
Carol Chami, R.N. 
Juanita Andrews 
Melinda Flood 
Julianne Human 
Kelly Redmond 
Becky Fillingham 
Jeffrey Zhang 
Amy Li 
Kevin Pollard 
Abuchi Agu 
Michael T. Balco 
Lauren Lambert 
Cayden Maican 
Margaret Cavenagh 
Ben Kim 
Alexandra Sachs 
Russell McDaniel  
 
 

EAY131-F 
1 
Molecular Analysis for Therapy 
Choice (MATCH) 
MATCH Treatment Subprotocol F: Crizotinib in Patients 
with Tumors (Other Than Adenocarcinoma of Lung or 
ALCL) with ALK Rearrangements 
CRIZOTINIB/ALK TREATMENT SUBPROTOCOL 
CHAIR: 
Alice Tsang Shaw, M.D., Ph.D. 
CRIZOTINIB/ALK TREATMENT SUBPROTOCOL 
CO-CHAIR: 
Ranee Mehra, M.D. 
CRIZOTINIB/ALK TRANSLATIONAL CHAIR: 
Alexander Drilon, M.D. 
Version Date:  March 11, 2019 
NCI Update Date:  August 12, 2015 
NOTE: This subprotocol (EAY131-F) 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 
August 12, 2015 
SUBPROTOCOL PRE-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 
Addendum #19 
Agent 
IND# 
NSC# 
Supply 
Crizotinib 
749005 
NCI Supplied 
Rev. 8/15 
Rev. 3/17 
Rev. Add13 
Rev. Add19 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
NCI Update Date: August 12, 2015 
2 
Table of Contents 
Molecular Analysis for Therapy Choice (MATCH) ...................................................... i 
MATCH Treatment Subprotocol F: Crizotinib in Patients with Tumors (Other Than 
Adenocarcinoma of Lung or ALCL) with ALK Rearrangements ........................... 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 4 
1.
Introduction ........................................................................................................ 5 
1.1 Crizotinib ................................................................................................... 5 
1.2 Supporting Preliminary Data ..................................................................... 5 
2.
Selection of Patients ........................................................................................... 7 
2.1 Eligibility Criteria ....................................................................................... 7 
3.
Crizotinib Treatment Plan ................................................................................... 9 
3.1 Administration Schedule ........................................................................... 9 
3.2 Adverse Event Reporting Requirements ................................................... 9 
3.3 Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Crizotinib (PF-02341066, NSC 749005) ................................................... 12 
3.4 Dose Modifications ................................................................................. 16 
3.5 Supportive Care ....................................................................................... 19 
3.6 Duration of Agent-specific treatment ..................................................... 20 
3.7 Duration of Follow-Up ............................................................................. 21 
4.
Study Parameters .............................................................................................. 22 
4.1 Therapeutic Parameters for Crizotinib Treatment ................................. 22 
5.
Drug Formulation and Procurement ................................................................. 24 
5.1 Crizotinib (NSC #749005) ........................................................................ 25 
6.
Translational Studies ......................................................................................... 27 
7.
References ........................................................................................................ 27 
Appendix I  Patient Pill Calendar ............................................................................. 29 
Appendix II   CYP3A4 Inducers and Inhibitors ......................................................... 31 
Appendix III   Information On Possible Drug Interactions ....................................... 32 
Appendix IV  Actionable Mutations for Sub-Protocol EAY131-F ............................. 35 
Appendix V  Medications That May Cause QTc Prolongation ................................. 39 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
3 
TREATMENT SUBPROTOCOL CHAIR 
Alice Shaw, MD PhD 
Massachusetts General Hospital Cancer 
32 Fruit Street 
Boston, MA 02114 
Phone: 617-724-4000  
Fax: 617-726-0453  
E-mail: ashaw1@partners.org 
 
TREATMENT SUBPROTOCOL CO-CHAIR  
Ranee Mehra, MD 
The Sidney Kimmel Comprehensive Cancer 
Center at Johns Hopkins 
1550 Orleans Street CRB II 5M.43 
Baltimore, MD 21287-0014 
Phone: 443-287-8312 
Fax: 410-502-0677 
E-mail: rmehra1@jhmi.edu 
 
