A Phase 1b Biomarker-Driven Combination Trial of Copanlisib, Olaparib, and Durvalumab (MEDI4736) in Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Advanced Malignant Solid Neoplasm, Metastatic Malignant Solid Neoplasm, Unresectable Malignant Solid Neoplasm
Sponsor: National Cancer Institute (NCI)

  
i 
 
To:  
CTEP Protocol and Information Office 
From: 
Timothy Yap, M.D., Ph.D. 
Branch: 
Investigational Drug Branch, CTEP, DCTD, NCI  
Date:  
9/25/2024 
Re: 
Amendment 20 of Protocol #10217: “A Phase 1b Biomarker-Driven Combination 
Trial of Copanlisib, Olaparib, and Durvalumab (MEDI4736) in Patients with 
Advanced Solid Tumors” 
————————————————————————————————————— 
SUMMARY OF CHANGES – Protocol 
 
I. 
PI-initiated changes: 
 
# 
Section 
Comments 
1. 
Title page and 
throughout 
 
PI Response: The protocol version date was updated throughout the 
protocol on the title page and headers 
 
New Text: May 13, 2024 
 
New Text: September 25, 2024 
 
II. 
CTEP-requested protocol language changes for specimen transfer: 
 
# 
Section 
Comments 
2. 
5.5.1.4 
The EET Biobank is moving to a new facility effective 10/7/24.  
Accordingly, revise the Shipping Address for the EET Biobank to the 
following: 
EET Biobank 
2200 International Street 
Columbus, OH 43228 
PH: (614) 722-2865 
FAX: (614) 722-2897 
E-mail:  BPCBank@nationwidechildrens.org 
 
PI Response: Changes were made to section 5.5.1.4 as specified above 
 
3. 
5.5.1.5 
Revise the Contact Information for Assistance to update the EET Biobank’s 
phone number to the following: 
For all queries, please use the contact information below:  

  
ii 
# 
Section 
Comments 
EET Biobank 
Phone: (614) 722-2865 
E-mail: BPCBank@nationwidechildrens.org 
  
PI Response: Changes were made to section 5.5.1.5 as specified above 
 
4. 
5.5.3 
In the Biomarker Plan Table, replace the laboratory in the Assay Laboratory 
and Lab PI Column for the WES (tumor and blood), RNAseq, and ctDNA 
sequencing as shown: 
 
MoCha, Frederick National Laboratory for Cancer Research (FNLCR)  
Chris Karlovich 
 
PI Response: Changes were made to section 5.5.3 as specified above. 
 
5. 
5.7.2.2 -5.7.2.4 
For WES, replace the current text in Section 5.7.2.2 -5.7.2.4 with the 
following revised text: 
  
5.7.2.2 Site Performing Correlative Study 
  
WES will be conducted at the MoCha, Frederick National Laboratory for 
Cancer Research (FNLCR) under the leadership of Chris Karlovich, Ph.D. 
(chris.karlovich@nih.gov). 
  
5.7.2.3 Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study 
  
Specimens will be shipped from the EET Biobank to: 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
  
  
5.7.2.4 Contact information for notification of specimen shipment 
  
Thomas Forbes (mochasamplereceiving@nih.gov) 
  
PI Response: Changes were made to sections 5.7.2.2 -5.7.2.4 as specified 
above. 
 
6. 
5.8.1.2-5.8.1.4 
For RNAseq, replace the current text in Section 5.8.1.2 -5.8.1.4 with the 
following revised text: 

  
iii 
# 
Section 
Comments 
  
5.8.1.2 Site Performing Correlative Study 
  
RNAseq will be conducted at the MoCha, Frederick National Laboratory for 
Cancer Research (FNLCR) under the supervision of Chris Karlovich, Ph.D. 
(chris.karlovich@nih.gov). 
  
5.8.1.3 Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study 
  
Specimens will be shipped from the EET Biobank to: 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 
  
5.8.1.4 Contact information for notification of specimen shipment 
  
Thomas Forbes (mochasamplereceiving@nih.gov) 
 
PI Response: Changes were made to sections 5.8.1.2 - 5.8.1.4 as specified 
above. 
 
7. 
5.8.2.2-5.8.2.4 
For ctDNA sequencing, replace the current text in Section 5.8.2.2 -5.8.2.4 
with the following revised text: 
  
5.8.2.2 Site Performing Correlative Study 
  
ctDNA sequencing will be conducted at the MoCha, Frederick National 
Laboratory for Cancer Research (FNLCR) under the supervision of Chris 
Karlovich, Ph.D. (chris.karlovich@nih.gov). 
  
5.8.2.3 Shipment of Specimens from the EET Biobank to Site Performing 
Correlative Study 
  
Specimens will be shipped from the EET Biobank to: 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 

  
iv 
# 
Section 
Comments 
  
5.8.2.4 Contact information for notification of specimen shipment 
  
Thomas Forbes (mochasamplereceiving@nih.gov) 
 
PI Response: Changes were made to sections 5.8.2.2-5.8.2.4  as specified 
above. 
 
8. 
13.5 
Remove Section 13.5 Genomic Data Sharing Plan 
PI Response: Section 13.5 was removed as specified above. 
9. 
13.6 
MoCha will not report incidental findings.  Accordingly, please remove 
Section 13.6. 
 
PI Response: Section 13.6 was removed as specified above. 
 
 
III. 
Recommendations: 
 
# 
Section 
Comments 
10. 6.1.3.1 
Based on updated information, please change durvalumab infusion duration 
from: 
“Durvalumab will be administered over 60 minutes (± 15 minutes)” 
  
Change to: 
“Durvalumab will be administered over 60 minutes (± 10 minutes)” 
PI Response: Changes were made to section 6.1.3.1 as specified above. 
 
11. 
9.2 
Per the previous comment, please insert an “International Estimated 
Enrollment Report” table for the treatment phase of the study since Princess 
Margaret Cancer Center is listed as a participant. 
PI Response: As no new enrollment will be supported for this study, we 
kindly request not to update the enrollment table at this time given that 
Princess Margaret Cancer Center did not enroll any patients to this trial. 
  
New comment: Kindly include the International Estimated Enrollment Table 
as per the requirements. The figures should be considered "estimated." If 
necessary, please fill in any empty spaces with zeros to represent the 
enrollment numbers. 

  
v 
# 
Section 
Comments 
PI Response: An ‘International Estimated Enrollment Table’ was added 
section 9.2 as specified above. 
 
12. 
13.2 
Please revise within this section as shown as shown, to reflect the 
updated CTEP protocol template language. 
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 to the study in Rave will be automatically granted. To accept the 
invitation, site staff must either click on the link in the email or log in to 
iMedidata via the CTSU members’ website  under Data Management > 
Rave Home and click to accept the invitation in the Tasks pane located in the 
upper right corner of the iMedidata screen.  Site staff will not be able to 
access the study in Rave until all required Medidata and study specific 
trainings are completed.  Trainings will be in the form of electronic 
learnings (eLearnings) and can be accessed by clicking on the eLearning 
link in the Tasks pane located in the upper right corner of the iMedidata 
screen.  If an eLearning is required for a study and has not yet been taken, 
the link to the eLearning will appear under the study name in the Studies 
pane located in the center of the iMedidata screen; once the successful 
completion of the eLearning has been recorded, access to the study in Rave 
will be granted, and a Rave EDC link will replace the eLearning link under 
the study name.  
  
No action will be required by Ssite 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 will 
receive a separate invitation from iMedidata to activate their 
account. 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 Data Management Help Topics > Rave resource materials the 
Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by email at 
ctsucontact@westat.com.   
PI Response: Changes were made to section 13.2 as specified above 
 

  
vi 
# 
Section 
Comments 
13. 
10.3.3 
PI Response: The expedited reporting guidance in section 10.3.3. was 
updated to reflect the most recent AE reporting table (effective date 08-30-
2024). 
 
 

NCI Protocol #:  10217 
Version Date:   September 25, 2024 
7 
NCI Protocol #: 
10217 
 
Local Protocol #: 
NCI10217 
 
ClinicalTrials.gov Identifier:  TBD 
 
TITLE:  A Phase 1b Biomarker-Driven Combination Trial of Copanlisib, Olaparib, and 
Durvalumab (MEDI4736) in Patients with Advanced Solid Tumors  
 
Corresponding Organization: LAO-TX035 / University of Texas MD Anderson Cancer 
Center LAO   
 
Principal Investigator: 
Timothy A. Yap 
University of Texas MD Anderson Cancer Center 
1515 Holcombe Blvd., Unit 455 
Houston, TX  77030, USA 
(T):  713-563-1784 
(F):  713-794-4130 
tyap@mdanderson.org 
 
Participating Organizations Dose Escalation: 
 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
 
Participating Organizations Dose Expansion: 
 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / UPMC Cancer Center LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
 
Statistician: 
 
Study Coordinator: 
 
Yuan, Ying  
Jessica Rhudy  
 
1515 Holcombe Blvd., Unit 1411 
Department of Investigational Cancer 
 
Houston, TX  77030, USA 
Therapeutics 

NCI Protocol #:  10217 
Version Date:   September 25, 2024 
8 
 
(T):  713-563-4271 
University of Texas MD Anderson 
 
(F):  713-563-4243 
Cancer Center 
 
yyuan@mdanderson.org  
1515 Holcombe Blvd., Unit 455 
 
 
 
 
           Houston, TX 77030, USA 
 
 
 
(T): 713-745-5474 
 
 
 
(F): 713-563-4002 
 
 
 
jrhudy@mdanderson.org 
 
Responsible Research Nurse: 
Responsible Data Manager: 
Jessica Rhudy 
Kim Beltran Ruiz 
Department of Investigational Cancer  
Department of Investigational Cancer 
Therapeutics 
Therapeutics 
University of Texas MD Anderson 
University of Texas MD Anderson 
Cancer Center 
Cancer Center 
1515 Holcombe Blvd., Unit 455 
7007 Bertner Ave, 1MC13.3206 
Houston, TX 77030, USA 
Houston, TX 77030, USA 
(T): 713-745-5474 
(T): 713-745-0937 
(F): 713-563-4002                                                      KRBeltran@mdanderson.org 
jrhudy@mdanderson.org 
 
 
NCI-Supplied Agents:  Copanlisib (NSC 784727), Olaparib (AZD2281; NSC 747856), and 
Durvalumab (MEDI4736; NSC 778709) 
 
IND #:  
 
IND Sponsor:  DCTD, NCI  
 
Protocol Type / Version # / Version Date: 
Original / July 9, 2018 
 
Revision 1 / September 14, 2018 
 
Revision 2 / November 5, 2018 
 
Revision 3 / December 12, 2018 
 
Revision 4 / January 7, 2019 
 
Revision 5a / March 28, 2019 
 
Revision 6 / May 8, 2019 
 
Revision 7 / May 31, 2019 
 
Revision 8/ June 21 2019 
 
Revision 9/ August 15 2019 
 
Revision 10/March 2 2020 
 
Amendment/August 13, 2020 
 
Amendment/October 22, 2020 
 
Amendment/ January 20, 2021 
 
Amendment/ September 15, 2021 
 
Amendment/ September 25, 2021 
 
Amendment/ October 11, 2021 
 
Amendment/ April 4, 2022 
 
Amendment/ July 29, 2022 
 
Amendment/January 20, 2023 

NCI Protocol #:  10217 
Version Date:   September 25, 2024 
9 
 
Amendment/May 10, 2023 
 
Amendment/ July 20, 2023 
 
Amendment/December 14, 2023 
 
Amendment/ May 13, 2024 
 
Amendment/September 25, 2024 

NCI Protocol #:  10217 
Version Date:   September 25, 2024 
10 
SCHEMA 
 
 
 
 
Dose escalation schema for the doublet combination of copanlisib and olaparib (Step 1) 
 
Dose Escalation Schedule 
 
Copanlisib* 
Olaparib* 
Level -1** 
45 mg (D1, D15), 28-day 
cycle 
200 mg BID 
Level 1*** 
45 mg QW, D1, D8, D15, 
28-day cycle 
200 mg BID 
Level 2 
45 mg QW, D1, D8, D15, 
28-day cycle 
300 mg BID 
Level 3**** 
60 mg QW, D1, D8, D15, 
28-day cycle 
300 mg BID 
Level 3a 
60 mg D1 and D15, 28-day 
cycle 
300 mg BID 
*Alternative schedules may be pursued depending on toxicities, pharmacokinetic and 
pharmacodynamic data generated from this and other trials.  
**Doses to pursue at dose level -1 will depend on the dose-limiting toxicities observed at dose 
level 1. 
***Starting dose level. 
**** If DLT is observed at dosing Level 3, and the dose escalation is complete, a maximum of 
6 patients will be treated with a less intensive schedule of copanlisib 60 mg Day 1 and 15 and 
olaparib 300 mg BID (dose level 3a) to improve the safety profile. 
 
D = Day; BID = twice a day; QW = once a week. 
 

NCI Protocol #:  10217 
Version Date:   September 25, 2024 
11 
Dose escalation schema for the triplet combination of copanlisib, olaparib, and durvalumab 
(MEDI4736) (Step 2) 
 
Dose Escalation Schedule 
 
Copanlisib 
Olaparib 
Durvalumab 
(MEDI4736) 
Level -1* 
45 mg (D1, D15), 28-
day cycle 
200 mg BID 
1500 mg D1 
28-day cycle 
(Starting Cycle 
2, Day 1) 
Level 1 
60 mg (D1, D15), 28-
day cycle 
300 mg BID 
1500 mg D1 
28-day cycle 
(Starting Cycle 
2, Day 1) 
*Doses to pursue at dose level -1 will depend on the dose-limiting toxicities observed at dose 
level 1. 
 
D = Day; BID = twice a day  
 
RP2D = recommended phase 2 dose; MTD = maximum tolerated dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NCI Protocol #:  10217 
Version Date:   September 25, 2024 
12 
 
 
TABLE OF CONTENTS 
SCHEMA 
....................................................................................................................10 
1. 
OBJECTIVES
 
……………………………………………………………..1
5 
1.1 
Primary Objective ..................................................................................................15 
1.2 
Secondary Objectives .............................................................................................15 
2. 
BACKGROUND ...............................................................................................................15 
2.1 
Study Diseases .......................................................................................................15 
2.2 
CTEP IND Agents .................................................................................................16 
2.3 
Rationale ................................................................................................................41 
2.4 
Correlative Studies Background ............................................................................43 
3. 
PATIENT SELECTION ....................................................................................................46 
3.1 
Eligibility Criteria for enrollment into Steps 1, 2, and 3 .......................................46 
3.2 
Eligibility Criteria for enrollment into Step 2 and 3 only ......................................49 
3.2.2 Life expectancy ≥16 weeks ....................................................................................49 
3.3 
Exclusion Criteria for Steps 1, 2, and 3 .................................................................49 
3.4 
Exclusion Criteria for Steps 2 and 3 only ..............................................................52 
3.5 
Inclusion of Women and Minorities ......................................................................53 
4. 
REGISTRATION PROCEDURES ...................................................................................53 
4.1 
Investigator and Research Associate Registration with CTEP ..............................53 
4.2 
Site Registration .....................................................................................................55 
4.3 
Patient Registration ................................................................................................57 
4.4 
General Guidelines .................................................................................................59 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................59 
5.1 
Summary Table for Specimen Collection ..............................................................59 
5.2 
Specimen Procurement Kits and Scheduling .........................................................63 
5.3 
Specimen Collection ..............................................................................................64 
5.4 
Specimen Tracking System Instructions ................................................................67 
5.5 
Shipping Specimens from Clinical Site to the EET Biobank ................................71 
5.6 
Biomarker Plan ...................................................... Error! Bookmark not defined. 
5.7 
Integral Laboratory Studies ....................................................................................81 
5.8 
Integrated Correlative Studies ................................................................................81 
5.9 
Exploratory/Ancillary Correlative Studies ............................................................84 
6. 
TREATMENT PLAN ........................................................................................................85 
6.1 
Agent Administration .............................................................................................85 
6.2 
Definition of Dose-Limiting Toxicity ....................................................................92 
6.3 
Dose Expansion Cohorts: .......................................................................................93 
6.4 
General Concomitant Medication and Supportive Care Guidelines ......................93 

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Version Date:   September 25, 2024 
13 
6.5 
Restrictions During the Study ..............................................................................100 
6.6 
Duration of Therapy .............................................................................................102 
6.7 
Treatment Beyond Progression with Copanlisib + Olaparib or Copanlisib 
+ Olaparib + MEDI4736 (durvalumab) + Combination ......................................103 
6.8 
Duration of Follow Up .........................................................................................103 
7. 
DOSING DELAYS/DOSE MODIFICATIONS..............................................................104 
7.1 
Copanlisib ............................................................................................................104 
7.2 
Olaparib................................................................................................................111 
7.3 
MEDI4736 (durvalumab).....................................................................................116 
8. 
PHARMACEUTICAL INFORMATION ........................................................................137 
8.1 
CTEP IND Agents ...............................................................................................137 
9. 
STATISTICAL CONSIDERATIONS.............................................................................144 
9.1 
Study Design/Endpoints.......................................................................................144 
9.2 
Sample Size/Accrual Rate ....................................................................................149 
9.3 
Stratification Factors ............................................................................................150 
9.4 
Analysis of Secondary Endpoints ........................................................................150 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ..........................151 
10.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ...............151 
10.2 
Adverse Event Characteristics .............................................................................162 
10.3 
Expedited Adverse Event Reporting ....................................................................162 
10.4 
Routine Adverse Event Reporting .......................................................................166 
10.5 
Pregnancy .............................................................................................................168 
10.6 
Secondary Malignancy .........................................................................................169 
10.7 
Second Malignancy ..............................................................................................169 
11. 
STUDY CALENDAR .....................................................................................................170 
11.1 
Laboratory Assessments ......................................................................................179 
11.2 
ECG......................................................................................................................180 
12. 
MEASUREMENT OF EFFECT......................................................................................180 
12.1 
Antitumor Effect – Solid Tumors ........................................................................180 
12.2 
Other Response Parameters .................................................................................186 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ...........................................................................................................188 
13.1 
Study Oversight ...................................................................................................188 
13.2 
Data Reporting .....................................................................................................189 
13.3 
CTEP Multicenter Guidelines ..............................................................................192 
13.4 
Collaborative Agreements Language ...................................................................192 
13.5 
Genomic Data Sharing Plan .................................................................................193 
13.6 
Incidental/Secondary Findings Disclosure Procedure ......... Error! Bookmark not 
defined. 
14. 
REFERENCES ................................................................................................................194 

NCI Protocol #:  10217 
Version Date:   September 25, 2024 
14 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................198 
APPENDIX B 
LIST OF PROHIBITED MEDICATIONS WHILE ON 
COPANLISIB TREATMENT .........................................................................................199 
APPENDIX C 
PATIENT DRUG INFORMATION HANDOUT AND 
WALLET CARD FOR COPANLISIB AND OLAPARIB .............................................200 
APPENDIX D 
THE AVERAGE GLYCEMIC INDEX OF COMMON 
FOODS DERIVED FROM MULTIPLE STUDIES BY DIFFERENT 
LABORAORIES..............................................................................................................202 
APPENDIX E 
FROZEN BIOPSY SPECIMEN BATCH RECORD ..............................203 
APPENDIX F 
PATIENT MEDICATION DIARY .........................................................205 
APPENDIX G 
 ACCEPTABLE BIRTH CONTROL METHODS..................................207 
APPENDIX H 
ACTIONS REQUIRED IN CASES OF COMBINED 
INCREASE OF AMINOTRANSFERASE AND TOTAL BILIRUBIN – 
HY’S LAW 
208 
APPENDIX I 
PHARMACOKINETIC STUDY PLAN .................................................213 
APPENDIX J 
TISSUE BIOPSY VERIFICATION FORM ...........................................195 
 
 
 

NCI Protocol #:  10217 
Version Date:   September 25, 2024 
15 
1. 
OBJECTIVES 
 
Primary Objective 
1.1 
Primary Objective 
 
1.1.1 To evaluate the safety and establish the recommended phase 2 dose (RP2D) of the 
doublet combination of copanlisib and olaparib and of the triplet combination of 
copanlisib, olaparib and MEDI4736 (durvalumab) in patients with molecularly-selected 
solid tumors. 
 
1.2 
Secondary Objectives 
 
1.2.1 To observe and record anti-tumor activity of the doublet combination of copanlisib and 
olaparib, and of the triplet combination of copanlisib, olaparib and MEDI4736 
(durvalumab) in patients with molecularly-selected advanced solid tumors, as measured 
by objective response rate (ORR) (complete response [CR] + partial response [PR]).  
Although the clinical benefit of the doublet and triplet combination of these drugs has not 
yet been established, the intent of offering this treatment is to provide a possible 
therapeutic benefit, and thus the patient will be carefully monitored for tumor response 
and symptom relief in addition to safety and tolerability. 
 
1.2.2 To assess overall duration of response (DoR), progression free survival (PFS) and overall 
survival (OS). 
 
1.2.3 To assess the pharmacokinetic (PK) profiles of these combinations, and explore 
exposure-response relationships. 
 
1.2.4 To correlate molecular alterations with OR (CR+PR). 
 
 
2. 
BACKGROUND 
 
2.1 
Study Diseases 
 
The phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated 
pathogenic signaling routes in human cancers, making it a rational and important target for 
innovative anticancer drug development and precision medicine (Yap et al., 2015).  Different PI3K 
isoforms have the potential to interfere with cancer growth and survival, either by acting on the 
transformed cells directly, or by interfering with the supportive stroma and nutrient supply, or by 
stimulating more potent immune responses against the transformed cells (Figure 1).  PI3K alpha 
(α) inhibitors have shown promising results in cancers driven by activating PIK3CA mutations, 
such as p110α H1047R.  Evidence suggests that phosphate and tensin homolog (PTEN)-deficient 
tumors are often (but not always) more sensitive to PI3K beta (β) inhibitors.  PI3K gamma (γ) 
inhibition has been shown to reduce the infiltration of tumor-suppressive macrophages, diverting 
them from an immune suppressive (wound healing) M2 to an immunostimulatory M1 phenotype 
and reducing the production of fibroblast-stimulating growth factors.  PI3K delta (δ) inhibitors can 

NCI Protocol #:  10217 
Version Date:   September 25, 2024 
16 
stimulate a more potent CD8+ T-cell-mediated cytotoxic anti-tumor response by activating 
dendritic cells (DCs) to produce more interleukin 12 (IL-12) and by inhibiting regulatory T-cell 
(Treg) and myeloid derived suppressor cells (MDSCs), which antagonize cell-mediated immunity 
in tumors. 
 
Figure 1:  Direct and indirect anti-cancer effects of inhibiting PI3K isoform activity.  Different PI3K isoforms 
have the potential to interfere with cancer growth and survival, by acting on the transformed cells directly, by 
interfering with the supportive stroma or nutrient supply, or by stimulating more potent immune responses against the 
transformed cells (Okkenhaug et al., 2016) 
The three main classes of PI3K inhibitors currently in clinical testing comprise dual pan-Class I 
PI3K/ mechanistic target of rapamycin (mTOR) inhibitors, pan-Class I PI3K inhibitors lacking 
significant mTOR activity and isoform-selective PI3K inhibitors.  A major step forward in recent 
years is the progression of over 30 small molecule PI3K inhibitors into clinical trials and the first 
regulatory approval of the PI3Kδ inhibitor idelalisib for multiple B-cell malignancies.  Copanlisib 
has also demonstrated preliminary antitumor responses in patients with non-Hodgkins lymphoma 
(NHL), which is likely to be driven by its sub-nanomolar half maximal inhibitory concentration 
(IC50) potency against PI3Kδ.  However, despite favorable pharmacokinetic–pharmacodynamic 
profiles, only modest evidence of single agent antitumor activity has been observed in patients 
with advanced solid tumors with the pan-Class I PI3K inhibitors. 
 
2.2 
CTEP IND Agents 
 
2.2.1 Copanlisib (BAY 80-6946) 
 
Copanlisib (BAY 80-6946) is a novel small-molecule pan-class I PI3K inhibitor with exceptional 
inhibitory potency against δ and α PI3K isoforms (Copanlisib Investigator’s Brochure, 2017).  
Copanlisib is an active ingredient (free base) of copanlisib dihydrochloride (BAY 84-1236), 
which is intended for an intravenous (IV) administration in humans.  The copanlisib 
hydrochloride product for clinical use is formulated as a lyophilized product for reconstitution in 
saline to be administered by IV.  Copanlisib dihydrochloride product is supplied in three 
formulation strengths:  20 mg, 60 mg, or 80 mg (free base) in a 6 mL injection vial for 

NCI Protocol #:  10217 
Version Date:   September 25, 2024 
17 
reconstitution with 2 mL, 4.4 mL, or 4 mL of saline, respectively, to produce copanlisib solution 
for injection at concentration of 10 mg/mL, 15 mg/mL, or 20 mg/mL, respectively.  
 
On September 14, 2017, the FDA granted approval to copanlisib solution (IV) for the treatment 
of adult patients with relapsed follicular lymphoma who have received at least two prior systemic 
therapies (Food and Drug Administration, 2017). 
 
PI3K transmits signals from receptor tyrosine kinases (RTKs) to numerous cellular targets that 
are important for cell proliferation, survival, differentiation, and migration (Liu et al., 2013).  
PI3K/AKT signaling is commonly dysregulated in human cancers via various mechanisms, e.g., 
gene amplification, rearrangement, or activating and/or loss-of-function mutations of the 
pathway’s molecular components (Westin, 2014).  Aberrant activation of class I PI3Ks has been 
associated with intrinsic and acquired resistance of tumors to targeted agents, chemotherapy, and 
radiotherapy (Liu et al., 2013).  
 
Four PI3K isoforms (PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ), all of which have a catalytic p110 
subunit (p110α/β/γ/δ), comprise the class I PI3K subfamily (Liu et al., 2013; Westin, 2014).  
PI3Kα signaling is frequently active in human malignancies, and tumors with activating 
mutations in PIK3CA or loss of PTEN have been found to be sensitive to PI3Kα inhibitors.  
PI3Kδ-specific inhibitors have shown remarkable therapeutic efficacy in some human leukemias 
and lymphomas (Yang et al., 2015).  A major component of the mechanism of action of PI3Kδ 
inhibition in the B-cell malignancies is to attenuate the responsiveness of the tumor cells to 
supportive stimuli from the microenvironment (Okkenhaug and Burger, 2016).  Inhibition of 
PI3Kδ has been shown to protect mice against a broad range of cancers, including non-
hematological solid tumors (Ali et al., 2014).  Inactivation of PI3Kδ breaks Treg-mediated 
immune tolerance that unleashes a cytotoxic T-cell response and resulting in tumor regression.  
Copanlisib is a pan-class I PI3K small-molecule inhibitor exhibiting activity predominantly 
against the PI3Kα and PI3Kδ isoforms.  Preclinical data suggest that copanlisib may be more 
efficient in inhibiting survival of leukemia cells than idelalisib (PI3Kδ inhibitor) or duvelisib 
[PI3Kα/γ] (Gockeritz et al., 2015).  
 
2.2.1.1 
Nonclinical Studies 
 
A majority of nonclinical data were produced using the copanlisib free-base.  
 
2.2.1.1.1 
Mechanism of Action 
 
Copanlisib is a stronger inhibitor of PI3Kα (IC50 0.5 nmol/L) and PI3Kδ (IC50 0.7 nmol/L) than 
of PI3Kβ (IC50 3.7 nmol/L) or PI3Kγ [IC50 6.4 nmol/L] (Liu et al., 2013).  Compared to the PI3K 
isoforms, copanlisib was a much weaker inhibitor of mTOR (IC50=45 nmol/L).  In a panel of 
~220 kinases, copanlisib (1 mcmol/L) failed to achieve a 50% inhibition of any kinase other than 
PI3K isoforms and mTOR.  In tumor cell lines with hyperactive PI3K signaling, copanlisib 
antitumor activity was paralleled by a robust decrease in basal levels of phosphorylated protein 
kinase B (AKT), both at serine 473 (AKTpS473) and threonine 308 (AKTpT308), and by 
increases in caspase-9 levels, which is suggestive of induction of apoptosis.  
 

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2.2.1.1.2 
Nonclinical in vitro Antitumor Activity  
 
Copanlisib potently inhibited tumor cell proliferation (IC50 of 1-760 nmol/L) in human tumor 
cell lines of various histologies, including breast, ovary, endometrial, prostate, colon, lung, liver, 
brain, kidney, melanoma, pancreas, and hematological tumors (Figure 2); many of which exhibit 
constitutively activated PI3K signaling resulting from somatic mutations in PIK3CA and PTEN 
(Liu et al., 2013). 
 
 
Figure 2:  Antiproliferative activity against a panel of human tumor cell lines. 
Panel A:  Cell lines of various tumor histologies.  Panel B:  Breast cancer cell lines.  Panel C: Molecular and 
histological characterization of breast cancer cell lines shown in panel B.  Subtype Legend: B: basal–like breast 
cancer cell lines; L:  luminal-type breast cancer cell lines; H:  human epidermal growth factor receptor 2 (HER 2)-
positive breast cancer cell lines (Copanlisib Investigator’s Brochure, 2017). 
 
To further analyze a relationship between molecular features and copanlisib activity, copanlisib 
was tested against 24 breast cancer cell lines with known PI3KCA gene mutation, PTEN gene 
mutation or expression, and HER2 expression status (Liu et al., 2013).  Antiproliferation IC50s of 
copanlisib were ~40-fold lower in cells with activating mutations in PIK3CA (IC50=19 nmol/L; 
n=9) or HER2-positive cells (IC50=17 nmol/L; n=7) than for cells with PIK3CA wild-type (WT) 
and HER2-negative status (average IC50=774 nmol/L; n=11).  However, no clear correlation has 
been found between sensitivity of cells to copanlisib and the loss of PTEN.  Of note, copanlisib 
efficiently inhibited cell proliferation of breast cancer cell lines that are resistant to HER2 

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inhibitors (trastuzumab or lapatinib) such as T47D (mutant PIK3CA), ZR-75-1 (PTEN null), or 
MCF7 (mutant PIK3CA) with IC50s of 6, 24, and 27 nmol/L, respectively.   
 
Following a 24-hour incubation of the BT20 breast cancer cells (mutant PIK3CA and resistant to 
the HER2 inhibitor lapatinib) in the presence of copanlisib at a dose of 62 nmol/L induced 2- to 
3-fold increases in caspase-9 activities [Figure 3A] (Liu et al., 2013).  After 24-hour and 48-hour 
incubations with copanlisib (200 nmol/L), several fold increases in phosphorylated p53 at serine 
15 [p53pS15] (Figure 3B) and cleaved poly adenosine diphosphate ribose polymerase [PARP] 
(Figure 3C) were observed.  These results were consistent with increased caspase-9 activity.  In 
the lapatinib-sensitive breast cancer cell line BT474, copanlisib alone caused caspase-9 
activation at a half maximal effective concentration (EC50) of 340 nmol/L.  In contrast, lapatinib, 
was not able to activate caspase-9, even at a concentration as high as 10 mcmol/L.  When BT474 
cells were exposed to a combination of copanlisib and lapatinib, the same level of caspase-9 
activation was achieved at markedly lower concentrations of copanlisib (61 nmol/L) and 
lapatinib (184 nmol/L).   
 
Collectively, these data suggest that copanlisib could induce apoptosis in both HER2 inhibitor-
resistant and sensitive breast cancer cell lines at clinically achievable concentrations.  
 
 
Figure 3:  Induction of apoptosis by copanlisib (BAY 806946) in lapatinib-resistant breast cancer cell line 
BT20.  Panel A:  Activation of caspase-9 by copanlisib.  Panel B:  Induction of phosphorylation of p53 at serine 15 
by copanlisib.  Panel C:  Induction of cleaved PARP by copanlisib. 
 
Copanlisib was also tested against a panel of 32 human hematological cancer cell lines 

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(Copanlisib Investigator’s Brochure, 2016).  Copanlisib was a more potent inhibitor than 
idelalisib, the PI3Kδ-selective inhibitor; idelalisib IC50s were 1.4-fold to several thousand-fold 
higher than copanlisib IC50s against these cell lines.  Copanlisib IC50s were <100 nmol/L for 14 
cell lines, including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), 
NHL, and myeloma.  Some of the strongest responses to copanlisib (IC50 <10 nmol/L) occurred 
in AML (Kasumi-1, IC50=1.1 nmol/L), the Burkitt's lymphoma subtype of NHL (NAMALWA, 
IC50=1.7 nmol/L), the diffuse large B-cell lymphoma (DLBCL) subtype of NHL (Pfeiffer, 
IC50=0.8 nmol/L), and myeloma (MM-1R, IC50=1.0 nmol/L; and NCI-H929, IC50=2.7 and 2.2 
nmol/L in 2 different experiments).  Copanlisib was also more potent inhibitor against an 
aggressive NHL type such as DLBCL than idelalisib or a Bruton’s tyrosine kinase (BTK) 
inhibitor ibrutinib (Figure 4).   
 
 
Figure 4  Antiproliferative effects of copanlisib (BAY 80-6946), idelalisib  
(CAL-101), and ibrutinib (PCI-32765) against DLBCL cell lines.  Legend: IC50:  a drug concentration causing 
50% inhibition of cell proliferation. 
 
Concurrent treatment with copanlisib and ibrutinib resulted in synergistic effects of the two 
inhibitors against ibrutinib-sensitive cell lines but antagonistic effects in ibrutinib-resistant cell 
lines. 
 

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2.2.1.1.3 
In vivo Antitumor Activity  
 
Copanlisib demonstrated antitumor activity in vivo in a variety of xenograft models of tumors 
exhibiting an activated PI3K pathway (Liu et al., 2013).  The drug displayed robust antitumor 
activity in the nude rat xenograft model of the KPL4 breast tumor cell line, which is an estrogen-
independent HER2-positive breast carcinoma that carries a somatic PIK3CA mutation.  
Copanlisib was administered on day 14 post-implant at doses ranging from 0.5-6 mg/kg IV every 
second day (Q2D) for a total of five doses.  On day 25, 3 days after the last dose, tumor growth 
inhibition (TGI) rates of 77%-100% were observed in the dose range (Figure 5A).  The complete 
tumor regressions were observed in 100% of animals receiving dose of 3 or 6 mg/kg, and all rats 
remained tumor free at the termination of the study on day 73.  Delays in tumor growth of >25 
days were observed in the 0.5 and 1 mg/kg groups.  Copanlisib administered at 3 and 6 mg/kg IV 
Q2D x 5 in PIK3CA and mutant KRAS HCT 116 xenograft rat models resulted in the TGI of 75% 
and 88% (Figure 5B).  Copanlisib was also effective in the nude mouse patient-tumor xenografts 
of Lu7860 (erlotinib-resistant non-small cell lung carcinoma [NSCLC]) and MAXF1398 
(luminal breast tumor).  Copanlisib administered at 14 mg/kg twice a day (BID), Q2D for 10 
days resulted in the 88% TGI in the NSCLC model (Figure 5C) and 71% TGI in the breast 
cancer model (Figure 5D).  
 
