A Phase II Study of Olaparib and AZD6738 in Isocitrate Dehydrogenase (IDH) Mutant Solid Tumors
Phase: PHASE2
Conditions: Malignant Solid Neoplasm, Refractory Cholangiocarcinoma, Refractory Malignant Solid Neoplasm
Sponsor: National Cancer Institute (NCI)

i 
SUMMARY OF CHANGES – Protocol 
 
For Protocol Amendment #13 to: A Phase II study of olaparib and AZD6738 in isocitrate 
dehydrogenase (IDH) mutant solid tumors 
 
NCI Protocol #: 10222 
Local Protocol #: 10222 
 
NCI Version Date: April 4, 2025 
Protocol Date: April 4, 2025 
 
I. 
Revisions requested in CTEP Request for Amendment (RA) dated October 1, 2024: 
# 
Section 
Comments 
1. 
All 
Updated Version Date in Header 
2. 
Face Page 
Updated Protocol Type and Version Date 
3. 
TOC 
Updated Table of Contents 
4. 
Appendix 
G, Sec 5.6.3 
The current EET Biobank Shipping Address replaces the former ETCTN 
Biorepository address 
5. 
Appendix G 
Sect 6  
The current EET Biobank contact information phone number replaces that of the 
former ETCTN Biorepository 
 
II. 
Revisions requested in CTEP Global Safety Update dated August 22, 2024: 
# 
Section 
Comments 
1. 
10.3.4 
Table for “Expedited Reporting Requirements for Adverse Events that Occur on 
Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention” updated to “Effective Date: August 30, 2024” 
as per NCI Memorandum dated August 22, 2024. 
 
III. 
Revisions recommended in Review of Amendment #08 of Protocol #10222: “A Phase II 
Study of Olaparib and AZD6738 in Isocitrate Dehydrogenase (IDH) Mutant Solid 
Tumors” dated 05/08/2023 
# 
Section 
Comments 
1. 
4.1 
Please revise the excerpt below as indicated. 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all individuals contributing to NCI sponsored trials to register 
and to renew their registration annually.  To register, all individuals must obtain a 
Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) account at https://ctepcore.nci.nih.gov/iam.  In addition, persons with a 
registration type of Investigator (IVR), Non Physician Investigator (NPIVR), or 
Associate Plus (AP) must complete their annual registration using CTEP’s web
based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr.    
Food and Drug Administration (FDA) regulations require sponsors to select 
qualified investigators.  National Cancer Institute (NCI) policy requires all 

ii 
# 
Section 
Comments 
individuals contributing to NCI-sponsored trials to register with their 
qualifications and credentials and to renew their registration annually.  To register, 
all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity 
and Access Management (IAM) account at https://ctepcore.nci.nih.gov/iam.  
Investigators and clinical site staff who are significant contributors to research 
must register in the Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr/. The RCR is a self-service online person 
registration application with electronic signature and document submission 
capability.   
RCR utilizes five person registration types. 
• IVR Investigator (IVR):  MD, DO, or international equivalent, 
• NPIVR Non Physician Investigator (NPIVR):  advanced practice providers 
(e.g., NP or PA) or graduate level researchers (e.g., PhD), 
• AP Associate Plus (AP):  clinical site staff (e.g., RN or CRA) with data 
entry access to CTSU applications such as the Roster Update Management 
System (RUMS), OPEN, Rave, acting as a primary site contact, or with 
consenting privileges, 
• Associate (A):  other clinical site staff involved in the conduct of NCI-
sponsored trials, and 
• Associate Basic (AB):  individuals (e.g., pharmaceutical company 
employees) with limited access to NCI-supported systems. 
Please revise the excerpt below as indicated. 
An active CTEP-IAM user account with a linked ID.me account (the latter 
required immediately for new CTEP-IAM accounts, and appropriate RCR 
registration by July 1, 2023 for all users) is required to access all CTEP and 
participate in NCI clinical trials supported by the Cancer Trials Support Unit 
(CTSU) and to access all CTEP and CTSU websites and applications.  In addition, 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review 
Boards (IRBs) covering their practice sites on the FDA Form 1572 in RCR to 
allow the following: 
• Addition to a site roster, 
• Assign Selection as the treating, credit, consenting, or drug shipment (IVR 
only) tasks investigator or consenting person in OPEN, 
• Act Ability to be named as the site-protocol Principal Investigator (PI) on 
the IRB approval, and 
• Assign Assignment of the Clinical Investigator (CI) role task on the 
Delegation of Tasks Log (DTL).  
PI Response: 
All revisions made as recommended. 
2. 
4.2 
Please revise the excerpt below as indicated. 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) 

iii 
# 
Section 
Comments 
must meet the following criteria to complete for the site to be able to have an 
Approved status following processing of the IRB/REB approval record to be 
completed: 
• Holds Have an active CTEP status, 
• Active Have an active status at the site(s) on the IRB/REB approval on at 
least one participating organization’s roster, 
• If using NCI CIRB, be active on the NCI CIRB roster under the applicable 
CIRB Signatory Institution(s) record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 
1572 in the RCR profile, 
• Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 
1572 in the RCR profile; and 
• Holds Have the appropriate CTEP registration type for the protocol.  
Please revise the excerpt below as indicated. 
• Compliance with all applicable protocol-specific requirements (PSRs). 
PI Response: 
All revisions made as recommended. 
3. 
4.2.1 
Please revise the excerpt below as indicated. 
Download the site registration forms from the protocol-specific page located on 
the CTSU members’ website.  Permission to view and download this protocol and 
its supporting documents is restricted to institutions and its their associated 
investigators and staff on a participating roster.  To view/download site 
registration forms:   
• Log in to the CTSU members’ website (https://www.ctsu.org) using your 
CTEP-IAM username and password or linked ID.me account (ID.me 
accounts are required for all newly created CTEP-IAM accounts and by 
July 1, 2023 for all users), 
PI Response: 
All revisions made as recommended. 
4. 
4.2.3 
Please revise the excerpt below as indicated. 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately by phone or email: 1-
866-651-CTSU (2878), or CTSURegHelp@coccg.org in order to receive further 
instruction and support. 
PI Response: 
All revisions made as recommended. 
5. 
4.2.4 
Please revise the excerpt below as indicated. 
Site’s registration status may be verified on the CTSU members’ website.  

iv 
# 
Section 
Comments 
PI Response: 
All revisions made as recommended. 
6. 
4.3.1 
Please revise the excerpt below as indicated. 
• A valid CTEP-IAM account and linked ID.me account (ID.me accounts are 
required for all newly created CTEP-IAM accounts and by July 1, 2023 for 
all users). 
Please revise the excerpt below as indicated. 
 
Patient enrollment for this study will be facilitated using the Slot Reservation 
System in conjunction with the registration system patient enrollment in OPEN. 
Prior to discussing protocol entry with the patient, all site staff must use the CTSU 
OPEN Slot Reservation System or the IWRS Slot Reservation System to ensure 
that a slot on the protocol is available to the patient.  Once a slot reservation 
confirmation is obtained, site staff may then proceed to enroll the patient to this 
study.  
PI Response: 
All revisions made as recommended. 
7. 
Section 5.1 
and 
Appendix 
G, Section 
2.1 
Remove the following text from footnote 1 in the Specimen Collection Table: 
When completed, upload the corresponding pathology report to Rave and send a 
copy to the EET Biobank 
PI Response: 
All revisions made as recommended. 
8. 
5.7 
Revise the Table title as follows to add text as shown: 
List of Biomarker Assays in Order of Priority  
Note for participating sites: Please see Section 5.1 for details on specimens to 
collect.  The tissue/body fluid tested are not always the same specimens that are 
submitted by the site, as processing of blood and tissue will occur at the Biobank 
prior to testing 
PI Response: 
All revisions made as recommended. 
9. 
5.7 
Update the Biomarker Table to the following.  This: 
• Removes the Biomarker Review Requirement in the Assay column. 
• Deletes the Use of NCI Resources column.  
• Moves the laboratory information to a new, separate column and 
updates this information as will eventually needed for specimen 

v 
transfer.  
Biomark
er Name 
Assay 
and 
CLIA: 
Y/N 
Use 
(Integral, 
Integrated
, or 
Explorator
y) AND 
Purpose 
Tissue/Body 
Fluid Tested 
and Timing of 
Assay 
Mand
atory   
or 
Optio
nal 
Assay 
Laboratory, 
Lab PI, and 
Lab PI Email 
IDH1/2 
mutation 
detection 
 
Next-
generati
on 
sequenci
ng 
CLIA: 
Y 
Integral 
To screen 
potential 
patients 
(eligibility 
criterion) 
Diagnostic 
tissue 
M 
Any 
commercial 
lab 
2HG 
plasma 
and 
tumor 
concentr
ations 
 
LCMS/
MS 
CLIA: 
N 
 
Integrated 
To address 
the tumor 
and plasma 
concentrati
on of 2HG 
before and 
after 
therapy   
Plasma and 
frozen tissue 
specimens  
Tissue: Prior 
to initiation of 
treatment and 
after cycle 1; 5 
slides archival 
FFPE tissue 
Plasma: Prior 
to initiation of 
treatment and 
on day 1 of 
cycles 2, 4 and 
8 and at time 
of evidence of 
progression 
per study 
schema 
(plasma only; -
/+ 4 days) 
Ma 
Karmanos 
Cancer 
Institute, 
Wayne State 
University 
School of 
Medicine  
Jing Li, Ph.D. 
LiJing@wayne
.edu 

vi 
# 
Section 
Comments 
WES/R
NAseq 
 
Next-
generati
on 
sequenci
ng 
CLIA: 
N 
 
Integrated 
To confirm 
IDH1 and 
IDH2 
mutations 
Explorator
y 
To search 
for 
biomarkers 
of response 
and 
resistance 
DNA, cDNA, 
and RNA 
from:  
Archival tissue 
or formalin-
fixed tissue 
collected pre-
treatment 
Formalin-fixed 
tissue at Week 
4 
DNA from 
blood in 
EDTA 
Ma 
NCLN 
Genomics 
Laboratory or 
MoCha, 
Frederick 
National 
Laboratory for 
Cancer 
Research 
(FNLCR)  
Mickey 
Williams, 
Ph.D. 
mickey.willia
ms@nih.gov 
CyTOF 
DNA 
damage 
repair 
multiple
x  
 
Multipar
ametric 
flow 
CLIA: 
N 
 
Explorator
y 
To assess 
changes in 
DNA 
damage 
repair 
induced by 
olaparib/A
ZD6738 
FFPE tissue 
specimens  
Prior to 
initiation of 
treatment and 
after cycle 1 
 
M 
Schalper 
Laboratory, 
Department of 
Pathology, 
Yale 
University 
School of 
Medicine 
Kurt Schalper, 
MD, PhD 
kurt.schalper@
yale.edu 
Rad51 
 
IHC 
CLIA: 
N 
 
Explorator
y 
To assess 
changes in 
DNA 
damage 
repair 
induced by 
olaparib/A
ZD6738 
FFPE tissue 
specimens  
Prior to 
initiation of 
treatment and 
after cycle 1 
 
Ma 
Center for 
DNA Damage 
and Repair, 
Dana-Farber 
Cancer 
Institute 
(DFCI) 
Geoffrey 
Shapiro, MD, 
PhD 
geoffrey_shapi
ro@dfci.harvar
d.edu 

vii 
# 
Section 
Comments 
PI Response: 
All revisions made as recommended.  Note that, following the 01/07/2025 
Specimen Kick-off Call for Protocol# 10222 between Yale study personnel and 
the NCI biomarker committee, this table was further modified extensively (see 
changes in Section IV below).    
10. 
5.10.1 and 
5.10.2 
Please revise the second paragraph to add the NCLN Genomics Laboratory: 
Unstained slides will be prepared for macrodissection and nucleic acid extraction. 
After pathology review, macrodissection of demarcated tumor will be performed 
and nucleic acids will be extracted and distributed to the MoCha, Frederick 
National Laboratory for Cancer Research (FNLCR) or the NCLN Genomics 
Laboratory for analysis. Additional tissue remaining after creating unstained slides 
for IHC and nucleic acid extractions will be banked for long-term storage at 
ambient temperature. At MoCha/NCLN Genomics Lab, the steps will be:    
• 
DNA library prepared for WES. 
• 
RNA library prepared for RNA-Seq. 
• 
Library quantitation using ddPCR for both WES and RNA-Seq  
• 
Denaturing and clustering of DNA and RNA libraries for sequencing  
• 
Sequencing of WES and RNA-Seq libraries  
• 
Data analysis for WES and RNASeq  
PI Response: 
All revisions made as recommended.  Note that, following the 01/07/2025 
Specimen Kick-off Call for Protocol# 10222 between Yale study personnel and 
the NCI biomarker committee, reference to the NCLN Genomics laboratory were 
removed.    
11. 
5.10.1.4 
Revise the site performing the correlative study for WES to add the NCLN 
Genomics Laboratory: 
5.10.1.4 Site Performing Correlative Study   
NCLN Genomics Laboratory or MoCha, Frederick National Laboratory for 
Cancer Research (FNLCR) 
Dr. P. “Mickey” Williams, Ph.D. 
PI Response: 
All revisions made as recommended. Note that, following the 01/07/2025 
Specimen Kick-off Call for Protocol# 10222 between Yale study personnel and 
the NCI biomarker committee, reference to the NCLN Genomics laboratory were 
removed.    
12. 
5.10.2.4 
Revise the site performing the correlative study for RNAseq to add the NCLN 
Genomics Laboratory: 

viii 
# 
Section 
Comments 
5.10.2.4 Site Performing Correlative Study   
NCLN Genomics Laboratory or MoCha, Frederick National Laboratory for 
Cancer Research (FNLCR) 
Dr. P. “Mickey” Williams, Ph.D. 
PI Response: 
All revisions made as recommended. Note that, following the 01/07/2025 
Specimen Kick-off Call for Protocol# 10222 between Yale study personnel and 
the NCI biomarker committee, the assay contact was changed to Chris Karlovich 
instead of Mickey Williams and reference to the NCLN Genomics laboratory were 
removed. 
13. 
10.3.3 
Please verify if 10222 uses Rave CTEP-AERS Integration, and include this 
subsection as needed. 
1.1.1 Rave-CTEP-AERS Integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting 
System (CTEP-AERS) integration enables evaluation of Adverse Events 
(AEs) entered in Rave to determine whether they require expedited 
reporting and facilitates entry in CTEP-AERS for those AEs requiring 
expedited reporting.  Sites must initiate all AEs for this study in Medidata 
Rave. 
Include the following (highlighted) paragraphs about pre-treatment AEs 
only if the study requires reporting of pre-treatment AEs and the CTSU 
standard Pre-Treatment AE form is used. Pre-existing medical 
conditions are not considered adverse events and therefore should not be 
reported on the Pre-Treatment Adverse Event form. 
Pre-treatment AEs:  AEs that occur after informed consent is signed and 
prior to start of treatment are collected in Medidata Rave using the Pre-
treatment Adverse Event form.  
Pre-existing medical conditions (formerly referred to as baseline AEs) 
identified during baseline assessment are not considered AEs and therefore 
should not be reported on the Pre-treatment Adverse Event form. If these 
pre-existing conditions worsen in severity, the investigator must reassess 
the event to determine if an expedited report is required. Whether or not an 
expedited report is required, the worsened condition should be reported in 
Rave as a routine AE. 
Treatment-emergent AEs:  All AEs that occur after start of treatment are 
collected in Medidata Rave using the Adverse Event form, which is 
available for entry at each treatment course or reporting period and is used 
to collect AEs that start during the period or persist from the previous 
reporting period.  AEs that occur 30 days after the last administration of 
the investigational agent/intervention are collected using the Late Adverse 

ix 
# 
Section 
Comments 
Event form. 
Prior to sending AEs through the rules evaluation process, site staff should 
verify the following on the Adverse Event form in Rave: 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is 
query free.  
The CRA reports AEs in Rave at the time the Investigator learns of the 
event.  If the CRA modifies an AE, it must be re-submitted for rules 
evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE 
for rules evaluation by completing the Expedited Reporting Evaluation 
form (i.e., checking the box Send All AEs for Evaluation and save the 
form).  Both NCI and protocol-specific reporting rules evaluate the AEs 
submitted for expedited reporting.  A report is initiated in CTEP-AERS 
using information entered in Medidata Rave for AEs that meet reporting 
requirements.  The CRA completes the report by accessing CTEP-AERS 
via a direct link on the Medidata Rave Expedited Reporting Evaluation 
form.  Contact the CTSU Help Desk at 1-888-823-5923 or by email at 
ctsucontact@westat.com if you have any issues submitting an expedited 
report in CTEP-AERS. 
In the rare occurrence that internet connectivity is lost, a 24-hour 
notification is to be made to CTEP by telephone at 301-897-7497.  Once 
internet connectivity is restored, the 24-hour notification that was phoned 
in must be entered immediately into CTEP-AERS using the direct link 
from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on 
the CTSU members’ website: 
• Study specific documents:   Protocols > Documents> Protocol 
Related Documents> Adverse Event Reporting, and   
• Additional resources: Resources > CTSU Operations Information> 
User Guides & Help Topics. 
NCI requirements for SAE reporting are available on the CTEP website:  
• NCI Guidelines for Investigators:  Adverse Event Reporting 
Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic application
s/docs/aeguidelines.pdf. 
PI Response: 
All revisions made as recommended regarding Rave CTEP-AERS Integration. In 
an email dated 1/6/2025, Theradex confirmed that the CTSU standard pre-
treatment form is not in Rave for Theradex studies, including this one.  Therefore, 

x 
# 
Section 
Comments 
the relevant language above has not been added. 
14. 
13.2 
Please revise the excerpt below as indicated. 
Medidata Rave is a the clinical data management system being used for data 
collection for this trial/study.  Access to the trial in Rave is controlled through the 
CTEP-IAM system and role assignments.   
Requirements to access Rave via iMedidata: 
• 
A valid account, and CTEP-IAM account and linked ID.me account 
(ID.me accounts are required for all newly created CTEP-IAM accounts 
and by July 1, 2023 for all users), and 
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of:  
Rave CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave 
Investigator.   
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role, must have a minimum 
of an Associate Plus (AP) registration type, 
o Rave Investigator role, must be registered as an Non-Physician 
Investigator (NPIVR) or Investigator (IVR), and 
o Rave Read Only or Rave SLA role, site staff must have at a 
minimum an Associates (A) registration type. 
Please revise the excerpt below as indicated. 
Upon initial site registration approval for the study in the Regulatory Support 
System (RSS) application, all persons with Rave roles assigned on the appropriate 
roster will be sent a study invitation email from iMedidata. 
Please revise the excerpt below as indicated. 
Site staff that who have not previously activated their iMedidata/Rave account at 
the time of initial site registration approval for the study in RSS the Regulatory 
application will receive a separate invitation from iMedidata to activate their 
account.  Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account 
Activation and Study Invitation Acceptance).  Additional information on 
iMedidata/Rave is available on the CTSU members’ website in the Data 
Management > Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU 
Help Desk at 1-888-823-5923 or by email at ctsucontact@westat.com.   
PI Response: 
All revisions made as recommended. 
15. 
13.3 
Please verify if 10222 utilizes the Data Quality Portal, and add the following 
subsection as appropriate. 

xi 
# 
Section 
Comments 
1.2 Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to 
manage unanswered queries and form delinquencies, monitor data quality 
and timeliness, generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data 
Management.  The Rave Home section displays a table providing summary 
counts of Total Delinquencies and Total Queries.  DQP Queries, DQP 
Delinquent Forms, DQP Form Status and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent 
forms, forms with current status, and timeliness reports.  Site staff should 
review the DQP modules on a regular basis to manage specified queries 
and delinquent forms. 
The DQP is accessible by site staff who are rostered to a site and have 
access to the CTSU website.  Staff who have Rave study access can access 
the Rave study data via direct links available on the DQP modules. 
CTSU Delinquency Notification emails are sent to primary contacts at sites 
twice a month. These notifications serve as alerts that queries and/or 
delinquent forms require site review, providing a summary count of 
queries and delinquent forms for each Rave study that a site is participating 
in. Additional site staff can subscribe and unsubscribe to these notifications 
using the CTSU Report and Information Subscription Portal on the CTSU 
members’ website. 
To learn more about DQP use and access, click on the Help Topics button 
displayed on the Rave Home, DQP Queries, DQP Delinquent Forms, DQP 
Form Status, and DQP Reports modules. 
Include the following paragraph only if study is not using the Calendaring 
functionality in Rave; otherwise, delete. 
This study does not use the Rave Calendaring functionality and therefore 
the DQP Delinquent Forms module will not include details for this study, 
and the DQP Summary table on the Rave Home page will display N/A for 
the Total Delinquencies summary count. 
PI Response: 
All revisions made as recommended. 
16. 
Appendix G Under testing and storage facilitates, up the entry for MoCha to the following: 
RNA and DNA 
 
 
P. “Mickey” Williams, Ph.D. 
sequencing: 
 
 
NCLN Genomics Laboratory or 
MoCha, Frederick 
  National Laboratory for Cancer Research (FNLCR) 

xii 
# 
Section 
Comments 
PI Response: 
All revisions made as recommended. Note that, following the 01/07/2025 
Specimen Kick-off Call for Protocol# 10222 between Yale study personnel and 
the NCI biomarker committee, the contact was changed to Chris Karlovich instead 
of Mickey Williams and reference to the NCLN Genomics laboratory were 
removed.    
17. 
Appendix 
G, Section 
3 
Update the Table below to add the NCLN Genomics Laboratory to the MoCha 
entry: 
Testing Facility 
Platform 
Biomarker/Correlative 
Li Lab, Karmanos 
LC-MS/MS 
Determination of 2-HG in 
tissue and plasma 
NCLN Genomics 
Laboratory or 
MoCha, Frederick 
National  
Laboratory for 
Cancer Research 
(FNLCR) 
Illumina-based 
next-generation 
sequencing 
DNA whole exome 
sequencing and RNA 
transcriptomic sequencing 
Schalper Lab, Yale 
QIF/CyTOF-IMC 
In situ analysis of tumor 
DNA repair markers 
Shapiro Lab, Dana-
Farber 
Immunohistochemi
stry 
Detection of Geminin and 
RAD51 
PI Response: 
All revisions made as recommended. Note that, following the 01/07/2025 
Specimen Kick-off Call for Protocol# 10222 between Yale study personnel and 
the NCI biomarker committee, this table was further modified to remove reference 
to the NCLN Genomics Laboratory. 
18. 
Appendix G 
Sec 5.1.1 
Revise the URL for the EET Biobank Kit Management System as below: 
Kits for the collection and shipment of specimens to the EET Biobank can be 
ordered online via the Kit Management system: https://kits.bpc-apps.nchri.org/. 
PI Response: 
All revisions made as recommended. 
19. 
Appendix 
G, Section 
5.2.1 
Revise the third sentence in the third paragraph as follows: 
For newly acquired biopsies without a corresponding pathology report, the 

xiii 
# 
Section 
Comments 
radiology and operative report(s) must also be uploaded into Rave, when 
available. 
PI Response: 
All revisions made as recommended. 
20. 
Appendix 
G, Section 
5.2.3.2 
For Step 2, revise the last final sentence of the last bullet as follows.   
Do not redact SPID, block number, diagnosis or relevant dates (such as collection 
date) and include the UPID and patient study ID on each document (either by 
adding a label or hand writing).  
PI Response: 
All revisions made as recommended. 
21. 
Appendix 
G, Section 
5.6  
In the second paragraph in Section 5.6, replace “surgical” with “operative”. 
Insert the following text as new Section 5.6.1.  Renumber current Section 5.6.1 
Specimen Shipping Instructions as 5.6.2. 
 
5.6.1 Required Forms for Specimen Submissions 
Each document submitted with the specimen must be labeled with a label printed 
from the STS, or the Universal ID and Patient Study ID.  
Tissue  
Required Forms 
Archival  
1. Shipping List 
2. Corresponding Pathology Report 
New Biopsy 
 
1. Shipping List 
2. Tissue Biopsy Verification Form 
(Appendix G, Section 8) 
3. Diagnostic Pathology Report  
4. Operative and/or Radiology Report 
Blood  
1.   Shipping List 
 
PI Response: 
All revisions made as recommended. 
22. 
Appendix 
G, Section 
5.6.2.1 
In the fifth sentence, replace surgical with operative. 
Place the specimen(s) and a copy of the shipping manifest and corresponding 
reports such as operative or radiology reports into the insulated shipping container. 

xiv 
# 
Section 
Comments 
PI Response: 
All revisions made as recommended.  
 
 
 
IV. 
Revisions  following NCI#10222 Specimen  Kick-Off Call with NCI held on Tuesday, 
January 7, 2025 
# 
Section 
Comments 
1. 
5.1 
Reference to NCLN Genomics laboratory removed 
2. 
5.7  
Prioritization for use of tumor tissue specimens modified 
3. 
5.7 
Figure 7 modified to reflect changes to biomarker plan.  Note added that 2-HG 
assay will use remaining FFPE tissue that was sent to the EET Biobank 
4. 
5.7 
Table “List of Biomarker Assays in Order of Priority” rewritten to reflect changes 
to biomarker plan and assay performance locations 
5. 
5.9.1.1 
Note was added that no archival or frozen tissue specimens were received at the Li 
Laboratory as of April 2025. Instead, as of Amendment 13 (version April 4, 2025) 
of this protocol, this assay will use FFPE tissue collected at pre-treatment and on 
treatment cycle 1 remaining at EET Biobank following completion of the higher 
priority assays. 
6. 
5.10.3 
Section modified to add IF to look at gamma-H2AX and RAD51 and update 
biomarkers 
7. 
Appendix G 
Contact for RNA/DNA sequencing changed to Chris Karlovich 
8. 
Appendix G, 
Section 2 
Figure modified to reflect changes to biomarker plan.  Note added that 2-HG assay 
will use remaining FFPE tissue that was sent to the EET Biobank 
9. 
Appendix G, 
Section 2.1 
Prioritization for use of tumor tissue specimens modified 
10. 
Appendix G, 
Section 3 
MoCha lab detail added and clarification for mQIF and 
CyTOF-IMC assays 
11. 
Appendix G, 
Section 6 
Study PI changed from Navid Hafez to Patricia LoRusso.  Contact information 
updated 
12. 
Appendix G, 
Section 6 
EET biobank phone number updated 
13. 
Appendix G, 
Section 6 
Contact information for DNA and RNA sequencing added 
 
 
V. 
Additional revisions required by CTEP 
# 
Section 
Comments 
1. 
Face Page 
Removed EDDOP from list of participating Organizations 
2. 
3.3 
Word ‘genders’ replaced with ‘sexes’ to comply with 2025 Executive Order 
regarding Defending Women 
 
 

xv 
VI. 
Revisions made in response to CTEP review of Amendment 11 dated 03/21/2025 
 
a. Comments Requiring a Response– Administrative & Editorial Issues: 
# 
Section 
Comments 
1. 
10.3.4 
I noticed that the Table for “Expedited Reporting Requirements for NCI IND/IDE 
Agents” mistakenly included in the protocol is for Phase 1 and Early Phase 2 
Studies.   
Please update the Table for “Expedited Reporting Requirements for NCI IND/IDE 
Agents” for Late Phase 2 and Phase 3 Studies as per NCI Guidelines for 
Investigators, effective August 30, 2024. 
PI Response: 
The Table has been updated as requested.   
b. Company Comments – Requiring a Response:  
# 
Section 
Comments 
2. 
10.1.1.2 Identified Risks for Ceralasertib – MDS/AML is not specifically documented for 
Cera 
PI Response: 
CAEPR for AZD6738 (ceralasertib, NSC 802785) has been updated to Version 2.1 
(February 27, 2025) in response to CTEP Request for Rapid Amendment (RRA) 
dated April 3, 2025 and now references leukemia secondary to oncology 
chemotherapy and Myelodysplastic syndrome 
3. 
N/A 
MDS/AML is considered an AESI for Ceralasertib, but this is not identified in the 
protocol - this appears in Section 10.8 for Olaparib 
PI Response: 
As adding MDS/AML as an Adverse Event of Special Interest (AESI) requires 
NCI approval, an inquiry was made to CTEP regarding this comment and a 
response received 03/26/25:   
In terms of listing AML/MDS as an AESI, that can probably be updated in the 
information at annual review. 
Therefore, no changes have been made at this time.   
4. 
7.3 
• MDS/AML is considered an identified risk (ADR) for olaparib and 
potential risk for ceralasertib.  Both products incorporate the following 
guidance in their respect TMG/dose modification guidelines, recommend 
the site incorporate the same (or similar) 
Management of prolonged haematological toxicities 

xvi 
# 
Section 
Comments 
Participant should be referred to a haematologist for further 
investigations and management in the event of prolonged 
haematological toxicity such as: 
• ≥ 2week interruption/delay in study intervention due to CTCAE 
Grade 3 or worse anaemia and/or development of blood 
transfusion dependence 
• ≥ 2week interruption/delay in study intervention due to CTCAE 
Grade 3 or worse neutropenia (ANC < 1 × 109/L) 
≥ 2week interruption/delay in study intervention due to CTCAE 
Grade 3 or worse thrombocytopenia and/or development of platelet 
transfusion dependence (Platelets < 50 × 109/L) 
Consider checking weekly differential blood counts including 
reticulocytes and peripheral blood smear. Bone marrow analysis 
and/or blood cytogenetic analysis should be considered at this stage 
according to standard haematological practice.  
Study intervention should be discontinued if blood counts do not 
recover to CTC Grade 1 or better within 4 weeks of dose 
interruption. 
Development of a confirmed myelodysplastic syndrome or other clonal blood 
disorder should be reported as an SAE and full reports must be provided by the 
investigator to AstraZeneca Patient Safety. Study intervention should be 
discontinued if participant’s diagnosis of MDS and/or AML is confirmed. 
PI Response: 
This information has been added to Section 7.3 as recommended.   
 