TRANSLATIONAL CHAIR 
Alexander Drilon, MD  
Memorial Sloan-Kettering Cancer Center 
300 E. 66th St 
New York City, NY  10065   
Phone: 646-888-4206  
Fax: 646-888-4263  
E-mail: drilona@mskcc.org 
 
 
 
 
 
 
 
 
 
 
Rev. 12/16 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 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 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
5 
1. 
Introduction 
1.1 
Crizotinib 
Crizotinib is a first-in-class ATP-competitive small-molecule inhibitor of ALK, c-
Met/hepatocyte growth factor receptor (HGFR), and ROS receptor tyrosine 
kinases. (Investigator Brochure)  Crizotinib demonstrated concentration 
dependent inhibition of ALK kinase activity in biochemical assays and cell based 
assays.  In addition, crizotinib demonstrated growth inhibition and increased 
apoptosis of tumor cell lines with ALK fusion variants (EML4-ALK or NPM-ALK).  
Mice xenografts with ALK fusion variants also responded to crizotinib treatment 
in a dose dependent fashion. (IB)   
Based on its significant activity, crizotinib received FDA approval for ALK positive 
NSCLC in 2011.  Clinical investigation of this agent began in 2006, with the 
phase I first in human study with crizotinib.  With the discovery of the ALK gene 
rearrangements in NSCLC, an expansion cohort was added to include this 
population. This study showed a 60% response rate in this cohort with a median 
PFS of 9.7 months [10, 28]. A single arm phase II study PROFILE 1005, for 
patients with ALK+ NSCLC showed a comparable ORR of 53% and median PFS 
of 8.5 months.[26]  A phase III trial, PROFILE 1007, comparing crizotinib to 
standard chemotherapy in second line setting resulted in a better ORR (65% vs 
20%), shorter time to response (6.3 vs 12.6 weeks) and improved PFS with 
crizotinib (7.7 vs. 3m).[29]  In all these studies, toxicities were acceptable with 
some reversible visual disturbances, gastrointestinal side effects, fatigue, 
transaminitis and edema.  Currently crizotinib is also being studied in the setting 
of ROS1 translocations and Met amplification. (clinicaltrials.gov) 
1.2 
Supporting Preliminary Data  
Genomic alterations involving the anaplastic lymphoma kinase (ALK) gene are 
known oncogenic drivers of a variety of malignancies [1-4]. In the wild-type state, 
activation of the ALK protein is thought to be potentially mediated by ligand-
induced dimerization; however, the role that ALK plays in normal physiology 
remains poorly understood. Oncogenic activation of ALK can occur via a variety 
of mechanisms including mutation (e.g. in neuroblastomas) and recurrent gene 
rearrangements. In the rearranged state, the intact tyrosine kinase domain of 
ALK is fused to a variety of upstream partners, with the breakpoint of ALK being 
highly conserved across different fusions. These 5’ partners contribute leucine 
zipper or coiled-coil domains that result in ligand-independent activation and 
constitutive activation of the ALK tyrosine kinase. This, in turn, results in 
activation of downstream signaling involving the MAPK, PI3K, and JAK/STAT 
pathways and increased cell growth and proliferation [5]. 
ALK gene rearrangements in NSCLC were first discovered in 2007 [6, 7] and 
have since been identified in 3-9% of NSCLCs, mainly those with 
adenocarcinoma histology [8-12]. The most commonly characterized alteration in 
lung cancer is an inversion on the short arm of chromosome 2 that leads to 
fusion of the N-terminal of protein encoded by EML4 gene with the intracellular 