 
Figure 5:  Activity of copanlisib (BAY 80-6946) in xenograft models using Q2D treatment schedule.  Panel A:  
KPL4 breast cancer xenografts in nude rats (n=10/group).  Panel B:  HCT116 colon cancer xenografts in nude rats 
(n=10/group).  Panel C:  Lu7860 erlotinib-resistant, patient-derived NSCLC xenografts in nude mice (n=5/group).  
Panel D:  MAXF1398 patient-derived luminal breast cancer xenografts in nude mice (n=6/group).  Legend: Q2D:  
every 2 days; BID:  twice a day; IV:  intravenously; TGD:  tumor growth delay; PR:  partial response; CR:  
complete response 
 

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Copanlisib was also evaluated on a weekly schedule.  Two doses of 9 mg/kg on day 1/week 
caused 64% TGI in the HCT-116 xenograft model, which was equivalent to the effect of 
copanlisib given at 6 mg/kg Q2D for 10 doses (Figure 6A).   
 
 
Figure 6:  Activity of copanlisib (BAY 80-6946) in xenograft models using a twice a day (BID)  
once-weekly schedule.  Copanlisib was formulated in 5% mannitol vehicle.  Panel A:  HCT-116 colon cancer 
xenografts in nude rats (8 rats/group).  Panel B:  Lu7343 patient-derived NSCLC xenografts in nude mice (10 
mice/group).  Legend:  BID: twice a day; Q2D:  every 2 days 
 
In vivo antitumor activity of copanlisib was also tested in combination with cytotoxic agent 
paclitaxel in the mutant PIK3CA squamous cell NSCLC patient-derived Lu7343 xenograft 
mouse model (Liu et al., 2013).  Paclitaxel was given weekly at 15 or 25 mg/kg on days 14, 21, 
and 28, followed 24 hours later by copanlisib at 10 mg/kg BID on weekly schedule (days 15, 22, 
and 29) in a group of 10 animals.  In addition, both drugs were tested as single agents (n=10); the 
control group received a vehicle (no drug).  The drug combination was more potent in inhibiting 
tumor growth than either drug alone (Figure 6B).  Although single-agent paclitaxel dosed at the 
maximum-tolerated dose (MTD) of 25 mg/kg was highly efficacious for the duration of 
treatment (33 days), showing tumor regression in 70% of animals, discontinuation of the 
treatment dropped the response rate to 30% (day 55), with 60% of animals demonstrating tumor 
re-growth.  In contrast, the copanlisib + paclitaxel combination produced long-lasting tumor 
regressions, with a CR observed in 6/10 animals and a PR observed in 4/10 animals 22 days after 
stopping treatment (day 55).   
 
Copanlisib was well tolerated at all doses and schedules tested in these studies without producing 
any lethality (Liu et al., 2013).  The MTD in rats was 6 mg/kg Q2D.  A maximum mean body 
weight loss of 6%-10% occurred during the first few days at this dose and then consistently 
returned to the normal range by the end of the dosing period.  The MTD in mice was more than 

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14 mg/kg Q2D. 
 
Based on the promising in vitro antitumor activity of copanlisib against DLBCL cell lines, 
copanlisib was tested in vivo alone and in the combination with ibrutinib in the TMD-8 severe 
combined immunodeficiency (SCID) mouse model (Copanlisib Investigator’s Brochure, 2017).  
The TMD-8 DLBCL cell line harbors activating mutations in CD79B and MYD88.  Copanlisib 
hydrochloride was dosed at 14 mg/kg IV daily (QD) for 2 days on and 5 days off/week and 
ibrutinib was administered at 20 mg/kg orally (PO) QD.  The combination demonstrated 
synergistic activity, with 100% response rate (5 CRs and 3 PRs in 8 animals) observed compared 
to 12.5% (1 PR in 8 animals) and no responses seen in the copanlisib alone treatment group.    
 
2.2.1.1.4 
Nonclinical Pharmacokinetics and Pharmacodynamics 
 
Copanlisib plasma-free fraction across species was as follows:  35% in rats, 14% in mice, 33% in 
dogs, and 16% in humans (Liu et al., 2013).  The pharmacokinetic (PK) profile of copanlisib was 
evaluated following single and multiple IV doses in nude rats.  Single-dosed copanlisib exhibited 
a very large volume of distribution (Vd=32 L/kg), high plasma clearance (3.95 L/kg/h) and a long 
half-life [t1/2] (6.0 h).  The copanlisib PK parameters at repeat dosing (Q2D x 5 doses), were 
similar those from single-dosing studies and suggested no drug accumulation in plasma.  
Copanlisib had a higher clearance (16 L/kg/h), shorter t1/2 (0.7 h) and smaller volume of 
distribution [Vd] (12.9 L/kg) in mice than rats.  A single bolus IV dose of copanlisib (6 mg/kg) in 
the H460 NSCLC xenograft rat model produced 100 times higher concentration of the drug in 
tumor tissue than in plasma at 48 hours post-dosing; the drug clearance from the tumor was 
slower than from plasma.  The pharmacodynamics analysis showed 90% inhibition of 
AKTpS473 at 24 hours post-dosing compared to the control animals, and the AKTpS473 level 
remained suppressed up to 72 hours.  In addition, 65% and 75% reductions in Ki-67 and 
phospho-histone H3 levels, respectively, were observed at 24 hours in the copanlisib group 
compared to the control group, suggesting copanlisib-induced G0 cell-cycle arrest.  Copanlisib 
also demonstrated sustained inhibition (over 24-48 hours) of 18F-deoxyglucose (FDG) uptake in 
tumor.  These preclinical data suggested that high and prolonged copanlisib tumor exposures can 
be reached in vivo, and there was a correlation between copanlisib exposure and inhibition of the 
PI3K pathway in the tumor.  
 
In the rat tumor xenograft model studies, the efficacious exposure of copanlisib was estimated as 
the area under the concentration-time curve (AUC) for the unbound/free drug (AUCu) in plasma 
of 370 mcg•h/L based on weekly dosing (Copanlisib Investigator’s Brochure, 2017). 
 
2.2.1.1.5 
Summary of Nonclinical Metabolism  
 
Copanlisib is primarily metabolized by the cytochrome P450 (CYP)3A4 with a minor 
contribution of CYP1A1 (Copanlisib Investigator’s Brochure, 2017).  Copanlisib is a weak 
substrate of P-glycoprotein (P-gp) and of breast cancer resistance protein (BCRP).  There is a 
low risk for clinically relevant PK drug-drug interactions (DDI) through inhibition or induction 
of CYP enzymes, inhibition of uridine diphosphate glucuronosyltransferase (UGT) enzymes and 
inhibition of dihydropyrimidine dehydrogenase (DPD) by copanlisib.  Copanlisib also inhibited 
P-gp- and BCRP-mediated transport in vitro.  Furthermore, copanlisib was a strong inhibitor of 

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the drug transporter multidrug and toxin extrusion protein 2 (MATE2K).  Copanlisib also 
inhibited P-gp- and BCRP-mediated transport in vitro at concentrations much higher than those 
observed at the approved 60 mg clinical dose. 
 
2.2.1.1.6 
Summary of Nonclinical Safety 
 
IV infusion of copanlisib caused vasoconstriction, enhanced insulin and glucose levels, impaired 
glucose tolerance, reduced gastrointestinal (GI) motility, increased renal volume and electrolyte 
excretion, and central nervous system (CNS) depressant effects in nonclinical species 
(Copanlisib Investigator’s Brochure, 2017).  A majority of these effects could be explained by 
inhibition of PI3K-dependent signaling, and they occurred at or slightly above the plasma 
concentrations shown to be efficacious in tumor xenograft rat models (maximum concentration 
[Cmax]=30-80 mcg/L; Cmax of unbound fraction [Cmax,u] 11-28 mcg/L).  The CNS depressant 
effects occurred at high plasma concentrations and are considered secondary to hyperglycemia.  
At pharmacodynamically relevant concentrations, copanlisib does not interfere with cardiac 
repolarization in vitro or in vivo. 
 
Based on the findings from repeat-dose toxicity studies in nonclinical species, copanlisib is 
expected to adversely affect male and female reproduction.  Developmental and reproductive 
toxicity of PI3K inhibitors is known.  Maternal toxicity of increasing severity, severe post-
implantation loss, and developmental toxicity, including teratogenicity, were seen in rats starting 
at low doses.  Copanlisib was not genotoxic in vitro or in vivo.  There is no evidence that 
copanlisib has phototoxic potential.  Significant toxicities were observed in animals at doses 
achieving plasma concentrations observed in humans. 
 
2.2.1.2 
Effects in Humans  
 
2.2.1.2.1 
The First-in-Human Copanlisib Study 
 
In the first-in human (FIH) phase 1 trial in patients with advanced and/or refractory 
malignancies, of 57 patients (51 non-diabetic) treated, 17 took part in the dose-escalation phase 
with  copanlisib (0.1-1.2 mg/kg) administered IV weekly for 3 weeks of a 4-week cycle (Patnaik 
et al., 2016).  The copanlisib MTD was 0.8 mg/kg IV (1 h) weekly for 3 weeks on a 28-day 
cycle.  An additional 34 patients were treated in the MTD expansion cohorts:  the solid tumor 
cohort (n=25), NHL cohort (n=9; 6 patients with follicular lymphoma [FL] and 3 patients with 
DLBCL).  Finally, 6 patients with diabetes mellitus were treated with copanlisib at 0.4 mg/kg 
weekly x 3 weeks.   
 
2.2.1.2.2 
Clinical Safety 
 
The most common (≥20%) copanlisib-related adverse events [AEs] (regardless of grade) 
included hyperglycemia (63%), nausea (37%), and hypertension (21%).  The most common 
drug-related grade 3 AEs were hyperglycemia (30%), hypertension (14%), and rash (7%) 
(Patnaik et al., 2016).  Grade 3+ diarrhea occurred in one patient.  Two patients (4%) 
experienced three drug-related grade 4 AEs:  a dose-limiting hyperglycemia and increased 
aspartate aminotransferase (AST) in one patient and elevated serum amylase in another patient.  

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Overall, serious AEs (SAEs) with positive association to copanlisib were observed in six patients 
(11%):  grade 3 left ventricular systolic dysfunction (LVSD) which was a dose-limiting toxicity 
(DLT), chest pain, hypertension, and hyperglycemia (in one patient each), and pneumonitis (in 
two patients).  None of seven grade 5 AEs (12%) was considered drug related.  Dose 
modifications (delays, interruptions, and reductions) caused by drug-related AEs occurred in 14 
patients (25%).  Four patients discontinued treatment due to toxicity.  One drug-related AE 
(dose-limiting LVSD) led to permanent discontinuation of treatment.  No patient discontinued 
the study because of hyperglycemia.  
 
Hyperglycemia was transient, with a glucose level peaking at 5–8 hours after copanlisib infusion 
on cycle 1 day 1 and declining to baseline by the time of the next infusion.  Sixty-five percent of 
non-diabetic patients (33/51) received at least one dose of short-acting insulin to manage high 
blood glucose (>200 mg/dL).  There was no trend for increased pre-dose glucose values over 
time, and no patients developed diabetic ketoacidosis during the study.  Hemoglobin A1c 
(HbA1c) levels changed only modestly over the course of copanlisib treatment.  Post-infusion 
increases in blood pressure (BP) peaked at 1–2 hours and resolved within 24 hours post-infusion. 
 
A similar transient pattern of elevated blood glucose post-infusion was seen for the cohort of six 
diabetic patients treated with 0.4 mg/kg copanlisib, all of whom received insulin following the 
first copanlisib infusion.  The AE profile in the diabetic cohort of patients was similar to that in 
non-diabetic patients, with a total of four drug-related grade 3 AEs observed in three patients:  
hypertension in two patients, and hyperglycemia and rash/desquamation in one patient each.  
 
2.2.1.2.3 
Pharmacokinetics/Pharmacodynamics 
 
Copanlisib plasma Cmax was typically reached between 0.5 and 1 hour (time to maximum 
concentration [tmax]) following the infusion (Patnaik et al., 2016).  Copanlisib exposure, 
expressed either as Cmax or AUC between 0-25 hours (AUC0–25h), increased proportionally with 
dose between 0.1 and 1.2 mg/kg, and exhibited a moderate to high inter-patient variability.  The 
terminal t1/2 was 38.2 hours and no accumulation was observed after once-weekly administration.  
The trough levels of copanlisib on cycle 1 day 8 were 4.92 mcg/L (range, 2.74–23.0 mcg/L). 
 
A pharmacodynamic effect event was defined as an increase in plasma glucose level of ≥50 
mg/dL from baseline within 2 hours after the completion of the copanlisib infusion, and / or an 
increase in plasma insulin level to greater than two times the baseline value (Copanlisib 
Investigator’s Brochure, 2017).  At the MTD (0.8 mg/kg), 100% of patients showed the pre-
defined increases in glucose and insulin.  Overall, 53/57 (93%) patients experienced a predefined 
pharmacodynamics effect of an increased glucose plasma level following the first copanlisib 
infusion.  Increases in glucose levels strongly correlated with copanlisib exposure (AUC0-25h) 
(Patnaik et al., 2016).  A weak correlation between exposure and change in tumor FDG uptake 
(via 18FDG-positron emission tomography [PET]) from baseline to cycle 1 day 3 or day 4 was 
seen in 19/21 patients evaluated, with >25% reduction in the FDG uptake observed in the tumor 
of 7 patients (33%). 
 
2.2.1.2.4 
Antitumor Activity/Response  
 

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Among patients with solid tumors (n=48), clinical responses were observed only in patients 
treated at the copanlisib MTD (Patnaik et al., 2016).  The responses were:  1 CR (2%) in a 
patient with endometrial cancer, 2 PRs (4%) in patients with breast cancer, 15 cases of stable 
disease patients (SD) (31%), and 15 cases of progressive disease (PD) (31%) according to the 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.  In comparison, by clinical 
assessment, 7 patients (15%) had PD, and 8 patients (17%) were not assessed.  Overall clinical 
benefit rate (CBR) was 38%.   
 
The CR responder had endometrial cancer with PIK3CA and PTEN mutations and complete 
PTEN loss.  Of the two breast cancer patients who had PR, both had tumors positive for estrogen 
receptor (ER) and progesterone receptor.  One was negative and the other positive for HER2; 1 
had mutant and the other WT PIK3CA; and PTEN status was unavailable in both.  No clear 
relationship was found between PI3KCA mutational status and disease control (P=1.0). 
 
All 9 patients with NHL were evaluable for response using the International Working Group 
criteria.  There were 1 CR (FL), 6 PRs (5 FL and 1 DLBCL), and 2 PD (DLBCL).  A post-hoc 
radiologic review determined that two patients with FL achieved a CR.  In addition, two FL 
patients had long-term durable responses, one of whom was on treatment for approximately 4 
years before coming off study because of disease progression; the other patient was still on 
treatment as of 19 January 2016 (>3 years).  All seven NHL responders had PI3KCA WT status; 
by immunohistochemistry (IHC), one patient had complete PTEN loss, two had low PTEN 
expression, two had positive PTEN expression, and two had unknown PTEN expression.  Both 
patients with disease progression had low PTEN expression. 
 
2.2.1.2.5 
The Copanlisib Phase 2 Study in Refractory Lymphoma 
 
In the phase 2 study of copanlisib in patients with various indolent and aggressive, relapsed or 
refractory NHL, copanlisib demonstrated antitumor activity (Copanlisib Investigator’s Brochure, 
2017).  At the time of the data analysis, seven patients (8.3%) still were ongoing treatment, 
including four patients in the indolent NHL / chronic lymphocytic leukemia (CLL) cohort and 
three patients in the aggressive NHL cohort. 
 
Among 32 patients with indolent NHL (15 with FL, 3 with marginal-zone lymphoma [MZL], 
and 1 with small lymphocytic lymphoma [SLL]) and 13 patients with CLL, 14 patients achieved 
objective tumor responses (2 CR, 1 unconfirmed CR, and 11 PR) resulting in an ORR of 44%.  
In addition, 15 patients (47%) achieved SD; 1 patient had PD.  Of 48 patients with aggressive 
lymphoma, 13 patients achieved objective tumor responses (2 CR, 2 unconfirmed CR, and 9 PR) 
resulting in 27% ORR.  In addition, 11 patients achieved SD (23%); 16 had PD (33%).  The 
ORR was also analyzed by histological subtype; the data are summarized in the following table.   
 
Clinical Activity Stratified by Histology Subtype 
Histology 
N 
Total OR 
(ORR) 
CR 
CRu 
PR 
SD 
PD 
NE 
NA 
INDOLENT 
 
 
 
 
 
 
 
 
 
Indolent NHL 
19 
9 (47%) 
2 
1 
6 
9 
0 
0 
1 
FL 
15 
6 (40%) 
2 
2 
3 
8 
0 
0 
1 
MZL 
3 
2 (67%) 
0 
0 
2 
1 
0 
0 
1 

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Histology 
N 
Total OR 
(ORR) 
CR 
CRu 
PR 
SD 
PD 
NE 
NA 
SLL 
1 
1 (100%) 
0 
0 
1 
0 
0 
0 
0 
CLL 
13 
5 (38%) 
0 
0 
5 
6 
1 
0 
1 
AGGRESSIVE 
 
 
 
 
 
 
 
 
 
DLBCL 
15 
1 (6.7%) 
0 
0 
1 
0 
4 
1 
3 
MCL 
11 
7 (64%) 
0 
2 
5 
0 
3 
0 
1 
Transformed 
indolent NHL 
6 
2 (33%) 
0 
0 
2 
0 
3 
0 
1 
Peripheral  T-
cell lymphoma 
14 
3 (21%) 
2 
0 
0 
1 
5 
0 
1 
Mediastinal large 
B-cell lymphoma 
1 
 
 
 
 
 
 
 
 
FL grade3b 
1 
 
 
 
 
 
 
 
 
N:  total number of patients; NE:  non-evaluable; NA:  not available; OR:  objective response: ORR:  OR rate; CR:  
complete response; CRu:  unconfirmed complete response; PR:  partial response; SD:  stable disease; PD:  
progressive disease; NHL:  non-Hodgkin’s lymphoma; FL:  follicular lymphoma; CLL: chronic lymphocytic 
leukemi; MZL:  marginal-zone lymphoma; SLL: small lymphocytic lymphoma; DLBCL:  diffuse large B-cell 
lymphoma; MCL:  mantle cell lymphoma. Copanlisib Investigator’s Brochure, 2017.  
 
2.2.1.2.6 
Safety 
 
Hyperglycemia and hypertension are on-target AEs for PI3K inhibitors.  The most common 
copanlisib-related AEs (all grades), by the medical dictionary for regulatory activities preferred 
term (MedDRA PT), that occurred in ≥20% of the patients in this study were hyperglycemia 
(54.8%), hypertension (51.2%), diarrhea (32.1%), neutropenia (23.8%) [by Common 
Terminology Criteria for Adverse Events (CTCAE) terms: neutrophil count decreased (28.6%)], 
and fatigue [20.2%] (Copanlisib Investigator’s Brochure, 2017).   
 
2.2.1.2.7 
Copanlisib Clinical Pharmacology Summary  
 
Copanlisib plasma exposure (Cmax and AUC) increased in a dose-proportional manner over an 
absolute dose range of 5 to 93 mg (0.08 to 1.55 times the approved recommended dose of 60 
mg).  There is no time-dependency and no accumulation in the PK of copanlisib administered 
weekly.  The geometric mean terminal elimination half-life (CV%) of copanlisib was 39.1 h 
(40.8%) based on the pooled analysis of 3 Phase 1 studies (12871, 15205 and 16270).  The 
geometric mean clearance (CV%) was 17.9 L/hr (45.6%).  Copanlisib is eliminated 
predominantly via feces (64% of the administrative radioactive dose mean recovery with 30% 
unchanged copanlisib) compared to urine (22% mean recovery with 15% unchanged copanlisib) 
(Copanlisib Investigator’s Brochure, 2017).  
 
Population PK analyses suggest that body weight, age (20 to 90 years), gender, race (White, 
Asian, Hispanic and Black), smoking status, body weight (41 to 130 kg), mild hepatic 
impairment and mild to moderate renal impairment had no clinically significant effect on the 
pharmacokinetics of copanlisib (Copanlisib Investigator’s Brochure, 2017).  No dose adjustment 
is necessary based on these specific populations.  Preliminary analysis of central tendency and 
exposure-response analyses suggest that copanlisib does not prolong QT/QTc interval.   
Further details can be found in the latest available version of the investigator's brochure (2017), 
which contains comprehensive information on the study drug and also the US prescription drug 

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label. 
 
2.2.1.3 
Copanlisib Reference Safety Information  
 
2.2.1.3.1 
The recommended dose and administration of copanlisib 
 
Based on the FIH company-sponsored study, the MTD of copanlisib in non-diabetic patients 
with solid malignancies was 0.8 mg/kg (equivalent to 60mg approved dose) administered IV 
over 1 hour once weekly for 3 weeks (days 1, 8, and 15) on a 28-day cycle (Copansilib 
Investigator’s Brochure, 2017).   
 
A preliminary population PK analysis revealed no impact of either body weight, body surface 
area (BSA), or other body size-related factors on the clearance of copanlisib and thus a flat-dose 
regimen of copanlisib has been recommended (Copansilib Investigator’s Brochure, 2017).   
 
Based on these data, the RP2D of copanlisib monotherapy is 60 mg given over a 1-hour IV 
infusion once a week for 3 weeks (days 1, 8, and 15) every 4 weeks.  A dose reduction to 45 mg 
for toxicities have been allowed. 
 
2.2.1.3.2 
Drug-drug interactions 
 
Copanlisib metabolism is predominantly mediated by CYP3A4 (> 90%) and to a minor extent by 
CYP1A1 (< 10%) (Copanlisib Investigator’s Brochure, 2017).  Itraconazole, a strong CYP3A4 
inhibitor and a P-gp and BCRP transporter inhibitor, increased copanlisib (60 mg) AUC by 1.53-
fold with no effect on Cmax (1.03–fold).  If concomitant use with strong CYP3A inhibitors cannot 
be avoided, a dosage reduction to 45mg is recommended.  Rifampin, a strong CYP3A4 inhibitor 
and a P-gp transporter inhibitor, decreased the AUC of copanlisib (60 mg) by 63% with minimal 
effect on Cmax (15%) and strong inducers should be avoided (Copanlisib Investigator’s Brochure, 
2017). 
 
2.2.1.3.3 
Pregnancy and lactation 
 
Due to a mechanism of action as a PI3K inhibitor, adverse effects on development and 
reproduction are expected for copanlisib (Copanlisib Investigator’s Brochure, 2017).  
Nonclinical repeat-dose toxicity studies demonstrated adverse effects of copanlisib on male and 
female reproduction.  Maternal toxicity of increasing severity, severe post-implantation loss, and 
developmental toxicity, including teratogenicity were seen in a rat pilot developmental toxicity 
study beginning at a low dose.  In the rat study with 14C-labeled copanlisib, radioactivity was 
secreted into the milk of lactating animals although at a low extent (1.7% of dose).  No data are 
available on the distribution of copanlisib to human milk.  Therefore, unless potential benefits to 
patients outweigh unknown risks, women who are pregnant or nursing and children should be 
excluded from the clinical studies of copanlisib.  In addition, women of child-bearing potential or 
female partners of male patients will be required to use an adequately effective barrier method of 
birth control. 
 

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2.2.1.3.4 
Special safety warnings and precautions  
 
Nonclinical studies suggest and clinical studies confirm, blood glucose increases persisting for 
approximately 1-3 days after study copanlisib administration (Copansilib Investigator’s 
Brochure, 2017).  Blood or serum glucose, serum and urine ketones, and electrolytes should be 
monitored while on copanlisib treatment.  
 
Standard cardiovascular parameters, including pulse and BP should be monitored because of 
hypertension (during the first 3 h after start of infusion) that has been observed.  
 
Respiratory infections (including pneumonia, Pneumocystis jirovecii pneumonia, cryptococcosis 
and bronchopulmonary aspergillosis) have been observed in studies with monotherapy and 
combination therapies.  Some of these infections may have life-threatening or fatal outcome.  
Cases of pneumonitis observed in studies with monotherapy and in combination therapies were 
generally ≤grade 3 in severity and responded well to corticosteroid treatment; occasional events 
with life-threatening or fatal outcome have been observed.  Since the early symptoms of 
pneumonitis overlap with those of a respiratory infection, monitoring of patients for typical 
clinical symptoms like cough, dyspnea or fever and further evaluation for respiratory infections 
is recommended.  Patients suspected of having a respiratory infection or noninfectious 
pneumonitis should be promptly treated with appropriate antimicrobial agents and/or 
corticosteroids as indicated. 
 
2.2.2 Olaparib (AZD2281) 
 
In December 2014, the European Commission approved olaparib capsules as a maintenance 
treatment for platinum-sensitive, relapsed, high grade serious epithelial ovarian, fallopian tube, 
or primary peritoneal cancer in adult patients with breast cancer (BRCA) mutations (germline 
[gBRCAm] and/or somatic [sBRCAm]) who are in a CR or PR to platinum-based chemotherapy.  
In December 2014, the Food and Drug Administration (FDA) approved olaparib capsules as 
monotherapy for advanced ovarian cancer in patients with deleterious or suspected gBRCAm 
who have been treated with three or more prior lines of chemotherapy.  In August 2017, the FDA 
approved the tablet formulation of olaparib for the maintenance treatment of adult patients with 
recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a CR or PR 
to platinum-based chemotherapy; olaparib tablets were also approved for the December 2014 
indication.  On January 12, 2018, the FDA granted regular approval to olaparib tablets for the 
treatment of patients with deleterious or suspected deleterious germline gBRCAm, human 
epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been 
treated with chemotherapy either in the neoadjuvant, adjuvant, or metastatic setting.   
 
2.2.2.1 
Mechanism of action 
 
Olaparib inhibits PARP, a protein that repairs single-strand breaks (SSBs) via base excision 
repair (BER), a backup repair system to homologous recombination (HR) repair (Farmer et al., 
2005; Olaparib Investigator’s Brochure, 2018).  Olaparib potently inhibits PARP1 (IC50=5 nM), 
PARP2 (IC50=1 nM), and PARP3 (IC50=4 nM) in vitro (Olaparib Investigator’s Brochure, 2018).  
The inhibition of PARP and disruption of BER via olaparib treatment leads to accumulation of 

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double-strand breaks (DSBs); in tumors with defective components of HR repair, these DSBs 
cannot be accurately repaired, resulting in genomic instability and induction of synthetic lethality 
(Farmer et al., 2005; Olaparib Investigator’s Brochure, 2018).  Cultures of cells deficient in HR 
repair factors, notably BRCA1 and BRCA2, are particularly sensitive to treatment with olaparib 
(Olaparib Investigator’s Brochure, 2018).  Furthermore, olaparib may enhance the effects of 
DNA damage caused by ionizing radiation and chemotherapy. 
 
2.2.2.2 
Overview of Clinical Pharmacology  
 
Single PO dosing of olaparib tablets was rapidly absorbed with peak plasma concentrations 
typically observed at 1.5 hours (Olaparib Investigator’s Brochure, 2018).  A population PK 
analysis characterized the absorption phase of olaparib as a sequential zero- and first-order 
absorption and showed a significant impact of olaparib tablet strength on the absorption rate 
constant.  Once tmax was reached, plasma concentrations of olaparib declined in a biphasic 
manner with an average t1/2 of 14.9 hours (standard deviation [StD]: 8.2 hours).  The mean 
apparent clearance (CL) after a single dose of olaparib tablets at 300 mg PO was approximately 
7.4 L/h (StD: 3.9 L/h).  Olaparib exhibited a mean volume of distribution (Vd) of 158 L (StD: 
136 L), indicating distribution into the tissues.  The plasma protein binding in vitro was moderate 
and showed evidence of concentration dependence (81.9% at 10 mcg/ml).  
 
Multiple-dose PK was reasonably well predicted from single-dose data, and accumulation on 
multiple dosing was not extensive (Olaparib Investigator’s Brochure, 2018).  At a 300 mg BID 
dose, olaparib PK appeared to be slightly time dependent with a temporal change parameter 
(TCP; AUC at steady state/AUC following a single dose) of approximately 1.45 (StD: 0.6).  
Exposure (measured by AUC from zero to 12 hours [AUC0-12]) increased approximately 
proportionally with olaparib tablets at 25-450 mg; Cmax increased slightly less than 
proportionally for the dose range.  The estimated geometric mean (Gmean) maximum steady 
state plasma concentration (Cmax ss), AUC0-12, and minimum plasma concentration (Cmin) after 
dosing with 300 mg tablet BID were 9.13 mcg/mL, 57.9 mcg.h/mL and 1.76 mcg/mL:  
equivalent to unbound concentrations of 1.65 mcg/mL, 10.5 mcg.h/mL and 0.318 mcg.h/mL, 
respectively.  The inter-individual variability was moderate to high (36% for Cmax ss, 49% for 
AUC0-12, and 104% for the minimum steady state plasma concentration [Cmin ss]).  After 
administration of a radiolabeled dose of olaparib capsules (100 mg BID) in study D0810C00010, 
unchanged drug accounted for approximately 70% of the circulating material in the plasma with 
the remainder accounted for by three other components (each approximately 10% of the 
material), all of which were also present in the excreta.  Drug-related material was eliminated in 
the urine (approximately 44% of the dose) and in the feces (approximately 42% of the dose) 
predominantly as metabolites.  Metabolism was extensive.  The metabolites produced were 
predominantly a consequence of oxidation of the piperazine carboxycyclopropyl, the 
fluorophenyl, and phthalazinone ring systems.  The pharmacological activity of the three 
circulating metabolites is not known.  
 
Although based on limited data, there was no evidence of any marked ethnic difference in the PK 
of olaparib tablets between Japanese, Chinese, and Caucasian patients for the olaparib tablet 
formulation (Olaparib Investigator’s Brochure, 2018).  In a population analysis, age, body 
weight, and gender covariates were not found to be predictors of olaparib plasma exposure.  

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Data from a renal impairment study (D0816C00006) showed that olaparib tablets (300 mg BID) 
mean Cmax and AUC were approximately 15% and 24% higher, respectively, in patients with 
mild renal impairment (creatinine CL determined by Cockcroft-Gault: 51-80 mL/min; N=14), 
and olaparib mean Cmax and AUC were 26% and 44% higher, respectively, in patients with 
moderate renal impairment (creatinine CL determined by Cockcroft-Gault: 31-50 mL/min; 
N=14) (Olaparib Investigator’s Brochure, 2018).  
 
2.2.2.3 
Overview of Safety 
 
As of 15 December 2020, approximately 17209 patients are estimated to have received olaparib 
in the clinical programme including AstraZeneca-sponsored studies and AstraZeneca-Merck 
Alliance sponsored studies (8348 patients), a MAP (1880 patients), ISSs and collaborative group 
studies (6981 patients). An estimated 10228 patients with ovarian, breast, pancreatic, gastric, 
prostate and a variety of other solid tumors are estimated to have received treatment with 
olaparib in AstraZeneca-sponsored interventional studies and AstraZeneca-Merck Alliance 
sponsored studies (8348 patients) and the MAP (1880 patients). Since 2013, most new clinical 
studies have utilized the tablet formulation which was designed to deliver the therapeutic dose of 
olaparib in fewer dose units than the capsule. Of the 8348 patients, 1579 received the capsule 
formulation, 6744 received the tablet formulation and 25 received both capsule and tablet. In 
these studies, olaparib was given either as monotherapy (5333 patients) or in combination with 
chemotherapy or other anti-cancer agents (e.g., capecitabine, vinorelbine, eribulin, abiraterone, 
topotecan, gemcitabine, carboplatin and paclitaxel, paclitaxel or liposomal doxorubicin), 
including studies where patients received monotherapy and combination therapy sequentially 
(3015 patients). Approximately 3201 patients have received comparator or placebo across the 
olaparib development programme in AstraZeneca-sponsored studies and AstraZeneca-Merck 
Alliance sponsored studies. The recommended olaparib monotherapy capsule dose is 400 mg 
BID. The recommended olaparib monotherapy tablet dose is 300 mg BID. 
 
Administration of olaparib in combination with DTIC, topotecan, gemcitabine, cisplatin, 
paclitaxel or carboplatin + paclitaxel resulted in a lower MTD of olaparib compared with its 
administration as a monotherapyAdministration of olaparib with abiraterone in patients with 
mCRPC resulted in a numerical imbalance of cardiovascular events between the treatment arms 
in Part B, with a greater number of patients in the olaparib + abiraterone arm experiencing such 
events, most notably those of greater severity. The clinical significance of this is unclear and the 
interpretation is limited by the small sample size of the Safety Analysis Set, some imbalances in 
relevant baseline characteristics, lack of confirmation of cardiac failure diagnoses and lack of 
biological plausibility that olaparib would contribute to, and increase, the cardiovascular risk 
over that known for abiraterone monotherapy. 
 
Toxicities considered to be associated with administration of olaparib (ADRs) include 
hematological effects (anemia, neutropenia, lymphopenia, leukopenia, thrombocytopenia, MCV 
elevation), decreased appetite, nausea and vomiting, diarrhea, dyspepsia, stomatitis, upper 
abdominal pain, dysgeusia, fatigue (including asthenia), increase in blood creatinine, headache, 
dizziness, hypersensitivity, rash, dermatitis, cough, dyspnea, angioedema, MDS/AML, erythema 
nodosum, and venous thromboembolism (Olaparib Investigator’s Brochure, 2023).   

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Cases of pneumonitis and new primary malignancies have been reported. Evidence from across 
the development programme for olaparib does not support a conclusion that there is a causal 
relationship between olaparib and these events. These are AEs of special interest for olaparib and 
are being kept under close pharmacosurveillance. Similarly, MDS/AML remains an AE of 
special interest, despite being considered an ADR, and is still subject to additional reporting 
requirements. 
 
 
 
2.2.3 Durvalumab (MEDI4736) 
 
2.2.3.1 
Mechanism of action 
 
Durvalumab (MEDI4736) is a human monoclonal antibody (mAb) of the immunoglobulin (Ig) G 
(IgG) 1 kappa subclass that blocks the interaction of programmed cell death ligand (PD-L) 1 (but 
not PD-L2) with programmed cell death 1 (PD-1) on T cells and cluster of differentiation (CD) 
80 (B7.1) on immune cells [IC] (durvalumab [MEDI4736] Investigator’s Brochure, 2017).  
Durvalumab (MEDI4736) has been engineered to reduce antibody-dependent cellular 
cytotoxicity and complement-dependent cytotoxicity.  In vitro studies demonstrate that 
durvalumab (MEDI4736) antagonizes the inhibitory effect of programmed death ligand 1 (PD-
L1) on primary human T cells, resulting in their restored proliferation and release of interferon 
gamma (IFNγ) (Stewart et al., 2015).  
 
2.2.3.2 
Clinical pharmacokinetics and rationale for fixed dosing  
 
A population PK model was developed for durvalumab (MEDI4736) using monotherapy data from 
a Phase 1 study (study 1108; N=292; doses=0.1 to 10 mg/kg every two weeks (Q2W) or 15 mg/kg 
every 3 weeks (Q3W); solid tumors).  Population PK analysis indicated only minor impact of body 
weight (WT) on the PK of durvalumab (MEDI4736) (coefficient of ≤0.5).  The impact of body 
WT-based (10 mg/kg Q2W) and fixed dosing (750 mg Q2W) of durvalumab (MEDI4735) was 
evaluated by comparing predicted steady state PK concentrations (5th, median and 95th 
percentiles) using the population PK model.  A fixed dose of 750 mg was selected to approximate 
10 mg/kg (based on median body WT of ~75 kg).  A total of 1,000 patients were simulated using 
body WT distribution of 40–120 kg.  Simulation results demonstrate that body WT-based and fixed 
dosing regimens yield similar median steady state PK concentrations with slightly less overall 
between-patient variability with fixed dosing regimen (durvalumab [MEDI4736] Investigator’s 
Brochure, 2017).  
 
