Phase I/IB Safety and Pharmacodynamic Study of Neoadjuvant (NACT) Paclitaxel and Carboplatin With Ipatasertib as Initial Therapy of Ovarian Cancer PTMA 100805
Phase: PHASE1
Conditions: Fallopian Tube Endometrioid Adenocarcinoma, Fallopian Tube High Grade Serous Adenocarcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian High Grade Serous Adenocarcinoma, Primary Peritoneal Endometrioid Adenocarcinoma, Primary Peritoneal High Grade Serous Adenocarcinoma, Stage III Fallopian Tube Cancer AJCC v8, Stage III Ovarian Cancer AJCC v8, Stage III Primary Peritoneal Cancer AJCC v8, Stage IV Fallopian Tube Cancer AJCC v8, Stage IV Ovarian Cancer AJCC v8, Stage IV Primary Peritoneal Cancer AJCC v8, Unresectable Fallopian Tube Endometrioid Adenocarcinoma, Unresectable Fallopian Tube High Grade Serous Adenocarcinoma, Unresectable Ovarian Endometrioid Adenocarcinoma, Unresectable Ovarian High Grade Serous Adenocarcinoma, Unresectable Primary Peritoneal Endometrioid Adenocarcinoma, Unresectable Primary Peritoneal High Grade Serous Adenocarcinoma
Sponsor: National Cancer Institute (NCI)

i  
NRG-GY027 
Version Date: December 22, 2023 
For Protocol Amendment #03 to: NRG-GY027 
NCI Protocol #: NRG-GY027 
Local Protocol #: NRG-GY027 
NCI Version Date: 12/22/2023 
 
 
SUMMARY OF CHANGES 
Response to Comments Received 12/13/2023. 
Comments Requiring a Response – Major Issues: 
# 
Section 
Comments
1 
Cover Page 
For 
Regulatory 
Submission 
Please replace the following with the latest CTSU template 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 the Regulatory > Regulatory 
Submission.)  
Institutions with patients waiting that are unable to use the 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. 
Contact the CTSU Regulatory Help Desk at 1-866-651-CTSU (2878) for 
regulatory assistance. 
Please revise the excerpt below as indicated. 
The most current version of the study protocol and all supporting documents must 
be downloaded from the protocol-specific page 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.  
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) on the CTSU members’ website 
CTSU Regulatory Support System (RSS). 
PI Response: This change has been made.  
2 
2 
Please update the background to indicate the experience with the dose escalation 
and provide support for the dose selected for expansion.     
 
PI Response:  Section Now reads:
 
There have been 12 participants enrolled and treated on DL1 (200mg) and 
DL2 (300mg). Among these 12 eligible and treated participants, 11 have been 
off study treatment.
  
Dose Level 1 had two cohorts with 7 patients enrolled and treated including 
6 patients who were considered DLT-evaluable. Among these 6 DLT-
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Version Date: December 22, 2023 
# 
Section 
Comments
evaluable patients, 1 had DLT based on treatment discontinuation > 14 days 
due to grade 3 maculo-papular rash. 
For Dose Level 2, there were five patients in two cohorts with two DLTs. The 
DLTs were grade 2 diarrhea and grade 4 neutropenia. There was another 
participant during the postoperative period with a SAE for prolonged apneic 
arrest with anoxic injury. There were no delays in reaching surgical 
intervention in either DL1 or DL2. The MTD was determined to be 200mg 
daily. 
 
3 
6.3 
This section suggests that a maximum of 2 dose level reductions can occur for 
ipatasertib, however, there is only one dose level described in the protocol.  
Please clarify the statement to only allow 1 dose level reduction is permitted or 
clarify the permitted dose reductions. 
PI Response: Given the MTD is at DL1 of 200mg daily, there will be only one 
dose level reduction to 100mg daily. 
 
4 
8, 
Registration 
and Study 
Entry 
Procedures 
Please replace the following with the latest CTSU template language. 
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 Cancer Therapy Evaluation Program (CTEP) 
credentials necessary to access secure NCI Clinical Oncology Research 
Enterprise (CORE) systems. 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:
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iv  
NRG-GY027 
Version Date: December 22, 2023 
# 
Section 
Comments
(SSW) for Local Context to the CIRB using IRBManager to indicate their intent 
to open the study locally. The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact 
the CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site 
preferences for applying NCI CIRB approvals across their Signatory Network. 
Site preferences can be set at the network or protocol level. Questions about 
establishing site preferences can be addressed to the CTSU Regulatory Office by 
email or calling 1-888-651-CTSU (2878). 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on 
the IRB/REB approval) must meet the following criteria for the site to be able to 
have an Approved status following processing of the IRB/REB approval record: 
Have an active CTEP status; 
Have an active status at the site(s) on the IRB/REB approval (applies to US and 
Canadian sites only) on at least one participating organization’s roster; 
If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
Include the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile;  
List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in 
the RCR profile; and 
Have the appropriate CTEP registration type for the protocol.  
Additional Requirements
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 the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
Compliance with all applicable protocol-specific requirements (PSRs). 
PI Response: Section has been updated. 
6 
8.1, Cancer 
Trials 
Support Unit 
Registration 
Procedures 
The following paragraph can be deleted, as it is not a Protocol Specific 
Requirement. 
Protocol-Specific Requirements for Protocol NRG-GY027 Site Registration 
Upon site registration approval in RSS, the enrolling site may access OPEN to 
complete enrollments. The enrolling site will select their credentialed provider 
treating the subject in the OPEN credentialing screen, and may need to answer 
additional questions related to treatment in the eligibility checklist.  
PI Response: This has been deleted. 
7 
8.1, Cancer 
Trials 
Support Unit 
Registration 
Procedures
Please replace the following with the latest CTSU template language. 
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 
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v  
NRG-GY027 
Version Date: December 22, 2023 
# 
Section 
Comments
investigators and staff on a participating roster. To view/download site 
registration forms:  
Log in to the CTSU members’ website (https://www.ctsu.org);
Click on Protocols in the upper left of the screen: 
Enter the protocol number in the search field at the top of the protocol tree; or
Click on the By Lead Organization folder to expand, then select NRG, and 
protocol number NRG-GY027. 
Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration to download and complete the forms provided. 
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU.)  
PI Response: Section has been updated. 
8 
8.1, Cancer 
Trials 
Support Unit 
Registration 
Procedures 
Please revise the excerpt below as indicated. 
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 at 1-
866-651-2878 in order to receive further instruction and support. 
PI Response: Section has been updated. 
9 
8.1, Cancer 
Trials 
Support Unit 
Registration 
Procedures 
Please revise the excerpt below as indicated. 
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 include a 
Master Task List, which describes DTL task assignments, CI signature, and 
CTEP registration requirements, as well as include a Master Task List. 
PI Response: Section has been updated.  
10 
8.2.1, 
Oncology 
Patient 
Enrollment 
Network 
Please revise the excerpt below as indicated. 
A valid CTEP-IAM account; 
Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems;
Please revise the excerpt below as indicated. 
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vi  
NRG-GY027 
Version Date: December 22, 2023 
# 
Section 
Comments
(OPEN) 
All patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) HIPAA authorization form (if 
applicable) 
Please revise the excerpt below as indicated. 
Patient enrollment for this study will be facilitated using the Slot Reservation 
System in conjunction with patient enrollment the registration system in OPEN. 
Prior to discussing protocol entry with the patient, all site staff must use the 
CTSU OPEN Slot Reservation System to ensure that a slot on the protocol is 
available to the patient. Once a slot reservation confirmation is obtained, site staff 
may then proceed to enroll the patient to this study. 
PI Response: Section has been updated. 
11 
10.3.2.2 & 
10.3.3.2 
WES and RNAseq through the NCLN may be performed at either the NCLN 
Genomics Laboratory or the MoCha, Frederick National Laboratory for Cancer 
Research (FNLCR).    
Please update the update references to the “NCLN Genomics Laboratory” in 
Sections 10.3.2.2 and 10.3.3.2 to list both laboratories: “NCLN Genomics 
Laboratory or MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR)”.  
PI Response: Sections have been updated.  
12 
12.4, Rave-
CTEP-AERS 
Integration 
Please replace the following with the latest CTSU template language. 
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.  
Include the following highlighted paragraph about pre-treatment AEs only if the 
study requires reporting of pre-treatment AEs and the CTSU standard Pre-
Treatment AE form is used. Pre-existing medical conditions are not considered 
adverse events and therefore should not be reported on the Pre-Treatment 
Adverse Event form. 
Pre-treatment AEs: AEs that occur after informed consent is signed and prior to 
start of treatment are collected in Medidata Rave using the Pre-treatment Adverse 
Event form.  
Pre-existing medical conditions (formerly referred to as baseline AEs) identified 
during baseline assessment are not considered AEs and therefore should not be 
reported on the Pre-treatment Adverse Event form. If these pre-existing 
conditions worsen in severity, the investigator must reassess the event to 
determine if an expedited report is required. Whether or not an expedited report is 
required, the worsened condition should be reported in Rave as a routine AE. 
Treatment-emergent AEs: All AEs that occur after start of treatment are collected 
in Medidata Rave using the Adverse Event form, which is available for entry at 
each treatment course or reporting period and is used to collect AEs that start 
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vii  
NRG-GY027 
Version Date: December 22, 2023 
# 
Section 
Comments
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 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/aeguid
elines.pdf. 
PI Response: Section has been updated. 
13 
12.5, Data 
Quality 
Portal 
Please replace the following with the latest CTSU template language. 
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 
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viii  
NRG-GY027 
Version Date: December 22, 2023 
# 
Section 
Comments
Form Status and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, forms with current status, and 
timeliness reports. Site staff should review the DQP modules on a regular basis to 
manage specified queries and delinquent forms. 
The DQP is accessible by site staff who are rostered to a site and have access to 
the CTSU website. Staff who have Rave study access can access the Rave study 
data via direct links available 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 Topics button 
displayed on the Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form 
Status, and DQP Reports modules. 
PI Response: Section has been updated. 
14 
12.1, Data 
Management/
Collection
Please replace the following with the latest CTSU template language. 
12.1 
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:
Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems;
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); and 
Rave Read Only or Rave SLA role must have at a minimum an Associate (A) 
registration type.
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required. 
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. No action will be required; each study invitation 
will be automatically accepted and study access in Rave will be automatically 
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NRG-GY027 
5  
Version Date: December 22, 2023 
The most current version of the study protocol and all supporting documents must be 
downloaded from the protocol-specific page on the CTSU members’ website 
(https://www.ctsu.org).   
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) on 
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. 
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NRG-GY027 
6  
Version Date: December 22, 2023 
TABLE OF CONTENTS 
1.
OBJECTIVES ......................................................................................................10
1.1
Primary Objective ..................................................................................................10
1.2
Secondary Objectives .............................................................................................10
1.3
Translational Research Objectives (24-APR-2023) ...............................................10
2.
BACKGROUND ..................................................................................................11
3.
ELIGIBILITY AND INELIGIBILITY CRITERIA ........................................20
3.1
Eligibility Criteria ..................................................................................................20
3.2
Ineligibility Criteria ...............................................................................................22
4.
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-
UP 
24
4.1
PRE-TREATMENT ASSESSMENTS ..................................................................24
4.2
ASSESSMENTS DURING TREATMENT ..........................................................26
4.3
ASSESSMENTS IN FOLLOW UP .......................................................................27
5.
TREATMENT PLAN/REGIMEN DESCRIPTION ........................................28
5.1
Agent-Based Therapy ............................................................................................29
5.2
General Concomitant Medication and Supportive Care Guidelines ......................29
5.3
Duration of Therapy ...............................................................................................30
5.4
Definition of Dose-Limiting Toxicity (DLT) ........................................................30
5.5
Treatment and Dose Escalation Plan for Dose Escalation Phase ..........................31
5.6
Treatment Plan for Expansion Phase .....................................................................33
6.
TREATMENT MODIFICATIONS/MANAGEMENT ....................................34
6.1
General Guidelines .................................................................................................34
6.2
Stopping Criteria ....................................................................................................34
6.3
Ipatasertib Dose Modification and Supportive Care Guidelines for Drug-
Related Adverse Events .........................................................................................35
6.4
Adverse Event Management Guidelines ................................................................36
6.5
Paclitaxel and carboplatin Dose Modification and Supportive Care 
Guidelines for Drug-Related Adverse Events ........................................................46
7.
ADVERSE EVENTS REPORTING REQUIREMENTS ................................48
7.1
Protocol Agents ......................................................................................................48
7.2
Adverse Events and Serious Adverse Events ........................................................48
7.3
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Ipatasertib (NSC 781451) ......................................................................................49
7.4
Adverse Events for Commercial Study Agents .....................................................50
7.5
Routine Reporting Requirements for Adverse Events ...........................................53
7.6
Pregnancy ...............................................................................................................53
8.
REGISTRATION AND STUDY ENTRY  PROCEDURES ............................53
8.1
Cancer Trials Support Unit Registration Procedures .............................................54
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NRG-GY027 
7  
Version Date: December 22, 2023 
8.2
Patient Enrollment .................................................................................................57
9.
DRUG INFORMATION .....................................................................................58
9.1
Investigational Study Agent: Ipatasertib (GDC-0068) (NSC # 781451, 
IND # 
 .......................................................................................................58
9.2
PMB Useful Links and Contacts............................................................................60
9.3
Agent Ordering ......................................................................................................60
9.4
Commercial Agent—Carboplatin ..........................................................................61
9.5
Commercial Agent—Paclitaxel .............................................................................62
10.
Pathology/Biospecimen ........................................................................................62
10.1
Central Review .......................................................................................................62
10.2
Integral Biomarkers ...............................................................................................62
10.3
Integrated Biomarkers (24-APR-2023) ..................................................................62
10.4
Biospecimen Submission Tables ...........................................................................64
10.5
Exploratory Biomarkers .........................................................................................66
10.6
Banking Biospecimens for Future Research ..........................................................68
11.
ASSESSMENT OF EFFECT ..............................................................................68
11.1
Antitumor Effect – Solid Tumors ..........................................................................68
11.2
Response Criteria ...................................................................................................71
11.3
Duration of Response .............................................................................................74
11.4
Progression-Free Survival ......................................................................................74
11.5
Survival ..................................................................................................................74
12.
DATA AND RECORDS ......................................................................................74
12.1
Data Management/Collection ................................................................................74
12.2
NRG Data Management Forms .............................................................................76
12.3
Summary of Data Submission ...............................................................................76
12.4
Rave-CTEP-AERS integration ..............................................................................76
12.5
Data Quality Portal ................................................................................................77
12.6
Global Reporting/Monitoring ................................................................................78
13.
STATISTICAL CONSIDERATIONS ...............................................................78
13.1
Study Design ..........................................................................................................78
13.2
Stratification and Randomization ..........................................................................79
13.3
Study Endpoints .....................................................................................................79
13.4
Primary Objectives Study Design ..........................................................................79
13.5
Study Monitoring of Primary Objectives ...............................................................82
13.6
Accrual/Study Duration Considerations ................................................................82
13.7
Dose Level Guidelines ...........................................................................................82
13.8
Secondary Endpoints and Analysis Plans ..............................................................82
13.9
Translational Research Endpoints..........................................................................83
13.10 Gender/Ethnicity/Race Distribution .......................................................................84
14.
REFERENCES .....................................................................................................85
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NRG-GY027 
8  
Version Date: December 22, 2023 
APPENDIX I  – FIGO OVARIAN CANCER STAGING 2014 ..............................................88
APPENDIX II – PERFORMANCE STATUS CRITERIA ......................................................90
APPENDIX III – NYHA CLASSIFICATION ..........................................................................91
APPENDIX IV - CARBOPLATIN DOSE CALCULATION INSTRUCTIONS ..................92
APPENDIX V – GENERAL THERAPY GUIDELINES.........................................................94
APPENDIX  VI- CTEP COLLABORATIVE AGREEMENTS LANGUAGE .....................95
APPENDIX VII – BIOSPECIMEN COLLECTION AND SUBMISSION MANUAL.........97
APPENDIX VIII– CORRELATIVE SCIENCE .....................................................................110
APPENDIX IX- PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD
......................................................................................................................................................115
APPENDIX X- PATIENT DRUG DIARIES ..................................................................... - 117 -
 
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NRG-GY027 
10  
Version Date: December 22, 2023 
1. 
OBJECTIVES 
This Phase I/IB trial aims to evaluate the pharmacodynamic and pharmacokinetic 
endpoints for the use of ipatasertib in combination with paclitaxel and carboplatin in 
newly diagnosed stage III/IV ovarian cancer. 
 
1.1 
Primary Objective 
 
1.1.1 To estimate the maximum tolerated dose (MTD) and the dose limiting toxicities (DLTs) 
of ipatasertib in combination with paclitaxel and carboplatin as neoadjuvant 
chemotherapy for ovarian cancer 
 
1.1.2 To determine the feasibility of the treatment regimen once the MTD is estimated. 
 
1.2.3 To assess the toxicities of ipatasertib in combination with paclitaxel and carboplatin by 
the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. 
 