 
VII. 
Revisions requested in CTEP Request for Rapid Amendment (RRA) dated April 3, 
2025: 
 
# 
Section 
Comments 
1. 
10.1.1.2 
CAEPR for AZD6738 (ceralasertib, NSC 802785) updated to Version 2.1 (February 27, 
2025): 
• 
Added New Risk: 
• 
Less Likely: Headache 
• 
Rare but Serious: Leukemia secondary to oncology chemotherapy; 
Myelodysplastic syndrome 
• 
Also Reported on AZD6738 Trials But With Insufficient Evidence for 
Attribution: Acute kidney injury; Ascites; Chest pain - cardiac; Disease 
progression; Dysphagia; Electrocardiogram QT corrected interval 
prolonged; Heart failure; Hepatitis viral; Hepatobiliary disorders - Other 

xvii 
# 
Section 
Comments 
(biliary obstruction); Hepatobiliary disorders - Other (cholangitis); 
Hypokalemia; Pericardial effusion; Pulmonary edema; Renal and urinary 
disorders - Other (acute renal insufficiency);  Respiratory failure; Sepsis; 
Stroke; Superior vena cava syndrome; Thromboembolic event; Vascular 
disorders - Other (thrombophlebitis) 
 
• 
Increase in Risk Attribution: 
• 
Changed to Likely from Less Likely: Vomiting 
• 
Changed to Less Likely from Also Reported on AZD6738 Trials But 
With Insufficient Evidence for Attribution: Edema limbs; Infections and 
infestations - Other (COVID-19); Lung infection; Weight loss 
 
• 
Decrease in Risk Attribution:  
• 
Changed to Also Reported on AZD6738 Trials But With Insufficient 
Evidence for Attribution from Less Likely: Aspartate aminotransferase 
increased; Dizziness; Pain 
 
 
• 
Modified Specific Protocol Exceptions to Expedited Reporting (SPEER) 
reporting requirements:  
• 
Added: Diarrhea; Vomiting  
 
• 
Provided Further Clarification:         
• 
Gastrointestinal disorders - Other (gastroenteritis) (under Also Reported 
on AZD6738 Trials But With Insufficient Evidence for Attribution) is 
now reported as Infections and infestations - Other (gastroenteritis) 
(under Also Reported on AZD6738 Trials But With Insufficient Evidence 
for Attribution) 
 
 

 
1 
NCI Protocol #:  10222 
 
Local Protocol #: 2000027026  
 
ClinicalTrials.gov Identifier:  NCT03878095 
 
TITLE:  A Phase II study of olaparib and AZD6738 in isocitrate dehydrogenase (IDH) mutant 
solid tumors 
 
Corresponding Organization: LAO-CT018 / Yale University Cancer Center LAO 
 
Principal Investigator: 
Patricia LoRusso, DO, PhD (h)  
 
Yale Cancer Center 
 
333 Cedar Street, WWW217 
 
PO Box 208028 
 
New Haven, CT 06520-8028 
 
Phone: 203-785-3333 
 
E-mail: patricia.lorusso@yale.edu  
 
 
Participating Organizations  
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / UPMC Hillman Cancer Center LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
 
Statistician: 
 
Study Coordinator: 
Yu Shyr  
Ingrid Palma 
 
Center for Quantitative Sciences 
 
Yale University  
 
571 Preston Building 
 
MEDCCC Clinical Trial Operations 
 
Nashville, TN, 37232-6848 
300 George Street, New Haven, CT 06519 
 
615-636-2572 
Phone: (203) 737-5342 
 
 
615-936-2602 
Fax: (203) 785-4069  
 
Yu.shyr@vanderbilt.edu 
ingrid.palma@yale.edu 
 
 
 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
3
SCHEMA 
 
Synopsis:  
This is a phase II, open-label study of PARP inhibition (olaparib) and ATR inhibition 
(AZD6738) in subjects with recurrent/progressive, IDH1/2-mutant solid tumors.  
 
Objectives:  
Primary:  
1. To determine the overall response rates of olaparib and AZD6738 in subjects with 
recurrent/progressive IDH1/2-mutant solid malignant tumors, who will be recruited to 2 
cohorts:  
a. Cholangiocarcinoma (this cohort has closed to accrual) 
b. Other solid malignant tumors.  
 
Secondary:  
1. To assess the progression free survival (PFS) of olaparib and AZD6738 in adults with 
recurrent/progressive IDH1/2-mutant solid malignant tumors.  
2. To estimate the overall survival (OS) in adults with recurrent/progressive IDH1/2- 
mutant solid malignant tumors. 
3. To assess the duration of response in adults with recurrent/progressive IDH1/2-mutant 
solid malignant tumors.  
4. To assess the safety and tolerability of the combination of olaparib and AZD6738 
 
Exploratory: 
1. To evaluate 2HG concentration in plasma by mass spectrometry and correlate with 
treatment response, prior to beginning treatment and on day 1 of cycles 2, 4 and 8 of 
therapy and at time of confirmed evidence of progression. 
2. To evaluate 2HG levels in tumor biopsies prior to the beginning of treatment and while 
on therapy and correlate with treatment response. 
3. Correlate 2HG concentration in plasma and in tumor biopsies. 
4. To evaluate DNA double strand breaks (DSBs) as measured by CyTOF-IMC in tumor 
biopsies before and after treatment with olaparib and AZD6738. 
 
An overall treatment schema is shown below in Figure 1.  This is a phase II two-arm, open-label 
study of PARP inhibition (olaparib) and ATR inhibition (AZ6738) in subjects with 
recurrent/progressive, IDH1/2-mutant solid tumors. An overall treatment schema is shown 
below. Patients will be treated with olaparib 300 mg q12hrs each day of a 28-day cycle in tablet 
formation and AZD6738 160 mg qday on days 1-7 of a 28-day cycle in tablet formation until 
disease progression, unacceptable toxicity, withdrawal of consent or death. Tablet formation of 
olaparib is preferred over capsule formulation based on recent work demonstrating equivalent 
efficacy with a reduced pill burden (Mateo, Target Oncol, 2016).  
 
Patients with IDH1/2 mutations previously identified in a CLIA-certified laboratory are eligible 
for the trial. Whole exome sequencing and RNA sequencing will be performed prior to study 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
4
completion for the purpose of data analysis.  This analysis will be performed on pre-treatment 
biopsy tissue (see next paragraph) or archival formalin-fixed paraffin embedded (FFPE) 
specimens, if the former is not available and archival tissue is available. 
 
Patients will undergo a pre-treatment biopsy within 2 weeks of starting therapy.  Repeat biopsy 
will be required 4 weeks from the start of treatment.  The biopsy will consist of at least 6 passes 
of a large gauge needle (such as 16 or 18g) for core biopsy. Patients in these cohorts must have 
tumors determined to be easily accessible for biopsy. Tumor biopsies will be performed on the 
most accessible biopsable site of disease. All possible precautions to avoid complications will be 
taken, including discussions in multidisciplinary meetings, if needed.  
 
Correlative studies will include determination of 2HG levels in archival FFPE specimens and 
biopsy frozen tissue.  This will be done using LC-MS/MS, which will be performed in the 
Karmanos Cancer Institute Pharmacology Core.   Blood samples for 2-HG analysis will be 
collected prior to starting therapy and on day 1 of cycles 2, 4, and 8 of therapy and at time of 
confirmed evidence of progression.  A window of +/- 4 days for each intervention is permitted. 
 
All eligible patients will be imaged within 30 days prior to starting therapy, and then after every 
two cycles of therapy (8 weeks) for the first twelve months, or until time of progression, 
unacceptable toxicity, withdrawal of consent, death, or any other discontinuation criteria, 
whichever occurs first.  If partial response (PR) or complete response (CR) is documented, a 
confirmatory scan will be performed 4 weeks later for PR/CR (whichever occurs first). After 12 
months, patients will undergo tumor assessments every 12 weeks until confirmed disease 
progression. 
 
Patients will be imaged with CT and/or MRI scans of the chest, abdomen and pelvis. Patients 
who start a new anti-cancer therapy in the absence of disease progression should continue to 
follow the protocol schedule until there is confirmed disease progression, withdrawal of consent, 
death, or any other discontinuation criteria, whichever occurs first.  
 
Although pre- and post-treatment biopsies will be critical to evaluating treatment response with 
respect to 2-HG analysis, we understand that it is not always possible to obtain fresh biopsy 
tissue.  For example, a patient may have measurable disease that is not easily accessible for core 
needle biopsy.  Thus we will practice an opt-out policy, wherein a patient may opt out of pre- 
and on-treatment biopsies if biopsy is not possible or the patient does not consent to biopsy and 
permission of the study PI is obtained.  For all patients, archival formalin-fixed paraffin 
embedded (FFPE) specimens will be used, if possible, for baseline LC-MS measurement of 2HG 
levels in tumor. If a patient opts out of pre- and on-treatment biopsies, that patient must have an 
adequate archival specimen to enroll on the trial. Ten of the 14 patients in each arm of the first 
stage of this Simon two-stage study must consent to biopsies. Thus if 4 patients in an arm have 
already opted out, further patients may only enroll on that arm (in the first stage) if they agree to 
undergo the pre- and on-treatment biopsies. 
 
In order to maximize the availability of newly obtained specimens for 2-HG analysis, at least 10 
biopsies will be required in each group (cholangiocarcinoma and other solid tumors) of 14 
patients treated in the first stage of this Simon two-stage design. Patients will not be “replaced.”  

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
5
For example if 13 patients have been enrolled and 9 have agreed to biopsies, the 14th patient 
enrolled on that arm must be one who agrees to a biopsy.  However if that patient consents to the 
trial and withdraws consent for biopsies, that patient will continue participation on the trial. 
 
We expect to enroll between 28 and 50 patients on this trial. 
 
 
Figure 1. Study schema   
 
Study schema 
 
 
  
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
6
TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................9 
1.1 
Primary Objectives...................................................................................................9 
1.2 
Secondary Objectives...............................................................................................9 
1.3 
Exploratory Objectives ............................................................................................9 
2. 
BACKGROUND .................................................................................................................9 
2.1 
IDH mutant solid tumors .........................................................................................9 
2.2 
Rationale ................................................................................................................10 
2.3 
CTEP Agents .........................................................................................................14 
2.4 
Correlative Studies Background ............................................................................26 
3. 
PATIENT SELECTION ....................................................................................................29 
3.1 
Eligibility Criteria ..................................................................................................29 
3.2 
Exclusion Criteria ..................................................................................................32 
3.3 
Inclusion of Women and Minorities ......................................................................35 
4. 
REGISTRATION PROCEDURES ...................................................................................35 
4.1 
Investigator and Research Associate Registration with CTEP ..............................36 
4.2 
Site Registration .....................................................................................................37 
4.3 
Patient Registration ................................................................................................39 
4.4 
General Guidelines.................................................................................................41 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................43 
5.1 
Summary Table for Specimen Collection ..............................................................43 
5.2 
Specimen Procurement Kits and Scheduling .........................................................44 
5.3 
Specimen Collection ..............................................................................................44 
5.4 
Specimen Tracking System Instructions ................................................................44 
5.5 
Shipping Specimens from Clinical Site to the EET Biobank ................................44 
5.6 
Shipping of Specimens from Clinical Site to Other Laboratories .........................44 
5.7 
Correlative Studies .................................................................................................44 
5.8 
Integral Laboratory Studies ....................................................................................47 
5.9 
Integrated Correlative Studies................................................................................47 
5.10 
Exploratory/Ancillary Correlative Studies ............................................................49 
6. 
TREATMENT PLAN ........................................................................................................54 
6.1 
Agent Administration.............................................................................................54 
6.2 
General Concomitant Medication and Supportive Care Guidelines ......................55 
6.3 
Duration of Therapy ...............................................................................................58 
6.4 
Duration of Follow Up ...........................................................................................59 
7. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................60 
7.1 
General Guidance...................................................................................................60 
7.2 
Guidance for Dose Modification and Interruption.................................................60 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
7
7.3 
Management of Prolonged Hematological Toxicities .......................................62 
7.4 
Individual Stopping Criteria ..................................................................................63 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................63 
8.1 
CTEP IND Agents .................................................................................................63 
9. 
STATISTICAL CONSIDERATIONS...............................................................................69 
9.1 
Primary objective ...................................................................................................69 
9.2 
Baseline data analysis ............................................................................................69 
9.3 
Analysis of primary endpoint.................................................................................69 
9.4 
Toxicity evaluation ................................................................................................69 
9.5 
Sample Size/Accrual Rate ......................................................................................70 
9.6 
Stratification Factors ..............................................................................................71 
9.7 
Analysis of Secondary Endpoints ..........................................................................71 
9.8 
Analysis of Exploratory Endpoints ........................................................................71 
9.9 
Reporting and Exclusions ......................................................................................72 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................73 
10.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............73 
10.2 
Adverse Event Characteristics ...............................................................................78 
10.3 
Expedited Adverse Event Reporting ......................................................................79 
10.4 
Routine Adverse Event Reporting .........................................................................81 
10.5 
Pregnancy ...............................................................................................................83 
10.6 
Secondary Malignancy...........................................................................................84 
10.7 
Second Malignancy ................................................................................................84 
10.8 
Olaparib adverse events of special interest ............................................................84 
11. 
STUDY CALENDAR .......................................................................................................85 
11.1 
Study procedures ....................................................................................................88 
12. 
MEASUREMENT OF EFFECT........................................................................................90 
12.1 
Antitumor Effect – Solid Tumors ..........................................................................90 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................97 
13.1 
Study Oversight .....................................................................................................97 
13.2 
Data Reporting .......................................................................................................97 
13.3 
Data Quality Portal ..............................................................................................100 
13.4 
Collaborative Agreements Language ...................................................................100 
14. 
REFERENCES ................................................................................................................103 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................108 
APPENDIX B 
PATIENT DRUG INFORMATION HANDOUT AND 
WALLET CARD .............................................................................................................109 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
8
APPENDIX C 
ACTIONS REQUIRED IN CASES OF COMBINED 
INCREASE OF AMINOTRANSFERASE (AT) AND TOTAL 
BILIRUBIN (TBL) – HY’S LAW ...................................................................................112 
APPENDIX E 
Acceptable birth control methods ............................................................117 
APPENDIX F 
STUDY DRUG DIARY ..........................................................................118 
APPENDIX G  
LABORATORY MANUAL ....................................................................120 
 
 
 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
9
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1. To determine the overall response rates of olaparib and AZD6738 in subjects with 
recurrent/progressive IDH1/2-mutant solid malignant tumors, who will be recruited to 2 
cohorts:  
a. Cholangiocarcinoma (cohort has been closed to accrual) 
b. Other solid malignant tumors.  
 
1.2 
Secondary Objectives 
 
1. To assess the progression free survival (PFS) of olaparib and AZD6738 in adults with 
recurrent/progressive IDH1/2-mutant solid malignant tumors.  
2. To estimate the overall survival (OS) in adults with recurrent/progressive IDH1/2- 
mutant solid malignant tumors. 
3. To assess the duration of response in adults with recurrent/progressive IDH1/2-mutant 
solid malignant tumors.  
4. To assess the safety and tolerability of the combination of olaparib and AZD6738 
 
1.3 
Exploratory Objectives 
 
1. To evaluate 2HG concentration in plasma by mass spectrometry and correlate with 
treatment response. 
2. To evaluate 2HG levels in tumor biopsies prior to the beginning of treatment and while 
on therapy and correlate with treatment response. 
3. Correlate 2HG concentration in plasma and in tumor biopsies. 
4. To evaluate DNA double strand breaks (DSBs) as measured by CyTOF-IMC in tumor 
biopsies before and after treatment with olaparib and AZD673.  
 
 
2. 
BACKGROUND 
 
2.1 
IDH mutant solid tumors 
 
Mutations in isocitrate dehydrogenase (IDH) enzymes are most common in low grade tumors of 
the central nervous system, occurring in over 70% of secondary glioblastoma multiforme (GBM) 
and low grade gliomas. In these instances, IDH mutations conferred improved overall survival 
(OS) in patients with anaplastic astrocytomas and secondary GBM.  However, the prognosis 
remains poor in the latter, with an average survival of 14.6 months.1 IDH1/2 mutations have also 
been identified in 10-23% of patients with intrahepatic cholangiocarcinomas,2–4 with unclear 
effects on OS.2,3 Intrahepatic cholangiocarcinoma (IHCC), which represents about 20-30% of all 
cases of cholangiocarcinoma, is often found in patients with cirrhosis. Only 30-40% of IHCC 
patients have resectable disease at the time of diagnosis and survival rates are dismal, with 25% 
of patients alive at one year, and 5% alive at five years after diagnosis.5 The standard of care for 
advanced IHCC is chemotherapy with cisplatin and gemcitabine, which has a median overall 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
10 
survival (OS) of 11.7 months compared to 8.1 months with gemcitabine alone.6 However, poor 
liver function and low performance status, as well as advanced age often limit the use of 
combination chemotherapy for patients with IHCC.5 Among 203 patients with unresectable 
IHCC who did not opt for any therapy, the median survival was 3.0 months.7 There is no 
standard second-line therapy for advanced IHCC, making it imperative to explore alternate 
therapeutic approaches to this challenging disease. Finally, a low frequency (<5%) of IDH1/2 
mutations has been described in other solid tumors, including primary glioblastoma, colorectal 
cancer, esophageal cancer, bladder cancer, melanoma, prostate carcinoma, and breast 
adenocarcinoma.8,9 In summary, IDH1/2 mutations are found most frequently in a number of 
cancers with poor baseline prognoses, and may in fact confer additional risk. Establishing new 
therapeutic options for patients whose tumors harbor such mutations is thus a priority. 
 
 
2.2 
Rationale 
2.2.1 Introduction 
 
2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both 
are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-
dependent dioxygenases. The former is an oncometabolite that is induced by the 
neomorphic activity conferred by isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations, 
while the latter is produced under pathologic processes such as hypoxia. Our 
collaborators in the Bindra and Glazer laboratories recently made the novel discovery that 
IDH1/2 mutations induce a defect in homologous recombination repair (HRR) which 
renders tumor cells exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) 
inhibitors.10 Remarkably, this phenotype can be completely reversed by treatment with 
small molecule inhibitors of mutant IDH1, and it can be entirely recapitulated by 
treatment with 2HG alone in cells with WT IDH1/2.  
 
Our collaborators performed a comprehensive series of studies to test whether it was 
possible to detect mutant IDH1/2-dependent synergistic, synthetic lethal interactions 
using a variety of DNA repair inhibitors, demonstrating IDH1-dependent PARP and ATR 
inhibitor sensitivity in a range of clinically relevant models in vitro and PARP inhibitor 
growth restriction in vivo. These studies also revealed a marked interaction between 
PARP inhibitors and ATR inhibitors in IDH1-mutant cells. These data indicate that it is 
possible to induce highly effective levels of tumor cell kill without a DNA damaging 
agent. In parallel, another laboratory independently reported a similar synthetic lethal 
interaction between IDH1/2 mutations and PARP inhibitors.. Collectively, these findings 
directly challenge the current therapeutic strategy to block IDH-mutant function, and they 
instead provide a novel approach to treat these tumors with PARP inhibitors. 
Furthermore, these results uncover an unexpected link between oncometabolites, altered 
DNA repair, and genetic instability. 
 
This trial directly translates our collaborators’ recent findings into a biomarker-driven 
clinical trial. We will test the efficacy of olaparib combined with the ATR inhibitor, 
AZD6738, using the recommended Phase II dosing regimen that was recently 
established by AstraZeneca. This study will focus on IDH1/2-mutant solid tumors, and 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
11 
it will utilize a Simon 2-stage design.  
 
Previous data suggest that patients enrolled will most likely be affected by 
cholangiocarcinoma, for which there are very limited treatment options and thus there is a 
great unmet need. In addition to these patients, we will include a second group of patients 
who have tumors with IDH1/2 mutations in other tissue types. Multiple unique 
biomarkers will be employed in this trial, including 2HG detection by LC/MS in plasma 
and tumor biopsies and determination of γH2AX foci and other markers of DNA double 
strand breaks (DSBs) by CyTOF in tumor biopsies. 
 
These studies have the potential to establish a completely novel treatment approach for 
IDH1/2-mutant tumors, and they will lay the groundwork for future studies aimed at 
exploiting, rather than suppressing, 2HG-induced BRCAness in a wide range of solid 
tumors.  
 
2.2.2 Background 
 
The normal function of isocitrate dehydrogenase (IDH) enzymes is to catalyze the 
conversion of isocitrate to α-ketoglutarate (αKG) in the citric acid cycle. Recurring IDH1 
mutations were identified in two independent cancer genome sequencing projects focused 
on gliomas and acute myeloid leukemia (AML).11,12 Subsequent studies revealed that 
IDH1 mutations occur in more than 70% of low grade gliomas and up to 20% of higher 
grade tumors (e.g., secondary glioblastoma multiforme; GBM) and 10-23% of patients 
with intrahepatic cholangiocarcinomas.2–4  Additionally, mutations were also identified in 
IDH2, the mitochondrial homolog of IDH1, in about 4% of gliomas and 10% of AMLs.1,8 
Mutations in IDH1/2 also occur in a small percentage (<5%) of other solid tumors, 
including colorectal cancer, esophageal cancer, bladder cancer, melanoma, prostate 
carcinoma, breast adenocarcinoma.8,9  
 
Nearly all known IDH1/2 alterations are 
heterozygous missense mutations that confer a 
neomorphic activity on the encoded enzymes, 
such that they convert α-KG to (R)-2HG (Figure 
2).13 Emerging research indicates that (R)-2HG is 
an oncometabolite which exerts its effect via 
altering chromatin methylation, possibly by 
competitive inhibition of α-KG-dependent tumor 
suppressor enzymes.14 Another hypothesized 
mechanism is the induction of mitochondrial 
dysfunction and inability to manage oxidative 
stress.15 (R)-2HG appears to exert its regulatory 
effects via the inhibition of αKG-dependent 
dioxygenases.14 
 
 
Fig. 2. Proposed mechanism of action 
of mutant IDH1/2-induced BRCAness 
and consequent PARP inhibitor 
synthetic lethality. 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
12 
2.2.3 IDH1/2 mutated solid tumors induce a defect in homologous recombination repair 
 
In work recently published in Science Translational Medicine, our collaborators 
discovered that IDH1/2 mutations induce a defect in homologous recombination 
repair that renders tumor cells sensitive to inhibition of poly (ADP-ribose) 
polymerase (PARP) and ataxia-telangiectasia mutated and Rad3 related (ATR) gene 
products.10 When 2HG accumulates in IDH1-mutant cells, HRR is disrupted, causing 
cells to rely on alternative, low fidelity DNA repair pathways, thus hastening genomic 
instability and cell death. This phenotype renders them increasingly susceptible to agents 
that impair the DNA damage response, such as inhibitors of PARP and ATR. 
 
Multiple aspects of the IDH1/2-induced “BRCAness” phenotype were demonstrated in a 
range of clinically relevant models in vitro, including patient-derived glioma cell lines 
and primary AML bone marrow cultures. For example, our collaborators tested a 
collection of early-passage, patient-derived IDH1-WT and -mutant glioma cell lines 
available at our institution. IDH1 mutations were confirmed by sequencing as reported 
previously,16 and they also confirmed that it was possible to detect 2HG production in 
samples harboring an IDH1 R132H or R132C mutation. They detected increased baseline 
persistence of DSBs by comet assay in the primary glioma cell lines harboring IDH1 
mutations, which is a classic approach to assess functional DSB repair activity.17  
 
The HRR defect could be recapitulated in matched WT cells exposed to exogenous 2HG 
and was dose-dependent. Our collaborators detected PARP inhibitor sensitivity in the 
IDH1- mutant primary glioma cultures compared to two IDH1-WT cultures by 
clonogenic survival, and found that 2HG exposure could recapitulate PARP inhibitor 
sensitivity in WT cultures. Importantly, these data confirm that the IDH1-associated HRR 
defect can be detected in grades 2, 3, and 4 glioma. Mechanistically, this phenotype can 
be entirely recapitulated by exposure to either 2HG enantiomers, and it cannot be 
explained by the alterations in NAD+ levels that have been seen in IDH1/2-mutant 
cancers.18  In addition, they found that 2HG exposure induced elevated rates of DSBs in a 
range of cell lines with diverse genetic backgrounds, including immortalized astrocytes, 
primary melanoma cultures, breast cancer cell lines, and U2OS cells, suggesting that this 
is a fundamental effect of this oncometabolite. 
 
These data support our rationale to test IDH1/2-mutant tumors beyond gliomas. Recent 
data from the Gunel laboratory at Yale University showed that IDH1 mutations in 
gliomas that are initially present at diagnosis appear to persist after recurrence.16 
Similarly, persistence of the IDH1 mutation has also been found in relapsed AMLs that 
harbored the mutation at initial diagnosis.19 Thus, we expect that there will be persistent 
2HG production and subsequent HR deficiency in recurrent IDH1/2-mutant tumors, 
making this group a suitable population for our study.  
 
2HG-induced HR suppression appears to be mediated via direct inhibition of αKG-
dependent dioxygenases, in particular KDM4A. Our collaborators recapitulated the 
IDH1/2-associated HR-defective phenotype by treatment of WT cells with small 
molecule KDM4A inhibitors, and could reverse it in mutant cells by overexpression of 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
13 
KDM4A. Importantly, they found that treatment with a mutant IDH1-specific small 
molecule inhibitor known to potently suppress 2HG production reversed the observed HR 
defect and eliminated the associated PARP inhibitor sensitivity. They demonstrated this 
reversal in both mutant IDH1/2 cell lines, and in a cell line harboring an endogenous 
IDH1 mutation. Reversal of the mutant IDH1-associated DSB repair defect was 
confirmed using three unique small molecule inhibitors of the mutant protein, and with 
siRNAs targeting the IDH1 gene, thus ruling out potential off-target effects of the 
inhibitors. 
 
Our collaborators sought to harness the inherent HR deficiency in IDH1/2 mutant cells by 
targeting these specific mechanisms of DNA damage repair to achieve synthetic lethality. 
A focused, unbiased screen of their R132H IDH1 mutant HeLa cell line with a library of 
DNA damaging agents and DNA repair inhibitors revealed an unexpected sensitivity of 
IDH1 mutant cells to PARP (an enzyme critical to the repair of DNA single-strand breaks 
via base excision repair)20 or ATR (an enzyme recruited to stalled replication forks which 
enables the halting of the cell cycle via phosphorylation of CHK1 while replication forks 
are stabilized).21 Inhibition of either enzyme resulted in the accumulation of DNA double 
strand breaks as measured by γH2AX and 53BP1 foci. 
 
2.2.4 IDH1/2 mutated solid tumors are sensitive to inhibition with PARP and ATR 
inhibitors 
Our colleagues in the laboratory of Ranjit Bindra 
explored the HRR deficiency of IDH1/2 mutated 
solid tumors with a comprehensive cytotoxicity 
screen of our R132H IDH1 mutant HeLa cell line 
with a large collection of DNA damaging agents 
and DNA repair inhibitors.  This revealed an 
unexpected sensitivity of IDH1 mutant cells to 
inhibition of both PARP and ATR (Figure 3). 
Sensitivities to PARP inhibitors were profound, 
and approached a 50-fold difference compared to 
IDH1-wildtype (WT) cells with the FDA-approved PARP inhibitor, olaparib. They then 
demonstrated this PARP sensitivity across five unique and genetically diverse cell line 
pairs that were engineered to express either the wild-type (WT) or the mutant IDH1/2 
proteins and confirmed the observed DSB repair defect using multiple orthogonal 
functional assays. This interaction was demonstrated in several pre-clinical models, 
including IDH1/2-mutant primary patient-derived cell lines and genetically-matched 
tumor xenografts. Suppression of HR by 2HG was significant and was observed after the 
attenuation of two key HR genes, BRCA2 and Rad51, using the well-established DR-
GFP assay to measure the activity of this pathway.  
 
IDH1 mutant mouse xenografts treated with olaparib showed a statistically significant 
growth delay when compared to vehicle control. In contrast, no statistically significant 
differences were detected between olaparib and vehicle in IDH1-WT tumor xenografts 
(Figure 4). Given their recent screen demonstrating sensitivity of IDH1 mutated cells to 
ATR inhibition, our collaborators sought to test whether a combination of PARP and 
Figure 3. 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
14 
ATR inhibitors would be 
synergistic. Using 
Combenefit, an open-
access software tool that 
enables the visualization, 
analysis and quantification 
of drug combination 
effects,22 they confirmed a 
marked, synergistic 
interaction between PARP 
and ATR inhibitors, which was most dramatic in IDH1-mutant cells (Figure 5). 
 
Based on these findings, we have designed a Phase II clinical trial using the FDA-
approved PARP inhibitor olaparib and AZD6738, an ATR inhibitor, for patients 
with IDH1/2 mutated advanced solid tumors that have progressed despite standard 
therapy (Figure 6).  
 
 
 
2.3 
CTEP Agents 
 
2.3.1 Olaparib 
Investigators should be familiar with the current olaparib (AZD2281) Investigator’s 
Brochure. 
 
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly 
(ADP ribose)] polymerisation (PARP) inhibitor (PARP-1, -2 and -3) that is being 
developed as an oral therapy, both as a monotherapy (including maintenance) and for 
combination with chemotherapy and other anti-cancer agents. 
 
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA repair 
mechanisms.  PARP enzymes are essential for repairing DNA single strand breaks 
(SSBs).  Inhibiting PARPs leads to the persistence of SSBs, which are then converted to 
Figure 4. (Left) PARP inhibitors selectively kill HCT116 IDH1-mutant tumor xenografts 
with (Middle) minimal effects on IDH-WT xenografts; (Right) BLI monitoring of 
treatment responses 
Figure 6. Conceptual schema 
Figure 5. Example of synergy with regard to tumor cell viability 
between representative PARP and ATR inhibitors (BMN-673 
and VE-822, respectively) which is enhanced in IDH-mutant 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
15 
the more serious DNA double strand breaks (DSBs) during the process of DNA 
replication.  During the process of cell division, DSBs can be efficiently repaired in 
normal cells by homologous recombination repair (HR).  Tumors with HR deficiencies 
(HRD), such as ovarian cancers in patients with BRCA1/2 mutations, cannot accurately 
repair the DNA damage, which may become lethal to cells as it accumulates.  In such 
tumor types, olaparib may offer a potentially efficacious and less toxic cancer treatment 
compared with currently available chemotherapy regimens.  
 
BRCA1 and BRCA2 defective tumors are intrinsically sensitive to PARP inhibitors, both 
in tumor models in vivo23,24 and in the clinic.25 The mechanism of action for olaparib 
results from the trapping of inactive PARP onto the single-strand breaks preventing their 
repair.26,27  Persistence of SSBs during DNA replication results in their conversion into 
the more serious DNA DSBs that would normally be repaired by HR repair.  Olaparib has 
been shown to inhibit selected tumor cell lines in vitro and in xenograft and primary 
explant models as well as in genetic BRCA knock-out models, either as a stand-alone 
treatment or in combination with established chemotherapies. 
 
Olaparib was first reported as an inhibitor of PARP1/2 in 2008.28 The phase I study of 
olaparib, reported in 2009, initially enrolled 60 patients with a variety of advanced solid 
tumors, with a population enriched for carriers of BRCA1/2 mutations.29 Twenty-two 
participants had such a mutation and one more declined testing but was deemed a likely 
carrier due to family history. Responses were seen only in this subset of patients, of 
whom 47% responded by RECIST criteria and 63% had either stable disease or a 
response. Demonstrating proof of mechanism, the investigators used immunoblotting of 
post-treatment biopsies to prove that among patients who responded, PARP was 
effectively inhibited. Moreover, they found that γH2AX foci, a marker of DSBs, 
increased only six hours after treatment in plucked eyebrow hair follicles, proving that 
olaparib-mediated PARP inhibition results in the formation of unrepaired DSBs. 
Toxicities primarily included fatigue, nausea, and vomiting. An expansion cohort of 48 
patients with ovarian cancer and germline BRCA1/2 mutations again demonstrated the 
potential of PARP inhibition in BRCA mutated cancers, with an objective response rate 
(ORR) of 40%.30 Interestingly, responders were more likely to have platinum sensitive 
disease, which is increasingly considered a surrogate marker of HR deficiency.  
 