Similar findings have been reported by others (Ng et al., 2006, Wang et al., 2009, and Zhang et 
al., 2012).  Wang and colleagues (2009) investigated 12 monoclonal antibodies and found that 
fixed and body size-based dosing perform similarly, with fixed dosing being better for 7 of 12 
antibodies.  In addition, they investigated 18 therapeutic proteins and peptides and showed that 
fixed dosing performed better for 12 of 18 in terms of reducing the between-patient variability in 
pharmacokinetic/pharmacodynamics parameters (Zhang et al., 2012).  A fixed dosing approach is 
preferred by the prescribing community due to ease of use and reduced dosing errors.  Given 

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expectation of similar pharmacokinetic exposure and variability, we considered it feasible to 
switch to fixed dosing regimens.  Based on average body WT of 75 kg, a fixed dose of 1500 mg 
Q28D durvalumab (MEDI4736) is included in the current study. 
 
2.2.3.3 
Clinical safety summary 
 
Risks with durvalumab (MEDI4736) include diarrhea, colitis, pneumonitis /ILD, 
endocrinopathies (hypo- and hyper-thyroidism, type I diabetes mellitus, diabetes insipidus, 
hypophysitis and adrenal insufficiency) hepatitis/hepatotoxicity/increases in transaminases, 
neurotoxicities, nephritis/increases in creatinine, pancreatitis, rash/pruritus/dermatitis, infusion-
related reactions, anaphylaxis, hypersensitivity or allergic reactions, immune complex disease, 
pemphigoid, myositis/polymyositis, and immune thrombocytopenia.  Further information on 
these risks can be found in the durvalumab (MEDI4736) Investigator’s Brochure (2021). 
 
In monotherapy clinical studies, AEs (all grades) reported very commonly (≥20% of patients) are 
fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back pain, 
pyrexia, abdominal pain, anemia, arthralgia, peripheral edema, headache, rash, and pruritus. 
Approximately 10% of patients experienced an AE that resulted in permanent discontinuation of 
durvalumab and approximately 5% of patients experienced an SAE that was considered to be 
related to durvalumab by the study investigator.  A detailed summary of durvalumab 
(MEDI4736) monotherapy AE data can be found in the current version of the  durvalumab 
(MEDI4736) Investigator’s Brochure (2021). 
 
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see the Dosing Modification and Toxicity 
Management Guidelines Table in Section 7.3). 
 
2.2.3.3.1 
AEs of special interest (AESI): 
 
The AESIs reported in durvalumab (MEDI4736) studies are defined as AEs that include, but are 
not limited to, events with a potential inflammatory or immune-mediated mechanism that may 
require more frequent monitoring and/or interventions such as corticosteroids, 
immunosuppressants, and/or endocrine therapy durvalumab (MEDI4736) Investigator’s 
Brochure, 2021).   
 
Early recognition of signs and symptoms potentially related to an inflammatory or immune-
mediated mechanism is important for proper management of toxicities (durvalumab 
[MEDI4736] Investigator’s Brochure, 2021).  For guidance on identifying, evaluating, and 
treating AESIs/inflammatory or immune mediated adverse events (imAEs), see the Toxicity 
Management Guidelines.  
 
AESI/imAEs observed with anti PD-L1/PD-1 agents such as durvalumab (MEDI4736) include 
pemphigoid, diabetes insipidus, encephalitis, subcutaneous injection site reaction, immune 
thrombocytopenia, pneumonitis, hepatitis, diarrhea/colitis and intestinal perforation, 
endocrinopathies (hypo- and hyper-thyroidism, adrenal insufficiency, 

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hypophysitis/hypopituitarism and Type 1 diabetes mellitus), nephritis, rash/dermatitis, 
pancreatitis, myocarditis, myositis/polymyositis and rare/less frequent imAEs including 
neuromuscular toxicities such as myasthenia gravis and Guillain-Barre syndrome. 
 
Other inflammatory responses that are rare with a potential immune-mediated etiology include, 
but are not limited to, pericarditis, sarcoidosis, uveitis and other events involving the eye, skin, 
hematological and rheumatological events.  It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all organs. 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs. 
 
The summary information for the AESIs below, unless stated otherwise, are based on the data 
cut off (DCO) of July 12, 2017. 
 
Pneumonitis 
 
Across the durvalumab (MEDI4736) monotherapy pooled dataset pneumonitis events observed 
(pneumonitis, interstitial lung disease [ILD], acute interstitial pneumonitis, and pulmonary 
fibrosis) were reported at a frequency rate of Common (98/1889; 5.2%).  Most were Grade 1 or 2 
in severity and most were reported as pneumonitis (88 patients [4.7%]).  CTCAE Grade 3 
pneumonitis was reported in 15 patients (0.8%); CTC Grade 4 in 1 patient (<0.1%) and CTC 
Grade 5 pneumonitis in 5 patients (0.3%).  CTCAE Grade 3 ILD (pneumonitis) has been 
reported from studies outside of the pooled dataset.  There were no CTCAE Grade 4 or 5 events 
of ILD. 
 
Presentations of pneumonitis can range from asymptomatic lung infiltrates to those that mimic 
severe bacterial pneumonia (Teply and Lipson, 2014).  Early consideration of pneumonitis 
should be realized when patients present with new onset or worsening of respiratory symptoms 
such as dyspnea or cough.  Prompt treatment with steroids is important as per current established 
Toxicity Management Guidelines. 
 
Hepatitis 
 
Immune-mediated hepatitis/hepatic toxicity is the inflammation of the liver.  Hepatic AEs 
induced by PD-1/PD-L1 inhibitors commonly present as asymptomatic increase of AST and 
alanine aminotransferase (ALT), rarely total bilirubin.  A proportion of patients may be 
presenting with fatigue, fever and radiologic appearances including hepatomegaly, periportal 
lymphadenopathy and periportal edema (Zhang et al., 2016). 
 
As a grouped term, selected hepatic events including laboratory abnormalities were reportedly 
12.0% (227 patients) across 1889 patients who have received durvalumab (MEDI4736) 
monotherapy 10 mg/kg Q2W.  Hepatitis events (autoimmune hepatitis, hepatitis toxic, 
hepatocellular injury, hepatotoxicity and hepatitis) were reported at a frequency rate of 
uncommon (14 patients; 0.7%).  Seven of the 14 events of hepatitis were Grade 3.  There were 
no Grade 4 events with the exception of hepatitis acute (1 patient) reported outside of the pooled 

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dataset.  One patient experienced a CTCAE Grade 5 event of autoimmune hepatitis.  Other 
AESIs such as hepatic failure (5 patients), jaundice (5 patients), hyperbilirubinemia (15 patients) 
and laboratory abnormality AESIs have been observed, 3 of which were CTCAE Grade 5 
(hepatic failure, hyperbilirubinemia and transaminases increased).   
 
Monitoring liver function tests while receiving study medication is important as hepatitis often 
manifests as asymptomatic elevated levels of hepatic transaminases [ALT, AST, and bilirubin] 
(Kim et al., 2013).  Prompt treatment with steroids is important. 
 
Colitis 
 
Diarrhea is the most frequent AESI reported across the phase 1 to phase 3 clinical studies with 
durvalumab (MEDI4736) monotherapy with a frequency of very common (329/1889; 17.4%) in 
patients receiving 10 mg/kg durvalumab (MEDI4736) IV Q2W.  Most of these were Grade 1.  
Treatment-emergent colitis-type AESIs were reported at a frequency of common (21 of 1889 
patients; 1.1%).  Most were Grade 2 or 3.  CTCAE Grade 4 colitis was reported in 1 patient 
(rare; <0.1%). 
 
Patients should be monitored for signs and symptoms of colitis or diarrhea.  Investigators are 
instructed to begin diarrhea management early to minimize the risk of colitis (Section 7.3).  
Early initiation of diarrhea treatment guidelines has been shown to reduce bowel perforation and 
colectomy rates, drug-related diarrhea, and serious gastrointestinal imAEs by up to 50% in 
patients treated with ipilimumab (Tarhini, 2013). 
 
Intestinal perforation 
 
Full thickness injury of the bowel wall and subsequent perforation of the gastrointestinal tract 
can be due to a variety of etiologies, commonly instrumentation, surgery, bowel injury, bowel 
obstruction, neoplasms (particularly colon carcinoma) and concomitant medications such as 
prolonged use of non-steroidal inflammatory drugs (NSAIDs).  Spontaneous perforation can be 
related to inflammatory changes or tissues weakened by medications or connective tissue 
disorders. 
 
Across the durvalumab (MEDI4736) monotherapy pool of studies, intestinal perforation was 
reported at a frequency rate of Uncommon (2/1889; 0.1%); Grades 2 and 4.  There were no 
Grade 5 events. 
 
Monitor for symptoms that may be related to bowel perforation such as sepsis, peritoneal signs, 
and ileus (Section 7.3).  Investigators should adhere to the overall management for immune-
mediated toxicities by performing a thorough evaluation to rule out alternative etiologies and by 
initiating prompt treatment including steroids. 
 
Endocrinopathies 
 
Immune-mediated endocrinopathy is the inflammation of any organ in the hypothalamic-
pituitary-adrenal axis, but is most typically reported to affect the pituitary, thyroid and/or adrenal 

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glands, leading to hypophysitis/hypopituitarism, thyroid dysfunction, and/or adrenal 
insufficiency (Teply and Lipson 2014).  The clinical presentation of immune-mediated 
endocrinopathies most often include hypothyroidism, hyperthyroidism, and nonspecific 
symptoms of headache and fatigue, but may also include myalgias, visual field defects, 
behavioral changes, electrolyte disturbances, loss of appetite and hypotension (Tarhini, 2013).  
Patients with endocrinopathies may present with abnormal endocrine laboratory test results 
including thyroid stimulation hormone (TSH), free thyroxine 4 (T4), total and free T3, cortisol, 
adrenocorticotrophic hormone, luteinizing hormone, follicle-stimulating hormone, and 
testosterone. 
 
Frequencies for immune-mediated endocrinopathy, as grouped terms of AESIs including 
laboratory abnormality AEs, are indicated in the table below. 
 
Endocrinopathy AESIs 
 
Endocrinopathy 
durvalumab (MEDI4736) 
monotherapy 
(10 mg/kg Q2W) 
(N=1889) 
durvalumab (MEDI4736) + 
tremelimumab 
(20 mg/kg Q4W and 1 mg/kg) 
(N=1088) 
Hypothyroidism a 
Very common 206 (10.9%) 
Very common 137 (12.6%) 
Hyperthyroidism a 
Common 135 (7.1%) 
Common 78 (7.2%) 
Adrenal insufficiency a 
Uncommon 13 (0.7%) 
Common 21 (1.9%) 
Hypophysitis/Hypopituitarism a 
Rare 1 (<0.1%) 
Uncommon 24 (0.4%) 
Type 1 diabetes mellitus 
Rare 1 (<0.1%) 
0 (0.0%) 
a 
Grouped term based on a number of individual MedDRA PTs. 
AESI  adverse event of special interest; MedDRA  Medical Dictionary for Regulatory Activities; N  total number of 
patients; PT  preferred term; Q2W  every 2 weeks; Q4W  every 4 weeks. 
 
Most endocrinopathy events reported were Grade 1 or 2.  In the monotherapy pool, Grade 3 
events consisted of adrenal insufficiency (2 patients), hypophysitis/hypopituitarism (1 patient), 
hyperthyroidism (1 patient) and hypothyroidism (2 patients).  There were no CTCAE Grade 4 or 
5 events.  In the combination, AESIs for hypothyroidism and hyperthyroidism (including 
laboratory abnormalities) were the most frequently observed events with frequency rates of Very 
common (12.6%) and Common (7.2%), respectively.  The severity of these events are 
predominantly Grades 1 and 2 with Grade 3 events observed with hyperthyroidism only (0.5%).  
Adrenal insufficiency was reported as mostly Grades 2/3 with 1 Grade 4 event and no Grade 5 
events.  Hypophysitis or hypopituitarism was reported as mostly Grade 3 with no Grade 4 or 5 
events. 
 
Across the monotherapy pool of studies, 1 patient (<0.1%) experienced Grade 3 Type 1 
diabetes mellitus 
 
Prompt recognition and management of endocrinopathies is important.  Refer to the 
endocrinology section of Section 7.3. 
 
Nephritis 
 

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The major clinical syndromes produced by immune-mediated renal injury include nephrotic 
syndrome, rapidly progressive glomerulonephritis, and acute renal failure (Cunard and Kelly, 
2003).  In association to immune-checkpoint inhibitors, two different forms of ipilimumab-
induced renal damage are reported, acute kidney injury due to predominant acute granulomatous 
tubulointerstitial nephritis and nephrotic syndrome in lupus nephritis (Izzedine et al., 2014).  
Signs and symptoms include increase in serum creatinine, decrease in urine output, peripheral 
edema, hematuria, loss of appetite.  
  
As a grouped term, selected renal events including laboratory abnormalities were reported at a 
frequency of 6.3% (119 patients) across the 1889 patients included in the durvalumab 
(MEDI4736) monotherapy pool.  Blood creatinine was the most common event reported 
(4.0%), of which the majority were Grade 1 or 2 in severity.  Nephritis events were reported at 
a frequency rate of Uncommon (6 patients [0.3%]) with 1 event each of Grade 2 autoimmune 
nephritis, glomerulonephritis, glomerulonephritis membranous, and nephritis and 2 
tubulointerstitial nephritis (Grade 2 and 3). 
 
Patients should be monitored for changes in renal function (e.g., that manifest as elevated serum 
blood urea nitrogen and creatinine, decreased creatinine CL, electrolyte imbalance, decrease in 
urine output, or proteinuria and any other findings that may be indicative of nephritis) prior to 
and periodically during treatment.  Prompt treatment with steroids is important. 
 
Rash/dermatitis 
 
Immune-mediated dermatitis is generally mild and presents as mild local or diffuse maculo-
papular, erythematous rash on the trunk or extremities, which may be accompanied by pruritus, 
alopecia, and vitiligo, suggestive of inflammatory response to melanocytes (Lacouture et al., 
2014).  In rare cases, severe dermatitis has been reported to manifest as Stevens-Johnson 
syndrome, toxic epidermal necrolysis, or rashes complicated by dermal ulceration or necrotic, 
bullous, or hemorrhagic manifestations (Tarhini, 2013; Kaehler et al., 2010).  
 
AESIs of rash (as a composite term) were reported as very common in 283 (15.0%) patients 
receiving durvalumab (MEDI4736) monotherapy and very common in 256 (23.5%) patients 
receiving the combination.  The majority of events were CTCAE Grade 1, with 11 and 7 
patients, respectively, experiencing CTCAE Grade 3 events. 
 
AESIs falling under the grouped term of dermatitis include milder events such as pruritus, 
eczema and erythema to more specific or severe skin toxicities such as events of dermatitis 
bullous, dermatitis exfoliative or dermatitis psoriasiform.  Overall, these events have been 
reported as very common (n=299; 15.8%) in monotherapy.  Most events were Grade 1, with 3 
patients experiencing Grade 3 events in the monotherapy.  
 
Close monitoring, early detection and prompt treatment with steroids (topical or systemic based 
on severity) is important.  Refer to the Toxicity Management Guidelines. 
 
Myocarditis 
 

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In the literature for other immune checkpoint inhibitors, a variety of clinical presentations, 
diagnostic evidence (laboratory, imaging, histopathology), and resulting diagnoses have been 
described in cases of myocarditis, including heart failure, brady- and tachyarrhythmias, and 
acute coronary syndrome-like presentations without evidence of ischemia.  Treatments are 
variable, and include immunosuppression and beta blockers, angiotensin converting enzyme 
(ACE) inhibitors, and diuretics.  Outcomes can range from rapid response and resolution with 
immunosuppression to fulminant, fatal events.  
 
Across the durvalumab (MEDI4736) monotherapy pool of studies, as of the data cut off of July 
12, 2017, there has been 1 SAE of Grade 3 myocarditis and 2 additional cases (Grade 3 and 
Grade 4) outside of the pooled dataset.  In all cases the patients recovered or were improving 
with corticosteroid therapy. 
 
Investigators should be aware of such rare, but severe immune-mediated adverse events 
including myocarditis with its presenting signs/symptoms (e.g., decreased ejection fraction, 
arrhythmias, in particular occurrences of atrioventricular block).  For patients with suspected 
myocarditis, investigators should obtain a cardiology consult and institute full diagnostic work-
up (that includes exclusion of other alternate causes such as infection) and the appropriate 
management that includes discontinuing drug (permanently if myocarditis is confirmed) and the 
prompt use of steroids or other immunosuppressives.  Patients with pre-existing cardiac 
disorders should be closely monitored for deterioration in their cardiac condition, which could 
suggest new onset myocarditis. 
 
Myositis/polymyositis 
 
The diagnosis of myositis or polymyositis should be suspected in patients who present with 
proximal muscle weakness and the evaluation should include an examination of the skin, muscle 
enzyme measurement, antibody testing, any systemic disease manifestations and exclusion of 
other diseases including drug-induced myopathy.  Cases of myositis have been reported with 
myocarditis in which immune infiltration has been described in skeletal and cardiac muscle 
(Johnson et al., 2016). 
 
In the durvalumab (MEDI4736) pool of studies as of the data cut off, 3 patients (0.2%) 
reported the event of myositis, including 1 Grade 3 in severity.  Outside of the pooled dataset, 
there were 2 fatal events of polymyositis considered as treatment-related by the Investigator. 
 
Investigators should adhere to the Toxicity Management Guidelines by performing a thorough 
evaluation to rule out alternative etiologies and initiating prompt treatment with steroids and 
modification of study drug dose regimen depending on the severity of the event.  Refer to 
Section 7.3. 
 
Pancreatitis  
 
Pancreatitis is an inflammatory condition of the pancreas that typically manifests initially as 
asymptomatic elevations of amylase and lipase in patients treated with immune checkpoint 
inhibitors.  Clinical presentation frequently includes low-grade abdominal pain with 

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accompanying fever and malaise (Weber et al., 2012, Di Giacomo et al., 2010).  Biopsies 
showed diffuse T-cell infiltrate consistent with immune-mediated pancreatitis (Weber et al., 
2012). 
 
Across the 1,889 patients in the monotherapy program, events of pancreatitis were uncommon to 
Rare.  Four patients (0.2%) experienced pancreatitis (Grade 2, Grade 3 and Grade 4 in severity) 
and 1 patient (<0.1%) with Grade 3 acute pancreatitis.  Elevations in amylase and lipase were 
reported as Uncommon (0.6% and 0.5%, respectively).   
 
Patients should be monitored for signs and symptoms of pancreatitis including Grade 3 or 4 
elevations in lipase and/or amylase.  Close monitoring, early detection and prompt treatment of 
these events are important.  Refer to Section 7.3. 
 
Other rare or less frequent AESIs and immune-mediated adverse events  
 
Events with an inflammatory or immune mediated mechanism could occur in nearly all organs.  
ImAEs that are less frequent with a potential immune-mediated etiology include, but are not 
limited to:  pericarditis, sarcoidosis, uveitis, and other events involving the eye (e.g., keratitis and 
optic neuritis), skin (e.g., scleroderma and vitiligo), hematological (e.g., hemolytic anemia and, 
immune thrombocytopenic purpura) and rheumatological events (polymyalgia rheumatic and 
autoimmune arthritis).  
 
Neuropathy/neuromuscular toxicities such as Guillain-Barre Syndrome and myasthenia gravis 
have also been observed.  One patient receiving durvalumab (MEDI4736) monotherapy outside 
of the pooled dataset experienced Grade 4 myasthenia gravis.   
 
Prompt treatment of these conditions as per Section 7.3 is required. 
 
Infusion-related reactions, anaphylaxis and allergic reactions 
 
Adverse reactions that occur during or shortly after infusion may include fever, chills, 
hypotension, dyspnea, tachycardia, cyanosis, respiratory failure, urticarial and pruritus, 
angioedema, hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, 
hypertension rash, headache, flushing, sweating, myalgia, nausea, vomiting, unresponsiveness, 
and hemodynamic instability.  The typical onset can be within 30 minutes to 2 hours after the 
initiation of drug infusion, although symptoms may be delayed for up to 24 hours.  The majority 
of reactions occur after the first or second exposure to the agent, but between 10% and 30% 
occur during subsequent treatments. 
 
Anaphylaxis is a systemic, immediate hypersensitivity reaction that is mediated by interactions 
between factors released from immunoglobulin E (IgE) and mast cells; these interactions result 
in an antigen-antibody reaction.  Clinical manifestations of acute allergic reactions may range 
from localized skin reactions at the injection site to AEs, which can include, but are not limited 
to, those events similar to infusion-related reactions to severe reactions including anaphylaxis 
and drug hypersensitivity syndromes.  These reactions may be more common with higher rates 
of infusion, and in patients with a history of allergies. 

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Across the durvalumab (MEDI4736) monotherapy and durvalumab (MEDI4736) + 
tremelimumab combination therapy program, 52 (2.8%) and 49 (4.5%) patients, respectively, 
have experienced either an infusion related reaction or hypersensitivity/anaphylactic reaction.  
The majority of events were Grade 1 or 2, with 5 patients experiencing a Grade 3 infusion 
related reaction, 1 patient with Grade 3 urticaria, and 1 patient with Grade 4 hypersensitivity (all 
receiving durvalumab [MEDI4736] monotherapy).  There have been no reported Grade 5 events 
as of the DCO. 
 
Patients participating in durvalumab (MEDI4736) clinical studies should be closely monitored 
during and after infusions.  Severe hypersensitivity reactions should be managed according to 
standard clinical practice, and medical equipment and staff trained to treat acute anaphylactic 
reactions must be immediately available at all sites that perform mAb infusions.  
 
Immune-complex disease 
 
The potential risk of immune complex disease for durvalumab (MEDI4736) is theoretical based 
on the known risk associated with mAbs and other proteins.  The incidence of durvalumab 
(MEDI4736) anti-drug antibodies (ADA)-positive patients in clinical studies is low, and hence 
the risk of immune complex disease is likely to be low.  Specifically, of 1124 patients treated 
with durvalumab (MEDI4736) 10 mg/kg Q2W and evaluable for the presence of ADAs, 3.3% of 
patients tested positive for treatment-emergent ADAs.  Neutralizing antibodies against 
durvalumab (MEDI4736) were detected in 0.3% of patients.  The presence of ADAs did not 
have a clinically relevant effect on PK.  There have been no reported events of immune complex 
reactions in patients receiving durvalumab (MEDI4736) monotherapy or in combination with 
tremelimumab.  
 
Considering the low incidence of immunogenicity of durvalumab (MEDI4736) and the lack of 
clinically apparent immune complex disease to date, samples for ADA monitoring may be 
collected in studies if clinical AEs consistent with immune complex disease are observed. 
 
For guidance on identifying, evaluating, and treating an imAE please see Section 7.3. 
 
2.2.3.3.2 
Infections 
 
In addition to infections determined as adverse drug reactions (ADRs), other infections are 
considered as potential risks based on the potential mechanism of action of checkpoint inhibitors. 
 
Serious and/or ≥Grade 3 infections requiring hospitalization including, but not limited to, sepsis, 
pneumonia, lung infections, have been reported in clinical studies with durvalumab 
(MEDI4736), but are often confounded by underlying disease and use of concomitant 
medications (e.g., steroids and other immunosuppressives).  As of the data cut off, events from 
the MedDRA Infections and Infestations system organ class (SOC), events with a severity 
≥Grade 3 and frequency of ≥1% in the monotherapy pool included lung infection (n=19; 1%), 
pneumonia (n=51; 2.7%), sepsis (n=35; 1.9%) and urinary tract infection (n=21; 1.1%).  Overall, 
CTCAE Grade 3 events were reported in 143 patients (7.6%), CTCAE Grade 4 events were 

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reported in 36 patients (1.9%) and CTC Grade 5 infection events in 18 patients (1.0%).   
 
Non-serious infections have been reported in clinical studies with durvalumab (MEDI4736).  Of 
the ADRs under the MedDRA Infections and Infestations SOC, events reported as non-serious 
only and with a frequency of >1% included nasopharyngitis (n=92; 4.9%), oral candidiasis 
(n=49; 2.6%), pharyngitis (n=20; 1.1%) and rhinitis (n=39; 2.1%).   
 
2.2.3.4 
FDA-approved indications 
 
Durvalumab (MEDI4736) (IMFINZITM) is indicated for the treatment of:  1) patients with locally 
advanced or metastatic urothelial carcinoma and 2) patients with unresectable, stage III non-
small cell lung cancer (NSCLC) (IMFINZI™ Package Insert, 2018). 
 
2.3 
Rationale 
 
There have been modest clinical effects observed so far in patients with advanced solid tumors 
with single agent PI3K inhibitors.  The clinical activity is certainly less than that seen with 
serine/threonine-protein kinase B-raf (BRAF), mitogen activated protein kinase (MEK), 
epidermal growth factor receptor (EGFR), and anaplastic lymphoma kinase (ALK) inhibitors in 
the corresponding vulnerable cancer genotypes.  It is therefore important that rational 
combinations of PI3K inhibitors are pursued to maximize the chances of revealing their full 
therapeutic potential in patients with advanced cancers.  Moreover, this is additionally important 
because the PI3K pathway is a common mechanism of resistance to multiple targeted agents, and 
conversely, resistance to PI3K inhibitors may also develop due to aberrant compensatory 
signaling through other pathways.  
 
An example of rational combination therapy is that of PI3K pathway inhibitors with PARP 
inhibitors, which lead to an accumulation of DNA SSBs and result in synthetic lethality with 
different molecularly-driven tumors, such as BRCA1/2 mutant cancers.  The initial rationale for 
this combination is based on preclinical findings of synergy between buparlisib and the PARP 
inhibitor olaparib (Ibrahim et al., 2012; Juvekar et al., 2017) (Figure 7).  The underlying 
mechanism by which buparlisib sensitizes to PARP inhibitors is not entirely clear, but has been 
linked to the capacity of buparlisib on its own to increase markers of DNA damage and to reduce 
expression of the BRCA1/2 DNA repair enzymes. 
 

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upregulation of PD-L1 expression (Parkes, et al., 2017). A group at MD Anderson Cancer Center 
has shown that PARP inhibition inactivates glycogen synthase kinase-3 beta (GSK3β), leading 
to PD-L1 upregulation, and in vivo synergy between olaparib and PD-1/PD-L1 inhibition (Jiao et 
al., 2017).  Multiple clinical trials assessing the combination of PARP inhibitors with PD-1/PD-
L1 inhibitors are currently underway.  For example, the combination olaparib and the PD-L1 
inhibitor durvalumab (MEDI4736) has been shown to be safe and well tolerated, with 
preliminary antitumor responses.  This combination is currently being assessed in the phase II 
MEDIOLA trial (Domchek et al., 2016). 
 
There is already strong evidence from similar combinations for the doublet combination of 
copanlisib + olaparib to be efficacious in DNA damage response (DDR)-associated cancers, such 
as ovarian cancer.  Preliminary results from a phase 1b trial involving a similar olaparib + PI3K 
inhibitor combination recently demonstrated an OR of 29% in patients without gBRCA1/2 
mutations with platinum-resistant ovarian cancers.  This is an area of great unmet need where 
this combination of copanlisib + olaparib may show great promise.  There are also other areas 
where this combination may show great potential; these include the indications where olaparib 
has demonstrated antitumor activity, such as BRCA1/2 mutant breast, castration-resistant 
prostate and pancreatic cancers, as well as other non-BRCA1/2-related, DDR-associated cancers, 
such as castration-resistant prostate cancers.  Prostate cancer has a high frequency of PTEN loss, 
and therefore the combination of copanlisib and olaparib would make rational sense in this tumor 
context.  The addition of durvalumab (MEDI4736) is expected to synergize with both copanlisib 
and olaparib, with an expectation of manageable toxicity in patients.  Apart from all the 
indications above, such a triplet combination would also have a role in PD-1/PD-L1 inhibitor 
resistant patients, which is an area of unmet clinical need as discussed above.  By testing this 
triplet combination in molecularly-selected cohorts of patients, we will be able to select the 
optimal patient population for such a regimen. 
 
In this study, we therefore propose the development of rational doublet and triplet copanlisib-
based combinations in patients with molecularly-selected advanced solid tumors.  This trial is 
geared to test both doublet and triplet combinations in patients with germline and also somatic 
DDR aberrations, as well as PIK3CA and PTEN abnormalities.  These studies will be biomarker 
driven, through the use of both tumor biopsies and circulating tumor DNA taken sequentially. 
 
2.4 
Correlative Studies Background 
 
2.4.1 Integral Studies 
 
In this molecular targeted therapy study, patient eligibility will be determined based upon the 
following criteria:  i) activating mutations within the oncogene PI3K,  ii) inactivating mutations 
within the tumor suppressor gene PTEN,  iii) mutations within the DDR genes associated with 
increased response to PARP inhibitors.  
 
2.4.1.1 
PIK3CA Mutations 
 
To be eligible for this study, patients must have advanced solid tumors, with mutations in the 
PIK3CA gene.  Hotspot mutations in PIK3CA to be considered include:  E542, E545, and 

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H1047.  PIK3CA mutational status will be determined prior to study initiation based on next 
generation sequencing (NGS) or equivalent clinical laboratory improvements amendment 
(CLIA)-certified assay.  All mutational variants will be assessed for actionability by the MD 
Anderson Precision Oncology Decision Support (PODS) team.  Clinical benefit in patients with 
advanced solid tumors with PIK3CA mutations will be assessed, as measured by ORR.  PIK3CA 
mutations result in aberrant activation of the PI3K/Akt cell signaling pathway, causing 
proliferative and cell survival advantages to tumor cells.  By specifically targeting PIK3CA 
mutations, we hope to induce significant anti-tumor responses in patients with cancers harboring 
these mutations. 
 
2.4.1.2 
PTEN Mutations 
 
To be eligible for this study, patients must have advanced solid cancers, with actionable 
mutations in the PTEN gene.  PTEN mutational status will be determined prior to study entry 
based on NGS or equivalent CLIA-certified assay.  All mutational variants will be assessed for 
actionability by the MD Anderson PODS team.  Clinical benefit in patients with advanced solid 
tumors with PTEN mutations will be assessed by objective response rate.  PTEN is an important 
cellular phosphatase that regulates PI3K/Akt signaling.  As a tumor suppressor, PTEN functions 
to limit the PI3K/Akt pathway and prevent uncontrolled cell growth.  Therefore, tumor cells with 
defects in PTEN exhibit constitutive activation of the PI3K/Akt pathway, and proliferative and 
survival advantages. 
 
2.4.1.3 
DDR Mutations 
 
To be eligible for this study, patients must have advanced solid cancers, which may have 
germline or somatic mutations in genes involved in DDR.  Eligible genes include:  BRAC1 
associated RING domain 1 (BARD1), BRCA1, BRCA2, BRCA1 interacting protein C-terminal 
helicase 1 (BRIP1), Fanconi anemia complementation group A (FANCA), Nibrin (NBN), partner 
and localizer of BRAC2 (PALB2), RAD51, RAD51B, RAD51C, and RAD51D.  Aberrations in 
DDR genes will be determined prior to study entry using NGS or CLIA-certified equivalent 
assay.  All mutational variants will be assessed for actionability by the MD Anderson PODS 
team.  Clinical benefit in patients with germline or somatic DDR aberrations will be assessed by 
objective response rate. Defects in the ability of the cell to respond to DNA insults allow tumor 
cells to bypass cell cycle and DNA repair checkpoints and continually replicate and accumulate 
further malignant changes that allow them to grow and survive. 
 
2.4.2 Integrated Studies 
 
2.4.2.1 
Reverse Phase Protein Array (RPPA) 
 
RPPA assay will be used to assess treatment induced changes in PI3K pathway signaling (e.g. 
phosphorylated Akt (pAkt), phosphorylated ribosomal protein S6 (pS6), phosphorylated 4E 
binding protein 1 (p4EBP1), and to correlate said changes with treatment response and 
progression; and to evaluate changes in signaling pathways that may be reflective of treatment 
resistance. 
 

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2.4.2.2 
Whole Exome Sequencing (WES) 
 
The molecular landscape of cancer is just beginning to be defined.  However, we do not know 
enough about the genomic and molecular landscape of tumors from patients who enter early 
phase clinical trials.  With this study, we will attempt to learn more about specific molecular 
features of cancers from this patient subgroup.  It is particularly important to learn, as early as 
possible, if there are molecular features within a particular malignant histology or across 
malignant histologies that can inform about potential response or resistance to treatments in early 
phase clinical trials.  Such knowledge will be used to design more efficient later stage clinical 
trials for more efficient and more effective drug development. 
 
Whole exome sequencing will be used to correlate single nucleotide variation (SNV) and copy 
number variation (CNV) profiles with treatment response.  We will also use WES data to assess 
the correlation between tumor mutational burden (TMB) and treatment response. 
 
2.4.2.3 
Pharmacokinetics  
Copanlisib clearance is dependent (~40%) on CYP3A4 metabolism. Copanlisib is a p-gp and 
BCRP substrate, and may inhibit pgp, BCRP, MATE2K and MATE1. 
Olaparib is a CYP3A4/5 substrate, inhibits CYP3A4, and induces CYP1A2, 2B6, and 3A4. 
Olaparib is also a Pgp substrate, and may inhibit OATP1B1, OCT1, OCT2, OAT3, MATE1 and 
MATE2K; and is a weak inhibitor of Pgp and BCRP. 
Because of the theoretical risk of PK interactions between copanlisib and olaparib, we will study 
the PK of copanlisib and olaparib in their combination and compare this with historical data. 
In addition, we will evaluate exposure response relationships for all 3 drugs with limited sampling. 
 
2.4.2.4 
Rationale for Copanlisib Combination Treatment  
 
PI3K inhibitors have an effect on lymphocyte recruitment and activation, maintenance of 
vascular integrity, and various other aspects of the tumor microenvironment, ultimately slowing 
tumor growth by inducing apoptosis and boosting tumor immune surveillance.  As PI3K 
inhibition has been shown to sensitize tumors to T cell mediated cytotoxicity, the combination of 
copanlisib, olaparib, and durvalumab (MEDI4736) is expected to result in clinical benefit by 
driving robust anti-tumor T-cell responses and promoting immune-mediated tumor cell death. 
 
2.4.3 Exploratory Studies  
2.4.3.1 
Immune Correlates 
 
We will determine the expression of immune related genes in tumor biopsies using multiplex 
immunofluorescence characterization of immune cell infiltrate and immune checkpoint proteins, 
immune gene expression signature analysis using Nanostring platform, as well as RNA-
sequencing (RNA-Seq) and T-cell Receptor sequencing (TCR-Seq).  Immune correlates in blood 
samples will be studied using flow cytometry to determine the proportion of different immune 
cells, cytokine analysis, and circulating tumor DNA (ctDNA) genotyping using targeted NGS. 
 
2.4.3.2 
RNA Sequencing (RNA-seq) 
 

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RNA sequencing analysis will be used to correlate gene expression profiles with treatment 
response and resistance. 
 
2.4.3.3 
Circulating Tumor DNA (ctDNA) Sequencing 
 
We will undertake targeted NGS analysis using serial samples of ctDNA collected at baseline 
and at different time points on treatment and chart the levels of targeted DNA anomalies over 
time in patients and correlate these with levels of tumor burden over time.  We will also correlate 
ctDNA mutation profiles with tumor sequencing, assess changes in ctDNA mutations 
(particularly in DDR or PI3K pathway genes) during treatment, correlate changes in ctDNA 
variant allele frequencies with response, and assess emergent resistant mutations at progression 
(e.g., BRCA reversions).  Additionally, we will identify new resistance mechanisms by assessing 
ctDNA levels in long term responding patients who have developed disease progression. 
 
