A Randomized Phase II Trial Comparing the Combination of PI3K Inhibitor Copanlisib (BAY 80-6946) and PARP Inhibitor Olaparib (AZD2281) to Standard Chemotherapy in Patients With Recurrent Platinum Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Who Have Progressed Through Prior PARP Inhibitor Therapy
Phase: PHASE2
Conditions: Platinum-Refractory Fallopian Tube Carcinoma, Platinum-Refractory Ovarian Carcinoma, Platinum-Refractory Primary Peritoneal Carcinoma, Recurrent Fallopian Tube Endometrioid Adenocarcinoma, Recurrent Fallopian Tube High Grade Serous Adenocarcinoma, Recurrent Ovarian Endometrioid Adenocarcinoma, Recurrent Ovarian High Grade Serous Adenocarcinoma, Recurrent Platinum-Resistant Fallopian Tube Carcinoma, Recurrent Platinum-Resistant Ovarian Carcinoma, Recurrent Platinum-Resistant Primary Peritoneal Carcinoma, Recurrent Primary Peritoneal Endometrioid Adenocarcinoma, Recurrent Primary Peritoneal High Grade Serous Adenocarcinoma
Sponsor: National Cancer Institute (NCI)

Summary of Changes 
Amendment #1 
NCI Protocol #: NRG-GY029 
Local Protocol #: NRG-GY029 
NCI Version Date: December 28, 2022 
 
CTEP reviewed and disapproved Amendment 1. Please see our responses below to the review 
comments we received on 12/27/2022: 
# 
Section 
Comments 
1. 
Informed 
Consent 
The SOC for the Protocol Document states that the Risk Lists for docetaxel and 
paclitaxel protein bound have been added to the informed consent. 
Neither the informed consent SOC nor the ICD document risk lists include the stated 
updated. 
Please update the SOC and ICD. 
PI Response: The SOC response (Comment 3 in the below table) has been updated 
appropriately. Changes to the ICD are not required.  
2. 
Cover Page 
For 
Regulatory 
Requireme
nts 
Please revise the following language: 
Regulatory documentation must be submitted to the Cancer Trials Support Unit CTSU 
via the Regulatory Submission Portal.  
(Sign in at https://www.ctsu.org, and select Regulatory > Regulatory Submission.)  
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at by phone or email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to receive further instruction and support. 
Contact the CTSU Regulatory Help Desk at 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org for regulatory assistance.  
PI Response: The suggested changes have been made.  
3. 
Cover Page 
Protocol 
Document 
Access 
Please revise the following language: 
The most current version of the study protocol and all supporting documents must be 
downloaded from the protocol-specific page located on the CTSU members’ website 
(https://www.ctsu.org).  Access to the CTSU members’ website is managed through the 
Cancer Therapy and Evaluation Program - Identity and Access Management (CTEP-
IAM) registration system and requires log in with a 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). 
Permission to view and download this protocol and its supporting documents is 
restricted and is based on person and site roster assignment housed in the CTSU 
Regulatory Support System (RSS). Roster Maintenance application and in most cases 
viewable and manageable via the Roster Update Management System (RUMS) on the 

 
 
 
 
 
 
 
 
 
 
# 
Section 
Comments 
CTSU members’ website. 
PI Response: The suggested changes have been made. 
4. 
8.0 
Registratio
n and study 
entry 
procedures 
Please replace this section with the language from the new version of the CTSU 
logistics template: 
1. 
REGISTRATION AND STUDY ENTRY PROCEDURES 
Food and Drug Administration (FDA) regulations require sponsors to select qualified 
investigators. National Cancer Institute (NCI) policy requires all 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). The RCR is a self-service online person registration application with electronic 
signature and document submission capability. 
RCR utilizes five person registration types. 
• Investigator (IVR) — MD, DO, or international equivalent; 
• Non Physician Investigator (NPIVR) — advanced practice providers (e.g., NP or 
PA) or graduate level researchers (e.g., PhD); 
• 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. 
RCR requires the following registration documents: 
Documentation Required 
IV
R 
NPI
VR 
A
P 
A 
A
B 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, 
and certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
An active CTEP-IAM user account with a linked ID.me account (the latter required 
immediately for new CTEP-IAM accounts, and by July 1, 2023 for all users) is required 
to participate in NCI clinical trials supported by the Cancer Trials Support Unit (CTSU) 

 
 
 
 
 
 
 
 
 
 
# 
Section 
Comments 
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; 
• 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 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. 
PI Response: The suggested changes have been made. 
5. 
8.1 
IRB 
Approval 
Please revise the following: 
IRB Approval:  
For CTEP As of March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB) in order to participate in Cancer 
Therapy Evaluation Program (CTEP)  and Division of Cancer Prevention (DCP) studies 
open to the National Clinical Trials Network (NCTN) and NCI Community Oncology 
Research Program (NCORP) Research Bases after March 1, 2019, all U.S.-based sites 
must be members of the NCI Central Institutional Review Board (NCI CIRB). In 
addition, U.S.-based sites must accept the NCI CIRB review to activate new studies at 
the site after March 1, 2019. Local IRB review will continue to be accepted for studies 
that are not reviewed by the CIRB, or if the study was previously open at the site under 
the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
Sites participating with the 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). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 

 
 
 
 
 
 
 
 
 
 
# 
Section 
Comments 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation 
• IRB-signed CTSU IRB Certification Form; and/or 
• Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form 
In addition, the site-protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the 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 (applies to 
US sites only) and 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. 
Additional Requirements 
Additional site  requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• An active roster affiliation with the NCI-CIRB Signatory Institution (US sites 
only); and. 
Compliance with all applicable protocol-specific requirements (PSRs). 
PI Response: The suggested changes have been made. 
6. 
8.1 
Downloadi
ng Site 
Registratio
n 
Documents 
Please revise the following: 
Downloading Site Registration Documents   
Download the site registration forms from the NRG-GY026 page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted and its their associated investigators and staff participating roster 
to view/download site registration forms:  
• Log on 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 

 
 
 
 
 
 
 
 
 
 
# 
Section 
Comments 
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 NRG, and 
protocol # NRG-GY026. 
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 initiative, IRB data will load automatically to the CTSU.) 
PI Response: The suggested changes have been made. 
7. 
8.1 
Delegation 
of Tasks 
Log 
Please revise the following:  
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the 
DTL application in the Delegation Log section of the CTSU members’ website.  The 
Clinical Investigator (CI) is required to review and electronically sign the DTL prior to 
the site receiving an approved site registration status and enrolling patients to the study. 
To maintain an approved site registration status the CI must re-sign the DTL at least 
annually and when a new version of the DTL is released; and to activate new task 
assignments requiring CI sign-off. Any individual at the enrolling site on a participating 
roster may initiate the site DTL. Once the DTL is submitted for CI approval, only the 
designated DTL Administrators or the CI may update the DTL. Instructions on 
completing the DTL are available in the Help Topics button in the DTL application and 
include a Master Task List, which describes describe DTL task assignments, CI 
signature, and CTEP registration requirements., as well as include a Master Task List. 
PI Response: The suggested changes have been made. 
8. 
8.2.1 
Oncology 
Patient 
Enrollment 
Network 
(OPEN) 
Please revise the following language: 
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 Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN 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 participating organization roster with the role of 
Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
• If a Delegation of Tasks Log (DTL) is required for the study, the registrar(s) must 
hold the OPEN Registrar task on the DTL for the site; and 

 
 
 
 
 
 
 
 
 
 
# 
Section 
Comments 
Have an approved site registration for a protocol prior to patient enrollment. 
PI Response: The suggested changes have been made. 
9. 
14.1 
Data 
Submission 
1.1 
Data Management/Collection  
Medidata Rave is a 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.  
Rave role requirements: 
• Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type;  
• Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR) 
• Rave Read Only role must have at a minimum an Associates (A) registration 
type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
This study has a Delegation of Tasks Log (DTL). Therefore, those 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 Regulatory Support System 
(RSS), 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 museither 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 and has not yet been 
taken, the link to the eLearning will appear in the Studies pane located in the center of 
the e in 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 

 
 
 
 
 
 
 
 
 
 
# 
Section 
Comments 
the eLearning link study name.  
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 also 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: The suggested changes have been made. 
10. 
14.4 
Central 
Monitoring 
Please revise the following: 
 
Central Monitoring (CM)  
Central Monitoring (CM) Review is required for this protocol. CM allows Lead 
Protocol Organizations (LPOs) to remotely compare data entered in Rave to source 
documentation to ensure that sites are adhering to the protocol and central monitoring 
plan as well as accurately transcribing data from patients’ charts (i.e., source data 
verification). 
Sites can upload source documents required for CM Review as documented in the 
central monitoring plan using the Source Document Portal Source Document Portal 
(SDP). application. This application is also available on the CTSU members’ website 
under Auditing & Monitoring and may also be accessed using a direct link within Rave 
on the CM Alert form. Site staff with any of the CRA or Investigator Rave roles in Rave 
on a relevant site roster can view and upload source documents. Prior to saving source 
documents on the SDP, each site is responsible for removing or redacting any 
Personally Identifiable Information (PII) (note that functionality to do this redaction 
exists within the SDP itself). Designated LPO staff will review each document after it 
has been loaded on the SDP to ensure the appropriate documents have been uploaded 
and to ensure PII is redacted. 
Additional information on the SDP is available on the CTSU members’ website SDP 
application under Auditing & Monitoring > Source Browser > Document Portal 
Repository in the Help Topics button or by contacting the CTSU Help Desk (1-888-823-
5923 or ctsucontact@westat.com).   
PI Response: The suggested changes have been made. 
11. 
14.5 
Rave-
CTEP-
AERS 
Please revise the following: 
1.2 
Rave-CTEP-AERS integration  
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System 
(CTEP-AERS) Integration enables evaluation of Adverse Events (AE) entered in Rave 

 
 
 
 
 
 
 
 
 
 
# 
Section 
Comments 
Integration 
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. 
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 administration of the Investigational 
Agent/Intervention investigational study agent/intervention are collected using 
the Late Adverse 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 and   
• Protocol related Documents> Adverse Events 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 

 
 
 
 
 
 
 
 
 
 
# 
Section 
Comments 
Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/doc
s/aeguidelines.pdf. 
 
PI Response: The suggested changes have been made. 
12. 
14.6 
Data 
Quality 
Portal 
Please revise the following: 
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. Review 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 who are rostered to a site and have access to the 
CTSU website. Staff that who have Rave study access can access the Rave study data 
using a via direct link on links available in 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 icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms DQP Form Status, and DQP reports 
modules. 
PI Response: The suggested changes have been made. 

 
 
 
 
 
 
 
 
 
 
# 
Section 
Comments 
13. 5.2.2.2 
Per olaparib PI, both strong and moderate CYP3A4 inhibitor or inducers should be 
avoided for concomitant use.  
• If concomitant use of CYP3A inhibitor cannot be avoided, reduce olaparib dose 
as following, which can be used to update the current CSP 
 
• As CYP3A inducers would reduce olaparib efficacy, it is strongly recommend to 
avoid concomitant use. the efficacy should be closely monitored if CYP3A 
inducers must be used. The current language for inducer part is acceptable.  
PI Response: Thank you for the recommendation, however no changes will made 
at this time.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
Summary of Changes 
Amendment #1 
NCI Protocol #: NRG-GY029 
Local Protocol #: NRG-GY029 
NCI Version Date: December 28, 2022 
 
CTEP reviewed and disapproved Amendment 1 on 11/10/2022. Please see our responses below 
the review comments: 
 
# 
Section 
Comments 
1. 
6.1 
Please revise this sentence added during amendment 1 to read: “Note: Substitution 
for paclitaxel using docetaxel or paclitaxel protein-bound particles for injectable 
suspension (Abraxane) is only allowed for hypersensitivity reaction.  Should other 
issues arise, specifically a paclitaxel shortage, please contact the study team for 
review and approval prior to making the substitution.  This will be allowed on a 
case by case basis and will require documentation.”  
Neither docetaxel nor Abraxane are agents listed in this trial and paclitaxel is one 
agent possible in the SoC arm. 
PI Response:  No change has been made. It was not required as this was the 
language upon which CTEP and NRG came to agreement on after initial 
submission of this amendment and all that is required. It was discussed and 
agreed upon by Dr. Kohn, Dr. Aghajanian, and Dr. Johnson. 
2. 
9 
Please add new drug information sections (9.8 and 9.9) for docetaxel and 
paclitaxel protein-bound particles for injectable suspension (Abraxane). 
• Product description: 
• Solution preparation:  
• Route of administration 
• Agent Ordering  
PI Response: The suggested language is no longer required. Please see 
response above.  
3. 
ICD 
Please add the risk lists for docetaxel and paclitaxel protein-bound particles for 
injectable suspension (Abraxane) available at: 
https://ctep.cancer.gov/protocolDevelopment/sideeffects/drugs.htm  
PI Response: The suggested language is no longer required. Please see 
response to Comment #1. 

Summary of Changes 
Amendment #1 
NCI Protocol #: NRG-GY029 
Local Protocol #: NRG-GY029 
NCI Version Date: December 28, 2022 
 
Section 
Comments 
Title Pages 
• NCI Version Date is now December 28, 2022 
• Dana Farber Cancer Institute has been added to the NRG Oncology 
Participating Institutions for Safety Lead-ins 
• Amendment 1 and version date added to document history box 
 
TOC 
• Page numbers updated 
Schema 
• “weekly” removed from Arm 1 text box to agree with updated dosing 
in Section 5.1 
2.8 
• “Day 8” removed to correspond with DL-1 of the safety lead-in   
4.1 
• Statement added immediately following timing of registration 
assessments and starting of C1D1 
• Footnote lettering   
4.2 
• Updates made for clarity in Arm 1 table 
• Updates made for clarity in Arm 2 table 
• Footnote 2, in the Arm 1 table, updated to be consistent with imaging 
schedule in Arm 2 table 
5.1 
• Day 22 deleted to agree with current community standard dosing in 
Regimen 1 
• Daily Topotecan dosing added to Regimen 3 
5.2.2.2 
• Additional language added for clarification and consistency regarding 
CYP3A Inhibitors and Inducers paragraphs 
6.1 
• “If substitution of paclitaxel for Docetaxel or paclitaxel protein-
bound particles for injectable suspension (Abraxane) is required for 
reasons other than hypersensitivity reaction (e.g., drug shortage), 
contact the study team for review and approval prior to making the 
substitution” was added. 
7.5.2.1 
• Reporting table replaced to reflect AE reporting for commercial 
agents.  

 
This protocol was designed and developed by NRG Oncology. It is intended to be used only in 
conjunction with IRB approval for study entry. No other use or reproduction is authorized by NRG 
Oncology nor does NRG Oncology assume any responsibility for unauthorized use of this protocol. 
 
NRG-GY029 
- 1 -  
Version Date:  December 28, 2022 
 
NRG Oncology  
Four Penn Center 
1600 JFK BLVD Suite 1020  
Philadelphia, PA 19103 
Nrgoncology.org  
NRG-GY029: A Randomized Phase II trial comparing the combination of PI3K inhibitor 
Copanlisib (BAY 80-6946) and PARP inhibitor Olaparib (AZD2281) to standard chemotherapy 
in patients with recurrent platinum resistant ovarian, fallopian tube, or primary peritoneal cancer 
who have progressed through prior PARP inhibitor therapy 
 
ClinicalTrials.gov Identifier NCT TBD 
NCI Version Date: December 28, 2022 
 
 
Principal Investigator: 
Panagiotis A. Konstantinopoulos, MD, PhD  
Dana Farber Cancer Institute, YC-1424 
450 Brookline Avenue 
Boston, MA 02215 
617-632-5263 
Panagiotis_konstantinopoulos@dfci.harvard.edu 
 
 
Participating Organizations 
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
SWOG / SWOG 
 
 
Participating Sites  
 U.S. 
 Canada  
 Approved International Member Sites 
 Limited Participation  

 
 
 
NRG-GY029 
- 2 -  
Version Date:  December 28, 2022 
 
 
Protocol Agents: 
Agent 
Supply 
NSC# 
IND# 
IND Sponsor 
Copanlisib 
CTEP 
784727 
 
 
IND#  
 
 
 
DCTD, NCI 
Olaparib 
CTEP 
747856 
Paclitaxel 
Commercial 
673089 
Liposomal doxorubicin 
Commercial  
712227 
Topotecan 
Commercial 
609699 
 
 
NRG Oncology Participating Institutions for Safety Lead-ins  
AZ017 
Banner University Medical Center -Tucson 
CA249 
UC San Diego Moores Cancer Center 
CA070 
University of Colorado Hospital 
CT009 
Hartford Hospital 
FL015 
University of Florida Health Science Center - Gainesville 
GA020 
Augusta University Medical Center 
IA018 
University of Iowa/Holden Comprehensive Cancer Center 
IL057 
University of Chicago Comprehensive Cancer Center 
MA036 
Dana Farber Cancer Institute (28-DEC-2022) 
MD017 
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center 
MI020 
Wayne State University – Karmanos Cancer Institute 
MN022 
University of Minnesota/Masonic Cancer Center 
MO011 
Washington University School of Medicine 
NM004 
University of New Mexico Cancer Center 
NY016 
Memorial Sloan Kettering Cancer Center 
NY158 
Roswell Park Cancer Institute 
OH007 
Ohio State University Comprehensive Cancer Center 
OH027 
Cleveland Clinic Foundation 
OH029 
Case Western Reserve/University Hospital Cleveland Medical Center 
OH070 
University of Cincinnati Cancer Center-UC Medical Center 
OK003 
University of Oklahoma Health Science Center 
PA015 
UPMC Hillman Cancer Center 
PA075 
University of Pennsylvania/Abramson Cancer Center 
PA086 
Fox Chase Cancer Center 
PA121 
Thomas Jefferson University Hospital 
RI012 
Women and Infants Hospital 
TX035 
M D Anderson Cancer Center 
VA009 
University of Virginia Cancer Center 
VA010 
Virginia Commonwealth University Massey Cancer Center 
WA008 
Fred Hutchinson Cancer Research Center 
WI013 
Medical College of Wisconsin 
 
 

 
 
 
NRG-GY029 
- 3 -  
Version Date:  December 28, 2022 
 
 
Document History 
Initial 
June 02, 2022 
Amendment 1 
December 28, 2022 
 
 
 
 
STUDY TEAM  
 
PRINCIPAL INVESTIGATOR 
STATISTICIAN 
Principal Investigator-Gynecologic Oncologist 
Panagiotis A. Konstantinopoulos, MD, PhD 
Dana-Farber Cancer Institute, YC-1424 
Boston, MA 02215 
617-632-5269 
panagiotis_konstantinopoulos@dfci.harvard.edu  
 
Austin Miller, PhD 
NRG Oncology Statistics and Data Management 
Center-Buffalo  
Buffalo, NY 
716-845-5702 
millera@nrgoncology.org  
 
MODALITY CHAIRS 
Medical Oncology Chair 
Elizabeth Lee, MD 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215 
617-632-5269 
ElizabethK_Lee@dfci.harvard.edu   
 
Phase I Subcommittee Chair 
Stephanie Gaillard, MD, PhD 
Johns Hopkins University 
Baltimore, MD 
410-955-3774 
stephanie.gaillard@jhmi.edu 
Research Nurse 
Sarah Hindenach, BSN, RN, OCN 
Dana-Farber Cancer Institute  
450 Brookline Avenue 
Boston, MA 02215 
617-632-3472 
Sarah_Hindenach@dfci.harvard.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
NRG-GY029 
- 4 -  
Version Date:  December 28, 2022 
 
 
 
 
STUDY-SPECIFIC CONTACTS AND RESOURCES 
For questions/comments related to:                               Contact:  
Protocol Document, IRB review, informed 
consent documents and amendments 
 
Leah Madden, CCRP 
Protocol Coordinator 
NRG Oncology 
1600 JKF Blvd., Suite 1020 
Philadelphia, PA 19103 
215-854-0770 
maddenl@nrgoncology.org  
 
Data Management 
Including submission, eligibility  
 
 
Dolores Kirschner, MPH  
NRG Statistics and Data Management Center - Pittsburgh 
412-383-4912 
kirschnerd@nrgoncology.org  
 
Regulatory 
NRG-GY-Regulatory@nrgoncology.org  
NRG Oncology Gynecologic Oncology Chair  
 
Carol Aghajanian, MD 
Memorial Sloan Kettering Cancer Center 
New York, NY 
646-888-4217 
Aghajanc@mskcc.org  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
NRG-GY029 
- 5 -  
Version Date:  December 28, 2022 
 
CONTACT INFORMATION (28-DEC-2022) 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the Clinical Trials 
Support Unit (CTSU) via the 
Regulatory Submission Portal.  
(Sign in at https://www.ctsu.org,     
and select Regulatory > 
Regulatory Submission.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at by phone 
or email: 1-866-651-CTSU 
(2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878), or 
CTSURegHelp@cocc.org for 
regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN_SY
STEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions by phone or email: 1-
888-823-5923, or 
ctsucontact@westat.com. 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Refer to the data 
submission section of the 
protocol for further instructions.  
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website (https://www.ctsu.org).  Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires logging in with a 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). 
 
Permission to view and download this protocol and its supporting documents is restricted and is based on 
person and site roster assignment housed in the Roster Maintenance application and in most cases 
viewable and manageable via the Roster Update Management System (RUMS) or the CTSU members’ 
website.  
 
For clinical questions (i.e., patient eligibility or treatment-related) contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 
 
 
 

 
 
 
NRG-GY029 
- 6 -  
Version Date:  December 28, 2022 
 
 
TABLE OF CONTENTS 
1. 
OBJECTIVES ............................................................................................................... - 10 - 
1.1 
Primary Objective ............................................................................................. - 10 - 
1.2 
Secondary Objectives ........................................................................................ - 10 - 
2. 
BACKGROUND .......................................................................................................... - 10 - 
2.1 
Initial Evidence of PI3Ki/PARPi synergism in Breast Cancer Models ............ - 10 - 
2.2 
In Vivo PI3Ki/PARPi Synergism in Platinum Resistant and PARPi Resistant 
PDX Models of High Grade Serous Ovarian Cancer (HGSOC) ...................... - 11 - 
2.3 
In Vivo Proof of Mechanism Studies: PI3Ki inhibits HR in Platinum and 
PARPi Resistant ................................................................................................ - 13 - 
2.4 
Clinical Evaluation of PI3Ki/PARPi Combinations ......................................... - 14 - 
2.5 
Copanlisib ......................................................................................................... - 16 - 
2.6 
Rationale for Copanlisib/Olaparib in patients with platinum resistant ovarian    
cancer that has progressed through prior PARPi .............................................. - 21 - 
2.7 
Randomized Phase II Trial ................................................................................ - 22 - 
2.8 
Rationale for Copanlisib/Olaparib Starting Dose Regimen (31-MAY-2022) .. - 24 - 
3. 
ELIGIBILITY AND INELIGIBILITY CRITERIA ..................................................... - 26 - 
3.1 
Eligibility Criteria ............................................................................................. - 26 - 
3.2 
Ineligibility Criteria .......................................................................................... - 28 - 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..... - 31 - 
4.1 
Pre-Treatment Assessments .............................................................................. - 31 - 
4.2 
Assessments During Treatment ........................................................................ - 32 - 
4.3 
Assessments in Follow up ................................................................................. - 34 - 
5. 
TREATMENT PLAN/REGIMEN DESCRIPTION ..................................................... - 34 - 
5.1 
Treatment .......................................................................................................... - 34 - 
5.2 
General Concomitant Medication and Supportive Care Guidelines ................. - 38 - 
5.3 
Supportive/Ancillary Care ................................................................................ - 40 - 
5.4 
Vaccines ............................................................................................................ - 41 - 
5.5 
Other Anti-Cancer Agents and Participation in Other Trials ............................ - 41 - 
5.6 
Duration of Therapy .......................................................................................... - 41 - 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT ................................................ - 42 - 
6.1 
Arm 1 (Standard of Care/Control Arm) ............................................................ - 42 - 
6.2 
Arm 2: Copanlisib ............................................................................................. - 43 - 
6.3 
Arm 2: Olaparib ................................................................................................ - 49 - 
6.4 
Management of potentially Overlapping Toxicities ......................................... - 51 - 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS ............................................ - 55 - 
7.1 
Protocol Agents ................................................................................................. - 55 - 
7.2 
Adverse Events and Serious Adverse Events ................................................... - 56 - 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for Study 

 
 
 
NRG-GY029 
- 7 -  
Version Date:  December 28, 2022 
 
Agents ............................................................................................................... - 56 - 
7.4 
Adverse Events for Commercial Study Agents ................................................ - 61 - 
7.5 
Expedited Reporting of Adverse Events ........................................................... - 61 - 
7.6 
Routine Reporting Requirements for Adverse Events ...................................... - 65 - 
8. 
REGISTRATION AND STUDY ENTRY PROCEDURES ........................................ - 65 - 
8.1 
Cancer Trials Support Unit Registration Procedures ........................................ - 67 - 
8.2 
Patient Enrollment ............................................................................................ - 69 - 
9. 
DRUG INFORMATION .............................................................................................. - 70 - 
9.1 
Copanlisib (NSC# 784727, IND# XXXX) ....................................................... - 70 - 
9.2 
Olaparib (AZD2281) (NSC# 787856, IND# XXXX) ....................................... - 72 - 
9.3 
PMB Useful Links and Contacts....................................................................... - 75 - 
9.4 
Agent Ordering ................................................................................................. - 75 - 
9.5 
Commercial Agent—Paclitaxel (NSC# 673089) .............................................. - 76 - 
9.6 
Commercial Agent: Pegylated Liposomal Doxorubicin (PLD) (NSC# 
712227) ............................................................................................................. - 77 - 
9.7 
Commercial Agent: Topotecan (NSC# 609699) ............................................... - 78 - 
10. 
PATHOLOGY/BIOSPECIMEN .................................................................................. - 80 - 
11. 
SPECIAL STUDIES (Non-Tissue) ............................................................................... - 80 - 
12. 
MODALITY REVIEWS .............................................................................................. - 80 - 
13. 
ASSESSMENT OF EFFECT ....................................................................................... - 80 - 
13.1 
Antitumor Effect – Solid Tumors ..................................................................... - 80 - 
13.2 
Response Criteria .............................................................................................. - 83 - 
13.3 
Duration of Response ........................................................................................ - 86 - 
13.4 
Progression-Free Survival ................................................................................. - 86 - 
13.5 
Survival ............................................................................................................. - 86 - 
14. 
DATA AND RECORDS .............................................................................................. - 86 - 
14.1 
Data Management/Collection ........................................................................... - 86 - 
14.2 
NRG Data Management Forms ........................................................................ - 87 - 
14.3 
Summary of Data Submission .......................................................................... - 87 - 
14.4 
Central Monitoring (CM) .................................................................................. - 87 - 
14.5 
Rave-CTEP-AERS integration ......................................................................... - 88 - 
14.6 
Data Quality Portal ........................................................................................... - 89 - 
14.7 
Global Reporting/Monitoring ........................................................................... - 90 - 
15. 
STATISTICAL CONSIDERATIONS.......................................................................... - 90 - 
15.1 
Abstract ............................................................................................................. - 90 - 
15.2 
Stratification and Randomization ..................................................................... - 90 - 
15.3 
Patient Cohorts for Analysis ............................................................................. - 91 - 
15.4 
Primary Endpoint(s), Sample Size, and Analysis Plan ..................................... - 91 - 
15.5 
Monitoring/Oversight Committee ..................................................................... - 94 - 

