Molecular Analysis for Therapy Choice (MATCH)
Phase: PHASE2
Conditions: Advanced Lymphoma, Advanced Malignant Solid Neoplasm, Bladder Carcinoma, Breast Carcinoma, Cervical Carcinoma, Colon Carcinoma, Colorectal Carcinoma, Endometrial Carcinoma, Esophageal Carcinoma, Exocrine Pancreas Carcinoma, Gastric Carcinoma, Glioma, Head and Neck Carcinoma, Hematopoietic and Lymphoid Cell Neoplasm, Kidney Carcinoma, Liver Carcinoma, Lung Carcinoma, Lymphoma, Malignant Uterine Corpus Neoplasm, Malignant Uterine Neoplasm, Melanoma, Multiple Myeloma, Ovarian Carcinoma, Prostate Carcinoma, Rectal Carcinoma, Recurrent Bladder Carcinoma, Recurrent Breast Carcinoma, Recurrent Cervical Carcinoma, Recurrent Colon Carcinoma, Recurrent Colorectal Carcinoma, Recurrent Esophageal Carcinoma, Recurrent Gastric Carcinoma, Recurrent Glioma, Recurrent Head and Neck Carcinoma, Recurrent Liver Carcinoma, Recurrent Lung Carcinoma, Recurrent Lymphoma, Recurrent Malignant Solid Neoplasm, Recurrent Malignant Uterine Corpus Neoplasm, Recurrent Melanoma, Recurrent Multiple Myeloma, Recurrent Ovarian Carcinoma, Recurrent Pancreatic Carcinoma, Recurrent Prostate Carcinoma, Recurrent Rectal Carcinoma, Recurrent Skin Carcinoma, Recurrent Thyroid Gland Carcinoma, Refractory Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Multiple Myeloma, Skin Carcinoma, Thyroid Gland Carcinoma
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 
 
October 9, 2020 
 
Martha Kruhm, MS RAC 
Head, Protocol and Information Office 
Quality Assurance Section 
CTEP, DCT, NCI 
6130 Executive Blvd, EPN Room 7000 
Bethesda, MD   20892 
Dear Ms. Kruhm: 
Enclosed is Addendum #26 to EAY131, Molecular Analysis for Therapy Choice (MATCH). 
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permitted to conduct the study utilizing outdated versions of any MATCH protocol documents 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 protocol have been made in this addendum: 
 
Section 
Change 
1. 
Cover Page 
Updated Version Date and addendum number.  
2. 
Appendix IX 
Table 2: Updated addendum component version dates for the MATCH 
Master Protocol and all affected sub protocols. 
The following revisions to EAY131 Screening Protocol Consent Document have been made in 
this addendum: 
 
Section 
Change 
1. 
Page 1 
Updated Version Date. 
The following revisions to EAY131 Research Biopsy Consent Document have been made in this 
addendum: 
 
Section 
Change 
2. 
Page 1 
Updated Version Date. 
If you have any questions regarding this addendum, please contact aagu@ecog-acrin.org or 
857-504-2900. 

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

ECOG-ACRIN 
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Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: August 12, 2015 
2 
Table of Contents 
Molecular Analysis for Therapy Choice (MATCH) ...................................................... i 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 9 
1. Introduction ...................................................................................................... 10 
1.1 Description of Trial .................................................................................. 10 
1.2 Study Diseases ......................................................................................... 11 
1.3 Genomic Sequencing Research and Results Return ............................... 11 
1.4 Rationale for the Study ........................................................................... 12 
1.5 Rationale for Image Collection ................................................................ 17 
1.6 Rules for treatment selection ................................................................. 19 
2. Objectives ......................................................................................................... 22 
2.1 Primary Objective .................................................................................... 22 
2.2 Secondary Objectives .............................................................................. 22 
3. Selection of Patients ......................................................................................... 23 
3.1 Eligibility Criteria for Screening Biopsy (Step 0) ...................................... 23 
3.2 Eligibility Criteria for First Treatment (Step 1) ........................................ 30 
3.3 Eligibility Criteria for Second Screening (Step 2) ..................................... 31 
3.4 Eligibility Criteria for Second Treatment (Step 3) ................................... 32 
3.5 Eligibility Criteria for Third Screening (Step 4) ........................................ 32 
3.6 Eligibility Criteria for Third Treatment (Step 5) ....................................... 33 
3.7 Eligibility Criteria for Fourth Screening (Step 6) ...................................... 34 
3.8 Eligibility Criteria for Fourth Treatment (Step 7) .................................... 34 
3.9 Eligibility Criteria for Research Biopsy and Circulating Tumor DNA 
Collection (Step 8) ................................................................................... 34 
4. Registration Procedures.................................................................................... 36 
4.1 Pre-Registration to First Biopsy (Step 0) ................................................. 38 
4.2 Registration to First Treatment (Step 1) ................................................. 41 
4.3 Registration to Second Screening (Step 2) .............................................. 41 
4.4 Registration to Second Treatment (Step 3) ............................................ 42 
4.5 Registration to Third Screening (Step 4) ................................................. 43 
4.6 Registration to Third Treatment (Step 5) ................................................ 44 
4.7 Registration to Fourth Screening (Step 6) ............................................... 45 
4.8 Registration to Fourth Treatment (Step 7) ............................................. 45 
4.9 Registration to Research Biopsy AND Blood for Circulating Tumor DNA 
(Step 8) .................................................................................................... 46 
4.10 Instructions for Patients who Do Not Start Assigned Protocol Treatment46 
4.11 Data collection ........................................................................................ 47 
4.12 Biopsy Reimbursements.......................................................................... 47 

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5. Treatment Plan ................................................................................................. 49 
5.1 Study Design ............................................................................................ 49 
5.2 Administration Schedule Summary......................................................... 55 
5.3 Adverse Event Reporting Requirements ................................................. 55 
5.4 Dose Modifications ................................................................................. 64 
5.5 Duration of Therapy ................................................................................ 64 
5.6 Duration of Follow-Up ............................................................................. 65 
6. Measurement of Effect ..................................................................................... 66 
6.1 Solid Tumor Response ............................................................................. 66 
6.2 Lymphoma Response Criteria ................................................................. 74 
6.3 RANO Criteria for GBM Patients ............................................................. 79 
6.4 Response criteria for multiple myeloma ................................................. 82 
6.5 Duration of Response .............................................................................. 86 
6.6 Overall Survival ....................................................................................... 86 
6.7 Progression-Free Survival ........................................................................ 86 
6.8 Time to Progression ................................................................................ 87 
7. Study Parameters .............................................................................................. 88 
7.1 Step 0, 2, 4 and 6 Parameters (Registration to Screening Steps) ........... 88 
7.2 Biospecimen Submissions ....................................................................... 90 
8. Statistical Considerations .................................................................................. 95 
8.1 Accrual ..................................................................................................... 95 
8.2 Interim Monitoring.................................................................................. 97 
8.3 Safety Monitoring ................................................................................... 97 
8.4 Endpoints/Analysis Plan .......................................................................... 98 
8.5 Correlative Study ..................................................................................... 99 
8.6 Image Analysis Plan ............................................................................... 100 
8.7 Gender and Ethnicity ............................................................................ 100 
9. Biopsy Target Selection, Performance and Submission of Specimens ........... 101 
9.1 Schedule of Collection and Submission ................................................ 101 
9.2 Pathology Submissions .......................................................................... 103 
9.3 Optional Whole Blood Collections for Research ................................... 106 
9.4 NCI MATCH EAY131 Clinical Trial Specimen Kit Instructions for Specimen 
Collection and Shipping ......................................................................... 107 
9.5 Shipping Procedures ............................................................................. 109 
9.6 Biopsy Instructions ................................................................................ 109 
9.7 ECOG-ACRIN Sample Tracking System .................................................. 113 
9.8 Use of Specimens in Research .............................................................. 115 
9.9 Sample Inventory Submission Guidelines ............................................. 115 
9.10 Institutional Biopsy Reimbursements ................................................... 115 
10. Laboratory Clinical Research and Non-clinical Research Studies ................... 116 
10.1 Targeted Genetic Analysis for MATCH eligibility .................................. 116 
10.2 Research Studies ................................................................................... 118 

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NCI Update Date: August 12, 2015 
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11. Imaging Submissions ....................................................................................... 120 
12. Electronic Data Capture .................................................................................. 122 
12.1 Records Retention ................................................................................. 122 
13. Patient Consent and Peer Judgment .............................................................. 122 
14. References ...................................................................................................... 122 
Appendix I  Biopsy Workflow Schematic ............................................................... 125 
Appendix II  Pathology Submission Guidelines ..................................................... 127 
Appendix III  Patient Thank You Letter .................................................................. 137 
Appendix IV  CRADA/CTA ...................................................................................... 138 
Appendix V  ECOG Performance Status ................................................................ 140 
Appendix VI  CYP3A4 Inducers and Inhibitors ....................................................... 141 
Appendix VII  MATCH Actionable Mutations of Interest ....................................... 142 
Appendix VIII  Instructions for Reporting Pregnancies on a Clinical Trial ............. 144 
Appendix IX  List of MATCH Subprotocols and Associated Subprotocol Version 
Dates ............................................................................................................... 146 
Appendix X  Example MATCH-Assay Laboratory Reports ..................................... 154 
Appendix XI  ECOG-ACRIN/NCI MATCH Working Groups ..................................... 162 
Appendix XII  EAY131 Collection and Shipping Kit Order Form ............................. 167 
Appendix XIII  Medications Known to Prolong the QT Interval ............................. 168 
Appendix XIV  Screening Assessments for Designated Outside Assays ................ 172 
Appendix XV  Historical Record of the Original Screening Process ....................... 177 
Appendix XVI  CS-MATCH-0007  Comprehensive Genomic Analysis of NCI- MATCH208 
Appendix XVII  Dynamic aMOI Process ................................................................. 224 
Appendix XVIII  CS-MATCH-0009  Longitudinal Evaluation of Mutation Profile in 
NCI-MATCH Patients on All Treatment Arms through Evaluation of Archival 
Specimens ....................................................................................................... 227 
Appendix XIX  List of Subprotocol-Specific Correlative Studies ............................ 232 
Appendix XX  CS-MATCH-0014ct Genomic landscape of plasma-derived ctDNA 
from patients enrolled on the NCI-MATCH trial ............................................. 233 
Appendix XXI  CS-MATCH-0015ct  A Retrospective Study of Liquid Biopsies Using a 
Pan-Cancer NGS Assay in NCI-MATCH Patients with Less Common Tumor 
Histologies or Who Enrolled in Subprotocol Arms Z1D, T or M...................... 240 
Appendix XXII  CS-MATCH-0020  Discovery of Driver Fusions in MOI-Negative NCI-
MATCH Screening Samples ............................................................................. 262 
 
 
 
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Version Date: October 9, 2020 
 
NCI Update Date: August 12, 2015 
5 
ECOG-ACRIN STUDY CHAIR 
Keith Flaherty, MD 
Massachusetts General Hospital 
55 Fruit Street, LH 202 
Boston, MA 02114 
Phone: 617-724-4800 
Fax: 617-724-6898 
Email: kflaherty@partners.org 
NCI STUDY CHAIR 
Alice Chen, MD 
Early Clinical Trials Development Program 
DCTD/NCI 
Suite 31/3A44 
31 Center Drive 
Bethesda MD 20892 
Phone: 301-496-4291 
Fax: 240-276-7894 
Email: chenali@mail.nih.gov 
 
ECOG-ACRIN STUDY CO-CHAIR 
Peter O’Dwyer, MD 
University of Pennsylvania, Abramson 
Cancer Center 
16 Penn Tower 
3400 Spruce Street 
Philadelphia, PA 19104 
Phone: 215-662-7606 
Fax: 215-243-3268 
Email: peter.odwyer@uphs.upenn.edu 
 
NCI STUDY CO-CHAIR 
Lyndsay N. Harris, MD 
Cancer Diagnosis Program 
9609 Medical Center Drive MSC 9730 
Bethesda, MD 20892 
Phone: 240-276-6505 
Fax: 240-276-7889 
Email: lyndsay.harris@nih.gov 
ECOG-ACRIN SAFETY CO-CHAIR 
Edith Mitchell, MD, FACP 
Thomas Jefferson University Hospital 
233 South 10th Street 
BLSB, Suite 502 
Philadelphia, PA 19107 
Phone: 215-955-4652 
Fax: 215-503-4103 
Email: edith.mitchell@jefferson.edu 
 
NCI LABORATORY CO-LEAD 
James V. Tricoli, Ph.D. 
Chief Diagnostic Biomarkers and Technology 
Branch, Cancer Diagnosis Program 
9609 Medical Center Drive 
3 West, Room 526, MSC 9728 
Rockville, MD 20892 
Phone: (240) 276-5725 
Fax: (240) 276-7889 
Email: tricolij@mail.nih.gov 
 
MATCH TEAM ALIAS 
MATCH@jimmy.harvard.edu 
NCI SAFETY CO-CHAIR 
John J. Wright, MD, Ph.D. 
Investigational Drug Branch 
CTEP, DCTD, NCI, NIH 
9609 Medical Center Drive 
Room 5-W-454, MSC 9739 
Rockville, MD 20850 
Phone: 240-276-6105 
Fax: 240-276-7894 
Email: wrightj@ctep.nci.nih.gov 
 
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LABORATORY SITES: 
 
Molecular Characterization Laboratory at the NCI Frederick National 
Laboratory for Cancer Research 
LABORATORY PRINCIPAL INVESTIGATOR 
Mickey Williams, PhD 
Director of the Molecular Characterization Laboratory 
Leidos Biomedical Research Inc. 
Frederick National Laboratory for Cancer Research 
PO Box B 
Frederick, MD 21702 
Phone: 301-228-4654 
Fax: 301-846-5923 
Email: mickey.williams@nih.gov 
 
 
Massachusetts General Center for Integrated Diagnostics 
LABORATORY PRINCIPAL INVESTIGATOR 
John Anthony Iafrate MD PhD 
Translational Research Laboratory, Mass General Hospital 
70 Blossom Street, GRJ-1008 
Boston, MA 02114 
Phone: 617-726-0503 
Fax: 617-726-6974 
Email: aiafrate@partners.org 
 
MD Anderson Molecular Diagnostics NGS Laboratory 
LABORATORY PRINCIPAL INVESTIGATOR 
Stanley R. Hamilton MD 
M.D. Anderson Cancer Center 
Department of Pathology 
Unit 85 - Room G1.3540 
1515 Holcombe Boulevard 
Houston, TX 77030 
Phone: 713-792-2040 
Fax: 713-792-4094 
Email: shamilto@mdanderson.org 
 
Yale University, Clinical Molecular Pathology 
LABORATORY PRINCIPAL INVESTIGATOR 
Jeffrey Sklar MD, PhD 
Department of Pathology 
310 Cedar Street 
214A Lauder Hall PO Box 208023 
New Haven, CT 06520-8023 
Phone: 203-785-5439 
Fax: 203-785-3103 
Email: jeffrey.sklar@yale.edu 
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Version Date: October 9, 2020 
 
NCI Update Date: August 12, 2015 
7 
IMAGING CORE LABORATORY: 
 
IMAGING PRINCIPAL INVESTIGATOR 
Susanna I. Lee, MD, PhD 
Massachusetts General Hospital 
Department of Radiology 
55 Fruit St, White 270 
Boston, MA 02114 
Phone: 617-643-2009 
Fax: 617-726-4891 
Email: slee0@mgh.harvard.edu 
 
ECOG-ACRIN IMAGING STATISTICIAN 
Dr. Constantine Gatsonis PhD 
E-A Biostatistical Center – Providence 
Brown University 
Box G-121-7 
121 South Main Street, 7th Floor 
Providence, RI 02912 
Phone: 401-863-9183 
Fax: 401-863-9182 
Email: gatsonis@stat.brown.edu 
 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory 
tab.)  
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions on 
using the Oncology Patient Enrollment 
Network (OPEN) which can be accessed 
at https://www.ctsu.org/OPEN SYSTEM/ 
or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave. Please 
see the data 
submission section of 
the protocol for further 
instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. 
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS. 
For clinical questions (i.e. patient eligibility or treatment-related) Contact the MATCH Treatment 
Subprotocol PI. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or e-mail: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
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Version Date: October 9, 2020 
 
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9 
Schema 
Register to Screening – Step 03
< 6 months
No aMOI(s)2
Off study
Register to Treatment – Step 1
Study Drug
Toxicity or Progression
> 6 months
Register to Screening – Step 26
Additional 
aMOIs
Biopsy
Submit tissue for 
Molecular Profiling
No aMOI(s)
No
Follow-up
(Step 8)1
Register to Treatment – Step 3
Study Drug
Toxicity or Progression
< 6 months
> 6 months
Register to Screening – Step 4
Additional 
aMOIs
Biopsy
Submit tissue 
for Molecular 
Profiling
No aMOI(s)
No 
Register to Treatment – Step 5
Study Drug
Toxicity or Progression
< 6 months
> 6 months
Register to Screening – Step 6
Additional aMOIs
No 
Register to Treatment – Step 7
Study Drug
Toxicity or Progression
Biopsy
Submit tissue for 
Molecular Profiling
Register to Screening – Step 26
Register to Treatment – Step 3
Study Drug
Toxicity or Progression
< 6 months
> 6 months
Register to Screening – Step 4
Register to Treatment – Step 5
Study Drug
Toxicity or Progression
aMOIs
aMOIs
aMOIs
1. For patients that have consented to undergo the research biopsy and additional optional blood collections, register to Step 8 (see Section 3.9).
2. Patients may be eligible to be reconsidered for treatment. Please see Section 3.2.2 and Section 5.1.
3. Image Submission Requirements  see Section 11 for submission instructions.
4. For multiple myeloma patients (excluding plasmacytoma), a bone marrow aspirate is required.
5. Outside assay sequencing results from designated laboratory indicate an applicable 'rare variant' aMOI and the ordering physician received a specific notification of potential e igibility from the designated lab (see Appendix 
XIV). Tissue is to be submitted for central confirmation testing per Section 9.3.2.2.
6. Patients assigned to Step 1 using a rare variant determined by an 'Outside Assay" go to follow-up and are not eligible for registration to Step 2. Patients are eligible for Step 8.
Follow-up
(Step 8)1
Follow-up
(Step 8)1
Follow-up
(Step 8)1
Follow-up
(Step 8)1
Follow-up
(Step 8)1
Follow-up
(Step 8)1
Outside Assay indicates 
"Rare Variant 5
Outside Assay Process 
(See Appendix XIV)
Or
 
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1. 
Introduction 
This trial aims to establish whether patients with tumor mutations, amplifications or 
translocations in one of the genetic pathways of interest are likely to derive clinical 
benefit (primary objective: objective response; secondary objective: progression-free 
survival of at least 6 months) if treated with agents targeting that specific pathway in a 
single-arm design. 
The targets being evaluated in this study are listed in Appendix VII. 
The study design was developed in conjunction with experts in developmental 
therapeutics, clinical trial design, genetic sequencing, molecular oncology, cell biology, 
and statistics, who developed an algorithm that defines clinical action based on genetic 
variants reported in the genes of interest. 
Molecular profiling will be performed in a study-specific network of approved Clinical 
Laboratory Improvement (CLIA)-certified Molecular Characterization Laboratories. 
1.1 
Description of Trial 
This study is a type of basket trial designed with the flexibility to open and close 
subprotocols. The study drugs included in this trial are specified in Appendix VII 
and by subprotocol in Appendix IX, and include single agents and combinations 
that have at least a recommended phase 2 dose. Patients enrolled on study will 
have a tumor biopsy for molecular characterization and those with molecular 
variants addressed by treatments included in the trial will be offered treatment on 
MATCH.  
All profiling will be performed in specific CLIA-certified laboratories. The MATCH 
laboratories are MD Anderson Cancer Center Molecular Diagnostics NGS 
Laboratory, Massachusetts General Hospital Center for Integrated Diagnostics, 
Molecular Characterization Laboratory at the Frederick National Laboratory for 
Cancer Research and Yale University Clinical Molecular Pathology lab. The 
MATCH laboratories will perform profiling of fresh biopsies and of archived 
specimens of patients entering with a “rare variant  from an assay performed in a 
CLIA-certified laboratory outside of the MATCH laboratory group. The molecular 
profiling assays in the MATCH laboratories will include massively parallel tumor 
sequencing (next generation sequencing) using a targeted Ampliseq panel, and 
certain other molecular assays e.g. immunohistochemistry (IHC). The genes 
interrogated on the NGS assay are listed in Appendix X. 
After Step 0 registration, the “MATCH screening assessment  will differ 
depending on the method of study entry. For patients that previously entered the 
study via the original screening process (i.e. to submit tissue for testing by a 
MATCH laboratory), this assessment will consist of both molecular profiling by 
the MATCH assay and the subsequent process of assigning treatment. Please 
note, after 5/22/17, new patients may no longer be enrolled on the study through 
this process. For patients entering the study through testing performed by one of 
the designated labs outside of the MATCH laboratory group (i.e. the Outside 
Assay process; see Appendix XIV), the assessment will only consist of the 
study's determination of treatment assignment. This is the only method of study 
entry moving forward. 
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1.2 
Study Diseases  
Patients with histologically documented solid tumors, lymphomas and multiple 
myeloma whose disease has progressed following at least one line of standard 
systemic therapy or for whom no standard therapy exists will be registered on the 
screening step to undergo tumor biopsy and analysis 
For each agent (treatment), patients with tumors for which there is a U.S. Food 
and Drug Administration (FDA) approved indication, or with histologies that have 
been shown not to respond or not to have prolonged PFS will be ineligible. 
1.3 
Genomic Sequencing Research and Results Return 
This trial will collect somatic (tumor) genomic data from all patients enrolled to 
determine whether or not their tumors have a molecular abnormality in one of the 
pathways that can be addressed by the treatments in the MATCH trial (an 
actionable mutation of interest, or aMOI). We will screen for pre-defined 
variations in genes in a MATCH CLIA-certified laboratory and other designated 
laboratories (see below) for assignment of patient treatment on study. Only 
malignant tissue will be screened, not normal tissue, so definitive abnormalities in 
germline tissues (heritable diseases) cannot be identified with any certainty. 
Clinicians will receive the results of the molecular studies done in MATCH CLIA 
approved laboratories, along with a laboratory report detailing the 
genes/translocations interrogated. (See Appendix X) 
The protocol includes separate informed consent forms/processes for the 
screening versus treatment steps of the study.  A screening informed consent 
form will be presented at the time of registration to Step 0.  An additional 
informed consent form will be provided at the registration to each treatment step. 
Patients will know (by whether or not they are offered the option to participate in 
the treatment part of the study) whether their tumor has a variation in a gene of 
interest – a variant that is addressed by one of the subprotocols of MATCH 
(aMOI). The appended aMOI tables in each subprotocol are annotated using 
methods consistent with the NCI-MATCH assay, but there are potentially other 
annotations that represent the exact genomic mutations either at the protein or 
genomic level. All identical mutations will be considered as inclusion aMOIs for 
the purposes of NCI-MATCH enrollment. Information on tumor gene variants and 
other molecular assays (e.g. immunohistochemistry results) that form the basis of 
treatment assignment as well as those on the targeted testing that may not lead 
to treatment assignment will be sent to clinicians (via separate CLIA lab reports 
for IHC and for tumor sequencing), who will share them with the patient (example 
report in Appendix X). ECOG-ACRIN has a Certificate of Confidentiality from the 
NIH to help protect the privacy of all study participants. 
Some of the genes tested in the MATCH assay on the patient's tumor could be 
tumor specific, but could also be in the patient's germline (and may be passed to 
subsequent generations). We have discussed this possibility with a committee of 
multidisciplinary experts (genetics, oncology, laboratorians, bioethicists). There is 
no consensus on what type of findings on a tumor sequencing assay would imply 
the presence/absence of germline mutation. The tumor findings will be 
communicated to the treating clinician with advice to consider germline testing if 
clinical and/or family history is consistent with the presence of such an 
abnormality. In many cases we do not know the medical significance of genetic 
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variants that are beyond the aims of this study (e.g., for which a targeted 
treatment is not available) (4, 5). The gene panel and the policy of result return 
will continue to be evaluated by an interdisciplinary study team throughout the 
course of the trial to maintain the rigor and integrity of the study and the 
wellbeing of our patients.  
We are seeking consent from patients for optional research including whole-
exome sequencing of tumor and blood, tumor mRNA sequencing and potentially 
other tests that will explore potential correlations between molecular features and 
the patient’s disease, response, or course. Research on biopsies will only be 
done with excess samples, except at the end of the patient’s participation in the 
study when we will request a biopsy solely for research purposes after the 
patient’s tumor has progressed on the last MATCH treatment. These samples 
and results will be de-identified and are only for research to generate hypotheses 
concerning response or resistance to a particular treatment. We currently have 
no plans to validate or disclose for clinical use any whole exome sequencing or 
other sequencing conducted with de-identified samples collected in this study 
and no clinical decisions should be made based on the results of such research 
testing given the uncertain and/or unknown medical significance of some of these 
variants. To guard against the possibility of unintentional and potentially injurious 
disclosure of unvalidated research results, we will perform the optional whole 
exome or other sequencing as noted above on de-identified samples only. No 
genomic data will be shared with the patient other than the data from the targeted 
sequencing panel and other clinical tests performed for assessment of eligibility 
in one of the CLIA accredited laboratories. All other analyses will be performed 
on de-identified samples. 
This study affords a unique opportunity to collect information about the 
prevalence of mutations, translocations and amplifications in genes associated 
with cancer, as well as how patients’ tumors with such abnormalities respond to 
targeted therapy in the refractory tumor setting; DNA variants and changes in 
RNA expression from tumors collected when patients progress on study drugs is 
anticipated to illuminate resistance mechanisms that will inform subsequent 
studies and improve patient outcomes. The NCI Central IRB will be consulted 
and kept informed of progress of this study and other trials conducted with the 
study agents that may affect study design and conduct. 
For certain rare variants, described below, patients may enter a subprotocol 
using results from an assay performed in a CLIA certified laboratory outside of 
those laboratories engaged in the MATCH study. For these patients, we will 
request archived tissue for performing the MATCH assays, to judge concordance 
with results of the outside laboratory. Similar to the MATCH assays done with a 
fresh biopsy, the MATCH results on the archived tissue will be returned to the 
patient’s provider for sharing with the patient. 
1.4 
Rationale for the Study 
Since the first validation of the molecular, oncogene-targeted therapy with 
imatinib, the abl kinase inhibitor, in chronic myelogenous leukemia, it has been 
appreciated that treating the principal driver oncogene can have a powerful 
impact. However, in subsequent successful applications of molecularly targeted 
therapy, such as EGFR and ALK inhibitors in non-small cell lung cancer and 
BRAF inhibitors in melanoma, the presence of the target oncogene in a subset of 
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patients requires genomic pre-screening of patient’s tumor. Most recently, efforts 
to catalog driver mutations across the entire cancer population have identified 
very small fractions of patients with any given driver within any particular cancer 
type based on site of origin (see TCGA table below). To effectively investigate 
the efficacy of molecularly targeted treatment for such targets, and to understand 
the relative efficacy of the same therapy applied to oncogene-defined subsets 
across different tumor histologies, we propose to initiate a broad-based genomic 
pre-screening study to assign patients whose tumors harbor specific molecular 
abnormalities to relevant targeted treatments, regardless of tumor histology type. 
The study is designed to assign targeted treatment based on a biopsy obtained 
just before study entry. This biopsy is requested because tumors sometimes 
accrue additional mutations after various treatments or with continued growth 
and metastasis. In addition, the preanalytic procedures of biopsy handling, 
shipping, review and isolation of nucleic acids will be uniform, with minimal 
variation in suitability that can sometimes be seen with archived tissues. 
However, in certain cases, we will be able to accept tissue obtained relatively 
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In recent years, targeted agents have been shown to have benefit in many 
malignant diseases. Some of these agents have obtained FDA approval for 
different diseases with the same and/or different target. For example, imatinib 
was FDA approved for chronic myelogenous leukemia with BCR/ABL 
translocation, but is also approved for gastrointestinal stromal tumor carrying 
mutations in KIT, and for adult patients with relapsed or refractory Philadelphia 
chromosome positive acute lymphoblastic leukemia. Trastuzumab is approved 
for HER2 (ERBB2) overexpressing breast, gastric or gastroesophageal cancer. 
The current proposal is designed to address whether patients with underlying 
abnormalities (e.g. mutations, amplifications or translocations) in a given pathway 
in their tumor could achieve tumor shrinkage or prolonged time to progression 
with agents that target their tumor's particular molecular abnormality. 
1.4.1 
Levels of evidence for MATCH treatments 
We will include targeted agents in NCI-MATCH if one of the following 3 
criteria is met: 
1. The drug is FDA approved for a malignant indication and there is 
a molecular abnormality that can serve as a valid predictive 
marker. The subprotocol will not enroll patients with conditions for 
which the drug is approved, or patients with conditions for which 
the drug has been shown not to have benefit. 
2. The drug is investigational, but met a clinical endpoint (PFS, 
response) in any malignancy, has evidence of target inhibition and 
has evidence of a predictive molecular marker. 
3. The drug is investigational but has demonstrated clinical activity in 
any malignancy and evidence of target inhibition, and has 
evidence of a predictive molecular marker. 
In addition, targeted drugs or drug combinations must have at least a 
recommended phase 2 dose.   
1.4.2 
Levels of Evidence for Actionable Variants Within a Gene 
In order to use a given variant (mutation, insertion, deletion, 
amplification, translocation, protein expression) as a potential 
predictor of effect of a targeted treatment, the variant must meet one 
of the levels of evidence below: 
• 
Level 1: Gene variant credentialed for selection of an approved 
drug (e.g. BRAF V600E and vemurafenib in melanoma); such a 
variant will be considered level 1 in any tissue 
• 
Level 2: Gene variant is eligibility criterion for an ongoing clinical 
trial for that treatment OR gene variant has been identified as 
etiology of N of 1 response 
• 
Level 3: Preclinical inferential data (in vitro or in vivo models) 
providing biological evidence to support use of the variant for 
treatment selection. E.g.: 
• 
Models with variant respond to the drug while models without 
the variant do not 
• 
Gain of function mutations demonstrated in a preclinical 
model; e.g. D769H variant of ERBB2 results in increased 
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tyrosine kinase-specific activity and upregulates pathway 
signaling (clinical evidence not required) 
• 
Loss of function genes, tumor suppressor or pathway inhibitor 
(e.g. NF1) – variant produces a stop codon including 
frameshift or demonstrated loss of function of resultant protein 
in preclinical model (clinical evidence not required) 
NCI-MATCH now uses external “designated laboratories  (DL) to 
identify eligible patients (see Section 1.6 below). The DLs have 
identified several variants which are not currently designated as 
aMOIs, but which they consider potentially eligible for the study. NCI-
MATCH has articulated that additional aMOIs can be considered 
actionable (used to assign a treatment in NCI-MATCH), if they meet 
NCI-MATCH’s levels of evidence. We have classified these types of 
variants into six categories described in a study tool posted on the E-
A and CTSU websites. These new aMOIs will be assessed, confirmed 
and included as actionable variants for their associated subprotocols 
in a ‘dynamic’ fashion. This means they can be used immediately for 
patient treatment assignment, without the need for an amendment, 
provided they are shown by the DL, and confirmed by the study team, 
to meet LOE 3 or higher. Please refer to Appendix XVII for additional 
information. 
1.5 
Rationale for Image Collection 
1.5.1 
Noninvasive Biomarkers of Drug Resistance 
MATCH trial [15] tests whether tumors sharing common somatic 
genetic alterations will be variably responsive to therapies targeting 
the given oncogenic pathway. We hypothesize that measured 
changes during targeted therapy in quantitative radiomic tumor 
phenotypes, computationally extracted by mining conventional CT and 
MR image datasets at baseline and early in the course of treatment 
will yield candidate biomarkers to predict subsequent patient outcome 
and predict development of drug resistance.  We also hypothesize 
that specific associations between radiomic features and tumor gene 
mutation patterns can be demonstrated. 
Computational advances in the past decade now allow for high-
throughput extraction of quantitative features that convert digital 
medical images into mineable data and subsequent analysis of these 
data to support clinical decision-making. This is called radiomics. The 
first step is acquisition of tomographic imaging, CT or MRI, typically 
acquired in the course of standard care. Next, macroscopic tumor is 
defined on these images, usually using automated segmentation 
method in combination with manual editing. A large number of 
quantitative features are then extracted from the defined tumor 
volumes to generate a phenotype database using first- and higher-
order statistics. This, when integrated with clinical, biochemical, 
pathologic, and genomic information, allows for data mining to 
develop diagnostic, prognostic or predictive models relevant to patient 
care. 
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Large-scale sequencing analyses of tumor genomes over the past 
decade have demonstrated extensive heterogeneity that can be 
classified as intra-tumoral, inter-metastatic, intra-metastatic, and inter-
patient [26]. This heterogeneity allows for tumor evolution and has 
been shown to contribute to treatment failure [27]. An approach to 
molecularly targeted therapy that relies solely on biopsy samples is 
subject to sampling error and could underestimate the potential of the 
tumor for genomic adaptation to drug resistance. In contrast, imaging 
enables whole-body evaluation repeatedly during therapy and allows 
for quantitative assessment of heterogeneity at the pixel or voxel level 
[28]. Based on these features, we expect that imaging parameters 
may better distinguish patients with deep and durable responses from 
those with minimal and short-lived disease control. 
Radiomics has been successful at identifying CT or MRI phenotypes 
that describe tumor gene expression patterns and predict therapeutic 
outcome in a number of cancers. [29-34]. More recent radiomic 
studies have demonstrated tumor heterogeneity to be an independent 
predictor of patient survival in a number of cancers. Lung cancer 
heterogeneity has been captured with semantic (e.g., spiculation) and 
agnostic (e.g., entropy ratio) radiomic features. Several investigations 
have demonstrated these signatures of tumor heterogeneity to be 
predictors of patient survival in multivariate models [35]. Aerts and 
colleagues extracted 440 features quantifying tumor radiomic features 
from computed tomography data of 1019 patients with lung or head-
and-neck cancer [36]. They found significant associations between 
the signature features and gene-expression patterns. Signatures of 
tumor heterogeneity were strongly correlated with cell cycling 
pathways driving proliferation. The investigators demonstrated that 
these radiomic signatures could be used to predict outcome in 
completely independent cohorts with lung cancer from two separate 
institutions and could be applied to head and neck cancer patients 
with equivalent prognostic power. These studies demonstrate the 
potential of radiomics for the identification of prognostic imaging 
phenotypes generalizable to several forms of cancer. 
The analyses of the predictive performance of imaging features and 
their correlation with genomic profiles will primarily aim at discovery. 
The quality of the datasets significantly impacts on the numbers 
needed for modeling. As MATCH images will represent a collection 
exclusively enriched for specific genomic profiles, sample numbers 
required for successful radiomic modeling will likely prove lower than 
in analyses to date which have all been performed on datasets 
retrospectively acquired for other purposes of treatment or screening. 
Moreover, as oncologic molecular profiling increases in prevalence 
both in clinical practice and trials, we anticipate that other datasets 
with imaging, genomic, and clinical outcome data will be available to 
test the radiomic features modeled on the MATCH dataset. 
1.5.2 
Optimize Biopsy Yield for Molecular Profiling 
Collection of images from the biopsy procedure itself will address two 
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trial, it will enable central quality assurance of the biopsy procedure 
(i.e., target selection, needle placement) to optimize the yield of the 
molecular profiling.  With current practice standards, 10-15% of 
patients do not have sufficient material for Next Generation 
Sequencing molecular profiling [37]. The literature is silent on which 
variables of the biopsy technique (e.g. fine needle aspiration vs. core, 
number of passes, needle gauge), target lesion choice (e.g. size, 
length of needle throw, anatomic location) or needle placement (e.g. 
central, peripheral, tangential, etc.) impact on this yield. Collection of a 
pre-biopsy lesion assessment by the interventional radiologist, biopsy 
reports and images will enable identification of factors that impact on 
the yield of biopsies performed for genomic profiling. Second, for the 
purposes of radiomic biomarker analysis, biopsy images will enable 
precise localization of the tissue targeted for profiling and comparison 
of its imaging features with the phenotype of the overall tumor burden 
and assess its’ evolution under targeted on serial imaging. 
1.6 
Rules for treatment selection 
Patients will be assigned by consistent and locked rules to the agents/regimens 
targeted to their tumor's identified molecular abnormality. If more than one 
molecular abnormality is identified as actionable for treatment in MATCH, the one 
with the greater level of evidence (see Section 1.4.2) that tumors harboring the 
variant will respond will be used to assign treatment. The molecular profiling 
assays have 4 “parts  (point mutations or indels; amplification; translocation; 
IHC); levels of evidence from each of these parts will be compared, and the 
treatment will be assigned based on the highest (e.g. Level 1 or 2 or 3) level of 
evidence.  Additional molecular assays (e.g., FISH) when used, will also be 
considered “equal  (see below).  For SNV/indel, if more than one aMOI is present 
with equivalent level of evidence, then the abnormality with the higher allele 
frequency (must be > 15% higher than the next lower allele frequency) will be 
used to assign treatment. If two variants are equivalent using these 2 
parameters, the patient will be assigned to the subprotocol with fewer patients, or 
randomized between subprotocols if numbers of patients on the relevant 
subprotocols are equal. 
The following are considered equal: single nucleotide variants (SNV), 
insertions/deletions (indels), copy number variants (CNV) translocation/fusions, 
IHC, or other assay. 
For each component SNV, indel, CNV and translocation/fusion, IHC or other 
assay 
• 
Ascertain level of evidence (LOE) within each category of variant as above 
(levels 1 > 2 >3). 
• 
If > 1 SNV/indel with best LOE (1 > 2 > 3), and the allele frequency of one of 
the aMOIs is more than 15% greater than the next lower allele frequency, 
select aMOI with greater allele frequency. If the allele frequency of the 2 
variants is within 15% of each other, assign patient to subprotocol with fewer 
enrollees (or randomize if number of enrollees is equal ) 
• 
If > 1 aMOI with best LOE (1 > 2 > 3) and allele frequency of each is within 
15% of the other then assign patient to subprotocol with fewer enrollees 
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• 
Compare “winner  of each assay component SNV/indel, CNV, 
translocation/fusion, IHC, or other molecular assay: 
• 
LOE 1 "wins" over level 2, which “wins  over level 3 
• 
If > 1 best LOE, assign patient to subprotocol with fewer enrollees (or 
randomize if number of enrollees is equal). 
These rules will be applied by a rigorously validated informatics system to derive 
a tentative treatment assignment.  If a patient is ineligible for an assigned 
treatment but their tumor harbors additional abnormalities for which treatments 
are available on the study, the system will continue to provide assignments until 
all potentially available options are exhausted.  Subprotocol assignments will be 
monitored by a study steering committee throughout the course of the study. 
1.6.1 
“Rare Variant  Arm Enrichment 
Although NCI-MATCH will sequence biopsies from 6000 patients, 
certain variants are so rare that subprotocols with such eligibility are 
not expected to accrue adequate patients. As these treatments have 
evidence that they may be effective in patients whose tumors have 
these rare variants, NCI-MATCH plans to enhance the ability to recruit 
such patients with the help of several CLIA accredited laboratories 
that sequence large numbers of patient tumors. Additionally, on May 
22, 2017, accrual to central screening by the MATCH laboratories 
closed and NCI-MATCH will recruit patients for selected arms with 
assistance from designated and vetted outside laboratories (MATCH-
designated outside laboratories). Those arms open for recruitment 
via results determined by an outside laboratory and the 
applicable variants will be termed “rare variant” for the purposes 
of this trial. 
 MATCH-designated outside laboratories will notify the ordering 
physician that the patient with the “rare variant  may be eligible for 
NCI-MATCH. The designated outside laboratories will be eligible to 
notify the ordering physician on any of the “rare variant  arms for 
which their assay reports all aMOIs, including the exclusionary 
variants, as defined prior to the addition of any novel variants 
(inclusion or exclusion) of the trial arm. Designated laboratories with 
assays that detect the novel variants (inclusionary and/or 
exclusionary) are to include those variants when determining 
applicable referrals. These laboratories have agreed to participate 
with NCI-MATCH and will communicate to the medical provider the 
potential opportunity for patients with rare variants to enroll in NCI-
MATCH, but are not obligated to limit communication about potential 
trials to NCI-MATCH. It will be the provider’s and patient’s decision 
whether or not to enroll in NCI-MATCH, and the outside lab report will 
only be transmitted to NCI-MATCH if the patient decides to enroll in 
Step 0. 
Outside laboratories will identify patients whose tumors have been 
sequenced with the sequencing assay used by the outside 
laboratories and have rare variants that may be eligible for NCI-
MATCH. The outside laboratories will then notify the ordering clinician 
that the patient may be eligible for a treatment in NCI-MATCH and will 
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provide information on how to contact the MATCH trial. Clinicians and 
patients will decide whether to use that information to enroll into NCI-
MATCH. The form of notification will be at the discretion of the outside 
laboratory (e.g. by telephone, fax, electronic medical record, lab 
report, etc). Outside laboratories will not transfer any patient 
information directly to the NCI-MATCH study but will keep records as 
to the number of patients that were notified. 
A NCI-MATCH Trial Arm that has been designated as a “rare variant  
arm, based on either NCI-MATCH results to date or other similar data, 
will be considered a “rare variant  arm. Once it is deemed a “rare 
variant  arm, it will remain a “rare variant  arm. As additional arms are 
activated, other arms may be added into the “rare variant  arm group. 
Patients who have a “rare variant  by a designated “outside  assay, 
have specifically been notified of such by a NCI- MATCH designated 
outside laboratory, and are otherwise eligible will be permitted to 
enroll on the arm with the results of the “outside  assay. However, 
these results will be verified by the NCI-MATCH NGS assay, and NCI-
MATCH IHC assays. Only patients whose tumor samples have aMOIs 
that have been verified with the NCI-MATCH assay(s) will be included 
in the primary analysis for outcome, though all patients treated on the 
arm will be evaluable for toxicity. Patients without such verification 
may continue treatment, but will not be included in the primary 
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2. 
Objectives 
2.1 
Primary Objective 
2.1.1 
To evaluate the proportion of patients with objective response (OR) to 
targeted study agent(s) in patients with advanced refractory 
cancers/lymphomas/multiple myeloma. 
2.2 
Secondary Objectives 
2.2.1 
To evaluate the proportion of patients alive and progression free at 6 
months of treatment with targeted study agent in patients with 
advanced refractory cancers/lymphomas/multiple myeloma. 
2.2.2 
To evaluate time until death or disease progression. 
2.2.3 
To identify potential predictive biomarkers beyond the genomic 
alteration by which treatment is assigned or resistance mechanisms 
using additional genomic, RNA, protein and imaging-based 
assessment platforms. 
2.2.4 
To assess whether radiomic phenotypes obtained from pre-treatment 
imaging and changes from pre- through post-therapy imaging can 
predict Objective Response and Progression Free Survival and to 
evaluate the association between pre-treatment radiomic phenotypes 
and targeted gene mutation patterns of tumor biopsy specimens. 
 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met 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. 
NOTE: 
This checklist is for eligibility for the Master Screening Protocol only; each 
subprotocol will have additional eligibility criteria that will be outlined in 
Section 2.1 of the agent-specific subprotocol. 
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 3 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 3 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: 
Please refer to the Schema for details on the registration process. 
NOTE: 
Patients may not receive more than two rounds of treatment (e.g. may only 
be assigned 2 different treatments based on aMOIs) between biopsies. 
3.1 
Eligibility Criteria for Screening Biopsy (Step 0) 
3.1.1 
Patients must be ≥ 18 years of age. Because no dosing or adverse 
event data are currently available on the use of study investigational 
agents in patients < 18 years of age, children are excluded from this 
study. 
3.1.2 
Women of childbearing potential must have a negative serum 
pregnancy test within 2 weeks prior to registration. Patients that are 
pregnant or breast feeding are excluded. 
A female of childbearing potential is any woman, regardless of sexual 
orientation or whether they have undergone tubal ligation, who meets 
the following criteria: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
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Female of childbearing potential? ______ (Yes or No) 
Date of serum pregnancy test: ___________ 
3.1.3 
Women of childbearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, 
and for 4 months after completion of study. 
Should a woman become pregnant or suspect while she or her 
partner is participating in this study, she should inform her treating 
physician immediately.    
3.1.4 
Patients must have histologically documented solid tumors or 
histologically confirmed diagnosis of lymphoma or multiple myeloma 
requiring therapy and meet one of the following criteria: 
• 
Patients must have progressed following at least one line of 
standard systemic therapy and there must not be other 
approved/standard therapy available that has been shown to 
prolong overall survival (i.e. in a randomized trial against another 
standard treatment or by comparison to historical controls).  
Patients who cannot receive other standard therapy that has been 
shown to prolong overall survival due to medical issues will be 
eligible, if other eligibility criteria are met. If the patient is currently 
receiving therapy, the clinician must have assessed that the 
current therapy is no longer benefitting the patient prior to 
enrolling on MATCH, regardless of whether it is considered 
standard. 
OR 
• 
Patients for whose disease no standard treatment exists that has 
been shown to prolong overall survival. 
NOTE: No other prior malignancy is allowed except for the following:  
a) adequately treated basal cell or squamous cell skin 
cancer 
b) in situ cervical cancer 
c) adequately treated Stage I or II cancer from which the 
patient is currently in complete remission 
d) any other cancer from which the patient has been 
disease-free for 5 years. 
3.1.5 
Patients must have measurable disease as defined in Section 6. 
3.1.6 
Patients must meet the criteria below and have received results from 
one of the designated outside laboratories indicating a “rare variant  
that is an actionable Mutation of Interest (aMOI) for specific select 
subprotocols. See Appendix XIV for more information on the 
designated laboratories and applicable arms. 
The following requirements apply: 
• 
The outside laboratory specifically notified the site that patient 
may be a potential candidate for MATCH due to a detected “rare 
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variant.  The outside lab reports are NOT sufficient for this 
purpose. 
NOTE: 
The content and format of these specific notifications 
for the Outside Assay process will vary depending on 
the designated outside lab in question, as they are 
each responsible for their own outreach efforts. It is 
strongly recommended that the designated outside 
laboratory be contacted to confirm the format and 
receipt of this notification prior to registering any 
patients to Step 0. 
• 
Patients with an applicable “rare variant  must be able to meet the 
eligibility criteria for the appropriate subprotocols within 4 weeks 
following notification of treatment assignment, per Section 4.2. 
NOTE: 
The receipt of this notification (and the start of the 
associated deadline for Step 1 registration) may occur 
shortly after Step 0 registration, since these patients 
will not be submitting tissue for screening purposes. 
However, for certain “rare variant  arms, submission of 
archival tissue for central IHC testing may be required. 
• 
Registration to Step 0 must occur after stopping prior systemic 
anti-cancer therapy. There is no specific duration for which 
patients must be off treatment prior to registration to Step 0, as 
long as all eligibility criteria are met. 
• 
There is no particular window of time after notification of potential 
eligibility from an outside lab in which the patient must be 
registered to Step 0, but treatment slots will be assigned on a first 
come, first serve basis to those who do register to Step 0, and are 
not held for those notified of potential eligibility who do not register 
to Step 0. 
• 
Patients may have received other non-targeted, immunotherapy or 
targeted treatment between the prior genetic testing at the outside 
lab and registration to Step 0. The decision to stop such treatment 
in favor of participation in MATCH, if no further clinical benefit is 
expected, is per the treating physician's discretion. Documentation 
of a lack of response to the prior treatment is not required in these 
cases. The requirements in Section 3.1.4 still apply. 
NOTE: 
Other potential aMOIs that would be eligibility criteria 
for “NON RARE  arms, as determined by the 
designated laboratories, are not applicable for this 
process in MATCH. See additional requirements 
outlined in Section 4.1.5.4. 
NOTE: 
Tumor tissue for the confirmation of “rare variant  by 
the MATCH assay is to be submitted, preferably from 
the same time of collection as that evaluated by the 
designated outside laboratory, per Section 4.1.5, 
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3.1.7 
Patient must not require the use of full dose coumarin-derivative 
anticoagulants such as warfarin. Low molecular weight heparin is 
permitted for prophylactic or therapeutic use. Factor X inhibitors are 
permitted. 
NOTE: 
Warfarin may not be started while enrolled in the EAY131 
study. 
Stopping the anticoagulation for biopsy should be per site SOP. 
3.1.8 
Patients must have ECOG performance status ≤ 1 (see Appendix V) 
and a life expectancy of at least 3 months. 
3.1.9 
Patients must not currently be receiving any other investigational 
agents.  
3.1.10 
Patients must not have any uncontrolled intercurrent illness including, 
but not limited to: 
• 
Symptomatic congestive heart failure (NYHA classification of 
III/IV) 
• 
Unstable angina pectoris or coronary angioplasty, or stenting 
within 6 months prior to registration to Step 0, 2, 4, 6 
• 
Cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI CTCAE 
v4 Grade ≥ 2) 
• 
Psychiatric illness/social situations that would limit compliance 
with study requirements 
• 
Intra-cardiac defibrillators 
• 
Known cardiac metastases 
• 
Abnormal cardiac valve morphology (≥ grade 2) documented by 
ECHO (as clinically indicated); (subjects with grade 1 
abnormalities [i.e., mild regurgitation/stenosis] can be entered on 
study). Subjects with moderate valvular thickening should not be 
entered on study 
NOTE: 
To receive an agent, patient must not have any 
uncontrolled intercurrent illness such as ongoing or active 
infection. Patients with infections unlikely to be resolved 
within 2 weeks following screening should not be 
considered for the trial. 
3.1.11 
Patients must be able to swallow tablets or capsules.  A patient with 
any gastrointestinal disease that would impair ability to swallow, 
retain, or absorb drug is not eligible. 
3.1.12 
Patients who are HIV-positive are eligible if:  
___ CD4+ cell count greater or equal to 250 cells/mm3 
___ If patient is on antiretroviral therapy, there must be minimal 
interactions or overlapping toxicity of the antiretroviral therapy with the 
experimental cancer treatment; for experimental cancer therapeutics 
with CYP3A/4 interactions, protease inhibitor therapy is disallowed; 
suggested regimens to replace protease inhibitor therapy include 
dolutegravir given with tenofovir/emtracitabine; raltegravir given with 
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tenofovir and emtracitabine. Once daily combinations that use 
pharmacologic boosters may not be used. 
___ No history of non-malignancy AIDS-defining conditions other than 
historical low CD4+ cell counts 
___ Probable long-term survival with HIV if cancer were not present. 
3.1.13 
Any prior therapy, radiotherapy (except palliative radiation therapy of 
30 Gy or less), or major surgery must have been completed ≥ 4 
weeks prior to start of treatment. All adverse events due to prior 
therapy have resolved to a grade 1 or better (except alopecia and 
lymphopenia) by start of treatment. Palliative radiation therapy must 
have been completed at least 2 weeks prior to start of treatment. The 
radiotherapy must not be to a lesion that is included as measurable 
disease. 
NOTE: 
Prostate cancer patients may continue their LHRH agonist. 
NOTE: 
For patients entering the study via the original screening 
process, patients may receive non-protocol treatment after 
biopsy (if clinically indicated) until they receive notification 
of results; however, lack of response (per Section 6) must 
be documented prior to registration to Step 1. New non-
protocol treatment will NOT be permitted as intervening 
therapy after registration to Step 0. The only intervening 
treatment permitted is prior therapy that the patient already 
received prior to Step 0 registration. 
The decision to stop the intervening non-protocol treatment 
will be left up to the treating physician if patient has an 
aMOI. However, patients will need to be off such therapy 
for at least 4 weeks before receiving any MATCH protocol 
treatment. Please refer to Section 4.2 for additional 
relevant time restrictions. 
NOTE: 
For patients entering the study via a designated outside 
laboratory, no intervening systemic non-protocol treatment 
is permitted after Step 0 registration. All other eligibility 
requirements still apply to these patients, including the 
washouts for prior therapy noted above in this section, the 
time restrictions outlined in Section 4.2, and the eligibility 
criteria for the intended subprotocol. 
3.1.14 
Patients with brain metastases or primary brain tumors must have 
completed treatment, surgery or radiation therapy ≥ 4 weeks prior to 
start of treatment. 
3.1.15 
Patients must have discontinued steroids ≥ 1 week prior to registration 
to Step 0 and remain off steroids thereafter, except as permitted (see 
below). Patients with glioblastoma (GBM) must have been on stable 
dose of steroids, or be off steroids, for one week prior to registration to 
treatment step (Step 1, 3, 5, 7). 
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NOTE: 
The following steroids are permitted (in the list below, low 
dose steroid use is defined as prednisone 10 mg daily or 
less, or bioequivalent dose of other corticosteroid): 
• 
Temporary steroid use: e.g. for CT imaging in setting of contrast 
allergy 
• 
Low dose steroid use for appetite 
• 
Chronic inhaled steroid use 
• 
Steroid injections for joint disease 
• 
Stable dose of replacement steroid for adrenal insufficiency or low 
doses for non-malignant disease  
• 
Topical steroid 
• 
Steroids required to manage toxicity related to study treatment, as 
described in the subprotocols 
• 
Steroids required as pre- or post-chemotherapy medication for 
acceptable intervening chemotherapy 
NOTE: 
Steroids must be completed alongside last dose of 
chemotherapy. 
3.1.16 
Patients must have adequate organ and marrow function as defined 
below within 2 weeks prior to screening step registration and within 4 
weeks prior to treatment step registration: 
• 
Leukocytes ≥ 3,000/ mcL* 
Leukocyte Count: _________ 
Date of Test: ___________ 
• 
Absolute neutrophil count ≥ 1,500/ mcL* 
ANC______  
Date of Test_______ 
• 
Platelets ≥ 100,000/ mcL* 
Platelet Count______ 
Date of Test_______ 
NOTE: 
*Patients with documented bone marrow involvement 
by lymphoma are not required to meet the above 
hematologic parameters, but must have a platelet 
count of at least 75,000/mcL and neutrophil count of at 
least 1000/mcL. 
• 
Total bilirubin ≤1.5 X institutional ULN (unless documented 
Gilbert’s Syndrome, for which bilirubin ≤ 3 x institutional ULN is 
permitted) 
Total bilirubin______ 
Institutional ULN ______ Date of Test _______ 
• 
AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal 
(ULN) (up to 5 times ULN in presence of liver metastases) 
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AST______ ALT______ 
Institutional ULN _______  
Date of Test _______ 
• 
Creatinine clearance ≥ 45 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal 
Creatinine clearance ______  
As defined by the Cockcroft-Gault Equation 
CrCl (ml/min) =      (140 – age in years)  
   
 
           x actual wt (in kg)      x    0.85 (for female pts) 
      