In 2010, the results of phase II studies of olaparib in patients with BRCA1/2 mutated 
recurrent advanced ovarian and breast cancer were published, demonstrating ORRs of 
33% and 41%, respectively, in heavily pretreated patients who received olaparib at 
400mg bid.31,32 Notably, the breast cancer patients were evenly divided among subtypes, 
with 50% TNBC, 45% hormone positive, and 4% human epidermal growth factor-2 
(HER2) positive. Again, toxicities included mild fatigue and nausea in 40% of patients. 
Another phase II trial of olaparib in advanced metastatic or recurrent ovarian, BRCA 
mutated breast cancer, or triple negative breast cancer disappointingly observed no 
responses in any breast cancer patients.33 However, in addition to the 41% of BRCA 
mutated ovarian cancer patients who responded to olaparib, another 24% of BRCA 
wildtype (WT) ovarian cancer patients responded. A posthoc analysis found that 
responsiveness in both groups was highly correlated with platinum sensitivity, again 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
16 
suggesting the utility of platinum sensitivity as a marker for HR deficiency beyond that 
mediated by BRCA. 
 
In 2012, results of a randomized double blind phase II study of olaparib maintenance in 
patients with advanced ovarian cancer were published. Although olaparib improved 
progression-free survival (PFS), no improvement in OS was seen.34 An interim analysis 
two years later specifically examined patients with somatic and germline BRCA 
mutations, finding a significantly improved PFS for BRCA mutated patients. Still, no 
difference on OS was observed for those assigned to olaparib maintenance.35 However, a 
2015 phase II study of olaparib in patients with germline BRCA1/2 mutations found that 
the drug had promise in multiple tumor types, demonstrating ORRs of 12.9%, 31.1%, 
21.7%, and 50% in patients with breast, platinum resistant ovarian, pancreatic, and 
prostate cancers, respectively.36 In 2014, updated results of the phase II study of olaparib 
in BRCA1/2 mutated recurrent advanced ovarian cancer were released, demonstrating an 
ORR of 34% and median duration of response (DoR) of 7.9 months in patients who had 
received three or more prior lines of chemotherapy.37 As a result, the Food and Drug 
Administration (FDA) approved the use of olaparib in this patient population.38  
 
The potential of single agent olaparib in breast cancer was demonstrated in 2017 in the 
OlympiAD study, a randomized, open label, phase III trial of olaparib versus standard of 
care (SOC) chemotherapy in patients with germline BRCA mutated, HER2-negative 
MBC.39 The trial found an improved response rate in the olaparib group (59.9% vs. 
28.8% for SOC), as well as improved PFS (7.0 months for olaparib vs. 4.2 months for 
SOC). No difference was observed in OS, although the study was not powered to detect 
this, nor was it powered to differentiate among outcomes in patients stratified by 
hormone-receptor positive disease or history of platinum use. Nevertheless, this was the 
first phase III trial to definitively demonstrate a small but clear benefit of olaparib use in 
heavily pretreated patients with BRCA1/2 mutated MBC.  
 
Patients on this trial will be treated with olaparib 300 mg q12hrs each day of a 28-day 
cycle in tablet formation until disease progression, unacceptable toxicity, withdrawal of 
consent or death. Tablet formation is preferred over capsule formulation based on recent 
work demonstrating equivalent efficacy with a reduced pill burden.40 
 
2.3.1.1 
Pre-clinical experience 
 
The pre-clinical experience is fully described in the current version of the olaparib 
Investigator’s Brochure.    
 
2.3.1.2 
Toxicology and safety pharmacology summary 
 
The toxicology and safety pharmacology is fully described in the current version of 
the olaparib Investigator’s Brochure.    
 
2.3.1.3 
Clinical experience 
This section lists those ADRs that are currently regarded as expected for regulatory 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
17 
reporting purposes. 
 
Olaparib monotherapy has been associated with laboratory findings and/or clinical 
diagnoses, generally of mild or moderate severity (CTCAE Grade 1 or 2) and 
generally not requiring treatment discontinuation. 
 
The safety profile is based on pooled data from 1248 patients treated with olaparib 
monotherapy in clinical trials in the therapeutic indication at the recommended dose. 
 
The following adverse reactions have been identified in completed clinical trials with 
patients receiving olaparib monotherapy where patient exposure is known. Adverse 
Drug Reactions are organized by Medical Dictionary for Regulatory Activities 
(MedDRA) SOC and then by MedDRA preferred term. Within each SOC, preferred 
terms are arranged by decreasing frequency and then by decreasing seriousness. 
Frequencies of occurrence of adverse reactions are defined as: very common (≥1/10); 
common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to 
<1/1000); and very rare (<1/10,000) including isolated reports. 
 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
18 
Adverse Drug Reactions reported in Clinical Trials 
 
 
 
Description of selected adverse reactions 
 
Hematological toxicity 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
19 
Anemia and other hematological toxicities are generally low grade (CTCAE Grade 1 or 
2). However, there are reports of CTCAE Grade 3 and higher events. Anemia was the 
most common CTCAE Grade ≥3 adverse reaction reported in clinical studies with first 
onset generally reported in the first 3 months of treatment. An exposure-response 
relationship between olaparib and decreases in haemoglobin has been demonstrated. In 
clinical studies with olaparib, the incidence of CTCAE Grade ≥2 shifts (decreases) from 
baseline in haemoglobin was 20%, absolute neutrophils 15%, platelets 5%, lymphocytes 
30% and leukocytes 20% (all % approximate). 
 
The incidence of elevations in MCV from low to normal at baseline to above the upper 
limit of normal was approximately 55%. Levels appeared to return to normal after 
treatment discontinuation and did not appear to have any clinical consequences. 
Baseline testing, followed by monthly monitoring of complete blood counts is 
recommended for the first 12 months of treatment with olaparib, and periodically after 
this time to monitor for clinically significant changes in any parameter during treatment 
which may require dose interruption or reduction and/or further treatment. 
 
 
Other laboratory findings 
 
In clinical studies with olaparib, the incidence of CTCAE Grade ≥2 shifts (elevations) 
from baseline in blood creatinine was approximately 15%. Data from a double-blind 
placebo-controlled study showed median increase up to 23% from baseline remaining 
consistent over time and returning to baseline after treatment discontinuation, with no 
apparent clinical sequelae; 90% of patients had creatinine values of CTCAE Grade 0 at 
baseline and 10% were CTCAE Grade 1 at baseline. 
 
Nausea and vomiting 
 
Nausea was generally reported very early, with first onset within the first month of 
olaparib treatment in the majority of patients. Vomiting was reported early, with first 
onset within the first two months of olaparib treatment in the majority of patients. Both 
nausea and vomiting were reported to be intermittent for the majority of patients. 
 
Combination studies 
 
Safety data from studies in which olaparib has been administered in combination with 
other agents are discussed below. The degree of bone marrow suppression observed in 
some patients in the combination studies has however been greater than would be 
expected with the chemotherapy agent alone, as per label information. Myelotoxicity has 
been observed in studies evaluating olaparib with the following combination therapies: 
DTIC; carboplatin; paclitaxel; carboplatin + paclitaxel; gemcitabine; topotecan; cisplatin; 
doxorubicin, cisplatin + gemcitabine; or irinotecan. 
 
The principal hematological toxicities observed have been neutropenia, 
thrombocytopenia, and anemia. These findings are consistent with pre-clinical 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
20 
findings.24,41–43  
 
 
Safety: combination studies 
 
Administration of olaparib in combination with DTIC, topotecan, paclitaxel, carboplatin 
and paclitaxel, cisplatin and gemcitabine resulted in a lower MTD compared with 
administration of olaparib as a monotherapy. Olaparib doses ranging between 20 mg bd 
and 200 mg bid in combination with these other treatments resulted in an increase in 
myelotoxicity, especially neutropenia. In some cases this was despite administration of 
sub-optimal doses of olaparib and a reduction in the suggested dose of the combination 
study drug (eg, topotecan). Administration of bevacizumab at recommended doses with 
olaparib up to 400 mg bd was a well-tolerated combination treatment resulting in no 
unusual or unexpected AEs. Olaparib in combination with liposomal doxorubicin 40 
mg/m2 was generally well tolerated at dose levels ranging from 50 mg bd to 400 mg bd, 
with both a 7-day and a 28-day dosing schedule.  
 
 
Adverse events of special interest 
 
Myelodysplastic syndrome/acute myeloid leukemia 
 
The incidence of MDS/AML in patients treated in clinical trials with olaparib 
monotherapy, including long-term survival follow-up, was <1.5% and the majority of 
events had a fatal outcome. All patients had potential contributing factors for the 
development of MDS/AML, having received previous chemotherapy with platinum 
agents. Many had also received other DNA damaging treatments. The majority of reports 
were in germline BRCA mutation carriers and some of the patients had a history of 
previous cancer or of bone marrow dysplasia. If MDS and/or AML are confirmed while 
on treatment with olaparib, it is recommended that olaparib should be discontinued and 
the patient be treated appropriately.  
 
New Primary Malignancies other than MDS/AML 
New primary malignancies have been reported in <1% of patients. There were other 
contributing factors/potential alternative explanations for the development of the new 
primary malignancy in all cases, including documented BRCA mutation, treatment with 
radiotherapy and extensive previous chemotherapy including carboplatin, taxanes, 
anthracyclines and other alkylating and DNA damaging agents. 
 
Pneumonitis 
 
Pneumonitis has been reported in <1.0% patients treated with olaparib monotherapy in 
clinical studies. Reports of pneumonitis had no consistent clinical pattern and were 
confounded by a number of pre-disposing factors (cancer and/or metastases in lungs, 
underlying pulmonary disease, smoking history, and/or previous chemotherapy and 
radiotherapy). When olaparib was used in clinical studies in combination with other 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
21 
therapies there have been events with a fatal outcome. If patients present with new or 
worsening respiratory symptoms such as dyspnea, cough and fever, or anabnormal chest 
radiologic finding is observed, olaparib treatment should be interrupted and prompt 
investigation initiated. If pneumonitis is confirmed, olaparib treatment should be 
discontinued and the patient treated appropriately. 
 
Clinical experience with olaparib is fully described in the current version of the olaparib 
Investigator’s Brochure. 
 
2.3.2 AZD6738 
Investigators should be familiar with the current AZD6738 Investigator’s Brochure.  
AZD6738 is a potent, selective inhibitor of the serine/threonine-specific protein kinase, 
ataxia telangiectasia and Rad3-related protein (ATR), with good selectivity against other 
phosphatidylinositol 3-kinase-related kinase (PIKK) family members. ATR is an atypical 
kinase in one of the DNA-damage induced checkpoint pathways, and during normal 
DNA replication is recruited at stalled replication forks, which can progress to double 
strand breaks if left unrepaired. Following resection of double strand breaks ATR is 
recruited to single strand DNA coated with Replication Protein A (RPA) following single 
strand DNA damage. Recruitment and activation of ATR leads to cell cycle arrest in the 
S phase while the DNA is repaired and the stalled replication fork resolved, or nuclear 
fragmentation and entry into programmed cell death (apoptosis). Loss of ATR function 
leads to the inability to resolve stalled replication forks, the accumulation of DNA 
damage and rapid cell death exemplified by nuclear fragmentation.24,41–43 AZD6738 is 
being developed as an oral anti-tumor agent with an initial focus on patients with ATM-
deficient disease, although there is preclinical evidence for activity in broader malignant 
disease types. 
 
In patients with malignancies, an ATR inhibitor has the potential to have monotherapy 
activity, through synthetic lethality44 or combination activity, by leading to dependency 
on other mechanisms of DNA damage repair which may be targeted by other DNA 
damaging agents or inhibitors of DNA repair such as PARP inhibitors.   
 
Patients on this trial will be treated with AZD6738 160 mg qday on days 1-7 of a 28-day 
cycle in tablet formation until disease progression, unacceptable toxicity, withdrawal of 
consent or death. 
 
 
2.3.2.1 
Pre-clinical experience 
 
The pre-clinical experience is fully described in the current version of the AZD6738 
Investigator’s Brochure.    
 
2.3.2.2 
Toxicology and safety pharmacology summary 
 
The toxicology and safety pharmacology is fully described in the current version of 
the AZD6738 Investigator’s Brochure.    

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
22 
 
2.3.2.3 
Clinical experience 
 
This section lists those ADRs that are currently regarded as expected for regulatory 
reporting purposes. 
 
Adverse effects for patients who have received AZD6738 is available for those 
treated on four clinical trials.  D5330C00001 (NCT01955668) was a two-part phase I, 
open-label, multicentre study to assess the safety, tolerability, pharmacokinetics, 
pharmacodynamics and preliminary anti-tumor activity of multiple ascending doses 
of AZD6738 in patients with prospectively identified 11q-deleted relapsed/refractory 
chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL) or B cell 
lymphomas.  One 70 year old male patient, with 11q deleted CLL, has been dosed 
with AZD6738 (20 mg BD, 3weeks on/ 1 week off) for one cycle (28 days); study 
treatment was stopped due to disease progression. This study was stopped due to 
difficulties in recruiting the required patient population. Only one patient was treated 
on study. 
 
PATRIOT (D5330C00002) was a study of AZD6738 in advanced solid malignancies 
sponsored by the Royal Marsden Hospital and Institute for Cancer Research in 
London. The study opened to recruitment in June 2014 and has now terminated 
recruitment. The study comprises 3 parts: Part A, a monotherapy dose escalation in 
patients with advanced solid malignancies, who have exhausted other treatment 
options; Part B, a monotherapy expansion in prospectively selected ATM-deficient 
advanced solid cancer patients, to examine one or more schedules of AZD6738; and 
Part C, a radiotherapy combination expansion.   
 
As of the February 2019, forty-six patients enrolled and received at least 1 dose 
AZD6738 on the PATRIOT study. Patients received one of two different schedules at 
the established MTD of 160 mg BD. Seventeen of twenty-six (65%) patients in dose 
escalation and 7/20 (35%) in dose-expansion had Grade  ≥ 3 treatment-related adverse 
events (TRAEs). An intermittent schedule (2-week-on, 2-week-off) was better 
tolerated than continuous dosing, with Grade ≥ 3 TRAEs in 4/6 (67%) receiving 
continuous and 3/15 (20%) with intermittent dosing. The most common TRAEs were 
fatigue, anaemia, nausea and thrombocytopenia; Five (19%) patients in dose-
escalation and 1 (5%) in dose-expansion discontinued due to toxicity. Best overall 
response was confirmed partial response (PR) in 3 (7%) participants, unconfirmed PR 
in 1 (2%), stable disease (SD) in 22 (48%) and PD in 12 (26%).64  
 
VIKTORY is an externally sponsored basket study that is examining novel agents in 
combination with paclitaxel in 2nd line gastric cancer. Patients were assigned to 
treatment arms based upon the molecular profile of their tumor. The study was 
sponsored by the SAMSUNG Medical Center in Korea and the PI was Dr. Jeeyun 
Lee. In the phase 1 part of the study, eligible patients with solid tumors received 
escalating doses of ceralasertib in combination with a fixed dose of paclitaxel (80 
mg/m2 on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
23 
reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. 
Fifty-seven patients were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 
mg BD plus weekly paclitaxel. The RP2D was established as ceralasertib 240 mg BD 
days 1–14 plus paclitaxel 80 mg/m2 on D1, D8, D15 every 28 days. Cytopenias were 
the most common toxicity. With neutropenia in 39 patients (68%) anemia in 25 
patients (44%), and thrombocytopenia in 21 patients (37%). In the full analysis set of 
57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5–35.3).65 
 
Study D5330C00004 (NCT02264678) is an ongoing modular, phase I, 2 part, open-
label, multicentre study of AZD6738, administered orally, in combination with 
cytotoxic chemotherapy regimens or novel anticancer agents, to patients with 
advanced/metastatic solid malignancies. The study design allows an escalation of the 
dose of AZD6738 as monotherapy and in combination with the standard dose and 
schedule of either cytotoxic chemotherapies or novel anti-cancer agents, 
with intensive safety monitoring to ensure the safety of the patients. 
 
The first module, Module 1, of the study is investigating AZD6738 administered 
orally in combination with Carboplatin, to patients with advanced malignancies in 
order to establish the minimally biological active dose of AZD6738, with subsequent 
expansions in patients with ATM deficient Non-Small Cell Lung Cancer. 
 
The second module, Module 2, of the study is investigating AZD6738 administered 
orally in combination with olaparib, to patients with advanced malignancies. The 
purpose of this module is to establish the MBAD of AZD6738 given in combination 
with olaparib, and assess preliminary efficacy in a subsequent expansion(s) in patients 
with advanced ATM-deficient gastric adenocarcinoma (including the 
gastrooesophageal junction). 
 
The third module, Module 3, of the study is investigating AZD6738 administered 
orally in combination with MEDI4736, to patients with advanced Non-Small Lung 
Cancer (NSCLC) or Head and Neck Squamous Cell Carcinoma (HNSCC) with a 
subsequent expansion in HNSCC patients to assess preliminary efficacy. By the data 
lock point of this report (13th June 2016) 67 patients had received at least one dose of 
AZD6738 in the AstraZeneca-sponsored clinical development programme study 
D5330C00004. These are broken down as follows: 
 
• Thirty two (32) patients have received AZD6738 in combination with carboplatin 
• Twenty Seven (27) patients have received AZD6738 in combination with olaparib 
• Eight (8) patients have received AZD6738 in combination with the anti-PDL1 
antibody, durvalumab  
 
Several dose levels and schedules in each module have been investigated during this 
reporting period. Details of the first and third cohorts are contained in the module 
specific tables below: 
 
Module 1 – in combination with Carboplatin AUC 5 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
24 
 
G3 thrombocytopenia leading to a delay in subsequent cycles has been observed 
in cohorts 1-5. 
 
Module 3 – Combination with Durvalumab 
 
8 patients have been treated with 1500mg durvalumab (Day 1 of a 28 day cycle) 
combined with AZD6738 dosed for 80mg BD for 14 days as a monotherapy run-in 
then days 22 to 28 of each subsequent cycle. No attributable adverse events greater 
than CTCAE G2 have been reported. 
 
 
 
2.3.2.4 
Clinical experience of AZD6738 in combination with olaparib 
Module 2 of study D5330C00004 (NCT02264678) has examined AZD6738 alone 
and in combination with olaparib.   
 
The purpose of this module is to establish the Recommended Phase 2 Dose (RP2D) of 
AZD6738 given in combination with olaparib (Part A), and assess preliminary 
efficacy in a subsequent expansion(s) in patients with advanced ATM-deficient gastric 
adenocarcinoma (Part B1), ATM-proficient gastric adenocarcinoma (Part B2), breast 
cancer patients with BRCA mutations (somatic or germline) excluding HER2-positive 
breast cancer patients (Part B3) and TNBC patients with no known BRCA mutations 
(Part B4). Five doses and schedules were explored, and results were first reported in 
November 2016, at which time 27 patients had been treated. When AZD6738 was 
given for 14 days, 1 patient experienced G4 thrombocytopenia and 2 patients 
experienced G3 neutropenia. With shorter durations of AZD6738, the combination 
regimen was better tolerated.45  

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
25 
 
This study was last presented at the AACR annual meeting in April 2018, at which 
time 45 patients had been treated with the combination of olaparib and AZD6738. 
Grade ≥3 adverse events occurring in ≥20% of patients included thrombocytopenia (5 
patients), anemia (7), neutropenia (6), fatigue (1), anorexia (1), nausea, vomiting, 
constipation, diarrhea, and cough.  Dose-limiting toxicities were thrombocytopenia 
and neutropenia. Among 39 evaluable patients, 1 patient had a comprete response, 5 
had partial responses, and 1 patient had an unconfirmed partial response; all patients 
had BRCA1/2 mutations.46  Multiple expansion cohorts are still enrolling 
(NCT02264678). 
 
Several trials of the combination of olaparib and AZD6738 are ongoing.  These 
include NCT03462342, a phase 2 study in recurrent ovarian cancer; NCT03428607, a 
phase 2 study in relapsed small cell lung cancer; NCT03330847, a phase 2 study in 
metastatic triple negative breast cancer; NCT02937818, a phase 2 study in platinum 
refractory extensive stage small cell lung cancer; NCT02576444, a phase 2 study in 
advanced solid tumors with mutations in genes required for homologous 
recombination DNA repair; and NCT02264678, a phase 1/2 study of the combination 
in advanced solid malignancies. 
 
2.3.2.5 
Determination of recommended phase 2 dose of AZD6738 in combination with 
olaparib 
 
The Recommended Phase 2 Dose for expansion has been declared as AZD6738 160 
daily D1-7 with olaparib 300 mg BID continuously based on preliminary results from 
NCT02264678, a phase I study of AZD6738 in combination with multiple anti-cancer 
agents including olaparib, as described above in Section 2.3.2.4. Dose-limiting 
toxicities were thrombocytopenia and neutropenia.46  
 
The AZD6738 dosing schedule of 7 days on, 21 days off within each treatment cycle 
was supported by the PK-PD model of thrombocytopenia, predicting a period of 21 
days free of drug to achieve a full platelet recovery. The recommended dose 160 mg 
OD was predicted to maintain AZD6738 mean steady state concentrations above the 
estimated IC90 threshold (based on ATR enzyme inhibition assay in LoVo cells) and 
the GI90 threshold (based on the cellular growth inhibition activity in LoVo cells) 
across the full dosing interval i.e 24 h. Please refer to the AZD6738 Investigator’s 
Brochure for further information around the in-vitro threshold values. In addition, this 
daily dose level was associated with a decrease in peripheral monocytes in most of 
the patients and the preliminary blood cell count data from D5330C00004 and 
D5330C00002 studies suggested this decrease to be AZD6738 specific and dose 
dependent (monocyte decrease was not observed with either single agent olaparib or 
durvalumab). Monocytes have been characterized as being deficient in DNA base 
excision repair and PARP1 expression,47 suggesting an on-target synthetic lethal 
effect of AZD6738 mediated ATR inhibition in this cell type. Utilizing the monocyte 
decrease as a quantitative measure of AZD6738 pharmacological activity, the 
recommended Phase 2 dose of 160mg OD D1-7 was driven by maintaining 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
26 
maximally active exposure consistent with manageable safety. 
 
2.4 
Correlative Studies Background 
 
2.4.1 Rationale for CLIA laboratory confirmed IDH1/2 mutation  
 
IDH1/2 mutations are necessary for enrollment on the study because patients whose 
tumors harbor these mutations are a specific sub-population that we hypothesize will 
derive clinical benefit from PARP inhibition. These mutations can be established 
histologically or via standard sequencing methods available at a CLIA-certified pathology 
laboratory or a commercial entity, which is now considered a standard feature of 
pathology reports for solid tumors. Examples of centers/commercial laboratories with this 
capability include the Mayo Clinic (http://www.mayomedicallaboratories.com/test-
catalog/Overview/35854), MDACC (https://www.mdanderson.org/research/research-
resources/core-facilities/molecular-diagnostics-lab/services/idh1-mutation-analysis.html), 
and Foundation Medicine. This approach to select patients is commonly used in several 
recent and ongoing clinical trials focused on IDH1/2-mutant tumors (e.g., NCT02454634, 
NCT02771301, NCT02381886, NCT02826642, NCT02074839, NCT02746081, 
NCT01915498, NCT02481154).  
 
If a patient has an archived tumor specimen that has not been tested for tumor profiling, 
which includes evaluation of IDH1/2 mutations, his or her physician may do so at any 
time outside the bounds of this clinical trial, a process that typically takes 2-4 weeks. 
Should a qualifying IDH1/2 mutation be found in that patient’s tumor, this would make 
the patient preliminarily eligible to participate in the trial. 
 
Only specific mutations that lead to a neomorphic phenotype will be eligible for 
enrollment, and include those listed below: 
 
IDH1: R132V, R132G, R132S, R132L, R132C and R132H 
 
IDH2: R140W, R140L, R140Q, R172W, R172G, R172S, R172M, R172K 
 
Whole exome sequencing and RNA sequencing, which includes IDH analysis, will be 
performed prior to study completion for the purpose of data analysis.  This analysis will 
be performed on pre-treatment biopsy tissue and archival formalin-fixed paraffin 
embedded (FFPE) specimens, if the latter is available.  If a patient opts out of pre- and 
on-treatment biopsies, that patient must have an adequate archival specimen to enroll on 
the trial and this specimen will be analyzed.  
 
 
2.4.2 Rationale for LC-MS detection and quantification of 2HG in plasma and tissue 
biopsies 
In view of its role as the central oncometabolite in IDH-mutated tumors, we seek to 
determine whether 2-HG can potentially serve as a non-invasive biomarker of disease 
burden and response to treatment. We hypothesize that radiographic response to treatment 
will correlate with elevated pre-treatment tumor and plasma 2HG levels. In patients who 
respond to treatment, we hypothesize that a decrease in plasma 2HG levels will be 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
27 
observed. 
 
Our study focuses on tissue and plasma evaluation of 2HG using liquid chromatography-
mass spectrometry (LC-MS). In 2009, Dang et al. first used LC-MS to demonstrate that 
IDH1 mutated human glioblastoma tumors were characterized by significantly elevated 
levels of 2HG (as high as 35mM) compared to WT samples (<0.1 mM).48 More recently, 
LC-MS was used to demonstrate elevated tissue 2HG levels in patients with IDH1/2 
intrahepatic cholangiocarcinoma.  In two IDH1/2 mutated frozen intrahepatic 
cholangiocarcinoma specimens, tissue levels of 2HG were significantly elevated (849.9 
μg/g and 588.5 μg/g) when compared to compared to three WT specimens (average 3.41 
μg/g).4  
 
The value of plasma 2HG measurement has been well demonstrated in AML. In a study 
of 223 patients with de novo AML, 97% of mutant IDH1/2 AML samples had a 50-fold 
higher 2HG concentration in their sera (median, 3004 vs. 61 ng/mL, P < 0.0005).49  
Interestingly, 2-HG levels of >700 ng/mL could successfully differentiate patients with 
IDH1/2 mutations from those with WT malignancies. Further, 2-HG levels of >200 
ng/mL after therapy correlated with a shorter overall survival compared with patients 
with plasma 2HG levels <200 ng/mL (hazard ratio, 3.9; P = 0.02), illustrating the value of 
following this biomarker throughout treatment.49  
 
Several small studies have shown mixed results with plasma 2HG measurement in solid 
tumors. A 2012 study of 16 patients with gliomas, plasma levels of 2HG measured by 
GC-MS were not significantly higher in the ten patients with IDH1/2 mutated tumors, 
although a trend toward elevated levels was observed.50 More recently, studies of 38 and 
44 patients with IDH1/2mt gliomas compared to 46 and 16 WT patients, respectively, 
demonstrated no significant difference in mean plasma 2HG concentrations.51,52   
 
There is stronger evidence that 2HG plasma levels are elevated in patients with IDH1/2 
mutated cholangiocarcinoma. One study demonstrated that plasma levels of 2HG were 
significantly elevated in 11 patients with IDH1 mutant intrahepatic cholangiocarcinoma 
(median, 478 ng/mL) when compared to 20 IDH1/2 WT controls (median, 118 ng/mL, P 
< 0.0001).53  Plasma 2HG levels >= 170 ng/mL could predict the presence of an IDH1/2 
mutation with a sensitivity of 83% and a specificity of 90%.  These findings were verified 
in a validation cohort of 38 patients.  Additionally, circulating 2HG levels were felt to 
correlate directly with tumor burden.   
 
 
The relationship between plasma and tissue 2HG levels is unclear.  Early data suggests 
that plasma and tissue levels of 2HG are correlated in AML; the extent of their 
correlation in solid tumors is unknown.54,55 However, when LC-MS was used in the case 
of a patient with IDH1 mutated metastatic adenocarcinoma of the breast, plasma and 
urine 2HG levels were markedly elevated compared to those of six WT patients.56 Our 
proposed study enrolling at least 28 patients with IDH mutant tumors will allow us to test 
our hypotheses radiographic response to treatment will correlate with elevated pre-
treatment tumor and plasma 2HG levels and that a decrease in plasma 2HG levels will be 
observed in patients who respond to treatment. It will also provide compelling evidence 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
28 
for whether plasma levels of 2HG correlate well with tissue levels and thus can 
potentially serve as a useful and noninvasive predictor of response in solid tumors. 
 
2.4.3 Rationale for RNA sequencing and DNA sequencing 
Whole-exome DNA sequencing will be performed on tumor biopsy tissue to determine if 
other co-occurring genomic alterations potentiate, or interact with, the effects of IDH1/2 
mutations and oncometabolites, leading to differences in the efficacy of olaparib and 
AZD6738. DNA will be extracted from fresh frozen biopsies obtained before and during 
therapy and from archival specimens for those patients who opt out of biopsies. 
Mutations and copy number variants will be assessed to measure genomic correlates of 
response or resistance to therapy in the setting of IDH1/2 mutations. 
 
Beyond examining co-occurring mutations, we will use the sequencing data to analyze 
copy number alterations and mutational signatures that have been previously associated 
with homologous recombination deficiency.57–59 For example, specific patterns of allele-
specific copy number alterations have been associated with homologous recombination 
deficiencies.59 We will also use the sequencing data to attempt to identify novel 
mutational and genomic signatures that may be associated with an IDH1/2 mutation-
induced HR deficiency in particular. 
 
For the same reasons noted above, we will use RNAseq on our paired biopsy specimens 
to monitor gene expression and transcriptome changes during treatment with olaparib and 
AZD6738. This will allow us to detect changes in gene expression patterns and to 
characterize multiple forms of noncoding RNA.  
 
 
2.4.4 Rationale for assessing markers of DNA damage in tumor biopsies 
As presented above, our collaborators have identified an activated DNA damage response 
in IDH1/2-mutant cells, which includes elevated γH2AX and 53BP1 foci at baseline, in 
the absence of DNA damage. They have also found that inhibition of either PARP or 
ATR in IDH1/2 mutated cell lines resulted in the accumulation of DNA double strand 
breaks as measured by γH2AX and 53BP1 foci. Evidence of increased DNA damage, 
particular DNA double strand breaks, in patient samples after treatment with olaparib in 
combination with AZD6738 would thus demonstrate proof of enhanced DNA double 
strand breaks and serve as proof of mechanism.  
 
DNA damage signals associated with HRD can be recognized in conventional biopsy 
tumor samples by selective detection of targets associated with DNA repair. For example, 
γH2AX is a sensitive marker for DNA DSBs.60 Specifically, spatially resolved 
measurement of DNA-repair targets using in situ methods can report on the magnitude of 
DNA stress using minimum amounts of tissue and map specific location of signal within 
the tumor bed.  
 
As such, we will use multiplexed quantitative immunofluorescence (mQIF) and CyTOF-
IMC based panels to test whether we can detect these changes in pre-treatment and on-
treatment tumor biopsies. Markers included in the mQIF/IMC panels will include tumor 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
29 
cell markers (cytokeratin, GFAP), HRD-related sensors (γH2AX, p53BP1, NBS1) and 
eventually also mutant IDH proteins or immune cell markers. We will also expand our 
studies to look at multiple DNA damage response proteins and post-translational 
modifications. Protocols and strategies for mQIF on histology preparations from intact 
tumor specimens has been extensively performed and reported by the Schalper 
Laboratory at Yale. 
 
