INdividualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT)
Phase: PHASE2
Conditions: Glioblastoma
Sponsor: Patrick Wen, MD

16-443 INdividualized Screening trial of Innovative Glioblastoma Therapy (INSIGhT) 
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INdividualized Screening trial of Innovative Glioblastoma Therapy (INSIGhT)
Protocol Version Date:              December 4, 2024
 
Protocol Version No.:
Version 11.0
DF/HCC Protocol No.:
16-443
Coordinating Center:
Dana-Farber Cancer Institute
Principal Investigator
Patrick Wen, MD
Dana-Farber Cancer Institute
Center for Neuro-Oncology
450 Brookline Ave, DA-2122
Boston, MA 02115-6084
Phone: (617) 632-2166
Fax: (617) 632-4773
Patrick_Wen@dfci.harvard.edu 
Biostatistician
Lorenzo Trippa, PhD
Dana-Farber Cancer Institute
Biostatistics & Computational 
Biology
450 Brookline Ave
Boston, MA 02115-6084
Phone: (617) 582-9133
Fax: N/A
ltrippa@jimmy.harvard.edu
Co-Investigator 
Mehdi Touat, MD
Dana-Farber Cancer Institute 
Department of Oncologic 
Pathology
450 Brookline Ave, JF 215
Boston, MA 02115-6084
Phone: (617) 582-8767
Mehdi_Touat@dfci.harvard.edu
Co-Investigator
Keith Ligon, MD, PhD
Department of Pathology
Dana-Farber Cancer Institute
450 Brookline Ave, JFB 215B
Boston, MA 02115-6084
Phone : (617) 632-2357
Fax : (617) 582-8761
Keith_Ligon@dfci.harvard.edu 
Co-Investigator
Howard Colman, MD
Huntsman Cancer Institute
1950 Circle of Hope Dr
Salt Lake City, UT 84112
Phone: (801) 587-4042
Fax: (801) 585-4399
Howard.colman@hci.utah.edu
Co-Investigator
David Peereboom, MD 
Cleveland Clinic
9500 Euclid Avenue, S73
Cleveland, OH  44195
Phone: (216) 444-6833
Fax: (216) 444-0924
peerebd@ccf.org 
Co-Investigator
Jan Drappatz, MD
University of Pittsburgh Medical 
Center
5150 Centre Ave, Suite 301
Pittsburgh, PA  15232
Phone: (412) 864-7791
Fax: (412) 623-7862
drappatzj@upmc.edu 
Co-Investigator
David Schiff, MD
University of Virginia Health 
System
1215 Lee Street
Charlottesville, VA 22908
Phone: (434) 924-5610
Fax: (434) 982-6727
Ds4jd@virginia.edu
Co-Investigator
John DeGroot, MD
UT MD Anderson Cancer Center
1515 Holcombe Blvd, Unit 431
Houston, TX  77030
Phone: (713) 745-3072
Fax: (713) 794-4999
jdegroot@mdanderson.org 
Co-Investigator
Mary Welch, MD
Columbia University Medical
710 West 168th Street
New York, NY  10032
Phone: (212) 342-0571
Fax: (212) 342-1246
mw2517@cumc.columbia.edu
Co-Investigator
Isabel Arrillaga, MD
Massachusetts General Hospital
55 Fruit Street, Yawkey 9E
Boston, MA  02114
Phone: (617) 724-2887
Fax: (371) 643-2591
iarrillaga@mgh.harvard.edu
Co-Investigator
Eva Galanis, MD
Mayo Clinic
200 1st St SW
Rochester, MN
Phone: (507) 284-2511
Fax: (507) 284-8388
galanis.evanthia@mayo.edu 

16-443 INdividualized Screening trial of Innovative Glioblastoma Therapy (INSIGhT) 
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Co-Investigator 
Jaroslaw Hepel, MD
Rhode Island Hospital/Lifespan 
Comprehensive Cancer Center
593 Eddy Street
Providence, RI 02903
Phone: (401) 444-8311
JHepel@Lifespan.org
Co-Investigator
Ka-Wai G. Ho MD
Beth Israel Deaconess Medical 
Center
330 Brookline Avenue
Boston, MA 02215
Phone: (617) 667-1665
kho5@bidmc.harvard.edu 
Co-Investigator 
Thomas Kaley, MD
Memorial Sloan Kettering 
Cancer Center
1275 York Avenue New 
York, NY 10065 Phone: 
(212) 639-5122
kaleyt@mskcc.org
Co-Investigator
L. Burt Nabors, MD
University of Alabama at 
Birmingham
510 20th Street South
Faculty Office Tower 1020
Birmingham, AL 35294
Phone: (205) 934-1432
Fax: 205-975-7546
bnabors@uab.edu 
Responsible Research Nurse:
Lisa Doherty, APRN, BC, OCN
Dana-Farber Cancer Institute
Lisa_Doherty@dfci.harvard.edu 
DFCI Coordinating Center:
Jennifer Wiley
Research Project Manager
Dana-Farber Cancer Institute
 jennifer_wiley1@dfci.harvard.edu 
Agents:  
Neratinib: Puma Biotechnology
CC-115: Celgene Corp
Abemaciclib: Eli Lilly and Company
QBS10072S: Quadriga Biosciences
VBI-1901: VBI Vaccines
Balstilimab: VBI Vaccines
Temozolomide: commercially available
IND #: 
131617
IND Sponsor:  
Patrick Y. Wen, MD
Funding/Contractual Sponsor:
Dana-Farber/Partners Cancer Care, Inc.
Funding Support:
Puma Biotechnology, Inc.
Celgene Corp
Eli Lilly and Company 
Quadriga Biosciences
VBI Vaccines
Burroughs Wellcome Fund

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SCHEMA

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TABLE OF CONTENTS
SCHEMA ............................................................................................................................................................3
1.
OBJECTIVES .......................................................................................................................................18
1.1
Study Design .................................................................................................................18
1.2
Primary Objectives........................................................................................................18
1.3
Secondary Objectives....................................................................................................18
2.
BACKGROUND...................................................................................................................................19
2.1
Study Disease ................................................................................................................19
2.2
IND Agent(s).................................................................................................................19
2.3
Other Agent: Temozolomide.........................................................................................19
2.4
Rationale........................................................................................................................19
2.5
Correlative Studies Background....................................................................................21
3.
PARTICIPANT SELECTION ..............................................................................................................23
3.1
Eligibility: Inclusion Criteria.........................................................................................23
3.2
Eligibility: Exclusion Criteria .......................................................................................24
3.3
Inclusion of Women and Minorities..............................................................................27
4.
INITIAL INSIGHT REGISTRATION PROCEDURES ......................................................................28
4.1
General Guidelines for DF/HCC Institutions................................................................28
4.2
Registration Process for DF/HCC Institutions ..............................................................29
4.3
General Guidelines for Other Investigative Sites..........................................................29
4.4
Registration Process for Other Investigative Sites ........................................................29
5.
TREATMENT PLAN ...........................................................................................................................29
5.1
General Concomitant Medication and Supportive Care Guidelines .............................29
5.2
Criteria for Taking a Participant Off Protocol Therapy ................................................29
5.3
Duration of Follow Up ..................................................................................................29
5.4
Criteria for Taking a Participant Off Study...................................................................29
6.
DOSING DELAYS/DOSE MODIFICATIONS...................................................................................30
7.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS................................................30
Expedited Reporting to the Food and Drug Administration (FDA)..........................................30
8.
PHARMACEUTICAL INFORMATION .............................................................................................30
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES............................................................30
9.1
Biomarker Studies.........................................................................................................30
Assays specifically approved for use on INSIGhT ...................................................................31
9.2
Exploratory Correlative analysis to evaluate copy number alteration biomarker profiles 
as predictors of response in the INSIGhT clinical trial.................................................33
10.
SCREENING AND REGISTRATION STUDY CALENDAR............................................................34
11.
MEASUREMENT OF EFFECT...........................................................................................................36
11.1
Disease Assessment Evaluation ....................................................................................36
11.1.1 Determination of Radiologic Response.........................................................................36
11.1.2 Determination of Progression in Newly Diagnosed Glioblastoma ...............................37
11.2
Imaging Response Criteria ............................................................................................37

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11.2.1 Antitumor Effect – Definitions Evaluable for toxicity:..................................................37
Measurable disease:...................................................................................................................38
Non-measurable evaluable disease:...........................................................................................38
Number of Lesions:...................................................................................................................38
Definition of Clinical Deterioration: .........................................................................................38
Definition of Radiographic Response:.......................................................................................38
11.2.2 Pseudoprogression.........................................................................................................39
Table 1.
Criteria for Determining First Progression Depending on Time from Initial 
Radiotherapy .................................................................................................................39
11.2.3 RANO Response/Progression Categories Complete response (CR): ............................40
Participants with non-measurable disease cannot have a complete response. The best 
response possible is stable disease. ...................................................................40
Participants with non-measurable disease cannot have a partial response. The best 
response possible is stable disease. ...................................................................41
and/or one or more of the of the following: ..................................................................41
Note that if there is uncertainty regarding whether there is progression, the patient may 
continue on treatment and remain under close observation (e.g., evaluated at 4- week 
intervals). If subsequent evaluations suggest that the patient is in fact experiencing 
progression, then the date of progression should be the time point at which this issue 
was first raised...............................................................................................................42
Table 2: Summary of the RANO Response Criteria .................................................................42
11.2.5 Evaluation of Best Response.........................................................................................43
11.2.6 Other Effect Measures...................................................................................................43
Performance Status:...................................................................................................................43
Overall survival time:................................................................................................................43
Progression-free survival time: .................................................................................................43
Evaluable participants: ..............................................................................................................43
11.2.7 Central Radiology Review ............................................................................................43
12.
DATA REPORTING / REGULATORY REQUIREMENTS...............................................................44
12.1
Data Reporting...............................................................................................................44
All sites should notify the DFCI Coordinating Center of date of progression and date of death 
as soon as possible (either via monthly teleconferences hosted by the DFCI 
Coordinating Center, phone or email). Source documents confirming date of 
progression and date of death should be submitted to the DFCI Coordinating Center 
within 5 business days of the site learning of the event. Source documents can be sent 
directly to DFCI Coordinating Center personnel or to 
NeuroOnc_Coor@dfci.harvard.edu. .............................................................................45
12.2
Data Safety Monitoring.................................................................................................45
12.3
Multicenter Guidelines..................................................................................................45
13.
STATISTICAL CONSIDERATIONS ..................................................................................................46
13.1
Sample Size, Accrual Rate and Study Duration............................................................47
13.2
Stratification Factors .....................................................................................................48
13.3
Interim Monitoring Plan................................................................................................48
13.4
Analysis of Primary Endpoints......................................................................................48
13.5
Analysis of Secondary Endpoints..................................................................................48

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14.
PUBLICATION PLAN.........................................................................................................................48
15.
REFERENCES......................................................................................................................................50
APPENDIX A
PERFORMANCE STATUS CRITERIA......................................................................53
APPENDIX B
DATA SAFETY MONITORING PLAN......................................................................54
1.0
INTRODUCTION.................................................................................................................................56
1.1
Purpose..........................................................................................................................56
1.2
Multi-Center Data and Safety Monitoring Plan Definitions .........................................56
2.0
GENERAL ROLES AND RESPONSIBILITIES.................................................................................57
2.1
DF/HCC Sponsor ..........................................................................................................57
2.2
Coordinating Center ......................................................................................................58
2.3
Participating Institution .................................................................................................58
3.0
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS .................................................59
3.1
Protocol Distribution.....................................................................................................59
3.2
Protocol Revisions and Closures...................................................................................59
3.3
Informed Consent Requirements...................................................................................60
3.4
IRB Documentation.......................................................................................................60
3.5
IRB Re-Approval ..........................................................................................................60
3.6
Participant Confidentiality and Authorization Statement..............................................60
3.6.1 DF/HCC Multi-Center Protocol Confidentiality.............................................................61
3.7
DF/HCC Multi-Center Protocol Registration Policy.....................................................61
3.7.1
Participant Registration and Randomization at a non-DF/HCC Site.............................62
3.7.2
Initiation of Therapy......................................................................................................63
3.7.3
Eligibility Exceptions....................................................................................................63
3.8
DF/HCC Protocol Case Number ...................................................................................63
3.9
Protocol Deviations, Exceptions and Violations...........................................................64
3.9.1
Definitions.....................................................................................................................64
3.9.2
Reporting Procedures....................................................................................................64
3.10
Safety Assessments and Toxicity Monitoring...............................................................65
3.10.1 Guidelines for Reporting Serious Adverse Events........................................................65
3.10.2 Guidelines for Processing IND Safety Reports.............................................................65
3.11
Data Management .........................................................................................................66
3.11.1 Data Forms Review.......................................................................................................66
4.0
REQUISITIONING INVESTIGATIONAL DRUG.............................................................................66
5.0
MONITORING: QUALITY CONTROL .............................................................................................66
5.1
Ongoing Monitoring of Protocol Compliance...............................................................66
5.2
Evaluation of Participating Institution Performance.....................................................68
5.2.1 Monitoring Reports ..........................................................................................................68
5.3
Accrual Monitoring .......................................................................................................68
6.0
AUDITING: QUALITY ASSURANCE...............................................................................................68
6.1
Audit Plan: DF/HCC Sponsored Trials .........................................................................68
6.2
Audit Notification .........................................................................................................69
6.3
Audit Reports ................................................................................................................69

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6.4
Participating Institution Performance............................................................................69
6.4.1
Corrective Actions.........................................................................................................69
APPENDIX C
INFORMATION ON POSSIBLE DRUG INTERACTIONS ......................................70
APPENDIX D
RECOMMENDED MRI ACQUISITION PROTOCOL ..............................................73
APPENDIX E CONTROL ARM OF INSIGHT ..........................................................................................75
1.
BACKGROUND...................................................................................................................................77
1.1
Temozolomide...............................................................................................................77
2.
PARTICIPANT SELECTION ..............................................................................................................79
2.1
Eligibility Criteria Specific to the Control Arm ............................................................79
2.2
Second INSIGhT Registration: Registration to Control Arm........................................79
2.2.1
Registration Process for DF/HCC Institutions ..............................................................79
2.2.2
Registration Process for Other Investigative Sites ........................................................79
3.
TREATMENT PLAN ...........................................................................................................................80
3.1
Definition of Standard Radiation Therapy ....................................................................80
3.2
Concomitant Temozolomide during Radiation Therapy...............................................81
3.3
Rest Phase .....................................................................................................................81
3.4
Adjuvant (Post-Radiation) Temozolomide ...................................................................82
3.5
General and Concomitant Medication and Supportive Care Guidelines.......................82
3.6
Criteria for Taking a Participant Off Protocol Therapy ................................................83
3.7
Duration of Follow Up ..................................................................................................84
3.8
Criteria for Taking a Participant Off Study...................................................................84
4.
DOSING DELAYS/DOSE MODIFICATIONS...................................................................................84
4.1
Anticipated Toxicities ...................................................................................................85
4.1.1
Anticipated Toxicities for Radiation Therapy...............................................................85
4.1.2
Anticipated Toxicities for Temozolomide ....................................................................86
4.2
Dose Modifications/Delays for Temozolomide ............................................................86
Adjuvant Temozolomide Dose Levels......................................................................................87
Table 4.2: Criteria for dose-modification and re-initiation of Temozolomide treatment..........88
5.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS.................................................89
5.1
Expected Toxicities.......................................................................................................89
5.2
Adverse Event Characteristics.......................................................................................89

For expedited reporting purposes only:.........................................................................90
5.3
Expedited Adverse Event Reporting .............................................................................90
Table 5.3.3 Expedited AE Reporting by external sites to Coordinating Center/Overall PI ......91
5.4
Expedited Reporting to the Food and Drug Administration (FDA)..............................92
5.5
Expedited Reporting to Hospital Risk Management.....................................................92
5.6
Routine Adverse Event Reporting.................................................................................92
6.
PHARMACEUTICAL INFORMATION Temozolomide.............................................92
6.1.2
Form ..............................................................................................................................92
6.1.3
Storage and Stability .....................................................................................................93
6.1.4
Compatibility.................................................................................................................93
6.1.5
Handling........................................................................................................................93

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6.1.6
Availability....................................................................................................................93
6.1.7
Preparation ....................................................................................................................93
6.1.8
Administration...............................................................................................................93
6.1.9
Ordering ........................................................................................................................93
8.
MEASUREMENT OF EFFECT...........................................................................................................97
9.
REFERENCES......................................................................................................................................97
10.
DFCI REPORTABLE AE COVERSHEET – INSIGHT CONTROL ARM.....................................99
11.
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION 
THERAPY ..........................................................................................................................................100
Participant/Guardian Signature: ..........................................................................................................102
Date:
102
Participant/Guardian Signature:
 Date:.............................................................................................103
12.
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY FOLLOWING RADIATION 
THERAPY ..........................................................................................................................................112
APPENDIX F ABEMACICLIB ARM OF INSIGHT................................................................................114
1.
BACKGROUND.................................................................................................................................116
1.1
Temozolomide.............................................................................................................116
1.2
Abemaciclib (LY2835219)..........................................................................................117
2.
PARTICIPANT SELECTION ............................................................................................................122
2.1
Eligibility Criteria Specific to the Abemaciclib Arm..................................................122
2.2
Second INSIGhT Registration: Registration to Abemaciclib Arm .............................123
2.2.1
Registration Process for DF/HCC Institutions ............................................................123
2.2.2
Registration Process for Other Investigative Sites ......................................................123
3.
TREATMENT PLAN .........................................................................................................................123
3.1
Definition of Standard Radiation Therapy ..................................................................123
3.2
Concomitant Temozolomide during Radiation Therapy.............................................124
3.3
Rest Phase ...................................................................................................................125
3.4
Adjuvant (Post-Radiation) Abemaciclib .....................................................................125
3.5
General Concomitant Medication and Supportive Care Guidelines ...........................126
3.6
Guidelines for Diarrhea Management.........................................................................128
3.7
Criteria for Taking a Participant Off Protocol Therapy ..............................................128
3.8
Duration of Follow Up ................................................................................................129
3.9
Criteria for Taking a Participant Off Study.................................................................129
4.
DOSING DELAYS/DOSE MODIFICATIONS.................................................................................129
4.1
Anticipated Toxicities .................................................................................................130
4.1.1
Anticipated Toxicities for Radiation Therapy.............................................................130
4.1.2
Anticipated Toxicities for Temozolomide ..................................................................130
4.1.3
Anticipated Toxicities for Abemaciclib ......................................................................131
4.2
Dose Modifications/Delays for Temozolomide ..........................................................131
4.3
Dose Modifications/Delays for Abemaciclib..............................................................133

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5.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS...............................................140
5.1
Expected Toxicities.....................................................................................................140
5.2
Adverse Event Characteristics.....................................................................................141

For expedited reporting purposes only:.......................................................................141

Serious Adverse Event (SAE) Definition:...................................................................141
5.3
Expedited Adverse Event Reporting ...........................................................................142
Table 5.3.3 Expedited AE Reporting Requirements ...............................................................143
5.4
Expedited Reporting to the Food and Drug Administration (FDA)............................150
5.5
Expedited Reporting to Hospital Risk Management...................................................151
5.6
Routine Adverse Event Reporting...............................................................................151
PHARMACEUTICAL INFORMATION .......................................................................................................151
Temozolomide.........................................................................................................................151
6.1.2
Form ............................................................................................................................151
6.1.3
Storage and Stability ...................................................................................................151
6.1.4
Compatibility...............................................................................................................152
6.1.5
Handling......................................................................................................................152
6.1.6
Availability..................................................................................................................152
6.1.7
Preparation ..................................................................................................................152
6.1.8
Administration.............................................................................................................152
6.1.9
Ordering ......................................................................................................................152
6.2
Abemaciclib ................................................................................................................152
6.2.2
Form ............................................................................................................................153
6.2.3
Storage and Stability ...................................................................................................153
6.2.4
Compatibility...............................................................................................................153
6.2.5
Handling......................................................................................................................153
6.2.6
Availability..................................................................................................................153
6.2.7
Preparation ..................................................................................................................153
6.2.8
Administration.............................................................................................................153
6.2.9
Ordering ......................................................................................................................154
6.2.10 Accountability.............................................................................................................154
6.2.11 Destruction and Return................................................................................................154
7.
STUDY CALENDAR.........................................................................................................................155
8.
MEASUREMENT OF EFFECT.........................................................................................................157
9.
REFERENCES....................................................................................................................................157
10.
DFCI REPORTABLE AE COVERSHEET – INSIGHT ABEMACICLIB ARM..............................158
11.
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION 
THERAPY ..........................................................................................................................................159
Participant/Guardian Signature: ..........................................................................................................161
Date:
161
Participant/Guardian Signature:
 Date:.............................................................................................162
12.
ABEMACICLIB DOSING INSTRUCTIONS & DRUG DIARY......................................................163

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Participant/Guardian Signature: ..............................................................................................164
Date:
164
Participant/Guardian Signature:
 Date:.................................................................................165
APPENDIX G CC-115 ARM OF INSIGHT .............................................................................................166
1.
BACKGROUND.................................................................................................................................168
2.
PARTICIPANT SELECTION ............................................................................................................170
2.1
Eligibility Criteria Specific to the CC-115 Arm..........................................................170
2.2
Second INSIGhT Registration: Registration to CC-115 Arm .....................................171
2.2.1
Registration Process for DF/HCC Institutions ............................................................171
2.2.2
Registration Process for Other Investigative Sites ......................................................171
3.
TREATMENT PLAN .........................................................................................................................172
3.1
Definition of Standard Radiation Therapy ..................................................................172
3.2
Treatment Regimen – CC-115 Administration............................................................172
3.3
Safety Lead-In.............................................................................................................173
Table: Safety Lead-In CC-115 Dose Levels ...........................................................................174
3.5
General Concomitant Medication and Supportive Care Guidelines ...........................175
3.6
Criteria for Taking a Participant Off Protocol Therapy ..............................................177
3.7
Duration of Follow Up ................................................................................................178
3.8
Criteria for Taking a Participant Off Study.................................................................178
4.
DOSING DELAYS/DOSE MODIFICATIONS.................................................................................178
Table: CC-115 Dose Levels ....................................................................................................179
4.1.1
Anticipated Toxicities for Radiation Therapy.............................................................179
4.1.2
Suspected & Anticipated Toxicities for CC-115.........................................................180
4.2
Dose Modifications/Delays for CC-115......................................................................180
5.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS...............................................186
5.1
Expected Toxicities.....................................................................................................186
5.2
Adverse Event Characteristics.....................................................................................186

For expedited reporting purposes only:.......................................................................187

Attribution of the AE:..................................................................................................187

Serious Adverse Event (SAE) Definition:...................................................................187
5.3
Expedited Adverse Event Reporting ...........................................................................188
Table 5.3.3 Expedited AE Reporting Requirements to Celgene & DFCI Coordinating Center
.....................................................................................................................................189

Lymphopenia (grades 2-3). NOTE: all grade 4 lymphopenia events should be reported 
per expedited adverse event reporting requirements to the DFCI Coordinating Center
.....................................................................................................................................197
5.4
Expedited Reporting to the Food and Drug Administration (FDA)............................198
5.5
Expedited Reporting to Hospital Risk Management...................................................198
5.6
Routine Adverse Event Reporting...............................................................................198
5.7
Other Reporting Requirements....................................................................................198
Male Subjects ..........................................................................................................................199
5.7.2
Overdose......................................................................................................................199
5.7.3
IND Annual Reports....................................................................................................199

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6.
PHARMACEUTICAL INFORMATION CC-115 ..............................................................................200
6.1.1
Description ..................................................................................................................200
6.1.2
Form ............................................................................................................................201
6.1.3
Storage and Stability ...................................................................................................201
6.1.4
Compatibility...............................................................................................................201
6.1.5
Handling......................................................................................................................201
6.1.6
Availability..................................................................................................................201
6.1.7
Preparation ..................................................................................................................201
6.1.8
Administration.............................................................................................................201
6.1.9
Ordering ......................................................................................................................202
6.1.10 Accountability.............................................................................................................202
6.1.11 Destruction and Return................................................................................................202
7.
STUDY CALENDAR.........................................................................................................................203
8.
MEASUREMENT OF EFFECT.........................................................................................................205
9.
REFERENCES....................................................................................................................................205
DFCI REPORTABLE AE COVERSHEET – INSIGHT CC-115 ARM ........................................................206
RADIATION CC-115 DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION..................207
Participant/Guardian Signature:
 Date:.................................................................................210
POST RADIATION CC-115 DOSING INSTRUCTIONS & DRUG DIARY...............................................211
Participant/Guardian Signature:
 Date:.................................................................................212
Participant/Guardian Signature: ..............................................................................................213
Date:
213
APPENDIX H NERATINIB ARM OF INSIGHT .....................................................................................214
1.
BACKGROUND.................................................................................................................................216
1.1
Temozolomide.............................................................................................................216
1.2
Neratinib (PB-272, HKI-272)......................................................................................217
2.
PARTICIPANT SELECTION ............................................................................................................221
2.1
Eligibility Criteria Specific to the Neratinib Arm .......................................................221
2.2
Second INSIGhT Registration: Registration to Neratinib Arm...................................221
2.2.1
Registration Process for DF/HCC Institutions ............................................................221
2.2.2
Registration Process for Other Investigative Sites ......................................................222
3.
TREATMENT PLAN .........................................................................................................................222
3.1
Definition of Standard Radiation Therapy ..................................................................222
3.2
Concomitant Temozolomide during Radiation Therapy.............................................222
3.3
Rest Phase ...................................................................................................................223
3.4
Adjuvant (Post-Radiation) Neratinib Treatment .........................................................224
3.5
General Concomitant Medication and Supportive Care Guidelines ...........................224
3.5.15 Concurrent Prophylactic Administration of Loperamide............................................226
Loperamide Dosing.................................................................................................................227
Loperamide Dose Reduction Levels for Constipation ............................................................227
3.6
Criteria for Taking a Participant Off Protocol Therapy ..............................................228
3.7
Duration of Follow Up ................................................................................................228

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3.8
Criteria for Taking a Participant Off Study.................................................................228
4.
DOSING DELAYS/DOSE MODIFICATIONS.................................................................................229
4.1
Anticipated Toxicities .................................................................................................229
4.1.1
Anticipated Toxicities for Radiation Therapy.............................................................229
4.1.2
Anticipated Toxicities for Temozolomide ..................................................................230
4.1.3
Anticipated Toxicities for Neratinib............................................................................230
4.2
Dose Modifications/Delays for Temozolomide ..........................................................231
4.3
Dose Modifications/Delays for Neratinib ...................................................................232
4.3.1
General Dose Adjustments for Neratinib-Related Toxicities......................................233
Table 4.3.1: General criteria for dose-modification and re-initiation of neratinib treatment..233

Recommended dietetic measures ................................................................................235

Recommended pharmacological treatment .................................................................235

Recommended dietetic measures (same as above)......................................................235
Table 4.3.2 Gastrointestinal Toxicities Requiring Dose Adjustment of Neratinib .................236
Table 4.3.3 Liver Function Test Toxicities Requiring Dose Adjustment of Neratinib...........238
5.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS...............................................240
5.1
Expected Toxicities.....................................................................................................240
5.2
Adverse Event Characteristics.....................................................................................240

For expedited reporting purposes only:.......................................................................241

Serious Adverse Event (SAE) Definition:...................................................................241
5.3
Expedited Adverse Event Reporting ...........................................................................241
Table 5.3.3 Expedited AE Reporting Requirements ...............................................................243
5.4
Expedited Reporting to the Food and Drug Administration (FDA)............................252
5.5
Expedited Reporting to Hospital Risk Management...................................................252
5.6
Routine Adverse Event Reporting...............................................................................252
5.7
Reporting to Puma Biotechnology, Inc. ......................................................................252
By e-mail to PumaSAE@parexel.com....................................................................................252
6.
PHARMACEUTICAL INFORMATION ...........................................................................................253
6.1
Temozolomide.........................................................................................................................253
6.1.2
Form ............................................................................................................................253
6.1.3
Storage and Stability ...................................................................................................253
6.1.4
Compatibility...............................................................................................................253
6.1.5
Handling......................................................................................................................253
6.1.6
Availability..................................................................................................................253
6.1.7
Preparation ..................................................................................................................254
6.1.8
Administration.............................................................................................................254
6.1.9
Ordering ......................................................................................................................254
6.2
Neratinib..................................................................................................................................254
6.2.1
Description ..................................................................................................................254
6.2.2
Form ............................................................................................................................255
6.2.3
Storage and Stability ...................................................................................................255
6.2.4
Compatibility...............................................................................................................255
6.2.5
Handling......................................................................................................................255

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6.2.6
Availability..................................................................................................................255
6.2.7
Preparation ..................................................................................................................255
6.2.8
Administration.............................................................................................................256
6.2.9
Ordering ......................................................................................................................256
6.2.10 Accountability.............................................................................................................256
6.2.11 Destruction and Return................................................................................................256
8.
MEASUREMENT OF EFFECT.........................................................................................................260
9.
REFERENCES....................................................................................................................................260
10.
DFCI REPORTABLE AE COVERSHEET – INSIGHT NERATINIB ARM ...................................262
11.
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION 
THERAPY ..........................................................................................................................................263
Participant/Guardian Signature: ..........................................................................................................265
Date:
265
Date:
266
12.
NERATINIB DOSING INSTRUCTIONS & DRUG DIARY............................................................267
NERATINIB DOSING INSTRUCTIONS & DRUG DIARY........................................................................268
Participant/Guardian Signature: ..............................................................................................268
Date:
268
7.
ANTIDIARRHEAL DOSING INSTRUCTIONS & DOSING DIARY.............................................270
If you experience an increase of 4 or more stools a day after beginning neratinib, call your study 
doctor or nurse assoon as possible. .........................................................................................270
Record the date, time and dose(s) you take each day..........................................................................271
Record the date, time and dose(s) you take each day..........................................................................272
Participant/Guardian Signature:
 Date:.................................................................................272

Taking loperamide to prevent diarrhea is required for all patients. ...................273
APPENDIX I QBS10072S ARM OF INSIGhT.........................................................................................276
1.
BACKGROUND.....................................................................................................................277
1.1
STUDY DRUG QBS10072S ..................................................................................................277
Clinical Overview..........................................................................................................................................278
Nonclinical Overview....................................................................................................................................279
Benefit/Risk Assessment ...................................................................................................................280
2.
PARTICIPANT SELECTION................................................................................................282
2.1
Eligibility Criteria Specific to the QBS10072S Arm..............................................................282
2.2
Second INSIGhT Registration: Registration to QBS10072S Arm .........................................283
3.
TREATMENT PLAN .............................................................................................................284

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3.1
Definition of Standard Radiation Therapy..............................................................................284
3.2
Treatment Regimen – QBS10072S Administration................................................................285
3.3
Safety Lead-In.........................................................................................................................287
3.4
Definition of Dose-Limiting Toxicity (DLT)..........................................................................288
Dose Limiting Toxicity Definition................................................................................................................289
3.5
General Concomitant Medication and Supportive Care Guidelines.......................................289
3.6
Criteria for Taking a Participant Off Protocol Therapy..........................................................292
3.7
Duration of Follow Up............................................................................................................293
3.8
Criteria for Taking a Participant Off Study.............................................................................293
4.
DOSING DELAYS/DOSE MODIFICATIONS.....................................................................293
4.1
Anticipated Toxicities .............................................................................................................294
In order for an event to be expected (known correlation to study drug) for the purposes of adverse event 
reporting, the event must be included in this section..........................................................................294
4.2
Dose Modifications/Delays for QBS10072S ..........................................................................297
Table 4.2:
Criteria for dose-modification and re-initiation of QBS10072S treatment.................299
5.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS...................................301
5.1
Expected Toxicities.................................................................................................................301
5.2
Adverse Event Characteristics ................................................................................................301
5.3
Expedited Adverse Event Reporting.......................................................................................302
5.4
Expedited Reporting to the Food and Drug Administration (FDA)........................................305
5.5
Expedited Reporting to Hospital Risk Management...............................................................306
5.6
Routine Adverse Event Reporting...........................................................................................306
5.7
Other Reporting Requirements................................................................................................306
Male Subjects..................................................................................................................................................307
6.
PHARMACOKINETICS........................................................................................................308
7.
PHARMACEUTICAL INFORMATION...............................................................................311
QBS10072S.........................................................................................................................................311
8.
STUDY CALENDAR.............................................................................................................319
9.
Measurement of Effect............................................................................................................326
10.
REFERENCES........................................................................................................................326
DFCI REPORTABLE AE COVERSHEET – INSIGHT QBS10072S ARM......................................328
APPENDIX J Study Drug VBI-1901/BALSTILIMAB ARM OF INSIGhT.............................................329

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23.
BACKGROUND.....................................................................................................................331
24.
VBI-1901.................................................................................................................................331
1.
Virus-Like Particles to Design New Vaccines....................................................................................331
2.
Rationale for Selecting the Components of VBI-1901 ...............................................331
3.
MLV Gag Component.....................................................................................332
4.
HCMV pp65 Component ................................................................................332
5.
HCMV gB Component ...................................................................................333
6.
GM-CSF as Adjuvant......................................................................................333
7.
Supporting Clinical Data.................................................................................333
8.
Balstilimab (AGEN2034)....................................................................................................................336
9.
Supporting Nonclinical Data.......................................................................................336
10.
Supporting Clinical Data.............................................................................................336
11.
Rationale for Design, Dose Selection, and Treatment Schedule.........................................................338
12.
Potential Risks and Benefits................................................................................................................338
13.
Potential Risks.............................................................................................................338
14.
Potential Benefits ........................................................................................................339
25.
PARTICIPANT SELECTION................................................................................................339
26.
Eligibility Criteria Specific to the VBI-1901/Balstilimab (AGEN2034) Arm .......................339
28.
Second INSIGhT Registration: Registration to VBI-1901/Balstilimab Arm..........................340
29.
TREATMENT PLAN .............................................................................................................340
30.
Definition of Standard Radiation Therapy..............................................................................341
31.
Treatment Regimen – VBI-1901 Administration....................................................................341
32.
Treatment Regimen – Balstilimab Administration .................................................................342
33.
Definition of Dose-Limiting Toxicity.....................................................................................342
34.
General Concomitant Medication and Supportive Care Guidelines.......................................343
35.
Criteria for Taking a Participant Off Protocol Therapy..........................................................344
36.
Duration of Follow Up............................................................................................................345
37.
Criteria for Taking a Participant Off Study.............................................................................345
38.
DOSING DELAYS/DOSE MODIFICATIONS.....................................................................345
39.
Anticipated Toxicities .............................................................................................................346
IMMUNE-RELATED MANAGEMENT GUIDELINES..........................................................................348
Dermatological Immune-Related Adverse Events..............................................................................348
Table 2: Dermatological Immune-Related Adverse Event Management Algorithm..........................348
Gastrointestinal Immune-Related Adverse Events .............................................................................350
Table 3: Gastrointestinal Immune-Related Adverse Event Management Algorithm .........................350

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Pulmonary Immune-Related Adverse Events .....................................................................................352
Table 4: Pulmonary Immune-Related Adverse Event Management Algorithm .................................352
Hepatic Immune-Related Adverse Events ..........................................................................................353
Table 5: Hepatic Immune-Related Adverse Event Management Algorithm ......................................353
Endocrine Immune-Related Adverse Events ......................................................................................355
Table 6: Endocrine Immune-Related Adverse Event Management Algorithm ..................................355
Renal Immune-Related Adverse Events .............................................................................................358
Table 7: Renal Immune-Related Adverse Event Management Algorithm .........................................358
Neurological Immune-Related Adverse Events..................................................................................359
40.
Table 8: Neurological Immune-Related Adverse Event Management Algorithm..................359
41.
Dose Modification/Delays for Balstilimab .............................................................................359
42.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS...................................360
43.
Expected Toxicities.................................................................................................................360
44.
Adverse Event Characteristics ................................................................................................360
45.
Solicited Adverse Events ........................................................................................................361
46.
Expedited Adverse Event Reporting.......................................................................................362
50.
Expedited Reporting to the Food and Drug Administration (FDA)........................................365
51.
Expedited Reporting to Hospital Risk Management...............................................................365
52.
Routine Adverse Event Reporting...........................................................................................366
53.
Other Reporting Requirements................................................................................................366
58.
PHARMACEUTICAL INFORMATION...............................................................................367
59.
VBI-1901.................................................................................................................................367
60.
GM-CSF (Lyophilized Leukine®)...........................................................................................369
61.
Balstilimab (AGEN2034)........................................................................................................369
62.
Ordering ..................................................................................................................................371
63.
Accountability.........................................................................................................................371
64.
Destruction and Return............................................................................................................371
7.
STUDY CALENDAR.........................................................................................................................372
8.
MEASUREMENT OF EFFECT.............................................................................................376
9.
REFERENCES........................................................................................................................376
10.
DFCI REPORTABLE AE COVERSHEET – INSIGhT VBI-1901/Balstilimab 
(AGEN2034) ARM.................................................................................................................379

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11.
Grading of Local Reactions.....................................................................................................376

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1. OBJECTIVES
1.1
Study Design
INSIGhT (INdividualized Screening trial of Innovative Glioblastoma Therapy) is a biomarker- 
based, Bayesian adaptively randomized, multi-arm phase II platform screening trial designed to 
test multiple experimental therapy/biomarker hypotheses simultaneously for patients with newly 
diagnosed glioblastoma (GBM) and unmethylated MGMT promoters.
Patients presenting with newly diagnosed GBM will be enrolled and randomized either to control 
or one of the experimental arms following surgery, provided that their tumors have unmethylated 
MGMT promoters, are negative for IDH1 R132H mutation by immunohistochemistry, and have 
relevant genomic biomarker data either available or in process.
The trial will begin with an initial period of equal randomization among the various arms. 
Exceptions may occur with arms that need safety lead-ins to determine the safety of the study 
drug with radiotherapy. Following this initial period, toxicity and efficacy assessments will be 
made prior to additional randomization. For treatment arms with prior toxicity data, no specific 
decision-making based on toxicity will be made at this point. For treatment arms designed to 
give an experimental therapy concurrently with radiation requiring a safety run-in due to 
known phase II doses, but without prior data in combination with radiation therapy (RT), 
treatment arms will drop if there is excess toxicity (as described in Appendix G, Section 3.3). 
Efficacy assessments, based on progression-free and overall survival compared with control, 
will be made both for the overall treatment arm and within pre-specified a priori genomic 
biomarker groups for each treatment. This efficacy assessment will be formalized within the 
adaptive randomization procedure described below, and treatment arms that show evidence of 
efficacy will preferentially have additional patients randomized to that arm.
1.2
Primary Objectives

To determine whether experimental arms improve overall survival (OS) in patients 
with GBM harboring unmethylated MGMT promoters compared with standard 
therapy
1.3
Secondary Objectives

To determine whether specific a priori defined biomarkers predict the benefit from 
experimental therapy

To assess the toxicity of experimental arms

To assess progression-free survival (PFS) among experimental arms and biomarker 
groups

To assess OS among experimental arms and biomarker groups

To determine the association between PFS and OS effects of experimental agents

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2. BACKGROUND
2.1
Study Disease
There were an estimated 22,810 cases of primary malignant brain tumors in 2014 of which 
glioblastoma (GBM) is the most common type2. GBM accounts for 45% of primary malignant 
brain tumors with an average age adjusted incidence rate of 3.19/100,00 during the period of 
2006-20101. The prognosis for patients diagnosed with GBM is poor, with 1- and 5-year 
survival rates were only 35.0% and 4.7%, respectively.
The standard of care for treatment of newly diagnosed GBM patients is based on the results of 
the landmark European Organization for Research and Treatment of Cancer (EORTC)/National 
Cancer Institute of Canada (NCIC) trial CE.3 study2. This phase III trial randomized 573 
patients to concomitant and adjuvant TMZ and RT versus RT alone in patients with newly- 
diagnosed GBM following surgical resection and showed that the combination of TMZ with RT 
was well-tolerated and resulted in improved survival (median 14.6 months versus 12.1 months; 
p<0.0001). Methylation of the promoter of the 06-methylguanine-DNA-methyltransferase 
(MGMT) DNA-repair gene in this trial was an independent favorable prognostic factor3.
Furthermore, many in the neuro-oncology community have interpreted the MGMT results to 
suggest that there is very limited, if any, benefit from the addition of TMZ to radiation for 
patients with unmethylated MGMT promoters. As such, this population has been identified for 
clinical trials which omit TMZ, at least in experimental arms.
2.2
IND Agent(s)
Refer to section 1 of each sub-study appendix for background information on applicable 
investigational agents.
2.3
Other Agent: Temozolomide
Refer to section 1.1 of applicable sub-study appendices for background information on 
temozolomide.
2.4
Rationale
Currently, the development of drugs for newly-diagnosed glioblastoma is extremely slow and 
inefficient. The need for randomized phase II studies with adequate control arms results in half 
the patient population receiving standard therapy, a significant waste of limited resources and an 
unattractive situation for patients who have poor outcomes. In addition, the current practice of 
combining all drugs with radiation therapy and temozolomide (TMZ), even in MGMT 
unmethylated tumors where the benefit of temozolomide is negligible,2,4 frequently results in an 
additional two years of development as the recommended phase II does of the novel agent with 
radiation therapy and temozolomide is determined. Frequently, dose reduction of the novel agent 
is required because of overlapping toxicities with TMZ, resulting in an ineffective dose being 
utilized in the phase II trial with radiation therapy. This trial attempts to overcome some of these 
limitations and provide and more rapid and efficient framework for developing novel agents for

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patients with newly diagnosed glioblastoma with unmethylated MGMT promoters.
The overall rationale for this trial is to rapidly and efficiently screen therapies for impact on 
overall survival so that they can move on to confirmatory studies for registration purposes. The 
protocol framework employs an approach to provide efficient use of a single control arm 
with multiple experimental arms. The study will incorporate high-dimensional genomic data 
both for pre-specified predictive biomarker hypotheses testing and for biomarker hypothesis 
generation. The incorporation of biomarker data has the potential to make clinical trials more 
efficient by selecting only those populations that are more likely to respond, especially when the 
biomarker subgroup comprises a minority of the population and the relative effect in biomarker 
negative vs. positive is strong. Our approach is initially agnostic to biomarker subgroup- 
specific effects for randomizing patients to treatment arms but will utilize biomarker data 
that accumulates during the course of the study that supports biomarker-specific effects.
The primary endpoint will be overall survival. The randomization will be equal 
randomization to the treatment arms stratified by the biomarker/genomic signature status. 
Patient data hypothesized to be correlated with overall survival, elements such as progression 
status and neurocognitive metrics, and performance status, would be included in a model to 
estimate risk of death. As effects on PFS have been shown to translate to effects on OS for non 
anti-angiogenic agents in GBM, PFS will be used to inform the adaptive randomization 
procedure even though the final comparison will be done based on overall survival. As 
progression free survival outcome data accumulates during the course of the trial, randomization  
probabilities will be updated to preferentially assign patients to arms that show evidence of 
improved outcomes based on their biomarker status.
Experimental arms will either complete accrual or be dropped if the probability of a positive 
recommendation of confirmatory testing for a single arm falls below 10%. Futility and 
efficacy decisions will only be based on evidence directly generated from OS. New arms will 
be added through amendment of the protocol once an arm is graduated or dropped, and 
these experimental arms will be selected by the trial steering committee. This experimental 
arm vetting process will consider: strength of the proposed rationale for use in GBM, 
preclinical/clinical data supporting combination with radiation, preclinical/clinical data 
supporting specific biomarker subgroup effects, blood-brain barrier penetration, tumor tissue 
penetration, drug potency, efficacy in standard GBM cell lines both in vitro and in vivo, efficacy 
in human tumor derived cell lines both in vitro and in vivo, prior clinical data, and human safety 
data either as monotherapy or in combination with radiation therapy. Potential experimental 
arms will be evaluated and prioritized based on these data, while recognizing that the standard of 
care is inadequate therapy for these patients, and final recommendations for additional arms will 
be made by the INSIGhT steering committee. Once the committee has approved an additional 
arm, the trial documents will be amended accordingly. Individual investigators will be 
encouraged to take ownership over specific experimental arm additions and will be responsible 
for assembling the experimental arm proposal and for any publications related specifically 
related to that arm.
Another major consideration for this trial and any clinical trial for newly diagnosed GBM 
patients with unmethylated MGMT promoters is how temozolomide (TMZ) should be

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considered. The foundation for our decision-making on this issue is that TMZ may have a real 
but marginal benefit for these patients but that the addition of TMZ has an opportunity cost as 
well. Whether TMZ has any benefit in the unmethylated setting is certainly debatable, with the 
most compelling argument being that the benefit seen in the EORTC/NCIC study in 
unmethylated patients4 may have been more related to issues assaying true MGMT status or with 
histopathologic diagnostic errors. Even if this argument is accepted, we do not have a more valid 
mechanism for assaying MGMT status than in that trial as it relates to the predictive capability of 
determining who will derive any benefit from the addition of TMZ to RT so we must accept that 
there may be a small, marginal benefit in these unmethylated patients using our current 
biomarker technology. For the opportunity cost, there are two major factors to consider. The 
first is the potential for under dosing an experimental therapy that may have been an 
improvement over TMZ (whether alone or in combination with RT) at optimal dose due to 
combined toxicity with TMZ. Some examples of this are phase I trials of BKM120, 
hydroxychloroquine, and vandetanib in combination with radiation therapy. The second issue is 
one of time- delaying the entire drug development timeline so that phase I testing in combination 
with TMZ (which isn’t generally done prior to being introduced to a GBM population) can be 
performed. Informal polling of neuro-oncologists, radiation oncologists, and neurosurgeons from 
around the country also made it clear that omitting TMZ from clinical trials in an unmethylated 
population would be acceptable, an opinion reflected in the EORTC experience4. Considering 
these issues, a compromise solution adopted in the current clinical trial design is to keep TMZ as 
part of the regimen in places where an experimental therapeutic is absent. For example, if there 
is no radiosensitization hypothesis (as in the arms using neratinib and abemaciclib), TMZ will 
still be given concurrently with RT but replaced by the experimental therapy in the adjuvant 
phase. If there is a potential for radiosensitization in addition to single agent activity (CC-115 
arm), then TMZ will be omitted altogether.
2.5
Correlative Studies Background
From a diagnostic and treatment perspective, GBM is no 
longer considered one homogeneous disease. Advances in 
genetic, epigenetic, gene expression, metabolomic, and other 
profiling technologies have rapidly been applied to GBM to 
classify the disease into several different molecularly defined 
subtypes5-11. Such grouping may have direct relevance 
towards diagnostics, prognosis, and the application of 
targeted therapy. Currently, MGMT promoter methylation 
and IDH1 mutation status are routinely used as prognostic12- 
14 or predictive15-16 biomarkers in GBM with some success. 
Therapeutics directed at precise molecular targets logically 
lead to hypothetical interactions with alterations in tumor 
signaling pathways based on the available models or ‘wiring 
diagrams.’ The Cancer Genome Atlas identified three major
signaling pathways that had recurrent and mutually exclusive genomic alterations, suggesting 
critical roles for each: receptor tyrosine kinase (RTK)/Ras/phosphatidylinositol-3-kinase (PI3K), 
p53, and Rb (Figure 1)8.
Figure 1: Common genomic alterations in GBM

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Genomic analyses and tools are generally less complex and more reliable as biomarkers than 
RNA based assays and routine genomic analysis is increasingly used in clinical practice and is 
becoming progressively broader as sequencing costs decrease. Despite the success in other 
cancers, translating promising targeted therapies for biomarker-identified subgroups into 
efficacious clinical trials has had little success for GBM to date. Even so, there are many 
investigational agents that hypothetically interact with the frequently altered pathways listed 
above which are currently slated for clinical testing. The focus of the current trial is to provide a 
clinical trial framework to efficiently test these therapeutic hypotheses, both therapeutic efficacy 
and the predictive capability of the putative biomarker. For this reason, a comprehensive 
multiplexed genomic analysis will be conducted for each patient to identify biomarker signatures 
prior to treatment assignment. These biomarker signatures will be evaluated during the course of 
the trial for association with efficacy signals. Initial biomarker classifiers will be based on 4 
specific pathway markers- EGFR amplification/mutation(45%), PI3K activation (PTEN loss 
through homozygous deletion or mutation plus deletion, PIK3CA mutation, PIK3R1 
mutation)(49%), p53 status (MDM 2/4 amplification or p53 wild-type)(65%), and CDK 
(CDK4/6 amplification or CDKN2A nullisomy)(68%). Genotyping assays or combinations of 
assays that are able to assign biomarker categories based on these predetermined criteria will be 
acceptable for inclusion as outlined in Section 9.1.
Initially, patients would be randomized equally to the various treatment arms, regardless of 
biomarker signature, as there are no strong clinical data supporting the predictive capacity of a 
genomic biomarker for any of the initial experimental arms. During the course of the trial, the a 
priori biomarker hypotheses will be continuously evaluated for associations with drug efficacy 
and after the initial predetermined equal randomization period (so not as to be overly influenced 
by early and limited results) this accumulating clinical data would influence the randomization 
probability for future enrolled patients should an association be found. For example, if there is 
an efficacy signal for an EGFR inhibitor, but that signal is limited to the EGFR + group, EGFR – 
patients would be less likely assigned to the EGFR treatment arm vs. control or drop out 
altogether while EGFR + would continue to be assigned to EGFR treatment vs. control. In this 
manner, the initial agnostic randomization will start to utilize biomarker data if it is associated 
with a treatment effect. For new arms where there are no biomarker signatures randomization 
based on genomic biomarkers will be omitted.
While a focused panel for these specific genomic aberrations is a possibility, one of the unique 
aspects of the proposed trial is to acknowledge the lack of well-developed biomarker information 
in GBM so broader based, multiplexed platforms are encouraged to allow for unbiased 
discovery/testing of other focused hypotheses about response modifiers based on planned co- 
clinical trials, in response to other emerging pre clinical or clinical data, or through exploratory 
discovery analyses.

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3. PARTICIPANT SELECTION
Participants must meet all eligibility criteria below prior to initial registration to master INSIGhT 
protocol. Participants’ INSIGhT randomization assignment will be received by the treating 
study team once the initial registration is processed. See section 4 registration procedures and 
section 10 screening/registration study calendar for details.
Before beginning study treatment, a second registration confirmation to the assigned treatment 
arm must be received by the treating team. See section 2 of each sub-study appendix for details 
on registration procedure to assigned arm.
3.1
Eligibility: Inclusion Criteria
3.1.1
Participants must have histologically confirmed intracranial glioblastoma or gliosarcoma 
following maximum surgical resection. Tumors primarily localized in the infratentorial 
compartment will be excluded.
3.1.1.1 Participants with histology of astrocytoma with molecular alterations/features indicative of    
glioblastoma (WHO grade IV) will be eligible.
3.1.2
Participants may have had prior surgery for glioblastoma or gliosarcoma but no systemic 
therapy, interstitial chemotherapy (e.g., Gliadel wafers), or radiation therapy. 
Participants must be recovered from the effects of surgery.
3.1.3
Age ≥ 18 years.
3.1.4
Karnofsky performance status ≥60 (refer to Appendix A).
3.1.5
Participants must have normal organ and marrow function as defined below:

Leukocytes
≥3,000/μL (≥3 x 109/L)

Absolute neutrophil count
≥1,500/μL (≥1.5 x 109/L)

Platelets
≥100,000/μL (≥100 x 109/L)

Hemoglobin
≥ 9g/dl

Total bilirubin
Within normal institutional limits (except 
for participants with Gilbert’s disease)

AST(SGOT)/ALT(SGPT)
≤ 2.5 × institutional upper limit of normal

Creatinine
≤ institutional upper limit of normal 
OR

Creatinine clearance
≥ 60 mL/min/1.73 m2 for participants with creatinine
levels above institutional normal.

Potassium
Within normal institutional range, or correctable 
with supplements

Serum amylase
≤ 1.5 x institutional upper limit of normal

Serum lipase
≤ 1.5 x institutional upper limit of normal

INR
< 2.0

PTT
≤ institutional upper limit of normal, unless receiving 
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3.1.6
Must be able to swallow pills.
3.1.7
 Corticosteroid (dexamethasone or equivalent) dosage ≤ 2 mg daily that has been stable or decreasing 
for at least 5 days
3.1.8
Participants must plan to begin radiation therapy 14-42 days after surgical resection.
NOTE: Patients may be allowed to begin radiation therapy > 42 days after surgical 
resection provided documented approval is obtained by Dr. Wen - the study’s Overall PI
- PROSPECTIVELY.
3.1.9
Immunohistochemically negative for IDH1 R132H mutation.
3.1.10 Evidence that the tumor MGMT promoter is unmethylated by standard of care assays.
3.1.11 Genotyping data must be available or in process. 14 USS + 1 H&E will be collected. 
Confirmation of tissue availability is required for eligibility, but slides can be 
collected at a later date. NOTE: Patients who do not have sufficient tissue, or when 
obtaining the requested samples requires depletion of a patient’s FFPE block(s), may 
be eligible provided there is documentation of inadequate tissue AND documented 
approval is obtained by Dr. Wen - the study’s Overall PI - PROSPECTIVELY. All 
efforts should be made to obtain the maximum number of slides possible, even when 
prospective approval is granted.
3.1.12 MRI with gadolinium should be obtained within 21 days prior to beginning treatment. 
Patients without measurable disease are eligible. Participants must be able to undergo 
MRIs (CTs are not allowed for response assessment on study).
3.1.13 The effects of the experimental agents used in this study on the developing human fetus 
are unknown. For this reason and because other therapeutic agents used in this trial are 
known to be teratogenic, women of child-bearing potential (women who are not free from 
menses for > 2 years, post hysterectomy/oophorectomy, or surgically sterilized) and men 
must agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation unless 
otherwise specified in sub-study appendix that the participant is randomized to. Should a 
woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.
3.1.14 For women of child-bearing potential (women who are not free from menses for > 2 
years, post hysterectomy/oophorectomy, or surgically sterilized) a negative serum 
pregnancy test must be documented prior to initial registration. Women of child-
bearing potential must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) from date of initial dose and for 6 months 
following the last dose of study drug.   Men (including those who have had a 
vasectomy) must agree to use barrier contraception (latex condoms) when engaging 
in sexual activity with a woman of child-bearing potential from date of initial dose 
and for 6 months following the last dose of study drug.
3.1.15 Ability to understand and the willingness to sign a written informed consent document.

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3.2
Eligibility: Exclusion Criteria
3.2.1
Participants will not be eligible if the original diagnosis was a lower grade glioma and a 
subsequent histologic diagnosis revealed glioblastoma.
3.2.2
Planned major surgery.
3.2.3
Participants who are receiving any other investigational agents.
3.2.4
Participants who have had any prior cranial radiotherapy.
3.2.5
History of a different malignancy, unless (a) have been disease-free for at least 2 years 
and are deemed by the investigator to be at low risk for recurrence of that malignancy, 
and/or (b) malignancy was cervical cancer in situ, superficial bladder cancer or basal cell 
or squamous cell carcinoma of the skin, and malignancy has been treated. Patients who 
meet the above listed criteria and are only on preventative treatment will be deemed 
eligible.
3.2.6
History of intratumoral or peritumoral hemorrhage if deemed significant by the treating 
physician.
3.2.7
Impaired cardiac function or clinically significant cardiac diseases, including any of the 
following:
3.2.7.1
Active uncontrolled cardiac disease, including cardiomyopathy, 
congestive heart failure (New York Heart Association functional 
classification of ≥2), unstableangina, myocardial infarction within 12 
months of enrollment, or ventricular arrhythmia.
3.2.7.2
Known history of congenital QT prolongation or Torsade de pointes 
(TdP).
3.2.7.3
Complete left bundle branch or bifascicular block.
3.2.7.4
QTc interval > 450 ms for men or > 470 ms for women.
3.2.7.5
History of clinically meaningful ventricular arrhythmias or atrial 
fibrillation.
3.2.7.6
Unstable pectoris or myocardial infarction ≤ 3 months prior to starting 
study treatment.
3.2.7.7
Uncontrolled hypertension (blood pressure ≥ 160/95 mmHg).
3.2.7.8
Other clinically significant heart disease such as congestive heart failure 
requiring treatment.
3.2.8
Uncontrolled diabetes mellitus, or subjects with either of the following:
3.2.8.1
Blood glucose ≥ 200 mg/dL (7.0 mmol/L), or
3.2.8.2
HbA1c ≥ 8%
NOTE: HbA1c is not a required screening lab; however, if HbA1C is 
performed at screening, result must be <8%.
NOTE: If patient’s HbA1c is ≥ 8%, Team may proceed to register patient 
with documented explanation (e.g. patient has controlled Type 2 diabetes 

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mellitus, but steroid dose at time of screening labs has elevated result) and 
documented confirmation from treating MD that they feel patient is safe to 
proceed.

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3.2.9
Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, 
chronic liver disease (e.g., cirrhosis, hepatitis), chronic renal disease, pancreatitis, chronic 
pulmonary disease, or psychiatric illness/social situations that would limit compliance 
with study requirements. Subjects must be free of any clinically relevant disease (other 
than glioma) that would, in the treating investigator’s opinion, interfere with the conduct 
of the study or study evaluations. Participants with vitiligo, or hypothyroidism due to 
autoimmune condition only requiring hormone replacement therapy, psoriasis not 
requiring systemic therapy, or conditions not expected to recur in the absence of an 
external trigger are permitted to enroll.
3.2.10 Known immunosuppressive disease or active systemic autoimmune disease such 
as systemic lupus erythematosus, human immunodeficiency virus infection. 
Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNS 
[qualitative] is detected).
3.2.11 Known acute or chronic pancreatitis.
3.2.12 Participants with active diarrhea ≥ CTCAE grade 2 despite medical management.
3.2.13 Active infection requiring antibiotics.
3.2.14 Pregnant or breastfeeding.
3.2.15 Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, or extensive small bowel resection). Participants with 
unresolved diarrhea ≥ CTCAE grade 2 will be excluded as previously indicated.
3.2.16 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to any of the experimental agents or other agents used in study.
3.2.17 Participants taking an enzyme-inducing anti-epileptic drug (EIAED): phenobarbital, 
phenytoin, fosphenytoin, primidone, carbamazepine, oxcarbazepine, eslicarbazepine, 
rufinamide, and felbamate. Participant must be off any EIAEDs for at least 7 days prior 
to planned start of study investigational agent, excluding Temodar. A list of EIAED and 
other inducers of CYP3A4 is provided in Appendix C. Among non-EIAED, caution is 
recommended with use of valproic acid due to potential for drug interaction.
3.2.18 Participants taking a drug known to be strong inhibitors or inducers of isoenzyme 
CYP3A (Appendix C). Participant must be off CYP3A inhibitors and inducers for at least 
7 days prior to planned start of study treatment. NOTE: participants must avoid 
consumption of Seville orange (and juice), grapefruit or grapefruit juice, grapefruit 
hybrids, pummelos and exotic citrus fruits from 7 days prior to planned start of study 
treatment and during the entire study treatment period due to potential CYP3A4 
interaction.
3.2.19 Current use of herbal preparations/medications, including but not limited to: St. John’s 
wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, ginseng. Participants should stop using these herbal medications 

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7 days prior to planned start of study treatment.
3.2.20 Current use of warfarin sodium or any other coumadin-derivative anticoagulant. 
Participant must be off Coumadin-derivative anticoagulants for at least 7 days prior to 
planned start of study treatment. Low molecular weight heparin and factor Xa inhibitors 
are allowed.
3.2.21 Participants who may have experienced prior immune-mediated adverse events (e.g., 
life-threatening pneumonitis). 
3.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.

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4. INITIAL INSIGHT REGISTRATION PROCEDURES
Participants must meet all eligibility criteria outlined in the master protocol (section 3) and 
complete initial registration as described in this section below in order to receive INSIGhT 
randomization assignment.
Before beginning study treatment, a second registration confirmation to the assigned treatment 
arm must be received by the treating team. See section 2 of each sub-study appendix for details 
on registration procedure to assigned arm.
Following initial registration, any additional laboratory assessments prior to start of treatment 
will not be used to re-confirm eligibility. Refer to section 4 of this each sub-study appendix for 
toxicity management between registration and start of study treatment. Participants should not 
begin study treatment if a dose hold is required.
4.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore®. An initial and second registration must occur prior to the initiation of protocol 
therapy. Any participant not registered to both the master protocol and assigned arm before 
protocol therapy begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following initial registration, participants’ INSIGhT randomization assignment will be received 
by the treating study team.
Following second registration (see section 2 of each sub-study appendix for details on 
registration procedure to assigned arm), participants may begin protocol therapy. Issues that 
would cause treatment delays should be discussed with the Overall Principal Investigator (PI). If 
a participant does not receive protocol therapy following registration, the participant’s 
registration on the study must be canceled. Registration cancellations must be made in 
OnCore® as soon as possible.
4.2
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.
4.3
General Guidelines for Other Investigative Sites
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
DFCI Coordinating Center staff. All sites should contact the DFCI Coordinating Center to verify 
slot availabilities. A list of the required forms for registration can be found in Appendix B.

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Following second registration to assigned arm, participants should begin as soon as feasible. 
Issues that would cause treatment delays should be discussed with the Overall PI. If a participant 
does not receive protocol therapy following second registration, the participant’s registration on 
the study must be canceled. The Study Coordinator should be notified of cancellations as soon 
as possible.
4.4
Registration Process for Other Investigative Sites
Refer to Appendix B, Section 3.7 for registration details.
5. TREATMENT PLAN
Refer to section 3 of each sub-study appendix for treatment plan details of assigned treatment 
arm.
5.1
General Concomitant Medication and Supportive Care Guidelines
Refer to section 3 of each sub-study appendix for general concomitant medication and supportive 
care guidelines of assigned treatment arm.
5.2
Criteria for Taking a Participant Off Protocol Therapy
Refer to section 3 of each sub-study appendix for off-treatment details of assigned treatment arm.
5.3
Duration of Follow Up
Refer to section 3 of each sub-study appendix for duration of follow-up details of assigned 
treatment arm.
5.4
Criteria for Taking a Participant Off Study
Refer to section 3 of each sub-study appendix for off-study details of assigned treatment arm.
6. DOSING DELAYS/DOSE MODIFICATIONS
Refer to section 4 of each sub-study appendix for dosing delays/dose modification information of 
assigned treatment arm.
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
Refer to section 5 of each sub-study appendix for adverse event list and reporting requirements 
of assigned treatment arm to the corresponding manufacturer and Overall PI/DFCI Coordinating 
Center.

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Expedited Reporting to the Food and Drug Administration (FDA)
The Overall PI, as the study sponsor, will be responsible for all communications with the FDA. 
The Overall PI will report to the FDA, regardless of the site of occurrence or protocol treatment 
arm, any serious adverse event that meets the FDA’s criteria for expedited reporting following 
the reporting requirements and timelines set by the FDA. When sending reports to the FDA, the 
Overall PI will clearly indicate what arm of INSIGhT the participant was randomized to.
8. PHARMACEUTICAL INFORMATION
Refer to section 6 of each sub-study appendix for applicable pharmaceutical information of 
assigned treatment arm.
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1
Biomarker Studies
Patients eligible for treatment assignment on this study will have had prior genotyping performed 
under DF/HCC protocol #16-114 (or an alternative platform pre-approved by the Overall PI) 
including whole genome copy number analysis and whole exome sequencing or another 
comparable set of genotyping assays that are sufficient to define the biomarker categories below. 
We will set a priori biomarker categories on the basis of genetic aberrations for subsequent 
analyses:
For amplifications listed, the genotyping report must state clear gene amplification and not gain, 
which is typically greater than a log2 ratio of +2.0. Copy number losses would be values of less 
than -0.3 and more than single copy deletions are inferred relative to baseline for the 
chromosome on which they are located (e.g. single copy Chr 9 loss with additional loss of 
CDKN2A/B below this level in focal region). The general criteria to be included for mutations 
would be single nucleotide variants (SNV) that are present at >3% allelic fractions; and have > 
5 prior events reported in COSMIC or are well established hotspots known to be activating or 
inactivating mutations through experimental data. All genotyping data will be centrally 
reviewed by a neuropathologist for ultimate determination of biomarker categories.
It is important to note that biomarker groups were defined on the basis of hypothetical 
interactions with available therapeutics for study rather than hypothetical functional equivalence. 
Available supportive preclinical evidence is included below. Given that there is no prior clinical 
evidence to support a specific biomarker hypothesis and that the preclinical data is limited in 
some cases, we will learn about biomarker linkages primarily through the conduct of the trial.
For that reason, randomization will initially be equal, without regard to biomarker subgrouping 
or prioritization but biomarker categories will be assessed in the statistical model as outlined in 
that section.
Assays specifically approved for use on INSIGhT
OncoCopy
aCGH is performed using the Agilent SurePrint G3 1x1M stock chip, which allows analysis of ~ 

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1 million features per sample. Associated reagents include Genomic DNA ULS Labeling Kit (# 
5190-0419) and the Agilent Oligo aCGH Hybridization Kit (# 5188-5220). Processed chips are 
scanned using the Agilent G2565 Series Microarray Scanner (capacity 48 chips per run). The 
process for analyzing genomic DNA isolated from FFPE materials was initially developed at 
DFCI19 and the technique was validated according to ACMG practice guidelines for clinical 
implementation at the BWH CAMD. ~ 1,000 primary brain tumors specimens have since been 
analyzed for clinical testing through the Cytogenetics Lab.
Primary brain tumors will be submitted for analysis after review by the neuropathology team at 
BWH. Samples will have been fixed using standard formalin fixation. Neuropathologists select 
the most appropriate portions of FFPE blocks to submit for array analysis. FFPE materials 
received in CAMD are processed for DNA isolation by the Molecular Diagnostics component of 
CAMD using routine and standard protocols. The degree of DNA fragmentation is estimated by 
gel electrophoresis17 and the reference DNA is heat-fragmented to match that of the tumor 
specimen. We have demonstrated that this size matching is critical to improving the signal to 
noise ratio in the final aCGH analysis of FFPE specimens. aCGH is then performed using 
standard protocols.
The data collected for aCGH analysis should be considered semi-quantitative and ordered 
categorical. The genomic imbalances (losses or gains) reported from each analysis are either 
present or absent (hence, the data are categorical). The degree to which these imbalances are 
present or absent in a given tumor can vary (i.e., is one copy of a gene missing or are two copies 
of a gene missing, or do the data suggest that in a proportion of the tumor two copies, one copy 
or no copies of the gene are missing --- hence, the data are ordered). The absence or presence of 
a particular gene or chromosomal locus is called relative to a normal reference genome, and also 
assumes a diploid genome in the tumor. A combination of biological criteria and limitations of 
the assay prevent the data from being interpreted in a purely quantitative manner.
Whole exome sequencing
The CRSP Whole Exome Sequencing test takes, as an input, matched tumor and normal 
specimens from a single patient. Input materials for tumor can be genomic DNA, FFPE tissue, or 
frozen tissue. For normal sample we will accept whole blood, FFPE (slides or cores), fresh 
frozen tissue or buffy coats. CRSP performs a sample qualification assay on all samples that are 
going to be processed through next generation sequencing. Samples are genotyped using a panel 
of 94 highly polymorphic coding SNPs and a gender specific SNP on the Fluidigm platform.
These genotypes, which serve as a genetic fingerprint for each sample, are stored in the sample- 
tracking database and referenced by our production sequencing pipeline to compare with data 
from production processes. This “fingerprint” allows immediate confirmation of sample identity. 
Sample preparation and sequencing: Positive and negative controls are added to matrix plates 
containing samples. All fluid handling steps are automated on Agilent Bravo liquid handling 
robots that scan and record receptacle and plate barcodes. Next-generation sequencing libraries 
are created with custom oligonucleotide adapter molecules incorporating Broad’s validated set of 
96 x 96 dual indices for sample multiplexing. Indexed libraries are pooled prior to hybridization 
of target DNA probes. Selected regions of the genome are pulled down and amplified. Final 
libraries are quantitated by qPCR and loaded across the appropriate number of Illumina HiSeq 
2500 flowcell lanes to achieve the target coverage. Each sample will be sequenced to a mean 

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target coverage of 200X. Data processing and variant calling: Data from sequencing instruments 
will be processed through the Broad’s established and widely adopted pipelines. Read alignment 
and duplicate marking will be performed with the Picard analysis suite. Somatic SNV and Indel 
variants will be called using the latest validated release of the Firehose tools – MuTect18 and 
Indelocator.
Primary brain tumors will be submitted for analysis after review by the neuropathology team at 
BWH. Samples will have been fixed using standard formalin fixation and neuropathologist- 
reviewed to select areas of >50% tumor and adequacy for molecular analysis. Tumor enriched 
areas will be macrodissected from 5-10 five-micron sections (FFPE). Genomic DNA will be 
isolated using standard extraction methods (Qiagen, Valencia, CA) and quantified using 
Picogreen-based dsDNA detection (Life Technologies, Carlsbad, CA). Samples yielding 
between 50 and 200ng of DNA will be further processed.
The data collected for whole exome analysis should be considered semi-quantitative and ordered 
categorical. The genomic imbalances (losses or gains) reported from each analysis are either 
present or absent (hence, the data are categorical). The degree to which these imbalances are 
present or absent in a given tumor can vary (i.e., is one copy of a gene missing or are two copies 
of a gene missing, or do the data suggest that in a proportion of the tumor two copies, one copy 
or no copies of the gene are missing --- hence, the data are ordered). The absence or presence of 
a particular gene or chromosomal locus is called relative to a normal reference genome, and also 
assumes a diploid genome in the tumor. A combination of biological criteria and limitations of 
the assay prevent the data from being interpreted in a purely quantitative manner.
Other institutional or commercial genotyping assays may be accepted if biomarker categories are 
able to be determined. More specifically, genotyping assays that are eligible must be performed 
in a CLIA laboratory setting and assess the entire gene (approximating data from whole exome 
NGS) for the critical genes included in biomarker groupings described above and approach 
similar coverage (~ 100x average read depth) as the assays described above. For copy number 
analysis assays must have log2 ratio copy number data to quantitatively assess relative copy 
number gains/losses. For example, the assay must readily be able to distinguish single vs. 
greater than single copy number changes.
If new arms do not have biomarker signatures genomic studies will still be performed but 
biomarker data will not be used for randomization.
9.2
Exploratory Correlative analysis to evaluate copy number alteration biomarker 
profiles as predictors of response in the INSIGhT clinical trial
In collaboration with Dr. Orly Alter PhD at the University of Utah, we will correlate clinical trial 
outcomes data (e.g. progression free survival, overall survival) with novel copy-number 
signatures and other genomic and clinical parameters to identify predictors of patient response 
related to standard of care arm or experimental agents studied within the INSIGhT clinical trial.
To perform this additional exploratory, analysis clinical outcomes and other data will be shared 
and transferred between DFCI and Dr. Alter at University of Utah. All data will be shared in a 

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de-identified manner. Analysis will be performed and summarized data provided back to the 
collaborating investigators for integration with other parameters.
Data sharing
Data generated by the INSIGhT clinical trial will be shared publicly once studies are completed 
and results are approved for sharing by the study PI (Dr. Wen). Data planned to be shared will be 
de-identified clinical outcomes data and attached genomics data or copy number signature data. 
De-identified data is planned to be shared at public repositories for purposes of cancer research 
(e.g. NCI dbGAP, cBioPortal).

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10. SCREENING AND REGISTRATION STUDY CALENDAR
The below study calendar should be utilized for purposes of screening and initial registration to 
master INSIGhT protocol (see section 3 of master protocol for comprehensive eligibility 
requirements). Refer to section 7 study calendar of each sub-study appendix for additional on- 
study Day 1 assessments of assigned treatment arm.
NOTE: this table is not comprehensive of assessments required for Day 1 of on-study treatment 
for each arm.
Assessment
Screeninga
Registration/ 
Randomizationb
On-Study 
Treatmentc
Initial Informed Consentd
X
Medical Historye
X
Inclusion/Exclusion Criteriaf
X
Vital signsg
X
Physical Exam
X
Neurologic Exam
X
Karnofsky Performance Statush
X
Concomitant Medicationsi
X
Pregnancy Test (β-HCG)j 
X
Coagulationk
X
Hematologyl
X
Serum Chemistrym
X
EKG
X
Imaging – MRIn 
X
Archival Tumor Tissuet
X
Initial Registrationo
X
INSIGhT Randomization Assignmentp
X
Assigned Arm Informed Consentq
X
Registration to Assigned Armr
X
Radiation + Assigned Arm Treatments
Xc
a.
Screening: all screening procedures to be performed within 28 days of initial registration unless otherwise 
specified.
b.
Registration/Randomization: initial registration to the master INSIGhT protocol and second registration to 
subsequent assigned arm must occur prior to beginning study treatment.
c.
On-Study Treatment: study treatment may not begin until study team has received second registration 
confirmation and must begin no later than 42 days from participant’s surgical resection. Refer to section 7 study 
calendar of each sub-study appendix for additional on-study Day 1 assessments of specific treatment arms. 
NOTE: this table is not comprehensive of assessments required for Day 1 of on-study treatment.
d.
Initial Information Consent: must be obtained by MD attending. No study specific screening procedures outside 
of assessments considered standard of care may occur until after the initial informed consent process is 
completed. Initial informed consent may be obtained within 28 days of initial registration.
e.
Medical History: to include review of treatment history for GBM, any ongoing medical conditions and medical 
history pertaining to eligibility on study and involvement during study.
f.
Inclusion/exclusion criteria: source documentation providing investigator’s confirmation that the participant has 
met all master protocol eligibility criteria must be available prior to initial registration. See section 3 of master 
protocol for eligibility requirements.
g.
Vital Signs: weight, heart rate, blood pressure, respiration rate, temperature, and height.

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h.
Karnofsky Performance Status (KPS): see appendix A of master protocol.
i.
Concomitant Medications: concomitant medications and reason for administration should be documented from 
date of consent up to the 30-Day Post Drug Visit.
j.
Pregnancy Test: required for women of child bearing potential (please see master protocol section 3 for 
definition of women of child bearing potential). Pregnancy test can be either blood or urine sample.
k.
Coagulation: PT/INR, PT, PTT.
l.
Hematology: erythrocytes (RBC), hemoglobin, hematocrit, platelets, total WBC plus differential (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils).
m. Serum Chemistry: albumin, alkaline phosphatase (ALP), bicarbonate (HCO3), BUN, calcium, chloride, creatinine, 
glucose, potassium, SGOT (AST), SGPT (ALT), sodium, amylase, lipase, magnesium, blood glucose, total protein, 
total bilirubin (if total bilirubin is greater than the upper limit of normal, direct and indirect bilirubin should be 
performed).
n.
Imaging: gadolinium-enhanced contrast and non-contrast MRI. Initial imaging should be performed within 21 
days prior to beginning study treatment. When feasible at site, Appendix D Recommended MRI Acquisition 
Protocol should be adhered to and the same imaging technique should be used on a participant throughout the 
trial.
o.
Initial Registration: participants must be registered to the master INSIGhT protocol once eligibility for master 
INSIGhT protocol (section 3) has been confirmed. See section 4 of master protocol for details on initial 
registration procedure.
p.
INSIGhT Randomization Assignment: a participant’s randomization assignment will be received by the treating 
study team once the initial registration is processed.
q.
Assigned Arm Informed Consent: must be obtained by MD attending. Following receipt of initial 
registration/randomization assignment, participants must sign the consent form specific to the assigned 
treatment arm prior to initiating study treatment.
r.
Registration to Assigned Arm: before beginning study treatment, a second registration confirmation to the 
assigned treatment arm must be received by the treating study team. See section 2 of each sub-study appendix 
for details on registration procedure to assigned treatment arm.
s.
Radiation + Assigned Arm Treatment: study treatment may not begin until study team has received second 
registration confirmation and must begin no later than 42 days from participant’s surgical resection. Refer to 
section 7 study calendar of each sub-study appendix for additional on-study Day 1 assessments of specific 
treatment arms. NOTE: this table is not comprehensive of assessments required for Day 1 of on-study 
treatment.
t.
Archival tumor tissue may be sent to Stanford University for assay laboratory tests.

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11. MEASUREMENT OF EFFECT
11.1
Disease Assessment Evaluation
Radiologic assessment will be determined by the Response Assessment in Neuro-Oncology 
Working Group (RANO) Criteria using primarily bidirectional tumor measurements and include 
consideration of neurological function and corticosteroid use19. The RANO Criteria is outlined in 
detail in section 11.2 below.
Magnetic resonance imaging (MRI) is the most readily available and reproducible method of 
disease assessment and is required for this study. The largest and most representative lesions 
should be measured either on axial, coronal or sagittal slices, and chosen to be followed for 
response evaluation.
The recommended sequences are outlined in detail in Appendix D and should conform as closely 
as possible to the consensus recommendations for a standardized Brain Tumor Imaging Protocol 
in clinical trials20.
11.1.1 Determination of Radiologic Response
Radiographic response should be determined in comparison to the tumor measurement 
obtained at pretreatment baseline (most recent MRI prior to beginning investigational 
agents for applicable arms or temozolomide for control arm) for determination of 
response, and the smallest tumor measurement at either pretreatment baseline or after 
initiation of therapy should be used for determination of progression. In the event that the 
radiographic changes are equivocal and it is unclear whether the patient is stable or has 
developed progressive disease, it is permissible to continue treatment and observe the 
patient closely, for example at 4-week intervals. If subsequent imaging studies 
demonstrate that progression has occurred, the date of progression should be the date of 
the scan at which this issue was first raised.
The determination of radiographic response after treatment with agents that affect 
vascular permeability is particularly difficult. In all patients, consideration should be 
given to performing a second scan at 4 weeks to confirm the presence of response or 
stable disease.
All measurable and non-measurable lesions should be assessed using the same techniques 
as at baseline. Ideally, patients should be imaged on the same MRI scanner, or at least 
with the same magnet strength, for the duration of the study to reduce difficulties in 
interpreting changes.
Radiologic response and progression will be determined by the local site.

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11.1.2 Determination of Progression in Newly Diagnosed Glioblastoma
Approximately 10-30% of patients who received radiation therapy with concomitant 
temozolomide will have transient worsening of their MRI scans due to treatment effects 
that improve with time21. This phenomenon of “pseudoprogression” may potentially 
occur more frequently with radiosensitizing agents and immunotherapies.
Detailed discussion of pseudoprogression is outlined in section 11.2.2. In general, the 
goal is to try to keep patients on therapy as long as possible, provided that they are 
clinically stable.
The RANO criteria suggests that within the first 12 weeks of completion of radiation 
therapy, when pseudoprogression is most prevalent, progression can only be determined 
if the majority of the new enhancement is outside of the radiation field (for example, 
beyond the high-dose region or 80% isodose line) or if there is pathologic confirmation of 
progressive disease. In general, patients who remain clinically stable and are suspected to 
have pseudoprogression (preferably based on metabolic or vascular imaging) should 
continue with their current therapy during the first 12 weeks of completion of 
radiotherapy. More frequent imaging during this period (e.g. monthly MRIs) may be 
indicated. Patients should only be discontinued from therapy if there is significant clinical 
progression or strong suspicion of true progression. For a patient to progress during this 
period their MRI scan should show an increase by >25% in the sum of the products of 
perpendicular diameters compared to the first post-radiotherapy scan. Additional details 
are provided in section 11.2 below.
11.2
Imaging Response Criteria
Antitumor response will be evaluated by the Response Assessment in Neuro-Oncology 
(RANO) working group criteria in this study using primarily the product of the maximal cross- 
sectional enhancing diameters and include consideration of neurological function and 
corticosteroid use19.
Magnetic resonance imaging (MRI) is the most readily available and reproducible method of 
disease assessment and is required for this study. The largest and most representative lesions 
should be measured either on axial, coronal or sagittal slices, and chosen to be followed for 
response evaluation.
The recommended sequences will be outlined in detail in Appendix D and should conform as 
closely as possible to the consensus recommendations for a standardized Brain Tumor Imaging 
Protocol in clinical trials20.
11.2.1 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.

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Measurable disease:
Bidimensionally, contrast-enhancing, measurable lesions with clearly defined margins by 
MRI scan, with a minimal diameter of 10 mm, and visible on 2 axial slices which are at 
least 5 mm apart with 0 mm skip will be considered to be measurable. 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.
Patients without measurable disease, such as those who undergo a gross total resection, 
cannot respond and can only achieve stable disease as their best radiographic outcome.
Non-measurable evaluable disease:
Unidimensionally measurable lesions, masses with margins not clearly defined, lesions 
with maximal diameter < 10 mm.
Number of Lesions:
If there are multiple contrast-enhancing lesions, a minimum of the two largest lesions 
should be measured, and the sum of the products of the perpendicular diameters of these 
lesions should be determined. However, given the heterogeneity of high-grade gliomas 
and the difficulty in measuring some lesions, a maximum of five of the largest lesions may 
be measured. In general, the largest enlarging lesion(s) should be selected. However, 
emphasis should also be placed on lesions that allow reproducible repeated measurements.
Definition of Clinical Deterioration:
The definition of clinical deterioration is left to the discretion of the treating physician, but 
it is recommended that a decline in the 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 comorbid events 
or changes in corticosteroid dose. Similarly, a decline in the Eastern Cooperative 
Oncology Group and WHO performance scores from 0 or 1 to 2 or 2 to 3 would be 
considered neurologic deterioration.
Definition of Radiographic Response:
Radiographic response should be determined in comparison to the tumor measurement 
obtained at pretreatment baseline for determination of response, and the smallest tumor 
measurement at either pretreatment baseline or after initiation of therapy should be used 
for determination of progression. In the event that the radiographic changes are equivocal 
and it is unclear whether the patient is stable or has developed progressive disease, it is 
permissible to continue treatment and observe the patient closely, for example at 4 or 8- 
week intervals. If subsequent imaging studies demonstrate that progression has occurred, 
the date of progression should be the date of the scan at which this issue was first raised. 
Consideration should be given to performing a second scan at 4 weeks to confirm the 
presence of response or stable disease. All measurable and non-measurable lesions should 
be assessed using the same techniques as at baseline. Ideally, patients should be imaged on 
the same MRI scanner, or at least with the same magnet strength, for the duration of the 
study to reduce difficulties in interpreting changes.

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11.2.2 Pseudoprogression
Radiation Effects
The RANO criteria suggest that within the first 12 weeks of completion of radiotherapy, 
when pseudoprogression is most prevalent, progression can only be determined if the 
majority of the new enhancement is outside of the radiation field (for example, beyond 
the high-dose region or 80% isodose line) or if there is pathologic confirmation of 
progressive disease. It is recognized that the proposed histologic criteria have important 
limitations, but they provide guidance on the type of findings that are suggestive of 
progressive disease.
However, it should be noted that pseudoprogression can sometimes occur beyond the 12 
weeks after completion of radiotherapy and that new lesions can occur within the 
radiotherapy field.
In general, patients who remain clinically stable and are suspected to have 
pseudoprogression (preferably based on metabolic or vascular imaging) should continue 
with their current therapy especially during the first 12 weeks of completion of 
radiotherapy. More frequent imaging during this period (e.g. monthly MRIs) may be 
indicated. Patients should only be discontinued from therapy if there is significant 
clinical deterioration or strong suspicion of true progression. For a patient to progress 
during this period their MRI scan should show an increase by >25% in the sum of the 
products of perpendicular diameters compared to the first post-radiotherapy scan. New 
lesions within the radiation field will be allowed and will not on their own constitute 
progression.
NOTE: Study treatment may be held > 28 days in order to allow for surgical pathology to 
determine progression versus pseudoprogression outside of the 12-week consideration 
mark if it is prospectively confirmed with Overall PI to be clinically appropriate to do so.
Table 1.
Criteria for Determining First Progression Depending on Time 
from Initial Radiotherapy
First 
Progression
Definition
Progressive disease
< 12 weeks after 
completion of 
radiotherapy
Progression can only be defined using diagnostic imaging if there is new enhancement 
outside of the radiation field (beyond the high-dose region or 80% isodose line) or if there is 
unequivocal evidence of viable tumor on histopathologic sampling (e.g., solid tumor areas 
[i.e. > 70% tumor cell nuclei in areas], high or progressive increase in MIB-1 proliferation 
index compared with prior biopsy.
For a patient to progress during this period their MRI scan should show an increase by >25% 
in the sum of the products of perpendicular diameters compared to the first post-radiotherapy 
scan. New lesions within the radiation field will be allowed and will not constitute 
progression.
Note: Given the difficulty of differentiating true progression from pseudoprogression, 
clinical decline alone, in the absence of radiographic or histologic confirmation of 
progression, will not be sufficient for definition of progressive disease in the first 12 weeks 
after completion of concurrent chemoradiotherapy.