 
 
 
NRG-GY029 
- 8 -  
Version Date:  December 28, 2022 
 
15.6 
Secondary Endpoints and Analysis Plans ......................................................... - 95 - 
15.7 
Exploratory Endpoints ...................................................................................... - 96 - 
15.8 
Gender/Ethnicity/Race Distribution .................................................................. - 96 - 
16. 
REFERENCES ............................................................................................................. - 97 - 
Appendix I – FIGO OVARIAN CANCER STAGING 2014 ................................................... - 99 - 
APPENDIX II – PERFORMANCE STATUS ....................................................................... - 100 - 
APPENDIX III – NYHA CLASSIFICATION ....................................................................... - 101 - 
Appendix IV- ACTIONS REQUIRED IN CASES OF COMBINED INCREASE OF 
AMINOTRANSFERASE AND TOTAL BILIRUBIN – HY’S LAW....................... - 102 - 
APPENDIX V – LIST OF PROHIBITED MEDICATIONS WHILE ON COPANLISIB AND 
OLAPARIB TREATMENT ....................................................................................... - 106 - 
APPENDIX VI – GENERAL THERAPY GUIDELINES ..................................................... - 107 - 
APPENDIX VII – CTEP COLLABORATIVE AGREEMENTS LANGUAGE ................... - 108 - 
APPENDIX VIII– PATIENT CLINICAL TRIAL WALLET CARD FOR COPANLISIB AND 
OLAPARIB................................................................................................................. - 110 - 
APPENDIX IX – OLAPARIB DRUG DIARY...................................................................... - 111 - 
 
 
 

 
 
 
NRG-GY029 
- 9 -  
Version Date:  December 28, 2022 
 
Platinum Resistant Ovarian Cancer* that has progressed 
through prior PARP inhibitor 
Arm 2 (Experimental) 
Copanlisib + Olaparib 
Arm 1 (Standard)(28-DEC-
2022) 
Investigator Choice Chemotherapy 
(non-platinum): 

Paclitaxel  

Pegylated Liposomal 
Doxorubicin (PLD) 
NRG-GY029 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Ovarian cancer = ovarian, fallopian tube, and primary peritoneal cancer  
Eligible histology: 1) high grade serous, 2) endometrioid, grade 3, 3) Any histology with BRCA1 and/or BRCA2 
deleterious mutation (germline or somatic) 
 
 
 
 
1:1 Randomization 
Upfront declaration of planned chemotherapy regimen 
Stratified by: 
➢ BRCA status (deleterious vs. non-deleterious) 
➢ Timing of prior PARPi therapy (PARPi as last line of therapy prior to 
initiation of this trial vs. other intervening therapy prior to initiation of 
this trial) 
Safety Lead-In  
 
Disease Progression or Unacceptable Toxicity 
 

 
 
 
NRG-GY029 
- 10 -  
Version Date:  December 28, 2022 
 
1. 
OBJECTIVES 
 
We hypothesize that the combination of copanlisib/olaparib will be associated with 
improved clinical efficacy compared to standard chemotherapy, as measured by 
investigator-assessed progression free survival (PFS), in recurrent platinum resistant ovarian 
cancer that has progressed through prior PARP inhibitor therapy. 
 
1.1 
Primary Objective 
1.1.1 To assess the clinical efficacy of the combination of copanlisib/olaparib, as measured by 
investigator-assessed progression free survival (PFS), compared to standard chemotherapy 
in the setting of recurrent platinum resistant ovarian cancer that has progressed through prior 
PARP inhibitor therapy. 
 
1.2 
Secondary Objectives 
1.2.1 To assess the clinical efficacy of the combination of copanlisib/olaparib, as measured by 
objective response rate (ORR), per RECIST 1.1. 
1.2.2 To assess the clinical efficacy of the combination of copanlisib/olaparib, as measured by 
overall survival (OS), compared to standard chemotherapy in the setting of recurrent 
platinum resistant ovarian cancer that has progressed through prior PARP inhibitor therapy. 
1.2.1 To determine the nature, frequency and degree of toxicity as assessed by CTCAE v.5.0 for 
each treatment arm. 
 
2. 
BACKGROUND 
 
Combination of PARP inhibitors (PARPi) with agents that inhibit homologous 
recombination (HR) represents an effective strategy to sensitize HR proficient cancers to 
PARPi (Konstantinopoulos, 2015). In our preclinical work discussed below, we have 
demonstrated that PI3K inhibitors (PI3Ki) inhibit HR and sensitize platinum and PARPi 
resistant models to PARPi olaparib.  
 
Based on these preclinical data as well as clinical data (which are discussed below), we 
hypothesize that the addition of the PI3K inhibitor copanlisib to olaparib will sensitize 
platinum resistant ovarian cancers that have progressed through prior PARPi to olaparib and 
that the combination of olaparib and copanlisib will fare better than standard chemotherapy 
in this setting.  
 
2.1 
Initial Evidence of PI3Ki/PARPi synergism in Breast Cancer Models 
In vivo synergy of the oral pan-class I PI3K inhibitor BKM120 with the PARPi olaparib 
was initially reported in BRCA-proficient triple negative breast cancer (TNBC) (Ibrahim, 
2012) and in a mouse model of BRCA1-related breast cancer (Juvekar, 2012).  In BRCA-
proficient TNBC cells, PI3K inhibition led to DNA damage, downregulation of BRCA1/2, 
gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. 
Specifically, siRNA-induced silencing of PIK3CA in a BRCA wild type, PTEN mutant 
triple-negative cell line induced accumulation of phosphorylated histone H2AX (γ-H2AX), 
a marker of DNA damage, inferring that the loss of PIK3CA results in genomic instability, 
which was enhanced by the addition of the PARPi olaparib. Furthermore, pharmacologic 

 
 
 
NRG-GY029 
- 11 -  
Version Date:  December 28, 2022 
 
inhibition with a pan-PI3K inhibitor (BKM120) was accompanied by a concomitant 
reduction in the expression of BRCA1 and BRCA2 and a reduction in the cellular capacity 
to conduct HR (Ibrahim, 2012, Juvekar, 2012).  Consistent with the reduction in BRCA1/2 
expression, PI3K pathway blockade induced sensitivity to PARPi olaparib and ABT888 in 
vitro. These findings were validated in vivo in 3 patient-derived xenografts (PDX) of triple-
negative breast cancer, which confirmed elevated γ-H2AX and decreased BRCA1 
expression following treatment with a PI3K inhibitor in two of the three models. 
Furthermore, the decrease in BRCA1 expression correlated with an enhanced response to 
the combination of PARP inhibitor and PI3K inhibitor when compared with either drug 
alone. Mechanistically, downregulation of BRCA1/2 was mediated by ERK-dependent 
activation of the ETS transcription factor, which suppresses BRCA gene transcription, 
thereby causing a deficiency in HR and concomitant PARP inhibitor sensitivity (Ibrahim, 
2012, Rehman, 2012). 
 
Synergism between PI3Ki and PARPi was similarly demonstrated in the context 
of BRCA1 deficiency (Juvekar, 2012) in the MMTV-CreBrca1f/fp53+/− mouse (a genetically 
engineered model of spontaneous breast cancer in which tumors carry a hypomorphic 
BRCA1 allele) whereby both AKT and ERK phosphorylation are increased while PTEN and 
INPP4B expression are absent. FDG–positron emission tomographic (PET) imaging was 
used to determine the effects of PI3K inhibition, illustrating that the initially avid FDG 
uptake in tumors was reduced by a median of 46.7% within 48 hours of treatment with the 
pan-PI3K inhibitor BKM120, a biomarker effect sustained over a period of 2 weeks with 
continued treatment. This response was accompanied by a decrease in the levels of 
phosphorylated AKT and a reduction in the vascularity of tumors. As in the BRCA-
proficient TNBC models, PI3K inhibition led to an increase in γ-H2AX accumulation and a 
reduction in AKT phosphorylation, which was exacerbated by the addition of a PARPi. Of 
note, RAD51 foci formation and residual baseline HR function in the BRCA1 hypomorphic 
model was completely blocked by treatment with a PI3K inhibitor; a similar result was 
obtained by use of PI3K siRNA. Significant suppression of tumor growth was also observed 
in two patient-derived xenografts, with sustained responses to the combination of a PI3Ki 
and a PARPi. A subsequent report showed that the enhanced DNA damage induced by 
PI3Ki may be a consequence of impaired production of nucleotides needed for DNA 
synthesis and DNA repair (Juvekar, 2016). Specifically, PI3K inhibition disproportionately 
affects the nonoxidative pentose phosphate pathway that delivers Ribose-5-phosphate 
required for base ribosylation and induces reduction in all four nucleotide triphosphates. 
 
2.2 
In Vivo PI3Ki/PARPi Synergism in Platinum Resistant and PARPi Resistant PDX  
Models of High Grade Serous Ovarian Cancer (HGSOC) 
We have explored whether two PI3Ki (BKM120/buparlisib and BYL719/alpelisib) could 
enhance the efficacy of the PARPi olaparib in a group of ovarian cancer (OC) PDX models 
that have been established and molecularly characterized at Dana-Farber Cancer Institute; 
these HGSOC PDX models have been previously shown to faithfully model the clinical 
spectrum and responsiveness to standard-of-care chemotherapy (Liu, 2016). All models 
presented below (except for DF149) are from patients who have developed platinum 
resistant disease. Furthermore, all PDX models presented below are resistant to olaparib 
monotherapy. Of note, one of the PDX models (DF68) is from a patient who had progressed 

 
 
 
NRG-GY029 
- 12 -  
Version Date:  December 28, 2022 
 
through prior PARPi therapy. 
 
2.2.1 Olaparib/BKM120 in platinum resistant and PARPi therapy 
The evaluation of pan-PI3K inhibitor BKM120 (IC50 for p110α/β/δ/γ is 52 nM/166 nM/116 
nM/262 nM respectively) in combination with olaparib in HGSOC PDX models is shown in 
Figure 1. All models presented in Figure 1. (except for DF149) are from patients who have 
developed platinum resistant disease and all PDX models in Figure 1. are resistant to 
olaparib monotherapy. Of note, DF68 was derived from a patient who progressed through 
prior PARPi therapy. As shown in Figure 1, in all these models there was evidence of 
growth inhibition to the combination of BKM120 with olaparib, while there was no 
response to olaparib alone.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2.2 Olaparib/BYL719 
We also assessed the alpha specific PI3-Kinase inhibitor BYL719 (IC50 for p110α/β/δ/γ is 
5nM/1250nM/290nM/250 nM respectively) in combination with olaparib in platinum 
resistant and PARPi resistant HGSOC PDX models (Figure 2). All models presented in 
Figure 2 are from patients who have developed platinum resistant disease and all PDX 
models are resistant to olaparib monotherapy.  
 
As shown in Figure 2, in all these models there was evidence of growth inhibition to the 
combination of BYL719 with olaparib, while there was no response to olaparib alone. 
 
Weeks of treatment           Weeks of treatment 
Figure 1. Olaparib/BKM120 in HGSOC PDX models. 

 
 
 
NRG-GY029 
- 13 -  
Version Date:  December 28, 2022 
 
 
 
2.3 
In Vivo Proof of Mechanism Studies: PI3Ki inhibits HR in Platinum and PARPi 
Resistant  
In addition to the efficacy studies, we have performed proof of mechanism studies in the 
ovarian PDX models. As shown in Figure 3, BYL719 (alpelisib) inhibits HR in the platinum 
and PARPi resistant HGSOC DF216 model as evidenced by the decrease in the RAD51 foci 
positive cells after treatment with olaparib/alpelisib compared to treatment with olaparib 
alone. Specifically, ascites from mice harboring PDX model DF216 was collected and 
treated ex vivo with vehicle (VEH), BYL719 (BYL) or olaparib (OLA) individually or a 
combination of BYL719 and OLA for 48 hours. Paraffin sections of these cells were stained 
using an antibody specific to RAD51 (Figure 3A). The number of RAD51 foci/cell was 
highly reduced in the presence of olaparib/alpelisib when compared to olaparib treated cells 
(Figure 3B). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 3. BYL719 inhibits HR in the platinum and PARPi resistant DF216 HGSOC PDX 

 
 
 
NRG-GY029 
- 14 -  
Version Date:  December 28, 2022 
 
2.3.1 Similar data have been obtained with BKM120 in breast models. Specifically, BKM120 
inhibits HR as evident by the absence of RAD51 foci formation after ionizing radiation (IR) 
in breast cancer cells isolated from primary tumors from MMTV-CreBrca1f/fTrp53+/-mice 
treated with BKM120 (Figure 4E) compared to cells treated with vehicle control (Figure 
4C). As evident in Figure 4C, vehicle treated cells form RAD51 after IR while BKM-120 
treated cells do not (Figure 4E).  
 
 
 
 
 
2.4 
Clinical Evaluation of PI3Ki/PARPi Combinations 
We have now completed Phase I evaluation of both BKM120/olaparib and 
BYL719/olaparib in ovarian and breast cancer patients.  
 
2.4.1 Phase I Trial of Olaparib/BKM120 
Initially, we performed a Phase I dose escalation study BKM120 and olaparib for the 
treatment of recurrent ovarian and breast cancer (BC) patients with dose expansion cohorts 
in each tumor type (Matulonis, 2016). Detailed results of this study were published 
previously (Matulonis, 2016). Anticancer activity was observed in BC and OC and in 
patients both with and without BRCA mutations. Specifically, in the ovarian cancer cohort, 
the objective response rate (ORR) by RECIST 1.1 was 29% (12 of 41 patients, all partial 
responses (PRs). The ORR was seen irrespective of platinum sensitivity status; specifically, 
ORR was 32% in platinum sensitive disease (6 of 19 patients) and 27% in platinum resistant 
disease (6 of 22 patients) (Matulonis, 2016). 
 

 
 
 
NRG-GY029 
- 15 -  
Version Date:  December 28, 2022 
 
2.4.2 Phase I Trial of Olaparib/BYL719 
We have also evaluated the alpha specific PI3-Kinase inhibitor BYL719 in combination 
with olaparib in a Phase I study in recurrent ovarian cancer and breast cancer (BC) 
(Konstantinopoulous, 2019). 
 
Olaparib was administered twice daily (tablet formulation) and BYL719 daily on a 28-day 
cycle, both orally. Eligibility included recurrent TNBC or high grade serous OC, or any 
histology of OC or BC with presence of a germline BRCA mutation and performance status 
of 0-1. Patients with platinum sensitive or resistant or refractory OC were eligible; and prior 
PARP inhibitor use was allowed. Dose-expansion cohorts at the MTD were enrolled for 
both BC and OC. 
 
The olaparib/alpelisib combination showed evidence of clinical activity, with an ORR of 
36% (10/28 evaluable patients, all partial responses), (Figure 5). The proportion of all OC 
patients achieving a PR was similar for those with and without germline BRCA mutations 
(30% vs 35% respectively), (Figure 6) and was 35% in patients with platinum 
resistant/refractory disease. The objective response rate in patients which were BRCAwt 
(germline and somatic) and had platinum resistant/refractory tumors was 33%, markedly 
higher than that seen with olaparib monotherapy (4%) in prior studies (Gelmon, 2011, 
Moore, 2019). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 5. Olaparib/BYL719: Best response for target lesions by patient, based on 
maximal percentage of tumor reduction 

 
 
 
NRG-GY029 
- 16 -  
Version Date:  December 28, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.5 
Copanlisib 
PI3K/AKT signaling is commonly dysregulated in human cancers via various mechanisms, 
e.g., gene amplification, rearrangement, or activating and/or loss-of-function mutations of 
the pathway’s molecular components (Westin, 2014).  Aberrant activation of class I PI3Ks 
has been associated with intrinsic and acquired resistance of tumors to targeted agents, 
chemotherapy, and radiotherapy (Liu et al., 2013).   
 
Four PI3K isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ), all of which have a catalytic p110 
subunit (p110α/β/γ/δ), comprise the class I PI3K subfamily (Liu et al., 2013; Westin, 2014).  
Tumors with mutations in PIK3CA or loss of PTEN have been found to be sensitive to 
inhibitors targeting PI3Kα.  PI3Kδ-specific inhibitors have shown remarkable therapeutic 
efficacy in some human leukemias and lymphomas (Yang et al., 2015).  Inhibition of PI3Kδ 
in the B-cell malignancies was shown to attenuate the responsiveness of the tumor cells to 
supportive stimuli from the microenvironment (Okkenhaug and Burger, 2016).  Inactivation 
of PI3Kδ appears to break regulatory T-cell (Treg)-mediated immune tolerance unleashing 
cytotoxic T-cell response that leads to tumor regression (Ali et al., 2014).   
 
Copanlisib is a novel intravenous (IV) pan-class I PI3K inhibitor with predominant 
inhibitory potency against δ and α PI3K isoforms (Copanlisib Investigator’s Brochure, 
2018).  Preclinical data suggest that copanlisib may be more efficient in inhibiting survival 
of leukemia cells than idelalisib (PI3Kδ inhibitor) or duvelisib (PI3Kα/γ) (Gockeritz et al., 
2015). 
 
Nonclinical Studies 
 
Copanlisib free base (BAY 80-6946) is an active ingredient of copanlisib dihydrochloride 
salt (BAY 84-1236).  A majority of nonclinical data were produced using the copanlisib 
free-base.  
 
 
Figure 6. Ovarian Cancer Cohort: Best overall response by RECIST by BRCA 
mutation status (all patients) 

 
 
 
NRG-GY029 
- 17 -  
Version Date:  December 28, 2022 
 
Mechanism of Action 
Copanlisib is a stronger inhibitor of PI3Kα and PI3Kδ than of PI3Kβ or PI3Kγ as 
demonstrated by copanlisib 50% inhibitory concentrations (IC50s) for PI3Kα, PI3Kδ, PI3Kβ, 
and PI3Kγ IC50s0.5, 0.7, 3.7, and 6.4 nmol/L, respectively) (Liu et al., 2013).  Compared to 
the PI3K isoforms, copanlisib is a much weaker inhibitor of mTOR (IC50=45 nmol/L).  In a 
panel of ~220 kinases, copanlisib (1 mcmol/L) failed to inhibit any kinase other than PI3K 
isoforms and mTOR by 50%.  In tumor cell lines with hyperactive PI3K signaling, 
copanlisib antitumor activity was paralleled by a robust decrease in basal levels of 
phosphorylated AKT, both at serine 473 (AKTpS473) and threonine 308 (AKTpT308), and 
by increases in caspase-9 levels, which is suggestive of induction of apoptosis.  
 
Copanlisib has potent and broad in vitro antitumor activity (IC50 of 1-760 nmol/L) in 
cancers of the breast, ovary, ovary, prostate, colon, lung, liver, brain, kidney, melanoma, 
pancreas, fibrosarcoma, and in various hematological cancers (Copanlisib Investigator’s 
Brochure, 2018).  Copanlisib effectively inhibits tumor growth in diffuse large B-cell 
lymphoma (DLBCL) animal models where the PI3Kδ-selective inhibitor idelalisib is not 
active.  Intermittent dosing results in improved efficacy with better tolerability.   
 
Nonclinical Pharmacokinetics  
 
Copanlisib plasma-free fraction across species was as follows:  35% in rats, 14% in mice, 
33% in dogs, and 16% in humans (Liu et al., 2013).  The pharmacokinetic (PK) profile of 
copanlisib was evaluated following single and multiple IV doses in nude rats.  Single-dosed 
copanlisib exhibited a very large volume of distribution (Vd=32 L/kg), high plasma 
clearance (3.95 L/kg/h) and a long half-life (t1/2=6.0 h).  The copanlisib PK parameters at 
repeat dosing (Q2D x 5 doses), were similar to those from single-dosing studies and 
suggested no drug accumulation in plasma.   
 
In tumor xenograft model studies, the efficacious exposure of copanlisib, expressed as the 
area under the concentration-time curve (AUC) for the unbound/free drug (AUCu) in 
plasma, was estimated to be 370 mcg•h/L in rats and 170-460 mcg•h/L in mice based on 
weekly dosing (Copanlisib Investigator’s Brochure, 2018).  
 
Copanlisib had a higher clearance (16 L/kg/h), shorter t1/2 (0.7 h) and smaller Vd (12.9 L/kg) 
in mice than rats (Liu et al., 2013).  A single bolus IV dose of copanlisib (6 mg/kg) in the 
H460 NSCLC xenograft rat model produced 100 times higher concentration of the drug in 
tumor tissue than in plasma at 48 hours post-dosing; the drug clearance from the tumor was 
slower than from plasma.  The pharmacodynamics analysis showed 90% inhibition of 
AKTpS473 at 24 hours post-dosing compared to the control animals, and the AKTpS473 
level remained suppressed up to 72 hours. 
 
Nonclinical Pharmacology and Metabolism  
 
The extent of plasma protein binding of copanlisib was low in various species with free 
fractions between 10% and 42% (15.8% in human plasma).  Copanlisib demonstrated high 
distribution from blood to the organs and tissues and moderate penetration of the blood-

 
 
 
NRG-GY029 
- 18 -  
Version Date:  December 28, 2022 
 
brain barrier (BBB) and placental barrier, and high affinity to melanin-bearing tissues 
(Copanlisib Investigator’s Brochure, 2018). 
 
Copanlisib is primarily metabolized by the cytochrome P450 (CYP) isoform 3A4 
(CYP3A4), while CYP1A1 contributes to a minor extent (<10%) based on in vitro data 
(Copanlisib Investigator’s Brochure, 2018).  Copanlisib is a weak substrate of permeability 
glycoprotein (P-gp) and of breast cancer resistance protein (BCRP).  There is a low risk for 
clinically relevant PK drug-drug interactions (DDI) through inhibition or induction of CYP 
enzymes, inhibition of uridine diphosphate glucuronosyltransferase (UGT) enzymes and 
inhibition of dihydropyrimidine dehydrogenase by copanlisib.  Copanlisib also inhibits P-gp 
(IC50 7-7.6 mcmol/L) and BCRP (IC50=11.5 mcmol/L).  Furthermore, copanlisib was a 
strong inhibitor of the drug transporter multidrug and toxin extrusion protein 2 (MATE2K).  
 
Nonclinical Safety and Toxicity  
 
Based on clinical pathology and morphological findings in repeat-dosing IV studies, target 
organs were lymphoid and hematopoietic system, liver, kidneys, teeth, bone, heart, male, 
and female genital systems in the rat (Copanlisib Investigator’s Brochure, 2018).  Dogs 
showed adverse effects in the lymphoid and hematopoietic system, stomach, and male 
genital system.  Intravenous infusion of copanlisib caused vasoconstriction, enhanced 
insulin and glucose levels, impaired glucose tolerance, reduced gastrointestinal (GI) 
motility, increased renal volume and electrolyte excretion, and central nervous system 
(CNS) depressant effects in nonclinical species.  A majority of these effects could be 
explained by inhibition of PI3K-dependent signaling, and they occurred at or slightly above 
the plasma concentrations shown to be efficacious in tumor xenograft rat models (maximum 
concentration [Cmax]=30-80 mcg/L; Cmax of unbound fraction [Cmax,u] 11-28 mcg/L).  The 
CNS depressant effects occurred at high plasma concentrations and are considered 
secondary to hyperglycemia.  At pharmacodynamically relevant concentrations, copanlisib 
does not interfere with cardiac repolarization in vitro or in vivo. 
 
Based on the findings from repeat-dose toxicity studies in nonclinical species, copanlisib is 
expected to adversely affect male and female reproduction (Copanlisib Investigator’s 
Brochure, 2018).  Developmental and reproductive toxicity of PI3K inhibitors is known.  
Maternal toxicity of increasing severity, severe post-implantation loss, and developmental 
toxicity, including teratogenicity were seen in the rat starting at low doses.  Copanlisib was 
not genotoxic in vitro or in vivo.  Appropriate precautions should be taken to avoid 
pregnancy in female subjects included in the clinical trials.   
 
There is no evidence that copanlisib has phototoxic potential (Copanlisib Investigator’s 
Brochure, 2018).   
 
Effects in Humans 
 
Drug-Drug Interactions 
 
In vitro studies in human hepatocytes indicate that CYP3A4 is a major metabolizer (>90%) 

 
 
 
NRG-GY029 
- 19 -  
Version Date:  December 28, 2022 
 
while CYP1A1 contributes <10% to metabolism of copanlisib (Investigator’s Brochure, 
2018).  Preliminary results of copanlisib co-administered with rifampin, a strong inducer of 
CYP3A4, resulted in 63% decrease in the mean AUC of copanlisib with a minor effect on 
Cmax (15%).  Therefore, the concomitant use of copanlisib and strong inducers of CYP3A4 
(rifampin, phenytoin, carbamazepine, phenobarbital, enzalutamide, mitotane, and St. John’s 
Wort, etc.) should be avoided.  Co-administration of itraconazole (200 mg), a strong 
inhibitor of CYP3A4 with copanlisib (60 mg IV) resulted in 1.53-fold increase in copanlisib 
AUC but had no effect on its Cmax.  Increases in AUC between 1.25-fold and 2-fold are 
considered weak.  No dose adjustment of copanlisib is necessary when co-administered with 
CYP3A4 inhibitors but patients need to be closely monitored for toxicity when co-
administred with strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, 
ritonavir, indinavir, nelfinavir, saquinavir, etc.).  Because copanlisib is a substrate of P-gp 
and BCRP, inducers/inhibitors of these transporters have potential to affect copanlisib 
exposure. 
 