3. 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria for enrollment into Steps 1, 2, and 3 
 
3.1.1 Patients must have germline or somatic mutations in DDR genes: BARD1, BRCA1, 
BRCA2, BRIP1, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D; or 
actionable mutations in the PTEN gene, or hotspot mutations in the PIK3CA gene (E542, 
E545 or H1047 are accepted).  Local testing in CLIA-certified laboratory will be 
accepted. Only mutations that have been recognized as actionable by the MD Anderson 
PODS team will be accepted. 
 
3.1.2 Patients must have histologically confirmed malignancy that is metastatic or unresectable 
and for which standard curative or palliative measures do not exist or are no longer 
effective.   
 
3.1.3 Patients must have measurable disease by RECIST 1.1. 
 
3.1.4 Patients must be ≥3 weeks beyond treatment with any chemotherapy or ≥4 weeks beyond 
treatment with other investigational therapy to include hormonal, biological, or targeted 
agents; or at least 5 half-lives from hormonal, biological, or targeted agents, whichever is 
shorter at the time of treatment initiation. 
 
3.1.5 Age ≥18 years.  Because no dosing or AE data are currently available on the use of 
copanlisib in combination with olaparib ± durvalumab (MEDI4736) in patients <18 years 
of age, children are excluded from this study, but will be eligible for future pediatric 
trials. 
 
3.1.6 Patients with a mutation within both the DDR and PTEN/PIK3CA pathways will be 
assessed by the genomics Precision Oncology Decision Support group at MD Anderson, 
and the patient will be allocated to the PI3K or DDR expansion group deemed to be the 
main driver.  If the actionability between the groups is deemed to be equivocal, then the 

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patient will be allocated to the expansion cohort with fewer patients. 
 
3.1.7 ECOG performance status (PS) ≤1 (Karnofsky ≥60%, see Appendix A).  
 
3.1.8 Patients must have normal organ and marrow function as defined below: 
 
− 
hemoglobin 
 
≥10 g/dL with no blood transfusion in the past 28 
days 
− 
leukocytes  
 
≥3,000/mcL 
− 
lipase    
 
 
 
 
≤1.5 x upper limit of normal (ULN) 
− 
absolute neutrophil count 
 
≥1,500/mcL 
− 
platelets  
 
≥140,000/mcL 
− 
total bilirubin 
 
≤1.5 × institutional ULN 
− 
serum bilirubin 
 
≤1.5 × institutional ULN 
− 
AST(SGOT)/ALT(SGPT) 
 
≤2.5 × institutional ULN, unless liver metastases 
are present in which case they must be ≤5 × ULN 
− 
Activated partial thrombin time ≤1.5 x ULN unless subject is receiving 
anticoagulant therapy as long as prothrombin time 
(PT) or partial thromboplastin time (PTT) is within 
the therapeutic range of intended use of 
anticoagulants 
− 
International normalized ratio  
≤1.5 × ULN 
 
 
− 
glomerular filtration rate (GFR) ≥51 mL/min, based on a 24-hour urine test for 
creatinine clearance or estimated using the 
Cockcroft-Gault equation of: 
Estimated GFR = (140-age [years]) × weight (kg)   (× F)a 
serum creatinine (mg/dL) × 72 
 
a where F=0.85 for females and F=1 for males. 
 
3.1.9 Left ventricular ejection fraction (LVEF) ≥50%. 
 
3.1.10 Patients who are therapeutically treated with an agent such as warfarin or heparin will be 
allowed to participate provided that their medication dose and international normalized 
ratio (INR)/PTT is stable. 
 
3.1.11 Prophylactic antiemetics may be administered according to standard practice.  The 
routine use of standard antiemetics, including 5-Hydroxytryptamine type 3 (5-HT3) 
blockers, such as granisetron, ondansetron, or an equivalent agent, is allowed as needed.  
The use of corticosteroids as antiemetics prior to copanlisib administration will not be 
allowed. 
 
3.1.12 Postmenopausal or evidence of non-childbearing status, a negative urine or serum 
pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 

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1.  Postmenopausal is defined as: 
• Amenorrheic for 1 year or more following cessation of exogenous hormonal 
treatments 
• Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the 
postmenopausal range for women under 50 
• radiation-induced oophorectomy with last menses >1 year ago 
• chemotherapy-induced menopause with >1-year interval since last menses 
• surgical sterilization (bilateral oophorectomy or hysterectomy) 
 
3.1.13 Women of child-bearing potential MUST have a negative serum or urine human 
chorionic gonadotropin (HCG) test unless prior tubal ligation (>/= 1 year before 
screening), total hysterectomy or menopause (defined as 12 consecutive months of 
amenorrhea).  Patients should not become pregnant or breastfeed while on this study. 
 
3.1.14 Patients and their partners, if sexually active and of childbearing potential, must agree to 
the use of two highly effective forms of contraception in combination throughout the 
period of taking study treatment and for 6 months after last dose of study drug(s) to 
prevent pregnancy in the study patient or partner.  Male patients should avoid donating 
sperm for 3 months following the last dose of olaparib. 
 
3.1.15 Human Immunodeficiency Virus (HIV)-infected (HIV1/2 antibody-positive; HIV testing 
pre-study not required) patients may participate IF they meet all the following eligibility 
requirements:   
• They must be on an anti-retroviral regimen with evidence of at least two undetectable 
viral loads within the past 6 months on this same regimen; the most recent undetectable 
viral load must be within the past 12 weeks. 
• They must have a CD4 count ≥250 cells/mcL over the past 6 months on this same anti-
retroviral regimen and must not have had a CD4 count <200 cells/ mcL over the past 2 
years, unless it was deemed related to the cancer and/or chemotherapy-induced bone 
marrow suppression.  
o For patients who have received chemotherapy in the past 6 months, a CD4 count 
<250 cells/mcL during chemotherapy is permitted as long as viral loads were 
undetectable during this same chemotherapy. 
• They must have an undetectable viral load and a CD4 count ≥250 cells/mcL within 7 
days of enrolment. 
• They must not be currently receiving prophylactic therapy for an opportunistic infection 
and must not have had an opportunistic infection within the past 6 months.  
 
3.1.16 Ability to understand and the willingness to sign a written informed consent document.  
Patients with impaired decision-making capacity (IDMC) must have a legally authorized 
representative or caregiver who gives such consent. 
 
3.1.17 Patient is willing and able to comply with the protocol for the duration of the study, 
including undergoing treatment and scheduled visits and examinations. 
 
 

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3.1.18 Patients with a tumor that is readily accessible for biopsy. 
 
 
3.2 
Eligibility Criteria for enrollment into Step 2 and 3 only 
 
3.2.1 Body weight >30 kg. 
 
3.2.2 Life expectancy ≥16 weeks.  
 
3.3 
Exclusion Criteria for Steps 1, 2, and 3 
 
3.3.1 Persistent toxicities (>CTCAE Grade 2) caused by previous cancer therapy, excluding 
alopecia. 
 
3.3.2 Patients receiving any systemic chemotherapy or radiotherapy (except for palliative 
reasons) within 3 weeks prior to study treatment. 
 
3.3.3 Major surgery within 2 weeks of starting study treatment and patients must have 
recovered from any effects of any major surgery. 
 
3.3.4 Patients who are receiving any other investigational agents. 
 
3.3.5 Other malignancy unless curatively treated with no evidence of disease for ≥5 years 
except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of 
the cervix, ductal carcinoma in situ (DCIS), or Stage 1, grade 1 endometrial carcinoma.  
A patient with a history of localized triple negative breast cancer may be eligible, 
provided the patient completed the adjuvant chemotherapy >3 years prior to registration, 
and the patient remains free of recurrent or metastatic disease.  
 
3.3.6 Patients with MDS/AML or with bone marrow findings consistent with MDS/AML.   
 
3.3.7 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to olaparib, copanlisib, PI3K inhibitors or durvalumab (MEDI4736 or any of 
the excipients of any study products. 
 
3.3.8 Concomitant use of strong CYP3A inhibitors and inducers.   
Olaparib:  Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, 
telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, 
indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors 
(e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil).  The required 
washout period for strong or moderate CYP3A inhibitors prior to starting olaparib is 2 
weeks. 
 
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 

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medications need to be prescribed or if the patient is considering a new over-the-counter 
medicine or herbal product (Please refer to Appendix D).  
 
Concomitant use of known strong CYP3A inducers (e.g., phenobarbital, enzalutamide, 
phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or 
moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil).  The required washout period 
for strong or moderate CYP3A inducers prior to starting olaparib is 5 weeks for enzalutamide or 
phenobarbital and 3 weeks for other agents (Please refer to Appendix D). 
 
Copanlisib:  Copanlisib is primarily metabolized by CYP3A4.  Therefore, the concomitant use of 
strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, 
indinavir, nelfinavir and saquinavir), and strong inducers of CYP3A4 (e.g. rifampin, phenytoin, 
carbamazepine, phenobarbital, St. John’s Wort) are not permitted from 14 days prior to 
enrollment until the end of the study.   
 
Other medications that are prohibited while on copanlisib treatment:  
1. Herbal medications/preparations (except for vitamins) 
2. Anti-arrhythmic therapy other than beta blockers or digoxin 
 
For the list of specific medications prohibited while on copanlisib treatment refer to the 
Appendix B-List of Prohibited Meds.  Because the lists of these agents are constantly changing, 
it is important to regularly consult a frequently-updated medical reference for a list of drugs to 
avoid or minimize use of.  Appendix C should be provided to patients.  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. 
 
3.3.9 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
uncontrolled major seizure disorder, unstable spinal cord compression, superior vena 
cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed 
Tomography (HRCT) scan, symptomatic congestive heart failure, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.3.10 Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac 
conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled 
symptomatic arrhythmia, congestive heart failure, QT corrected by the Fridericia formula 
[QTcF] prolongation of >500 msec, electrolyte disturbances), or patients with congenital 
long QT syndrome. 
 
3.3.11 Women who are breast feeding or pregnant are excluded from this study because olaparib 
is a PARP inhibitor with the potential for teratogenic or abortifacient effects.  Because 
there is an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with olaparib, breastfeeding should be discontinued if the mother 
is treated with olaparib and copanlisib ± durvalumab (MEDI4736).   
 
3.3.12 Previous allogenic bone marrow transplant or double umbilical cord blood transplantation 

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(dUCBT). 
 
3.3.13 Packed red blood cell or platelet transfusion in the last 28 days prior to study entry. 
 
3.3.14 Whole blood transfusions in the last 120 days prior to study entry.  Whole blood 
transfusions performed within 120 days of study entry may interfere with blood samples 
taken for exploratory analysis. 
 
3.3.15 Patients should be excluded if they have a condition requiring systemic treatment with 
either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive 
medications within 14 days of study drug administration.  However, systemic 
corticosteroids may be indicated after starting the study drugs to treat immune-related 
adverse reactions.  Inhaled or topical steroids and adrenal replacement doses ≤ 10 mg 
daily prednisone equivalents are permitted in the absence of active autoimmune disease. 
 
3.3.16 Patients with non-healing wound, ulcer, or bone fracture. 
 
 
3.3.17 Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism 
within 6 months before the start of study medication 
 
3.3.18 Patients with active, clinically serious infections > Grade 2 (CTCAEv5.0).  Active 
infection including tuberculosis (clinical evaluation that includes clinical history, physical 
examination and radiographic findings, and TB testing in line with local practice), 
hepatitis B (known positive HBV surface antigen (HBsAg) result), or hepatitis C.  
Patients with a past or resolved HBV infection (defined as the presence of hepatitis B 
core antibody [anti-HBc] and absence of HBsAg) are eligible.  Patients positive for 
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for 
HCV RNA.  HBV/HCV screening is required 28 days prior to starting the study drug 
using a routine hepatitis virus lab panel.  
 
3.3.19 Active infection requiring IV antibiotics or other uncontrolled intercurrent illness 
requiring hospitalization. 
 
3.3.20 Patients unable to swallow orally administered medication and any medical condition or 
diagnosis that would likely impair absorption of an orally administered drug (e.g. 
gastrectomy, ileal bypass, chronic diarrhea, gastroparesis). 
 
3.3.21 Known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 
3.3.22 Known active CNS metastases and/or carcinomatous meningitis.  Subjects with 
previously treated brain metastases may participate provided they are stable (without 
evidence of progression by imaging for at least four weeks prior to the first dose of trial 
treatment and any neurologic symptoms have returned to baseline), have no evidence of 

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new or enlarging brain metastases, and are not using steroids for at least 7 days prior to 
trial treatment.  This exception does not include carcinomatous meningitis which is 
excluded regardless of clinical stability. 
 
3.3.23 New York Heart Association class III or IV heart disease. 
 
3.3.24 History or concurrent interstitial lung disease of any severity and/or severely impaired 
lung function (as judged by the investigator). 
 
3.3.25 Uncontrolled arterial hypertension despite optimal medical management (per 
investigator’s opinion).  
 
3.3.26 Patients with uncontrolled Type I or II diabetes mellitus, defined as fasting blood  
glucose ˃160 mg/dL and HbA1c ˃8%, are ineligible. 
 
3.4 
Exclusion Criteria for Steps 2 and 3 only 
 
3.4.1 Patients who have not recovered from Grade ≥2 adverse events due to prior anti-cancer 
therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the 
inclusion criteria. 
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Physician. 
 
3.4.2 Major surgical procedure (as defined by the Investigator) within 28 days prior to the first 
dose of IP.  Note:  Local surgery of isolated lesions for palliative intent is acceptable. 
 
3.4.3 Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g., colitis or Crohn’s disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion: 
• Patients with vitiligo or alopecia. 
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement. 
• Any chronic skin condition that does not require systemic therapy. 
• Patients without active disease in the last 5 years may be included but only after 
consultation with the Study Physician. 
• Patients with celiac disease controlled by diet alone. 
 
3.4.4 Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.  Note:  
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days 
after the last dose of IP. 
 
3.4.5 Patients with unstable angina pectoris. 
 

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3.4.6 Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4:   
• Must not have experienced a toxicity that led to permanent discontinuation of prior 
immunotherapy.  All AEs while receiving prior immunotherapy must have 
completely resolved or resolved to baseline prior to screening for this study. 
• Must not have experienced a Grade ≥3 immune-related AE or an immune-related 
neurologic or ocular AE of any grade while receiving prior immunotherapy.  Note:  
Patients with an endocrine AE of Grade ≤2 are permitted to enroll if they are stably 
maintained on appropriate replacement therapy and are asymptomatic. 
• Must not have required the use of additional immunosuppression other than 
corticosteroids for the management of an AE, not have experienced recurrence of an 
AE if re-challenged, and not currently require maintenance doses of >10 mg 
prednisone or equivalent per day. 
 
3.4.7 Live vaccination, including virus vaccination and yellow fever vaccination, within 6 
months before start of study treatment. 
 
3.4.8 Cytomegalovirus (CMV) infection.  Patients who are known to be CMV PCR positive at 
baseline will not be eligible. 
 
3.5 
Inclusion of Women and Minorities 
 
The National Institutes of Health (NIH) policy requires that women and members of minority 
groups and their subpopulations be included in all NIH-supported biomedical and behavioral 
research projects involving NIH-defined clinical research unless a clear and compelling rationale 
and justification establishes to the satisfaction of the funding Institute & Center (IC) Director that 
inclusion is inappropriate with respect to the health of the subjects or the purpose of the research.  
Exclusion under other circumstances must be designated by the Director, NIH, upon the 
recommendation of an IC Director based on a compelling rationale and justification.  Cost is not 
an acceptable reason for exclusion except when the study would duplicate data from other 
sources.  Women of childbearing potential should not be routinely excluded from participation in 
clinical research.  Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 
4. 
REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations require sponsors to select qualified 
investigators. National Cancer Institute (NCI) policy requires all individuals contributing to NCI-
sponsored trials to register with their qualifications and credentials and to renew their registration 
annually.  To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) 
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) at https://ctepcore.nci.nih.gov/rcr/.  
The RCR is a self-service online person registration application with electronic signature and 
document submission capability.  

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please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval 
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet (SSW) for Local Context to the CIRB using IRBManager to indicate 
their intent to open the study locally.  The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network.  Site preferences can be set at the network 
or protocol level.  Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following criteria for the site to be able to have an Approved status following processing of the 
IRB/REB approval record: 
• Have an Active CTEP status, 
• Have an active status at the site(s) on the IRB/REB approval (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, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile,  
• Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• Have the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
Additional site requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO),  
• An active roster affiliation with the NCI CIRB roster under at least one CIRB Signatory 
Institution (US sites only); and 
• Compliance with all applicable protocol-specific requirements (PSRs). 
 
 
 
 
 

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4.2.1 Downloading Site Registration Documents 
 
Download site registration forms from the protocol-specific page located on the CTSU members’ 
website.  Permission to view and download this protocol and its supporting documents is 
restricted to institutions and their associated investigators and staff on a participating roster. To 
view/download site registration forms: 
 
• Log on to the CTSU members’ website (https://www.ctsu.org) 
• Click on Protocols in the upper left of your screen.  
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-TX035 and 
protocol 10217. 
▪ Click on Documents, Protocol Related Documents, and use the Document Type filter and 
select Site Registration, to download and complete the forms provided.  (Note: For sites 
under the CIRB, IRB data will load automatically to the CTSU) 
 
4.2.2 Requirements For 10217 Site Registration 
 
• Specimen Tracking System Training Requirement: 
 
o All data entry users (Clinical Research Associate role) at each participating 
site will need to complete the Theradex-led training 
o Theradex will provide a certificate of completion, which will need to be 
submitted to the CTSU through the Regulatory Submission Portal 
The training is a one-time only requirement per individual. If an individual 
has previously completed the training for another ETCTN study, the training 
does not need to be completed again nor does the certificate of completion 
need to be resubmitted to the CTSU.  Users are strongly encouraged to take a 
refresher of the training if they have not entered specimen data for an 
extended period of time. 
o This training will need to be completed before the first patient enrollment at a 
given site 
o Please contact STS Support at Theradex for the training 
(STS.Support@theradex.com). 
 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office via 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 

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alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to receive further instruction and support. 
 
4.2.4 Checking Site Registration Status 
 
Site’s registration status may be verified on the CTSU members’ website. 
 
• Click on Regulatory at the top of your screen. 
• Click on Site Registration, and 
• Enter your 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
 
Note:  The status given only reflects institutional compliance with site registration requirements 
as outlined above.  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. 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
to users 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 patients or request slot reservations:  Must be on an LPO roster, 
ETCTN Corresponding roster, or PO roster with the role of Registrar.  Registrars must 
hold a minimum of an Associate Plus (AP) registration type.   
 
Have an approved site registration for a protocol prior to patient enrollment.  
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in 
OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR.  If a DTL is required for the study, the IVR or NPIVR must be 
assigned the appropriate OPEN-related tasks on the DTL. 

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Prior to accessing OPEN, site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  IWRS system also sends an email confirmation of the registration. You 
may print this confirmation for your records.   
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website.  
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with patient enrollment in OPEN.  Prior to discussing protocol entry with the patient, 
all site staff must use the CTSU OPEN Slot Reservation System to ensure that a slot on the 
protocol is available to the patient.  Once a slot reservation confirmation is obtained, site staff 
may then proceed to enroll the patient to this study.  
 
4.3.2 Special Instructions for Patient Enrollment  
 
Results from previous NGS or an equivalent local CLIA-certified assay will be used to 
molecularly stratify patients after all selected alterations are reviewed by MD Anderson’s 
Precision Oncology Decision Support (PODS) team prior to enrolling patients to this study in 
OPEN. A  de-identified NGS or CLIA-certified assay report that includes the mutation of interest 
will be sent by email to the PODS team (emailpct@mdanderson.org) at MD Anderson for 
actionability review. PODS will annotate whether the mutation identified is actionable and will 
send a response via email. For sites outside of MD Anderson, include the following details when 
emailing the PODS team: reference the NCI 10217 study number, the designated ETCTN site 
number of the site submitting the request, and a subject identification number. If a subject 
identification number is not available for this study, a temporary identification number should be 
submitted in the following format: ETCTN site number–patient date of birth (for example: 
TX035–MMDDYYYY), which is assigned and tracked by the submitting ETCTN site. Do not 
submit medical record numbers or any protected health information. 
 
Notify the lead site of any screen failures. Ensure that all patients who sign consent and 
subsequently screen fail are registered in OPEN as a screen failure and have data entered in the 
NCI’s clinical data management system, Medidata Rave. Sites cannot replace patients who 
screen fail using the slot originally designated to the screen failed patient. An additional slot 
must be requested and approved for all subsequent patients planned to sign consent and enroll on 
the study. 
 
This Study will use the ETCTN Specimen Tracking System (STS).  
• All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted.   

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• The system is accessed through special Rave user roles:  “Rave CRA” and “Rave CRA 
(Labadmin)” for data entry at the treating institutions and “Biorepository” for users 
receiving the specimens for processing and storage at reference labs and the NCI Early-
Phase and Experimental Clinical Trials Biospecimen Bank (EET Biobank, formerly 
known as the ETCTN Biorepository). 
• Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website in the Data Management section under the Rave Home tab and then 
under Rave Resource Materials.  
• Important:  Failure to complete required fields in STS may result in a delay in 
sample processing.  Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
 
Detailed instructions can be found in Section 4.5.4. 
 
4.3.3 OPEN/IWRS Questions? 
 
4.3.3.1 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional 
questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website:  http://www.theradex.com/clinicalTechnologies/?National-
Cancer-Institute-NCI-11.  This link to the Theradex website is also on the CTSU website OPEN 
tab.  For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk at 
855-828-6113 or Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 8 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
5.1 
Summary Table for Specimen Collection 
 
Note:  All blood collections are mandatory.  Tumor biopsy at baseline is mandatory.  Tumor 
biopsy at Cycle 1 Day 15 is mandatory.  Tumor biopsies at Cycle 2 and Cycle 24 (or disease 
progression, whichever comes first) are optional.  Tumor biopsies at Cycle 2, Day 15 are only for 
the Triplet Combination.  See Appendix I for further details on PK analysis of olaparib (O), 
copanlisib (C), and durvalumab (D). 
 
No PK collection will be performed on patients treated in Step 3 expansion cohorts.  

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be shipped on the same day of collection. 
• Tissue in formalin can be collected Monday through Wednesday and shipped overnight 
for arrival on Tuesday through Thursday at the EET Biobank at Nationwide Children’s 
Hospital. 
• Snap-frozen specimens/surgical resections may be shipped in a provided dry shipper or 
on dry ice on the same day of collection.  Tissue can be collected Monday through 
Thursday (FedEx Priority Overnight). 
• Fresh blood specimens may be collected and shipped Monday through Friday.  
 
 
5.2.3 Scheduling of Specimen Collections for UPMC Hillman Cancer Center (Jan Beumer) 
Blood samples will be collected at the timepoints specified in Section 5.1.  Frozen plasma and 
serum will be shipped overnight on either Monday, Tuesday, or Wednesday (and not before a 
federal or university holiday) to Dr. Beumer’s Laboratory at UPMC Hillman Cancer Center. 
 
5.3 
Specimen Collection 
 
5.3.1 Core Needle Biopsy (CNB) and Other Small Biopsy Specimens  
 
A maximum number of 3 cores (1 cm in length) or small biopsies (3 mm diameter) will be 
obtained from the procedure.  The number of specimens obtained will be affected by the 
patient’s clinical condition at the time of biopsy and determined by the specialist performing the 
procedure.  Core biopsy should be performed using a 16-18-gauge needle, condition permitting.   
• At least 2 cores (1 cm in length) or small biopsies (3 mm diameter) should be obtained 
for nucleic acid analysis.  At least 1 core (1 cm in length) or small biopsy (3 mm 
diameter) should be obtained for analysis at the MD Anderson RPPA Core Laboratory. 
• Alternating passes: First obtain a core for FFPE processing (core 1 is for WES), followed 
by a core for flash freezing (core 2 is for RPPA), followed by a core for FFPE (core 3 is 
for RNASeq). 
 
5.3.2 Collection of Frozen Biopsies 
 
Flash Freezing of Core Needle Biopsy and Surgical Resection Samples 
 
1. Arrive at the biopsy collection site early enough to allow sufficient time to set up 
laboratory supplies, collect relevant clinical information, and ensure rapid transport of 
specimens to the laboratory for placement at -80ºC (or lower) after collection.  
2. Bring all necessary lab supplies including: disposable tweezers, a minimum of two 1.5-
mL Sarstedt tubes (one for each whole biopsy core) pre-cooled on liquid nitrogen or dry 
ice/ethanol in an insulated bucket, and one pre-printed specimen label (see Section 
5.4.1.1) to give to the research nurse for the patient record. 
Note:  Pre-chill additional 1.5-mL Sarstedt tubes for specimen collection in case the 
interventional radiologist collects additional passes, or one of the other tubes is 
compromised prior to collection. 
3. The total time elapsed between biopsy collection and placement into the pre-chilled tube 
is of key importance to biomarker analysis; biopsies should be frozen within 2 min of 

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collection.  The interventional radiologist will eject the biopsy onto a sterile slide (for 
optimal analyte recovery the slide should be pre-chilled).  Start a stop watch (or note the 
time) at this point (Appendix E, Biopsy Collection) and immediately walk the slide to the 
sample preparation table.  
Note:  The preferred method of collection, when whole biopsies are collected, is for the 
interventional radiologist to eject the biopsy directly into the pre-chilled tube (next step). 
This minimizes the time between collection and fixation of analytes. 
4. Indicate if a full or halved biopsy is prepared in the Batch Record (Appendix E, Biopsy 
Collection).  
a. For whole biopsies:  Uncap an empty, prechilled 1.5-mL Sarstedt tube and using 
disposable tweezers, pick up the freshly collected needle biopsy with the tweezers 
at one end, and touch the opposite end of the biopsy to the inner surface of the 
prechilled 1.5-mL Sarstedt tube.  This should attach the tissue to the tube, 
allowing it to be dropped into the tube while releasing the tissue from the 
tweezers without sticking.  Dispose of the tweezers in the appropriate 
biohazardous waste container(s).  
b. For halved biopsies:  Use 1-2 disposable tweezers and cut/shear the biopsy in half 
cross-wise while it is on the slide (do not pull or stretch the biopsy 
longitudinally).  Use the tweezers to transfer the halved biopsies to sterile pre-
chilled tubes as indicated above.  
5. Immediately snap freeze the biopsy by placing the tube in liquid nitrogen or a dry 
ice/ethanol bath. 
6. Calculate the total time elapsed from biopsy collection to biopsy freezing and record the 
total number of minutes and seconds elapsed in the Batch Record (Appendix E, Biopsy 
Collection). 
7. If biopsy procedure details can be obtained from the interventional radiologist or research 
nurse, record them in the Batch Record (Appendix E, Biopsy Procedure Details).  Some 
information may not be available until a later time from the clinical staff. 
8. Transfer the frozen biopsy specimen(s) to -80ºC (or lower) for storage until shipment to 
the EET Biobank.  Record the date and time specimens are placed at -80ºC (or lower; 
Appendix E, Biopsy Storage). 
9. Review and finalize the Batch Record and document ANY and ALL deviations in the 
Batch Record (Appendix E, Notes). 
10. The appropriate laboratory personnel should review the Batch Record and sign to affirm 
the data contained within are correct (Appendix E, Review of Batch Record). 
 
5.3.3 Formalin-Fixed Tumor Biopsies  
 
1. Label formalin-filled containers according to instructions in Section 5.4.1.  
2. Obtain 2, 16-gauge or 18-gauge core needle biopsy specimens, and place one core in each 
cassette.  
3. Snap the cassette lids closed and place cassettes into a formalin-filled pre-labeled 
container as soon as possible after collection to prevent air drying.  Up to two cassettes 
may be placed in one formalin jar. 
4. Secure the container lids and package containers into the shipping kit according to 
instructions in Section 5.5.  Keep tissue in formalin jars at room temperature until 

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shipment to the EET Biobank 
 
5.3.4 Archival FFPE Tissues 
 
Even when patients are able to provide a biopsy/resection specimen, a prior (archived) 
representative tumor tissue block may be requested.  If previously-collected FFPE will be 
submitted, then the following criteria must be met: 
 
• Tissue should ideally have been collected within 6 months prior to registration.  Older 
archival material is acceptable unless otherwise specified by individual protocols.   
• A copy of the original pathology report must be provided, and the tissue collection date 
must be recorded so the sample age can be derived. 
• Formalin-fixed paraffin-embedded tumor tissue block(s) must be used to cut fresh 
unstained slides.  The optimal block is at least 30% tumor, however less tumor content is 
acceptable.  Preferred specimen size requirement is as follows: 
o Surface area:  25 mm2 is optimal.  Minimum is 5 mm2. 
o Volume:  1 mm3 optimal.  Minimum volume is 0.2 mm3 
 
If the archival block cannot be submitted, the following can be provided 
• Two (first and last cut) sectioned H&E slides (minimum of one is required), AND;  
• Fifteen to twenty (or other number specified by each correlative study) 4 µm unstained 
air-dried plus slides. 
 
5.3.5 Blood Collection and Processing 
 
5.3.5.1 
Streck Cell-Free DNA Tube (10 mL) 
 
• Label two 10 mL Streck cfDNA BCTs (Streck catalog # 218961, 218962, or 218992), as 
described in Section 5.4.  
• Collect 10 mL of blood into each pre-labeled tube and invert to mix.  Note: blood must 
be thoroughly mixed to ensure preservation of specimen. 
• After collection, blood in cfDNA Streck BCT should never be refrigerated, as this will 
compromise the specimen.  Blood collected in cfDNA Streck Tubes is stable at room 
temperature.  
 
5.3.5.2 
EDTA Purple-Top Vacutainer Tube for Plasma (for Beumer PK laboratory at UPMC 
Hillman Cancer Center) 
General 
Blood samples to be obtained through a peripheral or central line blood draw.  Samples should 
be drawn from the opposite arm if infusion is a peripheral infusion.  Samples should NOT be 
drawn from the infusion line. 
 

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Drawing and Processing 
Document exact start and stop times of each infusion and exact times of blood draws per 
Appendix K or L, respectively. 
1. Collect in a 3 or 4 mL purple top tube (e.g. BD vacutainer 367861 plastic 13 x 75 4 mL 
tube). 
2. Invert the vacutainer tubes several times to mix blood with EDTA anticoagulant and 
immediately place on ice. 
3. Processing should begin within 30 minutes of collection. 
4. Samples should be centrifuged for 10 min at approximately 1000 x g in a refrigerated 
tabletop centrifuge so as to produce plasma. 
5. The resulting plasma should be aspirated from the tubes, placed into appropriately-
labeled microcentrifuge tubes, and stored at -70 °C until shipment. 
 
5.3.5.3 
Red Top Vacutainer Tube for Serum (for Beumer laboratory at UPMC Hillman 
Cancer Center) 
General 
Blood samples to be obtained through a peripheral or central line blood draw.  Samples should 
be drawn from the opposite arm if infusion is a peripheral infusion.  Samples should NOT be 
drawn from the infusion line. 
 
Drawing and Processing 
Document exact times of blood draws per Appendix I. 
1. Collect in a 3 or 4 mL red-top tube (e.g. BD vacutainer 367812 plastic 13 x 75 4 mL 
tube). 
2. Allow blood to clot upright at room temperature for at least 30 minutes (maximum 60 
minutes) prior to processing.  If the blood is not immediately processed after the 
clotting period, then tubes should be stored (after the 30-60 minutes of clotting time) 
at 4°C for no longer than 4 hours.  Process serum from red top tubes by centrifuging 
for 10 minutes at 1,200 x g at room temperature. 
3. Using a transfer pipette, aliquot serum into a labeled cryovial at an aliquot volume of 
≥1 mL.  Avoid picking up red blood cells when aliquoting by keeping the pipet above 
the red blood cell layer and leaving a small amount of serum in the tube.  Tightly 
secure the cap of the vials before storage.  
4. Within 1 hour of centrifugation, store serum cryovials in a specimen box in an -70°C 
to -90°C or colder freezer until shipment.  
 
 
5.4 
Specimen Tracking System Instructions 
 
5.4.1 Specimen Tracking System Overview and Enrollment Instructions 
For the ETCTN STS, the following information will be requested: 
• Protocol Number 
• Investigator Identification  
o Institution and affiliate name 
o Investigator’s name 
• Eligibility Verification:  Patients must meet all the eligibility requirements listed in 

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Section 3. 
• Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate and 
unique identification numbers to the patient, a Universal patient ID (UPID) and a Treatment 
patient ID.  The UPID is associated with the patient and used each and every time the patient 
engages with the portion of this or any other protocol that uses the ETCTN Specimen Tracking 
System.  The UPID contains no information or link to the treatment protocol.  IWRS will 
maintain an association between the UPID for ETCTN biobanking and molecular 
characterization and any treatment protocols the patient participates in, thereby allowing analysis 
of the molecular characterization results with the clinical data.   
 
Immediately following enrollment, the institutional anatomical pathology report for the diagnosis 
under which the patient is being enrolled must be uploaded into Rave.  The report must include 
the surgical pathology ID (SPID), collection date, block number, and the IWRS-assigned UPID 
and patient study ID for this trial.  For newly acquired biopsies without a corresponding 
pathology report, the radiology and operative report(s) must also be uploaded into Rave, when 
available.  Important:  Remove any personally identifying information, including, but not 
limited to, the patient’s name, date of birth, initials, medical record number, and patient 
contact information from the institutional pathology report prior to submission.  
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software.   
 
For questions regarding the Specimen Tracking System, please contact STS Support at 
STS.Support@theradex.com. 
 
The Shipping List report must be included with all sample submissions. 
 
 
5.4.2 Specimen Labeling  
 
5.4.2.1 
Tissue Specimen Labels 
 
Include the following on all tissue specimens or containers (e.g. formalin jar).  
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., FFPE Block, Formalin Fixed Tissue, Fresh Tissue in Media, etc.) 
• Tissue type (e.g., P for primary or M for metastatic, or N for normal) 
• Surgical pathology ID (SPID) number   
• Block number from the corresponding pathology report (archival only) 
• Collection date (to be added by hand) 
• Core Number 

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5.4.2.2 
Blood Specimen Labels 
 
Include the following on blood specimens (including whole blood and frozen, processed blood 
products – like serum and plasma): 
• Patient Study ID 
• Universal patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., blood, serum) 
• Collection date (to be added by hand) 
 
5.4.2.3 
Example of Specimen Label Generated by STS 
 
STS includes a label printing facility, accessed via the Print Label CRF in the All Specimens 
folder. A generated PDF is emailed to the user as a result of saving that form.  
The following image is an example of a tissue specimen label printed on a label that is 0.5” high 
and 1.28” wide. 
 
  
The QR code in the above example is for the Specimen ID shown on the second line.   
Labels may be printed on a special purpose label printer, one label at a time, or on a standard 
laser printer, multiple labels per page. Theradex recommends the use of these low temperature 
waterproof labels for standard laser printers: https://www.labtag.com/shop/product/cryo-laser-
labels-1-28-x-0-5-cl-23-colors-available/ 
The last line item on the label includes the following data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the beginning of 
the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. An optional alpha-numeric code that is protocol specific and is only included if the 
protocol requires an additional special code classification 
Space is provided at the bottom of the label for the handwritten date and optional time.  