Mass Cytometry Time of Flight (CyTOF) has emerged as a powerful technique for 
multiparameter single cell analysis.61 The approach uses heavy metal ions as antibody 
labels, which overcomes many limitations associated with fluorescence-based cytometry. 
As such, dozens of unique molecular features can be analysed on single cells, which 
allows for detailed molecular profiling and assessments of tumor heterogeneity.62 More 
recently, this technique has been coupled to immunohistochemical and 
immunocytochemical methods with high-resolution laser ablation.63 This new approach 
allows one to image proteins and/or protein modifications at subcellular resolution, in 
frozen and FFPE tissue specimens. Yale has acquired the CyTOF Imaging Mass 
Cytometry (IMC) platform for this technique and has standardized assays for its use on 
clinical-grade fresh frozen and FFPE specimens. 
 
As such, we will use CyTOF-IMC to test whether we can detect these changes in pre-
treatment and on-treatment tumor biopsies.  
 
2.4.5 Rationale for assessing RAD51 foci  
A crucial event during Homologous Recombination (HR)-mediated DNA repair is the 
formation of the RAD51 nucleofilament at sites of double-strand breaks. These structures 
appear as sub-nuclear foci when detected by a RAD51 specific antibody and the presence 
of such sub-nuclear RAD51 foci is a surrogate functional marker for HR status.  In 
addition, HR-mediated DNA repair is restricted to cells in the S-phase of the cell cycle.  
Therefore, by staining for Geminin, a marker for cells in S-phase, and RAD51, it is 
possible to rapidly determine the functional status of HR in the sample.   
 
 
 
3. 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
1. Subjects must be able to understand the nature of this trial and provide written informed 
consent, prior to any study specific procedures. Patients with Impaired Decision Making 
Capacity (IDMC) who have a close caregiver or Legally Authorized Representative 
(LAR) may be considered eligible for this study at the treating Physician’s discretion, 
provided that the Physician is reasonably sure that the possible risks and benefits of the 
study are clear and that the patient will take the drug as prescribed. 
 
2. Subjects must be diagnosed with a solid malignant tumor (other than cholangiocarcinoma 
or primary CNS tumor) that has progressed despite standard therapy, or for which no 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
30 
effective standard therapy exists. Patients with cholangiocarcinoma are no longer allowed 
as this cohort has closed to accrual. Patient with primary CNS tumors, e.g. glioma, are 
not allowed. 
 
3. Patients must have biopsy-confirmed evidence of an IDH1 or IDH2 mutation, confirmed 
in a CLIA-certified laboratory, associated with neomorphic activity of the encoded 
proteins. See Section 2.4.1 for additional information on IDH1/2 mutation confirmation 
and those that are neomorphic.  
 
4. Patients must have tumors determined to be easily accessible for biopsy and must be 
willing to have serial biopsies. Tumor biopsies will be performed on the most accessible 
biopsable site of disease. All possible precautions to avoid complications will be taken, 
including discussions in multidisciplinary meetings, if needed. If a patient opts out of a 
pre-treatment biopsy, biopsy is not possible, or if a pre-treatment biopsy does not yield 
sufficient tissue for analysis, the patient must be willing to provide an sufficient archival 
FFPE specimen for LC/MS analysis of 2HG in order to enroll on the study. Permission of 
the study PI is required in all of the above scenarios.   
 
In order to maximize the availability of newly obtained specimens for 2-HG analysis, at 
least 10 biopsies will be required in each group (cholangiocarcinoma and other solid 
tumors) of 14 patients treated in the first stage of this Simon two-stage design. Thus if 4 
patients in an arm have already opted out, further patients may only enroll on that arm (in 
the first stage) if they agree to undergo the pre- and on-treatment biopsies. If a patient has 
agreed to undergo the two biopsies and undergoes the pre-treatment biopsy, he or she 
may not opt out of the second biopsy unless such a biopsy would not be safe (e.g. 
inaccessible tumor). Permission of the study PI is required in this scenario. 
 
All patients must be willing to provide 5 unstained archival slides, if available, for pre-
treatment 2-HG analysis and correlation with 2-HG levels in pre-treatment frozen 
specimens. 
 
5. Patients must be willing to undergo extra blood sampling for correlative studies.  
 
6. Patients must have measurable disease by RECIST v1.1.  
 
7. Patients must have at least one lesion, not previously irradiated, that can be accurately 
measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which 
must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance 
imaging (MRI) or ≥ 10 mm with callipers by clinical exam OR at least one lesion 
(measurable) that can be accurately assessed by CT/MRI/clinical exam at baseline and 
follow up visits. See Section 12 for the evaluation of measurable disease.   
 
8. Subjects must have progressive cancer at the time of study entry.  
 
9. Prior experimental (non-FDA approved) therapies (other than drugs that target ATR) and 
immunotherapies are allowed. Patients must not have received these therapies for 30 days 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
31 
or five half-lives of the drug (whichever is less) prior to the initiation of study treatment.  
 
10. Toxicities from prior therapies should have recovered to ≤ grade 1, with the exception of 
stable chronic grade 2 toxicities that are not overlapping with presumed toxicities of 
olaparib. 
 
11. Patients with treated brain metastases are eligible if there is no evidence of progression 
for at least 4 weeks after central nervous system (CNS)-directed treatment, as ascertained 
by clinical examination and brain imaging (MRI or CT scan) during the screening period. 
 
12. Patients with new or progressive brain metastases (active brain metastases) or 
leptomeningeal disease are eligible if the treating physician determines that immediate 
CNS specific treatment is not required and is unlikely to be required for at least 4 weeks 
(or scheduled assessment after the first cycle of treatment), and a risk-benefit analysis 
(discussion) by the patient and the investigator favors participation in the clinical trial 
 
13. If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be 
undetectable on suppressive therapy if indicated. If history of hepatitis C virus (HCV) 
infection, must be treated with undetectable HCV viral load. 
 
14. Female/male of age ≥18 years.  This is because no dosing or adverse event data are 
currently available on the use of olaparib or AZD6738 in patients <18 years of age, 
children are excluded from this study, but will be eligible for future pediatric trials. 
 
15. ECOG 0-1 (Karnofsky ≥70%, see APPENDIX A).  
 
16. Patients must have adequate organ and bone marrow function measured within 14 days 
prior to administration of study treatment as defined below: 
a. Hemoglobin ≥ 10.0 g/dL with no blood transfusion in < 14 days prior to starting 
therapy   
b. Leukocytes ≥ 3,000/mcL 
c. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
d. Platelet count ≥ 100 x 109/L 
e. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) 
f. Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase 
(SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate 
Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver 
metastases are present in which case they must be ≤ 5x ULN 
g. Patients must have creatinine clearance estimated using the Cockcroft-Gault 
equation of ≥51 mL/min or based on a 24 hour urine test: 
• Estimated creatinine clearance =(140-age [years]) x weight (kg) (x F)a 
serum creatinine (mg/dL) x 72 
a where F=0.85 for females and F=1 for males. 
 
17. No features suggestive of MDS/AML on peripheral blood smear when performed as 
clinically indicated. 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
32 
 
18. Patients must have a life expectancy of  ≥ 16 weeks, in the opinion of the treating 
physician. 
 
19. Patients must be willing and able to comply with the protocol for the duration of the 
study including undergoing treatment and scheduled visits and examinations including 
follow up. 
 
20. Prior radiation therapy is allowed.  Patients must not have received radiation therapy 
within 3 weeks prior to the initiation of study treatment. 
 
21. Women of child-bearing potential are expected to use highly effective contraception 
during the study and for 6 months after the last dose of study drug. See Appendix E for 
appropriate methods of contraception. Postmenopausal or evidence of non-childbearing 
status for women of childbearing potential: negative urine or serum pregnancy test within 
28 days of study treatment and confirmed prior to treatment on day 1. Postmenopausal is 
defined as: 
h. Amenorrheic for 1 year or more following cessation of exogenous hormonal 
treatments 
i. Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the 
post-menopausal range for women under 50 
j. Radiation-induced oophorectomy with last menses >1 year ago 
k. Chemotherapy-induced menopause with >1 year interval since last menses 
l. Surgical sterilisation (bilateral oophorectomy or hysterectomy) 
 
22. Male patients and their partners, who are sexually active and of childbearing potential, 
must agree to the use of two highly effective forms of contraception in combination, 
throughout the period of taking study treatment and for 6 months after last dose of study 
drug(s) to prevent pregnancy in a partner. See Appendix E for appropriate methods of 
contraception.  
 
23. Patients with human immunodeficiency virus (HIV) on effective antiretroviral therapy 
with undetectable viral load within 6 months are eligible for this trial. 
 
3.2 
Exclusion Criteria 
 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
 
1. Involvement in the planning and/or conduct of the study  
 
2. Previous enrollment in the present study 
 
3. Participation in another clinical study with an investigational product during the last 30 
days or five half-lives of the drug (whichever is less) prior to the initiation of study 
treatment  
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
33 
4. Any previous treatment with a PARP inhibitor. 
 
5. Any previous treatment with AZD6738 or any other ATR inhibitor. 
 
6. Patients receiving any systemic chemotherapy or radiotherapy within 3 weeks prior to 
study treatment. 
 
7. Other malignancy within the last 5 years except: adequately treated non-melanoma skin 
cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), 
Stage 1, grade 1 endometrial carcinoma, or other solid tumors including lymphomas 
(without bone marrow involvement) curatively treated with no evidence of disease for ≥5 
years.  Patients with a history of localized triple negative breast cancer may be eligible, 
provided they completed their adjuvant chemotherapy more than three years prior to 
registration, and that the patient remains free of recurrent or metastatic disease.  
 
8. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged 
by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, 
congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or 
patients with congenital long QT syndrome. 
 
9. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. 
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout 
period prior to starting study treatment is 2 weeks. 
 
10. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort ) or 
moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout 
period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 
3 weeks for other agents. 
 
11. Persistent toxicities caused by previous cancer therapy. Toxicities should have recovered 
to ≤ grade 1, excluding alopecia, or should be stable chronic grade 2 toxicities that do not 
overlap with presumed toxicities of olaparib and/or AZD6738.  
 
12. Patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) 
or features suggestive of MDS/AML. 
 
13. Patients with new or progressive brain metastases (active brain metastases) or 
leptomeningeal disease are not eligible if the treating physician determines that 
immediate CNS specific treatment is required, and a risk-benefit analysis (discussion) by 
the patient and the investigator does not favor participation in the clinical trial. A scan to 
confirm the absence of brain metastases is not required. The patient can receive a stable 
dose of corticosteroids before and during the study if these were started at least 4 weeks 
prior to treatment.  Patients with spinal cord compression unless considered to have 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
34 
received definitive treatment for this and evidence of clinically stable disease for 28 days.  
 
14. Major surgery within 2 weeks of starting study treatment. Major surgeries typically 
require general anesthesia, are associated with an estimated blood loss of >500mL, and 
require an overnight hospital stay.  Examples include laparoscopic surgery, open 
resection of organs, joint replacements and other orthopedic surgeries, and vascular or 
intracranial surgeries.  Examples of minor surgeries include those performed on an 
ambulatory basis, cataract surgery, dental surgeries, cutaneous, endoscopic, and 
arthroscopic procedures.  Effects from major surgeries should have recovered to ≤ grade 
1, with the exception of stable chronic grade 2 toxicities that are not overlapping with 
presumed toxicities of olaparib and/or AZD6738. 
  
15. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, 
non-malignant systemic disease or active, uncontrolled infection.  Examples include, but 
are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) 
myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord 
compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on 
High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that 
prohibits obtaining informed consent and would limit compliance with study 
requirements. 
 
16. Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication. 
 
17. Women who are actively breast feeding.  
 
18. Patients with a known hypersensitivity to olaparib or AZD6738 or any of the excipients 
of the products. History of allergic reactions attributed to compounds of similar chemical 
or biologic composition to olaparib or AZD6738. 
 
19. Previous allogeneic bone marrow transplant or double umbilical cord blood 
transplantation (dUCBT) 
 
20. Whole blood transfusions in the last 120 days prior to entry to the study (packed red 
blood cells and platelet transfusions are acceptable within the last 28 days) 
 
21. Patients who are receiving any other investigational agents. 
 
22. Pregnant women are excluded from this study because olaparib is an agent with the 
potential for teratogenic or abortifacient effects.  Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with olaparib, breastfeeding should be discontinued if the mother is treated with olaparib.  
 
23. Receiving, or having received during the 14 days prior to first dose, corticosteroids (at a 
dose > 10 mg prednisone/day or equivalent) for any reason 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
35 
 
24. Any of the following cardiac diseases currently or within the last 6 months (by New York 
Heart Association (NYHA) ≥ Class 2 where applicable): 
• Unstable angina pectoris 
• Congestive heart failure or known reduced LVEF < 55% 
• Acute myocardial infarction 
• Conduction abnormality not controlled with pacemaker or medication e.g. complete 
left bundle branch block, third degree heart block 
• Significant ventricular or supraventricular arrhythmias e.g. (patients with chronic 
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are 
eligible) 
 
25. Patients at risk of brain perfusion problems, e.g., medical history of carotid stenosis or 
pre-syncopal or syncopal episodes, history of TIAs   
 
26. Uncontrolled hypertension (grade 2 or above) requiring clinical intervention 
 
27. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such 
as congestive heart failure, unstable angina pectoris, acute myocardial infarction, 
hypokalaemia, congenital long QT syndrome, immediate family history of long QT 
syndrome or unexplained sudden death under 40 years of age, conduction abnormality 
not controlled with pacemaker or medication. 
 
28. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such 
as congestive heart failure, unstable angina pectoris, acute myocardial infarction, 
hypokalaemia, congenital long QT syndrome, immediate family history of long QT 
syndrome or unexplained sudden death under 40 years of age, conduction abnormality 
not controlled with pacemaker or medication. 
 
29. Patients with relative hypotension (<90/60 mm Hg) or clinically relevant orthostatic 
hypotension, including a fall in blood pressure of > 20 mm Hg 
 
30. Refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant 
bowel resection, with clinically significant sequelae that would preclude adequate 
absorption of AZD6738 
 
 
3.3 
Inclusion of Women and Minorities 
 
This is an open trial, recruiting adults affected by IDH1/2 mutated solid tumors. This trial 
will be recruiting women and members of minority groups because these diseases are 
found in all sexes, age and races.  
 
4. 
REGISTRATION PROCEDURES 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
37 
 
• Addition to a site roster, 
• Selection as the treating, credit, or drug shipment investigator or consenting person in 
OPEN, 
• Ability to be named as the site-protocol Principal Investigator (PI) on the IRB approval, 
and 
• Assignment of the Clinical Investigator (CI) task on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators acting as the Site-Protocol PI (Investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the Clinical 
Investigator (CI) on the DTL must be rostered at the enrolling site with a participating 
organization.  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
4.2 
Site Registration 
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet (SSW) for Local Context to the CIRB using IRBManager to indicate 
their intent to open the study locally.  The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network.  Site preferences can be set at the network 
or protocol level.  Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by email or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following criteria for the site to be able to have an Approved status following processing of the 
IRB/REB approval record: 
• Have an active CTEP status, 
• Have an active status at the site(s) on the IRB/REB approval on at least one participating 
organization’s roster, 
• If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record, 
• Include the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR 
profile, 
• List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• Have the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
38 
 
Additional site requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO),  
• An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only); and 
• Compliance with all applicable protocol-specific requirements (PSRs). 
 
4.2.1 Downloading Regulatory Documents 
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting documents 
is restricted to institutions and their associated investigators and staff on a participating roster.  
To view/download site registration forms:   
 
• Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password or linked ID.me account (ID.me accounts are required for all 
newly created CTEP-IAM accounts and by July 1, 2023 for all users), 
• Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-CT018, and 
protocol number 10222, 
• Click on Documents, Protocol Related Documents, and use the Document Type filter and 
select Site Registration to download and complete the forms provided.  (Note:  For sites 
under the CIRB, IRB data will load automatically to the CTSU.)  
 
4.2.2 Requirements For #10222 Site Registration 
 
• Specimen Tracking System Training Requirement: 
o All data entry users (Clinical Research Associate role) at each participating site will 
need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be submitted to 
the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual.  If an individual has 
previously completed the training for another ETCTN study, the training does not 
need to be completed again nor does the certificate of completion need to be 
resubmitted to the CTSU.  However, new versions of the Specimen Tracking System 
may require new training. 
o This training will need to be completed before the first patient enrollment at a given 
site. 
o Please contact STS Support at Theradex for the training 
(STS.Support@theradex.com, Theradex phone: 609-799-7580). 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
39 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ website.   
To access the Regulatory Submission Portal, log on to the CTSU members’ website, go to 
the Regulatory section, and select Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-
CTSU (2878), or CTSURegHelp@coccg.org to receive further instruction and support. 
 
4.2.4 Checking Site Registration Status 
 
Site’s registration status may be verified on the CTSU members’ website.  
• Click on Regulatory at the top of the screen, 
• Click on Site Registration, and  
• Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
 
Note:  The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol.  It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
 
4.3 
Patient Registration 
4.3.1 OPEN / IWRS 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment.  OPEN or IWRS will populate the 
patient enrollment data in NCI’s clinical data management system, Medidata Rave. 
 
Requirements for OPEN access:   
 
• A valid CTEP-IAM account and linked ID.me account (ID.me accounts are required for 
all newly created CTEP-IAM accounts and by July 1, 2023 for all users). 
• To perform enrollments or request slot reservations:  Must be on an LPO roster, ETCTN 
corresponding roster, or PO roster with the role of Registrar.  Registrars must hold a 
minimum of an Associate Plus (AP) registration type. 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
40 
• If a DTL is required for the study, the registrar must hold the OPEN Registrar task on the 
DTL for the site. 
• Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR.  If a DTL is required for the study, the IVR or NPIVR must be 
assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  IWRS system also sends an email confirmation of the registration.  You 
may print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website.  
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with patient enrollment in OPEN.  Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System or the IWRS 
Slot Reservation System to ensure that a slot on the protocol is available to the patient.  
Once a slot reservation confirmation is obtained, site staff may then proceed to enroll the 
patient to this study. 
 
 
4.3.2 Patient Enrollment Instructions 
 
Patients with neomorphic IDH1/2 mutations identified in a CLIA certified laboratory 
may be enrolled.  
 
4.3.3 Special Instructions for Patient Enrollment 
 
This Study will use the ETCTN Specimen Tracking System (STS). 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
41 
 
• All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted.   
• The system is accessed through Rave user roles: “Rave CRA” and “Rave CRA 
(Labadmin)” for data entry at the treating institutions and “Biorepository” for users 
receiving the specimens for processing and storage at reference labs and the NCI Early-
Phase and Experimental Clinical Trials Biospecimen Bank (EET Biobank, formerly 
known as the ETCTN Biorepository).   
• Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website in the Data Management section under the Rave Home tab and then 
under Rave Resource Materials. 
• Important:  Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
 
Detailed instructions on use of the STS can be found in Section 5.4. 
 
4.3.4 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is available on the Theradex website:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. This 
link to the Theradex website is also on the CTSU website OPEN tab. For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk at 855-828-6113 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.3.5 Registration Notification 
When a patient has been enrolled and an initial biopsy date set, please notify the 
following people so that they can be prepared to receive shipment and reserve time for 
their research equipment: 
 
• Jing Li, Ph.D.: LiJing@wayne.edu 
• NCI Early-Phase and Experimental Clinical Trials Biospecimen Bank (EET 
Biobank): BPCBank@nationwidechildrens.org 
 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 10 business days. Patients 
with previously identified IDH1/2 mutation in a CLIA certified laboratory are eligible, but the 
mutation must be verified prior to study completion in the central laboratory (MoCha, Frederick 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
 
42 
National Laboratory for Cancer Research (FNLCR) or the NCLN Genomics Laboratory). If an 
eligible IDH mutation is not confirmed centrally, those patients will be excluded from the final 
analysis. Issues that would cause treatment delays should be discussed with the Principal 
Investigator. If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be cancelled. The Study Coordinator should be notified of 
cancellations as soon as possible. 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
44 
5.2 
Specimen Procurement Kits and Scheduling  
 
 Refer to Appendix G, Lab Manual.  
 
5.3 
Specimen Collection  
 
 Refer to Appendix G, Lab Manual.  
 
5.4 
Specimen Tracking System Instructions 
 
 Refer to Appendix G, Lab Manual.  
 
5.5 
Shipping Specimens from Clinical Site to the EET Biobank  
 
 Refer to Appendix G, Lab Manual.  
 
 
5.6 
Shipping of Specimens from Clinical Site to Other Laboratories  
 
Refer to Appendix G, Lab Manual.  
 
5.7 
 Correlative Studies  
 
Patients will undergo tumor biopsies for integrated and exploratory correlative studies prior to 
starting therapy and at specific timepoints. The tumor tissue will be obtained by a surgical or 
imaging guided biopsy (most likely) procedure. Tissue will be obtained at the following 
timepoints: pre-treatment (within ≤ 2 weeks prior to cycle 1 Day 1 of treatment) and after cycle 
1 of treatment (4 weeks, +/- 7 days), as long as the patient has received a minimum of 1 cycle of 
treatment (or 21 of 28 days of treatment, given the +/-7 day window). Ideally each biopsy will 
consist of 6 passes of a large gauge needle (such as 16 or 18g) for core biopsy.  
 
For all patients, 5 unstained archival FFPE slides, if available, will be used to evaluate tissue 2-
HG levels at time of diagnosis. 
 
We will practice an opt-out policy, wherein a patient may opt out of pre- and post-treatment 
biopsies.  In this case, as well as in circumstances in which biopsy does not yield sufficient 
tissue for analysis or is not feasible to perform, archival formalin-fixed paraffin embedded 
(FFPE) specimens will be used, if possible, for pre-treatment LC-MS measurement of 2HG 
levels in tumor. In the three above scenarios, explicit permission of the study PI is required.  
 
Prioritization for use of tumor tissue specimens will be as follows:  
1. DNA whole exome sequencing 
2. RNA sequencing  
3. mQIF (including IF to look at g-H2AX and RAD51 )   
4. CyTOF (Schalper lab) 
5. 2-HG measurement  
6. RAD51 assay 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
45 
NOTE:  For each set of biopsies, 3 of the tumor cores will be formalin-fixed on site and sent to 
the EET Biobank, where they will be processed.  3 of the tumor cores will be flash frozen on 
site and sent directly to the Jing Li laboratory at the Karmanos Cancer Institute. Please see 
Appendix G, Laboratory Manual for details on sample collection, handling and shipping.  
 
These samples then will be distributed to the appropriate locations in the optimal formats, for 
the studies proposed below, based on the aforementioned tissue prioritization plan. 
 
All patients will undergo additional blood withdrawals for LC-MS detection and quantification 
of 2HG in plasma.  
 
Any remaining specimens received at the EET Biobank will be banked long-term.    
 
Our overall correlative and biomarker assay process flow and priority list is presented below. 
 
Figure 7. Patient sample and biomarker diagram.  * Note:  No archival or frozen tissue specimens were received 
directly by the Li Laboratory.  Instead, (per Amendment 13 [version April 4, 2025]), the 2-HG assay will be 
performed using remaining FFPE tissue that was sent to the EET Biobank 
 
List of Biomarker Assays in Order of Priority 
 
Note for participating sites: Please see Section 5.1 for details on specimens to collect.  The tissue/body 
fluid tested are not always the same specimens that are submitted by the site, as processing of blood 
and tissue will occur at the Biobank prior to testing 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
47 
Priority 
Biomarker Name 
AND Lab PI and Site 
Assay 
(CLIA: Y/N) 
 
Use (Integral, 
Integrated, or 
Exploratory) AND 
Purpose  
Tissue/Body Fluid Tested 
and Timing of Assay 
M/O  
1 
2HG plasma concentrations 
Karmanos Cancer Institute, Wayne 
State University School of 
Medicine  
Jing Li, Ph.D. 
LiJing@wayne.edu 
LCMS/MS 
CLIA: N 
 
Integrated 
To address the tumor 
and plasma 
concentration of 
2HG before and after 
therapy   
Plasma  
Prior to initiation of treatment 
and on day 1 of cycles 2, 4 
and 8 and at time of evidence 
of progression per study 
schema (plasma only; -/+ 4 
days) 
Ma 
2 
WES 
MoCha Laboratory, Frederick 
National Laboratory for Cancer 
Research (FNLCR) 
Chris Karlovich 
chris.karlovich@nih.gov 
Next-generation 
sequencing 
CLIA: N 
 
Integrated 
Germline control for 
tissue-based WES 
Germline DNA from blood in 
EDTA. 
 
Prior to initiation of treatment 
Ma 
a = Patients who opt out of pre- and on-treatment biopsies will not have fresh tissue.  However, their archival tissue will be 
tested for tissue 2-HG concentrations.  
 
5.8 
Integral Laboratory Studies 
5.8.1 IDH1/2 mutation detection 
The Bindra laboratory recently discovered that IDH1/IDH2 mutations induce a homologous 
recombination (HR) defect that renders tumor cells highly sensitive to inhibitors of poly (ADP-
Ribose) polymerase (PARP). IDH1-dependent PARP inhibitor sensitivity has been 
demonstrated in a range of clinically relevant models, including primary patient-derived glioma 
cells in culture and genetically-matched tumor xenografts in vivo. 
 
Based on these findings, the efficacy of olaparib in the treatment of IDH1/IDH2-mutant solid 
tumors will tested in a phase 2 study. Olaparib is a poly (ADP-ribose) polymerase (PARP) 
inhibitor that has already been approved as monotherapy in patients with deleterious or 
suspected deleterious germline BRCA mutations in advanced ovarian cancer who have been 
treated with three or more prior lines of chemotherapy. Patients will be recruited from 
participating ETCTN centers.  
 
To enroll on this study, patients must have biopsy-confirmed evidence of an IDH1 or IDH2 
mutation, confirmed in a CLIA-certified laboratory, associated with neomorphic activity of the 
encoded proteins.  These mutations are as follows: 
 
Mutations: IDH1: R132V, R132G, R132S, R132L, R132C and R132H  
IDH2: R140W, R140L, R140Q, R172W, R172G, R172S, R172M, R172K 
 
 
 
5.9 
Integrated Correlative Studies 
Patients will undergo tumor biopsies for integrated and exploratory studies pre-treatment and 
after 1 cycle of treatment (4 weeks). The tumor tissue will be obtained by a surgical or imaging 
guided biopsy (most likely) procedure. If less than 1 cycle of treatment was received, patients 
will not undergo a second biopsy procedure. When possible each biopsy will consist of 6 passes 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
48 
of a large gauge needle (such as 16 or 18g) for core biopsy. 
 
Three tumor cores will be formalin-fixed and sent to the EET Biobank and three will be flash-
frozen and sent to the Jing Li Lab at the Karmanos Cancer Institute, where they will be 
processed and stored.   
 
These samples then will be distributed to the appropriate locations in the appropriate formats, 
for the studies proposed below, based on the aforementioned tissue prioritization plan. 
 
In addition, patients will undergo additional blood withdrawals pre-treatment and on day 1 of 
cycles 2, 4, and 8 of therapy for LC-MS detection and quantification of 2HG in plasma.  
 
5.9.1 LC-MS detection and quantification of 2HG in plasma and tissue biopsies 
We seek to determine whether 2HG can potentially serve as a noninvasive biomarker of disease 
burden and response to treatment through serial measurements in patients with IDH1/2 mutant 
solid tumors. LC-MS/MS will be used to measure 2HG plasma concentration using the methods 
described above. Pretreatment plasma concentration will be compared to post-treatment 
concentrations collected on day 1 of cycles 2, 4 and 8 of treatment and at time of confirmed 
evidence of progression. Change in plasma 2HG concentration will be correlated to 
radiographic response. We will also compare 2HG concentrations in tumor tissue prior to 
treatment with pre-treatment plasma levels. We hypothesize that radiographic response to 
treatment will correlate with decreased plasma 2HG levels.  On the rationale for examining 
2HG levels in plasma and tissue, see Section 2.4.2. 
 
The LC-MS/MS methods for the quantitation of 2HG has been validated based on the FDA 
Guidance for Bioanalytical Method validation 
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/uc
m368107.pdf).  Method validation includes the tests of specificity/selectivity, intra-/inter-day 
precision and accuracy, recovery, short-/long-term stability and freeze-thaw to ensure that the 
method is specific, sensitive, reliable, and reproducible, and suitable for the intended analytical 
use. 
  
2HG levels in tumor and plasma will be compared in responders and nonresponders.  
 
 
5.9.1.1 
Collection of Specimen(s) 
The concentrations of 2HG will be determined in patient plasma and tumor samples. A pre-
treatment and on-treatment biopsy after 1 cycle of treatment will be performed, and blood 
samples will be collected at predefined time points (see Study Calendar). Archival FFPE 
samples will be analyzed for all patients, if available. If a patient does not consent to biopsy, 
biopsy is not possible, or the tissue obtained is insufficient for analysis, archival FFPE 
samples will be analyzed. 
 
NOTE:  No archival or frozen tissue specimens were received at the Li Laboratory as of 
April 2025. Instead, as of Amendment 13 (version April 4, 2025) of this protocol, this assay 
will use FFPE tissue collected at pre-treatment and on treatment cycle 1 remaining at EET 
Biobank following completion of the higher priority assays. 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
49 
Please refer to Appendix G, Laboratory Manual for specimen collection details. 
 
 
5.9.1.2 
Handling of Specimens(s) 
Please refer to Appendix G, Laboratory Manual for specimen handling details.  
 
5.9.1.3 
Shipping of Specimen(s) 
Please refer to Appendix G, Laboratory Manual for specimen shipping details.  
 
5.9.1.4 
Site(s) Performing Correlative Study 
 
Karmanos Cancer Institute 
Laboratory of Jing Li  
Associate Professor of Oncology  
Director, Pharmacology Core 
Karmanos Cancer Institute 
Wayne State University School of Medicine 
4100 John R street 
HWCRC/Room 523 
Detroit, MI 48201 
Phone: 313-576-8258 
Email: LiJing@wayne.edu  
 
 
5.10 
Exploratory/Ancillary Correlative Studies 
 
5.10.1 DNA sequencing in tumor biopsies 
We seek to determine whether co-occuring genomic alterations or changes in the genome can 
potentially serve as a biomarker of treatment response or resistance through serial assessment in 
patients with IDH1/2 mutant solid tumors treated with olaparib and AZD6738. Biopsies  pre-
treatment and on treatment will be performed in order to compare the baseline gene expression 
profile of the tumor to the one determined after treatment. DNA will be extracted from 
formalin-fixed tissue biopsies obtained before and during therapy. Mutations, copy number 
variants, and sub-clonal architecture will be assessed to measure genomic correlates of response 
or resistance to therapy in the setting of IDH1/2 mutations.  In addition, IDH1/2 mutations will 
be independently verified. 
 