 
 72 x serum creatinine (mg/dl) 
Date of Test_______ 
3.1.17 
Patients must have an electrocardiogram (ECG) within 8 weeks prior 
to registration to screening step and must meet the following cardiac 
criteria: 
3.1.17.1 
Resting corrected QT interval (QTc) ≤ 480 msec. 
NOTE: 
If the first recorded QTc exceeds 480 msec, two 
additional, consecutive ECGs are required and 
must result in a mean resting QTc ≤ 480 msec. 
It is recommended that there are 10-minute (± 5 
minutes) breaks between the ECGs. 
The following only need to be assessed if the mean QTc  
> 480 msec. 
• 
Check potassium and magnesium serum levels 
• 
Correct any identified hypokalemia and/or 
hypomagnesemia and may repeat ECG to confirm 
exclusion of patient due to QTc 
• 
For patients with HR 60-100 bpm, no manual read of 
QTc is required. 
• 
For patients with baseline HR < 60 or > 100 bpm, 
manual read of QT by trained personnel is required, 
with Fridericia correction applied to determine QTc. 
• 
Patient must not have hypokalemia (value  
< institutional lower limit of normal). 
3.1.17.2 
No factors that increase the risk of QTc prolongation or risk 
of arrhythmic events such as heart failure, congenital long 
QT syndrome, family history of long QT syndrome or 
unexplained sudden death under 40 years of age or any 
concomitant medication known to prolong the QT interval 
(For a list of these medications, please see Appendix XIII) 
Date of ECG:  _______________ 
NOTE: 
Patient must be taken off prohibited medication 
prior to registration to the screening Step (Step 
0, 2, 4, 6), and remain off these medications 
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thereafter, unless permitted on a subprotocol 
for the management of treatment related 
toxicity. Patient must be off the drug for at least 
5 half lives prior to registration to the treatment 
step (Step 1, 3, 5, 7). The medication half life 
can be found in the package insert for FDA 
approved drugs. 
3.2 
Eligibility Criteria for First Treatment (Step 1) 
3.2.1 
Eligibility requirements for registration onto Step 1 are outlined in 
Section 2.1 of the agent-specific subprotocol. 
NOTE: 
If patients have been biopsied or submitted archived tumor 
tissue obtained within the last 6 months for assessment 
with the MATCH assays, patients may receive non-
protocol treatment after biopsy/tissue submission (if 
clinically indicated) until they receive notification of results 
however, lack of response (per Section 6) must be 
documented prior to registration to Step 1. New non-
protocol treatment will NOT be permitted as intervening 
therapy after registration to Step 0. 
For patients entering Step 0 with assay results from 
outside laboratories, no systemic treatment is allowed after 
Step 0 registration. 
The decision to stop the intervening nonprotocol treatment 
will be left up to the treating physician if patient has an 
aMOI. Waiting periods as described in Section 3.1.13 will 
apply. 
3.2.2 
As MATCH is designed to add additional subprotocols, implement 
limited expansions of accrual for certain subprotocols, and/or amend 
existing arm-specific eligibility criteria, some patients entering under 
the original screening method may be eligible to have their results 
rerun in MATCHbox, even if they did not match to a treatment initially 
or did not receive a treatment assignment due to a lack of available 
assignment slots.  Patients whose sequence results will be rerun 
through MATCHbox must also meet the following criteria: 
3.2.2.1 
Samples must have been collected within 5 months of the 
activation of the addendum, as there is an additional 
month needed to get the patients on trial. 
3.2.2.2 
Patient has not had treatment within the 5 months that 
resulted in a PR or better after the performance of the 
screening assessment. 
3.2.2.3 
Patient must meet eligibility criteria, including performance 
status 1 or better and life expectancy of at least 3 months. 
3.2.2.4 
Patients must meet the eligibility requirements found in 
Section 3.1.13, with the following exceptions: 
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• 
Patients may have received other non-targeted, 
immunotherapy or targeted treatment, which could be 
stopped in favor of returning to MATCH, if no response 
to the interim treatment has occurred and no further 
benefit is expected from this interim treatment, per the 
treating physician's discretion. Documentation of a lack 
of response to the interim treatment is not required in 
these cases. 
However, the following restrictions apply: 
• 
Enrollment onto another investigational therapeutic 
study is not permitted. 
• 
Patient cannot be responding to interim treatment, 
since the benefit of the MATCH treatment is 
unknown and may deprive patient of an effective 
treatment if it were given when a patient is 
responding to another treatment. 
NOTE: 
Patients meeting these criteria will NOT be biopsied at this 
time point. Instead, their Step 0 results will be re-
interrogated to determine if another treatment is available. 
3.3 
Eligibility Criteria for Second Screening (Step 2) 
3.3.1 
Patient’s disease has progressed on Step 1 treatment (per Section 6) 
or patient could not tolerate assigned treatment. 
NOTE: 
PATIENTS ENTERING STEP 1 WITH A “RARE 
VARIANT” FROM AN “OUTSIDE” LAB ARE NOT 
ELIGIBLE FOR STEP 2. SEE SECTION 3.3.3 BELOW. 
3.3.1.1 
Patients must meet one of the following criteria: 
3.3.1.1.1 
No response and progression (or inability to 
tolerate further treatment) occurred < 6 
months from start of Step 1 treatment. 
NOTE: 
Patients meeting these criteria 
will NOT be biopsied at this time 
point. Instead, their Step 0 
MATCH assay results will be re-
interrogated to determine if 
another treatment is available 
upon registration to this study 
step. It is not necessary to 
confirm the availability of another 
potential treatment assignment 
in advance. Only aMOIs 
detected by the MATCH assay 
may be used for the 
determination of eligibility to a 
relevant subprotocol. 
OR 
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3.3.1.1.2 
Progression (or inability to tolerate further 
treatment) occurred after a (1) response OR 
(2) after ≥ 6 months from start of Step 1 
treatment. Patient must have tumor 
amenable to percutaneous biopsy and be 
willing and able to undergo a tumor biopsy 
or bone marrow aspirate for collection and 
submission of tumor tissue OR patient will 
be undergoing a procedure due to medical 
necessity during which the tissue may be 
collected for the central determination of the 
presence of one or more of the specific 
“actionable  mutations/amplifications of 
interest (aMOI) (defined in Appendix VII). 
See Section 9. Archived specimens cannot 
be accepted. 
3.3.2 
Patients must meet eligibility criteria as defined in Section 3.1 
(excluding Section 3.1.6). 
3.3.3 
Patient must not have been assigned to Step 1 treatment based on a 
“rare variant  determined by a designated outside laboratory (See 
Appendix XIV). 
3.4 
Eligibility Criteria for Second Treatment (Step 3) 
3.4.1 
Eligibility requirements for registration onto Step 3 are outlined in 
Section 2.1 of the agent-specific subprotocol.  
NOTE: 
If screening biopsy samples were submitted during 
Step 2, patients may receive non-protocol treatment after 
biopsy (if clinically indicated) until they receive notification 
of results however, lack of response (per Section 6) must 
be documented prior to registration to Step 3. New non-
protocol treatment will NOT be permitted as intervening 
therapy after registration to Step 2. 
The decision to stop the intervening nonprotocol treatment 
will be left up to the treating physician if patient has an 
aMOI. Waiting periods as described in Section 3.1.13 will 
apply. 
3.5 
Eligibility Criteria for Third Screening (Step 4) 
3.5.1 
Patient’s disease has progressed on Step 3 treatment or patient could 
not tolerate assigned treatment. 
3.5.1.1 
Patient must meet one of the following criteria: 
3.5.1.1.1 
No response and progression (or inability to 
tolerate further treatment) occurred < 6 
months from start of Step 3 (second) 
treatment AND a biopsy was performed at 
Step 2 screening. 
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NOTE: 
Patients meeting these criteria 
will NOT be biopsied at this time 
point. Instead, their latest 
MATCH assay results will be re-
interrogated to determine if 
another treatment is available 
upon registration to this study 
step. It is not necessary to 
confirm the availability of another 
potential treatment assignment 
in advance. 
OR 
3.5.1.1.2 
Progression (or inability to tolerate further 
treatment) occurred on Step 3 treatment 
and a biopsy was not performed at Step 2 
screening (due to presence of additional 
aMOIs at that stage). Patient must have 
tumor amenable to percutaneous biopsy 
and be willing and able to undergo a tumor 
biopsy or bone marrow aspiration for 
collection and submission of tumor tissue 
OR patient will be undergoing a procedure 
due to medical necessity during which the 
tissue may be collected for the central 
determination of the presence of one or 
more of the specific “actionable  
mutations/amplifications of interest (defined 
in Appendix VII). Biopsy must not be 
considered to be more than minimal risk to 
the patient. See Section 9. Archived 
specimens cannot be accepted. 
3.5.2 
Patients must meet eligibility criteria as defined in Section 3.1 
(excluding Section 3.1.6). 
NOTE: 
A patient may have a maximum of 2 screening biopsies 
(not including re-biopsy due to assay failure), and 2 
MATCH treatments per biopsy (if > 1 aMOI). 
See Section 4.12 for further information on biopsies. 
3.6 
Eligibility Criteria for Third Treatment (Step 5) 
3.6.1 
Eligibility requirements for registration onto Step 5 are outlined in 
Section 2.1 of the agent-specific subprotocol.  
NOTE: 
If screening biopsy was submitted on Step 4, patients 
may receive non-protocol treatment after biopsy (if 
clinically indicated) until they receive notification of results 
however, lack of response (per Section 6) must be 
documented prior to registration to Step 5. New non-
protocol treatment will NOT be permitted as intervening 
therapy after registration to Step 4. 
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The therapy cannot be an arm in the MATCH trial. The 
decision to stop the intervening nonprotocol treatment will 
be left up to the treating physician if patient has an aMOI. 
Waiting periods as described in Section 3.1.13 will apply. 
3.7 
Eligibility Criteria for Fourth Screening (Step 6) 
3.7.1 
Patient’s disease has progressed on Step 5 protocol treatment or 
patient could not tolerate assigned treatment. 
3.7.2 
Patient must have had no response, and progression (or inability to 
tolerate further treatment) occurred < 6 months from start of Step 5 
treatment AND a biopsy was performed at Step 4 screening. 
NOTE: 
Patients meeting these criteria will NOT be biopsied at this 
time point. Instead, based on their 2nd biopsy, their results 
will be interrogated to determine if another treatment is 
available upon registration to this study step. It is not 
necessary to confirm the availability of another potential 
treatment assignment in advance. 
3.7.3 
Patients must meet eligibility criteria as defined in Section 3.1 
(excluding Section 3.1.6). 
NOTE: 
For Step 6, biopsies to collect material for screening assay 
will NOT be performed.  A patient may have a maximum of 
2 successful screening assessments of submitted tissue 
(Steps 0 and 2 OR Steps 0 and 4), and 2 MATCH 
treatments per biopsy (if > 1 aMOI). See Section 4.12 for 
further information on biopsies. 
3.8 
Eligibility Criteria for Fourth Treatment (Step 7) 
Eligibility requirements for registration onto Step 7 are outlined in Section 2.1 of 
the agent-specific subprotocol.  
3.9 
Eligibility Criteria for Research Biopsy and Circulating Tumor DNA Collection 
(Step 8) 
NOTE: 
ALL PATIENTS SHOULD BE ENCOURAGED TO PARTICIPATE IN 
STEP 8, IF SAFE; IF BIOPSY IS REFUSED OR INADVISABLE, 
ENCOURAGE COLLECTION OF WHOLE BLOOD FOR 
CIRCULATING TUMOR DNA, PER SECTION 9.3.2.  
As a reminder, the submission of the Step 8 samples requires 
additional patient consent, as well as registration to Step 8. 
NOTE: 
Patients who entered the study (Step 0) with a “rare variant  
determined by an outside assay ARE potentially eligible and 
encouraged to participate in Step 8. 
3.9.1 
Patient has completed their most recent MATCH study treatment, will 
not undergo an additional screening biopsies, and will receive no 
additional treatment on MATCH. 
NOTE: 
If a 2nd Screening Biopsy was performed and showed no 
study-actionable abnormalities, and blood samples were 
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submitted with the screening biopsy, no additional end of 
treatment specimens are requested. 
3.9.2 
For patients who consent to undergo the optional research biopsy, 
patient’s disease responded to the most recent MATCH study 
treatment and then progressed (or unable to tolerate further 
treatment) OR the disease progression (or inability to tolerate further 
treatment) occurs > 6 months since the last screening biopsy. 
NOTE: 
Performance of a biopsy to collect tumor tissue for 
research is strongly encouraged but not required. It is 
acceptable to submit only the optional blood specimens. 
NOTE: 
If a biopsy will be performed solely to collect tumor 
specimens for research, the patient must be willing and 
able to undergo a tumor biopsy or bone marrow aspirate 
(for applicable multiple myeloma), per Section 9, for the 
collection and submission of tissue for research. 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
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4. 
Registration Procedures 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, RAVE, or TRIAD or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). 
Documentation requirements per registration type are outlined in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, 
training, employment, license, 
and certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if 
applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact 
the RCR Help Desk by email at RCRHelpDesk@nih.gov . 
CTSU Registration Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval: 
NOTE: 
Sites must utilize the CIRB as their IRB of record to participate in EAY131. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for the study 
are not required to submit separate IRB approval documentation to the CTSU 
Regulatory Office for initial, continuing or amendment review. However, sites must 
submit a Study Specific Worksheet for Local Context (SSW) to the CIRB (via IRB 
Manager) to indicate their intention to open the study locally. The CIRB’s approval of the 
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SSW is then communicated to the CTSU Regulatory Office for compliance in the RSS. 
The Signatory site must provide the CTSU Regulatory Office the participating institutions 
on the study. Other site registration requirements (i.e., laboratory certifications, protocol-
specific training certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
For sites under the CIRB initiative, IRB data will automatically load to RSS. 
Downloading Site Registration Documents: 
Site registration forms may be downloaded from the EAY131 protocol page located on 
the CTSU members’ website.  Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment 
housed in the CTSU RSS. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the ECOG-ACRIN link to expand, then select trial protocol EAY131 
• 
Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided. 
Checking Your Site’s Registration Status: 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website. 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
NOTE: 
The status given only reflects compliance with IRB documentation and 
institutional compliance with protocol-specific requirements outlined by the 
Lead Network. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status 
with the NCI or their affiliated networks. 
The CTSU encourages you to go to the following CTSU RSS webpage so that 
more information on RSS2.0 as well as the submission forms can be accessed. 
Log in to http://www.ctsu.org and click on the Regulatory tab to access the RSS 
webpage. If you have questions regarding regulatory document submission, please 
telephone the CTSU Help Desk at 1-888-823-5923 or E-mail 
CTSUContact@westat.com.  
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN). OPEN is a web-based registration system available on a 24/7 basis. To access 
OPEN, the site user must have an active CTEP-IAM account (check at 
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https://ctepcore.nci.nih.gov/iam) and a 'Registrar' role on either the LPO or participating 
organization roster. Registrars must hold a minimum of an AP registration type. 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the 
patient in the Rave database. OPEN can be accessed at https://open.ctsu.org or from 
the OPEN tab on the CTSU members’ side of the website at https://www.ctsu.org. To 
assign an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), 
or investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form 
FDA 1572 in RCR the IRB number used on the site’s IRB approval. 
Prior to accessing OPEN site staff should verify the following:  
• 
All eligibility criteria have been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the group or CTSU web site as a tool 
to verify eligibility. 
• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.  
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
4.1 
Pre-Registration to First Biopsy (Step 0) 
The following information will be requested: 
4.1.1 
Protocol Number  
4.1.2 
Investigator Identification  
• 
Institution and affiliate name 
• 
Investigator’s name 
4.1.3 
Patient Identification  
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Patient demographics 
− 
Gender 
− 
Birth date (mm/yyyy) 
− 
Race 
− 
Ethnicity 
− 
Nine-digit ZIP code 
− 
Method of payment 
− 
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4.1.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1 
4.1.5 
Additional Requirements  
4.1.5.1 
Sites must utilize the CIRB as their IRB of record to 
participate in EAY131. 
4.1.5.2 
Patients must provide a signed and dated, written informed 
consent form. 
NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office-Boston. 
4.1.5.3 
Archived specimens are to be submitted to the ECOG-
ACRIN CBPF (MD Anderson – MATCH Laboratory) for 
central testing, per Section 7.2 and Section 9, as follows: 
• 
It is requested that the samples be representative of 
what was submitted to the designated outside 
laboratory for assessment per Section 9.2.2. 
• 
If the site receives notification that archived tissue is 
required for additional central testing (e.g. IHC) to 
determine patient eligibility for treatment, submit tissue 
using the kit for submission of confirmation tissue 
within 2 weeks. It is requested that adequate tissue for 
these additional central tests AND confirmation testing 
be submitted. Treatment assignment cannot be 
determined until this assessment is complete. 
• 
For all other patients, tissue is to be submitted within 8 
weeks after registration to Step 1, for confirmation of 
the “rare variant  by the MATCH assay. Tissue not 
submitted within 8 weeks following registration to Step 
1 will be considered delinquent. 
• 
Log sample in the ECOG-ACRIN Sample Tracking 
System (STS) and include STS shipment manifest in 
the package. LOGGING THE SUBMISSION IN STS IS 
MANDATORY, as STS is an integral aspect for the 
informatics system for this trial. 
• 
Include paper copy of original diagnostic 
pathology report in submission. 
• 
Include completed CLIA Laboratory Sample 
Submission Form. The contact information for the 
treating physician must include FAX number as the 
CLIA report will be distributed only to the designated 
physician. Information on the CLIA submission form 
must be clearly legible. Do not use cursive. 
• 
Pathology reports submitted with specimens for 
confirmation testing are NOT to be redacted to ensure 
the appropriate materials have been submitted as the 
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results of the CLIA assessment will be returned to the 
site and will impact patient care. 
• 
A hard copy of the applicable sequencing report 
from the designated outside lab should be included 
inside the kit. 
NOTE: 
Notify the central MATCH laboratory (MD 
Anderson) of any delays pertaining to the 
submission of the pathology materials. In the 
event that archived tissue is not available, 
pathology reports and CLIA reports must still be 
submitted to the CBPF and nucleic acids from 
the designated outside laboratory may be 
requested for the confirmation assessments. 
The site will be informed of the receipt of 
nucleic acids by the ECOG-ACRIN CBPF, but 
results of the assays will not be returned to the 
site. 
4.1.5.4 
For patients for whom an applicable “rare variant  was 
identified by one of the designated laboratories per 
Appendix XIV, following registration to Step 0: 
NOTE: 
ALL OF THE FOLLOWING MUST BE 
UPLOADED FOR ACCURATE ASSIGNMENT. 
NOTE: 
This will be the only method of study entry 
for patients registered to Step 0 after May 
22nd, 2017 at 5:00 PM ET. 
• 
Upload the following to the relevant folders in Medidata 
Rave: 
• 
An electronic copy of the applicable sequencing 
report with “EAY131“ and patient case ID written on 
the form, and the following information 
appropriately redacted from every page of the 
report: patient name and date of birth. A copy of 
the full report must be uploaded.  If the size of the 
report is restrictive, separate the report into two 
parts and upload each part separately. 
AND 
• 
Upload an electronic copies of the pathology 
reports associated with the analyzed tumor tissue 
and the original diagnostic pathology (if different).  
AND 
• 
Notification of potential MATCH eligibility from the 
outside laboratory (if separate from the sequencing 
report). 
NOTE: 
Failure to upload the required outside assay 
and pathology reports will result in the inability 
to assign patient to treatment. 
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4.2 
Registration to First Treatment (Step 1) 
Patient registration can occur only after pre-treatment evaluation is complete, 
eligibility criteria have been met, and the patient has provided signed and dated 
informed consent (pertaining to the selected targeted treatment agent(s)).  
Patients must not start protocol treatment prior to registration to step 1. 
Treatment must start within seven days from registration to Step 1 and not 
before repeat pre-treatment imaging, if necessary, is completed. Study 
agent must be ordered after patient is registered to the treatment 
subprotocol as no starter supplies are available for this study. If expedited 
shipment is required, sites should provide an express courier account 
through the Online Agent Order Processing (OAOP) application. 
NOTE: 
If registration to Step 1 is not completed within 28 days of treatment 
assignment, the patient's slot will be released, and the patient will no 
longer be eligible for that treatment and will be taken off study. 
The following information will be requested: 
4.2.1 
The information requested in Section 4.1.1-Section 4.1.3. 
4.2.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1 (excluding Section 3.1.6) and 3.2. 
4.2.3 
Classification Factors 
4.2.3.1 
Patient's simplified disease code 
4.2.3.2 
1 versus > 1 applicable targeted treatment 
4.2.4 
Additional Requirements  
4.2.4.1 
Sites must utilize the CIRB as their IRB of record to 
participate in EAY131. 
4.2.4.2 
Patients must provide a signed and dated, written informed 
consent form associated with the applicable targeted 
agent(s). 
NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office-Boston. 
4.2.4.3 
Specimens for research are to be submitted, per patient 
consent, as defined within the EAY131 Master Protocol or 
MATCH treatment subprotocol, if applicable. Please refer 
to Section Error! Reference source not found.. 
4.3 
Registration to Second Screening (Step 2) 
NOTE: 
PATIENTS ENTERING STEP 1 WITH A “RARE VARIANT” FROM 
AN “OUTSIDE” LAB ARE NOT ELIGIBLE FOR STEP 2. SEE 
SECTION 3.3.3. 
4.3.1 
The information requested in Section 4.1.1-Section 4.1.3.  
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4.3.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.3 
4.3.3 
Additional Requirements  
4.3.3.1 
Sites must utilize the CIRB as their IRB of record to 
participate in EAY131. 
4.3.3.2 
To proceed to Step 3, either of the following must be done: 
• 
Tumor tissue from the re-biopsy is to be submitted as 
indicated in Section 9 for central assessment. See 
Section 4.1.5.3 in Appendix XV for submission 
requirements. 
NOTE: 
It may take up to 6 weeks for results to be 
returned to the site on a second biopsy and 
potential treatment assignments made 
available via Medidata Rave. Registration 
cannot proceed until the central 
determination is complete. 
OR  
• 
Patient's prior Biopsy Analysis indicated >1 targeted 
therapies.  
4.3.3.3 
Specimens for research are to be submitted, per patient 
consent, as defined within the EAY131 Master Protocol. 
Please refer to Section Error! Reference source not 
found.. 
4.3.4 
Classification Factors 
Time from start of Step 1 treatment to toxicity or progression: 
• 
< 6 months 
• 
≥ 6 months 
4.4 
Registration to Second Treatment (Step 3) 
Patient registration can occur only after the Step 2 evaluation is complete, 
eligibility criteria have been met, and the patients have signed and dated the 
relevant agent-specific informed consent document. 
Patients must not start protocol treatment prior to registration to Step 3 
Treatment must start within seven days from registration to Step 3 and not 
before repeat pre-treatment imaging, if necessary, is completed. Study 
agent must be ordered after patient is assigned to the treatment 
subprotocol as no starter supplies are available for this study. If expedited 
shipment is required, sites should provide an express courier account 
through the Online Agent Order Processing (OAOP) application. 
NOTE: 
If registration to Step 3 is not completed within 28 days of treatment 
assignment, the patient's slot will be released, and the patient will no 
longer be eligible for that treatment and will be taken off study. 
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The following information will be requested: 
4.4.1 
The information requested in Section 4.1.1-Section 4.1.3.  
4.4.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1 (excluding Section 3.1.6) and Section 3.4 
4.4.3 
Additional Requirements  
4.4.3.1 
Sites must utilize the CIRB as their IRB of record to 
participate in EAY131. 
4.4.3.2 
Patients must provide a signed and dated, written informed 
consent form for targeted treatments not previously 
consented for. 
NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office-Boston. 
4.4.3.3 
Specimens for research are to be submitted, per patient 
consent, as defined within the EAY131 Master Protocol or 
MATCH treatment subprotocol, if applicable. Please refer 
to Section Error! Reference source not found.. 
4.5 
Registration to Third Screening (Step 4) 
4.5.1 
The information requested in Section 4.1.1-Section 4.1.3. 
4.5.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.5. 
4.5.3 
Classification Factors  
Time from start of Step 3 treatment to toxicity or progression: 
• 
< 6 months 
• 
≥ 6 months 
Number of screening biopsies 
• 
0 
• 
1 
4.5.4 
Additional Requirements  
4.5.4.1 
Sites must utilize the CIRB as their IRB of record to 
participate in EAY131. 
4.5.4.2 
To proceed to Step 4, either of the following must be done: 
• 
Tumor tissue from the second screening biopsy is to be 
submitted as indicated in Section 9 for central 
assessment. See Section 4.1.5.3 in Appendix XV for 
submission requirements. 
NOTE: 
It may take up to 6 weeks for results to be 
returned to the site on a second biopsy and 
potential treatment assignments made 
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available via Medidata Rave. Registration 
cannot proceed until the central 
determination is complete. 
OR  
• 
Patient's prior second screening Biopsy Analysis 
indicated >1 targeted treatments.  
4.5.4.3 
Specimens for research are to be submitted, per patient 
consent, as defined within the EAY131 Master Protocol. 
Please refer to Section Error! Reference source not 
found.. 
4.6 
Registration to Third Treatment (Step 5) 
Patient registration can occur only after the Step 4 evaluation is complete, 
eligibility criteria have been met, and the patients have signed and dated the 
relevant agent-specific informed consent document. 
Patients must not start protocol treatment prior to registration to Step 5 
Treatment must start within seven days from registration to Step 5 and not 
before repeat pre-treatment imaging, if necessary, is completed. Study 
agent must be ordered after patient is assigned to the treatment 
subprotocol as no starter supplies are available for this study. If expedited 
shipment is required, sites should provide an express courier account 
through the Online Agent Order Processing (OAOP) application. 
NOTE: 
If registration to Step 5 is not completed within 28 days of treatment 
assignment, the patient's slot will be released, and the patient will no 
longer be eligible for that treatment and will be taken off study. 
The following information will be requested: 
4.6.1 
The information requested in Section 4.1.1-Section 4.1.3.  
4.6.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1 (excluding Section 3.1.6) and Section 3.6 
4.6.3 
Additional Requirements  
4.6.3.1 
Sites must utilize the CIRB as their IRB of record to 
participate in EAY131. 
4.6.3.2 
Patients must provide a signed and dated, written informed 
consent form for targeted treatments not previously 
consented for. 
NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office-Boston. 
4.6.3.3 
Specimens for research are to be submitted, per patient 
consent, as defined within the EAY131 Master Protocol or 
MATCH treatment subprotocol, if applicable. Please refer 
to Section Error! Reference source not found.. 
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4.7 
Registration to Fourth Screening (Step 6) 
4.7.1 
The information requested in Section 4.1.1-Section 4.1.3. 
4.7.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.7. 
4.7.3 
Additional Requirements  
4.7.3.1 
Sites must utilize the CIRB as their IRB of record to 
participate in EAY131. 
4.7.3.2 
To proceed to Step 6, the patient's second screening 
Biopsy Analysis indicated >1 unaddressed targeted 
treatments.  
NOTE: 
It may take up to 6 weeks for results to be returned and 
potential treatment assignments made available via 
Medidata Rave. Registration cannot proceed until the 
central determination is complete. 
4.7.4 
Classification Factors 
Time from start of Step 5 treatment to toxicity or progression: 
• 
< 6 months 
• 
≥ 6 months 
4.8 
Registration to Fourth Treatment (Step 7) 
Patient registration can occur only after the Step 6 evaluation is complete, 
eligibility criteria have been met, and the patients have signed and dated the 
relevant agent-specific informed consent document. 
Patients must not start protocol treatment prior to registration to Step 7 
Treatment must start within seven days from registration to Step 7 and not 
before repeat pre-treatment imaging is completed, if necessary. Study 
agent must be ordered after patient is assigned to the treatment 
subprotocol as no starter supplies are available for this study. If expedited 
shipment is required, sites should provide an express courier account 
through the Online Agent Order Processing (OAOP) application. 
NOTE: 
If registration to Step 7 is not completed within 28 days of treatment 
assignment, the patient's slot will be released, and the patient will no 
longer be eligible for that treatment and will be taken off study. 
The following information will be requested: 
4.8.1 
The information requested in Section 4.1.1-Section 4.1.3.  
4.8.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1 (excluding Section 3.1.6) and Section 3.8 
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4.8.3 
Additional Requirements  
4.8.3.1 
Sites must utilize the CIRB as their IRB of record to 
participate in EAY131. 
4.8.3.2 
Patients must provide a signed and dated, written informed 
consent form for targeted treatments not previously 
consented for. 
NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office-Boston. 
4.8.3.3 
Specimens for research are to be submitted, per patient 
consent, as defined within the EAY131 Master Protocol or 
MATCH treatment subprotocol, if applicable. Please refer 
to Section Error! Reference source not found.. 
4.9 
Registration to Research Biopsy AND Blood for Circulating Tumor DNA (Step 8) 
NOTE: 
Patients who entered the study (Step 0) with a “rare variant  
determined by an outside assay ARE potentially eligible and 
encouraged to participate in Step 8. 
Patient registration can occur only after the eligibility criteria outlined in Section 
3.9 have been met, and the patients have signed and dated the relevant 
Research Biopsy informed consent document. 
The following information will be requested: 
4.9.1 
The information requested in Section 4.1.1-Section 4.1.3.  
4.9.2 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.9. 
4.9.3 
Additional Requirements  
4.9.3.1 
Sites must utilize the CIRB as their IRB of record to 
participate in EAY131. 
4.9.3.2 
Patients must provide a signed and dated, written informed 
consent form for the performance of a biopsy and 
submission of the tissue and blood for research. 
NOTE: 
Copies of the consent are not collected by the 
ECOG-ACRIN Operations Office-Boston. 
4.9.3.3 
Specimens for research are to be submitted (research 
biopsy and whole blood collection). If the patient does not 
agree to the additional research biopsy, the site should 
still request the collection of the blood. These 
specimens should be obtained PRIOR to the start of any 
future treatment. Please refer to Section Error! Reference 
source not found.. 
4.10 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
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If a patient is not assigned to a Step 1 treatment subprotocol, no follow-up data is 
collected. 
If a patient registers to Step 1, but does not receive any assigned protocol 
treatment, baseline and follow-up data will still be collected and must be 
submitted through Medidata Rave according to the schedule in the MATCH 
Forms Completion Guidelines. 
4.11 
Data collection  
Data collection for this study will be done exclusively through Medidata Rave. 
Access to the trial in Rave is granted through the iMedidata application to all 
persons with the appropriate roles in RSS after IRB approval is obtained. To 
access iMedidata/Rave the site user must have an active CTEP IAM account 
(https://ctepcore.nci.nih.gov/iam). In addition, site users that are a member of 
ECOG-ACRIN must have the mapped ECOG-ACRIN roles or explicit Rave roles 
(Rave CRA, Read-Only, CRA, Lab Admin, SLA or Site Investigator) in RSS at the 
enrolling site. Site users that are not members of ECOG-ACRIN must have the 
Rave roles on the CTSU roster at the enrolling sites. The Site Administrator or 
Data Administrator at the enrolling site may assign the appropriate roles from the 
Site Roles tab on the CTSU website. To the hold Rave CRA role or CRA Lab 
Admin role, the user must hold a minimum of an AP registration type. To hold the 
Rave Site Investigator role, the individual must be registered as an NPIVR or 
IVR.  Associates can hold read-only roles in Rave. 
Upon initial site registration approval for the study in RSS, all persons with Rave 
roles assigned on the appropriate roster will be sent study invitation e-mail from 
iMedidata. To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept  link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on 
the link in the upper right pane of the iMedidata screen. 
Users that have not previously activated their iMedidata/Rave accounts will also 
receive a separate invitation from iMedidata to activate their account. Account 
activation instructions are located on the CTSU website, Rave tab under the 
Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU 
website under the Rave tab at http://www.ctsu.org/RAVE/ or by contacting the 
CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
4.12 
Biopsy Reimbursements 
Reimbursements are applicable to procedures performed to collect the samples 
for purposes of this trial only and thus are not billed to insurance. Acceptable 
procedures are those that are low risk, as detailed in Section 9, and do not 
include any open or laparoscopic surgery or endoscopic biopsies. Procedures 
which are performed as part of patient’s actual care and billed to insurance are 
not eligible to receive these reimbursements. 
For patients registered as of May 11, 2017 with treatment assignment via 
the “Rare Variant” determined by a designated outside laboratory: Biopsy 
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reimbursement for an on-trial biopsy is applicable only for those collected 
following registration to Step 8 after completion or discontinuation of treatment on 
Step 1. There are no reimbursements available for biopsies performed for the 
purpose of testing by a designated outside laboratory. 
For patients registered prior to May 23, 2017 with tissue collected following 
Step 0 registration for screening assessments performed by the MATCH 
LABORATORIES: Tumor samples will be obtained for patients enrolled on the 
EAY131 study up to a maximum of 5 biopsies (including bone marrow aspirations 
for applicable multiple myeloma) as indicated below (2 maximum screening 
biopsies [each with 1 potential re-biopsy due to assay failure] and 1 potential end 
of treatment biopsy): 
NOTE: 
The submission of tumor tissue for Step 0 Screening, collected prior 
to pre-registration (FFPE) or biopsy following pre-registration, is 
mandatory and all subsequent biopsies are part of the protocol, but 
performed based on study requirements and safety considerations. 
Summary of biopsy reimbursements: 
• 
Step 0 Screening: Biopsy to obtain tissue for the mandatory screening 
NOTE: 
If FFPE collected prior to pre-registration to Step 0 is used for the 
screening assessment, this reimbursement is not applicable. 
• 
Step 0 Screening: Re-biopsy if the initial tumor tissue submission was found 
inadequate for the screening assessments 
• 
Potential 2nd Screening Biopsy (Step 2 or 4, as applicable- see flow 
diagram): Biopsy to obtain tissue for screening for consideration of an 
additional treatment with different study drug 
• 
2nd Screening Biopsy: Re-biopsy if the 2nd Screening Biopsy was found 
inadequate for the screening assessments 
• 
Potential End of treatment Biopsy (Step 8): Biopsy to obtain tissue for 
research studies. This biopsy may or may not be performed depending on the 
patient’s status and continued agreement at the time all treatment has been 
completed on the MATCH study. Also, if a 2nd Screening Biopsy shows no 
study-actionable abnormalities, no additional end of treatment biopsy is 
needed. 
Reimbursements for these research biopsies will be made according to current 
NCTN processes.  Please see the EAY131 funding sheet on the CTSU web site 
for current reimbursement information. 
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5. 
Treatment Plan 
5.1 
Study Design 
After Step 0 registration, the “MATCH screening assessment  will differ 
depending on the method of study entry. For patients that previously entered the 
study via the original screening process (i.e. to submit tissue for testing by a 
MATCH laboratory), this assessment will consist of both molecular profiling by 
the MATCH assay and the subsequent process of assigning treatment. Please 
note, after 5/22/17, new patients may no longer be enrolled on the study through 
this process. For patients entering the study through testing performed by one of 
the designated labs outside of the MATCH laboratory group (i.e. the Outside 
Assay process; see Appendix XIV), the assessment will only consist of the 
study's determination of treatment assignment. This is the only method of study 
entry moving forward. 
Determination of aMOIs by the MATCH assay: 
A pre-treatment tumor biopsy and blood draw will be obtained from patients who 
sign the informed consent document to enroll in the study. The results of the 
evaluation of the biopsy specimens will determine if the patient's tumor has an 
aMOI (actionable mutation of interest) for which a MATCH treatment subprotocol 
is available. Additionally, subsequent tumor biopsies may be taken if the patient 
has response and/or stable disease for more than 6 months or at the time of 
disease progression and the patient wishes to be re-evaluated for additional 
molecular variants. Information about the gene mutations/alterations in pathways 
of interest is included in Appendix VII. 
No more than ONE mandatory biopsy and four conditional tumor biopsies will be 
obtained through Interventional Radiology by a percutaneous (bone marrow 
aspirate for multiple myeloma, radiology services not required) approach (see 
Section 9): 
• 
Step 0 Screening: Biopsy to obtain tissue for the mandatory screening OR 
submission of FFPE (metastatic tissue preferred) from a prior procedure. If 
previously collected tissue is submitted, the tissue must meet the criteria 
specified in Section 9 and Section 3.1.6 
NOTE: 
For patients for whom an applicable “rare variant  was identified 
by one of the designated outside laboratories (See Appendix XIV), 
archived tumor tissue is to be submitted within 8 weeks following 
registration to Step 1 for assessment by the MATCH assay to 
confirm the “rare variant.  Please refer to Section 4.1.5 for 
additional information and exceptions. 
• 
Step 0 Screening: Re-biopsy if the initial tissue submission was found 
inadequate for the screening assessments 
• 
2nd Screening Biopsy (Step 2 or 4, as applicable- see flow diagram): Biopsy 
to obtain tissue for screening for consideration of additional rounds of  
treatment with different study drug 
• 
2nd Screening Biopsy: Re-biopsy if the 2nd Screening Biopsy was found 
inadequate for the screening assessments 
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• 
End of treatment: Biopsy to obtain tissue for research studies per patient 
consent. If a 2nd Screening Biopsy shows no study-actionable abnormalities, 
no additional End of treatment biopsy is requested. 
Percutaneous biopsies for accrual on the trial will be performed on patients with 
solid tumors or lymphomas or myeloma plasmacytomas. Bone marrow aspirates 
are to be used for obtaining tumor cells in patients with other myelomas. 
Permitted Biopsy procedures should entail no more than minimal risk and are 
detailed in Section 9. 
Tissue specimens will be sent for analyses as defined in Section 9. Blood 
samples, per patient consent, will also be collected and submitted for research 
with the biopsy samples and either during or at the end of each MATCH 
treatment. 
If eligible, a patient may undergo up to two rounds of biopsy with up to two 
different MATCH treatments following each biopsy if additional variants of 
interest eligible for treatment on MATCH exist. Patient consent will occur in 
sequential steps. 
NOTE: 
Patients deemed ineligible for Step 1 treatment or who did not receive 
a treatment assignment due to a lack of available assignment slots 
may be eligible to have their MATCH assay screening results rerun 
through MATCHbox. Sites will be notified via e-mail if their patient is 
eligible to be rerun through the MATCHbox. Upon receipt of this 
notification, the site will be required to complete the appropriate form 
in Medidata Rave. This form may be completed within 6 months from 
the collection of specimen. If not completed by this date, the patient 
will not be reconsidered for treatment. Please refer to Section 3.2 to 
review the eligibility criteria. 
Determination of ‘Rare Variant  aMOIs by a designated Outside Laboratory: 
For patients for whom an applicable “rare variant  was identified by one of the 
designated laboratories (see Appendix XIV), notification of potential MATCH 
eligibility from the outside laboratory and an electronic copy of the applicable 
sequencing report is to be uploaded to the Outside Assay folder in Medidata 
Rave. A copy of the pathology reports associated with the analyzed tumor tissue 
and the original diagnostic pathology (if different) are also to be uploaded in 
Medidata Rave. 
Patients who enter screening for determination of treatment assignment based 
on an outside assay result are eligible for only one treatment assignment on 
MATCH.  If the patient is determined not to be eligible for a subprotocol open to 
outside assay “rare variant  results, the patient is off-study. 
Screening (Step 0 procedures): 
• 
Patients consent to the screening aspects of the study – biopsy and 
molecular characterization of their biopsy material and collection and 
submission of blood for research. 
NOTE: 
Step 0 screening consent includes consent for all screening steps 
(Steps 0, 2, 4, and 6). If treatment is to be determined based on a 
“rare variant  detected by an Outside Laboratory, a tissue biopsy 
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to collect screening materials will not be applicable. However, 
collection of blood is encouraged (see Sections 7.2 and 9). 
• 
Patients are registered to Step 0 in the OPEN Registration system. This “pre-
registration  step will capture information relevant to potential treatment 
assignment (TA), including but not limited to: site of disease and baseline 
eligibility characteristics. 
• 
Patients will undergo the mandatory tumor biopsy (or bone marrow aspirate 
for myeloma patients, if applicable) OR have FFPE tumor tissue (metastatic 
tissue preferred) available for analysis following a clinically indicated 
diagnostic or therapeutic procedure (e.g. craniotomy and tumor resection for 
brain tumors, lung wedge resection, endoscopic procedure) as described in 
Section 9 OR outside “rare variant  sequencing results will be uploaded to 
RAVE.  
NOTE: 
For patients for whom an applicable “rare variant  was identified by 
one of the outside designated laboratories as described in Appendix 
XIV, FFPE tumor tissue may be required to be submitted to MD 
Anderson for additional central assessments (e.g. IHC) prior to final 
treatment arm assignment based on the Outside Laboratory results. 
The collection and submission of archived tumor tissue for the 
confirmation of the “rare variant  must follow the guidelines for the 
submission of tissue for screening at Step 0 with the following 
changes: 
• 
FFPE tumor tissue may be submitted after but no later than 8 
weeks following registration to Step 1 
• 
FFPE tissue should be representative of the materials used by the 
designated outside laboratory and may have been collected more 
than 6 months prior to registration to Step 0.  Patients may have 
had treatment between the collection of the biopsy and 
registration to Step 0. 
• 
Treatment arm assignment will be based on the Outside 
Laboratory results.  The MATCH assay assessments will be 
reported to the site but will not, per protocol, impact patient’s 
eligibility for or continued treatment on the relevant Subprotocol on 
Step 1. However, for certain “rare variant  arms, submission of 
FFPE tumor tissue may be required for additional central 
assessments (e.g. IHC) prior to final treatment arm assignment 
based on the Outside Laboratory results. 
• 
Patients are potentially eligible for only one treatment assignment.  
Patients not assigned to treatment are off study. Patients not 
assigned to treatment are not eligible to undergo a biopsy for 
screening purposes. 
• 
The biopsy/tumor sample, blood, and fine needle aspiration specimens in the 
collection kit are submitted to the ECOG-ACRIN Central Biorepository and 
Pathology Facility in the Division of Pathology and Laboratory Medicine at the 
University of Texas MD Anderson Cancer Center for pre-analytic processing 
and quality control. 
NOTE: 
Previous clinical pathology report MUST be submitted with the 
specimen, or the sample will not be processed. 
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• 
Immunohistochemistry analytes, if applicable, are evaluated in the CLIA-
accredited clinical Immunohistochemistry and Image Analysis Laboratories in 
the Department of Pathology at MD Anderson. 
• 
The nucleic acid analytes will be forwarded to one of the four CLIA-certified 
laboratories in the study-specific network for molecular profiling to assess for 
the presence of specific, pre-defined mutations, amplifications or 
translocations of interest.  
• 
The laboratories will return notification of whether or not a biomarker for 
patient assignment to one of the clinical trial subprotocols has been detected 
to the accruing site, to the ECOG-ACRIN Operations Office-Boston, and to 
the NCI-EA informatics pipeline in approximately 2-4 weeks. 
NOTE: 
For patients pre-registered to the trial based on a “rare variant  
referral from a designated Outside Laboratory,it is estimated that 
the treatment assignment would be available in 2 weeks or less. 
• 
The automated rules engine will generate a list of potential treatment 
assignment (TA). 
• 
Prioritized TAs will be sent to the ECOG-ACRIN Operations Office. The 
highest priority TA will then be made available to the registering site via 
Medidata Rave. 
• 
Patient is assessed for eligibility and consents to treatment with an agent in 
the trial subprotocol. 
• 
If the patient is ineligible for highest priority TA, the treatment assignment 
process may be repeated, in order of priority, until either all TAs are 
exhausted or the patient is confirmed eligible and is registered to a treatment 
subprotocol. 
• 
In cases where insufficient tumor is obtained for biomarker analysis, the 
patient will be given the option to undergo a repeat PERCUTANEOUS or 
excisional qualifying biopsy of tumor to obtain more tissue unless the primary 
tumor tissue was obtained secondary to a clinically indicated procedure.  
Patients in whom sufficient tumor DNA material cannot be obtained for 
targeted analysis will be taken off-study. 
Register to First Treatment 
Treat until patient experiences either progression OR unacceptable toxicity OR 
voluntary discontinuation of treatment. 
The following options are available at treatment failure:  
• 
Discontinue treatment and enter follow-up, 
• 
Register to Step 2 for re-screening and the opportunity to receive a different 
targeted study agent. 
NOTE: 
From consenting patients, research blood samples are to be 
collected and submitted after cycle 2 or end of treatment, 
whichever occurs first (and before any subsequent investigational 
or other systemic treatment, such as the next cycle of treatment). 
Please refer to Section Error! Reference source not found.. 
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Register to Subsequent Screening (Steps 2, 4, 6) 
• 
Patients with Step 1 treatments assigned based on “rare variants  identified 
by designated outside laboratories are not eligible to proceed to Step 2. 
• 
Step 2 or 4: If progression (or inability to tolerate further treatment) occurred 
after a (1) response OR (2) after ≥ 6 months from start of Step 1 treatment, 
patients will undergo a second tumor biopsy using the collection and shipping 
kit, as described in Section 9.1.  Patients with tumor in non-minimal risk 
locations who were initially screened using tumor tissue obtained during a 
necessary clinical procedure (surgery, endoscopy) would not undergo a 
biopsy or second procedure unless clinically indicated or a new tumor site in 
a location of minimal risk develops. 
The biopsy, blood, and optional fine needle aspiration specimens are 
forwarded in the shipping kit to the ECOG-ACRIN Central Biorepository and 
Pathology Facility at MD Anderson for processing (protocol Section Error! 
Reference source not found.). Analytes will be prepared and distributed to 
the study-specific network of approved CLIA-certified Laboratories for 
molecular profiling to assess for the presence of specific, pre-defined 
mutations, amplifications,  translocations, and altered expression of genes of 
interest and notification of results done as in Step 0. 
NOTE: 
Submission of prior pathology reports with the screening 
samples are required, as they were in Step 0. 
The laboratory will return notification of whether an alteration of interest has 
been detected to the site and the ECOG-ACRIN Operations Office-Boston. 
Details about potential treatment subprotocol, assigned based on predefined 
criteria, will be made available via Medidata Rave. 
OR 
• 
Step 2, 4 or 6: Patients who progressed OR had unacceptable toxicity OR 
voluntarily discontinued treatment within 6 months AND who had additional 
actionable mutations, amplifications or translocations, as determined by the 
MATCH assay for which a treatment subprotocol is currently available will not 
undergo an additional biopsy, but may be offered additional TAs as below 
based on their Step 0 (or Step 2/4) results. 
NOTE: 
A single MATCH assay screening may be used to assign no more 
than two consecutive treatments regardless of the number of 
aMOIs detected. Further participation/treatment assignment 
requires submission and analysis of fresh tumor tissue. See Study 
Schema. 
Treatment Consent (prior to registration to Steps 3, 5, 7):  
Treatment assignment will occur in the same manner as that for the first round 
(Prior to Step 1)  
If patients experiences stable disease, complete or partial response, he or she 
will continue on study until disease progression or inability to tolerate treatment, 
at which time s/he will proceed to the next registration step or long term follow-up 
per Section 3. 
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NOTE: 
From consenting patients, research blood samples are to be collected 
and submitted after cycle 2 or end of treatment, whichever occurs first 
(and before any subsequent investigational or other systemic 
treatment, such as the next cycle of treatment). Please refer to 
Section Error! Reference source not found.. 
Consent for Collection of End of Treatment Research Tumor and Blood 
Specimens (prior to registration to Step 8): 
If patients meet the criteria outlined in Section 3.9 and consent is obtained, 
proceed to Step 8 registration and submit samples as outlined in Section 9. 
5.1.1 
Specimen qualification 
For a tumor biopsy sample to be considered adequate for sequencing 
a minimum of 70% of the biopsy should have non-necrotic tumor 
content; biopsy samples with lower tumor content will undergo 
macrodissection to enrich for non-necrotic tumor cells.  In cases 
where sufficient tumor DNA is not obtained for analysis in the initial 
screening biopsy, the patient will be given the option to undergo a 
repeat tumor biopsy to obtain more tissue.  Patients in whom sufficient 
tumor DNA material cannot be obtained for targeted analysis will be 
taken off-study. However, the assays will be attempted on biopsies 
that have at least 20% non-necrotic tumor cells present. 
5.1.2 
Immunohistochemistry alterations 
Changes in gene product expression in tumor cells will be reported as 
required by the individual analytes based upon evidence of 
association with agents of interest. These reports will be sent to the 
site separately from the sequencing results. 
5.1.3 
Detection of mutations, amplifications or translocations  
Nucleic acid alterations will be reported based upon their 
characteristics. Mutations will be reported based on their presence in 
tumor cells. For single nucleotide variants (SNV)/insertions and 
deletions (indels), the report will include percent of reads 
demonstrating the predefined mutation compared to reference 
sequence. Copy number variations will be reported as level of fold 
change.  Re-arrangements will be reported based upon genes 
involved. If mutations/alterations are detected in more than one 
pathway, treatment will be assigned based on levels of evidence 
(Section 1.4.2). If the subprotocols have equal number of patients, 
patients will be randomized between those subprotocols. If the patient 
stops treatment, and the patient still meets eligibility criteria, the 
patient will have the option to receive the other treatment regimen. For 
the purposes of assessing the primary endpoint of this trial, response 
to any assigned treatment will be used. 
5.1.4 
Treatment Assignment 
If mutations are detected in more than one pathway, treatment will be 
assigned based on levels of evidence as detailed above (Section 
1.4.2).  
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NOTE: 
Each treatment subprotocol will attempt to recruit only a 
limited number of patients from more common disease 
sites (e.g., lung, breast, prostate, colorectal). If the disease 
site cohort has been completed, either (1) the patient will 
be assigned the treatment based on another actionable 
mutation (if any), or (2) if the patient is only eligible for a 
single targeted agent, the patient will not be assigned to 
treatment and will not be followed. A completed 
subprotocol may be expanded to permit accrual of 
sufficient patients in a disease of interest (e.g., colorectal 
cancer) to permit a more accurate assessment of activity in 
the disease. Please refer to Section 8.1 for additional 
information concerning the treatment expansions. 
5.2 
Administration Schedule Summary 
All Administration instructions are contained in Section 3 of the corresponding 
treatment-specific subprotocol document. 
5.3 
Adverse Event Reporting Requirements 
The guidelines outlined here for EAY131 Adverse Event (AE) Reporting 
apply to all EAY131 subprotocols. However, each subprotocol contains its 
own AE Reporting section with agent specific stipulations and must be 
referenced to ensure all reporting requirements are met. 
NOTE: 
Starting April 1, 2018, CTEP-AERS reporting will use CTCAE v5. 
Please refer to each subprotocol to verify which version of the CTCAE 
should be used for dose modifications. Please refer to the instructions 
on the Adverse Event Case Report Form in Rave for instructions on 
which version of the CTCAE must be used for routine reporting. 
5.3.1 
Purpose 
Adverse event (AE) data collection and reporting, which are a 
required part of every clinical trial, are done so investigators and 
regulatory agencies can detect and analyze adverse events and risk 
situations to ensure the safety of the patients enrolled, as well as 
those who will enroll in future studies using similar agents.  
• 
Routine reporting: Adverse events are reported in a routine 
manner at scheduled times during a trial using the Medidata Rave 
clinical data management system. Please refer to Section 4 of this 
protocol for more information on how to access the Medidata 
Rave system and the subprotocol forms packet for instructions on 
where, when and what adverse events are to be reported 
routinely. 
• 
Expedited reporting: In addition to routine reporting, certain 
adverse events must be reported in an expedited manner for 
timelier monitoring of patient safety and care. The following 
sections provide information and instructions regarding expedited 
adverse event reporting. 
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5.3.2 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of an agent or intervention (biopsy) in 
humans, whether or not considered agent or intervention (biopsy) 
related. Therefore, an AE can be ANY unfavorable and 
unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the 
medicinal product. 
• 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment, using the following 
categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment. 
Unlikely 
The AE is doubtfully related to treatment. 
Possible 
The AE may be related to treatment. 
Probable 
The AE is likely related to treatment. 
Definite 
The AE is clearly related to treatment. 
• 
CAEPR (Comprehensive Adverse Events and Potential Risks 
List):  An NCI generated list of reported and/or potential AEs 
associated with an agent currently under an NCI IND.  Information 
contained in the CAEPR is compiled from the Investigator’s 
Brochure, the Package Insert, as well as company safety reports.   
• 
CTCAE:  The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting.  A grade (severity) is provided for each AE term.  
• 
Hospitalization (or prolongation of hospitalization):  For AE 
reporting purposes, a hospitalization is defined as an inpatient 
hospital stay equal to or greater than 24 hours.   
• 
Life Threatening Adverse Event:  Any AE that places the 
subject at immediate risk of death from the AE as it occurred.   
• 
Serious Adverse Event (SAE): Any adverse event occurring at 
any dose that results in ANY of the following outcomes:  
• 
Death  
• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours).  
• 
A persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
• 
A congenital anomaly/birth defect.  
• 
Important Medical Events (IME) that may not result in death, 
be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they 
may jeopardize the patient or subject and may require medical 
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or surgical intervention to prevent one of the outcomes listed in 
this definition. 
• 
SPEER (Specific Protocol Exceptions to Expedited 
Reporting):  A subset of AEs within the CAEPR that contains list 
of events that are protocol specific exceptions to expedited 
reporting. 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.   
5.3.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). The CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (857-504-2900) 
• 
the NCI (301-897-7497)  
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the NCI (301-897-7404). 
NCI Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457 
5.3.4 
Determination of Reporting Requirements 
Many factors determine the reporting requirements of each individual 
protocol, and which events are reportable in an expeditious manner, 
including:   
• 
the phase (0, 1, 2, or 3) of the trial  
• 
whether the patient has received an investigational or commercial 
agent or both 
• 
the seriousness of the event 
• 
the Common Terminology Criteria for Adverse Events (CTCAE) 
grade 
• 
whether or not hospitalization or prolongation of hospitalization 
was associated with the event 
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• 
when the adverse event occurred (within 30 days of the last 
administration of investigational agent vs. > 30 days after the last 
administration of investigational agent)  
• 
the relationship to the study treatment (attribution) 
Using these factors, please follow the instructions and use the tables 
in the following section, as well as refer to the AE section in each 
subprotocol, to comply with the adverse event reporting requirements 
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5.3.5 
Steps to determine if an adverse event is to be reported in an 
expedited manner 
5.3.5.1 
Guidelines for reporting adverse events OCCURRING 
WHILE ON PROTOCOL TREATMENT AND WITHIN 30 
DAYS of the last administration of the investigational 
agent(s) /intervention (biopsy).  
Determine if the event meets the 
definition of a Serious Adverse 
Event (SAE) as outlined by the 
six criteria in the top portion of the 
table below in Section 5.3.6 
Yes 
No 
Identify the type and 
grade of the event 
using CTCAE v5.0. 
Determine if the patient 
was hospitalized for  
≥ 24 hours for the event. 
With this information, 
review the chart in 
Section 5.3.6 to 
determine if event is 
reportable via CTEP-
Refer to the AE section in 
the subprotocol to 
determine if the event 
meets the subprotocol 
specific reporting 
requirements. If so, report 
the event via CTEP-AERS. 
Refer to the AE section in 
the subprotocol to 
determine if the event 
meets the subprotocol 
specific reporting 
requirements.  If so, report 
the event via CTEP-AERS. 
Is the event 
reportable? 
No 
Yes 
Report the event via CTEP-AERS. 
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5.3.5.2 
Guidelines for reporting adverse events OCCURRING 
GREATER THAN 30 DAYS after the last administration of 
the investigational agent(s) /intervention (biopsy). 
If the adverse event meets the definition of a Serious 
Adverse Event (SAE) as outlined by the six criteria in the 
top portion of the table below in Section 5.3.6 OR any 
agent specific requirements (refer to specific stipulations in 
each subprotocol) AND has an attribution of possible, 
probably or definite, the following events require reporting 
as follows: 
Expedited 24-hour notification followed by complete 
report within 5 calendar days for: 
• 
All Grade 3, 4 and Grade 5 AEs  
NOTE: 
Any death occurring greater than 30 days after 
the last dose of investigational 
agent/intervention (biopsy) with an attribution of 
possible, probable or definite must be reported 
via CTEP-AERS even if the patient is off study. 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or 
prolongation of hospitalization 
5.3.6 
Expedited Reporting Requirements for protocol EAY131 
Phase 1 and Early Phase 2 Studies 
Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention.1 
NOTE: 
Footnote 1 instructs how to report serious adverse events 
that occur more than 30 days after the last administration 
of investigational agent/intervention. 
NOTE: 
The following reporting requirements apply to all steps 
(both treatment steps and biopsy (screening) steps). If an 
event occurs that meets the reporting requirements below, 
it is a reportable event, regardless of the step. 
NOTE: 
In order to complete the CTEP-AERS reporting properly, if 
the event being reported is related to a biopsy, please be 
sure to add 'Screening Step Biopsy' to the 'Other 
Contributing Causes' section of the CTEP-AERS report 
and add any other pertinent information to the 'Description 
of Events' section. 
NOTE: 
For SAEs reported on a screening step (Step 0, 2, 4, 6) 
please always indicate if the event being reported is biopsy 
related or not 
NOTE: 
If a patient is registered to Step 0 and has a biopsy 
performed, the patient must be followed for 30 days from 
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NOTE: 
A death due to progressive disease should be reported as 
a Grade 5 “Disease progression  under the System Organ 
Class (SOC) “General disorder and administration site 
conditions . Evidence that the death was a manifestation of 
underlying disease (e.g. radiological changes suggesting 
tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted. 
Additional adverse event reporting instructions are contained in 
the treatment-specific subprotocol document. Each subprotocol 
must be referenced to ensure all reporting requirements are met. 
5.3.8 
Other recipients of adverse event reports and supplemental data 
DCTD/NCI will notify the pharmaceutical collaborator(s)of AE/SAEs in 
accordance with the contract with the company. Any additional written 
AE information requested MUST be submitted to BOTH the NCI and 
ECOG-ACRIN. 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.3.9 
Second Primary Cancer Reporting Requirements 
NOTE: 
The following are the standard requirements and 
instructions for reporting second primary cancers.  
However, some subprotocols have additional second 
primary reporting requirements and it is imperative the AE 
section of each subprotocol be carefully read to ensure all 
requirements are being met. 
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: 
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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. 
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. 
5.4 
Dose Modifications  
Please refer to treatment-specific subprotocol document. 
5.5 
Duration of Therapy  
Patients who were pre-registered (Step 0) only are not considered to be on-study 
and will not be followed. 
For all other patients who begin a treatment and progress, patients will be offered 
a biopsy unless: 
• 
Patients whose disease progresses (without objective response) within 6 
months of entry will be offered the opportunity to go through two different 
treatment regimens, if additional actionable variants were found.   
• 
Patients who respond to initial assigned treatment or progress after 6 months 
on study will be offered a 2nd biopsy and molecular profiling assay(s) and 
may be assigned new treatments if additional actionable molecular 
abnormalities are found. 
• 
All treatment regimens for the patient’s actionable molecular variants  of 
interest have been exhausted (see Section 5.1) 
• 
Intercurrent illness prevents further administration of treatment or safe 
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5.6 
Duration of Follow-Up 
For this protocol, all patients who enroll on a treatment subprotocol, including 
those who discontinue protocol therapy early, will be followed for response until 
progression, even if non-protocol therapy is initiated, and for survival for 3 years 
from the date of registration (every 3 months for ≤ 2 years and every 6 months 
for year 3). All patients must be followed through completion of all MATCH 
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6. 
Measurement of Effect 
6.1 
Solid Tumor Response  
For the purposes of this study, patients should be re-evaluated for response: 
• 
For treatments given in 21 day (3 week) cycles: every 3 cycles (9 weeks) for 
the first 33 cycles, and every 4 cycles thereafter (12 weeks) 
• 
For treatments given in 28 day (4 week) cycles: every 2 cycles (8 weeks) for 
the first 26 cycles, and every three cycles thereafter (12 weeks) 
• 
For treatments given in 42 day (6 week) cycles: every 2 cycles (12 weeks) 
Solid Tumors: Response and progression will be evaluated in this study using the 
international criteria proposed by the revised Response Evaluation Criteria in 
Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. 
Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used 
in RECIST. 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor 
burden at baseline of each treatment step to which subsequent 
measurements will be compared. All baseline evaluations should be 
performed as closely as possible to the beginning of treatment and never 
more than six weeks before registration to each treatment step. 
2. Measurable disease is defined by the presence of at least one measurable 
lesion. 
3. All measurements should be recorded in metric notation by use of a ruler or 
calipers.  
4. The same method of assessment and the same technique must be used to 
characterize each identified lesion at baseline and during follow-up.  
6.1.1 
Definitions 
Evaluable for Objective Response 
Only those patients who have measurable disease present at the 
baseline of each treatment step, have received protocol therapy, and 
have had their disease re-evaluated will be considered evaluable for 
response. These patients will have their response classified according 
to the definitions stated below. 
(NOTE: 
Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response 
Patients who, in addition to measurable disease, have lesions present 
at the baseline of each treatment step that are evaluable but do not 
meet the definitions of measurable disease, have received protocol 
therapy, and have had their disease re-evaluable will be considered 
evaluable for non-target lesion assessment. The response 
assessment is based on the presence, absence, or unequivocal 
progression of the lesions. 
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6.1.2 
Disease Parameters 
Measurable Disease 
Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) 
as ≥ 20 mm by chest x-ray, as  
≥ 10 mm with CT scan, or ≥ 10 mm with calipers by clinical exam. All 
tumor measurements must be recorded in millimeters. 
NOTE: 
Measurable or non-measurable disease must be present 
outside the previous radiation field or a new or progressing 
lesion inside the port must be present. 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and 
followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm 
short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as 
non-measurable. Non-measurable also includes lesions that are < 20 
mm by chest x-ray. 
NOTE: 
Cystic lesions that meet the criteria for radiographically 
defined simple cysts should not be considered as 
malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be 
considered as measurable lesions, if they meet the definition of 
measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target 
lesions. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be 
identified as target lesions and recorded and measured at baseline of 
each treatment step. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves 
to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can 
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A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum 
of the diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the 
disease. 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline of each treatment 
step.  Measurements of these lesions are not required, but the 
presence or absence of unequivocal progression of each should be 
noted throughout follow-up.  
6.1.3 
Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation 
using a ruler or calipers. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment and never more 
than six weeks before registration to each treatment step. 
The same method of assessment and the same technique must be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 
mm in diameter as assessed using calipers (e.g., skin nodules). In the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest X-ray 
Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, 
CT is preferable.  
Conventional CT and MRI  
This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also 
acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue. MRI has excellent contrast, 
spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is 
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performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of 
disease. Furthermore, as with CT, the modality used at follow-up must 
be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the 
scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases.  
Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible. 
PET-CT 
At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for 
use with RECIST measurements. However, if the site can document 
that the CT performed as part of a PET-CT provides image quality 
equivalent to a diagnostic CT then the CT portion of the PET-CT can 
be used for RECIST measurements and can be used interchangeably 
with conventional CT in accurately measuring cancer lesions over 
time. Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or 
serially performed. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement. Ultrasound examinations 
cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken 
from one assessment to the next.  If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may 
be used instead of CT in selected instances. 
Endoscopy, Laparoscopy 
The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor Markers 
Tumor markers alone cannot be used to assess response. If markers 
are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin 
Oncol 26:1148-1159, 2008]. In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria which are to be 
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integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
Cytology, Histology 
These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., 
residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment when the measurable tumor 
has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be 
a side effect of the treatment) and progressive disease. 
6.1.4 
Response Criteria for solid tumors (RECIST) 
6.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction 
in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline of each 
treatment step sum diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on that 
step (this includes the baseline sum if that is the smallest 
on that step). In addition to the relative increase of 20%, 
the sum must also demonstrate an absolute increase of at 
least 5 mm. 
NOTE: 
The appearance of one or more new lesions is 
also considered progression, See Section 
6.1.4.3 
NOTE: 
Clinical Progressive Disease can be determined 
using the following criteria: 
1. ECOG PS of at least 3 
2. Patient unable to have follow-up radiologic 
assessment due to performance status 
decline 
3. Symptomatic decline deemed related to 
patient's disease (not toxicity from therapy or 
concurrent illness) 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
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sum diameters while on that step. (Note: a change of 20% 
or more that does not increase the sum of the diameters by 
5 mm or more is coded as stable disease) 
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after registration to that treatment step at a minimum 
interval of 2 cycles (for cycles of 28 or 42 days length) of 
the treatment OR a minimum interval of 3 cycles (for cycles 
of 21 day length). 
6.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes 
must be non-pathological in size (< 10 mm short axis) 
Non-CR/Non-PD 
Persistence of one or more non-target lesions. 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions (see 
Section 6.1.4.3). Unequivocal progression should not 
normally trump target lesion status. It must be 
representative of overall disease status change, not a 
single lesion increase. 
When the patient also has measurable disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest 
“increase  in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of SD or 
PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the 
increase in overall disease burden should be comparable 
in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in 
tumor burden from “trace  to “large , an increase in nodal 
disease from “localized  to “widespread , or an increase 
sufficient to require a change in therapy. 
Although a clear progression of “non-target  lesions only is 
exceptional, the opinion of the treating physician should 
prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or 
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6.1.4.3 
Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive 
Disease (PD). 
A growing lymph node that did not meet the criteria for 
reporting as a measurable or non-measurable lymph node 
at baseline should only be reported as a new lesion (and 
therefore progressive disease) if it:  
a) increases in size to ≥ 15 mm in the short axis, or  
b) there is new pathological confirmation that it is disease 
(regardless of size). 
New effusion or ascites that appears during treatment 
should only be reported as a new lesion (and therefore 
progressive disease) if it has cytological confirmation of 
malignancy. 
6.1.4.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded 
from the start of the treatment step until disease 
progression/recurrence or non-protocol therapy taking as 
reference for progressive disease the smallest 
measurements recorded on that step (this includes the 
baseline sum, if that is the smallest on that step). The 
patient’s best response assignment will depend on the 
achievement of both measurement and confirmation 
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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions* 
Overall 
Response 
Best Overall Response 
determination 
CR 
CR 
No 
CR 
Confirmation needed: ≥ 4 weeks 
confirmation**** 
CR 
Non-CR***/Non-PD 
No 
PR 
Confirmation needed: ≥ 4 weeks 
confirmation**** 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD***/not evaluated 
No 
PR 
SD 
Non-PD***/not evaluated 
No 
SD 
Documented at least once at a 
minimum interval of 2 cycles (for 
cycles of 28 or 42 days) or 3 cycles 
(for cycles of 21 days) from  
registration to the treatment step 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD*** 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
*** PD in non-target lesions should not normally trump target lesion status. It must be representative of 
overall disease status change, not a single lesion increase. Please refer to the Evaluation of Non-
Target Lesions – Progressive Disease section for further explanation. 
**** It is recommended that the confirmation be obtained at the next scheduled evaluation. 
NOTE: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
6.1.4.5 
Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is 
first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as 
reference for progressive disease the smallest 
measurements recorded since the treatment started). 
The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date 
that progressive disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the baseline of each 
treatment step until the criteria for progression are met, 
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since the treatment started, including the baseline 
measurements.  
To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once 
after entry to that step at a minimum interval 2 cycles (for 
cycles of 28 or 42 days), or 3 cycles (for cycles of 21 
days). 
6.2 
Lymphoma Response Criteria 
NOTE: 
These criteria are based upon the criteria from the Revised Response 
Criteria for Malignant Lymphoma, (Cheson et al.), Journal of Clinical 
Oncology, 2014: 32: 3059-3067. 
The criteria use the following categories of response: Complete Response (CR), 
Partial Response (PR), Stable Disease (SD), Relapse and Progression (PD). In 
the case of stable disease, follow-up assessments must have met the SD criteria 
at least once after entry to that step at a minimum interval of eight weeks.  
The following guidelines are to be used for establishing tumor measurements at 
the baseline of each treatment step and for subsequent comparison: 
• 
The six largest measurable nodes or extranodal masses must be identified as 
Target Lesions at baseline.  
• 
If there are 6 or fewer measurable nodes and extranodal masses, all must be 
listed as Target Lesions 
• 
If there are more than 6 involved measurable nodes or extranodal masses, 
the 6 largest nodes or extranodal masses should be selected as Target 
Lesions according to the following features: a) they should be clearly 
measurable in at least two perpendicular measurements; b) they should be 
from as disparate regions of the body as possible; and c) they should include 
mediastinal and retroperitoneal areas of disease whenever these sites are 
involved. When there are more than 6 involved measurable nodes or 
extranodal masses, any lesions that are not included within these 6 Target 
Lesions will be considered non-measured lesions. 
• 
Nonmeasured lesions: Any disease not selected as measured, dominant 
disease and truly assessable disease should be considered not measured. 
These sites include any nodes, nodal masses, and extranodal sites not 
selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as any site of 
suspected disease that would be difficult to follow quantitatively with 
measurement, including pleural effusions, ascites, bone lesions, 
leptomeningeal disease, abdominal masses, and other lesions that cannot be 
confirmed, measured or followed by imaging. 
• 
Measurements for all Target Lesions will be reported at baseline of each 
treatment step. Measurements for non-measured lesions are not required. 
• 
The lymph nodes or extranodal masses selected as Target Lesions for 
measurement should be measured in two perpendicular diameters, one of 
which is the longest perpendicular diameter. The lymph nodes should be 
measured in centimeters to the nearest one tenth of a centimeter (e.g. 2.0 
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(LDi) greater than 1.5 cm. Measurable extranodal disease (eg, hepatic 
nodules) may be included in the six representative, measured lesions. A 
measurable extranodal lesion should have an LDi greater than 1.0 cm. 
• 
The two measured diameters of each Target Lesion should be multiplied 
giving a product for each nodal site or extranodal mass. The product of each 
site should be added, yielding the sum of products of the diameters (SPD). 
The SPD will be used in determining the definition of response for those who 
have less than a complete response. 
• 
In clinical trials where PET is unavailable to the vast majority of participants, 
or where PET is not deemed necessary or appropriate for use (e.g. a trial in 
patients with MALT lymphoma), response should be assessed as above, but 
only using CT scans.  However, residual masses should not be assigned 
CRu status, but should be considered partial responses.  
• 
PET-based response should use the following 5 point scale: PET 5 point 
scale: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake  
> mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly 
higher than liver and/or new lesions; X, new areas of uptake unlikely to be 
related to lymphoma. 
6.2.1 
Complete Response 
Complete disappearance of all detectable clinical evidence of disease, 
and disease-related symptoms if present prior to therapy. 
6.2.1.1 
PET-CT Based Criteria 
Complete metabolic response with a 5 – point scale score 
of 1, 2 or 3, with or without a residual mass. 
In patients with bone marrow involvement before treatment 
there must be no residual FDG uptake in the marrow. 
In patients with a typically FDG-avid lymphoma with no 
pre-treatment PET scan, or for lymphomas for which the 
PET scan was positive prior to therapy: a post-treatment 
residual mass of any size is permitted as long as it is PET-
negative. 
6.2.1.2 
CT Based Criteria 
For variably FDG-avid lymphomas without a pretreatment 
PET scan, or if a pretreatment PET scan was negative: all 
lymph nodes and extranodal masses must have regressed 
on CT to normal size (≤ 1.5 cm in their greatest transverse 
diameter for nodes > 1.5 cm prior to therapy). Previously 
involved nodes that were 1.1-1.5 cm in their long axis and 
> 1.0 cm in their short axis prior to treatment must have 
decreased to ≤ 1 cm in their short axis after treatment. 
The spleen and/or liver, if considered enlarged prior to 
therapy on the basis of a physical examination or CT scan, 
should not be palpable on physical examination, and 
nodules related to lymphoma should disappear. However, 
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in accurately evaluating splenic and hepatic size and 
involvement. For instance, a spleen considered normal 
size may contain lymphoma, whereas an enlarged spleen 
may not necessarily reflect the presence of lymphoma, but 
variations in anatomy, blood volume, the use of 
hematopoietic growth factors, or other causes. 
If the bone marrow was involved by lymphoma prior to 
treatment, the infiltrate must have cleared on repeat bone 
marrow biopsy. The biopsy sample on which this 
determination is made must be adequate (with a goal of  
> 20 mm unilateral core). If the sample is indeterminate by 
morphology, it should be negative by 
immunohistochemistry. A sample that is negative by 
immunohistochemistry but demonstrating a small 
population of clonal lymphocytes by flow cytometry will be 
considered a CR until data become available 
demonstrating a clear difference in patient outcome. 
NOTE: 
Complete Remission/unconfirmed (CRu): Using the above 
definition for CR and that below for PR eliminates the 
category of CRu. 
6.2.2 
Partial Response (PR) 
The designation of PR requires all of the following: 
6.2.2.1 
PET-CT Based Criteria 
Partial metabolic response with reduced uptake compared 
with baseline AND a 5 point scale score of 4 or 5. 
For a typically FDG-avid lymphoma with no pretreatment 
PET scan or one that was PET-positive prior to therapy, 
the post-treatment PET should be positive at any 
previously involved sites. 
In patients with bone marrow involvement before 
treatment, Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline (diffuse 
uptake compatible with reactive changes from 
chemotherapy allowed). If there are persistent focal 
changes in the marrow in the context of a nodal response, 
consideration should be given to further evaluation with 
MRI or biopsy or an interval scan. 
6.2.2.2 
CT Based Criteria 
For variably FDG-avid lymphomas/FDG-avidity unknown, 
without a pretreatment PET scan, or if a pretreatment PET 
scan was negative, CT scan criteria should be used.   
A ≥ 50% decrease in sum of the product of the diameters 
(SPD) of up to 6 of the largest Target Lesions. These 
nodes or masses should be selected according to the 
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2 perpendicular dimensions; if possible, they should be 
from disparate regions of the body; (b) they should include 
mediastinal and retroperitoneal areas of disease whenever 
these sites are involved. 
No increase in the size of other nodes, liver or spleen. 
Bone marrow assessment is irrelevant for determination of 
a PR if the sample was positive prior to treatment. 
However, if positive, the cell type should be specified, e.g., 
large-cell lymphoma or small cleaved cell lymphoma. 
No new sites of disease. 
Patients who achieve a CR by the above criteria, but who 
have persistent morphologic bone marrow involvement will 
be considered partial responders. 
When the bone marrow was involved before therapy and a 
clinical CR was achieved, but with no bone marrow 
assessment after treatment, patients should be considered 
partial responders. 
6.2.3 
Stable Disease (SD) 
6.2.3.1 
PET-CT Based Criteria: 
Absence of metabolic response, with a score of 4 or 5 AND 
no significant change from baseline at interim or end of 
treatment. 
In patients with bone marrow involvement before 
treatment, there must be no change from pre-treatment 
PET scan. 
No new areas of FDG uptake. 
6.2.3.2 
CT Based Criteria 
For variably FDG-avid lymphomas/FDG-avidity unknown: 
For patients without a pretreatment PET scan or if the pre-
treatment PET was negative, there must be no change in 
the size of the previous lesions on the post-treatment CT 
scan. 
Less than 50% decrease from baseline in SPD of up to 6 
Target Lesions. 
No increase in organ enlargement and non-measurable 
lesions compatible with progressive disease. 
6.2.4 
Progression (PD) and Relapse 
6.2.4.1 
PET-CT Based Criteria 
Progressive metabolic disease: 
• 
Individual target nodes and nodal masses must present 
increase intensity of uptake from baseline, with a 5 
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• 
Extranodal lesions with new FDG-avid foci consistent 
with lymphoma at interim or end of treatment 
assessment, or 
• 
New FDG-avid foci consistent with lymphoma rather 
than another etiology (e.g. infection, inflammation). If 
uncertain regarding the etiology of new lesions, a 
biopsy or repeat imaging scan should be considered. 
6.2.4.2 
CT Based Criteria 
For determination of relapsed and progressive disease, 
lymph nodes should be considered abnormal if the long 
axis is more than 1.5 cm, regardless of the short axis. If a 
lymph node has a long axis of 1.1 to 1.5 cm, it should only 
be considered abnormal if the short axis is more than 1 
cm.  Lymph nodes ≤ 1 x ≤ 1 cm will not be considered as 
abnormal for relapse or progressive disease. 
• 
At least a 50% increase from nadir in the SPD of any 
previously involved Target Lesions, or in a single 
involved node or extranodal mass, or the size of other 
lesions (e.g. splenic or hepatic nodules).      
• 
To be considered progressive disease, a lymph node 
or extranodal mass with a diameter of the long or short 
axis axis of ≤ 2.0 cm must have increased by at least 
0.5 cm; lesions larger than 2.0 cm must have increased 
by at least 1.0 cm. 
• 
In the setting of splenomegaly, the splenic length must 
increase by >50% of the extent of its prior increase 
from baseline. If no prior splenomegaly, must increase 
by at least 2.0cm from baseline. 
• 
New lesions: Regrowth of previously resolved lesions; 
or a new lymph node > 1.5cm in any axis; or a new 
extranodal site > 1.0 cm in any axis (new extranodal 
disease < 1.0 cm in any axis, can be considered 
progressive disease if its presence is unequivocal and 
attributable to lymphoma). 
• 
New or recurrent bone marrow involvement 
6.2.4.3 
Clinical Progressive Disease can be determined using the 
following criteria: 
• 
ECOG PS of at least 3 
• 
Patient unable to have follow-up radiologic Assessment 
due to performance status decline 
• 
Symptomatic decline deemed related to metastatic 
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6.3 
RANO Criteria for GBM Patients 
This trial will utilize the criteria recently proposed by the Response Assessment 
in Neuro-Oncology (RANO) working group (Wen, 2010). The RANO Criteria 
updates its established predecessor, the modified Macdonald Criteria, by adding 
assessment of non enhancing lesions. 
6.3.1 
Antitumor Effect – Definitions 
Evaluable for toxicity: All participants who receive at least one dose of 
study treatment will be evaluable for toxicity from the time of their first 
treatment. 
Evaluable for objective response: Only those participants who have 
measurable disease present at baseline of each treatment step and 
have received at least one dose of study treatment will be considered 
evaluable for response. These participants will have their response 
classified according to the definitions stated below.  
(NOTE: 
Participants who exhibit objective disease progression or 
die prior to the end of cycle 1 will also be considered 
evaluable.) 
Measurable disease: Bidimensionally, contrast-enhancing, 
measurable lesions with clearly defined margins by CT or MRI scan, 
with a minimal diameter of 1 cm, and visible on 2 axial slices which 
are at least 5 mm apart with 0 mm skip. Measurement of tumor 
around a cyst or surgical cavity, if necessary, requires a minimum 
thickness of 3 mm. If there are too many measurable lesions to 
measure at each evaluation, the investigator must choose the largest 
two to be followed before a participant is entered on study. The 
remaining lesions will be considered non-measureable for the purpose 
of objective response determination. Unless progression is observed, 
objective response can only be determined when all measurable and 
non-measurable lesions are assessed.  
Non measurable evaluable disease: Unidimensionally measurable 
lesions, masses with margins not clearly defined, lesions with 
maximal diameter < 1cm. 
6.3.2 
Response/Progression Categories 
NOTE: 
To be eligible, all patients must have measurable disease 
Complete response (CR). All of the following criteria must be met: 
a) Complete disappearance of all enhancing measurable and non-
measurable disease sustained for at least 4 weeks (for cycles of 
28 day length) or 3 weeks (for cycles of 21 day length). In the 
absence of a confirming scan 8-9 weeks later, this scan will be 
considered only stable disease. 
b) No new lesions. 
c) All measurable and non-measurable lesions must be assessed 
using the same techniques as baseline. 
d) Participants must be on no steroids or on physiologic replacement 
doses only. 
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e) Stable or improved non-enhancing (T2/FLAIR) lesions 
f) Stable or improved clinically, for clinical signs and symptoms 
present at baseline and recorded to be disease related 
Participants with any non-measurable disease cannot have a 
complete response. The best response possible is stable disease. 
Partial response (PR). All of the following criteria must be met: 
a) Greater than or equal to 50% decrease compared to baseline in 
the sum of products of perpendicular diameters of all measurable 
enhancing lesions sustained for at least 4 weeks. In the absence 
of a confirming scan 4 weeks later, this scan will be considered 
only stable disease. 
b) No progression of non-measurable disease. 
c) No new lesions. 
d) All measurable and non-measurable lesions must be assessed 
using the same techniques as baseline. 
e) The steroid dose at the time of the scan evaluation should be no 
greater than the dose at time of baseline scan. 
f) Stable or improved non-enhancing (T2/FLAIR) lesions on same or 
lower dose of corticosteroids compared to baseline scan. 
g) Stable or improved, for clinical signs and symptoms present at 
baseline and recorded to be disease related clinically. 
Participants with non-measurable disease cannot have a partial 
response. The best response possible is stable disease. 
Progressive disease (PD). The following criterion must be met: 
a) 25% increase in sum of the products of perpendicular diameters of 
enhancing lesions (over best response or baseline if no decrease) 
on stable or increasing doses of corticosteroids and/or one or 
more of the of the following:  
b) Significant increase in T2/FLAIR non-enhancing lesion on stable 
or increasing doses of corticosteroids steroids compared to 
baseline scan or best response following initiation of therapy, not 
due to co-morbid events (radiation therapy, demyelination, 
ischemic injury, infection, seizures, post-operative changes, or 
other treatment effects). 
c) Any new lesion 
d) Clear clinical deterioration not attributable to other causes apart 
from the tumor (e.g. seizures, medication side effects, 
complications of therapy, cerebrovascular events, infection, etc.). 
The definition of clinical deterioration is left to the discretion of the 
investigator but it is recommended that a decline in the Karnofsky 
Performance Score (KPS) from 100 or 90 to 70 or less, a decline 
in KPS of at least 20 from 80 or less, or a decline in KPS from any 
baseline to 50 or less, for at least 7 days, be considered 
neurologic deterioration, unless attributable to co-morbid events or 
changes in corticosteroid dose. 