Summary of Clinical Safety of Copanlisib and Special Warnings (Copanlisib 
Investigator’s Brochure, 2018) 
 
In clinical studies, the most serious adverse events (SAEs) reported in patients with NHL 
(indolent and aggressive) and solid tumors treated with copanlisib monotherapy included 
pneumonitis, lower respiratory tract infections (including pneumonia), and febrile 
neutropenia (Copanlisib Investigator’s Brochure, 2018).  In clinical studies, the most 
common adverse reactions (≥20%) were hyperglycemia, decreased general strength and 
energy (including fatigue and asthenia), hypertension, diarrhea, nausea, leukopenia and 
neutropenia. 
 
Infections  
Serious infections (including fatal infections) occurred in 19% of patients treated with 
copanlisib monotherapy (Copanlisib Investigator’s Brochure, 2018).  The most common 
infections were pneumonia, lung infection and lower respiratory tract infection.  Patients 
should be monitored for symptoms of infection and copanlisib dosing should be interrupted 
for Grade ≥3 infections until resolution.  Pneumocystis jirovecii pneumonia occurred in 
0.6% of patients treated with copanlisib.  Prophylaxis should be considered for patients at 
risk for this infection, and copanlisib should be interrupted for any grade of this infection. 
 
Non-Infectious Pneumonitis 
Non-infectious pneumonitis (all events were Grade ≤3) occurred in 5% of patients 
(Copanlisib Investigator’s Brochure, 2018).  Treatment with copanlisib should be 
permanently discontinued in patients experiencing non-infectious pneumonitis of Grade ≥3 
and if Grade 2 recurs.   
 
Neutropenia and Febrile Neutropenia 
Grade 4 neutropenia occurred in 9.1% of patients, including 1.9% of patients having febrile 
neutropenia (Copanlisib Investigator’s Brochure, 2018).  
 
 

 
 
 
NRG-GY029 
- 20 -  
Version Date:  December 28, 2022 
 
Transient Hypertension 
Treatment with copanlisib may result in transient hypertension; blood pressure increases 
were seen after cycle 1 day1 infusion of copanlisib and started to decrease approximately 2 
hours post-infusion.   Serious hypertension (Grade ≥3) occurred in 0.9% of patients 
(Copanlisib Investigator’s Brochure, 2018).  Copanlisib should be permanently discontinued 
for uncontrolled hypersensitivity or the Grade 4 event.  
 
Transient Hyperglycemia 
Treatment with copanlisib may result in transient hyperglycemia, with a peak in blood 
glucose level peak observed at 5-8 hours post-infusion followed by subsequent decline to 
baseline (Copanlisib Investigator’s Brochure, 2018).  More serious hyperglycemia (Grade 
≥3) occurred in 0.9% of patients.  Optimal glucose levels should be achieved before each 
infusion of copanlisib.  Copanlisib dosing should be delayed, reduced, or permanently 
discontinued depending on severity of the event.  
 
Embryo-Fetal Toxicity 
Based on the mechanism of action and non-clinical study finding in rats, copanlisib may 
cause embryo-fetal harm (Copanlisib Investigator’s Brochure, 2018).  Copanlisib should not 
be used during pregnancy.  Highly effective contraception in addition to a barrier method 
should be used by males and females of child-bearing potential.   
 
Pregnancy and Lactation 
There are no data on the use of copanlisib in pregnant women (Copanlisib Investigator’s 
Brochure, 2018).  It is not known whether copanlisib is excreted in human milk.  
Nonclinical studies in lactating rats showed that ~2% of radioactively labeled copanlisib 
was excreted into milk.  Therefore, copanlisib can potentially harm infants and 
breastfeeding must be discontinued while on copanlisib treatment. 
 
Recommended Phase 2 Dose of Copanlisib as Monotherapy (Copanlisib Investigator’s 
Brochure, 2018) 
 
The maximum tolerated dose (MTD) of a single-agent copanlisib in non-diabetic patients 
with solid malignancies was 0.8 mg/kg 1-hour IV administered once weekly for 3 weeks 
(days 1, 8, and 15) on a 28-day cycle (Copanlisib Investigator’s Brochure, 2018).  No 
impact of either body weight, body surface area (BSA), or other body size-related factors 
was found on the clearance of copanlisib, which was the basis to switch to a fixed-dose 
regimen of copanlisib based on the population PK. 
 
The recommended phase 2 dose (RP2D) of copanlisib monotherapy is 60 mg 1-hour IV 
given once weekly for 3 weeks (days 1, 8, and 15) on 4-week cycle.  A dose reduction to 45 
mg for toxicities is allowed.  No dose adjustment is required in patients with mild or 
moderate renal impairment or patients with mild hepatic impairment.  
 
The choice of copanlisib is supported by our preclinical data of olaparib/BKM120 and 
olaparib/alpelisib in the OC PDX models which indicate that pan-class I PI3K inhibition and 
alpha-specific PI3K inhibition are effective in sensitizing to PARPi therapy. The preclinical 

 
 
 
NRG-GY029 
- 21 -  
Version Date:  December 28, 2022 
 
data provided and in the literature (Juvekar, 2012, Rehman, 2012, Juvekar, 2016), as well as 
our clinical data (Matulonis, 2016, Konstantinopoulos, 2019) suggest that there is no 
difference between the pan-PI3Ki/PARPi (BKM120/olaparib) and the alpha-specific 
PI3Ki/PARPi (BYL719/olaparib) and that they both are efficacious. Accordingly, we 
anticipate that copanlisib, which is a pan class-I PI3K inhibitor with predominant activity 
against the alpha and delta isoforms, will be effective in sensitizing to the PARPi olaparib, 
similar to BYL719 and BKM120. 
 
Agent / IC50 (nM) 
α isoform 
β isoform 
γ isoform 
δ isoform 
BKM120 (buparlisib) 
52 
166 
116 
262 
BYL719 (alpelisib) 
5 
1250 
290 
250 
Copanlisib 
0.5 
3.7 
6.4 
0.7 
Table 1. IC50s of BKM120, BYL719 and copanlisib for the α/β/γ/δ PI3K isoforms. Copanlisib is a pan-PI3K 
inhibitor with predominant activity against the alpha and delta isoforms. 
 
In terms of safety, unlike BKM120 (buparlisib), copanlisib has not been associated with 
CNS toxicity. Specifically, neurotoxicity was not seen in clinical trials of single agent 
copanlisib in hematologic malignancies (Dreyling, 2017, Markham, 2017, Patnaik, 2016).  
This differs from our previous clinical experience with BKM120 and may be partly 
explained by the since-discovered CNS-penetrating abilities of BKM120 (de Gooijer, 2018), 
which have led to clinical trials of BKM120 in glioblastoma. Overall, copanlisib is well 
tolerated and has received FDA approval in follicular lymphoma (Markham, 2017).  
 
2.6 
Rationale for Copanlisib/Olaparib in patients with platinum resistant ovarian cancer  
that has progressed through prior PARPi 
This is a randomized phase 2 trial comparing the combination of the PI3-Kinase inhibitor 
copanlisib and the PARP-inhibitor olaparib to standard non-platinum chemotherapy in 
patients with recurrent platinum resistant ovarian, fallopian tube, or primary peritoneal 
cancer who have progressed through prior PARP-inhibitor therapy.  
 
Given the approval of PARPi as maintenance therapy after platinum-based chemotherapy 
both in the upfront and the recurrent setting regardless of BRCA mutation and HR status, an 
important clinical question that has evolved is what would be the ideal therapy for patients 
who progress on PARPi therapy. A number of these patients will stay on PARPi 
maintenance therapy for less than 6 months and would hence be characterized as platinum 
resistant OR will eventually become platinum resistant. Based on the preclinical and clinical 
data discussed above, we hypothesize that rechallenging these patients with PARPi therapy 
(olaparib) in combination with the PI3K inhibitor (copanlisib), will fare better than standard 
chemotherapy in this setting (i.e., in patients with platinum resistant ovarian cancers which 
have already progressed through PARPi therapy).  
 

 
 
 
NRG-GY029 
- 22 -  
Version Date:  December 28, 2022 
 
 
The rationale for this study is supported by preclinical in vivo data in PDX models, whereby 
both olaparib/BYL719 and olaparib/BKM120 showed activity in platinum resistant and 
PARPi resistant HGSOC PDX models (Figures 1 and 2) including a model (DF68) taken 
from a patient who had progressed through prior PARPi.   
 
 
In our proof of mechanisms studies in vitro and in vivo, we have shown that PIK3i 
(BKM120 and BYL719) inhibit homologous recombination (HR), i.e., induce “BRCAness”, 
and thus sensitize HR proficient tumors to PARPi olaparib. 
 
 
The rationale behind evaluating olaparib/copanlisib in this cohort of OC patients is further 
supported by the findings of the olaparib/BKM120 and olaparib/BYL719 studies discussed 
above. In these studies, ORR of approximately 30% was observed in recurrent ovarian 
cancer regardless of platinum sensitivity status and regardless of BRCA mutation status, 
with an ORR of 27% for olaparib/BKM120 and 35% for olaparib/BYL719 in recurrent 
platinum resistant disease. Notably, among non-BRCA mutation carriers with platinum 
resistant disease, the ORR of olaparib/BYL719 was 33%, much higher than what expected 
from olaparib monotherapy, which is 4% in this population (Gelmon, 2011).  
 
 
Given that platinum resistant ovarian cancers that have progressed through prior PARPi are 
enriched for HR proficiency (Konstantinopoulos, 2015), and based on our preclinical data, 
we hypothesize that copanlisib will inhibit HR, induce “BRCAness” and therefore sensitize 
these tumors to olaparib and thus the combination of olaparib and copanlisib will fare better 
than standard non-platinum chemotherapy in this setting.  
 
 
The choice of copanlisib is supported by the preclinical data which indicate that pan-class I 
PI3K inhibition and alpha-specific PI3K inhibition are effective in sensitizing to PARPi 
therapy. The preclinical data provided and in the literature (Juvekar, 2012, Rehman, 2012, 
Juvekar, 2016), as well as our clinical data (Matulonis, 2016) suggest that there is no 
difference between the pan-PI3Ki/PARPi (BKM120/olaparib) and the alpha-specific 
PI3Ki/PARPi (BYL719/olaparib) and that they both are efficacious. 
 
  
Accordingly, we expect that copanlisib, which is a pan class-I PI3K inhibitor with 
predominant activity against the alpha and delta isoforms, will be effective in sensitizing to 
the PARPi olaparib, similar to BYL719 and BKM120. Furthermore, copanlisib is well 
tolerated and has received FDA approval in follicular lymphoma (Markham, 2017) and, 
unlike BKM120 (buparlisib), copanlisib has not been associated with CNS toxicity 
(Dreyling, 2017, Markham, 2017, Patnaik, 2016).  
 
2.7 
Randomized Phase II Trial 
This is a randomized phase 2 trial comparing the combination of copanlisib and olaparib to 
standard non-platinum chemotherapy in patients with recurrent platinum resistant ovarian, 
fallopian or primary peritoneal cancer which has progressed through prior PARPi therapy.  
 
Patients will be randomized 1:1 to olaparib/copanlisib or standard chemotherapy in an open-
label manner. The planned standard of care chemotherapy regimen will be declared by the 
investigator prior to randomization. Standard non-platinum regimens will include pegylated 

 
 
 
NRG-GY029 
- 23 -  
Version Date:  December 28, 2022 
 
liposomal doxorubicin (PLD or Doxil), weekly paclitaxel or topotecan (weekly regimen). 
Use of chemotherapy in the standard arm will not be allowed if these drugs have been used 
previously in the recurrent setting (e.g., if a patient has already received PLD (alone or in 
combination) in the recurrent setting, PLD cannot be used in the standard arm). Treatments 
will take place in an outpatient setting. Due to the differing schedules and routes of 
administration, patients will not be blinded. Two stratification factors will be included: i) 
BRCA 1/2 status (Known or suspected deleterious germline OR somatic BRCA variant 
VERSUS non-deleterious/benign germline and somatic BRCA AND unknown somatic 
BRCA status) and ii) timing of prior PARPi therapy (PARPi as last line of therapy prior to 
initiation of this trial VERSUS other intervening therapy prior to initiation of this trial).  
 
Tumor reassessment will be time-based, and not cycle-based, with CT scan or MRI 
performed once every 8weeks (+/- 7 days) for the first year and every 12 weeks (+/- 7 days) 
after the first year, and at any other time if clinically indicated based on symptoms or 
physical signs suggestive of progressive disease. Imaging assessments can be discontinued 
if disease progression is confirmed according to RECIST 1.1. However, if a patient 
discontinues study treatment for any reason other than progression, imaging studies should 
continue on the protocol-outlined schedule until progression (or initiation of subsequent 
therapy). After 1 years of protocol therapy or follow-up (measured from approximately 
cycle 1, day 1), imaging studies will be conducted every 12 weeks. 
 
Based on the results of the phase I trial of copanlisib/olaparib/durvalumab (NCI 10217; 
NCT03842228), dosing of experimental arm will be: 45 mg Copanlisib IV days 1, 8, 15 and 
300 mg Olaparib PO BID of a 28-day cycle. An initial safety lead-in will be performed as 
described below. 
 
Specifically, in the Phase I NCI 10217 dose escalation study, in dose level 1 (DL1, 
copanlisib 45mg IV, Days 1,8,15 + olaparib 200mg po BID) 3 patients (all evaluable) were 
enrolled and no DLT was observed. However, rash occurred in all 3 patients, so 3 additional 
patients (all evaluable) were enrolled in the same DL1 (copanlisib 45mg IV, Days 1,8,15 + 
olaparib 200mg po BID) with 25 mg Benadryl IV prior to every copanlisib infusion initiated 
at C1D1. One DLT (LFT elevation) was observed, and rash was observed in 2 of these 3 
patients. Therefore, 3 additional patients (all evaluable) were enrolled in the same DL1 with 
the addition of 4 mg dexamethasone prior to every copanlisib infusion initiated at C1D1 to 
mitigate/prevent development of rash. No DLTs were observed and only one patient 
developed G1 rash. This prompted use of 25mg of diphenhydramine and 4 mg 
dexamethasone prior to every copanlisib infusion for all subsequent patients. Overall, 9 
patients (all evaluable) were enrolled in DL1 (copanlisib 45mg IV, Days 1,8,15 + olaparib 
200mg po BID) and only 1 DLT was observed (LFT elevation) prompting escalation to the 
next dose level (DL2). 
 
DL2 (copanlisib 45mg IV, Days 1,8,15 + olaparib 300mg po BID) was also well tolerated 
without DLTs (0 DLTs out of three evaluable patients), prompting escalation to DL3 
(copanlisib 60mg IV, Days 1,8,15 + olaparib 300mg po BID). Of the 6 patients enrolled in 
DL3, 2 patients were taken off study because of toxicities prior to restaging (one patient was 
an official DLT while the other was not an official DLT because he stopped olaparib on his 

 
 
 
NRG-GY029 
- 24 -  
Version Date:  December 28, 2022 
 
own and was therefore deemed unevaluable for DLT). Furthermore, a third patient in DL3 
had G3 platelet decrease and withdrew consent after 2.5 weeks on trial to pursue other 
treatment. Therefore, based on the toxicity observed in DL3, the recommended phase 2 dose 
used in the current study is the DL2 regimen of copanlisib 45mg IV, Days 1,8,15 + olaparib 
300mg po BID.  
 
This trial addresses a population of patients with OC that is only expected to grow with the 
recent FDA approvals allowing wider use of PARP inhibitors in upfront and recurrent 
setting regardless of BRCA mutation and HR status.  Patients with tumors which have 
progressed while on PARP inhibitor therapy and have become platinum resistant represent a 
great unmet need and face important therapeutic challenges: (1) subsequent chemotherapies 
do not address the restoration of homologous recombination the most prevalent mechanism 
of PARPi resistance; (2) there are no currently approved combination therapies that 
incorporate rechallenge with a PARP after progression through prior PARP, potentially 
prematurely truncating the therapeutic benefit of a PARP; and (3) there are very few trials 
that allow prior PARP exposure and even fewer allowing progression while on prior PARP 
inhibitor therapy. 
 
Demonstration of clinical efficacy with copanlisib/olaparib in patients with platinum 
resistant tumors who have progressed through prior PARPi would have significant 
implications on future practice.  This would confirm the biologic rationale and mechanism 
for restoring PARP inhibitor sensitivity and could inform on future therapeutic 
combinations.   
 
2.8 
Rationale for Copanlisib/Olaparib Starting Dose Regimen (02-JUN-2022) 
 
In this hypothesis generating Phase 2 study, the rationale and additional considerations for 
the starting dosing regimen of copanlisib (45 mg on Day 1, 8 and 15 of a 28-day cycle) and 
olaparib (300 mg QD) include the following: 
 
a) The starting dosing regimen of copanlisib (45 mg on Day 1, 8 and 15 of a 28-day 
cycle) and olaparib (300 mg QD) was based on the MTD identified in the dose 
escalation part of Study NCI 10217 (NCT03842228). Given that NRG-GY029 
evaluates an extremely challenging patient population (patients with platinum 
resistant ovarian cancer who have progressed through prior PARP inhibitor (PARPi) 
therapy) with no effective salvage treatment options, we employ the maximum 
tolerated dose of copanlisib (45 mg on Days 1, 8 and 15 of a 28-day cycle) plus 
olaparib (300 mg po BID) as determined in the NCI 10217 study. This strategy will 
afford these patients the maximum tolerated doses of olaparib/copanlisib that were 
deemed safe. 
 
b) In NCI 10217, the starting dosing regimen of copanlisib 45mg IV, Days 1,8,15 + 
olaparib 300 mg po BID was well tolerated without DLTs (0 DLTs out of three 
evaluable patients). Nonetheless, in NRG-GY029, the safety and tolerability of this 
dosing regimen of copanlisib/olaparib will be further evaluated in a safety run-in 

 
 
 
NRG-GY029 
- 25 -  
Version Date:  December 28, 2022 
 
whereby at least 10 patients will be assessed in this dose as described in our protocol 
(section 15.4.1). 
 
c) If the copanlisib 45mg IV, Days 1,8,15 + olaparib 300mg po BID is not tolerated in 
the safety run-in, then an alternative dosing regimen of copanlisib (45mg on Days 1, 
8 and 15 of a 28-day cycle) plus olaparib (300 mg po BID) will be evaluated for 
safety and tolerability, again in at least 10 patients.  
 
d) The starting dosing regimen of copanlisib (45 mg on Day 1, 8 and 15 of a 28-day 
cycle) and olaparib (300 mg QD) was not only well tolerated but also showed 
evidence of anti-tumor activity among patients who had previously received a 
PARP-inhibitor. Specifically, one patient with ovarian cancer who had previously 
received niraparib exhibited shrinkage of her tumor by 17% compared to baseline as 
well as experienced a drop in her CA125 by more than 50% (from 167.6 to a nadir of 
55.4). Of note, this patient stayed on study for 8 cycles, i.e., more than 6 months. 
This is highly relevant to the patient population of NRG-GY029 which includes 
patients who have progressed through prior PARPi therapy.  
 
e) Given that all patients enrolled in NRG-GY029 will have progressed through prior 
PARPi therapy, our intention is to rechallenge these patients with the highest 
tolerable dose of PARPi therapy, in this case olaparib 300mg BID that was the MTD 
in NCI 10217.  
 
f)   The preclinical rationale behind use of combined PARP/PI3K blockade is based on 
the fact that inhibition of PI3K pathway leads to abrogation of homologous 
recombination repair (HRR) and sensitization to PARPi therapy. Based on PK and 
PD data from copanlisib monotherapy, the on-target inhibition of the PI3K pathway 
by copanlisib occurs in a dose-dependent manner. Specifically, treatment with 
copanlisib reduced the PD marker pAKT in surrogate tissue platelet-rich plasma 
(PRP), with a median decrease up to 73.75% at the 0.4 mg/kg dose level and up to 
79.60% at the 0.8 mg/kg dose level compared with baseline. Furthermore, treatment 
with copanlisib was associated with transient modulation of blood glucose with 
corresponding changes in C-peptide and insulin in a dose-dependent manner (0.8 
mg/kg > 0.4 mg/kg). In addition, exposure-PD biomarker relationship studies were 
evaluated in Study 16790 using individual Cmax and average plasma concentration 
(Cavg) estimates derived from the population PK model for the same weekly 
copanlisib infusion during which the maximal biomarker change from baseline was 
observed. A significant relationship between copanlisib exposure (Cmax or Cavg) 
and glucose, insulin, C-peptide, and SUVmax was observed. There was also a 
positive correlation between copanlisib exposure Cmax and tumor pAKT S473 
inhibition (p=0.05). Based on all these, we selected the maximum tolerated dose of 
copanlisib (in this case 45mg on Days 1, 8 and 15) identified in 10217 in order to 
achieve the maximum possible inhibition of PI3K pathway to abrogate HR and 
resensitize to PARPi therapy. 
 

 
 
 
NRG-GY029 
- 26 -  
Version Date:  December 28, 2022 
 
As stated above, a safety lead-in is incorporated in NRG-GY029 (Section 15.4.1) with two 
dose levels evaluated: i) copanlisib (45 mg on Days 1, 8 and 15 of a 28-day cycle) plus 
olaparib (300 mg po BID) and ii) copanlisib (45 mg on Days 1 and 15 of a 28-day cycle) 
plus olaparib (300 mg po BID). If both dosing regimens are not tolerated in the incorporated 
safety lead-in, alternative copanlisib/olaparib dosing regimens may be pursued depending 
on toxicities, PK and PD data generated from NCI 10217 and other trials.(28-DEC-2022) 
 
3. 
ELIGIBILITY AND INELIGIBILITY CRITERIA 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center (see protocol cover page).  
 
3.1 
Eligibility Criteria 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
 
3.1.1 Patients with recurrent ovarian cancer. Ovarian cancer = fallopian tube cancer, ovarian 
cancer, primary peritoneal cancer 
  
The following histology types are eligible*: 
1) High grade serous 
2) Endometrioid, grade 3 
3) Any histology with BRCA1 and/or BRCA2 deleterious mutation (germline or 
somatic) 
 
*Histologic confirmation of the original primary tumor is required via the pathology report 
(upload of report required) 
 
Confirmation of BRCA1 and BRCA2 germline status is required for all entered 
patients (upload of report[s] required). 
 
Tumor/somatic genomic testing can be provided or entered as not done (upload of report[s] 
required). 
 
HRD testing can be provided or entered as not done (upload of report[s] required). 
 
Genetic/genomic testing results and HRD testing results, initially entered as not done, 
should be uploaded if they become available anytime during conduct of the study. 
 
3.1.2 Participants must have progressed by imaging while receiving PARP inhibitor therapy  
(irrespective of whether PARP inhibitor therapy was given as maintenance therapy or as 
primary recurrence therapy); rising CA125 only is not considered as evidence of 
progression. 
 
3.1.3 Platinum-resistant disease, defined as progression within < 6 months from completion of 

 
 
 
NRG-GY029 
- 27 -  
Version Date:  December 28, 2022 
 
platinum-based therapy, and inclusive of platinum refractory disease. The date should be 
calculated from the last administered dose of platinum therapy. 
 
3.1.4 Unlimited lines of cytotoxic therapy allowed in the platinum-sensitive setting; ≤ 2 lines of 
cytotoxic therapy allowed in the platinum-resistant setting. 
• Hormonal therapy (e.g., tamoxifen, aromatase inhibitors) will not count as a 
previous line of therapy. 
 
3.1.5 Prior use of bevacizumab in the upfront or recurrent setting is required. 
 
3.1.6 Participants must have evaluable disease – defined as RECIST 1.1 measurable disease OR 
non-measurable disease (defined as solid and/or cystic abnormalities on radiographic 
imaging that do not meet RECIST 1.1 definitions for target lesions OR ascites and/or pleural 
effusion that has been pathologically demonstrated to be disease-related in the setting of a 
CA125 > 2x ULN). . 
 
3.1.7 Age ≥ 18 
 
3.1.8 ECOG Performance Status of 0 or 1 or 2 (See Appendix II) 
 
3.1.9 Adequate hematologic function within 14 days prior to registration defined as follows: 
• Absolute Neutrophil Count (ANC) ≥ 1,500/mcl 
• Hemoglobin > 10 g/dL 
• Platelets ≥ 100,000/mcL 
 
3.1.10 Adequate renal function within 14 days prior to registration defined as follows: 
• Creatine clearance (CrCL) >=51 mL/min (estimated using Cockcroft-Gault equation) 
 
3.1.11 Adequate hepatic function within 14 days prior to registration defined as follows: 
• Total serum bilirubin level ≤ 1.5 x ULN (patients with known Gilbert’s disease who 
have bilirubin level ≤ 3 x ULN may be enrolled) 
• AST and ALT ≤ 3 x ULN  
 
3.1.12 Lipase ≤1.5 x ULN within 14 days of registration 
 
3.1.13 International normalized ration (INR) ≤1.5 x ULN (or an in-range INR, usually between 2 
and 3, if a patient is on a stable dose of therapeutic warfarin) and a PTT ≤ 1.5 times the 
upper limit of normal within 14 days of registration 
 
3.1.14 Patients with known history or current symptoms of cardiac disease, or history of treatment 
with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the 
New York Heart Association Functional Classification.  To be eligible for this trial, patients 
should be class 2B or better. (See Appendix III) 
 
3.1.15  Patients who are therapeutically treated with an agent such as warfarin or heparin will be 
allowed to participate provided that their medication dose and INR/PTT is stable.  Oral 

 
 
 
NRG-GY029 
- 28 -  
Version Date:  December 28, 2022 
 
anticoagulants are allowed provided there are no interactions as per Section 5.2. 
 
3.1.16  The effects of copanlisib and olaparib on the developing human fetus are unknown.  For this 
reason and because maternal toxicity, developmental toxicity and teratogenic effects have 
been observed in nonclinical studies and PI3K inhibitors agents as well as other therapeutic 
agents used in this trial are known to be teratogenic, women of child-bearing potential must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation, and for 1 month 
after the last dose of copanlisib and/or olaparib.  Should a woman become pregnant or 
suspect she is pregnant while she is participating in this study, she should inform her 
treating physician immediately. 
 