1.2 
Secondary Objectives 
 
1.2.1 Objective response rate by RECIST 1.1 prior to IDS. 
 
1.3 
Translational Research Objectives (24-APR-2023) 
 
1.3.1 To evaluate the change of pPRAS40 expression in the pre-treatment tumor vs. on-
treatment tumor. (Exploratory) 
 
1.3.2 To identify the pharmacokinetics of ipatasertib in the tissue and blood. (Integrated) 
 
1.3.3
To correlate antitumor response with genomic alterations in PI3K Pathway genes (PTEN, 
PIK3CA, PIK3R1, AKT1, p53 loss, KRAS, NF1, TSC1/TSC1). (Integrated) 
 
1.3.4
To correlate antitumor response with transcriptomic alterations in PI3K Pathway genes 
(PTEN, PIK3CA, PIK3R1, AKT1, p53 loss, KRAS, NF1, TSC1/TSC1). (Integrated)  
1.3.5 To correlate response with PTEN loss. (Integrated) 
 
1.3.6 To correlate phosphorylated AKT S473 and T308 with response to ipatasertib as 
neoadjuvant chemotherapy for ovarian cancer. (Exploratory)  
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(p4EPB1, pGSK3B, pmTOR) were found to be downregulated by ipatasertib in a dose-
dependent fashion (Figure 5) when comparing pre- to on-treatment tumor biopsies.  
We propose a Phase I/IB trial of ipatasertib in combination with paclitaxel and 
carboplatin in newly diagnosed ovarian cancer given the high percentage of alterations in 
PIK3CA/AKT/PTEN alterations.  
 
Pharmacodynamic and pharmacokinetic endpoints will be evaluated with baseline and 
post-ipatasertib tissue samples.  
 
We have completed the dose escalation. There have been 12 participants enrolled and 
treated on DL1 (200mg) and DL2 (300mg). Among these 12 eligible and treated 
participants, 11 have been off study treatment.  
  
Dose Level 1 had two cohorts with 7 patients enrolled and treated including 6 patients 
who were considered DLT-evaluable. Among these 6 DLT-evaluable patients, 1 had 
DLT based on treatment discontinuation > 14 days due to grade 3 maculo-papular rash.  
 
For Dose Level 2, there were five patients in two cohorts with two DLTs. The DLTs were 
grade 2 diarrhea and grade 4 neutropenia. There was another participant during the 
postoperative period with a SAE for prolonged apneic arrest with anoxic injury. There 
were no delays in reaching surgical intervention in either DL1 or DL2. The MTD was 
determined to be 200mg daily. (22-DEC-2023) 
 
Primary objectives and study design 
 
The primary study objectives are to estimate the MTD in dose escalation phase and to 
evaluate the feasibility in expansion phase after the MTD is established for ipatasertib in 
combination with paclitaxel and carboplatin as neoadjuvant chemotherapy for ovarian 
cancer. This study consists of two phases with a sample size ranging from 21 to 36 
patients: a dose-escalation phase for estimation of the MTD (PART I) and expansion 
phase (PART II). 
 
Secondary objective 
 
Objective response rate by RECIST 1.1 prior to IDS will be evaluated as a secondary 
endpoint. This is supported by a post-hoc exploratory analysis of ICON8, a randomized 
Phase 3 clinical trial.  Of the 564 women who had RECIST-evaluable disease at trial 
entry, 348 (62%) had a RECIST complete or partial response following neoadjuvant 
chemotherapy.  73 (42%) of the 172 women with RECIST stable disease following 
neoadjuvant chemotherapy had complete cytoreduction. Of the RECIST complete or 
partial responses, 187 (56%) of the 335 women had a complete cytoreduction (reviewed 
in Morgan et al., 2021). 
 
Ipatasertib 
 
Ipatasertib is a potent, highly selective small-molecule inhibitor of all three isoforms of 
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the serine/threonine kinase Akt (protein kinase B) intended for oral administration (PO) 
(Investigator’s Brochure, 2018).  Ipatasertib selectively binds to the active conformation 
of Akt and inhibits its kinase activity (Lin et al., 2012).  Ipatasertib is being developed for 
the treatment of cancers in which activation of the phosphatidylinositol 3-kinase (PI3K)-
Akt-mammalian target of rapamycin (mTOR) pathway may be relevant for tumor growth 
or therapeutic resistance.  
 
The serine/threonine kinase Akt is encoded by three closely related genes in mammals, 
AKT1, AKT2, and AKT3 (Investigator’s Brochure, 2018).  Akt is the central node of the 
PI3K-Akt-mTOR pathway, in which activation is associated with proliferation, cell cycle 
progression, and survival.  The direct product of PI3K activity, the lipid second 
messenger, phosphatidylinositol (3,4,5)-trisphosphate (PIP3), promotes membrane 
association of Akt.  Akt is phosphorylated at two critical residues for its full activation: a 
threonine residue in the activation loop of the kinase domain (threonine 308 in Akt1) by 
phosphoinositide-dependent kinase 1 (PDK1) and a serine residue within the hydrophobic 
motif of the regulatory domain (serine 473 in Akt1) by mTOR complex (mTORC) 2  
(reviewed in Bhaskar and Hay, 2007).  In turn, activated Akt phosphorylates and 
regulates the functions of numerous cellular proteins, including FOXO, mTORC1, and S6 
kinase (reviewed in Manning et al., 2007). 
 
The PI3K-Akt-mTOR pathway is activated by numerous genetic and non-genetic 
mechanisms across the spectrum of cancer (LoRusso, 2016).  The most commonly found 
alterations in this pathway result from decreased expression or inactivating mutations of 
PTEN, a 
deregulation of receptor tyrosine kinase signaling, and amplification or activating 
mutations of receptor tyrosine kinases.  In addition, alterations in Akt itself, including 
amplification and overexpression of individual Akt isoforms, as well as activating 
mutations in Akt, most commonly an E17K mutation in the pleckstrin homology (PH) 
domain of AKT1 that results in PI3K-independent membrane recruitment of Akt1, have 
been identified in a subset of human cancers (reviewed in Bellacosa et al., 2005; Brugge 
et al., 2007; Tokunaga et al., 2008). 
 
Hyperactivation of Akt also occurs via deregulated signaling of many cell surface 
receptors and intracellular linkers and signaling molecules, and amplification/mutation of 
the epidermal growth factor receptor/ErbB growth factor receptor family members 
(reviewed in Brugge et al., 2007).   Moreover, Akt activation has been associated with 
resistance to both chemotherapeutic agents and targeted agents such as trastuzumab and 
tamoxifen (Clark et al., 2002; Tokinaga et al., 2008). 
 
Beside being an important driver of cell proliferation, growth, and survival, all of which 
are involved in tumorigenesis, Akt also plays a key role in glucose homeostasis and 
mediates the metabolic effects of insulin downstream of the insulin receptor (a receptor 
tyrosine kinase) (Whiteman et al., 2002; Dummler et al., 2007; Sale et al., 2008).  
 
In summary, Akt is a central node in cell signaling downstream of growth factors, 
cytokines, and other cellular stimuli that play an important role in cancer development, 
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progression, and therapeutic resistance and is activated in most, if not all, human cancers 
(Deborah et al., 2005).  The ubiquity and importance of Akt activation in human cancers 
provide a strong rationale for the development of therapeutics targeting Akt. 
 
Mechanism of Action 
 
Ipatasertib selectively binds to the active conformation of Akt and inhibits its kinase 
activity (Lin et al., 2012).  Consistent with its mechanism of action in nonclinical studies, 
ipatasertib has proven to be especially effective on cells with activated Akt, including 
PTEN-null and PI3K-mutated tumor models, leading to suppression of the 
phosphorylation of its direct substrates.  Consistent with the role of Akt in insulin 
signaling, ipatasertib also exhibited dose-dependent and reversible elevation of serum 
glucose in nonclinical studies.  In vivo activity studies support the use of ipatasertib as a 
single agent or in combination with chemotherapeutic, hormonal, or targeted agents for 
the treatment of patients with advanced or metastatic solid tumors (Lin et al., 2013).  
 
Nonclinical Studies 
 
Extensive in vitro and in vivo pharmacology studies were performed to characterize the 
inhibitory potency and selectivity of ipatasertib for Akt isoforms and the effects of 
ipatasertib on cell proliferation, cell cycle progression, and apoptosis (Investigator’s 
Brochure, 2018).  In vivo activity was assessed in immunocompromised mice with 
human tumor xenografts representing multiple tumor types that are driven by PI3K-Akt 
pathway activation, including prostate cancer and breast cancer.  In addition, in vitro and 
in vivo studies of ipatasertib combined with standard chemotherapeutic agents or anti-
hormonal agents were carried out.  Combination studies were also carried out with 
ipatasertib and an anti-programmed death-ligand 1 (PD-L1) antibody in a syngeneic 
murine breast tumor model, with or without paclitaxel.  The results of these in vitro and 
in vivo pharmacology studies support the use of ipatasertib as a single agent or in 
combination with chemotherapeutic or targeted agents, including the anti-androgen 
agents abiraterone and enzalutamide, as well as an anti-PD-L1 antibody, for the treatment 
of patients with advanced or metastatic solid tumors. 
 
In Vitro Studies 
 
Ipatasertib is equipotent against all three Akt isoforms, with potencies ranging from 4 to 
18 nM (Investigator’s Brochure, 2018).  Protein kinase A is a closely related AGC kinase 
family member, particularly with respect to the ATP-binding pocket.  Ipatasertib was 
>100-fold less active at inhibiting the closely related kinase, protein kinase A.  
Representative IC50 values are as follows: 4 nM for Akt1, 18 nM for Akt2, 8 nM for 
Akt3, and 1,969 nM for protein kinase A.  The IC50 values of the N-dealkylated 
metabolite of ipatasertib, M1 (G-037720) are as follows: 11 nM for Akt1, 106 nM for 
Akt2, and 69 nM for Akt3.  
 
No significant off-
vitro biochemical binding assays that evaluated ipatasertib binding at 10 mcM against a 
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total of 66 pharmacologically significant receptors, ion channels, and transporters 
(Investigator’s Brochure, 2018).  When tested at 1 mcM, ipatasertib is selective for the 
Akt kinases over a panel of 230 kinases.  With the exception of PKG1 (relative to which 
ipatasertib is >5-fold more selective for Akt1), ipatasertib displays a >60-fold selectivity 
for Akt1 over the next most potently inhibited non-Akt kinase in the panel.  None of the 
toxicities observed in the repeat-dose studies were attributable to off-target kinase 
activity. 
 
Ipatasertib potently inhibits phosphorylation of the proximal Akt substrate PRAS40, and 
this activity correlates with the anti-proliferative properties of this compound in a cell 
line dependent on the Akt pathway for growth and survival (Investigator’s Brochure, 
2018).  Ipatasertib has demonstrated robust efficacy in nonclinical tumor models in which 
the PI3K-Akt pathway is activated through decreased expression of the PTEN tumor 
K3CA), 
including breast cancer models (Lin et al., 2013).  Treatment of PC-3, MCF-7-neo/HER2, 
and BT474M1 cells with ipatasertib resulted in a dose-dependent block of cell cycle 
progression at the G1 phase.  Ipatasertib treatment also caused a dose- and time-
dependent increase in apoptotic and necrotic populations of MCF-7-neo/HER2 and 
BT474M1 cells (Investigator’s Brochure, 2018).  Collectively, these effects contributed 
to a dose-dependent inhibition of overall cell viability in response to ipatasertib 
treatment. 
 
In addition to single-agent activity, the effect of ipatasertib was also evaluated in 
combination with chemotherapeutic agents.  Combination effects were evaluated using 
both the Bliss independence model and the highest single agent (HSA) model (Lehár et 
al., 2007).  Synergistic effects were seen in the androgen-independent prostate cancer cell 
line PC3M-LN4 when ipatasertib was combined with docetaxel.  Neither agent alone was 
effective at inhibiting the viability of this cell line, with maximum inhibition of 37% and 
27% observed at the highest concentrations of ipatasertib (20 mcM) and docetaxel (1 
mcM) tested, respectively.  Combination of the two agents resulted in increased 
inhibition of cell viability observed at lower concentrations of both ipatasertib and 
docetaxel, and maximum inhibition increased to 83%.  Positive Bliss scores were 
observed at ipatasertib concentrations of 0.74-20 mcM in combination with all docetaxel 
concentrations tested (0.00098-1 mcM), and positive HSA scores were observed at 
ipatasertib concentrations of 0.25-20 mcM in combination with all docetaxel 
concentrations tested.  Similar positive combination effects were observed in several 
other cancer cell lines, as well as with other chemotherapeutic agents such as 5-
fluorouracil (5-FU) and cisplatin (Investigator’s Brochure, 2018). 
In Vivo Studies 
In vivo efficacy of ipatasertib was established using various in vivo mouse xenograft 
models, in which the PI3K-Akt-mTOR pathway is aberrantly activated as a result of 
-
tumor activity was evaluated, shown as percentage of tumor growth inhibition (TGI) 
relative to vehicle controls for ipatasertib as a single agent or in combination with either 
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chemotherapeutics or targeted agents (e.g., docetaxel, paclitaxel, mFOLFOX6, 
abiraterone, and MDV3100).  These in vivo studies demonstrated that ipatasertib has 
robust anti-tumor activity as a single agent and improved efficacy when administered in 
combination with other marketed or experimental cancer agents. All dose levels and 
combinations in the summarized efficacy studies were tolerated based on <20% body 
weight loss. 
 
A pharmacodynamic (PD) and pharmacokinetic (PK) study was performed in nude mice 
bearing subcutaneous PC3-NCI prostate tumors to correlate plasma drug levels of 
ipatasertib with PD changes in the tumors (Investigator’s Brochure, 2018).  Following 
administration of a single oral dose of ipatasertib, plasma and tumor samples were 
collected between 1 and 24 hours for PK and PD analysis, respectively.  Robust Akt 
pathway inhibition with ipatasertib was determined in vitro on the basis of the 
suppression of phosphorylated PRAS40 (pPRAS40) and phosphorylated S6RP (pS6RP) 
in PC3-NCI prostate tumor cells.  Therefore, these PD markers relative to their total 
protein levels were also evaluated in vivo after mice bearing PC3-NCI prostate tumors 
were treated with ipatasertib.  The chosen dose levels for ipatasertib reflected a 
subefficacious dose (12.5 mg/kg), a minimum efficacious dose (MED) (25 mg/kg), and a 
maximum efficacious dose (MaxED) (100 mg/kg) when administered daily in the PC3-
NCI prostate model (Investigator’s Brochure, 2018).  Within 3 hours after drug 
administration, there was a dose-dependent decrease in the ratio of pPRAS40 to total 
PRAS40 (tPRAS40) compared with vehicle controls.  The greatest modulation in PD 
response was achieved at 100 mg/kg of ipatasertib, with a >95% reduction in the ratio of 
pPRAS40 to tPRAS40 within 3 hours after dosing.  At 8 hours post-dose, plasma levels 
of ipatasertib >2.6 mcM were achieved with 100 mg/kg, and this result correlated with a 
significant PD effect on the ratio of pPRAS40 to tPRAS40 (p<0.001) and, to a lesser 
extent, on the ratio of pS6RP to total S6RP (tS6RP) in PC3-NCI prostate tumors.  These 
data demonstrate that inhibition of the Akt pathway in PC3-NCI prostate tumors for at 
least 8 hours correlates with maximum in vivo efficacy of ipatasertib.  
 
Akt activation is associated with intrinsic and acquired resistance to chemotherapy (Clark 
et al., 2002; Tokunaga et al., 2008).  In vivo studies of ipatasertib combined with standard 
chemotherapeutic agents were carried out in multiple models (Investigator’s Brochure, 
2018).  In the HCI-001 TNBC xenograft model, the combination of docetaxel and 
ipatasertib enhanced TGI (89% for the combination) compared with either single agent 
alone (64% and 63%, respectively).  In the MCF-7 breast tumor xenograft model, the 
combination of paclitaxel and ipatasertib enhanced TGI (97% for the combination) 
compared with either single agent alone (83% and 42%, respectively).  Additionally, in 
the STO#240 primary gastric tumor xenograft model, the combination of ipatasertib and 
mFOLFOX6 enhanced TGI (90%) compared with either single agent alone (55% and 
54%, respectively) (Investigator’s Brochure, 2018).  All combinations were well 
tolerated, with no added body weight loss compared with docetaxel, mFOLFOX6, or 
paclitaxel alone. 
A combination study between ipatasertib, paclitaxel, and anti-PD-L1 was also carried out 
in the EMT6 syngeneic breast tumor model (Investigator’s Brochure, 2018).  The 
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combination of paclitaxel, ipatasertib, and anti-PD-L1 showed no antagonism either as a 
triple combination or double combination between any two agents, with a 89% TGI 
observed for the triple combination compared with each single agent alone (27%, 22%, 
and 66%, respectively).  All combinations were well tolerated.  To test the hypothesis of 
androgen receptor and PI3K-Akt-mTOR pathway crosstalk and reciprocal feedback 
activation, in vivo studies of ipatasertib combined with either the androgen biosynthesis 
inhibitor abiraterone or the androgen receptor antagonist enzalutamide (MDV3100) were 
conducted in the LuCaP35V primary prostate cancer model (Investigator’s Brochure, 
2018).  The combination of abiraterone and ipatasertib greatly enhanced TGI (57% for 
the combination) compared with either single agent alone (25% and 17%, respectively).  
Additionally, the combination of enzalutamide and ipatasertib greatly enhanced TGI 
(96% for the combination) compared with either single agent alone (46% and 57%, 
respectively).  In all studies, the treatment combinations were well tolerated. 
 
Safety Pharmacology 
 
The 23 mcM IC50 value for in vitro cardiac hERG channel inhibition is approximately 
38-fold greater than the steady-state unbound concentration of ipatasertib in patients 
administered the proposed clinical dose of 400 mg QD (280 ng/mL, 0.61 mcM) and is 
approximately 23-fold greater than the steady-state unbound concentration of ipatasertib 
in patients administered the MTD dose of 600 mg QD (463 ng/mL, 0.99 
mcM)(Investigator’s Brochure, 2018).  In addition, no ipatasertib-related effects on 
cardiovascular or respiratory parameters were observed in monkeys following ipatasertib 
administration at doses of up to 30 mg/kg in a dedicated Good Laboratory Practice 
(GLP), cardiovascular, safety pharmacology study, or in GLP repeat-dose toxicity studies 
of up to 26-week duration. 
 