portion of receptor tyrosine kinase coded by the ALK gene [6, 13]. This results in 
overexpression of a catalytically active kinase. A transgenic mouse model 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
6 
expressing EML4-ALK in type 2 pneumocytes resulted in the development of 
multiple lung adenocarcinomas [14].  
Over 20 variants of EML4-ALK fusions have been characterized [15]. There are 
other reported variants of ALK fusion proteins in lung cancer that do not involve 
the EML4 gene such as KIF5B-ALK, STRN-ALK, HIP1-ALK, VCL-ALK, NPM-
ALK and TGF-ALK [12, 16-18].  These rearrangements are often mutually 
exclusive with other major lung cancer drivers including EGFR and KRAS 
mutations [19, 20].  While treatment with ALK inhibitors is now standard for ALK-
rearranged NSCLC, there are likely other tumors that may benefit from inhibition 
of this pathway. 
ALK fusions have been identified as drivers of oncogenesis in a variety of other 
malignancies [21]. ALK-positive anaplastic large cell lymphomas (ALCLs) 
represent a distinct type subset of lymphomas that are associated with better 
outcomes in comparison to ALK-negative ALCLs. Up to 50% of ALK-positive 
ALCLs harbor ALK fusions, the most common of which is the t(2;5)(p23;q35) 
translocation, resulting in the formation of NPM-ALK. In fact, the ALK gene was 
first identified in 1994 as part of a fusion gene formed via chromosomal 
translocation in ALCL [1]. These fusions were subsequently found to be 
oncogenic in vitro and in vivo and lead to increased activation of the MAPK and 
PI3K pathways [22]. ALK rearrangements are also found in other lymphoid 
malignancies, such as a subset of patients with diffuse large B-cell lymphomas 
[23]. 
In solid tumors, ALK rearrangements including TPM4-ALK and TPM3-ALK have 
been identified in up to 50-75% of inflammatory myofibroblastic tumors (IMT). 
These fusions are transforming in various cell lines and animal models. 
Response to the ALK inhibitor crizotinib has been reported in ALK-rearranged 
IMT [24]. Recently, ALK rearrangements have been found in spitzoid neoplasms, 
a group of melanocytic tumors including Spitz nevi, spitzoid melanomas, and 
atypical Spitz tumors. The frequency of ALK fusions in this population is 
approximately 10%. These fusions include TPM3-ALK and DCTN1-ALK and are 
associated with increased ALK expression via immunohistochemistry. 
Expression of DCTN1-ALK in melan-a cells results in increased phosphorylation 
of the fusion protein and downstream activation of AKT, ERK, and S6. Activation 
of the MAPK and PI3K pathways is inhibited by crizotinib [25]. 
ALK fusions have also been identified in case reports from a number of other 
solid tumors including breast cancer, esophageal squamous cell carcinoma, 
renal cell carcinoma, and colorectal cancer [21], underscoring the role that these 
recurrent gene rearrangements play in oncogenesis. 
ALK Testing 
The current gold standard assay to diagnose ALK translocations in NSCLC was 
developed as a companion diagnostic in the phase I/II trials involving crizotinib 
[10, 26]. This test, Vysis ALK Break-apart FISH probe test kit (Abbott), was 
approved along with crizotinib by US- FDA in 2010. The determination of a 
positive result is set at more than 15% of tumor cells positive for split red and 
green signals, representing the 5’and 3’ ends of the ALK gene [10, 27].  It is 
possible for next generation sequencing platforms to detect ALK translocations 
as well, and this approach may have increased sensitivity. (Siraj et al., ASCO 
2014)  