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e) Failure to return for evaluation due to death or deteriorating 
condition 
Stable disease (SD). All of the following criteria must be met: 
a) Does not qualify for CR, PR, or progression. 
b) All measurable and non-measurable sites must be assessed using 
the same techniques as baseline. 
c) Stable non-enhancing (T2/FLAIR) lesions on same or lower dose 
of corticosteroids compared to baseline scan. In the event that the 
corticosteroid dose has been increased, the last scan considered 
to show stable disease will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose. 
d) Stable clinically. 
These RANO Response Criteria are also summarized in the following 
table: 
 
6.3.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, 
using a ruler, calipers, or digital measurement tool. All baseline 
evaluations should be performed as closely as possible to the 
beginning of each treatment step and never more than 14 days before 
the beginning of the treatment. 
The same method of assessment and the same technique should be 
used to characterize each identified and reported lesion at baseline 
and during follow-up. 
6.3.4 
Evaluation of Best Response 
The best overall response is the best response recorded from the 
baseline of each treatment step until disease progression (taking as 
reference for progressive disease the smallest measurements 
recorded since the treatment started). If a response recorded at one 
scheduled MRI does not persist at the next regular scheduled MRI, 
the response will still be recorded based on the prior scan, but will be 
designated as a non-sustained response. If the response is sustained, 
i.e. still present on the subsequent MRI, it will be recorded as a 
sustained response, lasting until the time of tumor progression. 

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Participants without measurable disease may only achieve SD or PD 
as their best “response.  
6.4 
Response criteria for multiple myeloma 
6.4.1 
Terms and definitions 
• 
M-protein: synonyms include M-spike, monoclonal protein and 
myeloma protein, paraprotein, M-component. Serum M-protein 
level is quantitated using densitometry on SPEP except in cases 
where the SPEP is felt to be unreliable, such as: 
• 
M-proteins migrating in the β-region (usually IgA M-proteins) 
• 
Cases in which the M-spike is so large and narrow on agarose 
(some specimens >4 g/dL) that they underestimate the actual 
immunoglobulin level (by greater than 1500 mg/dL) due to 
technical staining properties of the agarose gel 
• 
Cases in which there are multiple peaks of same monoclonal 
protein (aggregates or dimers) 
If SPEP is not available or felt to be unreliable (above examples) 
for routine M-protein quantitation, then quantitative 
immunoglobulin levels derived from nephelometry or turbidometry 
can be accepted. However, this must be explicitly reported at 
baseline, and only nephelometry can be used for that patient to 
assess response. SPEP derived M-spike values and quantitative 
nephelometric immunoglobulin values cannot be used 
interchangeably. 
Urine M-protein measurement is estimated using 24-hr UPEP 
only. Random or 24 hr urine tests measuring kappa and lambda 
light chain levels are not reliable and are not recommended. 
• 
FLC estimation is currently carried out using the serum FLC 
assay (Freelite, The Binding Site Limited, UK). Patients with 
kappa/lambda FLC ratio < 0.26 are defined as having monoclonal 
lambda FLC and those with ratios >1.65 as having a monoclonal 
kappa FLC. The monoclonal light chain isotype is considered the 
involved FLC isotype, and the opposite light chain type as the 
uninvolved FLC type. 
• 
Imaging studies for plasmacytoma: For patients with 
plasmacytoma alone (and no measurable serum or urine M 
protein or serum free light chain) who are followed by imaging 
studies, the same imaging modality should be used for follow up 
assessment. For patients who are not being followed by 
plasmacytoma(s), serial imaging is not required. 
• 
Response terms: The following response terms will be used to 
define M protein response: stringent Complete Response (sCR), 
complete response (CR), very good partial response (VGPR), 
partial response (PR), Minimal Response (MR), stable disease 
(SD), and progressive disease (PD). 
• 
Measurable disease: Patients who have a measurable serum or 
urine M-protein. 
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• 
Serum M-protein ≥ 1 g/dl 
• 
Urine M-protein ≥ 200 mg/24 h 
• 
Serum FLC assay: Involved FLC level ≥10 mg/dl provided 
serum FLC ratio is abnormal 
• 
For patients with only plasmacytoma, at least one lesion that 
has a single diameter of ≥ 2 cm 
The serum free light chain (FLC) assay is of particular use in 
monitoring response to therapy in patients who have oligo-
secretory or non-secretory disease and should be used in 
assessing response only if the baseline serum and/or urine M 
proteins are not “measurable” as above, and the baseline 
level of the involved FLC is “measurable.” When using this 
assay, it is important to note that the FLC levels vary considerably 
with changes in renal function and in patients with renal 
insufficiency, the levels of both the kappa and lambda may remain 
elevated, but the ratio normalizes with achievement of CR. Thus, 
both the level of the involved and the uninvolved FLC isotype (i.e., 
the involved/uninvolved ratio or involved-uninvolved difference) 
should be considered in assessing response. Patients included 
on the study on the basis of FLC alone (i.e., no measurable 
serum/urine m-spike) should be the only ones who are 
evaluated using FLC response criteria. The others should 
follow usual criteria and ignore FLC results with the exception 
of defining stringent complete response. 
6.4.2 
Clarification of test indications: Listed below are the minimal 
required tests required to assess response based on the 
characteristics of their disease at on study. 
Table 6.1 
Tests Required To Assess M protein Response (Must Be Done At Each Disease 
Measurement Visit except as indicated1,2) 
On Study Baseline Value 
SPEP 
24 hr 
UPEP 
Ig FLC 
BM Bx1,2 
Serum M-spike ≥ 1 g/dl, and urine M-
spike ≥ 200 mg/24 hrs 
X 
X 
 
 
Serum M-spike ≥1 g/dl, but urine M-
spike < 200 mg/24 hrs 
X 
 
 
 
Serum M-spike < 1 g/dl, and urine M-
spike ≥ 200 mg/24 hrs 
 
X 
 
 
Serum M-spike < 1 g/dl, urine M-spike  
< 200 mg/24 hrs, but involved Ig FLC is 
≥ 10 mg/dL 
 
 
X 
 
1  Immunofixation studies of both serum and urine are required to document CR 
regardless of registration values, and in addition FLC measurement and bone marrow 
immunophenotyping is required to document sCR. SPEP and UPEP are required to 
document VGPR regardless of registration values. 

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2  Bone marrow biopsy results do not need to be confirmed (i.e. repeated after 
documented response). 
6.4.3 
Confirmed response 
In order to be classified as an M protein response, confirmation of 
serum monoclonal protein, serum immunoglobulin free light chain 
(when primary determinant of response) and urine monoclonal protein 
(when primary determinant of response) results must be made by 
verification on two consecutive determinations. Bone marrow aspirate 
and biopsy are only required to document CR or sCR, except for 
patients with evaluable disease only, where a bone marrow is 
required to document all response categories including progression. 
However, a second confirmatory bone marrow is not required to 
confirm response in any case. Radiographic studies are not required 
to satisfy these response requirements; however, if radiographic 
studies were performed there should be no evidence of progressive or 
new bone lesions. 
Appropriate tests required to document and confirm response are 
listed in Table 6.1. 
6.4.4 
Bone progression 
Caution must be exercised to avoid rating progression or relapse on 
the basis of variation of radiologic technique alone. Compression 
fracture does not exclude continued response and may not indicate 
progression. When progression is based on skeletal disease alone, it 
should be discussed with the Study Chair before removing the patient 
from the study. 
6.4.5 
Response and Progression 
Criteria for response and progression are listed in Table 6.2. 
Progressive disease for all patients as defined in Table 6.2. Although 
the definition for “relapse from CR (or sCR) is listed, this will be 
documented as a response category in ONLY those protocols 
evaluating disease free survival. 
Table 6.2 
CATEGORY 
RESPONSE CRITERIA a 
Stringent 
complete 
response (sCR)e 
• CR as defined below plus all of the following: 
• Normal serum FLC ratio  
• Absence of clonal cells in bone marrow by immunohistochemistry or 
immunofluorescence b 
• Not applicable for those patients who do not have a “measurable  serum M-
spike, serum free light chain, or urine M-spike at baseline 
Complete 
response (CR) 
• Negative immunofixation of the serum and urine  
• <5% plasma cells in bone marrow  
• If at on study, the only measurable non-bone marrow parameter was FLC, 
normalization of FLC ratio 
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Table 6.2 
CATEGORY 
RESPONSE CRITERIA a 
Very good partial 
response (VGPR)e 
• PR as defined below plus all of the following: 
• Serum and urine M-component detectable by immunofixation but not on 
electrophoresis or 
• If at on study, serum measurable, ≥ 90% or greater reduction in serum M-
component plus urine M-component < 100 mg per 24 hr  
• If at on study, the only measurable non-bone marrow parameter was FLC, 
≥90% or greater reduction in the difference between involved and uninvolved 
free light chain levels 
• Not applicable for those patients who do not have a “measurable  serum M-
spike, serum free light chain, or urine M-spike at baseline 
Partial Response 
(PR) 
• 
One of the following: 
• If at on study, serum and urine measurable, a ≥ 50% reduction of serum M-
protein and reduction in 24-h urinary M-protein by ≥ 90% or to < 200 mg per 
24 hr 
• If at on study, only serum measurable (but urine not), a ≥ 50% reduction of 
serum M-protein  
• If at on study, urine measurable (but serum not), a reduction in 24-h urinary 
M-protein by ≥ 90% or to < 200 mg per 24 hr 
• If at on study, the only measurable parameter was FLC, a ≥ 50% decrease 
in the difference between involved and uninvolved FLC levels  
• If plasmacytoma was present at baseline, a ≥ 50% reduction in the size 
(SPD = sum of the products of the maximal perpendicular diameters of 
measured lesions) of soft tissue plasmacytomas is also required. 
Stable disease 
(SD) 
Not meeting criteria for sCR, CR, VGPR, PR, or progressive disease 
Progressive 
disease (PD) d 
Any one or more of the following:  
• Increase of 25% from lowest value in f 
• Serum M-component (absolute increase must be ≥ 0.5 g/dl)c  
• Serum M-component increase ≥ 1 g/dl, if lowest M component was ≥ 5 g/dl 
• Urine M-component (absolute increase must be ≥ 200 mg/24 h) 
• If at on study, the only measurable parameter was FLC, the difference 
between involved and uninvolved FLC levels (absolute increase must be 
>10 mg/dl) c  
• Bone marrow plasma cell percentage (absolute % must be ≥10%)c 
• Appearance of a new lesion(s), ≥ 50% increase from nadir in SPD of >1 
lesion, or ≥50% increase in the longest diameter of a previous lesion >1 cm 
in short axis 
Or any one or more of the following felt related to the underlying clonal plasma cell 
proliferative disorder 
• 
Hypercalcemia (≥11.5 mg/dl) if considered related to myeloma 
• 
Decrease in hemoglobin of ≥2 g/dl if considered related to myeloma 
• 
Serum creatinine level ≥2 mg/dl if considered related to myeloma 
a All response categories require two consecutive assessments made at anytime before the institution of 
any new therapy; sCR, CR, VGPR, PR, MR and SD categories also require no known evidence of 

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progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not 
required to satisfy these response requirements. Bone marrow assessments need not be confirmed. 
Each category, except for stable disease, will have a working subcategory of “unconfirmed  [prefix ‘u ] 
to designate first time point at which response category MAY have been achieved if confirmed. 
b Presence/absence of clonal cells is based upon the k/  ratio. An abnormal k/  ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for 
analysis. An abnormal ratio reflecting presence of an abnormal clone is k/  of >4:1 or <1;2. 
c Positive immunofixation alone in a patient previously classified as CR will not be considered 
progression. 
d Progressive disease should be confirmed. However, treatment may be discontinued for progressive 
disease that is unconfirmed per physician discretion. In this case, an objective status of PD should be 
entered on the measurement form and progressive disease should be reported on the event monitoring 
form. 
e Does not apply to EMD or PCL 
f In the case where a value is felt to be a spurious result per physician discretion (for example, a possible 
lab error), that value will not be considered when determining the lowest value. 
 
CR 
VGPR 
PR 
MR 
SD 
PD 
SPEP 
Absent M 
spike 
90% 
decrease 
>=50% 
decrease 
>=25% 
decrease 
< 50% 
decrease 
>=25% 
increase 
Serum IFE 
Negative 
Positive 
Positive 
Positive 
Positive 
Positive 
UPEP1 
Absent M 
spike 
< 100 mg 
<200 mg 
or >=90% 
decrease 
>=50% 
decrease 
< 50% 
decrease 
>=25% 
increase 
Urine IFE 
Negative 
Positive 
Positive 
Positive 
Positive 
Positive 
Serum FLC (only if 
serum and urine are 
not measurable) 
Normal 
ratio2 
>=90% 
decrease 
in dFLC3 
>=50% 
decrease 
in dFLC 
NA 
< 50% 
decrease 
>=25% 
increase 
Bone marrow (only for 
CR) 
< 5% PC 
NA 
NA 
NA 
NA 
NA 
1 Refers to 24-hour urine 
2 Normal FLC ratio is needed for a CR only in those patients with FLC as the measurable disease. 
3 dFLC is the absolute difference between the kappa and lambda light chains. 
6.5 
Duration of Response 
This is measured from the documented beginning of response (CR or PR) to the 
time of relapse. This is measured in responders.  
6.6 
Overall Survival 
Overall survival (OS) is evaluated specifically for each drug (or step). Specifically, 
OS is defined as the time from start of treatment that step until death, or 
censored at the date of last contact. 
6.7 
Progression-Free Survival 
Progression-free Survival (PFS) is defined as the time from start of treatment on 
that step until determination of disease progression or death from any cause, 
censored at the date of last disease assessment for patients who have not 
progressed (regardless of whether non-protocol therapy has been given). In the 
case of initiation of alternative therapy prior to disease progression, the following 
Rev. 12/16 
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sensitivity analyses will be performed: 1) censoring follow-up at start of 
alternative therapy; 2) counting treatment switches as events. 
6.8 
Time to Progression 
Time to progression (TTP) is defined as the time from start of treatment on that 
step until determination of disease progression or death due to disease, 
censored at the date of last disease assessment for patients who have not 
progressed. TTP is not as useful as PFS unless the majority of deaths on a study 
are unrelated to the malignancy due to the efficacy of the treatment and/or 
prolonged follow-up. 
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7. 
Study Parameters 
7.1 
Step 0, 2, 4 and 6 Parameters (Registration to Screening Steps) 
NOTE: 
Refer to the Study Schema for information on screening steps. 
1. On treatment Study Parameters will be detailed in the agent-specific subprotocol. 
2. Prestudy scans (CT, MRI, and PET) and x-rays used to assess all measurable or non-measurable sites of disease 
must be done within 3 months prior to registration to Step 0, 2, 4, 6. 
NOTE: 
For patients who register to treatment steps (Step 1, 3, 5, 7), scans must be done within 6 weeks prior to 
registration to treatment. 
NOTE: 
Patients with glioblastoma multiforme are required to have baseline imaging performed within 2 weeks of 
the start of treatment. 
NOTE: 
For patients with myeloma who register to treatment steps (Step 1, 3, 5, 7), labs must be performed 
within 2 weeks prior to registration to treatment. 
3. Vital signs, physical exams and all required prestudy tests, with the exception of the electrocardiogram (ECG) and 
as outlined in Section 3, should be done ≤ 2 weeks prior to registration to Step 0, 2, 4, 6 – unless specifically 
required on Day 1 as per protocol. 
Test/Assessment 
Prior to Registration to 
Steps 0, 2, 4 and 6 
During Step  
0, 2, 4, 6 
During Step  
1, 3, 5, 7 
Step 87 
Tumor biopsy for genetic analysis2 
 
X6 
 
X5 
H&P, weight, vital signs 
X 
 
 
 
Performance status 
X 
 
 
 
CBC w/diff, plts 
X 
 
 
 
Serum chemistry1 
X 
 
 
 
EKG  
X 
 
 
 
Radiologic evaluation4 
X 
 
 
 
-HCG3 
X 
 
 
 
Serum Protein electrophoresis (myeloma only) 
X 
 
 
 
24 hour urine protein electrophoresis (myeloma only) 
X 
 
 
 
Serum Free light chain assay (sFLC) (myeloma only) 
X 
 
 
 
Rev. 8/15 
Rev. 2/16 
Rev. 2/16 
Rev. 12/16 
Rev. 3/17 
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Test/Assessment 
Prior to Registration to 
Steps 0, 2, 4 and 6 
During Step  
0, 2, 4, 6 
During Step  
1, 3, 5, 7 
Step 87 
Quantitative immunoglobulins (myeloma only) 
X 
 
 
 
Blood Sample (EDTA and Streck vacutainers) 
 
X5 
X5 
X5 
1. Albumin, alkaline phosphatase, total bilirubin (if total bilirubin is elevated, direct bilirubin should be done), bicarbonate, BUN, calcium, 
creatinine, glucose, LDH, phosphorus, potassium, SGOT[AST], SGPT[ALT], sodium, magnesium. For eligibility purposes, participants with 
creatinine levels above institutional normal, Cockcroft-Gault will be used to calculate creatinine clearance. 
2. See Sections 7.2, 9 and 10. Pre-registration screening is MANDATORY. All specimen submissions must be logged into the ECOG-ACRIN 
Sample Tracking System (STS). See Section 7.2 and Section Error! Reference source not found.. 
a. FFPE from patients who qualify for “rare variant  arms, unless requested for additional central assessments prior to treatment assignment, 
is to be sent within 8 weeks following registration to Step 1 treatment as described in Sections 4.1.5.4, 7.2 and Error! Reference source 
not found.. If tissue is not available for confirmation testing, the CBPF must be notified and the pathology and CLIA reports are still 
required to be submitted. 
b. For patients with treatment assignment determined by the MATCH assay (i.e. original screening process; not via outside assay results), 
submission of tumor tissue is mandatory for all Step 0 patients, collected via tumor biopsy or bone marrow aspiration/biopsy (multiple 
myeloma, if applicable) during Step 0 OR FFPE tumor tissue available for analysis following a clinically indicated diagnostic or therapeutic 
procedure as described in Section 9. This is no longer applicable for new patients, since the original screening process has closed. 
c. For patients previously assigned to a study treatment via the MATCH assay, a second screening biopsy may be required either at Step 2 
or Step 4 for consideration of additional MATCH study treatments, as applicable per protocol. 
3. Blood pregnancy test (women of childbearing potential only) should be done within 2 weeks prior to registration to Step 0, 2, 4, 6. 
4. For treatments given in 21 day (3 week) cycles: every 3 cycles (9 weeks) for the first two years, and every 4 cycles thereafter (12 weeks); for 
treatments given in 28 day (4 week) cycles: every 2 cycles (8 weeks) for the first two years, and every three cycles thereafter (12 weeks); for 
treatments given in 42 day (6 week) cycles: every 2 cycles (12 weeks).  
5. OPTIONAL (but strongly encouraged for all patients, including patients entering a “rare variant  arm with outside assays). See Sections 7.2 
and 9. Submit from patients who have provided signed and dated, written informed consent form for the collection and submission of the 
specimens for research. Blood samples are collected and submitted with the biopsies (1 EDTA and 2 Streck tubes) AND either after the first 2 
cycles of each MATCH treatment (2 Streck tubes only) or the end of each MATCH treatment (2 Streck tubes only), whichever comes first.  End 
of treatment biopsy tissue and blood (Step 8) are provided from patients who meet the criteria specified in Section 3.9. Archived FFPE 
materials are also requested. 
6. Imaging from the performance of the biopsy are to be submitted as outlined in Section 11. Include image before needle placement, image with 
FNA or trocar needle in lesion, image with core biopsy or trocar needle in lesion, biopsy report describing target lesion location (organ, 
laterality or segment if applicable and image number on pre-biopsy imaging if available) and size. 
7. Registration to Step 8 and the submission of end of treatment blood and tumor tissue require additional consent for the collection and 
submission of these samples.  Blood specimens are required to be submitted from all patients registered to Step 8. Tumor specimens 
collected from SOC procedures of via optional biopsy are to be submitted. Biopsies to collect tumor tissue for research purposes must be 
minimal or less than minimal risk. 
Rev. 2/16 
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Rev. 3/17 
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7.2 
Biospecimen Submissions 
Failure to update Sample Tracking System (STS) appropriately may result in delays in the central assessments 
and reporting results to the site. See Section 9 for specific instructions regarding the collection and submission of 
specimens. 
The pathology and related available reports, including reports associated with general histological and 
sequencing, are to be submitted with every submission of tissue: 
• 
Reports associated with submitted tissue, 
• 
Original diagnostic reports, 
• 
The pathology reports associated with the tissue analyzed by the designated Outside Laboratory 
Pathology reports submitted with tissue specimens should NOT be redacted. Results from screening and 
confirmation MATCH-assay testing are returned to the site and may impact patient care. Adequate identification 
must be provided to ensure that the appropriate materials have been submitted and reporting is correct. 
Snapshot user’s guide for STS is provided in Section Error! Reference source not found.. Most information, if entered 
incorrectly, may be corrected by the site. To correct mistakes for sample type or timepoint, contact the ECOG-ACRIN 
Lab Team (ecog.tst@jimmy.havard.edu or 857-504-2900). Please do not delete samples and re-log to correct these 
errors, especially after samples have already been shipped. 
7.2.1 
Overall Summary of Options for Sample Submissions for Screening as of May 15, 2017: 
Step 
Disease 
Options for 
submissions 
Biopsy 1 
Biopsy Repeat 
Step 0 
“Rare Variant  report 
per Outside Laboratory 
Timepoint: “Confirmation of Pre-Registration Outside Results  
Submit: Pre-Trial FFPE3 
Screening 22 
(Step 2 or 4) 
MATCH assay screens 
 
Fresh Biopsy1 
Fresh biopsy (#2)1 
Step 8 
All 
 
Blood Specimens 
Fresh Biopsy1, if 
performed 
 
1. MULTIPLE MYELOMA REQUIRING FRESH BONE MARROW ASPIRATE ONLY: For all screenings and end of 
treatment, use 1 drop to make 4 – 5 smears, put 1 – 1.5 ml in one EDTA tube, and put remainder (5 - 10 ml) of bone 
marrow aspirate in the other EDTA tube. SUBMIT ASPIRATES FROM THE FIRST PULL OF AN ASPIRATION 
SITE FOR TESTING. The submitted smears should also be made from the same aspirate. 
2. Open only to patients assigned and accrued to Step 1 treatment based on the original MATCH-assay screening 
process. Patients assigned to treatment based on a referral from a designated laboratory (see Section 3.1.6 and 
Appendix XIV) are eligible for only one treatment on MATCH and are not to undergo a biopsy to collect material for 
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2. NOT APPLICABLE TO MYELOMA PATIENTS WITH ASPIRATE SUBMITTED FOR SCREENING. 
3. MULTIPLE MYELOMA REQUIRING FRESH BONE MARROW ASPIRATE ONLY. SUBMIT ASPIRATES FROM THE FIRST PULL OF AN 
ASPIRATION SITE FOR SCREENING. 
4. For Step 8, submission of blood specimens are mandatory. Biopsy for collection of the research fresh tumor specimens (or bone marrow from 
myeloma patients) is to be performed only if patient is amenable and biopsy is minimal risk or less OR if the procedure performed is standard of 
care.  If the fresh biopsy will not be submitted, indicate “Can’t Submit  in STS and provide the reason why. 
5. Collect blood end of Cycle 2 (prior to Cycle 3 treatment) or at end/discontinuation of MATCH treatment, whichever is earlier. Please refer to 
Section Error! Reference source not found.. 

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7.2.3 
Sample Tracking System (STS) Timepoint Summary: 
Timepoint 
Sample Submission Purpose 
Pre-trial Diagnostic Material 
Tissue from procedures performed prior to Step 0 registration which are submitted for 
research studies from patients who, on EAY131 Master Protocol Consent Form, answered 
“Yes  to “I agree to provide additional specimens for research  
Confirmation of Pre-Registration 
Outside Results 
MANDATORY: Archived formalin fixed tumor tissue (FFPE) submitted from patients 
assigned and subsequently registered to Step 1 treatment based on a referral from a 
designated outside laboratory (“rare variant  results).  
Sample is submitted AFTER registration to Step 1 treatment unless it is requested to be 
submitted for MANDATORY CENTRAL IHC for determination of treatment assignment. 
Step 0, Screening 1, Biopsy 1 
Accrual CLOSED May 22, 2017– Original MATCH-assay screening patients  
Step 0, Screening 1, Biopsy 
Repeat 
Accrual CLOSED May 22, 2017– Original MATCH-assay screening patients 
Screening 2, Biopsy 1 
NOT OPEN TO PATIENTS REFERRED BY A DESIGNATED OUTSIDE LABORATORY 
• 
Patients assigned and registered to treatment based original MATCH-assay screening  
• 
Patients registered to Step 2 or Step 4 
• 
Specimens obtained from a fresh biopsy and submitted for screening. 
• 
Peripheral blood collected for research per patient consent 
Screening 2, Biopsy Repeat 
NOT OPEN TO PATIENTS REFERRED BY A DESIGNATED OUTSIDE LABORATORY 
• 
Patients assigned and registered to treatment based original MATCH-assay screening  
• 
Patients registered to Step 2 or Step 4 
• 
Specimens obtained and submitted for screening after failure of “Screening 2, Biopsy 
1  assessment. 
Step 1, End of Cycle 2 
Step 3, End of Cycle 2 
Step 5, End of Cycle 2 
Step 7, End of Cycle 2 
Peripheral blood samples collected for research per patient consent at End of Cycle 2 (prior 
to start of Cycle 3 treatment) or upon discontinuation of treatment, whichever comes first.   
Progression (Step 8) 
Sample submissions for research from patients who signed the “Consent for additional 
sample collection for research studies” AND registered to Step 8.  Submission of 
peripheral blood (required) and fresh biopsy (from standard of care procedure OR if patient 
willing to undergo a “minimal risk  biopsy). 
 
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8. 
Statistical Considerations 
This is a multi-arm molecular profile-driven non-randomized phase II trial. Consenting 
patients who are eligible for the screening will have their tumors molecularly 
characterized and treatment will be directed by the tumor’s molecular feature profile.  All 
patients in a particular molecularly-defined subgroup will receive the treatment matched 
to that tumor alteration. Molecular characteristics to be assessed for each tumor include 
SNVs, indels, CNVs, translocations, and IHC-based markers, which will be quantified 
and recorded as described in Section 5.1. In cases for which more than one molecular 
abnormality is identified in the tumor, treatment assignment will be prioritized by the 
rules specified in Section 1.6. As many as 6452 patients will be screened and additional 
patients with outside assays sufficient to accrue approximately 35 patients (31 eligible, 
treated) in each biomarker-defined subgroup. 
The primary endpoint is objective response rate (ORR), defined as a complete or partial 
response, which is defined consistent with RECIST version 1.1 criteria for solid tumors, 
the Cheson (2014) criteria for lymphoma patients, the criteria listed in Section 6.4 for 
multiple myeloma and the RANO criteria for GBM patients (See Section 6). After 
completing participation in a given treatment subprotocol, patients may enroll on 
additional sub-studies if they have another actionable mutation and meet the eligibility 
requirements. Such patients will be counted toward the accrual, and their data will be 
included in the primary analysis, for any sub-studies in which they participated and were 
confirmed eligible. Patients who are determined to be ineligible for a subprotocol on 
which they are enrolled, or who do not start treatment on that subprotocol, will be 
excluded from the primary analysis for the subprotocol.  The OR rate will be compared 
against a null benchmark value of 5%. If the observed objective response rate is ≥ 5/31 
(16%), it will then be concluded that the agent is promising and worthy of further testing. 
Allowing for 10% ineligibility rate, 35 patients will need to be accrued to each treatment 
subprotocol in order to obtain 31 eligible patients for each arm. 
The proposed design has the following operating characteristics: 
Power is 91.8% to conclude an agent is promising if its true OR rate is 0.25; 
Type 1 error rate (one-sided) is 1.8% (this is the probability to conclude that a given 
agent is promising if its true OR rate is 0.05). 
If accrual to an arm is allowed to continue beyond 35 patients (see below) and more 
than 31 eligible, treated patients are available for analysis, the overall test of whether the 
response rate is > 5% will be conducted at the same type I error (1.8%). 
8.1 
Accrual 
The target screening accrual for this study is approximately 6452 patients, with 
the goal of obtaining samples for analysis for ~6000 patients and accruing 35 
patients in each treatment subprotocol.  Assuming approximately 5000 patients 
will be screened per year, the following table gives the number of patients that 
needed to have samples submitted and the approximate accrual duration 
needed, for a given subprotocol with alteration rate p: 
p 
# of patients with samples 
submitted 
Time (yr) 
0.86% 
5994 
1.29 
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p 
# of patients with samples 
submitted 
Time (yr) 
2% 
2578 
0.55 
5% 
1032 
0.22 
10% 
516 
0.115 
If after screening 500 patients, the total number of patients with actionable tumor 
alteration (therefore qualifying for treatment) is below 50 (overall actionable 
alteration rate of 10%), results will be presented to the steering committee for 
consideration of terminating the trial. Within any given subprotocol, if rate of 
enrollment is such that it is unlikely accrual can reach 25 patients by the time the 
overall study closes, and if 13 patients have been treated and no responses have 
been observed, then the steering committee may consider terminating accrual in 
that subgroup due to lack of feasibility. This rule is based on the fact that the 
exact binomial upper 97.5% confidence limit on the response rate will then be 
less than 25%. The eligibility rate will continue to be monitored periodically and 
presented to the steering committee for additional consideration if it remains 
below 15% once at least 22 arms are activated. 
If 35 patients have been enrolled on an arm and a replacement arm for the target 
is not ready for activation, and if the pharmaceutical collaborator agrees to 
support the expansion according to the terms of its agreement with CTEP, then 
accrual can continue until either the response data are available on the first 31 
eligible patients or for 6 additional months, whichever comes first, at which time 
accrual to the arm will be suspended. Also, based on the amounts of drug 
supplies that are currently approved by the pharmaceutical collaborators, accrual 
to any expansion cohort will not exceed 35 patients (up to a total of 70 patients). 
The arm will remain suspended until the response analysis of the first 31 eligible 
patients has been performed. The results will then be discussed with CTEP, and 
CTEP approval will be required for any further accrual to that arm to occur. 
Enrollment past 35 patients will take into account disease histology.  There will 
be no restriction on the number of patients with any eligible histology during the 
first 35 patients, but additional accrual beyond 35 will only be allowed for cancer 
types with less than 10 patients enrolled. During the additional accrual, once 10 
patients with a particular cancer type have been enrolled on the arm, that cancer 
type will be excluded from future enrollment on that arm. Because of the time lag 
between assignment to an arm and enrollment on the arm, patients who have 
already been assigned to the arm at the time the 10th patient with a particular 
cancer type is enrolled would still be allowed to enroll on the arm. 
As stated above, several MATCH subprotocols have as eligibility criteria 
molecular variants that are so rare that we do not expect to recruit 31 eligible 
patients even after sequencing 6000 patient tumors.  NCI-MATCH has entered 
into collaboration with certain CLIA certified laboratories that screen over 6000 
patients per year, such that the laboratories will notify clinical sites when a patient 
appears to be eligible for a subprotocol in MATCH that concerns “rare variants.   
We will attempt to confirm the molecular eligibility with archived tumor tissue from 
patients who were entered into a subprotocol of MATCH with results from an 
“outside  assay.  Eligible and treated patients who are entered based on the 
MATCH assay or who are entered based on outside assays and whose 
molecular abnormalities are confirmed by the MATCH assays will be included in 
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the primary analyses. As secondary analyses, outcome may also be reported by 
combining all patients, or separately for those patients with results from outside 
assays that were not confirmed by the MATCH assay. All treated patients will be 
evaluable for toxicity assessment. Patients enrolled based on outside assay 
results do not count towards the ~6452 screening accrual goal, and accrual from 
this cohort will be tracked separately. Patients enrolled on treatment arms based 
on outside assays whose molecular abnormalities are confirmed by the MATCH 
assay will count towards the accrual goals for the treatment arms. 
After Step 0 registration, the “MATCH screening assessment  will differ 
depending on the method of study entry. For patients that previously entered the 
study via the original screening process (i.e. to submit tissue for testing by a 
MATCH laboratory), this assessment will consist of both molecular profiling by 
the MATCH assay and the subsequent process of assigning treatment. Please 
note, after 5/22/17, new patients may no longer be enrolled on the study through 
this process. For patients entering the study through testing performed by one of 
the designated labs outside of the MATCH laboratory group (i.e. the Outside 
Assay process; see Appendix XIV), the assessment will only consist of the 
study's determination of treatment assignment. This is the only method of study 
entry moving forward. 
8.2 
Interim Monitoring 
An analysis of the distributions of actionable alterations and of tumor types, both 
overall and within treatment subprotocols, will be performed after 1000 additional 
patients have completed screening following the reactivation of the study in May 
2016, and the steering committee will be consulted regarding whether 
modifications, such as restrictions on tumor types, might be needed. Accrual will 
not be suspended for the additional interim analyses. For publication purposes, 
updated results may be reported. 
Given a number of unknown aspects about this study (e.g., prevalence of specific 
alterations), after 500 patients are screened the design will be reassessed to 
assure its appropriateness. An analysis of the distributions of actionable 
alterations and of tumor types, both overall and within treatment subprotocols, 
will continue to be performed after 1000 and 2000 additional patients have 
completed screening following the reactivation of the study in May 2016, and the 
steering committee will be consulted regarding whether modifications, such as 
restrictions on tumor types, might be needed. Accrual will not be suspended for 
these additional interim analyses. 
Patients who participate in multiple treatment sub-studies will be counted towards 
the accrual of each subprotocol in which they enroll, and they will be included in 
the primary analysis for each of those sub-studies. However, the proportion of 
patients who participate in multiple sub-studies will be monitored.  If a situation 
occurs where this proportion becomes too high (>25%), then a discussion with 
CTEP will take place to determine whether the study should be amended to 
reduce repeat participation. 
8.3 
Safety Monitoring 
Safety monitoring is the responsibility of the MATCH Steering Committee, the 
MATCH subprotocol study chairs, the study statisticians, and the study Safety 
Co-Chairs and toxicity monitors.  Adverse events are reported in a routine 
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manner at scheduled times using Medidata Rave. In addition, expedited reporting 
of certain adverse events through the CTEP-AERS mechanism is required, as 
described in each treatment-specific subprotocol document.  The ECOG-ACRIN 
data managers monitor the routine and expedited data to ensure that all required 
AEs have had expedited reports submitted.   
8.3.1 
MATCH Steering Committee 
The MATCH Steering Committee will meet regularly. At least one 
safety chair will be required to participate in each meeting and 
adverse events across all subprotocols will be routinely monitored. 
8.3.2 
Semiannual Reports 
Comprehensive analyses of interim toxicity data are routinely 
performed at least twice yearly. Reports of these analyses will be 
reviewed by the Steering Committee and the Chairs of the 
subprotocols.  These reports are also sent to the ECOG-ACRIN 
Principal Investigator or Senior Investigator at the participating 
institutions.  
8.3.3 
Monthly Toxicity Monitoring 
The study’s Safety Co-Chair(s) or designees will serve as toxicity 
monitors for this aspect of the study. As is true for all ECOG-ACRIN 
studies, adverse events reported through the CTEP-AERS 
mechanism for a subprotocol will be reviewed by the chair(s) of the 
subprotocol, the toxicity monitor and statistician in order to identify 
untoward or severe toxicities. In a given month, if the following trigger 
occurs, a report will be sent to the toxicity monitor, chair of the 
subprotocol and the statistician, asking them to review the events and 
determine if a more in-depth review is necessary. 
• 
one or more CTEP-AERS reports containing grade 3 or higher 
adverse events in the previous month. 
If any of the reviewers feel that further review is necessary, the 
reports are distributed and then discussed on a conference call with 
the Steering Committee.  If the reviewers feel it necessary, the 
subprotocol can then be amended or suspended. In the event of a 
very serious situation, one of the ECOG-ACRIN Co-Chairs can 
suspend the study prior to the detailed review. 
8.4 
Endpoints/Analysis Plan 
Primary analyses will be based on the group of eligible and treated patients 
excluding those who were entered into a subprotocol of MATCH with results from 
an “outside  assay that could not be confirmed by the MATCH assays or a 
validated orthogonal assay. For each treatment subprotocol, 90% two-sided 
confidence intervals will be calculated for the following two endpoints: OR rate 
(the primary endpoint, defined earlier in Section 8); proportion of patients alive 
and progression free at 6 months from start of treatment on that treatment step. 
For arms that enroll less than 31 eligible, treated patients, overall activity will be 
assessed using 5% one-sided exact binomial tests of the null hypothesis that the 
OR is ≤ 5%, regardless of the total number enrolled. 
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Descriptive statistics will be reported for the subgroup of patients who entered 
into a subprotocol of MATCH with results from an “outside  assay that could not 
be confirmed by the MATCH assay or a validated orthogonal assay. Secondary 
analyses combining these cases with the primary analysis set may also be 
reported. 
Given the potential heterogeneity of cancer types within each treatment 
subprotocol, separate exploratory analysis may be performed within other 
specific tumor types to evaluate whether certain tumor types might be worthy of 
further evaluation of the targeted therapy. There will be no automatic intention to 
pursue such promising restricted tumor subsets as part of this study.  These 
signals may be followed up in separate phase II studies, and would only be 
included within the MATCH study if an amendment was submitted and it was 
reviewed and approved by CTEP and CIRB. 
For each subprotocol, survival outcomes (OS, PFS, TTP, as defined in Sections 
6.6 - 6.8) will be estimated using the Kaplan-Meier method. Analysis population 
for survival outcomes will be defined as the population of patients who are 
eligible and receive any protocol treatment. For toxicity analysis, patients who 
receive any protocol treatment will be considered evaluable. 
8.5 
Correlative Study 
Within a given biomarker-defined subgroup, it may be possible to identify 
additional variants that are associated with differential activity of the experimental 
agent.  Biomarkers measured prior to treatment could be predictive of response 
or non-response to the agent; biomarkers measured at time of progression might 
provide clues for mechanisms of acquired resistance. We plan to perform whole 
exome and RNAseq and potentially other assays in patients who entered a 
treatment arm and consented to use of their tissue for research (Section 10.2.1). 
Analyses conducted to identify these types of biomarkers will be primarily 
exploratory and will consist of simple comparisons of biomarkers levels, either 
using binomial-based tests (for binary biomarkers), t-tests (continuous 
biomarkers, possibly transformed), or non-parametric tests, as appropriate 
depending on the distribution of the biomarker values.  Changes in biomarker 
levels from baseline (prior to receiving the treatment) to progression within 
patients will be assessed using paired tests appropriate for the type of biomarker 
measurement (e.g., paired t-tests for normally distributed biomarker values or 
McNemar tests for paired binary data).  It will also be assessed whether patterns 
of changes in biomarkers are different depending on length of time to 
progression. Given the exploratory nature of these analyses, p-values will be 
reported unadjusted. 
Specimens remaining after use for eligibility for MATCH and for whole exome 
and other sequencing (Section 10.2.1) will be prioritized for use: 1) to use as 
“bridge  specimens for a companion diagnostic assay in subprotocols that have a 
positive signal of activity, if requested by the pharmaceutical company along with 
a plan of analysis approved by appropriate review in NCTN/NCI; 2) additional 
correlative studies requested by investigators along with a plan of analysis 
approved by appropriate standard review in NCTN/NCI. 
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8.6 
Image Analysis Plan 
CT, MRI and nuclear medicine scans will be collected on MATCH participants 
and archived centrally for analyses addressing the corresponding protocol aims. 
Separate analyses will be performed within each arm of the trial, when adequate 
imaging, genomic and outcome data are available. In addition, cross-arm 
analyses will be performed, using data from multiple arms of the trial. For 
quantitative imaging markers already defined, such as measures of tumor 
heterogeneity, the analytic approaches will be similar to those described in 
Section 8.5. In further exploratory analyses, regularized regression will be used 
to study the predictive strength of sets of imaging-derived features (16). The 
association of imaging-derived features and gene expression features will be 
examined using methods such as unsupervised clustering and association map 
construction (17, 18, 19). 
8.7 
Gender and Ethnicity  
Assuming number of treated patients will be approximately 700, based on the 
past 2 years of accrual to ECOG-ACRIN coordinated therapeutic studies by any 
participating group, excluding leukemia, the anticipated accrual in subgroups by 
gender and race is as follows: 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic/Latino 
Hispanic/Latino 
Female 
Male 
Female 
Male 
American Indian or Alaskan Native 
2 
1 
0 
0 
3 
Asian  
15 
6 
0 
0 
21 
Native Hawaiian or other Pacific Islander 
1 
0 
0 
0 
1 
Black or African American 
40 
23 
1 
0 
64 
White 
320 
255 
27 
9 
611 
Total 
378 
285 
28 
9 
700 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses.  Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 
 