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Progressive disease
>12 weeks after 
radiotherapy 
completion
1. Stable, or increasing doses of corticosteroids.
2. Increase by >25% in the sum of the products of perpendicular diameters between the first 
post-radiotherapy scan, or a subsequent scan with smaller tumor size, and the scan at 12 
weeks or later on stable or increasing doses of corticosteroids.
3. Clinical deterioration not attributable to concurrent medication or comorbid conditions is 
sufficient to declare progression on current treatment.
4. For patients receiving anti-angiogenic therapy, significant increase in T2/FLAIR non-
enhancing lesion may also be considered progressive disease. The increased T2/FLAIR 
must have occurred with the patient on stable or increasing doses of corticosteroids 
compared with baseline scan or best response after initiation of therapy and not be a result 
of comorbid events (e.g., effects of radiation therapy, demyelination, ischemic injury, 
infection, seizures, postoperative changes, or other treatment effects).
Progressive Disease: Assessment Based on Contrast Enhancing Tumor 
Measurement
Immune-based therapies are expected to be associated with inflammatory changes that 
may include edema. RANO expanded radiologic criteria to define progressive disease to 
include the development of “significantly” increased T2 or FLAIR abnormality because 
such changes can be a major component defining radiographic progression following 
therapeutic use of VEGF/VEGFR-targeting therapeutics which are known to elicit potent 
anti-permeability changes that limit contrast uptake. Studies using immunotherapeutic 
agents will define radiographic progressive disease by assessment of contrast enhancing 
tumor burden only and will not incorporate assessment of T2 or FLAIR changes as 
outlined in RANO because:
1)
There is no expectation that immunotherapy agents will falsely diminish 
enhancing tumor burden as has been noted with anti-angiogenic therapies; and
2)
Immune-based therapies may be associated with increased edema and 
associated T2/FLAIR changes which may inaccurately be interpreted to 
represent tumor progression (i.e. pseudoprogression).
11.2.3 RANO Response/Progression Categories 
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. In the absence of a confirming scan 4 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.
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 non-measurable disease cannot have a complete response. The best 
response possible is stable disease.

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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.
e) Failure to return for evaluation due to death or deteriorating condition
f)
Patients with non-measurable enhancing disease whose lesions have significantly 
increased in size and become measurable (minimal bidirectional diameter of ≥ 10 
mm and visible on at least two axial slices that are preferably, at most, 5 mm apart 
with 0-mm skip will also be considered to have experienced progression. The 
transition from a non-measurable lesion to a measurable lesion resulting in 
progression can theoretically occur with relatively small increases in tumor size 
(e.g., a 9 × 9 mm lesion [non-measurable] increasing to a 10 × 11 mm lesion 

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[measurable]). Ideally, the change should be significant (> 5 mm increase in 
maximal diameter or ≥ 25% increase in sum of the products of perpendicular 
diameters of enhancing lesions). In general, if there is doubt about whether
the lesion has progressed, continued treatment and close follow-up evaluation will 
help clarify whether there is true progression.
Note that if there is uncertainty regarding whether there is progression, the patient 
may continue on treatment and remain under close observation (e.g., evaluated at 4- 
week intervals). If subsequent evaluations suggest that the patient is in fact 
experiencing progression, then the date of progression should be the time point at 
which this issue was first raised.
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.
Unknown response status:
Progressive disease has not been documented and one or more measurable or non- 
measurable lesions have not been assessed.
These RANO Response Criteria are summarized in the following table:
Table 2: Summary of the RANO Response Criteria
CR
PR
SD
PD#
T1-Gd +
None
≥50% decrease
<50% decrease-
<25% increase
≥25% increase*
T2/FLAIR
Stable or 
decrease
Stable or 
decrease
Stable or 
decrease
Increase*
New Lesion
None
None
None
Present*
Corticosteroids
None
Stable or
decrease
Stable or 
decrease
NA
Clinical Status
Stable or 
increase
Stable or 
increase
Stable or 
increase
Decrease*
Requirement for 
Response
All
All
All
Any*
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease 
#:
Progression occurs when any of the criteria with * is present
NA: Increase in corticosteroids alone will not be taken into account in determining progression 
in the absence of persistent clinical deterioration

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11.2.4 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 treatment and never more than 14 days before the beginning 
of the treatment (pretreatment baseline is the most recent MRI prior to beginning 
investigational agents for applicable arms or temozolomide for control arm). 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.
11.2.5 Evaluation of Best Response
The best overall response is the best response recorded from the most recent MRI prior to 
beginning investigational agents for applicable arms or temozolomide for control arm 
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. Participants without 
measurable disease may only achieve SD or PD as their best “response.”
11.2.6 Other Effect Measures 
Performance Status:
Participants will be graded according to KPS score.
Overall survival time:
From date of first dose to date of death due to any cause.
Progression-free survival time:
From date of first dose to date of progression or death.
Evaluable participants:
Participants included in primary analysis will be intention-to-treat. That is, all randomized 
patients will be analyzed according to their randomized treatment assignment, whether or 
not they were actually treated and whether or not they were treated appropriately.
11.2.7 Central Radiology Review
The central review of neuroimaging (MRI or CT) will be performed at Dana- Farber Cancer Institute on participants 
from all study arms when requested from the DFCI Coordinating Center on behalf of the Overall PI. All films of all 
views from pre-registration (including pre-enrollment scans documenting progression prior to study interventions) and 
subsequent scans (including all on-study and follow-up scans) will be requested for central review. CDs are preferred.
A copy of all scan reports should be attached for inclusion in the submission. Once the Central Review is complete the 
Reviewing Physician will document the review results. Once the Central Review is complete, the central review results 

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may be made available to the local PI or treating investigator.
 
When requested from the DFCI Coordinating Center, please send a copy of all scans to:
Dr. Patrick Wen c/o Kathryn Partridge
Center for Neuro-Oncology
Dana-Farber Cancer Institute
450 Brookline Ave
Boston, MA  02215 
ph: 617-582-9314
fax: 617-582-7782 
NeuroOnc_Coord@dfci.harvard.edu  
A memo must be submitted to the DFCI Coordinating Center each time submissions are made including DFCI study number, 
participant identifiers and details of what is being submitted. 
The submitting institution is responsible for the costs of shipping and handling.
12. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in section 5 of 
each sub-study appendix (Adverse Events: List and Reporting Requirements).
12.1
Data Reporting
12.1.1 Method
The ODQ will collect, manage, and perform quality checks on the data for this study.
12.1.2 Responsibility for Data Submission
All sites are responsible for submitting data and/or data forms to the ODQ according to 
the schedule set by the ODQ.
The schedule for completion and submission of case report forms (paper and electronic) 
to the ODQ is as follows:
Form
Submission Timeline
Eligibility Checklist
Complete prior to registration with ODQ, as applicable
On Study Form
Within 30 days of registration
Baseline Assessment Form
Within 30 days of registration
Treatment Form
Within 30 days of the last day of the cycle

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Adverse Event Report Form
Within 30 days of the last day of the cycle
Response Assessment Form
Within 30 days of the completion of the cycle required 
for response evaluation
Off Treatment/Off Study 
Form
Within 30 days of completing treatment or being taken 
off study for any reason
Follow up/Survival Form
Within 30 days of the protocol defined follow up visit 
date or call
12.1.3 Endpoint Data Notification & Source Document Submission
All sites should notify the DFCI Coordinating Center of date of progression and date of 
death as soon as possible (either via monthly teleconferences hosted by the DFCI 
Coordinating Center, phone or email). Source documents confirming date of progression 
and date of death should be submitted to the DFCI Coordinating Center within 5 business 
days of the site learning of the event. Source documents can be sent directly to DFCI 
Coordinating Center personnel or to NeuroOnc_Coor@dfci.harvard.edu.
12.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor study 
progress, toxicity, safety and other data from this study. The board is chaired by a medical 
oncologist from outside of DF/HCC and has external and internal representation. Information 
that raises any questions about participant safety or protocol performance will be addressed by 
the Overall PI, statistician and study team. Should any major concerns arise, the DSMB will 
offer recommendations regarding whether or not to suspend the study.
The DSMB will meet twice a year to review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMB may include: participant accrual; 
treatment regimen information; adverse events and serious adverse events reported by category; 
summary of any deaths on study; audit results; and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.
12.3
Multicenter Guidelines
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan. The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix B.

The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required.

Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site.

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
Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier. A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center.
13. STATISTICAL CONSIDERATIONS
The design is a randomized, controlled, multi-arm phase II screening trial designed to estimate 
the efficacy of various experimental arms through comparison with a single control arm based on 
overall survival. Randomization probabilities will be updated during the course of the study 
based on accumulating comparative data regarding progression-free survival. The adaptive 
algorithms developed by INSIGhT investigators has been previously discussed25,29,30.
Progression-free and overall survival times for simulations were based on prior clinical trial data 
for patients with GBM and unmethylated MGMT promoters as discussed in the Background 
section.
The primary endpoint is the overall survival (OS) of the enrolled patients. Additionally, statistical 
analyses will compare overall survival (OS) for the experimental arms and the control arm using 
the standard definition of OS. Power computations and the majority of the simulations used to 
evaluate the operating characteristics of the trial design and secondary analyses use the 
proportional hazards model both for PFS and OS.
Statistical analyses will classify patients accordingly to their positive or negative status for the 
following biomarkers: EGFR, PI3K, and CDK. A biomarker group is defined by the subpopulation 
of patients with identical status for all these three markers.
Patients will be randomized to the clinical trials arms using an adaptive algorithm that will update 
the randomization probabilities for the various arms by biomarker grouping monthly. The 
algorithm uses the available information generated by INSIGhT over the course of the study– the 
individual biomarker groups and individual PFS (possibly censored) of the enrolled patients– to 
determine the randomization probabilities that will be used to allocate patients for the subsequent 
month. These randomization probabilities will be allowed to vary across biomarker groups. The 
goal of the adaptive algorithm is to accelerate and provide a competitive advantage to those 
experimental arms associated with promising data early during the study. The adaptive algorithm 
has the scope of translating promising preliminary evidence based on the PFS data for a single 
experimental arm into unbalanced randomization probabilities.
INSIGhT investigators explored the advantages of adaptive randomization in accelerating the 
accrual rate on the most promising experimental arms for patients with GBM previously25,26. This 
work demonstrates that adaptation of randomization probabilities has a relevant effect on the trade- 
off between power and overall sample size. The adaptive algorithm will define randomization 
probabilities specific to each biomarker subgroup. This will reflect early evidence based only on 
preliminary data of treatment effects variations across biomarker subgroups.
We use the same definition of the randomization probabilities studied previously25,26. In particular, 

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the randomization probability to each of the experimental arms is proportional to the associated 
predicted probability of a positive treatment effect on PFS for the biomarker profile of the enrolled 
patient. This approach has been recently compared to alternative adaptive schemes for multi-arm 
adaptive trials with potential biomarker-treatment interactions.
13.1
Sample Size, Accrual Rate and Study Duration
INSIGhT will randomize 50- 70 patients to each of the experimental arms. The overall  size of the 
trial is not fixed by design because we include arm-dropping rules for futility and allow  for the 
possibility of arm addition by amendment. As more arms are added to the trial, we may add 
additional control patients for comparison requirements. Patients that are non-evaluable or 
withdraw prior to starting treatment may be replaced. The power computations illustrated below 
are the major justifications of the sample size. We estimate an accrual rate of 7 patients per month 
based on prior experience. Sensitivity analyses on the trial operating characteristics considered a 
range of hypothetical accrual rates, from 5 to 14 patients per month. Our power computations 
assumed the biomarker frequencies based on data that has been generated from prior genomic 
profiling31.
The monthly updates of the randomization probabilities are combined with a sequential decision 
rule that drops experimental arms when there is insufficient preliminary evidence to warrant 
further investigation of the treatment based on the primary endpoint. We use a standard linear 
boundary that thresholds p-values to define the decision rule. This simple early stopping rule 
reduces the average number of patients allocated to an experimental arm without treatment effects 
to 49.0, while the average sample size is 69.8 (69.0) with a HR of 0.6 (0.7) 32. We controlled with 
a sensitivity analysis for variations of the average sample size for arms without treatment effects. 
By varying accrual rate and treatment effects of the remaining arms we obtained averages between 
47 and 50 patients.
The choice of the sample size is primarily driven by power computations. We computed the power 
of detecting treatment effects under hypothetical scenarios using simulations. Importantely, 
sample size is justified by the power calculations in presence of treatment effects (i) in the 
overall populations and (ii) lower power (large differences >30%) of detecting treatment effects 
limited  to biomarker  subpopulations, as we report.
Power analysis, detection of PFS treatment effects: If any of the experimental arms has a PFS- 
HR equal to 0.6 (0.7) on the overall population, the power of rejecting the corresponding primary 
null hypothesis (overall population PFS-HR ≥ 1) at completion of the study is 0.9 (0.79). Power 
remains stable when we consider variations of accrual rates and outcome distributions for the 
remaining arms with values in 0.85-0.92. The power of rejecting the same primary null hypothesis 
decreases to 0.37 when only the smaller stratum of patients - CDK-positive patients - benefit from 
the treatment. While the power to reject the null in a biomarker subgroup is of course reduced, the 
power to detect a significant biomarker/treatment interaction (null hypothesis: no treatment effect 
in the CDK positive group) in the secondary analyses is higher (0.66). The fixed maximum number 
(70) patients per arm maintains the power of detecting a positive treatment effect for a specific 
experimental arm stable with respect to the presence or absence of treatment effects on the 
remaining arms.

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Power analysis, detection of OS treatment effects: We defined realistic simulation scenarios 
with comparable PFS and OS treatment effects measured by median increase under treatments. A 
similar power analysis as for PFS has been repeated for OS. When OS treatment effects are 
combined by PFS treatment effects the statistical power of rejecting the null hypothesis (OS-
HR) is preserved. With OS-HR equal to 0.6 (0.7) on the overall population, the power of 
rejecting the null hypothesis at completion of the study is 0.89 (0.77).
13.2
Stratification Factors
Outcomes will be evaluated by biomarker subgroupings as above.
13.3
Interim Monitoring Plan
The interim-monitoring plan will be performed in conjunction with the updates of randomization 
probabilities. The DFCI Coordinating Center will host monthly all-site teleconferences and will 
reach out to sites approximately monthly forupdates  regarding progression events, deaths, and 
censoring dates. This data will be compiled and sent to the statistician to update randomization 
probabilities at which time analyses for futility will be performed. Updated randomization tables 
will then be forwarded to the Office of Data Quality (ODQ) at the DF/HCC.
13.4
Analysis of Primary Endpoints
The statistical plan includes three primary null hypotheses. Each primary null hypothesis assumes 
the absence of a superior treatment effects on OS across all biomarker subgroups under a single 
experimental treatment compared to the control. The primary null hypotheses exclude the 
possibility of a positive treatment effect for any of the biomarker profiles. As motivated in the 
literature28, the statistical plan does not include multiplicity correction for testing these three 
hypotheses. These analyses will generate p-values under the proportional hazards model. The PI 
and the statisticians of INSIGhT have discussed the use of p-values for the analysis of data 
generated from adaptive design25-27. All the hypotheses’ tests bound the probability of type one 
errors at 5%.
13.5
Analysis of Secondary Endpoints
The secondary analyses will explore treatment effects variations across biomarker subgroups. 
These secondary analyses will include estimates of biomarker/treatment interaction coefficients 
under the stratified proportional hazards model and 95% confidence intervals. These secondary 
analyses will stratify with respect to patients’ biomarker groups. Additionally, secondary statistical 
analyses will compare PFS versus control. Similar to the primary analyses, the secondary analyses 
will generate three point estimates of the treatment effects, one for each experimental treatment, 
and 95% confidence intervals.
14. PUBLICATION PLAN
The results should be made public within 24 months of an arm completing accrual or dropping 
from the study due to futility. The end of the study is the time point at which the last data items 

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are to be reported, or after the outcome data are sufficiently mature for analysis, as defined in the 
section on Sample Size, Accrual Rate and Study Duration. If a report is planned to be published 
in a peer-reviewed journal, then that initial release may be an abstract that meets the 
requirements of the International Committee of Medical Journal Editors. A full report of the 
outcomes should be made public no later than three (3) years after the end of the study.

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15. REFERENCES
1.
Ostrom QT, Gittleman H, Farah P, et al. CBTRUS statistical report: Primary brain and 
central nervous system tumors diagnosed in the United States in 2006-2010. Neuro Oncol. 
2013; 15 Suppl 2:ii1-56.
2.
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant 
temozolomide for glioblastoma. The New England journal of medicine. 2005; 352(10):987- 
996.
3.
Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from 
temozolomide in glioblastoma. The New England journal of medicine. 2005; 352(10):997- 
1003.
4.
Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and 
adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a 
randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 
2009; 10(5):459-466..
5.
Noushmehr H, Weisenberger DJ, Diefes K, et al. Identification of a CpG island methylator 
phenotype that defines a distinct subgroup of glioma. Cancer cell. 2010; 17(5):510-522.
6.
Verhaak RG, Hoadley KA, Purdom E, et al. Integrated genomic analysis identifies 
clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, 
IDH1, EGFR, and NF1. Cancer cell. 2010; 17(1):98-110.
7.
Brennan CW, Verhaak RG, McKenna A, et al. The somatic genomic landscape of 
glioblastoma. Cell. 2013; 155(2):462-477.
8.
Comprehensive genomic characterization defines human glioblastoma genes and core 
pathways. Nature. 2008; 455(7216):1061-1068.
9.
Phillips HS, Kharbanda S, Chen R, et al. Molecular subclasses of high-grade glioma predict 
prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. 
Cancer cell. 2006; 9(3):157-173.
10.
Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human 
glioblastoma multiforme. Science. 2008; 321(5897):1807-1812.
11.
Reitman ZJ, Jin G, Karoly ED, et al. Profiling the effects of isocitrate dehydrogenase 1 and 
2 mutations on the cellular metabolome. Proceedings of the National Academy of Sciences 
of the United States of America. 2011; 108(8):3270-3275.
12.
Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from 
temozolomide in glioblastoma. The New England journal of medicine. 2005; 352(10):997- 
1003.
13.
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant 
temozolomide for glioblastoma. The New England journal of medicine. 2005; 352(10):987- 
996.
14.
Alexander BM, Mehta MP. Role of isocitrate dehydrogenase in glioma. Expert review of 
neurotherapeutics. 2011; 11(10):1399-1409.
15.
Malmström A, Grønberg BH, Marosi C, et al. Temozolomide versus standard 6-week 
radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with 
glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012; 13(9):916-926.
16.
Wick W, Platten M, Meisner C, et al. Temozolomide chemotherapy alone versus 
radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, 
phase 3 trial. Lancet Oncol. 2012; 13(7):707-715.

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17.
Craig JM, Vena N, Ramkissoon S, et al. DNA fragmentation simulation method (FSM) and 
fragment size matching improve aCGH performance of FFPE tissues. PLoS One. 2012; 
7(6):e38881.
18.
Cibulskis K, Lawrence MS, Carter SL, et al. Sensitive detection of somatic point mutations 
in impure and heterogeneous cancer samples. Nat Biotechnol. 2013; 31(3):213-219.
19.
Wen PY, Macdonald DR, Reardon DA, et al (2010) Updated response assessment criteria 
for
high-grade gliomas: response assessment in neuro-oncology working group. J Clin 
Oncol;28(11):1963-72.
20.
Ellingson BM, Bendszus M, Boxerman J, et al. Jumpstarting Brain Tumor Drug 
Development Coalition Imaging Standardization Steering Committee. Consensus 
recommendations for a standardized Brain Tumor Imaging Protocol in clinical trials. Neuro 
Oncol. 2015 Sep;17(9):1188-98.
21.
Brandsma D, Stalpers L, Taal W, et al. Clinical features, mechanisms, and management of 
pseudoprogression in malignant gliomas. Lancet Oncol. 2008 May;9(5):453-61.
22.
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clinical cancer research : an official
journal of the American Association for Cancer Research 2009;15:7412-20.
23.
Pollack IF, Jakacki RI, Butterfield LH, et al. Antigen-Specific Immune Responses and 
Clinical Outcome After Vaccination With Glioma-Associated Antigen Peptides and 
Polyinosinic-Polycytidylic Acid Stabilized by Lysine and Carboxymethylcellulose in 
Children With Newly Diagnosed Malignant Brainstem and NonBrainstem Gliomas. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
2014.
24.
Okada H, Weller M, Huang R, Finocchiaro G, Gilbert MR, Wick W, Ellingson BM, 
Hashimoto N, Pollack IF, Brandes A, Franceschi E, Herold-Mende C, Nayak L, Panigrahy 
A, Pope W, Prins R, Sampson JH, Wen PY, Reardon DA. Immunotherapy Response 
Assessment in Neuro-Oncology (iRANO): A Report of the RANO Working Group. Lancet 
Oncology (In Press).
25.
Trippa L, Lee EQ, Wen PY, et al. Bayesian adaptive randomized trial design for patients 
with recurrent glioblastoma. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology. 2012; 30(26):3258-3263.
26.
Wason JM, Trippa L. A comparison of Bayesian adaptive randomization and multi-stage 
designs for multi-arm clinical trials. Stat Med. 2014; 33(13):2206-2221.
27.
Ventz S, Trippa L. Bayesian designs and the control of frequentist characteristics: a 
practical solution. Biometrics. 2015; 71(1):218-226.
28.
Freidlin B, Korn EL, Gray R, Martin A. Multi-arm clinical trials of new agents: some 
design considerations. Clin Cancer Res. 2008; 14(14):4368-4371.
29.
Trippa L, Wen PY, Parmigiani G, Berry DA, Alexander BM. Combining progression-free 
survival and overall survival as a novel composite endpoint for glioblastoma trials. Neuro- 
oncology. 2015 Jan 7:nou345.
30.
Alexander BM, Wen PY, Trippa L, Reardon DA, Yung WK, Parmigiani G, Berry DA. 
Biomarker-based adaptive trials for patients with glioblastoma—lessons from I-SPY 2. 
Neuro-oncology. 2013 Aug 1;15(8):972-8.
31.
Ramkissoon, Shakti H., et al. "Clinical implementation of integrated whole-genome copy 
number and mutation profiling for glioblastoma." Neuro-oncology (2015): nov015.

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32.
Alexander, Brian M., et al. "Individualized Screening Trial of Innovative Glioblastoma Therapy 
(INSIGhT): A Bayesian Adaptive Platform Trial to Develop Precision Medicines for Patients 
With Glioblastoma. " JCO Precision Oncology (2019): DOI: 10.1200/PO.18.00071.

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APPENDIX A
PERFORMANCE STATUS CRITERIA
Karnofsky Performance Scale
Percent
Description
100
Normal, no complaints, no evidence of disease.
90
Able to carry on normal activity; minor signs or 
symptoms of disease.
80
Normal activity with effort; some signs or symptoms of 
disease.
70
Cares for self, unable to carry on normal activity or to 
do active work.
60
Requires occasional assistance, but is able to care for 
most of his/her needs.
50
Requires considerable assistance and frequent medical 
care.
40
Disabled, requires special care and assistance.
30
Severely disabled, hospitalization indicated. Death not 
imminent.
20
Very sick, hospitalization indicated. Death not 
imminent.
10
Moribund, fatal processes progressing rapidly.
0
Dead.

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APPENDIX B
DATA SAFETY MONITORING PLAN
DFCI IRB Protocol #: 16-443
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan

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Table of Contents
1.0
INTRODUCTION
57
1.1
Purpose
1.2
Multi-Center Data and Safety Monitoring Plan Definitions
57
2.0
GENERAL ROLES AND RESPONSIBILITIES
58
2.1
DF/HCC Sponsor
58
2.2
Coordinating Center
59
2.3
Participating Institution
59
3.0
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
60
3.1
Protocol Distribution
60
3.2
Protocol Revisions and Closures
60
3.3
Informed Consent Requirements
61
3.4
IRB Documentation
61
3.5
IRB Re-Approval
61
3.6
Participant Confidentiality and Authorization Statement
61
3.6.1 DF/HCC Multi-Center Protocol Confidentiality
62
3.7
DF/HCC Multi-Center Protocol Registration Policy
62
3.7.1
Participant Registration and Randomization at a non-DF/HCC Site
63
3.7.2
Initiation of Therapy
64
3.7.3
Eligibility Exceptions
64
3.8
DF/HCC Protocol Case Number
64
3.9
Protocol Deviations, Exceptions and Violations
65
3.9.1
Definitions65
3.9.2
Reporting Procedures
65
3.10
Safety Assessments and Toxicity Monitoring
66
3.10.1
Guidelines for Reporting Serious Adverse Events
66
3.10.2
Guidelines for Processing IND Safety Reports
66
3.11
Data Management
67
3.11.1 Data Forms Review
67
4.0
REQUISITIONING INVESTIGATIONAL DRUG
67
5.0
MONITORING: QUALITY CONTROL
67
5.1
Ongoing Monitoring of Protocol Compliance
67
5.2
Evaluation of Participating Institution Performance
69
5.2.1 Monitoring Reports
69
5.3
Accrual Monitoring
69
6.0
AUDITING: QUALITY ASSURANCE
69
6.1
Audit Plan: DF/HCC Sponsored Trials
69
6.2
Audit Notification
70
6.3
Audit Reports
70
6.4
Participating Institution Performance
70
6.4.1
Corrective Actions
70

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1.0
INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP should serve as reference for any sites external to DF/HCC 
that will be participating in the research protocol.
1.1
Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi- 
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures.
1.2
Multi-Center Data and Safety Monitoring Plan Definitions
DF/HCC Multi-Center Protocol: A research protocol in which one or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates.
Lead Institution: Among the Dana-Farber/Harvard Cancer Center sites (DFCI, MGH, 
BIDMC, CHB, BWH), the Dana-Farber Cancer Institute will be the Lead Institution and 
will be responsible for the coordination, development, submission, and approval of a 
protocol as well as its subsequent amendments per the DFCI IRB and applicable regulatory 
guidelines (FDA, etc.). The Lead Institution is the home of the Overall PI, Patrick Y. Wen, 
MD.
DF/HCC Sponsor: The person sponsoring the submitted Multi-Center protocol. Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for 
initiation, management and conduct of the protocol at all research locations. The DF/HCC 
Sponsor has ultimate authority over the protocol and is responsible for the conduct of the 
study at DF/HCC and all Participating Institutions. For this protocol the DF/HCC Sponsor 
is the same person as the DF/HCC Overall Principal Investigator, Patrick Y. Wen, MD.
Participating Institution: An institution that desires to collaborate with DF/HCC and 
commits to accruing participants to the DF/HCC protocol. The Participating Institution 
acknowledges the DF/HCC Sponsor as having the ultimate authority and responsibility for 
the overall conduct of the study.
Coordinating Center: The entity that provides administrative support to the DF/HCC 
Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol 
document and DSMP, and as specified in applicable regulatory guidelines. In general, the 
Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol.

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DF/HCC Office of Data Quality: A group within DF/HCC responsible for registering 
human subjects for trials, ensuring high-quality standards are used for data collection and 
the ongoing management of clinical trials, auditing, and data and safety monitoring. ODQ 
also coordinates quality assurance efforts related to multi-center clinical research.
2.0
GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general responsibilities:
2.1
DF/HCC Sponsor
The DF/HCC Sponsor, Patrick Y. Wen, MD, will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to:

Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments.

Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.

Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol.

Ensure all Participating Institutions are using the correct version of the protocol.

Ensure that each participating investigator and study team member receives 
adequate protocol training and/or a Site Initiation Visit prior to enrolling participants 
and throughout trial’s conduct as needed.

Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary 
language.

Monitor progress and overall conduct of the study at all Participating Institutions.

Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
(i.e. FDA) reporting requirements are met.

Review data and maintain timely submission of data for study analysis.

Act as the single liaison with FDA (investigator-held IND trials), as applicable.

Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol.

Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor.

Identify and qualify Participating Institutions and obtain accrual commitments prior 
to extending the protocol to that site.

Monitor accrual and address Participating Institutions that are not meeting their 
accrual requirements.

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2.2
Coordinating Center
The general responsibilities of the Coordinating Center may include but are not limited to:

Assist in protocol development

Maintain FDA correspondence, as applicable.

Review registration materials for eligibility and register participants from 
Participating Institutions with DF/HCC ODQ.

Distribute protocol and informed consent document updates to Participating 
Institutions as needed.

Oversee the data collection process from Participating Institutions.

Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violations submitted by Participating Institutions and provide to the 
DF/HCC Sponsor for timely review.

Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the DFCI IRB Adverse Event Reporting Policy to all Participating Institutions.

Provide Participating Institutions with information regarding DF/HCC requirements 
that they will be expected to comply with.

Carry out plan to monitor Participating Institutions either by on-site or remote 
monitoring.

Maintain Regulatory documents of all Participating Institutions which includes but 
is not limited to the following: local IRB approvals/notifications from all 
Participating Institutions, confirmation of Federal Wide Assurances (FWAs) for all 
sites, all SAE submissions, Screening Logs for all sites, IRB approved consents for 
all sites.

Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc) and maintain documentation of all relevant communications.
2.3
Participating Institution
Each Participating Institution is expected to comply with all applicable federal regulations 
and DF/HCC requirements, the protocol and HIPAA requirements.
The general responsibilities for each Participating Institution may include but are not limited 
to:

Document the delegation of research specific activities to study personnel.

Commit to the accrual of participants to the protocol.

Submit protocol and/or amendments to their local IRB.

Maintain regulatory files as per sponsor requirements.

Provide the Coordinating Center with regulatory documents or source documents as 
requested.

Participate in protocol training prior to enrolling participants and throughout the trial 
as required (i.e. teleconferences).

Update Coordinating Center with research staff changes on a timely basis.

Register participants through the Coordinating Center prior to beginning research

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related activities.

Submit Serious Adverse Event (SAE) reports to local IRB per local requirements 
and to the Coordinating Center, in accordance with DF/HCC requirements.

Submit protocol deviations and violations to local IRB per local requirements and 
to the DF/HCC Sponsor in accordance with DF/HCC requirements.

Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements.

Have office space, office equipment, and internet access that meet HIPAA standards.

Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings.

Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings.
3.0
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
The following section will clarify DF/HCC Requirements and further detail the expectations 
for participating in a DF/HCC Multi-Center protocol.
3.1
Protocol Distribution
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.
3.2
Protocol Revisions and Closures
The Participating Institutions will receive notification of protocol revisions and closures 
from the Coordinating Center. It is the individual Participating Institution’s responsibility 
to notify its IRB of these revisions.

Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB approved 
and implemented within 90 days from receipt of the notification.

Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc. Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval.

Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating Center. 
Closures and holds will be effective immediately. In addition, the Coordinating 
Center, will update the Participating Institutions on an ongoing basis about protocol 
accrual data so that they will be aware of imminent protocol closures.

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3.3
Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for Participating Institutions. The Participating Institution consent form must follow 
the consent template as closely as possible and should adhere to specifications outlined in 
the DF/HCC Guidance Document on Model Consent Language for PI-Initiated Multi-Center 
Protocols. This document will be provided separately to each Participating Institution.
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB for all consent 
versions.
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form for 
therapeutic protocols. Participating institutions must follow the DF/HCC requirement that 
only attending physicians obtain informed consent and re-consent to interventional trials 
(i.e. drug and/or device trials).
3.4
IRB Documentation
The following must be on file with the Coordinating Center:

Initial approval letter of the Participating Institution's IRB

Copy of the Informed Consent Form(s) approved by the Participating Institution’s IRB

Participating Institution’s IRB approval for all amendments

Annual approval letters by the Participating Institution’s IRB
3.5
IRB Re-Approval
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals.
The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval date.
3.6
Participant Confidentiality and Authorization Statement
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPAA). Any 
information, related to the physical or mental health of an individual is called Protected 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed.
In order for covered entities to use or disclose protected health information during the course 
of a study, the study participant must sign an authorization statement. This authorization 

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statement may or may not be separate from the informed consent document. The 
Coordinating Center, with the approval from the DFCI IRB, will provide a consent template, 
with information regarding authorization for the disclosure of protected health information.
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in 
its trials. However, because of the nature of these trials, certain protected health information 
must be collected. DF/HCC has chosen to use authorizations, signed by the participant in 
the trial, rather than limited data sets with data use agreements.
3.6.1 DF/HCC Multi-Center Protocol Confidentiality
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should 
be de-identified. It is recommended that the assigned DF/HCC ODQ case number (as 
described below) be used for all participant specific documents. Participant initials may be 
included or retained for cross verification of identification
3.7
DF/HCC Multi-Center Protocol Registration Policy
Eligible participants will be registered onto trial with the DF/HCC Office of Data 
Quality (ODQ) central registration system (by a Coordinating Center specialist, if 
participant is at a non-DF/HCC site). An initial and second registration must occur prior to 
the initiation of protocol therapy. Any participant not registered to both the master protocol 
and assigned arm before protocol therapy begins will be considered ineligible and 
registration will be denied.
A qualified member of the study team will confirm eligibility criteria and complete the 
protocol-specific eligibility checklist.
Issues that would cause treatment delays should be discussed with the Principal Investigator. 
If a participant does not receive protocol therapy following registration, the participant’s 
protocol status must be changed. Notify the ODQ Registrar (a Coordinating Center study 
coordination, if participant is at a non-DF/HCC site) of participant status changes as soon 
as possible.
In order to register a participant onto study, the following must be done:

Obtain written informed consent to master INSIGhT screening procedures from the 
participant prior to the performance of any study related procedures or assessments.

Complete the master INSIGhT initial registration eligibility checklist using the 
eligibility assessment documented in the participant’s medical/research record. To be 
eligible for initial registration to the study, the participant must meet each 
inclusion and exclusion criteria listed on the eligibility checklist (in accordance 
with section 3 of master INSIGhT protocol).

Once initial registration to master INSIGhT protocol is processed, participants’ 
INSIGhT randomization assigned will be received by the treating study team.

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
Obtain written informed consent to assigned sub-study.

Complete the assigned sub-study registration eligibility checklist.
Treatment may not begin without confirmation from the Coordinating Center 
that the participant has completed both initial and second registrations.
Randomization can only occur during ODQ’s normal business hours, Monday through 
Friday from 8:00 AM to 5:00 PM Eastern Time.
3.7.1 Participant Registration and Randomization at a non-DF/HCC Site
To register a participant at any non-DF/HCC site, the subsequent procedure is to be 
followed:
1. The participating site’s data manager/coordinator/research nurse should contact a 
DFCI Neuro-Oncology Coordinating Center team member via telephone or email 
to:

Notify regarding the pending registration

Confirm the methods of sending documents and communication for registration

Communicate desired timeline of the registration (i.e. within the hour, the next 
day).
Multi-Center DFCI Neuro-Oncology Designee contact information: E-
mail: NeuroOnc_Coor@dfci.harvard.edu
Telephone: 617-582-7101
2. The data manager/coordinator/research nurse should then send the following 
documents to the Coordinating Center specialist:

Completed DF/HCC study specific Eligibility Screening Worksheet

Copy of protocol required test results (e.g. coagulation studies, hematology 
panel, serum pregnancy test, serum chemistry panel, urinalysis -- all as 
applicable per protocol)

Copy of the pathology and surgical reports

List of current concomitant medications (obtained within the protocol- 
specified screening window) including sign/date by RN/other clinician and 
documentation of when reviewed/confirmed with patient

Copy of signed informed consent form

Copy of signed HIPAA authorization form (if separate from the informed 
consent document)

Copy of clinic note(s) and other medical records that document consenting 
process, screening and eligibility, if available***
Documents will be transmitted via one of the following methods:

Scanned and emailed to: NeuroOnc_Coor@dfci.harvard.edu or direct email 
of Coordinating Center specialist

Faxed to: 617-394-2683

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*** The Coordinating Center Specialists would like to review and monitor participant 
eligibility, informed consent, screening and baseline assessments on all participants. 
Providing an incomplete set of source documents prior to registration may delay registration. 
Participating Institutions will work with the Coordinating Center Specialists to determine 
what documents may feasibly be available for review prior to enrollment, and these documents 
are to be provided for pre-enrollment review. A complete set of documents will be provided 
to the Coordinating Center after registration; the timeline will be determined by the 
Coordinating Center Specialist based on the study team’s experience with the trial and prior 
monitoring findings. If there are persistent issues with eligibility at a site or with a study 
overall, the Coordinating Center may require that all source documentation relevant to 
participant eligibility be provided prior to proceeding with participant registration.
3. After having received all transferred documentation, the Designee (Coordinating 
Center specialist) will review the documents to verify eligibility, and notify the 
participating site of the result.
4. The Designee (Multi-Center Coordinating Center specialist) will register the 
participant with ODQ Registrar (who validates eligibility and registers the 
participant onto study), and subsequently inform the participating site of the 
successful registration via Fax or email, to include:

Participant case number

Applicable Dose Treatment level and treatment arm assignment
5. The Designee (Multi-Center Coordinating Center specialist) will follow-up to 
confirm registration.
3.7.2 Initiation of Therapy
Participants must be registered with the DF/HCC ODQ before receiving treatment. 
Treatment may not be initiated until the Participating Institution receives confirmation of 
the participant’s registration from the Coordinating Center. Therapy must be initiated per 
protocol guidelines. The DF/HCC Sponsor and DFCI IRB must be notified of any violations 
to this policy.
3.7.3 Eligibility Exceptions
The DF/HCC ODQ will make no exceptions to the eligibility requirements for a protocol 
without DFCI IRB approval. The DF/HCC ODQ requires each participating institution to 
fully comply with this requirement.
3.8
DF/HCC Protocol Case Number
At the time of registration, ODQ requires the following identifiers for all subjects: initials, 
date of birth, gender, race and ethnicity. Once eligibility has been established and the 
participant successfully registered, the participant is assigned a unique protocol case 

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number. 
Participating 
Institutions 
should 
submit 
all 
de-identified 
subsequent 
communication and documents to the Coordinating Center, using this case number to 
identify the subject.
3.9
Protocol Deviations, Exceptions and Violations
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible 
for reporting to the DFCI IRB.
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy 
for reporting to their local IRB.
3.9.1 Definitions
Protocol Deviation: Any departure from the defined procedures set forth in the IRB- 
approved protocol which is prospectively approved prior to its implementation.
Protocol Exception: Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria.
Protocol Violation: Any protocol deviation that was not prospectively approved by the IRB 
prior to its initiation or implementation.
3.9.2 Reporting Procedures
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 
and violations. The DF/HCC Sponsor will also be responsible for ensuring that all protocol 
violations/deviations are promptly reported per DFCI IRB guidelines.
Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 
Center who will then submit the deviation request to the Overall PI and DFCI IRB. Upon 
DFCI IRB approval the deviation is submitted to the Participating Institution IRB, per 
institutional policy. A copy of the Participating Institution’s IRB report and determination 
will be forwarded to the Coordinating Center within 10 business days after the original 
submission.
Protocol violations occurring at a Participating Institution will be submitted to that site’s 
own IRB per the IRB’s reporting policy. Whether or not a violation needs to be reported to 

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the local IRB, notification to the Coordinating Center of any violation should occur in a 
timely manner. If a report is made to the Participating Institution’s IRB, the report and 
determination should also be forwarded to the Coordinating Center in a timely manner.
Coordinating Center: Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for 
review. Subsequently, the Participating Institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines.
3.10 Safety Assessments and Toxicity Monitoring
The study teams at all participating institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events that 
occur during the course of a study help ensure the continuing safety of study participants.
All participants receiving investigational agents will be evaluated for safety. The safety 
parameters include all laboratory tests and hematological abnormalities, physical 
examination findings, and spontaneous reports of adverse events reported by participants. 
All toxicities encountered during the study will be evaluated according to the NCI criteria 
specified in the protocol. Life-threatening toxicities must be reported immediately to the 
DF/HCC Sponsor via the Coordinating Center and IRB, both DFCI and local as applicable.
Additional safety assessments and toxicity monitoring will be outlined in the protocol.
3.10.1 Guidelines for Reporting Serious Adverse Events
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol section 5 of each sub-study appendix.
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB Advert Event Reporting Policy.
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting Requirements. 
Participating Intuitions will review and submit to their IRB according to their institutional 
policies and procedures.
3.10.2 Guidelines for Processing IND Safety Reports
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety 
Reports are distributed to the Participating Institutions. Participating Institutions will review 
and submit to their IRB according to their intuitional policies and procedures.

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3.11 Data Management
The DF/HCC CTRIO develops case report forms (eCRFs), for use with the protocol. These 
forms are designed to collect data for the study. The DF/HCC CTRIO provides a web based 
training for eCRF users.
3.11.1 Data Forms Review
Data submissions are monitored for timeliness and completeness of submission. 
Participating Institutions are notified of their data submission delinquencies in accordance 
with the following:
Incomplete or Questionable Data
If study forms are received with missing or questionable data, the submitting institution will 
receive a written or electronic query from the DF/HCC ODQ Data Analyst, Coordinating 
Center or designee. Responses to all queries should be completed and submitted within 14 
calendar days. Responses may be returned within the electronic data capture (eDC) system.
Missing Forms
If study forms are not submitted on schedule, the Participating Institution will receive a 
Missing Form Report from the Coordinating Center noting the missing forms. These reports 
are compiled by the DF/HCC ODQ and distributed on a monthly basis. Timelines for data 
submission based on form type are defined in protocol section 12.1.2.
4.0
REQUISITIONING INVESTIGATIONAL DRUG
The ordering of investigational agents is specified in section 6 of each sub-study appendix.
5.0
MONITORING: QUALITY CONTROL
Monitoring and oversight of a clinical trial are federally mandated for all IND held trials. 
This quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy and the protection of the rights and welfare of participants. The 
Coordinating Center, with the aid of the ODQ, provides quality control oversight for the 
protocol.
5.1 Ongoing Monitoring of Protocol Compliance
The Participating Institutions may be required to submit participant source documents to the 
Coordinating Center for monitoring. Participating Institutions may also be subject to on- 
site monitoring conducted by the Coordinating Center.
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data 
quality, and participant safety. Monitoring will occur before the clinical phase of the 
protocol begins, continue during protocol performance and through study completion. 

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Additional monitoring practices may include but are not limited to; source verification, 
review and analysis of the following: eligibility requirements of all participants , informed 
consent procedures, adverse events and all associated documentation, study drug 
administration/treatment, regulatory files, protocol departures, pharmacy records, response 
assessments, and data management.
Interim monitoring visits will occur on the following schedule:

Once a site has registered a participant, up until all participants (and planned 
participants) have discontinued taking study agent (may be in follow-up), interim 
monitoring visits will occur at least twice per year. The first interim monitoring visit 
will occur approximately two months after the registration of the site’s first 
participant.

Once a site is closed to accrual and all participants have discontinued study agent, 
interim monitoring visits will occur virtually, and on-site as needed.
On-Site Monitoring: On-site monitoring will occur on a regular basis. Participating 
Institutions will be required to provide access to participants’ complete medical record and 
source documents for source documentation verification during the on-site visit. In 
addition, upon request from a monitor or auditor, Participating Institutions should provide 
access to regulatory documents, pharmacy records, local policies related to the conduct of 
research, and any other trial-related documentation maintained by the participating site. If 
there are concerns for protocol compliance, issues that impact subject safety or the integrity 
of the study are found, or trends identified based on areas of need, additional monitoring 
visits may be scheduled.
Virtual Monitoring: The Coordinating Center will request source documentation from 
participating Institutions as needed to complete monitoring activities. Participating 
Institutions will be asked to forward copies of participants’ medical record and source 
documents to the Coordinating Center to aid in source documentation verification.
Regular all-sites teleconferences will be hosted on a monthly basis by the Coordinating 
Center (unless otherwise specified by the Overall PI). During the teleconferences, sites 
should convey the following information:

Updates on participants: holds, dose reductions, significant events, how participant is 
doing, date of progression and date of death when available and if not already 
communicated to the Coordinating Center

Protocol status: which version is being used, and the status of any amendments

Any Reportable Adverse Events or Deviations/violations that have yet to be 
communicated to the Coordinating Center (informing the sponsor should not wait for 
the call, and the call does not supplant communicating the events via the regular email 
methods of communication).

Review of prospective participants
If sites are not able to have a representative participant, they should email this information 
to the Coordinating Center. During the teleconferences, the Coordinating Center may 
discuss any or all of the following information:

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
Accrual/enrollment updates

Pending amendments

Safety reports circulated or to be circulated

ODQ-generated numbers and percentage of missing of missing forms, number of 
open queries with date of oldest open query, and, for participants on treatment, the 
date of their last study agent form

Review of new deviations, violations

Review of recently received expedited adverse events
5.2 Evaluation of Participating Institution Performance
5.2.1 Monitoring Reports
The DF/HCC Sponsor will be provided with all monitoring reports for on-site and remote 
monitoring of Participating Institutions for review to ensure protocol compliance. The 
DF/HCC Sponsor may increase the monitoring activities at Participating Institutions that 
are unable to comply with the protocol, DF/HCC Sponsor requirements or federal and local 
regulations. Participating Institutions may also be subject to an audit as determined by the 
DF/HCC Sponsor.
5.3
Accrual Monitoring
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each participating institution. Accrual will be monitored for each 
participating institution by the DF/HCC Sponsor or designee. Sites that are not meeting 
their accrual expectations may be subject to termination.
As this is a Phase II study, Participating Institutions accrual requirement of 5 participants 
per site annually will be implemented.
6.0
AUDITING: QUALITY ASSURANCE
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards 
and procedures were followed. Auditing is the systematic and independent examination of 
all trial related activities and documents. Audits determine if evaluated activities were 
appropriately conducted and whether data was generated, recorded and analyzed, and 
accurately reported per the protocol, Standard Operating Procedures (SOPs), and the Code 
of Federal Regulations (CFR).
6.1 Audit Plan: DF/HCC Sponsored Trials
One on-site audit will be scheduled by the ODQ, assuming at least three participants have 
been treated on protocol at the site. Approximately 3-4 participants would be audited at the 
site over a 2 day period. If violations which impact participant safety or the integrity of the 
study are found, more participant records may be audited.

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6.2 Audit Notification
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve this 
protocol. All institutions will forward a copy of final audit and/or re-audit reports and 
corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after the 
audit date.
6.3 Audit Reports
The DF/HCC Sponsor will review all final audit reports and corrective action plans if 
applicable. The Coordinating Center, must forward these reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. Based upon the audit 
assessments the DF/HCC Audit Committee could accept or conditionally accept the audit 
rating and final report. Conditional approval could require the DF/HCC Sponsor to 
implement recommendations or require further follow-up. For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the DFCI IRB as applicable.
6.4 Participating Institution Performance
The DF/HCC Sponsor and DFCI IRB are charged with considering the totality of an 
institution’s performance in considering institutional participation in the DF/HCC Multi- 
Center protocol.
6.4.1 Corrective Actions
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely and accurate data, adherence to protocol requirements, and compliance with state and 
federal regulations, may be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during the 
probation period that deficiencies have been corrected, as evidenced by the improved 
performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation. A 
DF/HCC Sponsor and/or the DFCI IRB may terminate a site’s participation if it is 
determined that a site is not fulfilling its responsibilities as described above.

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APPENDIX C
INFORMATION ON POSSIBLE DRUG INTERACTIONS
See section 3 of each sub-study appendix for details for detailed instructions on concomitant 
medications, including use in clinically required situations.
Please note that these lists may not be comprehensive.
Table 1: List of CYP3A Inhibitors and CYP3A Inducers
CYP3A4,5,7 inhibitors
CYP3A4,5,7 inducers
indinavir1
carbamazepine
nelfinavir1
efavirenz
ritonavir1
nevirapine
clarithromycin1
phenobarbital
itraconazole1
phenytoin
ketoconazole1
pioglitazone
nefazodone1
rifabutin
erythromycin2
rifampin
grapefruit juice2
St. John’s Wort
verapamil2
troglitazone
suboxone2
diltiazem2
cimetidine3
amiodarone
NOT azithromycin
flyvoxamine
troleandomycin
voriconazole
1. A Strong inhibitor is one that causes a > 5-fold increase in the plasma AUC values or more than 80% decrease in 
clearance. Strong inhibitors are prohibited per section 3 of each sub-study appendix.
2. A Moderate inhibitor is one that causes a > 2-fold increase in the plasma AUC values or 50-80% decrease in 
clearance.
3. A Weak inhibitor is one that causes a > 1.25-fold but < 2-fold increase in the plasma AUC values or 20-50% 
decrease in clearance.
This list of CYP3A inhibitors and inducers was compiled from the Indiana University School of Medicine’s P450 Drug 
Interaction Table: Abbreviated “Clinically Relevant” Table. For the most comprehensive and up-to-date list, go to 
http://medicine.iupui.edu/clinpharm/ddis/ .
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of 
Medicine (2007). "/clinpharm/ddis/clinical-table/" Accessed October 2015

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Table 2: List of CYP450 Substrates to be used with caution
CYP1A2
CYP2B6
CYP2C8
CYP2C9
CYP2D6
CYP3A4,5,7
clozapine
artemisinin
paclitaxel
NSAIDs:
Beta Blockers:
Macrolide antibiotics:
cyclobenzaprine
bupropion
torsemide
diclofenac
carvedilol
clarithromycin
duloxetine
cyclophosphamide
amodiaquine
ibuprofen
S-metoprolol
erythromycin
fluvoxamine
efavirenz
cerivastatin
naproxen
propafenone
NOT azithromycin
haloperidol
Iiosfamide
repaglinide
piroxicam
timolol
telithromycin
imipramine
ketamine
Oral Hypoglycemics:
Antidepressants:
Anti-arrhythmics:
mexiletine
meperidine
tolbutamide
amitriptyline
quinidine→3-OH
nabumetone
methadone
glipizide
clomipramine
Benzodiazepines:
naproxen
nevirapine
glyburide
desipramine
alprazolam
olanzapine
propofol
Angiotensin II Blockers:
duloxetine
diazepam→3-OH
riluzole
selegiline
iosartan
fluoxetine
midazolam
tacrine
irbesartan
imipramine
triazolam
theophylline
Others:
paroxetine
Immune Modulators:
tizanidine
celecoxib
Antipsychotics:
cyclosporine
triamterene
fluvastatin
haloperidol
tacrolimus
zileuton
phenytoin
risperidone
sirolimus
zolmitriptan
rosiglitazone
thioridazine
HIV Antivirals:
torsemide
Others:
indinavir
valproic acid
aripiprazole
ritonavir
warfarin
atomoxetine
saquinavir
zafirlukast
codeine
nevirapine
dextromethorphan
Prokinetics:
doxepine
cisapride
flecainide
Antihistamines:
mexiletine
astemizole
ondansetron
chlorpheniramine
oxycodone
Calcium Channel 
Blockers:
risperidone
amlodipine
tamoxifen
diltiazem
tramadol
felodipine
venlafaxine
nisoldipine
nitrendipine
verapamil
HMG CoA Reductase 
Inhibitors:
atorvastatin
lovastatin
NOT pravastatin
NOT rosuvastatin
simvastatin
PDE-5 Inhibitors:

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sildenafil
tadalafil
vardenafil
Others:
alfentanyl
aripiprazole
Boceprevir
busprione
carbamazepine
gleevec
haloperidol
pimozide
quinine
tamoxifen
telaprevir
trazodone
vincristine
This list of CYP substrates was compiled from the Indiana University School of Medicine’s P450 Drug Interaction Table: 
Abbreviated “Clinically Relevant” Table. For the most comprehensive and up-to-date list, go to 
http://medicine.iupui.edu/clinpharm/ddis/ .
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine 
(2007). "/clinpharm/ddis/clinical-table/" Accessed October 2015

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APPENDIX D
RECOMMENDED MRI ACQUISITION PROTOCOL
Brain MRI will be acquired at baseline and every 8 weeks after treatment initiation as detailed in 
Study Calendars. All MRI exams will be performed based on standardized parameters 
recommended by the Jumpstarting Brain Tumor Drug Development Coalition Imaging 
Standardization Steering Committee (Ellingson et al. Neuro Oncol. 2015 Sep;17(9):1188-98).
The following sequences are included: (i) parameter-matched precontrast and postcontrast 
inversion recovery-prepared, isotropic 3D T1-weighted gradient-recalled echo; (ii) axial 2D T2- 
weighted turbo spin-echo acquired after contrast injection and before postcontrast 3D T1- 
weighted images to control timing of images after contrast administration; (iii) precontrast, axial 
2D T2-weighted fluid-attenuated inversion recovery; and (iv) precontrast, axial 2D, 3-directional 
diffusion-weighted images. The T2-weighted sequence should be performed following contrast 
injection, before acquisition of T1-weighted post-contrast sequences. The protocol can also 
include additional advanced imaging sequences such as perfusion weighted imaging (PWI) and 
susceptibility weighted imaging (SWI). Detailed parameters are listed in Table below.
When possible, MRI exams should be done using the same MRI scanner for each subject. If this 
is not achievable, patients should at the very least be scanned on MRI scanners with the same 
field strength (1.5T or 3T). The chemical composition and dose of gadolinium contrast agents 
should also be the same for each patient during trial and should be explicitly documented on the 
MR system during acquisition or labeled in the DICOM header.
Table: MRI Protocol
1. Localizer
2. Axial 3D T1w (IR-GRE)1
3. Ax 2D FLAIR2
4. Ax 2D SS-EPI DWI3
5. Ax GRE or Ax SWI
6. Contrast Injection
7. Ax EPI Perfusion
8. Ax 2D SE T2w4
9. Axial 2D SE T1w
10. Axial 3D T1w (IR-GRE)1
Sequence
Plane
TSEc
Axial
SS-EPIg
Axial
Contrast
Axial
Injectiona
TSEc
Sagittal/axial
IR-GREe,f
Mode
2D
2D
2D
3D

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TR [ms]
2100, TI [ms] 1100, Flip angle 10°–15°, Frequency ≥172, Phase ≥172, 
NEX ≥1, FOV 256 mm, Slice thickness ≤1.5 mm. Gap/spacing 0, Parallel imaging up to 
2x
TR [ms]
>6000, TE [ms],
100–140, TI [ms] 2000–2500, Flip angle 90°/≥160°,
Frequency ≥256, Phase ≥256, NEX ≥1, FOV 240 mm, Slice thickness ≤4 mm, 
Gap/spacing 0, Parallel imaging up to 2x
TR [ms]
>5000, TE [ms] , Flip angle 90°/180°, Frequency ≥128, Phase ≥128, NEX
≥1, FOV 240 mm, Slice thickness ≤4 mm, Gap/spacing 0, Parallel imaging up to 2x, b = 
0, 500, 1000 s/mm2 ≥3 directions
TR [ms]
>2500, TE [ms],
80–120, Flip angle 90°/≥160°, Frequency ≥256, 
Phase ≥256, NEX ≥1, FOV 240 mm, Slice thickness ≤4 mm, Gap/spacing 0, Parallel 
imaging up to 2x. Post-contrast sequence (10) should be obtained within 8 minutes from 
time of contrast injection.

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APPENDIX E CONTROL ARM OF INSIGHT
TABLE OF CONTENTS
1.
BACKGROUND ..................................................................................................................78
1.1
Temozolomide ......................................................................................................................78
2.
PARTICIPANT SELECTION..............................................................................................80
2.1
Eligibility Criteria Specific to the Control Arm....................................................................80
2.2
Second INSIGhT Registration: Registration to Control Arm ...............................................80
2.2.1
Registration Process for DF/HCC Institutions......................................................................80
2.2.2
Registration Process for Other Investigative Sites................................................................80
3.
TREATMENT PLAN...........................................................................................................81
3.1
Definition of Standard Radiation Therapy............................................................................81
3.2
Concomitant Temozolomide during Radiation Therapy.......................................................82
3.3
Rest Phase .............................................................................................................................82
3.4
Adjuvant (Post-Radiation) Temozolomide...........................................................................83
3.5
General and Concomitant Medication and Supportive Care Guidelines ..............................83
3.6
Criteria for Taking a Participant Off Protocol Therapy........................................................84
3.7
Duration of Follow Up..........................................................................................................85
3.8
Criteria for Taking a Participant Off Study ..........................................................................85
4.
DOSING DELAYS/DOSE MODIFICATIONS...................................................................85
4.1
Anticipated Toxicities...........................................................................................................86
4.1.1
Anticipated Toxicities for Radiation Therapy.......................................................................86
4.1.2
Anticipated Toxicities for Temozolomide ............................................................................87
4.2
Dose Modifications/Delays for Temozolomide....................................................................87
5.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS.................................90
5.1
Expected Toxicities...............................................................................................................90
5.2
Adverse Event Characteristics ..............................................................................................90
5.3
Expedited Adverse Event Reporting.....................................................................................91
5.4
Expedited Reporting to the Food and Drug Administration (FDA)......................................93
5.5
Expedited Reporting to Hospital Risk Management.............................................................93
5.6
Routine Adverse Event Reporting.........................................................................................93
6.
PHARMACEUTICAL INFORMATION - Temozolomide.................................................93
6.1.2
Form......................................................................................................................................93
6.1.3
Storage and Stability .............................................................................................................94
6.1.4
Compatibility ........................................................................................................................94
6.1.5
Handling................................................................................................................................94
6.1.6
Availability ...........................................................................................................................94
6.1.7
Preparation............................................................................................................................94
6.1.8
Administration ......................................................................................................................94
6.1.9
Ordering................................................................................................................................94
8.
MEASUREMENT OF EFFECT ..........................................................................................98

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9.
REFERENCES .....................................................................................................................98
10.
DFCI REPORTABLE AE COVERSHEET – INSIGHT CONTROL ARM...................100
11.
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION 
THERAPY........................................................................................................................................101
12.
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY FOLLOWING 
RADIATION THERAPY ................................................................................................................105

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1. BACKGROUND
1.1
Temozolomide
Background and preclinical data
Temozolomide is a member of the imidazotetrazine family that is structurally related to the 
alkylating agent dacarbazine and has shown efficacy against a variety of cancers, including high 
grade gliomas.
Under physiologic conditions, temozolomide is spontaneously converted to its active metabolite 
MTIC (5-(3-dimethyl-1-triazenyl)imidazole-4-carboxamide)1. The breakdown product of MTIC, 
methyldiazonium, is an actively alkylating agent that preferentially methylates guanine residues 
of the DNA molecule, thereby resulting in single and double DNA strand breaks and activation 
of apoptotic pathways.2 Temozolomide has linear and reproducible pharmacokinetics with 100%
p.o. bioavailability within 2 hours of drug administration and a rapid plasma drug clearance with 
a plasma half- life of 1.6-1.8 hours.3
Because of its lipophilic properties, temozolomide penetrates into the central nervous system 
(CNS) and was shown to reach acceptable CNS concentrations. In humans, the CSF penetration 
is estimated to be ~20-30% based on AUCplasma/AUCCSF ratios.4 In several preclinical rodent and 
primate models, it was demonstrated to have activity against CNS tumors thereby stimulating 
interest for investigations in humans.5-8
Clinical data
In these preclinical and clinical phase I studies, temozolomide demonstrated antitumor-activity in 
high-grade gliomas in adults.3,9 Based on these studies, the maximal tolerated dose (MTD) for 
humans has been defined as 150-200 mg/m2 per day depending on whether patients have 
received prior treatment with myelotoxic agensts.3,10,11 For patients with glioblastoma, the 
recommended temozolomide doses are 75 mg/m2 during radiation (concomitant phase) and 150- 
200 mg/m2 for 5 days out of a 28-day cycle for 6 months.4,12 Temozolomide in general is well 
tolerated and the most frequent toxicities are mild to moderate myelosuppression 
(thrombocytopenia and neutropenia) which is predictable and typically resolves spontaneously.
Subsequent phase II studies confirmed the activity of temozolomide against newly diagnosed and 
recurrent high-grade gliomas1,13,14 therefore leading to further evaluation of the drug by the 
European Organization for Research and treatment of Cancer (EORTC) and the National Cancer 
Institute of Cancada (NCIC) in a landmark phase III study15. In this clinical trial the efficacy of 
radiation with concomitant temozolomide followed by six monthly cycles of temozolomide 
compared to radiation alone for newly diagnosed glioblastoma was evaluated15. The combination 
of radiation and temozolomide prolonged median progression free survival from 5 to 6.9 months 
(95% CI 4.2-5.5) and median overall survival from 12.1 to 14.6 months ( 95% CI 11.2-13.0).
Treatment with temozolomide was overall well tolerated with grade 3 or 4 hematoxicity in 16% 
of study participants.
Based on these results, this concomitant use of temozolomide during radiation followed by 
monthly maintenance cycles has been widely accepted as the standard of care treatment for

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patients with newly diagnosed glioblastoma.
MGMT
The tumor suppressor gene MGMT (O6-methylguanine-DNA methyltransferase) on chromosome 
10q26 encodes a DNA-repair enzyme that removes alkyl groups from the O6 position of guanine, 
thereby repairing the lethal DNA-cross links induced by alkylating chemotherapeutic agents such 
as temozolomide16. Glioma cells with diminished MGMT activity are more responsive to the 
alkylating damage of these agents17,18. Epigenetic silencing of the MGMT promoter is present in
~40-68% of high grade gliomas and leads to reduced protein expression and cellular DNA repair 
activity. MGMT promoter methylation is associated with longer survival in patients with high 
grade gliomas treated with alkylating agents19, including temozolomide20,21 Therefore, MGMT 
promoter methylation represents a favorable prognostic marker for high grade gliomas which is 
routinely evaluated in neuropathological practice.
In a retrospective tumor tissue analysis of the patients enrolled in the EORTC/NCIC study, 
MGMT promoter methylation was confirmed to be a favorable prognostic factor for patients 
with glioblastoma.21 It also showed that the therapeutic benefit of temozolomide in addition to 
radiation was most pronounced in patients whose tumors contained a methylated MGMT 
promoter. In this patient group, combined chemoradiation compared to radiation alone prolonged 
progression-free survival from 5.9 (95% CI 5.3-7.7) to 10.3 (95% CI 6.5-14.0) months and
median overall survival from 15.3 (95% CI 13.0-20.9) to 21.7 (95% CI 17.4-30.4) months. In 
contrast, for patients without MGMT promoter methylation the combination of temozolomide 
plus radiation resulted in an only small survival benefit compared to radiation alone (progression 
free survival 4.4 vs, 5.3 months, overall survival 11.8 vs. 12.7 months).
Rationale
These data suggest a correlation between MGMT promoter methylation and treatment response 
to temozolomide. It therefore can be argued that temozolomide is useful only in the MGMT 
methylated setting. However, based on the small subgroup of study patients from the landmark 
EORTC-NCIC study whose tumors were MGMT unmethylated and survived more than 2 years 
(longer than the expected median survival), there seemed to be a survival benefit from combined 
radiation and temozolomide compared to radiation alone.22 In addition, because of issues with 
the reliability of the assay used to assess MGMT status in this EORTC-NCIC study, it has been 
debated whether these patients were incorrectly classified as MGMT unmethylated.
Nevertheless, based on these data, a real albeit marginal benefit from temozolomide even in the 
unmethylated setting cannot be excluded. Therefore, it continues to be common practice to use 
the combination of temozolomide and radiation in all patients with newly diagnosed 
glioblastoma irrespective of MGMT methylation status.

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2. PARTICIPANT SELECTION
2.1
Eligibility Criteria Specific to the Control Arm
Participants must meet all eligibility criteria outlined in the master protocol (section 3) and 
complete initial registration (section 4 of master protocol). Once the randomization assignment 
has been received following initial registration, all participants randomized to the control arm 
must meet the following criteria prior to participating in the control arm of the study.
2.1.1
Participants must be willing and able to provide written informed consent/assent for the 
control arm of the INSIGhT trial.
2.2
Second INSIGhT Registration: Registration to Control Arm
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore®. Registration to the control arm must occur following initial registration to master 
INSIGhT protocol and receipt of randomization assignment, and prior to the initiation of 
protocol therapy. Any participant not registered to their protocol specific assigned arm before 
protocol therapy begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria in section 2.1 of this sub-study appendix and a 
member of the study team will complete the protocol-specific eligibility checklist.
Following initial registration, any additional laboratory assessments prior to start of treatment 
will not be used to re-confirm eligibility. Refer to section 4 of this appendix for toxicity 
management between registration and start of study treatment.
Following second registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore® as soon as possible.
2.2.1
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.
2.2.2
Registration Process for Other Investigative Sites
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
DFCI Coordinating Center staff. All sites should contact the DFCI Coordinating Center to verify 
slot availabilities. A list of the required forms for registration can be found in Appendix B.
Following registration, participants should begin as soon as feasible. Issues that would cause 
treatment delays should be discussed with the Overall PI. If a participant does not receive

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protocol therapy following registration, the participant’s registration on the study must be 
canceled. The Study Coordinator should be notified of cancellations as soon as possible.
Refer to Appendix B, Section 3.7 for registration details.
3. TREATMENT PLAN
Participants treated on this study arm will receive daily radiation (60 Gy in 30 fractions) as 
described in section 3.1 of this appendix with concomitant temozolomide (75 mg/m2/day) daily 
as described in section 3.2, followed by a 28 (+14 days) day break, and followed by six adjuvant 
28-day cycles of temozolomide 150-200 mg/m2/day x 5 days as described in section 3.4.
Temozolomide will be administered on an outpatient basis. The investigator will instruct the 
participant to take the drug exactly as specified in the protocol. No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to treat 
the patient’s malignancy.
Participants will be instructed to fast at least 1 hour before and 1 hour after temozolomide 
administration. Prophylaxis with a 5-HT3 antagonist is recommended prior to administration of 
temozolomide doses and should be administered orally approximately 30 to 60 minutes before 
temozolomide treatment. Temozolomide should be taken with a glass of water and consumed 
over as short a time as possible. Participants should swallow the capsules as a whole and not 
chew them. Additional drug administration instructions, including missed dose policy, are 
described in section 6.1.8 of this appendix and are included in the participant pill diary (section 
11 & section 12 of this appendix).
All dosages prescribed and dispensed to the participant and all dose changes during the study 
must be recorded. If a participant requires a temozolomide dose delay of > 28 days from the 
previous dose, the participant must be discontinued from treatment completely. In the 
exceptional case where the investigator feels the patient would benefit from continuing therapy 
the case can be discussed with the Overall PI Patrick Y. Wen, MD at pwen@partners.org or 617- 
632-2166. Expected toxicities and dose reductions and modifications are detailed in section 4 of 
this appendix.
NOTE: Study treatment may be held > 28 days in order to allow for surgical pathology to 
determine progression versus pseudoprogression outside of the 12-week consideration mark if it 
is prospectively confirmed with Overall PI to be clinically appropriate to do so.
Participants will keep a medication diary (see section 11 & section 12 of this appendix). At the 
end of each cycle, the diary will be returned and a new one will be given to the participant.
3.1
Definition of Standard Radiation Therapy
The patient must undergo MRI based treatment planning (CT with contrast-based planning only 
if patient unable to undergo MRI). At a minimum, the contrast enhancing lesion (and/or surgical 
cavity) defined on a T1-weighted image (gross tumor volume; GTV) must be targeted with a

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minimum of a 1 cm dosimetric margin expansion to define a planning target volume (PTV).
The margin may be reduced around natural barriers to tumor growth, and also to allow sparing of 
organs at risk, if necessary. The PTV volume must be treated to a prescribed dose of 59.4 Gy in 
33 fractions or 60 Gy in 30 fractions. Treatment with larger volumes to the contrast-enhancing 
region is acceptable. Treatment or no treatment of the T2/FLAIR abnormality is acceptable.
Because this is optional, dosimetric expansion and dose-fractionation for the T2/FLAIR volume 
are not specified here. The prescribed dose to the T2/FLAIR volume may not exceed 60 Gy.
Radiation therapy must be completed within an overall treatment time of less than 52 calendar 
days. Maximum dose (defined as a volume greater than 0.03 cc) to critical structures include: 60 
Gy to the brainstem, 56 Gy to the optic chiasm, 55 Gy to the optic nerves, and 50 Gy to the 
retinae.
Participants are permitted to have radiotherapy as described in this section performed at any NCI 
funded cooperative group site without prospective Overall PI approval. Prospective Overall PI 
approval, or approval by his designee (other Coordinating Center radiation oncologists), is 
required for any radiotherapy site that is not an NCI funded cooperative group site. At the 
discretion of the DFCI Coordinating Center, a radiation plan may be requested to be 
prospectively approved for a non-NCI site prior to initiating radiotherapy at the site. Any 
questions regarding permitted sites should be directed to the DFCI Coordinating Center or 
Overall PI Patrick Y. Wen, MD.
3.2
Concomitant Temozolomide during Radiation Therapy
Treatment on concomitant therapy should begin no later than 6 weeks from surgery. 
Temozolomide 75 mg/m2/day will be administered orally on a continuous daily dosing schedule 
for a maximum of 49 days. Temozolomide will be initiated on Day 1 of radiation therapy, and 
the last dose will ideally be the last day of radiation; however, temozolomide may be 
administered for 42 days, or per your site’s institutional policy / standard.
The drug will be administered orally approximately 2-3 hours before each session of 
radiotherapy. During weekends or weekdays without radiotherapy (Saturday and Sunday), the 
drug should be taken in the morning when possible. The dose will be determined using actual 
body surface area (BSA) as calculated in square meters at the beginning of the concomitant 
treatment. The daily dose will be rounded to the nearest 5 mg.
No dose reductions are allowed during the concomitant phase of treatment. If a participant 
experiences a toxicity related to temozolomide during the concomitant phase of treatment, then 
temozolomide dosing will be interrupted according the rules described in Table 4.2 of this 
appendix.
3.3
Rest Phase
During the 28 day (+ 14 days) break after completion of radiotherapy, temozolomide will not be 
administered.

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3.4
Adjuvant (Post-Radiation) Temozolomide
Participants will receive up to 6 cycles of adjuvant temozolomide. Temozolomide will be 
administered orally once per day for 5 consecutive days (Days 1-5) of a 28-day cycle. The 
starting dose for the first adjuvant cycle will be 150 mg/m2/day. If the non-hematologic toxicities 
for Cycle 1 are Grade ≤ 2 (except for alopecia, nausea, vomiting, lymphopenia and constipation), 
absolute neutrophil count (ANC) is ≥ 1.5 x 109/L, and the platelet count is ≥ 100 x 109/L., then 
temozolomide dose may be escalated to 200 mg/m2/day for adjuvant cycle 2 at the discretion of 
the treating investigator. The dose remains at 200 mg/m2/day for subsequent cycles as long as a 
dose reduction is not requires as per Table 4.2. If the dose was not escalated at Cycle 2, 
escalation should not be done in subsequent cycles.
The start of the first adjuvant cycle will be scheduled 28 days (+ 14 days) after the last day of 
radiotherapy. The start of all subsequent cycles (2-6) will be scheduled every 4 weeks (28 days + 
7 days) after the first daily dose of temozolomide of the preceding cycle. The dose will be 
determined using local institutional standard policy. The daily dose will be rounded to the nearest 
5 mg.
3.5
General and Concomitant Medication and Supportive Care Guidelines
Participants should be instructed not to take any additional medications (including over-the- 
counter products) during the trial without prior consultation with the investigator. All 
medications taken from date of consent and up to 30-day follow-up contact should be recorded. 
If concomitant therapy must be added or changed, including over-the-counter medications or 
alternative therapies, the reason and name of the drug/therapy should be recorded.
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
participant are allowed, including drugs given prophylactically (e.g. antiemetics) with the 
following exceptions:
3.5.1
Herbal preparations/medications are not allowed throughout the study. These 
herbal medications include, but are not limited to: St. John’s wort, Kava, ephedra 
(ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, ginseng. Participants should stop using any herbal medications 7 days 
prior to first dose of study drug.
3.5.2
Corticosteroids should be used in the smallest possible dose to control symptoms 
of cerebral edema and mass effect, and discontinued if possible. Chronic dosing 
of corticosteroids is known to induce CYP3A enzymes, thereby increasing the 
risk of reducing abemaciclib drug exposure to sub-therapeutic levels.
3.5.3
Anti-seizure medications should be used as indicated. Only participants receiving 
non-EIAEDs are eligible (although protocol does allow for patients to register and 
initiate treatment with Temodar and radiation therapy while tapering off 
EIAEDs). If for unavoidable clinical reasons (emergency department visit, severe 
allergies, toxicities, etc.) a participant’s AED is switched to another AED, the 
following guidelines must be followed if applicable:
o
Participants should be started on another non-EIAED if at all possible.
o
Participants who are inadvertently and temporarily changed to an EIAED 

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should immediately be changed to an alternative non-EIAED.
o
Participants who need to permanently change anticonvulsant, but who 
cannot change to another non-EIAED, must be discussed with the Overall 
PI.
3.5.4
Febrile neutropenia may be managed according to the local institution's 
guidelines. Measures may include appropriate laboratory testing, including blood 
and urine cultures and the institution of broad-spectrum antibiotics. If a source for 
the fever is not identified or the fever resolves when the neutrophil count 
recovers, antibiotics may be discontinued and the participant observed.
3.5.5
G-CSF: Routine prophylactic use of G-CSF is not permitted. However, 
therapeutic use in participants with serious neutropenic complications, such as 
sepsis, may be considered at the investigator’s discretion.
3.5.6
Antiemetics: The use of antiemetics will be left to the investigators’ discretion.
3.5.7
Pneumocystis jirovecii pneumonia (PJP) prophylaxis: Since participants with 
GBM are at increased risk of developing PJP, especially if they are on 
corticosteroids, prophylaxis for PJP may be considered per institutional practice.
3.5.8
Anticoagulants: Because of the potential for its interaction with study 
medications, warfarin sodium (Coumadin®), or any other coumadin-derivative 
anticoagulant, is not permitted at any dose. Low-molecular weight heparin and Xa 
inhibitors are permitted. If for unavoidable clinical reasons (emergency 
department visit, severe allergy, toxicity, etc) participants are started on warfarin, 
they must change to a low molecular weight heparin immediately in the interest of 
subject safety.
3.5.9
Surgery: If neurosurgical management is required for reasons not due to tumor 
progression, these procedures must be documented, including the indications for 
surgery, the operative note, and pathology report.
3.5.10 Other anticancer or experimental therapies: with the exception of tumor treating 
fields (Optune®), no other anticancer therapy of any kind is permitted during the 
study treatment period. No other drug under investigation may be used 
concomitantly with the study drug.
3.5.11 Other concomitant medications: Therapies considered necessary for the well 
being of the participant may be given at the discretion of the investigator. Other 
concomitant medications should be avoided except for analgesics, chronic 
treatments for concomitant medical conditions, or agents required for life- 
threatening medical problems. All concomitant medications must be recorded.
3.6
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for 
6 adjuvant cycles on the control arm or until one of the following criteria applies:

Disease progression

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
Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply. The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
An ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the ODQ website or obtained from the ODQ 
registration staff.
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Patrick Y. Wen, MD, at 617-632-2166 or pwen@partners.org.
3.7
Duration of Follow Up
Participants will be followed until death with monthly visits, telephone contact, or medical 
record review. Participants removed from protocol therapy for unacceptable adverse event(s) 
will be followed until resolution or stabilization of the adverse event. Refer to section 7 study 
calendar within this appendix for follow-up requirements and time points.
3.8
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).
An ODQ Treatment Ended/Off Study Form will be filled out when a participant comes off study. 
This form can be found on the ODQ website or obtained from the ODQ registration staff.
4. DOSING DELAYS/DOSE MODIFICATIONS
For participants who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the participant on study drug. If administration of 
temozolomide must be interrupted because of unacceptable toxicity, drug dosing will be 

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interrupted or modified according to rules described in Table 4.2 of this appendix.
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.03 can be downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
In the case of toxicity, appropriate medical treatment should be used (including anti-emetics, 
anti-diarrheals, etc.).
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and the 30 day post study visit. Participants continuing to 
experience toxicity at the end-of treatment visits may be contacted for additional assessments 
until the toxicity has resolved or is deemed irreversible.
Temozolomide dose reductions are allowed only during the adjuvant cycles. No dose reductions 
are allowed during the concomitant phase of treatment. If a participant experiences a toxicity 
related to temozolomide during the concomitant phase of treatment, then temozolomide dosing 
will be interrupted according the rules described in Table 4.2 of this appendix.
4.1
Anticipated Toxicities
In order for an event to be considered expected (known correlation to study drug/treatment) for the 
purposes of adverse event reporting, the event must be included in this section or be included in 
the package insert or the informed consent document as a potential risk.
NOTE: For events that are secondary to an event deemed expected with a study agent/modality (e.g. 
rectal pain or hypokalemia as a result of diarrhea or gait disturbance as a result of edema cerebral), 
please record as “possibly related to” and “expected with” the agent/modality.
4.1.1
Anticipated Toxicities for Radiation Therapy
A list of adverse events of all grades suspected to be radiation therapy treatment related, 
organized by CTCAE v4.03 category, includes:

EAR AND LABYRINTH DISORDERS – external ear inflammation; other: dryness 
of ear canal; other: hardening of ear canal wax; external ear pain; other: hearing loss

ENDOCRINE DISORDERS - other: hypophysitis, or hypopituitarism

EYE DISORDERS – cataract; other: decreased vision

GASTROINTESTINAL DISORDERS – nausea; vomiting

GENERAL DISORDERS – fatigue

INJURY, POISONING AND PROCEDURAL COMPLICATIONS – dermatitis 
radiation; injury other: optic nerve

INVESTIGATIONS –lymphocyte count decreased

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS – generalized 
muscle weakness*

NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED – treatment related 

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secondary malignancy

NERVOUS SYSTEM DISORDERS – headache; seizure; memory impairment; 
cognitive disturbance; somnolence; dysgeusia; central nervous system necrosis; 
edema cerebral; other: tumor inflammation**

PSYCHIATRIC DISORDERS – personality change

SKIN AND SUBCUTANEOUS TISSUE DISORDERS – scalp pain; other: scalp 
redness; alopecia
4.1.2
Anticipated Toxicities for Temozolomide
A list of adverse events of all grades suspected to be temozolomide treatment related, 
organized by CTCAE v4.03 category, includes:

BLOOD AND LYMPHATIC SYSTEM DISORDERS – anemia; febrile neutropenia; 
bone marrow hypocellular

GASTROINTESTINAL DISORDERS – constipation; nausea; vomiting; diarrhea

GENERAL DISORDERS – gait disturbance; fatigue

IMMUNE SYSTEM DISORDERS – allergic reaction

INJURY, POISONING AND PROCEDURAL COMPLICATIONS – bruising; 
hemorrhage

INVESTIGATIONS – neutrophil count decreased; lymphocyte count decreased;
white blood cell decreased; platelet count decreased

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS – generalized 
muscle weakness*

NERVOUS SYSTEM DISORDERS – dizziness; memory impairment; headache; 
seizure

PSYCHIATRIC DISORDERS – insomnia

REPRODUCTIVE SYSTEM AND BREAST DISORDERS – infertility

SKIN AND SUBCUTANEOUS TISSUE DISORDERS – alopecia
*   “Generalized muscle weakness” to also include other CTCAE terms inclusive of a muscle weakness
** As CTCAE v. 4 recognizes ‘Edema cerebral’ only as a Gr4 event, please record events of ‘Edema 
cerebral’ deemed by Investigator to be Gr1-Gr3 or Gr5 as ‘Nervous system disorders, Other: Tumor 
inflammation’ (Gr1-Gr3 or Gr5, accordingly).
4.2
Dose Modifications/Delays for Temozolomide
4.2.1
When treatment must be held pending resolution of toxicity to grade 1 or return to 
baseline, and the toxicity is a non-hematologic lab abnormality, in cases where 
participant had a pre-existing non-hematologic laboratory abnormality at baseline, the 
toxicity can be considered “resolved” from a hold perspective when it has resolved to 
within 1 grade of the baseline value.
NOTE: For the purposes of data entry, values from screening assessments should be 
entered in as ‘baseline’ values. However, true “baseline values” - for the purpose of 
dose modifications on study, etc. - will be considered the last assessments/tests 
performed prior to initiation of study therapy.

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EXCEPTION: In instances where the value within 1 grade of the baseline value would 
still require a hold, continue to hold until resolution of toxicity to grade 1 or return to 
baseline.
4.2.2
Participants who experience an adverse event that requires a treatment delay or dose 
reduction should be monitored with appropriate laboratory testing or other clinical 
evaluation at least weekly until resolution.
4.2.3
Participants cannot be treated below dose level -1. If a participant whose temozolomide 
dose has been reduced to dose level -1 and requires another dose reduction, treatment on 
study must be stopped unless the participant has benefited from the study, in which case 
the investigator will contact the overall Principal Investigator, Dr. Patrick Y. Wen, to 
determine if the participant will remain in the study.
4.2.4
A treatment delay of up to 28 days is permitted. If the toxicity has not resolved after a 4- 
week delay, the participant must be removed from study treatment unless the participant 
has benefited from the study, in which case the investigator may contact the Overall 
Principal Investigator, Dr. Patrick Y. Wen, to determine if the participant will remain in 
the study.
4.2.4.1
NOTE: Study treatment may be held > 28 days in order to allow for surgical 
pathology to determine progression versus pseudoprogression outside of the 12-week 
consideration mark if it is prospectively confirmed with Overall PI to be clinically 
appropriate to do so.
4.2.5
Dose re-escalation (after dose reduction for toxicity) is never permitted in this study.
4.2.6
Study teams are not required to hold for lymphopenia.
4.2.7
Participants whose treatment is interrupted or permanently discontinued due to an 
adverse event or clinically significant laboratory value, must be followed as outlined in 
Table 4.2 of this appendix, at least once a week for 4 weeks, and subsequently at 4-week 
intervals, until resolution or stabilization of the event, whichever comes first. All 
participants must be followed for adverse events and serious adverse events for 30 days 
following the last dose of temozolomide. All SAEs must be reported as detailed in 
Section 5.3 of this appendix.
Adjuvant Temozolomide Dose Levels
Dose Level
Dose of 
Temozolomide 
(mg/m2/day)
Remarks
1
200
Escalated dose for adjuvant cycle 2*
0
150
Starting dose for adjuvant cycle 1
-1
100

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* Dose may be escalated to 200 mg/m2/day beginning adjuvant cycle 2 at the discretion 
of the treating investigator if the non-hematologic toxicities for Cycle 1 are Grade ≤ 2 
(except for alopecia, nausea, vomiting, lymphopenia and constipation), absolute 
neutrophil count (ANC) is ≥ 1.5 x 109/L, and the platelet count is ≥ 100 x 109/L.
Table 4.2: Criteria for dose-modification and re-initiation of Temozolomide treatment
For toxicities attributable to temozolomide (considered at least possibly related), Table 4.2 
should be adhered to as noted below. When the treating investigator feels that a hold or 
reduction of temozolomide is warranted for patient safety even though the toxicity is unrelated to 
temozolomide, discussion with the Overall Principal Investigator and Study Sponsor, Patrick Y. 
Wen, MD is strongly recommended.
Toxicity
(organized per CTCAE v 
4.03)
Concomitant Temozolomide
Adjuvant Temozolomide
Neutropenia
- Grade 2 (ANC 1.0 -  1.4 
x 109/L)
Interrupt until resolved to ≤ grade 
1, then resume TEMOZOLOMIDE at 
the current dose level.
Interrupt until resolved to ≤ grade 1, 
then resume TEMOZOLOMIDE at the current 
dose level.
If a dose reduction is required < 100 
mg/m2, then discontinue TEMOZOLOMIDE.
Neutropenia
- Grade 3 (ANC 0.5 - 0.9 
x 109/L) 
Interrupt until resolved to ≤ grade 
1, then resume TEMOZOLOMIDE at 
the current dose level.
Interrupt until resolution to ≤ grade 1, 
then resume TEMOZOLOMIDE at one lower 
dose level.
If a dose reduction is required < 100 
mg/m2, then discontinue TEMOZOLOMIDE.
Neutropenia
- Grade 4
(ANC < 0.5 x 109/L)
Discontinue TEMOZOLOMIDE
Discontinue TEMOZOLOMIDE
Thrombocytopenia
- Platelet count: 
50 - 99 x 109/L
Interrupt until platelet count 
recovers to ≥ 100 x 109/L, then resume 
TEMOZOLOMIDE at the current dose 
level.
Interrupt until platelet count recovers 
to ≥ 100 x 109/L, then resume 
TEMOZOLOMIDE at the current dose level.
If a dose reduction is required < 100 
mg/m2, then discontinue TEMOZOLOMIDE.
Thrombocytopenia
- Platelet count: 
10 - 49 x 109/L
Interrupt until platelet count 
recovers to ≥ 100 x 109/L, then resume 
TEMOZOLOMIDE at the current dose 
level.
Interrupt until platelet count recovers 
to ≥ 100 x 109/L, then resume 
TEMOZOLOMIDE at one lower dose level.
If a dose reduction is required < 100 
mg/m2, then discontinue TEMOZOLOMIDE.