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
7 
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 have an ALK rearrangement as defined via the MATCH 
Master Protocol and described in Appendix IV. See Appendix IV for 
information on the ALK mutations and corresponding Levels of 
Evidence. 
2.1.2 
Patients must not have non small cell lung cancer or ALCL. 
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. Add13 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
8 
2.1.7 
Patients must not have had prior ALK-targeted inhibitors, including 
crizotinib, ceritinib, alectinib, AP26113, TSR-011, X-396, RXDX-101, 
CEP-37440, PF-06463922 
2.1.8 
Patients must not have had brain metastases unless 1) treated and 
neurologically stable for at least 2 weeks, or 2) untreated, 
asymptomatic, and treatment is not indicated.  Steroids are permitted 
if doses are stable (or tapering) for 2 weeks prior to study enrollment.  
Date of last treatment ____________ 
2.1.9 
Patients using drugs or foods that are known potent CYP3A4 
inhibitors or inducers will be excluded. Please see Appendix II. 
 
 
 
 
 
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-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
9 
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, 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 
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 F 
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 F 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-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
10 
 
EAY131 – Subprotocol F specific expedited reporting 
exceptions: 
For subprotocol F, 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-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
11 
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-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
12 
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 
  
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 2) 
Rev. 5/16, 
8/17, Add18 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
13 
 
 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%)  
 
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 
 
  
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) 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
14 
 
 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%)  
 
 
 
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. 
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 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
15 
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) 
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. 
 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
16 
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-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
17 
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 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
18 
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-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
19 
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 
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 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
20 
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 
• 
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 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
21 
3.7 
Duration of Follow-Up  
Refer to the MATCH Master Protocol for specifics on the duration of follow-up. 
 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
22 
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 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 
Rev. 8/15, 
2/16, 5/16 
Rev. 2/16, 
12/16 
Rev. 2/16 
Rev. 2/16 
Rev. 3/17 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
23 
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. 
 
Rev. 2/16 
Rev. Add13 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
24 
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 
registration status. Questions about IB access may be directed to the PMB IB 
coordinator at IBCoordinator@mail.nih.gov. 
Rev.8/15 
Rev. 12/16 
Rev. 3/17 
Rev. Add13 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
25 
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. 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
26 
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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27 
6. 
Translational Studies 
Please refer to the MATCH Master Protocol for information on the Translational Studies. 
7. 
References 
1. 
Morris SW, Kirstein MN, Valentine MB et al. Fusion of a kinase gene, ALK, to a 
nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 1994; 263: 
1281-1284. 
2. 
Kelly LM, Barila G, Liu P et al. Identification of the transforming STRN-ALK fusion 
as a potential therapeutic target in the aggressive forms of thyroid cancer. Proc 
Natl Acad Sci U S A 2014; 111: 4233-4238. 
3. 
Azarova AM, Gautam G, George RE. Emerging importance of ALK in 
neuroblastoma. Semin Cancer Biol 2011; 21: 267-275. 
4. 
Fransson S, Hansson M, Ruuth K et al. Intragenic anaplastic lymphoma kinase 
(ALK) rearrangements: Translocations as a novel mechanism of ALK activation in 
neuroblastoma tumors. Genes Chromosomes Cancer 2014. 
5. 
Solomon B, Wilner KD, Shaw AT. Current status of targeted therapy for anaplastic 
lymphoma kinase-rearranged non-small cell lung cancer. Clin Pharmacol Ther 
2014; 95: 15-23. 
6. 
Soda M, Choi YL, Enomoto M et al. Identification of the transforming EML4–ALK 
fusion gene in non-small-cell lung cancer. Nature 2007; 448: 561-566. 
7. 
Mano H. Non‐solid oncogenes in solid tumors: EML4–ALK fusion genes in lung 
cancer. Cancer science 2008; 99: 2349-2355. 
8. 
Takeda M, Okamoto I, Sakai K et al. Clinical outcome for EML4-ALK-positive 
patients with advanced non-small-cell lung cancer treated with first-line platinum-
based chemotherapy. Annals of Oncology 2012; 23: 2931-2936. 
9. 
Takeuchi K, Choi YL, Soda M et al. Multiplex reverse transcription-PCR screening 
for EML4-ALK fusion transcripts. Clin Cancer Res 2008; 14: 6618-6624. 
10. 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-
1703. 
11. Koivunen JP, Mermel C, Zejnullahu K et al. EML4-ALK fusion gene and efficacy of 
an ALK kinase inhibitor in lung cancer. Clin Cancer Res 2008; 14: 4275-4283. 
12. Solomon B, Varella-Garcia M, Camidge DR. ALK gene rearrangements: a new 
therapeutic target in a molecularly defined subset of non-small cell lung cancer. 
Journal of Thoracic Oncology 2009; 4: 1450-1454. 
13. Chiarle R, Voena C, Ambrogio C et al. The anaplastic lymphoma kinase in the 
pathogenesis of cancer. Nat Rev Cancer 2008; 8: 11-23. 
14. Soda M, Takada S, Takeuchi K et al. A mouse model for EML4-ALK-positive lung 
cancer. Proc Natl Acad Sci U S A 2008; 105: 19893-19897. 
15. Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin 
Oncol 2013; 31: 1105-1111. 