Unstained slides will be prepared for macrodissection and nucleic acid extraction. After 
pathology review, macrodissection of demarcated tumor will be performed and nucleic acids 
will be extracted and distributed to the MoCha, Frederick National Laboratory for Cancer 
Research (FNLCR) for analysis. Additional tissue remaining after creating unstained slides for 
IHC and nucleic acid extractions will be banked for long-term storage at ambient temperature. 
At the MoCha Genomics Lab, the steps will be:    
• 
DNA library prepared for WES. 
• 
RNA library prepared for RNA-Seq. 
• 
Library quantitation using ddPCR for both WES and RNA-Seq  

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
50 
• 
Denaturing and clustering of DNA and RNA libraries for sequencing  
• 
Sequencing of WES and RNA-Seq libraries  
• 
Data analysis for WES and RNASeq  
 
5.10.1.1 
Specimen Receipt and Processing at the EET Biobank  
 
Formalin-fixed tissue from pre-treatment and Week 4 time points will be collected. Tissue 
in formalin will be processed and embedded upon receipt at the EET Biobank, and slides 
will be cut from the biopsies. For all tumor specimens, the first section will be stained with 
H&E for pathology quality control review to assess tumor content; unstained slides will be 
macrodissected, if needed, and scraped for DNA and RNA co-extraction. DNA (for WES) 
will be banked in a stock vial and RNA (for RNAseq) will be divided into 5 aliquots; all 
nucleic acids will be stored in a -80°C freezer until distribution for testing. 
 
Additional FFPE tissue remaining after creating unstained slides for IHC and nucleic acid 
extractions will be banked for long-term storage at ambient temperature. 
 
For patients who decline biopsy, archival FFPE (blocks or slides) will be collected and 
stored at the EET Biobank. 
 
DNA will be extracted from blood in EDTA tubes collected at Baseline. DNA will be stored 
in a -80°C freezer until distribution for testing.  
 
5.10.1.2 
Handling of Specimens(s) 
 
Please refer to Appendix G, Laboratory Manual for specimen handling details.  
 
5.10.1.3 
Shipping of Specimen(s) 
 
Please refer to Appendix G, Laboratory Manual for specimen shipping details. 
 
5.10.1.4 
Site Performing Correlative Study   
MoCha Laboratory, Frederick National Laboratory for Cancer Research (FNLCR) 
Chris Karlovich 
chris.karlovich@nih.gov  
 
5.10.2 RNA sequencing in tumor biopsies 
We seek to determine whether changes in gene expression can potentially serve as a 
biomarker of treatment response or resistance through serial assessment in patients with 
IDH1/2 mutant solid tumors treated with olaparib. RNA will be extracted from formalin-
fixed tissue samples.  
  
Unstained slides will be prepared for macrodissection and nucleic acid extraction. After 
pathology review, macrodissection of demarcated tumor will be performed and nucleic 
acids will be extracted and distributed to the MoCha, Frederick National Laboratory for 
Cancer Research (FNLCR) for analysis. Additional tissue remaining after creating 
unstained slides for IHC and nucleic acid extractions will be banked for long-term storage at 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
51 
ambient temperature. At the MoCha Genomics Lab, the steps will be:    
• 
DNA library prepared for WES. 
• 
RNA library prepared for RNA-Seq. 
• 
Library quantitation using ddPCR for both WES and RNA-Seq  
• 
Denaturing and clustering of DNA and RNA libraries for sequencing  
• 
Sequencing of WES and RNA-Seq libraries  
• 
Data analysis for WES and RNASeq  
 
5.10.2.1 
Specimen Receipt and Processing at the Biorepository  
 
Formalin-fixed tissue obtained pre-treatment (or archival FFPE tissue) and Week 4 time 
points will be used for this assay. Tissue in formalin will be processed and embedded upon 
receipt at the EET Biobank, and slides will be cut from the biopsies. For all tumor 
specimens, the first section will be stained with H&E for pathology quality control review 
to assess tumor content; unstained slides will be macrodissected, if needed, and scraped for 
DNA and RNA co-extraction. DNA (for WES) will be banked in a stock vial and RNA (for 
RNAseq) will be divided into 5 aliquots; all nucleic acids will be stored in a -80°C freezer 
until distribution for testing. 
 
Additional FFPE tissue remaining after creating unstained slides for IHC and nucleic acid 
extractions will be banked for long-term storage at ambient temperature. 
 
 
5.10.2.2 
Handling of Specimens(s) 
Please refer to Appendix G, Laboratory Manual for specimen handling details.  
 
5.10.2.3 
Shipping of Specimen(s) 
Please refer to Appendix G, Laboratory Manual for specimen shipping details. 
 
5.10.2.4 
Site Performing Correlative Study  
MoCha Laboratory, Frederick National Laboratory for Cancer Research (FNLCR) 
Chris Karlovich 
chris.karlovich@nih.gov 
 
5.10.3 Multiplexed Quantitative Immunofluorescence (mQIF) and CyTOF – Imaging Mass 
Cytometry (IMC)  
The goal of these studies is to evaluate the impact of IDH mutations, HRD and treatment with 
olaparib on tumor tissues. To address this, the Schalper laboratory will analyze intact paraffin-
embedded tumor slides using state of the art quantitative protein analysis strategies. The 
laboratory will also take advantage of multiplexing protocols to accommodate numerous targets 
in each experimental run allowing the visualization of spatial interactions and maximizing the 
use of tumor specimens. The laboratory will also study the association between circulating 
markers and tumor features at different time points during treatment. The Schalper laboratory 
has validated protocols for systematic analysis of human specimens using mQIF and IMC 
panels. 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
52 
Using spatially resolved mQIF assays, the Schalper laboratory will simultaneously map the 
levels of key DNA/HRD sensors, tumor-specific markers, mutant IDH proteins and 
stromal/immune cell components in conventional biopsy sections. Specifically, mQIF panels 
will include 4-6 individual markers such as DAPI for all nuclei, cytokeratin for tumor epithelial 
cells or GFAP for gliomas; γH2AX, RAD51, and/or mutant IDH1/2 proteins. Additional panels 
will be measured in consecutive tumor sections and include immune cell markers such as T/B-
cell indicators (e.g. CD3, CD4, CD8, CD20). The markers will be measured in user defined 
compartments using multispectral imagers and analyzed using automated tissue and cell 
segmentation algorithms. 
 
For the exploratory CyTOF/IMC studies, the Schalper laboratory will use previously validated 
metal-conjugated primary antibodies to analyze multiplexed panels for simultaneous detection 
of up to 35 individual markers in conventional tumor sections. The markers will include cancer 
and immune cell lineage indicators (Histone3, cytokeratin, ,Vimentin, E-cadherin, etc), DDR 
(gH2AX, RAD51, 53BP1, BRCA1, ATM, etc), major oncogenic drivers (EGFR, HER2, MET) 
and functional markers (Ki-67, GZB, LAMP1, etc) (see Figure below). They will be measured 
in selected tumor areas using the Hyperion/IMC instrument at Yale University. Data will be 
analysed using marker-assisted and visual tissue segmentation strategies with continuous 
marker scores as output. See image below for an example.   
 
Analysis of continuous protein target levels using mQIF and CyTOF/IMC will be performed 
using correlation functions, non-parametric tests and Cox proportional hazards models for 
survival. Selected markers will also be binarized to study categorical associations; and 
integrated into multi-modal signatures using regressive models. 
 
5.10.3.1 
Collection of Specimen(s) 
 
Please refer to Appendix G, Laboratory Manual for specimen collection details.  
 
5.10.3.2 
Handling of Specimens(s) 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
53 
Formalin-fixed tissue obtained pre-treatment (or archival FFPE tissue) and Week 4 time 
points will be used for this assay. Tissue in formalin will be processed and embedded upon 
receipt at the EET Biobank. The Biorepository will create 10 5-micron unstained, unbaked, 
charged slides to distribute for analysis. Remaining tissue from the core used for 
multiplexed QIF and CyTOF analysis will be used for the Rad51 assay (Section 5.10.4). 
 
Additional FFPE tissue remaining after creating unstained slides for IHC and nucleic acid 
extractions will be banked for long-term storage at ambient temperature.  
 
 
 
5.10.3.3 
Shipping of Specimen(s) 
 
Please refer to Appendix G, Laboratory Manual for specimen shipping details.  
 
5.10.3.4 
Site Performing Correlative Study   
Laboratory of Dr. Kurt A. Schalper 
Yale School of Medicine 
 
5.10.4 RAD51 focus formation assay 
A crucial event during Homologous Recombination (HR)-mediated DNA repair is the 
formation of the RAD51 nucleofilament at sites of double-strand breaks. These structures 
appear as sub-nuclear foci when detected by a RAD51 specific antibody and the presence of 
such sub-nuclear RAD51 foci is a surrogate functional marker for HR status.  In addition, HR-
mediated DNA repair is restricted to cells in the S-phase of the cell cycle.  Therefore, by 
staining for Geminin, a marker for cells in S-phase, and RAD51, it is possible to rapidly 
determine the functional status of HR in the sample.   
 
To perform the RAD51 assay, at the Shapiro laboratory at the Dana-Farber Cancer Institute, 
two 5µm thick serial sections of a formalin fixed paraffin embedded sample will be 
independently stained using antibodies to Geminin and RAD51.  Presence of Rad51 foci and 
Geminin positivity in tumor cells within the sample will be assessed.  There must be more than 
3 RAD51-foci in the nucleus to designate the tumor cell as RAD51-foci positive.  Presence of 
at least one RAD51 foci positive tumor cell in a minimum of four 40X fields are required to 
indicate HR proficiency.  If there are no RAD51 foci positive tumor cells and if greater than 3% 
of the tumor cells are Geminin positive, the sample is classified as HR-deficient.  If there are no 
RAD51 foci positive tumor cells and if fewer than 3% of tumor cells are Geminin positive, then 
it is not possible to assign HR status since the fraction of S-phase cells are low.   
 
5.10.4.1 
 Collection of Specimen(s) 
 
Please refer to Appendix G, Laboratory Manual for specimen collection details.  
 
5.10.4.2 
Handling of Specimens(s) 
 
Formalin-fixed tissue obtained pre-treatment (or archival FFPE tissue) and Week 4 time 
points will be used for this assay. Tissue in formalin will be processed and embedded upon 
receipt at the EET Biobank. Three (3) serially sectioned and numbered slides will be used 
for Rad51 analysis. 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
54 
 
Additional FFPE tissue remaining after creating unstained slides for IHC and nucleic acid 
extractions will be banked for long-term storage at ambient temperature. The Biorepository 
will create two 5-micron unstained, unbaked, charged slides to distribute for analysis. 
 
 
5.10.4.3 
Shipping of Specimen(s) 
 
Please refer to Appendix G, Laboratory Manual for specimen shipping details.  
5.10.4.4 
Site Performing Correlative Study   
Laboratory of Dr. Geoffrey Shapiro 
Dana Farber Cancer Institute 
 
 
6. 
TREATMENT PLAN 
 
6.1 
Agent Administration 
 
Patients will be treated with olaparib 300 mg q12hrs each day of a 28-day cycle in tablet 
formation and AZD6738 160 mg qday on days 1-7 of a 28-day cycle in tablet formation until 
disease progression, unacceptable toxicity, withdrawal of consent or death. 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 2.3.  Appropriate dose modifications are described in Section 7.  
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
For all centers, olaparib and AZD6738 tablets will be packed in high-density polyethylene 
(HDPE) bottles with child-resistant closures.  Each dosing container will contain sufficient 
medication for at least 28 days plus overage.  Olaparib and AZD6738 will be dispensed to 
patients on Day 1 and every 28 days thereafter until the patient completes the study, withdraws 
from the study or closure of the study.  Olaparib is available as a film-coated tablet containing 
100mg or 150mg of olaparib. AZD6738 is available as round white coated tablets containing 20 
or 80 mg of AZD6738. 
 
Patients will be administered olaparib orally twice daily at 300 mg BID continually. 300mg 
olaparib tablets should be taken at the same time each day, approximately 12 hours apart with 
one glass of water.  The olaparib tablets should be swallowed whole and not chewed, crushed, 
dissolved or divided.  
 
Patients will be administered AZD6738 orally once daily at 160 mg on days 1-7 of a 28-day 
cycle.  AZD6738 tablets should be taken at the same time each day with one glass of water.  
The AZD6738 tablets should be swallowed whole and not chewed, crushed, dissolved or 
divided.  
 
When AZD6738 is administered in combination with olaparib, patients should fast for 2 
hours before dosing and for 1 hour after dosing. 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
55 
If vomiting occurs shortly after the olaparib or AZD6738 tablets are swallowed, the dose should 
only be replaced if all the intact tablets can be seen and counted.  Should any patient enrolled 
on the study miss a scheduled dose for whatever reason (e.g., because of forgetting to take the 
tablets or vomiting), the patient will be allowed to take the scheduled dose up to a maximum of 
2 hours after that scheduled dose time.  If greater than 2 hours after the scheduled dose time, the 
missed dose is not to be taken and the patient should take their allotted dose at the next 
scheduled time. 
 
The patient will be requested to maintain a medication diary of each dose of medication (See 
APPENDIX F).  The medication diary will be returned to clinic staff at the end of each course. 
 
6.1.1 CTEP IND Agent: Olaparib 
 
Oral. Olaparib doses can be taken without regard to food. No routine premedications are 
required. 
 
6.1.2 CTEP IND Agent: AZD6738 
 
Oral. Do not eat or drink (except water only) for at least 2 hours prior to dosing and for at least 
1 hour after dosing AZD6738 tablets. Do not crush, chew or split the tablets. 
 
6.1.3 Other Modality(ies) or Procedures 
 
N/A 
 
6.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of olaparib and/or AZD6738 with other 
concomitantly administered drugs, the case report form must capture the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies.  Reason for use, dates of 
administration including start and end dates, and dosage information including dose and 
frequency will also be recorded in the CRF. The Principal Investigator should be alerted if the 
patient is taking any agent known to affect or with the potential for drug interactions. The study 
team should check a frequently-updated medical reference for a list of drugs to avoid or 
minimize use of.  APPENDIX B (Patient Drug Information Handout and Wallet Card) should 
be provided to patients. 
 
The use of any natural/herbal products or other traditional remedies should be discouraged, but 
use of these products, as well as use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the case report form (CRF). 
 
6.2.1 Medications that may NOT be administered 
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy (Hormone 
replacement therapy (HRT) is acceptable), radiotherapy, biological therapy or other novel 
agent) is to be permitted while the patient is receiving study medication. Live virus and live 
bacterial vaccines should not be administered while the patient is receiving study medication 
and during the 30 day follow up period. An increased risk of infection by the administration of 
live virus and bacterial vaccines has been observed with conventional chemotherapy drugs and 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
56 
the effects with olaparib and/or AZD6738 are unknown. 
 
Palliative radiotherapy  
 
Palliative radiotherapy is not allowed during the study.  
 
6.2.2 Restricted concomitant medications 
6.2.2.1 
Strong or Moderate CYP3A inhibitors and inducers  
 
Strong or moderate CYP3A inducers and inhibitors should not be taken with Olaparib or 
AZD6738. If the use of any strong or moderate CYP3A inducers are considered necessary 
for the patient’s safety and welfare this could diminish the clinical efficacy of olaparib and 
AZD6738. If a patient requires use of a strong or moderate CYP3A inducer or inhibitor 
after starting study treatment, then AZD6738 and olaparib should be discontinued and the 
patient must come off study treatment. If one drug is discontinued, both must be 
discontinued.  
 
6.2.2.2 
P-gp inhibitors 
It is possible that co-administration of P-gp inhibitors (eg amiodarone, azithromycin) may 
increase exposure to olaparib and/or AZD6738. Caution should therefore be observed. 
 
6.2.2.3 
Effect of olaparib on other drugs 
Based on limited in vitro data, olaparib may increase the exposure to substrates of CYP3A4, 
P-gp, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K.  
Based on limited in vitro data, olaparib may reduce the exposure to substrates of CYP3A4, 
CYP1A2, 2B6, 2C9, 2C19 and P-gp.  
The efficacy of hormonal contraceptives may be reduced if co administered with olaparib.  
Caution should therefore be observed if substrates of these isoenzymes or transporter 
proteins are co-administered. 
 
Examples of substrates include: 
• CYP3A4 – hormonal contraceptive, simvastatin, cisapride, cyclosporine, ergot 
alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine 
• CYP1A2 – duloxetine, melatonin 
• CYP2B6 – bupropion, efavirenz 
• CYP2C9 – warfarin  
• CYP2C19 - lansoprazole, omeprazole, S-mephenytoin 
• P-gp - simvastatin, pravastatin, digoxin, dabigatran, colchicine 
• OATP1B1 - bosentan, glibenclamide, repaglinide, statins and valsartan 
• OCT1, MATE1, MATE2K – metformin 
• OCT2  - serum creatinine 
• OAT3  - furosemide, methotrexate 
 
6.2.2.4 
Effect of AZD6738 on other drugs 
Based on limited in vitro data, AZD6738 may increase the exposure to substrates of BCRP, 
CYP3A4, CYP1A2, CYP2B6, OATP1B1, MATE1, MATE2K, OATP1B3, and P-gp.   
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
57 
Based on limited in vitro data, AZD6738 may reduce the exposure to substrates of 
CYP1A2, CYP2B6 and CYP3A4. 
 
Examples of substrates include: 
• BCRP – topotecan, rosuvastatin, sulfasalazine, diflomotecan, imatinib, atorvastatin, 
and methotrexate 
• CYP3A4 – hormonal contraceptive, simvastatin, cisapride, cyclosporine, ergot 
alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine 
• CYP1A2 – duloxetine, melatonin 
• CYP2B6 – bupropion, efavirenz 
• P-gp - simvastatin, pravastatin, digoxin, dabigatran, colchicine 
• OATP1B1 - bosentan, glibenclamide, repaglinide, statins and valsartan 
• MATE1, MATE2K – metformin 
 
6.2.2.5 
Anticoagulant Therapy 
 
Patients who are taking warfarin may participate in this trial; however, it is recommended 
that international normalized ratio (INR) be monitored carefully at least once per week for 
the first month, then monthly if the INR is stable. Subcutaneous heparin, low molecular 
weight heparin and novel oral anticoagulants (NOACs) are permitted. 
 
6.2.2.6 
Anti-emetics/Anti-diarrheals 
 
If a patient develops nausea, vomiting and/or diarrhea, these symptoms should be reported 
as AEs (see Section 7.4.2) and appropriate treatment should be administered. 
 
6.2.2.7 
Administration of other anti-cancer agents 
 
Patients must not receive any other concurrent anti-cancer therapy, including investigational 
agents, while on study treatment. Patients may continue the use of bisphosphonates or 
denosumab for bone disease and corticosteroids for the symptomatic control of brain 
metastases provided the dose is stable before and during the study and they were started at 
least 4 weeks prior to beginning study treatment.  
 
6.2.2.8 
Subsequent therapies for cancer  
 
Details of first and subsequent therapies for cancer and/or details of surgery for the 
treatment of the cancer, after discontinuation of treatment, will be collected.  Reasons for 
starting subsequent anti-cancer therapies including access to other PARP inhibitors or 
investigational drugs will be collected and included in the exploratory assessments of OS. 
 
6.2.2.9 
Grapefruit juice 
 
It is prohibited to consume grapefruit juice while on olaparib therapy. 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
58 
6.2.3 Contraception 
 
Women of childbearing potential and their partners, who are sexually active, must agree to the 
use of TWO highly effective forms of contraception in combination (as described in 
APPENDIX E).  This should be started from the signing of the informed consent and continue 
throughout the period of taking study treatment and for at least 6 months after last dose of study 
drug(s), or they must totally/truly abstain from any form of sexual intercourse (as described in 
APPENDIX E). 
Male patients must use a condom during treatment and for 6 months after the last dose of 
olaparib when having sexual intercourse with a pregnant woman or with a woman of 
childbearing potential.  Female partners of male patients should also use a highly effective form 
of contraception (as described in APPENDIX E) if they are of childbearing potential.  Male 
patients should not donate sperm throughout the period of taking olaparib and for 6 months 
following the last dose of olaparib.  
For details of acceptable methods of contraception refer to APPENDIX E, Acceptable Birth 
Control Methods. 
 
 
 
6.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
• 
Disease progression 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 
 
• 
Patient decides to withdraw from the study. The patient is at any time free to discontinue 
treatment, without prejudice to further treatment.  If a patient ceases taking either olaparib 
or AZD6738, either by choice or due to toxicities, he or she must cease taking the other 
agent and will no longer be on active treatment.  
 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
• 
Clinical progression 
 
• 
Severe patient non-compliance with the study protocol 
 
• 
Pregnancy 
 
o All women of child bearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
59 
period) at any time during study participation. 
 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
• 
Termination of the study by sponsor 
 
• 
The drug manufacturer can no longer provide the study agent 
 
• 
Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute myeloid 
leukemia (AML) 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
6.4 
Duration of Follow Up 
 
Patients will be followed for 30 days after removal from study or until death, whichever occurs 
first.  Patients removed from treatment for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
Patients who discontinue study treatment for reasons other than disease progression (e.g., 
toxicity) will continue scheduled tumor assessments until disease progression, withdrawal of 
consent, death, or any other discontinuation criteria, whichever comes first. Patients who start a 
new anti-cancer therapy in the absence of disease progression should continue to follow the 
protocol schedule until there is confirmed disease progression, withdrawal of consent, death, or 
any other discontinuation criteria, whichever occurs first.

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
60 
 
 
7. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
7.1 
General Guidance 
 
Any clinically significant and/or unacceptable toxicity observed during the course of the 
study should be managed in the first instance by interruption of the dose of study 
treatment, dose reductions if necessary and administration of supportive therapy.  
If the toxicity resolves or reverts to ≤CTCAEv5 grade 1 or 2 (depending on the toxicity, 
see Table 1) treatment with ceralasertib and/or olaparib may be restarted using the rules 
in section 7.2 for dose modifications. Patients who have their dose previously reduced to 
the lowest possible dose and who have demonstrated an acceptable response to the dose 
interruption may be permitted to restart at the lowest dose level at the discretion of the 
Investigator. 
If the toxicity does not resolve to ≤ CTCAEv5 grade 1 or 2 (depending on the toxicity) or 
the patient is not showing clinical benefit, then the patient should be discontinued from 
treatment and observed until resolution of the toxicity. 
Repeat dose interruptions are allowed as required for a maximum of 28 days on each 
occasion as recommended in Table 1. If the duration of ceralasertib or olaparib dose 
interruption is longer than 28 days, the case should be discussed with the Principal 
Investigator. 
 
Study treatment dose interruption for conditions other than toxicity resolution should be 
kept as short as possible. If a patient cannot restart study treatment within 28 days for 
resolution of intercurrent conditions not related to disease progression or toxicity, the 
case should be discussed with the Study Physician.  
Study treatment should be stopped at least 3 days prior to planned surgery and restarted 
10 days post-surgery if the wound has healed.  If the wound has not healed well, a further 
14 days may be allowed and the patient can recommence ceralasertib if there is no 
evidence of disease progression based on the clinical judgement. No stoppage of study 
treatment is required for any biopsy procedure. Study treatment should be discontinued 
for a minimum of 3 days before a patient undergoes palliative radiation treatment. Study 
treatment should be restarted within 4 weeks as long as any bone marrow toxicity has 
recovered. 
 
The dose of ceralasertib and olaparib must not be adjusted under any other circumstances 
unless prior agreement is given by the Sponsor. 
 
All dose modifications and interruptions (including any missed doses) and the reasons for 
the modifications/interruptions are to be recorded in the CRF.  
 
7.2 
Guidance for Dose Modification and Interruption 
 
Refer to Table 1, Table 2 and Table 3 for dose modification and stopping criteria for 
ceralasertib and olaparib.  

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
61 
Please note that for simultaneous toxicities (for example, anaemia and neutropenia), the 
event should be considered singular and no further dose modification should be made 
providing that both toxicities resolve within 28 days. However, sequential toxicities (for 
example, anaemia followed by neutropenia) should follow the guidance below; if a recent 
dose reduction has been made, a second modification may be required before beginning 
the next cycle. Once dose is reduced, escalation is not permitted. 
 
Table 1. Dose interruption and stopping criteria for ceralasertib and olaparib 
Event  
Action  
Grade 1 neutropenia and/or 
thrombocytopenia 
Ceralasertib and olaparib dosing may continue if neutrophil 
count is ≥ 1500/mm3 and/or platelet count is ≥75,000/mm3 
Grade 1-2 toxicities (except 
neutropenia and 
thrombocytopenia) 
Investigator decision whether to interrupt ceralasertib and/or 
olaparib (max 28 days) or continue treatment. Treatment may 
be resumed at the same dose level prior to interruption. 
Grade 2 neutropenia or Grade 
3 anaemia 
Interrupt ceralasertib and olaparib (max 28 days) and give 
appropriate supportive treatment e.g. transfusion, until AE 
improves to at least neutrophil count ≥1500/mm3 and 
haemoglobin ≥8.0 g/dL, then restart reducing the dose of 
ceralasertib by 1 level. 
Grade 2-3 thrombocytopenia 
First occurrence 
Interrupt ceralasertib only (max 28 days) and give 
appropriate supportive treatment until platelets improve to at 
least ≥100,000/mm3. At resolution, it is not mandatory to 
lower the dose as blood counts may recover during the “off 
period” on the intermittent schedule. If blood counts do not 
recover by the start of the next dosing period, ceralasertib 
should be restarted with a dose reduction by 1 level for 
ceralasertib. 
Subsequent occurrences 
Interrupt ceralasertib only (max 28 days) and give 
appropriate supportive treatment. Treatment may be restarted 
with a reduced dose of ceralasertib when the toxicity is 
resolved or investigator discretion to stop treatment. 
Grade 4 thrombocytopenia 
 
Interrupt ceralasertib and olaparib (max 28 days) and give 
appropriate supportive treatment; investigator discretion on 
whether to restart treatment with a dose reduction by 1 dose 
level for both drugs or stop treatment when the platelet count 
has recovered to ≥100,000/mm3.  
Grade 3-4 toxicity (except 
grade 3 anaemia and grade 3-4 
thrombocytopenia)  
First occurrence 
Interrupt ceralasertib and /or olaparib (max. 28 days) and 
given appropriate supportive treatment; restart treatment with 
a dose reduction by 1 level for ceralasertib and/or olaparib 
when the toxicity is resolved (grade ≤1 or 2 depending on the 
toxicity or returns to baseline).  

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
62 
Subsequent occurrences 
Interrupt ceralasertib and /or olaparib (max 28 days) and give 
appropriate supportive treatment. Investigator discretion 
whether to restart treatment with a reduced dose of 
ceralasertib and/or olaparib or to stop treatment.  
Vomiting 
If vomiting occurs shortly after ceralasertib is swallowed, the 
dose should only be replaced if all of the intact capsules can 
be counted. Resume with the following scheduled dose. 
Missed dose 
Allowed to take the scheduled dose up to 2 hours after the 
scheduled dose time. If greater than 2 hours, the missed dose 
should not be taken, and patient should continue with next 
dose at allotted time.  
 
Table 2. Dose reduction levels for ceralasertib 
Initial dose 
160 mg OD days 1–7 
Level 1 dose reduction 
120 mg OD days 1–7 
Level 2 dose reduction 
80 mg OD days 1–7 
Level 3 dose reduction 
Stop treatment 
 
Table 3. Dose reduction levels for olaparib 
Initial dose 
300 mg twice daily 
Level 1 dose reduction 
250 mg twice daily 
Level 2 dose reduction 
200 mg twice daily 
Level 3 dose reduction 
Stop treatment 
 
 
7.3 
Management of Prolonged Hematological Toxicities 
 
If a patient develops prolonged hematological toxicity such as:  
• ≥2 week interruption or delay in study treatment due to CTCAE grade 3 or 
worse anemia and/or development of blood transfusion dependence 
•  ≥2 week interruption/delay in study treatment due to CTC grade 3 or 
worse neutropenia (ANC < 1 x 109/L) 
•  ≥2 week interruption/delay in study treatment due to CTC grade 3 or 
worse thrombocytopenia (platelets < 50 x 109/L) 
 
Weekly differential blood counts including reticulocytes and peripheral blood smear 
should be performed. Study treatment should be discontinued if blood counts do not 
recover to CTC Grade 1 or better within 4 weeks of dose interruption. 
If any blood parameters remain clinically abnormal after 4 weeks of dose interruption, the 
patient should be referred to a hematologist for further investigations. Bone marrow 
analysis and/or blood cytogenetic analysis should be considered at this stage according to 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
63 
standard hematological practice. 
 
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder 
should be reported as detailed in Section 10.6. Study treatment should be discontinued if 
diagnosis of MDS and/or AML is confirmed. 
 
7.4 
Individual Stopping Criteria 
  
Hepatic 
ALT or AST or ALP* > 5 x ULN 
ALT or AST or ALP* > 3 x ULN with the appearance of symptoms associated with a 
clinical diagnosis of hepatitis including right upper quadrant pain or tenderness, fever, 
rash or eosinophilia (>5%) 
[ALT or AST > 3 x ULN] and [total bilirubin > 2 x ULN or INR+ > 1.5 or other evidence 
of impairment to the synthesis function of the liver] 
* In the presence of bone mets assess bone specific isoform of raised ALP in the presence 
of a raised gamma-GT (to ensure the ALP change is specific to the liver) 
+ Unless patient is receiving warfarin 
Please refer to Appendix C “Actions Required in Cases of Combined Increase of 
Aminotransferase and Total Bilirubin - Hy’s Law.” 
 
Cardiovascular 
Clinically significant hypotension defined as an asymptomatic decrease of more than 20 
mmHg in systolic blood pressure to below 70 mmHg persisting for at least 10 minutes. 
Symptomatic orthostatic fall in systolic blood pressure of more than 20 mmHg compared 
to resting supine systolic blood pressure. 
 
 
8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 10.1. 
 
8.1 
CTEP IND Agents 
 
8.1.1 Olaparib (NSC# 747856) 
 
Chemical Name:  4-[(3-[[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl]-4-
fluorophenyl)methyl]phthalazin-1(2H)-one 
 
Other Names: AZD2281; KU-0059436; CO-CE 42 
 
Classification: PARP inhibitor 
 
CAS Registry Number: 763113-22-0 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
64 
Molecular Formula: 
 C24H23FN4O3 
 
M.W.: 434.46 
 
Approximate Solubility: 0.1 mg/mL pH independent solubility across physiologic range 
 
Mode of Action: Olaparib is an inhibitor of subclasses 1, 2, and 3 of polyadenosine 5’ 
diphosphoribose polymerase (PARP-1, PARP-2, and PARP-3). In tumors that are 
deficient in the homologous recombination DNA repair pathway (example, BRCA 
mutants), inhibition of PARP by olaparib causes accumulation of DNA double-strand 
breaks and genomic instability. Olaparib may also enhance the effects of DNA damage 
caused by ionizing radiation and chemotherapy.  
 
Description: crystalline solid 
 
How Supplied: AstraZeneca supplies and the CTEP, DCTD distributes olaparib in 100 
mg and 150 mg strengths.  
 