3.1.17 Patients with a prior or concurrent malignancy whose natural history or treatment does not 
have the potential to interfere with the safety or efficacy assessment of the investigational 
regimen are eligible for this trial. 
 
3.1.18 HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 
6 months of registration are eligible for this trial. 
 
3.1.19 Patients with evidence of chronic hepatitis B virus (HBV) infection must have an 
undetectable HBV viral load on suppressive therapy, if indicated. 
 
 
Patients with a history of hepatitis C virus (HCV) infection must have been treated and 
cured.  For patients with HCV infection who are currently on treatment, they are eligible if 
they have an undetectable HCV viral load. 
 
3.1.20 Patients with treated brain metastases are eligible if follow-up brain imaging after CNS-
directed therapy shows no evidence of progression and must be off steroids and stable at 
least one month. 
 
3.1.21 The patient or a legally authorized representative must provide study-specific informed 
consent prior to study entry and, for patients treated in the U.S., authorization permitting 
release of personal health information. 
 
3.2 
Ineligibility Criteria 
 
Patients with any of the following conditions are NOT eligible for this study. 
 
3.2.1 Prior therapy: 
• No chemotherapy or radiotherapy within 4 weeks of registration.  
• No hormonal therapy within 2 weeks of registration. Patients receiving raloxifene for 
bone health as per FDA indication may remain on raloxifene absent other drug 
interactions. 
• No investigational agents within 4 weeks of registration. 
• No prior PI3K-AKT-mTOR pathway inhibitor therapy. 
 
3.2.2 History of allergic reactions attributed to compounds of similar chemical or biologic 

 
 
 
NRG-GY029 
- 29 -  
Version Date:  December 28, 2022 
 
composition to olaparib, copanlisib, or other agents used in this study.  
 
3.2.3 Copanlisib and olaparib are primarily metabolized by CYP3A4. Therefore, the concomitant 
use of strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, 
ritonavir, indinavir, nelfinavir and saquinavir), and strong inducers of CYP3A4 (e.g., 
rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort) are not permitted from 
14 days prior to registration until the end of the study. (See Appendix V for a specific list of 
medications prohibited while on copanlisib treatment).  
 
3.2.4 Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent 
is not permitted while on study.  Patients may be using topical or inhaled corticosteroids.  
 
3.2.5 Use of concomitant herbal medications/preparations (except for vitamins), 
alternative/complimentary medications, immunosuppressive therapy, or other prohibited 
medications per Section 5.2.  
 
3.2.6 Patients with uncontrolled Type I or II diabetes mellitus; uncontrolled diabetes is defined as  
HbAlc >8.5%. 
 
3.2.7 Patients with arterial or venous thrombotic or embolic events such as cerebrovascular 
accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary 
embolism within 3 months before registration. 
 
3.2.8 Gastrointestinal conditions that would preclude consumption (swallowing), retention, and/or 
absorption of oral medications. 
 
3.2.9 Patients with drainage gastrostomy tube are not allowed.  
 
3.2.10 Patients with dependency on IV hydration or TPN are not allowed. 
 
3.2.11 Patients with uncontrolled intercurrent illness, including but not limited to: 
• Persistent Grade ≥2 adverse events due to prior anti-cancer therapy with the 
exception of alopecia, hypothyroidism requiring medication, vitiligo, and the 
laboratory values defined in the inclusion criteria. 
• Known psychiatric illness/social situations that would limit compliance with study 
requirements. 
• History of or current autoimmune disease 
• Non-healing wound, ulcer, or bone fracture 
• Active, clinically serious infections >Grade 2 (CTCAE v5.0) 
 
3.2.12 Women who are pregnant or unwilling to discontinue nursing. 
 
3.2.13 Patients who have a history of non-infectious pneumonitis/ILD that required steroids, or 
current non-infectious pneumonitis/ILD. 
 
 

 
 
 
NRG-GY029 
- 30 -  
Version Date:  December 28, 2022 
 
NIH Participant Population Inclusion Policy  
NIH policy requires that participants regardless of gender identity and members of minority 
groups and their subpopulations be included in all NIH-supported biomedical and 
behavioral research projects involving NIH-defined clinical research unless a clear and 
compelling rationale and justification establishes to the satisfaction of the funding Institute 
& Center (IC) Director that inclusion is inappropriate with respect to the health of the 
subjects or the purpose of the research.  Exclusion under other circumstances must be 
designated by the Director, NIH, upon the recommendation of an IC Director based on a 
compelling rationale and justification.  Cost is not an acceptable reason for exclusion except 
when the study would duplicate data from other sources.  Women of childbearing potential 
should not be routinely excluded from participation in clinical research.  Please see 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
NRG-GY029 
- 31 -  
Version Date:  December 28, 2022 
 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 
 
4.1 
PRE-TREATMENT ASSESSMENTS (28-DEC-2022) 
 
The following studies done for registration can be used for pretreatment assessment also: 
CA-125, INR/PTT, Radiographic Tumor Measurement, History and Physical, Concomitant 
Medications, Vital Signs, Height, Weight, Performance Status, Toxicity Assessment, 
HgbA1C, Lipase and Electrocardiogram.  
 
Assessments 
 
 
Prior to Registration 
(calendar days) 
Prior to Treatment 
(calendar days) 
(Cycle 1, Day 1)* 
History and Physical 
≤ 14 days 
≤ 14 days 
Concomitant Medications 
≤ 14 days 
≤ 14 days 
Vital Signs (blood 
pressure, heart rate, 
temperature, and oxygen 
saturation)g 
≤ 14 days 
X 
Heighta 
X 
- 
Weight 
≤ 14 days 
≤ 14 days 
Performance Status 
≤ 14 days 
≤ 14 days 
Toxicity Assessment 
≤ 14 days 
≤ 14 days 
CBC/Differential/Platelets 
≤ 14 days 
≤ 14 days 
Chemistries (BUN, 
creatinine, sodium, 
potassium, chloride, CO2, 
calcium, glucose, total 
bilirubin, total protein, 
albumin, alkaline 
phosphatase, AST, ALT)h 
≤ 14 days 
≤ 14 days 
CA-125 
≤ 28 days 
≤ 28 days 
INR/PTTb 
≤ 28 days 
≤ 28 days 
HgbA1C c 
≤ 28 days 
≤ 28 days 
Lipase 
≤ 28 days 
≤ 28 days 
Electrocardiogram (ECG) 
≤ 3 months 
≤ 3 months  
MUGA or 
echocardiograme 
≤ 28 days 
≤ 28 days 
Pregnancy test (for women 
of childbearing potential) 
Urine or serum testing is 
permittedf 
≤ 14 days 
≤ 14 days 
Radiographic Tumor 
Measurementd 
≤ 28 days 
≤ 28 days 
*Prior to Registration Assessments should be used for Cycle 1, Day,1 as long as they are within the stated Cycle 1, Day 1 window. 
a Height measurement is performed on adult participants during admission or at initial visit to an outpatient 
facility per clinical practice. As height measurement on adults is not routinely performed during follow up 

 
 
 
NRG-GY029 
- 32 -  
Version Date:  December 28, 2022 
 
visits, the height measurement previously recorded for adult participants may be used for calculating drug 
dosages or body surface area as applicable and can be used for baseline and follow up visits data capture. 
b Patients who are taking warfarin may participate in this trial. It is recommended that the INR be monitored     
carefully at least once per week for the first month, then monthly if the INR is stable.  
c For patients with Type I or Type II diabetes. 
dRadiographic tumor measurements should be obtained via imaging of the chest (CT chest [preferred] or 
CXR), and abdomen and pelvis (CT or MRI) to establish the location and extent of disease. See RECIST 1.1 
for allowable imaging modalities used to assess disease at baseline (and subsequent assessments). Contrast 
CT is the preferred modality. 
e MUGA or echocardiogram to be performed only for patients planned to receive PLD (as per Section 5.1 the  
  planned standard of care chemotherapy regimen must be declared by the investigator prior to randomization) 
fPregnancy test need only be done once for WOCBP within 14 days prior to registration and C1D1 
g Patients randomized to Arm 2 will receive additional blood pressure monitoring before, during, and after 
copanlisib infusion on C1D1. See Section 6.2.5. 
hPatients randomized to Arm 2 will receive additional glucose monitoring before, during, and after copanlisib   
infusion on C1D1. See Section 5.1.1.  
 
4.2 
ASSESSMENTS DURING TREATMENT 
 
ARM 1 (Non-platinum single agent chemotherapy) (28-DEC-2022): 
 
Assessments 
Prior to day 1 of 
each cycle of 
therapy (after 
Cycle 1 Day 1) 
 
Weekly Topotecan 
Days 8 and 15 (if 
applicable) 
Timed (Treatment 
Cycle Independent) 
History and Physical 
≤ 3 days  
 
 
Concomitant Medications 
≤ 3 days 
 
 
Toxicity Assessment 
≤ 3 days 
 
 
Vital Signs, weight 
required 
≤ 3 days 
 
 
Performance Status 
≤ 3 days 
 
 
CBC/Differential/Platelets 
≤ 3 days 
≤ 1 days 
 
Chemistries1 
≤ 3 days 
 
 
CA125 
≤ 3 days 
 
 
Radiographic Tumor 
Measurement 
 
 
See footnote2 
MUGA or echocardiogram 
 
 
See footnote3 
1 Serum chemistry includes sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, total protein, albumin, 
calcium, AST, ALT, alkaline phosphatase, total bilirubin. 
2 Tumor reassessment will be time-based, and not cycle-based, with CT scan or MRI performed once every 8 
weeks (+/- 7 days) from cycle 1 day 1, for the first 12 months, then every 12 weeks (+/- 7 days) thereafter, and at 
any other time if clinically indicated based on symptoms or physical signs suggestive of progressive disease. Imaging 
assessments can be discontinued if disease progression is confirmed according to RECIST 1.1. However, if a patient 
discontinues study treatment for any reason other than progression, imaging studies should continue every 8 weeks 
(+/- 7 days) for the firt 12 months, then every 12 weeks (+/- 7 days) thereafter until progression (or initiation of 
subsequent therapy). Utilize same imaging modality of abdomen and pelvis +/- chest (for patients with evidence of 
measurable disease on baseline chest imaging; then subsequent radiographic tumor assessments must also include 
chest imaging). A tool is provided to calculate dates of re-imaging. Utilize same imaging modality of abdomen, 
pelvis and chest (see footnote under Pre-Treatment Assessments) as for pre-cycle 1 baseline assessment. PET CT 

 
 
 
NRG-GY029 
- 33 -  
Version Date:  December 28, 2022 
 
should not be used.  
3 For patients receiving PLD, when the cumulative dose of PLD exceeds 550 mg/m2, it is recommended that repeat  
echocardiogram or MUGA scan be performed every other cycle or according to institutional standards. 
 
 
ARM 2 (Copanlisib and Olaparib)(28-DEC-2022) 
 
Assessments 
Prior to 
Each Cycle, 
Day 1 (after 
Cycle 1, Day 
1) 
Every week for 
first 8 weeks of 
study therapy  
(in person, 
telemedicine, or 
phone) 
Timed 
(Treatment 
Cycle 
Independent) 
History and Physical 
≤ 3 days 
 
 
Concomitant Medications 
≤ 3 days 
 
 
Toxicity Assessment 
≤ 3 day 
X 
 
Vital Signs, weight 
required 
≤ 3 day 
 
 
Performance Status 
≤ 3 days 
 
 
CBC/Differential/Platelets ≤ 3 days 
 
 
Chemistries1 
≤ 3 days 
 
 
CA125 
≤ 3 days 
 
 
Radiographic Tumor 
Measurement2 
 
 
X 
Review of olaparib pill 
diary to assess treatment 
compliance 
X 
 
 
1 Serum chemistry includes sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, total    
  protein, albumin, calcium, AST, ALT, alkaline phosphatase, total bilirubin.  
2Tumor reassessment will be time-based, and not cycle-based, with CT scan or MRI performed once  
     every 8 weeks (+/- 7 days) from cycle 1 Day 1, for the first 12 months, then every 12 weeks (+/- 7 days) 
thereafter, and at any other time if clinically indicated based on symptoms or physical signs suggestive of 
progressive disease. Imaging assessments can be discontinued if disease progression is confirmed 
according to RECIST 1.1. However, if a patient discontinues study treatment for any reason other than 
progression, imaging studies should continue every 8 weeks (+/- 7 days), for the first 12 months, then every 
12 weeks (+/- 7 days) thereafter until progression (or initiation of subsequent therapy). Utilize same 
imaging modality of abdomen and pelvis +/- chest (for patients with evidence of measurable disease on 
baseline chest imaging; then subsequent radiographic tumor assessments must also include chest imaging). 
A tool is provided to calculate dates of re-imaging. Utilize same imaging modality of abdomen, pelvis, and 
chest (see footnote under Pre-Treatment Assessments) as for pre-cycle 1 baseline assessment. PET CT 
should not be used.  
 
Patients randomized to Arm 2 will receive additional blood pressure monitoring (see 
Section 6.2.5) and glucose monitoring (see Section 5.1.1) before each copanlisib 
infusion after C1D1.  
 
Please note: Glucose measurements on C1D1, and subsequent infusion days, may be 
done by laboratory analysis or in capillary blood. (28-DEC-2022) 
    

 
 
 
NRG-GY029 
- 34 -  
Version Date:  December 28, 2022 
 
 
 
 
 
4.3 
ASSESSMENTS IN FOLLOW UP 
 
Assessments 
From end of treatment 
Vital Status 
1 
Toxicity Assessment 
2 
Radiographic tumor measurement 
3 
 
1 
Every 3 months for 2 years and then every 6 months for 3 years.  Follow-up Forms are collected for the 5-
year follow-up period or until study termination, whichever occurs first. 
2 
Patients who discontinue treatment for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event.  For reporting of delayed toxicity, see Section 7. 
3 
In the case that protocol-directed therapy is discontinued for reasons other than disease progression, 
follow radiographic tumor measurement schedule as defined under Assessments During Treatment (until 
disease progression documented by RECIST 1.1 or until patient initiates a subsequent cancer therapy). 
Patients who discontinue treatment, electively (e.g. withdrawal of consent for treatment) or not, should 
remain on study until primary endpoint or initiation of other anti-neoplastic intervention.  The study team 
should clarify with the patient if withdrawal of consent is for treatment or for treatment and follow up. 
 
Definition of Disease Assessments 
Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
For this study, a rise in CA-125 alone is not sufficient to declare progression, and 
progression events should be determined by radiographic evidence of progression. 
 
5. 
TREATMENT PLAN/REGIMEN DESCRIPTION 
 
Each cohort will undergo 1:1 randomization to one of two treatment arms, with stratification 
as noted. 
 
Protocol treatment should begin within 7 days of registration. 
 
5.1 
Treatment 
 
Arm 1 (Standard of Care/Control Arm): 
 
Non-platinum chemotherapy per investigator’s discretion.  Standard non-platinum regimens 
will include pegylated liposomal doxorubicin PLD, weekly paclitaxel or topotecan (weekly 
regimen).  
 
Patients randomized to the non-platinum-based chemotherapy arm may be treated with one 

 
 
 
NRG-GY029 
- 35 -  
Version Date:  December 28, 2022 
 
of the three regimens specified in this section per investigator discretion (the planned 
regimen must be specified prior to randomization). The number of cycles of therapy should 
be administered as clinically appropriate. 
 
➢ Regimen 1: Paclitaxel 80 mg/m2 intravenously (IV) over approximately 60 minutes 
on day(s) 1, 8, and 15 every 28 days until disease progression or adverse events 
prohibit further therapy. (28-DEC-2022) 
 
➢ Regimen 2: Pegylated liposomal doxorubicin (PLD) 40 mg/m2 intravenously over 
approximately 60 minutes on day 1 every 28 days until disease progression or 
adverse events prohibit further therapy. 
 
➢ Regimen 3: Topotecan 4 mg/m2 IV over approximately 30 minutes on days 1, 8, and 
15 every 28 days or 1.25 mg/m2 IV over approximately 30 minutes on days 1 to 5 
every 21 days until disease until disease progression or adverse events prohibit 
further therapy. (28-DEC-2022) 
 
No modification of the assigned regimens, such as addition of bevacizumab or other 
agents is allowed.  
 
Use of chemotherapy agents in the standard arm will not be allowed if these drugs have 
been used previously in the recurrent setting (e.g., if a patient has already received PLD 
(alone or in combination) in the recurrent setting, PLD cannot be used in the standard arm).  
 
The planned standard of care chemotherapy regimen must be declared by the 
investigator prior to randomization. 
 
Arm 2 (Experimental Arm): 
Combination therapy with copanlisib and olaparib. 
 
Treatment will be administered on an outpatient basis. No investigational or commercial 
agents or therapies other than olaparib and copanlisib may be administered with the intent to 
treat the patient's malignancy. 
 
Copanlisib is given as an intravenous (IV) infusion and olaparib is given as an oral (PO) 
pill.   
 
Patients on Arm 2 will need to keep a medication diary. See Appendix IX. 
 
See Appendix V for general treatment guidelines. 
 
5.1.1 Copanlisib 
 
Based on NCI 10217, copanlisib will be administered at a dose of 45 mg over 1 hour as an 
IV infusion weekly for 3 weeks (Days 1, 8, and 15) every 4 weeks (Days 1 ,8, and 15 of a 
28-day cycle). A copanlisib dose reduction to 45 mg on Days 1 and 15 of a 28-day cycle 
will be allowed for toxicities (see Section 6.2). 

 
 
 
NRG-GY029 
- 36 -  
Version Date:  December 28, 2022 
 
 
Administer copanlisib as an IV infusion over one hour.  After administration, flush the line 
with 0.9 % sodium chloride to ensure complete dose is given.  No IV glucose preparations 
should be administered on the days of infusion.   
 
Use of antiemetics should not be needed since each patient will receive 25 mg 
diphenhydramine and 4 mg dexamethasone to prevent copanlisib-induced rash. Should a 
patient require antiemetics after the first infusion, use of additional corticosteroids is not 
allowed. Prior to every copanlisib infusion, premedication will be administered that includes 
25 mg Diphenhydramine IV (or other equivalent H1 receptor antagonist) and 4 mg 
dexamethasone (orally or intravenously). Copanlisib will be administered as an IV infusion 
over one hour. After administration, line will be flushed with 0.9 % sodium chloride to 
ensure complete dose is given. No IV glucose preparations should be administered on the 
days of infusion. 
 
Dexamethasone will be used as premedication in this protocol to mitigate/prevent 
development of rash. Specifically, in NCI 10217, in the first 6 patients treated in DL1 
(copanlisib 45mg IV Days 1, 8, 15 / olaparib 200 mg BID) without dexamethasone 
premedication, 5 of 6 patients developed G2 or G3 rash. When the 4 mg dexamethasone was 
added prior to each copanlisib infusion, the incidence of rash decreased (only 2 of 6 patients 
had G2 or G3 rash and in both patients, the rash did not reappear after resolution).  
 
Importantly, the 4mg dose of dexamethasone prior to each copanlisib infusion did not 
exacerbate copanlisib-associated hyperglycemia; only 1 out of 12 patients premedicated 
with 4 mg dexamethasone developed hyperglycemia (this patient had G1 hyperglycemia and 
was treated in DL3 with the 60 mg dose of copanlisib which is above the DL2 (45 mg 
copanlisib) which will be used in this study). 
 
NOTE: On days that both copanlisib and olaparib are given, olaparib should be given 30 
minutes prior to copanlisib infusion. 
 
Recommendations on meal timing on copanlisib infusion days 
Because of an inhibitory effect on the PI3Kα-isoform, which is implicated in insulin 
metabolism, copanlisib infusions could be associated with temporarily increase in blood 
glucose.  Consuming a meal in close proximity to copanlisib infusion may exacerbate a 
glucose level increase.  On infusion days, a low carbohydrate diet is recommended.  The 
timing and content of meal intake, and additional glucose testing (if clinically indicated), 
should be managed and monitored by the investigators based on glucose response patterns 
during prior treatment days.   
 
NOTE: If patient needs to take a meal, then glucose testing should be taken prior to meal 
intake.  All glucose measurements, oral glucose lowering medication and/or insulin 
administration, if applicable, pre-dose fasting/non-fasting status, and meal intake timing on 
infusion days will be collected as part of the clinical source documentation.  
 
NOTE: Caloric intake and timing recommendations for diabetic patients who require 

 
 
 
NRG-GY029 
- 37 -  
Version Date:  December 28, 2022 
 
insulin treatment prior to the infusion at any cycle visit should be managed by the 
investigator based on consultation with treating physician or diabetes/endocrinologist 
physician. 
 
 
 
Pre-dose glucose levels (prior to copanlisib infusion) should be: 
 
Period 
     Pre-dose glucose 
levels  
(first glucose 
measurement) 
Day 1 of 
cycle 1 
<160 mg/dL (fasting*) 
 < 200 mg/dL (non-
fasting**)  
Subsequent infusions after Cycle 
1 Day 1 
 <160 mg/dL (fasting*) 
 < 200 mg/dL (non-
fasting**)  
*Fasting refers to a ≥ 8 h fast. 
**Non-fasting status includes any caloric intake such as meals and also 
juice, snacks, and other caloric intake not consistently called a meal. 
 
 
Glucose monitoring is required before and after the C1D1 copanlisib infusion and before 
each subsequent copanlisib infusion.  The glucose testing is scheduled as follows:   
 
On Cycle 1 Day 1:  Glucose test is performed before starting copanlisib IV infusion at time 
0 hour (pre-dose), at the end of the infusion (1 hour after starting infusion), 1 hour after 
completing the infusion, and 2 hours after completing the infusion (a window of ± 10 
minutes is allowed except for pre-dose measurement).   
 
All subsequent visits:  Glucose test is performed before starting copanlisib IV infusion at 
time 0 hour.  Additional measurements are to be performed at the clinic as clinically 
indicated at the investigator’s discretion.  Review blood glucose measurements/meal 
timing/insulin administration/oral glucose lowering medication, if applicable. 
 
5.1.2 Olaparib 
Patients will be administered olaparib BID every day (Days 1-28 of a 28-day cycle) at a 
starting dose of 300 mg PO BID. 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. Olaparib tablets can be 
taken with or without food. Consumption of grapefruit, grapefruit juice, or Seville oranges 
while on olaparib therapy is prohibited. 
 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted. Should any patient enrolled on 

 
 
 
NRG-GY029 
- 38 -  
Version Date:  December 28, 2022 
 
the study miss a scheduled dose for whatever reason (e.g., as a result 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. 
 
NOTE: On days that both copanlisib and olaparib are given, olaparib should be given 30 
minutes prior to copanlisib infusion. 
 
Refer to Section 6.3 for guidance on dose interruption or dose reduction of olaparib. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
5.2.1 Copanlisib 
Because there is a potential for interaction of copanlisib 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. The PI should be alerted if the patient 
is taking any agent known to affect or with the potential for drug interactions. The known 
potential targets for drug interaction are CYP3A4 inducers or inhibitors, as well as drugs 
modulating glucuronidation, P-gp, BCRP, and MATE2K function.  
 
Substrates of P-gp and/or BCRP with narrow therapeutic index should be used with caution 
and patients monitored for any sign of toxicity. Furthermore, sensitive substrates of the renal 
drug transporter MATE2K (e.g. metformin) need to be used with caution. Metformin should 
be interrupted for 48 hours after receiving iodinated contrast media. Please see prescribing 
information for further information. 
 
Patients taking medications with a narrow therapeutic index should be proactively 
monitored if these medications cannot be avoided. These medications may include 
quinidine, cyclosporine, and digoxin. 
 
Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent 
is not permitted while on study.  As indicated in Section 5.1.1, dexamethasone 4 mg will be 
permitted as premedication to prevent development of skin rash. Patients may be using 
topical or inhaled corticosteroids. The use of corticosteroids as antiemetics prior to 
copanlisib administration will not be allowed.  
 
5.2.2  Olaparib 
Because there is a potential for interaction of olaparib with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all other drugs, 
over-the-counter medications, vitamins, nutritional supplements, or alternative therapies at 
the time of enrollment and throughout the study. The CRF should capture the dates of 
administration (including start/end dates if known), dosage (including dosing 
frequency/schedule), and reason for use. The PI 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.  

 
 
 
NRG-GY029 
- 39 -  
Version Date:  December 28, 2022 
 
 
5.2.2.1 Dietary Restrictions  
It is prohibited to consume grapefruit, grapefruit juice, Seville oranges, or Seville orange 
juice while on olaparib therapy. The use of any natural/herbal products or other traditional 
remedies should be discouraged. 
 
5.2.2.2 Restricted Concomitant Medications (28-DEC-2022) 
 
Strong or Moderate CYP3A Inhibitors 
Known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, boosted 
protease inhibitors, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) should not be 
taken with olaparib. If a patient requires use of moderate CYP3A inhibitors (ciprofloxacin, 
erythromycin, diltiazem, fluconazole, verapamil) then they must be monitored carefully for 
any change in efficacy of olaparib.  
 
  
Strong or Moderate CYP3A Inducers 
Strong (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide and St John’s Wort) should not be taken with olaparib. If a patient 
requires use of moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil) of CYP3A 
then they must be monitored carefully for any change in efficacy of olaparib.  
 
If the use of any moderate CYP3A inducers are considered necessary for the patient’s safety 
and welfare, this could diminish the clinical efficacy of olaparib. If a patient requires use of 
a moderate CYP3A inducer or inhibitor, then they must be monitored carefully for any 
change in efficacy of olaparib. 
 
P-gp inhibitors 
It is possible that co-administration of P-gp inhibitors (e.g., amiodarone, azithromycin) may 
increase exposure to olaparib. Caution should therefore be exercised. 
 
5.2.2.3 Effect of olaparib on other drugs 
The efficacy of hormonal contraceptives may be reduced if co-administered with olaparib. 
Based on limited in vitro data, olaparib may increase the exposure to substrates of CYP3A4, 
or organic transporting polypeptides 1B1 (OATP1B1), organic cation transporter 1 (OCT1), 
OCT2, organic anion transporter 3 (OAT3), MATE1, and MATE2K. 
 
Based on limited in vitro data, olaparib may reduce the exposure to substrates of CYP2B6. 
Caution should therefore be exercised if substrates of these isoenzymes or transporter 
proteins are co-administered. 
 