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Toxicity
(organized per CTCAE v 
4.03)
Concomitant Temozolomide
Adjuvant Temozolomide
Thrombocytopenia
- Platelet count:
< 10 x 109/L
Discontinue TEMOZOLOMIDE
Discontinue TEMOZOLOMIDE
Non-hematologic toxicity 
(except for alopecia, nausea, 
vomiting, constipation, 
weight loss, & anorexia)
- Grade 2
Interrupt until resolved to ≤ grade 
1, then resume TEMOZOLOMIDE at 
the current dose level.
Interrupt until resolution to ≤ grade 1, 
then resume TEMOZOLOMIDE at one lower 
dose level.
If a dose reduction is required < 100 
mg/m2, then discontinue TEMOZOLOMIDE.
Non-hematologic toxicity 
(except for alopecia, nausea, 
vomiting, constipation)
- Grade 3
Discontinue TEMOZOLOMIDE
Interrupt until resolution to ≤ grade 1, 
then resume TEMOZOLOMIDE at one lower 
dose level.
If a dose reduction is required < 100 
mg/m2, then discontinue TEMOZOLOMIDE.
Non-hematologic toxicity 
(except for alopecia, nausea, 
vomiting, constipation)
- Grade 4
Discontinue TEMOZOLOMIDE
Discontinue TEMOZOLOMIDE
5. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of reported and/or potential AEs (section 4.1 of this appendix) and the 
characteristics of an observed AE (Section 5.2 of this appendix) will determine whether the event 
requires expedited reporting in addition to routine reporting.
This section specifies reporting requirements to the FDA, Overall PI/Coordinating Center, 
DF/HCC IRB, and manufacturer as applicable.
5.1
Expected Toxicities
Refer to section 4.1 of this appendix for expected toxicities for assigned study treatment 
arm.
5.2
Adverse Event Characteristics

CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version
4.03 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.03. A copy of the CTCAE version 4.03 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

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
For expedited reporting purposes only:
-
AEs for the agent(s) that are listed in section 4.1 of this appendix should be reported 
only if the adverse event varies in nature, intensity or frequency from the expected 
toxicity information which is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol- 
Specific Expedited Adverse Event Reporting Exclusions.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
5.3
Expedited Adverse Event Reporting
5.3.1
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment.
5.3.2
For multi-institution studies where a DF/HCC investigator is serving as the Overall 
Principal Investigator, each participating institution must abide by the reporting 
requirements set by the DF/HCC. This applies to any medical event that is Serious, 
Unexpected, and there is a Reasonable Possibility (i.e., possible, probable, or definitive 
attribution) the Adverse Event is related to the study intervention.
5.3.3
Expedited Reporting Guidelines to Overall PI/Coordinating Center
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.
External investigative sites will report AEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. As mentioned in 5.3.2, 
external investigative sites will reports AEs per table below in accordance with DF/HCC 
reporting policy. If an event must be reporting per table 5.3.3:
1. Document/describe reportable AE(s) on the following:
a.
MedWatch 3500A
b. DFCI Reportable AE Coversheet found in section 10 of this appendix
2. Email above documents to NeuroOnc_SAE@dfci.harvard.edu with the subject 
title “INSIGHT SAE”
a.
All AE reports received at this account are forwarded immediately to 
Overall Principal Investigator (Dr. Patrick Y. Wen), and to Coordinating 
Center personnel.

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Table 5.3.3 Expedited AE Reporting by external sites to Coordinating Center/Overall PI
DF/HCC Reportable AEs
Attribution
Gr. 2 & 3 AE
Expected
Gr. 2 & 3 AE
Unexpected
Gr. 4 AE Expected
Gr. 4 AE
Unexpected
Gr. 5 AE
Expected or 
Unexpected
Unrelated 
Unlikely
Not required
Not required
5 business days#
5 business days
1 business day*
Possible 
Probable 
Definite
Not required
5 business days
5 business days#
5 business days
1 business day*
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported.
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 1 business day of learning of the event.
The Overall PI will submit AE reports from outside institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting adverse events.
5.3.4
Protocol-Specific Expedited Adverse Event Reporting Exclusions
For this protocol only, the AEs/grades listed below do not require expedited reporting to 
the Overall PI or the DFCI IRB. However, they still must be reported through the routine 
reporting mechanism (i.e. case report form).

Lymphopenia (grades 2-4)

A visit to the emergency room or other hospital department < 24 hours, that 
does not result in admission (unless considered an important medical or life- 
threatening event)

Emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission

Elective surgery, planned prior to signing consent

Routine health assessment requiring admission for baseline/trending of health 
status (eg, routine colonoscopy)

Hospitalization for routine treatment or monitoring of the studied indication, 
not associated with any deterioration in condition, or for elective procedures

Hospitalization for elective or pre-planned treatment for a pre-existing 
condition that did not worsen

Hospitalization for respite care not associated with an adverse event attributed 
to the study drug

Hospitalization for treatment of patient’s underlying disease after coming off 
study treatment (e.g. admission after patient is removed from active study 
treatment for craniotomy)

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5.4
Expedited Reporting to the Food and Drug Administration (FDA)
As study sponsor, the Overall PI (or his designee) will be responsible for all communications 
with the FDA. The Overall PI will report to the FDA, regardless of the site of occurrence, any 
serious adverse event that meets the FDA’s criteria for expedited reporting following the 
reporting requirements and timelines set by the FDA.
5.5
Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.
5.6
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms. AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
6. PHARMACEUTICAL INFORMATION 
Temozolomide
6.1.1
Description
The chemical name of Temozolomide is 3,4-dihydro-3methyl-4-oxoimidazo[5,1-d]-as- 
tetrazine-8-carboxamide and the molecular weight is 194.15, which acts as an alkylating 
agent.
In humans, the terminal elimination half-life (t1/2) in plasma ranges from approximately
1.6 to 1.88 hours. Following oral administration, the drug, Temozolomide, is rapidly 
absorbed and then hydrolyzed to the active metabolite 5-(3-methyltriazen-1-yl) 
imidazole-4-carboxamide (MTIC). MTIC spontaneously degrades to CO2 and 5- 
aminoimidazole-4-carboxamide (AIC) and excreted via the urine. CYP isoenzymes play 
an only minor role in Temozolomide metabolism.
6.1.2
Form
Temozolomide drug will be supplied commercially.
Each capsule for oral use contains either 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 
mg of Temozolomide and the inactive ingredients sodium starch glycolate, tartaric acid, 
stearic acid, and colloidal silicon dioxide.
The body of the capsules is made of gelatin, and is opaque white. The cap is also made of 
gelatin, and the colors vary based on the dosage strength.

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6.1.3
Storage and Stability
Temozolomide is stable at room temperature.
6.1.4
Compatibility
There are no known compatibility issues.
6.1.5
Handling
Routine chemotherapy handling is recommended.
6.1.6
Availability
Temozolomide is available through special pharmacy and can be prescribed by the 
treating physician.
6.1.7
Preparation
None
6.1.8
Administration
o
Temozolomide capsules should not be opened or chewed; they must be 
swallowed whole with a glass of water one hour before or after food and other 
medications.
o
If vomiting occurs during the course of treatment, no re-dosing of the participant 
is allowed before the next scheduled dose. The occurrence and frequency of any 
vomiting during a treatment cycle must be recorded as an adverse event.
o
If the participant forgets to take his/her temozolomide dose more than 10 hours 
from intended dosing time, then that dose should be withheld and temozolomide 
should be restarted at the time of the next planned dose.
6.1.9
Ordering
Temozolomide drug will be supplied commercially and should be ordered per local 
policy.

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7.
STUDY CALENDAR
Concomitant
Adjuvant Cycles
Assessment
Screen
-inga
D1b
D8c
D15c
D22 c
D29 c
D36 c
D43-
49 d
Reste
D1f
D22g
End of Txh
30-Day 
Post 
Drugi
Active 
Follow- 
Upj
Long 
Term
Follow-Upk
Informed Consentl
X
Medical Historym
X
Inclusion/Exclusion Criterian
X
Vital signso
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
Neurologic Exam
X
X
X
X
X
X
Karnofsky Performance Statusp
X
X
X
X
X
X
Concomitant Medicationsq
X
Adverse Eventsr
X
Pregnancy Test (β-HCG)s
X
X
X
X
X
Coagulationt
X
Hematologyu
X
X
X
X
X
X
X
X
Xcc
X
X
X
Serum Chemistryv
X
X
X
X
Xcc
X
X
EKGw
X
Radiationx
---------------------------X----------------------------
Temozolomide
---------------------------X----------------------------
X
Imaging – MRIy
X
X
X
X
X
Response Assessmentz
X
X
X
Post-treatment therapiesaa
X
X
Survivalbb
X
X
Archival Tumor Tissueh
X
a.
All screening procedures to be performed within 28 days of initial registration unless otherwise noted. NOTE: refer to section 10 of master protocol for comprehensive 
details on screening assessments, initial registration, randomization assignment and second registration timing.
b.
Concomitant radiation and temozolomide must begin no later than 42 days following initial surgery. Day 1 assessments must be performed within 3 days of starting 
study treatment. Screening assessments may be utilized as baseline assessments if they fall within window.
c.
+/- 2 day window for weekly assessments during concomitant phase.
d.
Day 43-49 visit to occur within +/- 7 days of completing radiation.
e.
Rest period is 28-42 days.
f.
Adjuvant cycles to begin >28 (+14) days following end of radiation. Subsequent adjuvant cycle to begin >28 (+7) days from day 1 of previous cycle. Adjuvant cycles can be 

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extended > 28 days per protocol when the next cycle’s treatment is held. Day 1 adjuvant assessments to be performed within 4 days prior to Day 1 temozolomide.
h.
End of Treatment: assessments to be performed within 7 days after last drug administration or within 7 days after decision to end treatment.
i.
30-Day Post Drug: a contact/visit is to be performed 30 days (+/-7 days) after date of last drug taken on study. This may be performed via documented phone conversation 
with a study nurse or clinician or a clinic visit. All participants will be followed until resolution or stabilization of any serious or reportable adverse events occurring during 
treatment or starting within 30 days of last drug. If the 30-day Post Drug window falls within the End of Treatment time point, a separate contact does not need to be 
obtained.
j.
Active Follow-Up: participants who discontinue study treatment for reasons other than disease progression will be followed every 4 weeks (+/-1 week) via contact or medical 
record review and study team must continue monitoring participant’s disease status by radiologic imaging at 8 week intervals (+/- 1 week) until (1) documented disease 
progression, (2), death, (3) participant withdraws from follow-up, or (4) end of study, whichever occurs first.
k.
Long Term Follow-Up: participants will be followed every 4 weeks (+/-1 week) via contact or medical record review until death. Participants must be followed for survival 
data at every long-term follow-up time point and for post-treatment therapies and reason for stopping those therapies when available.
l.
Informed Consent: must be obtained by MD attending. No study specific screening procedures may occur until after the initial informed consent process is completed. Initial 
informed consent may be obtained within 28 days of initial registration. Following initial registration and receipt of INSIGhT randomization assignment, participants must be 
sign the consent form specific to the assigned treatment arm prior to initiating treatment for that study arm.
m. Medical History: to include review of treatment history for GBM, any ongoing medical conditions & medical history pertaining to eligibility on study and involvement during 
study.
n.
Inclusion/exclusion criteria: source documentation providing investigator’s confirmation that the participant had met all master protocol eligibility criteria must be available 
prior to initial registration. See section 3 of master protocol for eligibility requirements for initial registration. See section 2 of this appendix for arm specific eligibility 
criteria.
o.
Vital Signs: weight, heart rate, blood pressure, respiration rate, temperature. Vital signs must be performed prior to administration of treatment on treatment days. 
Height required only at screening.
p.
Karnofsky Performance Status (KPS): see appendix A of master protocol.
q.
Concomitant Medications: Concomitant medications & reason for administration should be documented in the case history from date of consent up to the 30-Day Post Drug Visit.
r.
Adverse Events: adverse events experienced by participants will be collected and recorded from the first dose of treatment on-study up to the 30-Day Post Drug Visit of the 
last dose of study medication (+/- 7 days depending on when 30-Day Post Drug visit/contact occurs).
s.
Pregnancy Test: required for women of child bearing potential (see section 3 of master protocol for definition of women of child bearing potential). ).
t.
Coagulation: PT/INR, PT, PTT required at screening only and then as clinically indicated.
u.
Hematology: erythrocytes (RBC), hemoglobin, hematocrit, platelets, total WBC plus differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils).
v.
Serum Chemistry: albumin, alkaline phosphatase (ALP), BUN, calcium, creatinine, glucose, potassium, SGOT (AST), SGPT (ALT), sodium, total bilirubin (if total bilirubin is 
greater than the upper limit of normal, direct and indirect bilirubin should be performed)
w.
EKG: required at screening only and then as clinically indicated.
x.
Radiation: see section 3.1 of this sub-study appendix for definition of standard radiation therapy per protocol.
y.
Imaging: gadolinium-enhanced contrast and non-contrast MRI. Initial imaging should be performed within 21 days prior to beginning study treatment. When feasible at 
site, Appendix D Recommended Acquisition Protocol should be adhered to and the same imaging technique should be used on a participant throughout the trial. Local 
reading (investigator assessment) will be used to determine eligibility and for participant management. Adjuvant C1D1 imaging should be performed within 7 days prior 
to starting adjuvant treatment; subsequent imaging should be performed within 7 days prior to Day 1 of odd cycles.
z.
Response Assessment: Per RANO criteria (see section 11 of master protocol).
aa. Post-treatment Therapies: start/stop dates, names of treatment regimens and reason for stopping should be collected when available. 

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bb. Survival: date of death and reason must be collected for overall survival purposes.
cc. Hemes & Serum Chemistries will be done as per SOC during patient’s post-RT.
dd. Archival tumor tissue may be sent to Stanford University for assay laboratory tests.

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8. MEASUREMENT OF EFFECT
Refer to section 11 of master INSIGhT protocol for details on measurement of effect.
9. REFERENCES
1.
O'Reilly SM, Newlands ES, Glaser MG, et al. Temozolomide: a new oral cytotoxic 
chemotherapeutic agent with promising activity against primary brain tumours. Eur J 
Cancer. 1993; 29A(7):940-942.
2.
Koukourakis GV, Kouloulias V, Zacharias G, et al. Temozolomide with radiation therapy 
in high grade brain gliomas: pharmaceuticals considerations and efficacy; a review 
article. Molecules. 2009; 14(4):1561-1577.
3.
Newlands ES, Blackledge GR, Slack JA, et al. Phase I trial of temozolomide (CCRG 
81045: M&B 39831: NSC 362856). Br J Cancer. 1992; 65(2):287-291.
4.
Ostermann S, Csajka C, Buclin T, et al. Plasma and cerebrospinal fluid population 
pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res. 2004; 
10(11):3728-3736.
5.
Patel M, McCully C, Godwin K, Balis FM. Plasma and cerebrospinal fluid 
pharmacokinetics of intravenous temozolomide in non-human primates. J Neurooncol. 
2003; 61(3):203-207.
6.
Stevens MF, Hickman JA, Langdon SP, et al. Antitumor activity and pharmacokinetics in 
mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; 
M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res. 
1987; 47(22):5846-5852.
7.
Friedman HS, Dolan ME, Pegg AE, et al. Activity of temozolomide in the treatment of 
central nervous system tumor xenografts. Cancer Res. 1995; 55(13):2853-2857.
8.
Plowman J, Waud WR, Koutsoukos AD, Rubinstein LV, Moore TD, Grever MR. 
Preclinical antitumor activity of temozolomide in mice: efficacy against human brain 
tumor xenografts and synergism with 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res. 
1994; 54(14):3793-3799.
9.
Brada M, Judson I, Beale P, et al. Phase I dose-escalation and pharmacokinetic study of 
temozolomide (SCH 52365) for refractory or relapsing malignancies. Br J Cancer. 1999; 
81(6):1022-1030.
10.
Hammond LA, Eckardt JR, Baker SD, et al. Phase I and pharmacokinetic study of 
temozolomide on a daily-for-5-days schedule in patients with advanced solid 
malignancies. J Clin Oncol. 1999; 17(8):2604-2613.
11.
Dhodapkar M, Rubin J, Reid JM, et al. Phase I trial of temozolomide (NSC 362856) in 
patients with advanced cancer. Clin Cancer Res. 1997; 3(7):1093-1100.
12.
Stupp R, Dietrich PY, Ostermann Kraljevic S, et al. Promising survival for patients with 
newly diagnosed glioblastoma multiforme treated with concomitant radiation plus 
temozolomide followed by adjuvant temozolomide. J Clin Oncol. 2002; 20(5):1375- 
1382.
13.
Bower M, Newlands ES, Bleehen NM, et al. Multicentre CRC phase II trial of 
temozolomide in recurrent or progressive high-grade glioma. Cancer Chemother 
Pharmacol. 1997; 40(6):484-488.

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14.
Yung WK, Albright RE, Olson J, et al. A phase II study of temozolomide vs. 
procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer. 2000; 
83(5):588-593.
15.
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and 
adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352(10):987-996.
16.
Kaina B, Christmann M, Naumann S, Roos WP. MGMT: key node in the battle against 
genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA Repair 
(Amst). 2007; 6(8):1079-1099.
17.
Jaeckle KA, Eyre HJ, Townsend JJ, et al. Correlation of tumor O6 methylguanine-DNA 
methyltransferase levels with survival of malignant astrocytoma patients treated with bis- 
chloroethylnitrosourea: a Southwest Oncology Group study. J Clin Oncol. 1998; 
16(10):3310-3315.
18.
Silber JR, Blank A, Bobola MS, Ghatan S, Kolstoe DD, Berger MS. O6-methylguanine- 
DNA methyltransferase-deficient phenotype in human gliomas: frequency and time to 
tumor progression after alkylating agent-based chemotherapy. Clin Cancer Res. 1999; 
5(4):807-814.
19.
Esteller M, Garcia-Foncillas J, Andion E, et al. Inactivation of the DNA-repair gene 
MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med. 2000; 
343(19):1350-1354.
20.
Hegi ME, Diserens AC, Godard S, et al. Clinical trial substantiates the predictive value of 
O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma 
patients treated with temozolomide. Clin Cancer Res. 2004; 10(6):1871-1874.
21.
Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from 
temozolomide in glioblastoma. N Engl J Med. 2005; 352(10):997-1003.
22.
Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and 
adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a 
randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 
2009; 10(5):459-466.

100
10. DFCI REPORTABLE AE COVERSHEET – INSIGHT CONTROL ARM
DF/HCC Protocol No. 16-443
Date:
Number of pages including cover sheet: 
From:
Institution:
Phone No.:
Fax No.:
Participant # and Initials:
Date Event Met Reporting Criteria (as defined in protocol):
Type of Report: Initial Follow-up
Hospitalization?  Yes
 No
CTCAE Event #1 Description:
CTCAE Event #2 Description (if applicable):
NOTE: use another coversheet if more than 2 events are being reported 
at this time
Meets Definition of Serious AE:
 Serious
 Non-serious
Meets Definition of Serious AE:
 Serious
 Non-serious
Toxicity Grade:
G1/mild G2/moderate G3/severe
G4/life threatening G5
Toxicity Grade:
G1/mild G2/moderate G3/severe
G4/life threatening G5
Expectedness to Radiation Therapy:
Expected Unexpected
Expectedness to Radiation Therapy:
Expected Unexpected
Attribution to Radiation Therapy:
Unrelated Unlikely
Possible
Probable
Definite
Attribution to Radiation Therapy:
Unrelated Unlikely
Possible
Probable
Definite
Expectedness to Temozolomide:
Expected
Unexpected
Expectedness to Temozolomide:
Expected Unexpected
Attribution to Temozolomide:
Unrelated Unlikely
Possible
Probable
Definite
Attribution to Temozolomide:
Unrelated Unlikely
Possible
Probable
Definite
Reporting Investigator (print):
Signature of Reporting Investigator:
Date: 
To (check off recipient of this AE):
 Dr. Patrick Y. Wen and Dana-Farber Coordinating Center 
Email: NeuroOnc_SAE@dfci.harvard.edu

101
11.
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION THERAPY
This treatment diary is for you to indicate that you took the study drug as prescribed. Please bring this treatment diary and your pill 
bottle(s) with you to each clinic visit. At the end of the cycle, please sign and date the bottom of the treatment diary.
Temodar Instructions
During radiation therapy, Temodar should be taken daily (including weekends and holidays) – your Clinical Team will confirm the total # 
of days you will take Temodar.

Temodar capsules should be taken whole (do not chew or open capsules), two to three hours prior to radiation with a full 
glass of water on an empty stomach (one hour before or after food and other medications).

If you realize you have missed a dose by more than 10 hours, the dose should not be retaken and the next dose should not 
be increased to make up for the missed dose. Please indicate missed doses on this diary.

If a dose is vomited, the capsules are not to be replaced and you can indicate this vomited dose on the diary.

On days when you do not have radiation, Temodar should be taken in the morning on an empty stomach (one hour before or 
after food and other medications) with a full glass of water.

If your course of radiation extends beyond 42 days because of delays, the course of Temodar may be extended to a 
maximum of 49 days.
Please check with your study treatment team if you have any questions regarding how or when you should take your Temodar doses.
To be completed by study personnel:
Patient ID #
Patient Initials: 
Month & Year:                     Temodar Dose:
mg 
Take
capsule(s) at
mg strength +
capsule(s) at
mg strength
+
capsule(s) at
mg strength

102
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
    
     TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION THERAPY
DAY 1
DAY 2
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
DAY 8
DAY 9
DAY 10
DAY 11
DAY 12
DAY 13
DAY 14
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
DAY 15
DAY 16
DAY 17
DAY 18
DAY 19
DAY 20
DAY 21
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Participant/Guardian Signature:
Date:  

103
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION THERAPY
DAY 22
DAY 23
DAY 24
DAY 25
DAY 26
DAY 27
DAY 28
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
DAY 29
DAY 30
DAY 31
DAY 32
DAY 33
DAY 34
DAY 35
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
DAY 36
DAY 37
DAY 38
DAY 39
DAY 40
DAY 41
DAY 42
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Participant/Guardian Signature:
Date:  

104
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION THERAPY
DAY 43
DAY 44
DAY 45
DAY 46
DAY 47
DAY 48
DAY 49
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Participant/Guardian Signature:
Date:  

105
12.
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY FOLLOWING RADIATION THERAPY
This treatment diary is for you to indicate that you took the study drug as prescribed. Please bring this treatment diary and your pill 
bottle(s) with you to each clinic visit. At the end of the cycle, please sign and date the bottom of the treatment diary.
Temodar Instructions

Temodar should be taken daily on days 1-5 of each 28-day cycle.

Temodar capsules should be taken whole (do not chew or open capsules), at approximately the same time each day with a 
full glass of water on an empty stomach (one hour before or one hour after food).

If you realize you have missed a dose by more than 10 hours, the dose should not be retaken and the next dose should not 
be increased to make up for the missed dose. Please indicate missed doses on this diary.

If a dose is vomited, the capsules are not to be replaced and you can indicate this vomited dose on the diary.
Please check with your study treatment team if you have any questions regarding how or when you should take your Temodar doses.
To be completed by study personnel:
Patient ID #
Patient Initials:                Month & Year:
Temodar Dose:
mg 
Take
capsule(s) at
mg strength +
capsule(s) at
mg strength
+
capsule(s) at
mg strength

106
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY FOLLOWING RADIATION THERAPY
DAY 1
DAY 2
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
OFF Temodar
Date:
OFF Temodar
DAY 8
DAY 9
DAY 10
DAY 11
DAY 12
DAY 13
DAY 14
Date:
OFF Temodar
Date:
OFF Temodar
Date:
OFF Temodar
Date:
OFF Temodar
Date:
OFF Temodar
Date:
OFF Temodar
Date:
OFF Temodar
DAY 15
DAY 16
DAY 17
DAY 18
DAY 19
DAY 20
DAY 21
Date:
OFF Temodar
Date:
OFF Temodar
Date:
OFF Temodar
Date:
OFF Temodar
Date:
OFF Temodar
Date:
OFF Temodar
Date:
OFF Temodar
DAY 22
DAY 23
DAY 24
DAY 25
DAY 26
DAY 27
DAY 28
Date:
OFF Temodar
Date:
OFF Temodar
Date:
OFF Temodar
Date:
OFF Temodar
Date:
OFF Temodar
Date:
OFF Temodar
Date:
OFF Temodar
Participant/Guardian Signature:
Date:  

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APPENDIX F ABEMACICLIB ARM OF INSIGHT
TABLE OF CONTENTS
1.
BACKGROUND.....................................................................................................................109
1.1 Temozolomide.................................................................................................109
1.2 Abemaciclib (LY2835219)..............................................................................110
2.
PARTICIPANT SELECTION ................................................................................................115
2.1 Eligibility Criteria Specific to the Abemaciclib Arm......................................115
2.2 Second INSIGhT Registration: Registration to Abemaciclib Arm .................116
2.2.1Registration Process for DF/HCC Institutions................................................116
2.2.2Registration Process for Other Investigative Sites..........................................116
3.
TREATMENT PLAN .............................................................................................................116
3.1 Definition of Standard Radiation Therapy ......................................................116
3.2 Concomitant Temozolomide during Radiation Therapy.................................117
3.3 Rest Phase .......................................................................................................118
3.4 Adjuvant (Post-Radiation) Abemaciclib .........................................................118
3.5 General Concomitant Medication and Supportive Care Guidelines ...............119
3.6 Guidelines for Diarrhea Management.............................................................121
3.7 Criteria for Taking a Participant Off Protocol Therapy ..................................121
3.8 Duration of Follow Up ....................................................................................122
3.9 Criteria for Taking a Participant Off Study.....................................................122
4.
DOSING DELAYS/DOSE MODIFICATIONS.....................................................................122
4.1 Anticipated Toxicities .....................................................................................123
4.1.1Anticipated Toxicities for Radiation Therapy.................................................123
4.1.2Anticipated Toxicities for Temozolomide ......................................................123
4.1.3Anticipated Toxicities for Abemaciclib..........................................................124
4.2 Dose Modifications/Delays for Temozolomide ..............................................124
4.3 Dose Modifications/Delays for Abemaciclib..................................................126
5.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS...................................133
5.1 Expected Toxicities.........................................................................................133
5.2 Adverse Event Characteristics.........................................................................134
5.3 Expedited Adverse Event Reporting ...............................................................135
5.4 Expedited Reporting to the Food and Drug Administration (FDA)................137
5.5 Expedited Reporting to Hospital Risk Management.......................................138
5.6 Routine Adverse Event Reporting...................................................................138
PHARMACEUTICAL INFORMATION.......................................................................................138
Temozolomide ........................................................................................................138
6.1.2Form................................................................................................................138
6.1.3Storage and Stability .......................................................................................138
6.1.4Compatibility ..................................................................................................139
6.1.5Handling..........................................................................................................139
6.1.6Availability .....................................................................................................139
6.1.7Preparation......................................................................................................139
6.1.8Administration ................................................................................................139

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6.1.9Ordering..........................................................................................................139
6.2 Abemaciclib ....................................................................................................139
6.2.2Form................................................................................................................140
6.2.3Storage and Stability .......................................................................................140
6.2.4Compatibility ..................................................................................................140
6.2.5Handling..........................................................................................................140
6.2.6Availability .....................................................................................................140
6.2.7Preparation......................................................................................................140
6.2.8Administration ................................................................................................140
6.2.9Ordering..........................................................................................................141
6.2.10
Accountability.....................................................................................141
6.2.11
Destruction and Return........................................................................141
7.
STUDY CALENDAR.............................................................................................................142
8.
MEASUREMENT OF EFFECT.............................................................................................144
9.
REFERENCES........................................................................................................................144
10. DFCI REPORTABLE AE COVERSHEET – INSIGHT ABEMACICLIB ARM..................145
11. TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION 
THERAPY ..............................................................................................................................146
12. ABEMACICLIB DOSING INSTRUCTIONS & DRUG DIARY..........................................150

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1.
BACKGROUND
1.1
Temozolomide
Background and preclinical data
Temozolomide is a member of the imidazotetrazine family that is structurally related to the 
alkylating agent dacarbazine and has shown efficacy against a variety of cancers, including high 
grade gliomas.
Under physiologic conditions, temozolomide is spontaneously converted to its active metabolite 
MTIC (5-(3-dimethyl-1-triazenyl)imidazole-4-carboxamide)1. The breakdown product of MTIC, 
methyldiazonium, is an actively alkylating agent that preferentially methylates guanine residues 
of the DNA molecule, thereby resulting in single and double DNA strand breaks and activation 
of apoptotic pathways.2 Temozolomide has linear and reproducible pharmacokinetics with 100%
p.o. bioavailability within 2 hours of drug administration and a rapid plasma drug clearance with 
a plasma half- life of 1.6-1.8 hours.3
Because of its lipophilic properties, temozolomide penetrates into the central nervous system 
(CNS) and was shown to reach acceptable CNS concentrations. In humans, the CSF penetration 
is estimated to be ~20-30% based on AUCplasma/AUCCSF ratios.4 In several preclinical rodent and 
primate models, it was demonstrated to have activity against CNS tumors thereby stimulating 
interest for investigations in humans.5-8
Clinical data
In these preclinical and clinical phase I studies, temozolomide demonstrated antitumor-activity in 
high-grade gliomas in adults.3,9 Based on these studies, the maximal tolerated dose (MTD) for 
humans has been defined as 150-200 mg/m2 per day depending on whether patients have 
received prior treatment with myelotoxic agensts.3,10,11 For patients with glioblastoma, the 
recommended temozolomide doses are 75 mg/m2 during radiation (concomitant phase) and 150- 
200 mg/m2 for 5 days out of a 28-day cycle for 6 months.4,12 Temozolomide in general is well 
tolerated and the most frequent toxicities are mild to moderate myelosuppression 
(thrombocytopenia and neutropenia) which is predictable and typically resolves spontaneously.
Subsequent phase II studies confirmed the activity of temozolomide against newly diagnosed and 
recurrent high-grade gliomas1,13,14 therefore leading to further evaluation of the drug by the 
European Organization for Research and treatment of Cancer (EORTC) and the National Cancer 
Institute of Canada (NCIC) in a landmark phase III study15. In this clinical trial the efficacy of 
radiation with concomitant temozolomide followed by six monthly cycles of temozolomide 
compared to radiation alone for newly diagnosed glioblastoma was evaluated15. The combination 
of radiation and temozolomide prolonged median progression free survival from 5 to 6.9 months 
(95% CI 4.2-5.5) and median overall survival from 12.1 to 14.6 months ( 95% CI 11.2-13.0).
Treatment with temozolomide was overall well tolerated with grade 3 or 4 hematoxicity in 16% 
of study participants.
Based on these results, this concomitant use of temozolomide during radiation followed by 
monthly maintenance cycles has been widely accepted as the standard of care treatment for 

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patients with newly diagnosed glioblastoma.
MGMT
The tumor suppressor gene MGMT (O6-methylguanine-DNA methyltransferase) on chromosome 
10q26 encodes a DNA-repair enzyme that removes alkyl groups from the O6 position of guanine, 
thereby repairing the lethal DNA-cross links induced by alkylating chemotherapeutic agents such 
as temozolomide16. Glioma cells with diminished MGMT activity are more responsive to the 
alkylating damage of these agents17,18. Epigenetic silencing of the MGMT promoter is present in
~40-68% of high grade gliomas and leads to reduced protein expression and cellular DNA repair 
activity. MGMT promoter methylation is associated with longer survival in patients with high 
grade gliomas treated with alkylating agents19, including temozolomide20,21 Therefore, MGMT 
promoter methylation represents a favorable prognostic marker for high grade gliomas which is 
routinely evaluated in neuropathological practice.
In a retrospective tumor tissue analysis of the patients enrolled in the EORTC/NCIC study, 
MGMT promoter methylation was confirmed to be a favorable prognostic factor for patients 
with glioblastoma.21 It also showed that the therapeutic benefit of temozolomide in addition to 
radiation was most pronounced in patients whose tumors contained a methylated MGMT 
promoter. In this patient group, combined chemoradiation compared to radiation alone prolonged 
progression-free survival from 5.9 (95% CI 5.3-7.7) to 10.3 (95% CI 6.5-14.0) months and
median overall survival from 15.3 (95% CI 13.0-20.9) to 21.7 (95% CI 17.4-30.4) months. In 
contrast, for patients without MGMT promoter methylation the combination of temozolomide 
plus radiation resulted in an only small survival benefit compared to radiation alone (progression 
free survival 4.4 vs, 5.3 months, overall survival 11.8 vs. 12.7 months).
Rationale
These data suggest a correlation between MGMT promoter methylation and treatment response 
to temozolomide. It therefore can be argued that temozolomide is useful only in the MGMT 
methylated setting. However, based on the small subgroup of study patients from the landmark 
EORTC-NCIC study whose tumors were MGMT unmethylated and survived more than 2 years 
(longer than the expected median survival), there seemed to be a survival benefit from combined 
radiation and temozolomide compared to radiation alone.22 In addition, because of issues with 
the reliability of the assay used to assess MGMT status in this EORTC-NCIC study, it has been 
debated whether these patients were incorrectly classified as MGMT unmethylated.
Nevertheless, based on these data, a real albeit marginal benefit from temozolomide even in the 
unmethylated setting cannot be excluded. Therefore, it continues to be common practice to use 
the combination of temozolomide and radiation in all patients with newly diagnosed 
glioblastoma irrespective of MGMT methylation status.
1.2
Abemaciclib (LY2835219)
Rationale & Proposed Biomarker Association
Rb signaling plays an important role in cell growth and division. During the cell cycle, the G1 
restriction point controls entry into S phase and is essential for maintaining control of cell 
division23,24. The CDK4/CyclinD complex regulates the G1 restriction point through 
phosphorylation of the Rb tumor suppressor protein. With the possible exception of those 

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tumors with complete inactivation of Rb, which functions downstream of the CDK4/6-cyclinD 
complex, all these cancers are potentially sensitive to pharmacologic inhibition of CDK4/6.
From a therapeutic standpoint, the goal of inhibiting CDK4/6 with a small molecule inhibitor is 
to prevent cell cycle progression through the G1 restriction point, thus arresting tumor growth. 
LY2835219 is a selective and potent small molecule CDK4/6 dual inhibitor that demonstrates 
significant inhibition of tumor growth in GBM xenograft models with an intact, functional RB1 
protein.
Selective inhibition of CDK4/6 results in a reversible arrest of cancer cells at the restriction point 
when used as a single agent in cells containing functional Rb protein. Other cell biology has 
confirmed and demonstrated that LY2835219 mesylate inhibits CDK4/6 to induce G1 arrest 
specifically in Rb-proficient tumors. Orthotopic xenograft experments with primary human 
GBM cell lines showed that treatment with LY2835219 extended survival in CDK6 amplified 
and Rb wild type lines.
Preclinical data
Abemaciclib demonstrates significant inhibition of tumor growth in GBM human xenograft 
models. Xenograft growth inhibition is generally dose dependent from 25 to 100 mg/kg 
following daily oral administration for 21 days to 28 days. In preclinical species, abemaciclib 
demonstrates moderate to high bioavailability, with a terminal elimination half-life (t1/2) in 
plasma ranging from approximately 17 to 38 hours. The radioactivity associated with 
[14C]LY2835219 distributes well into tissues and organs, with concentrations measurable 
through 24 hours post-dose in various parts of brain in rat. Abemaciclib therefore distributes 
extensively to the brain in vivo and produces a statistically significant and dose dependent 
improvement in survival in a rat orthotopic brain tumor model (Figure 1). Median survival 
was improved 8 and 12 days compared to vehicle following daily oral treatment at 40 mg/kg and 
80 mg/kg for 21 days, respectively. Preclinical data demonstrates that abemaciclib inhibits 
CDK4/6 to induce G1 arrest specifically in Rb-proficient tumors.
Figure 1: Improvement in overall survival with LY2835219 in rat orthotopic 
brain model.
In primary human tumor xenograft models, abemaciclib also demonstrates tumor growth delay 
and a prolongation of survival. Abemaciclib was initiated day 6 post tumor cell injection as oral 
gavage once daily at either 45 or 90 mg/kg/administration. Normalized bioluminescence was 
reduced in tumors treated with either dose level, which led to a statistically significant 
improvement in survival (Figure 2, left two panels) in the GBM43 line, which has wild-type RB. 
Similar results were shown for GBM39, a primary human tumor line with CDK6 amplification 
(Figure 2, right two panels).

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Other
Figure 2: Reduced bioluminescence and improved overall survival in primary 
human tumor xenograft models with wild-type Rb (left two panels) or CDK6 
amplification (right two panels).

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CDK4/6 inhibitors have also shown preclinical efficacy in GBM. Palbociclib, a CDK 4/6 
inhibitor from Pfizer, extended survival in an intracranial xenograft GBM model (Figure 3). Of 
note, RT followed by CDK 4/6 inhibition seemed to produce the most favorable survival in 
comparison to concurrent therapy or inhibition followed by RT. While the palbociclib results 
were also compelling, abemaciclib was felt to have superior BBB penetration in comparison.
Figure 3: Improved survival for palbociclib following RT in an intracranial 
xenograft model.

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Clinical data
There are 7 studies completed and 13 studies ongoing. Study JPBA is a multicenter, 
nonrandomized, open-label Phase 1 study of abemaciclib in patients with advanced cancer. In 
Part A (the dose-escalation phase), patients were treated on 2 different schedules: either at 50, 
100, 150, and 225 mg every 24 hours (Q24H), or at 75, 100, 150, 200, and 275 mg every 12 
hours (Q12H). In Parts B, C, D, E, and F the tumor-specific expansion phases), patients are 
treated on the twice-daily schedule at a dose no greater than the MTD with administration of 
abemaciclib on Days 1 through 28 of a 28-day cycle, The MTD was not reached for the once-
daily schedule and for the twice-daily schedule was established at 200 mg Q12H. Based on 
the frequency of Grade 1/2 diarrhea during an interim analysis and the observation of clinical 
activity at doses below the below the MTD, the initial starting dose was changed to 150 mg 
Q12H to gain additional PK data and clinical experience around safety/tolerability. As the 
diarrhea was found to be managable with standard antidiarrheal agents, early treatment with 
antidiarrheal agents was recommended and the initial starting dose was returned to 200 mg 
Q12H. The Phase 2 study, JPBB, is a proof-of-concept trial for patients with mantle cell 
lymphoma. Abemaciclib is administered orally at 200 mg Q12H on Days 1 through 28 of a 
28- day cycle. Study JPBD is an open-label study to determine the disposition of labeled 
abemaciclib in healthy surgically sterile or postmenopausal females or sterile males following 
oral administration of a single 150-mg dose of abemaciclib containing approximately 5μCi of 
[14C]- abemaciclib. No data is available at this time for Study JPBD.
As of 14 October 2015, validated safety data for 572 patients treated with abemaciclib were 
available in Studies JPBA, JPBB, JPBC, JPBH, JPBJ, and JPBN. The most common TEAEs 
possibly related to study drug included diarrhea (73.3%), fatigue (48.6%), nausea (48.3%), 
neutropenia (32.9%), vomiting (25.3%), decreased appetite (25.2%), thrombocytopenia (22.9%), 
anemia (22.4%), leukopenia (20.3%), abdominal pain (18.2%), and blood creatinine increased 
(14.0%). As of 14 October 2015, 146 patients in ongoing and completed studies experienced 222 
SAEs possibly related to study drug. SAEs that were experienced by more than 5 patients 
included diarrhea (17 patients), anemia (13 patients), neutropenia (12 patients), dehydration (11 
patients), acute kidney injury and nausea (10 patients each), pneumonia (8 patients), pulmonary 
embolism (7 patients), febrile neutropenia (6 patients), and vomiting (5 patients).
In the tumor expansion cohorts, plasma and CSF was collected for patients with primary brain 
tumors and metastases. Plasma and CSF concentrations from patients were obtained after 
reaching steady state with < 2.5 hours between plasma and CSF sampling (Figure 4) and 
supported the preclinical observations of distribution extensively in the CSF.

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Figure 4: Plasma and CSF concentrations for 10 patients treated with abemaciclib.
Seventeen patients with GBM that had progressed or recurred after radiotherapy and/or 
chemotherapy enrolled in Part C of Study I3Y-MC-JPBA. Abemaciclib was given as a single 
agent at a dose of 200 mg orally every 12 hours on Days 1 through 28 of a 28-day cycle. In this 
progressive/recurrent GBM cohort, the disease control rate (DCR = response + stable disease) 
was 17.6% and median PFS was 1.1 months. It should be noted that 13 of the 17 patients were 
heavily pretreated patients who had failed bevacizumab. In the 4 heavily pretreated patients who 
had not received bevacizumab, 2 patients experienced prolonged disease stability (1 patient has 
received 19 cycles and 1 patient received 23 cycles. Both remained on treatment with stable 
disease at data cutoff.
There is no compelling data to combine abemaciclib with RT in a radiosensitizing strategy so the 
experimental arm will maintain TMZ during RT and then abemaciclib will replace TMZ in the 
adjuvant phase.
2. PARTICIPANT SELECTION
2.1
Eligibility Criteria Specific to the Abemaciclib Arm
Participants must meet all eligibility criteria outlined in the master protocol (section 3) and 
complete initial registration (section 4 of master protocol). Once the randomization assignment 
has been received following initial registration, all participants randomized to the abemaciclib 
arm must meet the following criteria prior to participating in the abemaciclib arm of the study.
2.1.1
Participants must be willing and able to provide written informed consent/assent for the 
abemaciclib arm of the INSIGhT trial.
2.1.2
Women of child bearing potential (women who are not free from menses for > 2 years, 
post hysterectomy/oopherectomy, or surgically sterile) and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) from 
date of intial dose and for 3 months following the last dose of abemaciclib.
2.2
Second INSIGhT Registration: Registration to Abemaciclib Arm
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore®. Registration to the abemaciclib arm must occur following initial registration to master 
INSIGhT protocol and receipt of randomization assignment, and prior to the initiation of 
protocol therapy. Any participant not registered to their protocol specific assigned arm before 
protocol therapy begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria in section 2.1 of this sub-study appendix and a 
member of the study team will complete the protocol-specific eligibility checklist.
Following initial registration, any additional laboratory assessments prior to start of treatment 
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management between registration and start of study treatment.
Following second registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore® as soon as possible.
2.2.1
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.
2.2.2
Registration Process for Other Investigative Sites
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
DFCI Coordinating Center staff. All sites should contact the DFCI Coordinating Center to verify 
slot availabilities. A list of the required forms for registration can be found in Appendix B.
Following registration, participants should begin as soon as feasible. Issues that would cause 
treatment delays should be discussed with the Overall PI. If a participant does not receive 
protocol therapy following registration, the participant’s registration on the study must be 
canceled. The Study Coordinator should be notified of cancellations as soon as possible.
Refer to Appendix B, Section 3.7 for registration details.
3. TREATMENT PLAN
Participants treated on the abemaciclib arm will receive daily radiation (60 Gy in 30 fractions) as 
described in section 3.1 of this appendix with concomitant temozolomide (75 mg/m2/day) daily 
as described in section 3.2, followed by a 28 (+14 days) day break, and followed by continuous 
twice daily dosing of abemaciclib as described in section 3.4 below.
3.1
Definition of Standard Radiation Therapy
The patient must undergo MRI based treatment planning (CT with contrast-based planning only 
if patient unable to undergo MRI). At a minimum, the contrast enhancing lesion (and/or surgical 
cavity) defined on a T1-weighted image (gross tumor volume; GTV) must be targeted with a 
minimum of a 1 cm dosimetric margin expansion to define a planning target volume (PTV). The 
margin may be reduced around natural barriers to tumor growth, and also to allow sparing of 
organs at risk, if necessary. The volume must be treated to a prescribed dose of 59.4 Gy in 33 
fractions or 60 Gy in 30 fractions. Treatment with larger volumes to the contrast-enhancing 
region is acceptable. Treatment or no treatment of the T2/FLAIR abnormality is acceptable.
Because this is optional, dosimetric expansion and dose-fractionation for the T2/FLAIR volume 
are not specified here. The prescribed dose to the T2/FLAIR volume may not exceed 60 Gy.
Radiation therapy must be completed within an overall treatment time of less than 52 calendar 
days. Maximum dose (defined as a volume greater than 0.03 cc) to critical structures include: 60 
Gy to the brainstem, 56 Gy to the optic chiasm, 55 Gy to the optic nerves, and 50 Gy to the 
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Participants are permitted to have radiotherapy as described in this section performed at any NCI
funded cooperative group site. Prospective Overall PI approval, or approval by his designee 
(other Coordinating Center radiation oncologists), is required for any radiotherapy site that is not 
an NCI funded cooperative group site. At the discretion of the DFCI Coordinating Center, a 
radiation plan may be requested to be prospectively approved for a non-NCI site prior to 
initiating radiotherapy at the site. Any questions regarding permitted radiotherapy sites should 
be directed to the DFCI Coordinating Center or Overall PI Patrick Y. Wen, MD.
3.2
Concomitant Temozolomide during Radiation Therapy
Treatment on concomitant therapy should begin no later than 6 weeks from surgery. 
Temozolomide 75 mg/m2/day will be administered orally on a continuous daily dosing schedule 
for a maximum of 49 days. Temozolomide will be initiated on Day 1 of radiation therapy, and 
the last dose will ideally be the last day of radiation; however, temozolomide may be 
administered for 42 days, or per your site’s institutional policy / standard.
The drug will be administered orally approximately 2-3 hours before each session of 
radiotherapy. During weekends or weekdays without radiotherapy (Saturday and Sunday), the 
drug should be taken in the morning when possible. The dose will be determined using actual 
body surface area (BSA) as calculated in square meters at the beginning of the concomitant 
treatment. The daily dose will be rounded to the nearest 5 mg.
No dose reductions are allowed during the concomitant phase of treatment. If a participant 
experiences a toxicity related to temozolomide during the concomitant phase of treatment, then 
temozolomide dosing will be interrupted according the rules described in Table 4.2 of this 
appendix.
Temozolomide will be administered on an outpatient basis. The investigator will instruct the 
participant to take the drug exactly as specified in the protocol. No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to treat 
the patient’s malignancy.
Participants will be instructed to fast at least 1 hour before and 1 hour after temozolomide 
administration. Prophylaxis with a 5-HT3 antagonist is recommended prior to administration of 
temozolomide doses and should be administered orally approximately 30 to 60 minutes before 
temozolomide treatment. Temozolomide should be taken with a glass of water and consumed 
over as short a time as possible. Participants should swallow the tablets as a whole and not 
chew them. Additional drug administration instructions, including missed dose policy, are 
described in section 6.1.8 of this appendix and are included in the participant pill diary (section 
11 of this appendix).
All dosages prescribed and dispensed to the participant and all dose changes during the study 
must be recorded. If a participant requires a temozolomide dose delay of > 28 days from the 
previous dose, the participant must be discontinued from further temozolomide treatment. If a 
participant discontinues temozolomide due to toxicity, the participant may continue study 
treatment with adjuvant cycles of abemaciclib as described in section 3.4 below. In the 
exceptional case where the investigator feels the patient would benefit from continuing therapy 
the case can be discussed with the Overall PI Patrick Y. Wen, MD at pwen@partners.org or 617- 
632-2166. Expected toxicities and dose reductions and modifications are detailed in section 4 of 
this appendix.

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NOTE: Study treatment may be held > 28 days in order to allow for surgical pathology to 
determine progression versus pseudoprogression outside of the 12-week consideration mark if it 
is prospectively confirmed with Overall PI to be clinically appropriate to do so.
Participants will keep a temozolomide diary (see section 11 of this appendix). After completion 
of radiation, the diary will be returned.
3.3
Rest Phase
During the 28 day (+ 14 days) break after completion of radiotherapy, temozolomide will not be 
administered.
3.4
Adjuvant (Post-Radiation) Abemaciclib
Adjuvant cycles of abemaciclib should begin no sooner than 28 days (+ 14 days) following the 
completion of radiation therapy.
Participants cannot begin adjuvant abemaciclib if they meet 
any criteria requiring a dose modification as outlined in section 4.3 of this appendix. All adjuvant 
cycle 1, day 1 assessments (as noted in section 7 study calendar of this appendix) must be 
resulted and reviewed prior to initiating treatment with abemaciclib.
The study drug, abemaciclib, will be administered on an outpatient basis. The investigator will 
instruct the participant to take the study drug exactly as specified in the protocol. No 
investigational or commercial agents or therapies other than those described in this appendix may 
be administered with the intent to treat the patient’s malignancy.
Participants should be instructed to take the dose of abemaciclib every 12 hours. Cycle length 
will be 28 days, even if treatment is held mid-cycle for toxicity. The first cycle of 
abemaciclib will be dosed at 150 mg every 12 hours. If a patient has not required dose 
reduction(s) due to toxicity, then the dose of abemaciclib may be escalated at the start of Cycle 2 
to 200 mg every 12 hours if the investigator determines that it is in the best interest of the patient.
Abemaciclib should be taken with a glass of water and consumed over as short a time as 
possible. Participants should swallow the tablets as a whole and not chew them. Participants 
must avoid consumption of Seville orange (and juice), grapefruit or grapefruit juice, grapefruit 
hybrids, pummelos and exotic citrus fruits from 7 days prior to the first dose of study drug and 
during the entire study treatment period due to potential CYP3A4 interaction. Additional drug 
administration instructions, including missed dose policy, are described in Section 6.2.8 of this 
appendix and are included in the abemaciclib participant pill diary (section 12 of this appendix).
All dosages prescribed and dispensed to the participant and all dose changes during the study 
must be recorded. If a participant requires an abemaciclib dose delay of > 28 days from the 
previous dose, the participant must be discontinued from treatment completely. In the 
exceptional case where the investigator feels the patient would benefit from continuing therapy 
the case can be discussed with the Overall PI Patrick Y. Wen, MD at pwen@partners.org or 617- 
632-2166. Expected toxicities and dose reductions and modifications are detailed in section 4 of 
this appendix.
NOTE: Study treatment may be held > 28 days in order to allow for surgical pathology to 
determine progression versus pseudoprogression outside of the 12-week consideration mark if it 
is prospectively confirmed with Overall PI to be clinically appropriate to do so.
Participants will keep a medication diary (see section 12 of this appendix). At the end of each 

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cycle, the diary will be returned and a new one will be given to the participant. Participants are to 
return all pill bottles and unused pills.
3.5
General Concomitant Medication and Supportive Care Guidelines
Participants must be instructed not to take any additional medications (including over-the- 
counter products) during the trial without prior consultation with the investigator. All 
medications taken from date of initial consent and up to 30-day follow-up contact should be 
recorded. If concomitant therapy must be added or changed, including over-the-counter 
medications or alternative therapies, the reason and name of the drug/therapy should be recorded.
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
participant are allowed, including drugs given prophylactically (e.g. antiemetics) with the 
following exceptions:
3.5.1
Strong CYP3A inhibitors and CYP3A inducers are prohibited. In vitro studies 
suggest that abemaciclib is a sensitive CYP3A4 substrate. Co-administration of 
abemaciclib with strong CYP3A4 inhibitors is predicted to increase the systemic 
exposure to abemaciclib; likewise CYP3A inducers can be expected to decrease 
systemic exposure to abemaciclib, possibly resulting in sub-therapeutic drug 
levels. Refer to Appendix C of master INSIGhT protocol for a list of prohibited 
drugs. Please note that this list may not be comprehensive.
3.5.2
Caution should be exercised when co-administering abemaciclib with narrow 
therapeutic drugs that are substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2D6, or CYP3A. Participants receiving such medications must be monitored 
for potentiation of toxicity due to any individual concomitant medications, and 
may require dose titration or reduction of the drug substrate. Refer to Appendix C 
of master INSIGhT protocol for a list of drugs. Please note that this list may not 
be comprehensive
3.5.3
Abemaciclib is an inhibitor of P-gp; therefore, caution should be exercised when 
coadministering abemaciclib with P-gp substrate drugs with narrow therapeutic 
index (e.g., digoxin). Abemaciclib may also inhibit the clearance of substrates of 
the renal transporter MATE1, such as endogenous creatinine and metformin.
3.5.4
Herbal preparations/medications are not allowed throughout the study. These 
herbal medications include, but are not limited to: St. John’s wort, Kava, ephedra 
(ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, ginseng. Participants should stop using any herbal medications 7 days 
prior to first dose of study drug.
3.5.5
Corticosteroids should be used in the smallest possible dose to control symptoms 
of cerebral edema and mass effect, and discontinued if possible. Chronic dosing 
of corticosteroids is known to induce CYP3A enzymes, thereby increasing the 
risk of reducing abemaciclib drug exposure to sub-therapeutic levels.
3.5.6
Anti-seizure medications should be used as indicated. Only participants receiving 
non-EIAEDs are eligible (although protocol does allow for patients to register and 
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EIAEDs). If for unavoidable clinical reasons (emergency department visit, severe 
allergies, toxicities, etc.) a participant’s AED is switched to another AED, the 
following guidelines must be followed if applicable:
o
Participants should be started on another non-EIAED if at all possible.
o
Participants who are inadvertently and temporarily changed to an EIAED 
should immediately be changed to an alternative non-EIAED.
o
Participants who need to permanently change anticonvulsant, but who 
cannot change to another non-EIAED, must be discussed with the PI.
3.5.7
Febrile neutropenia may be managed according to the local institution's 
guidelines. Measures may include appropriate laboratory testing, including blood 
and urine cultures and the institution of broad-spectrum antibiotics. If a source for 
the fever is not identified or the fever resolves when the neutrophil count 
recovers, antibiotics may be discontinued and the participant observed.
3.5.8
G-CSF: Routine prophylactic use of G-CSF is not permitted. However, 
therapeutic use in participants with serious neutropenic complications, such as 
sepsis, may be considered at the investigator’s discretion.
3.5.9
Antiemetics: The use of antiemetics will be left to the investigators’ discretion.
3.5.10 Pneumocystis jirovecii pneumonia (PJP) prophylaxis: Since participants with 
GBM are at increased risk of developing PJP, especially if they are on 
corticosteroids, prophylaxis for PJP may be considered per institutional practice.
3.5.11 Anticoagulants: Because of the potential for its interaction with study 
medications, warfarin sodium (Coumadin®), or any other coumadin-derivative 
anticoagulant, is not permitted at any dose. Low-molecular weight heparin and Xa 
inhibitors are permitted. If for unavoidable clinical reasons (emergency 
department visit, severe allergy, toxicity, etc) a participant is started on 
Coumadin, they must change to a low molecular weight heparin immediately in 
the interest of subject safety.
3.5.12 Surgery: If neurosurgical management is required for reasons not due to tumor 
progression, these procedures must be documented, including the indications for 
surgery, the operative note, and pathology report.
3.5.13 Other Anticancer or Experimental Therapies: No other anticancer therapy of any 
kind is permitted during the study treatment period. No other drug under 
investigation may be used concomitantly with the study drug.
3.5.14 Other Concomitant Medications: Therapies considered necessary for the well 
being of the participant may be given at the discretion of the investigator. Other 
concomitant medications should be avoided except for analgesics, chronic 
treatments for concomitant medical conditions, or agents required for life- 
threatening medical problems. All concomitant medications must be recorded.
3.6
Guidelines for Diarrhea Management
At enrollment, participants should receive instructions on the prompt management of diarrhea. In 
the event of diarrhea, supportive care measures should be initiated as early as possible. These 
include the following:

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o
At the first sign of loose stools, the patient should initiate antidiarrhea therapy (eg 
loperamide) and notify the investigator for further instructions and appropriate follow- 
up.
o
Patients should also be encouraged to drink fluids (eg, 8-10 glasses of clear liquids per 
day).
o
Site personnel should assess response within 24 hours
o
If diarrhea does not resolve within antidiarrheal therapy within 24 hours to either 
baseline or Grade 1, then abemaciclib should be suspended until diarrhea is resolved to 
baseline or Grade 1.
o
When abemaciclib recommences the dose should be adjusted (see Table 4.2: Criteria for 
dose-modification and re-initiation of abemaciclib treatment).
3.7
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue on 
the abemaciclib arm until one of the following criteria applies:

Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator

Cases of pregnancy that occur during maternal exposures to abemaciclib should be 
reported (3 months following last dose). If a patient or spouse/partner is determined to 
be pregnant following abemaciclib initiation, she must discontinue treatment 
immediately. Data on fetal outcome and breast-feeding are collected for regulatory 
reporting and drug safety evaluation.
Participants will be removed from the protocol therapy when any of these criteria apply. The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
A ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the ODQ website or obtained from the ODQ 
registration staff.
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Patrick Y. Wen, MD, at 617-632-2166 or pwen@partners.org.
3.8
Duration of Follow Up

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Participants will be followed until death with monthly visits, telephone contact, or medical 
record review. Participants removed from protocol therapy for unacceptable adverse event(s) 
will be followed until resolution or stabilization of the adverse event. Refer to section 7 study 
calendar within this appendix for follow-up requirements and time points.
3.9
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).
A ODQ Treatment Ended/Off Study Form will be filled out when a participant comes off study. 
This form can be found on the ODQ website or obtained from the ODQ registration staff.
4. DOSING DELAYS/DOSE MODIFICATIONS
For participants who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the participant on study drug. If administration of 
temozolomide or abemaciclib must be interrupted because of unacceptable toxicity, drug dosing 
will be interrupted or modified according to rules described in this section.
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.03 can be downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
In the case of toxicity, appropriate medical treatment should be used (including anti-emetics, 
anti-diarrheals, etc.).
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and the 30 day post study visit. Participants continuing to 
experience toxicity at the end-of treatment visits may be contacted for additional assessments 
until the toxicity has resolved or is deemed irreversible.
4.1
Anticipated Toxicities
In order for an event to be considered expected (known correlation to study drug/treatment) for the 
purposes of adverse event reporting, the event must be:

Included in this section for Abemaciclib.

Included in this section or included in the package insert or the informed consent document 
as a potential risk for Temozolomide and radiation therapy.
NOTE: For events that are secondary to an event deemed expected with a study agent/modality (e.g. 

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rectal pain or hypokalemia as a result of diarrhea or gait disturbance as a result of edema cerebral), 
please record as “possibly related to” and “expected with” the agent/modality.
4.1.1
Anticipated Toxicities for Radiation Therapy
A list of adverse events of all grades suspected to be radiation therapy treatment related, 
organized by CTCAE v4.03 category, includes:

EAR AND LABYRINTH DISORDERS – external ear inflammation; other: dryness 
of ear canal; other: hardening of ear canal wax; external ear pain; other: hearing loss

ENDOCRINE DISORDERS - other: hypophysitis, or hypopituitarism

EYE DISORDERS – cataract; other: decreased vision

GASTROINTESTINAL DISORDERS – nausea; vomiting

GENERAL DISORDERS – fatigue

INJURY, POISONING AND PROCEDURAL COMPLICATIONS – dermatitis 
radiation; injury other: optic nerve

INVESTIGATIONS –lymphocyte count decreased

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS – generalized 
muscle weakness*

NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED – treatment related 
secondary malignancy

NERVOUS SYSTEM DISORDERS – headache; seizure; memory impairment; 
cognitive disturbance; somnolence; dysgeusia; central nervous system necrosis; 
edema cerebral; other: tumor inflammation**

PSYCHIATRIC DISORDERS – personality change

SKIN AND SUBCUTANEOUS TISSUE DISORDERS – scalp pain; other: scalp 
redness; alopecia
4.1.2
Anticipated Toxicities for Temozolomide
A list of adverse events of all grades suspected to be temozolomide treatment related, 
organized by CTCAE v4.03 category, includes:

BLOOD AND LYMPHATIC SYSTEM DISORDERS – anemia; febrile neutropenia; 
bone marrow hypocellular

GASTROINTESTINAL DISORDERS – constipation; nausea; vomiting; diarrhea

GENERAL DISORDERS – gait disturbance; fatigue

IMMUNE SYSTEM DISORDERS – allergic reaction

INJURY, POISONING AND PROCEDURAL COMPLICATIONS – bruising; 
hemorrhage

INVESTIGATIONS – neutrophil count decreased; lymphocyte count decreased; 
white blood cell decreased; platelet count decreased

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS – generalized 
muscle weakness*

NERVOUS SYSTEM DISORDERS – dizziness; memory impairment; headache; 
seizure

PSYCHIATRIC DISORDERS – insomnia

REPRODUCTIVE SYSTEM AND BREAST DISORDERS – infertility

SKIN AND SUBCUTANEOUS TISSUE DISORDERS – alopecia

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4.1.3
Anticipated Toxicities for Abemaciclib
A list of adverse events of all grades suspected to be abemaciclib treatment related 
according to review of Investigator’s Brochure, organized by CTCAE v4.03 category, 
includes:

BLOOD & LYMPHATIC SYSTEM DISORDERS – white blood cell decreased; 
neutrophil count decreased; platelet count decreased; anemia

GASTROINTESTINAL –diarrhea; dry mouth; nausea; vomiting; mucositis oral

GENERAL DISORDERS- fatigue

INFECTIONS & INFESTATIONS – conjunctivitis infective; pharyngitis; sinusitis; 
upper respiratory infection; urinary tract infection; vaginal infection

INVESTIGATIONS – creatinine increased; weight loss; aspartate aminotransferase 
increased; alanine aminotransferase; GGT increased

METABOLISM & NUTRITION DISORDERS – anorexia

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Muscle 
weakness (left-sided, lower limb, right-sided, trunk, & upper limb)

NERVOUS SYSTEM DISORDERS – dizziness; dysgeusia

SKIN AND SUBCUTANEOUS TISSUE DISORDERS – alopecia; pruritis

VASCULAR DISORDERS – thromboembolic event
*   “Generalized muscle weakness” to also include other CTCAE terms inclusive of a muscle weakness
** As CTCAE v. 4 recognizes ‘Edema cerebral’ only as a Gr4 event, please record events of ‘Edema 
cerebral’ deemed by Investigator to be Gr1-Gr3 or Gr5 as ‘Nervous system disorders, Other: Tumor 
inflammation’ (Gr1-Gr3 or Gr5, accordingly).
4.2
Dose Modifications/Delays for Temozolomide
4.2.1
No temozolomide dose reductions are allowed during the concomitant phase of treatment. 
If a participant experiences a toxicity related to temozolomide during the concomitant 
phase of treatment, then temozolomide dosing will be interrupted according the rules 
described in Table 4.2 of this appendix.
4.2.2
When treatment must be held pending resolution of toxicity to grade 1 or return to 
baseline, and the toxicity is a non-hematologic lab abnormality, in cases where 
participant had a pre-existing non-hematologic laboratory abnormality at baseline, the 
toxicity can be considered “resolved” from a hold perspective when it has resolved to 
within 1 grade of the baseline value.
NOTE: For the purposes of data entry, values from screening assessments should be 
entered in as ‘baseline’ values. However, true “baseline values” - for the purpose of 
dose modifications on study, etc. - will be considered the last assessments/tests 
performed prior to initiation of study therapy.
EXCEPTION: In instances where the value within 1 grade of the baseline value would 
still require a hold, continue to hold until resolution of toxicity to grade 1 or return to 
baseline.
4.2.3
Participants who experience an adverse event that requires a treatment delay should be 
monitored with appropriate laboratory testing or other clinical evaluation at least weekly 

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until resolution.
4.2.4
A treatment delay of up to 28 days is permitted. If the toxicity has not resolved after a 4- 
week delay, the participant must be removed from study treatment unless the participant 
has benefited from the study, in which case the investigator may contact the Overall 
Principal Investigator, Dr. Patrick Y. Wen, to determine if the participant will remain in 
the study.
4.2.4.1
NOTE: Study treatment may be held > 28 days in order to allow for surgical 
pathology to determine progression versus pseudoprogression outside of the 12-week 
consideration mark if it is prospectively confirmed with Overall PI to be clinically 
appropriate to do so.
4.2.5
Study teams are not required to hold for lymphopenia.
4.2.6
Participants whose treatment is interrupted or permanently discontinued due to an 
adverse event or clinically significant laboratory value, must be followed as outlined in 
Table 4.2 of this appendix, at least once a week for 4 weeks, and subsequently at 4-week 
intervals, until resolution or stabilization of the event, whichever comes first. All 
participants must be followed for adverse events and serious adverse events for 30 days 
following the last dose of study treatment. All SAEs must be reported as detailed in 
Section 5.3 of this appendix.

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Table 4.2: Criteria for dose-modification and re-initiation of temozolomide treatment
For toxicities attributable to temozolomide (considered at least possibly related), Table 4.2 
should be adhered to as noted below. When the treating investigator feels that a hold of 
temozolomide is warranted for patient safety even though the toxicity is unlikely or unrelated to 
temozolomide, discussion with the Overall Principal Investigator and Study Sponsor, Patrick Y. 
Wen, MD is strongly recommended.
Toxicity
(organized per CTCAE v 4.03)
Concomitant Temozolomide
- Grade 2  (ANC 1.0 -  1.4 x 109/L)
- Grade 3  (ANC 0.5 - 0.9 x 109/L)
Interrupt until resolved to ≤ grade 1, then resume 
TEMOZOLOMIDE at the current dose level
Neutropenia
- Grade 4 (ANC < 0.5 x 109/L)
Discontinue TEMOZOLOMIDE
- Platelet count: 50 - 99 x 109/L
- Platelet count: 10 - 49 x 109/L
Interrupt until platelet count recovers to ≥ 100 x 109/L, 
then resume TEMOZOLOMIDE at the current dose level.
Thrombocyto-
penia
- Platelet count: < 10 x 109/L
Discontinue TEMOZOLOMIDE
- Grade 2
Except for alopecia, nausea, vomiting, 
constipation, weight loss, & anorexia)
Interrupt until resolved to ≤ grade 1, then resume 
TEMOZOLOMIDE at the current dose level.
- Grade 3
Except for alopecia, nausea, vomiting, 
constipation)
Discontinue TEMOZOLOMIDE
Non-
hematologic 
toxicity
- Grade 4
Except for alopecia, nausea, vomiting, 
constipation)
Discontinue TEMOZOLOMIDE
4.3
Dose Modifications/Delays for Abemaciclib
All participants will be initially treated at Dose Level 0.
Abemaciclib Dose Levels
Dose Level
Dose of Abemaciclib
1*
200 mg every 12 hours
0
(starting dose)
150 mg every 12 hours
-1
100 mg every 12 hours
-2
50 mg every 12 hours
*If a patient has not required dose reduction(s) due to toxicity, then the dose 
of Abemaciclib may be escalated at the start of Cycle 2 to 200 mg every 12 
hours if the investigator determines that it is in the best interest of the patient.

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4.3.1
Table 4.3 should be adhered to for all toxicities considered at least possibly related to 
abemaciclib. If a participant experiences a toxicity unlikely or unrelated to treatment 
with abemaciclib, but may still warrant a hold or reduction of study drug for safety, 
discussion and approval by Overall Principal Investigator and Study Sponsor, Patrick Y. 
Wen, MD is strongly recommended.
4.3.2
When treatment must be held pending resolution of toxicity to grade 1 or return to 
baseline, and the toxicity is a lab abnormality, in cases where participant had a pre- 
existing laboratory abnormality at baseline, the toxicity can be considered “resolved” 
from a hold perspective when it has resolved to within 1 grade of the baseline value.
NOTE: For the purposes of data entry, values from screening assessments should be 
entered in as ‘baseline’ values. However, true “baseline values” - for the purpose of 
dose modifications on study, etc. - will be considered the last assessments/tests 
performed prior to initiation of study therapy.
EXCEPTION: In instances where the value within 1 grade of the baseline value would 
still require a hold, continue to hold until resolution of toxicity to grade 1 or return to 
baseline.
4.3.3
Participants who experience an adverse event that requires a treatment delay or dose 
reduction should be monitored with appropriate laboratory testing or other clinical 
evaluation at least weekly until resolution.
4.3.4
Following a dose delay which resumes mid cycle, day 1 procedures not associated with 
the adverse event do not need to be repeated.
4.3.5
No more than 2 levels of dose reduction are permitted in this study. Participants cannot 
be treated below dose level -2. If a participant whose abemaciclib dose has been reduced 
by 2 dose levels requires another dose reduction, treatment on study must be stopped 
unless the participant has benefited from the study, in which case the investigator will 
contact the overall Principal Investigator, Dr. Patrick Y. Wen, to determine if the 
participant will remain in the study.
4.3.6
A treatment delay of up to 28 days is permitted. If the toxicity has not resolved after a 4- 
week delay, the participant must be removed from study treatment unless the participant 
has benefited from the study, in which case the investigator may contact the Overall 
Principal Investigator, Dr. Patrick Y. Wen, to determine if the participant will remain in 
the study.
4.3.6.1
NOTE: Study treatment may be held > 28 days in order to allow for surgical 
pathology to determine progression versus pseudoprogression outside of the 12-week 
consideration mark if it is prospectively confirmed with Overall PI to be clinically 
appropriate to do so.
4.3.7
Dose re-escalation (after dose reduction for toxicity) is never permitted in this study.
4.3.8
Cycle length will be 4 weeks (28 days), even if treatment is held for toxicity. There is 
no stopping in counting cycles/days for those periods where a subject’s drug is withheld. 
All study evaluations and treatments should continue as if study treatment is not being 
held.
4.3.9
Participants whose treatment is interrupted or permanently discontinued due to an 
adverse event or clinically significant laboratory value, must be followed as outlined in 

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Table 4.3, at least once a week for 4 weeks, and subsequently at 4-week intervals, until 
resolution or stabilization of the event, whichever comes first. All participants must be 
followed for adverse events and serious adverse events for 30 days following the last 
dose of abemaciclib. All SAEs must be reported as detailed in section 5.3 of this 
appendix.
Table 4.3: Criteria for dose-modification and re-initiation of abemaciclib treatment
Table 4.3 should be adhered to for all toxicities attributable (considered at least possibly related) 
to abemaciclib as noted below. If a participant experiences a toxicity unlikely or unrelated to 
treatment with abemaciclib but may still warrant a hold or reduction of study drug for safety, 
discussion and written approval by Overall Principal Investigator and Study Sponsor, Patrick Y. 
Wen, MD is strongly recommended.
Toxicity
(organized per CTCAE v 4.03)
Actions
Investigations (for hyperglycemia, see metabolism disorders)
ALT/SGPT or AST/SGOT
- Grade 2 (>3.0- 5.0 x ULN)
First Occurrence:
Interrupt until resolution to ≤ grade 1, then

If resolution to grade ≤1 in ≤ 7 days, resume ABEMACICLIB at the 
current dose level

If resolution to ≤ grade 1 takes > 7 days, resume ABEMACICLIB at one 
lower dose level
Second/Third Occurrence:
Interrupt until resolution to ≤ grade 1, then resume ABEMACICLIB at one lower 
dose level
ALT/SGPT or AST/SGOT
- Grade 3
(> 5.0 - 20.0 x ULN)
First Occurrence:
Interrupt until resolution to ≤ grade 1, then

If resolution to grade ≤1 in ≤ 7 days, resume ABEMACICLIB at the 
current dose level

If resolution to ≤ grade 1 takes > 7 days, resume ABEMACICLIB at one 
lower dose level
Once resolved to ≤ grade 1, monitor liver function tests every other week or 
more frequently if clinically indicated until the end of treatment with study 
medication.
Second/Third Occurrence:

Interrupt until resolution to ≤ grade 1, then resume ABEMACICLIB at 
one lower dose level
Once resolved to ≤ grade 1, monitor liver function tests every other week or 
more frequently if clinically indicated until the end of treatment with study 
medication.

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ALT/SGPT or AST/SGOT
- Grade 4 (>20.0 x ULN)
Interrupt ABEMACICLIB until resolution to ≤ grade 1, then resume ABEMACICLIB 
at one lower dose level
Once resolved to ≤ grade 1, monitor liver function tests every other week or 
more frequently if clinically indicated until the end of treatment with study 
medication.
Amylase, asymptomatic
- Grade 3 (> 2.0 - 5.0 x ULN)
First Occurrence:
Interrupt until resolved to ≤ grade 1, then:

If resolution to grade ≤1in ≤ 7 days, resume ABEMACICLIB at the current 
dose level;

If resolution to grade ≤1 in > 7 days, resume ABEMACICLIB at one lower 
dose level
Second/Third Occurrence:

Interrupt until resolution to ≤ grade 1, then resume ABEMACICLIB at 
one lower dose level
Amylase
- Grade 4 (> 5.0 x ULN)
Discontinue ABEMACICLIB
Bilirubin*
- Grade 2
(>1.5 - 3 x ULN)
First Occurrence:
Interrupt ABEMACICLIB until resolution to ≤ grade 1, then:

If resolution to grade ≤1 in ≤ 7 days, resume ABEMACICLIB at the 
current dose level;

If resolution to ≤ grade 1 takes > 7 days, resume ABEMACICLIB at one 
lower dose level
Second/Third Occurrence:

Interrupt until resolution to ≤ grade 1, then resume ABEMACICLIB at 
one lower dose level
Bilirubin*
- Grade 3
(> 3.0 – 10.0 x ULN)
Interrupt ABEMACICLIB until resolution to ≤ grade 1, then:

If resolution to grade ≤1 in ≤ 7 days, resume ABEMACICLIB at one lower 
dose level;

If resolution to ≤ grade 1 takes > 7 days, discontinue ABEMACICLIB
Bilirubin
- Grade 4 (> 10.0 x ULN)
Discontinue ABEMACICLIB
* For participants with a baseline hyperbilirubinemia of 1.0-1.5 x institution’s ULN that is not felt to be 
clinically significant, the clinician may choose to continue ABEMACICLIB for elevations in total bilirubin that 
are two times the participant’s baseline value (screening value). For total bilirubin that is greater than two 
times the baseline value, follow dose modification guidelines as outlined in the above table.
However, in place of resolution to ≤ grade 1, ABEMACICLIB may resume once resolution to ≤ 2 x baseline 
value.

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Creatinine*
- Grade 2
(>1.5 - 3 x ULN)
First Occurrence:
Interrupt treatment until resolution to ≤ grade 1, then

If resolved to ≤ grade 1 in ≤ 7 days, resume ABEMACICLIB at the current 
dose level

If resolution to ≤ grade 1 takes > 7 days, resume ABEMACICLIB 
decreased by one dose level
Second/Third Occurrence:

Interrupt until resolution to ≤ grade 1, then resume ABEMACICLIB at 
one lower dose level
Creatinine *
- Grade 3
(> 3.0 - 6.0 x ULN)
- Grade 4 (> 6.0 x ULN)
Discontinue ABEMACICLIB
* Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion of 
creatinine without affecting glomerular function. Increases in serum creatinine occurred within the first 2 weeks 
of treatment, remained stable through the treatment period and were reversible upon treatment 
discontinuation. If deterioration of renal function is suspected, serum creatinine should not be the only measure 
used to assess a patient’s renal function.
Lipase elevation, 
asymptomatic
- Grade 3 (> 2.0 - 5.0 x ULN)
First Occurrence:
Interrupt until resolved to ≤ grade 1, then:

If resolution to grade ≤1 in ≤ 7 days, resume ABEMACICLIB at the 
current dose level;

If resolution to grade ≤1 in > 7 days, resume ABEMACICLIB at one lower 
dose level
Second/Third Occurrence:

Interrupt until resolution to ≤ grade 1, then resume ABEMACICLIB at 
one lower dose level
Lipase elevation, 
asymptomatic
- Grade 4 (> 5.0 x ULN)
Discontinue ABEMACICLIB
Neutropenia
- Grade 3
(ANC 0.5 - 0.9 x 109/L) 
- Grade 4
(ANC < 0.5 x 109/L)
(see Blood Disorders for 
Febrile Neutropenia)
First Occurrence:
Interrupt until resolved to ≤ grade 1, then:

If resolution to grade ≤1 in ≤ 7 days, then resume ABEMACICLIB at the 
current dose level

If resolution to grade ≤1 in > 7 days, then resume ABEMACICLIB at one 
lower dose level
Second/Third Occurrence:

Interrupt until resolution to ≤ grade 1, then resume ABEMACICLIB at 
one lower dose level

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Thrombocytopenia
First Occurrence:
- Grade 3
(PLT 25-49 x 109/L)
Interrupt until resolved to ≤ grade 1, then:

If resolution to grade ≤1 in ≤ 7 days, resume ABEMACICLIB at the 
current dose level

If resolution to grade ≤1 in > 7 days, then resume ABEMACICLIB at one 
lower dose level
Second/Third Occurrence:

Interrupt until resolution to ≤ grade 1, then resume ABEMACICLIB at 
one lower dose level
Thrombocytopenia
- Grade 4
(PLT < 25 x 109/L)
Interrupt until resolved, then resume ABEMACICLIB at one lower dose level
Blood and lymphatic system disorders
Febrile neutropenia
- ANC < 1.0 x 109/L with a 
single temperature of > 38.3 °C 
(101 F) or a sustained temperature 
of ≥ 38°C (100.4 F) for more than 
one hour
Interrupt treatment until resolved, then resume ABEMACICLIB at one 
lower dose level. Febrile neutropenia should be managed promptly with 
broad-spectrum antibacterial therapy, including coverage for enteric 
(gram-negative and anaerobic) bacteria. If neutropenic fever persists for 5 
days despite broad-spectrum antibacterial therapy, empiric antifungal 
therapy should be initiated. Anemia and thrombocytoenpia should be 
treated supportively and if necessary, with red cell or platelet 
transfusions.
Gastrointestinal Disorders
Diarrhea
- Grade 2
(4-6 stools/day > pretx)
Early treatment of diarrhea is recommended. Patients should be 
instructed to initiate anti-diarrheal therapy (such as loperamide) and 
notify the investigator at the first sign of loose stool. Investigators should 
assess the response of anti-diarrheal therapy within 24 hours of 
notification. If diarrhea can be controlled with optimal anti-diarrheal 
treatment within 24 hours to either baseline or grade 1, continue 
ABEMACICLIB. If not, interrupt treatment until resolved to ≤ grade 1, then 
resume ABEMACICLIB at the current dose (treating investigators may 
reduce by 1 dose level at their own discretion for first occurrence). If 
diarrhea returns as ≥ grade 2, then interrupt treatment until resolved to ≤ 
grade 1, then resume ABEMACICLIB at one lower dose level
Diarrhea
- Grade 3
(≥7 stools/day > pretx)
- Grade 4
(urgent intervention 
indicated)
(requires hospitalization)
Early treatment of diarrhea is recommended. Patients should be 
instructed to initiate anti-diarrheal therapy (such as loperamide) and 
notify the investigator at the first sign of loose stool. Investigators should 
assess the response of anti-diarrheal therapy within 24 hours of 
notification. If diarrhea can be controlled with optimal anti-diarrheal 
treatment within 24 hours to either baseline or grade 1, continue 
ABEMACICLIB. If not, for diarrhea ≥ Grade 3, interrupt treatment until 
resolved to ≤ grade 1, then resume ABEMACICLIB at one lower dose level.

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General Disorders
Fatigue Grade 1 & 2
Maintain dose level. Initiating a stimulant agent is recommended.
Fatigue
- Grade 3
First Occurrence:
Interrupt ABEMACICLIB until resolved to ≤ grade 1, then:

If resolved in ≤ 7 days, resume ABEMACICLIB at the current dose 
level

If resolved in > 7 days, resume ABEMACICLIB at one lower dose 
level
Second/Third Occurrence:

Interrupt until resolution to ≤ grade 1, then resume 
ABEMACICLIB at one lower dose level
Metabolism and Nutrition disorders
Hypercalcemia 
Grade 1-3
Management of hypercalcemia per local institutional guidelines. 
ABEMACICLIB administration will continue daily. For patients requiring 
hospitalization for management of hypercalcemia, ABEMACICLIB 
administration should be held until resolution to < grade 1 and resumed at 
one dose level lower.
Hypercalcemia 
Grade 4
Management of hypercalcemia per local institutional guidelines.
ABEMACICLIB administration should be held until resolution to < grade 1 
and resumed at one dose level lower.
Hyperuricemia 
Grade 1-4
Management of hyperuricemia per local institutional guidelines.
ABEMACICLIB administration will continue daily. If grade 4 persists > 14 
days despite medical management, ABEMACICLIB administration should be 
held until resolution to < grade 1 and resumed at one dose level lower.
Hypophosphatemia 
Grade 1-4
Initiate phosphorous supplementation daily. ABEMACICLIB 
administration will continue daily. If grade 4 persists > 14 days despite 
medical management, ABEMACICLIB administration should be held until 
resolution to < grade 1 and resumed at one dose level lower.
Nervous system disorders
Neurotoxicity ≥ 1 CTCAE grade 
level increase, attributable to 
drug
Maintain dose level
Neurotoxicity ≥ Grade 3, 
attributable to drug
Interrupt ABEMACICLIB until resolved to ≤ grade 1 or baseline, then 
resume ABEMACICLIB at one lower dose level

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Skin and subcutaneous tissue disorders
Any Rash 
Grade 1
Maintain dose level. Consider initiating appropriate skin toxicity 
therapy such as antihistamines.
Any Rash 
Grade 2
Maintain dose level. Initiate/intensify appropriate skin toxicity therapy 
such as antihistamines.
Any Rash 
Grade 3
Interrupt ABEMACICLIB until resolution to CTCAE Grade ≤ 1, then:

If resolved in ≤ 7 days, resume ABEMACICLIB at one lower dose 
level

If resolved in > 7 days (despite appropriate skin toxicity therapy), 
discontinue participant from study drug treatment.
Any Rash
Grade 4
Discontinue ABEMACICLIB
Other unspecified RELATED adverse events
Other unspecified Grade 1 and 2 
events considered at least 
possibly related to 
ABEMACICLIB
Maintain treatment with ABEMACICLIB
Other unspecified clinically 
significant Grade 3 clinically 
significant events considered at 
least possibly related to 
ABEMACICLIB
Interrupt treatment until resolution to ≤ grade 1 or returned to 
baseline, treatment may resume at the same dose level or a 1 dose level 
decrease, at the investigator’s discretion. Continuation of ABEMACICLIB is 
permitted upon recovery to stable Grade 2 if the investigator and overall 
principal investigator (Dr. Patrick Y. Wen) agree that the event is not 
considered clinically significant.
Other unspecified Grade 4 
events considered at least 
possibly related to 
ABEMACICLIB
Discontinue ABEMACICLIB
5. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of reported and/or potential AEs (section 4.1 of this appendix) and the 
characteristics of an observed AE (Section 5.2 of this appendix) will determine whether the event 
requires expedited reporting in addition to routine reporting.
This section specifies reporting requirements to the FDA, Overall PI/Coordinating Center, 
DF/HCC IRB, and manufacturer as applicable.
5.1
Expected Toxicities
Refer to section 4.1 of this appendix for expected toxicities for assigned study treatment 
arm.