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9. 
Biopsy Target Selection, Performance and Submission of Specimens 
Please review the study schema, Section 5.1 and Section 7.2 for a summary of 
submissions. Specimens to be submitted during screening steps or from all consenting 
patients on any treatment arm are outlined in the Master protocol. Specimen 
submissions associated with only a specific study subprotocol are be outlined in the 
specific subprotocol. 
As of May 22, 2017, patients are referred by designated Outside Laboratories to 
EAY131 based on standard of care genetic assessments performed by the designated 
laboratories. The historical information for the prior Step 0 MATCH-assay screening 
process is located in Appendix XV. 
The date and time of collection and shipping date must be entered into the ECOG-
ACRIN Samples Tracking System (STS) for all submitted specimens. Failure to update 
STS appropriately may result in delays in the applicable central assessments and 
reporting results to the site. 
Results from central MATCH-assay assessments will be reported only for the 
following: 
• 
Original MATCH-assay screening on fresh biopsy on Step 0 (closed May 22, 2017), 
Step 2, or Step 4. 
• 
Original MATCH-assay screening on archived tissue obtained within 6 months prior 
to registration to Step 0 (closed May 22, 2017). 
• 
Central “Confirmation of pre-registration outside results  assessments performed on 
diagnostic tissue submitted directly from the treating sites to MD Anderson during 
Step 0 or Step 1. 
Results of assessments performed on derivatives generated by non-MATCH 
laboratories, even for purposes of confirmation testing, will not be returned to the treating 
site. Additionally, results of research only studies will not be returned to the treating site. 
LABELING: All samples are to be labeled with the ECOG-ACRIN protocol number 
EAY131, the assigned ECOG-ACRIN patient sequence number, date and time of 
collection, and type of material. 
For results and specimen submission inquiries: 
MATCHTRIAL@mdanderson.org & MATCH@jimmy.harvard.edu 
Phone: 1-844-744-2420 (OPTION 4) Fax: 713-745-4925 
For all kit related inquiries: 
EACBPF@mdanderson.org 
Phone: 1-844-744-2420 (OPTION 5) Fax: 713-563-6506 
To order kits, email or fax the kit order form, located in Appendix XII, to the CBPF. See 
Section 9.4 
9.1 
Schedule of Collection and Submission 
Summary of submissions and schedules are provided in table format in Section 
7.2. 
1. Step 0: 
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FFPE tumor tissue is to be submitted only if requested for central screening 
IHC assessments where results are required for treatment assignment. 
Otherwise, submit after registration to Step 1. 
2. Step 1: 
• 
MANDATORY: Pre-trial FFPE tumor tissue submitted for “Confirmation of 
Pre-Registration Outside Results  submitted within 8 weeks following 
registration to Step 1. Materials are to be submitted utilizing the provided 
kit. 
NOTE: 
In the event that FFPE tissue is not available from patients 
assigned to treatment based on a referral from a designated 
outside laboratory, residual nucleic acids from the designated 
laboratory may be requested by the CBPF/MD Anderson TQL 
for the required confirmation sequencing. 
• 
From patients who answered “Yes  to “I agree to provide additional 
specimens for research  on the EAY131 MASTER Screening Protocol 
Consent 
• 
Additional pre-trial diagnostic material (FFPE tumor tissues) from 
procedures separate from that required for confirmation testing.  
Primary tumor tissue is preferred if material from only one procedure 
can be submitted. 
• 
Peripheral blood prior to start of treatment 
• 
Peripheral blood at end of Cycle 2, prior to Cycle 3 treatment or end of 
treatment if treatment discontinued prior to Cycle 3 
NOTE: 
Additional On-Treatment blood draws outlined within the 
applicable subprotocols require additional consent as dictated by 
the relevant subprotocol and subprotocol consent document and 
specimen collection and submission guidelines are outlined within 
that subprotocol. 
3. Step 2 (or Step 4): Original MATCH-assay screened patients ONLY 
• 
MANDATORY: Fresh tumor tissue biopsy must be submitted for MATCH-
assay central assessment if the original MATCH-assay screening results 
do not indicate an additional aMOI which may be used to assign a patient 
to treatment. Materials are to be submitted utilizing the provided kit. 
4. 
Step 3 (or Step 5): From patients who answered “Yes  to “I agree to 
provide additional specimens for research  on the EAY131 MASTER 
Screening Protocol Consent 
• 
Peripheral blood at Prior to start of treatment (can be collected and 
submitted at time of Step 2 (or Step 4) fresh biopsy 
• 
Peripheral blood at end of Cycle 2, prior to Cycle 3 treatment or end of 
treatment if discontinued prior to Cycle 3 
NOTE: 
Additional On-Treatment blood draws outlined within the 
applicable subprotocols require additional consent as dictated by 
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5. Step 8, progression: From patients who signed the “Consent for additional 
sample collection for research studies  AND registered to Step 8. 
• 
MANDATORY: Peripheral blood 
• 
Fresh tissue biopsy or tissue from standard of procedure 
9.2 
Pathology Submissions 
The submitting pathologist and clinical research associate should refer to 
Appendix II (Pathology Submission Guidelines) for guidelines and summary of 
submission requirements. 
9.2.1 
Documentation Submissions 
Do NOT redact the reports. Adequate identification must be 
provided to retain “chain-of-custody”, ensure that the 
appropriate materials have been submitted and allow appropriate 
and correct reporting. Results from MATCH-assay screening and 
confirmation assessments on tissue submitted by the site are returned 
to the site and will impact patient care. 
NOTE: 
In the event that FFPE tissue is not available from patients 
assigned to treatment based on a referral from a 
designated outside laboratory, the pathology, clinical and 
sequencing reports outlined in Section A below are still 
required to be submitted.   
A. The following must be submitted with every submission of 
pathology materials: 
• 
Previous clinical pathology reports, including the original 
diagnostic pathology report for the primary, MUST be 
submitted with every pathology submission. 
• 
Related immunological, immunohistochemical, and external 
sequencing reports. 
• 
ECOG-ACRIN Sample Tracking System shipping manifest. 
B. Required additional documentation from sites which submitted 
materials for “Confirmation of outside results  or for “Screening 2, 
biopsy 1  (or “Biopsy Repeat ): 
• 
Completed patient CLIA Laboratory Sample Submission Form. 
Information on the CLIA submission form must be clearly 
legible. Do not use cursive. This form is not to be submitted 
with tissue collected for research only (registration to Step 8). 
FAX numbers must be provided for those individuals who are 
required to obtain the results; to prevent reporting errors, 
please double check these numbers are correct. 
9.2.2 
Formalin-fixed Paraffin-embedded Tumor Tissue Submissions: 
MANDATORY: For patients registered to Step 0 based on a referral 
from a designated outside laboratory for confirmation of the outside 
sequencing results per the MATCH-assay. It is preferred that the 
material be representative of that analyzed by the outside laboratory 
or a specimen obtained as close to the collection date of that one 
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analyzed. Tissue is to be submitted within 8 weeks following 
registration to Step 1 unless requested for mandatory Step 0 central 
screening IHC assessments for selected candidate arms only. 
Optional from patients who answer “Yes  to “I agree to provide 
additional specimens for research  on the EAY131 MASTER 
Screening Protocol Consent: Additional archived tissue from 
procedures performed prior to patient entry to Step 0.  Primary tumor 
tissue is preferred if material from only one procedure can be 
submitted.   
A. Formalin-fixed paraffin-embedded tumor tissue block(s) must be 
submitted. The optimal block is 70% tumor tissue. Specimen size 
requirement is as follows: 
• 
Surface area: 25mm2 is optimal.  Minimum is 5mm2 
• 
Volume: 1mm3 optimal.  Minimum volume is 0.2mm3, however 
the success of DNA extraction decreases at suboptimal tissue 
volume 
Specimens of suboptimal size, cellularity, or tumor content will 
require submission of more than one tumor block 
If an existing block is not available, the following is to be 
submitted: 
• 
One (1) H&E slide, AND 
• 
Twenty (20) or more recently cut 4 – 5 micron unstained 
sections on positively charged slides to meet the surface area 
and volume requirements outlined above. 
NOTE: 
In the event that FFPE tissue is not available for 
confirmation testing from patients assigned to treatment 
based on a referral from a designated outside laboratory, 
residual nucleic acids from the designated laboratory may 
be requested by the CBPF/MD Anderson TQL. Sites will 
be informed of the receipt of nucleic acids as the 
submissions will be logged into STS by the CBPF, but 
results from assessment of the nucleic acids will NOT be 
reported to the site. 
9.2.3 
Fresh Tumor Biopsy Submissions: 
NOTE: 
For Step 0 patients registered after May 22nd, 2017, 
fresh biopsy submissions for Step 0 screening are not 
allowed. Assignment to treatment is based on a 
referral from a designated outside laboratory only and 
tissue submissions are outlined in Section 9.2.2.   
Material must be submitted in the appropriate MATCH-screening or 
Progression Kit. Guidelines for the performance of the biopsy are 
outlined in Section 9.6.   
Submit for: 
• 
Screening 2, Biopsy 1 (or 2) at Step 2 (or Step 4) – patient must 
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the original MATCH-assay and registered to the appropriate 
registration step prior to submission of the biopsy materials. 
Tumor biopsy sample must be considered adequate for evaluation 
for sequencing to be performed; assays will be attempted on 
tissue specimens that have at least 20% non-necrotic tumor cells 
present if deemed potentially adequate. If insufficient tumor is 
obtained for sequencing analysis, patients will be given the option 
to undergo repeat tumor biopsy to attempt to obtain more tissue. 
Patients in whom sufficient tumor material cannot be obtained for 
targeted sequencing analysis will not proceed to be treatment 
assignment for Step 3 (or Step 5). 
• 
Patients on Step 8, patients must be consented to the “Consent 
for additional sample collection for research studies  and 
registered to Step 8. If patient does not have a lesion amenable to 
a minimal risk biopsy or is not willing to undergo a biopsy, submit 
blood samples as outlined in Section 9.3 only. 
Specimen collection days: Specimen collection can be done Monday 
through Friday with overnight shipping for arrival on Tuesday through 
Saturday at the ECOG-ACRIN Central Biorepository and Pathology 
Facility (EA CBPF).  To order kits, email or fax the kit order form, 
located in Appendix XII, to the CBPF. 
1. For patients with solid tumors: Submission of fresh tumor tissue 
cores in formalin and FNA cells in cytolyte is required. See 
Section 9.6. 
For the collection of biopsy specimens, fine needle aspiration 
followed by core needle biopsy, with submission of the FNA and 
the biopsy cores, is required. The tumor cellularity yielded by FNA 
may be superior to core needle biopsy in some patients, 
particularly when the lesion is comprised predominantly of fibrosis, 
bone, or other non-tumor tissue. 
• 
The FNA sampling with at least 2 passes should be sufficient 
to provide a specimen for preparation of smears and a cell 
block.   
• 
Immediately fix one slide in 95% ethanol (provided by 
enrolling institution) and air dry another slide for each FNA 
pass. The air dried slide will be stained by Diff-Quik 
method to assess tumor cell quantity and quality 
• 
Rinse FNA needle into the 30 ml CytoLyt tube, secure the 
tube cap, and place the tube into the shipping kit. 
• 
At least four (preferred) core biopsies 16-18 gauge in diameter 
and at least 1 cm in length after a fine needle aspiration 
specimen are obtained.  Place two cores between sponges in 
each of the two cassettes (total of four cores), snap the 
cassette lids in place, place the two cassettes into the 
formalin-filled container, secure the container lid, and place the 
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NOTE: 
If touch preparation slides of cores are made, place 
them in the dry slide container. Secure the slide 
container lid and place it in the shipping kit. 
Screening samples with loss of MLH1 or MSH2, as determined by 
IHC, will result in a request for the submission of pre-trial 
diagnostic tumor tissue as outlined in Section 9.2.2 for central 
confirmation of this result. The results of the confirmation will be 
reported to the site. This additional assessment will not impact the 
Step 2 (or 4) screening assessment timeline and treatment 
assignment will not be held pending the outcome of the 
confirmation assessments. If the results are completed prior to 
treatment assignment, the confirmation results will be used by 
MATCHbox. 
OR 
2. MULTIPLE MYELOMA ONLY: SUBMIT ASPIRATES FROM THE 
FIRST PULL. 
For patients with plasmacytomas, follow the instructions for the 
submission of solid tumors. If aspirate will be submitted for 
screening, draw the bone marrow aspirate materials into a plain 
syringe, then: 
1. Use 1 drop to make 4 – 5 smears. 
2. Put 1 – 1.5 ml in one EDTA tube. 
3. Put remainder (5 - 10 ml) of bone marrow aspirate in the other 
EDTA tube. 
9.3 
Optional Whole Blood Collections for Research 
Whole blood is to be collected and submitted: 
• 
From those who answer “Yes  to “I agree to provide additional specimens for 
research  on the EAY131 MASTER Screening Protocol Consent 
• 
Prior to start treatment 
• 
End of cycle 2, prior to cycle 3 treatment (or end of treatment if 
discontinued prior to cycle 3) 
• 
MANDATORY from those who signed the “Consent for additional sample 
collection for research studies  AND registered to Step 8 
Additional sub-protocol specific submissions are outlined within the relevant 
subprotocol and consented to at the time of completing consent to participate in 
the subprotocol. 
Samples are to be submitted at ambient temperatures on the day of collection.  
To order kits for these collections, please see Appendix XII. 
9.3.1 
Collection and submission guidelines. 
Blood draws are to occur in the following order: EDTA, Streck 
1. 7-10 mL of whole blood into one (1) EDTA vacutainer collected at 
• 
Prior to start of protocol treatment 

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• 
Following Step 8, registration 
2. 18-20 mL of whole blood into two (2) Streck vacutainers collected 
at: 
• 
Prior to start of protocol treatment 
• 
End of Cycle 2, prior to treatment on Cycle 3 (or end of 
treatment, if applicable) 
• 
Following Step 8, registration 
9.4 
NCI MATCH EAY131 Clinical Trial Specimen Kit Instructions for Specimen 
Collection and Shipping 
For all kit related inquiries: 
EACBPF@mdanderson.org 
Phone: 1-844-744-2420 (OPTION 5) Fax: 713-563-6506 
Kits to submit the tissue for confirmation testing and the pre-treatment and on-
study blood specimens will be provided automatically upon registration to Step 1. 
To order follow-up kits, email or fax the kit order form, located in Appendix XII, to 
the CBPF.  
9.4.1 
Contents of “Rare Variant  shipping kit for Formalin Fixed Paraffin-
Embedded Tumor Sample for Confirmation of “Rare Variant” 
Results Determined by Designated Outside Laboratory. 
This kit may be ordered after either receiving notification to submit 
tissue for mandatory central IHC required to determine treatment 
assignment OR after receiving treatment assignment. Kits contain all 
materials to ship tissue and blood samples separately. 
1. One patient CLIA Laboratory Sample Submission Form. 
2. Two EDTA venipuncture blood collection tube and four Streck 
venipuncture blood collection tubes with labels and absorbent 
protective packing material for the two time points. 
3. Materials to submit the required tissue 
4. One pre-printed FedEx shipping label sticker pre-addressed to the 
EA Central Biorepository and Pathology Facility. Contact the EA-
CBPF to discuss additional shipment airbills for the separate 
shipments. 
5. Neon green address labels – to be used with submission of 
the mandatory tissue 
6. Cold pack, warm pack, and temperature monitor device. 
7. Strip of specimen labels. 
8. Kit instructions. 
9.4.2 
Instructions for use of screening or Step 8 shipping kit: 
Reminder: Patients must be consented for the collection and 
submission of these additional specimens, and subsequently 
registered to Step 8 prior to ordering the kit. 

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A: Fresh tissue and research blood submission 
If a research or clinical biopsy or other clinical procedure will be 
performed to obtain the fresh tissue (or bone marrow for multiple 
myeloma) follow the instructions outlined in Section 9.2.3 and 9.6. 
Procedure checklist: 
1. Label blood collection tubes and, if applicable, relevant 
supplies for the tissue submission, including the frosted-tip 
slides, cassettes and all collection containers. 
2. If tissue will be submitted: 
a. Complete CLIA Laboratory Sample Submission Form. 
Information on the CLIA submission form must be clearly 
legible. Do not use cursive. 
b. Perform the biopsy or relevant clinical procedure to obtain 
the fresh tissue (or bone marrow) 
3. Perform venipuncture for collection of blood into labeled EDTA 
and Streck tubes and place filled labeled tubes into biohazard 
bag with absorbent protective packing material. 
4. Log the samples into the EA Sample Tracking System and 
print the STS generated shipping manifest. 
5. Place the following forms into the shipping kit: 
___ This checklist 
___ Prior clinical pathology reports, and any immunologic, 
immunohistochemical, or molecular study reports 
performed on pre-trial diagnostic tumor specimen. Do 
NOT redact the reports. 
___ CLIA Laboratory Sample Submission Form completely 
filled out. Information on the CLIA submission form must 
be clearly legible. Do not use cursive. 
___ The Sample Tracking System (STS) generated shipping 
manifest. 
6. Activate the temperature monitor by pressing and holding the 
start button for 10-15 seconds. The green LED light will be 
solid, and then both red and green LED’s will be solid. At this 
time, release the start button, and the green LED will blink 
rapidly for 3 seconds. Place the unit in the kit inside the blood 
tube packaging – it will flash red and green LED for 15 
minutes. For temperature control, add cold pack or warm pack, 
dependent on time of year specimen is shipped. Use warm 
pack if outside temperature at your site or along transit route 
will be below freezing. 
7. Use one kit per patient. Do not place specimens from more 
than one patient into a kit. Secure the packing, seal the kit, 
and apply the following shipping labels: Three neon green 
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separate shipping guide document for pictures of label 
placement and further shipping guidelines. Contact FedEx for 
pickup. Package must be picked up the same day 
specimen is collected. 
9.5 
Shipping Procedures 
Specimen collection can be done Monday through Friday with overnight 
shipping for arrival on Tuesday through Saturday at the ECOG-ACRIN 
Central Biorepository and Pathology Facility (EA CBPF).   
Use one kit per patient. Do not place specimens from more than one patient into 
a kit. Use the shipping kit provided.  See Appendix XII for the EAY131 Collection 
and Shipping Kit Order Form and instructions for ordering. Line the styrofoam 
containers with enough absorbent material to absorb any contents that may leak. 
Follow directions enclosed in the shipping kit. Ship to the following 
address: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3598 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
Sites must use the pre-printed, prepaid FedEx airbill within the specimen 
collection kit. If the kit does not include an airbill or additional airbills are 
required, please contact the CBPF at 1-844-744-2420 (OPTION 5). 
9.6 
Biopsy Instructions 
A pre-treatment tumor biopsy or bone marrow aspirate (myeloma patients only) 
on Step 0 [closed May 22, 2017] and Step 2 (or 4) [Step 0 MATCH-assay 
screened patients only] will be obtained from patients who sign the consent to 
enroll in the study as detailed in Section 5. Step 8 end-of-treatment biopsies are 
requested from patients who have provided additional consent and meet the 
criteria outlined in Section 3.9. 
Brain biopsies will be permitted if the patient has medical necessity for 
craniotomy for clinical care. Mediastinal, laparoscopic, gastrointestinal, or 
bronchial endoscopic biopsies can be obtained incidentally to a clinically 
necessary procedure and not for the sole purpose of the clinical trial.  Acceptable 
biopsy procedures are: 
• 
Percutaneous biopsy with local anesthetic and/or sedation with an expected 
risk of severe complications < 2% 
• 
Excisional cutaneous biopsy with local anesthetic and/or sedation with an 
expected risk of severe complications < 2% 
• 
Biopsy with removal of additional tumor tissue during a medically necessary 
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• 
Removal of additional tumor tissue during a medically necessary surgical 
procedure 
• 
Bone marrow aspirate (myeloma patients only, if applicable) 
No open surgical, laparoscopic endoscopic procedure will be performed 
solely to obtain a biopsy for this protocol. 
9.6.1 
Contraindications to percutaneous biopsy: 
1. Significant coagulopathy that cannot be adequately corrected.  
2. Severely compromised cardiopulmonary function or hemodynamic 
instability. 
3. Lack of a safe pathway to the lesion.  
4. Inability of the patient to cooperate with, or to be positioned for, 
the procedure. 
9.6.2 
Tissue specimens will be sent for analyses as defined in Section 
Error! Reference source not found.. Specimens are generally 
expected to provide 20 nanograms of nucleic acids. If a site is 
deemed appropriate for biopsy with minimal risk (no more than 2% 
risk of serious complication requiring hospitalization) to the participant 
by agreement between the investigators and Interventional Radiology, 
an attempt at biopsy will be made. 
The biopsy procedure to be used in this protocol is described below; 
local anesthesia will be administered as needed. Sedation may be 
used for comfort if considered safe for the patient.  Such biopsies can 
be safely performed as evidenced by literature reports [12,13, 20], as 
well as, experience at the NIH Clinical Center, where, among 244 
research tumor biopsies (18G needle) in liver (126), 
subcutaneous/chest wall/abdominal wall (36), intramuscular (18), lung 
and lymph nodes, there were 8 minor cases of bleeding, and one 
pneumothorax requiring 48h hospitalization (21) and MD Anderson 
Cancer Center (22). Most biopsies will probably be in liver. The 
complication rate at Massachusetts General Hospital (23) of 
percutaneous liver biopsy similar to those that will be done for this trial 
is 1.2 % of 732 cases. Risks of the procedure include, but are not 
limited to, bleeding, infection, pain, and scarring. 
9.6.3 
Complications associated with any screening biopsy or end-of-
treatment biopsy will be reported and tracked as protocol-related AEs 
within Medidata Rave. 
9.6.3.1 
Severe or major complications are considered to be (13): 
• 
Requires therapy, minor hospitalization (more than 
overnight only but < 48 h) 
• 
Requires major therapy; unplanned increase in level of 
care, prolonged hospitalization> 48h 
• 
Permanent adverse sequelae 
• 
Death 

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9.6.3.2 
Minor complications 
• 
No therapy, no consequence 
• 
Nominal therapy, no consequence - includes overnight 
admission for observation only 
9.6.4 
Pre-biopsy Lesion Assessment (for those undergoing biopsy by 
Interventional Radiologist) 
The Interventional Radiologist should provide the investigator with an 
assessment of whether a lesion that is likely to yield enough material 
for molecular profiling can be found and biopsied with acceptable risk.  
Three main factors are considered: 
i. 
whether a suitable lesion (viable tumor) for biopsy is present 
(yield) 
ii. whether the lesion selected for biopsy can be sampled 
aggressively (yield) 
iii. the expected level of risk of major complication to the patient (< 
2% major complication to be eligible for biopsy) 
9.6.4.1 
A pre-biopsy lesion scoring system (scale from 1-3) 
adapted from the one used by Interventional Radiology at 
the MD Anderson Cancer Center (courtesy of Dr. Michael 
Wallace, Chair Ad-Interim of the Department of 
Interventional Radiology) will be used to assign a value to 
the interventional radiologist’s assessment of the lesion. 
An analogous 5-point subjective scale has been internally 
studied at MD Anderson Cancer Center and lesions given 
a score of ≤ 2 were found to have a lower yield rate for 
CMS-46 testing when compared to lesions that were 
scored ≥ 4 (24). 
9.6.4.2 
The radiologist will refer to the Radiology Biopsy Manual 
for case examples and detailed criteria for scoring and 
assign a pre-biopsy lesion score to the patient. Briefly, the 
qualitative assessment criteria for the 3-point scale is as 
follows: 
Pre-Biopsy Lesion Scoring Scale (courtesy MD Anderson Cancer 
Center) 
Score 
Assigned 
Likelihood of 
Yield 
Reason for Score & Biopsy 
Disposition 
1 
Low (< 25%) 
Reason: no target amenable to 
biopsy, high risk procedure. 
Biopsy disposition: should not be 
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Score 
Assigned 
Likelihood of 
Yield 
Reason for Score & Biopsy 
Disposition 
2 
Uncertain (25-
75%) 
Reason: Uncertainty about 
success either due to technical 
challenges or lesion 
characteristics (e.g., small size, 
necrotic, sub-solid lesion, 
sclerotic, not FDG–avid, 
technically difficult biopsy). 
Sclerotic bone lesion usually low 
yield. 
Biopsy disposition: 
Communication with investigator 
for these types of lesions should 
occur to determine whether to 
proceed with biopsy. 
3 
High (> 75%) 
Reason: viable tumor 
demonstrated on diagnostic 
imaging (enhancing lesion, 
growing lesion) that can be 
sampled aggressively. 
Disposition: Proceed with biopsy. 
9.6.4.3 
Record the pre-biopsy lesion score and the name of the 
interventional radiologist on the screening eCRF in Rave. If 
a lesion is rated 1 or 2, the reason should be denoted on 
the CRF and this suspicion for low likelihood of success 
should be communicated to the investigator to discuss 
whether or not to proceed with the biopsy.  Final 
disposition of the discussion (to proceed or not to proceed) 
should be documented on the CRF. 
9.6.4.4 
Pre-biopsy imaging and CRF with lesions score 
assessment and interventional radiologist’s name are 
submitted in all cases, including those where decision is 
made to not proceed with biopsy. 
9.6.5 
Biopsy Procedure 
This section applies to patients who have not had tumor tissue 
acquired through normal clinical care for either diagnostic or 
therapeutic procedures.  Tumor tissue acquired during regular clinical 
care would be harvested by the appropriate physician (e.g., 
neurosurgeon during craniotomy).   
9.6.5.1 
If a non-cutaneous lesion site is deemed appropriate for 
biopsy with minimal risk to the participant by agreement 
between the investigators, patient and Interventional 
Radiologist an attempt at biopsy will be made. All internal 
organ biopsies will be done by the Interventional 
Radiologist with a percutaneous approach, or during a 
clinically necessary surgical/endoscopic procedure, 
including craniotomy for brain metastasis or tumor. 
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• 
No endoscopic, laparoscopic, or surgical procedure will 
be done solely to obtain a biopsy for this protocol. 
9.6.5.2 
The choice of imaging modality to be used to facilitate 
tissue acquisition during the biopsy procedure will be 
decided by members of the Interventional Radiology team 
at the clinical site and may include ultrasound, CT scan, or 
MRI.  Should CT scan be needed for biopsy, the number of 
scans for each procedure will be limited to the minimum 
number needed to safely obtain a biopsy. Tumor biopsies 
will be performed only if they are considered to be of low 
risk (< 2% major complication rate) to the participant as 
determined by the investigators and Interventional 
Radiologist.  Biopsies will be performed under local 
anesthesia and/or sedation. 
9.6.5.3 
For the collection of biopsy specimens, fine needle 
aspiration followed by core needle biopsy, with submission 
of the FNA and the biopsy cores, is required. For all 
specimen types, the tumor cellularity yielded by FNA may 
be superior to core needle biopsy in some patients, 
particularly when the lesion is comprised predominantly of 
fibrosis, bone, or other non-tumor tissue. The FNA 
sampling with at least 2 passes should be sufficient to 
provide a specimen for preparation of smears and a cell 
block. It is preferred that at least four core biopsies 16-18 
gauge in diameter and at least 1 cm in length after a fine 
needle aspiration specimen are obtained as described 
below. Biopsies will be sent for analyses as defined in the 
protocol. 
9.6.5.4 
Biopsy images should be submitted to IROC at the ACR 
Core Laboratory (see Section 11) and include image 
before needle placement, image with FNA or trocar needle 
in lesion, image with core biopsy or trocar needle in lesion, 
biopsy report describing target lesion location (organ, 
laterality or segment if applicable and image number on 
pre-biopsy imaging if available) and size. 
9.7 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS).  The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password. 
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst 
Important: 
Failure to complete required fields in STS may result in assay 
result reporting delays. Any case reimbursements associated 
with sample submissions will not be credited if samples are not 
logged into STS. 
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Additionally, please note that the STS software creates pop-up 
windows, so you will need to enable pop-ups within your web 
browser while using the software.  A user manual and interactive 
demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html Please take a moment to 
familiarize yourself with the software prior to using the system. 
A shipping manifest form must be generated and shipped with all sample 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu 
Study Specific Notes 
A time point summary (for STS) is provided in Section 7.2.3. 
A Generic Specimen Submission Form (#2981) will be required only if STS is 
unavailable at time of sample submission. Indicate the appropriate Lab on the 
submission form: 
• 
ECOG-ACRIN Central Biorepository and Pathology Facility 
Retroactively enter all collection and shipping information when STS is available 
Note: If the CBPF/MD Anderson TQL requests and receive nucleic acids from a 
designated outside laboratory, the receipt of materials will be logged into STS by 
the EA-CBPF.   
Snapshot STS users guide for NCI-MATCH EAY131: 
Most information, if entered incorrectly, may be corrected by the site.  To correct 
mistakes for sample type or timepoint, contact the ECOG-ACRIN Lab Team 
(ecog.tst@jimmy.havard.edu or 857-504-2900) or the CBPF 
(eacbpf@mdanderson.org or (844) 744-2420). Please do not delete samples and 
re-log to correct these errors, especially after samples have already been 
shipped. 
1. For protocol, enter “EAY131  
2. For Patient, enter the ECOG-ACRIN patient ID assigned upon pre-
registration to step 0 
3. Click “Log Samples  
4. Select the relevant time point (s) (see table below) and click “Select These 
Timepoints  
5. Select the sample types to be submitted.  If the sample type is not listed, click 
on the blue word “Show  next to the preferred sample type and the alternative 
sample options will appear. If a sample type will not be submitted, it is 
requested that “Can’t submit  be indicated and a simple reason provided. 
6. Click on “Ship Selected Samples  
7. Complete all information for the samples.  Modify Pathology Status indicating 
if the tissue is “Tumor, Primary  or “Metastasis  and select the anatomical site 
from which the specimen was collected. Please provide specifics for 
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8. Click “Create New Shipment .  NOTE:  For EAY131, please do not pack 
samples from other trials or patients within the kit. One set of patient samples 
for one patient per kit. 
9. Complete the shipping date, courier, and tracking number information.  
Indicate if the required documents are included in the shipment. 
10. Click “Save  at the bottom of the page. 
Print two copies of the shipping manifest, one to provide in the Box, the other for 
your own records. 
9.8 
Use of Specimens in Research 
Specimens will be distributed to investigators for the laboratory research studies 
defined in Section 10.  
Specimens from patients who consented to allow their specimens to be used for 
future approved research studies, including residuals from the currently defined 
research studies, will be retained in an ECOG-ACRIN-designated central 
repository.  For this trial, specimens will be retained at the ECOG-ACRIN Central 
Biorepository and Pathology Facility at the University of Texas MD Anderson 
Cancer Center. 
Samples will be retained, if at all possible, to allow “bridging  to an assay 
intended to be a companion diagnostic by the company providing the treatment 
drug(s). 
For studies in which the ORR or PFS at 6 months is promising, every effort will 
be made to preserve tissue samples for "bridging" diagnostic studies. Specimens 
submitted will be processed to maximize their utility for current and future 
research projects and may include, but not be limited to, extraction of plasma, 
serum, peripheral blood leukocytes, serum, DNA, and RNA, and proteins. 
If future use is denied or withdrawn by the patient, the samples will be removed 
from consideration for use in any future study. 
9.9 
Sample Inventory Submission Guidelines 
Inventories of all samples submitted from institutions will be tracked via the 
ECOG-ACRIN STS. Receipt and usability will be verified by the receiving 
laboratory.  Inventories of specimens forwarded and utilized for approved 
laboratory research studies will be submitted by the investigating laboratories to 
the ECOG-ACRIN Operations Office-Boston upon request in an electronic format 
defined by the ECOG-ACRIN Operations Office-Boston. 
9.10 
Institutional Biopsy Reimbursements 
Research biopsies will be obtained from the primary tumor or metastasis at the 
time of screening biopsy or the time of end-of-treatment biopsy. Information on 
reimbursement for these research biopsies is provided in Section 4.12. 
 

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10. 
Laboratory Clinical Research and Non-clinical Research Studies 
The molecular profiling assays performed by the MATCH-assay laboratories will include 
massively parallel tumor sequencing (next generation sequencing) using a targeted 
Ampliseq panel, and certain other molecular assays e.g. immunohistochemistry (IHC). 
The genes interrogated on the NGS assay are listed in Appendix X . 
All MATCH-assay laboratories are CLIA or CAP/CLIA certified laboratories with 
experience in clinical next generation sequencing on the Ion Torrent PGM or S5. 
Analytical validation studies assessing reproducibility, accuracy, precision, lower limit of 
detection, false positive and false negative rates have been completed; proficiency 
assessments are planned every 6 months. Analytical validation and proficiency 
assessments will be performed any time the assay is "versioned" (gene variant added or 
deleted), and the assay will be locked for the updated version. Specific ongoing QA/QC 
measures are noted below. 
MD Anderson Cancer Center Molecular Diagnostics NGS Laboratory will also serve as 
the receiving laboratory for all specimens, will be responsible for the preanalytic 
procedures and will also perform all mandatory immunohistochemical (IHC) 
assessments required to be conducted centrally. This laboratory will lead the 
performance of procedures and documentation required, as necessary, for New York 
State Department of Health licensure. 
The Molecular Characterization Laboratory at the Frederick National Laboratory for 
Cancer Research will lead the validation planning and procedures required for the U.S 
Food and Drug Administration Center for Diagnostics and Radiologic Health. 
The Massachusetts General Hospital Center for Integrated Diagnostics, and the Yale 
University Clinical Molecular Pathology lab will participate with all the labs in carrying out 
assay validation and performance proficiency procedures. Additionally, a new CLIA 
certified/CAP accredited laboratory, the Dartmouth-Hitchcock Laboratory for Clinical 
Genomics and Advanced Technologies, will join the NCI-MATCH laboratory network and 
begin NGS testing of MATCH FFPE specimens in 2017. All the labs will participate as 
NGS sequencing centers for patient diagnostics in the NCI-MATCH trial. 
For confirmation testing, some tumors may undergo additional orthogonal assessments 
on different platforms to confirm variants that may not be analyzed by the MATCH-
assay. Results from orthogonal assessments are separate from the MATCH-assay and 
will not be reported to the site or the patient. 
10.1 
Targeted Genetic Analysis for MATCH eligibility   
The tumor biopsy materials will be processed as follows (See Appendix I for work 
flow): 
10.1.1 
DNA extraction and RNA Extraction: The H&E section will serve to 
confirm original diagnosis and also estimate tumor nuclei content.  
The remaining biopsy and whole blood will be extracted for nucleic 
acids using the Qiagen FFPET All-Prep procedure.   
10.1.2 
Genomic Analysis 
Molecular profiling will be performed in a study-specific network of 
approved CLIA-certified Molecular Characterization Laboratories 
noted above. 
Rev. 2/16 
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DNA will be assessed for quantity and quality by spectroscopy (OD 
260/280) and a PCR-based amplification quality assessment test.  All 
specimens that meet necessary quantity and quality will be 
sequenced using a targeted sequencing assay.  This assay will 
identify those mutations that are used for treatment assignment.   
Sequencing will be done on the Ion Torrent PGM or S5 using a 
targeted ampliseq panel of about 161 genes, (see Appendix X). The 
assay will report SNV, indel, amplifications and translocations; a 
subset of these will be actionable based on treatments in MATCH. 
Mutations will be reported based on their presence in tumor cells and 
the number of reads demonstrating the pre-defined mutation as 
indicated.  Amplifications will be reported as fold amplified; 
translocations will be reported by genes involved. If actionable 
mutations are detected in more than one pathway, treatment will be 
assigned based on the level of evidence and treatment assignment 
rules as stated in Section 1.5 
The laboratory will return MATCH assay results (whether a 
mutation/amplification/translocation of interest has been detected and 
the results of any additional molecular diagnostic tests), including 
details about the specific mutation/pathways for assignment to a 
treatment subprotocol based on predefined criteria. Patients in whom 
actionable mutations, amplifications or translocations are not detected 
during Step 0 screening will not continue to Step 1 registration and will 
not be followed. The analysis could take up to 4 weeks, or longer if 
additional procedures are required to obtain enough tissue of 
appropriate quality to run the assay. 
For the original screening process (i.e. submission of tissue for testing 
by a MATCH laboratory), all specimens will be assessed for 
expression or no expression of PTEN, MLH1 and MSH2. Rb by IHC 
will only be done in patients who are positive for CCND1, 2, or 3 
amplification or CDK4 or CDK6 amplification. Additional tumor tissue 
specimens may be requested from selected patients for the 
performance of repeat MLH1 and MSH2 IHC assessments for 
confirmation of eligibility for relevant treatment arms. 
Patients who enter MATCH subprotocols with an approved “rare 
variant  via an outside assay will have archived tissue (as similar as 
possible to the tissue that was sequenced by the outside assay) 
assessed by the NCI-MATCH molecular profiling assays, as above. 
No IHC assessments will be performed on these specimens, unless 
necessary for eligibility on the applicable arms. Results of these 
assays will be returned to the clinical site for sharing with the patient. 
10.1.3 
Site Notification of Pre-defined Mutations  
If adequate materials are submitted, the mutation status will be 
completed within 4 weeks of receipt of materials. Results will be 
forwarded from the laboratory directly to the site contact. Only 
MATCH-assay assessment results on tissue or bone marrow 
submitted directly by the participating site will be returned to sites. 
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Results will not be distributed to sites for confirmation sequencing 
assessments performed on residual nucleic acids received from any 
referring Designated Outside laboratory. 
For patients who will be evaluated for treatment assignment based on 
a MATCH-assay screening assessment, it may take a few days from 
the receipt of biopsy results for potential treatment assignments to be 
made available via Medidata Rave. For these patients, registration to 
treatment cannot occur until the central review determination is 
complete. 
10.1.4 
Turnaround Time Monitoring 
We will monitor turnaround time on at least a monthly basis, as it is 
tracked in MATCHbox. If turnaround time extends beyond 21 days 
median, we will bring this to the steering committee for consideration 
of remedies, which may include increasing laboratory or pathology 
capacity. 
Because there are a number of reasons why results may be delayed, 
a dedicated call center has been created at MD Anderson that will 
monitor specimen progress and alert the clinical site when there are 
expected to be delays or when a specimen is not adequate and may 
need to be repeated. 
10.2 
Research Studies 
10.2.1 
Whole Exome and other Sequencing 
This assessment will be performed on samples from patients who 
agree to allow their samples to be used for optional research studies 
(not for treatment assignment). These assays will not be done in a 
clinical laboratory (e.g. CLIA certified) and results will not be returned 
to the clinical site, but will be used to understand response or non-
response in patients who have been treated on one of the MATCH 
treatment arms. 
De-identification of patient biospecimens will be performed in a secure 
manner prior to use for research purposes. The de-identified data will 
be stored on a controlled access database for use by other 
researchers. 
If sufficient DNA is available, whole-exome, mRNA and other 
sequencing will be performed retrospectively for research purposes 
on samples with identifiers de-linked. RNA sequence will be 
performed if sufficient RNA is available. These studies will be 
exploratory, and will assess other molecular features that may have 
influence on response or lack of response to the treatment, as well as 
potential resistance mechanisms.  
Whole blood and plasma will also be sequenced to compare to tumor 
sequencing (deidentified). 
Other researchers may apply for remaining specimens for MATCH 
using standard mechanisms developed by CTEP and the NCTN.  
Proposals will be reviewed for scientific merit.  Funding will not be 
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provided for these studies, but will need to be provided by the 
applicants.  Such studies may include bridging studies for companion 
diagnostics proposed by pharmaceutical companies participating in 
MATCH. 
10.2.2 
Sample Inventory Submission Guidelines 
Inventories of all samples submitted from institutions will be tracked 
via the ECOG-ACRIN STS and receipt and usability verified by the 
receiving laboratory.  Inventories of specimens forwarded and utilized 
for approved laboratory research studies will be submitted by the 
investigating laboratories to the ECOG-ACRIN Operations Office-
Boston on a monthly basis in an electronic format defined by the 
ECOG-ACRIN Operations Office-Boston. 
10.2.3 
Lab Data Transfer Guidelines  
The data collected on the above mentioned laboratory research 
studies will be submitted electronically using a secured data transfer 
to a central NCI database by the investigating laboratories on a 
quarterly basis. 
 

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11. 
Imaging Submissions 
ACR Imaging Core Laboratory, through funding provided under IROC, will perform 
image collection via TRIAD® software v4. TRIAD can be installed on one or several 
computers of choice within the institutional “firewall  and on the institutional network. The 
TRIAD application can then be configured as a DICOM destination on a scanner and/or 
PACS system for direct network transfer of study related images into the TRIAD 
directory. Once configured, TRIAD software de-identifies, encrypts, and performs a 
lossless compression of the images before they are transferred to the ACR Imaging 
Core Laboratory and image archive in Philadelphia. Subjects enrolled at 
screening/registration (Step 0) via RSS / OPEN will be selectable in TRIAD following 
registration by the participating institution. CTEP IAM credentials will be used to access 
TRIAD software for image submission via CD/DVD, PACS or scanner. Image 
submission will require a 'TRIAD site user' role, a designation that can be obtained 
through the CTSU Administrator. 
The following categories of imaging will be collected: 
1. Pre-enrollment imaging – all subjects including those who do not go forward with 
biopsy nor with treatment. 
2. Biopsy imaging – all subjects 
a. Image before needle placement 
b. Image with FNA or trocar needle in lesion 
c. Image with core biopsy or trocar needle in lesion 
d. Biopsy report describing target lesion location (organ, laterality or segment if 
applicable and image number on pre-biopsy imaging if available) and size. 
3. Followup imaging on targeted therapy – all subjects on all therapy arms and all 
timepoints 
4. Imaging documenting progression on targeted therapy – all subjects in therapy arms 
5. Imaging at re-biopsy – all subjects who undergo re-biopsy 
For categories 1, 3, and 4, CT, MRI and nuclear medicine (including PET-CT) of all body 
parts will be collected. Plain film X-ray, ultrasound, and fluoroscopy images will not be 
collected. For categories 2 and 5, images of any modality used for biopsy will be 
collected. The images and time points to be collected are represented in the schema 
below: 
 
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A separate Image Submission Manual will describe the specifics of the image collection 
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12. 
Electronic Data Capture 
Please refer to the MATCH Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office-Boston to CTEP by electronic means. 
12.1 
Records Retention  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
All records pertaining to the trial (including source documents) must be 
maintained for: 
• 
two years after the FDA approves the marketing application, or 
• 
two years after the FDA disapproves the application for the indication being 
studied, or 
• 
two years after the FDA is notified by the sponsor of the discontinuation of 
trials and that an application will not be submitted.  
Please contact the ECOG-ACRIN Operations Office-Boston prior to destroying 
any source documents. 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
References 
1. 
Tabor HK, Berkman BE, Hull SC, Bamshad MJ. Genomics really gets personal: 
How exome and whole genome sequencing challenge the ethical framework of 
human genetics research. American Journal of Medical Genetics Part A 
2012;155(12):2916-2924. 
1. 
Kass NE, Hull SC, Natowicz MR, Faden RR, Plantinga L, Gostin LO, et al. Medical 
privacy and the disclosure of personal medical information: The beliefs and 
experiences of those with genetic and other clinical conditions. American Journal 
of Medical Genetics Part A 2004;128A(3):261-270. 
2. 
Dressler LG, Terry SF. How Will GINA Influence Participation in 
Pharmacogenomics Research and Clinical Testing? Clin Pharmacol Ther 
2009;86(5):472-475. 
3. 
Caulfield T, McGuire AL, Cho M, Buchanan JA, Burgess MM, Danilczyk U, et al. 
Research Ethics Recommendations for Whole-Genome Research: Consensus 
Statement. PLoS Biol 2008;6(3):e73. 
4. 
Berg JS, Khoury MJ, Evans JP. Deploying whole genome sequencing in clinical 
practice and public health: Meeting the challenge one bin at a time. Genet Med 
2011;13(6):499-504. 
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5. 
Dowlati A, Haaga J, Remick SC, Spiro TP, Gerson SL, Liu L, et al. Sequential 
tumor biopsies in early phase clinical trials of anticancer agents for 
pharmacodynamic evaluation. Clin Cancer Res 2001;7(10):2971-6. 
6. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. 
New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer 2009;45(2):228-47. 
7. 
Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, et al. 
Eligibility and response guidelines for phase II clinical trials in androgen-
independent prostate cancer: recommendations from the Prostate-Specific Antigen 
Working Group. J Clin Oncol 1999;17(11):3461-7. 
8. 
Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, et al. 
Re: New guidelines to evaluate the response to treatment in solid tumors (ovarian 
cancer). J Natl Cancer Inst 2004;96(6):487-8. 
9. 
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design 
and end points of clinical trials for patients with progressive prostate cancer and 
castrate levels of testosterone: recommendations of the Prostate Cancer Clinical 
Trials Working Group. J Clin Oncol 2008;26(7):1148-59. 
10. 
Vergote I, Rustin GJ, Eisenhauer EA, Kristensen GB, Pujade-Lauraine E, Parmar 
MK, et al. Re: new guidelines to evaluate the response to treatment in solid tumors 
[ovarian cancer]. Gynecologic Cancer Intergroup. J Natl Cancer Inst 
2000;92(18):1534-5. 
11. 
Dowlati A, et al. Sequential Tumor Biopsies in Early Phase Clinical Trials of 
Anticancer Agents for Pharmacodynamic Evaluation.  Clin Cancer Res 2001; 7: 
2971-76. 
12. 
Gupta S et al.  Quality Improvement Guidelines for Percutaneous Needle Biopsy. J 
Vasc Interv Radiol 2010; 21:969-75  
13. 
Wen PY, Macdonald DR, Reardon DA et al.  Updated response assessment 
criteria for high-grade giomas:  Response assessment in neuro-oncology working 
group.  J Clin Oncol 2010; 28(11): 1963-72 
14. 
Cheson BD, Fisher EL, Barrington SF, Schwartz LH, Zucca E, Listner TA. 
Recommendations for initial evaluation, staging, and response assessment of 
Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 
2014;32(27):3059-68. PubMed PMID: 25113753  
15. 
National Cancer Institute. NCI-Molecular Analysis for Therapy Choice (NCI-
MATCH) Trial.  http://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-
supported/nci-match. Accessed November 9, 2015. 
16. 
Hastie T. et al. The elements of statistical learning. 2nd Ed, Springer 2009. 
17. 
Aerts HJ, Velazquez ER, Leijenaar RT, et al. Decoding tumour phenotype by 
noninvasive imaging using a quantitative radiomics approach. Nat Commun. 
2014;5:4006. 
18. 
Segal, E. et al. Module networks: identifying regulatory modules and their condition 
specific regulators from gene expression data. Nat. Genet. 34, 166–176 (2003). 
19. 
Segal E, Sirlin CB, Ooi C, et al. Decoding global gene expression programs in liver 
cancer by noninvasive imaging. Nat Biotechnol 2007;25(6):675–680. 

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20. 
Overman MJ, Modak J, Kopetz S, Murthy R, Yao JC, Hicks ME, Abbruzzese JL, 
Tam AL. Use of research biopsies in clinical trials: are risks and benefits 
adequately discussed? J Clin Oncol. 2013 Jan 1;31(1):17-22. 
21. 
J. Doroshow, personal communication. 
22. 
M. Wallace and S. Hamilton personal communication. 
23. 
K. Flaherty, personal communication. 
24. 
Unpublished data.  
25. 
Vogelstein B, Papadopoulos N, Velculescu VE, et al. Cancer genome landscapes. 
Science 2013;339(6127): 1546–1558. 
26. 
Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched 
evolution revealed by multiregion sequencing. N Engl J Med 2012;366(10):883–
892. 
27. 
O'Connor JP, Rose CJ, Waterton JC, et al. e. Clin Cancer Res. 2015;21(2):249-57. 
28. 
Segal E, Sirlin CB, Ooi C, et al. Decoding global gene expression programs in liver 
cancer by noninvasive imaging. Nat Biotechnol 2007;25(6):675–680. 
29. 
Diehn M, Nardini C, Wang DS, et al. Identification of noninvasive imaging 
surrogates for brain tumor gene-expression modules. Proc Natl Acad Sci U S A 
2008;105(13):5213–5218. 
30. 
Rusinek D, et al. BRAFV600E-Associated Gene Expression Profile: Early Changes 
in the Transcriptome, Based on a Transgenic Mouse Model of Papillary Thyroid 
Carcinoma. PLoS One. 2015 Dec 1;10(12):e0143688. doi: 
10.1371/journal.pone.0143688. 
31. 
Seo JS, et al. The transcriptional landscape and mutational profile of lung 
adenocarcinoma. Genome Res. 2012 Nov;22(11):2109-19.   
32. 
Johansson P, et al. Confirmation of a BRAF mutation-associated gene expression 
signature in melanoma. Pigment Cell Res. 2007 Jun;20(3):216-21. 
33. 
Dressman MA, Baras A, Malinowski R, et al. Gene expression profiling detects 
gene amplification and differentiates tumor types in breast cancer. Cancer Res. 
2003;63(9):2194-9 
34. 
Gevaert O, Xu J, Hoang CD, et al. Non-small cell lung cancer: identifying 
prognostic imaging biomarkers by leveraging public gene expression microarray 
data—methods and preliminary results. Radiology 2012;264(2):387–396. 
35. 
Aerts HJ, Velazquez ER, Leijenaar RT, et al. Decoding tumour phenotype by 
noninvasive imaging using a quantitative radiomics approach. Nat Commun. 
2014;5:4006. 
36. 
Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, et al. Development 
and validation of a clinical cancer genomic profiling test based on massively 
parallel DNA sequencing. Nat Biotechnol 2013; 31:1023-1031 
 

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Molecular Analysis for Therapy Choice (MATCH) 
Appendix II 
 
Pathology Submission Guidelines 
The following items are included in Appendix II: 
1. List of Required Materials for MATCH  
2. Instructional memo to submitting pathologists 
3. ECOG-ACRIN Generic Specimen Submission Form (#2981) 
4. CLIA Laboratory Sample Submission Form 
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List of Required Material 
MATCH:  Molecular Analysis for Therapy Choice (MATCH) 
REQUIRED PATHOLOGY MATERIALS: 
Please review the study schema for a summary on when tumor tissue for screening 
assessments (Step 0 and Step 2 or 4) and progression (Step 8 after completion of all 
treatment on MATCH) is to be submitted.  
NOTE: 
Performance of biopsies during Step 0 for screening was closed to enrollment 
on May 22, 2017. Step 2 (or 4) screening is open only for patients who were 
originally assigned and registered to Step 1 treatment based on MATCH-
assay screening results. 
A repeat biopsy procedure, or bone marrow aspirate for multiple myeloma (if applicable), 
may be requested if submitted screening biopsy materials are inadequate for the first 
attempted screening assessments for Step 0 or Step 2 (or 4). Blood samples, from 
consenting patients, will also be collected and submitted with each biopsy (see Section 
9), end of cycle 2 or treatment on each MATCH subprotocol, and at Step 8. 
For a tumor sample to be considered adequate for copy number variation evaluation, a 
minimum of 70% tissue must be tumor after manual microdissection for tumor cell 
enrichment at the MD Anderson Tissue Qualification Laboratory. However, the assays 
will be attempted on tissue specimens that have at least 20% non-necrotic tumor cells 
present, which have been shown to be adequate for sequencing. 
Prior clinical pathology and molecular studies reports, including prior sequencing 
assessments, from the original diagnostic procedures and/or most recent 
procedure performed prior to step 0 registration, are required for central 
confirmation of histology and MUST be submitted with all screening specimens, 
or the sample may not be processed (see Section Error! Reference source not 
found.). This information is required for treatment assignment and WILL RESULT 
IN DELAYS if not provided in a timely manner. 
Pathology reports submitted with tissue specimens are NOT to be redacted. 
Results from screening and confirmation testing are returned to the site and will 
impact patient care. Adequate identification must be provided to ensure that the 
appropriate materials have been submitted and reporting is correct and to 
maintain “chain-of-custody”. 
All sample submissions MUST be logged and tracked in the ECOG-ACRIN Sample 
Tracking System (STS). If STS is unavailable at time of submission, a completed ECOG-
ACRIN Generic Specimen Submission Form (#2981) may be submitted with the biopsy 
materials with STS updated retroactively as soon as possible. Failure to update STS 
may result in delays in the central assessments and reporting results to the site. 
Biopsy guidelines and blood submission guidelines are provided in Section 9. 
NOTE: 
The order form for sample submission Kits is located in Appendix XII. 
NOTE: 
For the collection of biopsy specimens, fine needle aspiration followed by 
core needle biopsy is the preferred technique.  
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A. 
Pre-Registration (Step 0) 
1. Screening by the MATCH-assay – CLOSED MAY 22, 2017 
Tumor tissue specimens are to be submitted following pre-registration to Step 0. If 
tumor tissue is collected for the trial by a procedure following pre-registration to step 
0, tissue is to be sent the day of collection. 
For multiple myeloma, not plasmacytomas, fresh bone marrow aspirates collected in 
an EDTA vacutainer and smears must be submitted for all screenings. For 
plasmacytomas, follow the instructions for the solid tumor tissue submission 
requirements. 
For all other disease sites, FFPE blocks which meet the criteria below may submitted 
in lieu of fresh biopsy material for the first or repeat (if performed) screening attempt 
on Step 0, but not both. 
Options for sample submissions: 
Step 0 
Biopsy 1 
Biopsy Repeat 
Option 1 
Fresh Biopsy 
Fresh biopsy (#2) 
Option 2 
Fresh Biopsy 
Pre-Trial FFPE1 
Option 3 
Pre-Trial FFPE1 
Fresh Biopsy 
Outside 
Assay 
Pre-Trial FFPE2 
N/A 
1 If archived FFPE is submitted for analysis and additional FFPE is requested to meet the needs for the 
screening, the additional materials are considered to be for the same assessment and are logged 
under the same time point as the initial FFPE submission in STS. 
2. For patients for whom an applicable “rare variant  was identified by one of the outside designated 
laboratories (see Appendix XIV), the collection and submission of tumor tissue for the confirmation of 
the “rare variant  must follow the guidelines for the submission of tissue for screening at Step 0, 
Biopsy 1 options with the following changes: 
• FFPE tissue may be submitted after but no later than 8 weeks following registration to Step 1. 
• Submission should be logged under the STS time point named “Confirmation of Pre-Registration 
Outside Results  
Submission Requirements 
• 
Screening tissue submissions: 
a) Four fresh core biopsies in 10% NBF. FNA slide and FNA cells in cytolyte 
also requested to be submitted.  FNA, with cyto-pathologist real-time review, 
is to be performed to verify tumor tissue is being collected. For alternative 
acceptable submissions, see Section 9. 
OR 
b) FFPE Block(s): Metastatic tissue preferred. Tissue must have been collected 
within 6 months prior to pre-registration to Step 0 and patient must not have 
received any intervening therapy as excluded in Section 3.1.6.3 (see 
Appendix XV). FFPE tumor tissue block(s) must be submitted.  The optimal 
block is 70% tumor tissue.  Specimen size requirement is as follows: 
• 
Surface area of 25mm2 is optimal.  Minimum is 5mm2 and 
• 
Volume: 1mm3 optimal.  Minimum volume is 0.2mm3, however the 
success of DNA extraction decreases at suboptimal tissue volume  
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Specimens of suboptimal size, cellularity, or tumor content will require 
submission of more than one tumor block 
OR 
c) MULTIPLE MYELOMA ONLY: SUBMIT ASPIRATES FROM THE FIRST 
PULL. For plasmacytomas, see (a) and (b) above. 
Draw the bone marrow aspirate materials into a plain syringe, then: 
1. Use 1 drop to make 4 – 5 smears. 
2. Put 1 – 1.5 ml in one EDTA tube. 
3. Put remainder (5 - 10 ml) of bone marrow aspirate in the other EDTA 
tube. 
• 
Forms and Reports 
a) STS-generated shipping manifest 
b) Completed CLIA Laboratory Sample Submission Form 
c) Pertaining to original diagnostic primary and most recent biopsies: 
• 
Pathology report 
• 
All molecular, histological, and cytological reports, including prior 
sequencing studies 
• 
Do NOT redact the reports. 
d) Upon completion of review, the Institutional pathology report is to be 
submitted via Medidata Rave. 
NOTE: If the submitted material is inadequate for testing, a repeat biopsy for 
the screening assessment will be requested if the patient agrees. 
2. Pre-trial representative tumor tissue  
Tissue requirements: The optimal block is 70% tumor tissue.  Specimen size 
requirement is as follows: 
• 
Surface area of 25mm2 is optimal.  Minimum is 5mm2 and 
• 
Volume: 1mm3 optimal.  Minimum volume is 0.2mm3, however the success of 
DNA extraction decreases at suboptimal tissue volume 
If an existing block cannot be provided, the number of slides needed are dictated by 
the surface area and volume requirements above. It is important that slides be sent 
as soon as possible after cutting to be adequate for nucleic acid extraction. 
a. Tissue submitted for confirmation of “rare variant  assessments, as determined 
by a laboratory outside of the MATCH trial, tissue from the same specimen and 
timepoint (if possible) to that assayed by the outside laboratory is to be submitted 
either (a) upon request for mandatory central IHC required to determine 
treatment assignment or (b) within 8 weeks following registration to Step 1 
treatment. If not available, submit any available archived tumor tissue. Tissue 
requirements in terms of tumor content are equivalent to that outlined above for 
screening submissions. 
It is essential that the tissue submitted meet the guidelines indicated above. If 
tissue is unavailable for submission, the UNREDACTED pathology report and a 
statement justifying reason for inability to submit tissue must still be provided to 
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the MD Anderson TQL. Additionally, the inability to submit the material must be 
documented in the EA Sample Tracking System. 
NOTE: For these types of submissions, PLEASE STATE ON THE SHIPPING 
MANIFEST IF ENCLOSED SUBMITTED TISSUE WAS COLLECTED AT 
THE SAME TIME AS THE TISSUE SENT TO THE OUTSIDE 
LABORATORY OR IF IT IS FROM A DIFFERENT COLLECTION DATE 
THAN THE TISSUE SENT TO THE OUTSIDE LABORATORY. This 
information may be important for assessment of discordant results. 
NOTE: If adequate tissue is not available for confirmation testing, the MD Anderson 
TQL may reach out to the referring designated outside laboratory to request 
residual nucleic acids to complete these assessments.  Results from 
residual nucleic acids will not be distributed to the site as sequencing 
results were already provided to the site by the original referring designated 
laboratory. 
b. Additional tissue submitted from patients who consented to allow additional 
tissue to be submitted for research. available tissue is requested from any 
procedure performed, but if materials are limited the primary tumor tissue is 
preferred. 
B. 
Progression following Treatment – Submission of material for SECOND 
SCREENING 
If progression occurs after a CR/PR or after 6 months on assigned study treatment or 
the first screening biopsy occurred > 6 months, to be considered for additional treatment 
a biopsy is required. Tissue is to be sent day of collection.  Delays of submission should 
be reported to the CBPF. 
Patients who are to be considered for a second round of treatment on this trial MUST be 
registered to a screening step (STEP 2 or STEP 4) prior to submission of the biopsy 
material in order for the submitted tissue to be tagged as SCREENING materials.   
• 
Tissue submissions: 
a) Four fresh core biopsies in 10% NBF. FNA slide and FNA cells in cytolyte also 
requested to be submitted.  FNA, with cyto-pathologist real-time review, is to be 
performed to verify tumor tissue is being collected. Fresh excisional biopsy or 
tumor captured during a clinical procedure may be submitted in lieu of the core 
biopsy and FNAs. For alternative acceptable submissions, see Section 9. 
OR 
b) MULTIPLE MYELOMA ONLY: IF BM ASPIRATE WILL BE SUBMITTED, 
SUBMIT ASPIRATES FROM THE FIRST PULL. 
NOTE: 
For plasmacytomas, follow (a) above. 
Draw the bone marrow aspirate materials into a plain syringe, then: 
1. Use 1 drop to make 4 – 5 smears. 
2. Put 1 – 1.5 ml in one EDTA tube. 
3. Put remainder (5 - 10 ml) of bone marrow aspirate in the other EDTA tube. 
• 
Forms and Reports 
a) STS-generated shipping manifest 
b) Completed CLIA Laboratory Sample Submission Form 
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c) Pertaining to original diagnostic primary and most recent biopsies: 
• 
Pathology report 
• 
All molecular, histological, and cytological reports 
• 
Do NOT redact the reports. 
d) Upon completion of review, if performed, the Institutional pathology report is to be 
submitted via Medidata Rave. 
NOTE: 
If the submitted material is inadequate for testing, a repeat biopsy for the 
screening assessment will be requested if the patient agrees. 
C. 
Progression after completion of all EAY131 Protocol Treatment 
NOTE: 
For plasmacytomas, follow the instructions in (a) above. 
A research biopsy will be requested upon progression once all treatment has been 
completed on the MATCH study for research purposes only in order to determine 
mechanisms of resistance. No results of the research tests performed to determine 
potential mechanisms of resistance will be provided to the physician or patients. This 
biopsy may or may not be performed depending on the patient’s status, signed patient 
consent and registration to Step 8. If disease progression on the last treatment that the 
patient receives on the MATCH study occurs within 6 months of the most recent 
screening biopsy, no “end of treatment  biopsy material is needed/requested. If this 
research biopsy is performed, the tissue is to be sent day of collection. Delays of 
submission should be reported to the CBPF. 
• 
Tissue submissions: 
a) Four fresh core biopsies in 10% NBF. FNA slide and FNA cells in cytolyte also 
requested to be submitted. FNA, with cyto-pathologist real-time review, is to be 
performed to verify tumor tissue is being collected. For alternative acceptable 
submissions, see Section 9. 
OR 
b) MULTIPLE MYELOMA ONLY: SUBMIT ASPIRATES FROM THE FIRST PULL. 
Draw the bone marrow aspirate materials into a plain syringe, then: 
1. Use 1 drop to make 4 – 5 smears. 
2. Put 1 – 1.5 ml in one EDTA tube. 
3. Put remainder (5 - 10 ml) of bone marrow aspirate in the other EDTA tube. 
• 
Forms and Reports 
a) STS-generated shipping manifest 
b) Completed CLIA Laboratory Sample Submission Form 
c) Pertaining to original diagnostic primary and most recent biopsies: 
• 
Pathology report 
• 
All molecular, histological, and cytological reports, including prior sequencing 
studies. 
• 
Do NOT redact the reports. 
d) Upon completion of review, if performed, the Institutional pathology report is to be 
submitted via Medidata Rave. 
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NOTE: 
If the submitted material is inadequate for testing, a repeat biopsy for the 
screening assessment will be requested if the patient agrees. 
D. 
SUBMISSION REQUIREMENTS: 
Samples must be labeled with 
Patient's name (last, first) 
Protocol number (EAY131) 
The patient's EAY131 ECOG-ACRIN case ID 
Date and time of sample collection 
Institution name 
Reminder: Prior clinical pathology and molecular studies reports, from the 
original diagnostic procedures and/or most recent procedure performed prior to 
step 0 registration, are required for central confirmation of histology and MUST be 
submitted with all screening specimens, or the sample may not be processed. 
Ship to the following address: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3598 
1515 Holcombe Blvd 
Houston, TX 77030 
For results and general inquiries: 
MATCHTRIAL@mdanderson.org & MATCH@jimmy.harvard.edu 
Phone: 1-844-744-2420 (OPTION 4) Fax: 713-745-4925 
For all kit related inquiries: 
EACBPF@mdanderson.org  
Phone: 1-844-744-2420 Fax: 713-563-6506 
 
Rev.5/16 
Rev. 12/16 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: August 12, 2015 
134 
 
MEMORANDUM 
TO:  
__________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
____________________________________ 
SUBJECT: 
Submission of Pathology Materials for EAY131: Molecular Analysis for 
Therapy Choice (MATCH) 
The patient named on the attached request has been entered onto an ECOG-ACRIN 
protocol by _____________________________ (ECOG-ACRIN Investigator). This 
protocol requires the submission of pathology materials for screening assessments and 
research. 
Keep copies of all submitted forms for your records and return the completed Requisition 
Form, the surgical pathology report(s), the slides and/or blocks and any other required 
material (see List of Required Material) to the Clinical Research Associate (CRA). The 
CRA will forward all required pathology material to MD Anderson Pathology Laboratory. 
Guidelines for performance of the biopsies are provided in Section 9 of the protocol. 
Reports submitted with the tissue are NOT to be redacted, as adequate identification is 
required to ensure the appropriate materials have been received and to maintain “chain-
of-custody  of the materials. 
A report of the screening results or confirmation testing results from the evaluation of 
tissue or bone marrow provided by the site, including the identification of the trial-specific 
actionable targets, will be returned to the site and may impact patient care. 
Residual materials from specimens submitted for this study will be retained at the 
ECOG-ACRIN Central Biorepository for future studies. If you have any questions 
regarding this request, please call 1-844-744-2420 (713-745-4440 Local or International 
Sites), Fax: 713-745-4925, or Email: MATCHTRIAL@mdanderson.org. 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
 
Thank you. 
 