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NCI Update Date: August 12, 2015 
28 
16. Choi YL, Takeuchi K, Soda M et al. Identification of novel isoforms of the EML4-
ALK transforming gene in non–small cell lung cancer. Cancer research 2008; 68: 
4971-4976. 
17. Takeuchi K, Choi YL, Togashi Y et al. KIF5B-ALK, a novel fusion oncokinase 
identified by an immunohistochemistry-based diagnostic system for ALK-positive 
lung cancer. Clinical Cancer Research 2009; 15: 3143-3149. 
18. Weickhardt AJ, Camidge DR. The therapeutic potential of anaplastic lymphoma 
kinase inhibitors in lung cancer: rationale and clinical evidence. Clinical 
Investigation 2011; 1: 1119-1126. 
19. Wong DW, Leung EL, So KK et al. The EML4-ALK fusion gene is involved in 
various histologic types of lung cancers from nonsmokers with wild-type EGFR and 
KRAS. Cancer 2009; 115: 1723-1733. 
20. Paik JH, Choi CM, Kim H et al. Clinicopathologic implication of ALK rearrangement 
in surgically resected lung cancer: a proposal of diagnostic algorithm for ALK-
rearranged adenocarcinoma. Lung Cancer 2012; 76: 403-409. 
21. Shaw AT, Hsu PP, Awad MM, Engelman JA. Tyrosine kinase gene 
rearrangements in epithelial malignancies. Nat Rev Cancer 2013; 13: 772-787. 
22. Ferreri AJ, Govi S, Pileri SA, Savage KJ. Anaplastic large cell lymphoma, ALK-
positive. Crit Rev Oncol Hematol 2012; 83: 293-302. 
23. Beltran B, Castillo J, Salas R et al. ALK-positive diffuse large B-cell lymphoma: 
report of four cases and review of the literature. J Hematol Oncol 2009; 2: 11. 
24. Butrynski JE, D'Adamo DR, Hornick JL et al. Crizotinib in ALK-rearranged 
inflammatory myofibroblastic tumor. N Engl J Med 2010; 363: 1727-1733. 
25. Wiesner T, He J, Yelensky R et al. Kinase fusions are frequent in Spitz tumours 
and spitzoid melanomas. Nat Commun 2014; 5: 3116. 
26. Kim D-W, Ahn M-J, Shi Y et al. Results of a global phase II study with crizotinib in 
advanced ALK-positive non-small cell lung cancer (NSCLC). ASCO Meeting 
Abstracts 2012; 30: 7533. 
27. Camidge DR, Kono SA, Flacco A et al. Optimizing the detection of lung cancer 
patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements 
potentially suitable for ALK inhibitor treatment. Clin Cancer Res 2010; 16: 5581-
5590. 
28. Camidge DR, Bang Y-J, Kwak EL et al. Activity and safety of crizotinib in patients 
with< i> ALK</i>-positive non-small-cell lung cancer: updated results from a phase 
1 study. The lancet oncology 2012. 
29. 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: 2385-2394 

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NCI Update Date: August 12, 2015 
29 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol F: Crizotinib/ALK 
Appendix I 
 
Patient 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. 
 
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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: _____________ 

ECOG-ACRIN 
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Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
31 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol F: Crizotinib/ALK 
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 
 
 

ECOG-ACRIN 
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Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
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Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol F: Crizotinib/ALK 
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 enzyme. 
• 
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-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
34 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
35 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol F: Crizotinib/ALK 
Appendix IV 
 