Overview of Clinical Development 
 
There are currently no FDA approved AKT inhibitors for cancer treatment.  Ipatasertib is 
currently under investigation in phase 1, 2, and 3 clinical trials in castration resistant 
prostate cancer and metastatic breast cancer.  In a three-stage study, 30 patients were 
enrolled in the dose-escalation (stage I) and 22 patients in the two dose expansion cohorts 
(11 metastatic breast cancer and 5 patients with metastatic castration-resistant prostate 
cancer; stage II), or all solid tumors (n=6, stage III) (Saura et al, 2017).  The most 
common cancers were breast cancer (n=16) or colorectal cancer (n=14), with a median of 
six prior lines of therapy (range, 1-17).  Oral ipatasertib was administered daily for 21 
days followed by 7 days off (21/7 day dosing schedule) every 28 days with doses ranging 
from 25-800 mg.  Dose limiting toxicities (DLTs) at 800 mg were asthenia and nausea.  
The maximum tolerated dose for ipatasertib was 600 mg daily on a 21-day on/7-day off 
schedule which was used for the expansion cohorts in stage II and stage III. Although the 
MTD was 600mg daily, the recommended dose for further development is 400 mg daily 
based upon overall tolerability profile. Furthermore, a Phase Ib/II trial of ipatasertib 
200mg vs 400mg daily dosing in combination with abiraterone 1000mg and 
prednisone/prednisolone 5mg twice daily was completed (deBono et al., 2018).  This 
study demonstrated that the most common AEs leading to discontinuation in the 
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ipatasertib 400mg arm were diarrhea (2/84 = 2.4%) and hyperglycemia (2/84 = 2.4%). 
AEs that led to discontinuation occurred in 10 (11.9%) and 7 (8%) patients in the 
ipatasertib 400mg and 200mg cohort respectively. There were no deaths related to study 
treatment thus supporting 400mg daily dosing.   
 
In 51 treated patients in the single agent study, the most common causally-related grade 2 
or greater adverse events across all dose levels were as follows: diarrhea (35%), nausea 
(27%), asthenia (25%), hyperglycemia (10%), decreased appetite 6%, rash (6%), and 
vomiting (6%).  Grade 3 events were diarrhea (n=4), asthenia (n=3), 
hypercholesterolemia (n-1), hyperglycemia (n=1), hypophosphatemia (n=1), nausea 
(n=1), and toxic skin eruption (n=1).  No grade 4 events were observed.  Timing to the 
first onset of diarrhea, nausea, fatigue, and rash typically occurred during cycle 1.  As 
demonstrated in platelet-
inhibition was observed. In addition, comparing pretreatment and on-treatment tumor 
biopsies, there was a reduction in pRAS40, pEBP1, pS6, and pmTOR in a dose-
dependent manner, as measured by reverse phase protein array. 
 
There is clinical evidence of anti-cancer activity with ipatasertib.  Across all dosing 
cohorts, 16 of 47 patients (34%) had stable disease (SD) or incomplete response, per 
RECIST criteria, and 6 patients had a progression free survival (PFS) >6 months (18% in 
those who received 400 mg or 600 mg).  Of the 41 patients with known molecular status, 
SD was observed in 6/9 patients with PTEN loss, PIK3CA, or AKT mutations in their 
tumor, as compared to 3/9 who had progression.  Those with a PIK3CA mutation (n=6) 
or AKT mutation (n=1) remained on study longer with ipatasertib compared to those 
without these mutations (n=33); median treatment time was 84 vs. 63 days.
 
Notably, the one patient with an AKT1 mutation (E17K) had a HER2- negative 
metastatic breast cancer that had progressed on liposomal doxorubicin, 
cyclophosphamide, and most recently capecitabine (on drug for ~90 days); while on 
ipatasertib her CA15-3 declined by >50% and she remained on study for 235 days 
(confidential: Genentech).  These data suggest that AKT inhibition with ipatasertib may 
provide a novel therapeutic approach and serve as the rationale for investigating this 
agent in patients with AKT mutated tumors. 
 
LCM-RPPA-based  pAKT S473 and T308 as Exploratory Biomarkers for 
Ipatisertib Response Prediction 
Despite extensive genomic and transcriptomic profiling, it remains unknown how 
signaling pathways are differentially activated and how tumors are differentially 
sensitized to certain perturbations. Triple-negative breast cancer (TNBC) is an aggressive 
form of breast cancer with poor prognosis and high recurrence and metastasis rate, 
highlighting the need for more effective therapeutic approaches with appropriate 
diagnostic biomarkers. Due to the molecular heterogeneity of TNBC, a key aspect for 
targeted therapy is identifying tumors that are most likely to be sensitive to the specific 
oncogenic signaling perturbation to maximize the clinical benefit. 
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In our recently published study with Genentech, we aimed to characterize AKT signaling 
activity and its association with other genomic or IHC-based PI3K/AKT pathway 
biomarkers as well as the clinical activity of ipatasertib (AKT inhibitor) in the 
FAIRLANE trial. 151 patients with early triple-negative breast cancer (TNBC) were 
randomized 1:1 to receive paclitaxel with ipatasertib or placebo for 12 weeks prior to 
surgery. We used a laser capture microdissection (LCM) reverse-phase protein 
microarray (RPPA) based workflow to examine the total level and/or phosphorylation 
states of over 100 proteins including the quantitative activation levels of AKT, the direct 
drug target of ipatisertib,  as well as other members of the PI3K/AKT and mTOR 
signaling pathway as well in the isolated tumor epithelium. 
 
One hundred and twenty-five baseline/pre-treatment tumors were analyzed. Our recently 
published results showed that of all genomic and protein/phosphoprotein biomarkers 
considered only baseline pAKT S473 and T308 levels predicted for benefit of ipatasertib 
in TNBC. Importantly, tumors with high pAKT  S473 and T308 levels exhibited 
association with enriched ipatasertib activity regardless of genomic PIK3CA/AKT/PTEN 
status. This study provides proof-of-concept that the baseline phosphorylation levels of 
AKT, the direct target of ipatasertib, could have predictive value and may possess an 
improved means of biomarker-based patient selection for AKT inhibitors and diagnostic 
utility for precision medicine. (24-APR-2023) 
 
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). 
 
Submission of tissue is required. Investigators should check with their pathology 
department regarding release of tissue before approaching patients about participation in 
the trial (see Sections 3.1.4, 4.1, and 10 for details).  
3.1 
Eligibility Criteria
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met.
 
3.1.1 Pathologically proven diagnosis of ovarian cancer (Ovarian cancer = fallopian tube 
cancer, ovarian cancer, primary peritoneal cancer).  Required data element:  submission 
of pathology report. 
Patients with the following histologic cell types are eligible: 
a. High grade serous 
b. Endometrioid adenocarcinoma, grade 3 
 
Genomic/genetic testing results will be a data collection element if performed as part of 
usual care (Germline genetic testing, tumor genomic testing, HRD testing).  
Genetic/genomic testing results should be uploaded if they become available anytime 
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during conduct of the study. 
3.1.2 Appropriate stage for study entry defined as Stage III or Stage IV based on the following 
diagnostic workup: 
a. History/physical examination within 14 days prior to registration 
b. Imaging with CT C/A/P within 28 days prior to registration; 
Please see protocol-specific assessment requirements in section 4.1 Pre-treatment 
Assessment Table. 
 
3.1.3
Patients must have evaluable disease or measurable disease defined by RECIST v 1.1.  
Measurable disease is defined as at least one lesion that can be accurately measured in at 
m in short axis when 
measured by CT or MRI. 
3.1.4  Pre-treatment formalin-fixed, paraffin-embedded (FFPE) tumor block collected from 
laparoscopy (preferred) or five 18G cores by radiology/interventional radiology 
(acceptable) must be available for submission.  
3.1.5 Disease must be considered unresectable via primary debulking surgery and in need of 
neoadjuvant chemotherapy (NACT) prior to debulking surgery.  This assessment of 
unresectability can be made via imaging or laparoscopic scoring. 
3.1.6 No prior therapy directed at ovarian cancer.   
3.1.7
  years  
3.1.8
ECOG Performance Status 
within 14 days prior to registration.  
3.1.9 Adequate hematologic function within 14 days prior to registration defined as follows: 
a. 
000/mcl 
b. 
 
c. Hemoglobin  10g/dl (07-AUG-2023)
3.1.10  Adequate renal function within 14 days prior to registration defined as follows: 
 or Creatinine 
clearance (CrCL) or estimated Glomerular filtration rate 
60 mL/min 
estimated using either the Cockcroft-Gault equation, the Modification of Diet in Renal 
Disease Study, or as reported in the comprehensive metabolic panel/basic metabolic 
panel (eGFR). 
3.1.11 Adequate hepatic function within 14 days prior to registration defined as follows: 
a. 
(patients with known Gilbert’s disease who have bilirubin 
 
b. 
 
 
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3.1.12 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. As clinically indicated, patients with a 
history of cardiac disease or history of cardiotoxic agents should have an echocardiogram 
or MUGA within 28 days of treatment showing an EF of  50%. (07-AUG-2023) (See 
Appendix III.) 
3.1.13  Women of childbearing potential (WOCBP) must agree to use two forms of birth control 
(hormonal or barrier method of birth control; abstinence) agree to remain abstinent 
(refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of 
 1% per year during the treatment period and for at least 28 days after the last dose of 
ipatasertib and agreement to refrain from donating eggs during this same period. 
3.1.14 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.
3.1.15 Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral 
therapy with undetectable viral load within 6 months are eligible for this trial. 
 
3.1.16 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral 
load must be undetectable on suppressive therapy, if indicated. 
 
3.1.17 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. 
3.1.18  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.  
 
3.1.19 Ability to understand and willingness to sign an IRB approved written informed consent 
document (or that of legally authorized representative, if applicable). 
 
3.2 
Ineligibility Criteria 
 
Patients with any of the following conditions are NOT eligible for this study. 
3.2.1
Prior treatment with agent(s) targeting PI3K/AKT/mTor pathway. 
 
3.2.2 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ipatasertib, paclitaxel or carboplatin. 
 
3.2.3 Currently receiving any other investigational agents or has received an investigational 
agent within 4 weeks of  study registration. 
 
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3.2.4
Abnormal gastrointestinal function.  This includes GI obstruction or bleeding or 
signs/symptoms thereof within 3 months of study registration.   
 
3.2.5 Patients with a history of abdominal fistula will be considered eligible if the fistula was 
surgically repaired or has healed, there has been no evidence of fistula for at least 6 
months, and patient is deemed to be at low risk of recurrent fistula.
3.2.6 Received prior radiotherapy to any portion of the abdominal cavity or pelvis.  
 
3.2.7 Patients with uncontrolled intercurrent illness.
 
3.2.8 Patients with psychiatric illness/social situations that would limit compliance with study 
requirements. 
 
3.2.9 Patients with active infections requiring intravenous antibiotics.
 
3.2.10  Patients with diabetes either requiring insulin therapy or with a baseline fasting glucose 
>160 mg/dL and/or high HbA1c (>8), suggesting poorly controlled diabetes. Fasting is 
defined as abstaining from food and drink (with the exception of water) for at least 8 
hours.  (See protocol section 4.1for the definition of fasting). 
3.2.11 Patients with Grade  2 uncontrolled or untreated hypercholesterolemia (>300 mg/dL) or 
hypertriglyceridemia (>300 mg/dL). 
3.2.12 Known congenital long QT syndrome or screening QT interval corrected using 
Fridericia's formula (QTcF) > 470 milliseconds. (07-AUG-2023)
 
3.2.13  History of or active inflammatory bowel disease (e.g., Crohn's disease and/or ulcerative 
colitis) or active bowel inflammation (e.g., diverticulitis). 
 
3.2.14 Lung disease:  pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic 
fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections 
(pneumocystis pneumonia or cytomegalovirus pneumonia). 
3.2.15 Patients with known brain metastases or leptomeningeal disease are not eligible, as prior 
treatment directed at ovarian cancer is not allowed. 
3.2.16 Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 
drug-elimination half-lives, whichever is longer, prior to registration.   
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated medical reference.  As part of the enrollment/informed 
consent procedures, the patient will be counseled on the risk of interactions with other 
agents, and what to do if new medications need to be prescribed or if the patient is 
considering a new over-the-counter medicine or herbal product.   
Please see Appendix IX for drug interactions handout.  
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tissue block
Frozen normal tissue and 
tumor
 
Mandatory2
Plasma 
 
Mandatory2
Na Hep whole blood
Optional2
(07-AUG-2023) 
1 First assessment scan occurs at 3 weeks (+/- 7 days) post cycle 3 of neoadjuvant 
paclitaxel, carboplatin, and ipatasertib and prior to IDS.  Radiographic tumor 
measurements are obtained until disease progression is confirmed; at the investigator’s 
discretion, they can be repeated any other time if clinically indicated based on symptoms 
or physical signs suggestive of new or progressive disease. Utilize the same imaging 
modality of chest, abdomen, and pelvis (see footnote under Pre-Treatment Assessments) 
as for pre-cycle 1 baseline assessment. PET CT is NOT to be used for any disease 
assessment or reassessment. 
 
2
 Collected at interval debulking surgery (IDS). 
4.3 
ASSESSMENTS IN FOLLOW UP 
 
Assessments 
Timing
Post-operative chemotherapy 
Post-operative chemotherapy (e.g., paclitaxel/carboplatin or 
other) will be given as per usual care. Dates, drug names, 
and drug doses of post-operative chemotherapy will be 
collected.
Vital Status 
90 days after last dose of ipatasertib (+/- 14 days)
Toxicity Assessment
Safety follow-up visits will be conducted at 30 days (+/- 7 
days) after the last dose of ipatasertib and 90 days (+/- 14 
days) after the last dose of ipatasertib. These follow-ups 
may be conducted in person, via telemedicine, or via phone. 
Patients who discontinue treatment for unacceptable adverse 
event(s) will be followed until resolution or stabilization of 
the adverse event.   
For all adverse events that occur within 30 days of last 
protocol treatment please report on the Toxicity form for the 
last cycle of therapy administered. For reporting of delayed 
toxicity, see Section 7. 
 
Radiographic tumor measurement 
Radiographic tumor measurement will be completed 
at 3 weeks (+/- 7 days) after 3 cycles of paclitaxel, 
carboplatin, ipatasertib and before IDS.
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) 
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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.
5. 
TREATMENT PLAN/REGIMEN DESCRIPTION
Protocol treatment should begin within 7 days of registration. Patients with newly 
diagnosed ovarian cancer, who have fulfilled the eligibility requirements according to 
Section 3, will receive neoadjuvant (NACT) chemotherapy of ipatasertib in combination 
with paclitaxel and carboplatin for 3 cycles (1 cycle = 21 days) followed by single-agent
ipatasertib until 24 hours prior to interval debulking surgery. Ipatasertib will be 
administered according to the following dose escalation schema (Table 1).
Table 1. Dose escalation schema
Dose Escalation Schedule
Dose Level
Dose*
Ipatasertib
Paclitaxel
Carboplatin
Level -1 
100mg 
175mg/m2 
AUC 5
Level 1+
200mg 
175mg/m2 
AUC 5
Level 2
300mg 
175mg/m2 
AUC 5
Level 3
400mg 
175mg/m2 
AUC 5
+ The maximum tolerated dose of ipatasertib was determined to be dose level 1 200 mg. The trial 
is now only open to accrual for the expansion phase. (22-DEC-2023) 
The dose of ipatasertib will begin at 200mg oral daily, continuously (one cycle = 21 days) 
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for 3 cycles taken concurrently with paclitaxel and carboplatin. The dose escalation 
scheme is DL1 at 200mg, DL2 at 300mg, and DL3 at 400mg with a de-escalation (DL-1) 
at dose level of 100mg. The dose escalation phase of this trial has concluded as of 
December 22, 2023.  
Each dose of ipatasertib should be taken with a minimum of 3 ounces (90 mL) of fluid.  
Ipatasertib may be taken with or without food.  If a dose is missed or omitted (not taken 
within 8 hours after the scheduled dosing time), the patient should resume dosing with 
the next scheduled dose the following day.  Missed, omitted, or vomited doses will not be 
made up. 
5.1 
Agent-Based Therapy  
See Appendix IV – Carboplatin Dose Calculation Instructions 
See Appendix V – General Therapy Guidelines
 
Paclitaxel 175 mg/m2 IV over 3 hours Day 1 
Carboplatin AUC 5 IV over approximately 30-60 minutes Day 1 
Paclitaxel and Carboplatin will be administered every 3 weeks for a total of 3 cycles. 
5.1.1
Pre-medication for Paclitaxel 
For all cycles where paclitaxel is to be administered, it is recommended that a preparative 
regimen be employed, to reduce the risk associated with hypersensitivity reactions.  This 
regimen should include a standard dose of dexamethasone (either IV or PO), an 
antihistamine H1 (diphenhydramine 25-50 mg IV or orally, or an alternate H1blocker), 
and a standard dose of antihistamine H2 IV (such as famotidine). Paclitaxel preparative 
regimen can be altered at the discretion of the treating investigator. 
 
Because of the risk of hyperglycemia with ipatasertib, it is recommended that
dexamethasone doses be minimized to the extent that is clinically feasible. 
For example, if Cycle 1 is tolerated without apparent hypersensitivity reaction, a
reduction in dexamethasone premedication dose should be considered for subsequent 
cycles if permitted by institutional standard of care.
 