Examples of substrates include (check a frequently-updated resource for more 
comprehensive lists): 
 
• CYP3A4 – hormonal contraceptive, simvastatin, cisapride, cyclosporine, ergot 
alkaloids, fentanyl, pimozide, sirolimus, tacrolimus, and quetiapine 
• CYP2B6 – bupropion, efavirenz 

 
 
 
NRG-GY029 
- 40 -  
Version Date:  December 28, 2022 
 
• OATP1B1 – bosentan, glibenclamide, repaglinide, statins, and valsartan 
• OCT1, MATE1, MATE2K – metformin 
• OCT2 – serum creatinine 
• OAT3 – furosemide, methotrexate 
 
5.3 
Supportive/Ancillary Care 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication. 
 
5.3.1 Herbal Supplements, Vitamins, Alternative Therapies  
The concomitant use of herbal therapies is not permitted, as their pharmacokinetics, safety 
profiles, and potential drug-drug interactions are generally unknown. Patients should stop 
using herbal medications at least 14 days prior to the first dose of study therapy. Herbal 
medications include, but are not limited to: St. John’s Wort, Kava, ephedra, gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng. 
 
The use of general nutritional foundation supplements will be allowed including calcium 
with vitamin D and/or minerals, Omega3s (fish oil), Vitamin B6, Vitamin B12, basic 
multivitamins, L-glutamine, or probiotics oral supplements will be permitted either at or 
below the recommended dosing by a healthcare provider. Herbal-based multivitamins are 
not allowed.  
 
5.3.2 Anti-emetics 
Prophylactic antiemetics may be administered according to standard practice.  The routine 
use of standard antiemetics, including 5-HT3 blockers, such as granisetron, ondansetron, or 
an equivalent agent, is allowed as needed.  The use of corticosteroids as antiemetics is not 
allowed for participants receiving copanlisib.   
 
5.3.3  Anti-diarrheals 
Diarrhea is a common problem experienced by many patients and is a risk with olaparib, 
copanlisib, and chemotherapy agents. If it is not controlled quickly, it can lead to 
dehydration.  Patients are recommended to have loperamide (Imodium) on hand at home 
before starting study therapy. 
 
Participants should be advised to notify the treating investigator and their clinical team if:  
• Fever of 100.3°F (38°C) or higher, with diarrhea. 
• First onset of diarrhea after starting therapy 
• If diarrhea persists after 24 hours, or more than 6 loose bowel movements are 
experienced, despite use of Imodium. 
 
Anti-diarrheal therapies may be administered according to standard practice.  An example of 
diarrhea management includes: 
- 
For the first episode of diarrhea, take 4mg of loperamide.  For subsequent episodes of 
diarrhea during the daytime, take 2mg of loperamide after each episode of diarrhea. 
- 
Encourage aggressive oral hydration, such as water, electrolyte-replacement drinks (e.g. 

 
 
 
NRG-GY029 
- 41 -  
Version Date:  December 28, 2022 
 
Gatorade), clear soup or broth.  Caffeinated beverages should be avoided. 
- 
Advise a BRAT diet (bananas, rice, applesauce, toast) or similar bland, low-fiber foods. 
 
5.3.4 Use of hematopoietic agents and transfusions 
• Myeloid growth factors (including biosimilars) may be used per institutional 
Standards and/or NCCN and/or ASCO guidelines. 
• Transfusions may be administered as clinically indicated for management of anemia 
and thrombocytopenia. 
 
5.3.5 Bone strengthening agents 
Patients may continue the use of bisphosphonates, or denosumab for bone disease. 
 
5.4 
Vaccines 
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 the effects with olaparib and copanlisib are unknown. 
 
5.5 
Other Anti-Cancer Agents and Participation in Other Trials 
No other anti-cancer therapy is permitted while on study, including other chemotherapy, 
immunotherapy, radiotherapy, biologic therapy, or other novel agents.  Hormone/endocrine 
therapy is prohibited if used as an anti-cancer therapy.  Hormone replacement therapy 
(HRT) is acceptable. 
 
Concurrent participation in other therapeutic trials is prohibited.  However, trials that do not 
add experimental agents are allowed (e.g., imaging trials, quality of life, etc.).  
 
5.6 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or 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 
• General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
• Pregnancy 
• Death 
 
Note:  
▪ Patient has the right to refuse further treatment, but that does not necessitate 
withdrawing consent for participation in the study (e.g. follow-up) (See Section 
8.2.2 study consent withdrawal) 
▪ See Section 6 to determine if individual treatment components can be stopped 
independently. 

 
 
 
NRG-GY029 
- 42 -  
Version Date:  December 28, 2022 
 
▪ If all protocol treatment is discontinued, follow-up and data collection will 
continue as specified in the protocol. 
 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT 
 
• Toxicity assessments will be done using NCI Common Terminology Criteria for 
Adverse Events (CTCAE v.5). CTCAE is identified and located on the CTEP 
website at 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
• For adverse events (AEs) that are unrelated to the study drugs, study treatment may 
be held for up to 14 days at the discretion of the treating investigator.  Drug holds of 
greater than 14 days for unrelated AEs where the patient is experiencing ongoing 
clinical benefit may be considered after discussion with the Study Chair. 
• All AEs experienced by participants will be collected from the time of the first dose 
of study treatment, through the study and until the final study visit. Participants 
continuing to experience toxicity at the off-study visit may be contacted for 
additional assessments until the toxicity has resolved or is deemed irreversible. 
• There will be no dose escalations or re-escalations on this study. 
• 
Dose modifications for Arm 1 should follow “institutional and compendium 
guidelines”.  
 
6.1 
Arm 1 (Standard of Care/Control Arm) 
 
Table 6.1.A:  Guidelines for dose reductions 
Drug         
 Initial dose level 
First reduction 
Second reduction 
Paclitaxel1 
80 mg/m2 
Decrease dose to 70 mg/m2 
Decrease dose to 60 mg/ m2 
Pegylated 
liposomal 
doxorubicin 
40 mg/m2 
Decrease dose to 30 mg/m2 
Decrease dose to 20 mg/ m2 
Topotecan 
weekly 
4 mg/m2 
Decrease dose to 3.5 mg/m2 
Decrease dose to 3 mg/m2 
1Up to 2 dose reductions (70 mg/m2 and 60 mg/m2) are acceptable for paclitaxel. Instead of a second dose 
reduction, 70 mg/m2 can be maintained if subsequently one weekly dose is omitted within one cycle and 
paclitaxel is given 70mg/ m2 days #1, #8, and #15.  For selected patients, after discussion with Study Chair, a 
third dose reduction in paclitaxel to 60 mg/m2 days #1, #8, and #15 can be considered. 
 
Standard of care chemotherapy will be administered according to prescribing information or 
treatment guidance in general use by the site, including any required premedication and/or 
supportive care medications (e.g., antiemetics). 
 
• Initial treatment modifications will consist of cycle delay and/or dose reduction as 
indicated below for each regimen. 
• All Arms require ANC of 1500/mm3 and platelets of 100,000/mm3 for treatment 
initiation. All Arms require ANC of 1000/mm3 and platelets of 100,000/mm3 for the 
start of each subsequent cycle (Day #1). 
• Investigators should follow local standard clinical practice regarding dose 
modifications for standard of care chemotherapy. 

 
 
 
NRG-GY029 
- 43 -  
Version Date:  December 28, 2022 
 
 
Note: If substitution of paclitaxel for Docetaxel or paclitaxel protein-bound particles for 
injectable suspension (Abraxane) is required for reasons other than hypersensitivity reaction 
(e.g., drug shortage), contact the study team for review and approval prior to making the 
substitution. (28-DEC-2022) 
 
6.2 
Arm 2: Copanlisib 
 
Treatment modifications/management of toxicities potentially related to be both olaparib 
and copanlisib are discussed in Section 6.4. 
 
Copanlisib will be administered at a dose of 45 mg over 1 hour as IV infusion weekly for 3 
weeks (Days 1, 8, and 15) every 4 weeks (Days 1 ,8, and 15 of a 28-day cycle).  Dose 
reduction may be indicated for management of toxicities. 
 
Copanlisib Dose Reductions  
Starting Dose 
First Dose Reduction 
Second Dose 
Reduction 
45mg IV on Days 1,8, 
15 every 4 weeks 
45mg IV on Days 1, 15 
every 4 weeks 
Discontinue 
copanlisib 
 
In the case of olaparib discontinuation (toxicity), patient may continue single agent 
copanlisib. 
 
6.2.1 Gastrointestinal Toxicity 
 
 
 
See Section 6.4 for management of nausea and vomiting. 
 
Diarrhea 
Management/Next Dose for Copanlisib 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1. Resume at same dose level. 
Grade 3 
Hold* until < Grade 2. Resume at one dose level 
lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Copanlisib may be held for up to 14 days. Drug holds of greater than 14 
days where the patient is experiencing ongoing clinical benefit may be 
considered after discussion with the study team/chair.  
**Patients requiring more than 1 dose reduction of copanlisib should 
discontinue copanlisib to continue olaparib alone . 
Recommended management: Loperamide antidiarrheal therapy (see 
Section 5.3.3) 
Dosage schedule: 4 mg at first onset, followed by 2 mg with each loose 
stool until diarrhea-free for 12 hours (maximum dosage: 16 mg/24 
hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when 
used. 

 
 
 
NRG-GY029 
- 44 -  
Version Date:  December 28, 2022 
 
 
 
6.2.2 Hematologic Toxicity 
 
See Section 5.3.4 for guidance on hematopoietic agents and transfusions.  
 
See Section 6.4.4 for management of neutropenia and thrombocytopenia. 
 
6.2.3 Rash 
 
Rash 
Management/Next Dose for Copanlisib 
Grade ≤1 
(<10% BSA 
with active skin 
toxicity*) 
· Maintain dose level. 
· Initiate topical corticosteroids 3-4 x daily, preferred compounds to 
use are triamcinolone and betamethasone for up to 28 days, as long 
as skin toxicity is active. 
For participants with symptoms like burning, stinging and/or 
pruritus, add a non-sedating anti-histamine such as cetirizine once 
daily during daytime and a sedating anti-histamine such as 
diphenhydramine once daily at night. 
Grade 2 (10-
30% BSA with 
active skin 
toxicity*) 
· Maintain dose level. 
· Initiate or intensify topical corticosteroids 3-4x daily, preferred 
compounds to use are triamcinolone or betamethasone for up to 28 
days, as long as skin toxicity is active 
· Add systemic corticosteroids 20-40mg daily. 
· If rash improves to ≤ Grade 1 within 10 days, systemic 
corticosteroid may be discontinued.  
For participants with symptoms like burning, stinging and/or 
pruritus add a non-sedating anti-histamine such as cetirizine once 
daily during daytime and a sedating anti-histamine such as 
diphenhydramine once daily at night. 
Grade 3 (> 30% 
BSA with 
active skin 
toxicity*)  
· Omit copanlisib dose until rash /skin toxicity has improved to ≤ 
Grade 1 or resolved, recommend documentation by photography 
and consider performing a skin biopsy. 
· Initiate topical corticosteroids 3-4x daily, preferred compounds to 
use are triamcinolone or betamethasone for at least 28 days. 
· Add systemic corticosteroids (methylprednisolone 20-40 mg or 
equivalent) daily. 
· If rash improves to ≤ Grade 1 within 10 days, systemic 
corticosteroid may be discontinued. 
· Re-start copanlisib dose once rash /skin toxicity is fading, but no 
longer active (Grade 1): 
- At reduced dose in case of first occurrence. 

 
 
 
NRG-GY029 
- 45 -  
Version Date:  December 28, 2022 
 
- If rash/skin toxicity still active in up to 10% BSA after more than 
14 days, continue oral corticosteroid for at least 48 hours upon re-
challenge with copanlisib; if rash and/or pruritus do not reoccur 
within 48 hours after re-challenge with copanlisib, systemic 
corticosteroid may be discontinued. 
For participants with symptoms like burning, stinging and/or 
pruritus, add a non-sedating anti-histamine such as cetirizine once 
daily during daytime and a sedating anti-histamine such as 
diphenhydramine once daily at night. Antihistamine regimen should 
be continued for a minimum of 28 days after re-challenge with 
copanlisib. 
Grade 4  
· Permanently discontinue participant from copanlisib. Patient may 
continue olaparib alone. 
· Consult a dermatologist, ensure documentation by photography 
and obtain a skin biopsy. 
· Treatment may follow guidelines for Grade 3 above with the 
exception of rechallenge. 
· Additional measures may be taken as per local treatment guidance. 
Any Grade of 
Stevens-
Johnson-
Syndrome / 
Toxic 
Epidermal 
Necrolysis/ 
Drug Reaction 
with 
Eosinophilia 
and Systemic 
Symptoms or 
other 
SJS/TEN/DRES
S like severe 
skin reactions  
· Permanently discontinue participant from copanlisib. Patient may 
continue olaparib alone. 
· Consult a dermatologist, ensure documentation by photography, 
and obtain a skin biopsy. 
· Follow local treatment guidelines for SJS/TEN/DRESS. 
* “Active” skin toxicities: If there are no new lesions or new areas of involvement 
developing, and if lesion appearance is changing color from red to pale or light brown, 
it is likely the skin toxicity has begun to fade and is not to be considered “active” any 
longer. Treatment reduction can be considered for these areas. The appearance of skin 
toxicity may fade slowly, over 10 days or more but not requiring ongoing therapy. 
 
6.2.4 Dose Modification Rules for Transient Post-Infusion Hyperglycemia 
 
Patients who develop transient post-infusion glucose >250 mg/dL after study drug 
administration may continue treatment. However, the next infusion must be delayed until 

 
 
 
NRG-GY029 
- 46 -  
Version Date:  December 28, 2022 
 
the patient’s pre-infusion glucose levels return to <160 mg/dL (fasting) or <200 mg/dL 
(non-fasting).  
 
Guidelines for the management of transient glucose increases are given in the tables below.  
 
Continuing occurrence of post-infusion blood glucose >500 mg/dL, based on repeated 
laboratory analysis despite optimal glucose lowering therapy after 2 infusions of copanlisib, 
will require dose reduction by one dose level.  Dose re-escalation is allowed when a patient 
has achieved controlled glucose levels per investigator’s judgment. 
 
Persistent occurrence of post-infusion blood glucose >500 mg/dL based on laboratory 
analysis which occurred at the lowest dose level despite optimal glucose lowering therapy 
(after at least one cycle of treatment) with consultation of a diabetes specialist requires 
permanent discontinuation of copanlisib; patient may continue olaparib alone.  
 
 
Management of Glucose Increase on the Day of Copanlisib Infusion 
 
 
Criteria 
Recommendation 
Suggested Treatment 
Asymptomatic 
glucose 
increase ≤250 
mg 
• Does not generally require 
treatment  with glucose lowering 
medication. 
None 
Asymptomatic 
glucose increase 
>250 mg/dL 
• Should have repeated laboratory 
glucose determination. 
• If the repeated glucose value is 
decreasing, the glucose may be 
followed without glucose 
lowering medication. 
• If the repeated glucose value is 
persistent or rising, glucose 
lowering medication should be 
administered. 
• Consultation with 
endocrinologist is recommended. 
• Hydration if appropriate. 
• Short acting insulin may be 
given as per institutional 
standard of care.  
• When planning next infusion 
consider prophylaxis with 
oral glucose lowering 
medication. 

 
 
 
NRG-GY029 
- 47 -  
Version Date:  December 28, 2022 
 
Symptomatic 
glucose increase 
>250 mg/dL  
• Hydration status should be 
clinically assessed 
• Glucose lowering medication 
should be administered, and 
repeat glucose value should be 
obtained to ensure 
improvement. 
• Obtain consultation from an 
endocrinologist. 
• Hydration if clinical 
assessment is consistent with 
intravascular volume depletion 
• Short acting insulin and 
other supportive care may be 
given as per institutional 
standard of care.  
• When planning next infusion 
consider prophylaxis with oral 
glucose lowering medication. 
 
 
 
 
 
Management of Glucose Increase on Subsequent Days Following Copanlisib Infusion 
 
Criteria 
Recommendation 
Suggested Treatment 
Highest post 
infusion 
glucose >200 
mg/dL noted on 
days following 
copanlisib 
infusion 
• Oral glucose lowering 
medication recommended 
on subsequent days. 
• Consultation with 
endocrinologist is 
recommended. 
• Treatment with glucose lowering 
medication suggested according to 
the local standards of practice. 
Based on the mechanisms of 
action  and decreased risk of 
hypoglycemia; metformin, 
sodium-glucose co-transporter-2 
(SGLT-2) inhibitor or dipeptidyl 
peptidase-4 (DPP-4) inhibitor 
might be useful treatment options. 
• The use of 
sulfonylurea/metaglinides or 
insulin secretagogues to manage 
increased glucose levels post drug 
infusions is not recommended. 
 
 
 
 
The need for glucose monitoring at home should be determined by the investigator based on 
post-infusion glucose profile and clinical status of the patient. 
 
6.2.4.1 Monitoring of diabetic patients  
 
If the patient already monitors their blood glucose as part of routine anti-diabetic care, the 
routine measurements should not be replaced by the study specific measurements. 

 
 
 
NRG-GY029 
- 48 -  
Version Date:  December 28, 2022 
 
 
6.2.5 Treatment of Blood Pressure Increases Associated with Copanlisib 
 
It is important that patients with pre-existing arterial hypertension adhere to their regular 
medication schedule and take their usual doses on the days of study drug infusion. 
 
Blood pressure measurement on treatment days 
The patient should rest for 5-10 min before blood pressure (BP) is obtained.  BP will be 
measured every 5-10 minutes prior to each copanlisib dose (no more than 4 measurements) 
until there are two consecutive results <150/90 mmHg.  
 
On infusion days, BP will be measured at 0 hour (pre-dose),and 60 minutes (end of infusion), 
 
NOTE: A window of ±10 minutes is allowed for all BP measurements, except for pre-dose 
(0 hour) measurement. 
 
The management of acute BP increases following copanlisib will need to be individualized 
for each patient, but experience from a Bayer-sponsored phase 1 study with copanlisib has 
suggested  the benefit of dihydropyridine calcium channel blockers (i.e., amlodipine, 
felodipine). Verapamil and diltiazem (non-dihydropyridine calcium  channel blockers and 
moderate inhibitors of CYP3A4) should be used with caution due to a potential CYP3A4 
interaction. In general, it is advisable for sites to be prepared, so that anti-hypertensive 
medication is readily available in case of need.  See the below Table 6.2.5 for management 
of hypertension.  
 
Dose Modification of Copanlisib for Arterial Hypertension  
 
     Table 6.2.5: Management of Hypertension 
Toxicity (CTCAE) 
Study drug action 
Recommendation 
Pre-dose measurements 
BP ≥150/90 mmHg 
No dose should be given 
until recovery to <150/90 
mmHg 
Consider BP lowering medication. 
Dosing can proceed on the 
scheduled day if after at least 2 
consecutive measurements BP 
returns to <150/90 mmHg.  If BP 
doesn’t return to <150/90 mmHg, 
delay dosing until next visit. 

 
 
 
NRG-GY029 
- 49 -  
Version Date:  December 28, 2022 
 
Post-dose: 
Drug-related 
BP ≥160/100 mmHg 
(Grade 3) b 
– 
Administration of BP lowering 
therapy should be initiated 
according to local standard of 
care. 
Additional measurements to be 
performed as clinically indicated 
until recovery to <150/90 mmHg. 
Subsequent study drug 
administrations may be reduced by 
1 dose level at the investigator’s 
discretionb 
Malignant hypertension, 
hypertensive crisis 
(Grade 4) 
Permanent discontinuation – 
a: The next dose level is 45 mg on Days 1 and 15 of a 28-day cycle (Section 6.2 for copanlisib 
dose reduction table) 
b: Not manageable despite optimal antihypertensive treatment. 
CTCAE = Common Terminology Criteria for Adverse Events; BP = blood pressure, 
 
 
6.2.6 Non-Infectious Pneumonitis   
See Section 6.4.2 for management of non-infectious pneumonitis. 
 
6.3 
Arm 2: Olaparib 
Treatment modifications/management of toxicities potentially related to be both olaparib 
and copanlisib are discussed in Section 6.4. 
 
Except where otherwise specified, the table below provides olaparib dose reduction 
recommendations from the initial dose of 300 mg BID. 
 
Olaparib dose reductions for study treatment 
Initial Olaparib Dose 
Following re-challenge post 
interruption: Dose 
reduction 1 
Dose reduction 2 
300 mg BID 
200 mg BID 
150 mg BID 
 
Toxicities may be managed by dose interruption or dose reduction, as guided in the 
following sections.  Olaparib may be held for up to 14 days. Drug holds of greater than 14 
days where the patient is experiencing ongoing clinical benefit may be considered after 
discussion with the study Chair.  
 
Once the dose is reduced, re-escalation is not permitted. 
 
In the case of copanlisib discontinuation (toxicity), patient may continue single agent 
Olaparib. 
 

 
 
 
NRG-GY029 
- 50 -  
Version Date:  December 28, 2022 
 
6.3.1 Dose Reduction/Discontinuation for Organ Dysfunction 
 
6.3.1.1 Hepatic Impairment  
The effect of mild or moderate impairment (Child-Pugh classification A or B) on single 
dose of PK of olaparib has been characterized and no olaparib dose adjustment in patients 
with mild or moderate hepatic impairment is required. 
 
Olaparib is not recommended for use in patients with severe hepatic impairment as the PK 
and safety of olaparib in patients with severe hepatic impairment has not been studied. 
 
In case a patient shows an AST or ALT ≥3×ULN or total bilirubin ≥2×ULN, please refer to 
Appendix IV: Actions Required in Cases of Combined Increase of Aminotransferase and 
Total Bilirubin – Hy’s Law for further instructions. 
 
6.3.2 Management of Hematologic Toxicity 
See Section 5.3.4 for guidance on hematopoietic agents and transfusions.  
6.3.2.1 Management of Anemia 
 
Common treatable causes of anemia (e.g., iron, vitamin B12, or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed.  Blood transfusions are 
allowed if determined to be necessary by the treating investigator.   
 
 
 
Hemoglobin (Hb) 
(CTCAE Severity) 
Action to be taken 
Hb <10 but ≥8 g/dL 
(Grade 2) 
First Occurrence: 
• Give appropriate supportive treatment and investigate 
causality. 
• Continue olaparib with supportive treatment (e.g., 
transfusion).. 
 
Subsequent Occurrence:  
• If Hb <10 but ≥9 g/dL, continue olaparib with supporting 
treatment (e.g., transfusion)   
• If Hb <9 but ≥8 g/dL, hold olaparib (for max of 2 weeks) 
until Hb ≥9 g/dL and upon recovery dose reduction to the 
next lower dose level (Section 6.3 Olaparib dose reduction 
table)   
 
Hb <8 g/dL 
(Grade 3) 
• Give appropriate supportive treatment (e.g. transfusion) and 
investigate causality. 
• Hold olaparib for a maximum of 2 weeks until improved to 
Hb ≥9 g/dL. 
• Upon recovery dose reduce to the next lower dose level 

 
 
 
NRG-GY029 
- 51 -  
Version Date:  December 28, 2022 
 
(Section 6.3 Olaparib dose reduction table) 
  
• Hold olaparib for grade 3 anemia, transfuse and reduce dose 
v. introduce epo-stimulating agents (some patients benefit 
from these, not all) 
 
 
6.3.2.2 Management of Neutropenia, and Thrombocytopenia 
 
See Section 6.4.3. 
 
6.3.3 Management of Non-Hematological Toxicity 
 
6.3.3.1 Management of Non-Infectious Pneumonitis 
 
See Section 6.4.2. 
 
6.3.3.2 Management of Nausea and Vomiting  
See Section 6.4.1. 
 
6.3.3.3 Interruption for Intercurrent Non-Toxicity Related Events 
 
Olaparib dose interruption for conditions other than toxicity resolution should be kept as 
short as possible. If a patient cannot restart olaparib within 4 weeks for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with the CTEP Medical Monitor. 
 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the electronic CRF (eCRF). 
 
6.3.3.4 Interruption for Procedures 
Olaparib should be stopped at least 3 days prior to planned surgery or a procedure. After 
surgery/procedure, olaparib can be restarted when the wound has healed. No stoppage of 
study treatment is required for needle biopsy procedures. 
 
6.3.3.5 Management of Fatigue 
 
 
Fatigue 
 
Grade 1-2 
Supportive care. Maintain olaparib dose.  
Grade 3 
Hold for up to 14 days until resolved to < Grade 2, then reduce 
olaparib to 200mg BID. If patients experience > Grade 2 fatigue at 
the 200mg BID dose, further reduce olaparib dose to 150mg BID. 
 
6.4 
Management of potentially Overlapping Toxicities 
 
6.4.1 Management of Nausea/Vomiting 

 
 
 
NRG-GY029 
- 52 -  
Version Date:  December 28, 2022 
 
 
6.4.2 Management of Non-infectious Pneumonitis 
 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiographic pulmonary 
abnormalities develop, effort should be made to determine the etiology.  If a clear diagnosis 
(e.g., allergic, infectious, aspiration) is not evident, olaparib/copanlisib dosing should be 
interrupted and further diagnostic workup obtained to exclude a drug-related pneumonitis.  
Per the judgment of the treating investigator, evaluation may include a high-resolution CT 
Chest, infectious studies, pulmonary function tests, and/or referral to a pulmonologist. 
The investigator is requested to differentiate between non-infectious pneumonitis, and 
infectious pneumonitis (viral, bacterial, or fungal), aspiration pneumonitis, or other 
pneumonitis clearly not due to a potential hypersensitivity reaction to the copanlisib infusion 
Nausea and 
Vomiting 
Management/Next Dose  
Grade 1-2 
First occurrence:  
• Initiate appropriate anti-emetic treatment as required, in 
accordance with local treatment practice guidelines. 
Alternatively, olaparib tablets can be taken with a light 
meal/snack (i.e., two pieces of toast or a couple of cookies, 
crackers, or biscuits) to abrogate nausea/vomiting. 
• If antiemetics are not sufficient to control nausea, then omit 
olaparib and resume at the same dose when nausea has 
subsided. 
Second occurrence: 
• If participant still complains of significant nausea despite 
antiemetics and previous olaparib interruption, omit olaparib 
again. 
• When nausea has subsided, resume olaparib and decrease at 
one dose level lower. 
• If olaparib has been dose reduced twice, then decrease 
copanlisib by one dose level**.   
Grade 3 
• Hold olaparib and copanlisib until resolved to < Grade 2. 
Then decrease olaparib one dose level.   
• If olaparib has been dose reduced twice, then decrease 
copanlisib by one dose level**.   
• Hold olaparib and copanlisib for ≥ Grade 3 vomiting or 
Grade 3 nausea only if the vomiting or nausea cannot be 
controlled with optimal antiemetic as per local standard 
of care*. 
Grade 4 
Off protocol therapy 
The time a given drug is held should not exceed 14 days. 
*Grade 3 nausea/vomiting that does not resolve to grade 0-2 within 14 days despite maximum 
supportive care after treating patient at the lowest reduced dose level of olaparib and copanlisib 
should lead to discontinuation of protocol therapy.  
**Patients requiring more than 1 dose reduction should go off protocol therapy. 
Recommended management: antiemetics.  The use of corticosteroids as antiemetics is not allowed 
for participants receiving copanlisib. 