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Molecular Analysis for Therapy Choice (MATCH) 
Appendix III 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the ECOG-ACRIN web site at http://www.ecog.org. As this is a 
personal letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ______________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we will improve treatment and quality of life for those with your type of cancer.  
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank 
you again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 

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Version Date: October 9, 2020 
 
NCI Update Date: August 12, 2015 
138 
Molecular Analysis for Therapy Choice (MATCH) 
Appendix IV 
 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s) ) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator  
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI. If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement. A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
2. For a clinical protocol where there is an Agent used in combination with (an)other 
investigational Agent(s), each the subject of different Collaborative Agreements, the access 
to and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data ): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order, as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually Identifiable 
Health Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 

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5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication. Collaborator(s) will have 30 days from the date 
of receipt for review.  Collaborator shall have the right to request that publication be delayed 
for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings. Press 
releases and other media presentations must also be forwarded to CTEP prior to release. 
Copies of any manuscript, abstract and/or press release/ media presentation should be sent 
to: 
Email: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 

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Version Date: October 9, 2020 
 
NCI Update Date: August 12, 2015 
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Molecular Analysis for Therapy Choice (MATCH) 
Appendix V 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 

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

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Molecular Analysis for Therapy Choice (MATCH) 
Appendix VII 
 
MATCH Actionable Mutations of Interest 
Cell survival 
PI3K pathway 
• 
mTOR : MLN0128/TAK-228 
• 
TSC1/2: MLN0128/TAK-228 
• 
PTEN Mutation or Deletion:  
• 
GSK2636771 (arm completed/closed); 
• 
copanlisib 
• 
PTEN loss:  
• 
GSK2636771 (arm completed/closed); 
• 
copanlisib 
• 
PIK3CA:  
• 
taselisib (arm completed/closed); 
• 
copanlisib (arm completed/closed) 
• 
AKT mutations/amplifications:  
• 
AZD5363 (arm completed/closed) 
• 
ipatasertib 
MAP Kinase pathway 
• 
BRAF mutations:   
• 
BRAF nonV600 mutations/fusions:  
• 
trametinib (arm completed/closed) 
• 
BVD-523FB (ulixertinib) 
• 
BRAF V600E or K mutations: trametinib/dabrafenib (arm completed/closed) 
• 
NRAS mutations: binimetinib (arm completed/closed) 
• 
NF1 mutations: trametinib (arm completed/closed) 
• 
GNAQ, GNA11 mutations: trametinib 
• 
NF2 loss: VS6063 (defactinib) (arm completed/closed) 
Growth Factors 
• 
EGFR:  
• 
Rare activating mutations: afatinib 
• 
T790M mutations, certain rare activating mutations: AZD9291 
• 
HER2 mutation: afatinib, (arm completed/closed) 
• 
HER2 amplification: 
• 
TDM1 (arm completed/closed); 
• 
trastuzumab/pertuzumab 
• 
FGFR translocation/mutation:  
Rev. 8/15 
Rev. 2/16 
Rev.5/16 
Rev.12/16 
Rev. 3/17 
Rev. 5/17 
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NCI Update Date: August 12, 2015 
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• 
AZD4547 (arm completed/closed) 
• 
JNJ-42756493 (erdafitinib) 
• 
C-KIT: sunitinib 
• 
ALK rearrangements: crizotinib 
• 
ROS translocation: crizotinib 
• 
MET amplification: crizotinib (arm completed/closed) 
• 
MET exon 14 skipping: crizotinib 
• 
Hedgehog pathway: vismodegib  
• 
NTRK fusions: LOXO-101 
Cell cycle inhibitors: 
• 
CCND1, 2, 3 amplification: palbociclib (arm completed/closed) 
• 
CDK4, CDK6 amplification: palbociclib (arm completed/closed) 
DNA Repair: 
• 
BRCA1, BRCA2: AZD1775 (arm completed/closed) 
• 
Mismatch repair: nivolumab (arm completed/closed) 
Other 
• 
DDR2 mutation: dasatinib (arm closed) 
Please refer to Section 1.4.2 and Appendix XVII for information on the definitions of the 
study’s Levels of Evidence (LOEs) for agents and variants, and the process by which 
certain types of specific aMOIs (within the categories noted above) may be added 
dynamically to the study. 
NOTE: 
The information above does not reflect the accrual status of the subprotocols 
in real time. Please refer to the following website for information on the 
accrual status of each subprotocol: http://ecog-acrin.org/trials/nci-match-
eay131 
 

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Version Date: October 9, 2020 
 
NCI Update Date: August 12, 2015 
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Molecular Analysis for Therapy Choice (MATCH) 
Appendix VIII 
 
Instructions for Reporting Pregnancies on a Clinical Trial 
What needs to be reported? 
All pregnancies and suspected pregnancies (including a positive or inconclusive pregnancy 
test regardless of age or disease state) of a female patient while she is on the MATCH 
subprotocol treatment or within 28 days of the female patient’s last dose of the MATCH 
subprotocol treatment must be reported in an expeditious manner. The outcome of the 
pregnancy and neonatal status must also be reported. 
How should the pregnancy be reported? 
The pregnancy, suspected pregnancy, or positive/inconclusive pregnancy test must be 
reported via CTEP’s Adverse Event Reporting System (CTEP-AERs) 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm) 
When does a pregnancy, suspected pregnancy or positive/inconclusive pregnancy 
test need to be reported? 
An initial report must be done within 24 hours of the Investigator’s learning of the event, 
followed by a complete expedited CTEP-AERs report within 5 calendar days of the initial 24-
hour report. 
What other information do I need in order to complete the CTEP-AERs report for a 
pregnancy? 
• 
The pregnancy (fetal exposure) must be reported as a Grade 3 “Pregnancy, puerperium 
and perinatal conditions – Other (pregnancy)  under the System Organ Class (SOC) 
“Pregnancy, puerperium and perinatal conditions  
• 
The pregnancy must be reported within the timeframe specified in the Adverse Event 
Reporting section of the protocol for a grade 3 event.   
• 
The start date of the pregnancy should be reported as the calculated date of conception.   
• 
The potential risk of exposure of the fetus to the investigational agent(s) or 
chemotherapy agent(s) should be documented in the “Description of Event  section of 
the CTEP-AERs report.  
What else do I need to know when a pregnancy occurs to a patient? 
• 
The Investigator must follow the female patient until completion of the pregnancy and 
must report the outcome of the pregnancy and neonatal status via CTEP-AERs.  
• 
The decision on whether an individual female patient can continue protocol treatment will 
be made by the site physician in collaboration with the study chair and ECOG-ACRIN 
Operations Office – Boston.  Please contact the ECOG-ACRIN Operations Office – 
Boston to ask for a conference call to be set up with the appropriate individuals.   
• 
It is recommended the female subject be referred to an obstetrician-gynecologist, 
preferably one experienced in reproductive toxicity for further evaluation and counseling.  
Rev. Add13 
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How should the outcome of a pregnancy be reported? 
The outcome of a pregnancy should be reported as an amendment to the initial CTEP-AERs 
report if the outcome occurs on the same cycle of treatment as the pregnancy itself.  
However, if the outcome of the pregnancy occurred on a subsequent cycle, a new and 
separate CTEP-AERs report should be initiated reporting the outcome of the pregnancy. 
What constitutes an abnormal outcome? 
An abnormal outcome is defined as any pregnancy that results in the birth of a child with 
persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions (formerly referred to as disabilities), congenital anomalies, or birth defects.  For 
assistance in recording the grade or category of these events, please contact the CTEP 
AEMD Help Desk at 301-897-7497 or aemd@tech-res.com, for it will need to be discussed 
on a case by case basis.   
Reporting a Pregnancy Loss 
A pregnancy loss is defined in CTCAE as “A death in utero.  
It must be reported via CTEP-AERs as Grade 4 “Pregnancy Loss  under the System Organ 
Class (SOC) “Pregnancy, puerperium and perinatal conditions”.   
A pregnancy loss should NOT be reported as a Grade 5 event as currently CTEP-AERs 
recognizes this event as a patient’s death. 
Reporting a Neonatal Death 
A neonatal death is defined in CTCAE as “A newborn death occurring during the first 28 
days after birth  that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention. However, for this protocol, any neonatal death that occurs 
within 28 days of birth, without regard to causality, must be reported via CTEP-AERs AND 
any infant death after 28 days that is suspected of being related to the in utero exposure to 
the MATCH subprotocol treatment must also be reported via CTEP-AERs. 
It must be reported via CTEP-AERs as Grade 4 “Death neonatal  under the System Organ 
Class (SOC) “General disorder and administration site conditions . 
A neonatal death should NOT be reported as a Grade 5 event as currently CTEP-AERs 
recognizes this event as a patient’s death. 
Additional Required Forms: 
When submitting CTEP-AERs reports for pregnancy, pregnancy loss, or neonatal loss, the 
CTEP 'Pregnancy Information Form' must be completed and faxed along with any 
additional medical information to CTEP (301-897-7404). This form is available on CTEP's 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/PregnancyReport
Form.pdf) 

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Version Date: October 9, 2020 
 
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Molecular Analysis for Therapy Choice (MATCH) 
Appendix IX 
 
List of MATCH Subprotocols and Associated Subprotocol Version Dates 
Table 1. List of MATCH Subprotocols 
EAY131-A 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol A: Phase II Trial of Afatinib in Patients with Solid Tumors 
(Other than Small Cell and Non-Small Cell Lung Cancer) or Lymphomas, That Have Activating Mutations of EGFR and Have Progressed After 
Standard Treatment 
EAY131-B 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol B: Phase II Study of Afatinib in Patients with Tumors with 
HER2 Activating Mutations 
EAY131-C1 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol C1: Crizotinib in Patients with Tumors with MET 
Amplification 
EAY131-C2 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol C2: Crizotinib in Patients with Tumors with MET Exon 14 
Deletion 
EAY131-E 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol E: AZD9291 in Patients with Tumors Having EGFR T790M 
Mutations (Except Non-Small Cell Lung Cancer) or Rare Activating Mutations of EGFR 
EAY131-F 
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 
EAY131-G 
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) 
EAY131-H 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol H: Phase II Study of Dabrafenib and Trametinib in Patients 
with Tumors with BRAF V600E or V600K Mutations (Excluding Melanoma, Thyroid Cancer, and Colorectal Adenocarcinoma) 
EAY131-I 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol I: GDC-0032 (taselisib) in Patients with Tumors (other than 
breast cancer) with PIK3CA Mutation but without KRAS Mutation or PTEN Loss 
EAY131-J 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol J: Trastuzumab and Pertuzumab (HP) in Patients with Non-
Breast, Non-Gastric/GEJ Cancers with HER2 Amplification 
EAY131-K1 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol K1: Phase 2 Study of JNJ-42756493 (Erdafitinib) in Patients 
with Tumors with FGFR Amplifications 
EAY131-K2 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol K2: Phase 2 Study of JNJ-42756493 (erdafitinib) in Patients 
with Tumors with FGFR Mutations or Fusions 
EAY131-L 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol L: Phase II Study of MLN0128 (TAK-228) in Patients with 
Tumors with mTOR Mutations 
Rev. 8/15, Rev. 2/16, 5/16 
Rev. 3/17 
Rev. 5/17 
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Rev. Add20 
Rev. Add21 
Rev. Add22 
Rev. Add23 
Rev. Add25 
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EAY131-M 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol M: Phase II Study of MLN0128 (TAK-228) in Patients with 
Tumors with TSC1 or TSC2 Mutations 
EAY131-N 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol N: Phase II Study of PI3K Beta Specific Inhibitor, 
GSK2636771, in Patients with Tumors with PTEN Mutation or Deletion, with PTEN Expression on IHC 
EAY131-P 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol P: Phase II Study of PI3K Beta Specific Inhibitor, 
GSK2636771, in Patients with Tumors with PTEN Loss by IHC 
EAY131-Q 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol Q: Ado-trastuzumab Emtansine in Patients with Tumors with 
HER2 Amplification (Except Breast and Gastric/Gastro-Esophageal Junction (GEJ) Adenocarcinomas) 
EAY131-R 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol R: Phase II Study of Trametinib in Patients with BRAF 
Fusions, or with Non-V600E, Non-V600K BRAF Mutations 
EAY131-S1 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol S1: Phase II Study of Trametinib in Patients with Tumors 
with NF1 mutations 
EAY131-S2 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol S2: Phase II Study of Trametinib in Patients with Tumors 
with GNAQ or GNA11 mutations 
EAY131-T 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol T: GDC-0449 (vismodegib) in Patients with Tumors (except 
basal cell skin carcinoma) with Smoothened (SMO) or Patched 1 (PTCH1) Mutations 
EAY131-U 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol U: VS-6063 (Defactinib) in Patients with Tumors with NF2 
Loss 
EAY131-V 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol V: Phase II Study of Sunitinib in Patients with Tumors with 
cKIT Mutations (Excluding GIST, Renal Cell Carcinoma or Pancreatic Neuroendocrine Tumor) 
EAY131-W 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol W: Phase II Study of AZD4547 in Patients with Tumors with 
Aberrations in the FGFR Pathway 
EAY131-X 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol X: Phase II Study of Dasatinib in Patients with Tumors with 
DDR2 Mutations 
EAY131-Y 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol Y: AZD5363 in Patients with Tumors with AKT Mutations 
EAY131-Z1A 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol Z1A: Binimetinib in Patients with Tumors (Other Than 
Melanoma) with NRAS Mutations 
EAY131-Z1B 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol Z1B: Phase II Study of Palbociclib in Patients with Tumors 
with CCND1, 2, 3 Amplification 
EAY131-Z1C 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol Z1C: Phase II Study of Palbociclib (PD-0332991) in Patients 
with Tumors with CDK4 or CDK6 Amplification and Rb Protein Expression by IHC 
EAY131-Z1D 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol Z1D: Nivolumab in Patients with Tumors with Mismatch 
Repair Deficiency (Excluding Colorectal Cancer) 

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EAY131-Z1E 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol Z1E: LOXO-101 in Patients with Tumors with NTRK Fusions 
EAY131-Z1F 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol Z1F: Phase II Study of Copanlisib in Patients with Tumors 
with PIK3CA Mutations (PTEN Loss Allowed) 
EAY131-Z1G 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol Z1G: Phase II Study of Copanlisib in Patients with Tumors 
with PTEN Loss by IHC and any PTEN Sequencing Result 
EAY131-Z1H 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol Z1H: Phase II Study of Copanlisib in Patients with Tumors 
with Deleterious PTEN Sequencing Result and PTEN Expression by IHC 
EAY131-Z1I 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol Z1E: Phase II Study of AZD1775 in Patients with Tumors 
Containing BRCA1 and BRCA2 Mutations 
EAY131-Z1K 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol Z1K: Ipatasertib in Patients with Tumors with AKT Mutations 
EAY131-Z1L 
Molecular Analysis for Therapy Choice (MATCH) - MATCH Treatment Subprotocol Z1L: BVD-523FB (Ulixertinib) in Patients with Tumors with 
BRAF Fusions, or with Non-V600E, Non-V600K BRAF Mutations 
Table 2. Index of MATCH Subprotocol Version Dates 
The EAY131 study is considered one study under one IND consisting of a Master Protocol component and multiple subprotocol 
components, with each component being contained in its own separate document.  Each “component” consists of the protocol 
document and its associated informed consent document. Since each subprotocol component operates independently from the 
other subprotocol components contained in EAY131, each has its own version date. As changes are made in the various 
components of the EAY131 study over time via addendum/amendment or update, the version date for a particular subprotocol 
component (i.e., protocol document and associated informed consent document) will change ONLY IF there are changes made in 
that subprotocol. In order to keep track of changes in the various component documents over the course of the study, the index 
below will track each addendum/amendment or update made and list the version date of each component of EAY131 associated 
with that addendum/amendment or update. The Master Protocol component of EAY131 will change if there are ANY changes in ANY 
of the subprotocols as the Master Protocol component will always need to include the updated version dates for all subprotocol 
components in the index below. 
The index will allow the sites enrolling patients on the EAY131 study or any stakeholder overseeing various aspects of the study 
(e.g., Network Group, NCI/DCTD, NCI CIRB, FDA) to know if changes have been made in any of the EAY131 study components 
over time, and if so, in relation to which addendum/amendment or update and the date of that change. 
EAY131 
Component 
EAY131 Component Version Date 
Pre-
Activation 
For Add #1/ 
Activation 
For Add #2 
For Add #3 
For Add #4 For Add #5 For Add #6 
For Add #7 
For Add #8 
For Add #9 
For Add #10 
EAY131 
(Master 
Protocol) 
5/7/2015 
8/6/2015 
1/20/2016 
5/25/2016 
7/1/2016 
11/9/2016 
12/6/2016 
2/6/2017 
2/15/2017 
3/8/2017 
4/10/2017 
Rev. 8/15 
Rev. 7/16 
Rev. 12/16 
Rev. 1/17 
Rev. 3/17 
Rev. 8/17 
Rev. Add12 
Rev. Add14 
Rev. Add15 
Rev. Add16 
Rev. Add17 
Rev. Add18 
Rev. Add19 

ECOG-ACRIN 
EAY131 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: August 12, 2015 
149 
EAY131 
Component 
EAY131 Component Version Date 
Pre-
Activation 
For Add #1/ 
Activation 
For Add #2 
For Add #3 
For Add #4 For Add #5 For Add #6 
For Add #7 
For Add #8 
For Add #9 
For Add #10 
EAY131-A 
N/A 
8/6/2015 
1/20/2016 
3/3/2016 
3/3/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/15/2017 
2/15/2017 
2/15/2017 
EAY131-B 
N/A 
8/6/2015 
1/20/2016 
3/3/2016 
3/3/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/15/2017 
2/15/2017 
2/15/2017 
EAY131-C1 
N/A 
N/A 
N/A 
5/3/2016 
5/3/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-C2 
N/A 
N/A 
N/A 
5/3/2016 
5/3/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-E 
N/A 
8/6/2015 
1/20/2016 
3/3/2016 
7/1/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-F 
5/7/2015 
8/6/2015 
1/20/2016 
5/3/2016 
5/3/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-G 
5/7/2015 
8/6/2015 
1/20/2016 
5/3/2016 
5/3/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-H 
5/7/2015 
8/6/2015 
1/20/2016 
5/3/2016 
5/3/2016 
11/9/2016 
12/6/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-I 
N/A 
N/A 
1/20/2016 
3/3/2016 
7/1/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-J 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
2/6/2017 
2/6/2017 
2/6/2017 
4/10/2017 
EAY131-K1 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
EAY131-K2 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
EAY131-L 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
2/6/2017 
2/6/2017 
3/8/2017 
3/8/2017 
EAY131-M 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
2/6/2017 
2/6/2017 
3/8/2017 
3/8/2017 
EAY131-N 
N/A 
N/A 
1/20/2016 
3/3/2016 
3/3/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-P 
N/A 
N/A 
1/20/2016 
1/20/2016 
1/20/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-Q 
N/A 
8/6/2015 
1/20/2016 
3/3/2016 
3/3/2016 
11/9/2016 
12/6/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-R 
5/7/2015 
8/6/2015 
1/20/2016 
5/3/2016 
5/3/2016 
11/9/2016 
12/6/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-S1 
N/A 
N/A 
1/20/2016 
5/3/2016 
5/3/2016 
11/9/2016 
12/6/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-S2 
N/A 
N/A 
1/20/2016 
5/3/2016 
5/3/2016 
11/9/2016 
12/6/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-T 
N/A 
N/A 
1/20/2016 
5/3/2016 
5/3/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/6/2017 
2/6/2017 
4/10/2017 
EAY131-U 
N/A 
8/6/2015 
1/20/2016 
3/3/2016 
7/1/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-V 
N/A 
8/6/2015 
1/20/2016 
3/3/2016 
3/3/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-W 
N/A 
N/A 
N/A 
5/25/2016 
7/1/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-X 
N/A 
N/A 
1/20/2016 
1/20/2016 
1/20/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-Y 
N/A 
N/A 
N/A 
5/3/2016 
7/1/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-Z1A 
N/A 
N/A 
N/A 
5/3/2016 
5/3/2016 
11/9/2016 
12/6/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 

ECOG-ACRIN 
EAY131 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: August 12, 2015 
150 
EAY131 
Component 
EAY131 Component Version Date 
Pre-
Activation 
For Add #1/ 
Activation 
For Add #2 
For Add #3 
For Add #4 For Add #5 For Add #6 
For Add #7 
For Add #8 
For Add #9 
For Add #10 
EAY131-Z1B 
N/A 
N/A 
N/A 
5/3/2016 
5/3/2016 
11/9/2016 
11/9/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-Z1C 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-Z1D 
N/A 
N/A 
N/A 
5/3/2016 
7/1/2016 
11/9/2016 
12/6/2016 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-Z1E 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-Z1F 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
EAY131-Z1G 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
EAY131-Z1H 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
EAY131-Z1I 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-Z1K 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
EAY131-Z1L 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
 
EAY131 
Component 
EAY131 Component Version Date 
For Add 
#11 
For Add #12 For Add #13 For Add #14 For Add #15 For Add #16 For Add #17 For Add #18 For Add #19 For Add #20 For Add #21 
EAY131 
(Master 
Protocol) 
7/19/2017 
1/29/2018 
5/16/2018 
6/21/2018 
7/26/2018 
12/11//2018 
1/8/2019 
1/25/2019 
3/11/2019 
5/14/2019 
7/10/2019 
EAY131-A 
2/15/2017 
2/15/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
3/11/2019 
3/11/2019 
7/10/2019 
EAY131-B 
2/15/2017 
2/15/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
7/10/2019 
EAY131-C1 
7/19/2017 
7/19/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
1/25/2019 
1/25/2019 
1/25/2019 
1/25/2019 
EAY131-C2 
7/19/2017 
7/19/2017 
5/16/2018 
5/16/2018 
5/16/2018 
12/11/2018 
12/11/2018 
1/25/2019 
3/11/2019 
3/11/2019 
3/11/2019 
EAY131-E 
2/6/2017 
1/29/2018 
5/16/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
EAY131-F 
7/19/2017 
7/19/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
1/25/2019 
3/11/2019 
3/11/2019 
3/11/2019 
EAY131-G 
7/19/2017 
7/19/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
1/25/2019 
1/25/2019 
1/25/2019 
1/25/2019 
EAY131-H 
2/6/2017 
2/6/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
3/11/2019 
3/11/2019 
7/10/2019 
EAY131-I 
2/6/2017 
2/6/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
1/25/2019 
1/25/2019 
1/25/2019 
1/25/2019 
EAY131-J 
4/10/2017 
4/10/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
1/25/2019 
1/25/2019 
1/25/2019 
7/10/2019 
EAY131-K1 
N/A 
N/A 
5/16/2018 
5/16/2018 
5/16/2018 
12/11/2018 
12/11/2018 
12/11/2018 
3/11/2019 
3/11/2019 
3/11/2019 

ECOG-ACRIN 
EAY131 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: August 12, 2015 
151 
EAY131 
Component 
EAY131 Component Version Date 
For Add 
#11 
For Add #12 For Add #13 For Add #14 For Add #15 For Add #16 For Add #17 For Add #18 For Add #19 For Add #20 For Add #21 
EAY131-K2 
N/A 
N/A 
5/16/2018 
5/16/2018 
5/16/2018 
12/11/2018 
12/11/2018 
12/11/2018 
3/11/2019 
3/11/2019 
3/11/2019 
EAY131-L 
3/8/2017 
3/8/2017 
5/16/2018 
5/16/2018 
5/16/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
EAY131-M 
3/8/2017 
3/8/2017 
5/16/2018 
5/16/2018 
5/16/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
EAY131-N 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-P 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-Q 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
12/11/2018 
1/8/2019 
1/8/2019 
1/8/2019 
1/8/2019 
1/8/2019 
EAY131-R 
2/6/2017 
2/6/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
3/11/2019 
3/11/2019 
3/11/2019 
EAY131-S1 
2/6/2017 
2/6/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
3/11/2019 
3/11/2019 
3/11/2019 
EAY131-S2 
2/6/2017 
2/6/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
3/11/2019 
3/11/2019 
3/11/2019 
EAY131-T 
4/10/2017 
4/10/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
7/10/2019 
EAY131-U 
7/19/2017 
7/19/2017 
7/19/2017 
7/19/2017 
7/19/2017 
7/19/2017 
7/19/2017 
7/19/2017 
7/19/2017 
7/19/2017 
7/10/2019 
EAY131-V 
2/6/2017 
2/6/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
3/11/2019 
3/11/2019 
7/10/2019 
EAY131-W 
2/6/2017 
2/6/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
EAY131-X 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-Y 
7/19/2017 
7/19/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
7/10/2019 
EAY131-Z1A 
2/6/2017 
2/6/2017 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
EAY131-Z1B 
2/6/2017 
2/6/2017 
5/16/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
EAY131-Z1C 
2/6/2017 
2/6/2017 
5/16/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
EAY131-Z1D 
2/6/2017 
2/6/2017 
5/16/2018 
5/16/2018 
7/26/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
EAY131-Z1E 
2/6/2017 
1/29/2018 
5/16/2018 
6/21/2018 
6/21/2018 
6/21/2018 
1/8/2019 
1/8/2019 
1/8/2019 
1/8/2019 
1/8/2019 
EAY131-Z1F 
N/A 
N/A 
5/16/2018 
5/16/2018 
5/16/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
EAY131-Z1G 
N/A 
N/A 
5/16/2018 
5/16/2018 
5/16/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
EAY131-Z1H 
N/A 
N/A 
5/16/2018 
5/16/2018 
5/16/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
EAY131-Z1I 
2/6/2017 
2/6/2017 
5/16/2018 
6/21/2018 
6/21/2018 
6/21/2018 
1/8/2019 
1/8/2019 
1/8/2019 
1/8/2019 
7/10/2019 
EAY131-Z1K 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
5/14/2019 
5/14/2019 
EAY131-Z1L 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
5/14/2019 
5/14/2019 
 

ECOG-ACRIN 
EAY131 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: August 12, 2015 
152 
EAY131 
Component 
EAY131 
Component 
Version Date 
EAY131 
Component 
Version Date 
EAY131 
Component 
Version Date 
EAY131 
Component 
Version Date 
EAY131 
Component 
Version Date 
For Add #22 
For Add #23 
For Add #24 
For Add25 
For Add26 
EAY131 
(Master 
Protocol) 
8/12/2019 
10/03/2019 
2/28/2020 
9/15/2020 
10/09/2020 
EAY131-A 
7/10/2019 
7/10/2019 
7/10/2019 
9/15/2020 
9/15/2020 
EAY131-B 
7/10/2019 
7/10/2019 
7/10/2019 
7/10/2019 
7/10/2019 
EAY131-C1 
1/25/2019 
1/25/2019 
2/28/2020 
8/19/2020 
8/19/2020 
EAY131-C2 
3/11/2019 
3/11/2019 
2/28/2020 
8/19/2020 
8/19/2020 
EAY131-E 
6/21/2019 
10/03/2019 
10/03/2019 
8/19/2020 
8/19/2020 
EAY131-F 
3/11/2019 
3/11/2019 
3/11/2019 
3/11/2019 
3/11/2019 
EAY131-G 
1/25/2019 
1/25/2019 
1/25/2019 
1/25/2019 
1/25/2019 
EAY131-H 
7/10/2019 
7/10/2019 
7/10/2019 
8/19/2020 
8/19/2020 
EAY131-I 
7/10/2019 
7/10/2019 
7/10/2019 
7/10/2019 
7/10/2019 
EAY131-J 
8/12/2019 
8/12/2019 
8/12/2019 
8/19/2020 
8/19/2020 
EAY131-K1 
3/11/2019 
3/11/2019 
3/11/2019 
3/11/2019 
3/11/2019 
EAY131-K2 
3/11/2019 
3/11/2019 
3/11/2019 
8/19/2020 
8/19/2020 
EAY131-L 
12/11/2018 
10/03/2019 
10/03/2019 
8/19/2020 
8/19/2020 
EAY131-M 
12/11/2018 
10/03/2019 
2/28/2020 
8/19/2020 
8/19/2020 
EAY131-N 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-P 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-Q 
1/8/2019 
1/8/2019 
2/28/2020 
8/19/2020 
8/19/2020 
EAY131-R 
3/11/2019 
3/11/2019 
3/11/2019 
8/19/2020 
8/19/2020 
EAY131-S1 
3/11/2019 
3/11/2019 
3/11/2019 
8/19/2020 
8/19/2020 
EAY131-S2 
3/11/2019 
3/11/2019 
3/11/2019 
8/19/2020 
8/19/2020 
EAY131-T 
7/10/2019 
7/10/2019 
7/10/2019 
8/19/2020 
8/19/2020 
EAY131-U 
7/10/2019 
7/10/2019 
7/10/2019 
7/10/2019 
7/10/2019 
EAY131-V 
7/10/2019 
7/10/2019 
7/10/2019 
8/19/2020 
8/19/2020 
EAY131-W 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 

ECOG-ACRIN 
EAY131 
Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: August 12, 2015 
153 
EAY131 
Component 
EAY131 
Component 
Version Date 
EAY131 
Component 
Version Date 
EAY131 
Component 
Version Date 
EAY131 
Component 
Version Date 
EAY131 
Component 
Version Date 
For Add #22 
For Add #23 
For Add #24 
For Add25 
For Add26 
EAY131-X 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
2/6/2017 
EAY131-Y 
7/10/2019 
7/10/2019 
7/10/2019 
8/19/2020 
8/19/2020 
EAY131-Z1A 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
5/16/2018 
EAY131-Z1B 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
6/21/2018 
EAY131-Z1C 
6/21/2018 
6/21/2018 
2/28/2020 
8/19/2020 
10/9/2020 
EAY131-Z1D 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
12/11/2018 
EAY131-Z1E 
1/8/2019 
10/03/2019 
10/03/2019 
8/19/2020 
8/19/2020 
EAY131-Z1F 
8/12/2019 
8/12/2019 
8/12/2019 
8/12/2019 
8/12/2019 
EAY131-Z1G 
8/12/2019 
8/12/2019 
8/12/2019 
8/19/2020 
8/19/2020 
EAY131-Z1H 
8/12/2019 
8/12/2019 
8/12/2019 
8/19/2020 
8/19/2020 
EAY131-Z1I 
7/10/2019 
7/10/2019 
7/10/2019 
7/10/2019 
7/10/2019 
EAY131-Z1K 
5/14/2019 
5/14/2019 
5/14/2019 
8/19/2020 
8/19/2020 
EAY131-Z1L 
5/14/2019 
5/14/2019 
5/14/2019 
8/19/2020 
8/19/2020 
 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: October 9, 2020 
 
NCI Update Date: August 12, 2015 
154 
Molecular Analysis for Therapy Choice (MATCH) 
Appendix X 
 
Example MATCH-Assay Laboratory Reports 
This appendix provides templates of reports that may be distributed from a MATCH-
assay laboratory providing the results of the MATCH-assay screening or confirmation 
assessments performed by the MATCH-assay laboratories. These results are used to 
assign patients to treatment if they entered the screening step of the trial prior to May 21, 
2017 and to confirm the evaluability of patients who were assigned treatment via a 
referral from a Designated Laboratory. Reminder, the MATCH-assay confirmation 
assessments are performed only after a patient is enrolled on an assigned treatment 
arm and will not affect treatment assignment or patient participation in EAY131. When 
the sequencing results arrive, please read the notes especially regarding potential 
germline findings. 
NOTE: 
For templates of reports distributed by designated Laboratories that provide 
referrals for MATCH, please contact the specific designated Laboratory. 
NOTE: 
Results of additional central assessments, including IHC and histology 
confirmation reports, are provided separately. For patients enrolled on 
EAY131 based on a referral from a Designated Laboratory, results of any 
central assessments which impact treatment assignment, such as IHC, will 
be performed and reported prior to treatment assignment.   
 
 
Rev. 8/15 
Rev. 2/16 
Rev. Add13 
Rev. Add24 
Rev. Add25 

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  Comments:   
 
SIGNATURE APPROVAL:   
The signature below attests that the signee has reviewed the 
data and results reported and concurs with the stated 
conclusions. 
 
_____________________________                                          
Laboratory Director             Date                                                
DISCLAIMER:  This assay was developed specifically for the 
NCI-MATCH clinical trial and is considered an investigational 
device limited by Federal (United States) law to investigational 
use.  Its performance characteristics have been determined 
through extensive testing by the NCI-MATCH network 
laboratories. It has not been cleared by the US Food and Drug 
Administration and such approval is not required for clinical 
implementation. Furthermore, any Comments included in this 
report are strictly interpretive and the opinion of the reviewer 
and may not be specifically relevant to the NCI-MATCH clinical 
trial. The _________________is registered under Clinical 
Laboratory 
Improvement 
Amendments 
(CLIA) 
for 
the 
performance of high-complexity molecular testing for clinical 
purposes. 
 
Comments:   
 
SIGNATURE APPROVAL:   
The signature below attests that the signee has 
reviewed the data and results reported and concurs 
with the stated conclusions. 
 
_________________________________________      
Laboratory Director                                 Date   
DISCLAIMER:  This assay was developed specifically 
for the NCI-MATCH clinical trial and is considered an 
investigational device limited by Federal (United States) 
law to investigational use.  Its performance 
characteristics have been determined through 
extensive testing by the NCI-MATCH network 
laboratories. It has not been cleared by the US Food 
and Drug Administration and such approval is not 
required for clinical implementation. Furthermore, any 
Comments included in this report are strictly interpretive 
and the opinion of the reviewer and may not be 
specifically relevant to the NCI-MATCH clinical trial.  
The _________________is registered under Clinical 
Laboratory Improvement Amendments (CLIA) for the 
performance of high-complexity molecular testing for 
clinical purposes. 
 

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Version Date: October 9, 2020 
 
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The NCI-MATCH NGS Assay 
Methodology: The NCI-MATCH NGS Assay is a next-generation sequencing (NGS) assay that 
utilizes a multiplex polymerase chain reaction (PCR) with DNA and RNA extracted from 
formalin-fixed tissue for sequencing on the Ion Torrent S5 XL platform and analyzed by Torrent 
Suite Software and Ion Reporter. The NCI-MATCH NGS Assay currently can reliably identify the 
presence or absence of greater than 3,000 known MOIs in the 161 unique genes listed below, 
with results compared to the Human Reference Genome hg19.  The NCI-MATCH assay utilizes 
the Thermo Fisher Scientific Oncomine® Comprehensive Assay (formerly the Oncomine Cancer 
Panel). 
Analytical Sensitivity and Specificity: The NCI-MATCH NGS Assay has been determined to 
be suitably analytically sensitive and specific for the various types of actionable abnormalities 
(aMOIs) within its reportable range. Details are found in the NCI-MATCH NGS Assay version 3 
Validation Report. Treatment threshold has been established at ≥ 0.05 Variant Allele Frequency 
(VAF) for variants annotated as MOIs, at ≥ 0.10 VAF for novel nonsense SNV and frame-shift 
indel variants in tumor suppressor genes, and ≥ 7 copies/cell as identified by the MATCH assay, 
or the MATCH equivalent of 7 or greater as identified by a designated laboratory assay for 
CNVs. All quality measures for this assay were within defined assay parameters. 
Scope and Application: The NCI-MATCH NGS Assay is a research test classified as an 
investigational device and limited by Federal law for investigational use only.  This assay was 
not designed for routine clinical use.  It was developed to determine eligibility for assignment to 
investigational treatment in the NCI-MATCH clinical trial and is not intended for any other use.  
This test was designed to find gene mutations within tumors (somatic mutations). It was not 
designed to find gene mutations that are passed down in families (hereditary or germline 
mutations). 
Hereditary and germline mutations: This assay examines tumor tissue only and does not 
examine normal (non-tumor) tissue.  Mutations detected by the assay may be present only in 
the tumor, or in every cell of the body (including non-tumor cells). This test also cannot tell 
whether a potential germline mutation causes or will cause a hereditary cancer syndrome. If the 
patient’s personal and/or family history are suggestive of a hereditary cancer predisposition, it is 
recommended that the physician arrange for the patient to meet with a genetic counselor and, if 
warranted, undergo the appropriate genetic test on normal (i.e. non-tumor) tissue (blood or cells 
brushed from the oral surface of the cheek) to check for a germline abnormality, regardless of 
the results of this research study. 
Mutations that are tested for by the NCI-MATCH NGS Assay and that, when present in normal 
tissue, are associated with hereditary cancer conditions (a predisposition to certain types of 
cancer) are listed in Attachment 1. Genes on the list were selected based on available 
published data about known associations with certain health issues. Results demonstrating a 
mutation in one of these genes may or may not be compatible with a germline mutation.  Please 
refer to the publication “American Society of Clinical Oncology Expert Statement: collection and 
use of a cancer family history for oncology providers  [Lu KF et al. J Clin Oncol. 2014; 
32(8):833-841] for further information. 
Rev. Add24 

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Key to Variant Types: 
Hotspot: 
Recurrent missense or indel mutation in one of the identified oncogenes or 
one of the identified tumor suppressor genes 
Deleterious: 
Nonsense or frameshift mutation in one of the tumor suppressor genes 
Amplification: 
Increased copy number in one of the copy number identified genes  
Fusion: 
Gene fusion Involving one of the fusion driver genes 

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The MATCH sequencing assay is performed on somatic tissue only with no testing on germline 
material.  During study development, most available literature and guidance documents on the 
topics of Incidental Findings (IFs) and return of individual research results that were consulted(1-
4) were predicated on the assumption that germline material was the subject of the research 
test. Although this is not the case for this study, they formed the framework of an Incidental 
Findings return strategy for MATCH. It is assumed that this area will continue to evolve and the 
MATCH Incidental Findings policy will be periodically reviewed by the study Steering Committee 
and revised as necessary during the conduct of the study.  For purposes of this study, the term 
Incidental Finding (IF) indicates any detected variant which may be compatible with heritable 
risk for cancer if present in germline tissues. 
The MATCH NGS assay is a research test developed to serve as an investigational assay for 
eligibility for assignment to investigational treatments in the MATCH protocol.  It is not intended 
for any other use.  It was not designed to find hereditary (germline) gene mutations. This assay 
examines tumor tissue only and does not examine normal (non-tumor) tissue. Mutations 
detected by the assay may be present only in the tumor, or in every cell of the body (including 
non-tumor cells).  Furthermore, this test also cannot tell whether a potential germline mutation is 
pathogenic. 
However, some variants on the assay panel, when present in normal tissue, have published 
associations with hereditary cancer conditions.  A patient’s assay result showing a mutation in 
one of these genes may or may not be compatible with a germline mutation.   
All variant (mutation) results, including those that are actionable (have a study-available 
treatment) as well as study-defined IFs (including variants of unknown significance as well as 
variants which are significant but not matched to an active study subprotocol treatment), will be 
reported as present or not on a report sent from the sequencing lab to the treating physician. An 
incidental findings coversheet and gene list will accompany these results. The coversheet will 
explain the assay and its use (as summarized above) followed by a list of genes that have 
hereditary cancer implications, annotated with associated conditions and a reference. The 
genes were selected for the list based on the guiding principles of the ACMG1 (Is penetrance 
high?  Are there confirmatory approaches to medical diagnosis available? Are preventive 
measures and/or treatment available? Might individuals with pathogenic mutations be 
asymptomatic for long periods of time?). 
It is expected that in most cases physicians will share the MATCH assay report and the IF 
documents with the patient as part of their care or provide these materials upon request. 
Patients may also directly request their study results under current CLIA and HIPAA 
regulations5. It is hoped that caregivers will be available to review results with patients and 
answer questions, but the coversheets were written to be readable outside the clinic setting with 
attempts to simply define concepts and rely less on medical terminology. 
As stated, the MATCH assay was designed to find gene mutations within tumors, and was not 
designed to find hereditary (germline) gene mutations. 
A patient’s MATCH assay result may or may not be compatible with a germline mutation. If the 
patient’s personal and/or family history are suggestive of a hereditary cancer predisposition, it is 
recommended that the physician arrange for the patient meet with a genetic counselor and, if 
warranted, undergo the appropriate genetic test on normal (i.e. non-tumor) tissue to assess for 
a germline abnormality, regardless of the results of this research study6. 
Rev. Add24 

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Version Date: October 9, 2020 
 
NCI Update Date: August 12, 2015 
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References: 
1. 
Green RC1, Berg JS, Grody WW, et al. ACMG recommendations for reporting of 
incidental findings in clinical exome and genome sequencing.  Genet Med 2013; 
15(7):565-74.  
2. 
Wolf SM, Lawrenz FP, Nelson CA, et al. Managing incidental findings in human subjects 
research: analysis and recommendations. J Law Med Ethics 2008; 36:219–248  
3. 
Presidential Commission for the Study of Bioethical Issues. Anticipate and Communicate 
Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and 
Direct-to-Consumer Contexts. 2013; Dec 
4. 
Williams Parsons D, Roy A, Plon SE, et al. Clinical Tumor Sequencing: An Incidental 
Casualty of the American College of Medical Genetics and Genomics Recommendations 
for Reporting of Incidental Findings.  J Clin Oncol 2014;  32(21):2203-2205 
5. 
https://www.federalregister.gov/articles/2014/02/06/2014-02280/clia-program-and-hipaa-
privacy-rule-patients-access-to-test-reports 
6. 
Lu, KF, Wood ME, Daniels M, et al.  American Society of Clinical Oncology Expert 
Statement: collection and use of a cancer family history for oncology providers.  J Clin 
Oncol 2014; 32(8):833-841 

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Version Date: October 9, 2020 
 
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Molecular Analysis for Therapy Choice (MATCH) 
Appendix XIII 
 
Medications Known to Prolong the QT Interval 
Generic Name 
Brand Names  
(Partial List) 
Drug Class 
Therapeutic Use 
Route 
Amiodarone 
Cordarone®, 
Pacerone®, 
Nexterone® 
Anti-arrhythmic 
Abnormal heart 
rhythm 
oral, injection 
Anagrelide 
Agrylin®, Xagrid® 
Phosphodiestera
se 3 inhibitor 
Thrombocythemi
a 
oral 
Arsenic trioxide 
Trisenox® 
Anti-cancer 
Cancer 
(leukemia) 
injection 
Astemizole 
(Removed from US 
Market) 
Hismanal® 
Antihistamine 
Allergic rhinitis 
oral 
Azithromycin 
Zithromax®, Zmax® 
Antibiotic 
Bacterial infection 
oral, injection 
Bepridil (Removed 
from US Market) 
Vascor® 
Anti-anginal 
Angina Pectoris 
(heart pain) 
oral 
Chloroquine 
Aralen® 
Anti-malarial 
Malaria 
oral 
Chlorpromazine 
Thorazine®, 
Largactil®, 
Megaphen® 
Anti-psychotic / 
Anti-emetic 
Schizophrenia, 
nausea, many 
others 
oral, injection, 
suppository 
Cilostazol 
Pletal® 
Phosphodiestera
se 3 inhibitor 
Intermittent 
claudication 
oral 
Ciprofloxacin 
Cipro®, Cipro-XR®, 
Neofloxin® 
Antibiotic 
Bacterial infection 
oral, injection 
Cisapride 
(Removed from US 
Market) 
Propulsid® 
GI stimulant 
Increase GI 
motility 
oral 
Citalopram 
Celexa®, Cipramil® 
Anti-depressant, 
SSRI 
Depression 
oral 
Clarithromycin 
Biaxin®, Prevpac® 
Antibiotic 
Bacterial infection 
oral 
Cocaine 
Cocaine 
Local anesthetic 
Anesthesia 
(topical) 
topical 
Disopyramide 
Norpace® 
Anti-arrhythmic 
Abnormal heart 
rhythm 
oral 
Dofetilide 
Tikosyn® 
Anti-arrhythmic 
Abnormal heart 
rhythm 
oral 
Domperidone (On 
non US Market) 
Motilium®, 
Motillium®, Motinorm 
Costi®, Nomit® 
Anti-nausea 
Nausea, vomiting 
oral, injection, 
suppository 
Donepezil 
Aricept® 
Cholinesterase 
inhibitor 
Dementia 
(Alzheimer's 
Disease) 
oral 
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Generic Name 
Brand Names  
(Partial List) 
Drug Class 
Therapeutic Use 
Route 
Dronedarone 
Multaq® 
Anti-arrhythmic 
Abnormal heart 
rhythm 
oral 
Droperidol 
Inapsine®, 
Droleptan®, Dridol®, 
Xomolix® 
Anti-psychotic / 
Anti-emetic 
Anesthesia 
(adjunct), nausea 
injection 
Erythromycin 
E.E.S.®, 
Robimycin®, 
EMycin®, Erymax®, 
Ery-Tab®, Eryc 
Ranbaxy®, Erypar®, 
Eryped®, Erythrocin 
Stearate Filmtab®, 
Erythrocot®, E-
Base®, Erythroped®, 
Ilosone®,  MY-E®, 
Pediamycin®, 
Zineryt®, Abboticin®, 
Abboticin-ES®, 
Erycin®, PCE 
Dispertab®, 
Stiemycine®, 
Acnasol®, Tiloryth® 
Antibiotic 
Bacterial 
infection, 
increase GI 
motility 
oral, injection 
Escitalopram 
Cipralex®, Lexapro®, 
Nexito®, Anxiset-E® 
(India), Exodus® 
(Brazil), Esto® 
(Israel), Seroplex®, 
Elicea®, Lexamil®, 
Lexam®, Entact® 
(Greece), Losita® 
(Bangladesh), 
Reposil® (Chile), 
Animaxen® 
(Colombia), Esitalo® 
(Australia), Lexamil® 
(South Africa) 
Anti-depressant, 
SSRI 
Depression 
(major), anxiety 
disorders 
oral 
Flecainide 
Tambocor®, 
Almarytm®, 
Apocard®, Ecrinal®, 
Flécaine® 
Anti-arrhythmic 
Abnormal heart 
rhythm 
oral 
Fluconazole 
Diflucan®, Trican® 
Anti-fungal 
Fungal infection 
oral, injection 
Gatifloxacin 
(Removed from US 
Market) 
Tequin® 
Antibiotic 
Bacterial infection 
oral, injection 
Grepafloxacin (Off 
market worldwide) 
Raxar® 
Antibiotic 
Bacterial infection 
oral 
Halofantrine 
Halfan® 
Anti-malarial 
Malaria 
oral 
Haloperidol 
Haldol® (US & UK), 
Aloperidin®, 
Anti-psychotic 
Schizophrenia, 
agitation 
oral, injection 

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Generic Name 
Brand Names  
(Partial List) 
Drug Class 
Therapeutic Use 
Route 
Bioperidolo®, 
Brotopon®, Dozic®, 
Duraperidol® 
(Germany), Einalon 
S®, Eukystol®, 
Halosten®, 
Keselan®, Linton®, 
Peluces®, 
Serenace®, 
Serenase®, 
Sigaperidol® 
Ibutilide 
Corvert® 
Anti-arrhythmic 
Abnormal heart 
rhythm 
injection 
Levofloxacin 
Levaquin®, Tavanic® 
Antibiotic 
Bacterial infection 
oral, injection 
Levomethadyl 
(Removed from US 
Market) 
Orlaam® 
Opiate 
Narcotic 
dependence 
oral 
Mesoridazine 
(Removed from US 
Market) 
Serentil® 
Anti-psychotic 
Schizophrenia 
oral 
Methadone 
Dolophine®, 
Symoron®, 
Amidone®, 
Methadose®, 
Physeptone®, 
Heptadon® 
Opiate 
Narcotic 
dependence, 
pain 
oral, injection 
Moxifloxacin 
Avelox®, Avalox®, 
Avelon® 
Antibiotic 
Bacterial infection 
oral, injection 
Ondansetron 
Zofran®, Anset®, 
Ondemet®, 
Zuplenz®, Emetron®, 
Ondavell®, Emeset®, 
Ondisolv®, 
Setronax® 
Anti-emetic 
Nausea, vomiting 
oral, injection 
Pentamidine 
Pentam® 
Antifungal 
Fungal infection 
(Pneumocystis 
pneumonia) 
injection 
Pimozide 
Orap® 
Anti-psychotic 
Tourette's 
Disorder 
oral 
Probucol (Removed 
from US Market) 
Lorelco® 
Antilipemic 
Hypercholesterol
emia 
oral 
Procainamide (Oral 
off US mkt) 
Pronestyl®, Procan® 
Anti-arrhythmic 
Abnormal heart 
rhythm 
injection 
Propofol 
Diprivan®,  
Propoven® 
Anesthetic, 
general 
Anesthesia 
injection 
Quinidine 
Quinaglute®, 
Duraquin®, 
Quinact®, 
Anti-arrhythmic 
Abnormal heart 
rhythm 
oral, injection 

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Generic Name 
Brand Names  
(Partial List) 
Drug Class 
Therapeutic Use 
Route 
Quinidex®, Cin-
Quin®, Quinora® 
Sevoflurane 
Ulane®, Sojourn® 
Anesthetic, 
general 
Anesthesia 
inhaled 
Sotalol 
Betapace®, 
Sotalex®, Sotacor® 
Anti-arrhythmic 
Abnormal heart 
rhythm 
oral 
Sparfloxacin 
(Removed from US 
Market) 
Zagam® 
Antibiotic 
Bacterial infection 
oral 
Sulpiride (On non 
US Market) 
Dogmatil®, 
Dolmatil®, Eglonyl®, 
Espiride®, Modal®, 
Sulpor® 
Anti-psychotic, 
atypical 
Schizophrenia 
oral 
Terfenadine 
(Removed from US 
Market) 
Seldane® 
Antihistamine 
Allergic rhinitis 
oral 
Thioridazine 
Mellaril®, 
Novoridazine®, 
Thioril® 
Anti-psychotic 
Schizophrenia 
oral 
Vandetanib 
Caprelsa® 
Anti-cancer 
Cancer (thyroid) 
oral 

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Molecular Analysis for Therapy Choice (MATCH) 
Appendix XIV 
 
Screening Assessments for Designated Outside Assays 
NOTE: 
“RARE VARIANT” is defined as variants which are associated with 
selected subprotocols (“rare variant” arms) for which screening of 
aMOIs and exclusion variants are performed by MATCH-designated 
“outside” laboratories prior to entry on the screening protocol (Step 0). 
For patients for whom an applicable “rare variant  was identified by one of the 
designated laboratories (as noted below), the following requirements apply for the 
patient to be eligible for use of the outside assessment for possible treatment 
assignment on MATCH: 
− 
Patient must meet the eligibility criteria in Section 3.1 
− 
The outside laboratory notified the site that the patient may be a potential 
candidate for MATCH due to a detected “rare variant.” The testing reports from 
the designated labs are NOT sufficient for this purpose. MATCH is NOT an option for 
a patient until this study-specific notification/referral has been received. 
− 
Patients with an applicable “rare variant  must be able to meet the eligibility criteria 
for the appropriate subprotocols within 4 weeks following notification of treatment 
assignment, per Section 4.2. Please note, the receipt of this notification (and the start 
of the associated deadline for Step 1 registration) may occur shortly after Step 0 
registration, since these patients will not be submitting tissue for screening purposes. 
Patients who enter screening for determination of treatment assignment based on an 
outside assay result are eligible for only one treatment assignment on MATCH.  If the 
patient is determined not to be eligible for a subprotocol open to outside assay “rare 
variant  results, the patient is off-study. 
It is important that the designated laboratory has indicated that the patient is a potential 
patient for a MATCH subprotocol based on results of their genetic assay. Only a subset 
of the screened alterations may be considered aMOIs for this trial.  
The designated outside laboratories may only act (i.e. refer patients) on any of the “rare 
variant  arms for which their assay reports all aMOIs, including the exclusionary variants, 
as defined prior to the addition of any novel variants (inclusion or exclusion) of the trial 
arm. Designated laboratories with assays that also detect any of the novel variants 
(inclusionary and/or exclusionary) are to include those variants when determining 
applicable referrals. 
NOTE: 
The content and format of these specific notifications/study referrals for the 
Outside Assay process will vary depending on the designated outside lab in 
question, as they are each responsible for their own outreach efforts. It is 
strongly recommended that the designated outside laboratory be contacted to 
confirm the format and receipt of this notification of patient eligibility prior to 
registering any patients to Step 0. 
NOTE: 
Please refer to Section 1.4.2 for information on the definitions of the study’s 
Levels of Evidence (LOEs) for agents and variants, and the process by which 
certain types of specific aMOIs may be added dynamically to the study. 
Rev. 5/17 
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The list of designated laboratories and applicable subprotocols can be found on 
the following webpages: 
Designated Laboratories: http://ecog-acrin.org/nci-match-eay131-designated-labs 
Applicable Subprotocols: http://ecog-acrin.org/trials/nci-match-eay131 
New designated laboratories may be considered for addition to the outside laboratory 
network, and will be incorporated into the webpage noted above on a rolling basis. 
Outside laboratories submit an application for review and approval by the NCI-MATCH 
Steering Committee and have undergone vetting to ensure referrals are consistent with 
the requirements of the MATCH trial. Laboratories added to the outside laboratory 
network will have met the following general requirements: 
• 
Testing is performed in a CLIA-certified laboratory 
• 
Outside laboratory NGS panels are analytically and clinically validated, with 
performance characteristics that meet NCI-MATCH outside laboratory requirements 
as defined by the Steering Committee. 
• 
Outside laboratory NGS test panels interrogate all actionable mutations of interest 
(aMOIs) required for enrollment into the “Rare Variant  Arms (please refer to the 
webpage noted above) 
• 
Outside laboratories agreed to use the existing workflow established by the core 
outside laboratories to identify patients for the “Rare Variant  Arms.  This includes 
use of the MATCH “Rare Variant  template to identify aMOIs for submission to 
MATCHBox. 
• 
The outside laboratory NGS test underwent central qualification review, during which 
the performance of the outside laboratory test may be compared with the NCI-
MATCH central laboratory test to ensure good agreement with that assay. Any 
additional assay or platform that will be used by the outside laboratory to refer 
patients must also undergo a similar concordance assessment prior to 
implementation in their referral process. 
• 
Outside laboratories must agree to formally collaborate with NCI (e.g. signed a 
collaboration agreement).   
Summary of Requirements: 
Below is a brief summary of requirements following patient registration to Step 0: 
− 
For the copy of the report uploaded to Medidata Rave, modify a COPY of the 
sequencing report as follows: 
• 
Write “EAY131  and the patient’s EAY131 case ID on each page of the report. 
• 
REDACT patient NAME and DATE OF BIRTH from every page of the report. 
− 
Complete all required eCRFs in Medidata Rave including uploading electronic copies 
of: 
• 
The applicable sequencing report. A copy of the full report must be uploaded. If 
the size of the report is restrictive, separate the report into two parts and upload 
each part separately. Any available documentation of the notification of potential 
MATCH eligibility from the outside laboratory is also requested. 
• 
An electronic copy of the pathology reports indicating disease histology 
associated with the analyzed tumor tissue and the original diagnostic pathology 
(if different). 

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− 
Notify the MATCH-designated Outside Laboratory of the patient’s participation in the 
trial. At a minimum, the site will be required to provide the trial information (EAY131) 
and the patient’s EAY131 Case ID. The Outside Laboratory may require additional 
documentation authorizing the Outside Laboratory to release the data directly to 
MATCHbox and ECOG-ACRIN. Contact the outside lab directly to obtain guidance 
regarding their required documentation requirements. 
− 
Archived tumor specimens are to be submitted to the MD Anderson MATCH trial 
laboratory as follows: 
• 
Copies of pathology reports and the report from the outside lab should be 
submitted with the tissue samples. Do NOT redact the reports. Write “EAY131  
and the patient’s EAY131 patient number on every page of the documents. 
Submission of these reports are required even if tissue is not available for the 
confirmation assessments. 
• 
If the site receives notification that archived tissue is required for central 
immunohistochemical (IHC) testing to determine patient eligibility for treatment, 
submit tissue using the kit for submission of confirmation tissue within 2 weeks. It 
is requested that adequate tissue for the IHC and confirmation testing be 
submitted. Treatment assignment cannot be determined until this assessment is 
complete. 
• 
For all other patients, tissue is to be submitted within 8 weeks following 
registration to Step 1. Tissue not submitted within 8 weeks following registration 
to Step 1 will be considered delinquent. 
− 
If possible, submit tissue from the same specimen and time point as analyzed by the 
outside laboratory.  This tissue can have been from more than 6 months prior to 
registration to MATCH if necessary and the patient can have received intervening 
cancer treatment between collection of the tissue and Step 0 registration.  See 
Section 9 for tissue submission guidelines. Section Error! Reference source not 
found. describes the specifications for the submitted tissue. 
− 
Notify the MD Anderson laboratory of any delays pertaining to the submission of the 
required IHC or central confirmation pathology materials. A hard copy of the 
applicable sequencing report from the designated outside lab should be 
included with the tissue samples submitted to MD Anderson. 
Log sample in the ECOG-ACRIN Sample Tracking System (STS) and include STS 
shipment manifest in the package. LOGGING THE SUBMISSION IN STS IS 
MANDATORY, as STS is an integral aspect for the informatics system for this trial. 
NOTE: 
Failure to submit tissue for central IHC testing (if applicable) will result in the 
inability to assign patient to treatment. 

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1) Deidentification for RAVE upload: Redact Patient Name and Date of Birth ONLY. Write 
in patient Initials, “EAY131 , and the EAY131 Patient Case ID on each page of the 
documents.  Do not redact any other pathology or report identification numbers. 
2) ECOG-ACRIN will provide the protocol number (EAY131), the EAY131 Case ID, and the 
Outside Laboratory’s patient or report identifier (provided by the site in RAVE) to the 
Outside Laboratory.  Verification of the patient’s participation must be provided by the Site 
directly to the Outside Laboratory.  At a minimum, the site will be required to provide the 
trial information (EAY131) and the patient’s EAY131 Case ID. The Outside Laboratory 
may require additional documentation authorizing the Outside Laboratory to release the 
data directly to MATCHbox and ECOG-ACRIN. Contact the Outside Lab directly to obtain 
guidance regarding their required documentation requirements. 
3) Archival tissue is to be representative of that analyzed by the MATCH-designated Outside 
Laboratory. Do not redact reports submitted to the MD Anderson TQL to allow the 
laboratory to verify that the tissue received is from the appropriate patient, to retain “chain-
of-custody  of the tissue submitted for evaluation, and to ensure proper reporting of results 
to the site. 
 