It is anticipated that nausea and vomiting may be a significant side effect of this regimen 
(due to carboplatin administration).  An antiemetic regimen is suggested (per 
institutional, NCCN and/or ASCO guidelines).  Antiemetic regimen can be altered at the 
discretion of the treating investigator.  
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
5.2.1 Supportive/Ancillary Care and Concomitant Medications 
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. 
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Herbal and Nutritional Supplement 
The concomitant use of herbal therapies is generally not recommended, as their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown. However 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.  
 
Because there is a potential for interaction of ipatasertib 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 Principal Investigator 
should be alerted if the patient is taking any agent known to affect or with the potential 
for drug interactions.  The study team should check a frequently-updated medical 
reference for a list of drugs to avoid or minimize use of.  Appendix IX (Patient Drug 
Interactions Handout and Wallet Card) should be provided to patients. 
5.3 
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 defined per RECIST 1.1, 
 Intercurrent illness that prevents further administration of treatment, 
 Unacceptable adverse event(s), as described in Section 6 
 Patient decides to withdraw consent for participation in the study, or 
 General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 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 re study consent withdrawal) 
See Section 6.1 to determine if individual treatment components can be 
stopped independently. 
If all protocol treatment is discontinued, follow-up and data collection will 
continue as specified in the protocol. 
 
5.4
Definition of Dose-Limiting Toxicity (DLT)
Dose-limiting toxicities (DLTs) will be defined by drug related adverse effects that occur 
within the first cycle of neoadjuvant chemotherapy and include at least possibly related to 
any of the 3 drugs and meet the criteria below as evaluated by NCI CTCAE v.5 unless 
clearly unrelated to study therapy.  
The definition of DLT include the following: 
1. Inability to tolerate assigned ipatasertib dose for at least 16 of the planned 21 doses.
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2. Grade  3 fasting hyperglycemia  
3. Grade
 2 ALT, AST, or total bilirubin elevation >2x ULN 
4. Grade  2 colitis/enterocolitis 
5.   Grade  2 diarrhea – persistent despite medical management. Ipatasertib-related 
diarrhea could be prevented with a prophylactic dose of loperamide 2 mg every 4 
hours. Duration of diarrhea can be minimized by taking ipatasertib with food.  
6.   Grade  3 rash – persistent despite medical management.  
7.   Grade  2 pneumonitis 
8. Neutropenic fever 
9. 
-hematologic toxicity (exceptions may include Grade 3+ amylase or 
lipase elevation NOT associated with symptoms or clinical manifestations of pancreatitis; 
 
10. 
 
11. 
 for >72 hours despite adequate antiemetic and other 
supportive care   
12. 
– persistent for > 72 hours despite medical management  
13. For patients with hepatic metastases, AST or ALT >8xULN or AST or ALT >5x 
ULN for >=14 days 
14. Any death not clearly due to the underlying disease or extraneous causes 
 
 
5.5 
Treatment and Dose Escalation Plan for Dose Escalation Phase 
The dose escalation phase indicated Dose Level 1 as the MTD.  Based on the safety data 
review by the study team and CTEP, patients enrolled to the expansion phase will be 
treated at Dose Level 1 (See Section 5 Table 1) (22-DEC-2023) 
Dose escalation decisions and the maximum tolerated dose will be defined based on DLTs 
that occur within the first cycle of neoadjuvant chemotherapy. 
 
A standard 3+3 with dose de-escalation design will be used to determine the MTD of 
ipatasertib in combination with paclitaxel and carboplatin in dose escalation phase. 
Patients will be accrued in cohorts of size 3. The dose level combinations and orders are 
presented in Table 1.  
 
The starting dose level (Dose Level 1, DL1) will consist of paclitaxel 175mg/m2, 
carboplatin (AUC 5), every 21 days, and ipatasertib at 200 mg po daily. 
 
Three patients will be enrolled at Dose Level 1 (DL1). Up to 3 patients will be enrolled 
and treated at the assigned dose level. If no DLTs are observed in the first 3 patients, then 
dose escalation may continue, and 3 new patients may be enrolled at the next dose level. 
If only one patient is observed with a DLT event in the first 3 patients, up to 3 additional 
patients will be enrolled and treated at the same dose level before dose escalation can 
proceed. If no further DLTs are observed, then dose escalation may continue. When two 
or more patients at a dose level have experienced a DLT, that dose level will be 
discontinued, and the previous dose level will be considered: if six patients have been 
treated at that dose level, it will be considered as the MTD; if three patients have been 
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Patients who miss 5 or more doses of ipatasertib (less than 80% of the dosage cycle) 
unrelated to ipatasertib toxicity of any grade will be considered for replacement after 
discussion with CTEP. The reason for not completing the cycle needs to be determined 
and well annotated.   
 
Safety data will be reviewed with CTEP prior to opening expansion phase. The design of 
the expansion phase is described in Section 13.4.  
 
The dose escalation phase indicated Dose Level 1 as the maximum tolerated dose 
(MTD).  Based on the safety data review by the study team and CTEP, patients enrolled 
to the expansion phase will be treated at Dose Level 1 (See Section 5 Table 1) (22-DEC-
2023).  
 
6. 
TREATMENT MODIFICATIONS/MANAGEMENT
6.1 
General Guidelines 
Dose modifications for paclitaxel and carboplatin chemotherapy will be performed 
according to standard practice of institutional guidelines; details in this section can be 
used as a guidance. Reasons for dose modifications or delays, the supportive measures 
taken, and the outcome will be documented in the patient’s chart and recorded in the 
eCRF.  
 
General guidelines for dosage/schedule modification can be summarized as follows: 
 For toxicities assessed by the investigator to be unlikely to develop into serious or 
life-threatening events, treatment may be continued at the same dose without 
reduction or interruption. 
 If any observed toxicity is attributable to only one drug as assessed by the 
investigator, the dose of the other drug(s) may not require modification. 
 Patients who require chemotherapy dose reductions and tolerate the reduced dose 
for more than one cycle (28 days) may be allowed to increase back to a 100% 
dose at the treating physician’s discretion.
 Chemotherapy may be delayed to manage toxicity. Delays up to 4 weeks 
(approximately 28 days) are permitted. Any delay longer than 4 weeks for an 
adverse event will require permanent discontinuation of paclitaxel and carboplatin 
treatment, but the patient may continue the ipatasertib, after discussion with the 
Medical Monitor.  
 
6.2 
Stopping Criteria 
 
The criteria to stop the study will be if 3 or more patients are unable to proceed with 
their debulking surgery (due to unresolved toxicities precluding the ability to have 
surgery) or if there is an unreasonable delay in the ability to complete debulking 
surgery due to excessive toxicity. 
 
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6.3 
Ipatasertib Dose Modification and Supportive Care Guidelines for Drug-Related 
Adverse Events 
 
Ipatasertib can be taken with or without food.  If a dose is missed or omitted (not taken 
within 8 hours after the scheduled dosing time), the patient should resume dosing with 
the next scheduled dose the following day.  Missed, omitted, or vomited doses will not be 
made up.   
 
In general, patients should be closely monitored for GI effects and patients experiencing 
nausea, vomiting, stomatitis/oral mucositis, or diarrhea are to be treated and managed per 
standard of care and per protocol guidelines, including hydration if clinically indicated to 
prevent renal insufficiency due to fluid depletion.  If the GI effects are attributable to 
ipatasertib as assessed by the investigator, the ipatasertib dose may be interrupted or 
reduced.  Patients whose GI symptoms cannot be adequately managed should discontinue 
ipatasertib. 
 
Fasting glucose levels should be carefully monitored per protocol guidelines. Patients 
should be instructed to report symptoms associated with hyperglycemia such as thirst, 
frequent urination, and blurred vision. Hyperglycemia should be managed per 
institutional standards of care, and per protocol guidelines. Use of oral anti-
may be interrupted or reduced per protocol guidelines. Endocrinology consultation 
should be considered for management of hyperglycemia, especially prior to use of insulin 
for asymptomatic hyperglycemia (due to the risk of hypoglycemia). 
 
Treatment-related rash, including cases of Grade 3 and Grade 4 rash, has occurred in 
patients receiving ipatasertib treatment.  In general, the rash commonly manifested as a 
maculopapular type with or without pruritus.  Most of the observed Grade 3 rashes 
occurred approximately 1-3 weeks after the first dose of ipatasertib.  In most of the cases 
with Grade 3 rash requiring dose interruption, ipatasertib dosing was resumed with dose 
reduction without recurrence of rash.  Rash and other dermatologic events should be 
closely monitored and managed per standard of care and protocol guidelines.  In general, 
for severe rash, dosing of ipatasertib should be held and patients should be treated with 
supportive therapy per standard of care; use of topical antihistamines as well as topical or 
systemic corticosteroids should be considered.
 
Dosage Modification for Ipatasertib 
 
If the patient does not tolerate the QD dosing of the ipatasertib, dosing with food may be 
used to alleviate gastrointestinal symptoms, including nausea, vomiting, and/or diarrhea.  
No more than two dose reductions of ipatasertib per patient (Dose re-escalation is not 
permitted for ipatasertib). Given the MTD is at DL1 of 200mg daily and per the dose-
expansion, there will only one dose level reduction to 100mg daily. (22-DEC-2023) 
 
Treatment Interruption 
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Ipatasertib treatment may be temporarily interrupted in patients who experience toxicity 
considered to be related to study drug.  If ipatasertib has been withheld for 
 2 weeks 
because of treatment-related toxicity, the patient should be discontinued from ipatasertib.  
Ipatasertib treatment may be suspended for reasons other than toxicity (e.g., surgical 
procedures). Any hold for toxicity should be considered a DLT.  If there is a length of 
time longer than 2 weeks or concomitant requirement to modify primary chemotherapy, 
this should result in discontinuation of ipatasertib. 
Ipatasertib Adverse Events of Special Interest (AESIs) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event).  Adverse 
events of special interest for ipatasertib include the following: 
 Cases of potential drug-induced liver injury that include an elevated ALT or 
AST in combination with either an elevated bilirubin or clinical jaundice, as 
defined by Hy's Law  
 Suspected transmission of an infectious agent by the study drug, as defined 
below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected. 
 Grade  3 fasting hyperglycemia  
 Grade  3 hepatotoxicity including ALT/AST elevations 
 Grade  2 colitis/enterocolitis 
Grade  2 diarrhea 
 Grade  3 rash 
Grade  2 pneumonitis  
 
6.4 
 Adverse Event Management Guidelines 
Guidelines for management of specific adverse events are provided in the subsections 
below. 
6.4.1 Diarrhea Management Guidelines 
Specific guidelines for managing diarrhea to improve safety and tolerability are provided 
in Table 2. All patients should receive loperamide (2 mg oral twice a day or 4 mg once a 
day) as prophylaxis for diarrhea in the first cycle if allowed by local guidance, except 
when the Investigator approves omission (e.g., if there are clinical concerns that preclude 
the use of loperamide prophylaxis in the first cycle). Investigators are encouraged to 
continue this dosing for the remainder of the study, and the prophylaxis dose may be 
adjusted as necessary, using their discretion based on clinical judgment and per local 
guidance. If diarrhea occurs, it should be managed per guidelines; upon resolution or when 
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Table 2 
Diarrhea Management Guidelines (cont.)
Severity of Diarrhea a 
Management Guideline 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated 
 
Rule out infectious etiology. 
 
Treat per Grade 2 management guidelines and 
supportive care. 
 
Permanently discontinue ipatasertib/. 
A gastroenterologist consultation should be considered for 
management and discontinuation of drug 
ADL  activities of daily living; BID  twice a day; NCI CTCAE v5.0  National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 5.0; QD  once a day. 
a  Diarrhea, as defined by NCI CTCAE v5.0,  A disorder characterized by an increase in frequency and/or 
loose or watery bowel movements. 
6.4.2  Fasting Hyperglycemia 
Fasting is defined as abstaining from food and drink (with the exception of water) for at 
least 8 hours.  The treatment goals for glycemic control should be:  1) fasting glucose under 
160 mg/dL and 2) HbA1c 
 8%. 
 
Dose modification guidelines for fasting hyperglycemia attributable to study treatment are 
outlined below (see Table 3) and are intended to provide guidance for fasting glucose 
measurements assessed in the clinic.  Decisions regarding study treatment should be made 
on fasting levels drawn in the clinic whenever possible. 
 
In the event of ipatasertib interruption, anti-diabetic medications may need to be held or 
reduced (per investigator judgement) and glucose should be monitored closely to minimize 
the risk of hypoglycemia. 
 
Because the hyperglycemia observed with ipatasertib treatment is consistently associated 
with endogenous elevations in insulin, insulin-based therapy to manage any hyperglycemia 
should be used with caution because severe hypoglycemic episodes could potentially occur.  
Therefore, initial treatment should be considered with biguanides (preferred), sulfonylureas, 
and other hypoglycemic treatments. 
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(
27.8 mmol/L); 
life-threatening 
consequences * 
Treat hyperglycemia as per standard of care, noting risk of 
hypoglycemia if insulin is used. Start (or increase dose of) oral anti-
diabetic medications (e.g., metformin).  
 
Assess for volume depletion and appropriate intravenous or oral 
hydration.  
 
Encourage a diabetic diet and initiate home glucose monitoring.  
 
Upon recovery of fasting glucose to 160 mg/dL, reduce ipatasertib 
by one dose level (see Table 1) when treatment is restarted.  
 
If glucose value  500 mg/dL recurs, permanently discontinue 
ipatasertib and contact Medical Monitor. If glucose values are > 500 
mg/dL discontinue ipatasertib.  
 
If Grade 4 hyperglycemia recurs, permanently discontinue 
ipatasertib. 
ULN upper limit of normal. 
* For all grades, the patient should receive education on a diabetic diet. 
6.4.3  Neutropenia  
Addition of hematopoietic growth factors is allowed.  If a dose delay is required as a 
result of neutropenia at any grade, patients should receive prophylactic granulocyte 
colony-stimulating factor or granulocyte-macrophage colony-stimulating factor per 
institutional standards.  Patients should be counseled as to the risk of fever and infection 
and to the importance of contacting their treating physician immediately if these 
conditions occur so that they can be promptly and appropriately managed.  Dosage 
modification guidelines for neutropenia and/or thrombocytopenia attributable to 
ipatasertib are outlined in Table 4. 
 
Table 4 
Neutropenia Management Guidelines 
Severity of Neutropenia 
and/or Thrombocytopenia 
Management Guideline 
Grade 2 
Ipatasertib may be continued at the original dose.  
Grade 3 
 
Ipatasertib should both be held until recovery to Grade 1 and if 
clinically appropriate based on the investigator’s medical 
judgment to Grade 2 as long as G-CSF is used to manage the 
neutropenia. Please see guidelines in this table regarding 
treatment for ongoing Grade 2 hematological toxicities.   
– 
First episode: Reduce ipatasertib by one dose level. If 
recovery to Grade 1 is achieved with the use of G-CSF, 
then continued use of G-CSF is recommended once 
dosing of the study drug is resumed. 
– 
Recurrent episode: Ipatasertib should be reduced by one 
dose level when treatment is restarted.   
 
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Dose limiting hematologic toxicities are defined as: 
 Febrile neutropenia 
 Prolonged grade 4 neutropenia persisting for greater than 7 days 
Grade 4 thrombocytopenia (platelet count <25,000) 
 Bleeding associated with grade 3 thrombocytopenia (25,000 to <50,000) 
Dose modification for dose limiting hematologic toxicity or cycle delay > 7 days due to 
hematologic toxicity:
ANC 
PLT 
First Occurrence 
Second 
Occurrence 
Third 
Occurrence
Yes 
No 
Add filgrastim, 
pegfilgrastim or 
biosimilar
Reduce 
paclitaxel one 
dose level
Reduce 
paclitaxel one 
more dose level 
Yes 
Yes 
Add filgrastim, 
pegfilgrastim or 
biosimilar AND 
reduce 
carboplatin one 
AUC unit 
Reduce 
paclitaxel one 
dose level 
Reduce 
paclitaxel one 
more dose level
No 
Yes 
Reduce 
carboplatin one 
AUC unit 
Reduce 
carboplatin one 
more AUC unit 
Reduce 
paclitaxel one 
dose level 
Note:  For patients meeting criteria for dose modification after third recurrence, notify 
study chair 
 
Peripheral neuropathy:  for grade 2 (or greater) peripheral neuropathy:
Hold paclitaxel until recovered to grade 1, then paclitaxel should be reduced one dose 
level. Chemotherapy can be delayed for a maximum of 3 weeks.  If neuropathy does not 
recover to grade 1, paclitaxel should be omitted from subsequent cycles. 
 
Renal toxicity:  Renal toxicity is not expected from paclitaxel and/or carboplatin as a 
direct complication of chemotherapy in this patient population given the required 
treatment free interval in the pre-treated population.  As such, there are no specific dose 
modifications for renal toxicity.  However, see Appendix IV for carboplatin dose 
calculation instructions for criteria for recalculation of dose.
 
Hypersensitivity reaction:  In general, the occurrence of a hypersensitivity reaction to 
paclitaxel and/or carboplatin can be managed with administration of medication to 
prevent hypersensitivity reactions and/or adjustments in infusion rates, per institutional 
standards.  If patient experiences hypersensitivity reaction that requires discontinuation of 
paclitaxel and/or carboplatin, the patient will discontinue protocol directed treatment.  If 
this occurs prior to completion of cycle 1 treatment, patient will be replaced and deemed 
as DLT-inevaluable. 
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7. 
ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1 
Protocol Agents 
 
Investigational Agents 
The investigational agent administered in NRG-GY027 is Ipatasertib (NSC#781451), 
which is being made available under an IND sponsored by DCTD, NCI   
 
 
Commercial Agents 
The commercial agents in NRG-GY027 are Paclitaxel (NSC #125973) and Carboplatin 
(NSC #201345).
 