 
 
 
NRG-GY029 
- 53 -  
Version Date:  December 28, 2022 
 
or olaparib; and provide the basis for his/her assessment that it is infectious or other, as 
appropriate.  The investigator is requested to report with the most specific clinical terms to 
describe the condition, not simple “pneumonitis”.  
 
If symptoms resolve and no pulmonary abnormalities are observed on imaging, then study 
treatment can be restarted if deemed appropriate by the treating investigator.   
In the event of suspected non-infectious pneumonitis, modify copanlisib and olaparib 
treatment as per table below.  
 
Dose Adjustments for non-infectious pneumonitis 
Suspected or confirmed 
NIP per CTCAE 
Action Taken 
Re-treatment dose after 
recovery  
Grade 1 
No change to 
copanlisib/olaparib dosing 
NA 
Grade 2 
Hold copanlisib and olaparib 
until recovery to ≤ Grade 1 
Treat NIP, consider seeking 
Pulmonology consultation. 
Decrease copanlisib and 
olaparib dose by one dose 
levela 
Grade 2  
(second occurrence) 
Discontinue protocol therapy NA 
Grade 3 
Discontinue protocol therapy NA 
Grade 4 
Discontinue protocol therapy NA 
NA=Not applicable; NIP=Non-infectious pneumonitis; CTCAE=Common Terminology Criteria for Adverse 
Events  
aIf olaparib or copanlisib have already been dose reduced to the lowest dose level, then discontinue protocol 
therapy.  
 
 
6.4.3 Management of Neutropenia and Thrombocytopenia 
 
Toxicity   
(CTCAE Severity) 
      Study treatment dose adjustment 
Grade 1-2 
Appropriate supportive treatment and causality investigation.  
Continue olaparib and copanlisib at the same dose.  
Grade 3-4 
• Appropriate supportive treatment and causality 
investigation. 
• Interrupt olaparib and copanlisib dosing for a maximum 
of 2 weeks, until recovered to Grade 1 or better and dose 
reduce olaparib. 
• If repeat Grade 3-4 occurrence, then dose reduce olaparib 
to the next lower dose level (Section 6.3 Olaparib dose 
reduction table). If olaparib has been dose reduced to the 
lowest level, then dose reduce copanlisib. If both drugs 
have been dose reduced to the lowest level, then 

 
 
 
NRG-GY029 
- 54 -  
Version Date:  December 28, 2022 
 
discontinue protocol therapy. 
• For cases where patients develop prolonged 
hematological toxicity with ≥2 week interruption/delay in 
study treatment due to CTCAE grade 3 or worse, refer to 
Section 6.4.4. 
 
Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is not permitted 
for participants receiving olaparib.  However, use of G-CSF/filgrastim may be used as per 
national guidelines (See Section 5.3.4).  G-CSF should not be used within 24 hours of the 
last dose of study treatment. 
 
Platelet transfusions, if indicated, should be administered if deemed necessary by the 
treating investigator and according to local institutional guidelines. 
  
6.4.4  Management of Prolonged Hematological Toxicities While on Study Treatment 
 
If a patient develops prolonged hematological toxicity such as: 
• ≥2 week interruption/delay in olaparib due to CTCAE Grade 3 or worse anemia 
and/or development of blood transfusion dependence 
• ≥2 week interruption/delay in olaparib due to CTCAE Grade 3 or worse 
neutropenia (ANC <1×109/L) 
• ≥2 week interruption/delay in olaparib due to CTCAE Grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (platelets 
<50×109/L) 
 
Check weekly differential blood counts including reticulocytes and peripheral blood smear. 
Olaparib should be discontinued if blood counts do not recover to CTCAE Grade 1 or better 
within 4 weeks of dose interruption. Refer to a hematologist. 
 
If any blood parameters remain clinically abnormal after 4 weeks of dose interruption, the 
patient should be referred to a hematologist for further investigation. Patients with 
laboratory findings consistent with AML or MDS should receive a full work up as per the 
local standard of care for evaluation of a suspected hematological malignancy including, but 
not limited to, bone marrow aspirate/smear, flow cytometric evaluation of the marrow, and 
evaluation of cytogenetics. 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. 
 
Development of a confirmed MDS, AML, or other clonal blood disorder should be reported 
as an SAE via CTEP-AERS and full reports must be provided by the investigator to the 
CTEP Medical Officer. Olaparib and copanlisib treatment should be discontinued if a 
diagnosis of MDS and/or AML is confirmed. 
   
6.4.5   Management of Non-Hematological Toxicity (not covered in the above sections)  
Dose interruptions are allowed as required, for a maximum of 2 weeks on each occasion. If 
the interruption is longer than 2 weeks, the CTEP Medical Monitor must be informed. 

 
 
 
NRG-GY029 
- 55 -  
Version Date:  December 28, 2022 
 
Where toxicity reoccurs following re-challenge with olaparib and/or copanlisib, and where 
further dose interruptions are considered inadequate for management of toxicity, then the 
patient should be considered for dose reduction of the drugs (olaparib or copanlisib or both) 
causing the toxicity or must permanently discontinue the offending agents (olaparib or 
copanlisib or both).  
 
For treatment-related non-hematologic AEs not covered in the above sections:  
• Treatment must be interrupted if a grade 3 or 4 AE occurs which the investigator 
considers to be related to administration of study treatment. In that scenario, the 
offending agent should be dose reduced by one dose level (except for easily 
correctable, asymptomatic, G3 laboratory abnormalities). Patients who are at the 
lowest reduced dose level may have their drug resumed at that dose level after 
discussion with the Study Chair if evidence of clinical benefit. 
 
• One drug may be held or dose modified or discontinued independently if the 
observed toxicity is attributed to only one of the drugs, while the patient continues to 
receive the second drug not associated with the observed toxicity. The time a given 
drug is held should not exceed 14 days. 
 
• Grade 3 or 4 non-hematologic AE related to treatment that does not resolve to grade 
0-2 within 14 days despite maximum supportive care after treating patient at the 
lowest reduced dose level of the offending agent should prompt discontinuation of 
the offending agent. 
 
• Grade 3 or 4 non-hematologic AE related to treatment lasting > 14 days despite 
maximum supportive care and treatment being held should prompt discontinuation 
of the offending agent. 
 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS 
 
7.1 
Protocol Agents 
 
Investigational Agents 
The investigational agents administered in NRG-GY029 are copanlisib and olaparib, which 
are being made available under an IND sponsored by CTEP.  For patients receiving 
copanlisib and olaparib determination of whether an adverse event meets expedited 
reporting criteria, see the reporting table in Section 7.5.2.1 of the protocol. 
 
 
Commercial Agents 
The commercial agent(s) in NRG-GY029 are paclitaxel, pegylated liposomal doxorubicin 
and topotecan. For patients receiving paclitaxel, pegylated liposomal doxorubicin, and 
topotecan, determination of whether an adverse event meets expedited reporting criteria, see 
the reporting table in Section 7.4 of the protocol. 
 
 
 

 
 
 
NRG-GY029 
- 56 -  
Version Date:  December 28, 2022 
 
7.2 
Adverse Events and Serious Adverse Events 
 
 
7.2.1 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 website:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related.  Therefore, an AE can be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal (investigational) product, whether or not considered related to the 
medicinal (investigational) product (attribution of unrelated, unlikely, possible, probable, or 
definite). (International Conference on Harmonisation [ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited manner. 
 
 
7.3 
Comprehensive Adverse Events and Potential Risks (CAEPR) List for Study Agents 
 
7.3.1 Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride, NSC 784727) 
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 702 patients. Below is the CAEPR for 
Copanlisib dihydrochloride. 
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. 
 
Version 2.2, June 18, 20191 

 
 
 
NRG-GY029 
- 57 -  
Version Date:  December 28, 2022 
 
 
 Adverse Events with Possible Relationship to  
Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) 
 (CTCAE 5.0 Term) 
[n= 702] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
 
Febrile neutropenia 
  
GASTROINTESTINAL DISORDERS 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
 
 
Pancreatitis 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
Infection2 
 
 
 Infection2 (Gr 2) 
INVESTIGATIONS 
  
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr 2) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 2) 
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
Hyperglycemia 
 
 
 Hyperglycemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Muscle cramp 
 
 Muscle cramp (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis3 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
 
Erythroderma 
  
 
 
Pruritus 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contactingPIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
3Pneumonitis is a group term that includes interstitial lung disease, dyspnea, dyspnea at rest, and dyspnea exertional. 
 
Adverse events reported on Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) trials, but for which 
there is insufficient evidence to suggest that there was a reasonable possibility that Copanlisib dihydrochloride 
(BAY 80-6946 dihydrochloride) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Eosinophilia 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Left ventricular systolic dysfunction; Myocardial 
infarction; Sinus tachycardia 
GASTROINTESTINAL DISORDERS - Abdominal pain; Colitis; Constipation; Dry mouth; Dyspepsia; Esophagitis; 

 
 
 
NRG-GY029 
- 58 -  
Version Date:  December 28, 2022 
 
Flatulence; Gastritis; Gastroesophageal reflux disease; Oral dysesthesia; Oral pain; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Fever; General 
disorders and administration site conditions - Other (failure to thrive); Non-cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fracture; Infusion related reaction; Injury, 
poisoning and procedural complications - Other (drug eruption) 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alanine aminotransferase increased; Alkaline 
phosphatase increased; Aspartate aminotransferase increased; Blood bilirubin increased; CPK increased; Ejection 
fraction decreased; Electrocardiogram QT corrected interval prolonged; Electrocardiogram T wave abnormal; 
Investigations - Other (electrocardiogram U wave abnormal); Lipase increased; Lymphocyte count decreased; Serum 
amylase increased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypertriglyceridemia; Hyperuricemia; 
Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia; Metabolism and nutrition 
disorders - Other (blood insulin increased) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Generalized muscle weakness; 
Musculoskeletal and connective tissue disorder - Other (psoriatic arthropathy); Myalgia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor 
hemorrhage 
NERVOUS SYSTEM DISORDERS - Amnesia; Dizziness; Dysesthesia; Dysgeusia; Headache; Paresthesia; 
Peripheral sensory neuropathy; Presyncope; Reversible posterior leukoencephalopathy syndrome 
PSYCHIATRIC DISORDERS - Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other (renal 
insufficiency) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea3; Hypoxia; Pleural 
effusion; Pulmonary hypertension; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other 
(pulmonary congestion) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Purpura; Rash acneiform; Stevens-
Johnson syndrome 
VASCULAR DISORDERS - Hypotension; Thromboembolic event; Vascular disorders - Other (circulatory collapse) 
 
Note: Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) 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. 
 
7.3.2 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 

 
 
 
NRG-GY029 
- 59 -  
Version Date:  December 28, 2022 
 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
Version 2.5, July 1, 20211 
 
 Adverse Events with Possible  
 Relationship to Olaparib (AZD2281) 
 (CTCAE 5.0 Term) 
[n= 3449] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 4) 
 
 
 
Febrile neutropenia 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
  
Abdominal pain 
 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
                                            
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
INFECTIONS AND INFESTATIONS 
  
 
Upper respiratory 
infection 
 
  
 
Urinary tract infection 
 
  
INVESTIGATIONS 
  
 
Creatinine increased 
 
  
 
Neutrophil count 
decreased 
 
 Neutrophil count 
decreased (Gr 4) 
 
 
Platelet count decreased 
  
 
White blood cell 
decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 

 
 
 
NRG-GY029 
- 60 -  
Version Date:  December 28, 2022 
 
 
 Adverse Events with Possible  
 Relationship to Olaparib (AZD2281) 
 (CTCAE 5.0 Term) 
[n= 3449] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Muscle cramp 
 
  
 
Myalgia 
 
  
 
Pain in extremity 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS 
AND POLYPS) 
  
 
 
Leukemia secondary to 
oncology chemotherapy 
  
 
 
Myelodysplastic 
syndrome 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash maculo-papular 
 
  
 
 
Skin and subcutaneous 
tissue disorders - Other 
(angioedema) 
  
 
 
Skin and subcutaneous 
tissue disorders - Other 
(erythema nodosum) 
  
 
NOTE: 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. Most are not attributed to olaparib. 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
Adverse events reported on olaparib (AZD2281) trials, but for which there is insufficient evidence to suggest that 
there was a reasonable possibility that olaparib (AZD2281) caused the adverse event: 
 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (nodal rhythm); Chest pain - cardiac; Sinus 

 
 
 
NRG-GY029 
- 61 -  
Version Date:  December 28, 2022 
 
bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Hypothyroidism 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Colonic obstruction; Dry mouth; Dysphagia; Enterocolitis; 
Esophageal stenosis; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (gastrointestinal 
hemorrhage); Gastrointestinal disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other (intestinal 
perforation); Ileus; Jejunal perforation; Obstruction gastric; Pancreatitis; Periodontal disease; Rectal hemorrhage; Small 
intestinal obstruction; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Fever; Malaise; Non-
cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (systemic inflammatory response syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Dermatitis radiation; Fracture; 
Gastrointestinal anastomotic leak; Injury, poisoning and procedural complications - Other (vena cava injury); Wound 
dehiscence 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood bilirubin 
increased; GGT increased; Hemoglobin increased; Lipase increased; Lymphocyte count decreased; Serum amylase 
increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hypermagnesemia; 
Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Avascular necrosis; Bone pain; 
Generalized muscle weakness; Muscle weakness lower limb; Muscle weakness upper limb; Neck pain; Rotator cuff 
injury; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Treatment related 
secondary malignancy; Tumor pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Ataxia; Cognitive disturbance; Concentration impairment; 
Encephalopathy; Intracranial hemorrhage; Peripheral sensory neuropathy; Reversible posterior leukoencephalopathy 
syndrome; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Hallucinations; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other (decreased 
glomerular filtration rate); Renal and urinary disorders - Other (hydronephrosis); Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; Hypoxia; 
Oropharyngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other 
(chronic obstructive pulmonary disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Pruritus 
VASCULAR DISORDERS - Arterial thromboembolism; Flushing; Hot flashes; Hypertension; Hypotension; 
Peripheral ischemia; Thromboembolic event 
 
Note: Olaparib (AZD2281) 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. 
 
7.4 
Adverse Events for Commercial Study Agents  
Refer to the package insert for detailed pharmacologic and safety information. 
 
7.5 
Expedited Reporting of Adverse Events 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-AERS, 
accessed via the CTEP web site: 
https://ctepcore.nci.nih.gov/ctepaers/security/login  
 
For studies that utilize the RAVE-CTEP-AERS integration, expedited reports are initiated 
via RAVE: see Section 14.5. 

 
 
 
NRG-GY029 
- 62 -  
Version Date:  December 28, 2022 
 
 
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies 
NRG Oncology requirements for expedited adverse event reporting. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to CTEP for this study by telephone at 301-897-7497 and to NRG Regulatory Affairs 
by phone at 215-854-0770.  An electronic report must be submitted immediately upon re-
establishment of the Internet connection. 
 
7.5.1 Expedited Reporting Methods 
 
• Per CTEP NCI Guidelines for Adverse Events Reporting, a CTEP-AERs-24 Hour 
Notification requires that a CTEP-AERS 24-hour notification must be submitted within 
24 hours of learning of the AE.  Each CTEP-AERS 24-hour notification must be 
followed by a complete report within 5 days.  
 
• Supporting source documentation is requested by CTEP as the IND sponsor for this 
study and by NRG as needed to complete adverse event review. Deidentified supporting 
source documentation should be uploaded to the Source Document Portal via the CTEP-
AERS integration. 
 
• A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not recommended” 
must still be reported to fulfill NRG Oncology safety reporting obligations. Sites must 
bypass the “NOT recommended” assessment; the CTEP-AERS allows submission of all 
reports regardless of the results of the assessment.  
 
7.5.2 Expedited Reporting Requirements for Adverse Events  
 
 
7.5.2.1 Commercial Agent Studies: Expedited Reporting Requirements for Adverse 
Events that Occur in a Non-IND/IDE trial within 30 Days of the Last 
Administration of a Commercial Agent 1, 2 (For ARM 1)(28-DEC-2022) 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) 
Death 
2) 
A life-threatening adverse event 
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 

 
 
 
NRG-GY029 
- 63 -  
Version Date:  December 28, 2022 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via  
electronic submission  within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
10 Calendar Days 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via electronic submission within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and 
have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
• 
Grade 3 adverse events 
2 For studies using PET or SPECT agents, the AE 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: May 5, 2011 
 
 
7.5.2.2 Late Phase 2 and Phase 3 Studies: 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/Intervention1, 2 (For ARM 2) 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) 
Death 
2) 
A life-threatening adverse event 
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; 
ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
electronic submission within the timeframes detailed in the table below. 

 
 
 
NRG-GY029 
- 64 -  
Version Date:  December 28, 2022 
 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE: Protocol-specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via electronic submission within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and 
have an attribution of possible, probable, or definite require reporting as follows: Expedited 24-hour notification 
followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE 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: May 5, 2011 
 
7.5.2.3 Additional Protocol-Specific Instructions or Exceptions to Expedited Reporting  
Requirements 
N/A 
 
7.5.3 Reporting to the Site IRB/REB 
Investigators will report unanticipated problems to NCI CIRB according to the NCI CIRB 
SOPs.  
 
7.5.4 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 during or subsequent to treatment with 
an agent under an NCI IND/IDE be reported via CTEP-AERS. In addition, secondary 
malignancies following radiation therapy must be reported 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 

 
 
 
NRG-GY029 
- 65 -  
Version Date:  December 28, 2022 
 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
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. 
 
7.6 
Routine Reporting Requirements for Adverse Events 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions.  
 
7.6.1 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.  
 
8. 
REGISTRATION AND STUDY ENTRY PROCEDURES (28-DEC-2022) 
Food and Drug Administration (FDA) regulations require sponsors to select qualified 
investigators. National Cancer Institute (NCI) policy requires all 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). 
The RCR is a self-service online person registration application with electronic signature 
and document submission capability.  
 
RCR utilizes five person registration types. 
• Investigator (IVR) – MD, DO, or international equivalent; 
• Non Physician Investigator (NPIVR) – advanced practice providers (e.g., NP or PA) or 
graduate level researchers (e.g., PhD); 
• 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; 

 
 
 
NRG-GY029 
- 66 -  
Version Date:  December 28, 2022 
 
and 
• Associate Basic (AB) – individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
 
 
 
 
 
 
 
 
 
 
 
 
 
An active CTEP-IAM user account with a linked ID.me account (the latter required 
immediately for new CTEP-IAM accounts, and by July 1, 2023 for all users) is required to 
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; 
• 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 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. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A AB 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 

 
 
 
NRG-GY029 
- 67 -  
Version Date:  December 28, 2022 
 
8.1 
Cancer Trials Support Unit Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted 
and is based on the person and site roster assignment housed in the Roster Maintenance 
application and in most cases viewable and manageable via the Roster Update Management 
System (RUMS) on the Cancer Trials Support Unit (CTSU) members’ website. 
 
This study is supported by the NCI CTSU. 
 
IRB Approval 
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB) in order to participate in Cancer Therapy Evaluation Program 
(CTEP) and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases. In addition, U.S.-based sites must accept the NCI CIRB review to activate 
new studies at the site after March 1, 2019. Local IRB review will continue to be accepted 
for studies that are not reviewed by the CIRB, or if the study was previously open at the site 
under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
 
Sites participating with the 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 emailing the email address above or calling 1-888-651-CTSU (2878). 
 
In addition, the site-protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the 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 (applies to US and 
Canadian sites only) and on at least one participating organization’s roster; 
• If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 
Signatory Institutions(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. 
 
 
 

 
 
 
NRG-GY029 
- 68 -  
Version Date:  December 28, 2022 
 
Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO);  
• An active roster affiliation with NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only): and 
• Compliance with all applicable protocol-specific requirements (PSRs). 
 
Downloading Site Registration 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 on 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 NRG, and 
protocol # NRG-GY029. 
▪ 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 initiative, IRB data will load automatically to the 
CTSU.) 
 
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. 
 
Checking Site’s Registration Status 
 
Site registration status may be verified on the CTSU members’ website.   
 

 
 
 
NRG-GY029 
- 69 -  
Version Date:  December 28, 2022 
 
• 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 the NCI or their affiliated networks. 
 
Delegation of Tasks Log (DTL) 
 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the DTL 
application in the Delegation Log section of the CTSU members’ website.  The Clinical 
Investigator (CI) is required to review and electronically sign the DTL prior to the site 
receiving an approved site registration status and enrolling patients to the study. To maintain 
an approved site registration status the CI must re-sign the DTL at least annually and when a 
new version of the DTL is released; and to activate new task assignments requiring CI sign-
off. Any individual at the enrolling site on a participating roster may initiate the site DTL. 
Once the DTL is submitted for CI approval, only the designated DTL Administrators or the 
CI may update the DTL. Instructions on completing the DTL are available in the Help 
Topics button in the DTL application and describe DTL task assignments, CI signature, and 
CTEP registration requirements, as well as include a Master Task List. 
 
8.2 
Patient Enrollment 
 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  Patients 
must have signed and dated all applicable consents and authorization forms.   
 
8.2.1 Oncology Patient Enrollment Network (OPEN) 
 
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 Theradex Interactive Web Response 
System (IWRS) for retrieval of patient registration/randomization assignment. OPEN 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 participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 

 
 
 
NRG-GY029 
- 70 -  
Version Date:  December 28, 2022 
 
• If a Delegation of Tasks Log (DTL) is required for the study, the registrar(s) must hold 
the OPEN Registrar task on the DTL for the site; and 
• Have an approved site registration for a 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. 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. 
 
 
8.2.2    Patient-Initiated Consent Withdrawal from the Study 
If a patient chooses to have no further interaction regarding the study (i.e., allow no future 
follow up data to be submitted to NRG Oncology), the study applicable form should be 
completed in Medidata Rave to report the patient’s consent withdrawal.  
NOTE: This should not be done if the patient has only chosen to stop protocol treatment and 
is willing to still be followed. (See Section 5.6). 
 
9. 
DRUG INFORMATION  
 
General Patient Care Implications 
Patients must use highly effective contraception because the study treatment may be 
teratogenic. Highly effective contraception is defined as hormonal contraceptives (oral 
contraceptives, Nuvaring, Depo Provera), intrauterine device, true abstinence, two barrier 
methods of birth control including condoms with cervical cap or diaphragm, patient has 
received surgical sterilization. 
 
9.1 
Copanlisib (NSC# 784727, IND#)  
 
9.1.1 Chemical Name or Amino Acid Sequence: 2-amino-N-[7-methoxy-8-(3-morpholin-4-
ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide 
dihydrochloride 

 
 
 
NRG-GY029 
- 71 -  
Version Date:  December 28, 2022 
 
 
9.1.2 
Other Names: BAY 80-6946 (free base); BAY 84-1236 (dihydrochloride salt) 
 
9.1.3 
Classification: Pan class I PI3K inhibitor  
 
9.1.4 
Molecular Formula: C23H28N8O4 2HCl 
 
M.W.: 553.45 g/mol 
 
9.1.5 
Approximate Solubility: Freely soluble in water and 0.1 M hydrochloric acid (HCl) 
 
9.1.6 
Mode of Action: Copanlisib is a pan class I PI3K inhibitor with potent activity against the 
delta and alpha isoforms.  Class I PI3K is downstream of most cancer associated tyrosine 
kinase growth factor receptors or mesenchymal epithelial transition factor. PI3K delta has a 
critical role in regulating downstream events of the B-cell receptor. 
 
9.1.7 
Description: The powder is white to yellow solid substance. 
 
9.1.8 
How Supplied: Copanlisib is supplied by Bayer HealthCare AG and distributed by the 
Pharmaceutical Management Branch, CTEP, DCTD, NCI.  The agent is available as a 
lyophilized product containing 60 mg of copanlisib in a 6 mL injection vial.  The excipients are 
mannitol, sodium hydroxide, citric acid, and water for injection. 
 
9.1.9 
Preparation:  Using appropriate aseptic technique, reconstitute the 60 mg vial of copanlisib 
with 4.4 mL of 0.9% sodium chloride resulting in a concentration of 15 mg/ml.  Gently shake 
for 30 seconds and allow the vial to stand for 1 minute to let bubbles rise to the surface. Repeat 
if undissolved substance is still present. The reconstituted solution may be slightly yellow and 
should be clear prior to being withdrawn from the vial.   Withdraw the appropriate volume of 
the reconstituted solution and further dilute by adding to a 50-200 mL sterile 0.9% sodium 
chloride bag. Mix well by inverting.  
 
9.1.10 Storage: Store intact vials between 2°C and 8°C.  
 
If a storage temperature excursion is identified, promptly return copanlisib to between 2°C 
and 8°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. 
 
9.1.11 Stability:  Stability studies of the vials are ongoing. The diluted solution should be used 
immediately (stored up to 4 hours at room temperature including preparation and 
administration).  If the diluted solution for infusion is not used immediately, it is stable for up 
to 24 hours refrigerated between 2°C and 8°C. It takes approximately 60 minutes for the 
diluted solution to return to room temperature after refrigeration.  The infusion should be 
completed within 24 hours of preparation. 
 
 
 

 
 
 
NRG-GY029 
- 72 -  
Version Date:  December 28, 2022 
 
CAUTION:  The single-use lyophilized dosage form contains no antibacterial 
preservatives.  Therefore, it is advised that the reconstituted product be 
discarded 4 hours after initial entry.  
 