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The last line on the example label is for the handwritten date and optional time. 
 
5.4.3 Overview of Process at Treating Site 
 
5.4.3.1 
OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system.  OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization and any prescribed slot 
assignments.  If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration without eligibility specimen analysis:  
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal 
Patient ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 
5.4.3.2 
Rave Specimen Tracking Process Steps 
 
Step 0: Log into Rave via your CTEP-IAM account, then navigate to the appropriate 
participant. 
Step 1:  Complete the Histology and Disease form (but do not upload reports until a 
specimen label can be applied to them) and the Baseline forms regarding Prior 
Therapies. Enter the initial clinical specimen data:  
• Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, number of labels 
needed (include extra labels to apply to reports to be uploaded). CRF generates 
unique Specimen ID.  
 
Step 2:  Print labels using the Print Labels CRF located in the All Specimens folder, 
then collect specimen. 
• Label specimen containers and write collection date on each label. 
• After collection, store labeled specimens as described in Section 5.3. 
• Apply an extra specimen label to each report before scanning.  Return to the 
Histology and Disease form to upload any initial Pathology, Radiology, 
Molecular Reports (up to 4), and Surgical (or Operative) reports . Return to 
Specimen Tracking Enrollment CRF to upload any molecular report (one per 
specimen) and/or specimen specific pathology or related report (one per 
specimen) and/or the Tissue Biopsy Verification form (when applicable, 
Appendix J).  Uploaded reports should have PHI data like name, date of birth, 
mailing address, medical record number or SSN redacted.  Do not redact SPID, 

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block number, diagnosis or relevant dates (such as the collection date), and 
include the UPID and patient study ID on each document (either by label or hand 
writing).  
 
Step 3:  Complete specimen data entry. 
• Specimen Transmittal Form:  Enter Collection date and time and other required 
specimen details. 
 
Step 4:  When ready to ship, enter shipment information. 
• Shipping Status CRF:  Enter tracking number, your contact information, 
recipient, number of sample containers and ship date once for the 1st specimen in 
a shipment. 
• Copy Shipping CRF:  In the specimen folders for additional specimens (if any) 
that will be shipped with the initial specimen, please use the Copy Shipping form 
to derive common data into additional Shipping Status forms. A few unique 
fields will still need to be entered in Shipping Status.  . 
 
Step 5:  Print shipping list report and prepare to ship.  
• Shipping List report is available at the site level. 
• Print two copies of the shipping list, one to provide in the box, the other for your 
own records. 
• Print pathology or other required reports to include in the box. Be sure the printed 
copy includes the specimen label. 
 
Step 6:  Send email notification.  
• For only one of the specimens in the shipment, click “Send Email Alert” 
checkbox on the Shipping Status CRF to email recipient. 
 
Step 7:  Ship the specimen(s). 
 
Step 8: Monitor the Receiving Status form located in each specimen folder for 
acknowledgment of receipt and adequacy. 
 
 
5.5 
Shipping Specimens from Clinical Site to Other Laboratories 
5.5.1 Shipping Specimens from Clinical Site to the EET Biobank  
 
When kits are provided, the shipping container sent with kit contents should be used to ship 
specimens to the EET Biobank.  In winter months, please include extra insulation, such as bubble 
wrap, inside the shipping container. 
5.5.1.1 Required Forms for Specimen Submission 
Each document submitted with the specimen must be labeled with a label printed from the 
STS, or the Universal ID and Patient Study ID.  

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Tissue  
Required Forms 
New Biopsy 
 
1. Shipping List 
2. Tissue Biopsy Verification Form 
3. Diagnostic Pathology Report  
4. Operative and/or Radiology Report 
Blood  
1. Shipping List 
5.5.1.2 Specimen Shipping Instructions 
 
Tissue in formalin must be shipped on the day of collection.  Collect and ship on Monday 
through Wednesday. 
 
Frozen specimens may be shipped on Monday through Thursday.  
Fresh blood may be shipped on Monday through Friday.  Please select “Saturday Delivery” 
when shipping fresh blood on a Friday. 
5.5.1.3 Specimen Shipping Instructions 
 
5.5.1.3.1 Shipping Blood in an Ambient Shipper 
 
1. Before packaging specimens verify that each specimen is labeled according to the 
instructions above and that the lids of all primary receptacles containing liquid are tightly 
sealed.  
2. Place specimens into a biohazard envelope with absorbent material.  Expel as much air as 
possible and seal the envelope securely.  
3. Place the biohazard envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely.  
4. Place the specimen and a copy of the shipping manifest into the shipping box.  In winter 
months, please include extra insulation, such as bubble wrap, inside the shipping 
container, to prevent specimens from freezing. 
5. Close the box and attach a shipping label to the top.  
6. Place an Exempt Human Specimen sticker to the side of the container. 
7. Ship specimens via overnight courier to the address listed below.  FedEx Priority 
Overnight is strongly recommended to prevent delays in package receipt. 
 
5.5.1.3.2 Packaging Ambient Tissue and Blood in a Single-Chamber Kit 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that the lids of all primary receptacles containing liquid are tightly 
sealed.  Formalin jars should be wrapped in parafilm.  
2. Place the specimens in zip-lock bags.  Use a separate bag for each specimen type. 
3. Place specimens into a biohazard envelope with absorbent material.  Expel as much air as 
possible and seal the envelope securely.  
4. Place the biohazard envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely. 

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5. Place the specimen(s) and a copy of the shipping manifest and corresponding reports 
such as operative or radiology reports into the insulated shipping container.  In winter 
months, please include extra insulation, such as bubble wrap, inside the shipping 
container, to prevent specimens from freezing.  
6. Place the lid on top of the container.  Close the outer flaps and tape shut. 
7. Attach a shipping label to the top of the shipping container.  
8. Attach an Exempt Human Specimen sticker to the side of the container. 
9. Ship specimens via overnight courier to the address below. FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
5.5.1.3.3 Packaging Frozen Specimens in a Single-Chamber Kit 
 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that lids of all primary receptacles containing liquid are tightly 
sealed.  
2. Place the specimens in zip-lock bags.  Use a separate zip-lock bag for each specimen type 
and time point.  
3. Place the zip-lock bags in the biohazard envelope containing absorbent material.  Expel 
as much air as possible and seal securely.  
4. Put the secondary envelope into a Tyvek envelope.  Expel as much air as possible and 
seal securely.  
5. Place frozen specimens in the kit compartment with dry ice.  Layer the bottom of the 
compartment with dry ice until it is approximately one-third full.  Place the frozen 
specimens on top of the dry ice.  Cover the specimens with the dry ice until the 
compartment is almost completely full.  When packaging specimens, ensure that you 
leave enough room to include at least 5 pounds of dry ice in the shipment.    
6. Insert a copy of the required forms into a plastic bag and place in the kit chamber. 
7. Place the Styrofoam lid on top to secure specimens during shipment.  Do not tape the 
inner chamber shut. 
8. Close the outer lid of the Specimen Procurement Kit and tape it shut with durable sealing 
tape.  Do not completely seal the container. 
9. Complete a FedEx air bill and attach to top of shipping container. 
10. Complete a dry ice label. 
11. Attach the dry ice label and an Exempt Human Specimen sticker to the side of the 
shipping container. 
12. Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
5.5.1.3.4 Packaging Frozen Specimens in a Dual-Chamber Kit 
 
The Dual Chambered Specimen Procurement Kit is constructed to allow the shipment of frozen (on 
dry ice) and ambient (room temperature) specimens in the same container.  Dry ice may be placed 
in either compartment of the kit, but should not be put in both.  The dual chambered kit is only 
used for shipments that contain both frozen and ambient specimens.  If formalin-fixed tissue is 
shipped separately (not in the same shipment as frozen specimens), then it must be shipped using 
institutional shipping supplies.    

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• Frozen specimens may be shipped on Monday through Thursday.  Ensure that sufficient 
dry ice is included to completely encase the specimens to maintain specimen integrity 
during shipment.   
 
• Formalin-fixed tissue may be shipped on Monday through Thursday. 
 
• Before packaging specimens, verify that each specimen is labeled according to the 
instructions above and that lids of all primary receptacles containing liquid are tightly 
sealed.  If included in the shipment, formalin jar lids should be wrapped in parafilm. 
• Pre-fill one of the kit chambers about 1/3 with dry ice. 
• Place the specimens in zip-lock bags. Use a separate zip-lock bag for each specimen 
type. 
• Two biohazard envelopes are provided so that ambient and frozen specimens can be 
packaged separately.   
• Place the zip-lock bags containing room temperature specimens in a biohazard envelope with 
absorbent material.  Expel as much air as possible and seal the envelope securely.  
• Place the zip-lock bags containing frozen specimens into the other biohazard envelope 
containing absorbent material.  Expel as much air as possible and seal securely.  
• Put each secondary envelope into a Tyvek envelope.  Expel as much air as possible 
and seal each envelope securely.   
• Quickly place the Tyvek envelope containing frozen specimens (e.g. frozen tumor, 
serum, etc.) in the kit compartment that is pre-filled with dry ice.  Place the Tyvek 
envelope on top of the dry ice.  Cover the specimens with additional dry ice until the 
compartment is almost completely full.   
• Place the Styrofoam lid on top to secure specimens during shipment.  Do not tape the 
inner chamber shut. 
• Place the Tyvek envelope containing ambient temperature specimens (e.g. formalin-
fixed tissue) in the other kit compartment at room temperature.  
• Insert a copy of the required forms into a plastic bag and place in the kit chamber 
with the ambient specimens. 
• Place the Styrofoam lid on top of the kit compartment to secure specimens during 
shipment.  Do not tape the inner chamber shut. 
• Close the outer lid of the Specimen Procurement Kit and tape it shut with durable 
sealing tape.  Do not completely seal the container. 
• Complete a FedEx air bill and attach to top of shipping container. 
• Complete a dry ice label. 
• Attach the dry ice label and an Exempt Human Specimen sticker to the side of the 
shipping container. 
• Ship specimens via overnight courier to the address below.  FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt.  
 
5.5.1.4 Shipping Address 
 
Ship to the address below. Ship formalin-fixed and fresh blood specimens the same day of 

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specimen collection.  Do not ship specimens the day before a holiday. 
 
EET Biobank 
2200 International Street 
Columbus, OH 43228 
PH: (614) 722-2865 
FAX: (614) 722-2897 
E-mail:  BPCBank@nationwidechildrens.org 
 
 
FedEx Priority Overnight service is very strongly preferred.  There is no central Courier 
account for this study.  Sites are responsible for all costs for overnight shipment per specimen 
shipment to the EET Biobank, utilizing the site screening and base intervention payments.  
 
NOTE:  The EET Biobank FedEx Account will not be provided to submitting institutions. 
 
5.5.1.5 Contact Information for Assistance 
 
For all queries, please use the contact information below: 
 
EET Biobank  
Phone: (614) 722-2865 
E-mail:  BPCBank@nationwidechildrens.org 
 
 
5.5.2 Shipping Specimens from Clinical Site to the UPMC Hillman Cancer Center (Beumer PK 
laboratory) 
1. Specimen Shipping Instructions 
 
Preparing the shipment 
1. Samples should be stored in cardboard boxes (5 1/8” x 5 1/8” x 2”, L x W x H). 
2. Please organize the samples by Patient and Time point in the box. 
3. Do not store in plastic bags (they break on dry-ice and labels will detach). 
4. A copy of each of the pharmacokinetic sample collection forms for the respective patients 
should be included with each shipment.  To prevent problems with illegible writing on 
tubes, consider numbering them and numbering samples on the sample sheet. 
*Note the study number, PI, and the drugs used/to be measured. 
*A name, phone number, and email address should be included with the samples so that 
receipt can be acknowledged. 
5. Please notify the lab by telephone (412-623-3248) or fax (412-623-1212) at least 24 hours 
prior to shipment. 
 
Regulations 
Shipment of samples must comply with appropriate regulations as specified by the carrier.  At a 
minimum, all samples must be packaged within two containers with absorbent material between 
containers to control any spill or leakage.  The outer container must be puncture-resistant (e.g. 

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5.6 
Integral Laboratory Studies 
 
5.6.1 PIK3CA Mutations 
 
PIK3CA mutation status evaluation will be performed prior to registration.  Eligibility will be 
based on the presence of hotspot PIK3CA mutations such in E542, E545, and H1047 only. 
Hotspot PIK3CA mutations will be determined by the PODS group at MD Anderson.   
 
5.6.1.1 
Sites Performing Correlative Study 
 
A local CLIA-certified laboratory or Dr. Timothy Yap at MD Anderson will analyze samples.  
 
5.6.2 PTEN Mutations 
 
PTEN mutation status evaluation will be performed prior to registration.  Eligibility will be based 
on the presence of actionable PTEN mutations.  Actionability will be assessed by the PODS 
group at MD Anderson.   
 
5.6.2.1 
Sites Performing Correlative Study 
 
A local CLIA-certified laboratory or Dr. Timothy Yap at MD Anderson will analyze samples.  
 
5.6.3 DDR Mutations 
 
DDR mutation status evaluation will be performed prior to registration.  Eligible genes include:  
BARD1, BRCA1, BRCA2, BRIP1, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, and 
RAD51D.  Actionability will be assessed by the PODS group at MD Anderson.   
 
5.6.3.1 
Sites Performing Correlative Study 
 
A local CLIA-certified laboratory or Dr. Timothy Yap at MD Anderson will analyze samples.  
 
5.7 
Integrated Correlative Studies 
 
5.7.1 RPPA 
 
RPPA-based proteomic analysis will be performed using 181 high-quality antibodies that target 
total (n=128), cleaved (n=1), acetylated (n=1) and phosphorylated forms (n=51) of proteins in 
patient samples.  The function space covered by the antibodies used in the RPPA analysis 
encompasses major functional and signaling pathways of relevance to human cancer.  Different 
batches of RPPA data will be merged using an algorithm, called Replicates Based Normalization 
(RBN), which mitigates batch effects facilitating creation of a single protein dataset merging 
samples across different batches.  Two-way unsupervised hierarchical clustering analysis will be 
used to discover the groups of biological objects sharing common characteristics, and a two-
dimensional heat map to visualize protein expression patterns.  To detect the discriminating 

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biomarkers for each cluster (obtained by hierarchical clustering using the RPPA data normalized 
by RBN), LIMMA will be used to select biomarkers by comparing samples in each cluster with 
samples in all the other clusters together.  In addition, pathway activity scores will be computed 
using a series of pathway predictors developed based on member proteins selected by literature 
review. 
 
5.7.1.1 
Specimens Receipt and Processing at the EET Biobank 
 
Frozen tissue specimens received from the collection site should be stored at -80 or lower. 
 
5.7.1.2 
Sites Performing RPPA 
 
This assay will be performed at the MD Anderson RPPA Core Laboratory (Lab PI:  Yiling Lu).  
All of the samples from this study collected for this assay will be stored at the EET Biobank at 
the Nationwide Children’s Hospital and will be shipped later to MD Anderson RPPA Core 
laboratory for batch analysis.  
 
5.7.1.3 Shipment of specimens from the EET Biobank to Site Performing Correlative Study 
Specimens will be shipped from the EET Biobank to: 
Functional Proteomics RPPA Core Facility 
Attn: Doris Siwak, PhD 
6565 MD Anderson Blvd., Room Z4.2040 
Houston, TX 77030 
 
5.7.1.4 Contact Information for Notification of Shipment 
Email Dr. Lu at yilinglu@mdanderson.org 
 
5.7.2 Whole Exome Sequencing (WES) 
 
5.7.2.1 
Specimens Receipt and Processing at the EET Biobank 
 
Tumor tissue received in formalin will be paraffin-embedded.  DNA and RNA will be co-
extracted from tumor tissue.  The nucleic acids will be analyzed to determine concentration and 
quality.  Aliquots of DNA and RNA will be shipped to the central sequencing laboratory for 
analysis. 
 
5.7.2.2 
Sites Performing Correlative Study 
 
WES will be conducted at the MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR) under the leadership of Chris Karlovich, Ph.D. (chris.karlovich@nih.gov). 
 
 
 
 

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5.7.2.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
Specimens will be shipped from the EET Biobank to: 
Specimens will be shipped from the EET Biobank to: 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 
5.7.2.4 Contact information for notification of specimen shipment 
 
Thomas Forbes (mochasamplereceiving@nih.gov) 
 
5.7.3 Olaparib PK 
 
5.7.3.1 
Specimens Receipt and Processing at the Cancer Pharmacokinetics and 
Pharmacodynamics Facility, UPMC Hillman Cancer Center 
Fresh/Frozen plasma aliquots will be received at the Beumer laboratory for processing and 
storage. 
 
5.7.3.2 
Site Performing Olaparib PK 
This assay will be performed at the Cancer Pharmacokinetics and Pharmacodynamics Facility, 
UPMC Hillman Cancer Center. An assay is being implemented following a published method 
(Nijenhuis et al. Journal of Chromatography B, 940 (2013) 121– 125). The PK laboratory will 
take aliquots of these samples and ship to NorthEast Biolabs for analysis of copanlisib 
(contracted by Bayer). 
 
5.7.3.3 
Contact information for notification of specimen shipment: 
See Section 5.5.2. 
 
5.7.4 Copanlisib PK 
 
5.7.4.1 
Specimens Receipt and Processing at the Cancer Pharmacokinetics and 
Pharmacodynamics Facility, UPMC Hillman Cancer Center 
Fresh/Frozen plasma aliquots will be received at the Beumer laboratory for processing and 
storage. 
 
5.7.4.2 
Site Performing Copanlisib PK   
This assay will be performed at NorthEast Biolabs.  All of the samples from this study collected 
for this assay will be stored at the Cancer Pharmacokinetics and Pharmacodynamics Facility, 
UPMC Hillman Cancer Center and will be shipped later to NorthEast Biolabs for batch analysis.  
 
5.7.4.3 
Contact information for notification of specimen shipment:   
See Section 5.5.2. 
 

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5.7.5 Durvalumab PK 
 
5.7.5.1 
Specimens Receipt and Processing at the Cancer Pharmacokinetics and 
Pharmacodynamics Facility, UPMC Hillman Cancer Center 
Fresh/Frozen serum aliquots will be received at the Beumer laboratory for processing and 
storage. 
 
5.7.5.2 
Site Performing Durvalumab PK 
The assay for durvalumab, anti-drug antibody, and s-PD-L1 will be performed at MedImmune.  
All of the samples from this study collected for this assay will be stored at the Cancer 
Pharmacokinetics and Pharmacodynamics Facility, UPMC Hillman Cancer Center and will be 
shipped later to MedImmune or contracted designee for batch analysis.  
 
5.7.5.3 
Contact information for notification of specimen shipment: 
See Section 5.5.2. 
 
5.8 
Exploratory/Ancillary Correlative Studies 
 
5.8.1 Whole Transcriptome Sequencing (RNASeq) 
 
 
5.8.1.1 
Specimens Receipt and Processing at the EET Biobank 
 See Section 5.8.2.1 
 
5.8.1.2 
Sites Performing Correlative Study 
 
RNA Seq will be conducted at the MoCha, Frederick National Laboratory for Cancer Research 
(FNLCR) under the supervision of Chris Karlovich, Ph.D. (chris.karlovich@nih.gov). 
 
5.8.1.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 
5.8.1.4 Contact Information for Notification of Specimen Shipment 
 
Thomas Forbes (mochasamplereceiving@nih.gov)  
 
 

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5.8.2 ctDNA Sequencing 
 
 
5.8.2.1 
Specimens Receipt and Processing at the EET Biobank 
 
Upon receiving the Streck cfDNA Tube from the collection site, the Biorepository should 
prepare Plasma and PBMCs. 
• For each 10 mL Streck tube, create 4 plasma vials of 1 mL aliquots and store at -80°C. 
• Create at least one PBMC vial (~5 x 106 cells/mL depending on blood volume and study 
need).  Typical recovery can expect 1 x 107 cells from 10 mL tube. 
• Slow-freeze aliquots at -80°C in a freezing container for 24 hours (up to 14 days) 
followed by long-term cryopreservation in the vapor phase of a LN2 tank. 
5.8.2.2 
Site Performing Correlative Study 
 
ctDNA sequencing will be conducted at the MoCha, Frederick National Laboratory for Cancer 
Research (FNLCR) under the supervision of Chris Karlovich, Ph.D. (chris.karlovich@nih.gov). 
 
5.9.2.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
MoCha Lab, Frederick National Laboratory for Cancer Research (FNLCR) 
1050 Boyles St. 
Bldg. 459, Rm. 125 
Frederick, MD 21702 
Attn: Alyssa Chapman or Ruth Thornton 
 
 
5.9.2.4 
Contact Information for Notification of Specimen Shipment 
Thomas Forbes (mochasamplereceiving@nih.gov)  
 
6. 
TREATMENT PLAN 
 
6.1 
Agent Administration 
 
In Step 1, the doublet combination of copanlisib and olaparib will be investigated.  Dose 
escalation will be undertaken in patients with advanced solid tumors, with the population 
enriched for those with both PI3K-AKT pathway and DDR aberrations. If a DLT is observed at 
dosing Level 3 and the dose escalation has completed, a maximum of 6 patients will be treated 
with a less intense schedule of copanlisib 60 mg Day 1 and 15 and olaparib 300 mg BID (dose 
level 3a) to improve the safety profile. 
 
Step 2 will not commence until safety data from Step 1 has been formally reviewed and 
discussed by the study team and with CTEP. 

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In Step 2, the RP2D of the copanlisib/olaparib doublet combination is copanlisib 60 mg Days 1 
and 15 and olaparib 300 mg BID of each 28-day cycle. Durvalumab (MEDI4736) at 1500 mg 
Day 1 of each 28-day cycle will be added to form a novel triplet combination.  Patients will start 
treatment in Cycle 1 with copanlisib and olaparib alone. Durvalumab (MEDI4736) will be added 
on Cycle 2 Day 1 (C2D1). The dose escalation phase will involve patients with advanced solid 
tumors, with the population enriched for those with both PI3K-AKT pathway and DDR 
aberrations.  A protocol amendment will be required before the initiation of Step 2. 
 
In Step 3, dose expansion for the copanlisib/olaparib doublet combination can proceed upon 
completion of Step 1 and can proceed simultaneously with Step 2. The dose expansion for the 
copanlisib/olaparib/durvalumab (MEDI4736) triplet combination can proceed upon completion 
of Step 2 and can proceed simultaneously with dose expansion for copanlisib/olaparib doublet 
combination. Patient assignment to the doublet or triplet combinations will be based on slot 
availability. During cohort expansion, patients to be assessed include:  those with germline DDR 
aberrations (3A and 3C dose expansion cohorts), those with cancers with somatic DDR 
aberrations (3A and 3C dose expansion cohorts), patients with PIK3CA mutant cancers (3B and 
3D dose expansion cohorts), and those with PTEN mutations (3B and 3D dose expansion 
cohorts).  15 patients will be recruited to each of the 4 molecular dose expansion cohorts (3A, 
3B, 3C, 3D), for a total of 60 patients in dose expansion. 
 
Treatment will be administered on an outpatient basis.  Reported AEs and potential risks are 
described in Section 10.  Appropriate dose modifications are described in Section 7.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
 
 
Dose escalation schema for the doublet combination of copanlisib and olaparib (Step 1) 
Dose Escalation Schedule 
 
Copanlisib* 
Olaparib* 
Level -1** 
45 mg (D1, D15), 28-day 
cycle 
200 mg BID 
Level 1*** 
45 mg QW, D1, D8, D15, 
28-day cycle 
200 mg BID 
Level 2 
45 mg QW, D1, D8, D15, 
28-day cycle 
300 mg BID 
Level 3**** 
60 mg QW, D1, D8, D15, 
28-day cycle 
300 mg BID 
Level 3a 
60 mg D1 and D15, 28-day 
cycle 
300 mg BID 
*Alternative schedules may be pursued depending on toxicities, pharmacokinetic and 
pharmacodynamic data generated from this and other trials.  
**Doses to pursue at dose level -1 will depend on the dose-limiting toxicities observed at dose 
level 1. 
***Starting dose level. 

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**** If DLT is observed at dosing Level 3, and the dose escalation is complete, a maximum of 
6 patients will be treated with a less intensive schedule of copanlisib 60 mg Day 1 and 15 and 
olaparib 300 mg BID (dose level 3a) to improve the safety profile. 
   D = Day; BID = twice a day; QW = once a week. 
 
Dose escalation schema for the triplet combination of copanlisib, olaparib, and durvalumab 
(MEDI4736 (Step 2) 
Dose Escalation Schedule 
 
Copanlisib 
Olaparib 
Durvalumab 
(MEDI4736) 
 
Level -1* 
45 mg (D1, D15), 28-
day cycle 
200 mg BID 
1500 mg D1 
28-day cycle 
(Starting Cycle 
2, Day 1) 
Level 1 
60 mg (D1, D15), 28-
day cycle 
300 mg BID 
1500 mg D1 
28-day cycle 
(Starting Cycle 
2, Day 1) 
*Doses to pursue at dose level -1 will depend on the dose-limiting toxicities observed at dose 
level 1. 
 
D = Day; BID = twice a day  
 
RP2D = recommended phase 2 dose; MTD = maximum tolerated dose 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Copanlisib 
No IV glucose 
preparations should 
be administered on 
the days of infusion. 
Thirty mins prior to 
copanlisib infusions 
give 4 mg IV or PO 
dexamethasone and 
25 mg 
diphenhydramine IV 
or PO for prevention 
of rash. 
**45 mg 
IV over 1 
hour  
**D1, D8, 
and D15 
(or on D1 
and D15 
for dose 
level 3a) 
28 days  
(4 weeks) 
 
 
 
Olaparib 
Not Applicable 
**200 mg 
PO BID 
BID 
Durvalumab  
(MEDI4736)* 
Not Applicable 
***1500 mg IV over 1 
hour 
Q28D 
*Durvalumab (MEDI4736) should be administered before copanlisib for the triplet 
combination. 
**Doses and schedule as appropriate for assigned dose level. 

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Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
***Refer to Section 6.1.3 for weight ≤30kg. 
    IV = intravenously ; D = day; QW; once every week; BID = twice a day;  
   Q28D = once every 28 days 
 
The patient will be requested to maintain a medication diary of each dose of olaparib.  The 
medication diary (Appendix F) will be returned to clinic staff at the end of each course. 
 
6.1.1 Copanlisib 
 
Based on the company-sponsored studies with copanlisib in patients with oncologic 
malignancies, the RP2D of copanlisib monotherapy is 60 mg and will be administered by IV for 
1 hour on Days 1, 8, and 15 of every 28-day cycle. A copanlisib dose reduction to 45 mg has 
been allowed for toxicities (Copanlisib Investigator’s Brochure, 2017).  The starting dose for this 
combination trial is 45 mg. For patients treated at dose level 3a, dose level 1 of the triplet dose 
escalation, and dose expansion for both the doublet and triplet combinations, copanlisib 60 mg 
will be administered by IV for 1 hour on Days 1 and 15 of every 28-day cycle. 
 
6.1.1.1 
Agent Administration 
 
Use of antiemetics prior to copanlisib administration is not allowed. Use of antiemetics should 
not be needed since each patient will receive 25 mg diphephydramine (IV or PO) and 4 mg 
dexamethasone (IV or PO) to prevent copanlisib-induced rash. Should a patient require 
antiemetics after the first infusion, use of additional corticosteroids is not allowed. Administer 
copanlisib as an IV infusion over one hour (+/-10 minutes).  After administration, flush the line 
with 0.9 % sodium chloride to ensure complete dose is given.  No IV glucose preparations 
should be administered on the days of infusion.   
 
On days both copanlisib and olaparib are given, follow the treatment order below: 
 
1.) Premedication with 25 mg diphenhydramine (IV or PO) and 4 mg dexamethasone (IV or 
PO) 
2.) Olaparib dose (can be given at the same time as the premedications)  
3.) Copanlisib infusion over 60 minutes (+/-10 minutes) will begin at least 30 minutes 
AFTER Olaparib dose 
 
Note: If the Olaparib dose is held, there is no window between the premedication and copanlisib 
infusion. 
 
Recommendations on meal timing on copanlisib infusion days 
 
Because of an inhibitory effect on PI3Kα-isoform, which is implicated in insulin metabolism, 
copanlisib infusions could be associated with temporarily increase in blood glucose.  Consuming 
meal in close proximity to copanlisib infusion may exacerbate a glucose level increase.  It is 

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recommended that timing and content of caloric intake on infusion days is monitored by the 
investigators.  Consultation with diabetologist or endocrinologist is advised. 
 
The investigator may manage the timing of post-infusion meals based on the glucose profile 
during prior infusion days to minimize glucose increases.  This is in addition to glucose lowering 
medication.  On infusion days a low carbohydrate diet is recommended, the timing and content 
of meal intake and additional glucose testing (if clinically indicated) is managed and monitored 
by the investigators based on glucose response patterns during prior treatment days.   However, 
caloric restriction is not intended for the population under study.  Refer to Appendix D for 
glycemic indices of common foods.  
 
NOTE:  If patient needs to take a low glycemic meal, then glucose test should be taken prior to 
meal intake and at 1 and/or 2 hours after the meal.  All glucose measurements, oral glucose 
lowering medication and/or insulin administration, if applicable, and meal timing will be 
collected as part of the clinical source documentation.  
 
NOTE:  Caloric intake and timing recommendations for diabetic patients who require insulin 
treatment prior to the infusion at any cycle visit should be managed by the investigator based on 
consultation with treating physician or diabetes/endocrinologist physician. 
Pre-dose glucose levels 
Period 
Pre-dose glucose levels 
(first glucose measurement) 
 
  
Day 1 of 
cycle 1 
<160 mg/dL (fasting*) 
 < 200 mg/dL (non-fasting**)  
 
Subsequent 
infusions after 
Cycle 1 Day 1 
 
 
 <160 mg/dL (fasting*) 
 < 200 mg/dL (non-fasting**)  
 
 
 
 
 
*Fasting refers to a ≥ 8 h fast. 
**Non-fasting status includes any caloric intake such as meals and also 
juice, snacks, and other caloric intake not consistently called a meal. 
 
From Cycle 1 Day 1 onwards, glucose measurements at the site may be done either by laboratory 
analysis or in capillary blood. 
 
Post-dose glucose monitoring after C1D1 is performed as clinically indicated at the 
investigator’s discretion. 
 
All glucose measurements done at the site, oral glucose lowering medication and/or insulin 
administration, if applicable, fasting/non-fasting status and meal intake timing on infusion days 
will be collected as part of the clinical source documentation.  

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6.1.2 Olaparib 
 
6.1.2.1 
Agent Administration 
 
Patients will be administered olaparib BID.  Olaparib tablets should be taken at the same time 
each day, approximately 12 hours apart with one glass of water.  The olaparib tablets should be 
swallowed whole and not chewed, crushed, dissolved or divided.  Olaparib tablets can be taken 
with or without food.  Consumption of grapefruit, grapefruit juice, or Seville oranges while on 
olaparib therapy is prohibited. On days that both copanlisib and olaparib are given, follow the 
treatment order below: 
 
1.) Premedication with 25 mg diphenhydramine (IV or PO) and 4 mg dexamethasone (IV or 
PO) 
2.) Olaparib dose (can be given at the same time as the premedications)  
3.) Copanlisib infusion over 60 minutes (+/-10 minutes) will begin at least 30 minutes 
AFTER Olaparib dose 
 
Note: If the Olaparib dose is held, there is no window between the premedication and copanlisib 
infusion. 
 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted.  Should any patient enrolled on the 
study miss a scheduled dose for whatever reason (e.g., as a result of forgetting to take the tablets 
or vomiting), the patient will be allowed to take the scheduled dose up to a maximum of 2 hours 
after that scheduled dose time.  If greater than 2 hours after the scheduled dose time, the missed 
dose is not to be taken and the patient should take their allotted dose at the next scheduled time. 
 
6.1.3 Durvalumab (MEDI4736) 
 
6.1.3.1 
Agent Administration  
 
Durvalumab (MEDI4736) will only be administered for the triplet combination.  Durvalumab 
(MEDI4736) should be administered before copanlisib starting on Cycle 2 Day 1 of the triplet 
combination therapy.  For patients >30 kg, use flat dosing: 1500 mg durvalumab (MEDI4736) 
via IV infusion D1 Q28D for a maximum of 24 months or until disease progression (whichever 
is earlier), unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met.   
 
If a patient’s weight falls to ≤30 kg, the patient should receive weight-based dosing equivalent 
to 20 mg/kg of durvalumab (MEDI4736) Q4W until the weight improves to >30 kg, at which 
point, the patient should start receiving the fixed dosing of durvalumab (MEDI4736) at 1500 mg 
Q4W.   
 
Standard infusion time is 60 minutes (± 10 minutes).  In the event that there are interruptions 
during infusion, the total allowed time should not exceed 8 hours at room temperature. 

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On days when olaparib, copanlisib, and durvalumb are to be administered, follow the treatment 
order below: 
 
1.) Durvalumab will be administered over 60 minutues (± 10 minutes) 
2.) Premedication with 25 mg diphenhydramine (IV or PO)  and 4 mg dexamethasone (IV or 
PO) AFTER durvalumab infusion is completed 
3.) Olaparib dose (can be given at the same time as the premedications) 
4.) Copanlisib infusion over 60 minutes (+/- 10 minutes) will begin at least 30 minutes 
AFTER Olaparib dose 
 
In the event olaparib is held, follow the treatment order below: 
 
1.) Durvalumab will be administered over 60 minutues (± 10 minutes) 
2.) Premedication with 25 mg diphenhydramine (IV or PO) and 4 mg dexamethasone (IV or 
PO) AFTER durvalumab infusion is complete 
3.) Copanlisib infusion over 60 minutes (+/-10 minutes) AFTER premedications are 
administered 
 
In the event copanlisb is held, follow the treatment order below: 
 
1.) Durvalumab will be administered over 60 minutues (± 10 minutes) 
2.) Olaparib dose AFTER durvalumab infusion is complete 
 
Note: If the Copanlisib dose is held, there is no need to administer the premedications. 
 
6.1.3.2 
Supportive Care 
 
Patients will be monitored during and after the infusion with assessment of vital signs at the 
times specified in the Study Protocol. 
 
• In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may 
be decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of 
the initial rate until completion of the infusion.  For patients with a ≤Grade 2 infusion 
related reaction, subsequent infusions may be administered at 50% of the initial rate.  
Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent 
medications per institutional standard may be administered at the discretion of the 
investigator. 
• If the infusion related reaction is ≥Grade 3 or higher in severity, study drug will be 
discontinued.  For management of patients who experience an infusion reaction, please 
refer to the toxicity and management guidelines in Section 7. 
 
NOTE:  As with any antibody, allergic reactions to dose administration are possible.  
Appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat anaphylaxis.  
The study site must have immediate access to emergency resuscitation teams and equipment in 

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addition to the ability to admit patients to an intensive care unit if necessary. 
 