Since patients are receiving investigational and commercial agents on the same treatment 
are, Investigationl Agent reporting guidelines will apply.  To determine whether an 
adverse event meets expedited reporting criteria, see the reporting table in section 7.4.2 of 
the protocol. 
 
7.2 
Adverse Events and Serious Adverse Events
7.2.1
This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 
reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
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. 
 
 
 
 
 
 
 
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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 
reporting unless otherwise specified. 
 
7.5 
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 
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 
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 Cancer Therapy Evaluation Program (CTEP) 
credentials necessary to access secure NCI Clinical Oncology Research Enterprise (CORE) 
systems. 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. 
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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). 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on the 
IRB/REB approval) must meet the following criteria for the site to be able to have an 
Approved status following processing of the IRB/REB approval record: 
 
Have an active CTEP status; 
 
Have an active status at the site(s) on the IRB/REB approval (applies to US and 
Canadian sites only) on at least one participating organization’s roster;
 
If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
 
Include the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile;  
 
List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
 
Have the appropriate CTEP registration type for the protocol.  
Additional Requirements 
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 the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
 
Compliance with all applicable protocol-specific requirements (PSRs). 
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 an Active CTEP status;
 Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) 
and on at least one participating roster; 
 If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
 Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
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 Holds the appropriate CTEP registration type for the protocol. 
 
Additional Requirements 
Additional 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 
 Compliance with all 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 in to the CTSU members’ website (https://www.ctsu.org); 
 
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 number NRG-GY027. 
 
Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration to download and complete the forms provided. 
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU.)  
 
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. 
(22-DEC-2023). 
 
Checking Site’s Registration Status 
Site registration status may be verified on the CTSU members’ website.  
 
 Click on Regulatory at the top of the screen; 
 Click on Site Registration; and 
 Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
 
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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 
describes DTL task assignments, CI signature, and CTEP registration requirements, as 
well as include a Master Task List. (22-DEC-2023) 
 
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:   
  Active CTEP registration with the credentials necessary to access secure NCI/CTSU 
IT systems; 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 
 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 
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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. 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with patient enrollment in OPEN. Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System to ensure that a 
slot on the protocol is available to the patient. Once a slot reservation confirmation is 
obtained, site staff may then proceed to enroll the patient to this study.  
 
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 5.3) 
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 
Investigational Study Agent: Ipatasertib (GDC-0068) (NSC # 781451, IND # 
 
Chemical Name:  [(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-
dihydro-5H- 
cyclopenta [d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino) propan-1-one
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Other Names: GDC-0068 
Classification: AKT inhibitor 
Molecular Formula: C24H32ClN5O2
M.W.: 458.00 g/mol as free base 
494.46 g/mol as mono-HCl salt 
Approximate Solubility:  The apparent solubility of ipatasertib drug substance is high 
(> 10 mg/mL) across a pH range of 1.1-7.0. 
Mode of Action: Ipatasertib is a potent, selective, ATP-competitive small-molecule 
inhibitor of all three isoforms of Akt. Ipatasertib selectively binds to the active 
conformation of Akt and inhibits its kinase activity.  
Description: Ipatasertib drug substance is a white-to-tan powder. 
 
How Supplied: 
Genentech supplies and CTEP, DCTD, NCI distributes ipatasertib as 100 mg or 200 mg 
oval, film-coated tablets in a 30 count bottle.  The 100 mg tablet is greyish yellow and the 
200 mg tablet is brownish pink.  In addition to the ipatasertib drug substance, each tablet 
contains microcrystalline cellulose, pregelatinized maize starch, croscarmellose sodium, 
colloidal silicon dioxide, povidone, magnesium stearate and either Opadry II Yellow film 
coat (100 mg) or Opadry II Pink film coat (200 mg).   
 
Storage: 
Do not store above 25°C / 77°F 
 
If a storage temperature excursion is identified, promptly return ipatasertib to less than 
25°C and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:  Stability studies are ongoing.
 
Route of Administration: oral
 
Method of Administration: Ipatasertib can be administered without regard to food. 
 
Potential Drug Interactions: 
Ipatasertib is primarily metabolized by CYP3A and is a substrate of P-glycoprotein.  
Strong inhibitors and inducers of CYP3A may result in increased or decreased ipatasertib 
exposures, respectively. The following drugs should be avoided, or used with caution 
when administering ipatasertib. If using of one of these drugs is necessary, the risks and 
benefits should be evaluated prior to its concomitant use with ipatasertib:
 Strong CYP3A inhibitors: such as but not limited to atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, 
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saquinavir, telithromycin, troleandamycin, voriconazole, and/or grapefruit juice or 
grapefruit supplements
 Strong CYP3A inducers: such as but not limited to rifampin, carbamazepine, 
rifapentine, phenytoin, phenobarbital, and/or St. John’s wort or hyperforin 
 Ipatasertib is a moderate inhibitor of CYP3A4. CYP3A4 substrates with a narrow 
therapeutic index: such as but not limited to 
alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide,
quinidine, sirolimus, tacrolimus, ergot alkaloids ergotamine, and/or 
dihydroergotamine should be avoided or administered with caution. 
Patient Care Implications: 
 Because the PI3K-Akt-mTOR pathway is involved in glucose metabolism, 
inhibition of this signaling network and its target mTOR can cause 
hyperglycemia, which is a toxicity common to the class of PI3K-Akt-mTOR 
inhibitors. 
 Agents such as proton pump inhibitors (e.g., omeprazole, pantoprazole) are not 
expected to affect ipatasertib PK. 
 Ipatasertib is not expected to prolong the QTc interval. 
 
9.2 
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) 
 
 
9.3 
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. 
 
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Sites can order study agents in OAOP when a patient is enrolled to treatment. Agent 
orders can be expedited overnight Monday-Thursday when sites provide expedited 
courier information.
 
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.   
 
9.3.1
Investigator Brochure Availability
The current versions of the Ipatasertib (NSC # 781451) IB 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. 
 
9.3.2
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 
agent, strength, formulation and ordering investigator on this protocol.  
9.4 
Commercial Agent—Carboplatin  
 
Please see Section 5.1 for administration instructions.  Please refer to the current FDA-
approved package insert provided with each drug for pharmacologic information, drug 
preparation, handling, and storage.  
 
9.4.1 Product Description 
Carboplatin is commercially available.  Carboplatin aqueous solution injection is a 
premixed aqueous solution of 10 mg/mL carboplatin.  Dosage forms include 50mg/5mL, 
150 mg/15mL, 450 mg/45mL and 600 mg/60 mL aqueous solution in multidose vials. 
9.4.2 Solution Preparation 
See the carboplatin package insert for preparation instructions. 
9.4.3 Availability/Supply  
 
Carboplatin is obtained by the investigator from commercial supply. 
 
9.4.4 Adverse Events 
 
Hair loss, Vomiting/Nausea, Infection, Anemia, Bruising/Bleeding, Belly pain, 
Diarrhea/Constipation, Peripheral Neuropathy, Allergic Reaction. 
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Please refer to the package insert or current Health Canada approved product monograph 
and the site-specific pharmacy for toxicity and safety information. 
 
9.5 
Commercial Agent—Paclitaxel 
 
 
Please see Section 5.1 for administration instructions.  Please refer to the current FDA-
approved package insert provided with each drug for pharmacologic information, drug 
preparation, handling, and storage.  
 
9.6.1 Adverse Events 
 
Please refer to the package insert and the site-specific pharmacy for toxicity and safety 
information. 
 
9.6.2 Availability/Supply  
 
Paclitaxel is obtained by the investigator from commercial supply. 
 
 
10. 
PATHOLOGY/BIOSPECIMEN 
10.1
Central Review 
Not applicable 
10.2 Integral Biomarkers 
Not applicable 
 
10.3
Integrated Biomarkers (24-APR-2023) 
A detailed description of the integrated biomarker testing can be found in the Correlative Science 
Appendix (Appendix VIII). 
10.3.1 Ipatasertib Pharmacokinetics 
10.3.1.1 
Integrated Biomarker to be Tested 
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) 
 
No review required 
 
10.3.1.2 
Integrated Biomarker Assay Summary 
Frozen plasma (at least 500µL) and snap-frozen IDS tumor and normal tissue (250mg each) will 
be used for LC-MS/MS. The EET Biobank will batch ship frozen plasma aliquots and tissue to 
the Analytical Pharmacology Core (City of Hope) at study closure. Ipatasertib and its active 
metabolite, M1, will be measured using an LC-MS/MS assay developed and validated in the 
U24-funded PITT-CAL PK Resource Laboratory under the supervision of Dr. 
 at the 
City of Hope. 
10.3.1.3 
Integrated Biomarker Results Reporting
Dr. 
will provide biomarker results to the NRG SDMC for analysis. Sites will not receive 
biomarker results.
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10.3.2 Whole Exome Sequencing 
10.3.2.1 
Integrated Biomarker to be Tested 
Whole exome sequencing (WES) 
National Clinical Laboratory Network (NCLN) approved 
10.3.2.2 
Integrated Biomarker Assay Summary 
DNA extracted from pre-treatment archival FFPE tumor tissue and whole blood will be used for 
WES. The EET Biobank perform a pathology QA review and macrodissect tumor tissue only 
when needed to enrich tumor content. The EET Biobank will then co-extract DNA and RNA 
from tumor tissues following NCLCN standard operating procedures (SOPs). DNA and RNA 
will be stored in a -80°C freezer until distribution. The remaining FFPE block and H&E stained 
slide(s) will be stored at room temperature (22-DEC-2023). For this assay, the EET Biobank will 
batch ship aliquots of DNA to the NCLN Genomics Laboratory or MoCha, Frederick National 
Laboratory for Cancer Research (FNLCR) at study closure. WES will be done as per NCI-
approved NCLN SOPs under the supervision of Dr. 
. 
10.3.2.3 
Integrated Biomarker Results Reporting
Dr. 
will provide biomarker results to the NRG SDMC for analysis. Sites will not 
receive biomarker results. 
10.3.3 RNAseq 
10.3.3.1
Integrated Biomarker to be Tested 
RNAseq 
National Clinical Laboratory Network (NCLN) approved 
10.3.3.2 
Integrated Biomarker Assay Summary 
RNA extracted from pre-treatment archival FFPE tumor tissue will be used for RNAseq. The 
EET Biobank will batch ship aliquots of RNA to the NCLN Genomics Laboratory or MoCha, 
Frederick National Laboratory for Cancer Research (FNLCR) at study closure. (22-DEC-2023)
RNAseq will be done as per NCI-approved NCLN SOPs under the supervision of Dr. 
 
 
10.3.3.3 
Integrated Biomarker Results Reporting
Dr. 
will provide biomarker results to the NRG SDMC for analysis. Sites will not 
receive biomarker results. 
10.3.4 PTEN Loss
10.3.4.1
Integrated Biomarker to be Tested 
PTEN IHC
Biomarker Review Committee (BRC) approved 
 
10.3.4.2 
Integrated Biomarker Assay Summary 
Three unstained slides (charged, 4µm) from archival FFPE pre-treatment tumor tissue will be 
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Aperio-Leica Scanscope-associated algorithms. H-score will be determined as the product of the 
staining intensity (0, absent; 1, weak staining; 2, moderate staining; and 3, strong staining) 
multiplied by the percentage of positive cells quantified. 
10.5.2.3 
Exploratory Biomarker Results Reporting 
Dr. 
 will provide biomarker results to the NRG SDMC for analysis. Sites will not receive 
biomarker results.
10.5.3 Immune Cell Subsets 
10.5.3.1 
Exploratory Biomarker to be Tested
CyTOF 
Testing of banked biospecimens will not occur until an amendment to this protocol (or a 
separate correlative science proposal) is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies. (24-APR-2023) 
 
 
10.5.3.2 
Exploratory Biomarker Assay Summary 
Baseline and IDS whole blood will be used for CyTOF. Upon approval, the EET Biobank will 
batch ship CyTOF whole blood with PROT1 to Dr. 
 at study closure. These 
biospecimens will undergo a next generation of single-cell analysis technology called mass 
cytometry, which overcomes the limitations of flow cytometry (i.e., measuring a maximum of 
ten markers per panel). The CyTOF is a mass spectrometer-flow cytometer hybrid instrument 
that uses stable isotopes instead of fluorophores as reporters. 
10.5.3.3 
Exploratory Biomarker Results Reporting 
Dr. 
 will provide biomarker results to the NRG SDMC for analysis. Sites will not receive 
biomarker results.
10.5.4 Protein pathway activation mapping of the AKT-mTOR signaling pathway by 
LCM-RPPA (24-APR-2023) 10.5.4.1 
Exploratory Biomarkers to be Tested (24-APR-
2023) 
Twenty-three members of the AKT-mTOR protein signaling pathway will be quantitatively 
measured by LCM-RPPA based analysis of the pre-treatment baseline FFPE tissue samples. See 
Appendix VIII, Section 2.2 for details.
Testing of banked biospecimens will not occur until an amendment to this protocol (or a 
separate correlative science proposal) is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies. 
10.5.4.2 
Exploratory Biomarker Assay Summary 
Pre-treatment and IDS tumor tissue will be used for LCM-RPPA. Upon approval and provided 
that sufficient FFPE materials remain, the EET Biobank will batch ship 2-3 8µm fresh-cut 
uncharged sections of archival FFPE tumor tissue to the Center for Applied Proteomics and 
Molecular Medicine (George Mason University) at study closure. Multiple members (. See 
Appendix VIII, Section 2.2 for details.) of the AKT-mTOR signaling pathway including 
phosphorylated AKT S473 and T308 will be measured using the LCM-RPPA workflow 
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originated in the Petricoin-Liotta lab and under the supervision of Dr. 
. (24-APR-
2023) 
10.5.4.3 
Exploratory Biomarker Results Reporting 
Dr. 
 will provide all RPPA biomarker results to the NRG SDMC for analysis. Sites will 
not receive biomarker results. (24-APR-2023) 
10.6
Banking Biospecimens for Future Research 
Additional biomarker testing of banked biospecimens will not occur until an amendment to this 
treatment protocol or separate correlative science protocol is reviewed and approved in 
accordance with National Clinical Trials Network (NCTN) policies. 
 
Details regarding the banking and use of biospecimens for future research can be found in 
Appendix VII.
 
 
11. 
ASSESSMENT OF EFFECT 
 
11.1 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.  
  
11.1.1 Disease Parameters  
Measurable disease: Measurable lesions are defined as those that can be accurately 
-
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 
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 
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.  
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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 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. 
  
11.1.2 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 
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assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body 
scans), 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 
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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. 
 
11.2 Response Criteria 
Determination of response should take into consideration all target (See 11.2.1) and non-
target lesions (See 11.2.2). 
 
11.2.1 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.  
 
11.2.2 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). 
 
11.2.3 Evaluation of Best Overall Response  
The best overall response is the best time point response recorded from the start of the 
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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)
*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
)
Target
Lesions
Non-Target
Lesions
Biomarker
CA-125
New
Lesions*
Time Point
Response
CR
CR
Within
normal
limits
No
CR
CR
Non-CR/Non-PD
Any value
No
PR
CR
NE
Any value
No
PR
PR
Non-PD or NE
Any value
No
PR
SD
Non-PD or NE
Any value
No
SD
NE
Non-PD
Any value
No
NE
PD
Any
Any value
Yes or No
PD
Any
PD**
Any value
Yes or No
PD
Any
Any
Any value
Yes
PD
Non-Target Lesions
Biomarker
CA-125
New Lesions*
Time Point
Response
CR
Within
normal limits
No
CR
CR
Above
normal limits
No
Non-CR/non-PD*
Non-CR/non-PD
Any value
No
Non-CR/non-PD*
NE
Any value
No
NE
Unequivocal PD
Any value
Yes or No
PD
Any
Any value
Yes
PD
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11.2.4 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-GY027, confirmation of response is not required. 
 
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 
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(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. 
 
Patients with a global deterioration of health status requiring discontinuation of treatment 
or 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. 
 
11.3 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. 
 
11.4 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, or date of last contact if neither 
progression nor death has occurred. 
11.5 Survival 
Survival is defined as the duration of time from study entry to time of death or the date of 
last contact. 
 
12. 
DATA AND RECORDS 
 
12.1 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: 
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Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; 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); and 
 
Rave Read Only or Rave SLA role must have at a minimum an Associate (A) 
registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
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. No action will be required; each study invitation will be 
automatically accepted and study access in Rave will be automatically granted. Site staff 
will not be able to access the study in Rave until all required Medidata and study-specific 
trainings are completed. Trainings will be in the form of electronic learnings (eLearnings) 
and can be accessed by clicking on the eLearning link in the Tasks pane located in the 
upper right corner of the iMedidata screen. If an eLearning is required for a study and has 
not yet been taken, the link to the eLearning will appear under the study name in the 
Studies pane located in the center of the iMedidata screen; once the successful 
completion of the eLearning has been recorded, access to the study in Rave will be 
granted, and a Rave EDC link will replace the eLearning link under the study name.  
No action will be required by site staff (to activate their account) who have not 
previously activated their iMedidata/Rave account at the time of initial site registration 
approval for the study in the Regulatory application.  Pending study invitations 
(previously sent but not accepted or declined by a site user) will be automatically 
accepted and study access in Rave will be automatically granted for the site user.  
Account activation instructions are located on the CTSU website in the Data 
Management section under the Data Management Help Topics > Rave resource materials 
(Medidata Account Activation and Study Invitation). 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.   
 