9.1.12 Route of Administration: IV infusion  
 
9.1.13 Method of Administration:  The diluted solution for infusion is administered IV over 1 hour. 
After administration, flush the line to ensure complete dose is given.  No IV glucose 
preparations should be administered on the days of infusion. 
 
9.1.14 Potential Drug Interactions:  In vitro, copanlisib is metabolized primarily via CYP 3A4 and 
to a minor extent by CYP1A1.  It is also a substrate of P-gp and BCRP, but not a substrate of 
MATEs, OCTs, OATs, or OATPs. Concomitant administration with strong inhibitors or 
inducers of CYP3A4 should be avoided.  Use caution when administered with strong inhibitors 
and inducers of CYP1A1, P-gp, and BCRP.   
 
In vitro, copanlisib is a strong inhibitor of MATE2K.  Copanlisib and its metabolite M-1 have a 
low risk for inhibition or induction of CYP isoforms, inhibition of UGT isoforms, and 
inhibition of dihydropyrimidine dehydrogenase.  Copanlisib does not inhibit P-gp, BCRP, 
OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, bile salt export pump (BSEP), MRP2, or 
MATE1 at therapeutic 60 mg dose plasma concentrations. Use caution when administered with 
sensitive drug substrates of MATE2K.   
 
Copanlisib is not an inducer of CYP1A2, 2B6, and 3A. 
 
9.1.15 Special Handling: Copanlisib is not genotoxic in vitro or in vivo.  Copanlisib is expected to 
adversely affect male and female reproduction. 
 
9.1.16 Patient Care Implications: Females of child-bearing potential and male patients must use 
adequate contraception while receiving copanlisib and for 1 month after last dose of copanlisib.  
Do not breastfeed during treatment with copanlisib and for at least 1 month after the last dose 
of copanlisib. 
 
Hypertension is frequently observed within the first 3 hours after start of infusion and 
hyperglycemia is frequently observed persisting for approximately 1-3 days after study drug 
administration. Refer to protocol document for treatment and monitoring guidelines. 
 
9.2 
Olaparib (AZD2281) (NSC# 787856, IND#) 
 
9.2.1 
Chemical Name:  4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-
fluorophenyl)methyl]phthalazin-1(2H)-one 
 
9.2.2 
Other Names: AZD2281; KU-0059436; CO-CE 42 
 
9.2.3 
Classification: PARP inhibitor 

 
 
 
NRG-GY029 
- 73 -  
Version Date:  December 28, 2022 
 
 
9.2.4 
CAS Registry Number: 763113-22-0 
 
9.2.5 
Molecular Formula:  C24H23FN4O3  
M.W.: 434.46 
 
9.2.6 
Approximate Solubility: 0.1 mg/mL pH independent solubility across physiologic range 
 
9.2.7 
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.  
 
9.2.8 
Description: crystalline solid 
 
9.2.9 
How Supplied: AstraZeneca supplies and the CTEP, DCTD distributes olaparib as green, 
film-coated tablets 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. 
 
9.2.10 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.   
 
9.2.11 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. 
 
9.2.12 Route and Method of Administration:  Oral. Take tablets without regard to meals.  
 
9.2.13 Potential Drug Interactions:  In vivo data indicate that CYP3A4/5 is important for olaparib 
metabolism and clearance in humans. For this reason, avoid concomitant administration of 

 
 
 
NRG-GY029 
- 74 -  
Version Date:  December 28, 2022 
 
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. 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. 
 
9.2.14 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 one (1) month after the last dose of olaparib.  It is not known 
whether olaparib is found in seminal fluid, so as a precaution, male study participants must use 
a condom during treatment and for three (3) months after the last dose and should avoid 
fathering a child or donating sperm during this same time period. The study investigator should 
discuss the most appropriate forms of highly effective contraceptive methods for each patient.  
 
Lactation is a protocol exclusion criterion and not advised since there is potential for serious 
adverse reactions in breastfed infants. Advise lactating women to not breastfeed during study 
treatment and for one (1) month after receiving the last dose of olaparib.  
 
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. 
 
There are no data on the effect of olaparib on wound healing, therefore as a precaution, 
olaparib treatment should be stopped at least 3 days prior to planned surgery. After surgery 
olaparib can be restarted when the wound has healed. No stoppage of olaparib is required 
for any needle biopsy procedure. 
 
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
therapeutic or palliative radiation treatment. Study treatment should be restarted within 4 
weeks as long as any bone marrow toxicity has recovered. 
 

 
 
 
NRG-GY029 
- 75 -  
Version Date:  December 28, 2022 
 
 
The investigator brochure for this drug will be supplied by [insert source/link].  
 
9.3 
PMB 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/  
• 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) 
 
 
9.4 
Agent Ordering  
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. 
 
Sites can order study agents in OAOP when a patient is enrolled to treatment and 
randomization. Agent orders can be expedited overnight Monday-Thursday when sites 
provide expedited courier information. 
 
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.   
 
9.4.1 Investigator Brochure Availability 
The current versions of the copanlisib and olaparib IBs 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. 
 

 
 
 
NRG-GY029 
- 76 -  
Version Date:  December 28, 2022 
 
9.4.2 Agent Accountability 
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 
study participant and ordering investigator on this protocol. 
 
9.5 
Commercial Agent—Paclitaxel (NSC# 673089) 
 
 
9.5.1 Formulation:  
Paclitaxel is supplied as a 6mg/mL non-aqueous solution in multi-dose vials containing 
30mg/5mL, 100mg/16.7mL, or 300mg/50mL of paclitaxel. In addition to 6mg of paclitaxel, 
each mL of sterile non-pyrogenic solution contains 527mg of purified Cremophor® EL 
(polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP. 
 
9.5.2  Storage/Stability  
Storage: Unopened vials of paclitaxel are stable to the date indicated on the package when 
stored between 20 to 25°C (68 to 77°F). Protect from light. 
 
Stability: Commercially available paclitaxel will be labeled with an expiration date. All 
solutions of paclitaxel exhibit a slight haziness directly proportional to the concentration of 
drug and the time elapsed after preparation, although when prepared as described below, 
solutions of paclitaxel (0.3-1.2 mg/ml) are physically and chemically stable for 27 hours. 
 
 
9.5.3 Preparation:  
Paclitaxel must be diluted prior to infusion. Paclitaxel should be diluted in 0.9% Sodium 
Chloride for Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium 
Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 
to 1.2mg/mL.  The solutions are physically and chemically stable for up to 27 hours at 
ambient temperature (approximately 25°C / 77°F) and room lighting conditions.   
 
NOTE: In order to minimize patient exposure to the plasticizer DEHP, which may be 
leached from PVC infusion bags or sets, diluted paclitaxel solutions should be stored in 
bottles (glass, polypropylene) or plastic (polypropylene, polyolefin) bags and administered 
through polyethylene-lined administration sets. 
 
Paclitaxel should be administered through an inline filter with a microporous membrane not 
greater than 0.22 microns. Use of filter devices such as IVEX-2® or IVEX-HP®, which 
incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching 
of DEHP.   
 
All patients should be premedicated with corticosteroids, diphenhydramine, and H2 
antagonists prior to paclitaxel administration in order to prevent severe hypersensitivity 

 
 
 
NRG-GY029 
- 77 -  
Version Date:  December 28, 2022 
 
reactions. Patients who experience severe hypersensitivity reactions to paclitaxel may be re-
challenged with the drug.  
 
9.5.4 Adverse Effects: Consult the package insert for the most current and complete information.  
 
Please refer to the current FDA-approved package insert provided with each drug and the 
site-specific pharmacy for toxicity information and instructions for drug preparation, 
handling, and storage. 
 
9.6 
Commercial Agent: Pegylated Liposomal Doxorubicin (PLD) (NSC# 712227) 
 
 
 Pegylated liposomal doxorubicin (PLD) is commercially available.  All commercially 
available sources are allowed. 
 
Refer to the PLD package insert for the most complete and current information on the 
following: 
 
9.6.1 Formulation:  
PLD (doxorubicin HCl liposome injection) is supplied as a sterile, translucent, red liposomal 
dispersion in 5 mL (commercially available), 10 mL, or 30 mL glass, single-use vials. Each 
vial contains doxorubicin HCl at a concentration of 2 mg/mL.  
 
9.6.2 Storage: 
Refrigerate unopened vials of PLD at 2°–8°C (36°–46°F). Avoid freezing. Prolonged 
freezing may adversely affect liposomal drug products; however, short-term freezing (less 
than 1 month) does not appear to have a deleterious effect on PLD. 
 
9.6.3 Preparation: 
PLD doses up to 90 mg must be diluted in 250 mL of 5% Dextrose Injection, USP prior to 
administration. Doses exceeding 90 mg should be diluted in 500 mL of 5% Dextrose 
Injection, USP prior to administration. Aseptic technique must be strictly observed since no 
preservative or bacteriostatic agent is present in PLD. Diluted PLD should be refrigerated at 
2°C–8°C (36°F–46°F) and administered within 24 hours. 
• Do not mix with other drugs. 
• Do not use with any diluent other than 5% Dextrose Injection.  
• Do not use any bacteriostatic agent, such as benzyl alcohol.  
• PLD is not a clear solution but a translucent, red liposomal dispersion.  
• Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. Do not 
use if a precipitate or foreign matter is present.  
• Do not use in-line filter. 
 
9.6.4 Procedure for Handling and Proper Disposal: 
Caution should be exercised in the handling and preparation of PLD.  
 
The use of gloves is required.  

 
 
 
NRG-GY029 
- 78 -  
Version Date:  December 28, 2022 
 
 
If PLD comes into contact with skin or mucosa, immediately wash thoroughly with soap 
and water.  
 
PLD should be considered an irritant and precautions should be taken to avoid 
extravasation. With intravenous administration of PLD, extravasation may occur with or 
without an accompanying stinging or burning sensation, even if blood returns well on 
aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, 
the infusion should be immediately terminated and restarted in another vein. PLD must not 
be given by the intramuscular or subcutaneous route. 
  
PLD should be handled and disposed of in a manner consistent with other anticancer drugs.  
 
9.6.5 Adverse Effects: Consult the PLD package insert for the most current and complete 
information. 
 
9.6.6 Supplier: 
Commercially available. 
 
Consult the American Hospital Formulary Service Drug Information guide, Facts and 
Comparisons, or the package insert for additional information. 
 
 
Please refer to the current FDA-approved package insert provided with each drug and the 
site-specific pharmacy for toxicity information and instructions for drug preparation, 
handling, and storage. 
 
9.7 
Commercial Agent: Topotecan (NSC# 609699) 
 
9.7.1 Formulation:   
Topotecan is a cell cycle specific inhibitor of the nuclear enzyme topoisomerase I. It has a 
mean half-life of approximately three hours. Topotecan’s metabolism and clearance are 
complex but it is estimated that approximately 40% of the drug undergoes renal clearance.  
 
9.7.2 Supplier/How Supplied:   
Topotecan is commercially available and is supplied in a sterile form for intravenous use 
only.  
• Topotecan for Injection (lyophilized powder) is available generically as a sterile, 
lyophilized, buffered, light yellow to greenish powder available in single use vials 
containing topotecan hydrochloride equivalent to 4 mg of topotecan as the free base, 
with mannitol 48 mg and tartaric acid 20 mg. Hydrochloric acid and sodium 
hydroxide may be used to adjust the product pH.  Available products do not contain 
an antimicrobial preservative; thus any unused product should be discarded within 
24 hours of initial vial entry. 
• Topotecan Injection (solution) is available generically in individually-packaged 
single-use vials containing a sterile, non-pyrogenic, clear, yellow to yellow-green 

 
 
 
NRG-GY029 
- 79 -  
Version Date:  December 28, 2022 
 
solution of topotecan HCl equivalent to 4 mg of topotecan as the free-base at a 
concentration of 1 mg/mL.   
 
 
9.7.3 Solution Preparation:   
 
Topotecan for Injection (lyophilized powder) reconstitution: 
 
• Reconstitute lyophilized topotecan HCl with 4 mL sterile Water for Injection, USP (SWFI), 
to produce a yellow to yellow-green solution with concentration equal to 1 mg/mL and a pH 
within the range, 2.5 – 3.5. 
• Dilute an amount of drug appropriate for a patient’s dose in 50 – 250 mL of either 0.9% 
Sodium Chloride Injection (0.9%NS) or 5% Dextrose Injection (D5W), USP. 
 
 
  
Topotecan Injection (solution) reconstitution: 
• Each milliliter of solution contains topotecan hydrochloride equivalent to 1 mg of topotecan 
(free base), with 5 mg tartaric acid, NF, and SWFI. Hydrochloric acid and/or sodium 
hydroxide may be added to adjust product pH within the range 2.6 – 3.2. 
• Dilute an amount of Topotecan Injection (1 mg/mL) appropriate for a patient’s dose in a 
minimum volume of 50 mL of either 0.9% Sodium Chloride Injection (0.9%NS) or 5% 
Dextrose Injection (D5W), USP. 
 
9.7.4  Storage/Stability:   
Topotecan for Injection (lyophilized powder) storage and stability: 
• Store intact vials protected from light in the original cartons at controlled room 
temperature between 20° – 25°C (68° – 77°F). 
• After reconstitution with SWFI, vials should be used immediately.  
• After dilution with 0.9% NS or D5W, solutions prepared with Topotecan Injection 
are stable for at least 24 hours when stored at 20° – 25°C under ambient lighting 
conditions. 
 
 
Topotecan Injection (solution) storage and stability: 
• Store intact vials under refrigeration at 2° – 8°C (35.6° – 46.4°F) and protected  
from light in the original packaging carton. 
• After dilution with 0.9% NS or D5W, solutions prepared with Topotecan Injection 
are stable for 24 hours when stored at 20° – 25°C (68° – 77°F) under ambient 
lighting. 
 
9.7.5   Adverse effects:  
➢ Hematologic:  thrombocytopenia, leukopenia, anemia, neutropenia 
➢ Gastrointestinal:  nausea and vomiting, mucositis, diarrhea 
➢ Skin: rash 
➢ Other:  alopecia, fever, flu-like symptoms 
 
Please refer to the current FDA-approved package insert provided with each drug and the 
site-specific pharmacy for toxicity information and instructions for drug preparation, 
handling, and storage. 
 

 
 
 
NRG-GY029 
- 80 -  
Version Date:  December 28, 2022 
 
10. 
PATHOLOGY/BIOSPECIMEN 
Not Applicable 
 
11. 
SPECIAL STUDIES (NON-TISSUE) 
Not applicable 
 
12. 
MODALITY REVIEWS 
Not appliable 
 
13. 
ASSESSMENT OF EFFECT 
 
13.1 
Antitumor Effect – Solid Tumors  
Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1). [Eur J Ca 45:228-247, 2009] Changes in the largest diameter (uni-dimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria.  
 
For this study, a rise in CA-125 alone is not sufficient to declare progression, and 
progression events should be determined by radiographic evidence of progression. 
  
13.1.1 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 ≥10 mm with CT 
scan, as ≥20 mm by chest x-ray, or ≥10 mm with calipers by clinical exam. All tumor 
measurements must be recorded in decimal fractions of centimeters. 
  
Note: Tumor lesions that are situated in a previously irradiated area will not be considered 
measurable unless progression is documented or a biopsy is obtained to confirm persistence 
at least 90 days following completion of radiation therapy. 
  
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
  
Non-measurable disease: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease. Leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pneumonitis, inflammatory breast disease, and 
abdominal/pelvic masses (identified by physical exam and not CT or MRI), are considered 
as non-measurable.  
 
Notes:  
Bone lesions: Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by CT or MRI can be considered as measurable lesions if 

 
 
 
NRG-GY029 
- 81 -  
Version Date:  December 28, 2022 
 
the soft tissue component meets the definition of measurability described above. Blastic 
bone lesions are non-measurable. 
 
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, and 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. 
  
13.1.2 Methods for Evaluation of Measurable Disease  
All measurements should be taken and recorded in metric notation using a ruler or calipers. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 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 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. 

 
 
 
NRG-GY029 
- 82 -  
Version Date:  December 28, 2022 
 
  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g. for body scans), but NOT 
lung. 
  
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, subsequent 
image acquisitions should use the same type of scanner and follow the baseline imaging 
protocol as closely as possible. If possible, body scans should be performed with breath-
hold scanning techniques. 
 
NRG will not allow PET-CT use for RECIST 1.1 response criteria.  
 
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. 
 
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. 
 
It is mandatory to obtain cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment when measurable disease has met criteria for 
response or stable disease. This confirmation is necessary to differentiate response or stable 
disease versus progressive disease, as an effusion may be a side effect of the treatment. 
 

 
 
 
NRG-GY029 
- 83 -  
Version Date:  December 28, 2022 
 
13.2 
Response Criteria 
Determination of response should take into consideration all target (See 12.2.1) and non-
target lesions (See 12.2.2). 
 
13.2.1 Evaluation of Target Lesions  
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
  
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline 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. (Note: the appearance of one or more 
new lesions is also considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters (i.e. the nadir) while on 
study.  
 
13.2.2 Evaluation of Non-Target Lesions  
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (<10 mm short axis). 
  
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 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 disease status change, not a single lesion increase. 
  
Not evaluable (NE): When at least one non-target lesion is not evaluated at a particular time 
point. 
  
Although a clear progression of only “non-target” lesions 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). 
 
13.2.3 Evaluation of Best Overall Response  
The best overall response is the best time point response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive disease 
the smallest sum recorded since baseline). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria in some 
circumstances. 
 
Time Point Response for Patients with Measurable Disease at baseline (i.e., Target Disease) 

 
 
 
NRG-GY029 
- 84 -  
Version Date:  December 28, 2022 
 
 
*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. 
 
Time Point Response for Patients with only Non-Measurable Disease at baseline (i.e., 
Non-Target Disease) 
 
 
*See RECIST 1.1 manuscript for further details on what is evidence of a new lesion 
** ‘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 
 
 
13.2.4 Best Overall Confirmed Response  
 
In non-randomized trials where response is the primary endpoint, confirmation of PR and 
CR is required to ensure responses identified are not the result of measurement error.  This 
will also permit appropriate interpretation of results in the context of historical data where 
response has traditionally required confirmation in such trials. 
 
However, in all other circumstances, i.e. in randomized trials (phase II or III) or studies 
where stable disease or progression are the primary endpoints, confirmation of response is 
not required since it will not add value to the interpretation of results.  Therefore, for NRG-
GY029, confirmation of response is not required. 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions* 
Time Point 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Non-Target Lesions 
New Lesions* 
Time Point 
Response 
CR 
No 
CR 
CR 
No 
Non-CR/non-PD* 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
NE 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 

 
 
 
NRG-GY029 
- 85 -  
Version Date:  December 28, 2022 
 
Time Point Response 
First time point 
Time Point Response 
Subsequent time 
point 
BEST overall confirmed 
response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR* 
CR 
SD 
SD provided minimum 
criteria for SD 
duration met, otherwise, PD 
CR 
PD 
SD provided minimum 
criteria for SD 
duration met, otherwise, PD 
CR 
NE 
SD provided minimum 
criteria for SD 
duration met, otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum 
criteria for SD 
duration met, otherwise, PD 
PR 
NE 
SD provided minimum 
criteria for SD 
duration met, otherwise, NE 
NE 
NE 
NE 
 
 
*If a CR is truly met at first time point, then any disease seen at a subsequent time point, 
even disease meeting PR criteria relative to baseline, makes the disease PD at that point 
(since disease must have reappeared after CR).  However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient 
had PR or SD, not CR at the first time point. Under these circumstances, the original CR 
should be changed to PR or SD and the best response is PR or SD. 
 
In non-randomized trials where response is part of the primary endpoint, confirmation of CR 
or PR is needed to deem either one the “best overall response.”   Responses (CR and PR) 
require confirmation at greater than or equal to 4 weeks from initial documentation. 
 
For this study, the minimum criteria for SD duration is 8 weeks. 
 
Patients with a global deterioration of health status requiring discontinuation of treatment or 

 
 
 
NRG-GY029 
- 86 -  
Version Date:  December 28, 2022 
 
die without objective evidence of disease progression at that time should be reported to be 
off study treatment due to “symptomatic deterioration.”  Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
 
13.3 
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 date of study entry, including the baseline measurements. 
 
13.4 
Progression-Free Survival 
Progression-Free Survival (PFS) is defined as the duration of time from study entry to time 
of progression or death, whichever occurs first.  Patients who are alive without 
documentation of disease progression will be censored on the date of their last tumor 
assessment. 
 
13.5 
Survival 
Survival is defined as the duration of time from study entry to time of death or the date of 
last contact. 
 
14. 
DATA AND RECORDS 
14.1 
Data Management/Collection 
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.  
 
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have an 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. 
 

 
 
 
NRG-GY029 
- 87 -  
Version Date:  December 28, 2022 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
This study has a Delegation of Tasks Log (DTL). Therefore, those 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 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 
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 also 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.   
 
14.2 
NRG Data Management Forms 
Refer to the CTSU member website for protocol Form Set. 
 
14.3 
Summary of Data Submission 
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. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Section 7.5 and Section 7.6 for information about expedited and 
routine reporting.   
 
14.4 
Central Monitoring (CM)  
Central Monitoring (CM) Review is required for this protocol. CM allows Lead Protocol 
Organizations (LPOs) to remotely compare data entered in Rave to source documentation to 
ensure that sites are adhering to the protocol and central monitoring plan as well as 
accurately transcribing data from patients’ charts (i.e., source data verification). 
 

 
 
 
NRG-GY029 
- 88 -  
Version Date:  December 28, 2022 
 
Sites can upload source documents required for CM Review as documented in the central 
monitoring plan using the Source Document Portal (SDP) application. This application is 
also available on the CTSU members’ website under Auditing & Monitoring and may also 
be accessed using a direct link within Rave on the CM Alert form. Site staff with any of the 
Rave roles on a relevant site roster can view and upload source documents. Prior to saving 
source documents on the SDP, each site is responsible for removing or redacting any 
Personally Identifiable Information (PII) (note that functionality to do this redaction exists 
within the SDP itself). Designated LPO staff will review each document after it has been 
loaded on the SDP to ensure the appropriate documents have been uploaded and to ensure 
PII is redacted. 
 
Additional information on the SDP is available on the CTSU SDP application under 
Browser > Document Repository in the Help Topics button or by contacting the CTSU Help 
Desk (1-888-823-5923 or ctsucontact@westat.com).   
 
14.5 
Rave-CTEP-AERS integration 
 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) Integration enables evaluation of Adverse Events (AE) 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. 
 
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 study agent/intervention are collected using the Late Adverse 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 

 
 
 
NRG-GY029 
- 89 -  
Version Date:  December 28, 2022 
 
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_applications/docs/aeguideli
nes.pdf. 
 
14.6 
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, 
form 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 in 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. 

 
 
 
NRG-GY029 
- 90 -  
Version Date:  December 28, 2022 
 
 
 
To learn more about DQP use and access, click on the Help Topics button displayed on the 
Rave Home, DQP Queries, DQP Form Status, and DQP Reports  modules. 
 
14.7 
Global Reporting/Monitoring 
 
Data for this study will be submitted via the Data Mapping Utility (DMU).  Cumulative 
protocol- and patient-specific data will be submitted weekly to CTEP electronically via the 
DMU.  DMU Light reporting consists of Patient Demographics, On/Off Treatment Status, 
Abbreviated Treatment and Course information, and Adverse Events as applicable.  
Instructions for setting up and submitting data via DMU are available on the CTEP Website: 
https://ctep.cancer.gov/protocolDevelopment/dmu.htm.   
 
Note:  All adverse events (both routine and serious) that meet the protocol mandatory 
reporting requirements must be reported via DMU in addition to expedited reporting of 
serious adverse events via CTEP-AERS.   
 
15. 
STATISTICAL CONSIDERATIONS 
 
15.1 
Abstract 
This is as a two-arm, multicenter, open-label, 1:1 randomized Phase 2 superiority trial to test 
the efficacy of the copanlisib/olaparib combination (Arm 2) relative to physicians’ choice 
standard chemotherapy (Arm 1).  The Phase 2 design includes one interim analysis for 
futility of Arm 2.  The trial starts with a safety lead-in among the first patients randomized 
to Arm 2.  The safety lead-in includes two dose levels and will determine the recommended 
Phase 2 dose (RP2D) for Arm 2.   
 
15.2 
Stratification and Randomization 
Treatments will be allocated 1:1 within randomly permuted blocks. This procedure tends to 
allocate the treatment regimens to an equal number of enrollees within the 4 groups defined 
by combinations of the stratification factors. The randomized treatment assignment will be 
revealed to the patient and physician at the end of the registration process. The following 
stratification factors will be incorporated into the randomization plan: 
 
• BRCA 1/2 status: Any germline or somatic BRCA variant known or suspected to be 
deleterious VERSUS a germline BRCA variant that is either non-deleterious or 
benign and a somatic BRCA variant that is either non-deleterious, benign or 
unknown 
 
• Timing of prior PARPi therapy: PARPi as last line of therapy prior to initiation of 
the trial VERSUS other intervening therapy prior to initiation of the trial 
 
 
 

 
 
 
NRG-GY029 
- 91 -  
Version Date:  December 28, 2022 
 
15.3 
Patient Cohorts for Analysis 
 
Table POPS: Population Definitions 
 
Population 
Description 
DLT Evaluable The DLT Evaluable population includes patients randomized to Arm 2 
and assessed for toxicity during the safety lead-in. Patients who stop 
protocol therapy for reasons other than toxicity, disease progression or 
death before the end of cycle 2 may be replaced, and will be excluded 
from the DLT Evaluable population. 
This population includes 2 possible subsets: those who are treated at 
the RP2D, and those who are not.  DLT Evaluable patients who are 
not treated at the RP2D will be excluded from the Phase 2 analysis 
populations described below. 
ITT[a] 
The ITT population includes all randomized patients.  Patients will be 
analyzed according to their randomized therapy assignment, 
regardless of compliance with that therapy.  This population will be 
used for demographics and baseline characteristics summaries, 
participant disposition, and analyses of PFS and OS endpoints.  
Safety[a] 
The Safety population includes all randomized patients who receive 
any amount of protocol therapy. Treatment groups are determined 
using the actual treatment received regardless of the randomized 
treatment assignment.  All adverse event analyses will be conducted 
using the safety population. 
Measurable 
Disease[a] 
The Measurable Disease population includes all randomized patients 
who 
1. receive any amount of protocol therapy 
2. have baseline measurable disease per RECIST 1.1 
3. have at least one tumor assessment, disease progression, or 
death, whichever occurs first, within 12 months of starting 
protocol therapy. 
Patients will be analyzed according to their randomized treatment 
assignment, regardless of compliance with that therapy.  This 
population will support all analyses related to ORR. 
 