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5.2
Adverse Event Characteristics

CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version
4.03 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.03. A copy of the CTCAE version 4.03 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

For expedited reporting purposes only:
-
AEs for the agent(s) that are listed in section 4.1 of this appendix should be reported 
only if the adverse event varies in nature, intensity or frequency from the expected 
toxicity information which is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol- 
Specific Expedited Adverse Event Reporting Exclusions.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.

Serious Adverse Event (SAE) Definition:
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless 
of causality that:
o
Results in death
o
Is life-threatening (i.e., in the opinion of the Investigator, the subject is at 
immediate risk of death from the AE);
o
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
o
Results in persistent or significant disability/incapacity (a substantial disruption of 
the subject’s ability to conduct normal life functions);
o
Is a congenital anomaly/birth defect;
o
Constitutes an important medical event. Important medical events are defined as 
those occurrences that may not be immediately life threatening or result in death, 
hospitalization, or disability, but may jeopardize the subject or require medical or 
surgical intervention to prevent one of the other outcomes listed above. Medical 
and scientific judgment should be exercised in deciding whether such an AE 
should be considered serious.

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5.3
Expedited Adverse Event Reporting
5.3.1
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment.
5.3.2
For multi-institution studies where a DF/HCC investigator is serving as the Overall 
Principal Investigator, each participating institution must abide by the reporting 
requirements set by the DF/HCC. This applies to any medical that is Serious, 
Unexpected, and there is a Reasonable Possibility (i.e., possible, probable, or definitive 
attribution) the Adverse Event is related to the study intervention.
5.3.3
Expedited Reporting Guidelines to Overall PI/Coordinating Center
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy.
External investigative sites will report AEs to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. A copy of the AE form should be forwarded 
to the Overall PI within the timeframes detailed in the table below. The Overall PI will submit 
AE reports from outside institutions to the DFCI OHRS according to DFCI IRB policies and 
procedures in reporting adverse events.
In addition to local IRB reporting policies, all sites are required to following the Table 5.3.3 
expedited reportable AE requirements:

136
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NOTE: Until patients initiate treatment with Abemaciclib on study, please report per Table 5.3.3 ‘Expedited AE Reporting by 
external sites to Coordinating Center/Overall PI’ of Appendix E (Control Arm).
Table 5.3.3 Expedited AE Reporting Requirements
Adverse Event Characteristics
Reporting Requirement
Serious- 
ness
Toxicity
Known Correlationf
Attribution to 
Abemaciclib
Eli Lilly and Company
-
Via Fax or Emailc
Use Reportable AE Coversheet c and 
Medwatch 3500A d
Overall PI (Patrick Y. Wen, MD) at the 
DFCI Coordinating Center
Via Email b
Use Reportable AE Coversheet c and 
Medwatch 3500A d
Seriouse
Any
Any
(Expected or 
Unexpected)
Any
Within 24 hours from notification a
Within 24 hours from notification a
Non- 
Serious
Grade 4
Any
(Expected or 
Unexpected)
Any
Not Required
Within 5 working days from 
notification a
Non- 
Serious
Grade 2 or 3
Unexpected
Possible, probable, 
definite
Not Required
Within 7 working days from 
notification a
a.
In the event that the participating investigator/site team does not become aware of an adverse event requiring expedited reporting immediately (e.g., participant sought 
treatment elsewhere), the participating investigator/site team is to report the event within the required hours/days noted above after learning of it and document the time of 
his or her first awareness of the adverse event. The initial report must be as complete as possible, including assessment of the causal relationship between the event and the 
investigational product(s). Information not available at the time of the initial report (e.g., an end date for the adverse event or laboratory values received after the report) must 
be documented on a follow-up report. A final report to document resolution of the SAE or reportable AE is required.
b.
Email the Medwatch 3500A form, reportable AE coversheet (section 10 of this appendix), and the local IRB SAE report (if applicable) to the DFCI Coordinating Center with the 
subject title as “INSIGHT SAE” to NeuroOnc_SAE@dfci.harvard.edu. All SAE reports received at this account are forwarded immediately to study’s Overall PI, Dr. Patrick Y. Wen, 
and to the DFCI Coordinating Center personnel.
c.
Reportable AE Coversheet is found in section 10 of this appendix. The coversheet contains all FAX numbers/e-mails and needed for reporting purposes.
d.
Medwatch 3500A downloadable form at http://www.fda.gov/medwatch/getforms.htm
e.
Seriousness is defined in section 5.2 of this appendix.
f.
Expected adverse events are those that have been previously identified as resulting from administration of the agent. For the purposes of this study, an adverse event is 
considered expected when it appears in the Anticipated Toxicities list (protocol section 4.1 of this appendix) which is derived from the Investigator’s Brochure and/or package 
insert (if applicable).

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5.3.4
How to report AEs to Lilly & DFCI Coordinating Center/Overall PI
1.
Document/describe reportable AE(s) on the following:
a.
MedWatch 3500A
i.
downloadable form at http://www.fda.gov/medwatch/getforms.htm
b.
DFCI Reportable AE Coversheet – INSIGhT Abemaciclib Arm
i.
Coversheet can be found in section 10 of this appendix. A modifiable 
Microsoft Word document is also available from the DFCI Coordinating 
Center.
2. Scan and email above documents to NeuroOnc_SAE@dfci.harvard.edu with the 
subject title “INSIGHT SAE”
a.
All AE reports received at this account are forwarded immediately to 
Overall Principal Investigator (Dr. Patrick Y. Wen), and to Coordinating 
Center personnel.
b. If available and applicable, also include the local IRB submission for this 
event in the submission to the DFCI Coordinating Center.
5.3.5
Protocol-Specific Expedited Adverse Event Reporting Exclusions
For this protocol only, the AEs/grades listed below do not require expedited reporting to 
the Overall PI or the DFCI IRB. However, they still must be reported through the routine 
reporting mechanism (i.e. case report form).

Lymphopenia (grades 2-4)

A visit to the emergency room or other hospital department < 24 hours, that 
does not result in admission (unless considered an important medical or life- 
threatening event)

Emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission

Elective surgery, planned prior to signing consent

Routine health assessment requiring admission for baseline/trending of health 
status (eg, routine colonoscopy)

Hospitalization for routine treatment or monitoring of the studied indication, 
not associated with any deterioration in condition, or for elective procedures

Hospitalization for elective or pre-planned treatment for a pre-existing 
condition that did not worsen

Hospitalization for respite care not associated with an adverse event attributed 
to the study drug

Hospitalization for treatment of patient’s underlying disease after coming off 
study treatment (e.g. admission after patient is removed from active study 
treatment for craniotomy)
5.4
Expedited Reporting to the Food and Drug Administration (FDA)
As study sponsor, the Overall PI (or his designee) will be responsible for all communications 
with the FDA. The Overall PI will report to the FDA, regardless of the site of occurrence, any 
serious adverse event that meets the FDA’s criteria for expedited reporting following the 
reporting requirements and timelines set by the FDA.

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5.5
Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.
5.6
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms. AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
PHARMACEUTICAL INFORMATION
Temozolomide
6.1.1
Description
The chemical name of Temozolomide is 3,4-dihydro-3methyl-4-oxoimidazo[5,1-d]-as- 
tetrazine-8-carboxamide and the molecular weight is 194.15, which acts as an alkylating 
agent.
In humans, the terminal elimination half-life (t1/2) in plasma ranges from approximately
1.6 to 1.88 hours. Following oral administration, the drug, Temozolomide, is rapidly 
absorbed and then hydrolyzed to the active metabolite 5-(3-methyltriazen-1-yl) 
imidazole-4-carboxamide (MTIC). MTIC spontaneously degrades to CO2 and 5- 
aminoimidazole-4-carboxamide (AIC) and excreted via the urine. CYP isoenzymes play 
an only minor role in Temozolomide metabolism.
6.1.2
Form
Temozolomide drug will be supplied commercially and should be ordered per local 
policy. The drug products are stable when stored according to instructions on the label.
Each capsule for oral use contains either 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 
mg of Temozolomide and the inactive ingredients sodium starch glycolate, tartaric acid, 
stearic acid, and colloidal silicon dioxide.
The body of the capsules is made of gelatin, and is opaque white. The cap is also made of 
gelatin, and the colors vary based on the dosage strength.
6.1.3
Storage and Stability
Temozolomide is stable at room temperature.

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6.1.4
Compatibility
There are no known compatibility issues.
6.1.5
Handling
Routine chemotherapy handling is recommended.
6.1.6
Availability
Temozolomide is available through special pharmacy and can be prescribed by the 
treating physician.
6.1.7
Preparation
None
6.1.8
Administration
o
Temozolomide capsules should not be opened or chewed; they must be 
swallowed whole with a glass of water one hour before or after food and other 
medications.
o
If vomiting occurs during the course of treatment, no re-dosing of the participant 
is allowed before the next scheduled dose. The occurrence and frequency of any 
vomiting during a treatment cycle must be recorded as an adverse event.
o
If the participant forgets to take his/her temozolomide dose more than 10 hours 
from the last dose, then that dose should be withheld and temozolomide should be 
restarted at the time of the next planned dose.
6.1.9
Ordering
Temozolomide drug will be supplied commercially and should be ordered per local 
policy.
6.2 Abemaciclib
6.2.1
Description
The chemical name is: [5-(4-Ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7- 
fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine.
Abemaciclib is also known as LY2835219 and is a selective, potent small molecule 
CDK4/6 dual inhibitor. The molecular weight is 506.60.
In humans, the terminal elimination half-life (t1/2) in plasma ranges from approximately 
17 to 38 hours. Following oral administration, abemaciclib was extensively metabolized

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140
followed by biliary excretion of metabolites. Strong CYP3A inhibitors may increase 
abemaciclib exposures, and strong inducers may decrease abemaciclib exposures.
Caution should be exercised when coadministering abemaciclib with narrow therapeutic 
drugs that are substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, or 
CYP3A.
6.2.2
Form
Abemaciclib drug product will be supplied for clinical trial use as abemaciclib with 
excipients in hypromellose tablets. The drug products are stable when stored according to 
instructions on the label.
Abemaciclib will be supplied as 50 mg hypromellose tablets as follows:
o a white hypromellose capsule containing 50 mg of abemaciclib and the inactive 
ingredients pregelatinized starch, dimethicone, and colloidal silicon dioxide.
6.2.3
Storage and Stability
Abemaciclib is stable at room temperature.
6.2.4
Compatibility
There are no known compatibility issues.
6.2.5
Handling
Routine chemotherapy handling is recommended.
6.2.6
Availability
Abemaciclib is an investigation agent and will be supplied free-of-charge from Lilly 
Pharmaceuticals.
6.2.7
Preparation
None.
6.2.8
Administration
o
Abemaciclib will be administered at a starting dose of 150 mg every 12 hours. If a 
patient has not required dose reduction(s) due to toxicity, then the dose of 
Abemaciclib may be escalated at the start of Cycle 2 to 200 mg every 12 hours if 
the investigator determines that it is in the best interest of the patient. Participants 
should fast one hour before and one hour after each dose. Participants should be 
instructed to take their doses, twice a day, at approximately the same times each 
day and approximately 12 ± 3 hours apart.

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141
o
If vomiting occurs during the course of treatment, no re-dosing of the participant 
is allowed before the next scheduled dose. The occurrence and frequency of any 
vomiting during a treatment cycle must be recorded as an adverse event.
o
If the participant forgets to take his/her abemaciclib dose more than 3 hours from 
the last dose, then that dose should be withheld and abemaciclib should be 
restarted at the time of the next planned dose.
6.2.9
Ordering
Drug supply will be ordered from Eli Lilly by site pharmacy personnel. A form, with 
drug information and email address for submission, will be supplied to each institution’s 
pharmacy by the coordinating center once local IRB approval is received. Anticipate 3-5 
business days to receive drug after the order is placed.
6.2.10 Accountability
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form. 
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.)
6.2.11 Destruction and Return
Abemaciclib will be destroyed on site according to institutional policies, documented in 
the Drug Accountability Record Form. At the time of expiration / study close, a drug 
disposition form provided by Lilly Pharmaceuticals Inc. will be sent out to be signed off 
by the Pharmacist and Investigator verifying the destruction of drug.

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7. STUDY CALENDAR
Concomitant
Adjuvant Cycles
Assessment
Screen
-inga
D1b
D8c
D15c
D22 c
D29 c
D36 c
D43-
49 d
Reste
D1f
D15g
End of Txh
30-Day 
Post 
Drugi
Active 
Follow- 
Upj
Long 
Term
Follow-Upk
Informed Consentl
X
Medical Historym
X
Inclusion/Exclusion Criterian
X
Vital signso
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
Neurologic Exam
X
X
X
X
X
X
Karnofsky Performance Statusp
X
X
X
X
X
X
Concomitant Medicationsq
X
Adverse Eventsr
X
Pregnancy Test (β-HCG)s
X
X
X
X
X
Coagulationt
X
Hematologyu
X
X
X
X
X
X
X
X
Xcc
X
X
Serum Chemistryv
X
X
X
X
Xcc
Xv
Xv
Xv
EKGw
X
X
X
Radiationx
---------------------------X----------------------------
Temozolomide
---------------------------X----------------------------
Abemaciclib
----------------X----------------
Imaging – MRI y
X
X
X
X
X
Response Assessmentz
X
X
X
Post-treatment therapiesaa
X
X
Survivalbb
X
X
a.
All screening procedures to be performed within 28 days of initial registration. NOTE: refer to section 10 of master protocol for comprehensive details on screening 
assessments, initial registration, randomization assignment and second registration timing.
b.
Concomitant radiation and temozolomide must begin no later than 42 days following initial surgery. Day 1 assessments must be performed within 3 days of starting study 
treatment. Screening assessments may be utilized as baseline/Day 1 assessments if they fall within window.
c.
+/- 2 day window for weekly assessments during concomitant phase.
d.
Day 43-49 visit to occur within +/- 7 days of completing radiation.
e.
Rest period is 28-42 days.
f.
Adjuvant C1D1 to begin >28 (+14) days following end of radiation. Cycle 1, Day 1 adjuvant assessments to be performed within 4 days of Day 1 abemaciclib. All adjuvant cycle 1, 
day 1 assessments must be resulted and reviewed prior to initiating treatment with abemaciclib; participants cannot begin adjuvant abemaciclib if they meet any criteria requiring 
a dose modification as outlined in section 4.3 of this appendix. Adjuvant cycles will be 28 days even if treatment is held. Day 1 assessments for subsequent adjuvant cycles to be 
performed within 4 days prior to Day 1 abemaciclib. (If utilizing the assessment window, that does not shorten the previous cycle or extend the upcoming cycle; each = 28 days.)

16-443 INdividualized Screening trial of Innovative Glioblastoma Therapy (INSIGhT) 
APPENDIX F: ABEMACICLIB ARM
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143
g.
Day 15 assessments required for adjuvant Cycle 1 visit only.
h.
End of Treatment: assessments to be performed within 7 days after last drug administration or within 7 days after decision to end treatment.
i.
30-Day Post Drug: a contact/visit is to be performed 30 days (+7 days) after date of last drug taken on study. This may be performed via documented phone conversation with a 
study nurse or clinician or a clinic visit. All participants will be followed until resolution or stabilization of any serious or reportable adverse events occurring during treatment or 
starting within 30 days of last drug.
j.
Active Follow-Up: participants who discontinue study treatment for reasons other than disease progression will be followed every 4 weeks (+/-1 week) via contact or medical 
record review andstudy team must continue monitoring participant’s disease status by radiologic imaging at 8 week intervals (+/- 1 week) until (1) documented disease 
progression, (2), death, (3) participant withdraws from follow-up, or (4) end of study, whichever occurs first.
k.
Long Term Follow-Up: participants will be followed every 4 weeks (+/-1 week) via contact or medical record review until death. Participants must be followed for survival data at 
every long-term follow-up time point and for post-treatment therapies and reason for stopping those therapies when available.
l.
Informed Consent: must be obtained by MD attending. No study specific screening procedures may occur until after the initial informed consent process is completed. Initial 
informed consent may be obtained within 28 days of initial registration. Following initial registration and receipt of INSIGhT randomization assignment, participants must be sign 
the consent form specific to the assigned treatment arm prior to initiating treatment for that study arm.
m. Medical History: to include review of treatment history for GBM, any ongoing medical conditions and medical history pertaining to eligibility on study and involvement during 
study.
n.
Inclusion/exclusion criteria: source documentation providing investigator’s confirmation that the participant had met all master protocol eligibility criteria must be available prior 
to initial registration. See section 3 of master protocol for eligibility requirements for initial registration. See section 2 of this appendix for arm specific eligibility criteria.
o.
Vital Signs: weight, heart rate, blood pressure, respiration rate, temperature. Vital signs must be performed prior to administration of treatment on treatment days. Height 
required only at screening.
p.
Karnofsky Performance Status (KPS): see appendix A of master protocol.
q.
Concomitant Medications: concomitant medications and reason for administration should be documented in the case history from date of consent up to the 30-Day Post Drug 
Visit.
r.
Adverse Events: adverse events experienced by participants will be collected and recorded from the first dose of treatment on-study up to the 30-Day Post Drug Visit of the last 
dose of study medication (+ 7 days depending on when 30-Day Post Drug visit/contact occurs).
s.
Pregnancy Test: required for women of child bearing potential (see section 3 of master protocol for definition of women of child bearing potential).).
t.
Coagulation: PT/INR, PT, PTT required at screening only.
u.
Hematology: erythrocytes (RBC), hemoglobin, hematocrit, platelets, total WBC plus differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils).
v.
Serum Chemistry: albumin, alkaline phosphatase (ALP), BUN, calcium, creatinine, glucose, potassium, SGOT (AST), SGPT (ALT), sodium, total bilirubin (if total bilirubin is greater 
than the upper limit of normal, direct and indirect bilirubin should be performed). In addition, LDH, uric acid, amylase, lipase and phosphorus are required during adjuvant 
cycles and End of Treatment chemistry time points.
w.
EKG: required at screening, adjuvant C2D1 and End of Treatment visit.
x.
Radiation: see section 3.1 of this sub-study appendix for definition of standard radiation therapy per protocol.
y.
Imaging: gadolinium-enhanced contrast and non-contrast MRI. Initial imaging should be performed within 21 days prior to beginning study treatment. When feasible at site, 
Appendix D Recommended MRI Acquisition Protocol should be adhered to and the same imaging technique should be used on a participant throughout the trial. Local reading 
(investigator assessment) will be used to determine eligibility and for participant management. Adjuvant C1D1 imaging should be performed within 7 days prior to starting 
adjuvant treatment; subsequent imaging should be performed within 7 days prior to Day 1 of odd cycles.
z.
Response Assessment: Per RANO criteria (see section 11 of master protocol).
aa. Post-treatment Therapies: start/stop dates, names of treatment regimens and reason for stopping should be collected when available. 
bb. Survival: date of death and reason must be collected for overall survival purposes.
cc. Hemes & Serum Chemistries will be done as per SOC during patient’s post-RT rest phase: hemes = weekly; chemistries need only be performed @ the end of RT visit and prior to 
adjuvant C1D1 (unless clinically indicated otherwise)

144
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APPENDIX F: ABEMACICLIB ARM
Version 11.0- December 4, 2024
8. MEASUREMENT OF EFFECT
Refer to section 11 of master INSIGhT protocol for details on measurement of effect.
9. REFERENCES
Ortega, S., et al. (2002). "Cyclin D-dependent kinases, INK4 inhibitors and cancer." Biochimica et 
biophysica acta 1602(1): 73-87.
Sherr, C. J. (1996). "Cancer Cell Cycles." Science (New York, NY) 274(5293): 1672-1677.
Stupp, R., et al. (2005). "Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma." 
N Engl J Med 352(10): 987-996.

145
10. DFCI REPORTABLE AE COVERSHEET – INSIGHT ABEMACICLIB ARM
DF/HCC Protocol No. 16-443
Date:
Number of pages including cover sheet: 
From:
Institution:
Phone No.:
Fax No.:
Participant # and Initials:
Date Event Met Reporting Criteria (as defined in protocol):
Type of Report: Initial Follow-up
Hospitalization:
 YES
 NO
CTCAE Event #1 Description:
CTCAE Event #2 Description (if applicable):
NOTE: use another coversheet if more than 2 events are being reported at this 
time
Meets Definition of Serious AE:
 Serious
 Non-serious
Meets Definition of Serious AE:
 Serious
 Non-serious
Toxicity Grade:
G1/mild G2/moderate G3/severe
G4/life threatening G5/death
Toxicity Grade:
G1/mild G2/moderate G3/severe
G4/life threatening G5/death
Expectedness to Radiation Therapy:
Expected Unexpected  N/A
Expectedness to Radiation Therapy:
Expected Unexpected  N/A
Attribution to Radiation Therapy:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Attribution to Radiation Therapy:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Expectedness to Temozolomide:
Expected Unexpected  N/A
Expectedness to Temozolomide:
Expected Unexpected
Attribution to Temozolomide:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Attribution to Temozolomide:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Expectedness to Abemaciclib:
Expected Unexpected  N/A
Expectedness to Abemaciclib:
Expected Unexpected  N/A
Attribution to Abemaciclib:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Attribution to Abemaciclib:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Reporting Investigator (print):
Signature of Reporting Investigator:
Date: 
To (check off recipient of this AE):
 Dr. Patrick Y. Wen and Dana-Farber Coordinating Center 
Email: NeuroOnc_SAE@dfci.harvard.edu
 Eli Lilly and Company
Fax: 866-644-1697; Email: MAILINDATA_GSMTINDY@LILLY.COM

146
11. TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION THERAPY
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
Take
capsule(s) at
mg strength +
capsule(s) at
mg strength
+
capsule(s) at
mg strength
This treatment diary is for you to indicate that you took the study drug as prescribed. Please bring this treatment diary and your pill 
bottle(s) with you to each clinic visit. At the end of the cycle, please sign and date the bottom of the treatment diary.
Temodar Instructions
During radiation therapy, Temodar should be taken daily (including weekends and holidays) – your Clinical Team will confirm the total # 
of days you will take Temodar.

Temodar capsules should be taken whole (do not chew or open capsules), two to three hours prior to radiation with a full 
glass of water on an empty stomach (one hour before or after food and other medications).

If you realize you have missed a dose by more than 10 hours, the dose should not be retaken and the next dose should not 
be increased to make up for the missed dose. Please indicate missed doses on this diary.

If a dose is vomited, the capsules are not to be replaced and you can indicate this vomited dose on the diary.

On days when you do not have radiation, Temodar should be taken in the morning on an empty stomach (one hour before or 
after food and other medications) with a full glass of water.

If your course of radiation extends beyond 42 days because of delays, the course of Temodar may be extended to a 
maximum of 49 days.
Please check with your study treatment team if you have any questions regarding how or when you should take your Temodar doses.

147
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION THERAPY
DAY 1
DAY 2
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
DAY 8
DAY 9
DAY 10
DAY 11
DAY 12
DAY 13
DAY 14
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
DAY 15
DAY 16
DAY 17
DAY 18
DAY 19
DAY 20
DAY 21
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials

148
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
Participant/Guardian Signature:  
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION THERAPY
Date:  
DAY 22
DAY 23
DAY 24
DAY 25
DAY 26
DAY 27
DAY 28
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
DAY 29
DAY 30
DAY 31
DAY 32
DAY 33
DAY 34
DAY 35
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
DAY 36
DAY 37
DAY 38
DAY 39
DAY 40
DAY 41
DAY 42
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials

149
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
Participant/Guardian Signature:
Date:  
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION THERAPY
DAY 43
DAY 44
DAY 45
DAY 46
DAY 47
DAY 48
DAY 49
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Participant/Guardian Signature:
Date:  

150
12. ABEMACICLIB DOSING INSTRUCTIONS & DRUG DIARY
To be completed by study personnel:
Patient ID #
Patient Initials:
Cycle #:
Month & Year:
Abemaciclib Dose:
mg, two times a day.
TAKE
pill(s) in the morning and
pill(s) in the evening.
Abemaciclib Description:

Your study drug (Abemaciclib) is supplied as 50 mg white, capsule
Abemaciclib Instructions – When and How:

Take study drug (Abemaciclib) twice a day, once in the morning and once in the evening.

Take the drugs at approximately the same time each morning and evening, so that you are taking the drugs 12 hours apart.

Fast one hour before and one hour after each dose. Take the pill(s) with a glass of water and swallow them whole; do not chew them or crush them.

Do not skip any doses.

If you forget to take your pills in the morning you can take your missed dose up to 3 hours after your normally scheduled time. If it has been more than 3 
hours, skip the dose and take the next scheduled dose at the usual time in the evening (one dose only). Please call your study nurse or doctor to discuss 
missed doses.

If you forget to take your pills in the evening, you can take your missed dose up to 3 hours after your normally scheduled time. If it has been more than 3 
hours, skip the dose and take the next scheduled dose at the usual time the next morning (one dose only). Please call your study nurse or doctor to discuss 
missed doses.

If you vomit your pills, write this down in your pill diary. Do not take a replacement dose. Take the next scheduled dose as usual (one dose only). Please 
call your study nurse or doctor to discuss vomited doses.
Additional Instructions:

You must avoid eating or drinking any foods with Seville oranges (like marmalade), grapefruit or foods or drink with grapefruit, and any exotic fruits during 
the entire treatment period.

You should drink 8 to 10 glasses of clear liquids a day for the entire treatment period.

Keep your study drug in the original container(s) at room temperature. Keep study drug away from children, persons cannot read the label, and pets.

Do not throw away empty bottles, and do not throw the study drug in the trash or flush into the toilet.

Bring this diary, all pill bottles, and any unused pills to each clinic visit. Your Treatment Team will collect your diary, all pill bottles and any unused study 
drug, and you will be given a new pill diary at that time.

Contact your study doctor or nurse if you are having any new or worsening side effects. Contact your study doctor or nurse as soon as possible if you are 
experiencing diarrhea.

Do not begin any new medication, over-the-counter drug, or herbal preparation without first checking with your study doctor or nurse to determine if it is 
acceptable to take while on this study.

Each cycle is 28 days of morning and evening pills. If you start the cycle in the evening (P.M. dose), you may end the cycle in the morning of the 29th day.

151
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
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Date:
A.M. DOSE 
No. of pills:   
 
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Date:
A.M. DOSE 
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Time:  
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Date:
A.M. DOSE 
No. of pills:   
 
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No. of pills:  
 
Time:  
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Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
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No. of pills:  
 
Time:  
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Date:
A.M. DOSE 
No. of pills:   
 
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Time:  
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Date:
A.M. DOSE 
No. of pills:   
 
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No. of pills:  
 
Time:  
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Date:
A.M. DOSE 
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Time:  
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Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
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No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
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No. of pills:  
 
Time:  
Initials
Participant/Guardian Signature:  
Date:  

152
Compare with drug diary entries made by participant or guardian. If discrepancy (in the # of bottles or the # of pills returned), please reconcile:
# of 50 mg Pills Returned:  
# of 50 mg Bottles Returned:  
To be completed by study personnel:
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
Each cycle is 28 days of morning and evening pills. If you start the cycle in the evening (P.M. dose), you may end the cycle in the morning of the 29th day.
Time:  
Participant/Guardian Signature:
Date:  
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:
Time:
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
Date:
A.M. DOSE 
No. of pills:   
 
Time:
Date:
A.M. DOSE 
No. of pills:   
 
Time:
P.M. DOSE 
No. of pills:
P.M. DOSE
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Time:
P.M. DOSE
No. of pills:  
 
Time:
P.M. DOSE
No. of pills:  
 
Time:
P.M. DOSE 
No. of pills:
P.M. DOSE
No. of pills:  
Time:
Initials
Initials
Initials
Time:
Initials
Initials
Initials
Day 29
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials

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APPENDIX G CC-115 ARM OF INSIGHT
TABLE OF CONTENTS
1.
BACKGROUND.....................................................................................................................155
2.
PARTICIPANT SELECTION ................................................................................................157
2.1
Eligibility Criteria Specific to the CC-115 Arm..............................................157
2.2
Second INSIGhT Registration: Registration to CC-115 Arm .........................158
2.2.1
Registration Process for DF/HCC Institutions ................................................158
2.2.2
Registration Process for Other Investigative Sites ..........................................158
3.
TREATMENT PLAN .............................................................................................................159
3.1
Definition of Standard Radiation Therapy ......................................................159
3.2
Treatment Regimen – CC-115 Administration................................................159
3.3
Safety Lead-In.................................................................................................160
Table: Safety Lead-In CC-115 Dose Levels ...............................................................161
3.5
General Concomitant Medication and Supportive Care Guidelines ...............162
3.6
Criteria for Taking a Participant Off Protocol Therapy ..................................164
3.7
Duration of Follow Up ....................................................................................165
3.8
Criteria for Taking a Participant Off Study.....................................................165
4.
DOSING DELAYS/DOSE MODIFICATIONS.....................................................................165
Table: CC-115 Dose Levels ........................................................................................166
4.1.1
Anticipated Toxicities for Radiation Therapy.................................................166
4.1.2
Suspected & Anticipated Toxicities for CC-115.............................................167
4.2
Dose Modifications/Delays for CC-115..........................................................167
5.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS...................................173
5.1
Expected Toxicities.........................................................................................173
5.2
Adverse Event Characteristics.........................................................................173
5.3
Expedited Adverse Event Reporting ...............................................................175
5.4
Expedited Reporting to the Food and Drug Administration (FDA)................178
5.5
Expedited Reporting to Hospital Risk Management.......................................178
5.6
Routine Adverse Event Reporting...................................................................178
5.7
Other Reporting Requirements........................................................................178
5.7.2
Overdose..........................................................................................................179
5.7.3
IND Annual Reports........................................................................................179
6.
PHARMACEUTICAL INFORMATION CC-115 ..................................................................180
6.1.1
Description ......................................................................................................180
6.1.2
Form ................................................................................................................181
6.1.3
Storage and Stability .......................................................................................181
6.1.4
Compatibility...................................................................................................181
6.1.5
Handling..........................................................................................................181
6.1.6
Availability......................................................................................................181
6.1.7
Preparation ......................................................................................................181
6.1.8
Administration.................................................................................................181
6.1.9
Ordering ..........................................................................................................182
6.1.10 Accountability.................................................................................................182
6.1.11 Destruction and Return....................................................................................182

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7.
STUDY CALENDAR.............................................................................................................183
8.
MEASUREMENT OF EFFECT.............................................................................................185
9.
REFERENCES........................................................................................................................185
DFCI REPORTABLE AE COVERSHEET – INSIGHT CC-115 ARM ............................................186
RADIATION CC-115 DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION......187
POST RADIATION CC-115 DOSING INSTRUCTIONS & DRUG DIARY...................................191

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1. BACKGROUND
1.1
CC-115 (CC0483115)
Rationale & Proposed Biomarker Association
CC-115 (CC0483115) is a potent and selective oral dual inhibitor of mammalian target of 
rapamycin (mTOR) kinase (both mTORC1 and mTORC2) and deoxyribonucleic acid-dependent 
protein (DNA PK) kinase (dual DNA-PKi/TORKi) that is in development for the treatment of
solid and hematologic malignancies [Mortensen 2015]. The PI3K/Akt/mTOR signaling axis 
plays a central role in cell growth, survival, motility, and metabolism in a variety of cancers 
[Fruman 2014, Engelman 2009], including GBM [Brennan 2013]. DNA-dependent protein 
kinase is a serine/threonine kinase involved in the repair of DNA double strand breaks [Collis 
2005, Bozulic 2008, Surucu 2008], which are considered to be the most lethal DNA lesion and 
the main driver of cellular death following treatment with ionizing radiation. Therefore, beyond 
its hypothesized growth-inhibitory effect as monotherapy, CC-115 has the potential to be a 
radiation sensitizing agent in the treatment of GBM [Zhao 2006]. There is no preclinical or 
clinical data to suggest a genomic subgroup which will be more likely to respond to treatment, 
but given the a priori hypothesis based on mechanism of action, we will consider aberrations to 
the PI3K pathway while evaluating treatment efficacy.
Preclinical data
The distribution of CC-115 into brain was investigated in male WT FVB mice and male MDR 1 
a/b KO mice (Report CC-115-DMPK-009). Following a single oral gavage dose of 5.0 mg/kg of 
CC-115, plasma exposure of CC-115 was similar in WT and KO mice. Brain exposure of CC- 
115 was 11% and 21% of plasma exposure in WT and KO mice, respectively. The brain to 
plasma ratio of exposure to CC-115 in KO mice was 1.9-fold higher than that in WT mice. These 
results suggest that P-gp contributed to some extent to the limited brain exposure of CC-115.
CC-115 inhibited U87MG xenograft tumor growth in a dose-dependent manner. The minimum 
dose required to obtain approximately 65% tumor volume reduction compared with vehicle 
control was 0.5 mg/kg QD. Significant inhibition of mTOR pathway markers S6RP and AKT 
(S473) was observed in tumor samples following a single oral dose of CC-115, indicating that 
the antitumor activity was mediated through the inhibition of both mTORC1 (S6RP) and 
mTORC2 (AKT [S473]).

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Using a GBM orthotopic PDX model with unmethylated MGMT promoter, single agent CC-115 
extended the survival of mice and was beyond that seen with mTORC1/2 inhibition alone (CC-
223) (Figure 1). No effects were seen in another model 
where MGMT was methylated (data not shown). CC- 
115 showed synergy in combination with ionizing 
radiation in several GBM neurosphere models in vitro 
(Figure 2) and enhanced the ability of radiation to limit 
tumor growth in vivo (Figure 3). Additional in vivo data 
has shown that radiation induces DNA-PK expression in 
GBM xenografts as part of the DNA damage response 
and that this response is attenuated with CC-115.
Figure 2: In vitro neurosphere formation assay demonstrating 
additivite or synergistic effect of CC-115 in combination with 
RT
Figure 3: CC-115 in combination with RT is more 
effective than either RT or CC-115 alone in limiting 
tumor growth in an in vivo GBM model.
Clinical data
One Phase 1a/1b multicenter open-label clinical study (CC-115-ST-001) demonstrated the 
maximum tolerated dose of CC-115 to be 40 mg QD and 15 mg BID, with near maximal 
inhibition of pAKT and partial inhibition of p4EBP1 at 10 mg BID. Durable mTOR inhibition 
throughout the dosing period was observed with the BID dosing schedules and was more 
pronounced at the maximum tolerated dosing schedule of 10 mg BID when compared with 25 
mg QD. DLTs in the BID cohorts were transaminase increase and stomatitis (15 mg BID).
While preclinical studies suggested limited blood-brain penetration, CC-115 showed reasonable 
penetration into GBM tissue in a surgical expansion cohort at 10 mg bid with a median 
GBM/plasma ratio of ~0.35 (0.04-1.71) (Table 1).
Table 1: Surgical expansion cohort demonstrating reasonable penetration of CC-115 into GBM at 10mg bid.
Figure 1: Improved survival in MGMT unmethylated GBM Patient Derived 
Xenograft (PDX) orthotopic model. CC-115 Dual PNA-PK/mTORC1/2i; 
CC-223 mTORC1/2i (Bergman et al. AACR 2015).

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Given the therapeutic hypothesis of radiosensitivity supported by preclinical data, CC-115 (10 
mg bid) will replace TMZ in both the concurrent and adjuvant phase of treatment. As this dose 
has never been combined with radiation therapy, we will conduct a safety lead in with the 
combination prior to expansion to the full phase II. Should this dose be found to be too toxic in 
combination with radiation, we will enroll one dose level lower. Should that combination be 
found too toxic, the combination will no longer be considered for further testing in combination 
with radiation therapy. In this case, the protocol will be amended to allow patients to receive 
radiation therapy with concomitant temozolomide followed by adjuvant single agent CC-115.
2. PARTICIPANT SELECTION
2.1
Eligibility Criteria Specific to the CC-115 Arm
Participants must meet all eligibility criteria outlined in the master protocol (section 3) and 
complete initial registration (section 4 of master protocol). Once the randomization assignment 
has been received following initial registration, all participants randomized to the CC-115 arm 
must meet the following criteria prior to participating in the CC-115 arm of the study.
2.1.1
Participants must be willing and able to provide written informed consent for the CC-115 
arm of the INSIGhT trial.
2.1.2
Women of child bearing potential (women who are not free from menses for > 2 years, 
post hysterectomy/oopherectomy, or surgically sterile) must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) from date of intial 
dose and for 28 days following the last dose of CC-115. Men (including those who have 
had a vasectomy) must agree to use barrier contraception (latex condoms) when engaging 
in sexual activity with a woman of child bearing potential from date of initial dose and 
for 28 days following the last dose of CC-115.

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2.2
Second INSIGhT Registration: Registration to CC-115 Arm
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore®. Registration to the CC-115 arm must occur following initial registration to master 
INSIGhT protocol and receipt of randomization assignment, and prior to the initiation of 
protocol therapy. Any participant not registered to their protocol specific assigned arm before 
protocol therapy begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria in section 2.1 of this sub-study appendix and a 
member of the study team will complete the protocol-specific eligibility checklist.
Following initial registration, any additional laboratory assessments prior to start of treatment 
will not be used to re-confirm eligibility. Refer to section 4 of this appendix for toxicity 
management between registration and start of study treatment.
Following second registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore® as soon as possible.
2.2.1
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.
2.2.2
Registration Process for Other Investigative Sites
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
DFCI Coordinating Center staff. All sites should contact the DFCI Coordinating Center to verify 
slot availabilities. The required forms for registration can be found in Appendix B.
Following registration, participants should begin as soon as feasible. Issues that would cause 
treatment delays should be discussed with the Overall PI. If a participant does not receive 
protocol therapy following registration, the participant’s registration on the study must be 
canceled. The Study Coordinator should be notified of cancellations as soon as possible.
Refer to Appendix B, Section 3.7 for registration details.

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3. TREATMENT PLAN
Participants treated on the CC-115 arm will receive daily radiation (60 Gy in 30 fractions) as 
described in section 3.1 of this appendix with concomitant twice daily oral dosing of CC-115, 
subsequently followed by continuous twice daily oral dosing of CC-115. Patients will not 
receive either concurrent or adjuvant temozolomide. Given the therapeutic hypothesis of 
radiosensitivity supported by preclinical data, an initial safety lead-in will be conducted as 
described in section 3.3 below.
3.1
Definition of Standard Radiation Therapy
The patient must undergo MRI based treatment planning (CT with contrast-based planning only 
if patient unable to undergo MRI). At a minimum, the contrast enhancing lesion (and/or surgical 
cavity) defined on a T1-weighted image (gross tumor volume; GTV) must be targeted with a 
minimum of a 1 cm dosimetric margin expansion to define a planning target volume (PTV). The 
margin may be reduced around natural barriers to tumor growth, and also to allow sparing of 
organs at risk, if necessary. The volume must be treated to a prescribed dose of 59.4 Gy in 33 
fractions or 60 Gy in 30 fractions. Treatment with larger volumes to the contrast-enhancing 
region is acceptable. Treatment or no treatment of the T2/FLAIR abnormality is acceptable.
Because this is optional, dosimetric expansion and dose-fractionation for the T2/FLAIR volume 
are not specified here. The prescribed dose to the T2/FLAIR volume may not exceed 60 Gy.
Radiation therapy must be completed within an overall treatment time of less than 52 calendar 
days. Maximum dose (defined as a volume greater than 0.03 cc) to critical structures include: 60 
Gy to the brainstem, 56 Gy to the optic chiasm, 55 Gy to the optic nerves, and 50 Gy to the 
retinae.
Participants are permitted to have radiotherapy as described in this section performed at any NCI 
funded cooperative group site. Prospective Overall PI approval, or approval by his designee 
(other Coordinating Center radiation oncologists), is required for any radiotherapy site that is not 
an NCI funded cooperative group site. At the discretion of the DFCI Coordinating Center, a 
radiation plan may be requested to be prospectively approved for a non-NCI site prior to 
initiating radiotherapy at the site. Any questions regarding permitted radiotherapy sites should 
be directed to the DFCI Coordinating Center or Overall PI Patrick Y. Wen, MD.
3.2
Treatment Regimen – CC-115 Administration
The study drug, CC-115, will be administered on an outpatient basis. The investigator will 
instruct the participant to take the study drug exactly as specified in the protocol. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient’s malignancy.
Participants should be instructed to take the oral dose of 10 mg CC-115 every 12 hours. CC-115 
should begin the same day as the participant’s radiation therapy and continue through radiation 
until beginning of adjuvant CC-115 cycles. The initial 10 weeks on-study will be referred to as 
the initiation cycle (approximately 6 weeks of RT + CC-115, followed by 4 weeks of CC-115) 
and after the initial 10-weeks cycles will be referred to as adjuvant cycles. Adjuvant cycle

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length will be 28 days, even if treatment is held mid-cycle for toxicity, and there will be no 
rest period between cycles. If a participant, including safety lead-in participants, is dose 
reduced during the initial 10 weeks of treatment, then the dose of CC-115 may be escalated one 
dose level at the start of adjuvant Cycle 2if the investigator determines that it is in the best 
interest of the participant.
CC-115 should be taken orally with water and consumed over as short a time as possible. Each 
morning dose will be taken with water and each evening dose (taken approximately 12 hours 
after the morning dose) should be taken with water. CC-115 may be taken up to 3 hours late if 
dosing has been delayed on a single day; otherwise that dose should be omitted.
Participants should swallow the capsules as a whole and not chew them. Participants must avoid 
consumption of Seville orange (and juice), grapefruit or grapefruit juice, grapefruit hybrids, 
pummelos and exotic citrus fruits from 7 days prior to the first dose of study drug and during the 
entire study treatment period due to potential CYP3A4 interaction. Additional drug 
administration instructions, including missed dose policy, are described in section 6.1.8 of this 
appendix and are included in the participant pill diary (section 11 & section 12 of this appendix).
All dosages prescribed and dispensed to the participant and all dose changes during the study 
must be recorded. If a participant requires a CC-115 dose delay of > 28 days from the previous 
dose, the participant must be discontinued from treatment completely. In the exceptional case 
where the investigator feels the patient would benefit from continuing therapy the case can be 
discussed with the Overall PI Patrick Y. Wen at pwen@partners.org or 617-632-2166. Expected 
toxicities and dose reductions and modifications are detailed in section 4 of this appendix.
NOTE: Study treatment may be held > 28 days in order to allow for surgical pathology to 
determine progression versus pseudoprogression outside of the 12-week consideration mark if it 
is prospectively confirmed with Overall PI to be clinically appropriate to do so.
Participants will keep a medication diary (see sections 11 & section 12 of this appendix). At the 
end of each cycle, the diary will be returned and a new one will be given to the participant.
Participants are to return all pill bottles and unused pills.
3.3
Safety Lead-In
Because there is no safety data available for CC-115 in combination with radiotherapy, a safety 
lead-in will be conducted utilizing a 3+3 design, including 3-6 patients in each cohort, to 
determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of CC-115 
when administered with radiation therapy.   The MTD will be defined as the dose at which ≤ 
33% of patients experience a DLT and the MTD/RP2D CC-115 dose will then be incorporated 
into the phase II portion of the arm. The first 12 participants enrolled to this arm will be 
considered as safety lead-in and observed for DLTs for 10 weeks (see section 3.4 below for DLT 
definitions) as follows:

If at Dose Level 0, ≤ 1 of the first 3 participants develop a DLT, 3 more participants will 
be enrolled at Dose Level 0. Then, if ≤ 2 of the 6 participants treated at Dose Level 0 
experience a DLT, an additional 6 participants will be enrolled at Dose Level 0. Then, if
≤ 3 of the 12 participants treated experience a DLT, Dose Level 0 will be considered the 
MTD.

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
If at Dose Level 0, > 1 of the first 3 participants , > 2 of the first 6 participants or > 3 of 
the first 12 participants develop a DLT, enrollment to Dose Level 0 will stop and 
subsequent enrollment will begin at Dose Level -1.

If at Dose Level -1, ≤ 1 of the first 3 participants develop a DLT, 3 more participants will 
be enrolled at Dose Level -1. Then, if ≤ 2 of the 6 participants treated at Dose Level -1 
experience a DLT, an additional 6 participants will be enrolled at Dose Level -1. Then, if
≤ 3 of the 12 participants treated experience a DLT, Dose Level -1 will be considered the 
MTD.

If at Dose Level -1, > 1 of the first 3 participants, > 2 of the first 6 participants, or > 3 of 
the first 12 participants develop a DLT, enrollment to Dose Level -1 will stop and 
subsequent enrollment will begin at Dose Level -2.

If at Dose Level -2, ≤ 1 of the first 3 participants develop a DLT, 3 more participants will 
be enrolled at Dose Level -2. Then if ≤ 2 of the 6 participants treated at Dose Level -2 
experience a DLT, an additional 6 participants will be enrolled at Dose Level -2. Then if
≤ 3 of the 12 participants treated experience a DLT, Dose Level -2 will be considered the 
MTD.

If at Dose Level -2, > 1 of the first 3 participants, > 2 of the first 6 participants, or > 3 of 
the first 12 participants treated at Dose Level -2 experience a DLT, administration of
CC-115 in combination with radiation therapy and the appendix will be amended to allow 
patients to receive therapy with concomitant temozolomide followed by adjuvant single 
agent CC-115.
Table: Safety Lead-In CC-115 Dose Levels
Dose Level
Dose of CC-115
0
(starting dose)
10 mg every 12 hours
-1
7.5 mg every 12 hours
-2
5 mg every 12 hours
3.4
Definition of Dose-Limiting Toxicity (DLT)
A DLT is defined as a clinically significant adverse event considered at least possibly related to 
CC-115 and meets any of the criteria below during the first 10 weeks of study treatment (referred 
to as the initiation cycle). If a participant comes off for reasons other than a dose-limiting 
toxicity during the DLT period, he/she will be replaced.
Dose limiting toxicities are defined below. A DLT must have an attribution of possible, 
probable, or definite to CC-115 and meets the below criteria. For patients experiencing a DLT 
during the safety lead-in portion of the study, CC-115 must be discontinued. If there is any 
question concerning a DLT, sites should contact the DFCI Coordinating Center to determine 
patient’s DLT status. The Coordinating Center with the Overall PI will make the final decision.

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
Hematological toxicities will be considered dose limiting if any of the following 
occur (grade 3 or 4 lymphopenia will not be considered a DLT):
o
ANC of < 500/mm3 for > 7 days
o
Platelets < 25,000/mm3 for > 48 hours or platelets < 50,000/mm3 with clinically 
significant bleeding
o
≥ Grade 3 febrile neutropenia (ANC < 1.0 × 109/L and fever > 101°F/38.3°C)
o
Any hematologic toxicity that prevents administration of CC-115 for > 28 days

Non-hematological toxicities will be considered dose limiting if any of the following 
occur:
o
Inability to complete ≥ 75% of RT due to toxicity related to or exacerbated by CC-115 
added to Radiation Therapy.
o
Grades 3-4 severity, with the following exceptions:

Nausea, vomiting, and diarrhea without sufficient prophylaxis

Grade 3 hyperglycemia lasting ≤ 4 days (with optimal medical 
management) and grade 4 hyperglycemia lasting < 12 hours (with optimal 
medical management)

≥ grade 3 rash of the acneiform or maculopapular type for no more than a 
4 day duration (with optimal medical management)

Grade 3 electrolyte disturbances that are asymptomatic and that respond to 
replacement or intervention (e.g. IV fluids) within 48 hours

Grade 3 neurologic toxicity responding within two weeks to steroids, 
anticonvulsants, or electrolyte correction

A subject’s first episode of deep venous thrombosis (DVT) or pulmonary 
embolism will not require dose modification or be considered a DLT since 
this is very common in glioblastoma patients
3.5
General Concomitant Medication and Supportive Care Guidelines
Participants must be instructed not to take any additional medications (including over-the- 
counter products) during the trial without prior consultation with the investigator. All 
medications taken from date of initial consent and up to 30-day follow-up contact should be 
recorded. If concomitant therapy must be added or changed, including over-the-counter 
medications or alternative therapies, the reason and name of the drug/therapy should be recorded.
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
participant are allowed, including drugs given prophylactically (e.g. antiemetics) with the 
following exceptions:
3.5.1
Strong CYP3A inhibitors and CYP3A inducers are prohibited. In vitro studies 
suggest that CC-115 is a sensitive CYP3A4 substrate. Co-administration of CC- 
115 with strong CYP3A4 inhibitors is predicted to increase the systemic exposure 
to CC-115; likewise CYP3A inducers can be expected to decrease systemic 
exposure to CC-115, possibly resulting in sub-therapeutic drug levels. Refer to 
Appendix C of master INSIGhT protocol for a list of prohibited drugs. Please note 
that this list may not be comprehensive.
3.5.2
Caution should be exercised when co-administering CC-115 with narrow 
therapeutic drugs that are substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2D6, or CYP3A. Participants receiving such medications must be monitored 

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for potentiation of toxicity due to any individual concomitant medications, and 
may require dose titration or reduction of the drug substrate. Refer to Appendix C 
of master INSIGhT protocol for a list of drugs. Please note that this list may not 
be comprehensive
3.5.3
Herbal preparations/medications are not allowed throughout the study. These 
herbal medications include, but are not limited to: St. John’s wort, Kava, ephedra 
(ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, ginseng. Participants should stop using any herbal medications 7 days 
prior to first dose of study drug.
3.5.4
Corticosteroids should be used in the smallest possible dose to control symptoms 
of cerebral edema and mass effect, and discontinued if possible. Chronic dosing 
of corticosteroids is known to induce CYP3A enzymes, thereby increasing the 
risk of reducing CC-115 drug exposure to sub-therapeutic levels.
3.5.5
Anti-seizure medications should be used as indicated. Only participants receiving 
non-EIAEDs are eligible. If for unavoidable clinical reasons (emergency 
department visit, severe allergies, toxicities, etc.) a participant’s AED is switched 
to another AED, the following guidelines must be followed if applicable:
o
Participants should be started on another non-EIAED if at all possible.
o
Participants who are inadvertently and temporarily changed to an EIAED 
should immediately be changed to an alternative non-EIAED.
o
Participants who need to permanently change anticonvulsant, but who 
cannot change to another non-EIAED, must be discussed with the PI.
3.5.6
Febrile neutropenia may be managed according to the local institution's 
guidelines. Measures may include appropriate laboratory testing, including blood 
and urine cultures and the institution of broad-spectrum antibiotics. If a source for 
the fever is not identified or the fever resolves when the neutrophil count 
recovers, antibiotics may be discontinued and the participant observed.
3.5.7
G-CSF: Routine prophylactic use of G-CSF is not permitted. However, 
therapeutic use in participants with serious neutropenic complications, such as 
sepsis, may be considered at the investigator’s discretion.
3.5.8
Antiemetics: The use of antiemetics will be left to the investigators’ discretion.
3.5.9
Pneumocystis jirovecii pneumonia (PJP) prophylaxis: Since participants with 
GBM are at increased risk of developing PJP, especially if they are on 
corticosteroids, prophylaxis for PJP may be considered per institutional practice.
3.5.10 Anticoagulants: Because of the potential for its interaction with study 
medications, warfarin sodium (Coumadin®), or any other coumadin-derivative 
anticoagulant, is not permitted at any dose. Low-molecular weight heparin and Xa 
inhibitors are permitted. If for unavoidable clinical reasons (emergency 
department visit, severe allergy, toxicity, etc) participants are started on warfarin, 
they must change to a low molecular weight heparin immediately in the interest of 
subject safety.
3.5.11 Surgery: If neurosurgical management is required for reasons not due to tumor 
progression, these procedures must be documented, including the indications for 
surgery, the operative note, and pathology report.
3.5.12 Other anticancer or experimental therapies: No other anticancer therapy of any 

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kind is permitted during the study treatment period. No other drug under 
investigation may be used concomitantly with the study drug.
3.5.13 Other concomitant medications: Therapies considered necessary for the well 
being of the participant may be given at the discretion of the investigator. Other 
concomitant medications should be avoided except for analgesics, chronic 
treatments for concomitant medical conditions, or agents required for life- 
threatening medical problems. All concomitant medications must be recorded.
3.5.14 CC-115 related mucositis and mouth ulcers should be treated as early as possible 
and according to institutional standard medical practice. This may include 
analgesics, topical preparations (suspensions, pastes), and short courses of 
systemic steroids with temporary dose interruption and/or dose reduction for more 
severe cases. Alcohol or peroxide-containing mouthwashes should be avoided.
3.5.15 Acute renal insufficiency has been reported with mTOR pathway inhibitors. 
Typically this has been associated with drug-related gastrointestinal toxicities 
(anorexia, nausea, vomiting, diarrhea, mucositis) leading to dehydration and 
electrolyte abnormalities. Subjects should be monitored closely for these 
toxicities and treated with rehydration, antiemetics, and antidiarrheals as 
medically indicated. CC-115 dose interruption or modification may be indicated 
to manage these toxicities.
3.5.16 Infections (including the SAEs of pneumonia, sepsis, and nonserious AEs of 
infection) and associated pyrexia were reported with CC-115. Vigilance for the 
signs and symptoms of infection should be practiced with subjects receiving 
treatment with CC-115 and managed according to institutional standard medical 
practice. Routine infectious disease prophylaxis is not recommended; however, 
antibiotic, antiviral, antipneumocystis, antifungal, or other prophylaxis may be 
implemented during the study at the discretion of the investigator.
3.6
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue on 
the CC-115 arm until one of the following criteria applies:

Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply. The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.

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A ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the ODQ website or obtained from the ODQ 
registration staff.
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Patrick Y. Wen, MD, at 617-632-2166 or pwen@partners.org.
3.7
Duration of Follow Up
Participants will be followed until death with monthly visits, telephone contact, or medical 
record review. Participants removed from protocol therapy for unacceptable adverse event(s) 
will be followed until resolution or stabilization of the adverse event. Refer to section 7 study 
calendar within this appendix for follow-up requirements and time points.
3.8
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).
A ODQ Treatment Ended/Off Study Form will be filled out when a participant comes off study. 
This form can be found on the ODQ website or obtained from the ODQ registration staff.
4. DOSING DELAYS/DOSE MODIFICATIONS
For participants who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the participant on study drug. If administration of CC- 
115 must be interrupted because of unacceptable toxicity, drug dosing will be interrupted or 
modified according to rules described in this section.
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.03 can be downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
In the case of toxicity, appropriate medical treatment should be used (including anti-emetics, 
anti-diarrheals, etc.).
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and the 30 day post study visit. Participants continuing to 
experience toxicity at the end-of treatment visits may be contacted for additional assessments 
until the toxicity has resolved or is deemed irreversible.
All participants will be initially treated at Dose Level 0.

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Table: CC-115 Dose Levels
Dose Level
Dose of CC-115
0
(starting dose)
10 mg every 12 hours
-1
7.5 mg every 12 hours
-2
5 mg every 12 hours
4.1
Anticipated Toxicities
In order for an event to be considered expected (known correlation to study drug/treatment) for the 
purposes of adverse event reporting, the event must be:

Included in this section for CC-115.

Included in this section or included in the package insert or the informed consent document 
as a potential risk for radiation therapy.
NOTE: For events that are secondary to an event deemed expected with a study agent/modality (e.g. 
rectal pain or hypokalemia as a result of diarrhea or gait disturbance as a result of edema cerebral), 
please record as “possibly related to” and “expected with” the agent/modality.
4.1.1
Anticipated Toxicities for Radiation Therapy
A list of adverse events of all grades suspected to be radiation therapy treatment related, 
organized by CTCAE v4.03 category, includes:

EAR AND LABYRINTH DISORDERS – external ear inflammation; other: dryness 
of ear canal; other: hardening of ear canal wax; external ear pain; other: hearing loss

ENDOCRINE DISORDERS - other: hypophysitis, or hypopituitarism

EYE DISORDERS – cataract; other: decreased vision

GASTROINTESTINAL DISORDERS – nausea; vomiting

GENERAL DISORDERS – fatigue

INJURY, POISONING AND PROCEDURAL COMPLICATIONS – dermatitis 
radiation; injury other: optic nerve

INVESTIGATIONS –lymphocyte count decreased

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS – generalized 
muscle weakness*

NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED – treatment related 
secondary malignancy

NERVOUS SYSTEM DISORDERS – headache; seizure; memory impairment; 
cognitive disturbance; somnolence; dysgeusia; central nervous system necrosis; 
edema cerebral; other: tumor inflammation**

PSYCHIATRIC DISORDERS – personality change

SKIN AND SUBCUTANEOUS TISSUE DISORDERS – scalp pain; other: scalp 
redness; alopecia

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4.1.2
Suspected & Anticipated Toxicities for CC-115
A list of adverse events of all grades suspected to be CC-115 treatment related according 
to review of Investigator’s Brochure, experience with other drugs in the same class and 
preclinical data, organized by CTCAE v4.03 category, includes:

BLOOD & LYMPHATIC SYSTEM DISORDERS – white blood cell decreased; 
platelet count decreased; anemia; lymphocyte count decreased

GASTROINTESTINAL –diarrhea; nausea; vomiting; mucositis oral

GENERAL DISORDERS- fatigue; fever

INFECTIONS & INFESTATIONS –infection***; sepsis

INVESTIGATIONS – creatinine increased; weight loss; aspartate aminotransferase 
increased; alanine aminotransferase

METABOLISM & NUTRITION DISORDERS – anorexia; dehydration; 
hyperglycemia; hyponatremia; cholesterol high; hypertriglyceridemia,

RENAL AND URINARY DISORDERS – acute kidney injury

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS – pneumonitis; 
hypoxia; pleural effusion; cough; dyspnea; respiratory failure

SKIN AND SUBCUTANEOUS TISSUE DISORDERS –rash acneiform; rash 
maculopapular; photosensitivity

VASCULAR DISORDERS – thromboembolic events
*
“Generalized muscle weakness” to also include other CTCAE terms inclusive of a muscle weakness
** As CTCAE v. 4 recognizes ‘Edema cerebral’ only as a Gr4 event, please record events of ‘Edema 
cerebral’ deemed by Investigator to be Gr1-Gr3 or Gr5 as ‘Nervous system disorders, Other: Tumor 
inflammation’ (Gr1-Gr3 or Gr5, accordingly).
*** General term “infection” to include all CTCAE infections
4.2
Dose Modifications/Delays for CC-115
4.2.1
Table 4.2 should be adhered to for all toxicities considered at least possibly related to 
CC-115. If a participant experiences a toxicity unlikely or unrelated to treatment with
CC-115, but may still warrant a hold or reduction of study drug for safety, discussion and 
approval by Overall Principal Investigator and Study Sponsor, Patrick Y. Wen, MD, is 
strongly recommended.
4.2.2
When treatment must be held pending resolution of toxicity to grade 1 or return to 
baseline, and the toxicity is a lab abnormality, in cases where participant had a pre- 
existing laboratory abnormality at baseline, the toxicity can be considered “resolved” 
from a hold perspective when it has resolved to within 1 grade of the baseline value.
NOTE: For the purposes of data entry, values from screening assessments should be 
entered in as ‘baseline’ values.   However, true “baseline values” - for the purpose of 
dose modifications on study, etc. - will be considered the last assessments/tests performed 
prior to initiation of study therapy.
EXCEPTION: In instances where the value within 1 grade of the baseline value would 
still require a hold, continue to hold until resolution of toxicity to grade 1 or return to 
baseline.

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4.2.3
Participants who experience an adverse event that requires a treatment delay or dose 
reduction should be monitored with appropriate laboratory testing or other clinical 
evaluation at least weekly until resolution.
4.2.4
Following a dose delay which resumes mid cycle, day 1 procedures not associated with 
the adverse event do not need to be repeated.
4.2.5
No more than 1 levels of dose reduction are permitted in this study. Participants cannot 
be treated below dose level -2. If a participant whose CC-115 dose has been reduced by 1 
dose levels requires another dose reduction, treatment on study must be stopped unless 
the participant has benefited from the study, in which case the investigator will contact 
the overall Principal Investigator, Dr. Patrick Y. Wen, to determine if the participant will 
remain in the study.
4.2.6
A treatment delay of up to 28 days is permitted. If the toxicity has not resolved after a 4- 
week delay, the participant must be removed from study treatment unless the participant 
has benefited from the study, in which case the investigator may contact the Overall 
Principal Investigator, Dr. Patrick Y. Wen, to determine if the participant will remain in 
the study.
4.2.6.1
NOTE: Study treatment may be held > 28 days in order to allow for surgical 
pathology to determine progression versus pseudoprogression outside of the 12-week 
consideration mark if it is prospectively confirmed with Overall PI to be clinically 
appropriate to do so.
4.2.7
Dose re-escalation (after dose reduction for toxicity) will only be permitted if a 
participant (including safety lead-in participants) is dose reduced during the initial 10 
weeks of treatment (DLT period), then the dose of CC-115 may be escalated at the start 
of adjuvant Cycle 1 to dose level 0 if the treating investigator determines that it is in the 
best interest of the participant. Otherwise, no dose re-escalation is permitted on study.
4.2.8
Cycle length will be 4 weeks (28 days), even if treatment is held for toxicity. There 
is no stopping in counting cycles/days for those periods where a subject’s drug is 
withheld. All study evaluations and treatments should continue as if study treatment is 
not being held.
4.2.9
Participants whose treatment is interrupted or permanently discontinued due to an 
adverse event or clinically significant laboratory value, must be followed as outlined in 
Table 4.2, at least once a week for 4 weeks, and subsequently at 4-week intervals, until 
resolution or stabilization of the event, whichever comes first. All participants must be 
followed for adverse events and serious adverse events for 30 days following the last 
dose of CC-115. All SAEs must be reported as detailed in section 5.3 of this appendix.

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Table 4.2: Criteria for dose-modification and re-initiation of CC-115 treatment
Table 4.2 should be adhered to for all toxicities attributable (considered at least possibly related) 
to CC-115 as noted below. If a participant experiences a toxicity unlikely or unrelated to 
treatment with CC-115 but may still warrant a hold or reduction of study drug for safety, 
discussion and written approval by Overall Principal Investigator and Study Sponsor, Patrick Y. 
Wen, MD is strongly recommended.
Toxicity
(organized by CTCAE v 4.03)
Actions
Investigations (for hyperglycemia, see Metabolism disorders)
ALT/SGPT or AST/SGOT
- Grade 2 (>3.0- 5.0 x ULN)
First Occurrence:
Interrupt until resolution to ≤ grade 1, then

If resolution to grade ≤1 in ≤ 10 days, resume CC-115 at the current 
dose level

If resolution to ≤ grade 1 takes > 10 days, resume CC-115 at one lower 
dose level
Second/Third Occurrence:
Interrupt until resolution to ≤ grade 1, then resume CC-115 at one lower dose 
level
ALT/SGPT or AST/SGOT
- Grade 3
(> 5.0 - 20.0 x ULN)
First Occurrence:
Interrupt until resolution to ≤ grade 1, then

If resolution to grade ≤1 in ≤ 10 days, resume CC-115 at the current 
dose level

If resolution to ≤ grade 1 takes > 10 days, resume CC-115 at one lower 
dose level
Once resolved to ≤ grade 1, monitor liver function tests every other week or 
more frequently if clinically indicated until the end of treatment with study 
medication.
Second/Third Occurrence:
Interrupt until resolution to ≤ grade 1, then resume CC-115 at one lower dose 
level.
Once resolved to ≤ grade 1, monitor liver function tests every other week or 
more frequently if clinically indicated until the end of treatment with study 
medication.
ALT/SGPT or AST/SGOT
- Grade 4 (>20.0 x ULN)
Interrupt CC-115 until resolution to ≤ grade 1, then resume CC-115 at one lower 
dose level
Once resolved to ≤ grade 1, monitor liver function tests every other week or 
more frequently if clinically indicated until the end of treatment with study 
medication.
Amylase, asymptomatic
- Grade 3 (> 2.0 - 5.0 x ULN)
First Occurrence:
Interrupt until resolved to ≤ grade 1, then:

If resolution to grade ≤1in ≤ 10days, resume CC-115 at the current dose 
level;

If resolution to grade ≤1 in > 10days, resume CC-115 at one lower dose 
level
Second/Third Occurrence:
Interrupt until resolution to ≤ grade 1, then resume CC-115 at one lower dose 
level

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Amylase
- Grade 4 (> 5.0 x ULN)
Discontinue CC-115
Bilirubin (for patients with Gilbert Syndrome, these dose modifications apply to changes in direct bilirubin 
only) will be fractionated if elevated
Bilirubin*
- Grade 2 (>1.5 - 3 x ULN)
First Occurrence:
Interrupt CC-115 until resolution to ≤ grade 1, then:

If resolution to grade ≤1 in ≤ 10days, resume CC-115 at the current 
dose level;

If resolution to ≤ grade 1 takes > 10days, resume CC-115 at one lower 
dose level
Second/Third Occurrence:
Interrupt until resolution to ≤ grade 1, then resume CC-115 at one lower dose 
level
Bilirubin*
- Grade 3
(> 3.0 – 10.0 x ULN)
Interrupt CC-115 until resolution to ≤ grade 1, then:

If resolution to grade ≤1 in ≤ 10days, resume CC-115 at one lower dose 
level;

If resolution to ≤ grade 1 takes > 10days, discontinue CC-115
Bilirubin
- Grade 4 (> 10.0 x ULN)
Discontinue CC-115
* For participants with Gilbert’s syndrome prior to registration, the clinician may choose to continue CC-115 for 
elevations in total bilirubin that are two times the participant’s baseline value (screening value). For total 
bilirubin that is greater than two times the baseline value, follow dose modification guidelines as outlined in the 
above table. However, in place of resolution to ≤ grade 1, CC-115 may resume once resolution to ≤ 2 x baseline 
value.
Cholesterol high and/or 
hypertriglyceridemia
-Grade 2
Maintain dose if tolerable; recommend initiating treatment
Cholesterol high and/or 
hypertriglyceridemia
-Grade 3
Omit dose of CC-115 and initiate treatment until resolved to ≤ grade 1, then 
restart at one lower dose level.
Cholesterol high and/or 
hypertriglyceridemia
-Grade 4
Discontinue CC-115
Creatinine
- Grade 2 (>1.5 - 3 x ULN)
First Occurrence:
Interrupt treatment until resolution to ≤ grade 1, then
• If resolved to ≤ grade 1 in ≤ 10days, resume CC-115 at the current dose level
• If resolution to ≤ grade 1 takes > 10days, resume CC-115 decreased by one 
dose level
Second/Third Occurrence:
Interrupt until resolution to ≤ grade 1, then resume CC-115 at one lower dose 
level
Creatinine
- Grade 3 (> 3.0 - 6.0 x ULN)
- Grade 4 (> 6.0 x ULN)
Discontinue CC-115
Lipase elevation, 
asymptomatic
- Grade 3 (> 2.0 - 5.0 x ULN)
First Occurrence:
Interrupt until resolved to ≤ grade 1, then:
• If resolution to grade ≤1 in ≤ 10 days, resume CC-115 at the current dose level;
• If resolution to grade ≤1 in > 10 days, resume CC-115 at one lower dose level 
Second/Third Occurrence:
Interrupt until resolution to ≤ grade 1, then resume CC-115 at one lower dose 
level

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Lipase elevation, 
asymptomatic
- Grade 4 (> 5.0 x ULN)
Discontinue CC-115
Neutropenia
- Grade 3
-  (ANC 0.5 - 0.9 x 
109/L)Grade 4
(ANC < 0.5 x 109/L)
(see Blood Disorders for 
Febrile Neutropenia)
First Occurrence:
Interrupt until resolved to ≤ grade 1, then:

If resolution to grade ≤1 in ≤ 7 days, then resume CC-115 at the current 
dose level

If resolution to grade ≤1 in > 7 days, then resume CC-115 at one lower dose 
level
Second/Third Occurrence:
Interrupt until resolution to ≤ grade 1, then resume CC-115 at one lower dose 
level
Thrombocytopenia
- Grade 3
(PLT 25-49 x 109/L)
First Occurrence:
Interrupt until resolved to ≤ grade 1, then:

If resolution to grade ≤1 in ≤ 14 days, resume CC-115 at the current dose 
level

If resolution to grade ≤1 in > 14 days, then resume CC-115 at one lower 
dose level
Second/Third Occurrence:
Interrupt until resolution to ≤ grade 1, then resume CC-115 at one lower dose 
level
Thrombocytopenia
- Grade 4 (PLT < 25 x 109/L)
Interrupt until resolved to ≤ grade 1, then resume CC-115 at one lower dose 
level
Blood and lymphatic system disorders
Febrile neutropenia
- ANC < 1.0 x 109/L with a single 
temperature of > 38.3 °C (101 F) or 
a sustained temperature of ≥ 38°C 
(100.4 F) for more than one hour
Interrupt treatment until resolved, then resume CC-115 at one lower 
dose level. Febrile neutropenia should be managed promptly with broad- 
spectrum antibacterial therapy, including coverage for enteric (gram- 
negative and anaerobic) bacteria. If neutropenic fever persists for 5 days 
despite broad-spectrum antibacterial therapy, empiric antifungal therapy 
should be initiated. Anemia and thrombocytoenpia should be treated 
supportively and if necessary, with red cell or platelet transfusions.
Gastrointestinal Disorders
Diarrhea
- Grade 2 (4-6 stools/day > pretx)
Early treatment of diarrhea is recommended. Patients should be 
instructed to initiate anti-diarrheal therapy (such as loperamide) and 
notify the investigator at the first sign of loose stool. Investigators should 
assess the response of anti-diarrheal therapy within 24 hours of 
notification. If diarrhea can be controlled with optimal anti-diarrheal 
treatment within 48 hours to either baseline or grade 1, continue CC-115. 
If not, interrupt treatment until resolved to ≤ grade 1, then resume CC- 
115 at the current dose.
Diarrhea
- Grade 3 (≥7 stools/day > pretx)
- Grade 4
(urgent intervention indicated)
Early treatment of diarrhea is recommended. Patients should be 
instructed to initiate anti-diarrheal therapy (such as loperamide) and 
notify the investigator at the first sign of loose stool. Investigators should 
assess the response of anti-diarrheal therapy within 24 hours of 
notification. If diarrhea can be controlled with optimal anti-diarrheal 
treatment within 48 hours to either baseline or grade 1, continue CC-115. 
If not, for diarrhea ≥ Grade 3, interrupt treatment until resolved to ≤ 
grade 1, then resume CC-115 at one lower dose level.

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General Disorders
Fatigue Grade 1 & 2
Maintain dose level. Initiating a stimulant agent is recommended.
Fatigue
- Grade 3
First / Second Occurrence:
Interrupt CC-115 until resolved to ≤ grade 1, then:

If resolved in ≤ 14 days, resume CC-115 at the current dose level

If resolved in > 14 days, resume CC-115 at one lower dose level 
Third Occurrence:
Interrupt until resolution to ≤ grade 1, then resume CC-115 at one lower 
dose level
Metabolism and Nutrition disorders
Hypercalcemia 
Grade 1-3
Management of hypercalcemia per local institutional guidelines. CC-115 
administration will continue daily. For patients requiring hospitalization for 
management of hypercalcemia, CC-115 administration should be held until 
resolution to < grade 1 and resumed at one dose level lower.
Hypercalcemia 
Grade 4
Management of hypercalcemia per local institutional guidelines. CC-115 
administration should be held until resolution to < grade 1 and resumed at 
one dose level lower.
Hyperuricemia 
Grade 1-4
Management of hyperuricemia per local institutional guidelines. CC-115 
administration will continue daily. If grade 4 persists > 14 days despite 
medical management, CC-115 administration should be held until resolution 
to < grade 1 and resumed at one dose level lower.
Hypophosphatemia 
Grade 1-4
Initiate phosphorous supplementation daily. CC-115 administration will 
continue daily. If grade 4 persists > 14 days despite medical management, 
CC-115 administration should be held until resolution to < grade 1 and 
resumed at one dose level lower.
Nervous system disorders
Neurotoxicity ≥ 1 CTCAE grade 
level increase, attributable to 
drug
Maintain dose level
Neurotoxicity ≥ Grade 3, 
attributable to drug
Interrupt CC-115 until resolved to ≤ grade 1 or baseline, then resume CC- 
115 at one lower dose level
Skin and subcutaneous tissue disorders
Any Rash 
Grade 1
Maintain dose level. Consider initiating appropriate skin toxicity therapy 
such as antihistamines.
Any Rash 
Grade 2
Maintain dose level. Initiate/intensify appropriate skin toxicity therapy such 
as antihistamines.
Any Rash 
Grade 3
Interrupt CC-115 until resolution to CTCAE Grade ≤ 1, then:

If resolved in ≤ 7 days, resume CC-115 at one lower dose level

If resolved in > 7 days (despite appropriate skin toxicity therapy), 
discontinue participant from study drug treatment.
Any Rash
Grade 4
Discontinue CC-115

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Other unspecified RELATED adverse events
Other unspecified Grade 1 and 2 
events considered at least 
possibly related to CC-115
Maintain treatment with CC-115
Other unspecified Grade 3 
clinically significant events 
considered at least possibly 
related to CC-115
Interrupt treatment until resolution to ≤ grade 1 or returned to baseline, 
treatment may resume at the same dose level or a 1 dose level decrease, at 
the investigator’s discretion. Continuation of CC-115 is permitted upon 
recovery to stable Grade 2 if the investigator and overall principal 
investigator (Dr. Patrick Y. Wen) agree that the event is not considered 
clinically significant.
Other unspecified Grade 4 
events considered at least 
possibly related to CC-115
Discontinue CC-115
5. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of reported and/or potential AEs (section 4.1 of this appendix) and the 
characteristics of an observed AE (section 5.2 of this appendix) will determine whether the event 
requires expedited reporting in addition to routine reporting.
This section specifies reporting requirements to the FDA, Overall PI/Coordinating Center, 
DF/HCC IRB, and manufacturer as applicable.
5.1
Expected Toxicities
Refer to section 4.1 of this appendix for expected toxicities for assigned study treatment 
arm.
5.2
Adverse Event Characteristics

Adverse Event (AE) Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a preexisting medical condition in a clinical investigation subject 
administered an investigational (medicinal) product and that does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of investigational product, whether or not considered 
related to the investigational product.
Abnormal laboratory values or diagnostic test results constitute adverse events only if 
they induce clinical signs or symptoms or require treatment or further diagnostic tests.
Adverse events experienced by participants will be collected and reported from initiation 
of study medication, throughout the study, and within 30 days of the last dose of study

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medication. Participants who experience an ongoing adverse event related to a study 
procedure and/or study medication beyond 30 days will continue to be contacted by a 
member of the study team until the event is resolved, stabilized or determined to be 
irreversible by an investigator.

CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version
4.03 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.03. A copy of the CTCAE version 4.03 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

For expedited reporting purposes only:
-
AEs for the agent(s) that are listed in section 4.1 of this appendix should be reported 
only if the adverse event varies in nature, intensity or frequency from the expected 
toxicity information which is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol- 
Specific Expedited Adverse Event Reporting Exclusions.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.

Serious Adverse Event (SAE) Definition:
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless 
of causality that:
o
Results in death
o
Is life-threatening (i.e., in the opinion of the Investigator, the subject is at 
immediate risk of death from the AE);
o
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
o
Results in persistent or significant disability/incapacity (a substantial disruption of 
the subject’s ability to conduct normal life functions);
o
Is a congenital anomaly/birth defect;
o
Constitutes an important medical event. Important medical events are defined as 
those occurrences that may not be immediately life threatening or result in death, 
hospitalization, or disability, but may jeopardize the subject or require medical or 
surgical intervention to prevent one of the other outcomes listed above. Medical 
and scientific judgment should be exercised in deciding whether such an AE 
should be considered serious.

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5.3
Expedited Adverse Event Reporting
5.3.1
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment.
5.3.2
For multi-institution studies where a DF/HCC investigator is serving as the Overall 
Principal Investigator, each participating institution must abide by the reporting 
requirements set by the DF/HCC. This applies to any medical event that is Serious, 
Unexpected, and there is a Reasonable Possibility (i.e., possible, probable, or definitive 
attribution) the Adverse Event is related to the study intervention.
5.3.3
Expedited Reporting Guidelines to Overall PI/Coordinating Center & Celgene
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.
Other investigative sites outside of DF/HCC will report AEs to their respective IRB 
according to the local IRB’s policies and procedures in reporting adverse events. A copy 
of the AE form should be forwarded to the Overall PI within the timeframes detailed in 
the table below. The Overall PI will submit AE reports from outside institutions to the 
DFCI OHRS according to the DFCI IRB policies and procedures in reporting adverse 
events.
In addition to local IRB reporting policies, all sites are required to follow the Table 5.3.3 
expedited reportable AE requirements:

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NOTE: Until patients initiate treatment with CC-115 on study, please report per Table 5.3.3 ‘Expedited AE Reporting by 
external sites to Coordinating Center/Overall PI’ of Appendix E (Control Arm).
Table 5.3.3 Expedited AE Reporting Requirements to Celgene & DFCI Coordinating Center
Adverse Event Characteristics
Reporting Requirement
Serious- 
ness
Toxicity
Known Correlationf
Attribution to CC-115
Celgene Corp
-
Via Fax or emailc
Use Reportable AE Coversheet c and 
Medwatch 3500A d
Overall PI (Patrick Y. Wen, MD) at the 
DFCI Coordinating Center
Via Email b
Use Reportable AE Coversheet c and 
Medwatch 3500A d
Seriouse
Any
Any
(Expected or 
Unexpected)
Any
Within 24 hours from notification a
Within 24 hours from notification a
Non- 
Serious
Grade 4
Any
(Expected or 
Unexpected)
Any
Not Required
Within 5 working days from 
notification a
Non- 
Serious
Grade 2 or 3
Unexpected
Possible, probable, 
definite
Not Required
Within 7 working days from 
notification a
a.
In the event that the participating investigator/site team does not become aware of an adverse event requiring expedited reporting immediately (e.g., participant sought 
treatment elsewhere), the participating investigator/site team is to report the event within the required hours/days noted above after learning of it and document the time 
of his or her first awareness of the adverse event. The initial report must be as complete as possible, including an assessment of the causal relationship between the event 
and the investigational product(s). Information not available at the time of the initial report (e.g., an end date for the adverse event or laboratory values received after the 
report) must be documented on a follow-up report. A final report to document resolution of the SAE or reportable AE is required.
b.
Email the Medwatch 3500A form, reportable AE coversheet (section 10 of this appendix), and the local IRB SAE report (if applicable) to the DFCI Coordinating Center with the 
subject title as “INSIGHT SAE” to NeuroOnc_SAE@dfci.harvard.edu. All SAE reports received at this account are forwarded immediately to study’s Overall PI, Dr. Patrick Y. Wen, 
and to the DFCI Coordinating Center personnel.
c.
Reportable AE Coversheet is found in section 10 of this appendix. The coversheet contains all FAX numbers/e-mails and needed for reporting purposes.
d.
Medwatch 3500A downloadable form at http://www.fda.gov/medwatch/getforms.htm
e.
Seriousness is defined in section 5.2 of this appendix.
f.
Expected adverse events are those that have been previously identified as resulting from administration of the agent. For the purposes of this study, an adverse event is 
considered expected when it appears in the Anticipated Toxicities list (protocol section 4.1 of this appendix) which is derived from the Investigator’s Brochure.

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5.3.4
How to report expedited AEs to Celgene & DFCI Coordinating Center/Overall PI
3. Document/describe reportable AE(s) on the following:
a.
MedWatch 3500A
i. downloadable form at http://www.fda.gov/medwatch/getforms.htm
b. DFCI Reportable AE Coversheet – INSIGhT CC-115 Arm
i. Coversheet can be found in section 10 of this appendix. The 
coversheet contains contact information for DFCI Coordinating 
Center and Celgene safety groups. A modifiable Microsoft Word 
document is also available from the DFCI Coordinating Center.
4. Scan and email above documents to NeuroOnc_SAE@dfci.harvard.edu with the 
subject title “INSIGHT SAE”
a.
All AE reports received at this account are forwarded immediately to 
Overall Principal Investigator (Dr. Patrick Y. Wen), and to Coordinating 
Center personnel.
b. If available and applicable, also include the local IRB submission for this 
event in the submission to the DFCI Coordinating Center.
5.3.5
Protocol-Specific Expedited Adverse Event Reporting Exclusions
For this protocol only, the AEs/grades listed below do not require expedited reporting to 
the Overall PI or the DFCI IRB. However, they still must be reported through the routine 
reporting mechanism (i.e. case report form).

Lymphopenia (grades 2-3). NOTE: all grade 4 lymphopenia events should 
be reported per expedited adverse event reporting requirements to the 
DFCI Coordinating Center

A visit to the emergency room or other hospital department < 24 hours, that 
does not result in admission (unless considered an important medical or life- 
threatening event)

Emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission

Elective surgery, planned prior to signing consent

Routine health assessment requiring admission for baseline/trending of health 
status (eg, routine colonoscopy)

Hospitalization for routine treatment or monitoring of the studied indication, 
not associated with any deterioration in condition, or for elective procedures

Hospitalization for elective or pre-planned treatment for a pre-existing 
condition that did not worsen

Hospitalization for respite care not associated with an adverse event attributed 
to the study drug

Hospitalization for treatment of patient’s underlying disease after coming off 
study treatment (e.g. admission after patient is removed from active study 
treatment for craniotomy)

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5.4
Expedited Reporting to the Food and Drug Administration (FDA)
As study sponsor, the Overall PI (or his designee) will be responsible for all communications 
with the FDA. The Overall PI will report to the FDA, regardless of the site of occurrence, any 
serious adverse event that meets the FDA’s criteria for expedited reporting following the 
reporting requirements and timelines set by the FDA.
5.5
Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.
5.6
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms. AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
5.7
Other Reporting Requirements
5.7.1
Pregnancies
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) in either a female subject or a partner of a male subject occurring while the subject 
is on investigational product (IP), or within 28 days of the subject’s last dose of IP, are 
considered immediately reportable events. IP is to be discontinued immediately and the subject 
instructed to return any unused CC-115. The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Celgene Drug Safety immediately by facsimile, or other 
appropriate method, using the Initial Pregnancy Report Form.
The female may be referred to her obstetrician-gynecologist or another appropriate healthcare 
professional for further evaluation.
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Follow-up Pregnancy Report Form as a follow-up to the initial 
pregnancy report.
If the outcome of the pregnancy was abnormal (eg, spontaneous or therapeutic abortion [any 
congenital anomaly detected in an aborted fetus must be documented], stillbirth, neonatal death, 
or congenital anomaly [including that in an aborted fetus]), the Investigator should report the 
abnormal outcome as an AE. If the abnormal outcome meets any of the serious criteria, it must 
be reported as an SAE to Celgene Drug Safety immediately by facsimile, or other appropriate 
method, within 24 hrs of the Investigator's knowledge of the event using the SAE Report Form 
or approved equivalent form.