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12.2 NRG Data Management Forms 
Refer to the CTSU member website for protocol Form Set. 
 
12.3 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 sections 7.4 and section 7.5. for information about expedited 
and routine reporting.   
 
12.4 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. 
Pre-treatment AEs: AEs that occur after informed consent is signed and prior to 
start of treatment are collected in Medidata Rave using the Pre-treatment Adverse 
Event form.  
Pre-existing medical conditions (formerly referred to as baseline AEs) identified 
during baseline assessment are not considered AEs and therefore should not be 
reported on the Pre-treatment Adverse Event form. If these pre-existing 
conditions worsen in severity, the investigator must reassess the event to 
determine if an expedited report is required. Whether or not an expedited report is 
required, the worsened condition should be reported in Rave as a routine AE 
Treatment-emergent AEs: All AEs that occur after start of treatment are collected 
in Medidata Rave using the Adverse Event form, which is available for entry at 
each treatment course or reporting period and is used to collect AEs that start 
during the period or persist from the previous reporting period. AEs that occur 30 
days after the last administration of the investigational 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. 
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Upon completion of AE entry in Medidata Rave, the CRA submits the AE for 
rules evaluation by completing the Expedited Reporting Evaluation form (i.e., 
checking the box Send All AEs for Evaluation and save the form). Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited 
reporting. A report is initiated in CTEP-AERS using information entered in 
Medidata Rave for AEs that meet reporting requirements. The CRA completes the 
report by accessing CTEP-AERS via a direct link on the Medidata Rave 
Expedited Reporting Evaluation form. Contact the CTSU Help Desk at 1-888-
823-5923 or by email at ctsucontact@westat.com if you have any issues 
submitting an expedited report in CTEP-AERS. 
In the rare occurrence that internet connectivity is lost, a 24-hour notification is to 
be made to CTEP by telephone at 301-897-7497. Once internet connectivity is 
restored, the 24-hour notification that was phoned in must be entered immediately 
into CTEP-AERS using the direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the 
CTSU members’ website: 
 Study specific documents: Protocols > Documents> Protocol Related 
Documents> Adverse Event Reporting; and   
 Additional resources: Resources > CTSU Operations Information> User 
Guides & Help Topics. 
NCI requirements for SAE reporting are available on the CTEP website:  
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.p
df. 
 
12.5 Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms, DQP 
Form Status and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, forms with current status, and 
timeliness reports. Site staff should review the DQP modules on a regular basis to 
manage specified queries and delinquent forms. 
The DQP is accessible by site staff who are rostered to a site and have access to 
the CTSU website. Staff who have Rave study access can access the Rave study 
data via direct links available 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 
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require site review, providing a summary count of queries and delinquent forms 
for each Rave study that a site is participating in. Additional site staff can 
subscribe and unsubscribe to these notifications using the CTSU Report and 
Information Subscription Portal on the CTSU members’ website. 
To learn more about DQP use and access, click on the Help Topics button displayed on 
the Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP 
Reports modules. 
 
12.6 Global Reporting/Monitoring 
DMU Complete 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 Complete reporting consists of Patient Demographics, Baseline 
Abnormalities, On/Off Treatment/Study Status, Treatment/Course/Dosing information, 
Adverse Events, Late Adverse Events, and Response data 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.   
 
 
 
 
 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 Study Design 
This is a single arm, open label, limited multi-center, phase I study of ipatasertib in 
combination with paclitaxel and carboplatin as neoadjuvant chemotherapy in patients 
with newly diagnosed ovarian cancer. A total of 4 dose levels of ipatasertib are planned: 
200 mg (DL1), 300 mg (DL2), 400 mg (DL3), and a DL-1 of 100 mg.  
 
This trial has two phases: a dose-escalation phase to estimate the maximum tolerated 
dose (MTD) of ipatasertib, and an expansion phase in which the feasibility will be further 
to be examined after the MTD is established. This trial has a sample size ranging from 21 
to 36. 
 
The dose-escalation phase will follow a standard 3+3 design with dose escalation and de-
escalation to estimate the MTD based on dose-limiting toxicities (DLTs) that occur in the 
first cycle beginning with dose level 1. DLT window is 1 cycle = 21 days. 
  
The expansion phase will utilize a single-stage design with a total of 18 patients treated at 
the MTD including the 6 patients during dose escalation and the 12 at dose expansion).  
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The dose escalation phase indicated Dose Level 1 as the MTD.  Based on the safety data 
review by the study team and CTEP, patients enrolled to the expansion phase will be 
treated at Dose Level 1 (See Section 5 Table 1) (22-DEC-2023). 
 
13.2 Stratification and Randomization 
There is no stratification and randomization. 
 
13.3 Study Endpoints 
 13.3.1 Primary Endpoints 
1) DLTs that occur within the first cycle of neoadjuvant chemotherapy (as defined in 
Section 5.4) in the dose escalation phase. 
2) DLTs that occur within the first cycle of neoadjuvant chemotherapy (as defined in 
Section 5.4) in the expansion phase. 
3) The frequency and severity of adverse events as assessed by CTCAE v5.  
 
13.3.2 Secondary Endpoints 
1) Tumor response (partial or complete) assessed by RECIST 1.1. 
 
13.3.3 Translational Research Endpoints  
1) Measurements for pPRAS40 expression in the pre-treatment tumor and on-treatment 
tumor. 
2) Measurements of tissue and blood pharmacokinetics for ipatasertib.  
3) Tumor response assessed by RECIST 1.1, and measurements for genomic alterations 
in PI3K Pathway genes (PTEN, PI3KCA, PIK3R1, AKT1, p53 loss, KRAS, NF1, 
TSC1/TSC1). 
4) Tumor response assessed by RECIST 1.1, and measurements for transcriptomic 
alterations in PI3K Pathway genes (PTEN, PI3KCA, PIK3R1, AKT1, p53 loss, KRAS, 
NF1, TSC1/TSC1).   
5) Tumor response assessed by RECIST 1.1, and measurement for PTEN loss. 
6) Tumor response assessed by RECIST 1.1, and measurements for the 23 individual 
AKT-mTOR protein pathway activation mapping proteins/phosphoproteins  measured by 
LCM-RPPA listed in 10.5.4.1. (24-APR-2023) 
 
13.4 Primary Objectives Study Design
13.4.1 Primary Hypothesis and Endpoints 
Primary hypothesis for dose escalation phase: Ipatasertib can be safely combined with 
paclitaxel and carboplatin as neoadjuvant chemotherapy in patients with newly diagnosed 
ovarian cancer. 
Primary hypothesis for expansion phase: The study regimen will be considered feasible if 
the probability of a patient experiencing a DLT in cycle 1 is 15% or less.  The study 
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treatment is considered infeasible if the probability of a patient experiencing a DLT in 
cycle 1 is 35% or higher. 
Primary endpoints: see Section 13.3.1. 
 
13.4.2  How Primary Endpoints Will be Analyzed 
 
The primary study objectives are to estimate the MTD in dose-escalation phase and to 
evaluate the feasibility in expansion phase once the MTD is established for ipatasertib in 
combination with paclitaxel and carboplatin as neoadjuvant chemotherapy for ovarian 
cancer. This study consists of two phases with a sample size ranging from 21 to 36 
patients: a dose-escalation phase for estimation of the MTD (PART I) and expansion 
phase (PART II). 
 
           Dose-Escalation Phase (Part I) 
            A standard 3+3 with dose de-escalation design will be used to determine the MTD.          
Patients will be accrued in cohorts of size 3.  DLTs will be evaluated during the first 21-
day cycle. The dose level combinations and orders are presented in Section 5 Table 1. 
           The starting dose level (Dose Level 1, DL1) will consist ofpaclitaxel 175mg/m2 every 21 
days, carboplatin (AUC 5), and ipatasertib at 300 mg po daily.  
 For DLT evaluation purpose, a patient is treated as having completed the first cycle of 
neoadjuvant chemotherapy if this patient completes at least 80% of ipatasertib out the 21 
daily ipatasertib doses. 
Patients who miss 5 or more doses of ipatasertib (less than 80% of the dosage cycle) 
related to ipatasertib toxicity of any grade will be considered a DLT  by the definition in 
5.4.  
Patients who miss 5 or more doses of ipatasertib (less than 80% of the dosage cycle) 
unrelated to ipatasertib toxicity of any grade will be considered for replacement after 
discussion with CTEP, and these patients deem to be DLT-unevaluble. The reason for not 
completing the cycle needs to be determined and well annotated.   
 
Dose escalation rules are outlined in Section 5.5. 
            Safety data will be reviewed with CTEP prior to opening expansion phase. 
            Expansion Phase (Part II) 
Once the MTD is determined from the dose-escalation phase, that dose will be used for 
the feasibility phase unless clinical judgement indicates that a lower dose be used. DLTs 
will be based the first 21-day cycle.  
            For DLT evaluation purpose, a patient is treated as having completed the first cycle of 
neoadjuvant chemotherapy if this patient completes at least 80% of ipatasertib out the 21 
daily ipatasertib doses. 
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Patients who miss 5 or more doses of ipatasertib (less than 80% of the dosage cycle) 
related to ipatasertib toxicity of any grade will be considered a DLT  by the definition in 
5.4.  
 
Patients who miss 5 or more doses of ipatasertib (less than 80% of the dosage cycle) 
unrelated to ipatasertib toxicity of any grade will be considered for replacement after 
discussion with CTEP, and these patients deem to be DLT-unevaluble. The reason for not 
completing the cycle needs to be determined and well annotated.   
 
            Twelve additional patients will be treated at the MTD for a total of 18 patients treated at 
that dose. If 5 or fewer out of these 18 patients have DLTs in the first cycle of neoadjuvant
chemotherapy, then the regimen will be considered feasible for further evaluation, 
otherwise the regimen will be considered infeasible. 
 
            Among these 12 participants enrolled in the expansion phase, it is anticipated that 10 
participants will have evaluable biopsies for evaluation of the change of pPRAS40 based 
on prior clinical trials in which 10% will not have interval debulking surgery. These 10 
patients with evaluable biopsies will provide a 90% power to detect a decrease of 1 
standard deviation in pPRAS40 after neoadjuvant treatment by a one-sided paired t-test at 
0.05 significance level. 
 
          For the overall evaluation of adverse events,  all patients who receive any study drug will 
be evaluable. For  DLT evaluation, the DLT-evaluable patients will only include those 
eligible patients who have a DLT within the first cycle of neoadjuvant chemotherapy, or 
complete the first cycle of neoadjuvant chemotherapy.   
 
          The estimation of the MTD and the determination of the feasibility is integrated in the 
design. The number of patients with DLTs will be summarized by dose level. Frequency 
and severity of adverse events as assessed by CTCAE v5 will be tabulated as descriptive 
statistics.  
 
13.4.1 Sample Size and Power Calculations 
Dose escalation phase 
A minimum of 9 patients and a maximum of 24 patients will be treated in the dose-
escalation phase.  
 
The table below summarizes the probabilities of dose escalation and de-escalation in a 
standard 3+3 design for a range of true DLT rates
           
True DLT rate 
10%
20% 
30% 
40% 
50% 
Probability of dose escalation 
0.91 
0.71 
0.49 
0.31 
0.17
Probability of dose de-escalation 
0.09 
0.29 
0.51 
0.69 
0.83
          Expansion phase 
A total of 18 patients will be treated at the MTD including the patients treated at the 
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MTD in the dose-escalation phase. Expansion phase has 88% probability of correctly 
declaring the regimen feasible and 81% probability of correctly declaring it infeasible 
with the feasibility decision rules.    
 
13.5 Study Monitoring of Primary Objectives 
During trial, all enrolling sites will be required to participate in a regularly scheduled 
teleconference including the study chairs, and phase I committee chair, study statistician, 
data management, and protocol administrator. DLTs and other toxicities will be discussed 
among this protocol monitoring team.  The decision to de-escalate or escalate is made by 
consensus of the study team in accordance with the decision rules outlined in the 
protocol. 
NRG Oncology Data Monitoring Committee (DMC) 
The NRG Oncology DMC will review the study twice a year with respect to patient 
accrual and AEs. The DMC also will review the study for protocol-specified interim 
analyses and on an “as needed” basis.   
 
NRG Early Phase Oversight Committee 
Study reports focusing on accrual and adverse event data will be prepared regularly and 
the PI/NRG study team will have regular conference calls (biweekly or at most monthly) 
to review the accrual/safety data.  Information from these calls will be reviewed quarterly 
by the NRG Oncology Early Phase Oversight Committee. 
 
13.6 Accrual/Study Duration Considerations 
           This study population is similar to patients in NRG-GY007 opened in May 2016. The 
phase I accrual rate was approximately 1.4 patients per month for NRG-GY007. The 
projected accrual rate for this trial is 2 patient per month.  
            The duration of accrual for the dose-escalation phase is a function of the unknown dose-
toxicity relationship and the resulting number of dose levels required.  
            The duration of accrual for the feasibility phase is approximately at least 6 months. The 
duration of neoadjuvant chemotherapy is 9 weeks, and it will be about 3 to 4 weeks up to 
6 weeks before patients have interval debulking surgery. The duration of follow-up is 30 
days after last dose of ipatasertib. The analysis for primary objectives can be 
accomplished within 4 - 7 months of final patient entry. The analysis including secondary 
objectives will require distribution of biospecimens, resolution of queries, completion of 
all laboratory tests, and collation of laboratory data with clinical data. These can be 
accomplished within 7-13 months of final patient entry. 
 
13.7 Dose Level Guidelines 
A standard 3+3 with dose de-escalation design will be used for regimens in this study. 
See section 5.5 for details. Definition of DLTs is in section 5.4. 
13.8 Secondary Endpoints and Analysis Plans  
13.8.1 Secondary Hypotheses and Endpoints
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            The secondary objectives focus on estimation and description; there are no specific 
hypotheses.  
            Secondary endpoints see section 13.3.2.  
13.8.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
Tumor response is assessed by RECIST 1.1, and will be summarized by dose level. The 
proportion of patients with objective tumor response will be estimated with their 
corresponding 90% confidence interval for expansion phase. 
13.9 Translational Research Endpoints 
13.9.1  Integrated Endpoints (24-APR-2023) 
The Ipatasertib pharmacokinetics will be summarized by protocol-specified collection 
time, dose level and bio-speciment type, and a mixed model will be used to identify the 
maximum concentration (Cmax) in plasma and tumor tissue whenever it is feasible.    
Genomic alterations in PI3K Pathway genes for each biomarker of PTEN, PI3KCA, 
PIK3R1, AKT1, p53 loss, KRAS, NF1, TSC1/TSC1 from archival FFPE will be 
summarized and tabulated. The correlations of tumor response with genomic alterations 
for each of these biomarkers will be assessed by 1-sided Spearman’s rank correlation 
coefficient tests at 10% signiciance level, respectively. The maximum sample size of 18 
in expansion phase will provide 90% power to detect a rank correlation coefficient as 0.6 
at 10% significance level (Figure 13.1). 
 
Figure 13.1  
 
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Similarly, transcriptomic alterations in PI3K Pathway genes for each biomarker of PTEN, 
PI3KCA, PIK3R1, AKT1, p53 loss, KRAS, NF1, TSC1/TSC1  from archival FFPE will 
be summarized. The associations of tumor response with transcriptomic alterations for 
each of these biomarkers will separately be evaluated by 1-sided Spearman’s rank 
correlation coefficient tests at 10% signiciance level. 
  
The proportion of patients who have PTEN loss by IHC from archival FFPE will be 
estimated with the corresponding 90% confidence interval. The correlation between 
PTEN loss by IHC and tumor response will be tested by 1-sided Spearman’s rank 
correlation coefficient tests at 10% signiciance level. 
  
13.9.2 Exploratory Endpoints (24-APR-2023) 
pPRAS40 expression in tumor will be summarized by collection time point and dose 
level. Wilcoxon signed rank test will be used to explore the change of pPRAS40 
expression in the pre-treatment vs on-treatment tumor in the patients who have been 
treated at the MTD and have evaluable biopsy specimen. 
 
Quantitative phosphorylated AKT S473 and T308, which are part of the 23 AKT-mTOR 
signaling pathway activation proteins obtianed LCM-RPPA from tumor tissue will be 
summarized by collection time point and dose level (see Appendix VIII, Section 2.2 for 
details). Spearman rank correlation coefficient tests will be used to investigate the 
associations of tumor response with baseline phosphorylated expression for AKT S473 
and T308 along with the other 21 AKT-mTOR signaling proteins. In addition, the 
relationship of phosphorylated protein expression change by treatment from baseline for 
each of the 23 RPPA biomarkers will be correlated with tumor response by Spearman 
rank correlation coefficient test. 
 
           Blood will be collected for CyTOF analysis. This analysis will focus on immune 
populations that change with those patients who may have responded to NACT + 
ipatasertib. We hypothesize that tumors that responded to treatment will have different 
immune population changes than those tumors that do not respond to treatment. 
 
          The purpose of translational research objectives is to explore and possibly generate 
hypotheses for future study. Therefore there will be no adjustment for multiple tests. Due 
to small sample size of this study, exact testing procedure, e.g., exact Spearman’s rank 
correlation test, may be used where it is appropriate. 
 
 
 
 
 
 
 
13.10 Gender/Ethnicity/Race Distribution 
            The expected gender/ethnicity/race distribution is based on patients from the NRG-
GY007 who had cell type as serous or endometroid, a phase I/II study of Ruxolitinib with 
front-line neoadjuvant and post-surgical therapy in patients with advanced ovarian, 
fallopian tube, or primary peritoneal cancer. 
 