• 
100 mg tablets are 14.5 mm x 7.25 mm oval-shaped 
• 
150 mg are 14.5 mm x 7.25 mm oval-shaped 
 
Tablets are packaged in induction-sealed high-density polyethylene (HDPE) bottles with 
child-resistant closures. Each bottle contains 32 tablets with desiccant.  
 
Tablet core components include active drug substance, copovidone, colloidal silicon 
dioxide, mannitol and sodium stearyl fumarate. Film coating contains hydroxypropyl 
methylcellulose (hypromellose), macrogol 400 (polyethylene glycol 400), titanium 
dioxide, iron oxide yellow and iron oxide black. 
 
Storage: Store in a secure location below 30° C (86° F).  
 
If a storage temperature excursion is identified, promptly return olaparib (AZD2281) to 
room temperature and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability.   
 
Stability:  Shelf-life studies are ongoing. Sites are not permitted to re-package tablets. 
Once the bottle is opened, olaparib tablets must be used within 3 months of the opening 
date; unused tablets should be discarded. Instruct patients not to open a bottle until they 
are ready to use it. 
 
Route and Method of Administration:  Oral. Take tablets without regard to meals. 
When AZD6738 is administered in combination with olaparib, patients should fast for 2 
hours before dosing and for 1 hour after dosing. 
  
 
Potential Drug Interactions:  In vivo data indicate that CYP3A4/5 is important for 
olaparib metabolism and clearance in humans. For this reason, avoid concomitant 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
65 
administration of strong and moderate CYP 3A4/5 inducers and inhibitors.  Consult the 
protocol document or study investigator prior to making any dose adjustments related to 
potential drug-drug interactions. 
 
In vitro data shows olaparib is a substrate for P-glycoprotein (P-gp), but not for organic 
anion-transporting polypeptides (OATP1B1 and OATP1B3), organic cation transporter 1 
(OCT1), multi-drug resistance protein 2 (MRP-2) efflux transporter or breast cancer 
resistance protein (BCRP). Administration of strong P-gp inhibitors and inducers should 
be avoided with concurrent olaparib.   
 
Based on in vitro data, olaparib inhibits CYP 3A4 and UGT1A1 enzyme systems and 
induces CYP 1A2, 2B6, and 3A4 and potentially induces CYP 2C9, 2C19 and P-gp. 
Therefore, avoid concomitant administration of sensitive substrates, particularly those 
with narrow therapeutic ranges.   
 
Olaparib is also an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, multi-drug and 
toxin extrusion proteins (MATE1 and MATE2K) and a weak inhibitor of BRCP, but not 
an inhibitor of OATP1B3 or MRP-2. In vitro studies suggest that olaparib may increase 
exposure of substrates of these transport systems, although the clinical relevance is not 
clear. The manufacturer recommends that statins, in particular, should be administered 
with caution when given concomitantly with olaparib. 
 
Patient Care Implications: Pre-clinical data indicate that olaparib adversely affects 
embryofetal survival and development. Therefore, women of child-bearing potential and 
their partners should agree to use two (2) highly effective forms of contraception 
throughout study participation and for at least six (6) months after the last dose of 
olaparib.  Male study participants should avoid fathering a child or donating sperm during 
the study and for six (6) months after the last dose of olaparib. The study investigator 
should discuss the most appropriate forms of highly effective contraceptive methods for 
each patient.  
 
Because the adverse events related to olaparib may include asthenia, fatigue and 
dizziness, patients should be advised to use caution while driving or using machinery. 
 
Olaparib is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
Olaparib is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 13.3) 
 
8.1.2 AZD6738 (NSC #802785) 
 
Chemical Name:  Imino-methyl-[1-[6-[(3R)-3-methylmorpholin-4-yl]-2-(1H-
pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl]cyclopropyl]-oxo-λ6-sulfane 
 
Other Names: AZ13386215 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
66 
 
CAS registry number: 1352226-88-0  
 
Classification: Ataxia Telangiectasia and Rad3-Related (ATR) protein kinase inhibitor  
 
Molecular Formula: C20H24N6O2S 
 
Molecular Weight: 412.51 g/mol 
 
Approximate Solubility: AZD6738 free base solubility is >100 mg/mL in Simulated 
Gastric Fluid (pH 1.6) and 0.76 mg/mL in Fasted State Simulated Intestinal Fluid (pH 6.5) 
 
Mode of Action: AZD6738 is a potent, selective inhibitor of the ATR protein, which is 
recruited to stalled DNA replication forks during DNA damage. ATR activation leads to cell 
cycle arrest in the S phase while DNA is repaired, and the stalled replication fork is 
resolved. ATR inhibition leads to the inability to resolve stalled replication forks, the 
accumulation of DNA damage and subsequent rapid cell death. 
 
Description: AZD6738 is a crystalline powder. 
 
How Supplied: AstraZeneca supplies and PMB, DCTD, NCI distributes AZD6738 as 20 
mg and 80 mg film-coated tablets. Each tablet contains a blend of AZD6738, mannitol, 
microcrystalline cellulose, sodium starch glycolate, magnesium stearate and silicon dioxide. 
The coating is Opadry® II white. Tablets are available in induction-sealed HDPE bottles as 
described: 
 
 
 
20 mg: 6-mm round, white tablets packaged in 24-count bottles 
 
 
80 mg: 11-mm round, white tablets packaged in 16-count bottles  
 
Storage: Store AZD6738 tablets  <30°C. Do not freeze. 
 
If a storage temperature excursion is identified, promptly return AZD6738 to <30°C and 
quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Stability studies are ongoing. The manufacturer does not have stability data to 
support repackaging tablets. Dispense tablets in the original container. 
 
Route and Method of Administration: Oral. Do not eat or drink (except water only) for at 
least 2 hours prior to dosing and for at least 1 hour after dosing AZD6738 tablets. Do not 
crush, chew or split the tablets. 
If vomiting occurs shortly after AZD6738 is swallowed, the dose should only be replaced 
if all of the intact tablets can be counted and then treatment resumed with the following 
scheduled dose. The scheduled dose can be taken up to 2 hours after the scheduled dose 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
67 
time. If greater than 2 hours, the missed dose should not be taken and patient should 
continue with next dose at the scheduled time. 
Potential drug interactions: AZD6738 is primarily metabolized by CYP3A4, with lesser 
contribution by CYP 2C8, 2C9, 2C19 and 3A5. CYP 1A2, 2A6, 2B6, 2D6 and 2E1 were 
not shown to metabolize AZD6738 in vitro.  Avoid co-administration of strong CYP3A4 
inducers and inhibitors. Advise patients not to consume grapefruit, grapefruit juice or 
Seville oranges (including marmalade, juice, etc) while participating in the study. Refer to 
the protocol document for additional guidance. 
 
AZD6738 is a substrate of P-gp and BCRP and a likely substrate of OATP1B1 and/or 
OATP1B3 transporter systems. Avoid co-administration of strong inhibitors or inducers of 
P-gp or BCRP. Refer to the protocol document for additional guidance. 
 
AZD6738 has the potential to inhibit P-gp, BCRP, OATP1B1, OATP1B3, MATE1 and 
MATE2K protein transporter systems. It did not show inhibition of OAT1, OAT3 or OCT2 
during in vitro studies. Use caution with co-administration of substrates of these transporter 
systems since their drug exposures may be increased. In vitro studies demonstrate that 
AZD6738 does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2B6, CYP2C8, 
and CYP3A4/5.  
 
In vitro studies show that AZD6738 has a low potential to induce CYP1A2, CYP2B6 and 
CYP3A4. Use caution with co-administration of substrates that are either completely 
metabolized by these enzymes or substrates with a narrow therapeutic index since their drug 
exposures may be decreased.  
 
Patient care implications: Advise women of child-bearing potential to use two (2) highly 
effective forms of contraception while receiving study treatment and for 1 (one) month after 
the last dose. 
  
Advise men who are sexually active to use barrier contraception while receiving study 
treatment and for one (1) week after the last dose. Male study participants must use barrier 
contraception while receiving study treatment and for 6 (six) months after the last dose if the 
female partner is pregnant. Female partners of male study participants should use a highly 
effective form of contraception for 6 (six) months after the last dose.  
 
Advise patients to avoid excessive sun exposure while receiving AZD6738. 
 
AZD6738 is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
AZD6738 is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 13.3). 
 
8.1.3 Agent Ordering and Agent Accountability 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
68 
8.1.3.1 
NCI-supplied agents may be requested by eligible participating Investigators (or 
their authorized designee) at each participating institution.  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational agents.  
The eligible participating investigators at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA Form 1572 
(Statement of Investigator), NCI Biosketch, Agent Shipment Form, and Financial 
Disclosure Form (FDF).  If there are several participating investigators at one 
institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead participating investigator at that institution. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status.  For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time.  
Refer to the PMB’s website for specific policies and guidelines related to agent 
management.   
 
Sites can order study agents in OAOP when a patient is enrolled to treatment. Agent 
orders can be expedited overnight Monday-Thursday when sites provide expedited 
courier information. 
 
8.1.3.2 
Agent Inventory Records: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.1.4 Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application.  Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account status, 
a “current” password and active person registration status.  Questions about IB access 
may be directed to the PMB IB Coordinator via email. 
 
8.1.5 Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application:  
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/  

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
69 
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• IB Coordinator:  IBCoordinator@mail.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
9. 
STATISTICAL CONSIDERATIONS 
The cholangiocarcinoma cohort has closed to accrual.  Protocol amendment version 
08/22/2022 reflects this closure.   
 
9.1 
Primary objective 
The primary objective of this phase II study is to determine the objective response rate 
(ORR) in subjects with recurrent/progressive IDH1/2-mutant solid tumors. Previous 
experiences suggest that response rate for this type of solid malignancies is 
approximately 20%.  
 
9.2 
Baseline data analysis 
Demographic information such as age and race will be tabulated.  Descriptive statistics, 
including means, medians, standard deviations, and ranges for continuous parameters, as 
well as percentages and frequencies for categorical parameters, will be presented.  
 
9.3 
Analysis of primary endpoint 
The effectiveness of the new combination in patients for each cohort will be 
independently assessed by objective response rate (ORR). The exact two-sided 95% 
confidence intervals for the ORR will be reported.  
 
9.4 
Toxicity evaluation 
Toxicities will be evaluated utilizing the National Cancer Institute Common Terminology 
Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0, available at 
https://ctep.cancer.gov).  Adverse medical events will be tabulated.  NCI toxicity Grade 3 
and Grade 4 laboratory abnormalities will be listed.  Reporting of adverse events is 
described in Sections 10.3 and 10.4.  All patients who receive any amount of study drugs 
will be evaluable for toxicity.   
 
An early review will be made of safety in the initial 10 patients treated on each arm. If 
unacceptable toxicity (defined below) occurs in 3 of these initial 10 patients enrolled on 
either arm, a dose de-escalation of olaparib will occur for all patients currently enrolled 
and any who enroll thereafter (250 mg PO bid continuously). After the 10th patient, we 
will delay treatment on the combination arm until the 10th patient has been assessed for 4 
weeks (28 day cycle).  
 
After the 10th patient is treated, the initial safety review will occur to obtain consensus 
from the participating physicians on how to proceed. If there are physicians participating 
in the study who are not able to be available for this discussion, we will send them the 
relevant information and ask them to respond regarding their assessment of the safety of 
this dosing regimen.  

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
72 
concentrations between patients with a response to treatment and those without. We will 
also apply analysis of covariance (ANCOVA) for post-treatment plasma concentration in 
2HG adjusted for the pre-treatment plasma concentration between patients with a 
response to treatment and those without. Differences with p ≤ 0.05 will be considered 
statistically significant. The area under the receiver operating characteristic curve (ROC 
AUC) will be calculated to determine the cutoff value of the 2HG difference. The optimal 
cutoff value will be determined at the point on the ROC curve at (sensitivity + specificity 
− 1) is maximized (Youden index). 
 
The primary objective of these biopsies is for the exploratory analysis.  The proposed 
minimum of 10 biopsy samples per arm for the first stage provides 90% power to detect 
an effect size of 1.5 with un-adjusted two-sided type I error = 5%. The effect size is 
defined as ratio of mean difference between two arms to the standard deviation. 
 
9.9 
Reporting and Exclusions 
 
9.9.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
AZD6738 and olaparib. 
 
9.9.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations.  The only exception to this rule is if a patient is 
found to be ineligible for the study.   
 
Each patient will be assigned one of the following categories:  1) complete response, 2) 
partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data).  [Note:  By arbitrary convention, category 9 
usually designates the “unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the exception of those who 
received no study medication) should be included in the main analysis of the response 
rate.  However, if a patient’s tissue is not confirmed centrally to have an eligible IDH1/2 
mutation, that patient will not be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered to have a treatment failure 
(disease progression).  Thus, an incorrect treatment schedule or drug administration does 
not result in exclusion from the analysis of the response rate.  Precise definitions for 
categories 4-9 will be protocol specific.  
 
Patients with previously identified IDH1/2 mutation in a CLIA certified laboratory are 
eligible, but the mutation must be verified later in the central laboratory. If IDH mutation 
fails to confirm those patients will be excluded from the final analysis. 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
73 
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided.  
 
10. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 
10.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
 
10.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. 
 
10.1.1 CAEPRs for CTEP IND Agents 
 
10.1.1.1 
CAEPR for Olaparib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Olaparib (AZD2281, NSC 747856) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 3449 patients. Below is the CAEPR for Olaparib 
(AZD2281). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
78 
Gastroesophageal reflux disease; Gastrointestinal disorders - Other (gastrointestinal hemorrhage)2; Mucositis oral; 
Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Disease progression; 
Fever; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (drug-induced liver injury); Hepatobiliary 
disorders - Other (biliary obstruction); Hepatobiliary disorders - Other (cholangitis) 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (hypogammaglobulinemia) 
INFECTIONS AND INFESTATIONS - Abdominal infection; Hepatitis viral; Herpes simplex reactivation; 
Infections and infestations - Other (diarrhea infectious); Infections and infestations - Other (gastroenteritis); Sepsis; 
Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood bilirubin 
increased; CD4 lymphocytes decreased; Creatinine increased; Ejection fraction decreased; Electrocardiogram QT 
corrected interval prolonged; Investigations - Other (elevated C-reactive protein); Lymphocyte count decreased; 
Lymphocyte count increased; Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS - Hypercalcemia; Hypokalemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Generalized 
muscle weakness; Musculoskeletal and connective tissue disorder - Other (groin pain); Myalgia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Peripheral sensory neuropathy; Stroke 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other (acute renal 
insufficiency) 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Reproductive system and breast disorders - Other 
(prostatitis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Epistaxis; Hypoxia; 
Oropharyngeal pain; Pleural effusion; Pneumonitis; Pulmonary edema; Respiratory failure; Respiratory, thoracic 
and mediastinal disorders - Other (chronic obstructive pulmonary disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Photosensitivity; Pruritus; Skin ulceration 
VASCULAR DISORDERS - Hypotension; Superior vena cava syndrome; Thromboembolic event; Vascular 
disorders - Other (thrombophlebitis) 
 
 
Note: AZD6738 (ceralasertib) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
 
10.2 
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 
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 that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 10.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
Section 10.3.4. 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
79 
 
• 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. 
 
10.3 
Expedited Adverse Event Reporting 
 
10.3.1 CTEP-AERS 
 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).  These requirements are briefly outlined in the tables below (Section 10.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
10.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
10.3.3 Rave-CTEP-AERS Integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) integration enables evaluation of Adverse Events (AEs) entered in Rave to 
determine whether they require expedited reporting and facilitates entry in CTEP-AERS 
for those AEs requiring expedited reporting.  Sites must initiate all AEs for this study in 
Medidata Rave. 
 
10.3.4 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
81 
• 
Within 5 calendar days for Grade 4-5 SAEs 
• 
Within 10 calendar days for Grade 1-3 SAEs 
2For studies using nuclear medicine or molecular imaging IND agents (NM, SPECT, or PET), the SAE 
reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest whole day, after the 
agent/intervention was last administered.  Footnote “1” above applies after this reporting period. 
 
Effective Date: August 30, 2024 
 
 
10.3.5 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS.  However, they still must be reported through the routine reporting 
mechanism (Section 10.4): 
 
CTCAE SOC 
Adverse Event 
Grade 
≥24h 
Hospitalizationa 
BLOOD AND LYMPHATIC 
SYSTEM DISORDERS 
Anemia 
2 
No 
GASTROINTESTINAL 
DISORDERS 
Abdominal pain 
2 
No 
GASTROINTESTINAL 
DISORDERS 
Constipation 
2 
No 
GASTROINTESTINAL 
DISORDERS 
Diarrhea 
2 
No 
GASTROINTESTINAL 
DISORDERS 
Dyspepsia 
2 
No 
GASTROINTESTINAL 
DISORDERS 
Nausea 
2 
No 
GASTROINTESTINAL 
DISORDERS 
Vomiting 
2 
No 
GENERAL DISORDERS AND 
ADMINISTRATION SITE 
CONDITIONS 
Fatigue 
2 
No 
METABOLISM AND NUTRITION 
DISORDERS 
Anorexia 
2 
No 
NERVOUS SYSTEM 
DISORDERS 
Headache 
2 
No 
RESPIRATORY, THORACIC 
AND MEDIASTINAL 
DISORDERS 
Dyspnea 
2 
No 
a Indicates that an adverse event required hospitalization for ≥24 hours or prolongation of 
hospitalization by ≥24 hours of a patient. 
 
10.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
82 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
10.4.1 Adverse Events based on signs and symptoms 
When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms.  However, if a diagnosis is known and there are 
other signs or symptoms that are not generally part of the diagnosis, the diagnosis and 
each sign or symptom will be recorded separately. 
 
10.4.2 Adverse Events based on examinations and tests 
Deterioration as compared to baseline in protocol-mandated determination (eg, laboratory 
values, vital signs) should therefore only be reported as AEs if they fulfill any of the SAE 
criteria or are the reason for discontinuation of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory 
result/vital sign will be considered as additional information.  Wherever possible the 
reporting investigator uses the clinical, rather than the laboratory term (eg, anemia versus 
low hemoglobin value). In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as AE(s s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, 
should not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical 
examination as compared with the baseline assessment will be reported as an AE. 
 
NB. Cases where a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN 
may need to be reported as SAEs, please refer to APPENDIX C ‘Actions required in 
cases of combined increase of Aminotransferase and Total Bilirubin – Hy’s Law’, for 
further instructions. 
 
10.4.3 Disease Progression 
Disease progression can be considered as a worsening of a subject’s condition 
attributable to the disease for which the investigational product is being studied.  It may 
be an increase in the severity of the disease under study and/or increases in the symptoms 
of the disease.  The development of new, or progression of existing metastasis to the 
primary cancer under study should be considered as disease progression and not an AE.  
Events, which are unequivocally due to disease progression, should not be reported as an 
AE during the study.  
 
10.4.4 Lack of Efficacy 
When there is deterioration in the condition for which the study treatment is being used, 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
83 
there may be uncertainty as to whether this is lack of efficacy or an AE.  In such cases, 
unless the Sponsor or the reporting physician considers that the study treatment 
contributed to the deterioration of the condition, or local regulations state to the contrary, 
the deterioration should be considered to be a lack of efficacy and not an AE. 
 
10.4.5 Overdose 
There is currently no specific treatment in the event of overdose with olaparib and 
possible symptoms of overdose are not established.  Olaparib must only be used in 
accordance with the dosing recommendations in this protocol. Any dose or frequency of 
dosing that exceeds the dosing regimen specified in this protocol should be reported as an 
overdose. The Maximum Tolerated Dose is 300 mg twice daily (tablet). 
Adverse reactions associated with overdose should be treated symptomatically and 
should be managed appropriately. 
 
10.4.6 Deaths 
All deaths that occur during the study, or within the protocol-defined 30-day post-study 
follow-up period after the administration of the last dose of study treatment, must be 
reported as follows: 
• Death clearly the result of disease progression should be reported to the study 
monitor at the next monitoring visit and should be documented in the eCRF but 
should not be reported as an SAE. 
• Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to the study monitor as a SAE 
within 24 hours (see Section  for further details).  The report should contain a 
comment regarding the co-involvement of progression of disease, if appropriate, 
and should assign main and contributory causes of death.  This information can be 
captured in the ‘death eCRF’. 
• Deaths with an unknown cause should always be reported as a SAE.  A post 
mortem maybe helpful in the assessment of the cause of death, and if performed a 
copy of the post-mortem results should be forwarded to Study PI within the usual 
timeframes. 
 
10.5 
Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included 
within the NCI Guidelines for Adverse Event Reporting Requirements must be 
completed and submitted to CTEP.  Any pregnancy occurring in a patient or patient’s 
partner from the time of consent to 90 days after the last dose of study drug must be 
reported and then followed for outcome.  Newborn infants should be followed until 30 
days old.  Please see the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” (at 
http://ctep.cancer.gov/protocolDevelopment/adverse effects.htm) for more details on 
how to report pregnancy and its outcome to CTEP.  
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
84 
10.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
10.7 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
10.8 
Olaparib adverse events of special interest 
 
Adverse events of special interest [AESI] are events of scientific and medical interest 
specific to the further understanding of olaparib’s safety profile and require close 
monitoring and rapid communication by the investigators to Study Principal Investigator. 
An AESI may be serious or non-serious. Adverse Events of Special Interest for olaparib 
are the Important Potential Risks of MDS/AML, new primary malignancy (other than 
MDS/AML) and pneumonitis.   
 
ANY event of MDS/AML, new primary malignancy, or pneumonitis should be reported 
to Study Principal Investigator whether it is considered a non-serious AE [eg non-
melanoma skin cancer] or SAE, and regardless of investigator’s assessment of causality 
or knowledge of the treatment arm.    
 
A questionnaire will be sent to any investigator reporting an AESI, as an aid to provide 
further detailed information on the event.  During the study there may be other events 
identified as AESIs that require the use of a questionnaire to help characterise the event 
and gain a better understanding regarding the relationship between the event and study 
treatment. 
 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
85 
11. STUDY CALENDAR 
 
Unless otherwise indicated, screening evaluations are to be conducted within 28 days prior to 
start of protocol therapy. Cycle 1 Day 1 ECG and laboratory results must be reconfirmed and 
remain within eligibility parameters as per section 3 for patient to be dosed. Scans and x-rays 
must be done <4 weeks prior to the start of therapy.  In the event that the patient’s condition is 
deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the 
next cycle of therapy. 
 
Biopsy procedures will occur at pre-treatment (biopsy within 2 weeks of starting therapy) and 
after 1 cycle of treatment (4 weeks), with the latter occurring only as long as the patient has 
received a minimum of 1 Cycle of treatment following the second biopsy procedure (or 21 of 28 
days given the +/- 7 day allowable window for the on treatment biopsy). Each biopsy will consist 
of 6 passes of a large gauge needle (such as 16 or 18g) for core biopsy. Unless otherwise 
indicated, there is a +/- 4 day window for all visits and assessments.  

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
86 
 
 
 
Screening  
(Day – 28 
to Day 1)A 
D1 
Cycle 
≥ 1 
C1D8 
C1D15 
4 weeks 
C2D8 
C2D15 
8 
weeks 
Every 8 
weeks 
Off 
studyB 
Follow 
Up 
Long 
term 
Follow 
Up  
OlaparibQ 
 
X-----------------------------------------------------------------------------------------------------------------------------X 
 
 
AZD6738R 
 
X-----------------------------------------------------------------------------------------------------------------------------X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
C 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Molecular Selection of 
Patients based on 
Archival Tumor Tissue 
determined in a CLIA 
certified laboratory
 D 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, 
including neurological 
examinationE 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
Weight 
X 
X 
 
 
 
 
 
X 
 
 
 
 
Vital signsF 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
 
ECOG Performance Status 
X 
X 
 
 
 
 
 
X 
 
X 
X 
 
Hematology G 
X 
XS 
X 
X 
 
X 
X 
 
 
  X 
 
 
Chemistry H 
X 
XS 
X 
X 
 
X 
X 
 
 
  X 
 
 
Urinalysis I 
X 
If clinically indicated 
 
 
Coagulation J 
X 
If clinically indicated, except for patients on Warfarin 
 
 
Bone marrow or blood 
cytogenetic analysis K 
 
If clinically indicated 
 
 
Concomitant medications 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
Dosing compliance 
 
X 
 
 
 
 
 
 
 
X 
 
 
Adverse events 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
Tumor Assessments 
L 
X 
 
 
 
 
 
 
XL 
XL 
X 
X 
 
2HG plasma 
concentrationM  
X 
 
 
 
 
 
 
XM 
XM 
XM 
 
 
2HG tumor tissueN 
concentrations 
X  
 
 
 
X N 
 
 
 
 
 
 
 
ECGO 
X 
X 
 
 
 
 
 
 
 
 
 
 
BiopsyP 
X 
 
 
 
X 
 
 
 
 
 
 
 
Whole blood in EDTA 
X 
 
 
 
 
 
 
 
 
 
 
 
Anti-cancer therapy    
follow-up 
 
 
 
 
 
 
 
 
 
 
 
X 
A Results of standard of care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Day 1 may be used; such tests do 
not need to be repeated for screening.  
B All patients with clinically significant abnormal laboratory results at treatment completion or study drug discontinuation visit are to be followed until the 
results return to normal (or patient’s baseline), or until a valid reason, other than a drug- related effect, is identified. Patients with an unresolved AE or SAE event 
at treatment completion or study drug discontinuation will be contacted by the investigator or his or her designee to determine the status of the event until the 
event is resolved or stabilized, the patient is lost to follow up, or it has been determined that the study treatment or participation is not the cause of the event.  
C Pregnancy tests on blood or urine samples will be performed for women of childbearing potential within 28 days prior to the start of study treatment, on Day 1 
of the study prior to commencing treatment and at each subsequent visit during study treatment and at the 30 day follow up visit. Tests will be performed by the 
hospital’s local laboratory. If results are positive the patient is ineligible/must be discontinued from the study.  In the event of a suspected pregnancy during the 
study, the test should be repeated. 
D Subjects must have biopsy-confirmed evidence of an IDH1 or IDH2 mutation associated with neomorphic activity of the encoded proteins. See Section 2.4.1 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
87 
for additional information on IDH1/2 mutation confirmation and those that are considered to be neomorphic.  
E A complete physical examination will be performed at the following timepoints: Screening Visit, Day 1 Every Cycle, Discontinuation Visit, Follow-up Visit. 
Constitutional symptoms will be collected during screening and pre-dose at all other visits. Constitutional symptoms will include the presence/absence of 
pruritus, night sweats, recurrent fever ≥38.0ºC, fatigue, weakness and nocturia (a history of weight loss is to be collected at screening visit only).  
F Vital signs (heart rate, systolic and diastolic blood pressure, oxygen saturation (pulse oximetry), respiration rate, weight, height (at screening) and 
temperature). At screening, vital signs should include postural blood pressure; this should be performed at subsequent visits if clinically indicated. 
G Full hematology assessments for safety (hemoglobin, red blood cells [RBC], platelets, mean cell volume [MCV], mean cell hemoglobin concentration 
[MCHC], mean cell hemoglobin [MCH], white blood cells [WBC], absolute differential white cell count (neutrophils, lymphocytes, monocytes, eosinophils and 
basophils) and absolute neutrophil count or segmented neutrophil count and Band forms should be performed at each visit and when clinically indicated. If 
absolute differentials not available please provide % differentials.  
H Biochemistry assessments for safety (sodium, potassium, calcium, magnesium, creatinine, total bilirubin, gamma glutamyltransferase [GGT], alkaline 
phosphatase [ALP], aspartate transaminase [AST], alanine transaminase [ALT], urea or blood urea nitrogen [BUN], total protein, albumin and lactic 
dehydrogenase [LDH]). 
I Urinalysis by dipstick should be performed at baseline and then only if clinically indicated. Microscopic analysis should be performed by the hospital’s local 
laboratory if required. 
J Coagulation [activated partial thromboblastin time (APTT) and international normalized ratio (INR) ] will be performed at baseline and if clinically indicated 
unless the patient is receiving warfarin. Patients taking warfarin may participate in this study; however, it is recommended that prothrombin time (INR and 
APTT) be monitored carefully at least once per week for the first month, then monthly if the INR is stable. 
K Bone marrow or blood cytogenetic analysis may be performed according to standard hematological practice for patients with prolonged hematological 
toxicities. Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic analysis and flow cytometry, and a core biopsy for bone 
marrow cellularity. If it is not possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then attempts should be made to carry out 
the tests on a blood sample. If findings are consistent with MDS/AML, study drug should be discontinued and a full description of findings should be submitted 
with an SAE report by the investigator to the Sponsor for documentation on the Patient Safety database. Presence or absence of blood cytogenetic abnormalities 
and flow cytometry will be documented on the clinical database.  Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
hematological toxicities. 
L Patients will be evaluated until objective disease progression by RECIST 1.1. If a chest CT scan at baseline (screening CT will be the baseline scan) is not 
performed as part of the RECIST assessment, the patient should undergo a chest CT scan in order to document the lung parenchyma status at baseline. High 
resolution CT should be performed if clinically indicated by pulmonary symptoms any time during the study. For any new respiratory symptoms (cough, 
dyspnea, lower respiratory infection) not clearly explained by other factors (eg, dyspnea associated with substantial drop in hemoglobin), patients should have 
oxygen saturation measured. If <92%, the high resolution CT scan of the chest should be repeated and pulmonary function tests should be performed. Scans will 
be performed  every 8 weeks (± 1 week) and it will continue until disease progression, consent withdrawal, or death, whichever occurs first. After 12 months, 
patients will undergo tumor assessments every 12 weeks (+/- 1 week) until confirmed disease progression. Patients who discontinue treatment for reasons other 
than disease progression (e.g., toxicity) will continue scheduled tumor assessments until disease progression, withdrawal of consent, or death, whichever occurs 
first. If partial response (PR) or complete response (CR) is documented, a confirmatory scan will be performed 4 weeks later for PR/CR (whichever occurs first). 
M. The concentrations of 2HG will be determined in patient plasma.  Blood samples will be collected at screening/pre-treatment (Days -14 to -1), on day 1 of 
cycles 2, 4 and 8 and at time of confirmed disease progression per study schema (plasma only; -/+ 4 days). Sample handling instructions can be found in Section 
5.2.1 and Section 5.3.1. 
N. The concentrations of 2HG will be determined in patient tumor samples. FFPE samples will be accepted for analysis if a biopsy is not obtainable or the 
patient declines biopsy. On treatment biopsy will occur on C2D1, +/- 7 days. Sample handling instructions can be found in Appendix G, Laboratory Manual 
O. ECGs are required within 28 days prior to starting study treatment in triplicate performed 2-5 minutes apart; on Day 1 of each cycle; and when clinically 
indicated. Cycle 1 Day 1 ECG results must be reconfirmed and remain within eligibility parameters as per section 3 for patient to be dosed. 
P. Biopsy procedures to occur at pre-treatment (biopsy within 2 weeks of starting therapy, Days -14 to -1) and after 1 cycle of treatment (4 weeks, +/- 7 days), as 
long as the patient has received a minimum of 1 Cycle of treatment. Each biopsy will consist of 6 passes of a large gauge needle (such as 16 or 18g) for core 
biopsy.  
Q. Olaparib: 300 mg orally BID continuously in 28-day cycles.  
R. AZD6738: 160 mg orally once daily on days 1-7 of a 28-day cycle. 
S. Cycle 1 Day 1 laboratory results must be reconfirmed and remain within eligibility parameters as per section 3 for patient to be dosed. 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
88 
11.1 
Study procedures 
11.1.1 Laboratory safety assessment 
Full hematology assessments for safety (hemoglobin, red blood cells [RBC], platelets, 
mean cell volume [MCV], mean cell hemoglobin concentration [MCHC], mean cell 
hemoglobin [MCH], white blood cells [WBC], absolute differential white cell count 
(neutrophils, lymphocytes, monocytes, eosinophils and basophils) and absolute 
neutrophil count or segmented neutrophil count and Band forms should be performed at 
each visit and when clinically indicated.  If absolute differentials not available please 
provide % differentials. Coagulation [activated partial thromboblastin time (APTT) and 
international normalised ratio (INR)] will be performed at baseline and if clinically 
indicated unless the patient is receiving warfarin. Patients taking warfarin may participate 
in this study; however, it is recommended that prothrombin time (INR and APTT) be 
monitored carefully at least once per week for the first month, then monthly if the INR is 
stable. 
 