6.2 
Definition of Dose-Limiting Toxicity  
 
6.2.1 DLTs for Steps 1 and 2 
Severity of AEs will be graded according to CTCAE v5.  Any of the following AEs occurring 
during the DLT observation period (Cycle 1 through Cycle 2 Day 1 for the doublet combination; 
Cycle 1 through Cycle 3 Day 1 for the triplet combination), which are attributable to at least one 
of the investigational products will be classified as DLTs: 
• Any Grade 2 toxicity that requires permanent discontinuation durvalumab (MEDI4736) 
or combination during the first 4 weeks. 
• Any Grade 5 toxicity. 
Hematological: 
• Grade 4 neutropenia (absolute neutrophil count [ANC] <0.5 x 109/L) lasting >7 days 
• Febrile neutropenia, defined as ANC <1000/mm3 with a single temperature of >38.3ºC 
(>101ºF) or a sustained temperature of ≥38ºC (100.4ºF) for more than 1 hour 
• Neutropenic infection (ANC <1,000/mm3 or <1.0 x 109/L, and Grade >3 infection 
• Grade ≥3 thrombocytopenia (platelet count <50.0 × 109/L) with bleeding 
• Grade 4 thrombocytopenia (platelet count <25.0 x 109/L) 
• Grade 4 anemia (life-threatening consequences; urgent intervention indicated) 
Non-hematological: 
• Non-hematological toxicities: 
o Grade ≥4 toxicities 
o Confirmation of QTc prolongation (>500 msec) or QTc increase >60 msec from 
baseline 
o Grade ≥ 3AE hyperglycemia or hypertension lasting ≤ 7 days (transient, 
intermittent, or reversible hyperglycemia and/or hypertension that can be 
optimally controlled with our without intervention will not be considered a DLT) 
o Grade 3 skin rash despite optimal medical intervention (e.g., IV steroids) 
o Grade 3 diarrhea despite maximal medical intervention (e.g., IV steroids). 
• Any other toxicity that is greater than that at baseline, is clinically significant and/or 
unacceptable, does not respond to supportive care and results in a disruption of dosing 
schedule of more than 14 days  
• Any event, including significant dose reductions or omissions, judged to be a DLT by the 
Safety Review Committee 
• Any other toxicity in any course of treatment that in the opinion of the investigators and 
medical monitors is dose-limiting 
Please see Section 7 for the management of DLTs. 

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The following toxicities will not be considered DLTs: 
• Alopecia of any grade 
• Isolated laboratory changes of any grade without clinical sequelae or clinical significance 
Evaluability criteria: 
 
To be considered evaluable for the specified DLT period in Steps 1/2 escalation cohorts or 
evaluable in Step 3 expansion cohorts, patients must have received at least 75% of Olaparib 
doses and have no missed Copanlisib doses. There will be an allowance for a 1 week delay 
within C1 for Copanlisib as long as all doses are administered 
 
6.2.2 DLTs for Step 2 only 
 
The following toxicities will not be considered DLTs: 
• Vitiligo of any grade 
• Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the patient is asymptomatic 
• Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.) 
• Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management 
• Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 3 days 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 7. 
 
6.3 
Dose Expansion Cohorts: 
 
Once the RP2D is reached for the doublet and/or triplet combinations, an additional 15 patients 
will be enrolled in each of 4 cohorts, namely, patients with germline or somatic DDR aberrations 
treated with the doublet combination (3A); patients with PIK3CA or PTEN mutations treated 
with the doublet combination (3B); patients with germline or somatic DDR aberrations treated 
with the triplet combination (3C); and patients with PIK3CA or PTEN mutations treated with the 
triplet combination (3D), for a total of 60 patients in the dose expansion who will be treated at 
either the RP2D/MTD of the doublet or triplet combination.  Monitoring of all safety and toxicity 
data is done by the PI and the Corresponding Organization on a real-time basis as data are 
entered into Medidata Rave using the Web Reporting Module.  All participating sites are 
expected to notify the Principal Investigator when a DLT has occurred according to the AEs 
summarized in section 6.2.1. 
 
6.4 
General Concomitant Medication and Supportive Care Guidelines 
 

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6.4.1 Copanlisib 
 
Because there is a potential for interaction of copanlisib with other concomitantly administered 
drugs, the case report form (CRF) must capture the concurrent use of all other drugs, over-the-
counter medications, or alternative therapies.  The PI should be alerted if the patient is taking any 
agent known to affect or with the potential for drug interactions.  The known potential targets for 
drug interaction are CYP3A4 inducers or inhibitors, as well as drugs modulating 
glucuronidation, P-gp, BCRP, and MATE2K function.  Concomitant use of medications listed in 
Appendix B is prohibited while on copanlisib.  Appendix C should be provided to patients if 
available. 
 
6.4.1.1 
Substrates with narrow therapeutic indices  
 
Substrates of P-gp and/or BCRP with narrow therapeutic index should be used with caution and 
patients monitored for any sign of toxicity.  Furthermore, sensitive substrates of the renal drug 
transporter MATE2K (e.g. metformin) need to be used with caution.  Metformin should be 
interrupted for 48 hours after receiving iodinated contrast media.  Please see prescribing 
information for further information. 
 
6.4.1.2 
Monitoring 
 
Patients taking medications with narrow therapeutic index should be proactively monitored if 
these medications cannot be avoided.  These medications may include quinidine, cyclosporine, 
and digoxin. 
 
6.4.1.3 
Systemic corticosteroid therapy 
 
Systemic corticosteroid therapy at a daily dose higher than 10 mg prednisone or equivalent is not 
permitted while on study.  Previous corticosteroid therapy must be stopped or reduced to the 
allowed dose at least 14 days prior to the CT/MRI screening.  If a patient is on chronic 
corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose 
before the screening.  Patients may be using topical or inhaled corticosteroids.  Short-term (up to 
7 days) systemic corticosteroids above 10 mg prednisolone or equivalent will be allowed for the 
management of acute conditions (e.g., treatment of non-infectious pneumonitis).  The use of 
corticosteroids as antiemetics prior to copanlisib administration will not be allowed. 
 
6.4.1.4 
Herbal Medications 
 
Patients should stop using herbal medications at least 7 days prior to the first dose of copanlisib.  
Herbal medications include, but are not limited to: St. John’s Wort, Kava, ephedra, gingko 
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng.   
 
6.4.2 Olaparib 
 
Because there is a potential for interaction of olaparib with other concomitantly administered 
drugs, the case report form must capture the concurrent use of all other drugs, over-the-counter 

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medications, vitamins, nutritional supplements, or alternative therapies at the time of enrollment 
and throughout the study.  The CRF should capture the dates of administration (including 
start/end dates if known), dosage (including dosing frequency/schedule), and reason for use.  The 
PI should be alerted if the patient is taking any agent known to affect or with the potential for 
drug interactions.  The study team should check a frequently-updated medical reference for a list 
of drugs to avoid or minimize use of.  Appendices C and D should be provided to patients if 
available. 
 
6.4.2.1 
Dietary Restrictions and Over-the-Counter/Self-Medication 
 
It is prohibited to consume grapefruit, grapefruit juice, Seville oranges, or Seville orange juice 
while on olaparib therapy.  The use of any natural/herbal products or other traditional remedies 
should be discouraged. 
 
6.4.2.2 
Medications that May NOT be Administered 
 
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy (hormone 
replacement therapy [HRT] is acceptable), radiotherapy (except palliative), biological therapy, or 
other novel agent) is to be permitted while the patient is receiving study medication. 
 
Live virus and live bacterial vaccines should not be administered 30 days prior to dosing study 
agents, while the patient is receiving study agents, and for 100 days after the last dose of study 
agents. Inactivated vaccines are permitted. An increased risk of infection by the administration of 
live virus and bacterial vaccines has been observed with conventional chemotherapy drugs and 
the effects with olaparib are unknown. 
 
6.4.2.3 
Restricted Concomitant Medications 
 
6.4.2.3.1 
Strong or Moderate CYP3A Inhibitors  
 
Known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, boosted 
protease inhibitors, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A 
inhibitors (ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) should not be taken 
with olaparib. 
 
If there is no suitable alternative concomitant medication, the dose of olaparib should be reduced 
for the period of concomitant administration (please refer to Section 7.2.2).  The dose reduction 
of olaparib should be recorded on the CRF with the reason documented as concomitant CYP3A 
inhibitor use.  Monitor the patient carefully for any change in efficacy of olaparib. 
 
• Strong CYP3A inhibitors – reduce the dose of olaparib to 100 mg BID for the duration of 
concomitant therapy with the strong inhibitor and for 5 half-lives afterwards. 
• Moderate CYP3A inhibitors - reduce the dose of olaparib to 150 mg BID for the duration 
of concomitant therapy with the moderate inhibitor and for 3 half-lives afterwards. 
• After the washout of the inhibitor is complete, the olaparib dose can be re-escalated. 

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6.4.2.3.2 
Strong or Moderate CYP3A Inducers 
 
Strong (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide and St John’s Wort) and moderate CYP3A inducers (e.g., bosentan, 
efavirenz, modafinil) of CYP3A should not be taken with olaparib. 
 
If the use of any strong or moderate CYP3A inducers are considered necessary for the patient’s 
safety and welfare, this could diminish the clinical efficacy of olaparib. 
 
If a patient requires use of a strong or moderate CYP3A inducer or inhibitor, then they must be 
monitored carefully for any change in efficacy of olaparib. 
 
6.4.2.3.3 
P-gp inhibitors 
 
It is possible that co-administration of P-gp inhibitors (e.g., amiodarone, azithromycin) may 
increase exposure to olaparib.  Caution should therefore be exercised. 
 
6.4.2.3.4 
Effect of olaparib on other drugs 
 
The efficacy of hormonal contraceptives may be reduced if co-administered with olaparib. 
 
Based on limited in vitro data, olaparib may increase the exposure to substrates of CYP3A4, or 
organic transporting polypeptides 1B1 (OATP1B1), organic cation transporter 1 (OCT1), OCT2, 
organic anion transporter 3 (OAT3), MATE1, and MATE2K.  
 
Based on limited in vitro data, olaparib may reduce the exposure to substrates of CYP2B6.  
 
Caution should therefore be exercised if substrates of these isoenzymes or transporter proteins 
are co-administered. 
 
Examples of substrates include (check a frequently-updated resource for more comprehensive 
lists): 
• CYP3A4 – hormonal contraceptive, simvastatin, cisapride, cyclosporine, ergot alkaloids, 
fentanyl, pimozide, sirolimus, tacrolimus, and quetiapine 
• CYP2B6 – bupropion, efavirenz 
• OATP1B1 – bosentan, glibenclamide, repaglinide, statins, and valsartan 
• OCT1, MATE1, MATE2K – metformin 
• OCT2 – serum creatinine 
• OAT3 – furosemide, methotrexate 
6.4.2.4 
Anticoagulant Therapy 
 
Patients who are taking warfarin may participate in this trial; however, it is recommended that 
the INR be monitored carefully at least once per week for the first month, then monthly if the 

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INR is stable.  Subcutaneous heparin and low molecular weight heparin are permitted. 
 
6.4.2.5 
Anti-emetics/Anti-diarrheals 
 
If a patient develops nausea, vomiting, and/or diarrhea, then these symptoms should be reported 
as AEs and appropriate treatment of the event given.  Diarrhea is a common problem experienced 
by many patients and is a risk with olaparib.  If it is not controlled quickly, it can lead to 
dehydration. 
 
6.4.2.5.1 
When to call your doctor to report diarrhea 
 
• Fever of 100.5°C (212°F) or higher with diarrhea. 
• If you are experiencing diarrhea for the first time after starting therapy.  Based on questions 
answered during that phone call, we will advise starting with 2 milligrams (mg) of loperamide 
(Imodium) if it seems the symptoms are related to the treatment. 
• If you still have diarrhea 24 hours, or more than 6 loose bowel movements after starting 
Imodium (your doctor may advise additional medications or want to evaluate you in 
person if there is a concern that you are becoming dehydrated). 
 
6.4.2.5.2 
Over the counter medication management of diarrhea 
 
• 
For diarrhea that occurs more than 2 episodes a day, use Imodium.  We recommend that 
the patient have Imodium on hand at home before starting therapy. 
o 1st episode of diarrhea:  Take 2 caplets (4 mg). 
o During day 1:  Take 1 caplet (2 mg) after each episode of diarrhea 
o During the night:  Take 2 caplets (4 mg) at bedtime if the patient still has diarrhea. 
o Do not take more than 8 tablets (8 mg) of loperamide in 24 hours.  
 
6.4.2.5.3 Drink plenty of fluids  
 
• 
Drink 8 to 19 large glasses of liquid a day to replace those lost by diarrhea.  Drink small 
quantities at a time slowly. 
• 
Avoid caffeinated, very hot, or very cold fluids.  Examples of acceptable fluids are:   
o Water (should only be part of the 8 to 10 glasses a day) 
o Jell-O / gelatin 
o Gatorade 
o Clear soup or broth 
o Other non-caffeinated fluid. 
 
6.4.2.5.4 
Eat small meals often  
 
• A good choice of foods for diarrhea is the BRAT diet: 
o B – bananas 
o R – rice 
o A – applesauce 
o T – toast 

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• When these foods are being well tolerated, than you can add other bland low fiber foods 
such as: 
o Chicken (white meat without skin), steamed rice, crackers, white bread, pasta 
noodles without sauce, and canned or cooked fruits without skins. 
o Foods high in potassium:  bananas, apricots without skin, peach nectar, potatoes 
without skin, broccoli, halibut, mushrooms, asparagus, and non-fat milk.  
• Foods that can make diarrhea and cramping worse: 
o Fatty, fried, grease, or spicy foods can cause more problems and discomfort. 
o High-fiber foods:  bran, whole grain cereals, dried fruit, fruit skins, popcorn, nuts, 
and vegetables. 
o Foods that cause gas:  beer, beans, cabbage, and carbonated drinks.  
 
6.4.2.6 
Palliative Radiotherapy  
 
Palliative radiotherapy may be used for the treatment of pain at the site of bony metastases that 
were present at baseline, provided the investigator does not feel that these are indicative of 
clinical disease progression during the study period.  Study treatment should be discontinued for 
a minimum of 3 days before a patient undergoes therapeutic palliative radiation treatment.  Study 
treatment should be restarted within 4 weeks as long as any bone marrow toxicity has recovered.  
 
6.4.2.7 
Administration of other Anti-Cancer Agents 
 
Patients must not receive any other concurrent anti-cancer therapy, except the study drugs, while 
on study treatment.  Patients may continue the use of bisphosphonates, luteinizing hormone 
releasing hormone (LHRH) agonists, or denosumab for bone disease and corticosteroids for the 
symptomatic control of brain metastases provided the dose is stable before and during the study 
and the agents were started at least 4 weeks prior to beginning study treatment.  
 
6.4.3 Durvalumab (MEDI4736) 
 
The PI must be informed as soon as possible about any medication taken from the time of 
screening until the end of the clinical phase of the study (final study visit). Any concomitant 
medication(s), including herbal preparations, taken during the study will be recorded in the CRF.  
 
Restricted, prohibited, and permitted concomitant medications are described in the following 
tables. Refer to Sections 6.4.3.1 and 6.4.3.2. 
 
6.4.3.1 
Permitted concomitant medications 
 

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Supportive medications 
Supportive medication/class of drug: 
Usage: 
Concomitant medications or treatments (e.g., 
acetaminophen or diphenhydramine) deemed necessary 
to provide adequate prophylactic or supportive care, 
except for those medications identified as “prohibited,” 
as listed above  
To be administered as prescribed by the 
Investigator. 
Best supportive care (including antibiotics, nutritional 
support, correction of metabolic disorders, optimal 
symptom control, and pain management [including 
palliative radiotherapy to non-target lesions, etc.]) 
Should be used, when necessary, for all 
patients. 
Inactivated viruses, such as those in the influenza 
vaccine 
Permitted 
 
6.4.3.2 
Excluded concomitant medications 
 
Prohibited concomitant medications 
Prohibited medication/class of drug: 
Usage: 
Any concurrent anticancer drugs other than 
those under investigation in this study. 
Should not be given concomitantly whilst the patient 
is on study treatment.  
Immunosuppressive medications including, but 
not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers 
Should not be given concomitantly, or used for 
premedication prior to the durvalumab (MEDI4736) 
infusions. The following are allowed exceptions: 
• 
Use of immunosuppressive medications for 
the management of IP-related AEs.  
• 
The use of corticosteroids as antiemetics 
prior to copanlisib administration will not be 
allowed 
• 
Use in patients with contrast allergies.  
• 
In addition, use of inhaled, topical, and 
intranasal corticosteroids is permitted. 
 
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential for 
the management of non-immunotherapy related 
events experienced by the patient (e.g., chronic 
obstructive pulmonary disease, radiation, nausea, 
etc.). 
Live attenuated vaccines 
Prohibited for 30 days prior to study agents, during 
the study, and for 100 days after the last dose of study 
drugs. Inactivated vaccines are permitted. 
Herbal and natural remedies which may have 
immune-modulating effects 
Should not be given concomitantly unless agreed by 
the sponsor 
 

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6.4.4 Monitoring for HIV-Infected Patients 
 
Monitoring for HIV-infected patients should include: 
• Viral load and CD4 count every 12 weeks.  
• If CD4 count drops to less than 200 cells/mcL while on study, initiate viral load test.  If 
viral load proves undetectable at this time, continue CD4 and viral load checks every 8 
weeks.  If 2 consecutive viral load tests are undetectable, revert to every 12 week testing 
for CD4 and viral load testing.  
o If an opportunistic infection occurs with a CD4 count of <200 cells/mcL, hold 
study treatment.  Initiate treatment of the infection and continue to hold study 
treatment; once clinically stable, CD4 count is >200 cells/mcL and viral load has 
remained undetectable, reinitiate study treatment. 
 
 
6.5 
Restrictions During the Study 
 
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after: 
 
Female patient of child-bearing potential (For Steps 1, 2, and 3) 
• Females of childbearing potential who are sexually active with a non-sterilized male 
partner must use at least two highly effective method of contraception (See the Highly 
effective methods of contraception table below and Appendix G) from signing the 
informed consent and continue throughout this period of taking study treatment and for at 
least six (6) months after the last dose of durvalumab (MEDI4736) + copanlisib + 
olaparib combination therapy or must totally abstain from any form of sexual intercourse 
(as described in Appendix G).  Non-sterilized male partners of a female patient must use 
male condom plus spermicide throughout this period.  Cessation of birth control after this 
point should be discussed with a responsible physician.  Not engaging in sexual activity 
for the total duration of the drug treatment and the drug washout period is an acceptable 
practice; however, periodic abstinence, the rhythm method, and the withdrawal method 
are not acceptable methods of birth control.  Female patients should also refrain from 
breastfeeding throughout this period. 
 
Male patients with a female partner of childbearing potential (For Steps 1, 2, and 3) 
• Non-sterilized males who are sexually active with a female partner of childbearing 
potential must use a male condom plus spermicide from screening through 6 months 
after receipt of the final dose of durvalumab (MEDI4736) + copanlisib + olaparib 
combination therapy.  Not engaging in sexual activity is an acceptable practice; however, 
occasional abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception.  Male patients should refrain from sperm donation for 3 
months following the last dose of olaparib. 
Female partners (of childbearing potential) of male patients must also use a highly 
effective method of contraception throughout this period (Highly effective methods of 
contraception Table below and Appendix G).  

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Female patients of child-bearing potential (For Steps 1, 2, and 3) 
• Females of childbearing potential are defined as those who are not surgically sterile (i.e., 
bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-
menopausal.  Women will be considered post-menopausal if they have been amenorrheic 
for 12 months without an alternative medical cause.  The following age-specific 
requirements apply:  
o Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).  
o Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses >1 year 
ago, had chemotherapy-induced menopause with last menses >1 year ago, or 
underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy). 
Highly effective methods of contraception, defined as one that results in a low failure rate (i.e., 
less than 1% per year) when used consistently and correctly are described in the Highly effective 
methods of contraception Table.  Note that some contraception methods are not considered 
highly effective (e.g., male or female condom with or without spermicide; female cap, 
diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; 
progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the 
primary mode of action [excluding Cerazette/desogestrel which is considered highly effective]; 
and triphasic combined oral contraceptive pills). 
 
Highly effective methods of contraception (<1% failure rate) 
Barrier/Intrauterine 
methods 
Hormonal Methods 
• 
Copper T intrauterine 
device 
• 
Levonorgestrel-releasing 
intrauterine system (e.g., 
Mirena®)a 
• 
Implants: Etonogestrel-releasing implants: e.g., Implanon® or 
Norplant®  
• 
Intravaginal: Ethinylestradiol/etonogestrel-releasing intravaginal 
devices: e.g., NuvaRing®  
• 
Injection: Medroxyprogesterone injection: e.g., Depo-Provera®  
• 
Combined Pill: Normal and low dose combined oral contraceptive pill 
• 
Patch: Norelgestromin/ethinylestradiol-releasing transdermal system: 
e.g., Ortho Evra®   
• 
Minipillc: Progesterone based oral contraceptive pill using desogestrel: 
Cerazette® is currently the only highly effective progesterone based 
pill 
a 
This is also considered a hormonal method 
 
Blood donation (For Steps 2 and 3 only) 
 

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Patients should not donate blood while participating in this study or for at least 120 days 
following the last infusion of durvalumab (MEDI4736).  
 
6.6 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 24 
months, as long as patients are gaining antitumor benefit as defined by PR or CR by RECIST 
v1.1, or until one of the following criteria applies: 
 
• Disease progression 
 
• Intercurrent illness that prevents further administration of treatment 
 
• Unacceptable adverse event(s) 
 
• Bone marrow findings consistent with MDS or AML, treatment with all agents will be 
stopped 
 
• Grade ≥3 infusion reaction 
 
• Patient decides to withdraw from the study 
 
• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
• Clinical progression 
 
• Patient non-compliance 
 
• Initiation of alternative anticancer therapy including other investigational agent 
 
• Pregnancy or intent to become pregnant  
 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed or 
late menstrual period) at any time during study participation. 
 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
• Termination of the study by sponsor 
 
• The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the CRF. 

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6.7 
Treatment Beyond Progression with Copanlisib + Olaparib or Copanlisib + Olaparib 
+ Durvalumab (MEDI4736) + Combination  
 
If progression occurs after confirmed response (CR or PR as defined by RECIST 1.1), continued 
therapy should not be permitted in the following cases:  
• Patients with rapid progression of disease at critical anatomical sites (e.g. cord 
compression) requiring urgent alternative medical intervention.  
• Patients who have clinically relevant worsening of laboratory values.  
• Patients who have a clinically significant decline in performance status at time of 
progression. 
Additionally, at the time that progression occurs, patients will be re-consented using a written 
informed consent document that details FDA-approved therapy, and its clinical benefit(s), that 
the patient will be foregoing in order to continue receiving the investigational products of the 
study. 
 
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 15 
mm).  Any new lesion considered non-measurable at the time of initial progression may become 
measurable and therefore included in the tumor burden measurement. 
 
Patients should follow the same treatment guidelines as stipulated in the protocol, including the 
same dose and frequency of treatments and the same schedule of assessments, and off-treatment 
criteria.  If PD is confirmed with subsequent staging scans, patient should be removed from the 
therapy.   
 
Clinically Stable 
Clinically Unstable 
 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat imaging at 
≥4 weeks to confirm 
PD 
May continue study 
treatment at the 
Investigator’s 
discretion while 
awaiting 
confirmatory scan 
Repeat imaging at 
≥4 weeks to confirm 
PD per physician 
discretion only 
Discontinue 
treatment 
Repeat scan 
confirms PD 
No additional 
imaging required 
Discontinue 
treatment 
No additional 
imaging required 
N/A 
Repeat scan 
shows SD, PR, or 
CR 
Continue regularly 
scheduled imaging 
assessments 
Continue study 
treatment at the 
local site 
Investigator’s 
discretion 
Continue regularly 
scheduled imaging 
assessments 
May restart 
study treatment 
if condition has 
improved 
and/or clinically 
stable per 
Investigator’s 
discretion 
 
6.8 
Duration of Follow Up 
 

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The study is expected to last between 18-24 months.  Thirty (30) days (± 7 days) after 
administration of the last dose of study drug, patients will return to the clinic for a final end-of-
study evaluation.  Any patient who prematurely discontinues the study for any reason will be 
instructed to return to the clinic and all procedures to be performed at the final end-of-study visit 
should be performed at this time.  Patients who discontinue the study prematurely due to an AE 
will be followed by the investigator until the AE is resolved or until the medical condition of the 
patient becomes stable.  After the end-of-study visit, patients will remain in long-term follow up 
until disease progression, start of a new cancer therapy, or for up to two years after the last dose 
of study drugs, whichever comes first.  During this time, the study staff will contact patients 
every 3 months (± 7 days)  via telephone for an AE assessment.  Each call should last 
approximately 5 minutes.  Patients will be monitored over the phone with local labs after 90 days 
and SAEs will only be reported if it is believed that there is a possibility they are related to 
treatment.  Depending on the findings of the telephone call, a follow up physical examination 
may be needed.   
 
The safety follow-up period will be at least 90 days after the administration of the last study drug 
for all patients, regardless of initiation of subsequent anticancer therapy. AEs and SAEs will be 
recorded from time of signature of informed consent, throughout the treatment period, up to 90 
days after the administration of the last dose of study drug. 
 
During the course of the study, all AEs and SAEs should be proactively followed up for each 
patient.  Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
 
If a patient discontinues from treatment for reasons other than disease progression, and therefore 
continues to have tumor assessments, drug or procedure-related SAEs must be captured until the 
patient is considered to have confirmed PD and will have no further tumor assessments. 
 
The investigator is responsible for following all SAEs until resolution, until the patient returns to 
baseline status, or until the condition has stabilized with the expectation that it will remain 
chronic, even if this extends beyond study participation. 
 
 
7. 
DOSING DELAYS/DOSE MODIFICATIONS FOR TREATMENT-RELATED 
TOXICITY 
 
7.1 
Copanlisib-Related Toxicity 
 
Recommended dose reductions for copanlisib: 
 
Any toxicity observed during the course of the study may be managed by interruption of the dose 
of study treatment or dose reductions. Repeat dose interruptions are allowed as required, for a 
maximum of 4 weeks on each occasion. Patients requiring a delay of >4 weeks should be taken 
off protocol therapy. If the interruption is any longer than 4 weeks, the lead study team must be 
informed. Patients requiring > 2 dose reductions should be taken off protocol therapy.  
 

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The lead study team must be informed if copanlisib is discontinued to determine if the patient 
may continue treatment on remaining therapies if continuing to receive clinical benefit. 
 
Copanlisib dose reductions for study treatment 
Initial copanlisib dose 
Dose reduction 1 
Dose reduction 2 
60 mg IV, Days 1 and 15 
45 mg IV, Days 1 and 15 
30 mg IV, Days 1 and 15 
 
 Dose delays/modifications for copanlisib-related toxicity: 
 
 
Nausea 
Management/Next Dose for Copanlisib 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level 
lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >4 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  antiemetics. 
 
Vomiting 
Management/Next Dose for Copanlisib  
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level 
lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >4 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  antiemetics. 
 
Diarrhea 
Management/Next Dose for Copanlisib  
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1.  Resume at same dose level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level 
lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >4 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:  4 mg at first onset, followed by 2 mg with each loose 
motion until diarrhea-free for 12 hours (maximum dosage:  16 mg/24 
hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when 
used. 

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Neutropenia 
Management/Next Dose for Copanlisib 
≤ Grade 1 
No change in dose 
Grade 2 
Investigator judgement to continue treatment or 
dose interruption; appropriate supportive treatment 
and causality investigation. Resume at same dose 
level. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level 
lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >4 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
 
Thrombocytopenia 
Management/Next Dose for Copanlisib 
≤ Grade 1 
No change in dose 
Grade 2 
Investigator judgement to continue treatment or 
dose interruption; appropriate supportive treatment 
and causality investigation. 
Grade 3 
Hold* until < Grade 2.  Resume at one dose level 
lower, if indicated.** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >4 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
 
7.1.1 Dose Modification Rules for Transient Post-Infusion Hyperglycemia 
 
Patients who develop transient post-infusion glucose >250 mg/dL after study drug administration 
may continue treatment.  However, the next infusion must be delayed until the patient’s pre-
infusion glucose levels return to <160 mg/dL (fasting) or <200 mg/dL (non-fasting).  Guidelines 
for the management of transient glucose increases are given in the tables below.  Continuing 
occurrence of post-infusion blood glucose >500 mg/dL, based on repeated laboratory analysis 
despite optimal glucose lowering therapy after 2 infusions of copanlisib, will require dose 
reduction by one dose level. 
• Further dose reduction (where appropriate per study design/population) is allowed as 
long as discontinuation criteria was not met. 
• Dose re-escalation is allowed when a patient has achieved controlled glucose levels per 
investigator’s judgment. 
• Persistent occurrence of post-infusion blood glucose >500 mg/dL based on laboratory 
analysis which occurred at the lowest dose level despite optimal glucose lowering therapy 
(after at least one cycle of treatment) with consultation of a diabetes specialist requires 
permanent discontinuation of the study drug. 
 
Management of post-infusion glucose increases 

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should be initiated. 
administrations may be reduced by 
1 dose level at the investigator’s 
discretion.a 
Post-dose:   
Drug-related 
CTCAE hypertension of 
grade 3 
or ≥160/100 mmHg b  
– 
Administration of BP lowering 
therapy should be initiated 
according to local standard of 
care.   
Additional measurements to be 
performed as clinically indicated 
until recovery to <150/90 mmHg.   
Subsequent study drug 
administrations may be reduced by 
1 dose level at the investigator’s 
discretion.b 
CTCAE hypertension of 
grade 4 
 
Permanent discontinuation – 
a:  The lowest dose level is 30 mg. 
b:  Not manageable despite optimal antihypertensive treatment. 
CTCAE = Common Terminology Criteria for Adverse Events; BP = blood pressure, 
 
Blood pressure measurement on treatment days 
BP will be measured every 5-10 minutes prior to each copanlisib dose (no more than 4 
measurements) until there are two consecutive results <150/90 mmHg.  If BP is ≥150/90 mmHg, 
the investigator can consider a medical intervention or delaying the infusion of study drug. The 
patient should rest for 5-10 min before blood pressure is recorded. 
On infusion days, BP will be measured at 0 hour (pre-dose), 30 minutes (mid-infusion), 60 minutes 
(end of infusion), and 1 hour after the end of infusion  
NOTE: A window of ±10 minutes is allowed for all BP measurements, except for pre-dose (0 
hour) measurement, which may apply a window of ±5 minutes. 
 
7.1.3 Non-Infectious Pneumonitis  
 
The investigator is requested to differentiate between non-infectious pneumonitis, and infectious 
pneumonitis (viral, bacterial, or fungal), aspiration pneumonitis, or other pneumonitis clearly not 
due to a potential hypersensitivity reaction to the copanlisib infusion; and provide the basis for 
his/her assessment that it is infectious or other, as appropriate.  The investigator is requested to 
report with the most specific clinical terms to describe the condition, not simple “pneumonitis”. 
 
In the event of suspected non-infectious pneumonitis, modify copanlisib treatment as per table 
below. 
 
Dose adjustment for non-infectious pneumonitis  
Suspected or confirmed NIP per 
Action Taken 
Re-treatment dose after recovery 

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CTCAE 
Grade 1 
No Change 
NA 
Grade 2 
Dose Interruption Until recovery to 
≤grade 1 
Decrease dose to the next lowest 
dose level a 
Grade 2 second re-occurrence 
Permanent Discontinuation 
NA 
Grade 3 
Permanent Discontinuation 
NA 
Grade 4 
Permanent Discontinuation 
NA 
NA = Not applicable; NIP = Non-infectious pneumonitis; CTCAE = Common Terminology Criteria for Adverse Events. 
a: Not applicable for 45 mg dose level. No re-escalation is allowed after the dose reduction. 
The lowest dose level is 45 mg; if a patient is already on the 45 mg dose level and cannot tolerate treatment study treatment will 
be discontinued permanently. 
 
7.2 
Olaparib-Related Toxicity 
 
Except where otherwise specified, the table below provides olaparib dose reduction 
recommendations from an assumed initial dose of 300 mg BID (the single-agent RP2D for 
olaparib).   
 
Any toxicity observed during the course of the study could be managed by interruption of the 
dose of study treatment or dose reductions.  Repeat dose interruptions are allowed as required, 
for a maximum of 4 weeks on each occasion.  If the interruption is any longer, the study team 
must be informed.  Study treatment can be dose reduced to 250 mg twice daily as a first step and 
to 200 mg twice daily as a second step.  If the reduced dose of 200 mg twice daily is not 
tolerable, further dose modifications can be discussed and approved by the PI and CTEP Medical 
Monitor and documented in writing.  
Once dose is reduced, escalation is not permitted (except following concomitant treatment with 
CYP3A4 inhibitors). 
 
The lead study team must be informed if olaparib is discontinued to determine if the patient may 
continue treatment on remaining therapies if continuing to receive clinical benefit. 
 
Olaparib dose reductions for study treatment 
Initial Olaparib Dose 
Following re-challenge post 
interruption: Dose reduction 1 
Dose reduction 2 
300 mg BID 
250 mg BID 
200 mg BID 
 
7.2.1 Dose Reduction/Discontinuation for Organ Dysfunction 
 
7.2.1.1 
Hepatic Impairment 
 
The effect of mild or moderate hepatic impairment (Child-Pugh classification A or B) on single 
dose PK of olaparib has been characterized and no olaparib dose adjustment in patients with mild 
or moderate hepatic impairment is required. 
 
Olaparib is not recommended for use in patients with severe hepatic impairment as the PK and 
safety of olaparib in patients with severe hepatic impairment has not been studied. 

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7.2.1.2 
Renal Impairment 
 
If, subsequent to study entry and while still on study therapy, a patient’s Cockcroft-Gault 
estimated CrCl falls below the threshold for study inclusion (≥51 mL/min), retesting should be 
performed promptly.  
 
A dose reduction is recommended for patients who develop moderate renal impairment (CrCl 
between 31 and 50 mL/min, as estimated by Cockcroft-Gault or based on a 24-hour urine test) 
for any reason during the course of the study: the dose of olaparib should be reduced to 200 mg 
BID. 
 
Because the CrCl determination is only an estimate of renal function, in instances where the CrCl 
falls to between 31 and 50 mL/min, the investigator should use his or her discretion in 
determining whether a dose change or discontinuation of therapy is warranted. 
 
The effect of mild and moderate renal impairment on the single dose PK of olaparib has been 
evaluated in a formal renal impairment study.  Olaparib has not been studied in patients with 
severe renal impairment (CrCl ≤30 mL/min) or end-stage renal disease; if patients develop 
severe impairment or end stage disease, is it recommended that olaparib be discontinued. 
 
Olaparib dose reduction if patient develops moderate renal impairment 
Initial Olaparib Dose 
Moderate renal impairment (calculated creatinine clearance by 
Cockcroft-Gault equation or based on a 24 hour urine test 
between 31 and 50 mL/min): Dose reduction  
 
300 mg BID 
200 mg BID 
 
7.2.2 Dose Reductions for Patients Receiving a Strong or Moderate CYP3A4 Inhibitor 
 
As noted in Sections 6.4.2.3.1 and 6.4.2.3.2, patients should avoid taking strong or moderate 
CYP3A4 inhibitors while receiving olaparib.  If there is no suitable alternative concomitant 
medication, the dose of olaparib should be reduced for the period of concomitant administration.  
The dose reduction of olaparib should be recorded on the CRF with the reason documented as 
concomitant CYP3A inhibitor use. 
  