 
 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories
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5. Clark, A.S., K. West, S. Streicher, et al.  (2002).  Constitutive and inducible Akt activity 
promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells.
Mol Cancer Ther.  1:707-17. 
 
6. de Bono, J. S., De Giorgi U, et al.  (2018). Randomized Phase II Study Evaluating Akt 
Blockade with Ipatasertib, in Combination with Abiraterone, in Patients with Metastatic 
Prostate Cancer with and without PTEN Loss. Clin Cancer Res 2019; 25(3): 928-936. 
  
7. Deborah, A.A., J.R. Testa.  (2005).  Perturbations of the AKT signaling pathway in human 
cancer.  Oncogene.  24:7455-64. 
 
8. Dummler, B., B.A. Hemmings.  (2007).  Physiological roles of PKB/Akt isoforms in 
development and disease.  Biochem Soc Trans.  35:231-5. 
 
9. Investigator’s Brochure.  (2018).  R05532961 (Ipatasertib, GDC-0068, G-035608).  F. 
Hoffman-LA Roche LTD.  Version 10.  September 29, 2018.  
 
10. Knisely AT, St Clair CM, Hou JY, Collado FK, Hershman DL, Wright JD et al. Trends in 
Primary Treatment and Median Survival Among Women With Advanced-Stage Epithelial 
Ovarian Cancer in the US From 2004 to 2016. JAMA Netw Open 2020; 3: e2017517. 
 
11. Kim SB, Dent R, Im SA, Espie M, Blau S, Tan AR et al. Ipatasertib plus paclitaxel versus 
placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer 
(LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. The 
lancet oncology 2017; 18: 1360-1372. 
 
12. Lehár, J., G.R. Zimmermann, A.S. Krueger, et al.  (2007).  Chemical combination effects 
predict connectivity in biological systems.  Mol Syst Biol.  3:80. 
 
13. Lin, K., J. Lin, W.I. Wu, et al.  (2012).  An ATP-site on-off switch that restricts 
phosphatase accessibility of Akt.  Sci Signal.  5:ra37. 
 
14. Lin J, Sampath D, Nannini MA, Lee BB, Degtyarev M, Oeh J et al. Targeting activated 
Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor 
models. Clinical cancer research : an official journal of the American Association for 
Cancer Research 2013; 19: 1760-1772. 
15. LoRusso, P.M.  (2016).  Inhibition of the PI3K/AKT/mTOR pathway in solid tumors.  J 
Clin Oncol.  doi:10.1200/jco.2014.59.0018. 
 
16. Manning, B.D., L.C. Cantley.  (2007).  AKT/PKB signaling: navigating downstream.  
Cell.  129:1261-74. 
 
17. Morgan , R.D., McNeish I.A., Cook A.D., et al. (2021).  Objective responses to first-line 
neoadjuvant carboplatin– paclitaxel regimens for ovarian, fallopian tube, or primary 
peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 
trial. Lancet Onc. 22: 277-288.   
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18. Saura C, Roda D, Rosello S, Oliveira M, Macarulla T, Perez-Fidalgo JA et al. A First-in-
Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates 
Robust and Safe Targeting of AKT in Patients with Solid Tumors. Cancer discovery 2017; 
7: 102-113. 
 
19. Sale, E.M., G.J. Sale.  (2008).  Protein kinase B: signaling roles and therapeutic targeting.  
Cell Mol Life Sci.  65:113-27. 
 
20. Shi Z, Wulfkuhle J, Nowicka M, Gallagher RI, Saura C, Nuciforo PG, Calvo I, Andersen 
J, Passos-Coelho JL, Gil-Gil MJ, Bermejo B, Pratt DA, Ciruelos EM, Villagrasa P, 
Wongchenko MJ, Petricoin EF, Oliveira M, Isakoff SJ. Functional Mapping of AKT 
Signaling and Biomarkers of Response from the FAIRLANE Trial of Neoadjuvant 
Ipatasertib plus Paclitaxel for Triple-Negative Breast Cancer. Clin Cancer Res. 2022 Mar 
1;28(5):993-1003. 
 
21. Tokunaga, E., E. Oki, A. Egashira, et al.  (2008).  Deregulation of the Akt pathway in 
human cancer.  Curr Cancer Drug Targets.  8:27-36. 
 
22. Whiteman, E.L., H. Cho, M.J. Birnbaum.  (2002).  Role of Akt/protein kinase B in 
metabolism. Trends Endocrinol Metab.  13:444-51. 
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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)  
 
IIIA1(ii) 
Metastasis > 10mm
IIIA2 
Microscopic, extrapelvic (above the brim) peritoneal involvement ± 
positive retroperitoneal lymph nodes 
IIIB 
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
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IVB
Hepatic and/or splenic parenchymal metastasis, metastasis to extra-abdominal 
organs (including inguinal lymph nodes and lymph nodes outside of the 
abdominal cavity). 
Other major recommendations are as follows: 
 Histologic type including grading should be designated at staging 
 Primary site (ovary, Fallopian tube or peritoneum) should be designated where possible 
Tumors that may otherwise qualify for stage I but involved with dense adhesions justify 
upgrading to stage II if tumor cells are histologically proven to be present in the 
adhesions 
 
 
 
 
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APPENDIX II – PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance but is 
able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent.
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly.
5 
Dead. 
0 
Dead. 
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APPENDIX III – NYHA CLASSIFICATION 
Congestive Heart Failure – New York Heart Association Classification 
Class 
Definition 
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.
Source: Criteria Committee, New York Heart Association, Inc. Diseases of the heart and blood 
vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston, Little, Brown and Co, 1964: 
114. 
 
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APPENDIX IV - CARBOPLATIN DOSE CALCULATION INSTRUCTIONS 
 
1) The Cockcroft-Gault formula will be used in NRG Oncology trials. 
 
Dosing of Carboplatin: 
1) The carboplatin dose will be calculated to reach a target area under the curve (AUC) according to the 
Calvert formula using creatinine clearance (mL/min) from the Cockcroft-Gault formula. 
 
2) In patients with an abnormally low serum creatinine (less than 0.7 mg/dl), the creatinine clearance 
should be estimated using a minimum value of 0.7 mg/dL.   
 
3) The initial dose of carboplatin must be calculated using GFR. In the absence of renal toxicity greater 
than or equal to CTCAE Grade 2 (serum creatinine >1.5 x ULN) or toxicity requiring dose 
modification, the dose of carboplatin will not need to be recalculated for subsequent cycles but will be 
subject to dose modification for toxicity as noted in the protocol. 
 
4) Carboplatin doses are required 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. 
 
5) At the time of dose modification, if the patient’s age had changed (the patient has had a birthday), the 
site can use the current age. 
 
CALVERT FORMULA:
Carboplatin dose (mg) = target AUC x (GFR [or estimated CrCl] + 25) 
NOTE:  the GFR used in the Calvert formula should not exceed 125 ml/min. 
Maximum carboplatin dose (mg) = target AUC (mg/ml x min) x 150 ml/min. 
 
The maximum allowed doses of carboplatin are: 
AUC 6 = 900 mg 
AUC 5 = 750 mg 
AUC 4 = 600 mg 
 
For the purposes of this protocol, the GFR is considered to be equivalent to the estimated 
creatinine clearance. The estimated creatinine clearance (mL/min) is calculated by the method of 
Cockcroft-Gault using the following formula: 
Creatinine Clearance (mL/min) =   [140-Age (years)] x actual body Weight* (kg)   {x 0.85 if female}  
 72 x serum creatinine (mg/dl)  
 
Notes: 
1) Weight in kilograms (kg): 
a. Body Mass Index (BMI) should be calculated for each patient. 
b. Actual weight should be used for estimation of GFR for patients with BMI of less than 25. 
c. Adjusted weight should be used for estimation of GFR for patients with BMI of greater 
than or equal to 25  
 
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d. Adjusted weight calculation: 
Ideal weight (kg) = (((Height (cm)/2.54) – 60) x 2.3) (+ 45.5 females) or (+ 50 for men)  
Adjusted weight (kg) = ((Actual weight – Ideal weight) x 0.40) + Ideal weight 
 
At the time of a dose modification for toxicity: 
If the creatinine at the time of a dose modification is lower than the creatinine used to 
calculate the previous dose, use the previous (higher) creatinine; if the creatinine at the time of a 
dose modification is higher than the creatinine used to calculate the previous dose, use the 
current (higher) creatinine. This will ensure that the patient is actually receiving a dose 
reduction. 
 
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APPENDIX V – 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 this being 
considered to be 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 required 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. 
 
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APPENDIX  VI- 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, 
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and the FDA, as appropriate and unless additional disclosure is required by 
law or court order as described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy 
of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), 
if there is a DMC for this clinical trial. 
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. 
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APPENDIX VII – BIOSPECIMEN COLLECTION AND SUBMISSION MANUAL
The NRG-GY027 Biospecimen Collection and Submission Manual provides essential 
information regarding: 
 
 Biospecimen(s) submission for correlative studies as described in Section 10 of the NRG-
GY027 protocol. 
These instructions should be distributed to all staff involved with any aspect of biospecimen 
collection and submission. 
Table of Contents
 
1........................................................................... Obtaining an NRG Bank ID for Biospecimens
........................................................................................................................................................98
2.............................................................................. Submitting Biospecimen Transmittal Forms
........................................................................................................................................................98
3............................................................................................................... Biospecimen Submission
........................................................................................................................................................98
3.1 
Mandatory Biospecimen Submission ............................................................................... 98 
3.1.1 Central Review .................................................................................................................. 98
3.1.2 Correlative Science ........................................................................................................... 98
3.2 
Optional Biospecimen Submission ................................................................................. 104 
3.2.1 Central Review ................................................................................................................ 104
3.2.2 Correlative Science ......................................................................................................... 104
4...................................................... Patient Withdrawal of Permission for Use of Biospecimens
......................................................................................................................................................107
5. Institution-Initiated Request for Return of Formalin-Fixed, Paraffin-Embedded 
(FFPE) Materials .....................................................................................................107 
6..................................................................................................................... Letter to Pathologists
......................................................................................................................................................109
 
 
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1. Obtaining an NRG Bank ID for Biospecimens
An NRG Bank ID is automatically assigned once the biospecimen consent questions are 
completed in Rave. The biospecimen consent questions are located on the Eligibilty Checklist. 
All biospecimens and accompanying paperwork must be labeled with this coded patient number. 
Please contact Support if you need assistance (Email: support@nrgoncology.org). 
2. Submitting Biospecimen Transmittal Forms 
A biospecimen transmittal form for each biospecimen will be available in the Translational 
Research Folder in Rave, once the biospecimen consent questions have been completed. 
An electronically (i.e., Rave) completed copy of the biospecimen transmittal form must 
accompany each biospecimen shipped to the EET Biobank. Handwritten forms will not be 
accepted. 
Biospecimen transmittal forms must be printed from the Translational Research Form screen in 
Rave using the “PDF File” link at the top of the form. Clicking this link will generate a single 
page PDF. Do not use the “Printable Version” or “View PDF” links at the bottom of the form or 
any other method to print the form, as these formats will not be accepted.  
Retain a printout of the completed form in the patient’s research record. 
Please contact Support if you need assistance (Email: support@nrgoncology.org). 
3. Biospecimen Submission 
3.1 Mandatory Biospecimen Submission  
The patient agrees to participate in mandatory biospecimen collection as part of the main 
trial. Participating sites are required to submit the patient’s biospecimens as outlined 
below. 
 
3.1.1 
Central Review 
Not applicable 
 
3.1.2 
Correlative Science 
 
3.1.2.1 
Mandatory Biospecimens Shipped to EET Biobank (22-DEC-2023) 
Biospecimen Kit(s)
One single-chamber biospecimen kit will be provided per patient for 
the collection and shipment of all mandatory and optional frozen 
biospecimens. 
 Collection tubes for the mandatory whole blood and plasma 
collection are not provided in the kit.
 PROT1 reagent for the optional CyTOF specimens is provided in 
the kit. Sodium heparin tubes for CyTOF whole blood collection 
are not provided in the kit. 
 
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7. Complete a FedEx airbill and attach to the top of the shipping 
container.  
8. Attach the dry ice label (UN1845) and the Exempt Human 
Specimen sticker.
3.1.2.1.3 Whole Blood 
Purpose
Integrated biomarker: WES, RNAseq
Required for
All patients
Biospecimen(s)
10mL whole blood drawn into purple top (EDTA) tube(s)
Collection time 
point(s) and 
biospecimen code(s) 
Baseline (WB01) prior to study treatment 
Biospecimen 
Labeling
Bank ID (N # # # # # # # # #)* 
NRG ID (X X # # # - GY027 - # # # # #) 
Biospecimen code (see above) 
Collection date (mm/dd/yyyy) 
 
*Leading zeros may be omitted when labeling biospecimens with the 
Bank ID.  For example, N000000010 may be written as N10.
Biospecimen 
Processing 
1.  Label the purple top (EDTA) collection tube(s) as described 
above. Multiple tubes may be used to collect the required amount.  
2. Draw 10mL of blood into the labeled purple top tube(s). 
3.  Immediately after collection, gently invert the tube 5-10 times to 
mix the blood and EDTA. 
4. Ship whole blood the day collected. If the whole blood absolutely 
cannot be shipped the day collected, the tube(s) should be 
refrigerated (4°C) and shipped within 24 hours. Do not collect 
whole blood the day before a holiday. 
Biospecimen 
Storage at Site
If absolutely cannot ship same day, refrigerate (4°C) and ship within 
24 hours. 
Required 
Documentation 
Biospecimen transmittal 
Shipping 
Instructions 
1. Place the whole blood biospecimen in a biohazard envelope 
containing absorbent material. Expel as much air as possible 
before sealing the bag. 
2. Wrap the biohazard envelope in bubble wrap or another padded 
material. 
3. Place the padded tube(s) into a Tyvek envelope. Expel as much air 
as possible before sealing the envelope. 
4. Place the Tyvek envelope in a sturdy shipping container. 
5. Insert a copy of the biospecimen transmittal for each biospecimen.  
6. Complete a FedEx airbill and attach to the top of the shipping 
container.  
7. Attach an Exempt Human Specimen sticker to the outside of the 
shipping container. 
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3.1.2.1.4 
Interval Debulking Surgery Plasma 
Purpose 
Integrated biomarker: PK 
Required for
All patients
Biospecimen(s) 
Plasma processed from 7-10mL whole blood drawn into purple top 
(EDTA) tube(s)
Collection time 
point(s) and 
biospecimen code(s) 
Interval debulking surgery (PB01) 
Biospecimen 
Labeling
Bank ID (N # # # # # # # # #)*
NRG ID (X X # # # - GY027 - # # # # #) 
Biospecimen code (see above) 
Collection date (mm/dd/yyyy) 
 
*Leading zeros may be omitted when labeling biospecimens with the 
Bank ID.  For example, N000000010 may be written as N10.
Biospecimen 
Processing 
Plasma should be processed and frozen within two hours of 
collection; within one hour is ideal.
1.  Label cryovials and 15mL conical tube as described above. Use 
2mL cryovials as plasma will be shipped to EET Biobank. 
2.  Draw 7-10mL of blood into lavender/purple top (EDTA) tube(s).  
3.  Immediately after collection, gently invert the blood collection 
tube 5-10 times to mix blood and EDTA. 
4.  Centrifuge blood at 1000g for 15 minutes at 4ºC (preferred) or 
room temperature to separate plasma (top, straw-colored layer) 
from red blood cells (bottom, red layer). 
5.  Transfer plasma into pre-labeled 15mL conical tube and gently 
mix. 
7. Quickly, evenly dispense (aliquot) plasma into pre-labeled 
cryovials and cap tubes securely. Place at least 0.25mL into each 
cryovial. Avoid any residual cells that pellet at the bottom of 
the conical tube. 
8.  Immediately freeze plasma in an upright position in a -70oC to -
80oC freezer or by direct exposure with dry ice until ready to ship.
Biospecimen 
Storage at Site
-70oC to -80oC freezer or direct exposure with dry ice. If a -70oC to -
80oC freezer is not available for storage, store and ship on dry ice 
within 24 hours of collection.
Required 
Documentation 
Biospecimen transmittal 
Shipping 
Instructions 
For all frozen biospecimens: 
1. Pre-fill the kit chamber about 1/3 full with dry ice. 
2. Place each biospecimen type and timepoint in a separate zip-lock 
bag. 
3. Place the zip-lock bags in the biohazard envelope containing 
absorbent material. Do not put more than 20 cryovials in a single 
chamber kit. Put the secondary envelope into a Tyvek envelope. 
Expel as much air as possible before sealing both envelopes.
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3. Immediately after collection, gently invert the green top tube 5-10 
times to mix the blood and sodium heparin. 
4. Transfer the 5mL of heparinized blood to the labeled empty 
conical tube and add 7mL of PROT1 (provided). Note: PROT1 is 
hypotonic; the solution must be added to the blood (rather 
than the blood added to the solution). 
5. Secure the conical tube cap and gently invert 10 times to mix the 
heparinized blood with the PROT1.  
6. Allow the heparinized blood/PROT1 mixture to sit at room 
temperature for 8 minutes. 
7. Transfer 2.4mL of the heparinized blood/PROT1 mixture to each 
of four 5mL Eppindorf tubes. Note: The blood should be 
transferred to Eppindorf tubes and frozen before 10 minutes 
has elapsed. 
8. Immediately transfer the Eppendorf tubes to a -80°C freezer or 
place in direct contact with dry ice. Note: It is critical to store at 
-80°C. Processed samples cannot be stored at temperatures 
warmer than -80°C. 
Biospecimen 
Storage at Site
-80°C freezer or place in direct contact with and completely cover in 
dry ice. Note: It is critical to store at -80°C. Processed samples 
cannot be stored at temperatures warmer than -80°C. 
Required 
Documentation 
Biospecimen transmittal 
4. 
Biospecimen Processing and Storage at the EET Biospecimen Bank (22-DEC-
2023) 
FFPE tissue blocks will be received and stored at room temperature until processed for
distribution for analysis. See Section 10.3.2.2 for details on DNA and RNA extractions and 
storage of nueclic acids.  
Germline DNA will be extracted from whole blood collected in EDTA tubes. DNA will be 
quantitated and stored in a -80°C freezer until distribution for analysis.  
Plasma will be stored in a -80°C freezer until distribution for analysis. 
 