Biochemistry assessments for safety (sodium, potassium, calcium, magnesium, fasting 
glucose, creatinine, total bilirubin, gamma glutamyltransferase [GGT], alkaline 
phosphatase [ALP], aspartate transaminase [AST], alanine transaminase [ALT], urea or 
blood urea nitrogen [BUN], total protein, albumin and lactic dehydrogenase [LDH]) 
should be performed at each visit and when clinically indicated. 
 
Urinalysis by dipstick should be performed at baseline [measuring hemoglobin, 
erythrocytes, blood, protein, albumin, and glucose] and then only if clinically indicated. 
Microscopic analysis should be performed by the hospital’s local laboratory if required. 
 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
hematological toxicities as defined in Section 7.3.4. 
 
These tests will be performed by the hospital’s local laboratory.  Additional analyses may 
be performed if clinically indicated. 
 
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the eCRF. 
 
In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer 
to APPENDIX C, ‘Actions required in cases of combined increase of Aminotransferase 
and Total Bilirubin – Hy’s Law’, for further instructions 
 
11.1.2 Physical examination 
A complete physical examination will be performed at the following timepoints: 
Screening visit, Day 1 every cycle, Discontinuation visit, Follow-up visit. Constitutional 
symptoms will be collected during screening and pre-dose at all other visits. 
Constitutional symptoms will include the presence/absence of pruritus, night sweats, 
recurrent fever ≥38.0ºC, fatigue, weakness and nocturia (a history of weight loss is to be 
collected at screening visit only). All adverse events should be recorded as explained in 
Section 10.4. 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
89 
11.1.3 Resting 12 lead EKG 
ECGs are required within 28 days prior to starting study treatment in triplicate performed 
2-5 minutes apart; on Day 1 of each cycle; and when clinically indicated. Cycle 1 Day 1 
ECG results must be reconfirmed and remain within eligibility parameters as per section 
3 for patient to be dosed.   
 
Twelve-lead ECGs will be obtained after the patient has been rested in a supine position 
for at least 5 minutes in each case.  The Investigator or designated physician will review 
the paper copies of each of the timed 12-lead ECGs on each of the study days when they 
are collected. 
 
ECGs will be recorded at 25 mm/sec.  All ECGs should be assessed by the investigator as 
to whether they are clinically significantly abnormal / not clinically significantly 
abnormal.  If there is a clinically significant abnormal finding, the Investigator will 
record it as an AE on the eCRF.  The original ECG traces must be stored in the patient 
medical record as source data. 
 
11.1.4 Vital signs 
 
11.1.4.1 
Pulse and blood pressure 
Supine blood pressure and pulse rate will be measured using a manual or automated 
blood pressure cuff after 5 minutes rest on a bed.  For timings of assessments refer to 
Study Calendar 
 
11.1.4.2 
Body temperature 
Body temperature will be measured in degrees Celsius using an automated 
thermometer at the times indicated in the Study Plan and Time Schedule. 
 
11.1.4.3 
Respiration rate 
Respiration rate will be measured in breaths per minute and it will be measured while 
patient is at rest.  
 
11.1.4.4 
Weight 
Weight will be measured in Kg. 
 
11.1.4.5 
Height 
Height will be measured in cm.  
 
11.1.5 Other safety assessments 
11.1.5.1 
Serum or urine pregnancy test 
Pregnancy tests on blood or urine samples will be performed for women of 
childbearing potential within 28 days prior to the start of study treatment, on Day 1 of 
the study prior to commencing treatment and at each subsequent visit during study 
treatment and at the 30 day follow up visit. Tests will be performed by the hospital’s 
local laboratory. If results are positive the patient is ineligible/must be discontinued 
from study treatment immediately.  Details of the pregnancy tests must be recorded in 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
90 
the patient’s medical records. 
 
11.1.5.2 
Bone marrow or blood cytogenetic analysis 
Bone marrow or blood cytogenetic analysis may be collected for patients with prolonged 
hematological toxicities as defined in Section 7.3.4. Bone marrow analysis should include an 
aspirate for cellular morphology, cytogenetic analysis and flow cytometry, and a core biopsy for 
bone marrow cellularity. If it is not possible to conduct cytogenetic analysis or flow cytometry 
on the bone marrow aspirate, then attempts should be made to carry out the tests on a blood 
sample. Full reports must be provided by the investigator for documentation on the Patient 
Safety database. These data are not required to be entered into CRF. 
 
12. MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 4 weeks following initial 
documentation of objective response. After 12 months, patients will undergo tumor assessments 
every 12 weeks until confirmed disease progression. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
12.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with AZD6738 and olaparib. 
 
Evaluable for objective response.  All of the patients who met the eligibility criteria (with 
the possible exception of those who received no study medication) should be included in 
the main analysis of the response rate. If a patient’s tissue is not confirmed centrally to 
have an eligible IDH1/2 mutation, that patient will not be included in the main analysis of 
the response rate. 
 
12.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
91 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
12.1.3 Methods for Evaluation of Measurable Disease 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
92 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT 
scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
93 
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
94 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.1.4 Response Criteria 
 
12.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
12.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
95 
disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
12.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
96 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
12.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
Patients who are lost to follow-up or who have not progressed or deveoped recurrent 
disease by the criteria above at the time of data cut-off will be censored for duration of 
response analysis at the time of their last study visit. 
 
12.1.6 Progression-Free Survival 
 
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment 
to time of progression or death, whichever occurs first. Patients who are lost to follow-up 
or who have not progressed at the time of data cut-off will be censored for PFS analysis 
at the time of their last study visit. 
 
 
12.1.7 Overall Survival 
Overall survival (OS) is defined as the duration of time from start of treatment to time of 
death. Patients who are lost to follow-up or who have not died at the time of data cut-off 
will be censored for OS analysis at the time of their last study visit. 
 
12.1.8 Response Review 
 
Central confirmatory radiology review for best radiographic response will be performed 
by the Tumor Imaging Metrics Core (TIMC) at the Yale Cancer Center for patients 
treated at Yale.  In the instance of a disagreement between a treating physician and the 
TIMC, the investigator will make the final decision as to whether a patient may continue 
on trial.  At the study’s conclusion, TIMC assessments will stand as the final 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
97 
determination of a patient’s response to therapy.  We encourage other participating sites 
to use their TIMC or equivalent. 
 
 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
During the Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and pharmacovigilance.  Decisions to proceed to the 
second stage of a Phase 2 trial will require sign-off by the Protocol Principal Investigator and the 
Protocol Statistician. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 
Data Reporting 
 
Medidata Rave is the clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.   
Requirements to access Rave via iMedidata: 
 
• 
A valid CTEP-IAM account and linked ID.me account (ID.me accounts are required for 
all newly created CTEP-IAM accounts and by July 1, 2023 for all users), and   
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of:  Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.   

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
98 
 
Rave role requirements: 
 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type, 
o Rave Investigator role, must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR), and 
o Rave Read Only or Rave SLA role must have at a minimum an Associate (A) 
registration type. 
• 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in the Regulatory application, all persons 
with Rave roles assigned on the appropriate roster will be sent a study invitation email from 
iMedidata.  To accept the invitation, site staff must either click on the link in the email or log in 
to iMedidata via the CTSU members’ website under Data Management > Rave Home and click 
to accept the invitation in the Tasks pane located in the upper right-corner of the iMedidata 
screen.  Site staff will not be able to access the study in Rave until all required Medidata and 
study specific trainings are completed.  Trainings will be in the form of electronic learnings 
(eLearnings) and can be accessed by clicking on the eLearning link in the Tasks pane located in 
the upper right corner of the iMedidata screen.  If an eLearning is required for a study and has 
not yet been taken, the link to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; once the successful completion of the eLearning 
has been recorded, access to the study in Rave will be granted, and a Rave EDC link will replace 
the eLearning link under the study name.  
 
Site staff who have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in the Regulatory application will receive a separate 
invitation from iMedidata to activate their account.  Account activation instructions are located 
on the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance).  Additional information on 
iMedidata/Rave is available on the CTSU members’ website in the Data Management > Rave 
section or by contacting the CTSU Help Desk at 1-888-823-5923 or by email at 
ctsucontact@westat.com. 
 
 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
99 
13.2.1 Responsibility for Data Submission 
 
Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-
site audits will be conducted on an 18-36 month basis as part of routine cancer center site 
visits. More frequent audits may be conducted if warranted by accrual or due to concerns 
regarding data quality or timely submission.  For CTMS monitored studies, after users 
have activated their accounts, please contact the Theradex Help Desk at (609) 619-7862 
or by email at CTMSSupport@theradex.com for additional support with Rave and 
completion of CRFs. 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 
 
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and 
Repository (caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
100 
integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines. 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
 
13.3 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management.  The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries.  DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP 
Reports modules are available to access details and reports of unanswered queries, 
delinquent forms, forms with current status and timeliness reports.  Site staff should 
review the DQP modules on a regular basis to manage specified queries and delinquent 
forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website.  Staff who have Rave study access can access the Rave study data via direct 
links available on the DQP modules. 
To learn more about DQP use and access, click on the Help Topics button displayed on the Rave 
Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP Reports modules. 
 
13.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
101 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
5. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 
the Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Col 
6. laborator(s) for advisory review and comment prior to submission for publication.  

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
102 
Collaborator(s) will have 30 days from the date of receipt for review.  Collaborator shall 
have the right to request that publication be delayed for up to an additional 30 days in 
order to ensure that Collaborator’s confidential and proprietary data, in addition to 
Collaborator(s)’s intellectual property rights, are protected.  Copies of abstracts must be 
provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as 
possible and preferably at least three (3) days prior to submission, but in any case, prior 
to presentation at the meeting or publication in the proceedings.  Press releases and other 
media presentations must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
103 
14. REFERENCES 
 
1.  
Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 
2009;360(8):765–73.  
2.  
Jiao Y, Pawlik TM, Anders RA, et al. Exome sequencing identifies frequent inactivating 
mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet 
2013;45(12):1470–3.  
3.  
Wang P, Dong Q, Zhang C, et al. Mutations in isocitrate dehydrogenase 1 and 2 occur 
frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with 
glioblastomas. Oncogene 2013;32(25):3091–100.  
4.  
Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of isocitrate dehydrogenase 
(IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. 
The Oncologist 2012;17(1):72–9.  
5.  
Squadroni M, Tondulli L, Gatta G, Mosconi S, Beretta G, Labianca R. 
Cholangiocarcinoma. Crit Rev Oncol Hematol 2017;116:11–31.  
6.  
Valle J, Wasan H, Palmer DH, et al. Cisplatin plus Gemcitabine versus Gemcitabine for 
Biliary Tract Cancer. N Engl J Med 2010;362(14):1273–81.  
7.  
Park J, Kim M-H, Kim K-P, et al. Natural History and Prognostic Factors of Advanced 
Cholangiocarcinoma without Surgery, Chemotherapy, or Radiotherapy: A Large-Scale 
Observational Study. Gut Liver 2009;3(4):298–305.  
8.  
Clark O, Yen K, Mellinghoff IK. Molecular Pathways: Isocitrate Dehydrogenase Mutations 
in Cancer. Clin Cancer Res 2016;22(8):1837–42.  
9.  
Yen KE, Bittinger MA, Su SM, Fantin VR. Cancer-associated IDH mutations: biomarker 
and therapeutic opportunities. Oncogene 2010;29(49):6409–17.  
10.  Sulkowski PL, Corso CD, Robinson ND, et al. 2-Hydroxyglutarate produced by 
neomorphic IDH mutations suppresses homologous recombination and induces PARP 
inhibitor sensitivity. Sci Transl Med 2017;9(375):eaal2463.  
11.  Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human 
glioblastoma multiforme. Science 2008;321(5897):1807–12.  
12.  Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute 
myeloid leukemia genome. N Engl J Med 2009;361(11):1058–66.  
13.  Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-
hydroxyglutarate. Nature 2010;465(7300):966.  
14.  Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor 
of α-ketoglutarate-dependent dioxygenases. Cancer Cell 2011;19(1):17–30.  

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
104 
15.  Losman J-A, Kaelin WG. What a difference a hydroxyl makes: mutant IDH, (R)-2-
hydroxyglutarate, and cancer. Genes Dev 2013;27(8):836–52.  
16.  Bai H, Harmancı AS, Erson-Omay EZ, et al. Integrated genomic characterization of IDH1-
mutant glioma malignant progression. Nat Genet 2016;48(1):59–66.  
17.  Olive PL, Banáth JP. The comet assay: a method to measure DNA damage in individual 
cells. Nat Protoc 2006;1(1):23–9.  
18.  Tateishi K, Wakimoto H, Iafrate AJ, et al. Extreme Vulnerability of IDH1 Mutant Cancers 
to NAD+ Depletion. Cancer Cell 2015;28(6):773–84.  
19.  Schnittger S, Haferlach C, Ulke M, Alpermann T, Kern W, Haferlach T. IDH1 mutations 
are detected in 6.6% of 1414 AML patients and are associated with intermediate risk 
karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 
status. Blood 2010;116(25):5486–96.  
20.  Sonnenblick A, de Azambuja E, Azim Jr HA, Piccart M. An update on PARP inhibitors—
moving to the adjuvant setting. Nat Rev Clin Oncol 2015;12(1):27–41.  
21.  Cimprich KA, Cortez D. ATR: an essential regulator of genome integrity. Nat Rev Mol Cell 
Biol 2008;9(8):616–27.  
22.  Di Veroli GY, Fornari C, Wang D, et al. Combenefit: an interactive platform for the 
analysis and visualization of drug combinations. Bioinformatics 2016;32(18):2866–8.  
23.  Hay T, Matthews JR, Pietzka L, et al. Poly(ADP-ribose) polymerase-1 inhibitor treatment 
regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor 
relapse in combination with carboplatin. Cancer Res 2009;69(9):3850–5.  
24.  Rottenberg S, Jaspers JE, Kersbergen A, et al. High sensitivity of BRCA1-deficient 
mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum 
drugs. Proc Natl Acad Sci U S A 2008;105(44):17079–84.  
25.  Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors 
from BRCA mutation carriers. N Engl J Med 2009;361(2):123–34.  
26.  Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: 
clearing up the misunderstandings. Mol Oncol 2011;5(4):387–93.  
27.  Murai J, Huang SN, Das BB, et al. Trapping of PARP1 and PARP2 by Clinical PARP 
Inhibitors. Cancer Res 2012;72(21):5588–99.  
28.  Menear KA, Adcock C, Boulter R, et al. 4-[3-(4-cyclopropanecarbonylpiperazine-1-
carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of 
poly(ADP-ribose) polymerase-1. J Med Chem 2008;51(20):6581–91.  
29.  Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
105 
from BRCA mutation carriers. N Engl J Med 2009;361(2):123–34.  
30.  Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose polymerase inhibition: frequent 
durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J 
Clin Oncol 2010;28(15):2512–9.  
31.  Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor 
olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a 
proof-of-concept trial. Lancet 2010;376(9737):245–51.  
32.  Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in 
patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept 
trial. Lancet 2010;376(9737):235–44.  
33.  Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-
grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a 
phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011;12(9):852–61.  
34.  Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-
sensitive relapsed ovarian cancer. N Engl J Med 2012;366(15):1382–92.  
35.  Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with 
platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of 
outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014;15(8):852–61.  
36.  Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients 
with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015;33(3):244–50.  
37.  Domchek SM, Aghajanian C, Shapira-Frommer R, et al. Efficacy and safety of olaparib 
monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and 
three or more lines of prior therapy. Gynecol Oncol 2016;140(2):199–203.  
38.  Kim G, Ison G, McKee AE, et al. FDA Approval Summary: Olaparib Monotherapy in 
Patients with Deleterious Germline BRCA-Mutated Advanced Ovarian Cancer Treated 
with Three or More Lines of Chemotherapy. Clin Cancer Res 2015;21(19):4257–61.  
39.  Robson M, Im S-A, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with 
a Germline BRCA Mutation. N Engl J Med 2017; 
40.  Mateo J, Moreno V, Gupta A, et al. An Adaptive Study to Determine the Optimal Dose of 
the Tablet Formulation of the PARP Inhibitor Olaparib. Target Oncol 2016;11(3):401–15.  
41.  Miknyoczki SJ, Jones-Bolin S, Pritchard S, et al. Chemopotentiation of Temozolomide, 
Irinotecan, and Cisplatin Activity by CEP-6800, a Poly(ADP-Ribose) Polymerase Inhibitor. 
Mol Cancer Ther 2003;2(4):371–82.  
42.  Menear KA, Adcock C, Boulter R, et al. 4-[3-(4-cyclopropanecarbonylpiperazine-1-
carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
106 
poly(ADP-ribose) polymerase-1. J Med Chem 2008;51(20):6581–91.  
43.  Evers B, Drost R, Schut E, et al. Selective inhibition of BRCA2-deficient mammary tumor 
cell growth by AZD2281 and cisplatin. Clin Cancer Res 2008;14(12):3916–25.  
44.  Tucker CL, Fields S. Lethal combinations. Nat Genet 2003;35(3):204–5.  
45.  Yap TA, Krebs MG, Postel-Vinay S, et al. Phase I modular study of AZD6738, a novel 
oral, potent and selective ataxia telangiectasia Rad3-related (ATR) inhibitor in combination 
(combo) with carboplatin, olaparib or durvalumab in patients (pts) with advanced cancers. 
Eur J Cancer 2016;69:S2.  
46.  Krebs MG, Lopez J, El-Khoueiry A, et al. Abstract CT026: Phase I study of AZD6738, an 
inhibitor of ataxia telangiectasia Rad3-related (ATR), in combination with olaparib or 
durvalumab in patients (pts) with advanced solid cancers. Cancer Res 2018;78(13 
Supplement):CT026–CT026.  
47.  Bauer M, Goldstein M, Christmann M, Becker H, Heylmann D, Kaina B. Human 
monocytes are severely impaired in base and DNA double-strand break repair that renders 
them vulnerable to oxidative stress. Proc Natl Acad Sci U S A 2011;108(52):21105–10.  
48.  Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-
hydroxyglutarate. Nature 2009;462(7274):739–44.  
49.  DiNardo CD, Propert KJ, Loren AW, et al. Serum 2-hydroxyglutarate levels predict 
isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. Blood 
2013;121(24):4917–24.  
50.  Capper D, Simon M, Langhans C-D, et al. 2-Hydroxyglutarate concentration in serum from 
patients with gliomas does not correlate with IDH1/2 mutation status or tumor size. Int J 
Cancer 2012;131(3):766–8.  
51.  Lombardi G, Corona G, Bellu L, et al. Diagnostic value of plasma and urinary 2-
hydroxyglutarate to identify patients with isocitrate dehydrogenase-mutated glioma. The 
Oncologist 2015;20(5):562–7.  
52.  Fathi AT, Nahed BV, Wander SA, et al. Elevation of Urinary 2-Hydroxyglutarate in IDH-
Mutant Glioma. The Oncologist 2016;21(2):214–9.  
53.  Borger DR, Goyal L, Yau T, et al. Circulating oncometabolite 2-hydroxyglutarate is a 
potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic 
cholangiocarcinoma. Clin Cancer Res 2014;20(7):1884–90.  
54.  Gross S, Cairns RA, Minden MD, et al. Cancer-associated metabolite 2-hydroxyglutarate 
accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 
mutations. J Exp Med 2010;207(2):339–44.  
55.  Fathi AT, Sadrzadeh H, Borger DR, et al. Prospective serial evaluation of 2-

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
107 
hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess 
disease activity and therapeutic response. Blood 2012;120(23):4649–52.  
56.  Fathi AT, Sadrzadeh H, Comander AH, et al. Isocitrate dehydrogenase 1 (IDH1) mutation 
in breast adenocarcinoma is associated with elevated levels of serum and urine 2-
hydroxyglutarate. The Oncologist 2014;19(6):602–7.  
57.  Watkins JA, Irshad S, Grigoriadis A, Tutt ANJ. Genomic scars as biomarkers of 
homologous recombination deficiency and drug response in breast and ovarian cancers. 
Breast Cancer Res BCR 2014;16(3):211.  
58.  Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in 
human cancer. Nature 2013;500(7463):415–21.  
59.  Nik-Zainal S, Davies H, Staaf J, et al. Landscape of somatic mutations in 560 breast cancer 
whole-genome sequences. Nature 2016;534(7605):47–54.  
60.  Sharma A, Singh K, Almasan A. Histone H2AX phosphorylation: a marker for DNA 
damage. Methods Mol Biol 2012;920:613–26.  
61.  Dempsey LA. CyTOF analysis of anti-tumor responses. Nat Immunol 2017;18(3):254.  
62.  Brodie TM, Tosevski V. High-Dimensional Single-Cell Analysis with Mass Cytometry. 
Curr Protoc Immunol 2017;118:5.11.1-5.11.25.  
63.  Giesen C, Wang HAO, Schapiro D, et al. Highly multiplexed imaging of tumor tissues with 
subcellular resolution by mass cytometry. Nat Methods 2014;11(4):417–22.  
64.   Dillon, M et al., Annals of Oncology (2019) 30 (suppl_5): v159-v193. 
10.1093/annonc/mdz244 
 
65.  Kim ST, Smith SA, Mortimer P, et al. Phase I Study of Ceralasertib (AZD6738), a Novel 
DNA Damage Repair Agent, in Combination with Weekly Paclitaxel in Refractory Cancer. Clin 
Cancer Res 1 September 2021; 27 (17): 4700–4709 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
108 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
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. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
109 
APPENDIX B 
PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD 
 
Information for Patients, Their Caregivers, and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drugs, olaparib and AZD6738.  This clinical trial is sponsored by the 
National Cancer Institute.  This form is addressed to the patient, but includes important 
information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
  
Olaparib interacts with a specific enzyme in your liver. 
 
• The enzyme(s) in question is CYP3A, and olaparib is broken down by this enzyme and 
may be affected by other drugs that inhibit or induce this enzyme.  
•  Based on limited in vitro data, olaparib may increase the exposure to substrates of 
CYP3A4, P-gp, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. It also may 
reduce reduce the exposure to substrates of CYP3A4, CYP1A2, 2B6, 2C9, 2C19 and P-
gp.  
 
AZD6738 interacts with certain specific enzymes in your liver and certain transport proteins that 
help move drugs in and out of cells.  
 
• The enzymes in question are CYP 3A4/5, 1A2 and 2B6. AZD6738 is broken down by 
CYP3A4/5 and may be affected by other drugs that inhibit or induce these enzymes. 
AZD6738 induces CYP1A2, 2B6 and 3A4 which may affect the levels of other drugs that 
are dependent on these enzymes to be broken down and cleared from the body.   
• Based on limited in vitro data, AZD6738 may increase the exposure to substrates of BCRP, 
CYP3A4, CYP1A2, CYP2B6, OATP1B1, MATE1, MATE2K, OATP1B3, and P-gp. 
Based on limited in vitro data, AZD6738 may reduce the exposure to substrates of 
CYP1A2, CYP2B6 and CYP3A4.  
• The proteins in question are P-gp, BCRP, OATP1B1, OATP1B3, MATE1 and MATE2K. 
AZD6738 is dependent on P-gp and BCRP protein transporters to be moved in and out of 
cells/organs. AZD7638 may reduce the ability of other drugs to be moved in and out of 
cells/organs by inhibiting P-gp, BCRP, OATP1B1, OATP1B3, MATE1 and MATE2K 
protein transporters. 
 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Olaparib and AZD6738 may interact with other drugs which can cause side effects. For this 
reason, it is very important to tell your study doctors of any medicines you are taking before you 
enroll onto this clinical trial.  It is also very important to tell your doctors if you stop taking any 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
110 
regular medicines, or if you start taking a new medicine while you take part in this study.  When 
you talk about your current medications with your doctors, include medicine you buy without a 
prescription (over-the-counter remedy), or any herbal supplements such as St. John’s Wort.  It is 
helpful to bring your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
These are the things that you and they need to know:  
 
Olaparib and AZD6738 must be used very carefully with other medicines that use certain liver 
enzymes to be cleared from your system. Before you enroll onto the clinical trial, your study 
doctor will work with your regular health care providers  to review any medicines and herbal 
supplements  that are considered strong inducers/inhibitors of CYP3A4/5; sensitive 
substrates of CYP 1A2, 2B6 or 3A4; strong inhibitors/inducers of P-gp or BCRP protein 
transporters; sensitive substrates of P-gp, BCRP, OATP1B1, OATP1B3, MATE1 or 
MATE2K protein transporters. 
 
 
• Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
• Avoid ingesting grapefruit, grapefruit juice or Seville oranges (including marmalade, juice, 
etc.) while participating in the study. 
• Avoid excessive sun exposure while on study. 
• Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is  
_____________________________________ and he or she can be contacted at  
 
_____________________________________. 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
111 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study  
drugs olaparib and AZD6738.  This clinical trial is sponsored by the 
NCI. Olaparib and AZD6738 may interact with drugs that are 
processed by your liver or use certain transport proteins in your 
body. Because of this, it is very important to: 
 Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
 Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
 
Olaparib interacts with a specific liver enzyme called CYP3A, and  AZD6738 
interacts with specific liver enzymes called CYP3A4/5, 1A2, 2B6 and transport 
proteins P-gp, BCRP, OATP1B1, OATP1B3, MATE1 and MATE2K. They must be 
used very carefully with other medicines that interact with these enzymes and 
transporters. 
 Before you enroll onto the clinical trial, your study doctor will work with 
your regular health care providers to review any medicines  and herbal 
supplements that are considered “strong inducers/inhibitors of CYP3A4/5; 
sensitive substrates of CYP 1A2, 2B6 or 3A4; strong inhibitors/inducers of P-
gp or BCRP protein transporters; sensitive substrates of P-gp, BCRP, 
OATP1B1, OATP1B3, MATE1 or MATE2K protein transporters.” 
 Before prescribing new medicines, your regular health care providers 
should go to a frequently-updated medical reference for a list of drugs to 
avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ and can be 
contacted at _________________________________.  

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
112 
APPENDIX C 
ACTIONS REQUIRED IN CASES OF COMBINED INCREASE OF 
AMINOTRANSFERASE (AT) AND TOTAL BILIRUBIN (TBL) – HY’S LAW 
 
Briefly, Hy’s Law cases have the following three components: 
 
The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug or 
placebo 
 
Among trial subjects showing such AT elevations, often with ATs much greater than 
3xULN, one or more also show elevation of serum TBL to >2xULN, without initial findings 
of cholestasis (elevated serum ALP) 
 
No other reason can be found to explain the combination of increased AT and TBL, such as 
viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of 
causing the observed injury 
 
Finding one Hy’s Law case in the clinical trial database is worrisome; finding two is considered 
highly predictive that the drug has the potential to cause severe drug induced liver injury (DILI) 
when given to a larger population. 
 
The following actions are required in cases of combined increase of aminotransferase and total 
bilirubin: 
 
1. Confirmation 
 
In general, an increase of serum AST/ALT to >3xULN should be followed by repeat testing 
within 48 to 72 hours of all four of the usual serum measures (ALT, AST, ALP, and TBL) to 
confirm the abnormalities and to determine if they are increasing or decreasing. There also 
should be inquiry made about symptoms. Serum AT may rise and fall quite rapidly, and waiting 
a week or two before obtaining confirmation of elevations may lead to a false conclusion that the 
initially observed abnormality was spurious. Of greater concern, delay in retesting may allow 
progression to severe worsening if the initial abnormality was the herald of a severe reaction to 
follow. The need for prompt repeat testing is especially great if AST/ALT is much greater than 
3xULN and/or TBL is greater than 2xULN. For outpatient trials, or trials in which subjects are 
far away from the trial site, it may be difficult for the subjects to return to the trial site promptly. 
In this case, the subjects should be retested locally, but normal laboratory ranges should be 
recorded, results should be made available to trial investigators immediately, and the data should 
be included in the case reports. If symptoms persist or repeat testing shows AST/ALT >3xULN 
for subjects with normal baseline measures or 2-fold increases above baseline values for subjects 
with elevated values before drug exposure, it is appropriate to initiate close observation to 
determine whether the abnormalities are improving or worsening. If close monitoring is not 
possible, the drug should be discontinued. 
 
 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
113 
2. Close Observation 
 
It is critical to initiate close observation immediately upon detection and confirmation of early 
signals of possible DILI, and not to wait until the next scheduled visit or monitoring interval. A 
threshold of aminotransferase levels greater than 3xULN seems reasonable, as lesser elevations 
are common and nonspecific. If additional testing, beyond that specified in the trial protocol, is 
carried out, it is important that the subject’s information be added to the case report forms and 
database. 
Close observation includes: 
 
Repeating liver enzyme and serum bilirubin tests two or three times weekly. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or the trial drug has been 
discontinued and the subject is asymptomatic. 
Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
Obtaining a history of concomitant drug use (including nonprescription medications and herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets. 
Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; non-
alcoholic steatohepatitis (NASH); hypoxic/ischemic hepatopathy; and biliary tract disease. 
Obtaining a history of exposure to environmental chemical agents. 
Obtaining additional tests to evaluate liver function, as appropriate (e.g., INR, direct bilirubin). 
Considering gastroenterology or hepatology consultations. 
 
3. Decision to Stop Drug Administration 
 
It has been observed that de-challenge (stopping drug administration) does not always result in 
immediate improvement in abnormal lab values. Abnormal test values and symptoms may 
progress for several days or even weeks after discontinuation of the drug that caused the 
abnormality. For example, rising TBL usually follows serum AT increases by a few days to 
weeks. The primary goal of close observation is to determine as quickly as possible whether 
observed abnormal findings are transient and will resolve spontaneously or will progress. For 
most DILI, no specific antidotes are available (except N-acetylcysteine for acute acetaminophen 
overdose if given promptly, and, possibly, intravenous carnitine for valproic acid hepatotoxicity). 
 