Olaparib dose reductions if patient must take a strong or moderate CYP3A inhibitor 
Initial Olaparib Dose 
Olaparib Dose if Receiving a 
Strong CYP3A inhibitor 
Olaparib Dose if Receiving a 
Moderate CYP3A inhibitor 
300 mg BID 
100 mg BID 
150 mg BID 
     
7.2.3 Management of Hematological Toxicity 
 

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7.2.3.1 
Management of Anemia 
 
Management of Anemia 
Hemoglobin (Hb) 
Action to be taken 
Hb <10 but ≥8 g/dL 
(CTCAE Grade 2) 
First occurrence: 
Give appropriate supportive treatment and investigate causality.  
Investigator judgement to continue olaparib with supportive treatment 
(e.g. transfusion) or interrupt dose for a maximum of 4 weeks.  Study 
treatment can be restarted if Hb has recovered to >9 g/dL.  
Subsequent occurrences: 
If Hb <10 but ≥9 g/dL, investigator judgement to continue olaparib with 
supporting treatment (e.g. transfusion) or dose interrupt (for max of 4 
weeks) and upon recovery dose reduction may be considered (to 250 mg 
twice daily as a first step and to 200 mg twice daily as a second step). 
If  Hb <9 but ≥8 g/dL, dose interrupt (for max of 4 weeks) until Hb ≥9 
g/dL and upon recovery dose reduction may be considered (to 250 mg 
twice daily as a first step and to 200 mg twice daily as a second step). 
Hb <8 g/dL 
(CTCAE Grade 3) 
Give appropriate supportive treatment (e.g. transfusion) and investigate 
causality.  
Interrupt olaparib for a maximum of 4 weeks until improved to Hb ≥9 
g/dL. 
Upon recovery dose reduce to 250 mg twice daily as a first step and to 
200 mg twice daily as a second step in the case of repeat Hb decrease. 
 
Common treatable causes of anemia (e.g., iron, vitamin B12, or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed.  In some cases, management 
of anemia may require blood transfusions.  For cases where patients develop prolonged 
hematological toxicity (≥2 week interruption/delay in study treatment due to CTCAE grade 3 or 
worse anemia and/or development of blood transfusion dependence), refer to Section 7.2.3.3 for 
the management of this.  
 
7.2.3.2 
Management of Neutropenia, Leukopenia and Thrombocytopenia 
 
Management of Neutropenia, Leukopenia and Thrombocytopenia 
Toxicity 
Study treatment dose adjustment 
CTCAE Grade 1-2 
Investigator judgement to continue treatment or if dose interruption, this 
should be for a maximum of 4 weeks; appropriate supportive treatment 
and causality investigation 
CTCAE Grade 3-4 
Dose interruption until recovered to CTCAE grade 1 or better for a 
maximum of 4 weeks.  If repeat CTCAE grade 3-4 occurrence, dose 
reduce olaparib to 250 mg twice daily as a first step and 200 mg twice 
daily as a second step 
 

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AEs of neutropenia and leukopenia should be managed as deemed appropriate by the 
investigator with close follow-up and interruption of study drug if CTCAE grade 3 or worse 
neutropenia occurs. 
 
Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is not recommended; 
however, if a patient develops febrile neutropenia, study treatment should be stopped and 
appropriate management including G-CSF should be given according to local hospital 
guidelines.  Please note that G-CSF should not be used within at least 24 hours (7 days for 
pegylated G-CSF) of the last dose of study treatment unless absolutely necessary. 
 
Platelet transfusions, if indicated, should be done according to local hospital guidelines. 
 
For cases where patients develop prolonged hematological toxicity (≥2 week interruption/delay 
in study treatment due to CTCAE grade 3 or worse), refer to the next section.  
 
7.2.3.3 
Management of Prolonged Hematological Toxicities While on Study Treatment 
 
If a patient develops prolonged hematological toxicity such as: 
• ≥2 week interruption/delay in study treatment due to CTCAE grade 3 or worse anemia 
and/or development of blood transfusion dependence 
• ≥2 week interruption/delay in study treatment due to CTCAE grade 3 or worse 
neutropenia (ANC <1×109/L) 
• ≥2 week interruption/delay in study treatment due to CTCAE grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (platelets 
<50×109/L) 
Check weekly differential blood counts including reticulocytes and peripheral blood smear.  
Study treatment should be discontinued if blood counts do not recover to CTCAE grade 1 or 
better within 4 weeks of dose interruption.  Refer to a hematologist. 
 
If any blood parameters remain clinically abnormal after 4 weeks of dose interruption, the patient 
should be referred to hematologist for further investigations.  Patients with laboratory findings 
consistent with AML or MDS should receive a full work up as per the local standard of care for 
evaluation of a suspected hematological malignancy including, but not limited to, bone marrow 
aspirate/smear, flow cytometric evaluation of the marrow, and evaluation of cytogenetics.  If it is 
not possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then 
attempts should be made to carry out the tests on a blood sample. 
 
Development of a confirmed MDS, AML, or other clonal blood disorder should be reported as 
an SAE via CTEP-AERS and full reports must be provided by the investigator to the CTEP 
Medical Officer.  Olaparib treatment should be discontinued if the patient’s diagnosis of MDS 
and/or AML is confirmed. 
 
7.2.4 Management of Non-Hematological Toxicity 
 

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Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion.  
If the interruption is longer than 4 weeks, the CTEP Medical Monitor must be informed.  Where 
toxicity reoccurs following re-challenge with study treatment, and where further dose 
interruptions are considered inadequate for management of toxicity, then the patient should be 
considered for dose reduction or must permanently discontinue study treatment. 
 
Study treatment can be dose reduced to 250 mg BID as a first step and to 200 mg BID as a 
second step.  Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 AE occurs which 
the investigator considers to be related to administration of study treatment. 
 
7.2.4.1 
Management of New or Worsening Pulmonary Symptoms  
 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormalities occur in 
the absence of a clear diagnosis, an interruption in study treatment dosing is recommended and 
further diagnostic workup (including a high-resolution CT scan) should be performed to exclude 
pneumonitis.  Guidance for immune-mediated pneumonitis is provided in the durvalumab 
toxicity management guidelines (Section 7.3).  
 
Following investigation, if no evidence of abnormality is observed on CT imaging and symptoms 
resolve, then study treatment can be restarted, if deemed appropriate by the investigator. If 
significant pulmonary abnormalities are identified, these need to be discussed with the CTEP 
Medical Monitor. 
 
7.2.4.2 
Management of Nausea and Vomiting 
 
Events of nausea and vomiting are known to be associated with olaparib treatment.  These events 
are generally mild to moderate (CTCAE grade 1 or 2) severity, intermittent, and manageable on 
continued treatment.  The first onset generally occurs in the first month of treatment for nausea 
and within the first 6 months of treatment for vomiting.  For nausea, the incidence generally 
plateaus at around 9 months, and for vomiting at around 6 to 7 months. 
 
No routine prophylactic anti-emetic treatment is required at the start of study treatment; however, 
patients should receive appropriate anti-emetic treatment at the first onset of nausea or vomiting 
and as required thereafter, in accordance with local treatment practice guidelines.  Alternatively, 
olaparib tablets can be taken with a light meal/snack (i.e., two pieces of toast or a couple of 
cookies, crackers, or biscuits). 
 
As per international guidance on anti-emetic use in cancer patients (European Society for 
Medical Oncology [ESMO], National Comprehensive Cancer Network [NCCN]), generally a 
single agent antiemetic should be considered, such as a dopamine receptor antagonist, 
antihistamine, or dexamethasone. 
 
7.2.4.3 
Interruptions for Intercurrent Non-Toxicity Related Events 
 
Study treatment dose interruption for conditions other than toxicity resolution should be kept as 
short as possible.  If a patient cannot restart study treatment within 4 weeks for resolution of 

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intercurrent conditions not related to disease progression or toxicity, the case should be discussed 
with the CTEP Medical Monitor. 
 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the electronic CRF (eCRF).  
 
Study treatment should be stopped at least 3 days prior to planned surgery.  After surgery study 
treatment can be restarted when the wound has healed.  No stoppage of study treatment is 
required for any needle biopsy procedure. 
 
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
radiation treatment. Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered. 
 
Because the AEs related to olaparib may include asthenia, fatigue, and dizziness, patients should 
be advised to use caution while driving or using machinery if these symptoms occur.  
 
7.3 
Durvalumab (MEDI4736)-Related Toxicity 
 
Guidelines for the management and dosing modifications for immune-mediated reactions, 
infusion-related reactions, and non-immune-mediated reactions for MEDI4736 (durvalumab) 
monotherapy are provided in the subsections below as follows: 
• 
General guidelines for toxicity management and dosing modifications  
• 
Toxicity management and dosing modification guidelines for specific immune-related 
adverse events (irAEs)/immune-mediated AEs (imAEs) and other irAEs/imAEs not 
specified  
• 
Toxicity management and dosing modification guidelines for infusion-related reactions  
• 
Toxicity management and dosing modifications guidelines for non-immune-mediated 
AEs  
 
Because immune-mediated events can occur in nearly any organ or tissue, therefore, these 
guidelines may not include all the possible immune-mediated reactions.  Investigators are 
advised to take into consideration the appropriate practice guidelines and other society guidelines 
(e.g., NCCN, ESMO) in the management of these events.  Dose reductions are not permitted.  
Dose may be delayed or permanently discontinued as directed by Dosing Modification 
Table below.   In case of doubt, the Investigator should consult with the Study Physician. 
 
The lead study team must be informed if durvalumab (MEDI4736) is discontinued to determine 
if the patient may continue treatment on remaining therapies if continuing to receive clinical 
benefit. 
 
 
TABLE 5a:  General Guidelines for Toxicity Management and Dosing Modifications for 
Durvalumab and/or Tremelimumab (Note – this guideline is consistent with TMG version 
October 2022 from Astra-Zeneca) 

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regimen will be based upon 
treating physician’s 
discretion and after 
completion of steroid taper 
(<10 mg prednisone or 
equivalent). 
− Promptly start systemic steroids (e.g., 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent). 
− Consider HRCT or chest CT with contrast, 
Repeat imaging study, as clinically 
indicated. 
− If no improvement within 3 to 5 days, 
additional workup should be considered 
and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day  
− If no improvement within 2 to 3 days 
despite IV methylprednisolone at 2 to 
4 mg/kg/day, promptly start 
immunosuppressive agent such as tumor 
necrosis factor (TNF) inhibitors 
(e.g., infliximab at 5 mg/kg IV once, may 
be repeated at 2 and 6 weeks after initial 
dose at the discretion of the treating 
provider or relevant practice guidelines).  
Caution: It is important to rule out sepsis 
and refer to infliximab label for general 
guidance before using infliximab. 
− Consider discussing with study PI. 
Grade 3 or 4 
 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4  
− Hospitalize the patient. 
− Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day or 
equivalent. 
− Obtain Pulmonary and Infectious Disease 
Consults; consider discussing with study 
PI, as needed. 
− Consider starting anti-infective therapy if 
infection is still a consideration on the 
basis of other diagnostic testing despite 
negative culture results. 
− Supportive care  (e.g., oxygen). 
− If no improvement within 2 days, 
additional workup should be considered 
and prompt treatment with additional 
immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg IV, 
may be repeated at 2 and 6 weeks after 
initial dose at the discretion of the 
treating provider or relevant practice 
guidelines).  Caution: rule out sepsis and 
refer to infliximab label for general 
guidance before using infliximab. 

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Diarrhea/ Colitis 
For Any Grade: 
− 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression,other medications, or infections), including testing for Clostridium difficile toxin, 
etc. 
− 
Monitor for symptoms that may be related to diarrhea/enterocolitis (abdominal pain, cramping, 
or changes in bowel habits such as increased frequency over baseline or blood in stool) or 
related to bowel perforation (such as sepsis, peritoneal signs, and ileus). 
− 
WHEN SYMPTOMS OR EVALUATION INDICATE AN INTESTINAL 
PERFORATION IS SUSPECTED, CONSULT A SURGEON EXPERIENCED IN 
ABDOMINAL SURGERY IMMEDIATELY WITHOUT ANY DELAY. 
− 
PERMANENTLY DISCONTINUE STUDY DRUG FOR ANY GRADE OF 
INTESTINAL PERFORATION. 
− 
Consider further evaluation with imaging study with contrast. 
− 
Consult a gastrointestinal (GI) specialist for consideration of further workup. 
− 
Steroids should be considered in the absence of clear alternative etiology, even for low-grade 
events, in order to prevent potential progression to higher grade events, including intestinal 
perforation. 
− 
Use analgesics carefully; they can mask symptoms of perforation and peritonitis. 
Grade 1 
 
No dose modifications. 
For Grade 1: 
− Monitor closely for worsening symptoms. 
− Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes (e.g., 
American Dietetic Association colitis 
diet), loperamide, and other supportive 
care measures. 
− If symptoms persist, consider checking 
lactoferrin; if positive, treat as Grade 2 
below. If negative and no infection, 
continue Grade 1 management. 
Grade 2 
 
Hold study drug/study regimen 
until resolution to Grade ≤1 
• If toxicity improves to Grade 
≤1, then study drug/study 
regimen can be resumed after 
completion of steroid taper 
(<10 mg prednisone, or 
equivalent). 
 
For Grade 2: 
− Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes (e.g., 
American Dietetic Association colitis 
diet), and loperamide and/or budesonide. 
− Consider further evaluation with imaging 
study with contrast. 
− Consider consult of a gastrointestinal (GI) 
specialist for consideration of further 
workup. 
− Promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− If event is not responsive within 2 to 3 days 
or worsens, obtain GI consult for 
consideration of further workup, such as 
imaging and/or colonoscopy, to confirm 
colitis and rule out perforation.  Promptly 
start IV methylprednisolone 1 to 2 
mg/kg/day. 
− If no improvement within 3 days despite 
therapy with 1 to 2 mg/kg IV 
methylprednisolone,  reconsult GI 
specialist and, if indicated, promptly start 
additional immunosuppressant agent such 
as infliximab at 5 mg/kg IV (may be 

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121 
repeated at 2 and 6 weeks after initial dose 
at the discretion of the treating provider or 
relevant practice guidelines)a.  Caution: it 
is important to rule out bowel perforation 
and refer to infliximab label for general 
guidance before using infliximab. 
− If perforation is suspected, consult a 
surgeon experienced in abdominal 
surgery immediately without any delay. 
− Consider, as necessary, discussing with 
study PI if no resolution to Grade ≤1 in 3 
to 4 days. 
Grade 3 or 4 
 
Grade 3 
For patients treated with 
durvalumab monotherapy, hold 
study drug/study regimen until 
resolution to Grade ≤1; study 
drug/study regimen can be 
resumed after completion of 
steroid taper (<10 mg 
prednisone per day, or 
equivalent). 
 
For patients treated with 
durvalumab in combination 
with other products (not 
tremelimumab), decision to be 
made at the discretion of the 
study investigator, in discussion 
with study PI. 
For patients treated with 
durvalumab in combination 
with tremelimumab or 
tremelimumab monotherapy, 
Permanently discontinue both 
durvalumab and 
tremelimumab for 1) Grade 3 
diarrhea/colitis or 2) Any 
grade of intestinal 
perforation 
 
Grade 4 
Permanently discontinue  
study drug/study regimen. 
For Grade 3 or 4: 
− Urgent GI consult and imaging and/or 
colonoscopy as appropriate. 
− Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent. 
− Monitor stool frequency and volume and 
maintain hydration. 
− If still no improvement within 2 days, 
continue steroids and promptly add further 
immunosuppressant agents (e.g., infliximab 
at 5 mg/kg IV, may be repeated at 2 and 6 
weeks after initial dose at the discretion of 
the treating provider or relevant practice 
guidelines).  Caution: Ensure GI consult to 
rule out bowel perforation and refer to 
infliximab label for general guidance before 
using infliximab. 
− If perforation is suspected, consult a 
surgeon experienced in abdominal 
surgery immediately without any delay. 
Hepatitis (elevated 
LFTs) 
 
Infliximab should not 
be used for 
management of 
immune-related 
hepatitis. 
 
PLEASE SEE 
For Any Grade: 
− 
Monitor and evaluate transaminases (aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], alkaline phosphatase [ALP]) and total bilirubin. 
− 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., viral 
hepatitis, disease progression, concomitant medications).Infliximab should not be used 
for immune-mediated hepatitis. 
 
Grade 1  
ALT or AST 
≤3×ULN or 
− No dose modifications. 
− If it worsens, then consider 
holding therapy. 
For Grade 1: 
− 
Continue transaminase and total bilirubin 
monitoring per protocol. 

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122 
shaded area 
immediately below 
this section to find 
guidance for 
management of 
“Hepatitis (elevated 
LFTS)” in 
hepatocellular 
carcinoma (HCC) 
patients 
(or secondary tumor 
involvement of the 
liver with abnormal 
baseline values 
[BLV]) 
total bilirubin 
≤1.5×ULN 
Grade 2  
ALT or AST 
>3× to 
≤5×ULN or 
total bilirubin 
>1.5× to 
≤3×ULN  
• Hold study drug/study 
regimen dose until Grade ≤1. 
Resume study drug/study 
regimen after completion of 
steroid taper (<10 mg 
prednisone or equivalent). 
• Permanently discontinue 
study drug/study regimen for 
any case meeting Hy’s law 
laboratory criteria (AST 
and/or ALT >3×ULN + 
bilirubin >2×ULN without 
initial findings of cholestasis 
(i.e., elevated ALP) and in 
the absence of any alternative 
cause. 
For Grade 2: 
− Regular and frequent checking of 
transaminases and total bilirubin (e.g., 
every 1 to 2 days) until transaminases and 
total bilirubin elevations improve or 
resolve. 
− If no resolution to Grade ≤1 in 1 to 2 days, 
consider, as necessary, discussing with 
study PI. 
− If event is persistent (>2 to 3 days) or 
worsens, promptly start prednisone 1 to 
2 mg/kg/day PO or IV equivalent. 
Grade 3 
(ALT or AST 
>5× to 
≤10×UL) 
• Hold study drug/study 
regimen. Resume study 
drug/study regimen if 
elevations downgrade to 
Grade ≤1 after completion of 
steroid taper (<10 mg 
prednisone, or equivalent). 
• If in combination with 
tremelimumab, do not 
restart tremelimumab. 
For Grade 3: 
• Promptly initiate empiric IV 
methylprednisolone at 1 to 2 mg/kg/day or 
equivalent. 
• Perform Hepatology Consult, abdominal 
workup, and imaging as appropriate. If still 
no improvement within 2 to 3 days despite 1 
to 2 mg/kg/day methylprednisolone IV or 
equivalent, promptly start treatment with an 
additional immunosuppressant (i.e., 
mycophenolate mofetil 0.5 – 1 g every 12 
hours then taper in consultation with 
hepatology consult or relevant practice 
guidelines).  Discuss with Study PI if 
mycophenolate is not available.  Infliximab 
should NOT be used. 
Grade 4 
ALT or AST 
>10×ULN 
OR total 
bilirubin 
>3×ULN 
 
Hy’s Law 
criteria 
Concurrent 
ALT or AST 
>3×ULN 
AND total 
bilirubin 
>2×ULN 
• Permanently discontinue 
study drug/study regimen.  
For Grade 4: 
− Promptly initiate empiric IV 
methylprednisolone at 1 to 2 mg/kg/day or 
equivalent. 
− If still no improvement within 2 to 3 days 
despite 1 to 2 mg/kg/day 
methylprednisolone IV or equivalent, 
promptly start treatment with an additional 
immunosuppressant (i.e., mycophenolate 
mofetil 0.5 – 1 g every 12 hours then taper 
in consultation with hepatology consult or 
relevant practice guidelines).  Discuss with 
Study PI if mycophenolate is not available.  
Infliximab should NOT be used. 
Perform Hepatology Consult, abdominal 
workup, and imaging as appropriate. 

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Nephritis and/or 
renal dysfunction 
(elevated serum 
creatinine) 
Any Grade: 
− Consider consulting a nephrologist. 
− Consider imaging studies to rule out any alternative etiology. 
− Monitor for signs and symptoms that may be related to changes in renal function (e.g., routine 
urinalysis, elevated serum BUN and creatinine, decreased creatinine clearance, electrolyte 
imbalance, decrease in urine output, or proteinuria). Follow urine protein/creatinine ratio every 
3-7 days. 
− Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression or infections).  
− Steroids should be considered in the absence of clear alternative etiology even for low-grade 
events (Grade 2), in order to prevent potential progression to higher grade event. 
 
Grade 1 
 
No dose modifications. 
For Grade 1: 
− Monitor serum creatinine weekly and any 
accompanying symptoms. 
• If creatinine returns to baseline, resume 
regular monitoring per study protocol. 
• If creatinine worsens, depending on the 
severity, treat as Grade 2, 3, or 4. 
− Consider hydration, electrolyte replacement, 
and diuretics, as clinically indicated. 
− Consider nephrologist consult if not 
resolved within 14 days, or earlier as 
clinically indicated. 
Grade 2 
 
Hold study drug/ study regimen 
until resolution to Grade ≤1 or 
baseline.  
− If toxicity improves to 
Grade ≤1 or baseline, then 
resume study drug/study 
regimen after completion of 
steroid taper (<10 mg 
prednisone, or equivalent). 
For Grade 2: 
− Consider including hydration, electrolyte 
replacement, and diuretics, as clinically 
indicated. 
− Follow urine protein/creatinine ratio every 
3-7 days. 
− Carefully monitor serum creatinine as 
clinically warranted. 
− Consult nephrologist and consider renal 
biopsy if clinically indicated. 
− Start prednisone 0.5 – 1 mg/kg/day if other 
causes are ruled out. 
− If event is persistent (beyond 5 days) or 
worsens, increase to prednisone up to 2 
mg/kg/day PO or IV equivalent. 
− If event is not responsive within 5 days or 
worsens despite prednisone at 1 to 2 
mg/kg/day PO/IV equivalent, consider 
additional workup. 
− When event returns to baseline, resume 
study drug/study regimen and routine serum 
creatinine monitoring per study protocol. 
Grade 3 or 4 
 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− Carefully monitor serum creatinine daily. 
− Follow urine protein/creatinine ratio every 
3-7 days. 
− Consult nephrologist and consider renal 
biopsy if clinically indicated. 
− Promptly start prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
− If event is not responsive within 3 to 5 days 
of steroids or worsens despite prednisone at 

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1 to 2 mg/kg/day PO or IV equivalent, 
consider additional workup and prompt 
treatment with an immunosuppressant. 
Rash or Dermatitis  
 
General Guidance 
For Any Grade: 
− 
Patients should be thoroughly evaluated to rule out any alternative etiology. 
− 
Monitor for signs and symptoms of dermatitis (rash and pruritus). 
HOLD STUDY DRUG IF GRADE 3 PEMPHIGOID OR SEVERE CUTANEOUS 
ADVERSE REACTION (SCAR)1 IS SUSPECTED. 
− 
PERMANENTLY DISCONTINUE STUDY DRUG IF SCAR OR GRADE 3 
PEMPHIGOID IS CONFIRMED. 
 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, 
including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and 
topical therapy (e.g., emollient, lotion, or 
institutional standard). 
Grade 2 
For persistent (>1 week) 
Grade 2 events, hold scheduled 
study drug/study regimen until 
resolution to Grade ≤1 or 
baseline. 
• If toxicity improves to Grade 
≤1 or baseline, resume 
drug/study regimen after 
completion of steroid taper 
(<10 mg prednisone or 
equivalent). 
For Grade 2: 
− 
Consider dermatology consult and skin 
biopsy, as indicated. 
− 
Consider symptomatic treatment, 
including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and 
topical therapy. 
− 
Consider moderate-strength topical 
steroid. 
− 
If no improvement of rash/skin lesions 
occurs within 1 week or is worsening 
despite symptomatic treatment and/or use 
of moderate strength topical steroid, 
consider discussing with study PI and 
promptly start systemic steroids such as 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
Grade 3 
Hold study drug/study regimen 
until resolution to Grade ≤1 or 
baseline. 
 
If toxicity improves to Grade 
≤1 or baseline, then resume 
drug/study regimen after 
completion of steroid taper  
(<10  mg  prednisone,  or 
equivalent). 
For Grade 3: 
− 
Reconsult a dermatologist. Consider skin 
biopsy (preferably more than 1) as 
clinically feasible. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 
− 
Consider, as necessary, discussing with 
study PI. 
Grade 4 
Permanently discontinue study 
drug. 
For Grade 4: 
Same as grade 3. 

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Endocrinopathy 
(e.g., hyperthyroidism, 
thyroiditis, 
hypothyroidism, Type 
1 diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency) 
Any Grade 
(Depending on the type of endocrinopathy, refer to NCI CTCAE applicable version in study 
protocol for defining the CTCAE grade/severity.) 
General Guidance 
For Any Grade: 
− Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression including brain metastases, or infections). 
− Consider consulting an endocrinologist for endocrine events. 
− Consider discussing with study PI, as needed. 
− Monitor patients for signs and symptoms of endocrinopathies. (Non-specific symptoms include 
headache, fatigue, behavior changes, mental status changes, photophobia, visual field cuts, 
vertigo, abdominal pain, unusual bowel habits, polydipsia, polyuria, hypotension, and 
weakness.) 
− Depending on the suspected endocrinopathy, monitor and evaluate thyroid function tests: 
thyroid stimulating hormone (TSH), free T3 and free T4 and other relevant endocrine and 
related labs (e.g., blood glucose and ketone levels, hemoglobin H1c (HgA1c)). If a patient 
experiences an AE that is thought to be possibly of autoimmune nature (e.g., thyroiditis, 
pancreatitis, hypophysitis, or diabetes insipidus), the investigator should send a blood sample for 
appropriate autoimmune antibody testing. 
− Investigators should ask subjects with endocrinopathies who may require prolonged or 
continued hormonal replacement, to consult their primary care physicians or endocrinologists 
about further monitoring and treatment after completion of the study. 
Grade 1 
No dose modifications. 
For Grade 1 (including asymptomatic TSH 
elevation): 
− 
Monitor patient with appropriate 
endocrine function tests. 
− 
For suspected 
hypophysitis/hypopituitarism, consider 
consulting an endocrinologist to guide 
assessment of early-morning 
adrenocorticotropin hormone (ACTH), 
cortisol, TSH and free T4; also consider 
gonadotropins, sex hormones, and 
prolactin levels, as well as cosyntropin 
stimulation test (though it may not be 
useful in diagnosing early secondary 
adrenal insufficiency). 
− 
If TSH <0.5 × LLN, or TSH >2 × ULN or 
consistently out of range in 2 subsequent 
measurements, include free T4 at 
subsequent cycles as clinically indicated 
and consider consultation of an 
endocrinologist. 
Grade 2, 3 or 
4 
 
− For Grade 2-4 
endocrinopathies other than 
hypothyroidism and type 1 
diabetes mellitus (T1DM), 
consider holding study 
drug/study regimen dose 
until acute symptoms 
resolve. 
− Study drug/study regimen 
can be resumed once patient 
stabilizes and after 
completion of steroid taper 
(<10 mg prednisone, or 
For Grade 2, 3 and 4: 
− 
Consult endocrinologist to guide 
evaluation of endocrine function and, as 
indicated by suspected endocrinopathy 
and as clinically indicated, consider 
pituitary scan. 
− 
For all patients with abnormal endocrine 
work-up, except those with isolated 
hypothyroidism or T1DM, and as guided 
by an endocrinologist, consider short-term 
corticosteroids (e.g., 1 to 2 mg/kg/day 
methylprednisolone or IV equivalent) and 
prompt initiation of treatment with 

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128 
equivalent). 
− Patients with 
endocrinopathies who may 
require prolonged or 
continued steroid 
replacement (e.g., adrenal 
insufficiency) can be 
retreated with study 
drug/study regimen if the 
patient is clinically stable as 
per investigator or treating 
physician’s clinical 
judgement. 
 
relevant hormone replacement. 
− 
Isolated hypothyroidism may be treated 
with replacement therapy, without 
study drug/study regimen interruption, 
and without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus (DM) 
may be treated with appropriate 
diabetic therapy, and without 
corticosteroids. Only hold study 
drug/study regimen in setting of 
hyperglycemia when diagnostic workup 
is positive for diabetic ketoacidosis.  
− 
For patients with normal endocrine 
workup (laboratory assessment or MRI 
scans), repeat laboratory assessments/MRI 
as clinically indicated. 
 
Amylase/ Lipase 
Increased 
For Any Grade:  
− 
Patients should be thoroughly evaluated to rule out any alternative etiology. 
− 
For modest asymptomatic elevations in serum amylase and lipase, corticosteroid treatment is 
not indicated as long as there are no other signs or symptoms of pancreatic inflammation.  
− 
Assess for signs/symptoms of pancreatitis.  
− 
Consider appropriate diagnostic testing (e.g., abdominal CT with contrast, MRCP if clinical 
suspicion of pancreatitis and no radiologic evidence on CT). 
− 
If isolated elevation of enzymes without evidence of pancreatitis, continue immunotherapy.  
Consider other causes of elevated amylase/lipase. 
− 
If evidence of pancreatitis, manage according to pancreatitis recommendations.  
Grade 1 
No dose modifications. 
See guidance above. 
Grade 2, 3, 
or 4 
In consultation with relevant 
gastroenterology specialist 
consider continuing study 
drug/study regimen if no 
clinical/radiologic evidence of 
pancreatitis ± improvement in 
amylase/lipase. 
See guidance above. 
Acute Pancreatitis 
For Any Grade:  
- 
Patients should be thoroughly evaluated to rule out any alternative etiology. 
- 
Consider Gastroenterology referral. 
Grade 2 
Consider holding study 
drug/regimen. 
- Consider IV hydration. 
- Consider Gastroenterology referral. 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen 
until resolution of elevated 
enzymes and no radiologic 
findings. 
If no elevation in enzymes or 
return to baseline values, then 
resume study drug/study 
regimen after completion of 
steroid taper (<10 mg 
prednisone, or equivalent). 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
- Promptly start systemic steroids prednisone 
1 to 2 mg/kg/day PO or IV equivalent. 
- IV hydration. 

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129 
Nervous System 
Disorders 
(for specific 
neurological AEs 
below, refer to 
separate 
management 
guidelines in 
subsequent rows:  
• aseptic meningitis,  
• encephalitis,  
• transverse myelitis,  
• peripheral 
neuropathy,  
• myasthenia gravis, 
and  
• Guillain-Barré) 
General Guidance 
For Any Grade: 
− Patients should be evaluated to rule out any alternative etiology (e.g., disease progression, 
infections, metabolic syndromes, or medications). 
− Monitor patient for general symptoms (headache, nausea, vertigo, behavior change, or 
weakness). 
− Consider appropriate diagnostic testing (e.g., electromyogram and nerve conduction 
investigations). 
− Perform symptomatic treatment with neurological consult as appropriate. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” recommendations 
above. 
− 
Treat mild signs/symptoms as Grade 1 
(e.g.  loss of deep tendon reflexes or 
paresthesia) 
Grade 2 
For acute motor 
neuropathies or 
neurotoxicity, hold study 
drug/study regimen dose until 
resolution to Grade ≤1. 
For sensory 
neuropathy/neuropathic pain, 
consider holding study 
drug/study regimen dose until 
resolution to Grade ≤1. 
 
Permanently discontinue 
durvalumab/ tremelimumab if 
Grade 2 imAE does not 
resolve to Grade ≤1 within 30 
days. 
 
If toxicity worsens, treat as 
Grade 3 or 4. 
Study drug(s) can be resumed 
after improvement to Grade 
≤1 and after completion of 
steroid taper. 
For Grade 2: 
− Consider, as necessary, discussing with the 
study PI. 
− Obtain neurology consult. 
− Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications (e.g., 
gabapentin or duloxetine). 
− Promptly start systemic steroids prednisone 1 
to 2 mg/kg/day PO or IV equivalent. 
− If no improvement within 2 to 3 days despite 
1 to 2 mg/kg/day prednisone PO or IV 
equivalent, consider additional workup and 
promptly treat with additional 
immunosuppressive therapy (e.g., IV Ig or 
other immunosuppressant depending on the 
specific imAE). 
Grade 3 or 4 
Permanently discontinue 
study drug/study regimen if 
Grade 3 imAE does not 
resolve to Grade ≤1 within 30 
days. 
For Grade 3 or 4: 
− Consider, as necessary, discussing with 
study PI. 
− Obtain neurology consult. 
− Consider hospitalization. 
− Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent. 
− If no improvement within 2 to 3 days despite 
IV corticosteroids, consider additional 
workup and promptly treat with additional 
immunosuppressants (e.g., IV IG or other 
immunosuppressant depending on the 
specific imAE). 
− Once stable, gradually taper steroids over 
≥28 days. 
 

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130 
Aseptic meningitis 
Any Grade 
Permanently discontinue 
study drug. 
For Any Grade: 
− Consider neurology consult. 
− Consider MRI brain with and without contrast 
with pituitary protocol and a lumbar puncture 
for 
− diagnosis. 
− Exclude bacterial and viral infections. (i.e., 
HSV). 
− Consider IV acyclovir until polymerase chain 
reactions are available. 
− Consider, as necessary, discussing with study 
PI. 
− Consider hospitalization. 
Encephalitis 
General Guidance 
− Symptoms may include confusion, altered behavior, headaches, seizures, short-term memory 
loss, depressed level of consciousness, focal weakness, and speech abnormality. 
For Any Grade: 
− Consider neurology consult. 
− Consider testing including MRI of the brain with and without contrast, lumbar puncture, 
electroencephalogram (EEG) to evaluate for subclinical seizures, ESR, CRP, antineutrophil 
cytoplasmic antibody (ANCA) (if vasculitic process suspected), thyroid panel including TPO 
and thyroglobulin and additional autoantibodies to rule out paraneoplastic disorders. 
− Exclude bacterial and viral infections. (i.e., HSV) 
− Consider IV acyclovir until polymerase chain reactions are available. 
Grade 2 
Permanently discontinue 
study drug/study regimen. 
− Consider, as necessary, discussing with study 
PI. 
− Once infection is ruled out, start 
methylprednisolone 1-2 mg/kg/day. 
− For progressive symptoms or if oligoclonal 
bands are present, consider 
methylprednisolone 1 g IV daily for 3-5 days 
plus IV Ig or plasmapheresis. 
Grade 3 or 4 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4: 
− Consider, as necessary, discussing with study 
PI. 
− Consider hospitalization. 
− Once infection is ruled out, start 
methylprednisolone 1 g IV daily for 3-5 days. 
For progressive symptoms, consider adding IV 
Ig or plasmapheresis. 
Transverse myelitis 
Any Grade 
− Permanently discontinue 
study drug/study regimen. 
− Consider MRI of the spine 
and brain. 
For Any Grade: 
− Consider neurology consult. 
− Inpatient care. 
− Consider prompt initiation of high 
methylprednisolone pulse dosing.  
− Strongly consider IV Ig or plasmapheresis. 