Rev. Add24 
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Molecular Analysis for Therapy Choice (MATCH) 
Appendix XV 
 
Historical Record of the Original Screening Process 
Please see below for the eligibility criteria that were originally in place for patients submitting 
tissue to the MATCH trial laboratories for testing/screening purposes after Step 0 registration 
(i.e. the original screening process). As of 5:00 PM ET on May 22nd, 2017, patients can longer 
be registered to the study for this original screening process. 
3.1.6.1 
Patients must have tumor amenable to image guided or 
direct vision biopsy and be willing and able to undergo a 
tumor biopsy for molecular profiling. Patients with multiple 
myeloma other than plasmacytomas are to have a bone 
marrow aspirate to obtain tumor cells. Biopsy must not be 
considered to be more than minimal risk to the patient. See 
Section 9. 
NOTE: 
Registration to screening steps (Step 0, 2, 4, 6) 
must occur after stopping prior therapy. There 
is no specific duration for which patients must 
be off treatment prior to registration to the 
relevant screening step (and subsequently, the 
biopsy), as long as all other eligibility criteria are 
met. 
OR 
3.1.6.2 
Patient will be undergoing a procedure due to medical 
necessity during which the tissue may be collected. 
NOTE: 
Registration to screening steps (Step 0, 2, 4, 6) 
must occur after stopping prior therapy. There 
is no specific duration for which patients must 
be off treatment prior to registration to the 
relevant screening step (and subsequently, the 
biopsy), as long as all other eligibility criteria are 
met. 
OR 
3.1.6.3 
Formalin-fixed paraffin-embedded tumor tissue block(s) 
are available for submission following pre-registration (not 
applicable for bone marrow aspirate specimens). Criteria 
for the submission of FFPE tissue are: 
• 
Tissue must have been collected within 6 months prior 
to pre-registration to Step 0 
• 
Patient may receive treatment after tissue 
collection; however, lack of response (per Section 
6) must be documented prior to Step 1. The 
following restrictions apply: 
• 
Enrollment onto another investigational study is not 
permitted. 
Rev.5/16 
Rev. 12/16 
Rev.5/16 
Rev. 12/16 
Rev. 12/16 
Rev. 3/17 
Rev. 3/17 
Rev.3/17 
Rev. 5/17 
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• 
Intervening therapy that constitutes a new, 
molecularly targeted therapy is not permitted. 
Please note, immunotherapy is not considered 
molecularly targeted. 
• 
Continuation of an agent/regimen for which 
disease progression has been observed prior to 
biopsy is permitted, including targeted therapy. 
• 
A new immunotherapy regimen is permitted; but, 
lack of response must also be documented prior to 
registration to Step 0. 
• 
Formalin-fixed paraffin-embedded tumor tissue block(s) 
must meet the minimum requirements outlined in 
Section Error! Reference source not found. 
Please see below for the registration procedures section that was previously in place for 
specimen submission in the original screening process (Step 0): 
4.1.5.3 
Specimens must be submitted to the ECOG-ACRIN CBPF 
for central testing. Notify the laboratory of any delays 
pertaining to the submission of the pathology materials. 
• 
Log sample in the ECOG-ACRIN Sample Tracking 
System (STS) and include STS shipment manifest in 
the package. LOGGING THE SUBMISSION IN STS IS 
MANDATORY, as STS is an integral aspect for the 
informatics system for this trial. 
• 
Include paper copy of original diagnostic pathology 
report in submission, and upload electronically in 
Medidata Rave. 
• 
Include completed CLIA Laboratory Sample 
Submission Form. The contact information for the 
treating physician must include FAX number as the 
CLIA report will be distributed only to the designated 
physician. Information on the CLIA submission form 
must be clearly legible. Do not use cursive. 
• 
Upload electronic copy of pathology report for the 
submitted biopsy tissue (if performed) in Medidata 
Rave when available (within 5 days of the performance 
of the biopsy) 
Failure to complete these steps may result in assay result 
reporting delays 
It may take up to 14 days from the time the treatment 
assignment is made available in RAVE for results to be 
returned by fax to the physician designated on the CLIA 
Laboratory Sample Submission and potential treatment 
assignments made available via Medidata Rave. 
Registration cannot proceed until the central determination 
is complete, unless treatment assignment is based on 
results from a designated outside laboratory. 
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Rev. 2/16 
Rev.5/16 
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Please see below for the specimen collection and submission procedures section that 
was previously in place for specimen submission in the original screening process (Step 
0) from Sections 7.2 and Section 9: 
7.2 
Biospecimen Submissions 
Failure to update Sample Tracking System (STS) appropriately may result 
in delays in the central assessments and reporting results to the site. See 
Section 9 for specific instructions regarding the collection and submission of 
specimens. 
Pathology reports from original diagnostic and/or most recent biopsy prior 
to registration to Step 0 MUST be submitted with all screening specimen 
submissions, regardless of the screening step. Failure to provide the 
reports, and thus, the inability to confirm histology, will result in delay of 
notification of treatment assignment. 
Pathology reports submitted with tissue specimens should NOT be 
redacted. Results from screening and confirmation testing are returned to 
the site and will impact patient care. Adequate identification must be 
provided to ensure that the appropriate materials have been submitted and 
reporting is correct. 
Snapshot user’s guide for STS is provided in Section 9.6. Most information, if 
entered incorrectly, may be corrected by the site. To correct mistakes for sample 
type or timepoint, contact the ECOG-ACRIN Lab Team 
(ecog.tst@jimmy.havard.edu or 857-504-2900). Please do not delete samples 
and re-log to correct these errors, especially after samples have already been 
shipped. 
i. 
Overall Summary of Options for Sample Submissions for Screening: 
Step 
Disease 
Options for 
submissions 
Biopsy 1 
Biopsy 
Repeat 
Step 01 
Solid Tumor 
Lymphoma 
Plasmacytoma 
Option 1 
Fresh Biopsy 
Fresh biopsy 
(#2) 
Option 2 
Fresh Biopsy 
Pre-Trial 
FFPE1 
Option 3 
Pre-Trial 
FFPE1 
Fresh Biopsy 
Step 0 
Myeloma 
requiring bone 
marrow 
aspirate2 
 
Fresh Biopsy 
Fresh biopsy 
(#2) 
Step 0 
“Rare Variant  
report per 
Outside 
Laboratory 
Timepoint: “Confirmation of Pre-Registration 
Outside Results  
Submit: Pre-Trial FFPE3 
Screening 
2 
(Step 2 or 
4) 
All3 
 
Fresh Biopsy 
Fresh biopsy 
(#2) 
Step 8 
All 
 
Blood 
Specimens 
Fresh Biopsy, 
if performed 
 

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Time Point 
Sample Type 
Alternatives 
In STS, Click “SHOW  to view 
Alternatives 
Comment 
Each Screening 
Submission 
• Periph Bld K2-ETDA 
(1) 
• Peripheral blood, 
Streck Cell-Free DNA 
Tube (2) 
 
On EAY131 Master Protocol 
Consent Form, patient 
answered “Yes  to “I agree to 
provide additional specimens 
for research   
Step 1, 3, 4, 6: 
End of Cycle 2 or 
End of Treatment5 
Peripheral blood, Streck 
Cell-Free DNA Tube (2) 
 
On EAY131 Master Protocol 
Consent Form, patient 
answered “Yes  to “I agree to 
provide additional specimens 
for research  
Progression, End 
of Treatment 
Biopsy 
• Periph Bld K2-ETDA 
(1) 
• Peripheral blood, 
Streck Cell-Free DNA 
Tube (2) 
 
Consent to submission of 
progression samples (Step 8) 
• Fresh Tissue Cores in 
Formalin 
• Cells, Fine Needle 
Aspirate in Cytolyte 
• FNA smears 
If Multiple Myeloma requiring 
aspirate4 
- 
BM aspirate, EDTA 
- 
BM aspirate smear (4) 
1. Exceptions to submission requirements must receive approval from the MATCH pathologist. 
2. If previously collected FFPE will be submitted for Step 0 screening, the following criteria must be met: 
• 
Tissue must have been collected within 6 months prior to pre-registration to Step 0 and patient 
must not have received any targeted intervening therapy (see Section 3.1.6.3 in Appendix XV) for 
their cancer since the collection of the tumor sample. This does not apply for patients entering a 
“rare variant  arm via an outside assay. 
• 
Formalin-fixed paraffin-embedded tumor tissue block(s) must be submitted.  The optimal block is 
70% TUMOR CELLULARITY. Specimen size requirement is as follows: 
3. NOT APPLICABLE TO MYELOMA PATIENTS WITH ASPIRATE SUBMITTED FOR SCREENING. 
Screening tumor samples with loss of MLH1 or MSH2, as determined by IHC, will result in a request 
for the submission of pre-trial diagnostic tumor tissue for central confirmation of this result. Tissue, if 
available, is to be submitted within 8 weeks of request or within 8 weeks of assignment to treatment 
subprotocol EAY131-Z1D. The results of the confirmation will be reported to the site. This additional 
assessment will not impact the screening assessment timeline and treatment assignment will not be 
held pending the outcome of the confirmation assessments. If the results are complete prior to 
treatment assignment, the confirmation results will be used by MATCHbox. 
4. MULTIPLE MYELOMA REQUIRING FRESH BONE MARROW ASPIRATE ONLY. SUBMIT 
ASPIRATES FROM THE FIRST PULL OF AN ASPIRATION SITE FOR SCREENING. Step 8 
submissions may be from first or second pull. See Section 7.2.1 (footnote 2). 
For Step 8, submission of blood specimens are mandatory.  Biopsy for collection of the research 
fresh tumor specimens is to be performed only if patient is amenable and biopsy is minimal risk or 
less OR if the procedure performed is standard of care.  If the fresh tumor will not be submitted, 
indicate “Can’t Submit  in STS and provide the reason why 
5. Collect blood end of Cycle 2 (prior to Cycle 3 treatment) or at end/discontinuation of MATCH 
treatment, whichever is earlier. Please refer to Section Error! Reference source not found.. 

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7.2.2 
Sample Tracking System (STS) Timepoint Summary: 
Timepoint 
Sample Submission Purpose 
Pre-trial Diagnostic 
Material 
Archived Formalin fixed tumor tissue  (FFPE) collected prior to 
registration to Step 0 and  submitted only for banking (future 
research) or if requested for MHL1/MSH2 confirmation 
Confirmation of Pre-
Registration Outside 
Results 
Submitted from patients screened for treatment assignment 
based on “rare variant  results determined by designated outside 
laboratories. Archived Formalin fixed tumor tissue (FFPE) 
collected prior to registration to Step 0 representative of tissue 
analyzed by designated outside laboratories.  
Indicate if sample submitted for MANDATORY IHC. 
Step 0, Screening 1, 
Biopsy 1 
• 
Specimens submitted for screening, see table in Section 
7.2.1 for sample type options. 
• 
Peripheral blood collected for research per patient consent. 
Step 0, Screening 1, 
Biopsy Repeat 
• 
Specimens submitted for screening after failure of 
“Screening 1, Biopsy 1  assessment. See table in Section 
7.2.1 for sample type options. Specimens submitted for 
screening, see table in Section 7.2.1 for sample type 
options.  
• 
Peripheral blood collected for research per patient consent. 
Screening 2, Biopsy 1 
• 
Specimens obtained from a fresh biopsy and submitted for 
screening. 
• 
Peripheral blood collected for research per patient consent. 
Screening 2, Biopsy 
Repeat 
• 
Specimens obtained and submitted for screening after 
failure of “Screening 2, Biopsy 1  assessment. 
• 
Peripheral blood collected for research per patient consent. 
Step 1, End of Cycle 
2 
Step 3, End of Cycle 
2 
Step 5, End of Cycle 
2 
Step 7, End of Cycle 
2 
Peripheral blood samples collected for research per patient 
consent at End of Cycle 2 (prior to start of Cycle 3 treatment) or 
upon discontinuation of treatment, whichever comes first.   
Step 8 
Sample submissions for research only: Fresh biopsies and 
peripheral blood. 
9. 
Biopsy Target Selection, Performance and Submission of Specimens 
Please review the study schema, Section 5.1 and Section 7.2 for a summary on when a 
biopsy for screening assessments (Step 0 and Step 2 or 4) and progression (Step 8 after 
completion of all treatment on MATCH) is to be performed. A repeat biopsy may be 
requested if submitted screening biopsy materials are inadequate for the screening 
assessments. Blood samples, from consenting patients, will also be collected and 
submitted with each biopsy (1 EDTA tube and 2 Streck tubes) and EITHER at end of 
cycle 2 or discontinuation of treatment on each MATCH subprotocol treatment (2 Streck 
tubes only), per Section Error! Reference source not found.. 
NOTE: 
For the collection of fresh biopsy specimens, fine needle aspiration followed 
by core needle biopsy, with submission of the FNA and the biopsy cores, is 
required. 
NOTE: 
If a report of a “rare variant  determined by one of the designated outside 
laboratories (Appendix XIV) is used for Step 0 screening, representative 
(from the same tissue analyzed by the outside lab, if possible) archived tumor 
tissue is to be submitted as outlined in Section Error! Reference source not 
found. for confirmation of the  “rare variant  by the MATCH assay. The 
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impact assignment to or continuation of treatment on MATCH. However, for 
certain “rare variant  arms, submission of FFPE tumor tissue may be required 
for additional central assessments (e.g. IHC) prior to final treatment arm 
assignment based on the Outside Laboratory results. FNA aspirations and 
fresh biopsies should not be submitted for these patients. However, 
submission of optional blood specimens as described below (2 Streck tubes 
and one EDTA tube) is encouraged. 
Specimen submissions associated with a specific study subprotocol will be outlined in 
the specific subprotocol. 
The date and time of collection and shipping date must be entered into the ECOG-
ACRIN Samples Tracking System (STS) for all submitted specimens. Failure to update 
STS appropriately may result in delays in the central assessments and reporting 
results to the site. 
KIT for specimen collection and shipping: order form is located in Appendix XII. 
LABELING: All samples are to be labeled with the ECOG-ACRIN protocol number 
EAY131, the assigned ECOG-ACRIN patient sequence number, date and time of 
collection, and type of material. 
The submitting pathologist and clinical research associate should refer to Appendix II 
(Pathology Submission Guidelines) for guidelines and summary of submission 
requirements. 
NOTE: 
Previous clinical pathology report MUST be submitted with the specimen, or 
the sample will not be processed. Do NOT redact the pathology reports. 
9.1 
Biopsy Instructions 
NOTE: 
For Multiple Myeloma, bone marrow aspirate must be submitted. See 
Section Error! Reference source not found. 
A pre-treatment tumor biopsy or bone marrow aspirate (myeloma patients only) 
(Step 0 and Step 2 or 4) will be obtained from patients who sign the consent to 
enroll in the study as detailed in Section 5. End-of-treatment biopsies are 
requested from patients who have provided additional consent and meet the 
criteria outlined in Section 3.9. 
Brain biopsies will be permitted if the patient has medical necessity for 
craniotomy for clinical care. Mediastinal, laparoscopic, gastrointestinal, or 
bronchial endoscopic biopsies can be obtained incidentally to a clinically 
necessary procedure and not for the sole purpose of the clinical trial.  Acceptable 
biopsy procedures are: 
• 
Percutaneous biopsy with local anesthetic and/or sedation with an expected 
risk of severe complications < 2% 
• 
Excisional cutaneous biopsy with local anesthetic and/or sedation with an 
expected risk of severe complications < 2% 
• 
Biopsy with removal of additional tumor tissue during a medically necessary 
mediastinoscopy, laparoscopy, gastrointestinal endoscopy, bronchoscopy or 
craniotomy 
• 
Removal of additional tumor tissue during a medically necessary surgical 
procedure 

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• 
Bone marrow aspirate (myeloma patients only, if applicable) 
No open surgical, laparoscopic endoscopic procedure will be performed 
solely to obtain a biopsy for this protocol. 
NOTE: 
For Step 0, biopsy 1, pre-trial FFPE tumor tissue that meets the 
criteria in Section Error! Reference source not found. may be 
submitted for analysis in lieu of a fresh biopsy sample for Biopsy 1 or 
the repeat biopsy (if performed) but not both. 
9.1.1 
Contraindications to percutaneous biopsy: 
1. Significant coagulopathy that cannot be adequately corrected.  
2. Severely compromised cardiopulmonary function or hemodynamic 
instability. 
3. Lack of a safe pathway to the lesion.  
4. Inability of the patient to cooperate with, or to be positioned for, 
the procedure. 
9.1.2 
Tissue specimens will be sent for analyses as defined in Section 
Error! Reference source not found.. Specimens are generally 
expected to provide 20 nanograms of nucleic acids. If a site is 
deemed appropriate for biopsy with minimal risk (no more than 2% 
risk of serious complication requiring hospitalization) to the participant 
by agreement between the investigators and Interventional Radiology, 
an attempt at biopsy will be made. 
The biopsy procedure to be used in this protocol is described below; 
local anesthesia will be administered as needed. Sedation may be 
used for comfort if considered safe for the patient.  Such biopsies can 
be safely performed as evidenced by literature reports [12,13, 20], as 
well as, experience at the NIH Clinical Center, where, among 244 
research tumor biopsies (18G needle) in liver (126), 
subcutaneous/chest wall/abdominal wall (36), intramuscular (18), lung 
and lymph nodes, there were 8 minor cases of bleeding, and one 
pneumothorax requiring 48h hospitalization (21) and MD Anderson 
Cancer Center (22). Most biopsies will probably be in liver. The 
complication rate at Massachusetts General Hospital (23) of 
percutaneous liver biopsy similar to those that will be done for this trial 
is 1.2 % of 732 cases. Risks of the procedure include, but are not 
limited to, bleeding, infection, pain, and scarring. 
9.1.3.1 
Complications associated with any screening biopsy or 
end-of-treatment biopsy will be reported and tracked as 
protocol-related AEs within Medidata Rave. 
9.1.3.2 
Severe or major complications are considered to be (13): 
• 
Requires therapy, minor hospitalization (more than 
overnight only but < 48 h) 
• 
Requires major therapy; unplanned increase in level of 
care, prolonged hospitalization> 48h 
• 
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• 
Death 
9.1.3.3 
Minor complications 
• 
No therapy, no consequence 
• 
Nominal therapy, no consequence – includes overnight 
admission for observation only 
9.1.4 
Pre-biopsy Lesion Assessment (for those undergoing biopsy by 
Interventional Radiologist) 
The Interventional Radiologist should provide the investigator with an 
assessment of whether a lesion that is likely to yield enough material 
for molecular profiling can be found and biopsied with acceptable risk.  
Three main factors are considered: 
iv. whether a suitable lesion (viable tumor) for biopsy is present 
(yield) 
v. whether the lesion selected for biopsy can be sampled 
aggressively (yield) 
vi. the expected level of risk of major complication to the patient (< 
2% major complication to be eligible for biopsy) 
9.1.4.1. 
A pre-biopsy lesion scoring system (scale from 1-3) 
adapted from the one used by Interventional Radiology at 
the MD Anderson Cancer Center (courtesy of Dr. Michael 
Wallace, Chair Ad-Interim of the Department of 
Interventional Radiology) will be used to assign a value to 
the interventional radiologist’s assessment of the lesion. 
An analogous 5-point subjective scale has been internally 
studied at MD Anderson Cancer Center and lesions given 
a score of ≤ 2 were found to have a lower yield rate for 
CMS-46 testing when compared to lesions that were 
scored ≥ 4 (24). 
9.1.4.2. 
The radiologist will refer to the Radiology Biopsy Manual 
for case examples and detailed criteria for scoring and 
assign a pre-biopsy lesion score to the patient. Briefly, the 
qualitative assessment criteria for the 3-point scale is as 
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Pre-Biopsy Lesion Scoring Scale (courtesy MD Anderson Cancer Center) 
Score Assigned 
Likelihood of Yield 
Reason for Score & Biopsy Disposition 
1 
Low (< 25%) 
Reason: no target amenable to biopsy, high risk 
procedure. 
Biopsy disposition: should not be performed. 
2 
Uncertain (25-75%) 
Reason: Uncertainty about success either due to 
technical challenges or lesion characteristics (e.g., small 
size, necrotic, sub-solid lesion, sclerotic, not FDG–avid, 
technically difficult biopsy). Sclerotic bone lesion usually 
low yield. 
Biopsy disposition: Communication with investigator for 
these types of lesions should occur to determine 
whether to proceed with biopsy. 
3 
High (> 75%) 
Reason: viable tumor demonstrated on diagnostic 
imaging (enhancing lesion, growing lesion) that can be 
sampled aggressively. 
Disposition: Proceed with biopsy. 
9.1.4.3. 
Record the pre-biopsy lesion score and the name of the 
interventional radiologist on the screening eCRF in Rave. If 
a lesion is rated 1 or 2, the reason should be denoted on 
the CRF and this suspicion for low likelihood of success 
should be communicated to the investigator to discuss 
whether or not to proceed with the biopsy.  Final 
disposition of the discussion (to proceed or not to proceed) 
should be documented on the CRF. 
9.1.4.4. 
Pre-biopsy imaging and CRF with lesions score 
assessment and interventional radiologist’s name are 
submitted in all cases, including those where decision is 
made to not proceed with biopsy. 
9.1.5. 
Biopsy Procedure 
This section applies to patients who have not had tumor tissue 
acquired through normal clinical care for either diagnostic or 
therapeutic procedures.  Tumor tissue acquired during regular clinical 
care would be harvested by the appropriate physician (e.g., 
neurosurgeon during craniotomy).   
9.1.5.1. 
If a non-cutaneous lesion site is deemed appropriate for 
biopsy with minimal risk to the participant by agreement 
between the investigators, patient and Interventional 
Radiologist an attempt at biopsy will be made. All internal 
organ biopsies will be done by the Interventional 
Radiologist with a percutaneous approach, or during a 
clinically necessary surgical/endoscopic procedure, 
including craniotomy for brain metastasis or tumor. 
• 
No endoscopic, laparoscopic, or surgical procedure will 
be done solely to obtain a biopsy for this protocol. 
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9.1.5.2. 
The choice of imaging modality to be used to facilitate 
tissue acquisition during the biopsy procedure will be 
decided by members of the Interventional Radiology team 
at the clinical site and may include ultrasound, CT scan, or 
MRI.  Should CT scan be needed for biopsy, the number of 
scans for each procedure will be limited to the minimum 
number needed to safely obtain a biopsy. Tumor biopsies 
will be performed only if they are considered to be of low 
risk (< 2% major complication rate) to the participant as 
determined by the investigators and Interventional 
Radiologist.  Biopsies will be performed under local 
anesthesia and/or sedation. 
9.1.5.3. 
For the collection of biopsy specimens, fine needle 
aspiration followed by core needle biopsy, with submission 
of the FNA and the biopsy cores, is required. For all 
specimen types, the tumor cellularity yielded by FNA may 
be superior to core needle biopsy in some patients, 
particularly when the lesion is comprised predominantly of 
fibrosis, bone, or other non-tumor tissue. The FNA 
sampling with at least 2 passes should be sufficient to 
provide a specimen for preparation of smears and a cell 
block. It is preferred that at least four core biopsies 16-18 
gauge in diameter and at least 1 cm in length after a fine 
needle aspiration specimen are obtained as described 
below. Biopsies will be sent for analyses as defined in the 
protocol. 
9.1.5.4. 
Biopsy images should be submitted to IROC at the ACR 
Core Laboratory (see Section 11) and include image 
before needle placement, image with FNA or trocar needle 
in lesion, image with core biopsy or trocar needle in lesion, 
biopsy report describing target lesion location (organ, 
laterality or segment if applicable and image number on 
pre-biopsy imaging if available) and size. 
9.1.5.5. 
The date and time of collection and shipping date must be 
entered into the ECOG-ACRIN Sample Tracking System 
(STS) for all submitted specimens. 
9.1.5.6. 
LABELING: All samples are to be labeled with the ECOG-
ACRIN protocol number EAY131, the assigned ECOG-
ACRIN patient sequence number, date and time of 
collection, and type of material. 
9.1.5.7. 
The submitting pathologist and clinical research associate 
may refer to Appendix II (Pathology Submission 
Guidelines) for guidelines and summary of submission 
requirements. 
9.2. 
NCI MATCH EAY131 Clinical Trial Specimen Kit Instructions for Specimen 
Collection and Shipping 
For results and specimen submission inquiries: 

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MATCHTRIAL@mdanderson.org & MATCH@jimmy.harvard.edu 
Phone: 1-844-744-2420 (OPTION 4) Fax: 713-745-4925 
For all kit related inquiries: 
EACBPF@mdanderson.org 
Phone: 1-844-744-2420 (OPTION 5) Fax: 713-563-6506 
Specimen collection days: 
Specimen collection can be done Monday through Friday with overnight 
shipping for arrival on Tuesday through Saturday at the ECOG-ACRIN 
Central Biorepository and Pathology Facility (EA CBPF).  For Step 0, kit 
requests are automatically sent to the CBPF upon patient registration. For 
subsequent steps (including Step 0 repeat biopsy), email or fax the kit order 
form, located in Appendix XII, to the CBPF. 
9.2.1 
Acceptable specimen types 
• 
Core needle biopsy, fine needle aspiration smears and rinses. 
Submission of FNA alone is not acceptable 
• 
Excisional cutaneous biopsy tissue 
• 
Additional endoscopic, laparoscopic, or surgical tissue acquired 
during medically necessary procedure for clinical care 
• 
Pleural biopsy with effusions (contact MD Anderson prior to 
performance of the biopsy and sample collection to confirm 
adequacy) 
• 
Bone marrow aspirate (myeloma patients only, if applicable) 
• 
Archived FFPE tissue or unstained slide alternative 
9.2.2. 
Contents of screening or Step 8 shipping kit for solid tumor patients 
(for multiple myeloma patients for whom bone marrow aspirates 
will be submitted, see Section Error! Reference source not found.): 
1. One patient CLIA Laboratory Sample Submission Form. 
2. One EDTA venipuncture blood collection tube and two Streck 
venipuncture blood collection tubes with labels and absorbent 
protective packing material. 
3. Five frosted-tip slides in container, for use in preparation of FNA 
smears.   
4. One 30 mL container of Cytolyt for rinsing of FNA needle. 
5. Two tissue specimen cassettes and four sponges for core needle 
biopsy specimens. 
6. One neutral-buffered formalin-filled container for fixing the 
collected core biopsies. 
7. One pre-printed FedEx shipping label sticker pre-addressed to the 
EA Central Biorepository and Pathology Facility. 
8. Three neon green address labels. 
9. Cold pack, warm pack, and temperature monitor device. 
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1. UN3373 IATA labels 
2. LockMailer 
3. Shipping guide document 
4. Image-guided biopsy manual 
5. Kit instructions. 
9.2.3. 
Contents of screening or Step 8 shipping kit for Myeloma patients 
only who will have a bone marrow aspirate collected: 
1. One patient CLIA Laboratory Sample Submission Form. 
2. One EDTA venipuncture blood collection tube and two Streck 
venipuncture blood collection tubes with labels and absorbent 
protective packing material 
3. Two EDTA collection tubes for Bone Marrow Aspirate collection. 
4. Five frosted-tip slides in containers. 
5. Two plain syringes. 
6. One pre-printed FedEx shipping label sticker pre-addressed to the 
EA Central Biorepository and Pathology Facility. 
7. Three neon green address labels. 
8. Cold pack, warm pack, and temperature monitor device. 
9. Strip of specimen labels. 
10. IATA labels (UN3373).  
11. Shipping guide document 
12. Kit instructions. 
9.2.4. 
Contents of “Rare Variant  shipping kit for Formalin Fixed Paraffin-
Embedded Tumor Sample for Confirmation of “Rare Variant” 
Results Determined by Designated Outside Laboratory. 
1. One patient CLIA Laboratory Sample Submission Form. 
2. One EDTA venipuncture blood collection tube and two Streck 
venipuncture blood collection tubes with labels and absorbent 
protective packing material. 
3. Five slide containers. 
4. One pre-printed FedEx shipping label sticker pre-addressed to the 
EA Central Biorepository and Pathology Facility. 
5. Three neon green address labels. 
6. Cold pack, warm pack, and temperature monitor device. 
7. Strip of specimen labels. 
8. Kit instructions. 
9.2.5. 
Instructions for use of screening or Step 8 shipping kit (select 
procedure type A, B, C, D, E or F): 
A: Fine needle aspiration and core needle biopsy procedure: 
For the collection of biopsy specimens, fine needle aspiration 
followed by core needle biopsy, with submission of the FNA and 
the biopsy cores, is required. For all specimen types, the tumor 
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cellularity yielded by FNA may be superior to core needle biopsy 
in some patients, particularly when the lesion is comprised 
predominantly of fibrosis, bone, or other non-tumor tissue. The 
FNA sampling with at least 2 passes should be sufficient to 
provide a specimen for preparation of smears and a cell block.  It 
is preferred that at least four core biopsies 16-18 gauge in 
diameter and at least 1 cm in length after a fine needle aspiration 
specimen are obtained.  Biopsies will be sent for analyses as 
defined in the protocol.  
FNA sampling should provide sufficient material for preparation of 
smears and a cell block. 
Preferred procedure checklist: 
_____ 1. Verify patient identification, enrollment in OPEN, and 
signed consent for EAY131. 
_____ 2. Complete CLIA Laboratory Sample Submission Form 
and label blood collection tubes, frosted-tip slides, 
cassettes and all specimen collection containers. 
Information on the CLIA submission form must be 
clearly legible. Do not use cursive.   
_____ 3. Perform venipuncture for collection of blood into 
labeled EDTA and Streck tubes and place filled 
labeled tubes into biohazard bag with absorbent 
protective packing material. 
_____ 4. Perform image-guided or visually-guided fine needle 
aspiration (FNA) of lesion. The FNA sampling with at 
least 2 passes should be sufficient to provide a 
specimen for preparation of smears and a cell block. 
_____ 5. If a cytopathologist and/or cytologic technologist is 
available on site, immediately fix one slide in 95% 
ethanol (provided by enrolling institution) and air dry 
another slide for each FNA pass. The air dried slide 
will be stained by Diff-Quik method to assess tumor 
cell quantity and quality (see examples below) 
 
  
Optimal specimen 
                                   
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Satisfactory specimen 
If a cytopathologist and/or cytologic technologist is 
unavailable for immediate assessment, please skip 
Step 6 and proceed to Step 7 below. 
____ 
6. If the first FNA specimen has low tumor cellularity (see 
illustrations above for examples of satisfactory FNA 
smears), repeat the FNA in a different location in 
larger sized lesions (> 2cm) or in a different lesion if 
one is accessible. 
_____ 7. If on-site cytopathologic assessment is not available, 
collect tumor sample by FNA. Label slides and 
prepare smears for each FNA pass. Immediately fix 
one slide in 95% ethanol (provided by enrolling 
institution) in a LockMailer and air dry another slide. 
Place the air dried slide in the dry slide container 
provided. Secure the lid of the LockMailer and place it 
inside the biohazard bag containing an adsorbent. 
Place this in the kit. Secure the lid of the slide 
container and place it in the shipping kit. 
_____ 8. Rinse FNA needle into the 30 ml CytoLyt tube, secure 
the tube cap, and place the tube into the shipping kit.    
 _____ 9. It is preferred that at least four core biopsies 16-18 
gauge in diameter and at least 1 cm in length after a 
fine needle aspiration specimen are obtained. Place 
two cores between sponges in each of the two 
cassettes (total of four cores), snap the cassette lids in 
place, place the two cassettes into the formalin-filled 
container, secure the container lid, and place the 
container into the shipping kit. If touch preparation 
slides of cores are made, place them in the dry slide 
container. Secure the slide container lid and place it in 
the shipping kit. 
_____ 10. If your institution requires pathologic examination of 
removed tissue, place a fifth core in a labeled 
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specimen container with fixative for transport to your 
Pathology Department. (This specimen container is 
not provided in the shipping kit.) Results of this review 
must be uploaded to Medidata Rave as soon as 
available. 
_____ 11. Log the samples into the EA Sample Tracking System 
and print the STS generated shipping manifest. 
_____ 12. Place the following forms into the shipping kit: 
____ This checklist 
____ Prior clinical pathology reports, and any 
immunologic, immunohistochemical, or 
molecular study reports performed on pre-trial 
diagnostic tumor specimen. Do NOT redact the 
reports. 
____ CLIA Laboratory Sample Submission Form 
completely filled out. Information on the CLIA 
submission form must be clearly legible. Do not 
use cursive. 
____ The Sample Tracking System (STS) generated 
shipping manifest. 
_____ 13. Activate the temperature monitor by pressing and 
holding the start button for 10-15 seconds. The green 
LED light will be solid, and then both red and green 
LED’s will be solid. At this time, release the start 
button, and the green LED will blink rapidly for 3 
seconds. Place the unit in the kit inside the blood tube 
packaging – it will flash red and green LED for 15 
minutes. For temperature control, add cold pack or 
warm pack, dependent on time of year specimen is 
shipped. Use warm pack if outside temperature at 
your site or along transit route will be below freezing. 
_____ 14. Use one kit per patient. Do not place specimens from 
more than one patient into a kit. Secure the packing, 
seal the kit, and apply the following shipping labels: 
Three neon green address labels, FedEx airbill, and 
UN3373 IATA label. Refer to separate shipping guide 
document for pictures of label placement and further 
shipping guidelines. Contact FedEx for pickup. 
Package must be picked up the same day 
specimen is collected. 
B. Excisional cutaneous biopsy specimens checklist: 
_____ 1. Verify patient identification, enrollment in OPEN, and 
signed consent for EAY131. 
_____ 2. Complete CLIA Laboratory Sample Submission Form 
and label blood collection tubes, cassettes and all 
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specimen collection containers. Information on the 
CLIA submission form must be clearly legible. Do not 
use cursive. 
_____ 3. Perform venipuncture for collection of blood into 
labeled EDTA and Streck tubes and place filled 
labeled tubes into biohazard bag with absorbent 
protective packing material. 
_____ 4. Obtain tumor biopsy tissue, place between the 
sponges in one or two of the cassettes as needed 
depending upon the size of the tissue, place the 
cassette(s) in the formalin-filled container, secure the 
container lid, and place the container into the 
specimen kit. 
_____ 5. If your institution requires pathologic examination of 
removed tissue, place a portion of the biopsy 
specimen in a labeled specimen container with fixative 
for transport to your Pathology Department. (This 
specimen container is not provided in the shipping kit.)  
Results of this review must be uploaded to Medidata 
Rave as soon as available. 
_____ 6. Log the samples into the EA Sample Tracking System 
and print the STS generated shipping manifest. 
_____ 7. Place the following forms into the shipping kit: 
____ This checklist 
____ Prior clinical pathology reports, and any 
immunologic, immunohistochemical, or 
molecular study reports performed on pre-trial 
diagnostic tumor specimen. Do NOT redact the 
reports. 
____ CLIA Laboratory Sample Submission Form 
completely filled out. Information on the CLIA 
submission form must be clearly legible. Do not 
use cursive. 
____ The Sample Tracking System (STS) generated 
shipping manifest. 
_____ 8. Activate the temperature monitor by pressing and 
holding the start button for 10-15 seconds. The green 
LED light will be solid, and then both red and green 
LED’s will be solid. At this time, release the start 
button, and the green LED will blink rapidly for 3 
seconds. Place the unit in the kit inside the blood tube 
packaging – it will flash red and green LED for 15 
minutes. For temperature control, add cold pack or 
warm pack, dependent on time of year specimen is 
shipped. Use warm pack if outside temperature at 
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_____ 9. Use one kit per patient. Do not place specimens from 
more than one patient into a kit. Secure the packing, 
seal the kit, and apply the following shipping labels: 
Three neon green address labels, FedEx airbill, and 
UN3373 IATA label. Refer to separate shipping guide 
document for pictures of label placement and further 
shipping guidelines. Contact FedEx for pickup. 
Package must be picked up the same day 
specimen is collected. 
C. Additional specimens from medically necessary endoscopic, 
laparoscopic, or surgical procedures performed for clinical 
care 
See instructions and use checklist for excisional cutaneous biopsy 
specimens in Section B above. 
D. Multiple Myeloma – If bone marrow aspirate to be submitted.  
See Section Error! Reference source not found. 
For patients with plasmacytomas, follow the instructions outlined 
above for solid tumors. FOR MULTIPLE MYELOMA WHICH 
REQUIRE BM ASPIRATES ONLY: SUBMIT ASPIRATE FROM 
THE FIRST PULL. 
Perform venipuncture for collection of blood into labeled EDTA 
and Streck tubes and place filled labeled tubes into shipping kit 
with protective packing material. 
Draw the bone marrow aspirate materials into a plain syringe, 
then: 
1. Use 1 drop to make 4 – 5 smears. 
2. Put 1 – 1.5 ml in one EDTA tube.  
3. Put remainder (5 - 10 ml) of bone marrow aspirate in the other 
EDTA tube. 
E. Archival FFPE tissue or unstained slides alternative: 
1. Verify patient identification, enrollment in OPEN, and 
signed consent for EAY131. 
2. Complete CLIA Laboratory Sample Submission Form 
and label blood collection tubes. 
3. Perform venipuncture for collection of blood into labeled 
EDTA and Streck tubes and place filled labeled tubes 
into biohazard bag with absorbent protective packing 
material. 
4. Log the samples into the EA Sample Tracking System 
and print the STS generated shipping manifest. Log 
screening tissue under time point “Step 0, Screening 1, 
Biopsy 1 . The time point “Pre-trial Diagnostic Material  
is for research tissue submission only. 
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5. Place the following forms into the shipping kit (archival 
FFPE submission for screening must be sent in the 
provided specimen collection kit): 
____ This checklist 
____ Prior pathology reports, and any immunologic, 
immunohistochemical, or molecular study 
reports performed on pre-trial diagnostic tumor 
specimen. Do NOT redact the reports. 
____ CLIA Laboratory Sample Submission Form 
completely filled out. 
____ The Sample Tracking System (STS) generated 
shipping manifest. 
6. Discard any unused supplies from the kit prior to 
shipping. 
7. Activate the temperature monitor by pressing and 
holding the start button for 10-15 seconds. The green 
LED light will be solid, and then both red and green 
LED’s will be solid. At this time, release the start button, 
and the green LED will blink rapidly for 3 seconds. 
Place the unit in the kit inside the blood tube packaging 
– it will flash red and green LED for 15 minutes. For 
temperature control, add cold pack or warm pack, 
dependent on time of year specimen is shipped. (Use 
warm pack if outside temperature at your site or along 
transit route will be below freezing.) 
8. Use one kit per patient. Do not place specimens from 
more than one patient into a kit. Secure the packing, 
seal the kit, and apply the following shipping labels: 
Three neon green address labels, FedEx air bill, and 
UN3373 IATA label. Refer to separate shipping guide 
document for pictures of label placement and further 
shipping guidelines. Contact FedEx for pickup. Package 
must be picked up the same day specimen is 
collected.  
F. “Rare variant” confirmation testing (submit archival FFPE or 
unstained slides alternative): 
9. Verify patient identification, enrollment in OPEN, and 
signed consent for EAY131. 
10. Complete CLIA Laboratory Sample Submission Form 
and label blood collection tubes. 
11. Perform venipuncture for collection of blood into labeled 
EDTA and Streck tubes and place filled labeled tubes 
into biohazard bag with absorbent protective packing 
material. 
12. Log the samples into the EA Sample Tracking System 
and print the STS generated shipping manifest. Log it 
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under the time point "Confirmation of Pre-
Registration Outside Results”. Do not select the time 
point “Step 0, Screening 1, Biopsy 1  or “Pre-trial 
Diagnostic Material  for submission of “rare variant  
material. 
13. Place the following forms into the shipping kit (archival 
FFPE submission for screening must be sent in the 
provided specimen collection kit): 
INCLUSION OF ALL REQUESTED MATERIALS IS 
VERY IMPORTANT. 
____ This checklist 
____ Prior pathology reports, and any immunologic, 
immunohistochemical, or molecular study 
reports performed on pre-trial diagnostic tumor 
specimen. Do NOT redact the reports. 
____ The molecular study report with the “rare 
variant” result is required for submission of 
“rare variant” material. 
____ CLIA Laboratory Sample Submission Form 
completely filled out. 
____ The Sample Tracking System (STS) generated 
shipping manifest. 
14. Discard any unused supplies from the kit prior to 
shipping. 
15. Activate the temperature monitor by pressing and 
holding the start button for 10-15 seconds. The green 
LED light will be solid, and then both red and green 
LED’s will be solid. At this time, release the start button, 
and the green LED will blink rapidly for 3 seconds. 
Place the unit in the kit inside the blood tube packaging 
– it will flash red and green LED for 15 minutes. For 
temperature control, add cold pack or warm pack, 
dependent on time of year specimen is shipped. (Use 
warm pack if outside temperature at your site or along 
transit route will be below freezing.) 
16. Use one kit per patient. Do not place specimens from 
more than one patient into a kit. Secure the packing, 
seal the kit, and apply the following shipping labels: 
Three neon green address labels, FedEx air bill, and 
UN3373 IATA label. Refer to separate shipping guide 
document for pictures of label placement and further 
shipping guidelines. Contact FedEx for pickup. Package 
must be picked up the same day specimen is 
collected. 
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The date and time of collection and shipping date must be entered 
into the ECOG-ACRIN Samples Tracking System (STS) for all 
submitted specimens. STS shipment manifest must be included in the 
package, along with CLIA Laboratory Sample Submission Form. 
NOTE: 
Previous clinical pathology report MUST be submitted with 
the specimen, or the sample will not be processed. 
Pathology reports submitted with tissue specimens 
should NOT be redacted. Results from screening and 
confirmation testing are returned to the site and will 
impact patient care. Adequate identification must be 
provided to ensure that the appropriate materials have 
been submitted and reporting is correct. 
Specimen collection and shipping kit order form is located in 
Appendix XII. 
LABELING: All samples are to be labeled with the ECOG-ACRIN 
protocol number EAY131, the ECOG-ACRIN patient sequence 
number, patient’s name (last, first), date and time of collection, and 
type of material. 
The submitting pathologist and clinical research associate should 
refer to Appendix II (Pathology Submission Guidelines) for guidelines 
and summary of submission requirements. 
14.2 
Materials Required For This Protocol 
14.2.1 
Forms 
Copies of the following forms and reports are required to be included 
with all submissions of pathology materials: 
• 
The pathology report(s) on tumor from original, if available, and 
the most recent pre-trial diagnostic biopsy or surgery specimen(s) 
NOTE: 
Pathology reports submitted with tissue specimens 
should NOT be redacted. Results from screening and 
confirmation testing are returned to the site and will 
impact patient care. Adequate identification must be 
provided to ensure that the appropriate materials have 
been submitted and reporting is correct. 
NOTE: 
The prior diagnostic clinical pathology reports are required 
for central confirmation of histology and MUST be 
submitted with all screening specimen submissions. 
Failure to provide the reports, and thus, the inability to 
confirm histology, will result in the delay of notification 
of treatment assignment. 
• 
Reports on immunologic, immunohistochemical, or molecular 
studies, including prior sequencing studies, performed on pre-trial 
diagnostic and most recent metastatic tumor specimens 
• 
A completed CLIA Laboratory Sample Submission Form (available 
at end of Appendix II) - Submit with MATCH screening specimens 
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legible. Do not use cursive. This form is not to be submitted with 
tissue collected for research only (registration to Step 8). FAX 
numbers must be for those individuals who are required to obtain 
the results. 
• 
The Sample Tracking System (STS) generated shipping manifest 
NOTE: 
The pathology report for the submitted biopsy material, if 
pathology review was performed locally, is required to be 
uploaded into RAVE as soon as it is available. 
NOTE:  
For patients for whom an applicable “rare variant  was 
identified by one of the outside designated laboratories 
(see Appendix XIV), the appropriate documentation must 
be uploaded to Medidata Rave as outlined in Section 
4.1.5.4. Time frame for treatment assignment is dependent 
on upload of the reports and MATCH committee review of 
the reports. 
For the submission of archived tumor tissue for 
confirmatory testing, a hard copy of the applicable 
sequencing report from the designated outside lab 
should be included inside the kit. 
14.2.2 
Biological Material 
14.2.2.1 
Tumor Sample for Screening 
NOTE: 
For patients registered after May 22nd, 2017 
at 5:00 PM ET for the Outside Assay 
process, only the Step 8 collections noted in 
this section apply. 
ALL TISSUE SAMPLES SUBMITTED FOR SCREENING 
MUST BE LOGGED UNDER THE APPROPRIATE 
SCREENING TIMEPOINT (e.g. Step 0, Screening 1, 
Biopsy 1, OR Screening 2, Biopsy 1). 
The schema for the trial should be consulted to determine 
time frames and rules for the collection and submission of 
specimens for MATCH screening versus final progression 
biopsies. 
All tumor tissue cores collected during biopsy procedures 
performed at Steps 0, 2 or 4, and 8 are fixed in the formalin 
provided in the kit and submitted. FNA specimens (slides 
and cells in cytolyte) from procedures performed as 
outlined in Section Error! Reference source not found. 
are also required. 
For a tumor biopsy sample to be considered adequate for 
copy number variation evaluation, a minimum of 70% 
tissue must be tumor after manual microdissection for 
tumor cell enrichment at the MD Anderson Tissue 
Qualification Laboratory. However, the assays will be 
attempted on tissue specimens that have at least 20% 
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non-necrotic tumor cells present, which have been shown 
to be adequate for sequencing. In cases where insufficient 
tumor is obtained for sequencing analysis, patients will be 
given the option to undergo repeat tumor biopsy to attempt 
to obtain more tissue. Patients in whom sufficient tumor 
material cannot be obtained for targeted sequencing 
analysis will not proceed to be registered/randomized to 
treatment. 
For patients for whom an applicable “rare variant  was 
identified by one of the outside designated laboratories 
(see Appendix XIV): the collection and submission of tumor 
tissue for the confirmation of the “rare variant  must follow 
the guidelines for the submission of tissue for screening at 
Step 0, Biopsy 1 options with the following changes: 
o FFPE tissue may be submitted after, but no later than 8 
weeks following registration to Step 1. 
1) MANDATORY TUMOR SPECIMEN: Step 0, Screening 
1, Biopsy 1. Tissue is collected either: 
1. During the mandatory tumor biopsy following pre-
registration. Submission of fresh tumor tissue cores 
in formalin are required. The additional submission 
of FNA cells in cytolyte is required. See Sections 
9.1-Error! Reference source not found.. 
OR 
2. Tumor tissue is already available for analysis 
following a clinically indicated diagnostic or 
therapeutic procedure performed prior to pre-
registration. Requirements for existing FFPE 
submission are outlined below. 
OR 
3. MULTIPLE MYELOMA ONLY: SUBMIT 
ASPIRATES FROM THE FIRST PULL. 
For patients with plasmacytomas, follow the 
instructions for the submission of solid tumors. If 
aspirate will be submitted for screening, draw the 
bone marrow aspirate materials into a plain syringe, 
then 
1. Use 1 drop to make 4 – 5 smears. 
2. Put 1 – 1.5 ml in one EDTA tube. 
3. Put remainder (5 - 10 ml) of bone marrow 
aspirate in the other EDTA tube. 
If the submitted material results in a failed screening 
assay, due to inadequate materials or assay failure, a 
second tumor tissue specimen may be submitted for a 
repeat screening. 
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Options for sample submissions for Step 0: 
Step 0 
Biopsy 1 
Biopsy Repeat 
Option 1 
Fresh Biopsy 
Fresh biopsy (#2) 
Option 2 
Fresh Biopsy 
Pre-Trial FFPE1 
Option 3 
Pre-Trial FFPE1 
Fresh Biopsy 
1. 
If archived FFPE is submitted for analysis and additional FFPE 
is requested to meet the needs for the screening, the additional 
materials are considered to be for the same assessment and 
are logged under the same time point as the initial FFPE 
submission in STS. 
Fresh biopsy materials are to be collected and 
submitted as outlined in Section 9.1-Error! Reference 
source not found. above. 
If previously collected FFPE will be submitted, the 
following criteria must be met (see Section 3.1.6.3 in 
Appendix XV): 
Tissue must have been collected within 6 months prior to 
pre-registration to Step 0. 
Patient may receive treatment after tissue collection; 
however, lack of response (per Section 6) must be 
documented prior to Step 1. The following restrictions 
apply: 
• 
Enrollment onto another investigational study is not 
permitted. 
• 
Intervening therapy that constitutes a new, molecularly 
targeted therapy is not permitted. Please note, 
immunotherapy is not considered molecularly targeted. 
• 
Continuation of an agent/regimen for which disease 
progression has been observed prior to biopsy is 
permitted, including targeted therapy. 
• 
A new immunotherapy regimen is permitted; but, lack 
of response must also be documented prior to 
registration to Step 0. 
• 
Formalin-fixed paraffin-embedded tumor tissue block(s) 
must be submitted. The optimal block is 70% tumor 
tissue. Specimen size requirement is as follows: 
• 
Surface area: 25mm2 is optimal.  Minimum is 5mm2 
• 
Volume: 1mm3 optimal. Minimum volume is 0.2mm3, 
however the success of DNA extraction decreases at 
suboptimal tissue volume 
Specimens of suboptimal size, cellularity, or tumor content 
will require submission of more than one tumor block 
If an existing block cannot be submitted, the following is 
requested: 
• 
One (1) H&E slide, AND 
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• 
Twenty (20) or more recently cut 4 - 5 micron 
unstained sections on positively charged slides. 
NOTE: 
Screening tumor samples with loss of MLH1 
or MSH2, as determined by IHC, will result 
in a request for the submission of pre-trial 
diagnostic tumor tissue (See Section Error! 
Reference source not found.) for central 
confirmation of this result. The results of the 
confirmation will be reported to the site. This 
additional assessment will not impact the 
screening assessment timeline and 
treatment assignment will not be held 
pending the outcome of the confirmation 
assessments. If the results are complete 
prior to treatment assignment, the 
confirmation results will be used by 
MATCHbox. 
2) 
Biopsy at progression for second screening 
assessment  (Screening 2, Biopsy 1 at Step 2 or Step 
4) – patient must be registered to the appropriate 
registration step prior to submission of the biopsy 
materials: 
1. Submission of fresh tumor tissue cores in formalin 
is required. The additional submission of FNA cells 
in cytolyte is required. See Sections 9.1-Error! 
Reference source not found.. 
OR 
2. MULTIPLE MYELOMA ONLY: SUBMIT 
ASPIRATES FROM THE FIRST PULL. 
For patients with plasmacytomas, follow the 
instructions for the submission of solid tumors. If 
aspirate will be submitted for screening, draw the 
bone marrow aspirate materials into a plain 
syringe, then: 
4. Use 1 drop to make 4 – 5 smears. 
5. Put 1 – 1.5 ml in one EDTA tube. 
6. Put remainder (5 - 10 ml) of bone marrow 
aspirate in the other EDTA tube. 
3) Biopsy and blood collection at progression upon 
discontinuation of all EAY131 protocol treatment 
(Step 8) from patients who provide additional consent 
for the collection. Submission of this tissue is for 
research purposes only. 
Submission of blood samples from patients registered 
to Step 8 is mandatory. Performance of biopsy to 
collect tumor tissue for research purposes only from 
patients willing to undergo the research biopsy, is to be 
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performed only if the procedure will be minimal or less 
than minimal risk as defined in Section 9.1. 
NOTE: 
If a SOC procedure or research biopsy will 
not be performed, indicate in STS that the 
tumor tissue will not be submitted. 
1. During the tumor biopsy, if performed, following 
registration to Step 8. Submission of fresh tumor 
tissue cores in formalin is requested. The additional 
submission of FNA cells in cytolyte is strongly 
encouraged, but not required. See Sections 9.1-
Error! Reference source not found.. 
OR 
2. MULTIPLE MYELOMA ONLY: SUBMIT 
ASPIRATES FROM THE FIRST PULL 
(PREFERRED) OR SECOND PULL 
(ACCEPTABLE) OF AN ASPIRATION SITE FOR 
TESTING. Do not submit samples beyond the 
second pull of the same aspiration site.   
NOTE: 
For plasmacytomas, follow the 
directions above for submission of solid 
tumor tissue specimens. 
Draw the bone marrow aspirate materials into a 
plain syringe, then: 
7. Use 1 drop to make 4 – 5 smears. 
8. Put 1 – 1.5 ml in one EDTA tube. 
9. Put remainder (5 - 10 ml) of bone marrow 
aspirate in the other EDTA tube. 
14.1.1.1 
Formalin Fixed Paraffin-Embedded Tumor Sample for 
Confirmation of “Rare Variant” Results Determined by 
Designated Outside Laboratory 
Submit: 
o Within 2 weeks following notification that archived 
FFPE specimens are required for central IHC 
assessments for purposes of treatment assignment 
OR 
o Within 8 weeks following Step 1 registration, if not 
required for mandatory IHC assessments. 
FFPE to be submitted using regular Screening Kit. 
Log Samples in STS under time point: Confirmation of Pre-
Registration Outside Results 
Submit archived (previously collected) FFPE tumor tissue 
representative (from the same tissue that was sequenced 
by the outside lab if possible, otherwise any prior tumor 
tissue) of that analyzed by the designated outside 
laboratory for central confirmation of the outside assay 
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results. PLEASE STATE ON THE SHIPPING MANIFEST 
IF ENCLOSED SUBMITTED TISSUE WAS COLLECTED 
AT THE SAME TIME AS THE TISSUE SENT TO THE 
OUTSIDE LABORATORY OR IF IT IS FROM A 
DIFFERENT COLLECTION DATE THAN THE TISSUE 
SENT TO THE OUTSIDE LABORATORY. This 
information may be important for assessment of 
discordant results. 
The optimal block is 70% tumor tissue.  Specimen size 
requirement is as follows: 
− 
Surface area: 25mm2 is optimal. Minimum is 5mm2 
− 
Volume: 1mm3 optimal. Minimum volume is 0.2mm3; 
however the success of DNA extraction decreases at 
suboptimal tissue volume 
If an existing block cannot be submitted, the following is 
requested:  
− 
One (1) H&E slide, AND 
− 
Twenty (20) or more recently cut 4 – 5 micron 
unstained sections on positively charged slides. 
NOTE: 
Failure to submit the requested material will not 
impact patient treatment on the trial, but will 
impact the evaluability of the clinical data from 
the patient during data analysis for the trial 
endpoints. If tissue is unavailable for 
submission, the UNREDACTED pathology 
report and a statement justifying reason for 
inability to submit tissue must be provided to 
the MD Anderson TQL. Additionally, indicate in 
STS the reason for inability to submit the 
required materials. 
14.1.1.2 
Formalin Fixed Paraffin-Embedded Tumor Sample for 
Research 
In STS, please log these samples under “Pre-trial 
Diagnostic Material .  DO NOT USE THIS TIMEPOINT IN 
STS FOR THE SUBMISSION OF SCREENING 
SAMPLES OR THE SUBMISSION OF SAMPLES FOR 
CONFIRMATION OF A “RARE VARIANT” DETERMINED 
BY AN ASSAY OUTSIDE OF MATCH. 
NOTE:  
Kits are not available for specimens submitted 
separately from the screening submission. 
NOTE: 
Screening tumor samples with loss of MLH1 or 
MSH2, as determined by IHC, will result in a 
request for the submission of pre-trial 
diagnostic tumor tissue for central confirmation 
of this result. 
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Additionally, a pre-trial representative tumor tissue block is 
requested from patients who consent “Yes“ to “I agree to 
provide additional samples for research.“ Tissue may be 
submitted with the Step 0 Screening biopsy material, or 
separately upon Registration to Step 1. If FFPE tissue is 
submitted as the screening sample on Step 0, additional 
materials may be requested, if the remaining material from 
the archival screening sample is insufficient for banking 
purposes. 
If a block cannot be submitted, the following is requested: 
o One (1) H&E slide, and 
o Twenty (20) or more recently cut 4 – 5 micron 
unstained sections on positively charged slides. 
14.1.1.3 
Optional Whole Blood Collections for Research 
Whole blood is to be collected and submitted from patients 
who consent to allow the submission of blood for research. 
Samples are to be submitted at ambient temperatures on 
the day of collection. To order kits for these collections, 
please see Appendix XII.  
Screening and Step 8 Kits – Kit descriptions are provided 
above in Section 9.2. 
On-Treatment Kits – At time of registration to subprotocol 
treatment, provide the receiving address for 
collection/shipping kit, which will automatically be shipped 
to the site upon registration. If the patient did not consent 
to the optional blood submissions, answer question with 
“Not Consented”. Kit contents include: 
i. 
Two Streck venipuncture blood collection tubes with 
label and protective packing material. 
ii. One pre-printed FedEx shipping label pre-addressed to 
the EA Central Biorepository and Pathology Facility. 
iii. Cold pack, warm pack, and temperature monitor 
device. 
iv. Strip of specimen labels. 
v. Kit instructions. 
Collection and submission guidelines. 
A. From patients who answer “YES  to “I agree to provide 
additional samples for research  on the EAY131 
MASTER Screening Protocol Consent 
 
1. 7-10 mL of whole blood into one (1) EDTA 
vacutainer collected at: 
a. For patients enrolled on the study via the 
original screening process (tissue analyzed by 
central MATCH labs): 
• 
Step 0, screening 1, biopsy 1 
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• 
Step 0, screening 1, biopsy repeat 
• 
Screening 2 (Step 2 or 4), biopsy 1 
• 
Screening 2 (Step 2 or 4), biopsy repeat 
b. For patients enrolled on the study via the 
outside assay process (“rare variants  identified 
by a designated lab): 
• 
Step 1, prior to treatment 
2. 18-20 mL of whole blood into two (2) Streck 
vacutainers collected at: 
a. For patients enrolled on the study via the 
original screening process (tissue analyzed by 
central MATCH labs): 
• 
Step 0, screening 1, biopsy 1 
• 
Step 0, screening 1, biopsy repeat 
• 
Screening 2 (Step 2 or 4), biopsy 1 
• 
Screening 2 (Step 2 or 4), biopsy repeat 
b. For patients enrolled on the study via the 
outside assay process (“rare variants  identified 
by a designated lab): 
• 
Step 1, prior to treatment 
c. For all patients: 
• 
On Treatment, End of Cycle 2 (Cycle 3, day 
1 prior to start of treatment) of each MATCH 
subprotocol treatment. If treatment is 
discontinued prior to completion of cycle 2 
treatment, samples are requested to be 
collected and submitted at the time of the 
patient’s next clinical blood draw. 
B. Step 8:  From patients who consented to and were 
registered to Step 8. Disease status is progression and 
completion of all MATCH subprotocol treatments 
(patients will not be screened for consideration for 
another treatment on MATCH). Collect: 
• 
7-10 mL of whole blood into one (1) EDTA 
vacutainer 
• 
18-20 mL of whole blood into two (2) Streck 
vacutainers 
NOTE: 
If the patient does not agree to the 
additional research biopsy, the site should 
still request the patient’s participation on 
Step 8 for the collection of the blood 
samples alone.  
If On Treatment blood samples were already submitted for 
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treatment they received, as outlined above, and a biopsy 
for research will not be performed, registration to Step 8 is 
not requested. 
 