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All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hrs of the Investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form.
Male Subjects
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking IP should notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately.
5.7.2
Overdose
Overdose, as defined for this protocol, refers to CC-115 dosing only.
On a per dose basis, an overdose is defined as a dose of CC-115 at any amount over the protocol- 
specified dose assigned to a given patient, regardless of any associated adverse events or 
sequelae.
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form.
Notify the DFCI Coordinating Center at NeuroOnc_SAE@dfci.harvard.edu of any potential 
overdose as soon as possible.
5.7.3
IND Annual Reports
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual 
report is provided to the FDA within 60-days of the IND anniversary date. 21 CRF 312.33 
provides the data elements that are to be submitted in the report. The Annual Report should be 
filed in the study's Regulatory Binder, and a copy provided to Celgene Corporation as a 
supporter of this study as follows:
Celgene Corporation
Attn: Medical Affairs Operations 
86 Morris Avenue
Summit, NJ 07901
Tel: (908) 673-9000

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6. PHARMACEUTICAL INFORMATION 
CC-115
6.1.1
Description
The chemical name for CC-115 is 1-ethyl-7-(2-methyl-6-(4H-1,2,4-triazol-3-yl)pyridin- 
3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. CC-115 is also known as 
CC0483115 and has an empirical formula of C16H16N8O and a molecular weight of 
336.35.
In vitro metabolism studies demonstrated that CC-115 is subject to metabolism via 
multiple pathways: oxidative metabolism primarily catalyzed by CYP3A4 and CYP2C8 
(and to a minor extent by CYP1A2, CYP2C19 and CYP2D6), and direct glucuronidation 
by UGT1A1. The relative contribution of each of these enzymes to the overall in vivo 
clearance of CC-115 is not known at this time. Therefore, caution should be exercised 
when CC-115 is co-administered with potent CYP3A4 inhibitors (eg, ketoconazole, 
ritonavir, grapefruit juice, clarithromycin), CYP2C8 inhibitors (eg, montelukast, 
gemfibrozil, trimethoprim), and CYP2C8/3A4 inducers (eg, rifampicin, phenytoin, 
carbamezepine, phenobarbital). Since CC-115 is subject to glucuronidation by UGT1A1, 
exercise caution also when treating subjects with Crigler-Najjar and Gilbert's syndromes.
The metabolite M2 (keto-CC-115) was the predominant circulating human metabolite 
constituting approximately 20% of drug-related component, and this M2 metabolite has 
demonstrated minimal pharmacological activity towards the mTOR target.
In humans, CC-115 is rapidly absorbed with mean peak plasma levels generally observed 
between 30 minutes and 3 hours after single and multiple oral doses of CC-115. The 
range of geometric mean terminal half-life of CC-115 is approximately 4 to 8 hours after 
single dose administration. Following single and multiple once-daily administration of 
CC-115, mean CC-115 exposure (AUC24, AUCt, and Cmax) increased in an approximate 
linear, dose-proportional manner over the 4- to 40-mg dose range.
CC-115 accumulation in plasma was minimal to moderate with exposure generally 
increasing from approximately 20% to 60% based on overall CC-115 exposure (ratio of 
geometric mean AUC24 Day 15/Day 1) after repeated once-daily and twice-daily 
administration of CC-115. Renal clearance of CC-115 was negligible and only a small 
fraction of the CC-115 dose (< 1%) was excreted as unchanged CC-115 in urine.
In vitro CYP inhibition studies demonstrated that CC-115 produced no or only weak 
inhibition of CYP and no induction of CYP; thus, CC-115 is not expected to precipitate 
clinically relevant drug-drug interactions due to CYP interactions. CC-115 is not a 
substrate but is an inhibitor of human P-gp. CC-115 is a substrate and an inhibitor of 
human BCRP. Therefore, it is recommended that caution be exercised when CC-115 is 
coadministered with P-gp substrates (eg, digoxin and new oral anticoagulants), BCRP 
substrates (eg, topotecan), and BCRP inhibitors.

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6.1.2
Form
CC-115 drug is manufactured and supplied by the Celgene Corporation. The formulation 
of CC-115 to be administered in the clinical studies is a reddish brown hard gelatin 
capsule in the appropriate strengths (10mg, 5mg and 7.5mg), containing only the active 
pharmaceutical ingredient. No other excipients are used in the product capsules.
Both the CC-115 capsules are packaged in high-density polyethylene bottles fitted with 
induction seals and child-resistant polypropylene closures.
6.1.3
Storage and Stability
Store as directed on the label.
6.1.4
Compatibility
There are no known compatibility issues.
6.1.5
Handling
Routine chemotherapy handling is recommended.
6.1.6
Availability
CC-115 is an investigation agent and will be supplied free-of-charge from Celgene 
Corporation.
6.1.7
Preparation
None.
6.1.8
Administration
o
CC-115 will be administered at a starting dose of 10 mg every 12 hours. 
Participants should be instructed to take their doses, twice a day, at approximately 
the same times each day and approximately 12 ± 3 hours apart.
o
If vomiting occurs during the course of treatment, no re-dosing of the participant 
is allowed before the next scheduled dose. The occurrence and frequency of any 
vomiting during a treatment cycle must be recorded as an adverse event.
o
If the participant forgets to take a CC-115 dose more than 3 hours from the 
intended time, then that dose should be withheld and CC-115 should be restarted 
at the time of the next planned dose.

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6.1.9
Ordering
The agent will be ordered from each institution’s individual pharmacy (or designee) using 
a Celgene Corporation online drug ordering system. Access to this system will be 
requested for each institution’s pharmacy by the DFCI Coordinating Center once local 
IRB approval is received. Anticipate 3-5 business days to receive drug after the order is 
placed.
6.1.10 Accountability
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form. 
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.)
6.1.11 Destruction and Return
CC-115 will be destroyed on site according to institutional policies, documented in the 
Drug Accountability Record Form. At the time of expiration / study close, a drug 
disposition form provided by Celgene Corporation will be sent out to be signed off by the 
Pharmacist and Investigator verifying the destruction of drug. At the end of the study, 
unused supplies of CC-115 should be destroyed according to institutional policies.
Destruction will be documented in the Drug Accountability Record Form.

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7. STUDY CALENDAR
Initiation Cycle
Adjuvant 
Cycles
Assessment
Screen
-inga
D1b
D8c,e
D15c,e
D22 c
D29
c,e
D36
c,e
D43-
49 d
D57c,e
D64c,e
D1f
End of 
Txg
30-Day 
Post 
Drugh
Active 
Follow- 
Upi
Long 
Term
Follow-Upj
Informed Consentk
X
Medical Historyl
X
Inclusion/Exclusion Criteriam
X
Vital signsn
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
Neurologic Exam
X
X
X
X
X
X
Karnofsky Performance Statuso
X
X
X
X
X
X
Concomitant Medicationsp
X
Adverse Eventsq
X
Pregnancy Test (β-HCG)r
X
X
X
X
X
Coagulations
X
Hematologyt
X
X
X
X
X
X
X
X
X
X
X
X
8-hour Fasting Serum 
Chemistryu
X
X
X
X
X
X
X
X
X
X
X
X
HbA1cbb
X
X
X
X
8 –hour Fasting Lipid Profile
X
X
X
X
12-lead ECGv
X
Xv
Xv
Xv
Xv
Radiationw
---------------------------X----------------------------
CC-115
X
Imaging – MRIx
X
X
X
X
X
Response Assessmenty
X
X
X
Post-treatment therapiesz
X
X
Survivalaa
X
X
a.
All screening procedures to be performed within 28 days of initial registration. NOTE: refer to section 10 of master protocol for comprehensive details on screening 
assessments, initial registration, randomization assignment and second registration timing.
b.
Concomitant radiation and CC-115 must begin no later than 42 days following initial surgery. Day 1 assessments must be performed within 3 days of starting study treatment. 
Screening assessments may be utilized as baseline/Day 1 assessments if they fall within window.
c.
+/- 2 day window for weekly assessments during concomitant phase.
d.
Day 43-49 visit to occur within +/- 7 days of completing radiation.
e.
Clinic Visits required for Safety Lead-In patients only (weekly AE assessments for 10-week DLT period); non-Safety Lead-In patients may have these assessments performed locally.
f.
Adjuvant C1D1 to begin >28 (+14) days following end of radiation. Cycle 1, Day 1 adjuvant assessments to be performed within 4 days of Day 1 CC-115. All adjuvant cycle 1, day 1 
assessments must be resulted and reviewed prior to initiating treatment with CC-115. Adjuvant cycles will be 28 days even if treatment is held. Day 1 assessments for

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subsequent adjuvant cycles to be performed within 4 days prior to Day 1 CC-115. (If utilizing the assessment window, that does not shorten the previous cycle or extend the 
upcoming cycle; each = 28 days.)
g.
End of Treatment: assessments to be performed within 7 days after last drug administration or within 7 days after decision to end treatment.
h.
30-Day Post Drug: a contact/visit is to be performed 30 days (+7 days) after date of last drug taken on study. This may be performed via documented phone conversation with a 
study nurse or clinician or a clinic visit. All participants will be followed until resolution or stabilization of any serious or reportable adverse events occurring during treatment or 
starting within 30 days of last drug.
i.
Active Follow-Up: participants who discontinue study treatment for reasons other than disease progression will be followed every 4 weeks (+/-1 week) via contact or medical 
record review andstudy team must continue monitoring participant’s disease status by radiologic imaging at 8-week intervals (+/- 1 week) until (1) documented disease 
progression, (2), death, (3) participant withdraws from follow-up, or (4) end of study, whichever occurs first.
j.
Long Term Follow-Up: participants will be followed every 4 weeks (+/-1 week) via contact or medical record review until death. Participants must be followed for survival data at 
every long-term follow-up time point and for post-treatment therapies and reason for stopping those therapies when available.
k.
Informed Consent: must be obtained by MD attending. No study specific screening procedures may occur until after the initial informed consent process is completed. Initial 
informed consent may be obtained within 28 days of initial registration. Following initial registration and receipt of INSIGhT randomization assignment, participants must be sign 
the consent form specific to the assigned treatment arm prior to initiating treatment for that study arm.
l.
Medical History: to include review of treatment history for GBM, any ongoing medical conditions & medical history pertaining to eligibility on study and involvement during study.
m. Inclusion/exclusion criteria: source documentation providing investigator’s confirmation that the participant had met all master protocol eligibility criteria must be available prior 
to initial registration. See section 3 of master protocol for eligibility requirements for initial registration. See section 2 of this appendix for arm specific eligibility criteria.
n.
Vital Signs: weight, heart rate, blood pressure, respiration rate, temperature. Vital signs must be performed prior to administration of treatment on treatment days. Height 
required only at screening.
o.
Karnofsky Performance Status (KPS): see appendix A of master protocol.
p.
Concomitant Medications: concomitant medications & reason for administration should be documented in the case history from date of consent up to the 30-Day Post Drug Visit.
q.
Adverse Events: adverse events experienced by participants will be collected and recorded from the first dose of treatment on-study up to the 30-Day Post Drug Visit of the last 
dose of study medication (+ 7 days depending on when 30-Day Post Drug visit/contact occurs).
r.
Pregnancy Test: required for women of child bearing potential (see section 3 of master protocol for definition of women of child bearing potential).
s.
Coagulation: PT/INR, PT, PTT required at screening only.
t.
Hematology: erythrocytes (RBC), hemoglobin, hematocrit, platelets, total WBC plus differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils).
u.
8-hour Fasting Serum Chemistry: albumin, alkaline phosphatase (ALP), BUN, calcium, creatinine, glucose, potassium, SGOT (AST), SGPT (ALT), sodium, total bilirubin (if total 
bilirubin is greater than the upper limit of normal, direct and indirect bilirubin should be performed), amylase, lipase, and magnesium.
v.
12-Lead ECG: required at screening, concomitant day 1 pre-dose and 1.5 hours (+/- 30 minutes) after dosing, concomitant day 15 1.5 hours (+/- 30 minutes) after dosing, and 
concomitant 29 1.5 hours (+/- 30 minutes) after dosing. 12-Lead ECGs will then be required concurrently with adjuvant cycles that require radiographic disease assessments (i.e., 
C1, C3, C5, etc.) at 1.5 hours (+/- 30 minutes) after dosing unless clinically significant abnormalities have been detected. No ECGs are required beyond adjuvant Cycle 5 unless 
clinically indicated.
w.
Radiation: see section 3.1 of this sub-study appendix for definition of standard radiation therapy per protocol.
x.
Imaging: gadolinium-enhanced contrast and non-contrast MRI. Initial imaging should be performed within 21 days prior to beginning study treatment. When feasible at site, 
Appendix D Recommended MRI Acquisition Protocol should be adhered to and the same imaging technique should be used on a participant throughout the trial. Local reading 
(investigator assessment) will be used to determine eligibility and for participant management. Adjuvant C1D1 imaging should be performed within 7 days prior to starting 
adjuvant treatment; subsequent imaging should be performed within 7 days prior to Day 1 of odd cycles.
y.
Response Assessment: Per RANO criteria (see section 11 of master protocol).
z.
Post-treatment Therapies: start/stop dates, names of treatment regimens and reason for stopping should be collected when available. 
aa. Survival: date of death and reason must be collected for overall survival purposes.
bb. HbA1c & 8-hour fasting lipid profile: do not need to be resulted and reviewed prior to initiating CC-115 with RT in the concomitant phase.

185
16-443 INdividualized Screening trial of Innovative Glioblastoma Therapy (INSIGhT) 
APPENDIX G: CC-115 ARM
Version 10.0- March 10, 2024
8. MEASUREMENT OF EFFECT
Refer to section 11 of master INSIGhT protocol for details on measurement of effect.
9. REFERENCES
Mortensen DS, Perrin-Ninkovic SM, Shevlin G, Elsner J, Zhao J, Whitefield B, et
al. Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) 
Kinase Inhibitors and the Discovery of CC-115. J Med Chem. 2015 Jul 23;58(14):5599-608.
Fruman, D. A.; Rommel, C. PI3K and cancer: lessons, challenges and opportunities. Nat. Rev. 
Drug Discovery 2014, 13, 140−156.
Engelman JA. Targeting PI3K signaling in cancer: opportunities, challenges and 
limitations. Nat Rev Cancer 2009;9(8):550-62.
Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The 
somatic genomic landscape of glioblastoma. Cell 2013; 155: 462-77.
Collis SJ, DeWeese TL, Jeggo PA, Parker AR. The life and death of DNA-PK. Oncogene 
2005;24:949-961.
Bozulic L, Surucu B, Hynx D, Hemmings BA. PKBα/Akt1 acts downstream of DNA-PK in the 
DNA double-strand break response and promotes survival. Mol Cell 2008;30:203-213.
Surucu B, Bozulic L, Hynx D, Parcellier A, Hemmings BA. In vivo analysis of protein kinase B 
(PKB)/Akt Regulation in DNA-PKcs-null mice reveals a role for PKB/Akt in DNA damage 
response and tumorigenesis.  J Biol Chem 2008;283:30025–30033.
Khanna KK, Jackson SP. DNA double-strand breaks: signaling, repair, and the cancer 
connection. Nature Genetics 2001; 27: 247-254.
Zhao Y, Thomas HD, Batey MA, Cowell IG, Richardson CJ, Griffin RJ, et al. Preclinical 
evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res 
2006;66:5353-5362.
Sarkaria JN, Galanis E, Wu W, et al. North Central Cancer Treatment Group Phase I Trial 
N057K Of Everolimus (RAD001) And Temozolomide In Combination With Radiation Therapy 
In Patients With Newly Diagnosed Glioblastoma Multiforme. Int. J. Radiation Oncology Biol. 
Phys., 2011;81:468–475.

186
DFCI REPORTABLE AE COVERSHEET – INSIGHT CC-115 ARM
DF/HCC Protocol No. 16-443
Celgene Tracking No. CC-115-CL-GBM-PI-007141
Date:
 
sheet: 
Number of pages including cover
To (check off recipient of this AE):
 Dr. Patrick Y. Wen and Dana-Farber Coordinating Center 
Email: NeuroOnc_SAE@dfci.harvard.edu
 Celgene Corporation Fax: 908-673-9115
Email: drugsafety@celgene.com
From:
Institution:
Phone No.:
Fax No.:
Participant # and Initials:
Date Event Met Reporting Criteria (as defined in protocol):
Type of Report: Initial Follow-up
Hospitalization?  Yes
 No
CTCAE Event #1 Description:
CTCAE Event #2 Description (if applicable):
NOTE: use another coversheet if more than 2 events are being reported at this 
time
Meets Definition of Serious AE:
 Serious
 Non-serious
Meets Definition of Serious AE:
 Serious
 Non-serious
Toxicity Grade:
G1/mild G2/moderate G3/severe
G4/life threatening G5/death
Toxicity Grade:
G1/mild G2/moderate G3/severe
G4/life threatening G5/death
Expectedness to Radiation Therapy:
Expected Unexpected  N/A
Expectedness to Radiation Therapy:
Expected Unexpected  N/A
Attribution to Radiation Therapy:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Attribution to Radiation Therapy:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Expectedness to CC-115:
Expected Unexpected  N/A
Expectedness to CC-115:
Expected Unexpected  N/A
Attribution to CC-115:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Attribution to CC-155:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Reporting Investigator (print):
Signature of Reporting Investigator:
Date: 

187
RADIATION CC-115 DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION
CC-115 Description:

Your study drug (CC-115) is supplied as a 5mg, 7.5mg or 10mg reddish brown capsule
CC-115 Instructions – When and How:

Take study drug (CC-115) twice a day, once in the morning and once in the evening.

Take the drugs at approximately the same time each morning and evening, so that you are taking the drugs around 12 hours apart.

Take the pill(s) with a glass of water and swallow them whole; do not chew them or crush them.

Do not skip any doses.

If you forget to take your pills in the morning you can take your missed dose up to 3 hours after your normally scheduled time. If it has been more 
than 3 hours, skip the dose and take the next scheduled dose at the usual time in the evening (one dose only). Please call your study nurse or doctor 
to discuss missed doses.

If you forget to take your pills in the evening, you can take your missed dose up to 3 hours after your normally scheduled time. If it has been more 
than 3 hours, skip the dose and take the next scheduled dose at the usual time the next morning (one dose only). Please call your study nurse or 
doctor to discuss missed doses.

If you vomit your pills, write this down in your pill diary. Do not take a replacement dose.
Take the next scheduled dose as usual (one dose only). 
Please call your study nurse or doctor to discuss vomited doses.
Additional Instructions:

You must avoid eating or drinking any foods with Seville oranges (like marmalade), grapefruit or foods or drink with grapefruit, and any exotic fruits 
during the entire treatment period.

Keep your study drug in the original container(s) at room temperature. Keep study drug away from children, persons cannot read the label, and 
pets.

Do not throw away empty bottles, and do not throw the study drug in the trash or flush into the toilet.

Bring this diary, all pill bottles, and any unused pills to each clinic visit. Your Treatment Team will collect your diary, all pill bottles and any unused 
study drug, and you will be given a new pill diary at that time.

Contact your study doctor or nurse if you are having any new or worsening side effects.

Do not begin any new medication, over-the-counter drug, or herbal preparation without first checking with your Treatment Team to determine if it 
is acceptable to take while on this study.

CC-115 absorbs ultraviolet (UV) light. It is not yet known if CC-115 may make your skin or eyes more sensitive to sunlight. As a precaution, it is 
advised you avoid prolonged exposure to natural or artificial sunlight (UVA/B) while taking CC-115 by wearing sun-protective clothes, applying 
effective sun block to exposed skin, and by wearing UV protective sunglasses.
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
CC-115 Dose:
mg, two times a day.
TAKE
pill(s) in the morning and
pill(s) in the evening.

188
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
CC-115 Dose:
mg
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials

189
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
CC-115 Dose:
mg
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Day 29
Day 30
Day 31
Day 32
Day 33
Day 34
Day 35
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Day 36
Day 37
Day 38
Day 39
Day 40
Day 41
Day 42
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials

190
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
CC-115 Dose:
mg
Time:  
Participant/Guardian Signature:
Date:  
To be completed by study personnel:
# of 5 mg Bottles Returned:  
# of 7.5 mg Bottles Returned:  
 
# of 10 mg Bottles Returned:  
# of 5 mg Pills Returned:  
  
# of 7.5 mg Pills Returned:  
 
# of 10 mg Pills Returned:  
Compare with drug diary entries made by participant or guardian. If discrepancy (in the # of bottles or the # of pills returned), please reconcile:
Day 43
Day 44
Day 45
Day 46
Day 47
Day 48
Day 49
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:
Time:
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
Date:
A.M. DOSE 
No. of pills:   
 
Time:
Date:
A.M. DOSE 
No. of pills:   
 
Time:
P.M. DOSE 
No. of pills:
P.M. DOSE
No. of pills:  
 
Time:
P.M. DOSE
No. of pills:  
 
Time:
P.M. DOSE
No. of pills:  
 
Time:
P.M. DOSE 
No. of pills:
P.M. DOSE
No. of pills:  
Time:
Initials
Initials
Initials
Time:
Initials
Initials
Initials

191
POST RADIATION CC-115 DOSING INSTRUCTIONS & DRUG DIARY
To be completed by study personnel:
Patient ID #
Patient Initials:
Cycle #:
Month & Year:
CC-115 Dose:
mg, two times a day.
TAKE
pill(s) in the morning and
pill(s) in the evening.
CC-115 Description:

Your study drug (CC-115) is supplied as a 5mg, 7.5mg or 10mg reddish brown capsule
CC-115 Instructions – When and How:

Take study drug (CC-115) twice a day, once in the morning and once in the evening.

Take the drugs at approximately the same time each morning and evening, so that you are taking the drugs around 12 hours apart.

Take the pill(s) with a glass of water and swallow them whole; do not chew them or crush them.

Do not skip any doses.

If you forget to take your pills in the morning you can take your missed dose up to 3 hours after your normally scheduled time. If it has been more than 3 
hours, skip the dose and take the next scheduled dose at the usual time in the evening (one dose only). Please call your study nurse or doctor to discuss 
missed doses.

If you forget to take your pills in the evening, you can take your missed dose up to 3 hours after your normally scheduled time. If it has been more than 3 
hours, skip the dose and take the next scheduled dose at the usual time the next morning (one dose only). Please call your study nurse or doctor to discuss 
missed doses.

If you vomit your pills, write this down in your pill diary. Do not take a replacement dose. Take the next scheduled dose as usual (one dose only). Please 
call your study nurse or doctor to discuss vomited doses.
Additional Instructions:

You must avoid eating or drinking any foods with Seville oranges (like marmalade), grapefruit or foods or drink with grapefruit, and any exotic fruits during 
the entire treatment period.

Keep your study drug in the original container(s) at room temperature. Keep study drug away from children, persons cannot read the label, and pets.

Do not throw away empty bottles, and do not throw the study drug in the trash or flush into the toilet.

Bring this diary, all pill bottles, and any unused pills to each clinic visit. Your Treatment Team will collect your diary, all pill bottles and any unused study 
drug, and you will be given a new pill diary at that time.

Contact your study doctor or nurse if you are having any new or worsening side effects.

Do not begin any new medication, over-the-counter drug, or herbal preparation without first checking with your Treatment Team to determine if it is 
acceptable to take while on this study.

Each post-radiation cycle is 28 days of morning and evening pills. If you start the cycle in the evening (P.M. dose), you may end the cycle in the morning of 
the 29th day.

CC-115 absorbs ultraviolet (UV) light. It is not yet known if CC-115 may make your skin or eyes more sensitive to sunlight. As a precaution, it is 
advised you avoid prolonged exposure to natural or artificial sunlight (UVA/B) while taking CC-115 by wearing sun-protective clothes, applying 
effective sun block to exposed skin, and by wearing UV protective sunglasses.

192
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
CC-115 Dose:
mg
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Participant/Guardian Signature:
Date:  

193
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
CC-115 Dose:
mg
Each cycle is 28 days of morning and evening pills. If you start the cycle in the evening (P.M. dose), you may end the cycle in the morning of the 29th day.
Time:  
Participant/Guardian Signature:  
To be completed by study personnel:
# of 5 mg Bottles Returned:  
# of 7.5 mg Bottles Returned:  
 
# of 10 mg Bottles Returned:  
Date:  
# of 5 mg Pills Returned:  
  
# of 7.5 mg Pills Returned:  
 
# of 10 mg Pills Returned:  
Compare with drug diary entries made by participant or guardian. If discrepancy (in the # of bottles or the # of pills returned), please reconcile:
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials
Date:
A.M. DOSE 
No. of pills:
Time:
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
Date:
A.M. DOSE 
No. of pills:   
 
Time:
Date:
A.M. DOSE 
No. of pills:   
 
Time:
P.M. DOSE 
No. of pills:
P.M. DOSE
No. of pills:  
 
Time:
P.M. DOSE
No. of pills:  
 
Time:
P.M. DOSE
No. of pills:  
 
Time:
P.M. DOSE 
No. of pills:
P.M. DOSE
No. of pills:  
Time:
Initials
Initials
Initials
Time:
Initials
Initials
Initials
Day 29
Date:
A.M. DOSE 
No. of pills:   
 
Time:  
 
P.M. DOSE
No. of pills:  
 
Time:  
Initials

16-443 INdividualized Screening trial of Innovative Glioblastoma Therapy (INSIGhT) 
APPENDIX H: NERATINIB ARM
Version 11.0- December 4, 2024
194
APPENDIX H NERATINIB ARM OF INSIGHT
TABLE OF CONTENTS
1.
BACKGROUND .........................................................................................................................196
1.1
Temozolomide .....................................................................................................196
1.2
Neratinib (PB-272, HKI-272)..............................................................................197
2.
PARTICIPANT SELECTION.....................................................................................................201
2.1
Eligibility Criteria Specific to the Neratinib Arm................................................201
2.2
Second INSIGhT Registration: Registration to Neratinib Arm ...........................201
2.2.1
Registration Process for DF/HCC Institutions.....................................................201
2.2.2
Registration Process for Other Investigative Sites...............................................202
3.
TREATMENT PLAN..................................................................................................................202
3.1
Definition of Standard Radiation Therapy...........................................................202
3.2
Concomitant Temozolomide during Radiation Therapy......................................202
3.3
Rest Phase............................................................................................................203
3.4
Adjuvant (Post-Radiation) Neratinib Treatment..................................................204
3.5
General Concomitant Medication and Supportive Care Guidelines....................204
3.5.15 Concurrent Prophylactic Administration of Loperamide ....................................206
3.6
Criteria for Taking a Participant Off Protocol Therapy.......................................208
3.7
Duration of Follow Up.........................................................................................208
3.8
Criteria for Taking a Participant Off Study .........................................................208
4.
DOSING DELAYS/DOSE MODIFICATIONS..........................................................................209
4.1
Anticipated Toxicities..........................................................................................209
4.1.1
Anticipated Toxicities for Radiation Therapy .....................................................209
4.1.2
Anticipated Toxicities for Temozolomide...........................................................210
4.1.3
Anticipated Toxicities for Neratinib ....................................................................210
4.2
Dose Modifications/Delays for Temozolomide...................................................211
4.3
Dose Modifications/Delays for Neratinib............................................................212
4.3.1
General Dose Adjustments for Neratinib-Related Toxicities ..............................213
5.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .......................................220
5.1
Expected Toxicities .............................................................................................220
5.2
Adverse Event Characteristics .............................................................................220
5.3
Expedited Adverse Event Reporting....................................................................221
5.4
Expedited Reporting to the Food and Drug Administration (FDA) ....................225
5.5
Expedited Reporting to Hospital Risk Management ...........................................225
5.6
Routine Adverse Event Reporting .......................................................................225
5.7
Reporting to Puma Biotechnology, Inc................................................................225
6.
PHARMACEUTICAL INFORMATION....................................................................................226
6.1
Temozolomide .................................................................................................................226
6.1.2
Form.....................................................................................................................226
6.1.3
Storage and Stability............................................................................................226
6.1.4
Compatibility .......................................................................................................226
6.1.5
Handling ..............................................................................................................226
6.1.6
Availability ..........................................................................................................226

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6.1.7
Preparation...........................................................................................................227
6.1.8
Administration .....................................................................................................227
6.1.9
Ordering...............................................................................................................227
6.2
Neratinib ..........................................................................................................................227
6.2.1
Description...........................................................................................................227
6.2.2
Form.....................................................................................................................228
6.2.3
Storage and Stability............................................................................................228
6.2.4
Compatibility .......................................................................................................228
6.2.5
Handling ..............................................................................................................228
6.2.6
Availability ..........................................................................................................228
6.2.7
Preparation...........................................................................................................228
6.2.8
Administration .....................................................................................................229
6.2.9
Ordering...............................................................................................................229
6.2.10 Accountability......................................................................................................229
6.2.11 Destruction and Return ........................................................................................229
8.
MEASUREMENT OF EFFECT .................................................................................................233
9.
REFERENCES ............................................................................................................................233
10.
DFCI REPORTABLE AE COVERSHEET – INSIGHT NERATINIB ARM............................235
11.
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION 
THERAPY...................................................................................................................................236
12.
NERATINIB DOSING INSTRUCTIONS & DRUG DIARY ....................................................240

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1. BACKGROUND
1.1
Temozolomide
Background and preclinical data
Temozolomide is a member of the imidazotetrazine family that is structurally related to the 
alkylating agent dacarbazine and has shown efficacy against a variety of cancers, including high 
grade gliomas.
Under physiologic conditions, temozolomide is spontaneously converted to its active metabolite 
MTIC (5-(3-dimethyl-1-triazenyl)imidazole-4-carboxamide)1. The breakdown product of MTIC, 
methyldiazonium, is an actively alkylating agent that preferentially methylates guanine residues 
of the DNA molecule, thereby resulting in single and double DNA strand breaks and activation 
of apoptotic pathways.2 Temozolomide has linear and reproducible pharmacokinetics with 100%
p.o. bioavailability within 2 hours of drug administration and a rapid plasma drug clearance with 
a plasma half- life of 1.6-1.8 hours.3
Because of its lipophilic properties, temozolomide penetrates into the central nervous system 
(CNS) and was shown to reach acceptable CNS concentrations. In humans, the CSF penetration 
is estimated to be ~20-30% based on AUCplasma/AUCCSF ratios.4 In several preclinical rodent and 
primate models, it was demonstrated to have activity against CNS tumors thereby stimulating 
interest for investigations in humans.5-8
Clinical data
In these preclinical and clinical phase I studies, temozolomide demonstrated antitumor-activity in 
high-grade gliomas in adults.3,9 Based on these studies, the maximal tolerated dose (MTD) for 
humans has been defined as 150-200 mg/m2 per day depending on whether patients have 
received prior treatment with myelotoxic agensts.3,10,11 For patients with glioblastoma, the 
recommended temozolomide doses are 75 mg/m2 during radiation (concomitant phase) and 150- 
200 mg/m2 for 5 days out of a 28-day cycle for 6 months.4,12 Temozolomide in general is well 
tolerated and the most frequent toxicities are mild to moderate myelosuppression 
(thrombocytopenia and neutropenia) which is predictable and typically resolves spontaneously.
Subsequent phase II studies confirmed the activity of temozolomide against newly diagnosed and 
recurrent high-grade gliomas1,13,14 therefore leading to further evaluation of the drug by the 
European Organization for Research and treatment of Cancer (EORTC) and the National Cancer 
Institute of Cancada (NCIC) in a landmark phase III study15. In this clinical trial the efficacy of 
radiation with concomitant temozolomide followed by six monthly cycles of temozolomide 
compared to radiation alone for newly diagnosed glioblastoma was evaluated15. The combination 
of radiation and temozolomide prolonged median progression free survival from 5 to 6.9 months 
(95% CI 4.2-5.5) and median overall survival from 12.1 to 14.6 months ( 95% CI 11.2-13.0).
Treatment with temozolomide was overall well tolerated with grade 3 or 4 hematoxicity in 16% 
of study participants.
Based on these results, this concomitant use of temozolomide during radiation followed by 
monthly maintenance cycles has been widely accepted as the standard of care treatment for 
patients with newly diagnosed glioblastoma.

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MGMT
The tumor suppressor gene MGMT (O6-methylguanine-DNA methyltransferase) on chromosome 
10q26 encodes a DNA-repair enzyme that removes alkyl groups from the O6 position of guanine, 
thereby repairing the lethal DNA-cross links induced by alkylating chemotherapeutic agents such 
as temozolomide16. Glioma cells with diminished MGMT activity are more responsive to the 
alkylating damage of these agents17,18. Epigenetic silencing of the MGMT promoter is present in
~40-68% of high grade gliomas and leads to reduced protein expression and cellular DNA repair 
activity. MGMT promoter methylation is associated with longer survival in patients with high 
grade gliomas treated with alkylating agents19, including temozolomide20,21 Therefore, MGMT 
promoter methylation represents a favorable prognostic marker for high grade gliomas which is 
routinely evaluated in neuropathological practice.
In a retrospective tumor tissue analysis of the patients enrolled in the EORTC/NCIC study, 
MGMT promoter methylation was confirmed to be a favorable prognostic factor for patients 
with glioblastoma.21 It also showed that the therapeutic benefit of temozolomide in addition to 
radiation was most pronounced in patients whose tumors contained a methylated MGMT 
promoter. In this patient group, combined chemoradiation compared to radiation alone prolonged 
progression-free survival from 5.9 (95% CI 5.3-7.7) to 10.3 (95% CI 6.5-14.0) months and
median overall survival from 15.3 (95% CI 13.0-20.9) to 21.7 (95% CI 17.4-30.4) months. In 
contrast, for patients without MGMT promoter methylation the combination of temozolomide 
plus radiation resulted in an only small survival benefit compared to radiation alone (progression 
free survival 4.4 vs, 5.3 months, overall survival 11.8 vs. 12.7 months).
Rationale
These data suggest a correlation between MGMT promoter methylation and treatment response 
to temozolomide. It therefore can be argued that temozolomide is useful only in the MGMT 
methylated setting. However, based on the small subgroup of study patients from the landmark 
EORTC-NCIC study whose tumors were MGMT unmethylated and survived more than 2 years 
(longer than the expected median survival), there seemed to be a survival benefit from combined 
radiation and temozolomide compared to radiation alone.22 In addition, because of issues with 
the reliability of the assay used to assess MGMT status in this EORTC-NCIC study, it has been 
debated whether these patients were incorrectly classified as MGMT unmethylated.
Nevertheless, based on these data, a real albeit marginal benefit from temozolomide even in the 
unmethylated setting cannot be excluded. Therefore, it continues to be common practice to use 
the combination of temozolomide and radiation in all patients with newly diagnosed 
glioblastoma irrespective of MGMT methylation status.
1.2
Neratinib (PB-272, HKI-272)
Rationale & Proposed Biomarker Association
EGFR is a receptor tyrosine kinase that regulates cell growth and differentiation, and various 
mechanisms for oncogenic conversion in cancer have been described (Hynes and Lane, 2005). 
The evidence for a role of EGFR in oncogenesis is particularly compelling in glioblastoma where 
approximately 40% of tumors show amplification of the EGFR gene locus (Libermann et al, 
1985) and about half of these EGFR-gene amplified cases express the constitutively active

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mutant receptor EGFRvIII that harbors deletions of several exons within the extracellular ligand- 
binding domain (Yamazaki et al, 1988; Wong et al, 1992; Ekstrand et al, 1992).
Recent genome-wide cancer genomics studies have cataloged a diverse collection of EGFR gene 
abnormalities in glioblastoma (Brennan et al, 2013). These broad categories of EGFR mutations 
include:
1. Amplification of the EGFR genomic locus that may be non-mutated (‘wild-type’) 
or alternatively may be associated with one or more structural abnormalities in the 
EGFR gene (eg, deletions, point mutations) listed below,
2.
EGFRvIII, the most common and most thoroughly-characterized EGFR structural 
gene variant in glioblastoma, characterized by deletion of 267 amino acids in the 
ECD and leading to a receptor which is unable to bind ligand yet is constitutively 
active (Gan et al, 2009),
3.
Internal deletions of one or more exons in the EGFR gene, for example deletion of 
EGFR exons 12 &13, or exons 14 & 15, or exons 25, 26, and/or 27 (Brennan et al, 
2013)
4. Missense (or ‘point’) mutations in the EGFR gene, for example but not limited to 
R108K, A289V, A289T, A289D, G598V mutations, in the extracellular domain of 
EGFR in 14% of glioblastomas (Figure 1). Cells transformed by expression of 
these EGFR mutants were sensitive to small molecule EGFR kinase inhibitors (Lee 
et al, 2006).
5.
Novel fusion genes between the EGFR gene and one of a number of partner genes, 
for example SEPT14 or SEC61G (Brennan et al, 2013).
Neratinib is an orally available small molecule inhibitor of EGFR, HER2, and HER4, that has 
been successful in clinical trials of HER2 positive breast cancer. Preclinical data demonstrates 
reduction of EGFR and HER2 autophosphorylation, downstream signalling, and growth in 
EGFR and HER2 dependent cell lines22. Neratinib inhibited the EGFR-overexpressing cell line 
(A431), but was much less active on MDA-MB-435 and SW620 (a breast and a colon cancer cell 
line, respectively) that are EGFR and HER2-negative (IB). Neratinib also inhibited the growth 
of EGFR-overexpressing A431 tumor xenografts, consistent with its effects on the cells in vitro, 
with maximum inhibition of tumor growth observed at the 40 mg/kg/day dose (76% inhibition on 
Day 15). The in vivo activity of neratinib was dependent on expression of HER2 or EGFR, as no 
significant antitumor effects were observed in xenografts of MCF-7 and MX-1 cells that express 
low levels of these receptors (IB). In a study (Study 3144A1-200-WW/B1891037) of NSCLC 
patients, while 51% of the patients showed stable disease as best response, the only partial 
responders were patients with EGFR mutations (IB).

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Figure 1. EGFR Mutations in Glioblastoma Multiforme
Source: cBioPortal for Cancer Genomics, accessed: 21OCT2013.
Preclinical data
Neratinib (PB-272) is a potent irreversible pan ERBB inhibitor. Neratinib is an orally available 
small molecule that inhibits EGFR, HER2, and HER4 at the intracellular tyrosine kinase 
domains. Neratinib reduces EGFR and ERBB2 autophosphorylation, downstream signaling, and 
the growth of EGFR- and HER2- dependent cell lines. Preclinical data show that neratinib has 
antitumor activity in EGFR- and/or HER2-expressing carcinoma cell lines, with cellular IC50
<100 nM (Rabindran et al, 2004) and has been shown to be selectively active against EGFRvIII 
in vivo using mouse models which mimic amplified EGFRvIII driven lung cancer when 
compared to erlotinib and other early generation EGFR inhibitors (Ji H, et al 2006 PNAS PMID: 
16672372).
In glioblastoma, neratinib (HKI-272) has been shown to selectively cause cell death in cell lines 
harboring genetic activation of EGFR. In conventional GBM cell lines harboring extracellular 
domain mutations seen in GBM (Figure 2) and neratinib was much more effective than 
canertinib (CI-1033) and erlotinib (Vivanco et al., 2012). ). Neratinib has been shown to exhibit 
potential for selective inhibition of amplified EGFRvIII in GBM patient derived cell line models 
(Figure 3, 4; Francis J et al 2014). While the Neratinib dose response range in GBM PDCLs is 
higher than in other cancer cell line studies, this is possibly due to the presence of ultra-high 
levels of EGF added to the defined media which sustains these primary cell cultures. Neratinib is 
significantly more potent than lapatinib in limiting growth of primary GBM cell lines (Figure 
3,4). This is highly relevant motivation for studying neratinib in GBM given that negative 
human clinical trials with lapatinib have been attributed to the fact that tumor concentrations of 
the drug were estimated to be too low to induce cell death (Vivanco et al., 2012). The 
interactions of Neratinib with SNVs typicall seen in GBM has not yet been determined.
Figure 2: Cell death in GBM cell lines harboring extracellular domain mutations using 
neratinib (HKI-272) vs. another irreversible EGFRi (CI-1033)

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Figure 3: Growth inhibition of primary GBM tumor cell lines with neratinib (left), lapatinib 
(middle), or erlotinib (right).
Clinical data
Clinical benefit and antitumor activity have been shown in subjects with advanced or metastatic 
breast cancer who have received neratinib as a single agent or in combination with other 
anticancer agents. Positive results for neratinib 240 mg administered alone have been observed in 
women with HER2-positive locally advanced or metastatic breast cancer, with a response rate an 
overall response rate (ORR) of 53.8% and a PFS4 of 77.1% in patients without prior trastuzumab 
exposure (Investigator Brochure, IB). Clinical benefit has also been shown in 3 studies in which 
neratinib was co-administered with other anticancer therapies; ORR of 28.6% and PFS4 of 
44.8% when combined with trastuzumab in women with HER2-positive advanced breast cancer 
in Study 202/B1891013; ORR of 72.7% when combined with paclitaxel in women with HER2- 
positive metastatic breast cancer in Study 203/B1891014; ORR of 41.4% when combined with 
vinorelbine in women with HER2-positive metastatic breast cancer without prior lapatinib 
exposure in Study 3144A1-2204-WW/ B1891015 (IB). Neratinib (240 mg qd) combined with 
capecitabine showed an ORR of 64% in patients with no prior lapatinib exposure in another 
study (Saura et al., 2014). Neratinib was also the second agent to “graduate” to phase III testing 
in the I-SPY 2 clinical trial based on improved pathologic response compared to standard 
therapy.
Importantly, treatment with neratinib has shown responses in progressive brain metastases 
(Freedman et al., 2014) and paclitaxel plus neratinib may decrease the incidence of CNS 
metastes by up to 50%. 479 patients with HER2+ MBC were randomized in an international 
phase II trial to receive either neratinib plus paclitaxel or trastuzumab plus paclitaxel (NEfERTT 
trial) [ClinicalTrials.gov identifier: NCT00915018]. The results were the subject of a press 
release on 13 November 2014, reporting similar PFS between the two treatment arms but less 
brain metastases in those treated with neratinib versus trastuzumab (7.4 versus 15.6%, p = 
0.006). Data are expected to be presented at a meeting in the near future.
Given the lack of rationale or data to combine with radiation therapy (RT) and the potentially 
real but small known benefit to adding TMZ to RT in patients with unmethylated tumors, our 
experimental plan for this arm is to combine RT with TMZ in the concurrent phase, but to 
replace TMZ with neratinib in the adjuvant phase.

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2. PARTICIPANT SELECTION
2.1
Eligibility Criteria Specific to the Neratinib Arm
Participants must meet all eligibility criteria outlined in the master protocol (section 3) and 
complete initial registration (section 4 of master protocol). Once the randomization assignment 
has been received following initial registration, all participants randomized to the neratinib arm 
must meet the following criteria prior to participating in the neratinib arm of the study.
2.1.1
Participants must be willing and able to provide written informed consent/assent for the 
neratinib arm of the INSIGhT trial.
2.1.2
Women of child bearing potential (women who are not free from menses for > 2 years, 
post hysterectomy/oopherectomy, or surgically sterile) must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) from date of intial 
dose and for 28 days following the last dose of neratinib.   Men must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) during 
intercourse with women of childbearing potential from date of initial dose and for 3 
months following the last dose of Neratinib.
2.2
Second INSIGhT Registration: Registration to Neratinib Arm
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore®. Registration to the neratinib arm must occur following initial registration to master 
INSIGhT protocol and receipt of randomization assignment, and prior to the initiation of 
protocol therapy. Any participant not registered to their protocol specific assigned arm before 
protocol therapy begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria in section 2.1 of this sub-study appendix and a 
member of the study team will complete the protocol-specific eligibility checklist.
Following initial registration, any additional laboratory assessments prior to start of treatment 
will not be used to re-confirm eligibility. Refer to section 4 of this appendix for toxicity 
management between registration and start of study treatment.
Following second registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore® as soon as possible.
2.2.1
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.

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2.2.2
Registration Process for Other Investigative Sites
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
DFCI Coordinating Center staff. All sites should contact the DFCI Coordinating Center to verify 
slot availabilities. The required forms for registration can be found in Appendix B.
Following registration, participants should begin as soon as feasible. Issues that would cause 
treatment delays should be discussed with the Overall PI. If a participant does not receive 
protocol therapy following registration, the participant’s registration on the study must be 
canceled. The Study Coordinator should be notified of cancellations as soon as possible.
Refer to Appendix B, Section 3.7 for registration details.
3. TREATMENT PLAN
Participants treated on the neratinib arm will receive daily radiation (60 Gy in 30 fractions) as 
described in section 3.1 of this appendix with concomitant daily temozolomide (75 mg/m2/day) 
as described in section 3.2, followed by a 28 (+14 days) day break, and followed by continuous 
once daily dosing of neratinib as described in section 3.4 below.
3.1
Definition of Standard Radiation Therapy
The patient must undergo MRI based treatment planning (CT with contrast-based planning only 
if patient unable to undergo MRI). At a minimum, the contrast enhancing lesion (and/or surgical 
cavity) defined on a T1-weighted image (gross tumor volume; GTV) must be targeted with a 
minimum of a 1 cm dosimetric margin expansion to define a planning target volume (PTV). The 
margin may be reduced around natural barriers to tumor growth, and also to allow sparing of 
organs at risk, if necessary. The volume must be treated to a prescribed dose of 59.4 Gy in 33 
fractions or 60 Gy in 30 fractions. Treatment with larger volumes to the contrast-enhancing 
region is acceptable. Treatment or no treatment of the T2/FLAIR abnormality is acceptable.
Because this is optional, dosimetric expansion and dose-fractionation for the T2/FLAIR volume 
are not specified here. The prescribed dose to the T2/FLAIR volume may not exceed 60 Gy.
Radiation therapy must be completed within an overall treatment time of less than 52 calendar 
days. Maximum dose (defined as a volume greater than 0.03 cc) to critical structures include: 60 
Gy to the brainstem, 56 Gy to the optic chiasm, 55 Gy to the optic nerves, and 50 Gy to the 
retinae.
Participants are permitted to have radiotherapy as described in this section performed at any NCI 
funded cooperative group site. Prospective Overall PI approval, or approval by his designee 
(other Coordinating Center radiation oncologists), is required for any radiotherapy site that is not 
an NCI funded cooperative group site. At the discretion of the DFCI Coordinating Center, a 
radiation plan may be requested to be prospectively approved for a non-NCI site prior to 
initiating radiotherapy at the site. Any questions regarding permitted radiotherapy sites should 
be directed to the DFCI Coordinating Center or Overall PI Patrick Y. Wen, MD.
3.2
Concomitant Temozolomide during Radiation Therapy
Treatment on concomitant therapy should begin no later than 6 weeks from surgery. 

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Temozolomide 75 mg/m2/day will be administered orally on a continuous daily dosing schedule 
for a maximum of 49 days. Temozolomide will be initiated on Day 1 of radiation therapy, and 
the last dose will ideally be the last day of radiation; however, temozolomide may be 
administered for 42 days, or per your site’s institutional policy / standard.
The drug will be administered orally approximately 2-3 hours before each session of 
radiotherapy. During weekends or weekdays without radiotherapy (Saturday and Sunday), the 
drug should be taken in the morning when possible. The dose will be determined using actual 
body surface area (BSA) as calculated in square meters at the beginning of the concomitant 
treatment. The daily dose will be rounded to the nearest 5 mg.
No dose reductions are allowed during the concomitant phase of treatment. If a participant 
experiences a toxicity related to temozolomide during the concomitant phase of treatment, then 
temozolomide dosing will be interrupted according the rules described in Table 4.2 of this 
appendix.
Temozolomide will be administered on an outpatient basis. The investigator will instruct the 
participant to take the drug exactly as specified in the protocol. No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to treat 
the patient’s malignancy.
Participants will be instructed to fast at least 1 hour before and 1 hour after temozolomide 
administration. Prophylaxis with a 5-HT3 antagonist is recommended prior to administration of 
temozolomide doses and should be administered orally approximately 30 to 60 minutes before 
temozolomide treatment. Temozolomide should be taken with a glass of water and consumed 
over as short a time as possible. Participants should swallow the capsules as a whole and not 
chew them. Additional drug administration instructions, including missed dose policy, are 
described in section 6.1.8 of this appendix and are included in the participant pill diary (section 
11 of this appendix).
All dosages prescribed and dispensed to the participant and all dose changes during the study 
must be recorded. If a participant requires a temozolomide dose delay of > 28 days from the 
previous dose, the participant must be discontinued from further temozolomide treatment. If a 
participant discontinues temozolomide treatment due to toxicity, the participant may continue 
study treatment with adjuvant cycles of neratinib as described in section 3.4 below. In the 
exceptional case where the investigator feels the patient would benefit from continuing therapy 
the case can be discussed with the Overall PI Patrick Y. Wen, MD at pwen@partners.org or 617- 
632-2166. Expected toxicities and dose reductions and modifications are detailed in section 4 of 
this appendix.
NOTE: Study treatment may be held > 28 days in order to allow for surgical pathology to 
determine progression versus pseudoprogression outside of the 12-week consideration mark if it 
is prospectively confirmed with Overall PI to be clinically appropriate to do so.
Participants will keep a temozolomide diary (see section 11 of this appendix). After completion 
of radiation, the diary will be returned.
3.3
Rest Phase
During the 28 day (+14 days) break after completion of radiotherapy, temozolomide will not be 
administered.

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3.4
Adjuvant (Post-Radiation) Neratinib Treatment
Adjuvant cycles of neratinib should begin no sooner than 28 days (+ 14 days) following the 
completion of radiation therapy. Participants cannot begin adjuvant neratinib if they meet any 
criteria requiring a dose modification as outlined in section 4.3 of this appendix. All adjuvant 
cycle 1, day 1 assessments (as noted in section 7 study calendar of this appendix) must be 
resulted and reviewed prior to initiating treatment with neratinib.
The study drug, neratinib, will be administered on an outpatient basis. The investigator will 
instruct the participant to take the study drug exactly as specified in the protocol. No 
investigational or commercial agents or therapies other than those described in this appendix may 
be administered with the intent to treat the patient’s malignancy.
Participants should be instructed to take the dose of neratinib by mouth with food, preferably in 
the morning daily, starting at 240mg per day. Cycle length will be 28 days, even if treatment is 
held mid-cycle for toxicity. Primary prophylactic use of antidiarrheal medication will be 
required for all enrolled subjects (see below section 3.5.15 for more details). Participants
should swallow tablets as a whole and not chew them. Participants must avoid consumption of 
Seville orange (and juice), grapefruit or grapefruit juice, grapefruit hybrids, pummelos and exotic 
citrus fruits from 7 days prior to the first dose of study drug and during the entire study treatment 
period due to potential CYP3A4 interaction. Additional drug administration instructions, 
including missed dose policy, are described in section 6.2.8 of this appendix and are included in 
the neratinib pill diary (see section 12 of this appendix).
All dosages prescribed and dispensed to the participant and all dose changes during the study 
must be recorded. If a participant requires a neratinib dose delay of > 28 days from the previous 
dose, the participant must be discontinued from treatment completely. In the exceptional case 
where the investigator feels the patient would benefit from continuing therapy the case can be 
discussed with the Overall PI Patrick Y. Wen, MD at pwen@partners.org or 617-632-2166.
Expected toxicities and dose reductions and modifications are detailed in section 4 of this 
appendix.
NOTE: Study treatment may be held > 28 days in order to allow for surgical pathology to 
determine progression versus pseudoprogression outside of the 12-week consideration mark if it 
is prospectively confirmed with Overall PI to be clinically appropriate to do so.
Participants will keep a medication diary (see section 12 of this appendix). At the end of each 
cycle, the diary will be returned and a new one will be given to the participant. Participants are to 
return all pill bottles and unused pills.
3.5
General Concomitant Medication and Supportive Care Guidelines
Participants must be instructed not to take any additional medications (including over-the- 
counter products) during the trial without prior consultation with the investigator. All 
medications taken from date of initial consent and up to 30-day follow-up contact should be 
recorded. If concomitant therapy must be added or changed, including over-the-counter 
medications or alternative therapies, the reason and name of the drug/therapy should be recorded.
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
participant are allowed, including drugs given prophylactically (e.g. antiemetics) with the 
following exceptions:

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3.5.1
Strong CYP3A inhibitors and CYP3A inducers are prohibited. In vitro studies 
suggest that neratinib is a sensitive CYP3A4 substrate. Co-administration of 
neratinib with strong CYP3A4 inhibitors is predicted to increase the systemic 
exposure to neratinib; likewise CYP3A inducers can be expected to decrease 
systemic exposure to neratinib, possibly resulting in sub-therapeutic drug levels. 
Refer to Appendix C of master INSIGhT protocol for a list of prohibited drugs. 
Please note that this list may not be comprehensive.
3.5.2
Caution should be exercised when co-administering neratinib with narrow 
therapeutic drugs that are substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2D6, or CYP3A. Participants receiving such medications must be monitored 
for potentiation of toxicity due to any individual concomitant medications, and 
may require dose titration or reduction of the drug substrate. Refer to Appendix C 
of master INSIGhT protocol for a list of drugs. Please note that this list may not 
be comprehensive
3.5.3
The solubility of neratinib is pH dependent and treatments that alter 
gastrointestinal pH such as proton pump inhibitors (PPIs), H2-receptor 
antagonists, and antacids may lower the solubility of neratinib. It has been 
observed that a single 240-mg dose of neratinib combined with lansoprazole may 
decrease neratinib AUC by up to 70%. It is unknown whether separating PPI and 
neratinib doses reduce the interaction.
3.5.3.1
PPIs should be avoided whenever possible.
3.5.3.1.1.
Recommend that Teams contact the DFCI NOC Coordinating 
Center when there is no alternative and/or treating team wants 
to use PPIs, so that they may run by Overall PI for feedback.
3.5.3.2
If an H2-receptor antagonist such as ranitidine is required, neratinib 
should be taken 10 hours after the H2-receptor antagonist dosing and at 
least 2 hours before the next dose of the H2-receptor antagonist.
3.5.3.3
If antacids are necessary, the antacid dose and the neratinib dose should 
be separated by 2 to 4 hours.
3.5.4
Herbal preparations/medications are not allowed throughout the study. These 
herbal medications include, but are not limited to: St. John’s wort, Kava, ephedra 
(ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, ginseng. Participants should stop using any herbal medications 7 days 
prior to first dose of study drug.
3.5.5
Corticosteroids should be used in the smallest possible dose to control symptoms 
of cerebral edema and mass effect, and discontinued if possible. Chronic dosing 
of corticosteroids is known to induce CYP3A enzymes, thereby increasing the 
risk of reducing neratinib drug exposure to sub-therapeutic levels.
3.5.6
Anti-seizure medications should be used as indicated. Only participants receiving 
non-EIAEDs are eligible (although protocol does allow for patients to register and 
initiate treatment with Temodar and radiation therapy while tapering off 
EIAEDs). If for unavoidable clinical reasons (emergency department visit, severe 
allergies, toxicities, etc.) a participant’s AED is switched to another AED, the 
following guidelines must be followed if applicable:

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o
Participants should be started on another non-EIAED if at all possible.
o
Participants who are inadvertently and temporarily changed to an EIAED 
should immediately be changed to an alternative non-EIAED.
o
Participants who need to permanently change anticonvulsant, but who 
cannot change to another non-EIAED, must be discussed with the PI.
3.5.7
Febrile neutropenia may be managed according to the local institution's 
guidelines. Measures may include appropriate laboratory testing, including blood 
and urine cultures and the institution of broad-spectrum antibiotics. If a source for 
the fever is not identified or the fever resolves when the neutrophil count 
recovers, antibiotics may be discontinued and the participant observed.
3.5.8
G-CSF: Routine prophylactic use of G-CSF is not permitted. However, 
therapeutic use in participants with serious neutropenic complications, such as 
sepsis, may be considered at the investigator’s discretion.
3.5.9
Antiemetics: The use of antiemetics will be left to the investigators’ discretion.
3.5.10 Pneumocystis jirovecii pneumonia (PJP) prophylaxis: Since participants with 
GBM are at increased risk of developing PJP, especially if they are on 
corticosteroids, prophylaxis for PJP may be considered per institutional practice.
3.5.11 Anticoagulants: Because of the potential for its interaction with study 
medications, warfarin sodium (Coumadin®), or any other coumadin-derivative 
anticoagulant, is not permitted at any dose. Low-molecular weight heparin and Xa 
inhibitors are permitted. If for unavoidable clinical reasons (emergency 
department visit, severe allergy, toxicity, etc) a participant is started on 
Coumadin, they must change to a low molecular weight heparin immediately in 
the interest of subject safety.
3.5.12 Surgery: If neurosurgical management is required for reasons not due to tumor 
progression, these procedures must be documented, including the indications for 
surgery, the operative note, and pathology report.
3.5.13 Other Anticancer or Experimental Therapies: No other anticancer therapy of any 
kind is permitted during the study treatment period. No other drug under 
investigation may be used concomitantly with the study drug.
3.5.14 Other Concomitant Medications: Therapies considered necessary for the well 
being of the participant may be given at the discretion of the investigator. Other 
concomitant medications should be avoided except for analgesics, chronic 
treatments for concomitant medical conditions, or agents required for life- 
threatening medical problems. All concomitant medications must be recorded.
3.5.15 Concurrent Prophylactic Administration of Loperamide
Investigators must ensure that subjects have loperamide on hand when starting to take 
the investigational product. Loperamide is the recommended standard therapy to treat 
diarrhea in this study. If alternative antidiarrheal medication is used, the reason must 
be documented in the source documents. Acceptable reasons are non-tolerance of 
loperamide or lack of efficacy. A prescription for loperamide will be provided for the 
subject with the instruction to have loperamide on hand prior to taking the first dose 
of investigational product. The subject can also obtain loperamide “over-the-counter” 
prior to taking the first dose of investigational product on Day 1.

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
Inform patients that they will experience diarrhea while taking neratinib

Administer loperamide: For the first 14 days, loperamide 4 mg (2 
tablets/capsules) will be administered orally by patients 3 times a day (total 12 
mg a day). The initial dose of loperamide 4 mg will be administered orally withthe 
first dose of neratinib.

After the first 14 days, loperamide 4 mg (2 tablets/capsules) will be 
administered orally twice a day (total 8 mg a day) through the first cycle of 
therapy (Day 28) from start of neratinib dosing.

Thereafter, loperamide will be administered as needed (not to exceed 16 mg 
per day).
Loperamide Dosing
Day
Loperamide Dose
1-14
Daily dose of 12 mg in 3 divided doses of 4 mg
15-28
Daily dose of 8 mg in 2 divided doses of 4 mg
>28
Daily dose as needed (not to exceed 16 mg per day)
Loperamide Dose Adjustment
Patients are expected to take loperamide prophylaxis as directed. However, patients 
may require individualization of loperamide prophylaxis dose (up to a maximum dose 
of 16 mg per day) with the goal of titrating to 1-2 bowel movements a day.

For patients who develop diarrhea during Cycle 1, loperamide should be 
increased up to a maximum of 16 mg a day.

If a patient is unable to tolerate loperamide due to symptomatic constipation, 
loperamide should be held until after the first bowel movement and then resumed 
at a dose reduced by one level.

For recurrent symptomatic constipation events, hold loperamide until after the 
first bowel movement and then resume at a dose reduced to the next lower dose 
level.

If a patient is unable to tolerate once-daily loperamide due to constipation, hold 
loperamide and discuss subsequent loperamide dosing with the Overall PI.

Neratinib dosing should continue if loperamide is held.
Recommended dose reductions for loperamide are listed in the table below.
Loperamide Dose Reduction Levels for Constipation
Dose Level
Loperamide 
Dose
Tablets/Capsules per day
0
4 mg TID
6 tablets/capsules a day
-1
4 mg BID
4 tablets/capsules a day
-2
2 mg TID
3 tablets/capsules a day
-3
2 mg BID
2 tablets/capsules a day
-4
2 mg once a day
1 tablet/capsule a day
Abbreviations: BID = twice daily; mg=milligrams; TID= three times daily.
Refer to section 4.3.2 of this appendix for additional guidelines on management of 
diarrhea.

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3.6
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue on 
the neratinib arm until one of the following criteria applies:

Disease progression

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply. The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
A ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the ODQ website or obtained from the ODQ 
registration staff.
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Patrick Y. Wen, MD, at 617-632-2166 or pwen@partners.org.
3.7
Duration of Follow Up
Participants will be followed until death with monthly visits, telephone contact, or medical 
record review. Participants removed from protocol therapy for unacceptable adverse event(s) 
will be followed until resolution or stabilization of the adverse event. Refer to section 7 study 
calendar within this appendix for follow-up requirements and time points.
3.8
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).
A ODQ Treatment Ended/Off Study Form will be filled out when a participant comes off study. 
This form can be found on the ODQ website or obtained from the ODQ registration staff.

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4. DOSING DELAYS/DOSE MODIFICATIONS
For participants who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the participant on study drug. If administration of 
temozolomide or neratinib must be interrupted because of unacceptable toxicity, drug dosing will 
be interrupted or modified according to rules described in this section.
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.03 can be downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
In the case of toxicity, appropriate medical treatment should be used (including anti-emetics, 
anti-diarrheals, etc.).
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and the 30 day post study visit. Participants continuing to 
experience toxicity at the end-of treatment visits may be contacted for additional assessments 
until the toxicity has resolved or is deemed irreversible.
4.1
Anticipated Toxicities
In order for an event to be considered expected (known correlation to study drug/treatment) for the 
purposes of adverse event reporting, the event must be:

Included in this section for Neratinib.

Included in this section or included in the package insert or the informed consent document 
as a potential risk for Temozolomide and radiation therapy.
NOTE: For events that are secondary to an event deemed expected with a study agent/modality (e.g. 
rectal pain or hypokalemia as a result of diarrhea or gait disturbance as a result of edema cerebral), 
please record as “possibly related to” and “expected with” the agent/modality.
4.1.1
Anticipated Toxicities for Radiation Therapy
A list of adverse events of all grades suspected to be radiation therapy treatment related, 
organized by CTCAE v4.03 category, includes:

EAR AND LABYRINTH DISORDERS – external ear inflammation; other: dryness 
of ear canal; other: hardening of ear canal wax; external ear pain; other: hearing loss

ENDOCRINE DISORDERS - other: hypophysitis, or hypopituitarism

EYE DISORDERS – cataract; other: decreased vision

GASTROINTESTINAL DISORDERS – nausea; vomiting

GENERAL DISORDERS – fatigue

INJURY, POISONING AND PROCEDURAL COMPLICATIONS – dermatitis 
radiation; injury other: optic nerve

INVESTIGATIONS –lymphocyte count decreased

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS – generalized 
muscle weakness*

NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED – treatment related 
secondary malignancy

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
NERVOUS SYSTEM DISORDERS – headache; seizure; memory impairment; 
cognitive disturbance; somnolence; dysgeusia; central nervous system necrosis; 
edema cerebral; other: tumor inflammation**

PSYCHIATRIC DISORDERS – personality change

SKIN AND SUBCUTANEOUS TISSUE DISORDERS – scalp pain; other: scalp 
redness; alopecia
4.1.2
Anticipated Toxicities for Temozolomide
A list of adverse events of all grades suspected to be temozolomide treatment related, 
organized by CTCAE v4.03 category, includes:

BLOOD AND LYMPHATIC SYSTEM DISORDERS – anemia; febrile neutropenia; 
bone marrow hypocellular

GASTROINTESTINAL DISORDERS – constipation; nausea; vomiting; diarrhea

GENERAL DISORDERS – gait disturbance; fatigue

IMMUNE SYSTEM DISORDERS – allergic reaction

INJURY, POISONING AND PROCEDURAL COMPLICATIONS – bruising; 
hemorrhage

INVESTIGATIONS – neutrophil count decreased; lymphocyte count decreased; 
white blood cell decreased; platelet count decreased

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS – generalized 
muscle weakness*

NERVOUS SYSTEM DISORDERS – dizziness; memory impairment; headache; 
seizure

PSYCHIATRIC DISORDERS – insomnia

REPRODUCTIVE SYSTEM AND BREAST DISORDERS – infertility

SKIN AND SUBCUTANEOUS TISSUE DISORDERS – alopecia
4.1.3
Anticipated Toxicities for Neratinib
A list of adverse events of all grades suspected to be neratinib treatment related according 
to review of Investigator’s Brochure, organized by CTCAE v4.03 category, includes:

GASTROINTESTINAL DISORDERS: abdominal distention, dry mouth

INVESTIGATIONS: weight loss; aspartate aminotransferase increased; alanine 
aminotransferase increased; blood bilirubin increased

INFECTIONS AND INFESTATIONS – Urinary tract infection

MUSCUSKELETAL AND CONNECTIVE TISSURE DISORDERS – Muscle 
spasms

RESPIRATORY, THORACICAND MEDIASTINAL DISORDERS – 
Epistaxis; renal failure, blood creatinine increased

SKIN AND SUBCUTANEOUS TISSUE DISORDERS – erythema multiforme; rash 
pustular; rash follicular; rash generalized; dry skin; skin fissure; nail discoloration; 
paronychia; onychoclasis
*
“Generalized muscle weakness” to also include other CTCAE terms inclusive of a muscle weakness
** As CTCAE v. 4 recognizes ‘Edema cerebral’ only as a Gr4 event, please record events of ‘Edema 
cerebral’ deemed by Investigator to be Gr1-Gr3 or Gr5 as ‘Nervous system disorders, Other: Tumor 
inflammation’ (Gr1-Gr3 or Gr5, accordingly).

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4.2
Dose Modifications/Delays for Temozolomide
4.2.1
No temozolomide dose reductions are allowed during the concomitant phase of treatment. 
If a participant experiences a toxicity related to temozolomide during the concomitant 
phase of treatment, then temozolomide dosing will be interrupted according the rules 
described in Table 4.2 of this appendix.
4.2.2
When treatment must be held pending resolution of toxicity to grade 1 or return to 
baseline, and the toxicity is a non-hematologic lab abnormality, in cases where 
participant had a pre-existing non-hematologic laboratory abnormality at baseline, the 
toxicity can be considered “resolved” from a hold perspective when it has resolved to 
within 1 grade of the baseline value.
NOTE: For the purposes of data entry, values from screening assessments should be 
entered in as ‘baseline’ values. However, true “baseline values” - for the purpose of 
dose modifications on study, etc. - will be considered the last assessments/tests 
performed prior to initiation of study therapy.
EXCEPTION: In instances where the value within 1 grade of the baseline value would 
still require a hold, continue to hold until resolution of toxicity to grade 1 or return to 
baseline.
4.2.3
Participants who experience an adverse event that requires a treatment delay should be 
monitored with appropriate laboratory testing or other clinical evaluation at least weekly 
until resolution.
4.2.4
A treatment delay of up to 28 days is permitted. If the toxicity has not resolved after a 4- 
week delay, the participant must be removed from study treatment unless the participant 
has benefited from the study, in which case the investigator may contact the Overall 
Principal Investigator, Dr. Patrick Y. Wen, to determine if the participant will remain in 
the study.
4.2.4.1
NOTE: Study treatment may be held > 28 days in order to allow for surgical 
pathology to determine progression versus pseudoprogression outside of the 12-week 
consideration mark if it is prospectively confirmed with Overall PI to be clinically 
appropriate to do so.
4.2.5
Participants whose treatment is interrupted or permanently discontinued due to an 
adverse event or clinically significant laboratory value, must be followed as outlined in 
Table 4.2 of this appendix, at least once a week for 4 weeks, and subsequently at 4-week 
intervals, until resolution or stabilization of the event, whichever comes first. All 
participants must be followed for adverse events and serious adverse events for 30 days 
following the last dose of study treatment. All SAEs must be reported as detailed in 
Section 5.3 of this appendix.

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Table 4.2: Criteria for dose-modification and re-initiation of temozolomide treatment
For toxicities attributable to temozolomide (considered at least possibly related), Table 4.2 
should be adhered to as noted below. When the treating investigator feels that a hold of 
temozolomide is warranted for patient safety even though the toxicity is unlikely or unrelated to 
temozolomide, discussion with the Overall Principal Investigator and Study Sponsor, Patrick Y. 
Wen, MD is strongly recommended.
Toxicity
(organized per CTCAE v 4.03)
Concomitant Temozolomide
Neutropenia
- Grade 2  (ANC 1.0 -  1.4 x 109/L)
Interrupt until resolved to ≤ grade 1, then resume TEMOZOLOMIDE 
at the current dose level.
Neutropenia
- Grade 3  (ANC 0.5 - 0.9 x 109/L)
Interrupt until resolved to ≤ grade 1, then resume TEMOZOLOMIDE 
at the current dose level.
Neutropenia
- Grade 4 (ANC < 0.5 x 109/L)
Discontinue TEMOZOLOMIDE
Thrombocytopenia
- Platelet count: 50 - 99 x 109/L
Interrupt until platelet count recovers to ≥ 100 x 109/L, then resume 
TEMOZOLOMIDE at the current dose level.
Thrombocytopenia
- Platelet count: 10 - 49 x 109/L
Interrupt until platelet count recovers to ≥ 100 x 109/L, then resume 
TEMOZOLOMIDE at the current dose level.
Thrombocytopenia
- Platelet count: < 10 x 109/L
Discontinue TEMOZOLOMIDE
Non-hematologic toxicity (except for 
alopecia, nausea, vomiting, 
constipation, weight loss, & anorexia)
- Grade 2
Interrupt until resolved to ≤ grade 1, then resume TEMOZOLOMIDE 
at the current dose level.
Non-hematologic toxicity (except for 
alopecia, nausea, vomiting, 
constipation)
- Grade 3
Discontinue TEMOZOLOMIDE
Non-hematologic toxicity (except for 
alopecia, nausea, vomiting, 
constipation)
- Grade 4
Discontinue TEMOZOLOMIDE
4.3
Dose Modifications/Delays for Neratinib
All participants will be initially treated at Dose Level 0.
Neratinib Dose Levels
Dose Level
Dose of Neratinib
0
(starting dose)
240 mg daily
-1
160 mg daily
-2
120 mg daily

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4.3.1
General Dose Adjustments for Neratinib-Related Toxicities
Subjects should be withdrawn from the study if the 120-mg dose level of neratinib is not 
tolerable, or if the subject fails to recover to NCI grade 0 to 1 (or to within baseline of starting 
values for preexisting laboratory abnormalities) from treatment-related toxicity, leading to 
treatment delay of >4 weeks. Missed dose(s) of the investigational product will not be made up.
Table 4.3.1 should be adhered to for all toxicities attributable (considered at least possibly 
related) to neratinib as noted below unless otherwise specified in this appendix. If a participant 
experiences a toxicity unlikely or unrelated to treatment with neratinib but may still warrant a 
hold or reduction of study drug for safety, discussion and written approval by Overall Principal 
Investigator and Study Sponsor, Patrick Y. Wen, MD is strongly recommended.
Table 4.3.1: General criteria for dose-modification and re-initiation of neratinib treatment
NCI CTCAE v.4.03
Action
Grade 2 Neutropenia/Thrombocytopenia and non-hematologic toxicities
 1st appearance
 Hold neratinib until event resolves to Grade ≤1; then resume
neratinib at the starting dose level.
 2nd appearance
 Hold neratinib until event resolves to Grade ≤1; then resume
neratinib at 160 mg.
 3rd appearance
 Hold neratinib until event resolves to Grade ≤1; then resume
neratinib at 120 mg.
 4th appearance
 Discontinue neratinib permanently.
Grade 3 adverse reaction
 1st appearance
 Hold neratinib until event resolves to Grade ≤1; then resume
neratinib at 160 mg.
 2nd appearance
 Hold neratinib until event resolves to Grade ≤1; then resume
neratinib at 120 mg.
 3rd appearance
 Discontinue neratinib permanently.
Grade 4 adverse reaction
 1st appearance
 Discontinue neratinib permanently OR if Investigator deems 
it to be in the patient’s best interest to continue, hold neratinib 
until resolved to Grade ≤1; then resume neratinib at 160 mg.
 If the event occurs again despite one dose reduction, 
permanently discontinued neratinib.
4.3.2
Guidelines for the Management of Diarrhea
Diarrhea is the major DLT of neratinib with onset typically occurring early in the course 
of treatment (during the first few weeks of treatment). Primary prophylactic use of 
antidiarrheal medication is mandatory for all enrolled subjects receiving neratinib at any 

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dose for cycle 1. Loperamide is the recommended standard therapy to treat diarrhea in 
this study. If alternative antidiarrheal medication is proposed, this should be discussed 
with the Principal Investigator and the reason documented in the source documents.
Second-line antidiarrheal treatments and adjunctive therapies (i.e., octreotide 
[SANDOSTATIN®]) are also recommended for use when appropriate at the treating 
investigator’s discretion.
The investigator or designee must review with the subject the Patient Instructions for the 
Management of Diarrhea (section 14 of this appendix) and the Antidiarrheal Dosing 
Diary (section 13 of this appendix) for the subject’s daily recording of investigational 
product dose and use of loperamide use and/or other antidiarrheals during cycle 1.
Participants should be strongly encouraged to contact their treating team/physician as 
soon as possible following the first signs of diarrhea. Both the subject and the 
investigator or designee must sign the supplemental document Patient Instructions for the 
Management of Diarrhea (section 14 of this appendix) for the management of diarrhea.
Copies of both documents are handed to the subject before leaving the site with 
investigational product on Day 1 with clear instructions to contact the investigator or 
designee in the event of de novo onset or persistent ≥ grade 2 diarrhea to discuss the 
appropriate course of treatment. In addition, the Investigator or designee will contact the 
subject at 1 day, 2 days, and 3 days after the first dose of study drug is administered to 
inquire about any diarrhea.
A script for loperamide (or other antidiarrheal) must be provided prior to participant 
receiving day 1 with neratinib. It is very important to initiate treatment with loperamide 
concomitantly with the first dose of neratinib to minimize occurrence and severity of 
diarrhea.
Mandatory Prophylactic Cycle 1 Dosing Instructions

Administer loperamide:
o
Cycle 1, Day 1: initial dose of 4 mg (2 tablets/capsules) with the first dose of 
neratinib, followed by 4mg TID for a total of loperamide 16 mg within 24 
hours of cycle 1, day 1 neratinib dose.
o
Cycle 1, Days 2-14: loperamide 4mg TID for a total of 12mg/day
o
Cycle 1, Days 15-28: loperamide 4 mg BID for a total of 8 mg/day whether 
the patient is experiencing diarrhea or not.
o
Thereafter, loperamide will be administered as needed (not to exceed 16 mg 
per day).

For patients with persistent Grade 1 diarrhea (<4 stools per day above baseline) on 
loperamide, Lomotil® (diphenoxylate hydrochloride and atropine sulfate) 1 tablet 
(2.5 mg) every 6 to 8 hours may be added (or equivalent).

For Grade 2 diarrhea during the first 28 days (4 to 6 stools per day above baseline, 
despite intensive anti-diarrheal therapy), consider adding octreotide (short-acting) 150 
μg subcutaneous [SC] injection 3 times a day, or after initial dose of short-acting 
octreotide, if well tolerated, a single dose of octreotide LAR 20 mg by intramuscular 
(IM) injection (or equivalent).

After resolution of diarrhea, loperamide prophylaxis can be increased in 2 mg 

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increments with the goal of titrating to 1-2 bowel movements a day.

The Investigator or suitably trained and qualified delegate (e.g., MD, RN, NP, etc.) 
must contact the patient by phone on Cycle 1 Day 2, Cycle 1 Day 3, and Cycle 1 Day 
4 after the first dose of neratinib to inquire about compliance with loperamide and 
diarrhea or any other adverse events. (These phone calls are very important and 
should be recorded in the clinical records together with response from the patient and 
action taken.)

Instruct patients to promptly report diarrhea symptoms.

Instruct patient to report the number of stools per day and the dose of any anti- 
diarrheal medication taken each day for the first 28 days of therapy.
For new onset uncomplicated grade 1 or grade 2 diarrhea (in Cycle 2 and beyond)

Recommended dietetic measures

Stop all lactose-containing products

Drink 8 to 10 large glasses of clear liquids per day

Eat frequent small meals

Recommend low fat regimen enriched with bananas, rice, applesauce and 
toast (BRAT diet) until resolution of diarrhea.

Recommended pharmacological treatment

Administer loperamide: initial dose of 4 mg (2 tablets) with the first bout of 
diarrhea followed by 2 mg (1 tablet) every 4 hours or after every unformed 
stool (maximum 16 mg a day) and continue loperamide at this frequency until 
diarrhea free for 12 hours. Then titrate the amount of loperamide used to keep 
diarrhea controlled (< 4 stools/day).

For patients with persistent grade 1 diarrhea on a maximum dose of loperamide 
(16 mg per day), Lomotil (diphenoxylate hydrochloride and atropine sulfate) 1 
tablet (2.5 mg) every 6 hours to 8 hours may be added.

For grade 2 diarrhea (4 to 6 stools per day above baseline, despite intensive 
anti-diarrheal therapy), consider adding octreotide (short-acting) 150 
micrograms SC TID; or after initial dose of short-acting octreotide, if well 
tolerated, a single dose of octreotide LAR 20 mg IM.
For grade 3 or grade 4 diarrhea with complicating features (dehydration, fever, 
and/or grade 3-4 neutropenia

Recommended dietetic measures (same as above)

Recommended pharmacologic treatment

Administer loperamide: initial dose of 4 mg (2 tablets) with the first bout of 
diarrhea followed by 2 mg (1 tablet) every 4 hours or after every unformed 
stool (maximum 16 mg a day) and continue loperamide at this frequency until 
diarrhea free for 12 hours. Then titrate the amount of loperamide used to keep 
diarrhea controlled (< 4 stools/day).

Administer octreotide (SANDOSTAINE®) [100-150 μg SC BID or IV (25-50
μg/h) if dehydration is severe, with dose escalation up to 500 μg SC TID]

Use intravenous fluids as appropriate

Consider prophylactic antibiotics as needed (e.g., fluoroquinolones) especially 
if diarrhea is persistent beyond 24 hours or there is fever or grade 3-4 
neutropenia.

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Stool cultures should be done to exclude infectious causes of grade 3 or 4 diarrhea or 
diarrhea of any grade with complicating features (dehydration, fever, and/or grade 3 or 4 
neutropenia) per the investigator’s discretion. Results from occult blood, fecal leukocyte 
stain, Clostridium difficile, Campylobacter, Salmonella, and Shigella testing, when 
performed, should be reported.
Subjects with significant diarrhea who are unresponsive to medical treatment may require 
treatment interruption or dose reduction as listed in table below.
Table 4.3.2 Gastrointestinal Toxicities Requiring Dose Adjustment of Neratinib
Toxicity 
(organized per CTCAE v 4.03)
Actions
Grade 1 Diarrhea [Increase of <4 
stools per day over baseline; mild 
increase in ostomy output compared to 
baseline.]
OR
Grade 2 Diarrhea [Increase of 4-6 
stools per day over baseline; moderate 
increase in ostomy output compared to 
baseline;] lasting <5 days
OR
Grade 3 Diarrhea [Increase of ≥7 
stools per day over baseline; 
incontinence; hospitalization 
indicated; severe increase in ostomy 
output compared to baseline limiting 
self-care activities of daily living 
(ADL)] lasting < 2 days

Adjust anti-diarrheal treatment as per guidelines 
for management of diarrhea in section 4.3.2 of 
this appendix.

Continue neratinib at full dose.

Instruct patient to follow dietetic 
recommendations in the guidelines for 
management of diarrhea.

Fluid intake of ~2L should be maintained to 
avoid dehydration.

Once the event resolved to ≤ grade 1 or baseline, 
start loperamide 4 mg with each subsequent 
neratinib administration.

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Persisting and intolerable Grade 2 
Diarrhea lasting >5 days despite 
being treated with optimal medical 
therapy, or associated with fever, 
dehydration, or grade 3-4 
neutropenia
OR
Grade 3 Diarrhea lasting > 2 days 
despite being treated with optimal 
medical therapy, or associated with 
fever, dehydration, or grade 3-4 
neutropenia
OR
Any Grade 4 diarrhea [Life- 
threatening consequences; urgent 
intervention indicated]

Adjust anti-diarrheal treatment as per guidelines 
for management of diarrhea in section 4.3.2 of 
this appendix.

Hold neratinib until recovery to ≤ grade 1 or 
baseline.

Instruct patient to follow dietetic 
recommendations of the guidelines for 
management of diarrhea.

Fluid intake of ~2L should be maintained, 
intravenously if needed.

If recovery occurs:
o
≤1 week after withholding treatment, 
resume same dose of neratinib.
o
Within 1-3 weeks after withholding 
treatment, reduce neratinib dose to the 
next lower dose level.
o
If event recurs and the neratinib dose has 
not already been decreased, reduce 
neratinib dose to the next lower dose 
level.
o
If subsequent events occur, reduce 
neratinib dose to the next lower dose 
level.

Once the event resolved to ≤ grade 1 or baseline, 
start loperamide 4 mg with each subsequent 
neratinib administration.

If event recurs and the neratinib dose has already 
been reduced at the lowest level, discontinue 
neratinib.
4.3.3
Guidelines for the Management of Changes in Liver Function Tests
Changes in LFTs have been reported in subjects taking neratinib. Subjects experiencing 
grade 3 or 4 diarrhea requiring IV hydration and associated with any signs or symptoms 
of hepatotoxicity such as worsening of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash or eosinophilia should be evaluated for LFT changes.
Table below should be adhered to for AEs determined to be at least possibly related to 
neratinib.
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) 
concurrent with abnormal elevations in total bilirubin that meet the criteria in the table 
below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events.
The possibility of hepatic neoplasia (primary or secondary) should also be considered. 
During evaluation of potential hepatotoxicity, bilirubin should be fractionated and 

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prothrombin time should be measured. Also, liver imaging should be obtained for 
subjects with any signs or symptoms of hepatotoxicity and/or grade 3 or greater LFT 
elevations, or as clinically indicated.
Table 4.3.3 Liver Function Test Toxicities Requiring Dose Adjustment of Neratinib
Event
(Based on NCI CTC4.0)
Action
Grade 3 ALT (>5-20x ULN)
OR
Grade 3 Bili (>3-10x ULN) and direct 
bili ≥ 35% of total bili

For participants with AST/ALT <grade 1 at 
baseline, resume neratinib at one dose level lower 
if recovery to baseline occurs within 21 days.

If grade 3 AST, ALT or bilirubin recurs despite 
one dose reduction, resume neratinib at a further 
dose reduction if recovery to baseline occurs 
within 21 days.

If grade 3 AST/ALT or bilirubin occurs despite 
this second dose reduction, permanently 
discontinue neratinib. Report as SAE.

Evaluate alternative causes.
Grade 4 AST/ALT (>20x ULN)
OR
Grade 4 Bilirubin (>10x ULN)

Permanently discontinue investigational product 
(IP)

Evaluate alternative causes.

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ALT > 3x ULN and
Total bilirubin > 2x ULN and 
Alkphos < 2x ULN. (Potential Hy’s 
law indicators of drug-induced liver 
damage).
Hold IP and immediately contact the PI to discuss next 
steps, including evaluation of alternative causes, and 
management of IP. The patient should return to the 
investigational site and be evaluated as soon as 
possible, preferably within 48 hours from awareness 
of the abnormal results. This evaluation should 
include laboratory tests, detailed history and physical 
assessment. Laboratory assessment must include: 
repeat AST and ALT, albumin, total bilirubin, direct 
bilirubin, PT, PTT and alkaline phosphatase. A 
detailed history, including relevant information, such 
as review of ethanol, concomitant medications, 
recreational drug and supplement consumption, family 
history, sexual history, travel history, history of 
contact with a jaundiced patient, surgery, blood 
transfusion, history of liver or allergic disease, and 
work exposure, should be collected. Further testing for 
acute hepatitis A, B, or C infection and liver imaging 
(eg, biliary tract) may be warranted. All cases 
confirmed on repeat testing as meeting the criteria 
mentioned (i.e., ALT > 3 x ULN associated with 
bilirubin >2 x ULN and alkaline phosphatase <2 x 
ULN), with no other cause for liver function test 
abnormalities identified at the time should be 
considered potential Hy’s Law cases, irrespective of 
availability of all the results of the investigations 
performed to determine etiology of the abnormal liver 
function tests.
Contact Puma immediately to discuss next steps, 
including evaluation of alternative causes, and 
management of investigational product(s).