Actionable Mutations for Sub-Protocol EAY131-F 
Other novel ALK Fusion events 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 
ALK 
EML4-
ALK.E2A20.COSF479.1 
Fusion 
1 
ALK 
KIF5B-ALK.K24A19 
Fusion 
1 
ALK 
EML4-
ALK.E17int17Aint19E20 
Fusion 
1 
ALK 
EML4-ALK.E17ins68A20 
Fusion 
1 
ALK 
KIF5B-
ALK.K15A20.COSF1060.1 
Fusion 
1 
ALK 
TERT-ALK.T11A5 
Fusion 
1 
ALK 
KTN1-ALK.K43A19 
Fusion 
1 
ALK 
MCFD2-ALK.M1A20 
Fusion 
1 
ALK 
KIF5B-
ALK.K15A20.COSF1381 
Fusion 
1 
ALK 
MYH9-ALK.M9A6ins10 
Fusion 
1 
ALK 
CLIP4-ALK.C12A23 
Fusion 
1 
ALK 
RNF213-ALK.R20A20 
Fusion 
1 
ALK 
TFG-ALK.T6A20.COSF428 
Fusion 
1 
ALK 
EML4-ALK.E19A20 
Fusion 
1 
ALK 
PPFIBP1-ALK.P8A20ins49 
Fusion 
1 
ALK 
EML4-
ALK.E17A20.COSF1366.2 
Fusion 
1 
ALK 
TPM1-ALK.T8A20.NGS 
Fusion 
1 
ALK 
BEND5-ALK.B3A20 
Fusion 
1 
ALK 
EML4-ALK.E13ins90A20 
Fusion 
1 
ALK 
EML4-
ALK.E17A20.COSF1367.2 
Fusion 
1 
ALK 
SEC31A-
ALK.S21A20.COSF460 
Fusion 
1 
ALK 
PPP4R3B-ALK.P9A2 
Fusion 
1 
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NCI Update Date: August 12, 2015 
36 
Gene 
Variant ID 
Variant Description 
Level of Evidence 
ALK 
DCTN1-ALK.D29A20 
Fusion 
1 
ALK 
CLTC-
ALK.C31A20.COSF434 
Fusion 
1 
ALK 
EML4-
ALK.E14A20.COSF1064.1 
Fusion 
1 
ALK 
NPM1-
ALK.N4A20.COSF198 
Fusion 
1 
ALK 
KLC1-
ALK.K9A20.COSF1276 
Fusion 
1 
ALK 
CCDC88A-ALK.C12A20 
Fusion 
1 
ALK 
EML4-ALK.E6A17 
Fusion 
1 
ALK 
DCTN1-ALK.D26A20 
Fusion 
1 
ALK 
EML4-
ALK.E13A20.AB462411 
Fusion 
1 
ALK 
TPM3-
ALK.T7A20.COSF439 
Fusion 
1 
ALK 
MYH9-ALK.M34A20del23 
Fusion 
1 
ALK 
CLIP1-ALK.C13A20 
Fusion 
1 
ALK 
RANBP2-
ALK.R18A20.COSF415 
Fusion 
1 
ALK 
EML4-
ALK.E6A19.COSF1296.1 
Fusion 
1 
ALK 
CLTC-ALK.C31ins63A20 
Fusion 
1 
ALK 
PRKAR1A-
ALK.P2A20.NGS.2 
Fusion 
1 
ALK 
EML4-
ALK.E17ins30A20_V8a 
Fusion 
1 
ALK 
MSN-ALK.M11int12A20 
Fusion 
1 
ALK 
SQSTM1-
ALK.S5A20.COSF1051 
Fusion 
1 
ALK 
VCL-
ALK.V16A20.COSF1057 
Fusion 
1 
ALK 
EML4-ALK.E17ins65A20 
Fusion 
1 
ALK 
GTF2IRD1-ALK.G7A20 
Fusion 
1 
ALK 
CLTC-
ALK.C31A20.COSF470 
Fusion 
1 
ALK 
EML4-
ALK.E6bA20.AB374362 
Fusion 
1 
ALK 
PPM1G-ALK.P1A18 
Fusion 
1 