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Molecular Analysis for Therapy Choice (MATCH) 
Appendix XVI 
 
CS-MATCH-0007 
 
Comprehensive Genomic Analysis of NCI- MATCH 
Principal Investigators: 
NCI PI: 
Lyndsay Harris, MD, FRCP(C) 
NCI SCIENTIFIC LEAD: 
Lou Staudt, MD, PhD 
ECOG-ACRIN PI 
Peter O’Dwyer, MD, PhD 
 
Principal Investigators for Translational and Clinical Oncology: 
Stanley Hamilton, MD 
Alice Chen, MD 
James V. Tricoli, PhD 
Keith Flaherty, MD 
P. Mickey Williams, PhD 
Carlos Arteaga, MD 
 
Co-Investigators: 
BIOSTATISTICS 
Lisa McShane, PhD; BRB DCTD, NCI 
BIOSTATISTICS 
Laura Yee PhD; BRB DCTD, NCI 
BIOSTATISTICS 
Robert J. Gray, PhD; ECOG/ACRIN 
BIOSTATISTICS 
Shuli Li PhD; ECOG/ACRIN 
BIOINFORMATICS 
Lou Staudt, MD, PhD; CCG, NCI 
BIOINFORMATICS 
Jean-Claude Zenklusen, MS, PhD; CCG, NCI 
David Patton, PhD, CBITT, NCI 
GENOMIC SEQUENCING AND 
CHARACTERIZATION CENTER 
Roy Tarnuzzer, PhD. CCG, NCI 
BIOETHICS 
Carol Weil, JD, DEB, CDP, DCTD, NCI 
IMAGING 
Lalitha K. Shankar, MD, PhD; CIP, DCTD, NCI 
IMAGING 
Susanna I. Lee, MD, PhD; ECOG/ACRIN 
IMAGING 
Constantine Gatsonis, PhD; ECOG/ACRIN Imaging 
Statistician 
SUB-PROTOCOL PRINCIPAL INVESTIGATORS 
See Subprotocols PI list in the full CS-0007 protocol 
document (archived) 
DCTD STUDY RESEARCH COORDINATORS 
Margaret Cavenagh 
DCTD STUDY RESEARCH COORDINATORS 
Ben Kim 
CTSU PROTOCOL COORDINATOR 
Ben Kim 
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Precis 
This companion biomarker study to NCI-MATCH, “Comprehensive Genomic Analysis of NCI-
MATCH , aims to investigate additional underlying molecular factors associated with responses 
or lack of responses to a drug or class of drugs within the parent protocol. Despite the fact that 
all patients on a given treatment have the required molecular abnormality in their tumor, not all 
patients will respond to treatment and some may even respond exceptionally well to treatment. 
Each patient’s tumor was originally characterized with the NCI-MATCH next generation 
sequencing (NGS)  assay that interrogates targets from about 161 genes. A fuller genomic 
landscape of tumors from NCI-MATCH patients will be ascertained using comprehensive 
molecular analysis, such as whole exome sequencing (WES) and mRNA sequencing (RNA-
seq) in an effort to discover additional features that are predictive of response to treatment. 
This project will characterize tumor tissue DNA and RNA and matched germline DNA from all 
patients on any treatment subprotocol of NCI-MATCH who consented to allow their specimens 
to be used for future research. DNA and RNA samples will undergo WES and RNA-seq 
respectively. Those with sufficient nucleic acid quantities may undergo additional analyses (e.g., 
whole genome sequencing, microRNA (miRNA) sequencing, promoter methylation analysis, 
single nucleotide polymorphism (SNP) analysis, etc.). Each case will be annotated with 
demographic and clinical information, along with follow-up information sufficient to enable 
correlations between molecular profiles and drug response. Patient information and associated 
data will be de-identified prior to sending nucleic acid for sequencing, and this data will be 
placed in a controlled-access database for use by other investigators. 
Clinically-annotated tissue specimens will be provided by ECOG-ACRIN Central Biorepository 
and Pathology Facility (EA-CBPF) at MD Anderson Cancer Center (MDACC). The samples will 
be in the form of nucleic acids extracted at this biorepository from FFPE tissue collected on the 
MATCH trial. If existing nucleic acid was found to be insufficient for a given case, an attempt 
may be made to extract FFPE tissue for that case if enough material is available. This will be 
decided on an arm by arm basis if the sample size is inadequate for meaningful analysis. 
Nucleic acids that pass QC will be shipped to a sequencing and characterization center 
designated by the NCI Center for Cancer Genomics to perform designated sequencing and 
analysis. The Analysis Working Group (AWG), composed of investigators on this protocol and 
the sub-protocol principal investigators (PIs) of NCI-MATCH, will analyze the findings in relation 
to treatment and clinical outcome. Once published, the genomic and clinical data will be made 
available to the broader cancer research community through a controlled-access database 
(dbGAP). 
I. 
OBJECTIVES 
The main objective of this study is to explore the molecular basis of why patients 
enrolled in a treatment subprotocol of NCI-MATCH, with molecular abnormalities 
deemed predictive of response by NCI-MATCH ‘Levels of Evidence’ (LOE) as defined 
within the master protocol EAY131, do or do not respond to the drug or drug 
combination with which they were treated. 
Findings from this study may lead to confirmatory non-clinical or clinical studies to 
demonstrate the predictive qualities of one or more molecular features. Specifically, the 
objectives of this study are to: 
1.1. 
Identify molecular indicators of response or primary resistance in malignant 
tissues from patients who received therapy on NCI-MATCH subprotocols, using 
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1.2. 
Explore associations between the identified molecular indicators and the putative 
mechanism of action of the treatment received by the patient. 
1.3. 
Compare results from WES and RNA-seq studies to the results of the eligibility 
assays for NCI-MATCH. 
II. 
BACKGROUND AND RATIONALE 
The feasibility of this approach is supported by reports in the literature discovering 
mutations in patients who experienced an exceptional response to an agent that did not 
meet a phase 2 endpoint. In one of these studies, loss of function mutations in genes 
Tuberous Sclerosis 1 (TSC1) and in Neurofibromin 2 (NF2) were detected in a patient 
with urothelial cancer who had a multiyear complete response to everolimus in a phase 2 
trial (Iyer et al., 2012). Alterations in these genes had been associated with mammalian 
target of rapamycin complex (mTORC) dependence in preclinical studies, and 
everolimus inhibits this pathway. The investigators sequenced tumors from 96 other 
individuals with high-grade bladder cancer and found 5 additional patients with TSC1 
mutations. They then sequenced 13 patients with bladder cancer who had received 
everolimus on the trial and found that 4 of 5 patients with TSC1 mutations had some 
tumor shrinkage to everolimus, while those without such a mutation did not have tumor 
shrinkage. Of note, not all patients with the putative response biomarker (TSC1 
mutation) had a response. In a second report, Wagle et al. report finding novel 
mechanistic target of rapamycin (mTOR) mutations by WES in a patient with urothelial 
cancer who had a complete response to the experimental combination of everolimus and 
pazopanib (Wagle et al., 2014). This work demonstrated that mutations in mTOR are 
likely to predict clinical sensitivity to treatment with the mTOR inhibitor everolimus and 
laid the groundwork for the principles behind NCI-MATCH where specific molecular 
characteristics are required to select patients for a targeted therapy associated with that 
pathway. NCI-MATCH identifies LOE that need to be met to allow a drug into the study 
and includes other LOE to determine if a particular molecular abnormality can be used 
as an eligibility criterion.  Unfortunately, even when patients’ tumors possess a molecular 
abnormality targeted by a drug that is FDA approved for use in patients with that 
abnormality, 100% response rates are rare. Studying the tumors of patients enrolled in 
an NCI-MATCH subprotocol could identify novel or unknown molecular abnormalities 
that may be predictive of response or resistance to agents targeting the relevant 
pathway. The ultimate goal of NCI-MATCH is to prospectively identify patients who may 
respond to particular targeted agents, and as importantly, identify those who will not 
respond and for whom other treatments should be employed. However, the technology 
used to screen for NCI-MATCH is a targeted sequencing panel of only about 161 genes, 
which limits the discovery of mechanisms of response and resistance to the targeted 
therapy in question. For example, if a group of patients with various AKT mutations were 
treated with an AKT inhibitor, and some patients respond while others do not respond, it 
may be important to investigate additional molecular abnormalities in these patients. 
With only 161 genes interrogated in the initial eligibility panel, the ability to find the 
molecular lesion in question is limited - a broader molecular analysis may be needed to 
help identify abnormalities responsible for the response and/or resistance to treatments. 
To address this need, the study team will perform WES and RNA-seq in tumors from 
patients who received therapy on NCI-MATCH subprotocols. The ability to identify 
molecular features that predict a clinical response in these subsets of patients will 
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provide a better biological understanding of the complete or partial responses observed 
in this cohort of patients, perhaps leading to new and more effective treatments. 
For each patient that entered the NCI-MATCH trial, 4 cores of tissue or a recent archival 
specimen were requested at screening and profiled with the NCI-MATCH assays, which 
include the customized Oncomine NGS assay, as well as immunohistochemistry (IHC) 
assays for PTEN, MLH1 and MSH2. These initial NCI-MATCH tumor profiling assays will 
be used as a source of nucleic acid for WES and RNAseq. Of note, no additional tumor 
biopsy tissue will be collected for this study. 
An important aspect of this study is that it is not expected to satisfy the expectations of 
statistical power that are often associated with drug studies (i.e., large numbers of events 
that allow sufficient occurrences to not be explained by chance alone), even though 
patients will have been treated and followed in a uniform manner. The findings from this 
study will be the basis of further hypotheses that will then need to be tested in either 
larger, statistically well powered studies or by functional tests and investigations. It is 
also possible that the type of tumor and the state of the host will have a significant effect 
on response or non-response. Enrollment in a NCI-MATCH subprotocol arm is not 
defined by tumor type, and thus each arm will be composed of several different tumor 
histologies, each having the subprotocol’s specific molecular eligibility criteria, in some 
cases with several genes used for eligibility. 
This exploratory correlative study to NCI-MATCH seeks to generate a database intended 
to be shared, built upon, and examined further. It will also explore the feasibility of 
conducting such a study as there is a limited amount of available tissue for additional 
sequencing analysis. The output of the study might include a list of plausible mutations, 
putative mutations, or simply all the mutations found in the responder and non-responder 
cases – passenger, drivers, etc. This study will not involve downstream analyses, such 
as functional validation studies. Other investigators can seek to build on the data 
generated by this study by, for example, comparing their own dataset with the shared 
data. 
III. 
SELECTION OF PATIENTS AND TUMORS 
The following criteria are required to be met for patient and specimen inclusion: 
3.1. 
Patient started treatment on a sub-protocol of NCI-MATCH; 
3.2. 
Sub-protocol treatment was assigned using NCI-MATCH Oncomine® assay 
results; 
3.3 
Patient consented to use specimens for research; 
3.4. 
The amount of nucleic acid available for WES and/or RNAseq must meet 
minimum specimen requirements as described below in section IV; and 
3.5. 
Normal, germline DNA will be provided, if available. 
IV. 
BIOSPECIMEN REQUIREMENTS 
4.1. 
TISSUE REQUIREMENTS 
Samples collected most recently will be given the highest priority for molecular 
characterization to minimize chances of degradation during prolonged storage. 

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4.1.1. 
General Specimen Characteristics and Requirements: 
• 
Tissue samples from the initial screening trial will be utilized as a 
source of nucleic acids extracted for WES and RNAseq. If existing 
nucleic acid is found to be insufficient for a given case, an attempt 
may be made to extract FFPE tissue for that case if material is 
available. 
• 
Tumor specimens collected prior to the initiation of treatment on 
NCI-MATCH will be given priority if they are representative of 
specimens evaluated by the MATCH NGS assay (i.e., adjacent 
tumor tissue blocks, scrolls and/or sections). 
• 
Specimens should be accompanied by documentation of 
diagnosis (de-identified pathology report). 
4.1.2. 
Solid Tumor Tissue: 
All tumor samples underwent a pathology review in the MDACC 
pathology laboratory prior to nucleic acid extraction. The criteria for an 
acceptable sample is ultimately based on the presence of tumor in the 
specimen and amount of nucleic acid obtained, which can vary 
considerably by tumor histology and biopsy size. 
4.2. 
NORMAL SPECIMENS 
Peripheral blood, blood cells, purified DNA from blood, or a FFPE sample of 
normal tissue will be used to obtain germline DNA for this study. 
4.3. 
SAMPLE PROCESSING AND MOLECULAR CHARACTERIZATION 
4.3.1. 
Nucleic Acid Extraction from FFPE: 
Extraction from FFPE is performed at MD Anderson Cancer Center 
per the protocol utilized to extract nucleic acids for screening of tumor 
samples by the MATCH-assay. 
The analysis of a progression sample and its comparison to pre-
treatment samples might identify molecular lesions that would point to 
a molecular pathway that has relevant sensitivity or resistance to the 
targeted agent. If such progression biopsies are available, we may 
attempt to study those using similar methods. 
4.3.2. 
Molecular Characterization: 
Quality Metrics 
All DNA and/or RNA from tumor and germline control tissues must 
also meet quality metrics prior to molecular characterization. 
Sequencing 
Tumor characterization by platform will proceed in a step-wise manner 
to identify molecular features potentially predictive of response to 
therapy. Finding mutations in known cancer genes (oncogenes or 
tumor suppressors) will be the most readily interpretable and will be 
primarily determined by WES. RNA-seq will be performed, which can 
capture some mutations that are missed by exome sequencing if 
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sequencing will be considered if adequate amounts of material are 
available. The amount and integrity of tumor tissue may ultimately be 
the limiting factor in what methodologies will be employed. WES and 
RNA-seq have been successfully performed using nucleic acids 
purified from FFPE tissue. If the quantity and quality of DNA and RNA 
are sufficient, DNA methylation and miRNA characterization can also 
be performed. 
In general, the analysis will first focus attention first on clonal 
heterozygous or homozygous mutations. There are standard 
mechanisms to identify these (Carter et al., 2012). Subclonal 
mutations can be indicative that a particular signaling pathway is 
active in a tumor, which could be the reason for an observed 
therapeutic response. For this study, whole exomes will be sequenced 
to provide approximately 10 Gb of raw data per sample using 1/4 of 
an Illumina HiSeq 2000 lane (Illumina; San Diego, CA) and to achieve 
~150X coverage to afford sensitivity down to .05 or less. 
Batching 
Upon receipt at the molecular characterization centers, samples will 
be sequenced in batches using a common library protocol and 
sequencing strategy, such that sequencing results can be 
expeditiously reported every 3 months. 
Samples will be extracted and molecular characterization performed 
by treatment subprotocol arm, wherever possible, to reduce batch 
effect. 
Prioritization 
Tumor and normal tissue DNA will be characterized by WES, and 
tumor RNA will be characterized by transcriptome sequencing. The 
NCI-MATCH NGS Oncomine® assay used for eligibility and IHC for 
PTEN, MLH1, and MSH2 are available for analysis. Whole genome 
and other sequencing (e.g., miRNA) may be performed if enough 
tumor DNA is available. If tumor tissue is limiting, sequencing would 
be performed as prioritized and noted in Figure 1. If multiple 
independent samples are available for a case, more than one may be 
analyzed. Figure 1 demonstrates the flow of materials for the DNA 
sequencing and analysis. 

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Figure 1. DNA sequencing and analysis of tumor/normal pairs. Red boxes, genomic 
DNA; blue boxes, RNA. The DNA and RNA sequencing data flow is illustrated for tumor 
and normal tissue pairs. The amount of DNA or RNA (in µg or ng) required for every 
sequencing methodology is listed. RNA-seq utilizes tumor RNA. The types of mutations 
discovered by each sequencing platform are included in blue shaded area at the bottom 
of the figure (see Tables 1-3 for bioinformatics analysis). 
Sequencing Platforms 
1. Whole exomes will be sequenced to provide approximately 10 Gb 
of raw data per sample using 1/4 of an llumina HiSeq 2000 lane 
(Illumina; San Diego, CA) and to achieve ~150X mean coverage 
to afford sensitivity down to 5% or less. If DNA amounts are 
limiting, we will use the ThruPLEX® DNA-seq Kit (Rubicon 
Genomics; Ann Arbor, MI) to obtain libraries from 20 to 50 ng of 
DNA. 
2. Whole genome sequencing will be performed to generate 
approximately 150 Gb per tumor for a depth of 80X, and the 
matched normal specimens will generate approximately 90 Gb for 
a depth of 30X. The data will be analyzed to identify point 
mutations, copy number changes, and translocations. Illumina 
paired end libraries using 300 to 400 bp fragments will be utilized. 
If DNA amounts are limiting, we will use the ThruPLEX® DNA-seq 
Kit (Rubicon Genomics; Ann Arbor, MI) to obtain libraries from 20 
to 50 ng of DNA. 
3. Omni Express SNP arrays (Illumina; San Diego, CA) will be used 
as a quality control for sample identity and contamination. It will 
also provide orthogonal validation for copy number alterations. 
5. RNA-seq using a poly-A selection and a stranded protocol will be 
used to ascertain expression levels and search for fusion 

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transcripts. Please Note: New RNA capture protocols using both 
Illumina (San Diego, CA) and Roche NimbleGen (Madison, WI) 
reagents are actively being evaluated. We plan to use these 
approaches as the preferred alternative to the current RNA-seq 
pipelines. 
4.3.3. 
Other Molecular Characterization: 
Techniques are rapidly evolving for improved molecular 
characterization of FFPE specimens, tissue storage, and analyte 
isolation. If enough material tumor is available, other characterization 
methods, such as miRNA sequencing, and epigenetic sequencing 
may be performed. If it is not possible to perform RNA-seq on FFPE 
samples, expression array analyses will be considered. 
V. 
BIOINFORMATICS 
It is conceivable that a response or lack of response could be correlated with somatic 
variants affecting gene expression directly related to the mechanism of action of the drug 
associated with response or resistance. It is also conceivable that SNPs of genes 
involved in metabolism of the drug with which the response/resistance is associated 
could have played a role in the outcome. Once available, the data will be analyzed with 
these questions in mind. 
5.1. 
BIOINFORMATIC DATA PROCESSING 
The data from each platform will be analyzed for mutations with an impact on 
known cancer genes and genes involved in known cancer pathways. Genes will 
be ranked and reported based on their known or potential involvement in cancer. 
Genes of unknown significance will be reported as passengers. 
The DNA sequencing data flow is outlined in Figure 1 for tumor and normal 
tissue pairs. Sequencing will be prioritized from left to right based on available 
DNA and RNA. The types of mutations discovered by each sequencing platform 
are included at the bottom in the blue shaded area. The bioinformatics of 
sequence data includes alignment of DNA sequencing reads to the reference 
sequence (Table 1) generating Binary Alignment/Map format (BAM) files for 
storing the alignments, variant discovery and somatic mutation calling (Table 2), 
and annotation of the variants using a variety of normal and mutation databases 
(Table 3). Since the variant discovery is part of well-defined bioinformatics 
pipelines, its functions are presented in tabular format. 
The analyses in Tables 1 to 3 will be performed as a naive starting point for all 
patients. However, details of each patient’s disease, the drugs under study, and 
specific responses might draw attention to particular types of analyses, 
pathways, or types of mutations, ultimately varying the actual analyses 
performed. 
A BAM file, a compressed, indexed file format with the sequence aligned to a 
reference human genome, will be generated for each sample in this project. This 
format contains a basic DNA sequence alignment containing both germline and 
somatic information. BAM files are access controlled and will be deposited in 
NCI’s Genomic Data Commons (GDC). Further analysis for sequence variants 
and mutations will be performed, germline mutations will be filtered out, and the 
resulting annotated, tab-delimited mutation data will be stored in a Mutation 

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(the Catalogue of Somatic Mutations in Cancer): a resource to investigate 
acquired mutations in human cancer. Nucleic Acids Res.38:D652-7. PMID: 
19906727 
3. MacDonald JR, Ziman R, Yuen RK, Feuk L, Scherer SW. (2013). The 
database of genomic variants: a curated collection of structural variation in 
the human genome. Nucleic Acids Res. E pub. PMID: 24174537 
4. ClinVar: http://www.ncbi.nlm.nih.gov/clinvar/ 
5. Knox C, Law V, Jewison T, Liu P, Ly S, Frolkis A, Pon A, Banco K, Mak C, 
Neveu V, Djoumbou Y, Eisner R, Guo AC, Wishart DS. (2011). DrugBank 3.0: 
a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 
39:D1035-41. PMID: 21059682 
5.2. 
DATA SHARING 
All data will be shared utilizing infrastructure already established by NCI. All 
molecular data will be shared in a controlled access database with raw sequence 
data (BAM files) being shared via GDC, and the remainder of the data, including 
clinical data, being coordinated through The Cancer Genome Atlas Project 
(TCGA) data coordinating center. Procedures for controlled access will be 
implemented through the NIH dbGAP system 
(https://dbgap.ncbi.nlm.nih.gov/aa/wga.cgi?page=login). 
VI. 
STATISTICAL CONSIDERATIONS 
The study goal is to collect interpretable molecular results (WES, RNAseq and targeted 
deep sequencing) on patients who were treated on NCI-MATCH subprotocols. We 
anticipate approximately 700 patients will match to a MATCH treatment. However, not all 
these patients will have an adequate amount of residual DNA and/or RNA available for 
study assays. We anticipate that at least 50% of these patients will have available 
nucleic acid (DNA and/or RNA) for the genomic analyses proposed in this study. 
This biomarker study is hypothesis-generating. The hypotheses that we will try to 
generate will relate to genetic alterations in cancer cells. The plausibility of the 
hypothesis will be based on evidence that a certain mutation affects a component of a 
regulatory pathway that is relevant to the mechanism of action of the drug. 
The hypotheses generated by this study will need to be tested in larger patient cohorts 
with the same histology and treatment. Examples of the success of this methodology 
using patient tumor specimens have been published (Iyer et al., 2012). Importantly, all 
the data will be made publicly available (controlled access), so that other researchers 
who have specific knowledge of drug response predictors (e.g., from the DTP drug 
response database) will be able to generate and publish hypotheses and devise studies 
to test the hypotheses. 
As noted above, this study is not expected to satisfy the expectations of internal (i.e., 
within the data collection of the study) statistical power that are often associated with 
other drug studies. Here, even single instances will be considered and will be the basis 
of further hypotheses that will then need to be tested in either larger, statistically well 
powered studies or by functional tests. 
6.1. 
STATISTICAL ANALYSIS APPROACH 
The statistical plan centers around the following primary aims: 

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Aim 1: Identify molecular indicators of response or primary resistance in 
malignant tissues from patients who were treated on the NCI-MATCH clinical trial 
using WES, RNA-seq, as well as, potentially other sequencing and molecular 
characterization methods. 
The molecular features of patients’ tumors will be discernible as arising from the 
tumor by comparison to (i) samples from normal tissue in the same patient, if 
available, and (ii) databases of similar data for normal and other tumor types. The 
mode of (i) is the standard that has been used in most tumor studies to date and 
results in a low ‘noise’ per sample. In other words, the presence of the normal 
tissue allows definitive testing of the presence of the tumor and specific 
molecular changes. The mode of (ii) relies on deep database representations and 
imposes a higher burden on the rate of occurrence and the need for follow-up 
testing of hypotheses generated by these studies. 
Aim 2: Explore associations between identified molecular features and the 
putative mechanisms of action of the treatments that the patients received when 
they experienced response or lack of response. 
Statistical analyses will be primarily descriptive. Feasibility and success in 
discovering molecular features with potential therapeutic relevance (“promising 
discoveries ) will be assessed. 
Aim 3: To compare results from WES and RNA-seq studies to the results of the 
eligibility NGS assays for NCI-MATCH. 
Again, statistical analyses will be primarily descriptive. To characterize 
differences between the MATCH NGS assay used for eligibility and WES/RNA-
seq, we will describe discordances within the same sample between the NGS 
assay and WES/RNA-seq for all studied mutations. We will also summarize any 
discordance between WES and RNA-seq for samples that have both available. 
Feasibility will be assessed by calculation of the following statistics: 
1. Percentage of patients for which adequate nucleic acid material with 
appropriate informed consent is available. 
2. Percentage of acquired cases with nucleic acid material for which the 
minimum molecular characterization (i.e. WES, RNA-seq) is successfully 
obtained. 
Promising discoveries will be summarized for the group of cases for which the 
minimum molecular characterization was successfully obtained. For each such 
case, molecular data provided by the sequencing and characterization center, the 
NCI-MATCH NGS assay, and the data analysis center, will comprise a list of 
potentially relevant molecular abnormalities (e.g., mutations or amplifications 
from WES or the MATCH NGS assay, and if possible, mRNA expression data for 
pathway analysis), which will be reviewed by an expert panel, the AWG, to 
identify interesting features. The AWG will be composed of the investigators on 
this protocol, members of the data analysis center, as well as ad hoc panel 
members from the drug development and scientific community as necessary, as 
well as the PIs of the subprotocol on which the patient was treated. For each 
treatment, this AWG will be responsible for listing genetic abnormalities in 
pathways that would be affected by the treatment that produced the response or 
resistance. This will be done while the molecular characterization is ongoing. The 
notion of a molecular feature will be interpreted broadly. For example, a 

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molecular feature might refer to a specific mutation in a gene predicted to be the 
target of the NCI-MATCH treatment, or it could refer to activation or inactivation 
of an entire genetic pathway thought to be related to a mechanism of action of a 
drug. The AWG’s review will proceed in two steps for each evaluated case. 
The AWG will receive an initial report that lists all features of the molecular 
profile. These features will be categorized according to involvement in known 
pathways relevant to cancer (e.g., growth factor receptor, MAP kinase pathway, 
DNA repair pathways, PI3kinase pathway, cell cycle pathway, etc.) that have 
potential therapeutic relevance (either responsiveness or resistance to an 
investigational or approved drug or drug combination). After the AWG has 
reviewed and classified the molecular data into relevant pathways, the AWG will 
correlate this information with the putative mechanism of action of the drug that 
the patient received. 
We will summarize the outcome of this study by calculating the following 
statistics: 
1. Percentage of molecularly characterized cases for which the Molecular 
Characterization report identified at least one feature judged to have potential 
therapeutic relevance when compared to the putative mechanism of action of 
the specific treatment that was associated with the outcome. In addition to 
providing a potential molecular reason for the response or resistance, such 
cases will provide clinical evidence that molecular profiling may be useful in 
assigning a particular treatment for a specific molecular abnormality (even in 
the expected circumstance that more than one molecular abnormality will 
coexist in any given tumor). 
2. Percentage of cases with at least one additional feature from the targeted 
panel, WES or RNA-seq, in addition to molecular eligibility criteria for the 
MATCH subprotocol, that was judged to have potential therapeutic relevance 
to the specific class of drug that the patient received when the outcome was 
experienced. The additional features not found by the MATCH assay will be 
divided into two groups, with percentages calculated for both groups:  a) 
Additional features that were not found by the MATCH assay but are included 
in the MATCH assay (discordances with WES or RNA-seq), and b) additional 
features that were not found by the MATCH assay because they are not 
included in the MATCH assay (other potential targets as defined by WES or 
RNA-seq). 
3. Percentage of cases with at least one molecular feature that correlates with 
the mechanism of action or resistance to the specific agent or class of agents 
to which the outcome occurred, found after further analyzing WES or RNA-
seq and not identified in the original Molecular Characterization report. These 
analyses will again be split into groups—discordances and other potential 
targets. 
In the event that a patient experienced responses to multiple investigational 
agents, the multiplicity will be noted in study reports and publications, but each 
episode will be treated as though it was a distinct case for purposes of statistical 
summary calculation. 
All estimated proportions will be accompanied by exact 95% confidence intervals 
(Korn & Graubard, 1999). As this is an exploratory discovery study, no statistical 

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adjustment will be made for the fact that multiple confidence intervals will be 
computed. 
6.2. 
SAMPLE SIZE RATIONALE 
The targeted sample size for this study is based on achieving the goal of 
successful molecular characterization of tumor samples from patients enrolled on 
subprotocols of NCI-MATCH (EAY131). The number of tumor samples that will 
be screened and have molecular characterization attempted will depend on the 
success rates for remaining tissues adequate to perform WES and RNA-seq. If, 
after molecular assays have been attempted on samples from 100 cases, the 
number of cases for which WES or RNA-seq was successful (i.e., interpretable 
results) is less than 20, then shipment of samples from the ECOG/ACRIN 
Repository to the sequencing laboratories will be suspended for re-evaluation of 
study feasibility. If at least 20 but fewer than 49 of the first 100 samples yield 
useable WES results, the study investigators’ feasibility assessment will consider 
the number of molecular features with potential therapeutic relevance that were 
identified among the cases that yielded useable exome or transcriptome 
sequencing results. The study will be terminated when interpretable molecular 
results (minimum WES) have been obtained on at most 700 cases or when a 
total of 1400 (i.e. 700 each tumor/normal) molecular characterization assays 
have been attempted, whichever occurs first. 
The probability that the study will be suspended after assays have been 
attempted on the first 100 cases due to observed number of successes less than 
20 is at least 89% if the true assay success rate is at most 15%. The probability 
that the observed number of successful assays among the first 100 attempted will 
be 20 or more is at least 90% if the true assay success rate is at least 25%. 
Observed success percentages and sample size will determine the width of 2-
sided 95% confidence intervals calculated to estimate the true percentages, as 
demonstrated in the following table: 
 
Exact 2-sided 95% confidence interval for percentage 
Observed 
percentage 
N=200 
N=600 
N=1000 
10 
6.2, 15.0 
7.7, 12.7 
8.2, 12.0 
20 
14.7, 26.2 
16.9, 23.4 
17.6, 22.6 
30 
23.7, 36.9 
26.4, 33.8 
27.2, 32.9 
40 
33.2, 47.1 
36.1, 44.0 
36.9, 43.1 
50 
42.9, 57.1 
45.9, 54.1 
46.9, 53.1 
60 
52.9, 66.8 
56.0, 63.9 
56.9, 63.1 
70 
63.1, 76.3 
66.2, 73.6 
67.1, 72.8 
80 
73.8, 85.3 
76.6, 83.1 
77.4, 82.4 
90 
85.0, 93.8 
87.3, 92.3 
88.0, 91.8 
If a total of 600 assays are performed, and 50% of those assays yield 
interpretable molecular results, the 95% confidence interval for the overall assay 
success rate is 45.9-54.1%. If 20 of the 200 cases yielding interpretable 
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95% confidence for the promising discovery rate (among successfully performed 
assays) is 6.2-15.0 %. 
6.3. 
RESULTS INTERPRETATION AND NEXT STEPS 
This study is designed as a signal finding and hypothesis generating study. It is 
intended that interesting molecular features identified in this study will be 
investigated in other studies conducted outside of this protocol. These additional 
studies might include, for example, preclinical studies based on cell lines or 
xenografts, or retrospective studies using more clinical samples to examine 
whether the molecular features of interest for a particular drug can be found 
repeatedly in responders to that drug and not found in non-responders. Finally, 
the promising discoveries might lead to prospective clinical trials evaluating the 
drugs of interest in patients having the indicated molecular characteristics. 
VII. 
ETHICAL AND PRIVACY CONSIDERATIONS 
7.1. 
DATA ACCESS AND SHARING PLANS: 
This study proposes to conduct whole exome and mRNA sequencing, and if 
possible whole genome sequencing with previously collected tissue, including 
germline tissue, if available. 
It is imperative to know that this data will have been generated in a research 
setting, not in a CLIA certified laboratory, and no clinical decisions should be 
taken in response to data obtained in a facility that has not been CLIA certified. 
In addition, de-identified genomic data generated by the project will, in 
accordance with NIH policy, be made available to other researchers in a 
controlled access database, raising privacy considerations for subjects as well as 
genetic relatives, given evolving technological capabilities for re-identification. 
7.2. 
LINKED PROTOCOL AND “CODED” IDENTIFIERS 
This study operates as a “linked  protocol, with each participant ID being doubly 
de-referenced (i.e., “coded  twice) before data are distributed to sequencing 
sites. The first linking key is retained by ECOG-ACRIN and CBPF for participants 
enrolled in NCI-MATCH. Access to this key is under the purview of ECOG-ACRIN 
institutional policies. The second linking key is retained by the CDC and is only 
made available within the program for quality control purposes upon approval by 
the PI(s). The second key will also be provided to ECOG-ACRIN. The NCI-
MATCH subprotocol PIs may obtain sequencing results, if desired, for the 
patients enrolled onto this study. However, the results are not conducted in a 
CLIA certified laboratory, will not be returned to sites, and will not be used for 
clinical decision making. 
7.3. 
GENETIC DATA: CONTROLLED-ACCESS TIERS 
This study will generate genetic data unique to an individual (“genetic 
fingerprints  or genotypes). These data are not directly tied to an identified 
individual, and the clinical information associated with these data are de-identified 
as described above. Nevertheless, a risk exists that the genetic data could lead 
to the re-identification of a participant or relative. Consequently, NIH policy is that 
individual genetic data from the characterization studies are kept in a restricted-
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In accordance with the NIH Genome Data Sharing policy data, de-identified 
exome and RNA-seq data will be stored in an NIH controlled access database 
and made available to qualified researchers upon request. To be authorized to 
access the restricted tier of data, investigators must submit an application to a 
Data Access Committee (DAC) of the National Institutes of Health designated to 
review applications for the NCI-MATCH protocol. Upon approval by the DAC that 
the access request is for bona fide research purposes and consistent with any 
consent limitations under which the data were collected, the Investigator, 
scientists under their control, and their institution must subscribe to a Data Use 
Certification (DUC) that controls their ability to access the data, redistribute the 
data, prohibits the re- identification of participants, and includes requirements for 
data security. 
7.4. 
DISPOSITION OF SAMPLES AT THE END OF THE STUDY 
Residual samples and analytes will be distributed, retained, or destroyed at the 
discretion of the National Cancer Institute Center for Cancer Genomics. 
VIII. 
INTELLECTUAL PROPERTY CONSIDERATIONS 
8.1. 
PROPRIETARY INTELLECTUAL PROPERTY GENERATION 
This study is intended as a hypothesis generating study. Neither the sequencing 
centers, the Clinical Data Center, nor the NCI intend to generate proprietary 
intellectual property from this study. 
IX. 
REFERENCES 
1. Carter, S. L., Cibulskis, K., Helman, E., McKenna, A., Shen, H., Zack, T., et.al. 
(2012). Absolute quantification of somatic DNA alterations in human cancer. Nat 
Biotechnol, 30(5), 413-421. doi:10.1038/nbt.2203 
2. Iyer, G., Hanrahan, A. J., Milowsky, M. I., Al-Ahmadie, H., Scott, S. N., Janakiraman, 
M, et. al. (2012). Genome sequencing identifies a basis for everolimus sensitivity. 
Science, 338(6104), 221. doi:10.1126/science.1226344 
3. Korn, E. L., & Graubard, B. I. (1999). Analysis of health surveys. New York: Wiley. 
4. Wagle, N., Grabiner, B. C., Van Allen, E. M., Hodis, E., Jacobus, S., Supko, J. 
G.,et.al. (2014). Activating mTOR mutations in a patient with an extraordinary 
response on a phase I trial of everolimus and pazopanib. Cancer Discov, 4(5), 546-
553. doi:10.1158/2159-8290.CD-13-0353 

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Molecular Analysis for Therapy Choice (MATCH) 
Appendix XVII 
 
Dynamic aMOI Process 
As of Addendum #10, NCI-MATCH uses external “designated laboratories  (DL) to 
identify eligible patients. The DL have identified several variants which are not currently 
listed in the MATCH Huddle spreadsheet, but which the DL consider potentially eligible 
for MATCH. These include variants classified as actionable mutations of interest 
(aMOIs) by a DL but not specified as such by the MATCH protocol, as well as non-
hotspot variants not identified by the current MATCH assay.   
NCI-MATCH has articulated that additional aMOIs (inclusionary OR exclusionary) can be 
considered actionable (used to assign a treatment in NCI-MATCH) if they meet the NCI-
MATCH study’s levels of evidence. This document elaborates on the process by which 
aMOIs not currently considered to be actionable may be deemed actionable. Designated 
laboratories’ are to utilize novel aMOIs to determine an applicable referral for a specific 
arm if their assay are able to report the variants. 
We have classified variants identified by DL assays but not listed in the MATCH Huddle 
spreadsheet into six categories as below, grouped by the workflow required for enrolling 
the patient.  The MATCH Huddle spreadsheet is a direct representation of actionable 
variants listed in the subprotocol appendices. 
Category 1. 
A novel oncogene alteration that is classified by the DL as gain-of-
function. 
This alteration would not meet existing levels of evidence (LOE) for 
MATCH and would therefore require that the designated laboratory 
submit either published or unpublished data that meet our current levels 
of evidence for variants (Level 1, 2 or 3) to support the gain-of-function 
claim (see EAY131 Section 1.4.2). 
Examples: 
a. A mutation in the kinase domain of a receptor tyrosine kinase (RTK) 
which the DL predicts will result in constitutive activation of the RTK. 
b. An intragenic in-frame fusion event in an oncogene (e.g. novel MET 
ex14 event that additionally removes codons in ex13) that the DL 
predicts will be oncogenic. 
Category 2. 
A tumor suppressor gene alteration that is classified by the DL as loss-of-
function and which does not result in the introduction of a stop codon or 
frameshift at the protein level. 
This alteration would not meet existing LOE and would require that the 
designated laboratory submit either published or other data to support the 
loss-of-function claim. 
Examples: 
a. A missense mutation in a tumor suppressor gene 
b. A splice site alteration in a tumor suppressor gene. 
c. An intragenic deletion which preserves the open reading frame in a 
tumor suppressor gene. 
Rev. Add13 
Rev. Add24 
Rev. Add25 

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Category 3. 
A loss of function alteration in a tumor suppressor gene where the 
alteration results in the introduction of a stop codon, a frameshift 
alteration or a 3’ deletion of the gene that effectively introduces a stop 
codon in the predicted protein product. 
This alteration would meet existing Level 3 evidence in MATCH and 
would not require additional documentation from the designated 
laboratory. 
Examples: 
a. A 4 bp deletion that introduces a stop codon into the predicted protein 
of a gene. 
b. A large deletion of a tumor suppressor gene that removes the carboxy 
terminus of the predicted protein (e.g. deletion of exons 17-42 in 
TSC2, a 42-exon gene). 
c. A homozygous deletion that results in the complete loss of a tumor 
suppressor gene (e.g. TSC1, TSC2). 
Category 4. 
A novel fusion event of the kinase domain of an oncogene that the DL 
predicts will be oncogenic. 
Functional and clinical data from the literature suggest a novel fusion 
event that leaves the kinase domain of the oncogene partner intact will be 
activating. Therefore, this alteration would meet existing LOE for MATCH 
and would not require additional documentation from the designated 
laboratory. 
Examples: 
a. A novel BRAF fusion 
Category 5. 
A gain or loss-of-function alteration that is not identified by the MATCH 
assay at the DNA level, but which results in an alteration at the protein 
level that is identified in the MATCH Huddle spreadsheet. 
This alteration would meet existing LOE for MATCH and would not 
require additional documentation from the designated laboratory. 
Examples: 
a. EGFR, L858R  T->G COSM6224 (listed in Matchbox) 
b. EGFR, L858R   CT->AG (not listed in Matchbox but found by the DL) 
Category 6. 
All other alterations. 
These would be evaluated on a case-by-case basis and may or may not 
require supporting data, depending on the nature of the alteration.  The 
MATCHBox verification team will consider the supporting data, if any has 
been submitted by the DL, and render a decision regarding patient 
eligibility for MATCH for these cases.  Clinical sites should not be notified 
of potential eligibility until this determination is made. 
Moving forward, where a documented LOE is required from the DL (categories 1 and 2), 
the workflow below will be followed. For category 3, the rationale is that these cases 

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Molecular Analysis for Therapy Choice (MATCH) 
Appendix XVIII 
 
CS-MATCH-0009 
 
Longitudinal Evaluation of Mutation Profile in NCI-MATCH Patients on All Treatment 
Arms through Evaluation of Archival Specimens 
PRINCIPAL INVESTIGATOR: 
Stanley Hamilton, MD 
CO-INVESTIGATORS: 
P. Mickey Williams, PhD 
John Iafrate, MD 
Jeffrey Sklar, MD PhD 
 
Lyndsay Harris, MD 
 
BIOSTATISTICS 
Lisa McShane, PhD; BRB DCTD, NCI 
 
Laura Yee, PhD; BRB DCTD, NCI 
 
Robert J. Gray, PhD; ECOG/ACRIN 
 
Shuli Li, PhD; ECOG/ACRIN 
 
Rev. Add13 

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ABSTRACT: 
This project will characterize archival diagnostic specimens by next generation sequencing 
(NGS) assays, including but not limited to the NCI-MATCH Oncomine NGS assay, whole 
genome sequencing (WGS), whole exome sequencing (WES), and transcriptomic RNA 
sequencing (RNAseq) and compare the results to those obtained from similar genomic analyses 
of the matched pre-treatment NCI-MATCH tumor tissue. The project will initially focus on the 
approximately 700 patients assigned to one of the treatment arms. Sequencing will proceed in 
two phases: 1) pilot analysis of 100 samples, followed by a planned data analysis pause; and 2) 
sequencing of the remaining approximately 600 samples. Tumor biospecimens analyzed will be 
the archival diagnostic tissue and any intervening biopsy/resected tissues. Biospecimens will be 
sent to the NCI-MATCH biorepository within the MD Anderson Cancer Center (MDACC) 
Molecular Pathology Laboratory for pre-analytical processing, including pathology review, 
immunohistochemistry (IHC), and nucleic acid extraction. The NCI-MATCH Oncomine NGS 
assay will be performed within one of the five MATCH molecular characterization centers, 
MDACC, NCI-Frederick Molecular Characterization Laboratory (MoCha), Yale University, 
Massachusetts General Hospital (MGH), and Dartmouth College. Additional NGS assays (WES, 
WGS, RNAseq) will be performed at MoCha depending on funding. Data analysis will be 
performed by MDACC, MoCha, Yale, MGH, Dartmouth, and ECOG-ACRIN in conjunction with 
input from the Division of Cancer Treatment and Diagnosis (DCTD) at NCI. 
1. OBJECTIVES AND HYPOTHESES 
The main objective of this effort will be to determine if the actionable mutation of interest 
(aMOI) for which the patient was treated on NCI-MATCH exists in the archival, diagnostic 
and/or intervening tissues. The answer to this question will help drive full understanding of 
the NCI-MATCH clinical trial results. If a high concordance of aMOIs is observed between 
archival diagnostic specimens and the MATCH biopsies, this would suggest “fresh  
pretreatment biopsies are not required for genomic analysis and treatment assignment. This 
result would minimize trial costs and risk to patients, and therefore likely increase enrollment 
in future precision-medicine studies. In addition, if patient response is linked with concordant 
specimens, this would support the notion that the aMOI was a driver/truncal mutation. 
1.1. Objectives: 
• 
To determine if “fresh  biopsies are required for precision medicine studies. 
• 
To determine how the archival diagnostic mutation profile compares to the MATCH 
pretreatment biospecimen mutation profile. 
• 
To determine if a treatment-assignable aMOI was concordant between archival 
and MATCH pretreatment specimens in a particular patient and if better clinical 
outcomes were seen in those with discordant results. 
• 
To assess how the archival diagnostic mutation profile compares to the mutation 
profile in ctDNA (an additionally planned activity for NCI-MATCH) 
1.2. Hypotheses 
A true targetable oncogenic driver mutation will be present in all biopsies sampled over 
time, and patient response will correlate with the targetable oncogenic driver mutation 
in the archived diagnostic specimen. 

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2. BACKGROUND AND SIGNIFICANCE 
The NCI-MATCH clinical trial required a pretreatment “freshly  collected tumor for use in the 
NCI-MATCH screening assays (IHC and Oncomine NGS). The reason for requiring a fresh 
pretreatment tissue was to permit screening of the tumor just prior to MATCH trial treatment 
and after all previous therapies. Previous treatments have been demonstrated to alter the 
genomic landscape of the disease, with acquisition of newly acquired mutations, some 
leading to resistance to prior therapies and others resulting from rapid evolution and error 
prone cell division. Although new mutations can occur with treatment or with cancer 
progression, it is essential to know whether true drivers differ with time, and to correlate the 
presence of a driver from malignant tissue acquired earlier in the course of a patient’s 
malignancy with the IHC and NGS results obtained just prior to entry onto a NCI-MATCH 
treatment arm. Comparison of assay results from the archival diagnostic specimen and 
MATCH pretreatment specimen with response to the targeted treatment(s) may show 
whether the driver mutation is correlated with response. If so, then the need for a biopsy 
collection just prior to targeted treatment would be obviated. 
To date, there are limited studies comparing NGS (WES, WGS, RNAseq) results from 
different biopsies over time from the same patient, especially for solid cancers. The Cancer 
Genome Atlas (TCGA) initiative primarily examined primary tumors, as opposed to 
metastatic lesions that are typically refractory or relapsed. The TCGA only studied 
secondary tumors if they matched to a primary tumor as part of a series (germline, primary 
and metastasis). Recent work in paired primary and metastatic ovarian cancers showed an 
increase in copy number alterations in the metastatic lesions (Brodsky et al, PLoS One. 
2014). 
EGFR-mutant lung adenocarcinoma is one area where several studies comparing matched 
pre- and post-treatment tumor molecular profiles have been performed. These studies show 
that while resistance can arise by multiple means, the primary EGFR sensitizing mutation 
(i.e., Ex19del or L858R) continues to be present in all patients who progress on an EGFR-
targeted therapy. This result is consistent with the hypothesis that a true oncogenic driver 
mutation present at diagnosis will continue to be present after one or more rounds of 
therapy (Sequist et al, Sci. Transl. Med. 2011). 
3. RESEARCH DESIGN AND METHODS 
3.1. Biospecimens to be analyzed 
Archived FFPE specimens collected prior to screening on NCI-MATCH from patients 
assigned to a MATCH treatment and consented to allow their tissue to be submitted 
and used for research will be analyzed. The optimal tissue requirements are the same 
as those defined in Section 9.3.2.1 of the EAY131 Master Protocol. 
3.2. Laboratory methods 
The primary laboratory method will be targeted deep sequencing using the NCI-
MATCH Oncomine version 3 NGS assay. This assay has been validated in three labs 
to date and will be validated in all 5 MATCH network sequencing labs. The 3 network 
laboratories (MoCha, MDACC, and Dartmouth), performing all experiments as 
designed in the validation plan and using harmonized and locked SOPs, were able to 
demonstrate an overall sensitivity of 97.63%, overall specificity of 100%, overall 
accuracy of 99.99%, and an overall positive percent agreement of 99.99%. 

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The samples will undergo review, quality assurance/quality control evaluation, and 
processing in the same manner as the screening samples on NCI-MATCH, including: 
• 
Pathology review in the MDACC pathology laboratory (Stan Hamilton, PI) to: 1) 
confirm pathologic diagnosis; 2) confirm presence of tumor cells and specimen 
adequacy; and 3) perform any immunohistochemical assessments required. 
• 
DNA and RNA will be extracted and checked for sufficient quantity and quality. 
After processing, qualified cases will be shipped to one of the five MATCH 
molecular characterization centers (MCC) [MoCha, MDACC, Yale, MGH, 
Dartmouth]. All DNA and RNA from tumor and germline control tissues must also 
meet quality metrics before shipping to a MCC. 
• 
Tumor characterization by platform will proceed in a step-wise manner to identify 
molecular features potentially predictive of response to therapy. Finding mutations 
in known cancer genes (oncogenes or tumor suppressors) will be the most readily 
interpretable and will be primarily determined by the NCI-MATCH Oncomine NGS 
assay. Sequencing will be performed on Ion Torrent S5XL systems at the five MCC 
labs. NOTE: The amount and integrity of tumor tissue may ultimately be the limiting 
factor in what sequencing methodologies will be employed. 
• 
WES and RNAseq may be performed, depending on funding. WES and RNAseq 
have been successfully performed using FFPE tissue if quantity and quality of DNA 
and RNA are sufficient. If performed, WES and RNAseq will be done on Illumina 
machines, such as HiSeq 2500 or NovaSeq. 
3.3. Prioritization 
Tumor tissue will be characterized by targeted deep sequencing (NCI-MATCH 
Oncomine version 3 NGS assay). WES and RNAseq may be done if enough tumor 
DNA and RNA is available and sufficient funding exists. If tumor sample is limiting, the 
NCI-MATCH Oncomine NGS assay will be prioritized. 
4. DATA ANALYSIS AND STATISTICAL CONSIDERATONS 
Data from the NCI-MATCH Oncomine platform will be analyzed for concordance between 
mutations in the archival diagnostic and pretreatment biopsy specimens. The BAM files will 
be subjected to analysis through NCI-MATCHBox, the rules-based engine devoted to 
determining patient assignment. If data from other platforms (WES and RNAseq) is 
available, the data will be analyzed for mutations with an impact on known cancer genes 
and genes involved in known cancer pathways. 
Genes will be ranked and reported based on their known or potential involvement in cancer. 
Genes of unknown significance will be reported as passengers. MDACC, MoCha, Yale, 
MGH, Dartmouth, NCI, and ECOG-ACRIN will be responsible for the statistical and 
bioinformatic analyses of the data. 
4.1. Endpoints (outcomes) 
The primary endpoint is the NCI-MATCH Oncomine version 3 NGS assay. A 
secondary endpoint is concordance of immunohistochemistry, as appropriate, with that 
required by the screening assay. Tertiary endpoints may be WES and RNAseq. 
4.2. Case selection 
The study goal is to collect NCI-MATCH Oncomine version 3 NGS molecular results 
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allow their tissue to be submitted and used for possible research studies. To date, 
there are about 700 patients who were assigned to a MATCH treatment. After May 
2017, additional patients will be assigned based on outside assay results. We 
anticipate that at least 50% of assigned patients will have available and suitable 
archival and/or diagnostic tissue. Cases must meet the criteria for consent approval 
and response documentation, and each case must have sufficient tumor. 
The targeted sample size for this study is based on achieving the goal of successful 
molecular characterization of tumor samples from patients enrolled on treatment arms 
of NCI-MATCH. The number of tumor samples that will be screened and have 
molecular characterization attempted will depend on the success rates for remaining 
tissues adequate to perform the NCI-MATCH Oncomine NGS assay. If, after molecular 
assays have been attempted on samples from 100 cases, the number of cases for 
which Oncomine was successful (i.e., interpretable results) is less than 20, then 
sample processing and sequencing will be suspended for re-evaluation of study 
feasibility. 
4.3. Statistical analysis plan: 
4.3.1. Aim 1: To determine if “fresh  pretreatment biopsies are required for precision 
medicine studies. 
Statistical analyses will be primarily descriptive. To characterize differences 
between the archival diagnostic biopsy, intervening samples, and MATCH 
pretreatment biopsy, we will describe discordances in samples from the same 
patient using the MATCH targeted panel. We will provide summary statistics for 
concordance observed for putative oncogenic driver mutations. Analyses could 
potentially be stratified by driver mutation and by histology. Of note, the NCI-
MATCH Oncomine panel has been versioned with additions and subtractions 
of various genes. It is conceivable the current targeted panel version will 
identify aMOIs in the archival diagnostic sample that were not originally tested 
in the MATCH pretreatment biopsy sample. 
4.3.2. Aim 2: To determine how the archival diagnostic biopsy mutation profile 
compares to the MATCH pretreatment biopsy mutation profile. 
Statistical analyses will be primarily descriptive. We will describe discordances 
in the NCI-MATCH Oncomine NGS assay between the archival diagnostic 
sample and MATCH pretreatment biopsy sample (Step 0). 
4.3.3. Aim 3: To determine if a treatment-assignable aMOI was concordant between 
the archival and MATCH pretreatment specimens in a particular patient and if 
better clinical outcomes were seen than in those with discordant results. 
Statistical analyses will be primarily descriptive. Feasibility and success in 
discovering molecular features with potential therapeutic relevance (“promising 
discoveries ) will be assessed. 
4.3.4. Aim 4: To assess how the archival diagnostic mutation profile compares to the 
mutation profile in ctDNA (an additionally planned activity for NCI-MATCH). 
Statistical analyses will be primarily descriptive. We will describe discordances 
between the MATCH targeted panel and mutational profile in the baseline 
ctDNA sample (Step 0). The analysis of ctDNA samples have not been 
finalized and may include a targeted panel similar to the NCI-MATCH 
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Molecular Analysis for Therapy Choice (MATCH) 
Appendix XX 
 
CS-MATCH-0014ct 
Genomic landscape of plasma-derived ctDNA from patients enrolled on the NCI-MATCH trial 
PRINCIPAL INVESTIGATOR: 
Filip Janku, MD PhD 
CO-INVESTIGATORS: 
Funda Meric-Bernstam, PhD 
Stanley Hamilton, MD 
Rajyalakshmi Luthra, PhD 
Mark Routbort, MD PhD 
Richard Lanman, MD 
Victoria Raymond, MS 
Justin Odegaard, MD PhD 
BIOSTATISTICS: 
Kenneth Hess, PhD 
Lisa McShane, PhD; BRB DCTD, NCI 
Laura Yee, PhD; BRB DCTD, NCI 
Robert J. Gray, PhD; ECOG/ACRIN 
Shuli Li, PhD; ECOG/ACRIN 
5. 
INTRODUCTION 
Obtaining blood-based liquid biopsies is a minimally invasive approach, which allows to 
collect material such as plasma-derived cell-free DNA, which can contain fragments of 
ctDNA.1 ctDNA is released to the circulation from tumor cells undergoing apoptosis or 
necrosis from primary or metastatic cancer lesions and can be identified in the blood and 
other body fluids of patients with cancer (1). ctDNA can be detected and quantified in 
majority of patients with metastatic cancers and some patients with early disease (1). In 
metastatic cancers detection of molecular aberrations in ctDNA using PCR-based 
methods have acceptable concordance with the molecular profile of tumor tissue and 
molecular testing of liquid biopsies is being increasingly accepted in the clinical care 
(2,3). However, PCR-based molecular testing of liquid biopsies can probe only limited 
number of hot spot mutations in common cancer genes of known clinical relevance 
detected in small subsets of patients, which limits potential utility.(4-6) This can be 
overcome by introduction of technologies such as targeted NGS, which allow to test for 
large number of cancer genes; however, concordance with molecular testing of tumor 
tissue across multiple metastatic cancers has not been established except for small 
studies.(3,7,8) In addition, plasma-derived ctDNA can be used to assess cancer 
genotype at different time points and provide valuable information about genetic 
changes that occur during the disease trajectory reflecting the tumor clonal evolution, as 
this is not a static process (1) Also, dynamic changes in VAF for specific alterations in 
ctDNA isolated from blood or urine were found to correspond with response and 
progression-free survival to systemic targeted and non-targeted therapies in patients 
with advanced cancers and malignant histiocytosis.(9,10)  
The assay, Guardant360®, utilizes NGS-based digital sequencing to comprehensively 
profile 73 genes commonly altered in human cancer.(11) Of these 73 genes, 65 genes 
were also included in the assay, Oncomine, which was used for molecular profiling of 
pretreatment tumor biopsies in patients participating in the NCI-MATCH clinical trial. 
Guardant360®, is offered by Guardant Health, which is a CLIA certified, CAP-accredited, 
NYSDOH - approved molecular diagnostic laboratory, as a clinical test compliant with 
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information about clonal evolution to understand mechanisms of 
intrinsic and adaptive resistance.  
6.1.4. 
To demonstrate that molecular testing of plasma-derived ctDNA can 
detect actionable alterations in patients with insufficient tissue or failed 
results from the molecular testing of tumor tissue. 
6.2 
Hypotheses 
It is hypothesized that plasma-derived ctDNA reflects to molecular profile of the 
tumor tissue and that there is concordance between molecular testing of plasma-
derived ctDNA and molecular testing of tumor tissue DNA. We also hypothesize 
that dynamic changes in tumor genomic landscape in plasma-derived ctDNA can 
reflect therapeutic responses to cancer therapy. 
7. 
RESEARCH DESIGN AND METHODS 
7.1 
Biospecimens to be analyzed 
2 mLs of plasma to be analyzed were isolated from Streck tubes submitted:  
a. At baseline, the end of cycle 2, and at end of treatment from patient on the 
selected arms indicated in Table 2 below. The treatment arms were selected 
based on: 
• 
Therapeutically relevant molecular alteration, which is included in our 
Guardant360® NGS liquid biopsy assay.  
• 
Meaningful number of patients enrolled. 
• 
Inclusion of samples from consenting patients who enrolled onto any of the 
indicated treatment arms which are still actively accruing, including those 
from expansion cohorts, if applicable. 
A minimum of 600 plasma samples from 500 patients accrued to treatment will 
be analyzed. 
Table 2. Selected Treatment Arms 
Arm 
Drug 
Variant 
Rationale 
C1 
crizotinib 
MET amplification 
Detection of MET amplifications and other 
simultaneous alterations 
C2 
crizotinib 
MET exon 14 deletion 
Detection of MET exon 14 mutations and 
other simultaneous alterations 
E 
AZD9291 
EGFR (T790M) 
Detection of EGFRT790M mutations and 
other simultaneous alterations 
G 
crizotinib 
ROS1 
Detection of ROS1 rearrangement and 
other simultaneous alterations 
H 
dabrafenib and 
trametinib 
BRAF (V600E, V600K) 
Detection of BRAF mutations and other 
simultaneous alterations 
I 
Taselisib 
PIK3CA 
Detection of PIK3CA mutations and other 
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Arm 
Drug 
Variant 
Rationale 
J 
trastuzumab and 
pertuzumab 
HER2 (amplification) 
Detection of HER2 amplification and other 
simultaneous alterations 
L 
TAK228 
mTOR 
Detection of mTOR mutations and other 
simultaneous alterations 
Q 
ado-trastuzumab 
emtansine 
HER2 (amplification) 
Detection of HER2 amplification and other 
simultaneous alterations 
S1 
trametinib 
NF1 
Detection of NF1 mutations and other 
simultaneous alterations 
V 
sunitinib 
KIT 
Detection of KIT mutations and other 
simultaneous alterations 
W 
AZD4547 
FGFR 
Detection of FGFR alterations and other 
simultaneous alterations 
Y 
AZD5363 
AKT 
Detection of AKT mutations and other 
simultaneous alterations 
Z1A 
binimetinib 
NRAS 
Detection of NRAS mutations and other 
simultaneous alterations 
Z1E 
larotrectinib 
NTRK 
Detection of NTRK fusions and other 
simultaneous alterations 
Z1I 
AZD1775 
BRCA1, BRCA2 
Detection of BRCA1 and BRCA2 
mutations and other simultaneous 
alterations 
b. Baseline plasma samples from approximately 200 patients, if available, who 
were enrolled, but did not have tumor samples tested by the MATCH-assay 
because of insufficient biopsy sample or, who had attempted tissue 
sequencing, which failed to produce results.   
7.2 
Laboratory methods 
Cell-free DNA extraction, processing, and sequencing will be performed in a 
CLIA-certified, CAP accredited laboratory (Guardant Health, Inc.) as previously 
described. (7,11) Total of 5-30 ng of extracted cell-free DNA will be labeled with 
non-random oligonucleotide barcodes (IDT, Inc.) and used to prepare 
sequencing libraries, which will be then enriched by hybrid capture (Agilent 
Technologies, Inc.), pooled, and sequenced by paired-end synthesis (NextSeq 
500 and/or HiSeq 2500, Illumina, Inc.).  
Bioinformatics analysis and variant detection: All variant detection analyses will 
be performed using the locked clinical Guardant360 bioinformatics pipeline and 
reported unaltered by post-hoc analyses. All decision thresholds were 
determined using independent training cohorts, locked, and applied prospectively 
to all validation and clinical samples as previously described.7,8,11 Expected 
detection limit for single nucleotide variants (SNVs) is ~0.04% VAF, for indels 
~0.02% VAF and for fusions  ~0.04% VAF (Table 3).7  
Assay validation procedure and data: The Guardant360 assay was initially 
analytically and clinically validated for >50 cancer related genes and later on of 
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plasma-based comprehensive cancer genotyping assay (73 genes) utilizing 
orthogonal tissue- and plasma-based methodologies: In a validation study the 
test demonstrated exceptional sensitivity (LOD95 ≤0.3% for SNVs, indels, and 
fusions and near 2.2 copies for CNAs), while maintaining high PPV (>98%) even 
in sample cohorts enriched for alterations at or below the applicable LOD.7 
Specificity and precision are similarly high, allowing accurate variant identification 
as low as 0.02%-0.04%, which is critical for clinical ctDNA analysis as many 
relevant alterations are present at very low levels. Performance was verified in 
349 clinical samples using internal and blinded external comparison to clinical 
ddPCR, which demonstrated very high qualitative and quantitative concordance. 
Analysis of 543 matched tissue genotyping results demonstrated high PPVs 
relative to standard-of-care tissue diagnostics. Assay performance is 
summarized in Tables 3 and 4. 
Table 3. Analytical performance of Guardant360 (73 genes) 
Variant type 
Reporting 
threshold 
LOD95 
Sensitivity 
PPV 
Specificity 
Per sample 
Per call 
SNVs 
0.04%/2 
molecules 
>0.25% 
100% 
99.2% 
97% 
>99.9999% 
0.05-0.25% 
63.8% 
96.3% 
Indels 
0.02%/1 
molecule 
>0.02% 
100% 
98.2% 
100% 
100% 
0.05-.2% 
67.8% 
98.2% 
Fusions 
0.04%/2 
molecules 
>0.02% 
95% 
100% 
100% 
100% 
0.05-.2% 
83% 
100% 
Amplifications 
2.12 copies 
2.24-2.76 
copies 
95% 
100% 
100% 
100% 
Table 4. Clinical validation of Guardant360 (73 genes) 
Positive % agreement 
>99% 
Negative % agreement 
>99% 
Positive predictive value 
92%-100% 
Technical success rate 
>99.6% 
Clinical sensitivity 
85.9% 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATONS 
8.1. 
Aim 1: We will assess concordance between molecular testing of plasma-derived 
ctDNA and simultaneously collected tumor tissue on a gene-by-gene basis using 
the kappa coefficient. The inventory indicates 393 baseline samples. Therefore, 
we performed power calculations for 375 samples assuming that some samples 
might not be adequate for analysis.  With 375 patients we will have > 90% power 
to detect a kappa of 0.8 (very good agreement) as significantly different from 0.4 
(poor agreement) with a 2-sided 5% alpha and assuming true prevalence of 5%. 
For low prevalence aberrations, we will use exact methods of inference. Only 
genes and regions covered by both Guardant360 and Oncomine assays will be 
included for the concordance analysis. For a gene alteration with 10% 
prevalence, if sensitivity equals 89% (33/37) then a 95% Wilson confidence 
interval would extend from 75% to 96% and if specificity equals 90% (304/338) 

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then a 95% Wilson confidence interval would extend from 86% to 93%.Aim 2: To 
determine how the archival diagnostic biopsy mutation profile compares to the 
MATCH pretreatment biopsy mutation profile. 
8.2. 
Aim 2: (a) We will use logistic regression analysis to assess the association of 
presence of matched ctDNA alterations, number of simultaneous ctDNA 
alterations, and mutation burden with clinical benefit defined by RECIST 1.1 
(complete response/partial response/stable disease > 6 months).12 We will use 
Cox proportional hazards regression analysis to assess the association of 
presence of matched alterations, number of simultaneous alterations, and 
mutation burden with progression-free survival (PFS, defined as time from the 
start of study medication to progression or death). We will only look at the gene 
alterations associated with each arm of the study. A patient will be evaluated as 
“positive  if their ctDNA had the targeted alteration for their arm of the study and 
“negative  otherwise. The logistic regression model with have clinical benefit as 
the response variable and have 3 predictor variables: matched alteration status, 
number of simultaneous ctDNA alterations, and mutation burden. The Cox 
proportional hazard model with have PFS as the outcome and have 3 predictor 
variables: matched alteration status, number of simultaneous ctDNA alterations, 
and mutation burden. With 375 patients we will have  > 80% power to detect an 
odds ratio of 2.2 as significantly different from 1.0 (the null value) with a 2-sided 
5% alpha if the clinical benefit rate is 30% and the prevalence of the alteration is 
20%. For a 15% prevalence, the detectable odds ratio is 2.4; for 10% it is 2.8 and 
for 5% it is 3.9. With 100 PFS events (in 375 patients) we will have > 90% power 
to detect a hazard ratio of 2.3 as significantly different from 1.0 (the null value) 
with a 2-sided 5% alpha if the prevalence of the alteration is 20%. For a 15% 
prevalence, the detectable hazard ratio is 2.5; for 10% it is 3.0 and for 5% it is 
4.5. (b) We will conduct exploratory analyses assessing the association between 
dynamic changes in ctDNA profile in serially collected samples using logistic 
regression analysis for clinical benefit and Cox proportional hazards regression 
analysis for PFS. We will create an indicator variable that is “yes  if the cycle 2 
sample lacked the targeted alternation for the given treatment arm while the 
baseline sample had the targeted alteration and “no  otherwise and correlate this 
indicator with outcome. Graphical analyses will also be used. With 25 PFS 
events out of 90 patients with baseline and cycle 2 samples, we will have >80% 
power to detect a hazard ratio of 3.1 as significantly different from 1.0 (the null 
value) with a 2-sided 5% alpha if the prevalence of the indicator is 50% and 3.7 
for an indicator prevalence of 75%.  
8.3. 
Aim 3: This aim is descriptive not necessitating formal statistical analysis. 
8.4. 
Aim 4: For patients whose tumor tissue testing yielded no molecular aberrations, 
we will estimate the proportion of patients in which ctDNA molecular testing 
detected actionable alterations. We will randomly sample 25 patients from each 
of the 8 most common tumor types. With 200 patients, an exact 95% confidence 
interval for an estimate of 5% extends from 2.4% to 9.0% and for an estimate of 
2.5% extends from 0.8% to 5.7%. 
9. 
REFERENCES 
1. 
Polivka J, Jr., Pesta M, Janku F: Testing for oncogenic molecular aberrations in 
cell-free DNA-based liquid biopsies in the clinic: are we there yet? Expert Rev 
Mol Diagn 15:1631-44, 2015 

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2. 
Sacher AG, Paweletz C, Dahlberg SE, et al. Prospective Validation of Rapid 
Plasma Genotyping for the Detection of EGFR and KRAS Mutations in Advanced 
Lung Cancer. JAMA Oncol, 2016 
3. 
Janku F, Zhang S, Waters J, et al. Development and validation of an ultra-deep 
next-generation sequencing assay for testing of plasma cell-free DNA from 
patients with advanced cancer. Clin Cancer Res, 2017 
4. 
Janku F, Huang HJ, Claes B, et al. BRAF Mutation Testing in Cell-Free DNA 
from the Plasma of Patients with Advanced Cancers Using a Rapid, Automated 
Molecular Diagnostics System. Mol Cancer Ther 15:1397-404, 2016 
5. 
Janku F, Huang HJ, Fujii T, et al. Multiplex KRASG12/G13 mutation testing of 
unamplified cell-free DNA from the plasma of patients with advanced cancers 
using droplet digital polymerase chain reaction. Ann Oncol 28:642-650, 2017 
6. 
Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor 
dynamics. Nat Med 14:985-90, 2008 
7. 
Odegaard JI, Vincent JJ, Mortimer S, et al. Validation of a Plasma-Based 
Comprehensive Cancer Genotyping Assay Utilizing Orthogonal Tissue- and 
Plasma-Based Methodologies. Clin Cancer Res, 2018 
8. 
Zill OA, Banks KC, Fairclough SR, et al. The Landscape of Actionable Genomic 
Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer 
Patients. Clin Cancer Res, 2018 
9. 
Hyman DM, Diamond EL, Vibat CR, et al. Prospective blinded study of 
BRAFV600E mutation detection in cell-free DNA of patients with systemic 
histiocytic disorders. Cancer Discov 5:64-71, 2015 
10. 
Oxnard GR, Paweletz CP, Kuang Y, et al. Noninvasive detection of response and 
resistance in EGFR-mutant lung cancer using quantitative next-generation 
genotyping of cell-free plasma DNA. Clin Cancer Res 20:1698-705, 2014 
11. 
Lanman RB, Mortimer SA, Zill OA, et al. Analytical and Clinical Validation of a 
Digital Sequencing Panel for Quantitative, Highly Accurate Evaluation of Cell-
Free Circulating Tumor DNA. PLoS One 10:e0140712, 2015 
12. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria 
in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-
47, 2009. 
 