Report as SAE.
Signs or symptoms related to liver 
injury (abdominal pain, fever, jaundice, 
rash, eosinophilia, or drop in 
performance status) with either:
Grade 2 ALT (>3-5x ULN), or
Grade 2 ALT (>3-5x ULN) and 
Grade 2 Bili (>1.5-3x ULN) and direct 
bili ≥ 35% of total bili.

Permanently discontinue IP.

Evaluate alternative causes.

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4.3.4
Guidelines for the Management of Pulmonary Toxicity
Guidelines for adjusting doses of neratinib in the event of pulmonary toxicities are shown in 
Table 4.3.4. Interstitial lung disease, which can sometimes be fatal, has been reported with other 
oral tyrosine kinase inhibitors that target EGFR ±HER2 (ERBB2), including lapatinib, gefitinib, 
and erlotinib. Rare cases of pneumonitis (0.6%) and lung infiltration (0.4%) have been reported 
in patients treated with neratinib monotherapy, and considered drug-related. Patients receiving 
neratinib should be monitored for acute onset or worsening of pulmonary symptoms such as 
dyspnea, cough, and fever and treated appropriately.
Table 4.3.4: Pulmonary Toxicities Requiring Dose Adjustment of Neratinib
NCI CTCAE V4.03
Action
Grade 2 Pneumonitis/Interstitial Lung 
Disease [Symptomatic; medical 
intervention indicated; limiting 
instrumental ADL]
 Hold neratinib until recovery to ≤ Grade 1 
or baseline.
 Reduce neratinib to 160 mg or discontinue
neratinib as per Investigator’s best medical 
judgment.
Grade 3 Pneumonitis/Interstitial Lung 
Disease [Severe symptoms; limiting self- 
care ADL; oxygen indicated]
 Discontinue neratinib permanently.
5. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of reported and/or potential AEs (section 4.1 of this appendix) and the 
characteristics of an observed AE (Section 5.2 of this appendix) will determine whether the event 
requires expedited reporting in addition to routine reporting.
This section specifies reporting requirements to the FDA, Overall PI/Coordinating Center, 
DF/HCC IRB, and manufacturer as applicable.
5.1
Expected Toxicities
Refer to section 4.1 of this appendix for expected toxicities for assigned study treatment 
arm.
5.2
Adverse Event Characteristics

CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.03. A copy of the CTCAE version 4.03 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

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
For expedited reporting purposes only:
-
AEs for the agent(s) that are listed in section 4.1 of this appendix should be reported 
only if the adverse event varies in nature, intensity or frequency from the expected 
toxicity information which is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol- 
Specific Expedited Adverse Event Reporting Exclusions.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.

Serious Adverse Event (SAE) Definition:
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless 
of causality that:
o
Results in death
o
Is life-threatening (i.e., in the opinion of the Investigator, the subject is at 
immediate risk of death from the AE);
o
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
o
Results in persistent or significant disability/incapacity (a substantial disruption of 
the subject’s ability to conduct normal life functions);
o
Is a congenital anomaly/birth defect;
o
Constitutes an important medical event. Important medical events are defined as 
those occurrences that may not be immediately life threatening or result in death, 
hospitalization, or disability, but may jeopardize the subject or require medical or 
surgical intervention to prevent one of the other outcomes listed above. Medical 
and scientific judgment should be exercised in deciding whether such an AE 
should be considered serious.
5.3
Expedited Adverse Event Reporting
5.3.1
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment.
5.3.2
For multi-institution studies where a DF/HCC investigator is serving as the Overall 
Principal Investigator, each participating institution must abide by the reporting 
requirements set by the DF/HCC. This applies to any medical event that is Serious, 
Unexpected, and there is a Reasonable Possibility (i.e., possible, probable, or definitive 
attribution) the Adverse Event is related to the study intervention.

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5.3.3
Expedited Reporting Guidelines to Overall PI/Coordinating Center
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.
External investigative sites will report AEs to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the AE form should 
be forwarded to the Overall PI within the timeframes detailed in the table below. The 
Overall PI will submit AE reports from outside institutions to the DFCI OHRS according 
to DFCI IRB policies and procedures in reporting adverse events.
In addition to local IRB reporting policies, all sites are required to following the Table
5.3.3 expedited reportable AE requirements:

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NOTE: Until patients initiate treatment with Neratinib on study, please report per Table 5.3.3 ‘Expedited AE Reporting by 
external sites to Coordinating Center/Overall PI’ of Appendix E (Control Arm).
Table 5.3.3 Expedited AE Reporting Requirements
Adverse Event Characteristics
Reporting Requirement
Serious- 
ness
Toxicity
Known Correlationf
Attribution to 
Neratinib
Overall PI (Patrick Y. Wen, MD) at the DFCI Coordinating Center 
Via Email b
Use Reportable AE Coversheet c and Medwatch 3500A d
Seriouse
Any
Any
(Expected or 
Unexpected)
Any
Within 24 hours from notification a
Non- 
Serious
Grade 4
Any
(Expected or 
Unexpected)
Any
Within 5 working days from notification a
Non- 
Serious
Grade 2 or 3
Unexpected
Possible, probable, 
definite
Within 7 working days from notification a
a.
In the event that the participating investigator/site team does not become aware of the serious adverse event immediately (e.g., participant sought treatment elsewhere), the 
participating investigator/site team is to report the event within the required hours/days noted above after learning of it and document the time of his or her first awareness of 
the adverse event. The initial report must be as complete as possible, including assessment of the causal relationship between the event and the investigational product(s). 
Information not available at the time of the initial report (e.g., an end date for the adverse event or laboratory values received after the report) must be documented on a 
follow-up report.  A final report to document resolution of the SAE or reportable AE is required.
b.
Email the Medwatch 3500A form, reportable AE coversheet (section 10 of this appendix), and the local IRB SAE report (if applicable) to the DFCI Coordinating Center with the 
subject title as “INSIGHT SAE” to NeuroOnc_SAE@dfci.harvard.edu. All SAE reports received at this account are forwarded immediately to study’s Overall PI, Dr. Patrick Y. Wen, 
and to the DFCI Coordinating Center personnel.
c.
Reportable AE Coversheet is found in section 10 of this appendix. The coversheet contains all FAX numbers/e-mails and needed for reporting purposes.
d.
Medwatch 3500A downloadable form at http://www.fda.gov/medwatch/getforms.htm
e.
Seriousness is defined in section 5.2 of this appendix.
f.
Expected adverse events are those that have been previously identified as resulting from administration of the agent. For the purposes of this study, an adverse event is 
considered expected when it appears in the Anticipated Toxicities list (protocol section 4.1 of this appendix) which is derived from the Investigator’s Brochure and/or package 
insert (if applicable).

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5.3.4
How to report AEs to PUMA & DFCI Coordinating Center/Overall PI
1. Document/describe reportable AE(s) on the following:
a.
MedWatch 3500A
i. downloadable form at http://www.fda.gov/medwatch/getforms.htm
b. DFCI Reportable AE Coversheet – INSIGhT Neratinib Arm
i. Coversheet can be found in section 10 of this appendix. A 
modifiable Microsoft Word document is also available from the 
DFCI Coordinating Center.
2. Scan and email above documents to NeuroOnc_SAE@dfci.harvard.edu with the 
subject title “INSIGHT SAE”
a.
All AE reports received at this account are forwarded immediately to 
Overall Principal Investigator (Dr. Patrick Y. Wen), and to Coordinating 
Center personnel.
b. If available and applicable, also include the local IRB submission for this 
event in the submission to the DFCI Coordinating Center.
5.3.5
Protocol-Specific Expedited Adverse Event Reporting Exclusions
For this protocol only, the AEs/grades listed below do not require expedited reporting to 
the Overall PI or the DFCI IRB. However, they still must be reported through the routine 
reporting mechanism (i.e. case report form).

Lymphopenia (grades 2-4)

A visit to the emergency room or other hospital department < 24 hours, that 
does not result in admission (unless considered an important medical or life- 
threatening event)

Emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission

Elective surgery, planned prior to signing consent

Routine health assessment requiring admission for baseline/trending of health 
status (eg, routine colonoscopy)

Hospitalization for routine treatment or monitoring of the studied indication, 
not associated with any deterioration in condition, or for elective procedures

Hospitalization for elective or pre-planned treatment for a pre-existing 
condition that did not worsen

Hospitalization for respite care not associated with an adverse event attributed 
to the study drug

Hospitalization for treatment of patient’s underlying disease after coming off 
study treatment (e.g. admission after patient is removed from active study 
treatment for craniotomy)

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5.4
Expedited Reporting to the Food and Drug Administration (FDA)
As study sponsor, the Overall PI (or his designee) will be responsible for all communications 
with the FDA. The Overall PI will report to the FDA, regardless of the site of occurrence, any 
serious adverse event that meets the FDA’s criteria for expedited reporting following the 
reporting requirements and timelines set by the FDA.
5.5
Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.
5.6
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms. AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
5.7
Reporting to Puma Biotechnology, Inc.
Any serious adverse events which occur during the clinical study or within 30 days of receiving 
the last dose of study medication, whether or not related to the study drug, must be reported by the 
investigator. In addition, any SAEs which occur as a result of protocol specific diagnostic 
procedures or interventions must also be reported.
All serious adverse events, in addition to being reported to the FDA by the investigator, must be 
reported by email to Puma Biotechnology, Inc. as follows:
For expedited reports, DFCI Coordinating Center will send the MEDWATCH report to the 
Company no later than seven (7) days for initial life-threatening and death reports, and fifteen (15) 
days for all other initial or follow-up serious and unexpected suspected adverse reaction (SUSAR) 
as assessed by the investigator for causality and by the Investigator-Sponsor for causality and 
expectedness based on section 4.1 of this appendix from the time of receipt of the SAE by DFCI 
Coordinating Center. For non-expedited reports (i.e., unrelated to study drugs or listed/expected 
event), DFCI Coordinating Center will send the MEDWATCH report to the Company no later 
than thirty (30) days from the time of receipt of the SAE by DFCI OHRS.
By e-mail to PumaSAE@parexel.com
SAEs brought to the attention of the investigator at any time after cessation of neratinib and 
considered by the investigator to be related or possibly related to neratinib must be reported to 
Puma Biotechnology, Inc. if and when they occur. Additionally, in order to fulfill international 
reporting obligations, SAEs that are related to study participation (e.g., procedures, invasive tests, 
change from existing therapy) or are related to a concurrent medication will be collected and 
recorded from the time the subject consents to participate in the study until he/she is discharged 
from the study.

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6. PHARMACEUTICAL INFORMATION
6.1
Temozolomide
6.1.1
Description
The chemical name of Temozolomide is 3,4-dihydro-3methyl-4-oxoimidazo[5,1-d]-as- 
tetrazine-8-carboxamide and the molecular weight is 194.15, which acts as an alkylating 
agent.
In humans, the terminal elimination half-life (t1/2) in plasma ranges from approximately
1.6 to 1.88 hours. Following oral administration, the drug, Temozolomide, is rapidly 
absorbed and then hydrolyzed to the active metabolite 5-(3-methyltriazen-1-yl) 
imidazole-4-carboxamide (MTIC). MTIC spontaneously degrades to CO2 and 5- 
aminoimidazole-4-carboxamide (AIC) and excreted via the urine. CYP isoenzymes play 
an only minor role in Temozolomide metabolism.
6.1.2
Form
Temozolomide drug will be supplied commercially and should be ordered per local 
policy. The drug products are stable when stored according to instructions on the label.
Each capsule for oral use contains either 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 
mg of Temozolomide and the inactive ingredients sodium starch glycolate, tartaric acid, 
stearic acid, and colloidal silicon dioxide.
The body of the capsules is made of gelatin, and is opaque white. The cap is also made of 
gelatin, and the colors vary based on the dosage strength.
6.1.3
Storage and Stability
Temozolomide is stable at room temperature.
6.1.4
Compatibility
There are no known compatibility issues.
6.1.5
Handling
Routine chemotherapy handling is recommended.
6.1.6
Availability
Temozolomide is available through special pharmacy and can be prescribed by the 
treating physician.

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6.1.7
Preparation
None
6.1.8
Administration
o
Temozolomide capsules should not be opened or chewed; they must be 
swallowed whole with a glass of water one hour before or after food and other 
medications.
o
If vomiting occurs during the course of treatment, no re-dosing of the participant 
is allowed before the next scheduled dose. The occurrence and frequency of any 
vomiting during a treatment cycle must be recorded as an adverse event.
o
If the participant forgets to take his/her temozolomide dose more than 10 hours 
from the last dose, then that dose should be withheld and temozolomide should be 
restarted at the time of the next planned dose.
6.1.9
Ordering
Temozolomide drug will be supplied commercially and should be ordered per local 
policy.
6.2
Neratinib
6.2.1
Description
Neratinib (PB-272) is a potent irreversible pan erbB inhibitor. Neratinib is an orally 
available small molecule that inhibits erbB-1, erbB-2, and erbB-4 at the intracellular 
tyrosine kinase domains, a mechanism of action that is different from trastuzumab.
Preliminary pharmacokinetic analyses demonstrated that neratinib absorption was 
relatively slow, and the maximum concentration (Cmax) was generally attained within 3 
to 6 hours. After oral administration, the neratinib Cmax and area under the concentration 
versus time curve (AUC) increased in a dose-dependent manner in general. Mean 
steadystate Cmax and AUC values were 70.1 ng/mL and 975 ng·h/mL for the 180-mg 
dose group, respectively, 73.5 ng/mL and 939 ng·h/mL for the 240-mg dose group, 
respectively, 90.4 ng/mL and 1333 ng·h/mL for the 320-mg dose group, respectively, and 
105 ng/mL and 1704 ng·h/mL for the highest dose of 400 mg, respectively. The neratinib 
exposure (AUC) increased 1.2- to 2.7-fold (mean accumulation ratio) when comparing 
the steady-state exposure on day 21 after repeated daily administration with the exposure 
on day 1 after administration of 80 to 400 mg of neratinib. The mean accumulation ratio 
was 1.2 after a 240-mg dose, indicating no significant accumulation of neratinib after 
repeated daily dose administration at the dose to be used in this proposed trial. The data 
indicated a slow distribution of neratinib with a large apparent volume of distribution 
(Vz/F on day 1: about 3188 to 6181 L) after oral absorption. After oral administration on 
day 1, neratinib was eliminated with a mean apparent terminal half-life (t½) of 
approximately 13 to 17 hours. There was moderate to large variability in neratinib t½, 
Cmax, and AUC; coefficients of Version 02/05/15 Page 13 of 85 variation generally 
ranged from 8% to 90%.

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6.2.2
Form
Neratinib 40-mg tablets will be supplied by the sponsor. There are 210 pills per bottle. 
Repackaging of product is not allowed. Repackaging of product is allowed, provided site 
adheres to the following guidances:

FDA’s Repackaging of Certain Human Drug Products by Pharmacies and 
Outsourcing Facilities, and

USP General Chapter <795> Pharmaceutical Compounding —Nonsterile 
Preparations
6.2.3
Storage and Stability
Investigational products will be stored by sites in a secure location at the storage 
conditions listed on the label; store at 25°C (77°F) or below with desiccant (bottle 
contains the dessicant); do not freeze. Correspondingly, subjects must be instructed to 
store investigational products in a safe place at these same storage conditions. Storage in 
a refrigerator or cold room is acceptable as long as the temperature remains above 0 °C. 
The investigational product must be stored as indicated. Deviations from the storage 
requirements, including any actions taken, must be documented and reported to the 
sponsor. Once a deviation is identified, the investigational product must be quarantined 
and not used until the sponsor provides documentation of permission to use the 
investigational product. The investigational product is only to be administered to subjects 
who have provided informed consent. Once the investigational product has been assigned 
to a subject it must not be reassigned to another subject.
6.2.4
Compatibility
There are no known compatibility issues.
6.2.5
Handling
Routine chemotherapy handling is recommended.
6.2.6
Availability
Neratinib is an investigational agent and will be supplied free-of-charge from Puma 
Biotechnology, Inc.
6.2.7
Preparation
None.

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6.2.8
Administration
The number of tablets of neratinib taken will depend on the prescribed dose per the dose 
administration table. The investigational product will be taken by mouth with food, 
preferably in the morning. Participants should swallow tablets as a whole and not chew 
them. Participants should be instructed to take their dose at approximate the same time 
each day. If the participant forgets to take a neratinib dose more than 3 hours after the 
intended time, then the dose should be skipped and restarted on the next calendar day. If 
vomiting occurs during the course of treatment, no re-dosing of the participant is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting during a 
treatment cycle must be recorded as an adverse event.
6.2.9
Ordering
The agent will be ordered from each institution’s individual pharmacy (or designee) using 
a Puma Biotechnology Drug Supply Request Form. This form will be supplied to each 
institution’s pharmacy by the coordinating center once local IRB approval is received.
The number of tablets per bottle and the email address to where the form should be sent 
are detailed on the Drug Supply Request Form. Anticipate 3-5 business days to receive 
drug after the order is placed.
6.2.10 Accountability
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form. 
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.)
6.2.11 Destruction and Return
Neratinib will be destroyed on site according to institutional policies, documented in the 
Drug Accountability Record Form. At the end of the study, unused supplies of neratinib 
should be destroyed according to institutional policies. Destruction will be documented in 
the Drug Accountability Record Form.

16-443 INdividualized Screening trial of Innovative Glioblastoma Therapy (INSIGhT) 
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230
7.
STUDY CALENDAR
Concomitant
Adjuvant Cycles
Assessment
Screen
-inga
D1b
D8c
D15c
D22 c
D29 c
D36 c
D43-
49 d
Reste
D1f
End of Txg
30-Day 
Post Drugh
Active 
Follow-Upi
Long 
Term
Follow-Upj
Informed Consentk
X
Medical Historyl
X
Inclusion/Exclusion Criteriam
X
Vital signsn
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
Neurologic Exam
X
X
X
X
X
X
Karnofsky Performance Statuso
X
X
X
X
X
X
Concomitant Medicationsp
X
Adverse Eventsq
X
Pregnancy Test (β-HCG)r
X
X
X
X
X
Coagulations
X
Hematologyt
X
X
X
X
X
X
X
X
Xdd
X
X
Serum Chemistryu
X
X
X
X
Xdd
Xu
Xu
EKGv
X
Xv
Xv
ECHO/MUGAw
Xw
Xw
Radiationx
---------------------------X----------------------------
Temozolomide
---------------------------X----------------------------
Neratinib
X
Imaging – MRI oy
Xy
Xy
Xy
X
X
Response Assessmentz
X
X
X
Study Team Contactaa
Xaa
Post-treatment therapiesbb
X
X
Survivalcc
X
X
a.
All screening procedures to be performed within 28 days of initial registration. NOTE: refer to section 10 of master protocol for comprehensive details on screening 
assessments, initial registration, randomization assignment and second registration timing.
b.
Concomitant radiation and temozolomide must begin no later than 42 days following initial surgery. Day 1 assessments must be performed within 3 days of starting study 
treatment. Screening assessments may be utilized as baseline/Day 1 assessments if they fall within window.
c.
+/- 2 day window for weekly assessments during concomitant phase.
d.
Day 43-49 visit to occur within +/- 7 days of completing radiation.

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231
e.
Rest period is 28-42 days.
f.
Adjuvant C1D1 to begin >28 (+14) days following end of radiation. Cycle 1, Day 1 adjuvant assessments to be performed within 4 days of Day 1 neratinib. All adjuvant cycle 1, day 
1 assessments must be resulted and reviewed prior to initiating treatment with neratinib; participants cannot begin adjuvant neratinib if they meet any criteria requiring a dose 
modification as outlined in section 4.3 of this appendix. Adjuvant cycles will be 28 days even if treatment is held. Day 1 assessments for subsequent adjuvant cycles to be 
performed within 4 days prior to Day 1 neratinib. (If utilizing the assessment window, that does not shorten the previous cycle or extend the upcoming cycle; each = 28 days.)
g.
End of Treatment: assessments to be performed within 7 days after last drug administration or within 7 days after decision to end treatment.
h.
30-Day Post Drug: a contact/visit is to be performed 30 days (+7 days) after date of last drug taken on study. This may be performed via documented phone conversation with a 
study nurse or clinician or a clinic visit. All participants will be followed until resolution or stabilization of any serious or reportable adverse events occurring during treatment or 
starting within 30 days of last drug.
i.
Active Follow-Up: participants who discontinue study treatment for reasons other than disease progression will be followed every 4 weeks (+/-1 week) via contact or medical 
record review andstudy team must continue monitoring participant’s disease status by radiologic imaging at 8 week intervals (+/- 1 week) until (1) documented disease 
progression, (2), death, (3) participant withdraws from follow-up, or (4) end of study, whichever occurs first.
j.
Long Term Follow-Up: participants will be followed every 4 weeks (+/-1 week) via contact or medical record review until death. Participants must be followed for survival data at 
every long-term follow-up time point and for post-treatment therapies and reason for stopping those therapies and survival when available.
k.
Informed Consent: must be obtained by MD attending. No study specific screening procedures may occur until after the initial informed consent process is completed. Initial 
informed consent may be obtained within 28 days of initial registration. Following initial registration and receipt of INSIGhT randomization assignment, participants must be sign 
the consent form specific to the assigned treatment arm prior to initiating treatment for that study arm.
l.
Medical History: to include review of treatment history for GBM, any ongoing medical conditions and medical history pertaining to eligibility on study and involvement during 
study.
m. Inclusion/exclusion criteria: source documentation providing investigator’s confirmation that the participant had met all master protocol eligibility criteria must be available prior 
to initial registration. See section 3 of master protocol for eligibility requirements for initial registration. See section 2 of this appendix for arm specific eligibility criteria.
n.
Vital Signs: weight, heart rate, blood pressure, respiration rate, temperature. Vital signs must be performed prior to administration of treatment on treatment days. Height 
required only at screening.
o.
Karnofsky Performance Status (KPS): see appendix A of master protocol.
p.
Concomitant Medications: concomitant medications and reason for administration should be documented in the case history from date of consent up to the 30-Day Post Drug 
Visit.
q.
Adverse Events: adverse events experienced by participants will be collected and recorded from the first dose of treatment on-study up to the 30-Day Post Drug Visit of the last 
dose of study medication (+ 7 days depending on when 30-Day Post Drug visit/contact occurs).
r.
Pregnancy Test: required for women of child bearing potential (see section 3 of master protocol for definition of women of child bearing potential).
s.
Coagulation: PT/INR, PT, PTT required at screening only.
t.
Hematology: erythrocytes (RBC), hemoglobin, hematocrit, platelets, total WBC plus differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils).
u.
Serum Chemistry: albumin, alkaline phosphatase (ALP), BUN, calcium, creatinine, glucose, potassium, SGOT (AST), SGPT (ALT), sodium, total bilirubin (if total bilirubin is greater 
than the upper limit of normal, direct and indirect bilirubin should be performed). In addition, LDH, cholesterol (non-fasting), phosphorus and magnesium are required during 
adjuvant cycles and End of Treatment chemistry time points.
v.
EKG: required at screening, then within -4 days of C1D1 of adjuvant and within -4 days of day 1 every 3 cycles thereafter (C4D1, C7D1, etc.) during the treatment period. EKG to 
be performed at End of Treatment visit if one has not been performed within last 12 weeks.
w.
ECHO/MUGA: LVEF assessment must be performed within 21 days prior to C1D1 of adjuvant neratinib; an LVEF of ≥50% is required in order for participant to begin treatment 
with neratinib at adjuvant C1D1. If LVEF is 45-49%, site may reach out to Overall PI via Coordinating Center Team and request prospective approval to proceed with treatment.

16-443 INdividualized Screening trial of Innovative Glioblastoma Therapy (INSIGhT) 
APPENDIX H: NERATINIB ARM
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232
LVEF monitoring is not required during treatment unless clinically indicated. ECHO/MUGA to be performed at End of Treatment visit if one has not been performed within 
previous 12 weeks of date of progression. It is strongly recommended to use the same method of cardiac evaluation (ECHO or MUGA) at each time point for each subject.
x.
Radiation: see section 3.1 of this sub-study appendix for definition of standard radiation therapy per protocol.
y.
Imaging: gadolinium-enhanced contrast and non-contrast MRI. Initial imaging should be performed within 21 days prior to beginning study treatment. When feasible at site, 
Appendix D Recommended MRI Acquisition Protocol should be adhered to and the same imaging technique should be used on a participant throughout the trial. Local reading 
(investigator assessment) will be used to determine eligibility and for participant management. Adjuvant C1D1 imaging should be performed within 7 days prior to starting 
adjuvant treatment; subsequent imaging should be performed within 7 days prior to Day 1 of odd cycles.
z.
Response Assessment: Per RANO criteria (see section 11 of master protocol).
aa. Study Team Contact: On day 2, 3 and 4 of adjuvant cycle 1 only, the investigator or designee must contact the participant to inquire about any diarrhea. 
bb. Post-treatment Therapies: start/stop dates, names of treatment regimens and reason for stopping should be collected when available.
cc. Survival: date of death and reason must be collected for overall survival purposes.
dd. Hemes & Serum Chemistries will be done as per SOC during patient’s post-RT rest phase: hemes = weekly; chemistries need only be performed @ the end of RT visit and prior to 
adjuvant C1D1 (unless clinically indicated otherwise)

16-443 INdividualized Screening trial of Innovative Glioblastoma Therapy (INSIGhT) 
APPENDIX H: NERATINIB ARM
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233
8. MEASUREMENT OF EFFECT
Refer to section 11 of master INSIGhT protocol for details on measurement of effect.
9. REFERENCES
Brennan CW, Verhaak RGW, McKenna A, Campos B, et al. The Somatic Genomic Landscape 
of Glioblastoma. Cell 2013; 155:462–477.
Ekstrand AJ, Sugawa N, James CD, Collins VP. Amplified and rearranged epidermal growth 
factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of 
the N- and/or C-terminal tails. Proc Natl Acad Sci U S A. 1992 May 15; 89(10):4309-13.
Freedman RA, Gelman RS, Wefel JS, et al. TBCRC 022: Phase II trial of neratinib for patients 
(Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer and brain 
metastases (BCBM). ASCO Meeting Abstracts. 2014; 32(15_suppl):528.
Gan HK, Kaye AH, Luwor, RB. The EGFRvIII variant in Glioblastoma Multiforme. J. Clin. 
Neurosci 2009; 16:748 -754.
Gandhi L, Drappatz, J, Ramaiya NH, Otterson, GA. High-Dose Pemetrexed in Combination with 
High-Dose Crizotinib for the Treatment of Refractory CNS Metastases in ALK-Rearranged 
Non–Small-Cell Lung Cancer. J Thoracic Oncology 2013; 8:e3–e5.
Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev 
Cancer. 2005 May; 5(5):341-54.
Lee JC, Vivanco I, Beroukhim R, et al. Epidermal Growth Factor Receptor Activation in 
Glioblastoma through Novel Missense Mutations in the Extracellular Domain. PLOS Medicine 
2006; 3; 2264-2273.
Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, et al. Amplification, enhanced expression 
and possible rearrangement of EGF receptor gene in primary human brain tumours of glial 
origin. Nature. 1985 Jan 10 18;313(5998):144-7.
Neratinib Graduates to I-SPY 3. Cancer Discov. 2014; 4(6):624.
Rabindran SK, Discafani CM, Rosfjord EC, et al. Antitumor activity of HKI-272, an orally 
active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res 2004; 64(11): 3958-65.
Saura C, Garcia-Saenz JA, Xu B, et al. Safety and efficacy of neratinib in combination with 
capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive 
breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2014; 32(32):3626-3633.

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APPENDIX H: NERATINIB ARM
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234
Vivanco I, Robins HI, Rohle D, et al. Differential sensitivity of glioma- versus lung cancer- 
specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov. 2012; 2(5):458-471.
Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B. 
Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl 
Acad Sci U S A. 1992 Apr 1;89(7):2965-9.
Yamazaki H, Fukui Y, Ueyama Y, Tamaoki N, Kawamoto T, et al. Amplification of the 
structurally and functionally altered epidermal growth factor receptor gene (c-erbB) in human 
brain tumors. Mol Cell Biol.  1988 Apr;8(4):1816-20.

235
10. DFCI REPORTABLE AE COVERSHEET – INSIGHT NERATINIB ARM
DF/HCC Protocol No. 16-443
Date:
Number of pages including cover sheet: 
From:
Institution:
Phone No.:
Fax No.:
Participant # and Initials:
Date Event Met Reporting Criteria (as defined in protocol):
Type of Report: Initial Follow-up
Hospitalization?  Yes
 No
CTCAE Event #1 Description:
CTCAE Event #2 Description (if applicable):
NOTE: use another coversheet if more than 2 events are being reported at this 
time
Meets Definition of Serious AE:
 Serious
 Non-serious
Meets Definition of Serious AE:
 Serious
 Non-serious
Toxicity Grade:
G1/mild G2/moderate G3/severe
G4/life threatening G5/death
Toxicity Grade:
G1/mild G2/moderate G3/severe
G4/life threatening G5/death
Expectedness to Radiation Therapy:
Expected Unexpected  N/A
Expectedness to Radiation Therapy:
Expected Unexpected  N/A
Attribution to Radiation Therapy:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Attribution to Radiation Therapy:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Expectedness to Temozolomide:
Expected Unexpected  N/A
Expectedness to Temozolomide:
Expected Unexpected
Attribution to Temozolomide:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Attribution to Temozolomide:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Expectedness to Neratinib:
Expected Unexpected  N/A
Expectedness to Neratinib:
Expected Unexpected  N/A
Attribution to Neratinib:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Attribution to Neratinib:
Unrelated Unlikely
Possible
Probable
Definite
 N/A
Reporting Investigator (print):
Signature of Reporting Investigator:
Date: 
To (check off recipient of this AE):
 Dr. Patrick Y. Wen and Dana-Farber Coordinating Center 
Email: NeuroOnc_SAE@dfci.harvard.edu

236
11. TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION THERAPY
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
Take
capsule(s) at
mg strength +
capsule(s) at
mg strength
+
capsule(s) at
mg strength
This treatment diary is for you to indicate that you took the study drug as prescribed. Please bring this treatment diary and your pill 
bottle(s) with you to each clinic visit. At the end of the cycle, please sign and date the bottom of the treatment diary.
Temodar Instructions
During radiation therapy, Temodar should be taken daily (including weekends and holidays) – your Clinical Team will confirm the total # 
of days you will take Temodar.

Temodar capsules should be taken whole (do not chew or open capsules), two to three hours prior to radiation with a full 
glass of water on an empty stomach (one hour before or after food and other medications).

If you realize you have missed a dose by more than 10 hours, the dose should not be retaken and the next dose should not 
be increased to make up for the missed dose. Please indicate missed doses on this diary.

If a dose is vomited, the capsules are not to be replaced and you can indicate this vomited dose on the diary.

On days when you do not have radiation, Temodar should be taken in the morning on an empty stomach (one hour before or 
after food and other medications) with a full glass of water.

If your course of radiation extends beyond 42 days because of delays, the course of Temodar may be extended to a 
maximum of 49 days.
Please check with your study treatment team if you have any questions regarding how or when you should take your Temodar doses.

237
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION THERAPY
DAY 1
DAY 2
DAY 3
DAY 4
DAY 5
DAY 6
DAY 7
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
DAY 8
DAY 9
DAY 10
DAY 11
DAY 12
DAY 13
DAY 14
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
DAY 15
DAY 16
DAY 17
DAY 18
DAY 19
DAY 20
DAY 21
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials

238
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
Participant/Guardian Signature:  
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION THERAPY
Date:  
DAY 22
DAY 23
DAY 24
DAY 25
DAY 26
DAY 27
DAY 28
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
DAY 29
DAY 30
DAY 31
DAY 32
DAY 33
DAY 34
DAY 35
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
DAY 36
DAY 37
DAY 38
DAY 39
DAY 40
DAY 41
DAY 42
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials

239
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
Participant/Guardian Signature:  
TEMOZOLOMIDE DOSING INSTRUCTIONS & DRUG DIARY DURING RADIATION THERAPY
Date:  
DAY 43
DAY 44
DAY 45
DAY 46
DAY 47
DAY 48
DAY 49
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Date:
Temodar Dose:
mg 
Time of Temodar:  
Patient Initials
Participant/Guardian Signature:
Date:  

240
12. NERATINIB DOSING INSTRUCTIONS & DRUG DIARY
Neratinib Description:

Your study drug (neratinib) is supplied as 40 mg pills
Neratinib Instructions – When and How:

Take study drug (neratinib) once a day with food, preferably in the morning.

Take the drug at approximately the same time each day, so that you are taking the drug approximately 24 hours apart.

Swallow the pills whole; do not chew them or crush them.

Do not skip any doses.

If you forget to take your pills at your normal time, you can take your missed dose up to 3 hours after your normally scheduled time. If it has been 
more than 3 hours, skip the dose and take the next scheduled dose at the usual time the next calendar day. Please call your study nurse or doctor to 
discuss missed doses.

If you vomit your pills, write this down in your pill diary. Do not take a replacement dose.
Take the next scheduled dose as usual (one dose only). 
Please call your study nurse or doctor to discuss vomited doses.
Additional Instructions:

You must avoid eating or drinking any foods with Seville oranges (like marmalade), grapefruit or foods or drink with grapefruit, and any exotic fruits 
during the entire treatment period.

Keep your study drug in the original container(s) at room temperature. Keep study drug away from children, persons cannot read the label, and 
pets.

Do not throw away empty bottles, and do not throw the study drug in the trash or flush into the toilet.

Bring this diary, all pill bottles, and any unused pills to each clinic visit. Your Treatment Team will collect your diary, all pill bottles and any unused 
study drug, and you will be given a new pill diary at that time.

Contact your study doctor or nurse if you are having any new or worsening side effects.

Do not begin any new medication, over-the-counter drug, or herbal preparation without first checking with your Treatment Team to determine if it 
is acceptable to take while on this study.
To be completed by study personnel:
Patient ID #
Patient Initials:
Cycle #:
Month & Year:
Neratinib Dose:
mg, once a day
TAKE
pill(s) daily

241
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
NERATINIB DOSING INSTRUCTIONS & DRUG DIARY
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Participant/Guardian Signature:  
Date:  

242
To be completed by study personnel:
Patient ID #
Patient Initials:
Month & Year:
Temodar Dose:
mg
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Date:
No. of pills:   
 
Time:  
Initials
Date:
No. of pills:   
 
Time:  
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Date:
No. of pills:   
 
Time:  
Initials
Date:
No. of pills:   
 
Time:  
 
Initials
Participant/Guardian Signature:
Date:  
Date:  
Study Personnel Signature:  
Compare with drug diary entries made by participant or guardian. If discrepancy (in the # of bottles or the # of pills returned), please reconcile:
# of 40 mg Pills Returned:  
# of 40 mg Bottles Returned:  
To be completed by study personnel:

ANTIDIARRHEAL DOSING DIARY
243
7. ANTIDIARRHEAL DOSING INSTRUCTIONS & DOSING DIARY
This dosing diary is for you to indicate that you took the medication prescribed to you to help prevent diarrhea. It is very important that you take the 
medication as your doctor tells you to. Please sign this dosing diary at the end of the cycle and bring the dosing diary back to your next clinic visit.

You may experience diarrhea while taking neratinib; therefore, your study doctor will provide you with a prescription for a 
medication to help prevent diarrhea before you begin neratinib.

Unless directed by your study doctor otherwise, follow the below instructions for Cycle 1 only:

Administer loperamide: For the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered orally by patients 3 
times a day (total 12 mg a day). The initial dose of loperamide 4 mg will be self-administered orally with the first dose of neratinib.

After the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered orally twice a day (total 8 mg a day) through 
the first cycle of therapy (Day 28) from start of neratinib dosing.

Thereafter, loperamide will be administered as needed (not to exceed 16 mg per day).

After Cycle 1 of neratinib, please defer to your study doctor or nurse for dosing instructions.
If you experience an increase of 4 or more stools a day after beginning neratinib, call your study doctor or nurse as 
soon as possible.
To be completed by study personnel:
Patient ID #
Patient Initials:
Cycle #:
Month & Year:  
Prescribed Anti-Diarrheal:  

ANTIDIARRHEAL DOSING DIARY
244
To be completed by study personnel:
Patient ID #
Patient Initials:
Cycle #:
Month & Year:  
Prescribed Antidiarrheal:  
Record the date, time and dose(s) you take each day.
Participant/Guardian Signature:
Date:  
Date
Time
Dose
Date
Time
Dose

245
To be completed by study personnel:
Patient ID #
Patient Initials:
Cycle #:
Month & Year: 
Prescribed Antidiarrheal:  
Record the date, time and dose(s) you take each day.
Participant/Guardian Signature:
Date:  
Date
Time
Dose
Date
Time
Dose

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APPENDIX I QBS10072S ARM OF INSIGhT
TABLE OF CONTENTS
1.
BACKGROUND .....................................................................................................250
1.1
STUDY DRUG QBS10072S...................................................................................250
2.
PARTICIPANT SELECTION.................................................................................255
2.1
Eligibility Criteria Specific to the QBS10072S Arm...............................................255
2.2
Second INSIGhT Registration: Registration to QBS10072S Arm ..........................256
3.
TREATMENT PLAN..............................................................................................257
3.1
Definition of Standard Radiation Therapy...............................................................257
3.2
Treatment Regimen – QBS10072S Administration.................................................258
3.3
Safety Lead-In..........................................................................................................260
3.4
Definition of Dose-Limiting Toxicity (DLT) ..........................................................263
3.5
General Concomitant Medication and Supportive Care Guidelines........................264
3.6
Criteria for Taking a Participant Off Protocol Therapy...........................................267
3.7
Duration of Follow Up.............................................................................................268
3.8
Criteria for Taking a Participant Off Study .............................................................268
4.
DOSING DELAYS/DOSE MODIFICATIONS......................................................268
4.1
Anticipated Toxicities..............................................................................................269
4.2
Dose Modifications/Delays for QBS10072S ...........................................................272
5.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ...................276
5.1
Expected Toxicities..................................................................................................276
5.2
Adverse Event Characteristics .................................................................................276
5.3
Expedited Adverse Event Reporting........................................................................277
5.4
Expedited Reporting to the Food and Drug Administration (FDA) ........................280
5.5
Expedited Reporting to Hospital Risk Management................................................281
5.6
Routine Adverse Event Reporting ...........................................................................281
5.7
Other Reporting Requirements ................................................................................281
6.
PHARMACOKINETICS.........................................................................................283
7.
PHARMACEUTICAL INFORMATION................................................................285
8.
STUDY CALENDAR..............................................................................................293
9.
Measurement of Effect.............................................................................................300
10.
REFERENCES.........................................................................................................300
DFCI REPORTABLE AE COVERSHEET – INSIGHT QBS10072S ARM.......................302

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Subject medical information obtained by this study is confidential, and disclosure to third parties other than 
those noted below is prohibited. Upon the subject’s permission, medical information may be given to his or 
her personal physician or other appropriate medical personnel responsible for his or her welfare. Data 
generated by this study must be available for inspection upon request by representatives of the US FDA, 
national and local health authorities, Quadriga Biosciences, and the IRB for each study site, if appropriate. 
1. BACKGROUND
1.1 STUDY DRUG QBS10072S 
Rationale & Proposed Biomarker Association
QBS10072S, is a L-type amino acid transporter 1 (LAT-1 targeted alkylating agent associated with 
extensive and durable DNA damage utilizing LAT1 as both a transport and targeting mechanism. 
QBS10072S preferentially alkylates DNA at the N7 position of guanine and the N3 position of 
adenine, resulting in the formation of mono-adducts and intra- and inter-strand crosslinks (ICLs). 
ICLs distort the DNA double helix and cause the termination of DNA replication and the 
generation of double strand breaks near the cross-linked site, leading to critical cytotoxic lesions 
if not repaired [1]. The cytotoxic potential of tertiary bis(2-chloroethyl)amine drugs is much higher 
than mono-alkylators such as TMZ due to the ability of tertiary bis(2-chloroethyl)amine drugs to 
form lethal ICLs [2]. The increased potency of tertiary bis(2-chloroethyl)amine drugs may also be 
due to secondary mechanisms such as inhibition of mitotic checkpoints, inefficient DNA repair, 
and initiation of p53-dependent DNA-damage stress response, all of which lead to mitotic 
catastrophe and apoptosis. At least two DNA repair pathways are known to be involved in removal 
of ICLs: non-homologous DNA end-joining (NHEJ) and Rad51-related homologous 
recombinational repair (HRR); however, MGMT does not repair damages caused by tertiary bis(2-
chloroethyl)amine drugs such as chlorambucil, melphalan, cyclophosphamide, ifosfamide, or 
DNA chelating agents such as platinum compounds [3]. Therefore, since tertiary bis(2-
chloroethyl)amine drugs cross-link, rather than simply methylate DNA as TMZ does, they are 
more efficacious cytotoxic agents, and cells that are resistant to TMZ are frequently sensitive to 
tertiary bis(2-chloroethyl)amine drugs. Sensitivity to tertiary bis(2-chloroethyl)amine drugs is cell 
cycle dependent; thus rapidly proliferating cells such as tumor cells are much more susceptible, 
while quiescent cells such as the endothelial cells that form the blood-brain barrier (BBB) are not.
Therefore, based on the unique expression of LAT1 on both the BBB and tumor cells and the 
potent anti-tumor activity of the tertiary bis(2-chloroethyl)amine class of chemotherapeutics, 
Quadriga has discovered a novel chemical entity (QBS10072S), which combines the molecular 
characteristics of a selective LAT1 substrate with the validated therapeutic properties of tertiary 
bis(2-chloroethyl)amine drugs. QBS10072S combines elements necessary for a successful brain 
tumor treatment: (1) selective transport by LAT1, conferring BBB penetration and uptake into 
cancer cells, (2) strong tumor cell cytotoxicity using a mechanism distinct from TMZ, and (3) low 
off-target cytotoxicity in normal brain, BBB, and other systemic organs at therapeutic doses. 
QBS10072S is a novel BBB permeable compound utilizing a clinically proven alkylating moiety 
that has the potential to transform the therapy for TMZ-insensitive and relapsed/refractory GBM 
patients, for whom currently there are no other treatment options.

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Most anticancer drugs that are used for systemic tumors are ineffective for treating CNS tumors, 
in large part due to their inability to cross the BBB and to enter the tumor and peri-tumoral areas 
at therapeutically meaningful concentrations. The large neutral amino acid transporter type 1 
(LAT1) is expressed on both the luminal and abluminal membranes of the microvessels that form 
the BBB, facilitates uptake of neutral amino acids, such as L-leucine and L-phenylalanine, in a 
saturable and stereo-selective manner, and has the greatest transport capacity among the BBB 
amino acid influx transporters [4-6]. LAT1 expression is correlated with tumor progression and 
poor patient prognosis [7-11]. Quantitative PCR studies have shown a 40- to 400-fold 
overexpression of LAT1 in GBM compared to normal brain [12]. In gliomas specifically, as the 
tumor grade and stage increase, LAT1 expression increases in both the tumor cells and at the BBB 
of the tumor [10]. LAT1 expression in BBB cells in normal tissue adjacent to GBM, while present, 
is significantly lower than in high-grade glioma cells [10], indicating that LAT1 expression levels 
in non-cancerous tissues are much lower than GBM. The cytotoxic potential of tertiary bis(2-
chloroethyl)amine drugs is much higher than mono-alkylators such as TMZ due to the ability of 
tertiary bis(2-chloroethyl)amine drugs to form lethal ICLs [2]. Therefore, since tertiary bis(2-
chloroethyl)amine drugs cross-link, rather than simply methylate DNA as TMZ does, they are 
more efficacious cytotoxic agents, and cells that are resistant to TMZ are frequently sensitive to 
tertiary bis(2-chloroethyl)amine drugs. Sensitivity to tertiary bis(2-chloroethyl)amine drugs is cell 
cycle dependent; thus rapidly proliferating cells such as tumor cells are much more susceptible, 
while quiescent cells such as the endothelial cells that form the BBB are not. Therefore, based on 
the unique expression of LAT1 on both the BBB and tumor cells and the potent anti-tumor activity 
of the tertiary bis(2-chloroethyl)amine class of chemotherapeutics, QBS10072S combines the 
molecular characteristics of a selective LAT1 substrate with the validated therapeutic properties 
of tertiary bis(2-chloroethyl)amine drugs. QBS10072S combines elements necessary for a 
successful brain tumor treatment: (1) selective transport by LAT1, conferring BBB penetration 
and uptake into cancer cells, (2) strong tumor cell cytotoxicity using a mechanism distinct from 
TMZ, and (3) low off-target cytotoxicity in normal brain, BBB, and other systemic organs at 
therapeutic doses. QBS10072S is a novel BBB permeable compound utilizing a clinically proven 
alkylating moiety that has the potential to transform the therapy for TMZ-insensitive and 
relapsed/refractory GBM patients, for whom currently there are no other treatment options.
Clinical Overview
QBS10072S is currently studied in a Phase 1 solid tumor study in Australia. The safety data below 
is from a data cut on May 31, 2021 (see Investigator Brochure (IB).
It is important to note, however, that most alkylating agents cause gastrointestinal side effects and 
dose limiting toxicity to bone marrow with the major effect being a decreased granulocyte count. 
In addition to the effect on the bone marrow, alkylating agents are cytotoxic to mucosal cells 
resulting in oral mucosal ulceration and effects on the intestinal mucosa. Other organ systems 
affected by some alkylating agents include the lungs (pulmonary fibrosis) and the liver. The 
expected DLTs of QBS10072S are bone marrow and gastrointestinal based on GLP toxicology 
studies. Cardiovascular, respiratory, or neurological toxicities had not been observed in GLP safety 
pharmacology studies of QBS10072S (see IB).

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Nonclinical Overview
In vitro, QBS10072S demonstrated inhibition preference for LAT1 versus the most closely related 
homologous amino acid transporter, LAT2. QBS10072S inhibited growth and induced apoptosis 
in various tumor cell lines and demonstrated equivalent cytotoxicity in cells regardless of their 
MGMT expression status (see Investigator’s Brochure: Table 3). Treatment of GBM cells with 
QBS10072S resulted in a dose-dependent increase in the phosphorylation of H2AX at Ser 139 (γ-
H2AX) protein, a DNA damage repair pathway.
In vivo, QBS10072S demonstrated significant tumor growth inhibition in human tumor xenograft 
models. QBS10072S was effective at suppressing the growth of several tumor types grown both 
in the flank (melanoma, breast, and prostate cancer) and orthotopically [GBM, acute myeloid 
leukemia, and myeloma] (see Investigator’s Brochure: Table 4).
Using [14C]-QBS10072S, quantitative whole body autoradiography studies in both non-tumor and 
tumor bearing animals to quantify BBB penetration and brain tumor accumulation were conducted. 
One hour after administration of 5 mg/kg of [14C]-QBS10072S was dosed IV into a mouse bearing 
an intracranial GBM tumor (LN229), the tissue concentration of radioactivity was essentially 
equivalent in the blood and the tumor and significantly lower in the surrounding normal brain 
tissue, indicating that QBS10072S crossed the BBB and preferentially accumulated within the 
tumor .
Repeat dose toxicity studies followed by a 4-week recovery period were conducted in Sprague 
Dawley rats and cynomolgus monkeys. The overall adverse reactions observed in the presence of 
QBS10072S are generally consistent with the published findings with other alkylating agents, e.g. 
Evomela® (melphalan HCl).
In the two-cycle (4-week interval between dosing) repeat dose toxicity study in male and female 
Sprague Dawley rats, QBS10072S was administered (dosing on Day 1 and 29) via 3-minute 
intravenous infusion at dose levels of 2.5, 5, and 10 mg/kg (male) or 12 mg/kg (female) followed 
by a 4-week recovery period. The high dose of QBS10072S at 10 mg/kg (male) or 12 mg/kg 
(female) was not tolerated as most animals in this group were found dead or moribund during Days 
5 to 6. Males in the 5 mg/kg group and males/females in 10/12 mg/kg groups were noted with 
discolored feces, watery feces, crissum staining, food consumption decrease, and/or body weight 
decrease, while all test article treated animals showed white blood cell (WBC) decrease, 
reticulocyte (RET) decrease within one week after each dosing, while a recovery trend was noted 
in the second week. Target organs were defined as hematopoietic immune organs (bone marrow, 
spleen, thymus, mesenteric lymph node, submandibular lymph node, and Peyer’s patch), digestive 
organs (stomach, duodenum, jejunum, ileum, cecum, colon, rectum, liver, and submandibular 
salivary glands), and kidneys. Except for the atrophy in the white pulp of the spleen at ≥5 mg/kg, 
which showed a recovery trend, all findings above mentioned were completely recovered after 
four weeks of treatment-free period. All findings were recovered after four weeks of treatment-free 
period. Based on these findings, the severely toxic dose in 10% of animals (STD10) is considered 
to be 5 mg/kg for rats.
In the two-cycle (4-week interval between dosing) repeat dose toxicity study in male and female 
cynomolgus monkeys, QBS10072S was administered (dosing on Day 1 and 29) via 10-minute 
intravenous infusion at dose levels of 1.25, 2.5, and 5 mg/kg followed by a 4-week recovery period. 

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The high dose of 5 mg/kg QBS10072S was not tolerated, with decreased activity, nose 
hemorrhage, inability to rise, hindlimb swelling, hindlimb skin ulcer, and watery feces, while all 
dose levels showed decreases in WBC, red blood cell (RBC), platelet count (PLT), and RET within 
two weeks after each dosing, while a recovery trend was noted in the third week post each dose. 
All findings at dose levels up to 2.5 mg/kg recovered after four weeks of treatment-free period. 
Target organs were defined as thymus, spleen, lymph node, and bone marrow. Except for the 
pathological findings at 5 mg/kg, which showed a recovery trend, all findings at dose levels up to 
2.5 mg/kg recovered after four weeks of treatment-free period. Based on these findings, the highest 
non-severely toxic dose (HNSTD) in monkeys is considered to be 2.5 mg/kg.
Per the International Council for Harmonisation (ICH) guideline S9, the highest clinical starting 
dose for an anticancer small molecule should be equivalent or lower than 1/10 the STD10 in rodents 
or 1/6 the HNSTD in non-rodents. The STD10 in rats was considered to be 5 mg/kg based on results 
of Study No. 18141RD1, and the HNSTD in monkeys was reported to be 2.5 mg/kg in Study No. 
18141RD2. These doses correspond to 30 mg/m2 (Km = 6 for rat; Km = 12 for monkey) and provide 
approximately 10-fold safety margins when compared to the proposed first in human (FIH) dose 
(3 mg/m2 for a 60 kg human) (FDA 2005).
QBS100725 was administered to New Zealand White Rabbits in concentrations of 0.5 and 
1.0 mg/mL in a vascular and muscular irritation study. In contrast to other alkylating agents, no 
test article-related irritation reaction was observed in dosing site for both vascular and muscular 
administration. All findings noted in the vessel, such as thrombus, thrombus organization and 
perivascular hemorrhage, were incidental and considered to be mechanical stimulation related, 
thus were not related to QBS10072S
No QBS10072S related hemolysis (in vitro) or irritation (in vivo) was reported in rabbits up to 
1 mg/mL. No treatment effects on the CNS or respiratory system in rats after IV administration of 
QBS10072S by a single 3-minute IV infusion have been observed with a no observed effect level 
(NOEL) of 8 mg/kg. The human equivalent dose of this, is 16-fold higher than the proposed FIH 
dose (3 mg/m2 for a 60 kg human). In a cardiovascular safety study in telemetered monkeys, no 
statistically significant effect on cardiovascular parameters was observed after IV administration 
of QBS10072S by a single 10-minute IV infusion with a NOEL of 2.5 mg/kg. The human 
equivalent dose of this, is 10-fold higher than the proposed FIH dose (3 mg/m2 for a 60 kg human) 
(FDA 2005).
Benefit/Risk Assessment
A set of non-GLP and GLP toxicology studies has been performed with QBS10072S. Repeat dose 
toxicity studies and toxicokinetic evaluation followed by a 4-week recovery period were conducted 
in Sprague Dawley rats and cynomolgus monkeys. The overall adverse reactions observed in the 
presence of QBS10072S are generally consistent with the published findings with other alkylating 
agents, e.g. Evomela® (melphalan HCl). The key potential target organs for QBS10072S include: 
the bone marrow (e.g. hematological changes) and gastrointestinal tract (e.g., watery feces, weight 
loss) and skin ulcer, all of which are potentially relevant to humans. Notably for Evomela the 
warnings and precautions include:
Gastrointestinal toxicity: Nausea, vomiting, diarrhea or oral mucositis may occur; 
provide supportive care using antiemetic and anti-diarrheal medications as needed. 

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Anti-Nausea and Anti-Diarrheal Medication: Primary prophylaxis of nausea, 
vomiting and diarrhea is permitted in the first cycle after discussion with the 
Sponsor. Primary prophylaxis in subsequent cycles is at the Investigator’s 
discretion. The choice of the prophylactic drug is up to the Investigator (with 
Sponsor approval) as well as the duration of treatment, assuming there is no known 
or expected drug-drug interaction.
The most common adverse reactions observed in at least 50% of patients treated with Evomela 
(melphalan HCl) are neutrophil count decreased, WBC count decreased, lymphocyte count 
decreased, platelet count decreased, diarrhea, nausea, fatigue, hypokalemia, anemia, and vomiting. 
The following AEs would be expected with QBS10072S:
Bone Marrow Suppression: Periodic complete blood counts will be monitored, and 
supportive care will be provided for infections, symptomatic anemia and bleeding until 
there is adequate hematopoietic recovery 
Infection Prophylaxis: Patients, at the discretion of the Investigator, will be given anti-
infective agents as needed. Prophylaxis can begin at the time of screening and can 
continue for up to 1 month post the last QBS10072S administration or longer if 
CD4 counts are < 200 cells/μL. 
Herpes Virus and Epstein Barr Virus: Patients can receive valacyclovir orally or 
acyclovir intravenously if patient cannot take oral medications.
Pneumocystis: Patients can receive regimens of doses of sulfamethoxazole + 
trimethoprim as fixed combination beginning at the start of screening. Pentamidine 
may be substituted in patients with a sulfa allergy. 
Fungal: Fluconazole can be initiated and given either orally or as an IV dose. It 
should be continued until the ANC is > 1000 cell/mm3.
Gastrointestinal Toxicity: Nausea, vomiting, mucositis, and diarrhea may occur. Use of 
prophylactic antiemetic medications will be allowed and supportive care will be 
provided for nausea, vomiting, diarrhea, and mucositis. Including nutritional support 
and analgesics for patients with severe mucositis. 
Hepatotoxicity: Liver chemistries will be monitored, and supportive care provided for 
symptomatic hepatic disorders including such as hepatitis and jaundice.
Hypersensitivity: Acute hypersensitivity reactions, including anaphylaxis, may occur (e.g. 
urticaria, pruritus, edema, and skin rashes, tachycardia, bronchospasm, dyspnea, and 
hypotension.) supportive care will be provided for the reaction and QBS10072S will 
be discontinued for serious hypersensitivity reactions.
Embryo-Fetal Toxicity: Based on its mechanism of action, QBS10072S: can cause fetal 
harm when administered to a pregnant woman. Pregnant women will be excluded from 
this protocol.
Infertility: Based on its mechanism of action, QBS10072S: can cause suppression of 
ovarian function in premenopausal women resulting in persistent amenorrhea. Based 

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on its mechanism of action QBS10072S: can cause reversible or irreversible testicular 
suppression. 
Infusion Related Reactions: Infusion reactions may occur with QBS10072S 
administration. Infusion related reactions are typically characterized by fever, chills 
(rigor) and less commonly, hypotension. Patients must be pretreated with ondansetron 
and loratadine approximately 30 minutes prior to the next dose. However, the 
Investigator should follow institutional practices if the local standard of care is 
different. All pretreatment and other medications given must be recorded in the 
patient’s eCRF.  If infusion-related reactions are observed, it would be recommended 
to use diphenhydramine as needed, and ondansetron 8mg tid PRN subsequently if 
needed after infusion for nausea. 
Tumor Lysis Syndrome (TLS): TLS occurs when tumor cells release their content in the 
blood stream, either spontaneously or due to treatment, leading to metabolic 
disturbances including hyperuricemia, hyperkalemia, hypophosphatemia and 
hypocalcemia. The incidence and severity of TLS depends on tumor volume, potential 
for the tumor to lyse and patient characteristics. Preservation of kidney function is most 
important and management of cardiac and neuromuscular abnormalities. Allopurinol 
can be used to reduce the hyperuricemia and rasburicase can be used to preserve or 
improve renal function.
Because hyperkalemia can cause sudden death due to cardiac arrhythmias, patients 
should limit potassium and phosphorus intake during the TLS risk period (0-3 months).
Frequent measurements of serum electrolytes, continuous cardiac monitoring will 
occur, and the administration of oral sodium polystyrene will be provided as 
appropriate. Symptomatic hypocalcemia will be treated with calcium supplementation; 
non-symptomatic hypocalcemia will not require treatment.
As of the data cut off of May 31, 2021, 9 patients have been treated with QBS10072S; specifically, 
2 at 3 mg/m2, 2 at 6 mg/m2, 3 at 12 mg/m2 and 2 at 24 mg/m2, dose levels 1 to 4. The safety profiles 
of dose levels 1 to 3 were unremarkable with only grade 1, 2 adverse events reported. At dose level 
4 1 patient experienced hematologic DLT’s and the other patient experienced a fall (not considered 
related, nor a DLT). These events were reviewed by the cohort review committee and the decision 
was made to decrease the next dose to 18 mg/m2 (dose level 5). Dose level 5 is pending enrollment 
as of May 31, 2021
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of QBS10072S may be found in the Investigator’s Brochure which is the single 
reference safety document (SRSD) for this compound. 
2. PARTICIPANT SELECTION
2.1 Eligibility Criteria Specific to the QBS10072S Arm
Participants must meet all eligibility criteria outlined in the master protocol (section 3) and 
complete initial registration (section 4 of master protocol). Once the randomization assignment 

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has been received following initial registration, all participants randomized to the QBS10072S arm 
must meet the following criteria prior to participating in the QBS10072S arm of the study:
2.1.1 Participants must be willing and able to provide written informed 
consent/assent for the QBS10072S arm of the INSIGhT trial.
2.1.2 For women of child-bearing potential (women who are not free from menses for > 2 years, 
post hysterectomy/oophorectomy, or surgically sterilized) a negative serum pregnancy test must 
be documented prior to initial registration. Women of child-bearing potential must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) from date of 
initial dose and for 28 days following the last dose of study drug.   Men (including those who have 
had a vasectomy) must agree to use barrier contraception (latex condoms) when engaging in sexual 
activity with a woman of child-bearing potential from date of initial dose and for 28 days following 
the last dose of study drug.
2.2 Second INSIGhT Registration: Registration to QBS10072S Arm
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore®. Registration to the QBS10072S arm must occur following initial registration to master 
INSIGhT protocol and receipt of randomization assignment, and prior to the initiation of protocol 
therapy. Any participant not registered to their protocol specific assigned arm before protocol 
therapy begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria in section 2.1 of this sub-study appendix and a 
member of the study team will complete the protocol-specific eligibility checklist.
Following initial registration, any additional laboratory assessments prior to start of treatment will 
not be used to re-confirm eligibility.  Refer to section 4 of this appendix for toxicity management 
between registration and start of study treatment. 
Following second registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the study 
must be canceled. Registration cancellations must be made in OnCore® as soon as possible. 
2.2.1
Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.  
2.2.2
Registration Process for Other Investigative Sites
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
DFCI Coordinating Center staff.  All sites should contact the DFCI Coordinating Center to verify 
slot availabilities.  The required forms for registration can be found in Appendix B.

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Following registration, participants should begin as soon as feasible. Issues that would cause 
treatment delays should be discussed with the Overall PI.  If a participant does not receive protocol 
therapy following registration, the participant’s registration on the study must be canceled.  The 
Study Coordinator should be notified of cancellations as soon as possible.
Refer to Appendix B, Section 3.7 for registration details. 
3. TREATMENT PLAN
Participants treated on the QBS10072S arm will receive daily radiation (60 Gy in 30 fractions) as 
described in section 3.1 of this appendix with concomitant QBS10072S administered 
intravenously. QBS10072S infusion must be done prior to radiation treatment. Radiation must be 
started no sooner than 2 hours after the end of the QBS10072S infusion, and started no later than 
48 hours after the end of the QBS10072S infusion. After a 4-week break following completion of 
radiation therapy, QBS10072S will be administered once every 28 days. Patients will not receive 
either concurrent or adjuvant temozolomide.  Given the therapeutic hypothesis of radiosensitivity, 
an initial safety lead-in will be conducted as described in section 3.3 below. The trial will begin with 
12 patients registered to the safety lead-in arm. Following the completion of the safety lead-in, the 
randomized study will begin. Limited pharmcokinetic studies will be performed with the safety lead-
in cohort of patients only.
Treatment will continue for a maximum of 7 cycles (one infusion given on Day 1 of Radiation, 
and for 6 Adjuvant cycles) or development of progressive disease or unacceptable toxicities. 
Patients may continue to receive QBS10072S after six adjuvant cycles if they are receiving clinical 
benefit after agreement between the Investigator and study Primary Investigator.
3.1 Definition of Standard Radiation Therapy
The patient must undergo MRI based treatment planning (CT with contrast-based planning only if 
patient unable to undergo MRI). At a minimum, the contrast enhancing lesion (and/or surgical 
cavity) defined on a T1-weighted image (gross tumor volume; GTV) must be targeted with a 
minimum of a 1 cm dosimetric margin expansion to define a planning target volume (PTV). This 
volume must be treated to a prescribed dose of 59.4 Gy in 33 fractions or 60 Gy in 30 fractions. 
Treatment with larger volumes to the contrast-enhancing region is acceptable. Treatment or no 
treatment of the T2/FLAIR abnormality is acceptable. Because this is optional, dosimetric 
expansion and dose-fractionation for the T2/FLAIR volume are not specified here. The prescribed 
dose to the T2/FLAIR volume may not exceed 60 Gy. Radiation therapy must be completed within 
an overall treatment time of less than 52 calendar days.  Maximum dose (defined as a volume 
greater than 0.03 cc) to critical structures include: 60 Gy to the brainstem, 56 Gy to the optic 
chiasm, 55 Gy to the optic nerves, and 50 Gy to the retinae.
Participants are permitted to have radiotherapy as described in this section performed at any NCI 
funded cooperative group site.  Prospective Overall PI approval is required for any radiotherapy 
site that is not an NCI funded cooperative group site.  Any questions regarding permitted 

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radiotherapy sites should be directed to the DFCI Coordinating Center or Overall PI Patrick Y. 
Wen, MD.
3.2 Treatment Regimen – QBS10072S Administration
Participants treated on the QBS10072S arm will receive daily radiation (60 Gy in 30 fractions) as 
described in section 3.1 of this appendix with concomitant QBS10072S admistered intravenously 
once during Day 1 of chemoradiation and then every 28 days during the adjuvant period beginning 
4 weeks after completion of radiation therapy.  Patients will not receive either concurrent or 
adjuvant temozolomide (all participants have unmethylated MGMT promoter).
The study drug, QBS10072S will be intravenously administered on an outpatient basis.
QBS10072S has not been shown to be either an irritant or vesicant when administered 
intravenously preclinically. However, this class of medication may cause local tissue damage 
should extravasation occur. Do not administer by direct injection into a peripheral vein. Administer 
QBS10072S by injecting slowly (over 60 minutes) into a fast-running IV infusion or via an 
injection port, or via a central venous line.
QBS10072S should be inspected visually for particulate matter and discoloration prior to 
administration, whenever solution and container permit.
Identification of the most appropriate cannulation site should be undertaken before insertion. If 
venous access continually proves difficult, placement of a central venous access device should be 
considered. 
The following are among the conditions of the peripheral cannulation site:
Large veins in the forearm are recommended for peripheral administration.
Cannulation should be avoided over joints.
The inner wrist and the lower extremities should not be used.
Veins in the antecubital fossa or on the dorsum of the hand, particularly for potentially 
vesicant drugs, are not recommended.
Avoid cannulation where lymphoedema is present. 
Cannulation on the side of a mastectomy should be discussed with the Sponsor.
Preventive measures related to the type of peripheral cannula include:
Winged steel infusion devices (‘butterfly’ needles) must not be used for infusion of 
QBS10072S as the needle can be easily displaced or puncture the venous wall.
Flexible cannula should be used.
Patient related issues where central venous access is highly recommended:

Small and fragile veins.

Hard and/or sclerosed veins as a consequence of multiple previous chemotherapy 
courses or drug abuse.

Prominent but mobile veins (e.g. elderly persons).

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
Known diseases or situations associated with an altered or impaired circulation like 
Raynaud syndrome, advanced diabetes, severe peripheral vascular disease, 
lymphedema or superior cava syndrome.

Predisposition to bleeding, increased vascular permeability or those with 
coagulation abnormalities.

Obesity in which peripheral venous access is more difficult.

Sensory deficits that impair the patient’s ability to detect a change in sensation at 
the site of chemotherapy administration.
Procedures:
a.
After cannulation, check for blood flow. Then, flush with 10-ml normal saline and 
check for signs of extravasation.
Flushing with 10–20 mL of saline solution between different drug infusions is 
recommended.
A blood return (flashback) should always be obtained before drugs are administered and 
checked  per institutional practice/policy. 
Continue monitoring of the cannula insertion site and check regularly for appearance of 
symptoms such as swelling, pain, or redness sluggish infusion rate. 
QBS10072S dosages should be administered concurrently with a fast-running infusion of 
compatible IV fluid.
All dosages prescribed and dispensed to the participant and all dose changes during the study must 
be recorded. If a participant requires a QBS10072S dose delay of > 28 days from the next planned 
dose, the participant must be discontinued from treatment completely. In the exceptional case 
where the investigator feels the patient would benefit from continuing therapy the case can be 
discussed with the Overall PI Patrick Y. Wen at pwen@partners.org or 617-632-2166. Expected 
toxicities and dose reductions and modifications are detailed in section 4 of this appendix.

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3.3 Safety Lead-In
Because there is no safety data available for QBS10072S in combination with radiotherapy, a 
safety lead-in will be conducted utilizing a 3+3 design, including 3-6 patients in each cohort, to 
determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of 
QBS10072S when administered with radiation therapy.  During this part of the study no 
randomization will occur and all patients will receive QBS10072S. Randomization will begin after 
the MTD has been determined. 
The MTD will be defined as the dose at which ≤ 33% of patients experience a DLT and the 
MTD/RP2D QBS10072S dose will then be incorporated into the phase II portion of the arm.  The 
first 12 participants enrolled to this arm will be considered as safety lead-in and observed for DLTs 
for 10 weeks (1 cycle of QBS10072S with 6 weeks of radiation therapy and 4 additional weeks of 
observation) see section 3.4 section 3.5 below for DLT definitions) as follows:

Treatment will begin at Dose Level 0 (Table 1). Initially 3 participants will be enrolled.

If none of the 3 participants at a dose level experiences a DLT during the DLT evaluation 
period (10 weeks), then 3 new participants may be entered at the next higher dose level. 

If 1 of 3 participants experiences a DLT, then 3 more participants will be treated at the same 
dose level (for a total of 6 subjects in a cohort). If no more than 2 out of 6 participants 
experience a DLT at that dose, the next higher dose level cohort will be initiated. 

If more than 2 of 6 participants in a given cohort experience a DLT, no further participants 
will be started at that dose. Three (3) additional participants will be entered at the next lowest 
dose level if not already complete (6 participants have been enrolled at that dose level).

If < 1 participant experiences a DLT at the next lowest dose, three (3) additional participants 
will be entered at that dose level. If no more than 2 out of 6 participants experience a DLT 
this dose will be the putative MTD. 

Up to an additional 6 participants will be enrolled at the putative MTD for a maximum of 12 
patients.  Then, if ≤ 4 of the 12 participants treated experience a DLT, this dose will be 
considered the MTD

Dose escalation above level 2 or below level -2 will not occur (Table 1). If at Dose Level -2, 
> 1 of the first 3 participants, > 2 of the first 6 participants, or > 3 of the first 12 participants 
treated at Dose Level -2 experience a DLT, the appendix will be amended to allow patients to 
receive radiation therapy with concomitant temozolomide followed by adjuvant single agent 
QBS10072S.

An intermediate dose level between the one that leads to a DLT and the immediate lower level 
may be explored, if appropriate.

If > 2 out of 6 patients in the intermediate dose level experience a DLT, no further 
dose escalation will occur; the MTD would be exceeded, and the next lower dose 
level may be considered the MTD.

The study continues until the MTD is declared or the DSMC declares an optimal biologic 
dose.
The MTD is defined as the highest dose level at which ≤2 of 6 subjects or < 4 out of 12 participants 
experience a DLT during the DLT evaluation period. New dose levels may begin accrual only after 

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all subjects at the current dose level have been treated and observed for a minimum of 10 weeks 
from the first day of treatment. Toxicity will be graded and recorded according to National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE v5.0). The definition of DLT 
may be found in Section 3.4. 
Table 1: Safety Lead-In QBS10072S Dose Levels in combination with Radiotherapy
Dose Level (DL) *
Dose (mg/m2)
Maximum percent increase from previous dose
DL-2
3
DL -1
6
DL 0**
12
DL 1
15
33%
DL 2^
18
20%
* The proposed doses, schedule(s), and PK time points may be reconsidered and amended during the 
study based on safety data and observed systemic exposures 
** Starting dose DL 0; de-escalation to a lower dose level (DL -1) may be considered if DLT(s) at the 
starting dose are observed
^ Any additional dose levels will be increased to a maximum of 33% from the previous dose level.
 Note: Prophylaxis for Pneumocystis jiroveci pneumonia is recommended during concurrent 
chemoradiotherapy or if the lymphocyte counts decreased below 500/mm3.
Table 2: Adjuvant QBS10072S Dose Levels (monotherapy)
Dose Level (DL) *
Dose (mg/m2)
Maximum percent increase from previous dose
DL -1
6
DL 0**
12
DL 1
15
33%
DL 2^
18
20%
* The proposed doses, schedule(s), and PK time points may be reconsidered and amended during the 
study based on safety data and observed systemic exposures 
** Starting dose DL 0; de-escalation to a lower dose level (DL -1) may be considered if DLT(s) at the 
starting dose are observed
^ Any additional dose levels will be increased to a maximum of 33% from the previous dose level.
After a 4-week break from the last fraction of radiotherapy, patients receive adjuvant QBS10072S 
every 28 days. The QBS10072S dose will be administered at 12 mg/m2 for the first cycle, and 
maybe increased to 15 mg/m2 at the beginning of the second cycle if no hematological toxicity has 
occurred.
3.4 Expanded Safety Lead-In
As there was no safety data available for QBS10072S in combination with radiotherapy, a safety 
lead-in was initially planned utilizing a 3+3 design, including 3-6 patients in each cohort to 
determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of 
QBS10072S when administered with radiation therapy. Given an absence of DLT during the initial 

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safety lead-in testing (per section 3.3), an expanded safety lead-in will be conducted to evaluate 
dose escalation above 18mg/m2 every 4 weeks. For this segment of the study (expanded safety 
lead-in), randomization will continue to all other open arms and the expanded safety lead-in for 
QBS10072S. 
The MTDnew will be defined as the dose at which ≤ 33% of patients experience a DLT and there 
will be further consideration of evaluating QBS10072S at the MTDnew dose after completion of 
this expanded safety lead-in.  For this expanded safety lead-in, patients will be observed for DLTs 
for 10 weeks (1 cycle of QBS10072S with 6 weeks of radiation therapy and 4 additional weeks of 
observation) see section 3.5 below for DLT definitions) as follows:

Treatment will begin at Dose Level 0 (Table 3.4.1 and 3.4.2). Initially 3 participants will be 
enrolled.

If none of the 3 participants at a dose level experiences a DLT during the DLT evaluation 
period (10 weeks), then 3 new participants may be entered at the next higher dose level. 

If 1 of 3 participants experiences a DLT, then 3 more participants will be treated at the same 
dose level (for a total of 6 subjects in a cohort). If no more than 2 out of 6 participants 
experience a DLT at that dose, the next higher dose level cohort will be initiated. 

If more than 2 of 6 participants in a given cohort experience a DLT, no further participants 
will be started at that dose. Three (3) additional participants will be entered at the next lowest 
dose level if not already complete.

If < 1 participant experiences a DLT at the next lowest dose, three (3) additional participants 
will be entered at that dose level. If no more than 2 out of 6 participants experience a DLT, 
this dose will be the putative MTDnew. 

Up to an additional 6 participants will be enrolled at the putative MTDnew for a maximum of 
12 patients.  Then, if ≤ 4 of the 12 participants treated experience a DLT, this dose will be 
considered the MTDnew.

Dose escalation above level 1 or below level -1 will not occur (Table 3.5.1 and 3.5.2). If at 
Dose Level -1, > 1 of the first 3 participants, > 2 of the first 6 participants, or > 3 of the 
participants treated at Dose Level -1 experience a DLT, these increased dosing regimens will 
not be pursued further. 

An intermediate dose level between the one that leads to a DLT and the immediate lower level 
may be explored, if appropriate.

If > 2 out of 6 patients in the intermediate dose level experience a DLT, no further 
dose escalation will occur; the MTD would be exceeded, and the next lower dose 
level may be considered the MTDnew.

The study continues until the MTDnew is determined. 

The MTDnew is defined as the highest dose level at which ≤2 of 6 subjects or < 4 out of 12 
participants experience a DLT during the DLT evaluation period. New dose levels may begin 
accrual only after all subjects at the current dose level have been treated and observed for a 
minimum of 10 weeks from the first day of treatment. Toxicity will be graded and recorded 
according to National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE v5.0). The definition of DLT may be found in Section 3.4. 

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Table 3.4.1: Expanded Safety Lead-In QBS10072S Dose Levels in combination with Radiotherapy
Dose Level 
(DL) *
Dose 
(mg/m2)
Maximum percent 
increase from 
previous dose
ESL-DL -1
18
ESL-DL 0**
21
ESL-DL 1
21
14%
* The proposed doses, schedule(s), and PK time points may be reconsidered and amended during the 
study based on safety data and observed systemic exposures 
** Starting expanded safety lead-in dose level (ESL-DL 0); de-escalation to a lower dose level (ESL-DL -
1) may be considered if DLT(s) at the starting dose are observed
 Any additional dose levels will be increased to a maximum of 33% from the previous dose level.
 Note: Prophylaxis for Pneumocystis jiroveci pneumonia is recommended during concurrent 
chemoradiotherapy or if the lymphocyte counts decreased below 500/mm3. ESL-DL1 is same 
QBS10072S in combination with radiotherapy but increased frequency during the adjuvant monotherapy 
phase
Table 3.4.2: Expanded Safety Lead-In Adjuvant QBS10072S Dose Levels (monotherapy)
Dose Level 
(DL) *
Dose 
(mg/m2)
Frequency
Maximum percent increase from 
previous dose
ESL-DL -1
18
Every 3 weeks
ESL-DL 0**
21
Every 4 weeks
ESL-DL 1
21
Every 3 weeks
14%
* The proposed doses, schedule(s), and PK time points may be reconsidered and amended during the 
study based on safety data and observed systemic exposures 
** Starting expanded safety lead-in dose level (ESL-DL 0); de-escalation to a lower dose level (ESL-DL -
1) may be considered if DLT(s) at the starting dose are observed
 Any additional dose levels will be increased to a maximum of 33% from the previous dose level.
ESL-DL1 is same QBS10072S in combination with radiotherapy but increased frequency during the 
adjuvant monotherapy phase
After a 4-week break from the last fraction of radiotherapy, patients receive adjuvant QBS10072S 
every 28 days or 21 days depending on dose level. In the expanded safety lead-in, the QBS10072S 
dose will be administered at 21 mg/m2. 
3.5 Definition of Dose-Limiting Toxicity (DLT)
A DLT is defined as a clinically significant adverse event considered at least possibly related to 
QBS10072S and meets any of the criteria below during the first 10 weeks of study treatment 
(referred to as the initiation/concomitant cycle).  If a participant comes off for reasons other than 
a dose-limiting toxicity during the DLT period, he/she will be replaced.  

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Dose limiting toxicities are defined below. A DLT must have an attribution of possible, probable, 
or definite to QBS10072S and meets the below criteria.  For patients experiencing a DLT during 
the safety lead-in portion of the study, QBS10072S must be discontinued. If there is any question 
concerning a DLT, sites should contact the DFCI Coordinating Center to determine patient’s DLT 
status. The Coordinating Center with the Overall PI will make the final decision.

Hematological toxicities will be considered dose limiting if any of the following
occur (grade 3 or 4 lymphopenia will not be considered a DLT):
o
ANC of < 500/mm3 for > 7 days 
o
Platelets < 25,000/mm3 for > 48 hours or platelets < 50,000/mm3 with clinically 
significant bleeding
o
≥ Grade 3 febrile neutropenia (ANC < 1.0 × 109/L and fever > 101°F/38.3°C)
o
Any hematologic toxicity that prevents administration of QBS10072S for > 28 
days

Non-hematological toxicities will be considered dose limiting if any of the following occur:
o
Inability to complete ≥ 75% of RT due to toxicity related to or exacerbated by 
QBS10072S added to Radiation Therapy.  
o
Grade 3severity, with the following exceptions:

 Grade 3 nausea/vomiting or diarrhea for less than 72 hours with adequate 
antiemetic and other supportive care.Grade 3 hyperglycemia lasting ≤ 4 
days (with optimal medical management) and grade 4 hyperglycemia 
lasting < 12 hours (with optimal medical management)

≥ grade 3 rash of the acneiform or maculopapular type for no more than a 4 
day duration (with optimal medical management)

Grade 3 electrolyte disturbances that are asymptomatic and that respond to 
replacement or intervention (e.g. IV fluids) within 48 hours
Dose Limiting Toxicity Definition 
Severity of AEs will be graded according to the NCI CTCAE version 5.
3.6 General Concomitant Medication and Supportive Care Guidelines
Participants must be instructed not to take any additional medications (including over-the-counter 
products) during the trial without prior consultation with the investigator. All medications taken 
from date of initial consent and up to 30-day follow-up contact should be recorded. If concomitant 
therapy must be added or changed, including over-the-counter medications or alternative therapies, 
the reason and name of the drug/therapy should be recorded.
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
participant are allowed, including drugs given prophylactically (e.g. hematopoietic growth factors, 
antihistamine, anti-inflammatory agent and antiemetics) 
The following medications are permitted at the discretion of the Investigator:
H2-Receptor Antagonists for symptomatic treatment of gastrointestinal disorder 
(including, but not limited to famotidine, ranitidine, nizatidine).

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Local antacids for symptomatic treatment of gastrointestinal disorder (e.g., 
aluminum/calcium hydroxide, aluminum/calcium carbonate, bismuth subsalicylate).
Acid reducing agents (including proton pump inhibitors) can be used for symptomatic 
treatment of gastrointestinal disorder.
5-HT3 receptor antagonist can be used for the symptomatic treatment of gastrointestinal 
disorder (including but not limited to ondansetron or granisetron).
The following exceptions are below:
3.6.1
Herbal preparations/medications are not allowed throughout the study. These herbal 
medications include, but are not limited to: cannabinoids, St. John’s wort, Kava, 
ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, ginseng. Participants should stop using any herbal medications 7 days prior 
to first dose of study drug.
3.6.2
Corticosteroids should be used in the smallest possible dose to control symptoms of 
cerebral edema and mass effect, and discontinued if possible. Prophylactic 
administration prior to chemotherapy administration will be allowed per standard of 
care. Acute emergency administration corticosteroids, and acute and chronic topical 
applications, inhaled sprays, eye drops, or local injections of corticosteroids are 
allowed. Patients requiring corticosteroids must be on a stable dose for ≥ 5 days prior 
to each brain MRI assessment. 
3.6.3
Febrile neutropenia may be managed according to the local institution's guidelines. 
Measures may include appropriate laboratory testing, including blood and urine 
cultures and the institution of broad-spectrum antibiotics. If a source for the fever is 
not identified or the fever resolves when the neutrophil count recovers, antibiotics may 
be discontinued and the participant observed.
3.6.4
Hematopoietic growth factors: Routine prophylactic use of hematopoietic growth 
factors is not permitted. However, they may be used to treat treatment-emergent 
neutropenia as indicated by the current American Society of Clinical Oncology 
guidelines. 
Please see the clear definition below to remain on study as the ASCO guidelines which  
are referred to as a source have a disclaimer that the information provided should not 
be relied upon as being complete and accurate:
o
Patients experiencing Grade 3 or 4 potentially treatment-related toxicity or 
intolerable Grade 2 toxicity despite supportive care should have their treatment 
interrupted/delayed. Appropriate follow-up assessments should be done until 
adequate recovery occurs as assessed by the Investigator.
o
treatment delay or interruption of more than 28 days due to lack of recovery will 
result in discontinuation of the patient from treatment unless there is clinical benefit, 
and this is discussed with the Sponsor. A dose of study treatment may be given only 
if:
o
ANC ≥1,000/mm3.
o
Platelet count ≥75,000/ mm3.
o
Non hematologic toxicities have returned to baseline or Grade ≤1 severity 
(except for alopecia, nausea, and vomiting) or, at the Investigator discretion, 

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Grade ≤2 if not considered a safety risk for the patient.
o
If these conditions are not met, treatment must be delayed by 1 week. If, after a 1 
week delay, all toxicities have recovered within the limits described above, 
treatment with QBS10072S can be resumed. If the patient has not recovered after 1 
week of delay, treatment may be delayed by 2 more weeks. However, initiation of 
the next cycle can only be delayed by a maximum of 3 weeks. Therefore, if 
persisting toxicity does not allow QBS10072S treatment resumption within 49 days 
of Day 1 of the previous cycle (for the Q4W dosing regimen), treatment with 
QBS10072S will be permanently discontinued. A patient may continue on study 
after discussion with the Sponsor if there is documentation of clinical benefit 
following recovery of the AE to Grade 0 1 or baseline, only after discussion 
between the Investigator and Sponsor.
3.6.5
Antiemetics: The use of antiemetics will be left to the investigators’ discretion. 
3.6.6
Pneumocystis jirovecii pneumonia (PJP) prophylaxis: Since participants with GBM 
are at increased risk of developing PJP, especially if they are on corticosteroids, 
prophylaxis for PJP may be considered per institutional practice. 