[a] Excludes DLT Evaluable patients who were not treated at the RP2D. 
 
15.4 
Primary Endpoint(s), Sample Size, and Analysis Plan 
 
15.4.1 Safety Lead-In 
The study will start with a safety lead-in, with the primary objective to assess the safety and 
tolerability of the Arm 2 combination.  The following considerations characterize the safety 

 
 
 
NRG-GY029 
- 92 -  
Version Date:  December 28, 2022 
 
lead-in: 
 
1. The NRG Phase 1 Subcommittee and Early Phase Oversight Committees, with support 
from the study team, will review toxicity data, determine dose level changes, and make a 
final recommendation about continuing the study after completion of the safety lead-in. 
2. The primary endpoint is the proportion of DLT Evaluable patients with at least one dose 
limiting toxicity (DLT).   
3. A DLT is defined as any treatment-related adverse event requiring permanent 
discontinuation of copanlisib within the first two treatment cycles.   
4. Dose reductions for olaparib are permitted (as described in Section 6.3 Olaparib dose 
reduction table). Toxicity following olaparib dose-reduction and leading to a treatment 
delay of >30 days will be counted as a DLT. If more than two olaparib dose-reductions 
are needed, then this will be counted as a DLT.  
5. A dose level may be considered overly toxic whenever the proportion of evaluable 
patients with at least one DLT is π > 0.33.   
6. The evaluable patient set is the DLT Evaluable population, defined in Table POPS. 
7. The dose levels available for the safety lead-in are shown in Table SLDoses.  
 
Table SLDoses.  Safety Lead-in Dose Levels: 
 
Dose 
Level 
Copanlisib 
Olaparib 
1 
45mg D1, D8, D15 of a 28-day cycle 
300mg BID 
-1 
45mg D1, D15 of a 28-day cycle 
300mg BID 
 
The following decision rules guide the safety lead-in: 
 
1. The study treatments (olaparib+copanlisib vs chemotherapy) will be randomly 
allocated (1:1) to each individual enrolled during this component of the study.   
2. Patients randomized to Arm 2 will start accruing to dose level DL1.  Enrollment will 
proceed until at least n=10 patients receive any amount of the olaparib+copanlisib 
combination.  Patients who do not meet the DLT Evaluable criteria (Table POPS) 
may be replaced.   
3. At any time after n=3 DLT Evaluable patients have enrolled, if the DLT proportion 
among patients treated at DL1 is π > 0.33, or DL1 is otherwise considered 
intolerable, the Phase 1 Subcommittee and/or Early Phase Oversight Committee may 
suspend accrual to DL1, and open DL-1. 
4. After the tenth patient in the DLT Evaluable cohort enrolls, accrual may be 
suspended for DLT assessment. 
5. If accrual to DL-1 is opened, decision rules 1, 2, 3 and 4 will apply. 
6. When an Arm 2 dose level is considered safe based on this assessment, the protocol 
will be amended to allow participation of NCTN sites and activation of the full phase 
II trial. 

 
 
 
NRG-GY029 
- 93 -  
Version Date:  December 28, 2022 
 
7. If DL-1 is not tolerated, alternative copanlisib/olaparib dosing regimens may be 
pursued depending on toxicities, PK and PD data generated from NCI 10217 and 
other trials. (02-JUN-2022) 
15.4.2 Phase 2 Statistical Design 
 
This is as a two-arm randomized phase II study. The primary endpoint is investigator-
assessed progression-free survival (PFS), as defined in Section 13.4.  The null and 
alternative hypotheses with regard to the relative PFS event rate for the experimental arm 
versus standard of care arm are as follows: 
  
𝐻0: Δ =
𝜆2
𝜆1 ≥1.0  vs  𝐻1: Δ =
λ2
λ1 < 1.0 
  
where (λ2, λ1) are the PFS hazards in Arm 2 and Arm 1 respectively, and Δ is the 
corresponding hazard ratio. The design parameters are based on the following piecewise-
hazard assumptions for the standard of care arm, obtained from control arm of the 
AURELIA trial (Pujade-Lauraine (2014) PMID: 24637997) 
  
Months from 
Enrollment 
Proportion Alive and 
Progression Free 
0 
100 
1.5 
90 
3.4 (median) 
50 
6.0 
20 
15 and beyond 
1.0 
  
With a one-sided 𝛼=0.10, a total of 57 PFS events has power=0.90 to detect a hazard ratio 
of Δ=0.50.  If the PFS times are exponentially distributed, and the median PFS is 3.4 months 
in the reference arm, a hazard ratio of Δ=0.50 corresponds to a median PFS of 6.8 months in 
the experimental arm. The relationship between the power and minimum detectable hazard 
ratio (HR) is shown in the table below.  If the true HR is 0.55, the power decreases to 0.82. 
  
HR 
Power 
0.50 0.90 
0.55 0.82 
0.60 0.73 
   
15.4.3 Phase 2 Interim Futility Analyses 
 
The design includes an interim futility analysis, using a Lan-Demets (O'Brien-Fleming) type 
futility boundary.  The interim analysis is planned when a total of 29 PFS events (50% 
information) are observed. This is expected to occur approximately 11.4 months after 
starting accrual. If these assumptions hold and the HR estimate (Δ=λ2/λ1) is >1.07, 
consideration will be given to stopping the study for futility of the experimental arm. Under 
the null hypothesis, the probability of stopping for futility is 0.43, and under the alternative 

 
 
 
NRG-GY029 
- 94 -  
Version Date:  December 28, 2022 
 
hypothesis, the probability is 0.02 (i.e., 0.02 of the β = 0.10 is spent at the interim analysis).  
The interim analysis results will be examined by the NRG Data Monitoring Committee. The 
decision to terminate accrual will include consideration of toxicities, treatment compliance, 
and progression-free survival and other endpoints, and results from external studies. 
 
If the study is still accruing patients, accrual will not be suspended for the interim analysis. 
 
15.4.4 Accrual/Study Duration  
 
With an accrual rate of 8 eligible patients per month and a 10% dropout rate, a sample size 
of 96 patients will accrue over about 15 months.  A follow-up period of 2 months should 
provide the needed number of events. Total study duration is estimated to be 16 months. 
The final analysis will occur when at least 32 PFS events are observed in the standard of 
care arm (which is the expected number to occur with 57 events total and a hazard ratio of 
Δ=0.50). 
 
If necessary, accrual may be suspended during the safety lead-in for DLT assessment, and 
for determination of the RP2D.  No other accrual suspensions are planned. 
 
15.4.5 Analysis Plan  
 
The interim and primary analyses of PFS (defined in Section 13.4) will be based on a 
logrank test, stratified by the factors declared at randomization. These analyses will include 
all patients enrolled onto the study regardless of compliance to their assigned study regimen. 
Patients will be grouped by their randomized treatment for intention-to-treat analyses (ITT 
population, Section 15.3).  For the purposes of the primary analyses, the documentation of 
disease progression will be determined by the treating physician. 
 
The treatment hazard ratios and their 95% confidence intervals will be estimated using a 
multivariable proportional hazards model specified with main effects for the randomized 
treatment assignment (Arm 2 vs Arm 1) and covariate adjustment for the stratification 
factors declared at randomization. 
 
15.5 
Monitoring/Oversight Committee 
 
NRG Oncology Data Monitoring Committee (DMC) 
 
The NRG Oncology Data Monitoring Committee (DMC) meets twice a year to review the 
progress of all ongoing NRG Oncology randomized phase II or III trials. Approximately 
eight weeks prior to the scheduled meetings, the study database is locked for preparation of 
a study report. This study report includes summaries of accrual and adverse event data.  
Information related to the safety lead-in will be included in these DMC reports.   
 
The DMC will review the study for protocol-specified interim analyses on an “as needed” 
basis.  If the prerequisite number of events for an interim analysis has been attained, a report 
summarizing the interim analysis results is also prepared and presented to the DMC. The 

 
 
 
NRG-GY029 
- 95 -  
Version Date:  December 28, 2022 
 
decision to terminate accrual or to release study results includes consideration of toxicities, 
treatment compliance, and results from external studies. 
 
NRG Phase 1 Subcommittee and Early Phase Oversight Committee 
NRG Phase 1 Subcommittee and Early Phase Oversight Committee, with support from the 
study team, will review toxicity data, determine dose level changes, and make a final 
recommendation about continuing the study after completion of the safety lead-in. These 
findings will be presented to the DMC for final approval.  
 
15.6 
Secondary Endpoints and Analysis Plans  
[Each secondary endpoint will be a subsection with paragraph(s) as needed for the following 
info: define the endpoint, list hypothesis (if applicable), describe analysis plan, and address 
cohort size if different from overall sample size] 
 
15.6.1 (Objective 1.2.1) To assess the clinical efficacy of the combination of copanlisib/olaparib, as 
measured by objective response rate (ORR), per RECIST 1.1 measurement of target lesions. 
 
The Measurable Disease population (Section 15.3) will support these analyses.  The 
objective response rate (ORR) is defined as the binomial proportion of evaluable patients 
with a best overall response of CR or PR (by RECIST 1.1).  Responses reported by the 
treating physician will be used for these analyses.  
  
The ORR estimates by treatment arm will be supported by their 2-sided, 95% Wilson-Score 
confidence intervals (Wilson, 1927, Agresti, 1998).  The relative odds of response in the 
experimental group (vs. the reference group) will be estimated using a multivariable logistic 
regression model specified with main effects for the treatment group and covariate 
adjustments for the stratification factors reported at baseline. 
 
15.6.2 (Objective 1.2.2) To assess the clinical efficacy of the combination of copanlisib/olaparib, as 
measured by overall survival (OS), compared to standard chemotherapy in the setting of 
platinum resistant ovarian cancer that has progressed through prior PARP inhibitor therapy 
 
The OS treatment hypothesis test will be based on a logrank test, stratified by the factors 
specified at randomization.  These analyses will be supported by the ITT population 
(Section 15.3).   
 
The treatment hazard ratios and their 95% confidence intervals will be estimated using a 
multivariable proportional hazards model specified with main effects for the randomized 
treatment assignment (Arm 2 vs Arm 1) and covariate adjustment for the stratification 
factors used in the randomization. 
 
15.6.3  (Objective 1.2.3) To determine the nature, frequency, and degree of toxicity as assessed by 
CTCAE v.5.0 for each treatment arm  
 
The Safety Population (Section 15.3) will support these analyses.  The nature, frequency, 
and degree of toxicity will be tabulated at the System Organ Class and AE-specific term 

 
 
 
NRG-GY029 
- 96 -  
Version Date:  December 28, 2022 
 
levels using CTCAE v5.0.  Each patient will be represented according to the maximum 
grade observed for each term.  Tabulations will show the number and percentage of patients 
by maximum grade, within the treatment group received, regardless of the randomized 
treatment assignment.  No specific hypothesis test is pre-specified. 
 
15.7 
Exploratory Endpoints 
 
There are none. 
 
 
 
 
 
 
 
15.8 
Gender/Ethnicity/Race Distribution 
 
 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
1 
 
0 
0 
0 
1 
Asian 
5 
0 
0 
0 
5 
Native Hawaiian or Other 
Pacific Islander 
1 
0 
0 
0 
1 
Black or African American 
5 
0 
3 
0 
8 
White  
68 
0 
2 
0 
70 
More Than One Race 
0 
0 
0 
0 
0 
Total 
80 
0 
5 
0 
85 
 
 
 
Racial Categories 
INTERNATIONAL (including Canadian participants) 
PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
 
 
 
 
 
Asian 
 
 
 
 
 
Native Hawaiian or Other 
Pacific Islander 
 
 
 
 
 
Black or African American 
 
 
 
 
 
White  
 
 
 
 
 
More Than One Race 
 
 
 
 
 
Total 
 
 
 
 
 
 
 

 
 
 
NRG-GY029 
- 97 -  
Version Date:  December 28, 2022 
 
16. 
REFERENCES 
 
Agresti, A. and B. A. Coull. Approximate is better than "exact" for interval estimation of 
binomial proportions. The American Statistician 1998; 52 (2), 119-126. 
 
Ali, K., D.R. Soond, R. Pineiro, et al.  (2014).  Inactivation of PI(3)K p110delta breaks 
regulatory T-cell-mediated immune tolerance to cancer.  Nature.  510:407-411. 
 
 
de Gooijer MC, Zhang P, Buil LCM, et al. Buparlisib is a brain penetrable pan-PI3K 
inhibitor. Sci Rep. 2018;8(1):10784. 
 
Dreyling M, Morschhauser F, Bouabdallah K, et al. Phase II study of copanlisib, a PI3K 
inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol. 
2017;28(9):2169-2178. 
 
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):852-861. 
 
Gockeritz, E., S. Kerwien, M. Baumann, et al.  (2015).  Efficacy of phosphatidylinositol-3 
kinase inhibitors with diverse isoform selectivity profiles for inhibiting the survival of 
chronic lymphocytic leukemia cells.  Int J Cancer.  137:2234-2242. 
 
Ibrahim YH, Garcia-Garcia C, Serra V, et al. PI3K inhibition impairs BRCA1/2 expression 
and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer 
Discov. 2012;2(11):1036-1047. 
 
Investigator's Brochure (2018).  Copanlisib (BAY 80-6946).  Bayer AG.  Edition 11.0 
(August 10, 2018). 
 
Juvekar A, Burga LN, Hu H, et al. Combining a PI3K inhibitor with a PARP inhibitor 
provides an effective therapy for BRCA1-related breast cancer. Cancer Discov. 
2012;2(11):1048-1063. 
 
Juvekar A, Hu H, Yadegarynia S, et al. Phosphoinositide 3-kinase inhibitors induce DNA 
damage through nucleoside depletion. Proc Natl Acad Sci U S A. 2016;113(30):E4338-
4347. 
 
Konstantinopoulos PA, Barry WT, Birrer M, et al. Olaparib and alpha-specific PI3K 
inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-
expansion phase 1b trial. Lancet Oncol. 2019;20(4):570-580. 
 
Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D'Andrea AD. Homologous Recombination 
Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer. Cancer Discov. 
2015;5(11):1137-1154. 

 
 
 
NRG-GY029 
- 98 -  
Version Date:  December 28, 2022 
 
 
Liu JF, Palakurthi S, Zeng Q, et al. Establishment of Patient-Derived Tumor Xenograft 
Models of Epithelial Ovarian Cancer for Preclinical Evaluation of Novel Therapeutics. Clin 
Cancer Res. 2016;23(5):1263-1273. 
 
Liu, N., B.R. Rowley, C.O. Bull, et al.  (2013).  BAY 80-6946 is a highly selective 
intravenous PI3K inhibitor with potent p110alpha and p110delta activities in tumor cell 
lines and xenograft models.  Mol Cancer Ther.  12:2319-2330. 
 
Markham A. Copanlisib: First Global Approval. Drugs. 2017;77(18):2057-2062. 
 
Matulonis UA, Wulf GM, Barry WT, et al. Phase I dose escalation study of the PI3kinase 
pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor 
olaparib for the treatment of high-grade serous ovarian and breast cancer. Ann Oncol. 
2016;28(3):512-518. 
 
Moore KN, Secord AA, Geller MA, et al. Niraparib monotherapy for late-line treatment of 
ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. Lancet 
Oncol. 2019;20(5):636-648. 
 
Okkenhaug, K., and J.A. Burger.  (2016).  PI3K signaling in normal B cells and chronic 
lymphocytic leukemia (CLL).  Curr Top Microbiol Immunol.  393:123-142. 
 
 
Patnaik A, Appleman LJ, Tolcher AW, et al. First-in-human phase I study of copanlisib 
(BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in 
patients with advanced solid tumors and non-Hodgkin's lymphomas. Ann Oncol. 
2016;27(10):1928-1940. 
 
Rehman FL, Lord CJ, Ashworth A. The promise of combining inhibition of PI3K and PARP 
as cancer therapy. Cancer Discov. 2012;2(11):982-984. 
 
Westin, J.R.  (2014).  Status of PI3K/Akt/mTOR pathway inhibitors in lymphoma.  Clin 
Lymphoma Myeloma Leuk.  14:335-342. 
 
Wilson, E. B. Probable inference, the law of succession, and statistical inference. Journal of 
the American Statistical Association 1927; 22 (158), 209-212. 
 
 
 
 
 
 
 

 
 
 
NRG-GY029 
- 99 -  
Version Date:  December 28, 2022 
 
APPENDIX I – FIGO OVARIAN CANCER STAGING 2014  
 
STAGE I: Tumor confined to ovaries  
 
IA Tumor limited to 1 ovary, capsule intact, no rumor on surface, negative washings. 
 
IB Tumor involves both ovaries otherwise like 1A. 
 
IC Tumor limited to 1 or both ovaries 
 
IC1 
Surgical spill 
IC2 
Capsule rupture before surgery or tumor on ovarian surface 
IC3 
Malignant cells in the ascites or peritoneal washings 
 
STAGE II: 
Tumor involves 1 or both ovaries with pelvic extension (below the pelvic brim) 
 
or primary peritoneal cancer  
 
IIA Extension and/or implant on uterus and/or Fallopian tubes 
 
IIB Extension to other pelvic intraperitoneal tissues 
 
STAGE III: 
Tumor involves 1 or both ovaries with cytologically or histologically 
 
confirmed spread to the peritoneum outside the pelvis and/or metastasis to the 
 
retroperitoneal lymph nodes  
 
IIIA Positive retroperitoneal lymph nodes and/or microscopic metastasis beyond the 
pelvis 
 
 
IIIA1 Positive retroperitoneal lymph nodes only 
IIIA1(i)  
Metastasis ≤ 10 mm 
IIIA1(ii)    Metastasis > 10mm 
 
 
IIIA2 
Microscopic, extrapelvic (above the brim) peritoneal involvement ± 
positive retroperitoneal lymph nodes 
 
IIIB Macroscopic, extrapelvic, peritoneal metastasis ≤ 2 cm ± positive retroperitoneal 
lymph nodes.  Includes extension to capsule of liver/spleen. 
 
IIIC Macroscopic, extrapelvic, peritoneal metastasis > 2 cm ± positive retroperitoneal 
lymph nodes.  Includes extension to capsule of liver/spleen. 
 
STAGE IV: Distant metastasis excluding peritoneal metastasis 
 
IVA 
Pleural effusion with positive cytology 
 

 
 
 
NRG-GY029 
- 100 -  
Version Date:  December 28, 2022 
 
APPENDIX II – PERFORMANCE STATUS 
 
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. 
 
 
 

 
 
 
NRG-GY029 
- 101 -  
Version Date:  December 28, 2022 
 
APPENDIX III – NYHA CLASSIFICATION 
 
Congestive Heart Failure – New York Heart Association Classification 
 
Class 
Patient Symptoms 
I 
No limitation: Ordinary physical activity does not cause undue fatigue, dyspnea, or 
palpitation 
II 
Slight limitation of physical activity: Such patients are comfortable at rest. Ordinary 
physical activity results in fatigue, palpitations, dyspnea, or angina. 
III 
Marked limitation of physical activity: Although patients are comfortable at rest, less 
than ordinary physical activity will lead to symptoms. 
IV 
Inability to carry on physical activity without discomfort: Symptoms of congestive 
heart failure are present even with rest. With any physical activity, increased 
discomfort is experienced. 
 
Class 
Objective Assessment 
A 
No objective evidence of cardiovascular disease. No symptoms and no limitation in 
ordinary physical activity. 
B 
Objective evidence of minimal cardiovascular disease. Mild symptoms and slight 
limitation during ordinary activity. Comfortable at rest. 
C 
Objective evidence of moderately severe cardiovascular disease. Marked limitation in 
activity due to symptoms, even during less-than-ordinary activity. Comfortable only at 
rest. 
D 
Objective evidence of severe cardiovascular disease. Severe limitations. Experiences 
symptoms even while at rest. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
NRG-GY029 
- 102 -  
Version Date:  December 28, 2022 
 
APPENDIX IV- ACTIONS REQUIRED IN CASES OF COMBINED INCREASE OF 
AMINOTRANSFERASE AND TOTAL BILIRUBIN – 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/A:T 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. 
  
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.  

 
 
 
NRG-GY029 
- 103 -  
Version Date:  December 28, 2022 
 
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; 
nonalcoholic steatohepatitis; 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 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. 

 
 
 
NRG-GY029 
- 104 -  
Version Date:  December 28, 2022 
 
  
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.  
• Nonalcoholic steatohepatitis. Nonalcoholic steatohepatitis may be seen in obese, 
hyperlipoproteinemic, and/or diabetic patients and may be 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.  

 
 
 
NRG-GY029 
- 105 -  
Version Date:  December 28, 2022 
 
 
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, and the Study Chair consulted. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
NRG-GY029 
- 106 -  
Version Date:  December 28, 2022 
 
APPENDIX V – LIST OF PROHIBITED MEDICATIONS WHILE ON COPANLISIB AND 
OLAPARIB TREATMENT 
 
This list is not comprehensive. Refer to the protocol document concerning the co-administration of 
strong CYP3A inhibitors. 
 
Category 
Drug name 
Strong CYP3A Inhibitors 
Voriconazole, Boceprevir, clarithromycin, 
cobicistat, conivaptan, danoprevir/ritonavir, 
eltegravir/ritonavir, grapefruit juice, 
indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, 
saquinavir/ritonavir, telaprevir, telithromycin, 
tipranavir/ritonavir, troleandomycin, 
Strong CYP3A Inducers 
Avasimibe, carbamazepine, mitotane, 
phenobarbital, phenytoin, rifabutin, rifampin 
(rifampicin), St. John's wort (hypericum 
perforatum) 
Herbal Preparations/ 
Medications 
Herbal preparations/medications are prohibited 
throughout the study. These herbal medications 
include, but are not limited to: St. John’s Wort, 
Kava, ephedra (ma huang), ginkgo biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, and ginseng. Patients should stop using 
these herbal medications 14 days prior to first 
dose of study drug 
 
 
 

 
 
 
NRG-GY029 
- 107 -  
Version Date:  December 28, 2022 
 
APPENDIX VI – GENERAL THERAPY GUIDELINES  
 
 
• For cycle lengths greater than or equal to 21 days, a patient will be permitted to have 
a new cycle of chemotherapy delayed up to 7 days (without being considered a 
protocol violation) for major life events (e.g., serious illness in a family member, 
major holiday, vacation which is unable to be re-scheduled).  Documentation to 
justify this decision should be provided. 
• It will be acceptable for individual chemotherapy doses to be delivered within a “24-
hour window before and after the protocol-defined date” for “Day 1” treatment of 
cycle lengths greater than or equal to 21 days.  If the treatment due date is a Friday, 
and the patient cannot be treated on that Friday, then the window for treatment 
would include the Thursday (1 day earlier than due) through the Monday (day 3 past 
due). 
• For weekly regimens, it will be acceptable for individual chemotherapy doses to be 
delivered within a “24-hour window,” for example; “Day 8 chemotherapy” can be 
delivered on Day 7, Day 8, or Day 9 and “Day 15 chemotherapy” can be given on 
Day 14, Day 15, or Day 16. 
• Chemotherapy doses can be “rounded” according to institutional standards without 
being considered a protocol violation (most institutions use a rule of approximately 
+/- 5% of the calculated dose). 
• Chemotherapy doses are recommended to be recalculated if the patient has a weight 
change of greater than or equal to 10%.  Patients are permitted to have chemotherapy 
doses recalculated for < 10% weight changes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
NRG-GY029 
- 108 -  
Version Date:  December 28, 2022 
 
APPENDIX VII – CTEP COLLABORATIVE AGREEMENTS LANGUAGE 
 
The agent supplied by CTEP, DCTD, NCI used in this protocol is provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators. The protocol documents for 
studies utilizing Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI. If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual 
should sign a confidentiality agreement. A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an 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 

 
 
 
NRG-GY029 
- 109 -  
Version Date:  December 28, 2022 
 
(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. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication.  Collaborator(s) will have 30 
days from the date of receipt for review.  Collaborator shall have the right to request 
that publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected. Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and 
preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and other 
media presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
E-mail: 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. 
 
 
 
 
 
 
 

 
 
 
NRG-GY029 
- 110 -  
Version Date:  December 28, 2022 
 
APPENDIX VIII– PATIENT CLINICAL TRIAL WALLET CARD FOR COPANLISIB 
AND OLAPARIB 
 
 
 
 
CLINICAL TRIAL WALLET CARD 
Show this card to all of 
your healthcare 
providers and keep it 
with you in case you go 
to the emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:        
Study Drug(S):  Copanlisib and Olaparib 
 
 
 
Version JAN/2019 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
NRG-GY029 
- 111 -  
Version Date:  December 28, 2022 
 
APPENDIX IX – OLAPARIB DRUG DIARY 
Today’s Date ______________________________ 
               Cycle # ________________________ 
Patient Name ______________________________ 
               Patient Study ID _________________ 
1. Complete one form for each cycle (28 days).  
3. Record the date, the number of pills you took, and when you took them.  
4. Bring your pill bottles (including empty bottles) and this form to every appointment. 
5. Do not chew, dissolve, or crush medications. DO NOT make up vomited doses. 
6. If you miss a dose, you have up to 2 hours to make this dose up. Otherwise, write “missed” where you would normally write the 
time of your dose. 
7. The first row in the table below is an EXAMPLE ROW for how to complete this diary. 
 
 
 
 
 
 
 
 
 
 
 
OLAPARIB 
Take __(number) ____mg and __(number) ____ mg tablets twice a day 12 hours apart. 
Day 
Date 
100 mg 
150 mg 
AM 
PM 
1 
1/1/2021 
2 
0 
 
7:00 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
13 
 
 
 
 
 
14 
 
 
 
 
 
15 
 
 
 
 
 
16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
 
Patient’s Signature: ___________________________________                    Date: _____________ 
Physician/Nurse’s Signature ________________________    Date______________