 

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Molecular Analysis for Therapy Choice (MATCH) 
Appendix XXI 
 
CS-MATCH-0015ct 
 
A Retrospective Study of Liquid Biopsies Using a Pan-Cancer NGS Assay in NCI-MATCH 
Patients with Less Common Tumor Histologies or Who Enrolled in Subprotocol Arms 
Z1D, T or M 
PRINCIPAL INVESTIGATOR: 
P Mickey Williams, PhD 
CO-INVESTIGATORS: 
Alice P Chen, MD 
Naoko Takebe, MD PhD 
Phillip Febbo, MD 
Traci Pawlowski, PhD 
James V. Tricoli, PhD 
Chris Karlovich, PhD 
Biswajit Das, PhD 
BIOSTATISTICS 
Lisa McShane, PhD 
 
 
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1. 
INTRODUCTION 
The analysis of circulating tumor DNA (ctDNA) from cancer patient plasma is emerging 
as a powerful complement to tumor biopsies with the recent incorporation of plasma 
testing into the CAP/IASLC/AMP guideline for patients with non-small cell lung cancer1. 
While the potential clinical utility of liquid biopsies has now been extensively explored in 
more common tumor types (2) such as lung (3), colorectal (3), breast (3) and prostate 
(4) a comprehensive study in rare tumor histologies has not to our knowledge been 
published. Using a 523-gene ctDNA NGS assay platform, TSO500, we propose to test 
the plasma from ~2500 patients with less common/rare tumor types who were screened 
for NCI-MATCH but never underwent treatment. Results will be compared to tumor 
sequence data, and a comprehensive profile of the plasma mutational and biological 
landscape for each histology will be generated. As a secondary objective, we propose to 
test the plasma of patients who enrolled to arms T, M and Z1D to investigate 
mechanisms of resistance. A tertiary objective will be to test plasma from patients with 
“common  histologies (i.e. lung, breast, colon and prostate) who were never treated, and 
compare the results to tumor molecular profiles. 
The TSO500 assay is uniquely positioned to address the study objectives. This large 
ctDNA panel interrogates all but three of the 2445 SNV/Indel mutations of interest 
(MOIs) and actionable MOIs (aMOIs) interrogated by the 161-gene MATCH tumor panel 
(OCA), thus enabling a comprehensive comparison between plasma and OCA tumor 
results. Additionally, the TSO500 panel can be used to assess tumor mutational burden 
(TMB) and microsatellite instability (MSI) status (including Lynch syndrome loci) as well 
as known checkpoint inhibitor resistance mutations in JAK2 and B2M. Collectively, our 
proposed studies may provide novel translational insights and further advance the 
clinical potential of ctDNA. 
Our highest priority request and focus of our proposal (Workstream 1) is for plasma from 
patients with less common/rare cancer histologies who were never treated on NCI-
MATCH. As a second priority (Workstream 2), we propose to test plasma from patients 
treated on arms Z1D, T and M. Our Workstream 3 request is for plasma from patients 
with common histologies (i.e. lung, breast, colon and prostate) who never were treated 
on NCI-MATCH.  
1.1. 
Workstream 1 - Testing of ctDNA from patients with less common/rare cancer 
histologies in the NCI-MATCH cohort screened but not enrolled on a treatment 
arm [~60% of cases (~2500) among 4289 cases with pretreatment plasma] 
Approximately 60% of all screened NCI-MATCH patients had a less common 
(e.g. ovarian, head and neck) or rare cancer (e.g. cholangiocarcinoma, 
pancreatic endocrine), defined as a cancer type other than breast, lung, 
colorectal or prostate (6). To our knowledge, a comprehensive assessment of 
matched tumor and plasma molecular profiles in patients with rare histologies 
has not been conducted. We therefore propose to test the ctDNA of all patients 
with less common/rare histologies who provided a biopsy but did not enroll on a 
treatment arm of NCI-MATCH. We will compare TSO500 ctDNA results to 
matched OCA or whole exome sequencing (WES) tumor data (if available). 
When completed, we expect these assessments will provide new translational 
insights for the field of liquid biopsies. Specifically, data from our study will 
provide a comprehensive understanding of how ctDNA molecular profiles 
compare to and complement matched tumor molecular profiles in patients with 
rare histologies. Cases may even be identified where NCI-MATCH “mutations of 

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interest  (MOIs; defined as mutations interrogated by OCA for which evidence of 
oncogenicity exists in the literature and/or public databases such as COSMIC or 
ClinVar), and “actionable mutations of interest  (aMOIs; defined as mutations 
deemed clinically actionable because they are targeted by an NCI-MATCH study 
drug) are seen in plasma but not tumor because of tumor heterogeneity. Our 
study will additionally establish the fraction of patients in each less common/rare 
histology with ctDNA of sufficient quantity for evaluation. In aggregate, this 
information will help inform whether these patient populations would be good 
candidates for a liquid biopsy in future clinical trials and in clinical practice. 
A critical and distinguishing feature of the TSO500 ctDNA platform is its 
comprehensive panel design. TSO500 is a 523-gene panel (~2 megabases total, 
~1.3 megabases of which are protein-coding sequence) that covers the full 
exonic regions of all genes from FoundationOne, MSK IMPACT, TruSight170 
and TruSight Myeloid tumor panels, with additional custom designs. It is capable 
of detecting small variants in 523 genes, copy number events in 59 genes and 
fusions in 23 genes. The panel also includes HLA Class I loci to inform 
neoantigen prediction (Appendix B). Most notably, the panel interrogates all but 
three of the 2445 SNV and indel MOIs and aMOIs interrogated by the NCI-
MATCH OCA tumor test. It can assess MSI status and TMB in ctDNA more 
accurately than smaller gene panels, which would require at least 0.5 Mb of gene 
content for consistently accurate determination of clinically relevant levels of TMB 
(7). We therefore plan to characterize MSI status and TMB in untreated patients 
with rare histologies, and to compare the results to tumor assessments of MSI 
status and TMB from WES data, if available. Given the recent demonstration of 
MSI status and TMB as clinically validated biomarkers for checkpoint inhibitors 
(7,8,9), a successful retrospective demonstration that a blood test can accurately 
call both genomic features would be of great potential clinical utility. The 
bioinformatics pipeline associated with TSO500 can also provide information on 
percentage of ctDNA and clonal hematopoiesis, providing further information on 
the biology of malignancies. 
1.2. 
Workstream 2 - Treated patient arms Z1D, T and M (pre-treatment plasma, and 
where available paired pre-, on-treatment and/or post-treatment plasma) 
Circulating tumor DNA has shown great promise as a tool to identify putative 
mechanisms of primary and acquired resistance to targeted therapies in several 
tumor types (10) including lung (EGFR inhibitors) (11), prostate (PARP inhibitors) 
(12), ovarian (PARP inhibitors) (13), breast (PARP inhibitors) (13) and colorectal 
cancer (anti-EGFR antibodies) (14). Our workstream 2 proposal will hopefully 
extend these findings to other therapeutic areas. Specifically, we propose to test 
pre-treatment plasma, as well as matched pre-, on- treatment and/or post-
treatment plasma where available, to identify mechanisms of resistance in 
patients treated on arms Z1D (nivolumab for MMR deficiency), T (vismodegib for 
SMO and PTCH1 mutations) and M (TAK-228 for TSC1 and TSC2 mutations). 
We are requesting plasma from these arms because we believe our assay is 
best positioned to investigate mechanisms of resistance in them. Most 
commercial ctDNA assays do not interrogate all actionable mutations from arms 
T and M.  Further, we do not know of any commercial assay that can assess 
TMB, MSI status and B2M resistance mutations, which would be highly desirable 
for any proposed analysis of Z1D plasma specimens.  As mentioned previously, 

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a successful retrospective demonstration that a blood test can accurately call 
MSI and TMB would be of great potential clinical utility. 
Patients with matched baseline and progression plasma will be most informative 
and of primary interest for this proposal. This is because a putative mechanism of 
resistance should be present at a higher level (i.e. allele fraction) in post-
treatment ctDNA, reflecting clonal expansion of resistant tumor cell populations 
under the selection pressure of therapy. Given the numbers of patients with 
matched pre-treatment and progression blood samples will be small in these 
arms (Arm Z1D has 7 cases of matched pre- and on- treatment or post-treatment 
samples; Arm T has 3 cases of pre and on-treatment or post-treatment samples; 
Arm M has 11 cases of matched pre- and on-treatment or post-treatment 
samples), power for statistical tests is expected to be low and the analyses 
should be considered exploratory and hypothesis- generating. 
In most instances, only a pre-treatment sample will be available. While we 
propose to analyze all of these cases as well, our emphasis will be on the subset 
of patients who rapidly progressed. We hypothesize that the rapid progressors 
will be the ones mostly likely to have an identifiable candidate resistance 
mechanism present in pretreatment plasma. 
1.3. 
Workstream 3 -Testing of ctDNA from patients with “common  cancer histologies 
in the NCI- MATCH untreated cohort [40% of cases (~1700) among 4289 cases 
with pretreatment plasma]  
Our workstream 3 proposal is to test the ctDNA of all patients who provided a 
biopsy representing a “common  histology, but who never received treatment on 
NCI-MATCH. Similarly, as for rare histologies, we will compare TSO500 ctDNA 
results to matched Oncomine tumor results and to tumor WES data, if available.  
Compared with rare tumor histologies, more is known about plasma molecular 
profiles in common histologies (2,3,4). However, matched tumor and plasma data 
from NCI-MATCH patients with common histologies would be a meaningful 
addition to the body of literature for liquid biopsies in these patient populations. 
As discussed previously, we are well-positioned to perform a comprehensive 
comparison of matched ctDNA and tumor data because the TSO500 panel 
interrogates virtually all MOIs and aMOIs interrogated by the NCI-MATCH tumor 
test. 
2. 
OBJECTIVES AND HYPOTHESES 
2.1. 
Primary Objective 
To characterize the molecular landscape of each less common/rare tumor 
histology as profiled in ctDNA and compare it to the molecular landscape as 
assessed by the OCA tumor test used during patient selection 
2.2. 
Secondary Objectives 
2.2.1. To establish for each less common/rare tumor histology evaluated the 
distribution of ctDNA burden (i.e., percentage of ctDNA of all cfDNA) in 
patients, and the fraction of patients without any detectable ctDNA 
2.2.2. To determine the fraction of patients with an actionable mutation by OCA 
tumor test who also have the same actionable mutation by TSO500 
plasma test [i.e., the “Positive Percent Agreement  (PPAref_tumor) of the 

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TSO500 plasma test, with OCA tumor test as reference] in the selected 
untreated patient cohort, Arm Z1D, Arm T and Arm M. 
2.2.3. To determine the fraction of patients with an actionable mutation by 
TSO500 plasma test who have the same actionable mutation by OCA 
tumor test [i.e., the “Positive Percent Agreement  (PPAref_plasma) of the 
OCA tumor test, with TSO500 plasma test as reference] in the selected 
untreated patient cohort, Arm Z1D, Arm T and Arm M 
2.2.4. To identify, using the TSO500 plasma test, candidate molecular 
predictors of response and resistance in patients treated on Arms Z1D, T 
and M 
2.2.5. To characterize tumor heterogeneity using the TSO500 pan-cancer liquid 
biopsy assay and compare the results and degree of heterogeneity seen 
to that observed in matched tumor biopsies that had been assayed using 
the OCA tumor test 
2.3. 
Hypotheses 
2.3.1. The molecular landscape of rare tumor histologies profiled by plasma and 
tumor tests will be similar, except that more tumor heterogeneity will be 
observed in the ctDNA molecular profile assessed by the TSO500 plasma 
test. 
2.3.2. For patients for whom plasma is assessed by the TSO500 test, the 
positive percent agreement (PPAref_tumor) of the biomarker results from 
TSO500 with the OCA tumor test (as non-reference standard) will be 
>=85% as reported previously in similar comparisons (5). Conversely, the 
positive percent agreement (PPAref_plasma) of OCA tumor test to the 
TSO500 results will be >=85%. 
2.3.3. At least 85% of patients assigned to NCI-MATCH Arms Z1D, T and M 
would have been assigned the same treatment arm using an appropriate 
pan-cancer liquid biopsy assay (5). 
2.3.4. Prospective selection based on the TSO500 pan-cancer liquid biopsy 
assay with broad capabilities (e.g., MSI status, TMB) would have 
changed the clinical actionability of molecular finding for certain 
NCIMATCH patients screened by the OCA tumor test, especially those 
not assigned to treatment. Some of the patients not assigned to any 
treatment arms would have been eligible for other therapeutic options, 
including immunotherapy. 
2.3.5. The molecular landscape of common tumor histologies profiled by plasma 
and tumor tests will be similar, except that more tumor heterogeneity will 
be observed in the ctDNA molecular profile. 
3. 
RESEARCH DESIGN AND METHODS 
3.1. 
Biospecimens to be analyzed 
a. From NCI-MATCH treatment arms per Workstream #2: 
Plasma to be analyzed was isolated from 1-2 Streck tubes collected at baseline, 
on treatment, and progression from the following NCI-MATCH trial sub-protocol 
arms in decreasing order of priority: 

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• 
Arm Z1D: nivolumab in MMR-deficient tumors 
• 
Arm T: Smoothened (SMO) or Patched1 (PTCH1) mutations 
• 
Arm M: TSC1 or TSC2 
b. From patients screened by the MATCH-assay but not enrolled to NCI-
MATCH treatment arms as described for Workstreams #1 and #3: 
Plasma to be analyzed was isolated from 1-2 Streck tubes collected at baseline 
3.2 
Laboratory methods 
Testing will be completed using the Illumina ctDNA TruSight Oncology 500 
(TSO500) ctDNA assay on the Illumina NovaSeq instrument and S4 flow cells. 
After having reviewed various methods of assessing ctDNA available on the 
market and evaluating a number of these assays at MoCha, including both 
ddPCR and NGS assays, this TSO500 panel is unique not only because of its 
large size, but because of the ability to report somatic variants, tumor mutational 
burden (TMB), and microsatellite instability (MSI) status. The TSO500 assay 
uses reagents that are already on market in other research use only (RUO) kits, 
with the exception of the newly developed gene probe panel. The RUO assay 
including the 500-gene panel has undergone significant testing at Illumina to 
ensure the assay meets expectations for reproducibility, sensitivity and 
specificity. It will first be marketed as a “Research Use Only  assay and then 
submitted for CE-IVD and FDA approval (formulations for RUO and IVD are 
identical). The in vitro diagnostic (IVD) tissue assay is being developed in 
partnership with Bristol Myers Squibb (BMS) to identify patients who may benefit 
from BMS immunotherapeutics. Illumina has partnered with the MoCha 
laboratory to allow early access to this assay. 
The assay interrogates 1.3 megabases in coding regions in 523 genes to 
calculate TMB. The full assay size is 2.0 megabases, enabling the detection of 
single nucleotide variants (SNVs), insertions/deletions (indels), copy number 
variants (CNVs, amplifications only), and translocations from ctDNA. A subset of 
variants detected will be considered MOIs as described in the Definitions 
appendix. Through collaboration between MoCha and Illumina, raw variant 
results are available and detailed analysis is possible above and beyond the 
MOIs that are reported to further delve into the data as needed. 
This assay incorporates unique molecular identifiers (UMIs) to remove artifactual 
errors introduced during DNA extraction and storage, library preparation, and 
sequencing. With the use of UMIs, PCR duplicates belonging to the same DNA 
template are identified as families. PCR duplicates are first collapsed into one 
consensus read pair by template strand to remove random sequencing errors. 
When both strands of the same template are present, they are further collapsed 
to remove DNA damage introduced during DNA extraction and storage. After 
being collapsed into one consensus sequence, read pairs are stitched together 
as unique fragments. 

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Figure 1. Error suppression workflow. 
Using UMI technology and read collapsing algorithm, the overall error rate can be 
reduced from 0.1% to 0.002%, with the fraction of error free positions above 96% 
in ctDNA. Additional proprietary bioinformatic features of the assay can assess 
tumor fraction, clonal hematopoiesis, copy number variation, ctDNA fusions and 
detect SNVs and indels to 0.1% VAF. It is well known that DNA is susceptible to 
different types of damage such as oxidation and deamination which is a major 
source of false positives (22). The degree of damage usually varies from sample 
to sample. One unique aspect of the proprietary variant calling algorithm is that it 
measures sample-specific error profile and incorporates it into variant calling to 
achieve robust and uniform performance across a broad collection of samples 
collected over time and different conditions. 
Since this assay is an RUO assay, it requires a full analytical validation at the 
MoCha laboratory prior to implementation, which is ongoing. Preliminary 
feasibility data are provided in section 16 of this proposal. An extensive MoCha 
analytical validation of the assay is expected to be complete in the fall of this 
year, and the plan is described in section 16 of the proposal. If granted approval 
for the use of these valuable specimens, we would agree to submit the final 
analytical validation report for the TSO500 assay to the committee reviewing 
these proposals for its final review and approval prior to receiving any 
specimens. 
Cell-free DNA will be extracted and quantified. The recommended input is 30ng 
cfDNA, but the protocol allows for lower inputs as needed. Sensitivity may be 
affected by lower input, which will be determined as part of the full validation of 
the assay and a minimum input requirement will be established. 
Library preparation will follow the TruSight Oncology 500 cfDNA User Guide and 
use the associated reagents from Illumina. In summary, end repair and A-tailing 
will be done, followed by ligation of adapters and clean-up of reaction, indexing 
PCR, two rounds of hybridization and capture using TSO500 probes, 
amplification and clean-up of the enriched library. Library size will be evaluated 

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To demonstrate within-lab assay precision, initial testing has included two 
operators assaying SeraSeq ctDNA Mutation Mix v2 in two replicates each and 
results are presented in section 16. Two intra-run replicates by operator one 
were completed using the SeraSeq ctDNA Mutation Mix v2 purchased from 
Seracare as plasma, while two intra-run replicates by operator two were 
completed using the SeraSeq ctDNA Mutation Mix v2 purchased from Seracare 
as nucleic acid. This demonstrates precision between operators and run, even 
when considering the pre-analytical handling of the samples. As part of the full 
assay validation, precision will be further evaluated by multiple operators on 
different days using a larger sample set. 
If multiple laboratories will perform any testing, cross-lab reproducibility will first 
be thoroughly evaluated as part of the validation. The SOPs to be followed will be 
standardized and harmonized, so that each laboratory performs the procedures 
the same way. 
4. 
DATA ANALYSIS AND STATISTICAL CONSIDERATONS 
4.1. 
Primary objective: To characterize the molecular landscape of each less 
common/rare tumor histology as profiled in ctDNA and compare it to the 
molecular landscape as assessed by the OCA tumor test used during patient 
selection 
The molecular variants that TSO500 plasma and OCA tumor panels are capable 
of detecting have been compared to identify the overlapping (intersection) set to 
be used for cross-platform comparisons. As noted in section 11, TSO500 is a 
523-gene panel which interrogates all but three of the 2445 SNV and indel MOIs 
and aMOIs interrogated by the OCA gene panels which include OCAv1, v2 and 
v3 (most NCI- MATCH patients were screened with OCAv2). Based on 
information provided in the RFP and public presentations describing the 
distribution of tumor types observed in the study, we expect that approximately 
2500 baseline plasma samples (approximately 60% of the 4289 (4886-597) 
screened patients not enrolled on a treatment arm) will be available from patients 
with non-common tumors who were screened but did not enroll on a treatment 
arm in the trial. 
For each molecular variant detectable by each test (TSO500, OCA), we will 
tabulate the proportion of samples (n »2500) in which it was detected 
accompanied by an exact binomial two-sided 95% confidence interval (without 
correction for multiple comparisons). To assess for differences in detection rates 
for variants in the overlap of variants detectable by both tests, we will calculate a 
p-value associated with a 
Fisher’s exact test for difference in proportions detected with control of the false 
discovery rate (FDR) at 10% using the method of Benjamini and Hochberg26. 
4.2 
Secondary objectives: 
a) To establish for each less common/rare tumor histology evaluated the 
distribution of ctDNA burden (i.e., percentage of ctDNA of all cfDNA) in 
patients, and the fraction of patients without any detectable ctDNA 
For each sample, the proportion of ctDNA present in the cfDNA will be calculated 
and these proportions will be summarized by tumor type with graphical displays 
(e.g., violin plot or boxplot) and summary statistics including mean, median, 

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standard deviation (SD), minimum, maximum, and inter-quartile range (IQR). The 
proportion of patients with no detectable ctDNA within detectable cfDNA will be 
reported for each tumor type along with exact binomial two-sided 95% 
confidence intervals (CIs), If there are any patients with no detectable cfDNA, 
those proportions (with exact binomial two-sided 95% CIs) will be reported by 
tumor type as well. 
b) To determine the fraction of patients with an actionable mutation by OCA 
tumor test who also have the same actionable mutation by TSO500 plasma 
test (i.e., the “Positive Percent Agreement (PPAref_tumor)) of the TSO500 
plasma test, with OCA tumor test as reference) in the untreated patient 
cohort, Arm Z1D, Arm T and Arm M 
Based on the existing tumor sequencing results obtained by OCA, the set of 
aMOIs detected at baseline in each patient’s tumor will be identified. For each of 
these cases we will tabulate which of the aMOIs detected by the OCA tumor test 
were also detected in the baseline plasma sample using the TSO500 test 
(restricted to the overlap of the OCA and TSO500 panels) to calculate 
PPAref_tumor. The primary PPAs will be calculated separately by variant class 
(SNVs, Indels, CNVs, and fusions) across all patients and aMOIs as the 
proportion of aMOIs detected at baseline in tumor (OCA) that were also detected 
in baseline plasma (TSO500).  These proportions will be accompanied by exact 
binomial two-sided 95% CIs. If there are sufficient numbers of patients whose 
tumors had the same aMOIs (OCA) we will also calculate PPAref_tumor (with 
exact two-sided 95% CIs) for those specific aMOIs. We will separately tabulate 
any variant level discordant results (aMOIs detected by OCA test in tumor but the 
same aMOI not detected by the TSO500 test in baseline plasma). These 
calculations will be performed separately for the untreated cohort, and for Arm 
Z1D, T, and M cohorts. Patients who tested positive in tumor by OCA for a 
particular aMOI that would have made them eligible for arm Z1D, T, or M, but did 
not enroll on the treatment arm for any reason, will be considered part of the 
treatment arm cohort rather than the untreated cohort for purposes of these 
PPAref_tumor calculations. These calculations will be repeated separately by 
tumor type, but the arm-specific PPAs within tumor type might be based on very 
small numbers of cases, thus limiting their interpretability. If access is granted to 
all patient samples (common and less common/rare tumors), then these 
analyses will be performed for all tumor types; otherwise the analyses will be 
restricted to non-common tumor types. 
c) To determine the fraction of patients with an actionable mutation by TSO500 
plasma test who have the same actionable mutation by OCA tumor test (i.e., 
the “positive percent agreement  of the OCA tumor test, i.e., PPAref_plasma, 
with TSO500 plasma test as reference) in the untreated patient cohort, Arm 
Z1D, Arm T and Arm M 
Based on the TSO500 tests that will be performed, the set of aMOIs identified at 
baseline in each patient’s plasma will be identified. For each of these cases we 
will tabulate which of the aMOIs were also identified in the baseline tumor sample 
using the OCA test (restricted to the overlap of the OCA and TSO500 panels) to 
calculate PPAref_plasma (TSO500 as reference). The primary PPAref_plasma 
values will be calculated separately by variant class (SNVs, Indels, CNVs, and 
fusions) across all patients and aMOIs as the proportion of aMOIs detected at 

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baseline in plasma (TSO500) that were also detected in baseline tumor (OCA). If 
there are sufficient numbers of patients whose plasma samples had the same 
aMOIs (TSO500) we will also calculate PPAref_plasma (with exact binomial two-
sided 95% CIs) for those specific aMOIs. We will separately tabulate any variant 
level discordant results (aMOIs detected by the TSO500 test in baseline plasma 
but not detected by the OCA test in tumor). These calculations will be performed 
separately for the untreated cohort, and for Arm Z1D, T, and M cohorts. Patients 
who tested positive in tumor by OCA for particular aMOIs that would have made 
them eligible for arm Z1D, T, or M, but who did not enroll on the treatment arm 
for any reason (including that the variant was not detected in tumor), will be 
considered part of the treatment arm cohort rather than the untreated cohort for 
purposes of these PPA calculations. These calculations will be repeated 
separately by tumor type, but the arm-specific PPAref_plasma values within 
tumor type might be based on very small numbers of cases, thus limiting their 
interpretability.  Reported proportions will be accompanied by exact binomial two-
sided 95% CIs. If access is granted to all patient samples (common and less 
common/rare tumors), then these analyses will be performed for all tumor types; 
otherwise the analyses will be restricted to non-common tumor types. Any 
matched tumor/plasma pairs where a valid NGS result could not be obtained in 
tumor (e.g. because no tumor cells were present in the biopsy) will be deemed 
unevaluable for this analysis. Any matched tumor/plasma pairs where a valid 
NGS result could not be obtained in plasma (e.g. because the cfDNA tested 
failed to meet appropriate quality control metrics) will be deemed unevaluable for 
this analysis. 
d) To identify, using the TSO500 plasma test, candidate molecular predictors of 
response and resistance in patients treated on Arms Z1D, T and M 
This objective is considered exploratory because of the relatively small numbers 
of patients enrolled to these arms, and the fewer still who are likely to have the 
matched pre- and post-treatment blood samples that will be most informative for 
these analyses. The first analysis will be to compare, for each treatment arm 
(Z1D, T, and M) and MOI, the proportion of patients with a positive variant call in 
plasma (TSO500) at baseline for the responders (CR+PR) versus 
nonresponders. We will calculate for each variant a p-value associated with a 
Fisher’s exact test for each difference in proportions with control of the false 
discovery rate (FDR) at 10% using the method of Benjamini and Hochberg26.  
We will also examine serial plasma ctDNA results (TSO500) to identify which 
patients in these three arms had changes in detection calls over time for any 
MOIs. For each MOI for each patient, the MOI result will be scored as -1, 0, or +1 
to signify whether the change (from baseline to latest follow-up point with plasma 
sample available) was present-to- absent, no change, or absent-to-present. The 
distribution of these scores will then be compared visually between responders 
and nonresponders within each treatment arm. For select MOIs deemed a priori 
potentially relevant to the therapy, or found interesting by visual inspection using 
a criterion of greater  than 30% difference in proportion of -1 or +1 scores 
between responders and nonresponders, we will additionally explore the data 
using graphical displays. For these select MOIs, spaghetti plots will be 
constructed showing allele frequencies over time for each patient, separately for 
responders and nonresponders. Additionally, scatterplots will be constructed for 
these MOIs showing the relationship between change in allele frequency (x-axis) 

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versus time on treatment (plotting symbol formatted to denote alive and free of 
progression versus death, progression or off treatment for any reason). Due to 
the anticipated very small numbers of patients in any arm who have paired 
samples and the large numbers of comparisons, all of these “change analyses  
will be considered exploratory, and no formal statistical testing will be performed. 
We note also that these analyses must be restricted to patients who were 
positive for the qualifying variants in tumor and other eligibility criteria for the 
treatment arms, as patients who might have been eligible for enrollment on the 
arm based on plasma (TSO500) but not based on tumor assessment (OCA) 
would not have been identified as eligible for the treatment arms in the trial. 
Using baseline plasma ctDNA results as described in “Tumor Mutational Burden, 
Microsatellite Instability, and Tissue Concordance  from Section 16, we will 
determine the proportion of patients enrolled on arm Z1D who would have been 
confirmed as MMR-deficient based on plasma results. The proportion of 
responders will be compared for the group of patients who were confirmed MMR-
deficient versus not MMR-deficient according to the plasma-based assessments. 
The difference in response proportions will be assessed for statistical 
significance using a two-sided 0.05 level Fisher’s exact test.  This test may have 
low statistical power, so statistical significance may be unlikely, but an estimate 
of difference in response proportion (with two-sided 95% confidence interval) will 
be reported regardless. Similarly, in further exploratory analyses the difference in 
response proportions between two groups of patients defined by a cutoff applied 
to the plasma TMB score and between two groups defined by a cutoff applied to 
the plasma MSI score will be assessed. Optimal cutoffs for TMB score and MSI 
score in plasma have not yet been established. As the samples size will be small 
and the cohort enrolled onto arm Z1D represents a mixture of histologies, any 
suggested optimized cut-off will require verification in independent studies with 
suitable numbers of specific tumor types to confidently draw conclusions. 
As a supplementary analysis for this objective, we can also determine TMB and 
MSI status from plasma samples for any patients not enrolled on arm Z1D to 
describe the overall distribution of these measures across the range of tumor 
types (not restricted to patients determined eligible for arm Z1D based on tumor 
mutation profile). This will give a sense for how many more patients might be 
considered for immunotherapy based on TMB and MSI status determined from 
plasma in a future clinical trial or in clinical practice (in settings where 
immunotherapies are already approved). 
e) To characterize tumor heterogeneity using the TSO500 pan-cancer liquid 
biopsy assay and compare the results and degree of heterogeneity seen to 
that observed in matched tumor biopsies that had been assayed using the 
OCA tumor test 
Heterogeneity in detected MOIs will be characterized at both the trial level and 
the patient level. Separately for each tumor type, the different MOIs detected 
across the screened patients (regardless of enrollment on a treatment arm) will 
be tabulated and, for each MOI, expressed as the number and proportion of 
patients deemed positive based on tumor results (OCA). A similar tabulation will 
be produced for plasma results (TSO500). For patient-level analysis, we will 
score the comparison between tumor and plasma results (restricted to the 
overlap of the OCA and TSO500 panels) for each patient as follows: 

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-3  = Sets of MOIs detected in plasma (SO500) compared to tumor (OCA) are 
completely nonoverlapping, with number detected in plasma (TSO500) 
smaller than in tumor (OCA) 
-2  = Fewer MOIs detected in plasma (TSO500) compared to tumor (OCA); they 
overlap but MOIs detected in plasma are not a subset of those detected in 
tumor 
-1  = MOIs detected in plasma (TSO500) wholly contained within and strictly 
smaller than the set of MOIs detected in tumor (OCA) 
0  = Identical set of MOIs detected in plasma and tumor 
+1 = MOIs detected in tumor (OCA) wholly contained within (and not identical to) 
set of MOIs detected in plasma (TSO500) 
+2 = At least as many MOIs detected in plasma (TSO500) compared to tumor 
(OCA); they overlap but MOIs detected in tumor are not a subset of those 
detected in plasma 
+3 = Sets of MOIs detected in tumor (OCA) compared to plasma (TSO500) are 
completely nonoverlapping, with number detected in tumor (OCA) no 
greater than in plasma (OCA) 
For each possible score, we will tabulate the number and proportion of patients 
classified into that category and provide exact binomial two-sided 95% CIs for 
each proportion (with no adjustment for multiple comparisons). Initially these 
analyses will be performed considering agreement at the MOI level, but 
secondary analyses may be conducted that take into consideration whether 
differences in detected MOIs would have led to differences in treatment 
recommendations at the patient level.  If access is granted to all patient samples 
(common and less common/rare tumors), then these analyses will be performed 
for all tumor types; otherwise the analyses will be restricted to non-common 
tumor types. 
4.3 
Analyses evaluating specific hypotheses 
i) The molecular landscape of rare tumor histologies profiled by plasma and 
tumor tests will be similar, except that more tumor heterogeneity will be 
observed in the ctDNA molecular profile assessed by the TSO500 plasma 
test. 
This hypothesis will be addressed by the analyses described above for the 
primary objective and secondary objectives b, c, and e. 
ii) For patients for whom plasma is assessed by the TSO500 test, the positive 
percent agreement (PPAref_tumor) of the biomarker results from TSO500 
with the OCA tumor test (as non-reference standard) will be >=85% as 
reported previously in similar comparisons. Conversely, the positive percent 
agreement (PPAref_plasma) of OCA tumor test to the TSO500 results will be 
>=85%.  
This hypothesis will be addressed by the analyses described above for 
secondary objective b. 

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iii) At least 85% of patients assigned to NCI-MATCH Arms Z1D, T and M would 
have been assigned the same treatment arm using the TSO500 pan-cancer 
liquid biopsy assay.  
This hypothesis will be addressed by the analyses described above for 
secondary objective c, noting whether the reported exact binomial two-sided 95% 
CI for PPA for each arm-eligible cohort falls above 85%. 
iv) Prospective selection based on the TSO500 pan-cancer liquid biopsy assay 
with broad capabilities (e.g. MSI status, TMB) would have changed the 
clinical actionability of molecular finding for certain NCI-MATCH patients 
screened by the OCA tumor test, especially those not assigned to treatment. 
Some not assigned would have been eligible for other therapeutic options, 
including immunotherapy.  
This hypothesis will be addressed by the analyses described above for 
secondary objective d, including the suggested supplementary analysis. 
v) A pan-cancer liquid biopsy test samples ctDNA originating from multiple 
lesions and thus captures tumor heterogeneity that may not be present in a 
tumor biopsy. 
This hypothesis will be addressed by the analyses described above for the 
primary objective and secondary objectives b, c, and e. This hypothesis will be 
addressed by the analyses described above for secondary objectives b, c, and e. 
4.4 
Statistical justification for sample size 
The analyses proposed in this study are largely descriptive with the primary goal 
to comprehensively characterize the molecular landscape of each less 
common/rare tumor histology as profiled in ctDNA and compare it to the 
molecular landscape as assessed by the OCA tumor test used during patient 
selection. Based on the information available about patient accrual and plasma 
samples available, we estimate that the number of patients from whom we will be 
able to obtain baseline plasma ctDNA results  (accounting  for a small 
percentage of nonevaluable assays results due to inadequate samples or failed 
assays) will be approximately 2500 for the set of non-common tumors. Once 
these results are obtained, the same data can be used to address all other 
objectives and hypotheses; therefore, we base our sample size rationale on this 
primary objective (see below). If we are approved to receive plasma sample from 
all screened patients we assume that we would have baseline plasma ctDNA 
results on approximately 5000 patients. 
Plasma ctDNA results for 2500 patients will effectively ensure (100% probability) 
we will detect a MOI that is truly present in the population at prevalence 0.5%, in 
at least one patient sample.  Table10 below shows additional examples of the 
probability of detecting a MOI in at least one patient sample for a range of values 
for true MOI prevalence and sample size. The smaller sample sizes are 
applicable to detection of MOIs in subgroups, for example a particular tumor 
histology or treatment arm. 

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Table2.  Probability of detecting a MOI in at least one patient sample 
 
Prevalence of MOI in population (%) 
Number of 
patient 
samples 
0.1 
0.25 
0.5 
0.75 
1.0 
2.0 
3.0 
4.0 
5.0 
10.0 
5000 
99 
100 
100 
100 
100 
100 
100 
100 
100 
100 
2500 
92 
100 
100 
100 
100 
100 
100 
100 
100 
100 
1000 
63 
92 
99 
100 
100 
100 
100 
100 
100 
100 
500 
39 
71 
92 
98 
99 
100 
100 
100 
100 
100 
200 
18 
39 
63 
78 
87 
98 
100 
100 
100 
100 
100 
10 
22 
39 
53 
63 
87 
95 
98 
99 
100 
75 
7 
17 
31 
43 
53 
78 
90 
95 
98 
100 
50 
5 
12 
22 
31 
39 
64 
78 
87 
92 
99 
30 
3 
7 
14 
20 
26 
45 
60 
71 
79 
96 
20 
2 
5 
10 
14 
18 
33 
46 
56 
64 
88 
15 
1 
4 
7 
11 
14 
26 
37 
46 
54 
79 
10 
1 
2 
5 
7 
10 
18 
26 
34 
40 
65 
For analyses reporting exact binomial two-sided 95% CIs, the width of the CI will 
depend on the sample size (i.e., the denominator of the proportion) and the 
observed successes (i.e., the numerator of the proportion). Tables11.A – 11.H 
below provide example CIs for a range of scenarios. Example proportions of 
interest could include PPA, or prevalence of a particular MOI in the full group of 
patient samples or in subsets. 
A sample size of 2500 patients will provide a confidence interval width less then 
4 percentage points for any observed proportion. (Note: from Table11.B the 
confidence interval width is largest for an observed proportion equal to 50%, with 
a CI width of 51.98-48.02=3.96). 
Table3.A Exact binomial two-sided 95% confidence intervals for sample size 
n=5000 
Observed proportion expressed 
as % 
Lower CI limit 
(as %) 
Upper CI limit 
(as %) 
0/5000 = 0% 
0 
0.07 
5/5000 = 0.1% 
0.03 
0.23 
12/5000 = 0.24% 
0.12 
0.42 
25/5000 = 0.5% 
0.32 
0.74 
37/5000 = 0.74% 
0.52 
1.02 
50/5000 = 1.0% 
0.74 
1.32 
250/5000 = 5.0% 
4.41 
5.64 
500/5000 = 10.0% 
9.18 
10.87 

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Observed proportion expressed 
as % 
Lower CI limit 
(as %) 
Upper CI limit 
(as %) 
1250/5000 = 25.0% 
23.8 
26.22 
2500/5000 = 50.0% 
48.6 
51.4 
3750/5000 = 75.0% 
73.78 
76.2 
4000/5000 = 80.0% 
78.86 
81.1 
4500/5000 = 90.0% 
89.13 
90.82 
4750/5000 = 95.0% 
94.36 
95.59 
4850/5000 = 97.0% 
96.49 
97.46 
4900/5000 = 98.0% 
97.57 
98.37 
4950/5000 = 99.0% 
98.68 
99.26 
5000/5000 = 100% 
99.93 
100 
Table3.B Exact binomial two-sided 95% confidence intervals for sample size 
n=2500 
Observed proportion expressed 
as % 
Lower CI limit 
(as %) 
Upper CI limit 
(as %) 
0/2500 = 0% 
0 
0.15 
2/2500 = 0.08% 
0.01 
0.29 
6/2500 = 0.24% 
0.09 
0.52 
12/2500 = 0.48% 
0.25 
0.84 
19/2500 = 0.76% 
0.46 
1.18 
25/2500 = 1.0% 
0.65 
1.47 
125/2500 = 5.0% 
4.18 
5.93 
250/2500 = 10.0% 
8.85 
11.24 
625/2500 = 25.0% 
23.31 
26.75 
1250/2500 = 50.0% 
48.02 
51.98 
1875/2500 = 75.0% 
73.25 
76.69 
2000/2500 = 80.0% 
78.38 
81.55 
2250/2500 = 90.0% 
88.76 
91.15 
2375/2500 = 95.0% 
94.07 
95.82 
2425/2500 = 97.0% 
96.25 
97.63 
2450/2500 = 98.0% 
97.37 
98.51 
2475/2500 = 99.0% 
98.53 
99.35 
2500/2500 = 100% 
99.85 
100 

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Table3.C Exact binomial two-sided 95% confidence intervals for sample size 
n=500 
Observed proportion expressed 
as % 
Lower CI limit 
(as %) 
Upper CI limit 
(as %) 
0/500 = 0% 
0 
0.74 
1/500 = 0.2% 
0.01 
1.11 
3/500 = 0.6% 
0.12 
1.74 
5/500 = 1.0% 
0.33 
2.32 
25/500 = 5.0% 
3.26 
7.29 
50/500 = 10.0% 
7.51 
12.97 
125/500 = 25.0% 
21.26 
29.04 
250/500 = 50.0% 
45.53 
54.47 
375/500 = 75.0% 
70.96 
78.74 
400/500 = 80.0% 
76.22 
83.42 
425/500 = 85.0% 
81.56 
88.02 
450/500 = 90.0% 
87.03 
92.49 
475/500 = 95.0% 
92.71 
96.74 
485/500 = 97.0% 
95.1 
98.31 
495/500 = 99.0% 
97.68 
99.67 
500/500 = 100% 
99.26 
100 
Table3.D Exact binomial two-sided 95% confidence intervals for sample size 
n=250 
Observed proportion expressed 
as % 
Lower CI limit 
(as %) 
Upper CI limit 
(as %) 
0/250 = 0% 
0 
1.46 
1/250 = 0.4% 
0.01 
2.21 
2/250 = 0.8% 
0.1 
2.86 
3/250 = 1.2% 
0.25 
3.47 
13/250 = 5.2% 
2.8 
8.73 
25/250 = 10.0% 
6.58 
14.41 
63/250 = 25.2% 
19.94 
31.06 
125/250 = 50.0% 
43.63 
56.37 
187/250 = 74.8% 
68.94 
80.06 
200/250 = 80.0% 
74.5 
84.78 
212/250 = 84.8% 
79.74 
89.01 
225/250 = 90.0% 
85.59 
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Observed proportion expressed 
as % 
Lower CI limit 
(as %) 
Upper CI limit 
(as %) 
237/250 = 94.8% 
91.27 
97.2 
244/250 = 97.6% 
94.85 
99.11 
248/250 = 99.2% 
97.14 
99.9 
250/250 = 100% 
98.54 
100 
Table3.E Exact binomial two-sided 95% confidence intervals for sample size 
n=100 
Observed proportion expressed as % 
Lower CI limit (as 
%) 
Upper CI limit (as %) 
0/100 = 0% 
0 
3.62 
1/100 = 1.0% 
0.03 
5.45 
2/100 = 2.0% 
0.24 
7.04 
5/100 = 5.0% 
1.64 
11.28 
10/100 = 10.0% 
4.9 
17.62 
25/100 = 25.0% 
16.88 
34.66 
50/100 = 50.0% 
39.83 
60.17 
75/100 = 75.0% 
65.34 
83.12 
80/100 = 80.0% 
70.82 
87.33 
85/100 = 85.0% 
76.47 
91.35 
90/100 = 90.0% 
82.38 
95.1 
95/100 = 95.0% 
88.72 
98.36 
97/100 = 97.0% 
91.48 
99.38 
98/100 = 98.0% 
92.96 
99.76 
99/100 = 99.0% 
94.55 
99.97 
100/100 = 100% 
96.38 
100 
Table3.F Exact binomial two-sided 95% confidence intervals for sample size 
n=50 
Observed proportion expressed as % 
Lower CI limit (as %) Upper CI limit (as %) 
0/50 = 0% 
0 
7.11 
1/50 = 1.0% 
0.05 
10.65 
2/50 = 4.0% 
0.49 
13.71 
5/50 = 10.0% 
3.33 
21.81 
12/50 = 24.0% 
13.06 
38.17 
25/50 = 50.0% 
35.53 
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Observed proportion expressed as % 
Lower CI limit (as %) Upper CI limit (as %) 
37/50 = 74.0% 
59.66 
85.37 
40/50 = 80.0% 
66.28 
89.97 
43/50 = 86.0% 
73.26 
94.18 
45/50 = 90.0% 
78.19 
96.67 
48/50 = 96.0% 
86.29 
99.51 
49/50 = 98.0% 
89.35 
99.95 
50/50 = 100% 
92.89 
100 
Table3.G Exact binomial two-sided 95% confidence intervals for sample size 
n=30 
Observed proportion expressed as % 
Lower CI limit (as %) Upper CI limit (as %) 
0/30 = 0% 
0 
11.57 
1/30 = 3.3% 
0.08 
17.22 
2/30 = 6.7% 
0.82 
22.07 
3/30 = 10.0% 
2.11 
26.53 
8/30 = 26.7% 
12.28 
45.89 
15/30 = 50.0% 
31.3 
68.7 
23/30 = 76.7% 
57.72 
90.07 
24/30 = 80.0% 
61.43 
92.29 
26/30 = 86.7% 
69.28 
96.24 
27/30 = 90.0% 
73.47 
97.89 
29/30 = 96.7% 
82.78 
99.92 
30/30 = 100% 
88.43 
100 
Table3.H Exact binomial two-sided 95% confidence intervals for sample size 
n=15 
Observed proportion expressed as % 
Lower CI limit (as %) Upper CI limit (as %) 
0/15 = 0% 
0 
21.8 
1/15 = 6.7% 
0.17 
31.95 
2/15 = 13.0% 
1.66 
40.46 
3/15 = 20.0% 
4.33 
48.09 
6/15 = 40.0% 
16.34 
67.71 
9/15 = 60.0% 
32.29 
83.66 
12/15 = 80.0% 
51.91 
95.67 
13/15 = 86.7% 
59.54 
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Observed proportion expressed as % 
Lower CI limit (as %) Upper CI limit (as %) 
14/15 = 93.3% 
68.05 
99.83 
15/15 = 99.0% 
78.2 
100 
5. 
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Molecular Analysis for Therapy Choice (MATCH) 
Appendix XXII 
 
CS-MATCH-0020 
 
Discovery of Driver Fusions in MOI-Negative NCI-MATCH Screening Samples 
PRINCIPAL INVESTIGATOR: 
John Iafrate, MD PhD 
BIOSTATISTICS: 
Lisa McShane, PhD 
CO-INVESTIGATORS: 
Chris Karlovich, PhD 
Mickey Williams, PhD 
David Sims, PhD 
Jeffrey Sklar, MD PhD 
 
Rev. Add25 

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1. 
INTRODUCTION 
Anchored Multiplex PCR is a method developed in the MGH Molecular Diagnostics 
Laboratory to allow unbiased fusion detection when only one partner is known. The most 
recent version of AMP at MGH termed the Solid Fusion Assay (SFA) interrogates over 
100 known fusion partners using RNA as input. 
Figure 1. 
Using this assay, 7,771 clinical advanced cancer samples have been genotyped and 
fusions were detected in 667 or 8.5% (Figure 1). The majority of the fusions were mutually 
exclusive of other driver mutations. By cross-referencing the identified fusions with the 
Oncomine primer designs we calculate that Oncomine would have missed 30% of these 
fusions, including completely novel fusions, or a novel fusion partner. This strongly 
suggests that we would detect 30% more fusions in the NCI-MATCH cohort. 
Recent data from Memorial Sloan Kettering Cancer Center has revealed that their FDA-
approved MSK-Impact assay also failed to detect gene fusions. By using AMP in their 
driver-negative NSCLC cases they found 15% harbored gene fusions, many of which were 
actionable (1). This suggests that focusing on the MOI-negative subset of the NCI-MATCH 
screened population will provide the highest likelihood of identifying novel fusion driver 
cases missed by Oncomine. 
2. 
OBJECTIVES AND HYPOTHESES 
We hypothesize that gene fusions may be more prevalent as driver events in the NCI-
MATCH screened population than detected by Oncomine. 
The primary objective is to analyze the MOI-negative tumors from the screening cohort 
of 5,540 patients for driver gene fusion events using Anchored Multiplex PCR. Driver 
gene fusions are defined as in-frame fusions with at least 50 supporting reads, where at 
least one of the genes is a known fusion partner. We will identify the prevalence of 
fusions in the overall cohort, and in individual diseases where fusions may be particularly 
important (e.g. FGFR2 fusions in cholangiocarcinoma). 
3. 
RESEARCH DESIGN AND METHODS 

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1. 
Patient and Biospecimen Selection 
• 
Residual banked RNA from tissue utilized for screening from patients 
screened by the MATCH-assay. 
• 
No markers of interest were identified by the Oncomime MATCH-assay 
assessment. 
• 
Patient were not enrolled to NCI-MATCH treatment arms.  
• 
Patients consented to allow their specimens to be used for research. 
2. 
Laboratory methods 
The Solid Fusion Assay is a CLIA Next Generation Sequencing- based 
methodology for the clinical detection of gene fusions using a laboratory-
developed test version of Anchored Multiplex PCR (2). Over 10,000 
samples have been analyzed in the MGH clinical lab with this assay. The 
assay first involves conversion of tumor RNA to cDNA using random 
priming, following by end repair and sequencing adapter ligation. Two 
rounds of nested-PCR occurs next, with one primer anchored in the gene 
target of interest and the second primer pair annealing to sequences in the 
adapter. The Illumina NextSeq is used for sequencing the libraries. 
Validation Methods 
We validated the ability of the Fusion assay to detect translocations in 72 
cases with known fusion status. Findings were confirmed by FISH using the 
established protocols. Samples were interpreted as positive or negative for 
translocations according to the analysis guidelines in the Clinical Fusion 
Assay SOP and the Clinical Fusion Bioinformatics Analysis Pipeline. 
Greater than 90% concordance was expected between the established 
FISH protocol and the AMP Fusion protocol. 
Validation Results 
71 out of 72 samples have concordant results between FISH and 
sequencing assays. Concordance is measured at 98% and is considered 
acceptable. 
The following criteria are used to evaluate Fusion sequencing results: 
a. For known, non-novel fusions to be considered positive: ≥ 50 uniquely 
mapped positions on potential partners 
b. For novel fusions to be considered positive: ≥ 50 uniquely mapping 
positions on potential partners with in-frame fusion 
Sensitivity and Specificity 
Based on the Fusion and FISH results, sensitivity and specificity were 
calculated as:  
Sensitivity = 96% 
Specificity = 100% 
The lowest % tumor content of positive case for which a translocation was 
detected is 10%. For formal analytical sensitivity assessment, three 
translocation-positive cases (determined by FISH) were serially diluted with 

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a translocation-negative lung FFPE total nucleic acid (TNA) pool in order to 
obtain solutions between 50% and 3.125% (ALK and RET) and between 
60% and 3.75% (ROS1). 
The lowest level of analytical sensitivity at which translocations could be 
detected was determined by the original tumor percentage divided by the 
highest dilution at which a positive result was detected and was 3%. All 
MATCH samples will have a percentage substantially higher than this 
number since the cellularity is above 60% in the vast majority of samples. 
Precision 
Three negative and three positive clinical samples were assayed in triplicate 
(intra-assay) and three separate runs (inter-assay) to establish precision 
and reproducibility, 100% for both. 
QC 
We rely on two quality metrics to determine the quality of results for any 
given sample tested with our SFA Fusion assay. First, we have extensive 
experience with using a commercial qualitative reverse transcription real-
time PCR assay which amplifies the GAPDH gene after the second strand 
synthesis step of the protocol. We have found that for the SFA Fusion 
assay, CT values below 28 tend to produce good quality sequencing results 
to confidently pass a case. Values between 28 and 30 tend to be borderline 
for quality. Samples with CT values greater than 30 tend to fail. Passing a 
case for signout requires that the sample first pass this real-time PCR 
check. 
In addition to the GAPDH check, we also review the coverage from the 
sequencing data to have confidence in reporting our test results. Our 
extensive clinical experience with our targeted RNA-Seq has shown that it is 
difficult to maintain sequence coverage consistency for any one of the 
genes in our panel, particularly at the RNA (cDNA) level. There is great 
variability in tumors, tissue types, normal cell contamination in the samples 
that we test, and sequencing throughput in our assay, which may lead to 
unpredictable expression levels for any of the targeted genes. Because of 
this great variability, we rely on a global RNA abundance measure from the 
sequence analysis to qualify the performance of a sample.  This measure is 
based on alignment annotation to determine whether a read is RNA or DNA, 
and also the percentage of split-reads (highly likely to be RNA). Our current 
quality metric thresholds for good, passable sequencing results are: >30% 
split reads, >100,000 uniquely mapped reads, and >1.4 RNA:DNA ratio. 
QA 
The lab actively participates in proficiency testing, including CAP surveys, 
with no failed surveys since the SFA assay has been launched. The assay 
has received New York State approval and the Lab is accredited and regularly 
inspected by the Joint Commission. The MGH Laboratory will perform a pilot 
to ensure that the Yale Laboratory meets quality standards for running this 
assay prior to testing samples for this project. 

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4. 
DATA ANALYSIS AND STATISTICAL CONSIDERATONS 
1. 
Primary analysis: 
We will compute the number and proportion of all cases analyzed by the SFA 
that harbor driver gene fusion events. The proportion will be accompanied by 
an exact binomial 2-sided 95% confidence interval (CI). 
2. 
Secondary analyses: 
Secondary analyses will be largely descriptive. We will compute the 
distribution of number and proportion of driver gene fusion events by tumor 
histology and by patient age at time of screening for the NCI-MATCH trial. It 
is expected that tumors of certain histologies such as cholangiocarcinoma 
and sarcoma, and from younger patients, might have a higher likelihood of 
harboring driver gene fusion events.  For each of the histologic subgroups 
represented in the case set, we will also compute exact binomial 2-sided 
95% CIs for the proportion positive for driver gene fusion events unless the 
number of cases in the subgroup is too small for sensible CI calculation. 
Similarly, we will report numbers, proportions, and CIs for the AYA patients 
(age < 40 yrs) and older adults (age > 40 yrs). A Fisher’s exact test 
comparing proportion of cases positive for driver gene fusion events between 
AYA patients and older adults will be conducted and p-value reported. Given 
the potentially large number of histologic subtypes, formal statistical testing 
will not be attempted to assess differences in proportion of driver gene fusion 
events across histologies.  Given the exploratory nature of these secondary 
analyses, p-values and confidence levels (for CIs) will not be adjusted for 
multiple testing. 
3. 
Sample size estimate:  
Given that the number of cases with driver fusion events is expected to be 
fairly low, we are requesting RNA from all cases from the NCI-MATCH 
screening cohort for which no MOIs were identified and for which sufficient 
amount of RNA is available. According to information available to us, there 
are 849 cases from the NCI-MATCH screening cohort for which no MOIs 
were identified. We anticipate that approximately 15% of these cases will 
have insufficient RNA available for assay. Further, we will conservatively 
assume that up to 5% of assays will not successfully yield results (although in 
truth we expect that the assay failure rate will be much lower than 5%). 
Therefore, we will assume that we will have assay results for 685 cases, 
which we will round down to n=650 for purposes of sample size justification. 
For subset analyses in cholangiocarcinoma and sarcoma, there are 41 and 
44 cases, respectively, among the cases from the NCI-MATCH screening 
cohort for which no MOIs were identified. 
4. 
Rationale for the sample size estimate: 
Sample size justification is based on the width of the exact binomial 2-sided 95% 
confidence interval for the proportion of all cases with assay results that harbor 
driver gene fusion events. Example calculations are shown in Table 1. Based on 
the MGH and MSK data cited in above, we anticipate that the true proportions, 
for the full cohort and for the cholangiocarcinoma and sarcoma subgroups, could 
lie between 5% and 20%. Table 1 below provides confidence intervals based on 
observed proportions in a similar range and for sample sizes of 650 (full cohort) 

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NCI Update Date: August 12, 2015 
267 
and 30 (cholangiocarcinoma and sarcoma subgroups). In addition, we note that 
the probability of observing at least one case with a driver gene fusion event is at 
least 95% when the true proportion is 0.005 in the full cohort of 650 cases and 
0.095 in each of the cholangiocarcinoma and sarcoma subgroups (assuming 30 
cases in each). 
Table 1. Example exact binomial 2-sided 95% confidence intervals for an 
observed proportion 
N=650 (Full cohort) 
Observed proportion positive 
for driver gene fusion event 
Lower limit of exact 
binomial 2-sided 95% CI 
Upper limit of exact 
binomial 2-sided 95% CI 
32/650  = 0.049 
0.034 
0.069 
65/650  = 0.100 
0.078 
0.126 
97/650  = 0.149 
0.123 
0.179 
130/650 = 0.200 
0.170 
0.233 
N=30 (Histology subgroup) 
Observed proportion positive 
for driver gene fusion event 
Lower limit of exact 
binomial 2-sided 95% CI 
Upper limit of exact 
binomial 2-sided 95% CI 
1/30  = 0.033 
0.001 
0.172 
2/30  = 0.067 
0.008 
0.221 
3/30  = 0.100 
0.021 
0.265 
4/30  = 0.133 
0.038 
0.307 
5/30  = 0.167 
0.056 
0.347 
6/30  = 0.200 
0.077 
0.386 
5. 
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