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37 
Gene 
Variant ID 
Variant Description 
Level of Evidence 
ALK 
A2M-ALK.A22A19 
Fusion 
1 
ALK 
BIRC6-ALK.B10A20 
Fusion 
1 
ALK 
EML4-
ALK.E15A20.COSF413.1 
Fusion 
1 
ALK 
EML4-ALK.E14ins124A20.1 
Fusion 
1 
ALK 
EML4-
ALK.E20A20.COSF409.1 
Fusion 
1 
ALK 
TPM4-
ALK.T7A20.COSF441 
Fusion 
1 
ALK 
EML4-ALK.E14del36A20 
Fusion 
1 
ALK 
EML4-ALK.E21A20 
Fusion 
1 
ALK 
PPFIBP1-
ALK.P12A20.COSF1461 
Fusion 
1 
ALK 
EML4-ALK.E3p53insA20 
Fusion 
1 
ALK 
STRN-
ALK.S3A20.COSF1430 
Fusion 
1 
ALK 
FN1-
ALK.F23A19.COSF1301 
Fusion 
1 
ALK 
HIP1-ALK.H21A20 
Fusion 
1 
ALK 
TRMT61B-ALK.T1A9 
Fusion 
1 
ALK 
EML4-
ALK.E13A20.COSF1062.2 
Fusion 
1 
ALK 
KANK2-ALK.K4A16 
Fusion 
1 
ALK 
TPR-ALK.T4A20 
Fusion 
1 
ALK 
ACTG2-ALK.A2A18 
Fusion 
1 
ALK 
TPR-ALK.T15A20 
Fusion 
1 
ALK 
ATRNL1-ALK.A19A20 
Fusion 
1 
ALK 
NCOA1-ALK.N21A1.NGS 
Fusion 
1 
ALK 
STK32B-ALK.S11A20 
Fusion 
1 
ALK 
MEMO1-ALK.M2A7 
Fusion 
1 
ALK 
FN1-ALK.F20A19 
Fusion 
1 
ALK 
KIF5B-
ALK.K24A20.COSF1058 
Fusion 
1 
ALK 
KIF5B-
ALK.K17A20.COSF1257 
Fusion 
1 
ALK 
EML4-ALK.E6ins18A20 
Fusion 
1 
ALK 
SEC31A-
ALK.S22A20.COSF459 
Fusion 
1 

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Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
38 
Gene 
Variant ID 
Variant Description 
Level of Evidence 
ALK 
TRAF1-ALK.T6A20 
Fusion 
1 
ALK 
GFPT1-ALK.G18A20.1 
Fusion 
1 
ALK 
MSN-
ALK.M11A20.COSF421 
Fusion 
1 
ALK 
EML4-
ALK.E14A20.COSF477.1 
Fusion 
1 
ALK 
CAD-ALK.C35A20 
Fusion 
1 
ALK 
EML4-
ALK.E18A20.COSF487.1 
Fusion 
1 
ALK 
TFG-ALK.T4A20.COSF424 
Fusion 
1 
ALK 
EML4-
ALK.E20A20.COSF730.1 
Fusion 
1 
ALK 
CARS-
ALK.C17A20.COSF437 
Fusion 
1 
ALK 
TFG-ALK.T5A20.COSF426 
Fusion 
1 
ALK 
ALK-PTPN3.A11P3 
Fusion 
1 
ALK 
EML4-ALK.E6A18 
Fusion 
1 
ALK 
EML4-
ALK.E6aA20.AB374361 
Fusion 
1 
ALK 
EML4-
ALK.E14ins2del52A20 
Fusion 
1 
ALK 
EML4-ALK.E7A20.NGS 
Fusion 
1 
ALK 
TFG-ALK.T7A19 
Fusion 
1 
ALK 
ATIC-ALK.A7A20.COSF444 
Fusion 
1 
ALK 
KCNQ5-ALK.K1A10 
Fusion 
1 
ALK 
HIP1-ALK.H28A20 
Fusion 
1 
ALK 
GTF3C2-ALK.G1A18 
Fusion 
1 
ALK 
EML4-
ALK.E2A20.COSF478.1 
Fusion 
1 
ALK 
HIP1-ALK.H30A20 
Fusion 
1 
 

ECOG-ACRIN 
EAY131-F 
Cancer Research Group 
Version Date: March 11, 2019 
 
NCI Update Date: August 12, 2015 
39 
Molecular Analysis for Therapy Choice (MATCH) 
MATCH Treatment Subprotocol F: Crizotinib/ALK 
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-F 
Cancer Research Group 
Version Date: March 11, 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®