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3.6.7
Anticoagulants: Because of the potential for its interaction with study medications, 
warfarin sodium (Coumadin®), or any other coumadin-derivative anticoagulant, is not 
permitted at any dose. Low-molecular weight heparin and Xa inhibitors are permitted.  
If for unavoidable clinical reasons (emergency department visit, severe allergy, 
toxicity, etc) participants are started on warfarin, they must change to a low molecular 
weight heparin immediately in the interest of subject safety.
3.6.8
Surgery: If neurosurgical management is required for reasons not due to tumor 
progression, these procedures must be documented, including the indications for 
surgery, the operative note, and pathology report. Caution is advised on theoretical 
grounds for any surgical procedures during the study. The appropriate interval of time 
between surgery and QBS10072S required to minimize the risk of impaired wound 
healing and bleeding has not been determined. Stopping QBS10072S is recommended 
at least 28 days prior to surgery. Postoperatively, the decision to reinitiate QBS10072S 
treatment should be based on a clinical assessment of satisfactory wound healing and 
recovery from surgery.
3.6.9
Other anticancer or experimental therapies: No other anticancer therapy of any kind is 
permitted during the study treatment period. No other drug under investigation may 
be used concomitantly with the study drug.
3.6.10
Other concomitant medications: Therapies considered necessary for the wellbeing of 
the participant may be given at the discretion of the investigator. Other concomitant 
medications should be avoided except for analgesics, chronic treatments for 
concomitant medical conditions, or agents required for life-threatening medical 
problems. All concomitant medications must be recorded. 
3.6.11
QBS10072S related mucositis and mouth ulcers should be treated as early as possible 
and according to institutional standard medical practice.  This may include analgesics, 
topical preparations (suspensions, pastes), and short courses of systemic steroids with 
temporary dose interruption and/or dose reduction for more severe cases.  Alcohol or 
peroxide-containing mouthwashes should be avoided. 
3.6.12
Infections (including the SAEs of pneumonia, sepsis, and nonserious AEs of infection) 
and associated pyrexia were reported with QBS10072S. Vigilance for the signs and 
symptoms of infection should be practiced with subjects receiving treatment with 
QBS10072S and managed according to institutional standard medical practice. 
Routine infectious disease prophylaxis is not recommended; however, antibiotic, 
antiviral, anti-pneumocystis, antifungal, or other prophylaxis may be implemented 
during the study at the discretion of the investigator.
3.7 Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue on 
the QBS10072S arm until one of the following criteria applies:

Disease progression

Intercurrent illness that prevents further administration of treatment

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
Unacceptable adverse event(s)

Participant demonstrates an inability or unwillingness to comply with the every 28 day 
intravenous medication regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Patrick Y. Wen, MD, at 617-632-2166 or pwen@partners.org. 
3.8 Duration of Follow Up
Participants will be followed until death with monthly visits, telephone contact, or medical record 
review.  Participants removed from protocol therapy for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event.  Refer to section 7 study calendar 
within this appendix for follow-up requirements and time points. 
3.9 Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).
A ODQ Treatment Ended/Off Study Form will be filled out when a participant comes off study. 
This form can be found on the ODQ website or obtained from the ODQ registration staff. 
4. DOSING DELAYS/DOSE MODIFICATIONS
For participants who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the participant on study drug. If administration of 
QBS10072S must be interrupted because of unacceptable toxicity, drug dosing will be interrupted 
or modified according to rules described in this section.
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website

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 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
In the case of toxicity, appropriate medical treatment should be used (including anti-emetics, anti-
diarrheals, etc.).
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and the 30 day post study visit. Participants continuing to 
experience toxicity at the end-of treatment visits may be contacted for additional assessments until 
the toxicity has resolved or is deemed irreversible. 
The occurrence of any Grade 5 event or any two Grade 4 events considered at least possibly related 
to QBS10072S and unexpected with QBS10072S will trigger suspension of accrual and 
performance of a thorough safety review prior to resuming enrollment.
4.1 Anticipated Toxicities
In order for an event to be expected (known correlation to study drug) for the purposes of 
adverse event reporting, the event must be included in this section. 
4.1.1
Anticipated Toxicities for Radiation Therapy
A list of adverse events of all grades suspected to be radiation therapy treatment related, 
organized by CTCAE v5.0 category, includes:

EAR AND LABYRINTH DISORDERS – external ear inflammation; other: dryness of 
ear canal; other: hardening of ear canal wax; external ear pain; other: hearing loss

ENDOCRINE DISORDERS - other: hypophysitis, or hypopituitarism

EYE DISORDERS – cataract; other: decreased vision

GASTROINTESTINAL DISORDERS – nausea; vomiting

GENERAL DISORDERS – fatigue

INJURY, POISONING AND PROCEDURAL COMPLICATIONS – injury other: 
optic nerve

INVESTIGATIONS –lymphocyte count decreased

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS – generalized 
muscle weakness

NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED – treatment related 
secondary malignancy

NERVOUS SYSTEM DISORDERS – headache; seizure; memory impairment; 
cognitive disturbance; somnolence; dysgeusia; central nervous system necrosis

PSYCHIATRIC DISORDERS – personality change

SKIN AND SUBCUTANEOUS TISSUE DISORDERS – scalp pain; other: scalp 
redness; alopecia

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4.1.2
Suspected & Anticipated Toxicities for QBS10072S 
A list of adverse events of all grades suspected to be QBS10072S treatment related 
according to review of Investigator’s Brochure, potential for cross-sensitivity between 
other alkylating agents, and class effect toxicities and preclinical data, examples include:
Bendamustine Adverse Events of Interest and Safety Considerations [refer to Package insert]

Hepatic Impairment: Use not recommended in patients with moderate or severe hepatic 
impairment.

Renal Impairment: Use not recommended in patients with severe renal impairment.

Infusion Reactions and Anaphylaxis: Infusion reactions (e.g., fever, chills, pruritus, rash) 
occur commonly. Severe anaphylactic and anaphylactoid reactions reported rarely, mainly 
in the second and subsequent cycles of therapy.

Risk of severe (grade 3 or 4) and potentially fatal myelosuppression, manifested primarily 
as lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia. Neutropenic 
sepsis, diffuse alveolar hemorrhage, and cytomegalovirus (CMV) pneumonia reported.

Infections (e.g., pneumonia, sepsis, hepatitis) resulting in septic shock and death have 
occurred in adults and pediatric patients. Increased risk of infection in patients with 
myelosuppression.

Increased risk of reactivation of infections (e.g., HBV infection, CMV infection, 
tuberculosis, herpes zoster).

Tumor lysis syndrome reported, generally during the first cycle of therapy; without 
appropriate intervention, acute renal failure and death may occur.

Possible dermatologic reactions (e.g., rash, toxic skin reactions [Stevens-Johnson 
syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic 
symptoms {DRESS}], bullous exanthema); may be progressive and increase in severity 
with continued therapy.

Liver injury, sometimes fatal or serious, reported, although confounding factors (e.g., 
concomitant use of other antineoplastic agents, progressive disease, reactivation of HBV) 
reported in some cases. Generally occurs during initial 3 months of therapy.

Development of premalignant (e.g., myelodysplastic syndrome, myeloproliferative 
disorders) and malignant diseases (e.g., acute myelogenous leukemia, bronchial 
carcinoma) reported.

Extravasation may cause pain, erythema, and marked swelling and may result in 
hospitalization. Monitor infusion site for erythema, swelling, pain, infection, and necrosis 
during and after administration of bendamustine.

May cause fetal harm; increased resorptions, skeletal and visceral malformations, and 
decreased fetal body weights demonstrated in animals.

Avoid pregnancy during and for 3 months after discontinuance of therapy. If used during 
pregnancy or patient becomes pregnant, apprise of potential fetal hazard. Advise men with 
partners of childbearing potential to use a reliable method of contraception during and for 
3 months after discontinuance of therapy.
Chlorambucil Adverse Events of Interest and Safety Considerations [refer to package insert]

Possible leukemia or secondary malignancies; assess risk/benefits of therapy.

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
May cause fetal harm (e.g., unilateral renal agenesis); avoid pregnancy during therapy. If 
used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

High incidence of sterility (generally irreversible ) in prepubertal and pubertal males; 
potential for prolonged or permanent azoospermia in adult males. 

Amenorrhea reported in females.

Possible angioedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal 
necrolysis, and urticaria.

Potential for cross-sensitivity (rash) between chlorambucil and other alkylating agents.

Slowly progressive lymphopenia is common; return to normal lymphocyte counts 
generally occurs rapidly after completion of therapy.

Possible dose-dependent, reversible neutropenia after third week of continuous therapy and 
continuing for up to 10 days after last dose.

Risk of irreversible bone marrow damage increases rapidly with total dose ≥6.5 mg/kg in 
1 course of continuous dosing regimen.

Note: Adverse hematologic effects may be less severe with intermittent dosing than with 
continuous dosing.

Possible increased risk of seizures in children with nephrotic syndrome and patients 
receiving high pulse doses of chlorambucil.

Possible additive myelosuppressive effects; do not administer at full dosages within 4 
weeks after a full course of radiation therapy or myelosuppressive drugs.

Immunization: Avoid administration of live vaccines to immunocompromised patients.
Melphalan Adverse Events of Interest and Safety Considerations [refer to package insert]

Renal Impairment: In patients with renal impairment (BUN ≥30 mg/dL), reduce dosage by 
50%.

Risk of dose-limiting myelosuppression, manifested principally by leukopenia and 
thrombocytopenia; anemia also may occur.

Leukocyte and platelet nadirs generally occur 2–3 weeks after treatment; recovery usually 
occurs 4–5 weeks after treatment. Irreversible bone marrow depression has been reported.

Positive direct Coombs’ test results and concurrent hemolytic anemia have been reported.

Use with caution in patients with compromised bone marrow reserve (i.e., prior radiation 
therapy or prior therapy with other cytotoxic agents.

Possible leukemia or secondary malignancies.

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals. Avoid 
pregnancy during therapy. If used during pregnancy or patient becomes pregnant, apprise 
of potential fetal hazard. Pregnancy Category D. Melphalan may cause fetal harm when 
administered to a pregnant woman. While adequate animal studies have not been conducted 
with IV melphalan, oral (6 to 18 mg/m2/day for 10 days) and IP (18 mg/m2) administration 
in rats was embryolethal and teratogenic. Malformations resulting from melphalan 
included alterations of the brain (underdevelopment, deformation, meningocele, and 
encephalocele) and eye (anophthalmia and microphthalmos), reduction of the mandible 
and tail, as well as hepatocele (exomphaly). There are no adequate and well-controlled 
studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes 
pregnant while taking this drug, the patient should be apprised of the potential hazard to 

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the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Reversible and irreversible testicular suppression reported.

Ovarian suppression and amenorrhea reported in premenopausal females.

Extravasation may produce severe local tissue necrosis.

Hypersensitivity reactions, including anaphylaxis, urticaria, pruritus, edema, rashes, 
tachycardia, bronchospasm, dyspnea, and hypotension reported in 2% of patients receiving 
IV melphalan and rarely in patients receiving oral melphalan.

Potential for cross-sensitivity (rash) between melphalan and other alkylating agents.

Avoid administration of live vaccines to immunocompromised patients.

Pulmonary embolism sometimes fatal and fibrosis have been reported.

Increased bone marrow suppression and risk of severe leukopenia in patients with renal 
impairment receiving IV melphalan; dosage reduction should be considered.
4.2 Dose Modifications/Delays for QBS10072S 

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4.2.1
Table 4.2 should be adhered to for all toxicities considered at least possibly related to 
QBS10072S. If a participant experiences a toxicity unlikely or unrelated to treatment with 
QBS10072S but may still warrant a hold or reduction of study drug for safety, discussion 
and approval by Overall Principal Investigator and Study Sponsor, Patrick Y. Wen, MD, 
is strongly recommended.  
4.2.2
When treatment must be held pending resolution of toxicity to grade 1 or return to baseline, 
and the toxicity is a lab abnormality (with the exception of thrombocytopenia and 
neutropenia) in cases where participant had a pre-existing laboratory abnormality at 
baseline, the toxicity can be considered “resolved” from a hold perspective when it has 
resolved to within 1 grade of the baseline value. For thrombocytopenia and neutropenia 
please refer to Table 4.2. 
NOTE: For the purposes of data entry, values from screening assessments should be entered 
in as ‘baseline’ values.   However, true “baseline values” - for the purpose of dose 
modifications on study, etc. - will be considered the last assessments/tests performed prior to 
initiation of study therapy.
EXCEPTION: In instances where the value within 1 grade of the baseline value would still 
require a hold, continue to hold until resolution of toxicity to grade 1 or return to baseline.
4.2.3
Participants who experience an adverse event that requires a treatment delay or dose 
reduction should be monitored with appropriate laboratory testing or other clinical 
evaluation at least weekly until resolution.
4.2.4
No more than 2 levels of dose reduction are permitted in this study. Participants cannot be 
treated below dose level -2. If a participant whose QBS10072S dose has been reduced by 
2 dose levels requires another dose reduction, treatment on study must be stopped unless 
the participant has benefited from the study, in which case the investigator will contact the 
overall Principal Investigator, Dr. Patrick Y. Wen, to determine if the participant will 
remain in the study.
4.2.5
A treatment delay of up to 28 days is permitted. If the toxicity has not resolved after a 4-
week delay, the participant must be removed from study treatment unless the participant 
has benefited from the study, in which case the investigator may contact the Overall 
Principal Investigator, Dr. Patrick Y. Wen, to determine if the participant will remain in 
the study.
4.2.6
No dose re-escalation is permitted on study. 

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4.2.7
Cycle length will be 4 weeks (28 days), even if treatment is held for toxicity. There is 
no stopping in counting cycles/days for those periods where a subject’s drug is 
withheld. All study evaluations and treatments should continue as if study treatment 
is not being held. 
4.2.8
Participants whose treatment is interrupted or permanently discontinued due to an 
adverse event or clinically significant laboratory value, must be followed as outlined 
in Table 4.2, at least once a week for 4 weeks, and subsequently at 4-week intervals, 
until resolution or stabilization of the event, whichever comes first. All participants 
must be followed for adverse events and serious adverse events for 30 days following 
the last dose of QBS10072S. All SAEs must be reported as detailed in section 5.3 of 
this appendix.
Table 4.2:
Criteria for dose-modification and re-initiation of QBS10072S treatment 
Table 4.2 should be adhered to for all toxicities attributable (considered at least possibly related) 
to QBS10072S as noted below.  If a participant experiences a toxicity unlikely or unrelated to 
treatment with QBS10072S but may still warrant a hold or reduction of study drug for safety, 
discussion and written approval by Overall Principal Investigator and Study Sponsor, Patrick Y. 
Wen, MD is strongly recommended.
Event
Action
Serum bilirubin ≥2 x ULN or other Grade 3 or 
Grade 4 nonhematologic toxicity considered at least 
possibly related to QBS10072S per Investigator 
judgment (including persistent nausea, vomiting, 
diarrhea despite optimal medical therapy) 
Bilirubin (for patients with Gilbert Syndrome* 
these dose modifications apply to changes in direct 
bilirubin only) will be fractionated if elevated
Hold QBS10072S infusion until recovery to Grade 0-1, 
serum bilirubin < 2 xULN or baseline and reduce by 
1 dose level.
Discontinue QBS10072S if dose delay is more than 
3 weeks*.
If toxicity reoccurs despite reduction, patient may be 
dose reduced again by another dose level upon 
recovery to Grade 0-1 or baseline unless the patient is 
in the first dose group, then only 1 dose reduction is 
allowed. 
Prompt palliative measures are strongly encouraged 
(e.g., anti-emetics). 
Patients who experience Grade 4 nonhematologic 
toxicities despite optimal medical intervention should 
be discontinued from the study*. 
*  For participants with Gilbert’s syndrome prior to 
registration, the clinician may choose to continue 
QBS10072S for elevations in total bilirubin that are 
two times the participant’s baseline value (screening 
value). For total bilirubin that is greater than two times 
the baseline value, follow dose modification guidelines 
as outlined in the above table.  However, in place of 
resolution to ≤ grade 1, QBS10072S may resume once 
resolution to ≤ 2 x baseline value.

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Event
Action
Hematologic toxicity considered at least possibly 
related to QBS10072S per Investigator judgment
Grade 4 neutropenia, i.e., ANC 500/mm3
(0.5 x 109/L) for more than 7 days. 
Febrile neutropenia, i.e., fever with a single temp 
>38.3C or sustained temp 38C for more than
1 hour with ANC <1000/mm3.
Hold QBS10072S until recovery of ANC to 1.0 x 
109/L (1,000 cells/mm3) 
Reduce QBS10072S by 1 dose level.
If toxicity reoccurs despite dose reduction, patient may 
either be held until recovery and continuation at same 
dose or undergo further dose reduction by another dose 
level unless the patient is in the first dose group, then 
only 1 dose reduction is allowed.
Thrombocytopenia
Grade 4 thrombocytopenia, i.e., PLTS 
25,000/mm3 (25.0 x 109/L). 
Or Grade 3 thrombocytopenia with clinically 
significant or life-threatening bleeding.
Hold QBS10072S until platelets 100,000/mm3.
For platelet counts 10,000 – 25,000/mm3, continue 
monitoring every 3 days until recovery to 
≥25,000/mm3 (Grade 3 or less). For platelet counts 
≤10,000/mm3 monitor daily until recovery to 
≥25,000/mm3 (Grade 3 or less). 
Reduce QBS10072S by 1 dose level.
If toxicity reoccurs despite dose reduction, patient may 
either be held until recovery and continuation at same 
dose or undergo further dose reduction by another dose 
level unless the patient is in the first dose group, then 
only 1 dose reduction is allowed.
Discontinue for life-threatening bleeding.
Other Grade 4 hematologic toxicity despite medical 
therapy considered at least possibly related to 
QBS10072S and clinically significant per 
Investigator’s judgment
Hold QBS10072S until recovery to Grade 0-1 or 
baseline and reduce QBS10072S dose by 1 dose level.
If toxicity reoccurs despite dose reduction, patient may 
either be held until recovery and continuation at same 
dose or undergo further dose reduction by another dose 
level unless the patient is in the first dose group, then 
only 1 dose reduction is allowed.
No recovery of toxicities within 3 weeks of 
scheduled QBS10072S infusion
Discontinue treatment.*
Other unspecified Grade 1 and 2 events considered 
at least possibly related to QBS10072S
Maintain treatment with QBS10072S
Other unspecified Grade 3 clinically significant 
events considered at least possibly related to 
QBS10072S
Interrupt treatment until resolution to ≤ grade 1 or 
returned to baseline, treatment may resume at the same 
dose level or a 1 dose level decrease, at the 
investigator’s discretion. Continuation of QBS10072S 
is permitted upon recovery to stable Grade 2 if the 
investigator and overall principal investigator (Dr. 
Patrick Y. Wen) agree that the event is not considered 
clinically significant
Other unspecified Grade 4 events considered at least 
possibly related to QBS10072S
Discontinue QBS10072S

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5. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following 
list of reported and/or potential AEs (section 4.1 of this appendix) and the characteristics of an 
observed AE (section 5.2 of this appendix) will determine whether the event requires expedited 
reporting in addition to routine reporting.
This section specifies reporting requirements to the FDA, Overall PI/Coordinating Center, 
DF/HCC IRB, and manufacturer as applicable. 
5.1
Expected Toxicities
Refer to section 4.1 of this appendix for expected toxicities for assigned study treatment arm. 
5.2
Adverse Event Characteristics

Adverse Event (AE) Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening 
of a preexisting medical condition in a clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (such as 
an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of investigational product, whether or not considered related to the investigational product.
Abnormal laboratory values or diagnostic test results constitute adverse events only if
they induce clinical signs or symptoms or require treatment or further diagnostic tests.
Adverse events experienced by participants will be collected and reported from initiation 
of study medication, throughout the study, and within 30 days of the last dose of study 
medication.  Participants who experience an ongoing adverse event related to a study 
procedure and/or study medication beyond 30 days will continue to be contacted by a 
member of the study team until the event is resolved, stabilized or determined to be 
irreversible by an investigator. 

CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

For expedited reporting purposes only:
-
AEs for the agent(s) that are listed in section 4.1 of this appendix should be reported 
only if the adverse event varies in nature, intensity or frequency from the expected 
toxicity information which is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in the 

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next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.

Serious Adverse Event (SAE) Definition:
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless 
of causality that:
o
Results in death
o
Is life-threatening (i.e., in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);
o
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
o
Results in persistent or significant disability/incapacity (a substantial disruption of 
the subject’s ability to conduct normal life functions);
o
Is a congenital anomaly/birth defect;
o
Constitutes an important medical event. Important medical events are defined as 
those occurrences that may not be immediately life threatening or result in death, 
hospitalization, or disability, but may jeopardize the subject or require medical or 
surgical intervention to prevent one of the other outcomes listed above.  Medical 
and scientific judgment should be exercised in deciding whether such an AE should 
be considered serious.
5.3
Expedited Adverse Event Reporting 
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs after the 
initial dose of study treatment, during treatment, or within 30 days of the last dose of treatment.
For multi-institution studies where a DF/HCC investigator is serving as the Overall Principal 
Investigator, each participating institution must abide by the reporting requirements set by the 
DF/HCC. This applies to any medical event that is Serious, Unexpected, and there is a Reasonable 
Possibility (i.e., possible, probable, or definitive attribution) the Adverse Event is related to the 
study intervention.
Expedited Reporting Guidelines to Overall PI/Coordinating Center & Quadriga Biosciences 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy. 
Other investigative sites outside of DF/HCC will report AEs to their respective IRB according to 

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the local IRB’s policies and procedures in reporting adverse events. A copy of the AE form should 
be forwarded to the Overall PI within the timeframes detailed in the table below.  The Overall PI 
will submit AE reports from outside institutions to the DFCI OHRS according to the DFCI IRB 
policies and procedures in reporting adverse events.  
In addition to local IRB reporting policies, all sites are required to follow the Table 5.3.3 expedited 
reportable AE requirements: 

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Table 5.3.3 Expedited AE Reporting Requirements to Quadriga Biosciences Company & DFCI Coordinating Center 
Adverse Event Characteristics
Reporting Requirement
Serious-
ness
Toxicity
Known Correlationf
Attribution to 
QBS10072S
Quadriga Biosciences-
Via Fax or emailc 
Use Reportable AE Coversheet c and 
Medwatch 3500A d
Overall PI (Patrick Y. Wen, MD) at the 
DFCI Coordinating Center 
Via Email b
Use Reportable AE Coversheet c and 
Medwatch 3500A d 
Seriouse
Any
Any
(Expected or 
Unexpected)
Any
Within 24 hours from notification a
Within 24 hours from notification a
Non-
Serious
Grade 4 
Any
(Expected or 
Unexpected)
Any
Not Required
Within 5 working days  from 
notification a
Non-
Serious
Grade 2 or 3
Unexpected
Possible, probable, 
definite
Not Required
Within 7 working days  from 
notification a
a.
In the event that the participating investigator/site team does not become aware of an adverse event requiring expedited reporting immediately (e.g., participant sought 
treatment elsewhere), the participating investigator/site team is to report the event within the required hours/days noted above after learning of it and document the time 
of his or her first awareness of the adverse event.  The initial report must be as complete as possible, including an assessment of the causal relationship between the event 
and the investigational product(s).  Information not available at the time of the initial report (e.g., an end date for the adverse event or laboratory values received after the 
report) must be documented on a follow-up report. A final report to document resolution of the SAE or reportable AE is required. 
b.
Email the Medwatch 3500A form, reportable AE coversheet (section 10 of this appendix), and the local IRB SAE report (if applicable) to the DFCI Coordinating Center with the 
subject title as “INSIGHT SAE” to NeuroOnc_SAE@dfci.harvard.edu.  All SAE reports received at this account are forwarded immediately to study’s Overall PI, Dr. Patrick Y. Wen, 
and to the DFCI Coordinating Center personnel. 
c.
Reportable AE Coversheet is found in section 10 of this appendix.  The coversheet contains all FAX numbers/e-mails and needed for reporting purposes.  
d.
Medwatch 3500A downloadable form at  http://www.fda.gov/medwatch/getforms.htm
e.
Seriousness is defined in section 5.2 of this appendix.
f.
Expected adverse events are those that have been previously identified as resulting from administration of the agent.  For the purposes of this study, an adverse event is 
considered expected when it appears in the Anticipated Toxicities list (protocol section 4.1 of this appendix) which is derived from the Investigator’s Brochure.

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How to report expedited AEs to Quadriga Biosciences & DFCI Coordinating Center/Overall PI
1. Document/describe reportable AE(s) on the following:
a.
MedWatch 3500A
i. Downloadable form at http://www.fda.gov/medwatch/getforms.htm 
b. DFCI  Reportable AE Coversheet – INSIGhT QBS10072S Arm
i. Coversheet can be found in section 10 of this appendix. The coversheet contains 
contact information for DFCI Coordinating Center and Quadriga Biosciences 
safety groups.  A modifiable Microsoft Word document is also available from 
the DFCI Coordinating Center.  
2. Scan and email above documents to NeuroOnc_SAE@dfci.harvard.edu with the subject title 
“INSIGHT SAE”
a.
All AE reports received at this account are forwarded immediately to Overall Principal 
Investigator (Dr. Patrick Y. Wen), and to Coordinating Center personnel. 
b. If available and applicable, also include the local IRB submission for this event in the 
submission to the DFCI Coordinating Center.
Protocol-Specific Expedited Adverse Event Reporting Exclusions
For this protocol only, the AEs/grades listed below do not require expedited reporting to the 
Overall PI or the DFCI IRB.  However, they still must be reported through the routine reporting 
mechanism (i.e. case report form).

Lymphopenia (grades 2-4).  

A visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)

Emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission

Elective surgery, planned prior to signing consent

Routine health assessment requiring admission for baseline/trending of health status 
(e.g. routine colonoscopy)

Hospitalization for routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition, or for elective procedures

Hospitalization for elective or pre-planned treatment for a pre-existing condition that 
did not worsen

Hospitalization for respite care not associated with an adverse event attributed to the 
study drug

Hospitalization for treatment of patient’s underlying disease after coming off study 
treatment (e.g. admission after patient is removed from active study treatment for 
craniotomy)
5.4
Expedited Reporting to the Food and Drug Administration (FDA)
As study sponsor, the Overall PI (or his designee) will be responsible for all communications with 
the FDA. The Overall PI will report to the FDA, regardless of the site of occurrence, any serious 
adverse event that meets the FDA’s criteria for expedited reporting following the reporting 
requirements and timelines set by the FDA.

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5.5
Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant safety 
reports or sentinel events that require reporting according to institutional policy. 
5.6
 Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
5.7
Other Reporting Requirements
Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) in either a female subject or a partner of a male subject occurring while the subject 
is on investigational product (IP), or within 28 days of the subject’s last dose of IP, are considered 
immediately reportable events.  IP is to be discontinued immediately if the female subject becomes 
pregnant, if the partner of a male subject pregnant study continuation must be discussed with the 
primary investigator. The pregnancy, suspected pregnancy, or positive pregnancy test must be 
reported to the DFCI Coordinating Center and Overall PI (Dr. Patrick Wen) and to Quadriga 
Biosciences Drug Safety within 24 hours from notification using the DFCI Reportable AE 
Coversheet (INSIGhT QBS10072S arm). If the female partner of male participant becomes 
pregnant report will be made after obtaining the necessary signed informed consent from the 
female partner.
The female may be referred to her obstetrician-gynecologist or another appropriate healthcare 
professional for further evaluation.
The Investigator will follow the female subject until completion of the pregnancy and must notify 
the DFCI Coordinating Center and Overall PI (Dr. Patrick Wen) and Quadriga Biosciences Drug 
Safety immediately about the outcome of the pregnancy (either normal or abnormal outcome) 
using the DFCI Reportable AE Coversheet (INSIGhT QBS10072S arm) as a follow-up to the 
initial pregnancy report.
If the outcome of the pregnancy was abnormal (eg, spontaneous or therapeutic abortion [any 
congenital anomaly detected in an aborted fetus must be documented], stillbirth, neonatal death, 
or congenital anomaly [including that in an aborted fetus], ectopic pregnancy), the Investigator 
should report the abnormal outcome as a SAE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to the DFCI Coordinating Center and Overall PI (Dr. Patrick 
Wen) and Quadriga Biosciences Drug Safety within 24 hrs of the Investigator's knowledge of the 
event using the SAE Report Form.

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All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to the DFCI Coordinating Center 
and Overall PI (Dr. Patrick Wen) and Quadriga Biosciences Drug Safety within 24 hrs of the 
Investigator’s knowledge of the event using the SAE Report Form. 
Any post-study pregnancy-related SAE considered reasonably related to the study intervention by 
the investigator will be reported to the DFCI Coordinating Center and Overall PI (Dr. Patrick Wen) 
and Quadriga Biosciences Drug Safety within 24 hrs of the Investigator’s knowledge of the event 
using the SAE Report Form. While the investigator is not obligated to actively seek this 
information in former study participants /pregnant female partner, he or she may learn of an SAE 
through spontaneous reporting.
Male Subjects
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking IP should notify the Investigator, and the pregnant female partner should be advised 
to call their healthcare provider immediately.
Overdose
Overdose, as defined for this protocol, refers to QBS10072S dosing only.  
On a per dose basis, an overdose is defined as a dose of QBS10072S at any amount over the 
protocol-specified dose assigned to a given patient, regardless of any associated adverse events or 
sequelae.
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.  
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form.   
Notify the DFCI Coordinating Center at NeuroOnc_SAE@dfci.harvard.edu of any potential 
overdose as soon as possible. 
IND Annual Reports
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual report 
is provided to the FDA within 60-days of the IND anniversary date.  21 CRF 312.33 provides the 
data elements that are to be submitted in the report.  The Annual Report should be filed in the 
study's Regulatory Binder, and a copy provided to Quadriga Biosciences as a supporter of this 
study as follows:
Quadriga BioSciences, Inc.
339 S. San Antonio Road, Suite 2A
Los Altos, CA 94022
Tel: (908) 673-9000

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6.
PHARMACOKINETICS
6.1 Blood Collection for Pharmacokinetic Analysis
Blood samples of approximately 3 mL each will be collected over a 24-hour period at specified
time point predose (within 60 min prior to the start of IV infusion) and postdose as delineated in
Table 6 for PK analysis, which will allow assessment of systemic exposures, accumulation and
other PK properties of QBS10072S.
The actual date and time (24-hour clock time) of each sample will be recorded. It is essential that 
the actual date and time of study treatment administration and sample collection be recorded in the 
eCRF. Nominal PK blood sampling times and collection windows should be adhered to as closely 
as possible, in accordance with Table 6.1. Plasma concentration data will be used to determine PK 
parameters, including AUC0-t, AUCinf, Cmax, Cmin, Tmax, and t½, in all subjects during Cycle 
1 and Cycle 2, if applicable, and if data are evaluable. Metabolites of QBS10072S may be 
investigated if applicable.
During the course of the study, as data emerge and enhance the understanding of QBS10072S PK, 
PK sampling occasion days and collection times may be modified.
To avoid contamination of PK samples with infusion solution, blood samples for PK should be
collected from the contralateral arm.
Table 6.1: Plasma Collection Schedule for Pharmacokinetic Analysis For Safety Lead-In:
Study Day
Sample Times
Concomitant/Initiation 
C1D1
Predose, at 15 minutes (±5 m), 30 minutes (±5 m)* post start of 
infusion, End of Infusion (within 2m prior to EOI), and 5 minutes 
(+10 m), 30 minutes (± 5 m), 1 hour (± 5 m), 2 hours (± 5 m), 3 
hours (± 10 m), 5 hours (± 10 m), 7hours (± 20 m) post end of 
Infusion
Concomitant/Initiation 
C1D2 
24 hours (±1.0 hour) after C1D1 dose
Adjuvant C1D1 
Predose, at 15 minutes (±5 m), 30 minutes (±5 m)* post start of 
infusion, End of Infusion (within 2m prior to EOI), and 5 minutes 
(+10 m), 30 minutes (± 5 m), 1 hour (± 5 m), 2 hours (± 5 m), 3 
hours (± 10 m) post end of Infusion
6.2 Pharmacokinetic Analyses
Plasma QBS10072S concentrations and actual blood sampling times will be listed by dose level
and protocol specified assessment time point. They will be summarized using descriptive
statistics - number of measurements, arithmetic mean, SD, and % CV, geometric mean,
minimum, median, and maximum for each dose level at each scheduled assessment time point.
Individual and mean concentration-time profiles will be presented graphically for each treatment.
Pharmacokinetic parameters will be computed from the individual plasma concentrations using a
non-compartmental approach and will be summarized by treatment using descriptive statistics.

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6.3 Pharmacokinetic Collection and Processing
Labels, purple top and microtubes (containing HCL) will be supplied by the lab. 
Storage will be -70C or below.
Shipping will be on dry ice.
Please follow the Procedure for PK Plasma Collection and Processing  instructions located 
in the Laboratory Manual under section 5.1.

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7.
PHARMACEUTICAL INFORMATION
QBS10072S 
7.1.1
Description
The chemical name for QBS10072S is (S)-3-Amino-4-[5-[bis(2-chloroethyl)amino]-2-methyl-
phenyl]butanoic acid.. QBS10072Sis also has an empirical formula of C15H22Cl2N2O2 and a 
molecular weight of 333.25 g/mol. 
Pharmacokinetic data for QBS10072S are summarized in the IB. QBS10072S has a short half-life 
of 0.60 – 0.79 h at dose levels of 0.5 – 3.0 mg/kg in monkeys and 0.74 – 0.90 h at dose levels of 
0.5 – 4.5 mg/kg in rats, respectively.  Presumably, QBS10072S undergoes rapid hydrolysis in vivo 
as in the case of bendamustine to form QBS10150S which is further hydrolyzed to form the bis(2-
hydroxyethyl)amine product (i.e., QBS10151S). The rat PK parameters for QBS10072S and 
QBS100150S were determined. Specifically, the overall %AUCQBS10150S/QBS10072S was 8.80% and 
9.28% for female rats and male rats, respectively, indicating that a far greater percentage of 
QBS10072S is hydrolyzed in vivo than the percentage of QBS10150S present in both drug 
substance (DS) and DP. 
7.1.2
Form
QBS10072S for injection is supplied as a sterile white to off-white lyophilized powder in a single-
dose vial for intravenous use. Each vial contains 50 mg QBS10072S free base and 2700 mg 
Betadex Sulfobutyl Ether Sodium, NF. The lyophilized powder with excipient will be reconstituted 
with 0.9% Sodium Chloride Injection, USP to a concentration of 50 mg/10 mL (5 mg/mL). The 
resulting solution will be further diluted to 0.5 mg/mL for intravenous infusion.
7.1.3
Storage and Stability
QBS10072S vials are to be stored at 2 to 8° C.  
Personnel involved with the study should be aware of the location of study drug storage. 
All study drug is to be stored in a secured area and accessible only to appropriate study 
personnel. 
A daily temperature log must be maintained by the site.
The reconstituted solution (5 mg/mL) is stable for 24 hours at refrigerated temperature (2 to 8°C) 
and for 2 hours at room temperature (20 to 25°C). 
QBS10072S reconstituted solution (5 mg/mL) is to be stored at 2 to 8°C temperature if not to be 
used immediately for admixture preparation and it must be allowed to reach room temperature for 
15 minutes prior to use. 

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The admixture solution (0.5 mg/mL) is stable for 4 hours at room temperature in addition to 8 
hours at refrigerated temperature (2 to 8°C) following dilution, refers to the following table. 
QBS10072S admixture solution (0.5 mg/mL) is to be stored at 2 to 8°C temperature if not to be 
used immediately and it must be allowed to reach room temperature for 15 minutes prior to use. 
Infusion must be completed within 4 hours from taking the admixture solution out of the 
refrigerated condition.
 Stability of QBS10072S reconstituted solution (5 mg/mL) and admixture solution (0.5 
mg/mL)
Storage condition
Name
Container
 2 to 8 oC
Room 
temperature
Reconstituted solution
(5 mg/mL)
Original Vial
NMT* 24 hours 
NMT* 2 hour
Admixture solution
Terumo Syringe
(0.5 mg/mL)
Baxter Viaflex Infusion 
Bag
NMT* 8 hours
NMT* 4 hours
Note: The combined storage time of the reconstituted solution (5mg/ml) and the admixture solution (0.5 mg/mL) 
for the diluted drug product must not exceed 4 hours at room temperature or 24 hours under refrigerated conditions
*NMT- No More Than
Cold-chain monitoring is required for any drug product that is transferred to refrigerated storage 
prior to administration.
7.1.4
Compatibility
QBS10072S should be diluted in saline (0.9% Sodium Chloride Injection, USP). Do not mix 
QBS10072S with other injectable drug products.
7.1.5
Handling
QBS10072S is a cytotoxic drug and applicable special handling and disposal procedures must be 
followed.
7.1.6
Availability
QBS10072S is an investigational agent and will be supplied free-of-charge from Quadriga 
Biosciences.
7.1.7
Dose Preparation
Once the Investigator has confirmed all inclusion/exclusion criteria have been met and the Sponsor 
has approved enrolment of the patient, a completed prescription form will be signed by the 
Investigator and provided to the Pharmacy. 

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The prescription should be prepared in compliance with institution requirements and should 
include at a minimum the protocol number, study number, subjects date of birth, BSA, dose level 
and calculated dose (mg), (approximate volume for infusion (mL) – if local site practice mandates 
this) and be signed by an Investigator. The prescription may be sent in advance to the pharmacy 
to assist with dose preparation, however drug should not be released until a signed prescription 
form has been provided. Cycle 1 Day 1 Weight should be used to calculate BSA. Standard practice 
for each individual site to calculate BSA dosing should be used, for example, DFCI/BWH standard 
of practice is to calculate BSA for dosing and to recalculate doses when there is a >10% change in 
weight. Please note that DuBois formula can be used per DFCI Institutional Standard. 
QBS10072S drug products will be supplied as a sterile, white to off-white lyophilized powder, in 
single-dose glass vial in individual carton, for intravenous use. Each vial contains 50 mg 
QBS10072S free base and 2700 mg Betadex Sulfobutyl Ether Sodium, NF. The lyophilized 
powder with excipient will be reconstituted with 0.9% Sodium Chloride Injection, USP to a 
concentration of 50 mg/10 mL (5 mg/mL). The resulting solution will be further diluted to 0.5 
mg/mL for intravenous infusion. 
The study reconstitution and dilution instructions are described in the table below.

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Dose Preparation Instructions for syringe administration
E.g. Dose Level 1, 3 mg/m2, Patient Height 162cm, Weight
62kg
Step 1.
Reconstitute QBS10072S 
drug product in 
normalsaline solution 
(0.9% Sodium Chloride 
Injection, USP) to a 
concentration of
50 mg/10 mL (5 mg/mL)
Inject 8.3 mL 0.9% Sodium Chloride Injection into vial.The 
normal saline (0.9% Sodium Chloride Injection, USP) used 
to reconstitute each vial should appear to be
assisted or pulled into the vial by the negative 
pressure (partial vacuum) present in the vial. Discard 
any vial (and replace with another vial) if there is no 
vacuum present when reconstituting the vial with 
normal saline.
50 mg QBS10072S in 10 mL
Step 2
Calculate the Volume of
0.5 mg/mL QBS10072S
to be infused
Dose Level x BSA =
 
QBS10072S (mg)
= Volume to be infused
0.5 mg/mL (Infusion
(mL)
concentration)
3mg/m2 X 1.67m2 =5.01
5.01mg/ 0.5mg/mL= 10.02mL
Step 3
Determine primary dosing
container and 
consumables
Where volume to be infused is ≤20mL, drug will be 
administered using a syringe pump. A list of approved
syringes and consumables can be found in Appendix 1 
of the Pharmacy Manual.
10.02mL < 20mL
Step 4
Calculate the volume of
0.5 mg/mL solution to be
prepared.
[Volume to be infused (mL)+ priming volume*]+ 10%
overage = volume of 0.5 mg/mL solution to be 
prepared**
*Priming volumes are listed in Appendix 1 of the Pharmacy 
Manual.
**Round to the nearest 1mL
[10.02mL+1.2mL + 0.7mL]*1.1 = 13.11mL
13mL Rounded
Step 5
Admix the 5 mg/mL 
QBS10072S with 0.9%
Sodium Chloride UPS, in
the primary container 
using a 1/10 dilution
Volume (5 mg/mL) = Volume (0.5 mg/mL) x 0.5 mg/mL / 5 mg/mL
= XX.X mL
Volume (0.9% Sodium Chloride Injection, UPS) = Volume (0.5 mg/mL) –
Volume (5 mg/mL)
The volume of QBS10072S solution required is 13mL, with
concentration 0.5 mg/mL.
How much 5 mg/mL QBS10072S is needed?
Volume (5mg/mL) = 13ml * 0.5mg/ml / 5mg/ml = 1.3mL
How much 0.9% Sodium Chloride UPS is needed? Volume 
(0.9% Sodium Chloride Injection, UPS) 13mL-1.3mL = 11.7mL

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Dose Preparation Instructions for large volume infusion (Viaflex bag)
E.g. Dose Level 3, 12 mg/m2, Patient Height 162cm,
Weight 62kg
Step 1.
Reconstitute QBS10072S 
drug product in 
normalsaline solution 
(0.9% Sodium Chloride 
Injection, USP) to a 
concentration of
50 mg/10 mL (5 mg/mL)
Inject 8.3 mL 0.9% Sodium Chloride Injection into vial.
The normal saline (0.9% Sodium Chloride Injection, USP) usedto 
reconstitute each vial should appear to be assisted or 
pulled into the vial by the negative pressure (partial 
vacuum) present in the vial. Discard any vial (and replace 
with another vial) if there is no vacuum present when
reconstituting the vial with normal saline.
50 mg QBS10072S in 10 mL
Step 2
Calculate the Volume of
0.5 mg/mL QBS10072S
to be infused
Dose Level x BSA =
 
QBS10072S (mg)
= Volume to be infused
0.5 mg/mL (Infusion
(mL)
concentration)
12mg/m2 X 1.67m2 =20.04
20.04mg/ 0.5mg/mL= 40.08mL
Step 3
Determine primary dosing
container and 
consumables
Where volume to be infused is >20mL, drug will be 
administered using an Infusion pump. A list of approved
IV Bags and consumables can be found in Appendix 1 of 
the Pharmacy Manual.
*Please note that per standard practice at DFCI, volumes < 50ml 
are administered via syringe pump.
40.08mL > 20mL
Step 4
Calculate the volume of
0.5 mg/mL solution to be
prepared.
[Volume to be infused (mL)+ priming volume*]+ 10%overage 
= volume of 0.5 mg/mL solution to be prepared**
*Priming volumes are listed in Appendix 1 of the Pharmacy 
Manual.
**Round to the nearest 1mL
[40.08mL+ 25mL]*1.1 = 71.588mL
72mL Rounded
Step 5
Admix the 5 mg/mL 
QBS10072S with 0.9%
Sodium Chloride UPS, in
the primary container 
using a 1/10 dilution
Volume (5 mg/mL) = Volume (0.5 mg/mL) x 0.5 mg/mL / 5 mg/mL =
XX.X mL
Volume (0.9% Sodium Chloride Injection, UPS) = Volume (0.5 mg/mL) –
Volume (5 mg/mL)
The volume of QBS10072S solution required is 72mL,
with concentration 0.5 mg/mL.
How much 5 mg/mL QBS10072S is needed?
Volume (5mg/mL) = 72ml * 0.5mg/ml / 5mg/ml = 7.2mL
How much 0.9% Sodium Chloride UPS is needed?
Volume (0.9% Sodium Chloride Injection, UPS) 72mL-7.2mL =
64.8mL

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o
Please note: The pharmacy manual was originally written for a different trial but contains information applicable to 
the INSIGhT trial (DF/HCC #16-443).  Refer to Appendix 11 of the pharmacy manual for DFCI specific clarifications 
regarding dose levels, dose calculations and IP preparation instructions.
o
Medfusion 3500 syringe pumps (in use at MGH) have been approved by Quadriga for use. Cycle 1 Day 1 Weight should 
be used to calculate BSA.

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Use normal saline solution (0.9% Sodium Chloride Injection, USP) (8.3 mL as directed) to 
reconstitute QBS10072S and make a 50 mg/10 mL (5 mg/ mL) nominal concentration of 
QBS10072S. The normal saline used to reconstitute each vial should appear to be assisted or pulled 
into the vial by the negative pressure (partial vacuum) present in the vial. Discard any vial (and 
replace with another vial) if there is no vacuum present when reconstituting the vial with normal 
saline. The reconstituted QBS10072S drug product is stable for 24 hours at refrigerated 
temperature (2~8 oC) without any precipitation due to the high solubility. The reconstituted 
QBS10072S drug product is stable for 2 hour at room temperature.

Calculate the required volume of QBS10072S needed for a patient’s dose and withdraw 
that volume from the vial(s).

Add the required volume of QBS10072S to the appropriate volume of 0.9% Sodium 
Chloride Injection, USP to a final concentration of 0.5 mg/mL. The QBS10072S 
admixture solution is stable for 4 hours at room temperature.
The combined storage time of the reconstituted solution (5mg/mL) and the admixture 
solution (0.5 mg/mL) for the diluted drug product must not exceed 4 hours at room 
temperature or 24 hours under refrigerated conditions.
7.1.8
Administration
Upon receipt of the prepared syringe or bag, QBS10072S will be administrated by an appropriately 
qualified and experienced member of the study staff. 
QBS10072S has not been shown to be either an irritant or vesicant when administered 
intravenously preclinically. However, this class of medication may cause local tissue damage 
should extravasation occur. Do not administer by direct injection into a peripheral vein. 
Administer QBS10072S by injecting slowly into a fast-running IV infusion or via an injection 
port, or via a central venous line. QBS10072S dosages should be administered concurrently with 
a fast-running infusion of compatible IV fluid. 
Please note that Sodium Chloride 0.9% is the only compatible fluid to be run in conjunction 
with QBS10072S, and should be administered at a rate of 250mL/hr NS over 2 hours starting 
1 hr before study drug
The administration of QBS10072S should be in conjunction with free flowing compatible IV 
solution. For participants in safety lead in cohort with PKs being drawn, the volume and 
administration rate of the compatible solution during the 60-minute infusion should be fixed to 
enable consistency of interpretation of PK data to the greatest extent possible.
Identification of the most appropriate cannulation site should be undertaken before insertion. If 
venous access continually proves difficult, placement of a central venous access device should be 
considered.
Identification of the most appropriate cannulation site should be undertaken before insertion. If 
venous access continually proves difficult, placement of a central venous access device should be 
considered.

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QBS10072S should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit.
Identification of the most appropriate cannulation site should be undertaken before insertion. If 
venous access continually proves difficult, placement of a central venous access device should be 
considered.
Premedication is recommended for all patients, consistent with institutional guidelines, and may 
include an antihistamine, anti-inflammatory agent (including corticosteroids), or pain reliever.
Administer the QBS10072S diluted product over a minimum of 30 minutes. First infusion 
should be over 60 minutes, subsequent infusion times may be decreased upon determination 
of patient tolerance.
Complete administration within 4 hours of QBS10072S admixture solution.
7.1.9
Ordering
The agent will be ordered from each institution’s individual pharmacy (or designee) using a 
Quadriga Biosciences online drug ordering system.  Access to this system will be requested for 
each institution’s pharmacy by the DFCI Coordinating Center once local IRB approval is received.  
Anticipate 3-5 business days to receive drug after the order is placed.
7.1.10
Accountability
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.)
7.1.11
Destruction and Return
QBS10072S will be destroyed on site according to institutional policies, documented in the Drug 
Accountability Record Form. At the time of expiration / study close, a drug disposition form 
provided by Quadriga Biosciences will be sent out to be signed off by the Pharmacist and 
Investigator verifying the destruction of drug. At the end of the study, unused supplies of 
QBS10072S should be destroyed or returned to Quadriga Biosciences according to institutional 
policies. Destruction or return will be documented in the Drug Accountability Record Form.

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8.
STUDY CALENDAR - Initiation/Concomitant Cycle (All dose levels)
Initiation/Concomitant Cycle
Assessment
Screen
-inga
D1b
D8c
D15c
D22 c
D29 c
D36 c
D43-
49 d
D57e,c
D64e,c
Adjuvant 
Cycles-See 
Adjuvant 
Cycles 
Calendar
D1f
End of 
Txg
30-Day 
Post 
Drugh
Active 
Follow
-Upi
Long
Term 
Follow
-Upj
Informed Consentk
X
Medical Historyl
X
Inclusion/Exclusion Criteriam
X
Vital signsn
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
Neurologic Exam
X
X
X
X
X
Karnofsky Performance 
Status(KPS)o
X
X
X
X
X
Concomitant Medicationsp
-----------------------------------------------------------------------------X--------------------------------------------------------------------------------
Adverse Eventsq
----------------------------------------------------------------------X------------------------------------------------------------------------
Pregnancy Test (β-HCG)r
X
X
X
Coagulations
X
Hematologys
X
X
X
X
X
X
X
X
X
X
X
8-hour Fasting Serum 
Chemistryt
X
X
X
X
X
X
X
X
X
X
X
HbA1caa
X
X
X
8 –hour Fasting Lipid Profileaa
X
X
X
12-lead ECGu
X
Xu
Radiationv
---------------------------X----------------------------
QBS10072S
X
Imaging – MRI w
X
X
X
Response Assessmentx
X
X
Post-treatment therapiesy
X
X
Survivalz
X
X
Archival Tumor Tissuebb
X
Pharmacokinetic samplingdd
X
Premedication cc (e.g., 
ondansetron and  loratadine)
X
a.
All screening procedures to be performed within 28 days of initial registration unless otherwise specified.  NOTE: refer to section 10 of master protocol for 
comprehensive details on screening assessments, initial registration, randomization assignment and second registration timing. 
b.
Concomitant radiation and QBS10072S must begin no later than 42 days following initial surgery.  Day 1 assessments must be performed within 3 days of starting study 

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treatment. Screening assessments may be utilized as baseline/Day 1 assessments if they fall within window. 
c.
+/- 2 day window for weekly assessments during concomitant phase. 
d.
Day 43-49 visit to occur within +/- 7 days of completing radiation. 
e.
Assessment required for Safety Lead-In patients only. These assessments are able to be done locally.
f.
Adjuvant C1D1 to begin > 28 (+14) days following end of radiation. Cycle 1, Day 1 adjuvant assessments to be performed within 4 days of Day 1 QBS10072S. All 
adjuvant cycle 1, day 1 assessments must be resulted and reviewed prior to initiating treatment with QBS10072S. Day 1 assessments for subsequent adjuvant cycles to 
be performed within 4 day of Day 1 QBS10072S 
g.
End of Treatment:  For participants who discontinue study treatment assessments to be performed within 7 days after last drug administration or within 7 days after 
decision to end treatment. 
h.
30-Day Post Drug:  For participants who discontinue study treatment a contact/visit is to be performed 30 days (+7 days) after date of last drug taken on study. This 
may be performed via documented phone conversation with a study nurse or clinician or a clinic visit.  All participants will be followed until resolution or stabilization 
of any serious or reportable adverse events occurring during treatment or starting within 30 days of last drug. 
i.
Active Follow-Up: for participants who discontinue study treatment for reasons other than disease progression, study team must continue monitoring participant’s 
disease status by radiologic imaging at 8-week intervals (+/- 1 week) until (1) documented disease progression, (2), death, (3) participant withdraws from follow-up, or 
(4) end of study, whichever occurs first.  
j.
Long Term Follow-Up: participants will be followed every 8 weeks (+/-1 week) via contact or medical record review until death. Participants must be followed for 
survival data at every long-term follow-up time point and for post-treatment therapies and reason for stopping those therapies when available.  
k.
Informed Consent: must be obtained by MD attending.  No study specific screening procedures may occur until after the initial informed consent process is completed. 
Initial informed consent may be obtained within 28 days of initial registration.  Following initial registration and receipt of INSIGhT randomization assignment, 
participants must sign the consent form specific to the assigned treatment arm prior to initiating treatment for that study arm. 
l.
Medical History: to include review of treatment history for GBM, any ongoing medical conditions and medical history pertaining to eligibility on study and involvement 
during study. 
m. Inclusion/exclusion criteria: source documentation providing investigator’s confirmation that the participant had met all master protocol eligibility criteria must be 
available prior to initial registration.  See section 3 of master protocol for eligibility requirements for initial registration.  See section 2 of this appendix for arm specific 
eligibility criteria.  
n.
Vital signs must be performed prior to administration of treatment on treatment-days. Height required only at screening. Vital Signs: Includes temperature, sitting or 
semi recumbent (same position must be used throughout the study and documented in source notes) blood pressure (BP), and pulse rate (to be recorded in the sitting 
position after 5 minutes of rest) weight, respiration rate, temperature. On Day 1 of each cycle, vital signs should be measured prior to dosing (pre dose), BP, and pulse 
rate will be repeated 1 hour after dosing.
o.
Karnofsky Performance Status (KPS): see appendix A of master protocol. 
p.
Concomitant Medications:  concomitant medications and reason for administration should be documented in the case history from date of consent up to the 30-Day 
Post Drug Visit. 
q.
Adverse Events:  adverse events experienced by participants will be collected and recorded from the first dose of treatment on-study up to the 30-Day Post Drug Visit 
of the last dose of study medication (+ 7 days depending on when 30-Day Post Drug visit/contact occurs).
r.
Pregnancy Test: required for women of child-bearing potential (see section 3 of master protocol for definition of women of child-bearing potential).  Pregnancy test can 
be either blood or urine sample.
s.
Coagulation:  PT/INR, PT, PTT required at screening only.  Hematology:  erythrocytes (RBC), hemoglobin, hematocrit, platelets, total WBC plus differential (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils).
t.
8-hour Fasting Serum Chemistry: albumin, alkaline phosphatase (ALP), BUN, calcium, creatinine, glucose, potassium, SGOT (AST), SGPT (ALT), sodium, total bilirubin (if 
total bilirubin is greater than the upper limit of normal, direct and indirect bilirubin should be performed), amylase, lipase, and magnesium.  
u.
For Patients in Safety Run-In and Expanded Safety Run-In cohorts: Triplicate 12 lead ECG: At each time point, 3 consecutive 12-lead ECGs will be performed 

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approximately 2 minutes apart (+/- 3 minutes) to determine mean QTcF interval.  (See Table 2:  Electrocardiogram, Pharmacokinetic, and Biomarker 
Sampling Schedule).  Following safety lead-in and Expanded Safety Lead-in, EKG will be done at Screening and Initiation/Concomitant Cycle 1 Day 1 (if screening 
EKG is done within 7 days of Day 1, then EKG at Concomitant C1D1 is not required). 
v.
Radiation: see section 3.1 of this sub-study appendix for definition of standard radiation therapy per protocol. 
w.
Imaging: gadolinium-enhanced contrast and non-contrast MRI.  Initial imaging should be performed within 21 days prior to beginning study treatment.  When feasible 
at site, Appendix D Recommended MRI Acquisition Protocol should be adhered to and the same imaging technique should be used on a participant throughout the 
trial.  Local reading (investigator assessment) will be used to determine eligibility and for participant management.  
x.
Response Assessment:  Per RANO criteria (see section 11 of master protocol).
y.
Post-treatment Therapies:  start/stop dates, names of treatment regimens and reason for stopping should be collected when available.
z.
Survival:  date of death and reason must be collected for overall survival purposes.
aa. HbA1c & 8-hour fasting lipid profile: do not need to be resulted and reviewed prior to initiating QBS10072S with RT in the concomitant phase.  
bb. Archival tumor tissue may be sent to Stanford University for assay laboratory tests.
cc. Premedication is recommended for all patients, consistent with institutional guidelines, and may include an antihistamine, anti-inflammatory (including 
corticosteroids), or pain reliever (see Section 7.1.8).
dd. Pharmacokinetic (PK) sampling: will be performed for patients in the safety run-in and expanded safety run-in cohorts only. See Table 2:  Electrocardiogram, 
Pharmacokinetic, and Biomarker Sampling Schedule.

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Adjuvant Cycles
Treatment Cycle 1
Treatment Cycle 2
Treatment Cycle 3 and 
beyond
Study Day
Day 1
Day 8
Day 15
Day 22
Day 1
Day 8
Day 15
Day 22
Day 1
Day 15
Visit Window
28-42 days after 
RT completion
±2
±2
±2
±2
±2
±2
±2
±2
±2
General Assessments
Height
X
Weight
X
X
X
Physical Exam
X
X
X
Neurologic Exam
X
X
X
Adverse Events1
----------------------------------------------------------------------X--------------------------------------------------------------------------
Symptom directed physical exam2
----------------------------------------------------------------------X--------------------------------------------------------------------------
Vital Signs3
X
X
X
Triplicate ECG 4
X
X
KPS 5
X
X
X
Prior and Concomitant Medications 
and Procedures (e.g., surgeries)
X
X
X
Corticosteroid utilization6
X
X
X
Contraception check8
X
X
X
Laboratory Assessments – Local
Hematology9
X
X
X
X
X
X
X
X
X
X
Blood Chemistry10
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
Urine or Serum Pregnancy Test7
X
X
X
Laboratory Assessments – Central
Pharmacokinetic sampling4
X
QBS10072S Treatment (Q4W)
Premedication 11 (e.g., ondansetron 
and dexamethasone)
X
X
X
QBS10072S Infusion 12
X
X
X
Efficacy Measurements
MRI and Clinical Response 
Assessment (RANO)13
X
X
Adjuvant Cycles – 21-Day Dosing Regimen
Adjuvant Cycles – 28-Day Dosing Regimen

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Abbreviations:  = ongoing/continuous event; AE = Adverse event; ECG = electrocardiogram; EOS = End of study; EOT = End of treatment; MRI = Magnetic 
resonance imaging; PK = Pharmacokinetic; KPS = Karnofsky performance status; RANO = Response assessment in neuro-oncology; SAE = Serious adverse 
event. 
1.
Adverse Events: Adverse events experienced by participants will be collected and recorded from the date of first dose of treatment on-study until 30 
days (+/- 7 days) after the date of the last dose of study medication. Participants who experience serious or reportable adverse events during treatment or 
starting within 30 days of last dose of study medication will be followed until resolution or stabilization of the event(s).
2.
Symptom directed PE: should be performed as appropriate at other timepoints where complete physical examinations are not required.
Adjuvant Cycles
Treatment Cycle 1
Treatment Cycle 2
Treatment Cycle 3 and 
beyond
Study Day
Day 1
Day 8
Day 15
Day 1
Day 8
Day 15
Day 1
Day 15
Visit Window
28-42 days after RT 
completion
±2
±2
±2
±2
±2
±2
±2
General Assessments
Height
X
Weight
X
X
X
Physical Exam
X
X
X
Neurologic Exam
X
X
X
Adverse Events1
----------------------------------------------------------------------X--------------------------------------------------------------------------
Symptom directed physical exam2
----------------------------------------------------------------------X--------------------------------------------------------------------------
Vital Signs3
X
X
X
Triplicate ECG 4
X
X
KPS PS5
X
X
X
Prior and Concomitant Medications  and 
Procedures (e.g., surgeries)
X
X
X
Corticosteroid utilization6
X
X
X
Contraception Check8
Laboratory Assessments Local
Hematology9
X
X
X
X
X
X
X
X
Blood Chemistry10
X
X
X
X
X
X
X
X
Urinalysis
X
X
Urine or Serum Pregnancy Test7
X
X
X
Laboratory assessments Central
Pharmacokinetic sampling4
X
QBS10072S Treatment (Q3W)
Premedication 11 (e.g., ondansetron and 
dexamethasone)
X
X
X
QBS10072S Infusion 12
X
X
X
Efficacy Measurements 13
MRI and Clinical Response Assessment (RANO)
X
-------------------------------------------------------X------------------------------------------------------

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3.
Vital Signs: Includes temperature, sitting or semi-recumbent (same position must be used throughout the study and documented in source notes) blood 
pressure (BP), and pulse rate (to be recorded in the sitting position after 5 minutes of rest). On Day 1 of each cycle, vital signs should be measured prior 
to dosing (pre-dose). BP and pulse rate will be repeated 1 hour after the end of infusion (+/- 5 min).
4.
For Patients in Safety Run-In and Expanded Safety Run-in Cohorts only: See Table 3: Pharmacokinetic Sampling Schedule – Adjuvant Cycle 1 for 
adjuvant C1D1 ECG and PK timepoints.
5.
KPS: see Appendix A in master protocol
6.
Corticosteroid Utilization: Participants’ steroid dose will be recorded at each visit.
7.
Urine or Serum Pregnancy Test: Pregnancy test for female patients of childbearing potential. Test may also be repeated as per request of Institutional 
Review Board/Independent Ethics Committee (IRB/IECs), if required by local regulations. 
8.
Contraception Check: The patient will be informed of the need to use highly effective contraception consistently and correctly. The conversation and 
patient’s affirmation will be documented in the patient’s chart.
9.
Hematology: erythrocytes (RBC), hemoglobin, hematocrit, platelets, total WBC plus differential (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils). 
10. Serum Chemistry: albumin, alkaline phosphatase (ALP), BUN, calcium, creatinine, glucose, potassium, SGOT (AST), SGPT (ALT), sodium, total 
bilirubin (if total bilirubin is greater than the upper limit of normal, direct and indirect bilirubin should be performed).
11. Premedication is recommended for all patients, consistent with institutional guidelines, and may include an antihistamine, anti-inflammatory (including 
corticosteroids), or pain reliever (see Section 7.1.8).
12. Cycle 1, Day 1 adjuvant assessments to be performed within 4 days of Day 1 QBS10072S. All adjuvant cycle 1, day 1 assessments must be resulted and 
reviewed prior to initiating treatment with QBS10072S. Day 1 assessments for subsequent adjuvant cycles to be performed within 4 days of Day 1 
QBS10072S. QBS10072S Infusion: Initially QBS10072S will be administered intravenously over 1 hour on day 1 of the first adjuvant cycle. After the 
first dose, the infusion may be decreased to a minimum of 30 minutes at the discretion of the Investigator (N.B., another dosing regimen may be later 
considered in the study if supported by emerging clinical data). Treatment will continue until progressive disease, unacceptable toxicity or patient 
refusal, whichever occurs first. If progressive disease occurs during treatment, continuation of study drug may continue, under the following conditions: 
(a) presence of reasonable evidence of clinical benefit; (b) absence of any relevant toxicity; and (c) after discussion with the Sponsor. 
13. Efficacy Measurements: Tumor assessments will include all known or suspected disease sites brain MRI scans are to be performed every 8 weeks. The 
allowable time window for disease assessments is ±7 days. Tumor assessment should be repeated at the end of treatment visit if more than 4 weeks have 
passed since the last evaluation. When the study treatment is discontinued for reasons other than disease progression, patients should continue to have 
tumor assessments performed every 8 weeks (+/- 7 days) until (a) disease progression or death, (b) patient refusal or withdrawal of consent, or (c) start 
of another anticancer treatment, whichever occurs first. Tumor assessments should be fixed according to the calendar, regardless of treatment delays. 
Please see RANO Criteria for Time Point Responses in the Master Protocol.

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Table 2: Safety Lead-In and Expanded Safety Lead-In Electrocardiogram and 
Pharmacokinetic Sampling Schedule –  Concomitant/Initiation Cycle (QBS10072S + 
Radiation Therapy)
Concomitant Cycle 1
Unscheduled 
(as needed)4
Study Day
Day 1
Day 2
Post 
start of 
infusion
End of 
infusion
Post end of infusion4
Time Post-
dose1
Predose2
15 
m
30 
m
5 m
30 m 
1 h
2 h
3 h
5 h
7 h
24 h
Window
±5 
m
±5 
m
PK within 
2m prior to 
EOI
ECG within 
6m prior to 
EOI
+10 
m
±5 
m
±5 
m
±5 
m
±10 m
±10 m
±20 m
±1 h
Plasma for 
QBS10072S 
PK2
X
X
X
X
X
X
X
X
X
X
X
X
Triplicate 
ECGs3
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: ECG = Electrocardiogram; EOI = End of Infusion; h = hour; m = minute; PK = Pharmacokinetics.
1.
Collection Time: Sampling times are related to morning dose; this schedule assumes a 60-minute infusion 
period, adjustments will be made according to infusion time
2.
Pharmacokinetics: Blood samples for determination of plasma QBS10072S drug concentrations will be 
collected at the time points specified only on patients in the safety run-in cohort (NOTE: PK sampling time 
points may change [e.g., duration of infusion] pending PK data from early dose levels, but the total number of 
samples will remain the same).  
3.
For Safety Run-In cohort: Triplicate 12 lead ECG: At each time point, 3 consecutive 12-lead ECGs will be 
performed approximately 2 minutes apart (+/- 3 minutes) to determine mean QTcF interval. All ECG collection 
time points are with respect to QBS10072S dosing. When coinciding with blood sample draws for PK, ECG 
assessment should be performed prior to blood sample collection, such that the blood sample is collected at the 
nominal time. If the mean QTcF is prolonged (value of >480 msec), the ECGs should be reevaluated by a 
qualified person at the institution for confirmation.
4.
Additional samples may be collected at the discretion of the Investigator (e.g., adverse events).

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Table 3: Safety Lead-In and Expanded Safety Lead-In Pharmacokinetic Sampling 
Schedule – Adjuvant Cycle 1 
Adjuvant Cycle 1
Study Day
Day 1
Post start of infusion
End of infusion
      Post end of infusion4
Time Postdose1
Predose2
15 m
30 m
5 m
30 m
1 h
2 h
3 h
Window
±5 m
±5 m
PK within 2 m prior to 
EOI
ECG within 6m prior to 
EOI
+10 m
±5 m
±5 m
±5 m
±10 m
Plasma for 
QBS10072S 
PK2
X
X
X
X
X
X
X
X
X
Triplicate 
ECGs3
X
X
X
X
X
X
X
X
X
Abbreviations: ECG = Electrocardiogram; EOI = End of Infusion; h = hour; m = minute; PK = Pharmacokinetics.
1.
Collection Time: Sampling times are related to morning dose; this schedule assumes a 60-minute infusion 
period, adjustments will be made according to infusion time
2.
Pharmacokinetics: Blood samples for determination of plasma QBS10072S drug concentrations will be 
collected at the time points specified only on patients in the safety run-in cohort (NOTE: PK sampling time 
points may change [e.g., duration of infusion] pending PK data from early dose levels, but the total number of 
samples will remain the same). 
3.
Triplicate 12 lead ECG: At each time point, 3 consecutive 12-lead ECGs will be performed approximately 2 
minutes apart (+/- 3 minutes) to determine mean QTcF interval. Starting at Cycle 3, ECGs can be performed as 
clinically indicated. All ECG collection time points are with respect to QBS10072S dosing. When coinciding 
with blood sample draws for PK, ECG assessment should be performed prior to blood sample collection, such 
that the blood sample is collected at the nominal time. If the mean QTcF is prolonged (value of >480 msec), the 
ECGs should be reevaluated by a qualified person at the institution for confirmation.
4.
Additional samples may be collected at the discretion of the Investigator (e.g., adverse events).
9. Measurement of Effect
Refer to section 11 of master INSIGhT protocol for details on measurement of effect. 
10. REFERENCES
1.
Bessho, T. Induction of DNA Replication-mediated Double Strand Breaks by Psoralen DNA 
Interstrand Cross-links J. Bio Chem 2003 278: 5250-5254
2.
Colvin M. Alkylating Agents. In: Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. 
Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003. Available from: 
https://www.ncbi.nlm.nih.gov/books/NBK12772/

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3.
Preuss I, Thust R, Kaina B. Protective effect of O6-methylguanine-DNA methyltransferase 
(MGMT) on the cytotoxic and recombinogenic activity of different antineoplastic drugs. Int J 
Cancer. 1996;65(4):506- 12.
4.
Duelli R, Enerson BE, Gerhart DZ, Drewes LR. Expression of large amino acid transporter 
LAT1 in rat brain endothelium. J Cereb Blood Flow Metab. 2000;20(11):1557-62. 
5.
Matsuo H, Tsukada S, Nakata T, Chairoungdua A, Kim DK, Cha SH, et al. Expression of a 
system L neutral amino acid transporter at the blood-brain barrier. Neuroreport. 
2000;11(16):3507-11. 
6.
Killian DM, Chikhale PJ. Predominant functional activity of the large, neutral amino acid 
transporter (LAT1) isoform at the cerebrovasculature. Neurosci Lett. 2001;306(1-2):1-4. 
7.
Nawashiro H, Otani N, Shinomiya N, Fukui S, Ooigawa H, Shima K, et al. L-type amino acid 
transporter 1 as a potential molecular target in human astrocytic tumors. Int J Cancer. 
2006;119(3):484-92. 
8.
Sakata T, Ferdous G, Tsuruta T, Satoh T, Baba S, Muto T, et al. L-type amino-acid transporter 1 
as a novel biomarker for high-grade malignancy in prostate cancer. Pathol Int. 2009;59(1):7-18. 
9.
Ichinoe M, Mikami T, Yoshida T, Igawa I, Tsuruta T, Nakada N, et al. High expression of L-type 
amino- acid transporter 1 (LAT1) in gastric carcinomas: Comparison with non-cancerous 
lesions. Pathol Int. 2011;61(5):281-9. 
10. Haining Z, Kawai N, Miyake K, Okada M, Okubo S, Zhang X Relation of LAT1/4F2hc 
expression with pathological grade, proliferation and angiogenesis in human gliomas. BMC Clin 
Pathol. 2012;12:4. 
11. Isoda A, Kaira K, Iwashina M, Oriuchi N, Tominaga H, Nagamori S, et al. Expression of L-type 
amino acid transporter 1 (LAT1) as a prognostic and therapeutic indicator in multiple myeloma. 
Cancer Sci. 2014;105(11):1496-502. 
12. Youland RS, Kitange GJ, Peterson TE, Pafundi DH, Ramiscal JA, Pokorny JL, et al. The role of 
LAT1 in18F-DOPA uptake in malignant gliomas. Journal of neuro-oncology. 2013;111(1):11-8. 

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DFCI REPORTABLE AE COVERSHEET – INSIGHT QBS10072S ARM
DF/HCC Protocol No. 16-443              Quadriga Biosciences Tracking No. QBS10072S -
Date:____________________            Number of pages including cover sheet:____________
To (check off recipient of this AE):
        Dr. Patrick Y. Wen and Dana-Farber  Coordinating Center
    Email: NeuroOnc_SAE@dfci.harvard.edu
        Quadriga Biosciences Corporation 
Email: ron.weitzman@quadrigabiosciences.com 
Email: Trinh Le trinh@ccrc-inc.com 
From:
Institution:
Phone No.:
Fax No.:
Participant # and Initials:
Date Event Met Reporting Criteria (as defined in protocol):
Type of Report:    Initial   Follow-up
CTCAE Event #1 Description:
CTCAE Event #2 Description (if applicable): 
NOTE: use another coversheet if more than 2 events are being reported at this 
time
Meets Definition of Serious AE:   
   Serious        Non-serious
Meets Definition of Serious AE:   
   Serious         Non-serious
Toxicity Grade:     
G1/mild   G2/moderate   G3/severe   
G4/life threatening   G5/death
Toxicity Grade:     
G1/mild   G2/moderate   G3/severe   
G4/life threatening   G5/death
Expectedness to Radiation Therapy:    Expected   
Unexpected    N/A  
Expectedness to Radiation Therapy:    
Expected   Unexpected   N/A  
Attribution to Radiation Therapy:    
Unrelated   Unlikely    Possible    Probable    
Definite      N/A  
Attribution to Radiation Therapy:    
Unrelated   Unlikely    Possible    
Probable    Definite      N/A  
Expectedness to QBS10072S:   
 Expected   Unexpected   N/A  
Expectedness to QBS10072S:    
Expected   Unexpected   N/A  
Attribution to QBS10072S:    
Unrelated   Unlikely    Possible    Probable    
Definite      N/A  
Attribution to QBS10072S:    
Unrelated   Unlikely    Possible    
Probable    Definite      N/A  
Reporting Investigator (print):
Signature of Reporting Investigator: ______________________________  Date: _____________

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APPENDIX J Study Drug VBI-1901/BALSTILIMAB ARM OF INSIGhT
TABLE OF CONTENTS
Contents
APPENDIX J Study Drug VBI-1901/BALSTILIMAB ARM OF INSIGhT..................................303
1.
BACKGROUND .........................................................................................................305
1.1 Study Drug VBI-1901........................................................................................................305
2.
PARTICIPANT SELECTION.....................................................................................313
2.1 Eligibility Criteria Specific to the VBI-1901/Balstilimab (AGEN2034) Arm ..................313
2.2 Second INSIGhT Registration: Registration to VBI-1901/Balstilimab Arm ....................313
3.
TREATMENT PLAN..................................................................................................314
3.1
Definition of Standard Radiation Therapy...................................................................315
3.2
Treatment Regimen – VBI-1901 Administration ........................................................315
3.3
Treatment Regimen – Balstilimab Administration ......................................................316
3.4
Definition of Dose-Limiting Toxicity..........................................................................316
3.5
General Concomitant Medication and Supportive Care Guidelines............................317
3.6
Criteria for Taking a Participant Off Protocol Therapy...............................................318
3.7
Duration of Follow Up.................................................................................................319
3.8
Criteria for Taking a Participant Off Study .................................................................319
4.
DOSING DELAYS/DOSE MODIFICATIONS..........................................................320
4.1
Anticipated Toxicities..................................................................................................320
4.2
Immune Related Management Guidelines...................................................................322
4.3
Dose Modifications/Delays for Balstilimab.................................................................332
4.4
Potential Overlapping Toxicities From Radiotherapy, VBI-1901 and Balstilimab.....333
5.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .......................333
5.1 Expected Toxicities............................................................................................................333
5.2 Adverse Event Characteristics ...........................................................................................334
5.3 Solicited Adverse Events ...................................................................................................335
5.4 Expedited Adverse Event Reporting..................................................................................336
6.
PHARMACEUTICAL INFORMATION....................................................................341
6.1 VBI-1901 ...........................................................................................................................341

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6.2 GM-CSF (Lyophilized Leukine®)......................................................................................343
6.3 Balstilimab (AGEN2034) ..................................................................................................344
7.
STUDY CALENDAR..................................................................................................347
8.
MEASUREMENT OF EFFECT..................................................................................351
9.
GRADING OF LOCAL REACTIONS .......................................................................351
10.
REFERENCES.............................................................................................................351

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1. BACKGROUND
1.1 Study Drug VBI-1901
Virus-Like Particles to Design New Vaccines
Natural viruses are made of proteins associated with either DNA or RNA. They need to infect cells 
(e.g., human or animal cells) in order to hijack the cellular machinery and produce new viruses 
using the viral DNA and RNA component as a template. Moreover, some viruses, also called 
enveloped viruses, are released by budding through the infected cell membrane, therefore being 
enveloped in a fragment of the lipid bilayer from the host cell membrane.
Under certain conditions, virus-like particles (VLPs), very similar to the parental virus but devoid 
of the viral DNA or RNA, can be produced1. Moreover, VLPs can be engineered to carry 
heterologous antigens against other infectious diseases. VLPs are highly immunogenic leading to 
the development of several “third generation” prophylactic vaccines. For instance, VLPs are 
regarded as safe and efficient prophylactic vaccines against infectious diseases including human 
papillomavirus and hepatitis B2.
Enveloped virus-like particles (eVLPs) are an innovative new class of synthetic vaccines that are 
designed to closely mimic the structure of enveloped viruses and are comprised of a lipid bilayer 
and a protein core essentially of viral origin (see Figure 1 below). It is possible to design eVLPs 
carrying several antigens and for instance able to activate both the cellular and humoral immune 
responses.
Rationale for Selecting the Components of VBI-1901
VBI Vaccines Inc. (VBI) designed an eVLP based on a well-known retrovirus, the Moloney 
Leukemia virus that has been widely used in gene therapy, carrying two human cytomegalovirus 
(HCMV) antigens, glycoprotein B (gB) and 65-kiloDalton polypeptide (pp65). A summary of the 
design and rationale for the vaccine candidate VBI-1901 appears in Figure 1.
MLV Gag Component
Moloney Leukemia virus (MoMLV or MLV) belongs to the family of Retroviridae, 
Gammaretroviral Genus and has been widely used in gene therapy, including in clinical trials. All 
retroviruses express the group of antigens (Gag) protein although each Gag may be slightly 
different depending on the species and host. VBI’s eVLP platform technology uses MLV Gag 
polypeptides as the basis of VLP formation. In the retrovirus, Gag protein yields the viral matrix 
(MA), capsid (CA), and nucleocapsid (NC) proteins after being cleaved by viral and/or cellular 
proteases3-5. The capsid protein is the main structural element of mature virus particles, forming the 
core shell around the NC-RNA complex, while the MA remains linked to the viral lipid bilayer 
(envelope). Native viral Gag polypeptides inherently include in their C-terminal the Pol protein 
(containing protease, reverse transcriptase, and integrase functions). However, VLP formation does 
not require the presence of these components and VBI’s eVLP technology does not include the Pol 
polyprotein. Gag alone can assemble into VLPs6 and fusion of small proteins such as green 

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fluorescent protein to Gag does not alter this property7. To ensure expression of the HCMV 
tegument protein pp65 into the eVLP, pp65 is directly fused to the MLV Gag.
Figure 1:
Design of GBM HCMV eVLP Vaccine Candidate VBI-1901
CMV = cytomegalovirus; eVLP = enveloped virus-like particle; gB = glycoprotein B; GBM = glioblastoma; GM-CSF 
= granulocyte-macrophage colony-stimulating factor; HCMV = human cytomegalovirus; IFN-γ = interferon-γ; pp65 = 
65-kiloDalton polypeptide
Note: See references 8-10.
HCMV pp65 Component
Located within the tegument between the capsid and the viral envelope, HCMV pp65 is the major 
constituent of extracellular virus particle antigens. Antigen pp65 is a component specific to the 
therapeutic vaccine developed by VBI and is a major target of the cytotoxic T-cell response11. It is 
thought to play a major role in the immune evasion during HCMV infections by preventing 
infected cells from being destroyed by the immune system11.
HCMV gB Component
Glycoprotein B is one of the major B-cell antigens in HCMV, inducing neutralizing, protective 
immune responses and used as a target in several vaccine trials12. VBI has demonstrated that eVLPs 
expressing HCMV gB induce potent humoral immune responses in mice and rabbits13. In VBI-
1901, eVLPs are produced after transient transfection of HEK 293 cells with plasmid encoding 
murine leukemia virus Gag plasmid fused in-frame with HCMV pp65 antigen, which gives rise to 
particles. Co-transfected HCMV gB plasmid enables particles budding from the cell surface to 
incorporate the gB protein into the lipid bilayer.
The design schematic of VBI-1901 is presented in Figure 2.

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Figure 2: 
Design Schematic and Electron Microscopy Image of VBI-1901
CMV = cytomegalovirus; GAG = group of antigens; gB = glycoprotein B; MLV = murine leukemia virus; pp65 = 
65-kiloDalton polypeptide
GM-CSF as Adjuvant
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is used for the mobilization of 
hematopoietic progenitor cells after chemotherapy or before hematopoietic cell collection for 
transplantation14. Since initial studies demonstrating that vaccination with irradiated tumor cells 
genetically modified to produce GM-CSF promoted potent anti-tumor immunity15, an expanding 
role for GM-CSF in regulating immune responses has been recognized based upon its activity on 
the development and maturation of antigen presenting cells and its capability for skewing the 
immune system toward Th1-type responses16. As a consequence, GM-CSF has been proposed as an 
adjuvant in cancer immunotherapy17 including for the treatment of glioblastoma18.
Supporting Clinical Data
Safety data from 18 subjects who received VBI-1901 plus GM-CSF as Part A of the study 
demonstrated that the vaccine was well tolerated with no safety signals identified. The 
majority of adverse experiences associated with vaccinations were transient mild to 
moderate injection site reactions.
Table 1 lists the nine serious adverse events (SAEs) that occurred in six subjects during Part A 
of the study. All the SAEs were assessed by study investigators as either not related (n=4) or 
unlikely related (n=5) to the study vaccine.
Table 1:
Serious Adverse Events Observed with VBI-1901 plus GM-CSF

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Subject ID
AE Preferred Term a
AE Severity b
AE Causality b
01-003
Urinary tract infection
Grade 3
Not related
01-004
Metapneumovirus infection
Grade 1
Not related
01-004
Glioblastoma multiforme
Grade 4
Not related
01-018
Gait disturbance
Grade 3
Not related
03-001
Wound infection
Grade 3
Unlikely related
03-001
Embolism
Grade 4
Unlikely related
03-004
Seizure
Grade 1
Unlikely related
03-004
Seizure
Grade 1
Unlikely related
03-006
Colloid brain cyst
Grade 1
Unlikely related
a MedDRA v21.0
b Investigator's assessment
There were no on-study deaths reported during the Part A of the study. Three subjects with 
advanced GBM died following discontinuation from the study. The first subject (03-001), a 54- 
year-old white female with advanced GBM who completed 2 cycles of VBI-1901 vaccination at 
the intermediate dose (2 μg pp65), developed a thromboembolic event and decided to 
discontinue from the study to pursue palliative care. This subject later died off-study - the cause 
of death was not reported. The second subject (01-003), a 54-year-old white female with 
advanced GBM, completed 8 cycles of VBI-1901 vaccination at the low dose (0.4 μg pp65) 
before discontinuing from the study. This subject later died off-study - the cause of death was 
not reported. The third subject (01-009), a 57-year-old white male with advanced GBM, 
completed 2 cycles of VBI-1901 vaccination at the low dose (0.4 μg pp65) before discontinuing 
from the study. This subject later died off-study - the cause of death was not reported.
On December 19, 2018, the data and safety monitoring board (DSMB) reviewed the safety 
information for all the subjects that were enrolled in the high dose cohort. No concerns were 
identified, and the DSMB, in agreement with the sponsor and the medical monitor, 
unanimously recommended moving forward with the next phase of the study (Part B).  
Immunogenicity data have demonstrated that the vaccine boosts CMV-specific T cell and 
antibody responses in a subset of subjects across all dose levels.  Tumor responses (stable 
disease) were observed in 3/6 subjects in the high dose cohort but in only 1/12 subjects in the 
low and intermediate dose cohorts, prompting the sponsor to select the high (10 μg pp65) 
dose of VBI-1901 in the Part B extension phase of the study.
Four among 10 subjects treated in the Part B extension phase of the study with VBI-1901 
plus GM-CSF had tumor responses: 2 stable disease, 2 partial responses.  A disease control 
rate (SD+PR+CR) of 44% was observed when combining all patients that received the same 
high dose level of VBI-1901 plus GM-CSF (Figure 3).  No vaccine-related SAEs have been 
reported in Part B of the study.