CyTOF whole blood will be stored in a -80°C freezer until distribution for analysis. 
 
 
5. 
Patient Withdrawal of Permission for Use of Biospecimens  
If an enrolled patient chooses to withdraw permission for use of their biospecimen(s), a 
biospecimen consent withdrawal form must be submitted to the NRG Oncology Statistics and 
Data Management Center. Any data obtained from the biospecimen(s) distributed prior to 
submission of the form may be used. 
 
6. 
Institution-Initiated Request for Return of Formalin-Fixed, Paraffin-Embedded 
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(FFPE) Materials  
An FFPE Return Request must be submitted to the EET Biobank for any institution-initiated 
request to return FFPE materials. FFPE will be returned to the submitting institution at the 
institution’s expense. Note: The EET Biobank cannot ship to third party institutions/departments. 
The EET Biobank may process blocks prior to return as specified in the clinical trial protocol 
and/or request that blocks are re-submitted to the bank after use at the site
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7. Letter to Pathologists 
Dear Pathologist, 
Your site is a participant in NRG-GY027, “Phase I/IB safety and pharmacodynamic study of 
neoadjuvant (NACT) carboplatin and paclitaxel with ipatasertib in ovarian cancer (PTMA 
100805).” 
This study includes NCI-approved integrated biomarkers/secondary objectives. Given the 
biospecimen requirements for this biomarker testing, NRG GY027 requires all sites submit 
FFPE blocks only (i.e., unstained slides will not be accepted). Per Eligibility Section 3.1.3: 
“Pre-treatment archival formalin-fixed, paraffin-embedded tumor block collected from 
laparoscopy (preferred) or five 18G cores by radiology or interventional radiology (acceptable) 
must be available for submission.” 
 
Blocks may be submitted on a permanent or temporary basis. If submitted on a temporary basis, 
blocks will be returned after completion of the biomarker testing. 
 
If return of the block is requested, the EET Biobank will contact your institution for a Fed 
Ex Account number and shipping address after completion of the integrated biomarker 
testing. 
If you should have any questions, please do not hesitate to contact Drs. Katherine Fuh (PI) and 
 
 
We thank you in advance for your participation in this trial and your commitment to the 
successful completion of this study’s objectives. 
 
Sincerely, 
 
Katherine Fuh, MD, PhD 
 PhD, MPH 
 
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APPENDIX VIII– CORRELATIVE SCIENCE  
The following details the biomarker assays summarized in Section 10. Please refer to Section 2
for biomarker background and significance, and Sections 13.8 and 13.9 for biomarker statistical 
analysis plan. 
1. Integral Biomarkers 
Not applicable 
2. Integrated Biomarkers  
Not applicable 
3. Exploratory Biomarkers (24-APR-2023) 
3.1 
pPRAS40 Immunohistochemistry
BRC review required
3.1.1
Description of Assay 
for 
pPRAS40. Briefly, the tissue sections baked at 60oC, dewaxed, and rehydrated through 
successive alcohols xylene, 100% EtOH, 95% EtOH, 70% EtOH, and ddH2O2). Antigen 
retrieval will be performed using an antigen unmasking solution (pH6, Citrate-Based) (Vector, 
H-3300) at 95oC, and the endogenous peroxidase blocked with Bloxall (Vector, SP-6000). After 
washing in TBST (Santa Cruz, sc-36231-1). Antigens will be unmasked using a pH9, Tris-based 
solution (Vector, H-3301), in a Biocare decloaking chamber™ NxGen) (after pressurizing). The 
slides will be allowed to reach room temperature, washed extensively with ddH2O2 and TBST, 
and blocked with 3% donkey serum in TBST. The tissues will be then successively incubated 
with Phospho-PRAS40 (Thr246) (D4D2) XP® Rabbit mAb (RmAb; Cell Signaling; # 13175), 
anti-Rabbit HRP Polymer (Cell IDX, 2RH-015), washed in TBST, and developed with a brown 
chromogen (VWR, 95041-478). After 2X washes in ddH2O2, the tissues will be counterstained 
with Mayer’s Hematoxylin (Sigma, 51275-500ml), dehydrated and mounted with a xylene-based 
mounting medium. 
 
3.1.2 Analytical Performance of Assay 
All slides will be scanned using Aperio-Leica AT2 Digital Whole Slide Scanner 
(https://www.leicabiosystems.com/digital-pathology/scan/aperio-at2/) to generate full-slide 
digital images in the proprietary svs file format. This format is compatible with the image
analysis software to be used. The scanned images will be quantified using the QuPath open-
source application (https://doi.org/10.1038/s41598-017-17204-5). Region of interest (ROIs) are 
selected by using brush or polygon tools. If the sample contains 80% or more tumor cells, a full 
image annotation will be created. The QuPath positive cell detection (PCD) algorithm will be 
used to analyze the selected areas. This will generate a table with the number of positive event 
and the staining intensity.  
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The results of the immunohistochemistry quantification are reported as H-scores (Goulding H et 
al, Path. 26:291-294; 1995). The score is given as the sum of the percentage of staining 
multiplied by an ordinal value corresponding to the intensity level (0 = none, 1 = weak, 2 = 
moderate, 3 = strong). With these 4 intensity levels, the resulting score ranged from 0 (no 
staining in the tumor) to 300 (diffuse intense staining of the tumor). If there is significant 
immunoreactivity in stromal cells, the process will be repeated for the stroma, in this case using 
exclusively the brush or polygon tools. H-scores are exclusively evaluated for epithelial tumor 
cells; stromal positive cells are only reported as # of events per area. In each case, the paired T 
test method will be used to compare pre- and post-treatment values using GraphPad Prism 
version 7.00 for Windows (GraphPad Software, La Jolla California). 
3.2 AKT-mTOR Signaling Pathway  (24-APR-2023) 
Testing of banked biospecimens will not occur until an amendment to this protocol (or a 
separate correlative science proposal) is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies.
3.2.1
Description of Assay  (24-APR-2023) 
The assay is an antibody-based reverse phase protein array (RPPA) that semi-quantitatively 
measures the abundance of phosphorylated proteins and total proteins in cell lysates derived 
from cell culture, whole tissue, cellular isolates, microdissected cells, serum, or body fluids in a 
direct deposition micro dot-blot configuration.
The following 23 members of the AKT-mTOR protein signaling pathway will be quantitatively 
measured by LCM-RPPA based analysis of the pre-treatment baseline FFPE tissue samples.
PTEN (S380)
PTEN
PDK1 (S241) 
Akt (T308) 
Akt (S473)
FKHR/FOX01 (S256)
FKHR-FOX01 (T24)/FKHRL1-FOX03a (T32) 
PRAS40 (T246)
Tuberin/TSC2 (Y1571) 
SGK1 S78
GSK-3alpha/beta (S21/9) 
mTOR (S2448) 
mTOR (S2481) 
eIF4E (S209)
eIF4G (S1108) 
p70 S6 Kinase (S371) 
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p70 S6 Kinase (T389) 
p70 S6 Kinase (T412) 
S6 Ribosomal Protein (S235/236)  
S6 Ribosomal Protein (S240/244) 
4E-BP1 (T37/46)  
4EBP1 (S65)  
4EBP1 (T70)
All testing will be  performed at the RPPA laboratories in the CLIA/CAP accredited George 
Mason University Center for Applied Proteomics and Molecular Medicine (CAPMM; CLIA 
#49D2002076, CAP #7223012). 
Briefly, tumor cells are isolated from slides by laser microdissection (LMD). The tumor cells are 
lysed and proteins are extracted in a SDS-based chemical detergent. The protein extracts are 
printed onto nitrocellulose slides by automated arrayer. The arrayed slides are incubated with 
validated primary and secondary antibodies  Stained slides are scanned by a fluorescence slide 
scanner and spot intensity values are determined. Spot intensities for protein analyte slides are 
compared to a total protein normalization spot in order to facilitate data analysis. A normalized 
intensity value is used for correlative analysis. 
 
Analytical Performance of Assay (24-APR-2023) 
For tumor-based clinical and pre-clinical applications, RPPA coupled to LMD can provide a 
powerful workflow to study the tumor microenvironment whereby hundreds of protein and 
phosphoproteins can be measured and quantified at once in LMD enriched tumor epithelium and 
stroma and immune cell populations both proximal and distal to the invading epithelium. These 
populations are lysed and printed onto slides using an automated arrayer in a CLIA validated 
workflow that requires only a few nanoliter volume of lysate per slide with less than 2µg total 
protein needed to measure ~400 analytes. 
 
For immunohistochemistry (IHC), single antibodies directed against an epitope of interest are 
used to quantify the presence of proteins for an individual slide. The RPPA technology, which 
using many of the same primary antibodies as those used in IHC, can measure of hundreds of 
signaling proteins concomitantly from only a few thousand cells, facilitating targeted phospho-
proteomic analysis with 10-1000 fold less input material than mass spectrometry or IHC. 1-6
Previous studies by us and others have also revealed the absolute requirement for upfront 
histologically-guided microdissection-based cellular enrichment in order to produce clinically 
accurate information about drug target activation levels in individual patient tumor samples for 
clinical decision making.7.8 Thus, RPPA provides a critical means of broad-scale cell signaling 
analysis directly from tissue samples that other existing technologies cannot achieve. 
 
Using the RPPA technology, serial dilutions of each sample are printed along with known high 
and low controls, calibration curves from contrived ad-mixtures of cell lysates containing known 
amounts of each analyte, to maintain sample concentration.  Each spot contains a bait zone 
measuring only a few hundred microns in diameter.  The detection probe can be tagged and 
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signal amplified independently from the immobilized analyte protein.  Coupling the detection 
antibody with highly sensitive amplification systems can yield detection sensitivities to fewer 
than 1,000 to 5,000 molecules per spot with good linearity (correlation coefficient or R2 = 0.990-
0.999) and inter-experiment precision (R2= 0.973).  Between run and within run analytical 
precision is between a 3-13% CV (coefficient of variation).9 
 
References 
 
1. Shi Z, Wulfkuhle J, Nowicka M, Gallagher RI, Saura C, Nuciforo PG, Calvo I, 
Andersen J, Passos-Coelho JL, Gil-Gil MJ, Bermejo B, Pratt DA, Ciruelos EM, 
Villagrasa P, Wongchenko MJ, Petricoin EF, Oliveira M, Isakoff SJ. Functional 
Mapping of AKT Signaling and Biomarkers of Response from the FAIRLANE Trial 
of Neoadjuvant Ipatasertib plus Paclitaxel for Triple-Negative Breast Cancer. Clin 
Cancer Res. 2022 Mar 1;28(5):993-1003.  
2. LoRusso PM, Sekulic A, Sosman JA, Liang WS, Carpten J, Craig DW, Solit DB, Bryce 
AH, Kiefer JA, Aldrich J, Nasser S, Halperin R, Byron SA, Pilat MJ, Boerner SA, 
Durecki D, Hendricks WPD, Enriquez D, Izatt T, Keats J, Legendre C, Markovic SN, 
Weise A, Naveed F, Schmidt J, Basu GD, Sekar S, Adkins J, Tassone E, Sivaprakasam 
K, Zismann V, Calvert VS, Petricoin EF, Fecher LA, Lao C, Eder JP, Vogelzang NJ, 
Perlmutter J, Gorman M, Manica B, Fox L, Schork N, Zelterman D, DeVeaux M, Joseph 
RW, Cowey CL, Trent JM. Identifying treatment options for BRAFV600 wild-type 
metastatic melanoma: A SU2C/MRA genomics-enabled clinical trial. PLoS One. 2021 
Apr 7;16(4):e0248097. doi: 10.1371/journal.pone.0248097. PMID: 33826614; PMCID: 
PMC8026051. 
3. Wolf DM, Yau C, Wulfkuhle J, Brown-Swigart L, Gallagher RI, Magbanua MJM, 
O'Grady N, Hirst G; I-SPY 2 TRIAL Investigators, Asare S, Tripathy D, Berry D, 
Esserman L, Chien AJ, Petricoin EF 3rd, van 't Veer L. Mechanism of action biomarkers 
predicting response to AKT inhibition in the I-SPY 2 breast cancer trial. NPJ Breast 
Cancer. 2020 Oct 2;6:48. doi: 10.1038/s41523-020-00189-2. PMID: 33083527; PMCID: 
PMC7532145. 
4.
Wulfkuhle JD, Yau C, Wolf DM, Vis DJ, Gallagher RI, Brown-Swigart L, Hirst G, Voest 
EE, DeMichele A, Hylton N, Symmans F, Yee D, Esserman L, Berry D, Liu M, Park JW, 
Wessels LFA, Van't Veer L, Petricoin EF 3rd. Evaluation of the HER/PI3K/AKT Family 
Signaling Network as a Predictive Biomarker of Pathologic Complete Response for 
Patients With Breast Cancer Treated With Neratinib in the I-SPY 2 TRIAL. JCO Precis 
Oncol. 2018 Aug 16;2:PO.18.00024. doi: 10.1200/PO.18.00024. PMID: 32914002; 
PMCID: PMC7446527. 
5. Wulfkuhle JD, Berg D, Wolff C, Langer R, Tran K, Illi J, Espina V, Pierobon M, Deng J, 
DeMichele A, Walch A, Bronger H, Becker I, Waldhör C, Höfler H, Esserman L; I-SPY 
1 TRIAL Investigators, Liotta LA, Becker KF, Petricoin EF 3rd. Molecular analysis of 
HER2 signaling in human breast cancer by functional protein pathway activation 
mapping. Clin Cancer Res. 2012 Dec 1;18(23):6426-35. doi: 10.1158/1078-0432.CCR-
12-0452. Epub 2012 Oct 8. PMID: 23045247; PMCID: PMC5581198. 
6. Mueller C, deCarvalho AC, Mikkelsen T, Lehman NL, Calvert V, Espina V, Liotta LA, 
Petricoin EF 3rd. Glioblastoma cell enrichment is critical for analysis of phosphorylated 
Use of this document is governed by the terms of use on the first page of this document

NRG-GY027 
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Version Date: December 22, 2023 
drug targets and proteomic-genomic correlations. Cancer Res. 2014 Feb 1;74(3):818-28. 
doi: 10.1158/0008-5472.CAN-13-2172. Epub 2013 Dec 17. PMID: 24346432. 
7. Baldelli E, Haura EB, Crinò L, Cress DW, Ludovini V, Schabath MB, Liotta LA, 
Petricoin EF, Pierobon M. Impact of upfront cellular enrichment by laser capture 
microdissection on protein and phosphoprotein drug target signaling activation 
measurements in human lung cancer: Implications for personalized medicine. Proteomics 
Clin Appl. 2015 Oct;9(9-10):928-37. doi: 10.1002/prca.201400056. Epub 2015 Mar 24. 
PMID: 25676683; PMCID: PMC4547918. 
8. Rapkiewicz A, Espina V, Zujewski JA, Lebowitz PF, Filie A, Wulfkuhle J, Camphausen 
K, Petricoin EF 3rd, Liotta LA, Abati A. The needle in the haystack: application of breast 
fine-needle aspirate samples to quantitative protein microarray technology. Cancer. 2007 
Jun 25;111(3):173-84. doi: 10.1002/cncr.22686. PMID: 17487852. 
 
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APPENDIX IX- PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
Patient 
Name:
Diagnosis:  
Trial #: 
Study 
Doctor: 
      
Study Doctor 
Phone #:  
Study 
Drug(s):
Ipatasertib 
 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse 
practitioners, pharmacists), and tell them you are taking part in a clinical trial sponsored by the 
National Cancer Institute.  
 
These are the things that your healthcare providers need to know: 
Ipatasertib interacts with certain specific enzymes in your liver and certain transport proteins that help 
move drugs in and out of cells. 
 
Explanation 
CYP 
isoenzymes
The enzyme in question is CYP3A4.  Ipatasertib is metabolized by CYP3A4 and 
may be affected by other drugs that inhibit or induce this enzyme. Ipatasertib is an 
inhibitor of CYP3A4 and may affect the metabolism of other drugs. 
 
 
These are the things that you need to know:
The study drug, ipatasertib, may interact with other drugs which can cause side effects.  For this 
reason, it is very important to tell your doctors about all your medicines, including:  (a) 
medicines you are taking before this clinical trial, (b) medicines you start or stop taking during 
this study, (c) medicines you buy without a prescription (over-the-counter remedy), (d) herbals 
or supplements (e.g. St. John’s Wort).  It is helpful to bring your medication bottles or an 
updated medication list with you.  
Before you enroll onto the clinical trial, your study doctor will work with your regular health 
care providers to review any medicines and herbal supplements that are considered “strong 
inhibitors or inducers of CYP3A4 or sensitive substrates of CYP3A4.”
 
 Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
o Avoid ingestion of grapefruit, grapefruit juice or grapefruit supplements. 
 Make sure your doctor knows to avoid certain prescription medications.  
 Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  
 
 
 
 
 
 
  
 
Version JUN/2020 
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