Promptly stopping the offending drug usually is the only potentially effective therapy. 
 
Because transient fluctuations of ALT or AST are common, and progression to severe DILI or 
acute liver failure is uncommon, automatic discontinuation of trial drug upon finding a greater 
than 3xULN elevation of ALT or AST may be unnecessary. For most people, the liver appears 
capable of adapting to injury by foreign chemical substances, which may render a person tolerant 
to the drug despite continued exposure. Stopping a drug at the first hint of mild injury does not 
permit learning whether adaptation will occur, as it does for drugs such as tacrine, which cause 
liver injury but do not cause severe DILI. On the other hand, continuing drug appears 
unacceptably dangerous if there is marked serum aminotransferase elevation or evidence of 
functional impairment, as indicated by rising bilirubin or INR, which represent substantial liver 
injury. Although there is no published consensus on exactly when to stop a drug in the face of 
laboratory abnormalities and the decision will be affected by information on related drugs, the 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
114 
accumulating clinical experience, the clinical status of the patient, and many other factors, the 
following can be considered a basic guide. Discontinuation of treatment should be considered if: 
 
ALT or AST >8xULN 
ALT or AST >5xULN for more than 2 weeks 
ALT or AST >3xULN and (TBL >2xULN or INR >1.5) 
ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
 
It should be noted that although these guidelines have not been evaluated systematically in a 
prospective fashion, they represent an approach that is similar to current practice. 
 
4. Evaluating Data for Alternative Causes 
 
An important purpose of close observation is to gather additional clinical information to seek 
other possible causes of the observed liver test abnormalities, such as one of the following 
common causes: 
 
Acute viral hepatitis. The usual onset of hepatocellular DILI is indistinguishable from acute viral 
hepatitis A or B. Hepatitis C is much less often acute in its onset and tends to be insidious, but it 
sometimes can resemble acute DILI. The presence of acute viral hepatitis A, B, and C should be 
evaluated by serological markers. Viral hepatitis D (requires concomitant hepatitis B infection) 
and E are relatively rare in the United States. Hepatitis E is more common in developing 
countries, including Southeast Asia, and should be considered in recent travelers to those 
countries and in patients in trials conducted in those countries. Also rare are hepatocellular liver 
injuries caused by Epstein-Barr virus, cytomegalovirus, herpes simplex virus, toxoplasmosis, 
varicella, and parvovirus, although these infections are seen more typically in immuno- 
suppressed individuals. Adolescent and young adult patients with possible DILI should be tested 
for Epstein-Barr virus. Hepatitis is common among transplant patients with cytomegalovirus 
disease. 
 
Alcoholic and autoimmune hepatitis. Acute alcoholic hepatitis usually is recurrent, with a history 
of binging exposure to alcohol preceding episodes, and it has some characteristic features, such 
as associated fever, leukocytosis, right upper quadrant pain and tenderness, hepatomegaly, and 
AST >ALT, that may help distinguish it from other causes of liver injury. Other features of the 
physical examination may include the presence of stigmata of cirrhosis, such as spider nevi, 
palmar erythema, estrogenic changes in males, and Dupuytren’s contractures. Alcoholic and 
autoimmune hepatitis should be assessed by history, physical examination, and laboratory 
testing, including serologic testing (e.g., antinuclear or other antibodies). 
 
Hepatobiliary disorders. Biliary tract disease, such as migration of gallstones or intrahepatic 
lesions, more often causes cholestatic injury initially and should be investigated with gall bladder 
and ductal imaging studies, especially if ALP is increased. Malignant interruption of the biliary 
tract also should be considered. 
 
NASH. NASH may be seen in obese, hyperlipoproteinemic, and/or diabetic patients and may be 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
115 
associated with fluctuating aminotransferase levels, and hepatic and sometimes splenic 
enlargement. It is sometimes associated with cirrhosis and portal hypertension. 
 
Cardiovascular causes. Cardiovascular disease, especially right heart failure and hypotension or 
any cause of impaired oxygenation of the liver, may cause acute centrilobular hypoxic cell 
necrosis (ischemic hepatitis) with rapid and sometimes spectacular increases of serum AT (e.g., 
AT >10,000 U/L). Cardiovascular dysfunction or impaired liver oxygenation, including 
hypotension or right heart failure, should be assessed by physical examination and history. 
 
Concomitant treatments. It is critical to discover concomitant treatments, including exposure to 
nonprescription and dietary supplement products that might be responsible for injury. Many 
people take multiple drugs, perhaps less often in controlled clinical trials because of exclusion 
criteria, but subjects may not report taking disallowed drugs or other agents. The possible 
exposure to potentially toxic herbal or dietary supplement mixtures (sometimes of unknown 
composition), nonprescription medications such as acetaminophen, or to occupational chemical 
agents may not be volunteered unless subjects are specifically questioned. 
 
5. Follow-Up to Resolution 
 
All trial subjects showing possible DILI should be followed until all abnormalities return to 
normal or to the baseline state. DILI may develop or progress even after the causative drug  has 
been stopped. Results should be recorded on the case report form and in the database. Note that 
longer follow-up can sometimes reveal an off-drug repetition of what had appeared to be DILI, 
indicating that liver injury was related to underlying liver disease. 
 
6. Re-challenge 
 
Whether or not to re-challenge a subject who showed mild DILI is a difficult decision. Re- 
exposure may initiate a sometimes explosive and more severe reaction, as was observed with 
halothane several decades ago. Some cases of DILI show indicators of immunological reaction 
such as eosinophilia, rash, fever, or other symptoms or findings, and it is possible that such cases 
are more prone to recur with re-exposure. Re-challenge may not be considered negative unless 
the subject is exposed to and tolerates the same dose and treatment duration that preceded the 
original reaction. A negative re-challenge does not necessarily allow a conclusion that the drug 
did not cause the injury. Most people can adapt to xenobiotic substances, including new drugs, 
and develop tolerance for them. This has been observed even for drugs that can cause severe 
injury, such as isoniazid. The large majority of people showing hepatocellular injury while 
taking isoniazid recover fully or recover while continuing to take the drug, and some, but not all, 
can resume or continue taking the drug without further adverse consequence. If such tolerance 
has developed, the use of re-challenge to verify drug causation would give a false negative result. 
 
Generally, re-challenge of subjects with significant AT elevations (>5xULN) should not be 
attempted. If such subjects are re-challenged, they should be followed closely. Re-challenge can 
be considered if the subject has shown important benefit from the drug and other options are not 
available or if substantial accumulated data with the test drug do not show a potential for severe 
injury. The subject should be made aware of the potential risk, and consent to the re-challenge, 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
116 
and the PI consulted.

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
117 
APPENDIX E 
ACCEPTABLE BIRTH CONTROL METHODS 
 
Patients of child bearing potential and their partners, who are sexually active, must agree to the 
use of two highly effective forms of contraception throughout their participation in the study. 
Moreover, women study participants are expected to use highly effective contraception for 6 
months after the last dose of study drug and men are expected to use highly effective 
contraception for 6 months. Acceptable birth control methods are listed below.  
Condom with spermicide and one of the following: 
• 
Hormonal therapy (e.g. hormone implants) other than oral contraceptives 
• 
Placement of an intra-uterine device 
 
Acceptable non-hormonal birth control methods include: 
• 
Total sexual abstinence.  Abstinence must be for the total duration of the study and the 
drug washout period. 
• 
Vasectomised sexual partner plus male condom.  With participant assurance that 
partner received post-vasectomy confirmation of azoospermia 
• 
Tubal occlusion plus male condom with spermicide 
• 
Intrauterine Device (IUD) plus male condom+spermicide.  Provided coils are copper-
banded 
 
Acceptable hormonal methods: 
• 
Etonogestrel implants (eg, Implanon, Norplan)+male condom with spermicide 
• 
Norelgestromin/ethinyl estradiol (EE) transdermal system+male condom with spermicide 
• 
ntravaginal device+male condom with spermicide (eg, EE and etonogestrel) 
 
 
 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
120 
APPENDIX G  
LABORATORY MANUAL 
 
 
Testing / Storage Facilities  
 
LC-MS detection and  
 
Jing Li, Ph.D. 
quantification of 2HG: 
 
Pharmacology Core 
 
 
 
 
Karmanos Cancer Institute 
4100 John R, HWCRC – room 523 
Detroit, MI 48201 
Phone: (313) 576-8258 
Email: LiJing@wayne.edu 
  
 
RNA and DNA 
 
 
 
sequencing: 
Chris Karlovich  
Molecular Characterization (MoCha)  
Laboratory, Frederick National Laboratory for 
Cancer Research (FNLCR) 
Email:  chris.karlovich@nih.gov   
 
 
Multiplex  
 
 
Kurt A. Schalper, M.D. Ph.D. 
immunofluorescence/  
 
310 Cedar St. BML113, Department of  
Imaging Mass Cytometry  
 
Pathology 
 
 
 
 
Yale School of Medicine 
 
 
 
 
New Haven, CT 06520-8023 
Phone: 203-785-3588 
Email:  kurt.schalper@yale.edu 
 
 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
121 
1. INTRODUCTION 
This manual covers the procedures associated with acquisition of patient samples for correlative 
studies including processing, storage and shipment of these samples to central laboratories as 
required by the protocol.   
 
Sample collection procedures for routine hematology, serum chemistry, coagulation parameters, 
pregnancy testing, and urinalysis samples etc. should be done as per local laboratories’ 
requirements. 
 
2. SAMPLE FLOW OVERVIEW 
Tumor tissue (baseline biopsies/ on-treatment biopsies) and blood samples will be collected and 
sent to central laboratories for storage and analysis. The diagram below highlights the flow 
process for all lab samples.   
 
 
* Note:  No archival or frozen tissue specimens were received directly by the Li Laboratory.  Instead, (per 
Amendment 13 [version April 4, 2025]), the 2-HG assay will be performed using remaining FFPE tissue that 
was sent to the EET Biobank 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
123 
Research (FNLCR).  If submitting slides, then slides must be processed in order, and numbered 
sequentially (e.g., H&E stained slide is created first and labeled 1, unstained slides are then 
created and numbered 2 – 46). 
3 Draw blood prior to olaparib dosing.  
 
Prioritization for use of tumor tissue and blood specimens will be as follows: 
 
1. DNA whole exome sequencing 
2. RNA sequencing 
3.  mQIF/CyTOF-IMC studies (including IF to look at γ-H2AX and RAD51 ) 
4. 2-HG measurement 
5. RAD51 assay 
 
Any specimens remaining after the above-prioritized studies will be sent to Yale for 
consideration of additional prioritization or sample use strategies based on individual sample 
characteristics and quality after central pathology review at Yale. Any remaining specimens will 
be banked at Yale University.   
 
3. PLANNED SAMPLE ANALYSIS 
Serial blood samples and tissue from tumor biopsies will be collected and analyzed to include the 
following work:   
 
Testing 
Facility 
Platform 
Biomarker/Correlative 
Li Lab, 
Karmanos 
LC-MS/MS 
Determination of 2-HG in tissue and plasma 
MoCha, 
Frederick 
National  
Laboratory 
for Cancer 
Research 
(FNLCR) 
Illumina-based next-
generation sequencing 
DNA whole exome sequencing and RNA 
transcriptomic sequencing 
Schalper Lab, 
Yale 
mQIF and 
CyTOF-IMC 
In situ analysis of tumor DNA repair markers 
Shapiro Lab, 
Dana-Farber 
Immunohistochemistry Detection of Geminin and RAD51 
 
4. SAMPLING TIME POINTS 
 
4.1 
Tumor Tissue Sample Collection Time Points 
 
Time Point 
Note 
Pre-treatment (Day -14 to 
Day -1) 
Biopsy performed after patient is 
registered on study.  

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
124 
After 1 cycle of treatment 
(4 weeks, +/- 7 days) 
On treatment biopsy 
  
 
4.2 
Blood Sample Time Points   
 
4.2.1 Blood for 2-HG Collection Time Points 
All patients will have blood collected for LC-MS detection and quantification of 2HG in plasma.  
 
Time Point 
Note 
Pre-treatment (Day -14 to 
Day -1) 
Blood drawn after study registration. 
Cycle 2 Day 1  
Blood drawn prior to olaparib dosing.  
Cycle 4 Day 1 
Cycle 8 Day 1 
Time of tumor 
progression/relapse or End 
of study 
Blood drawn at End of Treatment visit 
 
4.2.2 Blood for Germline Mutation Analysis 
 
Time Point 
Note 
Screening (Day -14 to Day 
-1) 
Blood drawn after study registration. 
 
5. SAMPLE COLLECTION, PROCESSING AND SHIPPING PROCEDURES 
 
5.1 
Specimen Procurement Kits and Scheduling 
 
5.1.1 Specimen Shipping Kits 
 
Kits for the collection and shipment of specimens to the EET Biobank can be ordered online via 
the Kit Management system: (https://kits.bpc-apps.nchri.org/). 
 
Users at the clinical sites will need to set up an account in the Kit Management system and select 
a specific clinical trial protocol to request a kit. Please note that protocol may include more than 
one type of kit. Each user may order two kit types per protocol per day (daily max = 6 kits).  Kits 
are shipped ground, so please allow 5-7 days for receipt. A complete list of kit contents for each 
kit type is located on the Kit Management system website. 
 
Note: Kits or supplies are only provided for specimens shipped to the EET Biobank. Institutional 
supplies must be used for all other specimen collection and processing. 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
125 
5.1.2 Scheduling of Specimen Collections 
Please adhere to the following guidelines when scheduling procedures to collect tissue: 
Tumor tissue specimens fixed in formalin must be shipped on the same day of collection. 
Tissue can be collected Monday through Wednesday and shipped overnight for arrival on 
Tuesday through Thursday at the EET Biobank at Nationwide Children’s Hospital.   
Tumor and blood specimens submitted frozen can be collected on any day but must be stored 
frozen and shipped to the Jing Li laboratory at the Karmanos Cancer Institute on Monday 
through Thursday.  In the event that frozen specimens cannot be shipped immediately, they must 
be maintained at -80°C. 
Fresh blood specimens may be collected and shipped to the EET Biobank Monday through 
Friday. 
 
5.2 
Specimen Tracking System Instructions 
 
5.2.1 Specimen Tracking System Overview and Enrollment Instructions 
 
For the ETCTN STS, the following information will be requested: 
• Protocol Number 
• Investigator Identification  
o Institution and affiliate name 
o Investigator’s name 
• Eligibility Verification:  Patients must meet all the eligibility requirements listed in 
Section 3. 
• Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 
patient ID.  The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this or any other protocol that uses the ETCTN Specimen Tracking 
System.  The UPID contains no information or link to the treatment protocol.  IWRS will 
maintain an association between the UPID for ETCTN biobanking and molecular 
characterization and any treatment protocols the patient participates in, thereby allowing analysis 
of the molecular characterization results with the clinical data.   
 
Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave.  The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial.  For newly acquired biopsies without a corresponding 
pathology report, the radiology and operative report(s) must also be uploaded into Rave, when 
available. Important:  Remove any personally identifying information, including, but not 
limited to, the patient’s name, date of birth, initials, medical record number, and patient 
contact information from the institutional pathology report prior to submission. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software.   

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
126 
 
For questions regarding the Specimen Tracking System, please contact STS Support at 
STS.Support@theradex.com. 
 
The Shipping List report must be included with all sample submissions. 
 
5.2.2 Specimen Labeling 
 
5.2.2.1 
Blood Specimen Labels 
 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma): 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., blood, serum) 
• Collection date and time (to be added by hand) 
• CTEP Protocol Number (NCI#10222) – Blood Samples for 2-HG ONLY 
 
5.2.2.2 
Tissue Specimen Labels 
 
Include the following on all tissue specimens or containers (e.g., formalin jar):  
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., tissue in formalin-containing jars) 
• Tissue type (P for primary, M for metastatic or N for normal) 
• Surgical pathology ID (SPID) number (when applicable) 
• Collection date and time (to be added by hand)  
• Slide section number (only if archival tissue is submitted as slides)(to be added by 
hand) 
 
5.2.2.3 Example of Specimen Label Generated by STS 
 
STS includes a label printing facility, accessed via the Print Label CRF in the All Specimens 
folder. A generated PDF is emailed to the user as a result of saving that form.  
 
The following image is an example of a tissue specimen label printed on a label that is 0.5” high 
and 1.28” wide. 
 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
127 
  
 
The QR code in the above example is for the Specimen ID shown on the second line.   
 
Labels may be printed on a special purpose label printer, one label at a time, or on a standard 
laser printer, multiple labels per page. Theradex recommends the use of these low temperature 
waterproof labels for standard laser printers: https://www.labtag.com/shop/product/cryo-laser-
labels-1-28-x-0-5-cl-23-colors-available/ 
 
 
The last line item on the label includes the following data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. An optional alpha-numeric code that is protocol specific and is only included if the 
protocol requires an additional special code classification 
 
Space is provided at the bottom of the label for the handwritten date and optional time.  
The last line on the example label is for the handwritten date and optional time. 
 
5.2.3 Overview of Process at Treating Site 
 
5.2.3.1 
OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system.  OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization, and any prescribed slot 
assignments.  If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration without eligibility specimen analysis:  
 
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal 
Patient ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
128 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
5.2.3.2 
Rave Specimen Tracking Process Steps 
 
Step 0: Log into Rave via your CTEP-IAM account, then navigate to the appropriate participant. 
 
Step 1:  Complete the Histology and Disease form (but do not upload reports until a specimen 
label can be applied to them) and the Baseline forms regarding Prior Therapies.  Enter the 
initial clinical specimen data:  
• Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, and number of labels 
needed (include extra labels to apply to reports to be uploaded).  CRF generates 
unique Specimen ID.  
 
Step 2:  Print labels using the Print Labels CRF located in the All Specimens folder, then 
collect specimen. 
• Label specimen containers and write collection date and time on each label.  After 
collection, store labeled specimens as described in Appendix G, Section 5.2.2. 
• Apply an extra specimen label to each report before scanning.  Return to the 
Histology and Disease form to upload any initial Pathology, Radiology, Molecular 
Reports (up to 4), and Surgical (or Operative) reports.  Return to Specimen Tracking 
Enrollment CRF to upload any molecular report (one per specimen) and/or specimen 
specific pathology or related report (one per specimen) and/or the Tissue Biopsy 
Verification form (Appendix G, section 8).  Uploaded reports should have protected 
health information (PHI) data, like name, date of birth, mailing address, medical 
record number or social security number (SSN), redacted.  Do not redact SPID, block 
number, diagnosis or relevant dates (such as collection date) and include the UPID 
and patient study ID on each document (either by adding a label or hand writing). 
 
Step 3:  Complete specimen data entry. 
• Specimen Transmittal Form:  Enter collection date and time and other required 
specimen details. 
 
Step 4:  When ready to ship, enter shipment information. 
• Shipping Status CRF:  Enter tracking number, your contact information, recipient, 
number of sample containers and ship date once for the first specimen in a shipment. 
• Copy Shipping CRF:  In the specimen folders for additional specimens (if any) that 
will be shipped with the initial specimen, please use the Copy Shipping form to 
derive common data into additional Shipping Status forms. A few unique fields will 
still need to be entered in Shipping Status.   
 
Step 5:  Print shipping list report and prepare to ship.  
• Shipping List report is available at the site level. 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
129 
• Print two copies of the shipping list, one to provide in the box, the other for your own 
records. 
• Print pathology or other required reports to include in the box.  Be sure the printed 
copy includes the specimen label. 
 
Step 6:  Send email notification.  
• For only one of the specimens in the shipment, click “Send Email Alert” checkbox on 
the Shipping Status CRF to email recipient. 
 
Step 7:  Ship the specimen(s). 
 
Step 8: Monitor the Receiving Status form located in each specimen folder for acknowledgment 
of receipt and adequacy. 
 
5.3 
Tumor Tissue Sample Collection 
The tumor tissue will be obtained by a surgical biopsy or imaging-guided biopsy. In the instance 
that a patient has multiple measurable lesions, tumor biopsies will be performed on the most 
accessible site of disease. Each biopsy will consist of 6 passes of a large gauge needle (such as 
16 or 18 gauge); each core should be at least 1 cm in length.  
 
For each set of biopsies, 3 of the tumor cores will be formalin-fixed on site and sent to the 
EET Biobank, where they will be processed.  3 of the tumor cores will be flash frozen on 
site and sent directly to the Jing Li laboratory at the Karmanos Cancer Institute. If fewer 
than 6 cores are obtained, the cores will be divided evenly among formalin-fixed and flash 
frozen. 
 
5.3.1 Processing of formalin-fixed tissue samples 
Three (3) tissue cores are shipped in formalin on the same day as collection to the EET Biobank 
(see section 5.6). Specimens should be placed immediately into buffered formalin (provided in 
the kit) in the provided specimen collection container and handled as follows: 
 
Label formalin-filled containers according to instructions in section 5.2.1.  
Place one core in each cassette.  
Snap the cassette lids closed and place cassettes into a formalin-filled pre-labeled container as 
soon as possible after collection to prevent air drying.  Up to two cassettes may be placed in one 
formalin jar. 
Secure the container lids and place the containers into the shipping kit.  Keep tissue in formalin 
jars at room temperature until shipment to the EET Biobank.  
 
5.3.2 Processing of frozen tissue samples 
 
Immediately after tissue collection, transfer 3 cores of biopsy tissue to a screw-cap 
polypropylene cryogenic tube with external threads and snap-freeze in liquid nitrogen.   
Label the tubes according to instructions in section 5.2.1.  
These tumor specimens (3 cores) should be stored at -80°C until shipment directly to the 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
130 
Karmanos Cancer Institute Pharmacology Core. 
 
5.4 
Blood Sample Collection for Germline Mutation Analysis 
5.4.1 Collection of Blood in EDTA Tubes 
Label EDTA tubes according to the instructions in section 5.2.1. 
Collect 10 mL blood in EDTA tube and gently invert tube to mix. Note: blood must be 
thoroughly mixed to ensure preservation of specimen. (See Summary Table for Specimen 
Collection in Section 2 for amounts at each time point). 
Ship on day of collection (whenever possible) according to instructions below. 
If blood cannot be shipped on the day of collection (e.g., a late scheduled collection), then 
refrigerate until shipment.  
 
5.5 
Blood Sample Collection for Determination of 2-HG 
Blood samples (4 mL at each time point) will be collected into EDTA tubes.  Blood in EDTA 
tubes will be immediately placed on ice or refrigerated at 4°C until processed. The actual day 
and time of sample collection will be recorded on the “Shipping Manifest/Case Report Form for 
2-HG Blood Samples” (FORM A), which contains information on patient study number, 
diagnosis, age, weight, treatment (dose and time), blood sample collection day and time.   
 
Within 1 hour of collection, the blood sample will be centrifuged at 4°C, at 3000 rpm for 10 
minutes.  Immediately after centrifugation, plasma will be transferred to four screw-cap 
polypropylene cryogenic tubes with external threads (four aliquots, ~0.5 ml per aliquot), and 
blood cells will be kept in the original tube.  The tubes will be labeled with the patient’s initials, 
study number, sample collection day and time.  All samples will be stored at -80°C until 
shipment.  Blood samples will be processed at the study sites.  Note: Both plasma and blood cell 
samples will be shipped directly to Karmanos Cancer Institute Pharmacology Core. 
 
5.6 
Shipping Specimens from Clinical Site to the EET Biobank 
Core biopsies that are fixed in formalin and fresh whole blood should be shipped as one 
shipment at ambient temperature, whenever possible.  The same box sent with kit contents 
should be used to ship specimens to the EET Biobank.  In winter months, please include extra 
insulation, such as bubble wrap, inside the shipping container. 
 
For formalin-fixed biopsies, if the corresponding anatomical pathology report is not available at 
the time of shipment, then the operative and/or radiology report must be uploaded to the ETCTN 
specimen tracking system and included in the package, or the specimen will not be processed. 
 
5.6.1 Required Forms for Specimen Submissions 
Each document submitted with the specimen must be labeled with a label printed from the STS, 
or the Universal ID and Patient Study ID.  
Tissue  
Required Forms 
Archival  
3. Shipping List 
4. Corresponding Pathology Report 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
131 
Tissue  
Required Forms 
New Biopsy 
 
5. Shipping List 
6. Tissue Biopsy Verification Form 
(Appendix G, Section 8) 
7. Diagnostic Pathology Report  
8. Operative and/or Radiology Report 
Blood  
1.   Shipping List 
 
 
5.6.2 Specimen Shipping Instructions 
Tissue in formalin must be shipped on the day of collection.  Collect and ship on Monday 
through Wednesday.  
Archival FFPE tissue may be shipped Monday through Thursday.  
Fresh blood may be shipped on Monday through Friday.  Please select “Saturday Delivery” 
when shipping fresh blood on a Friday. 
 
5.6.2.1 Shipping Ambient Tissue and Blood in a Single Chamber Kit 
Before packaging specimens, verify that each specimen is labeled according to the instructions 
above and that the lids of all primary receptacles containing liquid are tightly sealed.  Formalin 
jars should be wrapped in parafilm.  
Place the specimens in zip-lock bags.  Use a separate bag for each specimen type. 
Place specimens into a biohazard envelope with absorbent material.  Expel as much air as 
possible and seal the envelope securely.  
Place the biohazard envelope into a Tyvek envelope. Expel as much air as possible and seal 
securely. 
Place the specimen(s) and a copy of the shipping manifest and corresponding reports such as 
operative or radiology reports into the insulated shipping container. In winter months please 
include extra insulation, such as bubble wrap, inside the shipping container to prevent specimens 
from freezing.  
Place the lid on top of the container. Close the outer flaps and tape shut. 
Attach a shipping label to the top of the shipping container.  
Attach an Exempt Human Specimen sticker to the side of the container. 
Ship specimens via overnight courier to the address below. FedEx Priority Overnight is strongly 
recommended to prevent delays in package receipt.  
 
5.6.3 Shipping Address 
Ship to the address below.  Ship formalin-fixed and fresh blood specimens the same day of 
specimen collection.  Do not ship specimens the day before a holiday. 
 
EET Biobank  
2200 International Street 
Columbus, OH 43228 
PH: (614) 722-2865 
FAX: (614) 722-2897 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
132 
 
Email: BPCBank@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred.   
 
NOTE:  The EET Biobank FedEx Account will not be provided to submitting institutions. 
 
5.4 Shipping Specimens from Clinical Site to the Li Lab (Blood and 3 frozen cores for 2-
HG) 
 
3 frozen cores and plasma and blood cell samples collected for determination of 2-HG will be 
shipped directly to Karmanos Cancer Institute Pharmacology Core at the following address: 
 
Attn: Jing Li 
Pharmacology Core 
Karmanos Cancer Institute 
4100 John R, HWCRC – room 523 
Detroit, MI 48201 
Phone: (313) 576-8258 
Email: LiJing@wayne.edu  
 
For shipping, all frozen plasma and blood samples should be placed in cardboard tray/box so 
samples remain upright. This tray/box is to be placed in a Styrofoam carton with 10-15 lbs of dry 
ice (block with or without pellets) to keep samples frozen during shipping.  A copy of the 
“Shipping Manifest/Case Report Form for 2-HG Blood Samples” (Form A), should be in the 
shipping box, reflecting the samples that are being sent.  Samples should be shipped via FedEx 
Priority Overnight service.  Please notify Jing Li via email (LiJing@wayne.edu) when samples 
are shipped and include the shipment tracking number. 
 
Samples can be batched and shipped.  
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
133 
6 CONTACT INFORMATION 
Please contact the team members listed below for any questions on sample collection, 
processing, storage and shipment. 
Study Coordinator 
Yale University / Yale 
Cancer Center 
Ingrid Palma  
Phone: (203) 737-5342 
Fax: (203) 785-4069 
Email: ingrid.palma@yale.edu  
Study PI 
Yale University 
Patricia M. LoRusso, D.O.,  
Associate Director for Experimental 
Therapeutics  
Yale Cancer Center 
333 Cedar St 
PO Box 208028 
New Haven, CT 06520-8028 
Office Number: 203-785-5944 
Fax: 203-785-4116 
Tumor Tissue 
Yale University 
Kurt A. Schalper, M.D., Ph.D. 
310 Cedar St. BML113 
Department of Pathology 
Yale School of Medicine 
New Haven, CT 06520-8023 
Phone: 203-785-3588 
Email: kurt.schalper@yale.edu  
Plasma for 2-HG  
Karmanos Cancer 
Institute 
Jing Li, Ph.D. 
Pharmacology Core 
Karmanos Cancer Institute 
4100 John R, HWCRC – room 523 
Detroit, MI 48201 
Phone: (313) 576-8258 
Email: LiJing@wayne.edu  
Tumor Tissue, Liquid 
Biopsy (ctDNA) & 
Blood for Germline 
Mutation Shipping 
EET Biobank 
EET Biobank 
Phone: (614) 722-2865 
Email:  
BPCBank@nationwidechildrens.org  
DNA and RNA 
sequencing 
MoCha Laboratory, 
Frederick National 
Laboratory for Cancer 
Research (FNLCR) 
 
Chris Karlovich  
Email:  chris.karlovich@nih.gov 
  
 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
134 
7 SHIPPING FORM (FROZEN TISSUE SPECIMENS AND BLOOD FOR 2-HG 
SAMPLES) 
Please copy this form for multiple shipments.   
 
Pre-printed label for research samples should contain:   
 
CTEP Protocol Number (NCI#10222) 
Collection Time Point 
Patient Study ID Number 
Date of Collection  
Time of Collection 
 
 
 

NCI Protocol #: 10222 
Version Date: April 4, 2025 
 
136 
8 TISSUE BIOPSY VERIFICATION  
 
A copy of the diagnostic pathology report must be shipped with all tissue specimens sent to the 
EET Biobank. 
 
If the corresponding pathology report is not available for the biopsy, then a copy of the 
radiology report or operative report from the biopsy procedure and the diagnostic 
pathology report must be sent to the EET Biobank. A completed copy of this appendix (i.e., 
Tissue Biopsy Verification) must also be submitted to the EET Biobank. 
 
Note: If this information is not provided with the biopsy specimen, then it will not be accepted by 
the EET Biobank. 
 
 
 
Please have the Clinician* responsible for signing out this patient’s case complete the following: 
 
ETCTN Universal Patient ID:  
 
 
ETCTN Patient Study ID:   
 
 
Date of Procedure (mm/dd/yyyy):   
 
 
Tissue Type (circle one): 
Primary 
Metastatic 
 
Time point (circle one):  Pre-treatment 
After Cycle 1 
 
Site Tissue Taken From:   
 
 
Diagnosis:   
 
 
I agree that this tissue may be released for research purposes only and that the release of this 
tissue will not have any impact on the patient’s care. 
 
 
 
Clinician Signature 
Date 
 
 
 
 
Clinician Printed Name 
 
 
 
*Note: For the purposes of this form, Clinician could include the Nurse Practitioner, Registered Nurse, Pathologist, 
Radiologist, Interventional Radiologist, Surgeon, Oncologist, Internist, or other medical professional responsible for 
the patient’s care.  
 
Version: 1 
Effective Date: 9/2019