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Figure 3: 
Tumor Responses Associated with VBI-1901+GM-CSF Treatment
A 12 month OS rate of 62.5% and mOS of 13 months seen with the high 10μg pp65 dose of 
VBI-1901 plus GM-CSF treatment compares favorably to historical standard of care 
treatments (Taal, 2014).
Figure 4: 
Clinical Responses Associated with VBI-1901+GM-CSF Treatment
Balstilimab (AGEN2034)
Balstilimab (AGEN2034) is a fully human monoclonal immunoglobulin G4 (IgG4) antibody designed to 
antagonize inhibitory signaling in a manner comparable to nivolumab by the programmed cell death protein 
1 (PD-1) pathway via blockade of PD-1 binding to programmed death ligand 1 (PD-L1) and programmed 
death ligand 2 (PD-L2).
Supporting Nonclinical Data
The utility of PD-1 as a therapeutic antibody target in human cancer has been well characterized. 
A human IgG4 antibody with Ig kappa light chains (IgG4κ) monoclonal antibody (mAb) 
directed against PD-1 (nivolumab, Opdivo®) has been evaluated in thousands of patients 
covering a range of intravenous (IV) doses, from 0.1 mg/kg to 20 mg/kg19. Balstilimab is 
physicochemically comparable to nivolumab (anti-PD-1 specific IgG4 antibodies with Igκ light 

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chains), and a side-by-side in vitro pharmacological characterization of balstilimab and 
nivolumab demonstrated that these two antibodies were functionally comparable.
Balstilimab toxicity was assessed in a 4-week Good Laboratory Practice (GLP) repeat dose 
study in cynomolgus monkeys and in a human tissue cross reactivity study. No clinically 
relevant findings were identified.
Details of these studies can be found in the Balstilimab Investigator’s Brochure.
The no-observed-adverse-effect level (NOAEL) of balstilimab from the 4-week cynomolgus 
monkey toxicity study was 40 mg/kg. Histopathology findings at 300 mg/kg included 
vascular/perivascular inflammation in a variety of tissues. The collective histology, 
immunohistochemistry, pharmacokinetics (PK) and anti-drug antibody (ADA) data were 
consistent with an immune-mediated vasculitis caused by ADA formation in a proportion of 
monkeys given 300 mg/kg balstilimab. ADA is a recognized phenomenon in non-human primate 
studies as it relates to the antigenicity of an administered humanized antibody and these types of 
events are typically not correlated with the formation of ADA in human patients20-22. Other 
treatment-related findings in the 4-week study were consistent with pharmacodynamic effects 
including changes in lymphoid cellularity in the spleen (increased at ≥ 40 mg/kg) and thymus 
(decreased at 300 mg/kg) and an increase in mononuclear cell infiltration in the brain 
(≥ 40 mg/kg). These findings related to some changes in organ weights that showed a trend 
towards recovery following the 4-week non-dosing phase. Cytokine measurements from the 
4-week toxicity study in cynomolgus monkeys and from an in vitro cytokine release assay in 
human whole blood revealed no findings that are considered related to cytokine release 
syndrome.
For detailed information on preclinical characterization, manufacturing, and administration of 
balstilimab, please refer to the Balstilimab Investigator’s Brochure.
Supporting Clinical Data
Currently, the balstilimab clinical program consists of multiple ongoing clinical studies, 
including C-700-01, C-550-01, C-750-01/GOG-3028, C-800-01, and C-1100-01, in patients with 
metastatic or locally advanced solid tumors (advanced tumors) (C-800-01 and C-1100-01) and 
with expansion into selected solid tumors (cervical cancer) (C-700-01 and C-550-01) or in 
advanced cervical cancer (C-750-01/GOG-3028). Balstilimab is being evaluated both as a single 
agent and in combination with either zalifrelimab, AGEN1181, or AGEN2373.
Study C-700-01 is an ongoing Phase 1/2, open-label clinical study of balstilimab as a single 
agent. Phase 1 is a dose escalation study in patients with metastatic or locally advanced solid 
tumor for which no standard therapy exists or standard therapy has failed. Phase 2 expansion 
evaluates the efficacy, safety, and PK in patients with locally advanced, recurrent, and/or 
metastatic cervical cancer and who have relapsed after platinum-based chemotherapy.
Study C-550-01 is an ongoing Phase 1/2 open-label clinical study of zalifrelimab (cytotoxic 
T-lymphocyte-associated antigen 4 [CTLA-4] antagonist) in combination with balstilimab. 
Phase 1 is a dose escalation study in patients with metastatic or locally advanced, solid tumor for 
which no standard therapy exists or standard therapy has failed. Phase 2 expansion evaluates the 

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efficacy, safety, and PK in patients with locally advanced, recurrent, and/or metastatic cervical 
cancer and who have relapsed after a platinum-based chemotherapy (first-line).
Study C-750-01/GOG-3028 is an ongoing Phase 2, randomized, blinded, noncomparative 
clinical study evaluating the efficacy and safety of balstilimab as monotherapy administered with 
placebo (Treatment Arm 1) or in combination with zalifrelimab (Treatment Arm 2) in women 
with metastatic, locally advanced, and/or recurrent cervical cancer (second line) - RaPiDs.
Study C-800-01 is an ongoing Phase 1/2 trial evaluating AGEN1181 (fragment crystallizable 
[Fc]-engineered CTLA-4 antagonist) as a monotherapy and in combination with balstilimab in 
patients with advanced and/or refractory malignancies.
Study C-1100-01 is an ongoing, Phase 1, open-label, multicenter clinical study using a 3+3 
design in patients with a histologically or cytologically confirmed diagnoses of metastatic or 
locally advanced solid tumor for which no standard therapy is available or standard therapy has 
failed. AGEN2373 will be evaluated in 3 treatment arms, AGEN2373 as monotherapy 
administered every 2 weeks (Q2W), as monotherapy administered every 4 weeks, or as 
combination therapy with balstilimab administered Q2W to assess the safety, tolerability, and 
dose-limiting toxicity (DLT) of AGEN2373.
Across the studies, the most frequently reported treatment-emergent adverse events (TEAEs) 
(≥ 10%) by preferred term (PT) regardless of relationship to study drug were anaemia (36.4%), 
nausea (29.5%), fatigue (26.5%), diarrhoea (25.4%), vomiting (22.0%), constipation (18.5%), 
urinary tract infection (18.5%), abdominal pain (18.1%), pyrexia (17.5%), asthenia (17.2%), 
decreased appetite (16.6%), back pain (15.1%), cough (13.4%), headache (12.3%), pruritus 
(11.4%), hypothyroidism (10.6%), blood creatinine increased (10.3%), and arthralgia (10.1%). 
The most frequently reported treatment-related TEAEs (≥ 10%) were fatigue (16.4%), diarrhoea 
(14.0%), and nausea (11.6%). Seven (1.5%) patients experienced Grade 4 treatment-related 
TEAEs including lipase increased, adrenal insufficiency, anaemia, lymphopenia, and uncoded (1 
patient each), and hypokalaemia (2 patients). Most treatment-related TEAEs were of mild or 
moderate intensity.
Across the studies, 208 patients experienced at least 1 serious adverse event (SAE). The most 
frequently reported SAEs by PT regardless of relationship occurring in ≥ 5 patients included 
acute kidney injury, general physical health deterioration, tumour pain, urinary tract infection, 
abdominal pain, pneumonia, immune-mediated enterocolitis, intestinal obstruction, renal failure, 
anaemia, cancer pain, pneumonitis, tumor hemorrhage, back pain, diarrhoa, pyrexia, vomiting, 
and sepsis. A total of 52 patients experienced at least 1 treatment-related SAE. Treatment-related 
SAEs that occurred in ≥ 3 patients by PT included immune-mediated enterocolitis (8 patients), 
diarrhoea (5 patients), pneumonitis (5 patients), vomiting (4 patients), colitis (3 patients), and 
immune-mediated nephritis (3 patients).
A total of 182 deaths were reported across the studies as of 20 December 2020. Grade 5 
treatment-related adverse events (AEs) occurred in 5 patients and included hepatitis, death, 
pneumonitis, immune-mediated nephritis, and sepsis.
Data from 464 patients enrolled in the C-700-01, C-550-01, C-750-01/GOG-3028, and C-800-01 

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studies are presented through a data cutoff date of 21 December 2020. Overall, balstilimab has 
been well tolerated. Balstilimab monotherapy or in combination with zalifrelimab or AGEN1181 
has demonstrated meaningful clinical activity across various tumor types and treatment settings.
Rationale for Design, Dose Selection, and Treatment Schedule
Participants will receive VBI-1901 vaccine (optimal dose of 10 μg pp65 content) administered with 
200 μg GM-CSF every 4 weeks until clinical disease progression. This dose schedule is consistent 
with data demonstrating that vaccinating more frequently than monthly can antagonize vaccine-
induced immunity23. Because frequencies of memory HCMV-specific CD4+ and CD8+ T cells in 
healthy, asymptomatic participants are among the highest associated with any viral infection24 the 
first immunization with VBI-1901 is anticipated to maximize the immunological response both by 
increasing the number of HCMV-specific CD4+ and CD8+ T cells and by converting memory cells 
into effector cells. Subsequent monthly vaccinations are intended to maintain high frequencies of 
effector T cells.
It is now well established that tumor-specific T cells can become “exhausted” due to chronic 
stimulation, and that blockade of PD-1 expression on such T cells can prolong their activity and 
confer clinical benefit in a variety of solid human tumors25. Balstilimab has demonstrated 
promising and durable clinical activity in patients with recurrent/metastatic cervical cancer26. 
Whereas vaccination with VBI-1901 is expected to restimulate CMV-specific T cells that can 
recognize and eliminate tumor cells in participants, concurrent and on-going administration of 
balstilimab is anticipated to sustain the activity of the anti-tumor response induced with VBI-1901.
Potential Risks and Benefits
Potential Risks
Successful therapy after vaccination with VBI-1901 may result in transient inflammatory reactions 
in the central nervous system (CNS) as with other modalities targeting other tumor antigens 
expressed by glioblastoma (GBM) tumor cells. In addition, off-target CNS AEs (e.g., increased 
cranial pressure, new neurological deficit, or changes in cognitive function) might also be observed 
as a result of a potential HCMV viremia. However, vaccination against HCMV in participants with 
primary GBM, or adoptive transfer of HCMV-specific T cells to participants with recurrent GBM, 
has not elicited any significant toxicity in early clinical trials with encouraging signs of clinical 
benefit9.
Preclinical studies in mice and rabbits have demonstrated no evidence of inherent toxicity 
associated with VBI-1901, and this has been confirmed in HCMV+ rhesus macaque monkeys 
vaccinated with a monkey-specific version of VBI-1901 with no evidence that boosting of HCMV-
specific immunity induced immune-mediated toxicity.
Extensive clinical safety experience has been generated with balstilimab and several other PD-1 
pathway–blocking monoclonal antibodies to-date27,28. Potential risks of exposure to balstilimab 
include infusion-related reactions and an increase in immune-related adverse events (irAEs), which 
constitute a unique spectrum of AEs that occur via activation of the subject’s immune system and 

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that can sometimes lead to serious and even fatal events27,28. irAEs are events that are drug-related 
and can be explained by an immune phenomenon after other etiologies have been ruled out.
The VBI-1901 vaccine, adjuvant GM-CSF, and anti-PD-1 mAb balstilimab have all been investigated in 
clinical studies previously.
Potential Benefits
Immunotherapy targeting HCMV antigens expressed by GBM tumors could help control residual 
disease after tumor resection, improving quality of life, progression free survival, and overall 
survival.
The importance of immune surveillance in controlling outgrowth of neoplastic transformation is 
well described and consistent with a correlation between prevalence of tumor-infiltrating 
lymphocytes in cancer tissues and favorable prognosis in various malignancies31. Inhibition of the 
PD-1 pathway by blockade of receptor-ligand interactions has been demonstrated to improve 
clinical outcome in a range of malignancies. Blockade of PD-1 in the presence of balstilimab is 
expected to improve anti-tumor responses and tumor control via immune-mediated mechanisms.
2. PARTICIPANT SELECTION
2.1 Eligibility Criteria Specific to the VBI-1901/Balstilimab (AGEN2034) Arm
Participants must meet all eligibility criteria outlined in the master protocol (section 3) and 
complete initial registration (section 4 of master protocol). Once the randomization assignment has 
been received following initial registration, all participants randomized to the VBI-1901/balstilimab 
arm must meet the following criteria prior to participating in the VBI-1901/balstilimab arm of the 
study.
Participants must be willing and able to provide written informed consent for the VBI-1901/balstilimab arm 
of the INSIGhT trial.
2.2 Second INSIGhT Registration: Registration to VBI-1901/Balstilimab Arm
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore®. Registration to the VBI-1901/balstilimab arm must occur following initial registration to 
master INSIGhT protocol and receipt of randomization assignment, and prior to the initiation of 
protocol therapy. Any participant not registered to their protocol specific assigned arm before 
protocol therapy begins will be considered ineligible and registration will be denied.
An investigator will confirm eligibility criteria in section 0of this sub-study appendix and a member 
of the study team will complete the protocol-specific eligibility checklist.

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Following initial registration, any additional laboratory assessments prior to start of treatment will 
not be used to re-confirm eligibility. Refer to section 4 of this appendix for toxicity management 
between registration and start of study treatment.
Following second registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the study 
must be canceled. Registration cancellations must be made in OnCore® as soon as possible.
Registration Process for DF/HCC Institutions
Dana-Farber/Harvard Cancer Center (DF/HCC) Standard Operating Procedure for Human Participant 
Research Titled Participant Protocol Registration (SOP #: REGIST-101) must be followed.
Registration Process for Other Investigative Sites
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute (DFCI) by the 
DFCI Coordinating Center staff. All sites should contact the DFCI Coordinating Center to verify slot 
availabilities. The required forms for registration can be found in Appendix B.
Following registration, participants should begin as soon as feasible. Issues that would cause treatment 
delays should be discussed with the Overall PI. If a participant does not receive protocol therapy following 
registration, the participant’s registration on the study must be canceled. The Study Coordinator should be 
notified of cancellations as soon as possible.
Refer to Appendix B, Section 3.7 for registration details.
3. TREATMENT PLAN
Participants treated on the VBI-1901/balstilimab arm will receive daily radiation (60 Gy in 30 fractions) as 
described in section 3.1 of this appendix, concurrent with monthly intradermal (ID) injections of VBI-1901 
+ GM-CSF and IV infusion every 2 weeks with balstilimab (anti-PD-1 mAb) (see Figure 3). Participants 
will receive adjuvant VBI-1901 + GM-CSF and Balstimimab as part of the overall protocol treatment plan. 
Participants will not receive either concurrent or adjuvant temozolomide. 

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Figure 3:
VBI-1901/Balstilimab (AGEN2034) Study Arm
GBM = glioblastoma; GM-CSF = granulocyte-macrophage colony-stimulating factor; mAb = monoclonal antibody; 
MRI/CT = magnetic resonance imaging/computed tomography; PD-1 = programmed cell death protein 1; TMZ = 
temozolomide
3.1Definition of Standard Radiation Therapy
The participant must undergo magnetic resonance imaging (MRI) based treatment planning (computed 
tomography [CT] with contrast-based planning only if participant unable to undergo MRI). At a minimum, 
the contrast enhancing lesion (and/or surgical cavity) defined on a T1-weighted image (gross tumor volume; 
GTV) must be targeted with a minimum of a 1 cm dosimetric margin expansion to define a planning target 
volume (PTV). This volume must be treated to a prescribed dose of 59.4 Gy in 33 fractions or 60 Gy in 30 
fractions. Treatment with larger volumes to the contrast-enhancing region is acceptable. Treatment or no 
treatment of the T2/fluid-attenuated inversion recovery (FLAIR) abnormality is acceptable. Because this is 
optional, dosimetric expansion and dose-fractionation for the T2/FLAIR volume are not specified here. The 
prescribed dose to the T2/FLAIR volume may not exceed 60 Gy. Radiation therapy must be completed 
within an overall treatment time of less than 28 calendar days. Maximum dose (defined as a volume greater 
than 0.03 cc) to critical structures include: 60 Gy to the brainstem, 56 Gy to the optic chiasm, 55 Gy to the 
optic nerves, and 50 Gy to the retinae.
Participants are permitted to have radiotherapy as described in this section performed at any National Cancer 
Institute (NCI) funded cooperative group site. Prospective Overall PI approval is required for any 
radiotherapy site that is not an NCI funded cooperative group site. Any questions regarding permitted 
radiotherapy sites should be directed to the DFCI Coordinating Center or Overall PI Patrick Y. Wen, MD.
3.2Treatment Regimen – VBI-1901 Administration
10 μg HCMV pp65 was determined to be the optimal dose for VBI-1901. All formulations of study vaccine 
will be administered ID in two sites with GM-CSF on Day 1, and then every 4 weeks (28 days ± 3 days) 
until clinical disease progression (see master protocol section 11.2.3) or until no longer in the best interest of 
the participant. The site of ID injection should be on the inner forearm, upper chest, and upper back, and will 
be standardized across all study sites beginning at first injection. Vaccine should be administered 
intradermally (ID) at two different injection sites (0.1 mL/site), 1 inch or more apart on the same selected 
area (e.g. inner forearm). The site of injection will also alternate each month such that sites are not injected 
with VBI-1901 more frequently than every 2 months. Participants will remain at the study center for 

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30 minutes after vaccination and will be evaluated by study center personnel for AEs before discharge and 2 
weeks post vaccination.
The participants enrolled in the study will receive injections of VBI-1901 every 4 weeks until withdrawal 
criteria are met (toxicity, confirmed clinical disease progression, no longer in best interest of participant).
While in treatment phase, participants will receive the study vaccine every 4 weeks and will come back 
approximately every 2 weeks for balstilimab administration and safety assessments. Immunogenicity 
assessments will be conducted every 3 months (see section Error! Reference source not found.).
3.3 Treatment Regimen – Balstilimab Administration
The anti-PD-1 mAb balstilimab will be administered by IV infusion every 2 weeks concurrent with 
VBI-1901 in the outpatient setting. The first dose of balstilimab will be administered at Day 15, and 
then every 2 weeks until clinical disease progression (see master protocol section 11.2.3) or until no 
longer in the best interest of the participant, as described in section 3.2). Balstilimab will be 
administered using weight-based dosing of 3mg/kg. Sites should follow their institutional standard of 
practice for dose recalculation with weight changes. 
Balstilimab should be administered via IV infusion over 30 (± 15) minutes in the 
VBI-1901/balstilimab arm. Patients must be observed for 10 minutes post-balstilimab infusion for 
infusion-related reactions. Infusions will be followed immediately with a saline flush of the IV line, 
per institutional guidelines. In the VBI-1901/balstilimab arm, balstilimab should be administered 
first. However, the treating neurooncologist may opt to administer VBI-1901 first if desired for 
ease/convenience of the treating neurooncologist and the patient.
3.4Definition of Dose-Limiting Toxicity
The first subject will be immunized with 10 μg/ml VBI-1901 plus GM-CSF concurrent with IV 
infusion of Balstilimab, with a safety review by the study site investigators 7-10 days after the 
first balstilimab dose (a timeframe ensuring the peak of immune response has occurred). The 
safety review of the first subject will be completed prior to further administration of Balstilimab 
and vaccination of the subject and prior to treatment of the next study subject. Safety data 
obtained during the first 10 weeks of study treatment with VBI-1901 plus GM-CSF and 
Balstilimab from the first 6 subjects will be reviewed by a Data and Safety Monitoring Board 
(DSMB).  If none of the six patients experiences a dose-limiting toxicity related to study drugs, 
then the DSMB may recommend that further subjects may be treated without the need for safety 
review of each subject before initiating treatment of another subject. The DSMB will also review 
the study every 3 months.
If  > 2 of the 6 patients experiences a DLT related to study drugs the study will proceed with just 
VBI-1901 alone without Balstilimab.
A DLT is defined as a clinically significant AE considered at least possibly related to VBI-1901 or 
balstilimab and meets any of the criteria below during the first 10 weeks of study treatment 

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(referred to as the concomitant/initiation cycle). If a participant comes off for reasons other than a 
dose-limiting toxicity during the DLT period, he/she will be replaced.
Dose limiting toxicities are defined below. A DLT must have an attribution of possible, probable, 
or definite to VBI-1901 or balstilimab and meet the below criteria. If there is any question 
concerning a DLT, sites should contact the DFCI Coordinating Center to determine participant’s 
DLT status. The Coordinating Center with the Overall PI will make the final decision.

Hematological toxicities will be considered dose limiting if any of the following occur (grade 3 or 4 
lymphopenia will not be considered a DLT):
o
Absolute neutrophil count (ANC) of < 500/mm3 for > 7 days 
o
Platelets < 25,000/mm3 for > 48 hours or platelets < 50,000/mm3 with clinically 
significant bleeding
o
≥ Grade 3 febrile neutropenia (ANC < 1.0 × 109/L and fever > 101°F/38.3°C)
o
Any hematologic toxicity that prevents administration of VBI-1901 or balstilimab for > 
28 days

Non-hematological toxicities will be considered dose limiting if any of the following occur:
o
Inability to complete ≥ 75% of radiotherapy due to toxicity related to or exacerbated by 
VBI-1901 or balstilimab added to Radiation Therapy. 
o
Hy’s Law (elevated ALT or AST by 3-fold or greater above the upper limit of normal 
together with elevation of their serum total bilirubin of greater than 2× the upper limit of 
normal, without findings of cholestasis and no other explanation for these elevations)
o
Grades 3-4 severity, with the following exceptions:

Grade 3 nausea/vomiting or diarrhea for less than 72 hours with adequate antiemetic 
and other supportive care 

Grade 3 or higher electrolyte abnormality that lasts up to 72 hours, is not clinically 
complicated, and resolves spontaneously or responds to conventional medical 
interventions 

Grade 3 or higher amylase or lipase that is not associated with symptoms or clinical 
manifestations of pancreatitis  

Grade 3 fatigue for greater than 1 week 
Death
The occurrence of any Grade 5 event or any two Grade 4 events considered at least possibly related to VBI-
1901 or balstilimab and unexpected with VBI-1901 or balstilimab will trigger suspension of accrual and 
performance of a thorough safety review prior to resuming enrollment. 
3.5General Concomitant Medication and Supportive Care Guidelines
Participants must be instructed not to take any additional medications (including over-the-counter 
products) during the trial without prior consultation with the investigator. All medications taken 
from date of initial consent and up to 30-day follow-up contact should be recorded. If concomitant 
therapy must be added or changed, including over-the-counter medications or alternative therapies, 
the reason and name of the drug/therapy should be recorded.
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
participant are allowed, including drugs given prophylactically (e.g., antiemetics) with the 
following exceptions:

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
Herbal preparations/medications are not allowed throughout the study. These herbal 
medications include, but are not limited to: St. John’s wort, Kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng. 
Participants should stop using any herbal medications 7 days prior to first dose of study 
drug.

Immunosuppressants other than corticoids, are not allowed in the study.

Febrile neutropenia may be managed according to the local institution's guidelines. 
Measures may include appropriate laboratory testing, including blood and urine cultures and 
the institution of broad-spectrum antibiotics. If a source for the fever is not identified or the 
fever resolves when the neutrophil count recovers, antibiotics may be discontinued and the 
participant observed.

Granulocyte colony-stimulating factor (G-CSF): Routine prophylactic use of G-CSF is not 
permitted, except as indicated in the study protocol. However, therapeutic use in 
participants with serious neutropenic complications, such as sepsis, may be considered at 
the investigator’s discretion.

Pneumocystis jiroveci pneumonia (PJP) prophylaxis: Since participants with GBM are at 
increased risk of developing PJP, especially if they are on corticosteroids, prophylaxis for 
PJP may be considered per institutional practice.

Surgery: If neurosurgical management is required for reasons not due to tumor progression, 
these procedures must be documented, including the indications for surgery, the operative 
note, and pathology report.

Other anticancer or experimental therapies: No other experimental anticancer therapy of any 
kind is permitted during the study treatment period. No other drug under investigation may 
be used concomitantly with the study drug.

Other concomitant medications: Therapies considered necessary for the well-being of the 
participant may be given at the discretion of the investigator. Other concomitant 
medications should be avoided except for analgesics, chronic treatments for concomitant 
medical conditions, or agents required for life-threatening medical problems. All 
concomitant medications must be recorded. 
Rescue Medications, Treatments, and Procedures
Participants will be closely monitored. Any signs of brain edema will be rapidly observed and therapeutic 
options will be provided. Of note, successful therapy after vaccination with VBI-1901 might result in 
transient inflammatory reactions in the CNS as with other modalities targeting other tumor antigens 
expressed by GBM tumor cells. If the participant requires hospitalization for presumed treatment-related 
effect, then the local clinician may give up to 8 mg dexamethasone to treat brain edema. Increased cranial 
pressure, new neurological deficit, or changes in cognitive function not responsive to up to 8 mg 
dexamethasone will require immediate imaging and, if any evidence of involvement of the brain outside of 
the region of tumor, treatment with ganciclovir and higher dose steroids to eliminate any potential HCMV 
viremia and inflammatory immune response that might be responsible for the observed AEs.
3.6Criteria for Taking a Participant Off Protocol Therapy

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Duration of therapy will depend on individual response, evidence of disease progression, and tolerance. In 
the absence of treatment delays due to AE(s), treatment may continue on the VBI-1901/balstilimab arm until 
one of the following criteria applies:

Disease progression (see section 11 of main INSIGhT protocol)

Intercurrent illness that prevents further administration of treatment

Unacceptable AE(s)

Participant demonstrates an inability or unwillingness to comply with the medication regimen and/or 
documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant’s condition render the participant unacceptable for 
further treatment in the judgment of the treating investigator 

Cases of pregnancy that occur during maternal exposures to VBI-1901/balstilimab either directly or 
through exposure of partner should be reported. If a participant is determined to be pregnant 
following VBI-1901/balstilimab initiation, she must discontinue study treatment immediately. Data 
on fetal outcome and breast-feeding will be collected for regulatory reporting and product safety 
evaluation (see section 0).
Participants will be removed from the protocol therapy when any of these criteria apply. The reason for 
removal from protocol therapy, and the date the participant was removed, must be documented in the case 
report form (CRF). Alternative care options will be discussed with the participant.
An Office of Data Quality (ODQ) Treatment Ended/Off Study Form will be filled out when a participant is 
removed from protocol therapy. This form can be found on the ODQ website or obtained from the ODQ 
registration staff.
In the event of unusual or life-threatening complications, treating investigators must immediately notify the 
Overall PI, Patrick Y. Wen, MD, at 617-632-2166 or pwen@partners.org. 
3.7Duration of Follow Up
Participants will be followed until death with scheduled clinic visits, telephone contact, or medical record 
review. Participants removed from protocol therapy for unacceptable AE(s) will be followed until resolution 
or stabilization of the AE. Refer to section Error! Reference source not found. study calendar within this 
appendix for follow-up requirements and time points.
3.8Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death
The reason for taking a participant off study, and the date the participant was removed, must be documented 
in the CRF.
An ODQ Treatment Ended/Off Study Form will be filled out when a participant comes off study. This form 
can be found on the ODQ website or obtained from the ODQ registration staff. 

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4. DOSING DELAYS/DOSE MODIFICATIONS
No modifications of VBI-1901 are planned to adjust a participant’s dose. If an ID injection is imperfect (e.g., 
subcutaneous injection) then it will be documented but no additional vaccine will be administered. If the 
investigator or qualified designee determines that the participant’s health on the day of administration 
temporarily precludes administration, the visit will be rescheduled within the allowed interval for this visit 
(+/-3 days).
No dose reductions are allowed for balstilimab. Each patient will stay on the dose levels assigned in 
the trial unless treatment needs to be stopped. Intra-patient dose reductions or dose escalations of 
balstilimab are not permitted.
4.1
Anticipated Toxicities
In order for an event to be expected (known correlation to study drug) for the purposes of AE reporting, the 
event must be included in this section.
Anticipated Toxicities for Radiation Therapy
A list of AEs of all grades suspected to be radiation therapy treatment related, organized by Common 
Terminology Criteria for Adverse Events (CTCAE) v5.0 category, includes:

EAR AND LABYRINTH DISORDERS – external ear inflammation; other: dryness of ear 
canal; other: hardening of ear canal wax; external ear pain; other: hearing loss

ENDOCRINE DISORDERS - other: hypophysitis, or hypopituitarism

EYE DISORDERS – cataract; other: decreased vision

GASTROINTESTINAL DISORDERS – nausea; vomiting

GENERAL DISORDERS – fatigue

INJURY, POISONING AND PROCEDURAL COMPLICATIONS – injury other: optic nerve

INVESTIGATIONS –lymphocyte count decreased

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS – generalized muscle 
weakness

NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED – treatment related secondary 
malignancy

NERVOUS SYSTEM DISORDERS – headache; seizure; memory impairment; cognitive 
disturbance; somnolence; dysgeusia; central nervous system necrosis

PSYCHIATRIC DISORDERS – personality change

SKIN AND SUBCUTANEOUS TISSUE DISORDERS – scalp pain; other: scalp redness; 
alopecia
Suspected & Anticipated Toxicities for VBI-1901 and GM-CSF
A list of AEs of all grades suspected to be VBI-1901 treatment related according to review of the 
Investigator’s Brochure, experience with other drugs in the same class, and preclinical data, includes:

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Very Common (≥10%):

Injection site pain

Injection site erythema

Injection site pruritus

Fever

Fatigue

Headache

Nausea

Myalgia

Arthralgia
Common (1-10%):

Injection site induration

Injection site rash

Chills

Vomiting
Some participants taking GM-CSF (LEUKINE®) may experience unwanted side effects, most of 
which are mild to moderate and not serious.
Some of the more common side effects include bone pain, feeling like participant has the flu, 
feeling tired or weak, muscle aches, diarrhea, or stomach upset. Participants may also get a low 
fever (less than 100.5°F or 38°C) about 1 to 4 hours after an injection, or they may have swelling, 
redness, and/or discomfort where GM-CSF is injected.
Some side effects or symptoms may be serious. These may be due to GM-CSF, the underlying 
illness, or other treatments participants may have received.
Participants will be instructed to contact the study team immediately if:

They develop a high fever (over 100.5°F or 38°C).

They notice any signs of infection including chills, sore throat, or congestion (such as a 
stuffy nose).

They have trouble breathing, or develop wheezing, fainting, extensive skin rash, hives, 
or feel they are having an allergic reaction.

They experience sudden weight gain or other signs of fluid build-up such as swollen 
legs or feet.

They develop chest pain, chest discomfort, or a rapid or irregular pulse.
Suspected & Anticipated Toxicities for Balstilimab

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Immuno-oncology agents such as balstilimab are associated with irAEs. Early recognition and 
management of irAEs may mitigate severe toxicity. A list of irAEs of all grades suspected to be 
balstilimab treatment related are reviewed in the Investigator’s Brochure. Investigators should 
monitor patients closely for potential irAEs, which may manifest at the earliest after weeks of 
treatment. Such events may consist of persistent rash, diarrhoea, colitis, encephalitis, arthritis, 
endocrine disorders, cardiomyopathy, or uveitis and other inflammatory eye conditions, among 
others. Management algorithms have been developed to assist Investigators in assessing and 
managing the following groups of irAEs: gastrointestinal, pulmonary, dermatological, renal, 
hepatic, neurological, and endocrine, among others.
AEs (both nonserious and serious) associated with drug exposure and consistent with an immune 
phenomenon may represent an immunologic etiology. These irAEs may be predicted based on the 
nature of the study drugs, their mechanism of action, and reported experience with 
immunotherapies that have a similar mechanism of action. An irAE can occur shortly after the first 
dose or several months after the last dose of study drug. Particular attention should be paid to AEs 
that may be suggestive of potential irAEs.
4.2
Immune Related Management Guidelines
Dermatological Immune-Related Adverse Events
Rule out non-immune causes, if non-immune cause is identified, treat accordingly, and continue 
therapy.
Table 2: Dermatological Immune-Related Adverse Event Management Algorithm
Dermatological Immune-Related Adverse Events
Grade of Rash 
(NCI- CTCAE 
v5.0)
Management
Follow-Up

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Grade 1–2
Covering ≤ 30% body 
surface area.
 Symptomatic 
therapy (eg, 
antihistamines, 
topical 
corticosteroids).
 Continue BAL therapy 
per protocol.
 If persists > 1 to 2 weeks or recurs, consider 
skin biopsy.
 Delay BAL therapy.
 Consider 0.5 to 1 mg/kg/day 
methylprednisolone intravenous (IV) or oral 
equivalent. Once improving, taper 
corticosteroids over at least 1 month; 
consider prophylactic antibiotics for 
opportunistic infections; and resume BAL 
therapy per protocol.
 If worsens: treat as Grade 3–4.
Grade 3–4
Covering > 30% body 
surface area; life- 
threatening 
consequences.
 Discontinue BAL 
therapy per 
protocol.
 Consider skin biopsy.
 Dermatology consult
 1 to 2 mg/kg/day 
methylprednisolone IV
or IV equivalent.
Abbreviations: BAL: balstilimab; NCI-CTCAE: National Cancer Institute Common Terminology Criteria for 
Adverse Events.

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Gastrointestinal Immune-Related Adverse Events
Rule out non-immune causes, if non-immune cause is identified, treat accordingly, and continue 
therapy. Opiates/narcotics may mask symptoms of perforation. Infliximab should not be used in 
cases of perforation or sepsis.
Table 3: Gastrointestinal Immune-Related Adverse Event Management Algorithm
Gastrointestinal Immune-Related Adverse Events
Severity of Diarrhea/Colitis 
(NCI-CTCAE v5.0)
Management
Follow-Up
Grade 1
Diarrhea: < 4 stools/day 
over baseline.
Colitis: asymptomatic.
 Continue BAL therapy per protocol.
 Symptomatic treatment including 
hydration, electrolyte replacement, 
dietary changes (eg, American 
Dietetic Association colitis diet), and 
loperamide for 2 to 3 days
 Close monitoring for 
worsening 
symptoms.
 Educate patient to 
report worsening 
symptoms immediately.
 If worsens: treat as Grade 2 or 
3– 4.
 Fecal lactoferrin and 
calprotectin can be considered 
to differentiate functional vs 
inflammatory diarrhea
Grade 2
Diarrhea: 4 to 6 stools per day 
over baseline; IV fluids 
indicated < 24 h; not 
interfering with activities of 
daily living (ADL).
Colitis: abdominal pain; blood 
in stool
 Delay BAL therapy per protocol.
 Delay treatment per protocol.
 Symptomatic treatment.
 Consider gastrointestinal (GI) consult.
 Work-up to rule out infectious 
etiology (Clostridium difficile toxin, 
stool cultures, etc.)
 Consider imaging computed 
tomography (CT) scan of abdomen 
and pelvis, GI endoscopy with biopsy
 If Immune Diarrhea/colitis - start
methylprednisolone or 
equivalent with initial dose of 1 
mg/kg/day
 If improves to Grade 1: 
resume treatment per 
protocol.
 When symptoms improve to 
Grade 1, taper corticosteroids 
over at least 1 month; resume 
treatment per protocol.
 If worsens or persists > 2 to 3 
days with oral corticosteroids: 
treat as Grade 3–4.
 Consider adding tumor 
necrosis factor (TNF)-alpha or 
integrin blockers.
Grade 3 to 4
Diarrhea (Grade 3): ≥ 7 
stools per day over 
baseline; incontinence; IV 
fluids
≥ 24 h; interfering with ADL.
Colitis (Grade 3): 
severe abdominal 
pain, medical 
intervention indicated, 
peritoneal signs.
Grade 4: life-threatening, 
 Discontinue treatment per protocol.
 Work-up to rule out alternate 
causes and infectious etiology
 Consider imaging (CT scan of 
abdomen and pelvis, GI 
endoscopy with biopsy)
 1 to 2 mg/kg/day 
methylprednisolone IV or 
equivalent.
 Consider GI consult.
 Consider inpatient care.
 Consider lower endoscopy. Note: 
Colonoscopy is contraindicated 
for Grade 4.
 If improves: continue 
corticosteroids until Grade 1, 
then taper over at least 1 month.
 If persists >1 to 2 days or recurs 
after improvement: add TNF- 
alpha or integrin blockers. 
Note: The use of integrin 
blockers (eg, vedolizumab)
may be considered in 
patients refractory to TNF-
alpha blockers and/or 
contraindication to use 
them.

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perforation
Abbreviations: BAL: balstilimab; NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Event

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Pulmonary Immune-Related Adverse Events
Rule out non-inflammatory causes, if non-inflammatory cause is identified, treat accordingly, 
and continue therapy per protocol. Evaluate with imaging and pulmonary consultation.
Table 4: Pulmonary Immune-Related Adverse Event Management Algorithm
Pulmonary Immune-Related Adverse Events
Grade of Pneumonitis 
(NCI-CTCAE v5.0)
Management
Follow-Up
Grade 1
Radiographic changes only.
 Consider delay of BAL 
therapy per protocol.
 Monitor for symptoms 
every 2 to 3 days.
 Consider pulmonary and 
infectious disease 
consults. Consider chest 
computed
tomography (CT) with 
contrast.
 Re-image every ≥3 weeks.
 If worsens: treat as Grade 2 or 
Grade 3–4.
Grade 2
Mild to moderate new 
symptoms
 Delay BAL therapy per 
protocol.
 Pulmonary and 
infectious disease 
consults.
 Monitor symptoms daily;
consider hospitalization.
 1 mg/kg/day 
methylprednisolone 
intravenous (IV) or oral 
equivalent.
 Consider bronchoscopy, lung 
biopsy.
 Re-image every 1 to 3 days.
 If improves: when symptoms return to 
near baseline, taper corticosteroids 
over at least 1 month, then resume 
BAL therapy per protocol, and 
consider prophylactic antibiotics.
 Consider chest CT with contrast.
 If not improving after 2 to 3 days 
of corticosteroids: treat as Grade 
3–4.
Grade 3–4
Severe new symptoms; new/ 
worsening hypoxia;
life- threatening.
 Discontinue BAL 
therapy per 
protocol.
 Hospitalize.
 Pulmonary and 
infectious disease 
consults.
 2 to 4 mg/kg/day 
methylprednisolone IV or IV 
equivalent.
 Add prophylactic antibiotics 
for opportunistic infections.
 Consider bronchoscopy, lung 
biopsy.
 If improves to baseline: taper 
corticosteroids over at least 6 
weeks.
 If not improving after 48 hours or 
worsening: add additional 
immunosuppression (eg, infliximab, 
cyclophosphamide, IV 
immunoglobulin, mycophenolate 
mofetil).
Abbreviations: BAL: balstilimab; NCI-CTCAE: National Cancer Institute Common Terminology Criteria for 
Adverse Events.

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Hepatic Immune-Related Adverse Events
Rule out non-inflammatory causes, if non-inflammatory cause is identified, treat accordingly, 
and continue therapy per protocol. Consider imaging for obstruction.
Table 5: Hepatic Immune-Related Adverse Event Management Algorithm
Hepatic Immune-Related Adverse Events
Grade of Liver Test Elevation 
(NCI-CTCAE v5.0)
Management
Follow-Up
Grade 1
AST or ALT >upper limit of 
normal (ULN) to 3 × ULN
 Continue BAL therapy per 
protocol with close 
monitoring.
 Continue liver function tests (LFT) 
monitoring 1 to 2 times/week
 If worsens: treat as Grade 2 or 
Grade 3–4.
Grade 2
AST or ALT >3 to ≤5 × ULN
 Delay BAL therapy per 
protocol.
 Increase frequency 
of monitoring to 
every 3 days.
 Patients should stop 
unnecessary medications, 
known hepatotoxic drugs 
and alcohol consumption
 If returns to baseline: resume 
routine monitoring; resume BAL 
therapy per protocol.
 If elevations persist > 5 to 7 days or 
worsen: 0.5 to 1 mg/kg/day 
methylprednisolone intravenous (IV) 
or oral equivalent. When liver 
function tests (LFT) return to Grade 1 
or baseline, taper corticosteroids over 
at least 1 month, consider 
prophylactic antibiotics for 
opportunistic infections,
and resume BAL therapy per protocol.
Grade 3–4
AST or ALT >5 × ULN
 Consider 
discontinuation of BAL 
per protocol.
 Increase frequency 
of monitoring to 
every 1 to 2 days.
 1 to 2 mg/kg/day 
methylprednisolone 
intravenous IV or oral 
equivalent*.
 Inpatient care and 
hepatology 
consult.
 Consider obtaining magnetic 
resonance 
imaging/computed 
tomography scan of liver 
and liver biopsy if clinically
warranted.
 If returns to Grade ≤ 2: taper 
corticosteroids over at least 1 
month.
 If corticosteroid refractory or does 
not improve in 3 days: consider 
mycophenolate mofetil (0.5 to 1 g 
every 12 hours). If returns to Grade
≤ 1 and after completion of a 
steroid taper, consider stopping 
mycophenolate at the same time.
 If no response within an additional 3 
to 5 days, consider other 
immunosuppressants per local 
guidelines.

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AST or ALT >3 ULN + Bilirubin
>2 × ULN
 Discontinue BAL per 
protocol.
 Consider inpatient care
 LFT monitoring every 2 
to 3 days
 1 to 2 mg/kg/day 
methylprednisolone IV 
or oral equivalent.
Patients should stop 
unnecessary
medications, known 
hepatotoxic drugs and 
alcohol consumption
 Consider obtaining MRI/CT 
scan of liver and liver biopsy if 
clinically warranted.
 If returns to Grade ≤ 1: taper 
corticosteroids after at least 1 month 
of full cycle treatment
 If corticosteroid refractory or no 
improvement after 3 days, consider 
mycophenolate mofetil (0.5 to 1 g every 
12 h). If returns to Grade ≤ 1 and after 
completion of steroid taper, consider 
stop of mycophenolate at the same 
time.
Anti-tumor necrosis factor-alfa agents 
should not be used for hepatitis.
Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; BAL: balstilimab; CT: computer 
tomography; MRI: magnetic resonance imaging; NCI-CTCAE: National Cancer Institute Common Terminology 
Criteria for Adverse Events.
*The recommended starting dose for Grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV.

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Endocrine Immune-Related Adverse Events
Rule out non-inflammatory causes, if non-inflammatory cause is identified, treat accordingly, and 
continue therapy per protocol. Consider visual field testing, endocrinology consultation, and 
imaging.
Table 6: Endocrine Immune-Related Adverse Event Management Algorithm
Endocrine Immune-Related Adverse Events
Endocrine Disorder
Management
Follow-Up
Asymptomatic 
hypothyroidism
 Continue BAL therapy per 
protocol.
 Monitor thyroid stimulating 
hormone (TSH), free thyroxine 
(FT4) every 4 to 6 weeks
 If TSH >10 or normal/high 
TSH and low FT4 consider 
oral levothyroxine at 
approximately 1.6 mcg/kg 
daily until TSH returns to 
normal levels
 Once adequately treated, 
monitor thyroid function 
every 4 to 6 weeks while on 
BAL, or as needed for 
symptoms
 Extreme elevations of TSH can 
be seen in the recovery phase 
of thyroiditis and can be 
watched in asymptomatic 
patients to determine whether 
there is recover to normal 
within 3 to 4 weeks
Symptomatic hypothyroidism
 Continue BAL therapy per 
protocol.
 Monitor TSH every 4 to 6 
weeks
 Endocrine consultation
 Start oral levothyroxine at 
approximately 1.6 mcg/kg 
daily until TSH returns to 
normal levels
 Exclude concomitant adrenal 
insufficiency
 Once adequately treated, 
monitor thyroid function 
every 4 to 6 weeks while on 
BAL, or as needed for 
symptoms
 Adrenal dysfunction, if present, 
must always be replaced before 
thyroid therapy is initiated.
Hyperthyroidism
 Endocrine consultation if 
symptomatic
 Consider b-Blocker (eg, 
atenolol, propranolol) 
for symptomatic relief.
 Restart therapy when Grade
≤ 2.
 Check thyroid functions every 
2 to 3 weeks.
 If Graves’ disease, treat 
with methimazole or 
radioactive iodine / surgery.
 For severe symptoms or 
concern for thyroid storm
 Monitor thyroid function 
every 4 to 6 weeks
 If resolved, not further 
treatment for 
hyperthyroidism
 Hyperthyroidism often evolves to 
hypothyroidism which will require 
thyroid hormone therapy.
 In case of steroid therapy - 
when symptoms return to 
near baseline, taper 
corticosteroids over 1 to 2 
weeks.

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Endocrine Immune-Related Adverse Events
Endocrine Disorder
Management
Follow-Up
hospitalize patient and initiate
prednisone 1 to 2 mg/kg/day 
or equivalent
Hypophysitis
 Delay protocol treatment 
until patient is stabilized on 
replacement hormones.
 Evaluate ACTH, cortisol 
(AM), TSH, FT4.
 Consider brain magnetic 
resonance imaging (MRI) ± 
contrast with 
pituitary/sellar cuts if 
symptomatic.
 Endocrine consultation.
 Consider visual field testing, 
hormonal supplementation 
as 
needed 
(for 
hypothyroidism,
adrenal insufficiency).
 In case of acute severe 
symptoms, carefully consider 
prednisone 1 to 2 mg/kg oral
daily or intravenous (IV) until 
symptoms resolve.
 Follow FT4 for thyroid hormone 
replacement titration.
 Always start corticosteroids first (if 
needed) when planning hormone 
replacement therapy.
 In case of steroid therapy, when 
symptoms return to near baseline, 
taper corticosteroids over at least to 
2 weeks.
 Patients with adrenal insufficiency 
may need to continue 
corticosteroids with 
mineralocorticoid component.
 No abnormal laboratory tests 
and/or pituitary MRI scan but 
symptoms persist: Repeat 
laboratory tests in 1 to 3 
weeks, MRI in 1 month.
Suspicion of adrenal crisis (eg, 
severe dehydration, 
hypotension, shock out of 
proportion to current illness)
 Delay or discontinue BAL therapy per protocol.
 Rule out sepsis.
 Stress dose of IV corticosteroids with mineralocorticoid activity.
 IV fluids.
 Consult endocrinologist.
 If adrenal crisis ruled out, patients with adrenal insufficiency may need 
to continue corticosteroids with mineralocorticoid component.
Abbreviations: ACTH: adrenocorticotropic hormone; BAL: balstilimab.

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Renal Immune-Related Adverse Events
Rule out non-inflammatory causes, if non-inflammatory cause is identified, treat accordingly, 
and continue therapy per protocol.
Table 7: Renal Immune-Related Adverse Event Management Algorithm
Renal Immune-Related Adverse Events
Grade of Creatinine 
Elevation (NCI- 
CTCAE v5.0)
Management
Follow-Up
Grade 1
Creatinine > upper limit of 
normal (ULN) and > than 
baseline but ≤ 1.5 ×
baseline.
 Continue BAL per 
protocol.
 Monitor creatinine weekly
 If returns to baseline: resume 
routine creatinine monitoring per 
protocol.
 If worsens: treat as Grade 2 or Grade 3–4.
Grade 2-3
Creatinine > 1.5 ×
baseline to ≤ 6 × ULN.
 Delay BAL per protocol.
 Rule-out alternate cause
 Monitor creatinine every 
2 to 3 days
 Follow urine protein/ 
creatinine ratio every 3 to 
7 days.
 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or 
oral equivalent.
 Consider renal biopsy
 If returns to Grade 1: taper corticosteroids 
over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume BAL and routine 
creatinine monitoring per protocol.
 If elevations persist > 7 days or worsen: 
treat as Grade 4.
Grade 4
Creatinine > 6 × ULN.
 Discontinue BAL 
therapy per 
protocol.
 Monitor creatinine daily.
 1.0 to 2.0 mg/kg/day 
methylprednisolone 
intravenous (IV)or IV 
equivalent.
 Consult nephrologist.
 Consider renal biopsy
 If returns to Grade 1: taper corticosteroids 
over at least 1 month and add prophylactic 
antibiotics for opportunistic infections.
 If kidney injury remains Grade > 2 after 4 
to 6 weeks of steroids consider adding 
one of the following: azathioprine, 
cyclophosphamide, cyclosporine,
mycophenolate mofetil, tumor 
necrosis factor -alpha blockers.
Abbreviations: BAL: balstilimab; NCI-CTCAE: National Cancer Institute Common Terminology Criteria for 
Adverse events.

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Neurological Immune-Related Adverse Events
Rule out non-inflammatory causes, if non-inflammatory cause is identified, treat 
accordingly, and continue therapy per protocol.
Table 8: Neurological Immune-Related Adverse Event Management Algorithm
Neurological Immune-Related Adverse Events
Grade of Neurological 
Toxicity (NCI CTCAE 
v5.0)
Management
Follow-Up
Grade 1
Asymptomatic or mild 
symptoms; intervention 
not indicated.
 Continue BAL therapy 
per protocol.
 Continue to monitor patient.
 If worsens: treat as Grade 2 or 
Grade 3–4.
Grade 2
Moderate symptoms; 
Limiting instrumental 
activities of daily life (ADL).
 Delay BAL therapy per 
protocol.
 Treat symptoms per 
local guidelines.
 Consider 0.5 to
1.0 mg/kg/day 
methylprednisolone
intravenous (IV) or oral 
equivalent.
 If returns to baseline: 
resume BAL therapy per 
protocol.
 If worsens: treat as Grade 3 to 4.
Grade 3-4
Severe symptoms; limiting 
self-care activities of daily 
life; life- threatening.
 Discontinue BAL therapy 
per protocol.
 Obtain neurology consult.
 Treat symptoms per 
local guidelines.
 1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
IV equivalent.
 Add prophylactic antibiotics 
for opportunistic infections.
 If improves to Grade 2: 
taper corticosteroids over at 
least 1month.
 If worsens or atypical presentation: 
consider IV immunoglobulin or other 
immunosuppressive therapies per 
local guidelines.
Abbreviations: BAL: balstilimab; NCI-CTCAE: National Cancer Institute Common Terminology Criteria 
for Adverse Events.
4.3
Dose Modifications/Delays for Balstilimab 
Immune checkpoint inhibitors (ICIs), such as Balstilimab, are the standard of care for the treatment of 
several cancers. While these immunotherapies have improved patient outcomes in many clinical settings, 
they bring accompanying risks of toxicity, specifically immune-related adverse events (irAEs).  While 
management varies according to the organ system affected, in general, no dose reductions are allowed.  
Each patient will stay on the dose level and/or combination assigned in the trial unless treatment needs to 
be stopped.  Balstilimab therapy should be continued with close monitoring for grade 1 toxicities, except 
for some neurologic, hematologic, and cardiac toxicities. Therapy may be suspended for most grade 2 
toxicities, with consideration of resuming when symptoms revert to grade 1. Corticosteroids may be 
administered. Grade 2-4 toxicities would warrant suspension of Balstilimab and the initiation of high-

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dose corticosteroids. Corticosteroids should be tapered over the course of at least 4-6 weeks. Some 
refractory cases may require other immunosuppressive therapy. In general, permanent discontinuation of 
Balstilimab is recommended with grade 3-4 toxicities, except for endocrinopathies that have been 
controlled by hormone replacement.  More specific treatment guidelines based on organ system and 
toxicity diagnosis, updated by ASCO in 2021, can be found 
here:https://ascopubs.org/doi/full/10.1200/JCO.21.01440.
4.4
Potential Overlapping Toxicities From Radiotherapy, VBI-1901 and 
Balstilimab
While the toxicities from radiotherapy, VBI-1901, and Balstilimab are largely non-overlapping, cerebral 
edema and fatigue are potentially overlapping toxicities. 
Cerebral edema
Grade 3 or greater cerebral edema developing during irradiation should be treated with high dose 
corticosteroids per institutional guidelines and all treatment should be held until improvement to baseline. 
Radiotherapy, VBI-1901 and Balstilimab may be resumed together with corticosteroids. If grade 3 
cerebral edema recurs, VBI-1901 and balstilimab should be discontinued. When clinically safe, 
radiotherapy should be resumed with corticosteroids to complete the course of treatment.
Grade 3 or greater cerebral edema during treatment with VBI-1901 and Balstilimab should be treated with 
high dose corticosteroids per institutional guidelines and all treatment should be held until improvement 
to baseline. VBI-1901 and Balstilimab may be resumed together with corticosteroids. If grade 3 cerebral 
edema recurs, VBI-1901 and balstilimab should be discontinued. 
Fatigue
Fatigue is common in patients receiving radiotherapy and to a lesser extent Balstilimab. 
During radiotherapy, patients with grade 3 or greater fatigue should have all treatment held until recovery 
to grade 2 when treatment may be resumed. 
During treatment with VBI-1901 and Balstilimab alone, patients with grade 3 or greater fatigue should 
have all treatment held until recovery to grade 2 when treatment may be resumed. If grade 3 fatigue 
recurs Balstilimab will be discontinued.  VBI-1901 may be continued.
5. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS
Adverse event monitoring and reporting is a routine part of every clinical trial. Safety data including 
solicited and unsolicited AEs and laboratory tests results will be obtained from the first injection until the 
final study visit. The following list of reported and/or potential AEs (section 4.1 of this appendix) and the 
characteristics of an observed AE (section 0 of this appendix) will determine whether the event requires 
expedited reporting in addition to routine reporting.
This section specifies reporting requirements to the Food and Drug Administration (FDA), Overall 
PI/Coordinating Center, DF/HCC Institutional Review Board (IRB), and manufacturer as applicable.
5.1 Expected Toxicities

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Refer to section 4.1 of this appendix for expected toxicities for assigned study treatment arm.
5.2 Adverse Event Characteristics

Adverse Event (AE) Definition:
An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical 
condition in a clinical investigation participant administered an investigational (medicinal) 
product and that does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of investigational product, whether or not 
considered related to the investigational product.
Abnormal laboratory values or diagnostic test results constitute AEs only if
they induce clinical signs or symptoms or require treatment or further diagnostic tests.
Adverse events experienced by participants will be collected and reported from initiation of study 
medication, throughout the study, and within 30 days of the last dose of study medication. Participants 
who experience an ongoing AE related to a study procedure and/or study medication beyond 30 days will 
continue to be contacted by a member of the study team until the event is resolved, stabilized or 
determined to be irreversible by an investigator. 

CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI CTCAE version 5.0 will be utilized for AE reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can 
be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

For expedited reporting purposes only:
-
AEs for the agent(s) that are listed in section 4.1 of this appendix should be reported only if 
the AE varies in nature, intensity or frequency from the expected toxicity information which 
is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in the next 
section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-Specific 
Expedited Adverse Event Reporting Exclusions.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.

Serious Adverse Event (SAE) Definition:
A SAE is any AE, occurring at any dose and regardless of causality that:
o
Results in death
o
Is life-threatening (i.e., in the opinion of the Investigator, the participant is at 
immediate risk of death from the AE);

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o
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
o
Results in persistent or significant disability/incapacity (a substantial disruption of 
the participant’s ability to conduct normal life functions);
o
Is a congenital anomaly/birth defect;
o
Constitutes an important medical event. Important medical events are defined as 
those occurrences that may not be immediately life threatening or result in death, 
hospitalization, or disability, but may jeopardize the participant or require medical 
or surgical intervention to prevent one of the other outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether such an 
AE should be considered serious.
5.3 Solicited Adverse Events
Adverse events in this list will be monitored after each injection of VBI-1901. They will be 
assessed for severity and seriousness and recorded in the CRF.

Injection Site Reaction

Pain (pain without touching) at injection site;

Tenderness (pain when area is touched) at injection site;

Erythema/redness at injection site;

Swelling at injection site;

Induration at site injection;

Itching at injection site.
For injection site reactions: it is permitted to add an ice pack to injection sites for redness, 
swelling, and pain, if needed. If further treatment is required, a topical antihistamine is permitted.
Systemic Reaction

Fever (oral temperature > 37.6 C);

Chills;

Arthralgia;

Headache;

Myalgia;

Nausea;

Vomiting;

Fatigue/Asthenia;

Acute systemic allergic reaction;

Rash.

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Grading of Local Solicited Adverse Events
Solicited AEs for VBI-1901 will be graded according to the FDA Guidance for Industry Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials (2007) - see section 9.
Reactogenicity
Reactions to vaccine will be assessed 30 minutes following each immunization and during the 
28 following days. Reactions to vaccine will be assessed at each visit and recorded in the CRF 
for the corresponding visit. If a reaction to vaccine meets the criteria of an SAE, the investigator 
or delegates will complete and submit an SAE report form (see also section 0).
For the purpose of standardizing recording of local reactions:

The largest diameter of redness or swelling at the injection site will be recorded.

Study participants will be asked to indicate the maximum pain they experience at the 
injection site on a scale from 0 to 3 (0: no pain 1: Mild discomfort to touch 2: 
Discomfort with movement 3: Significant discomfort at rest).
For injection site reactions: it is permitted to add an ice pack to injection sites for redness, 
swelling, and pain if needed. If further treatment is required, a topical antihistamine is permitted.
5.4 Expedited Adverse Event Reporting
Investigators must report to the Overall PI any SAE that occurs after the initial dose of study 
treatment, during treatment, or within 30 days of the last dose of treatment.
For multi-institution studies where a DF/HCC investigator is serving as the Overall PI, each 
participating institution must abide by the reporting requirements set by the DF/HCC. This 
applies to any medical event that is Serious, Unexpected, and there is a Reasonable Possibility 
(i.e., possible, probable, or definitive attribution) the Adverse Event is related to the study 
intervention.
Expedited Reporting Guidelines to Overall PI/Coordinating Center & Drug Company 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy.
Other investigative sites outside of DF/HCC will report AEs to their respective IRB according to 
the local IRB’s policies and procedures in reporting AEs. A copy of the AE form should be 
forwarded to the Overall PI within the timeframes detailed in the table below. The Overall PI 
will submit AE reports from outside institutions to the DFCI OHRS according to the DFCI IRB 
policies and procedures in reporting AEs. 

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In addition to local IRB reporting policies, all sites are required to follow Error! Reference 
source not found. expedited reportable AE requirements:

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Table 9
Expedited AE Reporting Requirements to VBI Vaccines Inc. & DFCI Coordinating Center 
Adverse Event Characteristics
Reporting Requirement
Seriousness
Toxicity
Known 
Correlationf
Attribution to VBI-
1901/Balstilimab
VBI Vaccines Inc.
-
Via Fax or emailc 
Use Reportable AE Coversheet c and 
Medwatch 3500A d
Overall PI (Patrick Y. Wen, MD) at 
the DFCI Coordinating Center 
Via Email b
Use Reportable AE Coversheet c and 
Medwatch 3500A d 
Seriouse
Any
Any
(Expected or 
Unexpected)
Any
Within 24 hours from notification a
Within 24 hours from notification a
Non-Serious
Grade 4 
Any
(Expected or 
Unexpected)
Any
Not Required
Within 5 working days from 
notification a
Non-Serious
Grade 2 or 3
Unexpected
Possible, probable, 
definite
Not Required
Within 7 working days from 
notification a
g.
In the event that the participating investigator/site team does not become aware of an adverse event requiring expedited reporting immediately (e.g., participant sought treatment 
elsewhere), the participating investigator/site team is to report the event within the required hours/days noted above after learning of it and document the time of his or her first 
awareness of the adverse event. The initial report must be as complete as possible, including an assessment of the causal relationship between the event and the investigational 
product(s). Information not available at the time of the initial report (e.g., an end date for the adverse event or laboratory values received after the report) must be documented on 
a follow-up report. A final report to document resolution of the SAE or reportable AE is required. 
h.
Email the Medwatch 3500A form, reportable AE coversheet (section 0 of this appendix), and the local IRB SAE report (if applicable) to the DFCI Coordinating Center with the 
participant title as “INSIGHT SAE” to NeuroOnc_SAE@dfci.harvard.edu. All SAE reports received at this account are forwarded immediately to study’s Overall PI, Dr. Patrick 
Y. Wen, and to the DFCI Coordinating Center personnel. 
i.
Reportable AE Coversheet is found in section 0 of this appendix. The coversheet contains all FAX numbers/e-mails and needed for reporting purposes. 
j.
Medwatch 3500A downloadable form at http://www.fda.gov/medwatch/getforms.htm
k.
Seriousness is defined in section 0 of this appendix.
l.
Expected adverse events are those that have been previously identified as resulting from administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the Anticipated Toxicities list (protocol section 4.1 of this appendix) which is derived from the Investigator’s Brochure.

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How to report expedited AEs to VBI Vaccines Inc. & DFCI Coordinating Center/Overall PI
1. Document/describe reportable AE(s) on the following: 
a. MedWatch 3500A
i. downloadable form at http://www.fda.gov/medwatch/getforms.htm 
b. DFCI Reportable AE Coversheet – INSIGhT VBI-1901/balstilimab Arm
i. Coversheet can be found in section 0 of this appendix. The coversheet contains contact 
information for DFCI Coordinating Center and VBI Vaccines Inc. safety groups. A modifiable 
Microsoft Word document is also available from the DFCI Coordinating Center.
2. Scan and email above documents to NeuroOnc_SAE@dfci.harvard.edu with the participant 
title “INSIGHT SAE”
a. All AE reports received at this account are forwarded immediately to Overall PI (Dr. 
Patrick Y. Wen), and to Coordinating Center personnel. 
b. If available and applicable, also include the local IRB submission for this event in the 
submission to the DFCI Coordinating Center.
Protocol-Specific Expedited Adverse Event Reporting Exclusions
For this protocol only, the AEs/grades listed below do not require expedited reporting to the 
Overall PI or the DFCI IRB. However, they still must be reported through the routine reporting 
mechanism (i.e. case report form).

Lymphopenia (grades 2-4). 

A visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event)

Emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission

Elective surgery, planned prior to signing consent

Routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)

Hospitalization for routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition, or for elective procedures

Hospitalization for elective or pre-planned treatment for a pre-existing condition that did 
not worsen

Hospitalization for respite care not associated with an AE attributed to the study drug

Hospitalization for treatment of participant’s underlying disease after coming off study 
treatment (e.g. admission after participant is removed from active study treatment for 
craniotomy)
Expedited Reporting to the Food and Drug Administration (FDA)
As study sponsor, the Overall PI (or his designee) will be responsible for all communications 
with the FDA. The Overall PI will report to the FDA, regardless of the site of occurrence, any 
serious AE that meets the FDA’s criteria for expedited reporting following the reporting 

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requirements and timelines set by the FDA.
Expedited Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy. 
Routine Adverse Event Reporting
All AEs must be reported in routine study data submissions to the Overall PI on the toxicity case 
report forms. AEs reported through expedited processes (e.g., reported to the IRB, FDA, 
etc.) must also be reported in routine study data submissions.
Other Reporting Requirements
Pregnancies
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) in either a female participant or a partner of a male participant occurring while the 
participant is on investigational product (IP), or within 28 days of the participant’s last dose of 
IP, are considered immediately reportable events. IP is to be discontinued immediately and the 
participant instructed to return any unused VBI-1901 and balstilimab. The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported to Drug Company Drug Safety 
immediately by facsimile, or other appropriate method, using the Initial Pregnancy Report Form.
The female may be referred to her obstetrician-gynecologist or another appropriate healthcare 
professional for further evaluation.
The Investigator will follow the female participant until completion of the pregnancy, and must 
notify Drug Company Drug Safety immediately about the outcome of the pregnancy (either 
normal or abnormal outcome) using the Follow-up Pregnancy Report Form as a follow-up to the 
initial pregnancy report.
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion [any 
congenital anomaly detected in an aborted fetus must be documented], stillbirth, neonatal death, 
or congenital anomaly [including that in an aborted fetus]), the Investigator should report the 
abnormal outcome as an AE. If the abnormal outcome meets any of the serious criteria, it must 
be reported as an SAE to Drug Company Drug Safety immediately by facsimile, or other 
appropriate method, within 24 hrs of the Investigator's knowledge of the event using the SAE 
Report Form or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Drug Company Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hrs of the Investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form.

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Male Participants
If a female partner of a male participant taking investigational product becomes pregnant, the 
male participant taking IP should notify the Investigator, and the pregnant female partner should 
be advised to call their healthcare provider immediately.
Overdose
Overdose, as defined for this protocol, refers to balstilimab dosing only.
On a per dose basis, an overdose is defined as a dose of balstilimab at any amount over the 
protocol-specified dose assigned to a given participant, regardless of any associated AEs or 
sequelae.
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency. 
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form. 
Notify the DFCI Coordinating Center at NeuroOnc_SAE@dfci.harvard.edu of any potential 
overdose as soon as possible. 
IND Annual Reports
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33 that an annual 
report is provided to the FDA within 60 days of the IND anniversary date. 21 CRF 312.33 
provides the data elements that are to be submitted in the report. The Annual Report should be 
filed in the study’s Regulatory Binder, and a copy provided to VBI Vaccines Inc. as a supporter 
of this study as follows:
VBI Vaccines Inc.
310 Hunt Club Road East
Ottawa, ON K1V 1C1
Canada
Tel: (613) 749-4200
6. PHARMACEUTICAL INFORMATION
6.1 VBI-1901
Description
VBI-1901 is an eVLP vaccine that has been formulated with GM-CSF. VBI-1901 consists of a 
suspension of eVLPs that express HCMV gB glycoprotein on the surface of the particle 

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membrane and the HCMV pp65 protein in the interior of the VLP. The VBI-1901 formulation 
contains 10 mM sodium phosphate and 8% sucrose at pH 7. The particles are produced in HEK 
293 mammalian cells transfected with the MLV gag gene and the HCMV gB and pp65 genes. 
Cell culture supernatants are collected and eVLPs purified by filtration, diafiltration, and anion 
exchange chromatography. VBI-1901 eVLPs are formulated with GM-CSF adjuvant just prior to 
injection. VBI-1901 is stable for at least 33 months when stored at -80°C±10°C.
Form
VBI-1901 is comprised of gB/pp65 eVLPs in an 8% sucrose solution with an opaque to milky 
appearance.
VBI-1901 will be supplied as vials of final drug product (FDP) comprised of gB/pp65 eVLPs at 
a dose of approximately 50 μg pp65/mL, in an 8% sucrose solution with an opaque to milky 
appearance.
VBI-1901 will be compounded at the hospital pharmacy with lyophilized GM-CSF (Leukine®), 
also supplied by the sponsor (see sections 0), as summarized below in section 0, and detailed in 
the Pharmacy Manual.
Storage and Stability
gB/pp65 eVLPs should be stored frozen at -80°C±20°C and are stable for at least 33 months, 
based on in-house stability study 19CH26. Additional stability data will be provided as it 
becomes available.
Compatibility
There are no known compatibility issues.
Handling
Routine vaccine and chemotherapy handling is recommended.
Availability
VBI-1901 is an investigational agent and will be supplied free-of-charge from VBI Vaccines Inc.
Preparation
VBI-1901 optimal dose (10 μg pp65 content) will be formulated with GM-CSF (200 μg). The 
study product will be compounded at the hospital pharmacy, under aseptic conditions according 
to a Pharmacy Manual provided by the Sponsor.
For preparation of VBI-1901 (≥50 μg/mL of pp65) with GM-CSF (Leukine® lyophilized powder, 
250 μg) study sponsor will supply four different types of vials for the compounding of the 

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optimal dose. The first type of vial will contain VBI-1901 final drug product (2 vials needed). 
The second type of vial will contain 10 mL of sterile 0.9% normal saline. A third type of vial 
will be an empty, sterile 10 mL vial. The fourth type of vial will contain GM-CSF (Leukine® 
lyophilized powder, 250 μg) (2 vials needed).
For the final admix formulation, an appropriate volume of VBI-1901 and 0.9% normal saline 
need to be added to the empty supplied vial. Then reconstitute separately 2 vials of lyophilized 
GM-CSF with 250 μL each of diluted VBI-1901 (50 μg/mL). After swirling for 30±10 seconds, 
withdraw 0.1 mL from each of the admixed formulation and administer in separate sites ID.
Only vials supplied by the sponsor should be used to compound the study product.
Administration
VBI-1901 will be administered in two equal ID injection in two sites with GM-CSF at Day 1, 
and then every 4 weeks (28 days ± 3 days) until clinical disease progression (see mater protocol 
section 11.2.3) or until no longer in the best interest of the participant, as described in 
section 3.2). In the VBI-1901/balstilimab arm, balstilimab should be administered first. 
However, the treating neurooncologist may opt to administer VBI-1901 first if desired for 
ease/convenience of the treating neurooncologist and the patient.
6.2 GM-CSF (Lyophilized Leukine®)
Description
GM-CSF (LEUKINE®; sargramostim) is a recombinant human granulocyte-macrophage colony 
stimulating factor (rhu GM-CSF) produced by recombinant DNA technology in a yeast 
(S. cerevisiae) expression system. GM-CSF is a hematopoietic growth factor which stimulates 
proliferation and differentiation of hematopoietic progenitor cells.
Form
Lyophilized LEUKINE® is available in vials containing 250 μg (1.4 × 106 International Units 
[IU]/vial) sargramostim.
Lyophilized LEUKINE® is a sterile, white, preservative-free powder.
Each vial of lyophilized LEUKINE® also contains 40 mg mannitol, USP; 10 mg sucrose, NF; 
and 1.2 mg tromethamine, USP, as excipients. Biological potency is expressed in IU as tested 
against the WHO First International Reference Standard. The specific activity of LEUKINE® is 
approximately 5.6 × 106 IU/mg.
Storage and Stability
LEUKINE® should be refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze or shake. Do not 
use beyond the expiration date printed on the vial.

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Lyophilized LEUKINE® vials contain no antibacterial preservative, and therefore solutions 
should be administered as soon as possible.
6.3 Balstilimab (AGEN2034)
Description
Balstilimab is a human monoclonal antibody that targets PD-1. Engagement of PD-1 by its 
ligands, PD-L1 and PD-L2, leads to signal transduction that inhibits important aspects of T-cell 
function including proliferation, cytokine production and cytolytic activity. Balstilimab potently 
inhibits PD-1 binding to PD-L1 and PD-L2 and is intended to reverse the immunosuppressive 
effects of this signaling pathway in the context of tumor immuno-surveillance by T cells.
Form
Balstilimab has IgG4 heavy chains and immunoglobulin kappa light chains (IgG4κ). Balstilimab 
is produced using recombinant deoxyribonucleic acid technology in a Chinese hamster ovary 
mammalian expression system. The balstilimab drug product is provided as a sterile, single-use 
solution at 50 mg in a United States (US) Pharmacopeia compliant type 1 borosilicate 2 mL glass 
vial. The drug product is intended for dilution with 0.9% normal saline for IV administration.
Storage and Stability
The drug product vials should be stored at 2°C to 8°C (36°F to 46°F) and should be protected 
from light. A comprehensive stability program for the balstilimab drug product is in place to 
ensure product quality throughout the length of ongoing clinical investigations. Based on 
available stability data, balstilimab is stable for at least 36 months when stored according to 
conditions specified in the clinical supplies labeling.
Availability
Balstilimab is an investigational agent and will be supplied free-of-charge from VBI Vaccines 
Inc.
Preparation
Balstilimab drug product must be diluted with 0.9% saline solution (sodium chloride injection). 
Detailed information on infusion bags and medical devices to be used for preparation of 
dilutions and subsequent administration is provided in the Pharmacy Manual.
Balstilimab will be shipped in transport cool containers (2°C to 8°C) that are monitored 
with temperature control devices.
Balstilimab drug product must be stored at 2°C to 8°C until use, with a temperature log 
maintained daily. All medication boxes supplied to each trial center must be stored 

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carefully, safely, and separately from other drugs.
Once the vial is punctured, the balstilimab drug product must be diluted into appropriate 
volume of 0.9% sodium chloride (normal saline) solution in an infusion bag immediately. 
Infusion from the bag should be completed within 4 hours of vial puncture when the bag is 
stored at room temperature or within 24 hours when the bag is stored at 5°C±3°C (refrigerated 
conditions).
Any unused portion of solution should be discarded in biohazard waste disposal, with 
final disposal by accepted local and national standards of incineration.
Administration
Balstilimab will be administered by IV infusion every 2 weeks concurrent with VBI-1901. The 
first dose of balstilimab will be administered at Day 15, and then every 2 weeks until clinical 
disease progression (see master protocol section 11.2.3) or until no longer in the best interest of 
the participant, as described in section 3.2).
Balstilimab should be administered via IV infusion over 30 (± 15) minutes in the 
VBI-1901/balstilimab arm. Patients must be observed for 10 minutes post-balstilimab infusion 
for infusion-related reactions. Infusions will be followed immediately with a saline flush of the 
IV line, per institutional guidelines. In the VBI-1901/balstilimab arm, balstilimab should be 
administered first. However, the treating neurooncologist may opt to administer VBI-1901 first if 
desired for ease/convenience of the treating neurooncologist and the patient.
Ordering
VBI-1901 will be supplied by the sponsor as vials of final drug product (FDP) comprised of 
gB/pp65 eVLPs in an 8% sucrose solution with an opaque to milky appearance.  It will be 
compounded at the hospital pharmacy with lyophilized GM-CSF (Leukine) supplied by the 
sponsor, as detailed in the Pharmacy Manual.
VBI-1901, GM-CSF, and Balstilimab will be ordered from each institution’s individual 
pharmacy (or designee).  The sponsor will work with the DFCI Coordinating Center once local 
IRB approval is received to ensure ample supplies of study agents are available at all approved 
sites. 
Accountability
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form. (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage.)
Destruction and Return

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VBI-1901 and balstilimab will be destroyed on site according to institutional policies, 
documented in the Drug Accountability Record Form. At the time of expiration / study close, a 
drug disposition form provided by Drug Company Corporation will be sent out to be signed off 
by the Pharmacist and Investigator verifying the destruction of drug. At the end of the study, 
unused supplies of VBI-1901 and balstilimab should be destroyed according to institutional 
policies. Destruction will be documented in the Drug Accountability Record For

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7. STUDY CALENDAR
D1b
Day 8
(±1 Day)
Day 15
(±3 days)
Day 29
(±3 days)
Day 43
(±3 days)
Day 
57
(±3 days)
Adjuvant 
Cycles
Day 1Z
(±3 days)
Adjuvant Cycles 
Day 15 (±3 days)
Assessment
Screen
-inga
Phone 
Call
End of
Txc
30-Day
Post 
Drugd
Active 
Follow-
Upe
Long
Term
Follow-Upf
Informed Consentg
X
Medical Historyh
X
X
X
X
X
X
X
X
Inclusion/Exclusion 
Criteriai
X
Vital signsj
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
Neurologic Exam
X
X
X
X
X
X
X
X
X
Karnofsky 
Performance Statusk
X
X
X
X
X
X
X
X
X
Pregnancy Test (β-
HCG)l
X
X
X
X
X
X
X
X
Coagulationm
X
Hematologyn
X
X
X
X
X
X
X
X
X
8-hour 
Fasting 
Serum 
Chemistryo
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
Adverse Eventsp
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medicationsq
X
X
X
X
X
X
X
X
X
X
X
Imaging – MRIr
X
X
X
X
Response 
Assessments
X
X
X
Radiationt
-------------------------------------X-----------------------------------
VBI-1901 Injectionu, v
X
X
X
X
Balstilimab Infusionv, 
x
X
X
X
X
X
X
HCMV viremiay
X
X
Serology (HIV, HCV, 
X

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HBV) 
Reactogenicityee
X
X
X
Post-treatment 
therapiescc
X
X
Survivaldd
X
X
GBM Biomarkersaa
X
Anti-HCMV gB IgG 
ELISA assay
Xbb
HCMV IFN-	 ELISPOT 
assay
Xbb
FT3, FT4 & TSH
X
X

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a. All screening procedures to be performed within 28 days of initial registration unless otherwise specified. NOTE: refer to section 10 of master protocol 
for comprehensive details on screening assessments, initial registration, randomization assignment and second registration timing.
b. Day 1 assessments must be performed within 3 days of starting study treatment. Screening assessments may be utilized as baseline/Day 1 
assessments if they fall within window.
 c. End of Treatment: assessments to be performed within 7 days after last drug administration or within 7 days after decision to end treatment. 
d. 30-Day Post Drug: a contact/visit is to be performed 30 days (+7 days) after date of last dose of drug taken on study. This may be performed via 
documented phone conversation with a study nurse or clinician or a clinic visit. All participants will be followed until resolution or stabilization of any 
serious or reportable adverse events occurring during treatment or starting within 30 days of last drug.
e. Active Follow-Up: participants who discontinue study treatment for reasons other than disease progression will be followed every 4 weeks (+/-1 
week) via contact or medical record review and study team must continue monitoring participant’s disease status by radiologic imaging at 8-week 
intervals (+/- 1 week) until (1) documented disease progression, (2), death, (3) participant withdraws from follow-up, or (4) end of study, whichever 
occurs first.
f. Long Term Follow-Up: participants will be followed every 8 weeks (+/-1 week) via contact or medical record review until death. Participants must be 
followed for survival data at every long-term follow-up time point and for post-treatment therapies and reason for stopping those therapies when 
available.
g. Informed Consent: must be obtained by MD attending. No study specific screening procedures may occur until after the initial informed consent 
process is completed. Initial informed consent may be obtained within 28 days of initial registration. Following initial registration and receipt of INSIGhT 
randomization assignment, participants must be sign the consent form specific to the assigned treatment arm prior to initiating treatment for that 
study arm.
h. Medical History: to include review of treatment history for GBM, any ongoing medical conditions & medical history pertaining to eligibility on study 
and involvement during study.
i. Inclusion/exclusion criteria: source documentation providing investigator’s confirmation that the participant had met all master protocol eligibility 
criteria must be available prior to initial registration. See section 3 of master protocol for eligibility requirements for initial registration. See section 2 
of this appendix for arm specific eligibility criteria.
j. Vital Signs: weight, heart rate, blood pressure, respiration rate, temperature. Vital signs must be performed prior to administration of treatment on 
treatment days. Height required only at screening.
k. Karnofsky Performance Status (KPS): see appendix A of master protocol.
l. Pregnancy Test: required for women of child bearing potential (see section 3 of master protocol for definition of women of child bearing potential). 
Pregnancy test can be either blood or urine sample.
m. Coagulation: PT/INR, PT, PTT required at screening only.
n. Hematology: erythrocytes (RBC), hemoglobin, hematocrit, platelets, total WBC plus differential (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils).
o. 8-hour Fasting Serum Chemistry: albumin, alkaline phosphatase (ALP), BUN, calcium, creatinine, glucose, potassium, SGOT (AST), SGPT (ALT), sodium, 
total bilirubin (if total bilirubin is greater than the upper limit of normal, direct and indirect bilirubin should be performed), amylase, lipase, and 
magnesium.
p. Adverse Events: adverse events experienced by participants will be collected and recorded from the first dose of treatment on-study up to the 30-
Day Post Drug Visit of the last dose of study medication (+ 7 days depending on when 30-Day Post Drug visit/contact occurs).
q. Concomitant Medications: concomitant medications & reason for administration should be documented in the case history from date of consent up 

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to the 30-Day Post Drug Visit.
r. Imaging: gadolinium-enhanced contrast and non-contrast MRI. Initial imaging should be performed within 21 days prior to beginning study treatment. 
When feasible at site, Appendix D Recommended MRI Acquisition Protocol should be adhered to and the same imaging technique should be used on a 
participant throughout the trial. Local reading (investigator assessment) will be used to determine eligibility and for participant management. Adjuvant 
C1D1 imaging should be performed within 7 days prior to starting adjuvant treatment; subsequent imaging should be performed within 7 days prior to 
Day 1 of odd cycles (i.e every 8 weeks).
s. Response Assessment: Per RANO criteria (see section 11 of master protocol). Tumor response is assessed after every MRI (MRIs are performed at D1 
of odd cycles)
t. Radiation: Refer to section 3.1 of this sub-study appendix for definition of standard radiation therapy per protocol.
u. VBI-1901+GM-CSF intradermal injections are to be administered once every 4 weeks (28 days ± 3 days) (section 3.2) beginning on Day 1 of radiation 
therapy. In the VBI 1901/balstilimab arm, balstilimab should be administered first. However, the treating neurooncologist may opt to administer VBI 
1901 first if desired for ease/convenience of the treating neurooncologist and the patient.
v. Dose may be cancelled in the following cases: (1) confirmation of tumor progression on the most recent MRI. (2) withdrawal of study treatment for 
unacceptable toxicity or for another reason such as withdrawal of consent. Schedule the end of study visit for approximately 35 days after the last study 
dose was received.
x. Balstilimab intravenous infusion is to be administered every 14 days (± 3 days) (section 3.3). The first dose of balstilimab will be administered at Day 
15.
y. HCMV viremia can be within 28 days.
z. 4 weeks +/- 3 days after radiation therapy completion patients will have restaging MRI and begin adjuvant cycles of treatment with VBI-1901+GM-
CSF intradermal injections and balstilimab on Day 1 ± 3 days, and balstilimab alone on day 15 ± 3 days of every adjuvant cycle.
aa. MGMT promoter status, EGFR, EGFRvIII, PTEN, and p53 obtained from participant’s medical records- Isocitrate dehydrogenase (IDH1/2) enzymes 
will be assessed on tumor specimen. 
bb. Immunogenicity assessments to be completed every 3 cycles starting at adjuvant C2D1 (e.g., cycles 2, 5, 8, 11, 14, and 17). Immunogenicity 
assessment to occur on treatment visits where VBI-1901 and balstilimab are both administered.
cc. Post-treatment Therapies: start/stop dates, names of treatment regimens and reason for stopping should be collected when available. 
dd. Survival: date of death and reason must be collected for overall survival purposes.
ee. Reactions to vaccine will be assessed 30 minutes following each immunization and during the 28 following days.

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8. MEASUREMENT OF EFFECT
Refer to section 11 of master INSIGhT protocol for details on measurement of effect. 
9. GRADING OF LOCAL REACTIONS
Table 1:
Grading of Local Reactions
Grade 1
Grade 2
Grade 3
Grade 4
Pain (pain without 
touching)
Does not interfere 
with activity
Repeated use of 
non-
narcotic pain 
reliever
> 24 hours or 
interferes with 
activity
Any use of
narcotic pain 
reliever or 
prevents daily 
activity
Emergency room 
(ER) visit or 
hospitalization
Tenderness
(pain when area is 
touched)
Mild discomfort to 
touch
Discomfort with 
movement
Significant 
discomfort at 
rest
ER visit or 
hospitalization
Pruritus associated with 
injection
See also Skin: Pruritus 
(itching - no skin 
lesions)
Itching localized to 
injection site AND 
Relieved 
spontaneously or 
with < 48 hours 
treatment
Itching beyond 
the injection site 
but not 
generalized OR 
Itching localized 
to injection
site requiring ≥ 
48 hours 
treatment
Generalized 
itching causing 
inability to 
perform usual 
social
&
functional 
activities
NA
Erythema/Redness*
2.5 – 5 cm
5.1 – 10 cm
> 10 cm
Necrosis or 
exfoliative 
dermatitis
Induration/Swelling**
2.5 – 5 cm and does 
not interfere with 
activity
5.1 – 10 cm or 
interferes with 
activity
> 10 cm or
prevents daily 
activity
Necrosis
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable.
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.
10.REFERENCES 
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DFCI REPORTABLE AE COVERSHEET – INSIGhT VBI-1901/Balstilimab (AGEN2034) ARM
DF/HCC Protocol No.    16-443           Drug Company  Tracking No. VBI-1901/AGEN2034-
Date:____________________     
Number of pages including cover sheet:____________
To (check off recipient of this AE):
        Dr. Patrick Y. Wen and Dana-Farber  Coordinating Center
    Email: NeuroOnc_SAE@dfci.harvard.edu
        VBI Vaccines Fax: 908-673-9115                            Email: vbi1901INSIGhTsae@vbivaccines.com 
From:
Institution:
Phone No.:
Fax No.:
Participant # and Initials:
Date Event Met Reporting Criteria (as defined in protocol):
Type of Report:    Initial   Follow-up
CTCAE Event #1 Description:
CTCAE Event #2 Description (if applicable): 
NOTE: use another coversheet if more than 2 events are being reported at this 
time
Meets Definition of Serious AE:   
   Serious        Non-serious
Meets Definition of Serious AE:   
   Serious         Non-serious
Toxicity Grade:     
G1/mild   G2/moderate   G3/severe   
G4/life threatening   G5/death
Toxicity Grade:     
G1/mild   G2/moderate   G3/severe   
G4/life threatening   G5/death
Expectedness with Radiation Therapy:    
Expected   Unexpected    N/A  
Expectedness with Radiation Therapy:    
Expected   Unexpected   N/A  
Attribution to Radiation Therapy:    
Unrelated   Unlikely    Possible    Probable    
Definite      N/A  
Attribution to Radiation Therapy:    
Unrelated   Unlikely    Possible    
Probable    Definite      N/A  
Expectedness with VBI-1901: 
 Expected   Unexpected   N/A  
Expectedness with VBI-1901:  
Expected   Unexpected   N/A  
Attribution to VBI-1901:  
Unrelated   Unlikely    Possible    Probable    
Definite      N/A  
Attribution to VBI-1901:
Unrelated   Unlikely    Possible    
Probable    Definite      N/A  
Expectedness with Balstilimab (AGEN2034)
Expected   Unexpected   N/A  
Expectedness with Balstilimab (AGEN2034)
Expected   Unexpected   N/A  
Attribution to Balstilimab (AGEN2034)
 Unrelated   Unlikely    Possible    Probable    
Definite      N/A  
Attribution to Balstilimab (AGEN2034)
 Unrelated   Unlikely    Possible    Probable    
Definite      N/A  
Reporting Investigator (print):
Signature of Reporting Investigator: ______________________________  Date:_____________