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131 
Peripheral 
neuropathy 
For Any Grade: 
− 
Patients should be evaluated to rule out any alternative etiology (e.g., disease progression, 
infections, metabolic syndromes or medications).  It should be noted that the diagnosis of 
immune-mediated peripheral neuromotor syndromes can be particularly challenging in patients 
with underlying cancer, due to the multiple potential confounding effects of cancer (and its 
treatments) throughout the neuraxis.  Given the importance of prompt and accurate diagnosis, 
it is essential to have a low threshold to obtain a neurological consult. 
− 
Neurophysiologic diagnostic testing (e.g., electromyogram and nerve conduction 
investigations, and “repetitive stimulation” if myasthenia is suspected) are routinely indicated 
upon suspicion of such conditions and may be best facilitated by means of a neurology 
consultation. 
Grade 1 
No dose modifications. 
For Grade 1: 
− Consider, as necessary, discussing with the 
study PI. 
− Care should be taken to monitor patients 
for sentinel symptoms of a potential 
decompensation as described above. 
− Monitor symptoms for interference with 
ADLS, gait difficulties, imblanace, or 
autonomic dysfunction. 
Grade 2 
Hold study drug/study regimen 
dose until resolution to Grade 
≤1. 
For Grade 2: 
− 
Obtain a neurology consult. 
− 
Consider electromyography (EMG)/ nerve 
conduction studies (NCS). 
− 
Observation for additional symptoms or 
consider initiating prednisone 0.5-1 mg/kg 
orally. 
− 
If progression, initiate methylprednisolone 
2-4 mg/kg/day and treat per Guillain-
Barré Syndrome (GBS) guidelines below. 
− 
Sensory neuropathy/neuropathic pain may 
be managed by appropriate medications 
(e.g., gabapentin or duloxetine). 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening 
events): 
− 
Consider, as necessary, discussing with 
study PI. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain 
neurological consult. 
− 
Treat per Guillain-Barré Syndrome (GBS) 
guidelines below. 
Guillain-Barré 
Syndrome (GBS) 
General Guidance 
For Any Grade: 
− 
Recommend hospitalization. 
− 
Obtain neurology consult. 
− 
Obtain MRI of spine to rule out compression lesion. 
− 
Obtain lumbar puncture. 
− 
Antibody tests for GBS variants. 
− 
Perform pulmonary function tests (PFT). 
− 
Obtain electromyography (EMG) and nerve conduction studies (NCS). 
− 
Frequently monitor PFTs and neurologic evaluations. 
− 
Monitor for concurrent autonomic dysfunction. 
− 
Initiate medication as needed for neuropathic pain. 
 
 

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132 
Grade 2-4 
Permanently discontinue. 
− See general guidelines above. 
− Start IV Ig or plasmapheresis in addition 
to methylprednisolone 1 gram daily for 5 
days, then taper over 4 weeks. 
Myasthenia gravis 
General Guidance 
For Any Grade: 
− 
Obtain neurology consult. 
− 
Recommend hospitalization. 
− 
Perform pulmonary function tests (PFT). 
− 
Obtain labs: ESR, CRP, creatinine phosphokinase (CPK), aldolase, and anti-striational 
antibodies. 
− 
Consider cardiac exam, ECG, troponin, transthoracic echocardiogram for possible 
concomitant myocarditis. 
− 
Obtain electromyography (EMG) and nerve conduction studies (NCS). 
− 
Consider MRI of brain/spine to rule out CNS involvement by disease. 
− 
Avoid medications that might exacerbate MG (e.g. beta blockers, some antibiotics, IV 
magnesium). 
Grade 2 
Permanently discontinue. 
− Consider pyridostigmine 30 mg three times 
daily and gradually increase based on 
symptoms (max dose 120 mg four times 
daily). 
− Consider starting low dose prednisone 20 
mg daily and increase every 3-5 days. 
(Target dose 1 mg/kg/day. Max dose 100 
mg daily.) 
Grade 3-4 
Permanently discontinue. 
− Start methylprednisolone 1-2 mg/kg/day. 
Taper steroids based on symptom 
improvement. 
− Start plasmapheresis or IV Ig. 
− Consider rituximab if refractory to 
plasmapheresis or IV Ig. 
− Frequent PFT assessments. 
− Daily neurologic evaluations. 
Myocarditis 
General Guidance for Any Grade: 
− 
The prompt diagnosis of immune-mediated myocarditis is important, particularly in 
patients with baseline cardiopulmonary disease and reduced cardiac function.  
− 
Consider discussing with the study PI. 
− 
Monitor patients for signs and symptoms of myocarditis (new onset or worsening chest 
pain, arrhythmia, shortness of breath, peripheral edema).  As some symptoms can overlap 
with lung toxicities, simultaneously evaluate for and rule out pulmonary toxicity as well as 
other causes (e.g., pulmonary embolism, congestive heart failure, malignant pericardial 
effusion).  Consult a cardiologist early, to promptly assess whether and when to complete 
a cardiac biopsy, including any other diagnostic procedures. 
− 
Initial workup should include clinical evaluation, BNP, cardiac enzymes, ECG, 
echocardiogram (ECHO), monitoring of oxygenation via pulse oximetry (resting and 
exertion), and additional laboratory workup as indicated.  Spiral CT or cardiac MRI can 
complement ECHO to assess wall motion abnormalities when needed. 
− 
Patients should be thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, other medications, or infections). 
− 
Discontinue drug permanently if biopsy-proven immune-mediated myocarditis 
regardless of grade. 
Any grade 
(Grade 2-4)  
 
Permanently discontinue study 
drug/study regimen. 
For Grade 2-4 (any grade): 
− Monitor symptoms daily, hospitalize. 
− Consider cardiology consultation and 
prompt start of high-dose/pulse 
corticosteroid therapy. 

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133 
− Supportive care (e.g., oxygen). 
− If no improvement, consider additional 
immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab), IV Ig or 
plasmapheresis or other therapies 
depending on the clinical condition of the 
patient, based on the discretion of the 
treating specialist consultant or relevant 
practice guidelines.  Caution: It is 
important to rule out sepsis and refer to 
infliximab label for general guidance 
before using infliximab.  Infliximab is 
contraindicated for patients who have 
heart failure. 
Myositis/ Polymyositis 
(“Poly/myositis”) 
 
 
For Any Grade: 
− 
Monitor patients for signs and symptoms of poly/myositis.  Typically, muscle weakness/pain 
occurs in proximal muscles including upper arms, thighs, shoulders, hips, neck and back, and ; 
also, difficulty breathing and/or trouble swallowing can occur and progress rapidly.  Increased 
general feelings of tiredness and fatigue may occur, and there can be new-onset falling, 
difficulty getting up from a fall, and trouble climbing stairs, standing up from a seated position, 
and/or reaching up. 
− 
If poly/myositis is suspected, a Neurology consultation should be obtained early, with prompt 
guidance on diagnostic procedures.  Myocarditis may co-occur with poly/myositis; refer to 
guidance under Myocarditis.  Given breathing complications, refer to guidance under 
Pneumonitis/ILD.  
Given possibility of an existent (but previously unknown) autoimmune disorder, consider 
Rheumatology consultation. 
− 
Consider, as necessary, discussing with the Clinical Study Lead. 
− 
Initial work-up should include clinical evaluation, creatine kinase, aldolase, lactate 
dehydrogenase (LDH), blood urea nitrogen (BUN)/creatinine, erythrocyte sedimentation rate 
or C-reactive protein level, urine myoglobin, and additional laboratory work-up as indicated, 
including a number of possible rheumatological/antibody tests (i.e., consider whether a 
Rheumatology consultation is indicated and could guide need for rheumatoid factor, 
antinuclear antibody, anti-smooth muscle, antisynthetase [such as anti-Jo-1], and/or signal-
recognition particle antibodies).  Confirmatory testing may include electromyography, nerve 
conduction studies, MRI of the muscles, and/or a muscle biopsy.  Consider Barium swallow 
for evaluation of dysphagia or dysphonia. 
− 
Patients should be thoroughly evaluated to rule out any alternative etiology. 
Grade 1 
- No dose modifications. 
For Grade 1: 
− Monitor and closely follow up in 2 to 4 
days for clinical symptoms and initiate 
evaluation as clinically indicated. 
− Consider Neurology consult. 
− Consider, as necessary, discussing with 
the study PI. 
Grade 2 
 
Hold study drug/study regimen 
dose until resolution to Grade 
≤1. 
Permanently discontinue study 
drug/study regimen if it does 
not resolve to Grade ≤1 within 
30 days or if there are signs of 
respiratory insufficiency. 
For Grade 2: 
− 
Monitor symptoms daily and consider 
hospitalization. 
− 
Consider Rheumatology or Neurology 
consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with 
the study PI. 
− 
If clinical course is rapidly progressive 
(particularly if difficulty breathing 
and/or trouble swallowing), promptly 

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134 
start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along 
with receiving input from Neurology 
consultant.  
− 
If clinical course is not rapidly 
progressive, start systemic steroids (e.g., 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent); if no improvement within 2 
to 3 days, continue additional work-up 
and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
− 
If after start of IV methylprednisolone at 
2 to 4 mg/kg/day there is no 
improvement within 3 days, consider 
additional immunosuppressive therapy 
such as TNF inhibitors (e.g., infliximab), 
IV Ig or plasmapheresis, or other 
therapies based on  at the discretion of 
the treating specialist consultant or 
relevant practice guidelines.  Caution:  
It is important to rule out sepsis and 
refer to infliximab label for general 
guidance before using infliximab. 
Grade 3 or 4 
 
For Grade 3: 
Hold study drug/study regimen 
dose until resolution to Grade 
≤1. 
Permanently discontinue 
study drug/study regimen if 
Grade 3 imAE does not resolve 
to Grade ≤1 within 30 days or if 
there are signs of respiratory 
insufficiency. 
 
For Grade 4: 
Permanently discontinue 
study drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening 
events): 
− 
Monitor symptoms closely; 
recommended hospitalization. 
− 
Consider Rheumatology and/or 
Neurology consult. 
− 
Consider discussing with the study PI, 
as needed. 
− 
Promptly start IV methylprednisolone 
2 to 4 mg/kg/day systemic steroids 
along with receiving input from 
Neurology consultant. 
− 
If after start of IV methylprednisolone 
at 2 to 4 mg/kg/day there is no 
improvement within 2 to 3 days, 
consider starting another 
immunosuppressive therapy such as a 
TNF inhibitor (e.g., infliximab at 
5 mg/kg IV, may be repeated at 2 and 
6 weeks after initial dose at the 
discretion of the treating provider or 
relevant practice guidelines).  
Caution:  It is important to rule out 
sepsis and refer to infliximab label for 
general guidance before using 
infliximab. 
− 
Consider whether patient may require 
IV Ig, plasmapheresis. 

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135 
Other immune-
mediated reactions 
General Guidance 
For Any Grade: 
− 
Note: It is possible that events with an inflammatory or immune mediated mechanism could 
occur in nearly all organs, some of them are not noted specifically in these guidelines (e.g. 
immune thrombocytopenia, hemolytic anemia, uveitis, vasculitis). 
− 
The study PI may be contacted for immune-mediated reactions not listed in the “specific 
immune-mediated reactions” section. 
− 
Thorough evaluation to rule out any alternative etiology (e.g., disease progression, 
concomitant medications, and infections). 
− 
Consultation with relevant specialist. 
− 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
- Monitor as clinically indicated. 
Grade 2 
- Hold study drug/study 
regimen until resolution to 
≤Grade 1 or baseline. 
- If toxicity worsens, then treat 
as Grade 3 or Grade 4. 
- Study drug/study regimen can 
be resumed once event 
stabilizes to Grade ≤1 after 
completion of steroid taper. 
- Consider whether study 
drug/study regimen should be 
permanently discontinued in 
Grade 2 events with high 
likelihood for morbidity 
and/or mortality when they 
do not rapidly improve to 
Grade <1 upon treatment 
with systemic steroids and 
following full taper. 
- Treat accordingly, as per institutional 
standard, appropriate clinical practice 
guidelines, and other society guidelines. 
Grade 3 
- Hold study drug/study 
regimen. 
- Treat accordingly, as per institutional 
standard, appropriate clinical practice 
guidelines, and other society guidelines. 
Grade 4 
- Permanently discontinue 
study drug/study regimen.  
- Treat accordingly, as per institutional 
standard, appropriate clinical practice 
guidelines, and other society guidelines. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 
2, please discuss with Study PI.” 
 
a ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow, MD. 
 
b FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical 
Evaluation. 
 
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT 
Alanine aminotransferase; AST Aspartate aminotransferase; BUN Blood urea nitrogen; CT Computed tomography; CTCAE 
Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE Immune-mediated adverse event; IG 
Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  Magnetic 
resonance imaging; NCI  National Cancer Institute; NCCN  National Comprehensive Cancer Network; PJP Pneumocystis 
jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); PO  By mouth; T3  Triiodothyronine; T4 
Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal. 
 

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137 
8. 
PHARMACEUTICAL INFORMATION 
 
A list of the AEs and potential risks associated with the investigational agents administered in 
this study can be found in Section 10.1. 
 
8.1 
CTEP IND Agents 
 
8.1.1 Copanlisib (NSC 784727) 
 
Chemical Name or Amino Acid Sequence: 2-amino-N-[7-methoxy-8-(3-morpholin-4-
ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide 
dihydrochloride 
 
Other Names: BAY 80-6946 (free base); BAY 84-1236 (dihydrochloride salt) 
 
Classification: Pan class I PI3K inhibitor  
 
Molecular Formula:  C23H28N8O4 2HCl  
M.W.:  553.45 g/mol 
 
Approximate Solubility:  Freely soluble in water and 0.1 M hydrochloric acid (HCl) 
 
Mode of Action: Copanlisib is a pan class I PI3K inhibitor with potent activity against the delta and 
alpha isoforms.  Class I PI3K is downstream of most cancer associated tyrosine kinase growth 
factor receptors or mesenchymal epithelial transition factor.  PI3K delta has a critical role in 
regulating downstream events of the B-cell receptor. 
 
Description:  The powder is white to yellow solid substance. 
 
How Supplied:  Copanlisib is supplied by Bayer HealthCare AG and distributed by the 
Pharmaceutical Management Branch (PMB), CTEP, Division of Cancer Treatment and Diagnosis 
(DCTD), NCI.  The agent is available as a lyophilized product containing 60 mg of copanlisib in a 6 
mL injection vial.  The excipients are mannitol, sodium hydroxide, citric acid, and water for 
injection. 
 
Preparation:  Using appropriate aseptic technique, reconstitute the 60 mg vial of copanlisib with 
4.4 mL of 0.9% sodium chloride resulting in a concentration of 15 mg/ml.  Gently shake for 30 
seconds and allow the vial to stand for 1 minute to let bubbles rise to the surface.  Repeat if 
undissolved substance is still present.  The reconstituted solution may be slightly yellow and should 
be clear prior to being withdrawn from the vial.  Withdraw the appropriate volume of the 
reconstituted solution and further dilute by adding to a 50-200 mL 0.9% sterile sodium chloride bag.  
Mix well by inverting.   
 
Storage:  Store intact vials between 2°C and 8°C.  
 
If a storage temperature excursion is identified, promptly return copanlisib to between 2°C and 
8°C and quarantine the supplies.  Provide a detailed report of the excursion (including 

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138 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:  Stability studies of the vials are ongoing.  The diluted solution should be used 
immediately (stored up to 4 hours at room temperature including preparation and administration).  If 
the diluted solution for infusion is not used immediately, it is stable for up to 24 hours refrigerated 
between 2°C and 8°C.  It takes approximately 60 minutes for the diluted solution to return to room 
temperature after refrigeration.  The infusion should be completed within 24 hours of preparation. 
 
CAUTION:  The single-use lyophilized dosage form contains no antibacterial 
preservatives.  Therefore, it is advised that the reconstituted product be 
discarded 4 hours after initial entry.  
 
Route of Administration:  IV infusion  
 
Method of Administration:  The diluted solution for infusion is administered IV over 1 hour.  
After administration, flush the line to ensure complete dose is given.  No IV glucose preparations 
should be administered on the days of infusion. 
 
Potential Drug Interactions:  In vitro, copanlisib is metabolized primarily via CYP3A4 and to a 
minor extent by CYP1A1.  It is also a substrate of P-gp and BCRP, but not a substrate of MATEs, 
OCTs, OATs, or organic anion transporting polypeptides (OATPs).  Concomitant administration 
with strong inhibitors or inducers of CYP3A4 should be avoided.  Use caution when administered 
with strong inhibitors and inducers of CYP1A1, P-gp, and BCRP.   
 
In vitro, copanlisib is a strong inhibitor of MATE2K.  Copanlisib and its metabolite M-1 have a low 
risk for inhibition or induction of CYP isoforms, inhibition of UGT isoforms, and inhibition of 
dihydropyrimidine dehydrogenase.  Copanlisib does not inhibit P-gp, BCRP, OATP1B1, 
OATP1B3, OAT1, OAT3, OCT1, OCT2, bile salt export pump (BSEP), multidrug resistant protein 
2 (MRP-2), or MATE1 at therapeutic 60 mg dose plasma concentrations.  Use caution when 
administered with sensitive drug substrates of MATE2K.   
 
Copanlisib is not an inducer of CYP1A2, 2B6, and 3A. 
 
Special Handling: Copanlisib is not genotoxic in vitro or in vivo.  Copanlisib is expected to 
adversely affect male and female reproduction. 
 
Patient Care Implications:  Females of child-bearing potential and male patients must use 
adequate contraception while receiving copanlisib and for 6 months after last dose of copanlisib.  
Do not breastfeed during treatment with copanlisib and for at least 1 month after the last dose of 
copanlisib. 
 
Hypertension is frequently observed within the first 3 hours after start of infusion and 
hyperglycemia is frequently observed persisting for approximately 1-3 days after study drug 
administration.  Refer to protocol document for treatment and monitoring guidelines. 

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Availability 
 
Copanlisib is an investigational agent supplied to investigators by the DCTD, NCI.  Copanlisib is 
provided to the NCI under a Collaborative Agreement between the Pharmaceutical Collaborator 
and the DCTD, NCI (see Section 13.4). 
 
8.1.2 Olaparib [AZD2281] (NSC 747856) 
 
Chemical Name:  4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-
fluorophenyl)methyl]phthalazin-1(2H)-one 
 
Other Names: AZD2281; KU-0059436; CO-CE 42 
 
Classification: PARP inhibitor 
 
CAS Registry Number: 763113-22-0 
 
Molecular Formula:  C24H23FN4O3 
 
M.W.: 434.46 
 
Approximate Solubility: 0.1 mg/mL pH independent solubility across physiologic range 
 
Mode of Action:  Olaparib is an inhibitor of subclasses 1, 2, and 3 of polyadenosine 5′ 
diphosphoribose polymerase (PARP-1, PARP-2, and PARP-3).  In tumors that are deficient in the 
homologous recombination DNA repair pathway (example, BRCA mutants), inhibition of PARP by 
olaparib causes accumulation of DNA double-strand breaks and genomic instability.  Olaparib may 
also enhance the effects of DNA damage caused by ionizing radiation and chemotherapy.  
 
Description: crystalline solid 
 
How Supplied:  AstraZeneca supplies and the CTEP, DCTD distributes olaparib as green, film-
coated tablets in 100 mg and 150 mg strengths.  
 
• 100 mg tablets are 14.5 mm x 7.25 mm oval-shaped 
• 150 mg are 14.5 mm x 7.25 mm oval-shaped 
 
Tablets are packaged in induction-sealed high-density polyethylene (HDPE) bottles with child-
resistant closures.  Each bottle contains 32 tablets with desiccant.  
 
Tablet core components include active drug substance, copovidone, colloidal silicon dioxide, 
mannitol and sodium stearyl fumarate.  Film coating contains hydroxypropyl methylcellulose 
(hypromellose), macrogol 400 (polyethylene glycol 400), titanium dioxide, iron oxide yellow and 
iron oxide black. 
 
Storage: Store in a secure location below 30° C (86° F).  
 

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If a storage temperature excursion is identified, promptly return olaparib (AZD2281) to room 
temperature and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability.   
 
Stability:  Shelf-life studies are ongoing. Sites are not permitted to re-package tablets.  Once the 
bottle is opened, olaparib tablets must be used within 3 months of the opening date; unused 
tablets should be discarded. Instruct patients not to open a bottle until they are ready to use it. 
 
Route and Method of Administration:  Oral.  Take tablets without regard to meals.  
 
Potential Drug Interactions:  In vivo data indicate that CYP3A4/5 is important for olaparib 
metabolism and clearance in humans.  For this reason, avoid concomitant administration of strong 
and moderate CYP 3A4/5 inducers and inhibitors.  Consult the protocol document or study 
investigator prior to making any dose adjustments related to potential drug-drug interactions. 
 
In vitro data shows olaparib is a substrate for P-gp, but not for organic anion-transporting 
polypeptides (OATP1B1 and OATP1B3), OCT1, MRP-2 efflux transporter or BCRP.  
Administration of strong P-gp inhibitors and inducers should be avoided with concurrent olaparib.   
 
Based on in vitro data, olaparib inhibits CYP 3A4 and UGT1A1 enzyme systems and induces CYP 
1A2, 2B6, and 3A4.  Therefore, avoid concomitant administration of sensitive substrates, 
particularly those with narrow therapeutic ranges.   
 
Olaparib is also an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, multi-drug and toxin 
extrusion proteins (MATE1 and MATE2K) and a weak inhibitor of BRCP, but not an inhibitor of 
OATP1B3 or MRP-2.  In vitro studies suggest that olaparib may increase exposure of substrates of 
these transport systems, although the clinical relevance is not clear.  The manufacturer recommends 
that statins, in particular, should be administered with caution when given concomitantly with 
olaparib. 
 
Patient Care Implications:  Pre-clinical data indicate that olaparib adversely affects embryofetal 
survival and development.  Therefore, women of child-bearing potential and their partners should 
agree to use two (2) highly effective forms of contraception throughout study participation and for 
at least six (6) months after the last dose of olaparib.  It is not known whether olaparib is found in 
seminal fluid, so as a precaution, male study participants must use a condom during treatment and 
for three (3) months after the last dose and should avoid fathering a child or donating sperm during 
this same time period.  The study investigator should discuss the most appropriate forms of highly 
effective contraceptive methods for each patient.  
 
Lactation is a protocol exclusion criterion and not advised since there is potential for serious adverse 
reactions in breastfed infants.  Advise lactating women to not breastfeed during study treatment and 
for one (1) month after receiving the last dose of olaparib.  
 
Because the adverse events related to olaparib may include asthenia, fatigue and dizziness, 
patients should be advised to use caution while driving or using machinery. 

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There are no data on the effect of olaparib on wound healing, therefore as a precaution, olaparib 
treatment should be stopped at least 3 days prior to planned surgery.  After surgery olaparib can 
be restarted when the wound has healed.  No stoppage of olaparib is required for any needle 
biopsy procedure. 
 
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
therapeutic or palliative radiation treatment.  Study treatment should be restarted within 4 weeks 
as long as any bone marrow toxicity has recovered. 
 
Availability 
 
Olaparib (AZD2281) is an investigational agent supplied to investigators by the DCTD, NCI. 
Olaparib (AZD2281) is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 13.4). 
 
8.1.3 Durvalumab [MEDI4736] (NSC 778709) 
 
 
Other Names: IMFINZI™ 
 
Classification: Anti-PD-L1 MAb 
 
Molecular Weight: ~ 149 kDa 
 
Mode of Action: Durvalumab (MEDI4736) inhibits binding of programmed cell death ligand 1 
(PD-L1) to PD-1 and CD80.  In-vitro studies demonstrate that durvalumab (MEDI4736) relieves 
PD-L1-mediated suppression of human T-cell activation.  Durvalumab (MEDI4736) does not 
trigger antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity in cell-
based functional assays. 
 
Description: Durvalumab (MEDI4736) is a human immunoglobulin G1 kappa (IgG1κ) 
monoclonal antibody. 
 
How Supplied: Durvalumab (MEDI4736) is supplied by AstraZeneca, and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI.  Durvalumab (MEDI4736) injection is a 
clear to slightly opalescent, colorless to slightly yellow solution for intravenous use.  Each vial 
contains 500 mg of durvalumab (MEDI4736) in 10 mL of solution.  Each 1 mL of solution contains 
50 mg of durvalumab (MEDI4736) and is formulated in: L-histidine (2 mg), L-histidine 
hydrochloride monohydrate (2.7 mg), α,α-trehalose dihydrate (104 mg), polysorbate 80 (0.2 mg), 
and Water for Injection, USP. 
 
Preparation: Durvalumab (MEDI4736) solution for infusion must be diluted prior to administration.  
To prepare the infusion solution add the dose volume of durvalumab (MEDI4736) to an infusion bag 
containing 0.9% Sodium Chloride Injection or Dextrose 5% in Water Injection, USP and mix by 
gentle inversion to ensure homogeneity of the dose in the bag.  The final concentration must be 

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between 1 mg/mL to 15 mg/mL.  
 
Infusion bags must be latex-free and can be made of polypropylene, polyethylene, polyolefin 
copolymers, or polyvinyl chloride. 
 
Storage: Store intact vials between 2-8°C (36-46°F).  Do not freeze.  Protect from light by storing in 
the original box.   
 
If a storage temperature excursion is identified, promptly return durvalumab (MEDI4736) to 
between 2-8°C and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Refer to the package label for expiration. 
 
Total in-use storage time from needle puncture of durvalumab (MEDI4736) vial to start of 
administration should not exceed 8 hours at room temperature or 24 hours at 2-8°C (36-46°F).  If 
the final product is stored at both refrigerated and ambient temperatures, the total time must not 
exceed 24 hours (that is, the individual storage time limits are not additive. Prior to the start of the 
infusion, ensure that the bag contents are at room temperature (approximately 25°C) to avoid an 
infusion reaction due to the administration of the solution at low temperatures.   
 
Route of Administration: IV infusion 
 
Method of Administration: Infuse over approximately 60 minutes using an infusion set containing 
a 0.22 or 0.2 μm in-line filter.  No incompatibilities between durvalumab (MEDI4736) and 
polyethylene, polypropylene, polyvinylchloride, or polyolefin copolymers have been observed.  
Flush the IV line with a volume of IV bag diluent equal to the priming volume of the infusion set 
used at the completion of infusion.  Do not co-administer other drugs through the same infusion line. 
 
Patient Care Implications: Refer to the protocol for information on evaluation and management 
of potential immune-related adverse events. 
 
 
 
8.1.4 Agent Ordering and Agent Accountability 
 
8.1.4.1 
NCI - supplied agents 
 
8.1.4.2 
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 

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institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead participating investigator at that institution. 
 
No starter supplies are allowed.  Agents may be ordered at the time of patient registration.  
Orders can be processed for delivery overnight Monday-Thursday when the site provides 
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.   
 
8.1.4.3 
Agent Inventory Records 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation, and ordering investigator on this protocol. 
 
8.1.5 Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators and research 
staff through the PMB OAOP application.  Access to OAOP requires the establishment of a 
CTEP IAM account and the maintenance of an “active” account status, a “current” password and 
active person registration status.  Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
 
8.1.6 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) 
 
 

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9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
9.1.1 Study Design  
 
In Step 1, the doublet combination of copanlisib and olaparib will be investigated.  Dose 
escalation will be undertaken in patients with advanced solid tumors, with the population 
enriched for those with both PI3K-AKT pathway and DDR aberrations. 
 
Step 2 will not proceed until the safety and toxicity data from Step 1 have been formally 
reviewed by and discussed with the study team and CTEP. 
 
In Step 2, the RP2D of the copanlisib/olaparib combination is copanlisib 60 mg Days 1 and 15 
and olaparib 300 mg BID of each 28-day cycle. Durvalumab (MEDI4736) at 1500 mg Day 1 of 
each 28-day cycle will be added to form a novel triplet combination.  The dose escalation phase 
will involve patients with advanced solid tumors, with the population enriched for those with 
both PI3K-AKT pathway and DDR aberrations. 
 
In Step 3, dose expansion for the copanlisib/olaparib doublet combination can proceed upon 
completion of Step 1 and can proceed simultaneously with Step 2. The dose expansion for the 
copanlisib/olaparib/durvalumab (MEDI4736) triplet combination can proceed upon completion 
of Step 2 and can proceed simultaneously with dose expansion for copanlisib/olaparib doublet 
combination. Patient assignment to the doublet or triplet combinations will be based on slot 
availability. During cohort expansion, patients to be assessed include: those with germline DDR 
aberrations, those with cancers with somatic DDR aberrations, patients with PIK3CA mutant 
cancers, and those with PTEN mutations.  15 patients will be recruited to each of 4 dose 
expansion cohorts, for a total of 60 patients in dose expansion. 
 
We will employ the Bayesian optimal interval (BOIN) design (Liu and Yuan, 2015; Yuan et al., 
2016) to determine the MTD.  The BOIN design is implemented in a simple way similar to the 
traditional 3+3 design, but is more flexible and possesses superior operating characteristics that 
are comparable to those of the more complex model-based designs, such as the continual 
reassessment method (CRM) (Zhou, et al., 2018). 
 
Doublet BOIN Design 
 
The target toxicity rate for the MTD is ɸ = 0.25 and the maximum sample size is 18. We will 
enroll and treat patients in cohorts of size 3. The trial design is illustrated in Figure 8 and 
described as follows: 
 
1. Patients in the first cohort are treated at dose level 1. 
2. To assign a dose to the next cohort of patients, conduct dose escalation/de-escalation 
according to the rule displayed in Table 3, which minimizes the probability of incorrect 
dose assignment. When using Table 3, please note the following:  

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estimate of the toxicity rate is closest to the target toxicity rate.  If there are ties, select the higher 
dose level when the isotonic estimate is lower than the target toxicity rate and select the lower 
dose level when the isotonic estimate is greater than or equal to the target toxicity rate. 
Expansion Phase:  Once we determine the MTD, an additional 15 patients will be enrolled for 
additional experience with safety and efficacy in each of 4 cohorts.  We will use the elimination 
boundaries in the dose escalation/de-escalation rule for the BOIN Design Table for toxicity 
monitoring during this phase. 
Operation Characteristics:  The operating characteristics of the BOIN Design for the doublet 
and triplet combinations tables below shows the operating characteristics of the trial design 
based on 1000 simulations of the trial using shiny app "BOIN" available at 
http://www.trialdesign.org.  The operating characteristics show that the design selects the true 
MTD, if any, with high probability and allocates more patients to the dose levels with the DLT 
rate closest to the target of 0.25. 
 
Operating characteristics of the BOIN Design for the doublet combination 
  
Dose Level 
Number of 
% Early 
  
1 
2 
3 
4 
Patients 
Stopping 
Scenario 1 
True DLT Rate 
0.25 
0.42 
0.5 
0.59 
13.53 
49.6 
Selection % 
39.9 
8.9 
1.4 
0.2 
# Pts Treated 
7.2 
5.1 
1.1 
0.1 
Scenario 2 
True DLT Rate 
0.1 
0.25 
0.4 
0.62 
16.58 
8.3 
Selection % 
44.4 
36.5 
10.4 
0.4 
# Pts Treated 
5.8 
7.2 
3 
0.6 
Scenario 3 
True DLT Rate 
0.02 
0.1 
0.25 
0.42 
17.5 
0.5 
Selection % 
11 
44.2 
34.2 
10.1 
# Pts Treated 
1.8 
7.4 
5.9 
2.4 
Scenario 4 
True DLT Rate 
0.05 
0.08 
0.12 
0.25 
17.81 
0.4 
Selection % 
8.3 
14 
38.5 
38.8 
# Pts Treated 
1.5 
5.2 
6 
5.1 
Scenario 5 
True DLT Rate 
0.45 
0.55 
0.65 
0.75 
9.36 
91.2 
Selection % 
7.1 
1.7 
0 
0 
# Pts Treated 
5.3 
3.7 
0.4 
0 
  
  
  
  
  
  
  
 
Operating characteristics of the BOIN Design for the triplet combination 
  
Dose Level 
Number 
of 
% Early 

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The first secondary objective is to assess ORR (CR + PR).  We will estimate ORR with 95% 
confidence intervals (CI).  Inferences and estimation are based on the exact binomial test.  With 
15 patients, the 95% CI for an observed ORR of 25% would extend from 7% to 53%.  A 
treatment will be declared worthy of further study if we see at least 2 patients (13%) out of 15 
with ORR; the probability of doing so would be 17% if the true OR rate was 5% and would be 
83% if the true ORR was 20%. 
 
The second secondary objective is to assess DOR, PFS, and OS.  We will use the Kaplan-Meier 
method to estimate these distributions. 
 
For correlative studies, we will assess immuno-modulatory changes using paired t-tests or 
Wilcoxon signed rank tests.  With 15 patients, we would have 85% power to detect an effect size 
(mean difference divided by standard deviation of differences) = 0.83 assuming Normal data 
with two-sided 5% alpha.  We will assess associations between marker levels and response using 
receiver operating characteristic (ROC) curve analysis, graphical analysis and logistic regression 
analysis as appropriate.  If success rate is 50%, then we would have 80% power to detect an area 
under the ROC curve of 0.83 as statistically different from the null value of 0.50 assuming a 20% 
alpha and 15 patients with data. 
 
 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
AE monitoring and reporting is a routine part of every clinical trial.  The following list of AEs 
(Section 10.1) and the characteristics of an observed AE (Sections 10.2 and 10.3) will determine 
whether the event requires expedited reporting via the CTEP Adverse Event Reporting System 
(CTEP-AERS) in addition to routine reporting. 
 
10.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential AEs associated with an agent using a uniform presentation of events by 
body system.  In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text.  This subset of AEs (SPEER) is a list of events that are protocol specific 
exceptions to expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. 
 
NOTE:  Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required.  
 
10.1.1 CAEPRs for CTEP IND Agents 
 

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MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Generalized 
muscle weakness; Musculoskeletal and connective tissue disorder - Other (psoriatic arthropathy); 
Myalgia; Pain in extremity; Soft tissue necrosis upper limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor 
hemorrhage 
NERVOUS SYSTEM DISORDERS - Amnesia; Dizziness; Dysesthesia; Dysgeusia; Headache; 
Paresthesia; Peripheral sensory neuropathy; Presyncope; Reversible posterior leukoencephalopathy 
syndrome; Syncope 
PSYCHIATRIC DISORDERS - Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Aspiration; Cough; Dyspnea3; 
Hypoxia; Pleural effusion; Pulmonary hypertension; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (pulmonary congestion); Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Eczema; Purpura; Rash 
acneiform; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Hypotension; Thromboembolic event; Vascular disorders - Other (circulatory 
collapse) 
 
 
 
Note: Copanlisib dihydrochloride (BAY 80-6946 dihydrochloride) in combination with other agents could 
cause an exacerbation of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 
 
 
 
 
 
 
 
 
 
 
 
10.1.1.2 
CAEPR for Olaparib (AZD2281) (NSC 747856)  
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for  
Olaparib (AZD2281, NSC 747856) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 3449 patients. Below is the CAEPR for Olaparib 
(AZD2281). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 

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Encephalopathy; Intracranial hemorrhage; Peripheral sensory neuropathy; Reversible posterior leukoencephalopathy 
syndrome; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Hallucinations; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other (decreased 
glomerular filtration rate); Renal and urinary disorders - Other (hydronephrosis); Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Hypoxia; Oropharyngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal disorders 
- Other (chronic obstructive pulmonary disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Pruritus 
VASCULAR DISORDERS - Arterial thromboembolism; Flushing; Hot flashes; Hypertension; Hypotension; 
Peripheral ischemia; Thromboembolic event 
 
 
 
Note: Olaparib (AZD2281) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.1.1.3 
CAEPR for durvalumab (MEDI4736, NSC 778709) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for  
Durvalumab (MEDI4736, NSC 778709) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 3006 patients. Below is the CAEPR for 
Durvalumab (MEDI4736). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
Version 2.5, February 29,20241 

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Dental caries; Dry mouth; Dysphagia; Esophagitis; Gastritis; Gastrointestinal disorders - Other 
(gastrointestinal hemorrhage); Ileal stenosis; Mucositis oral; Proctitis; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema trunk; 
General disorders and administration site conditions - Other (general physical health deterioration); 
General disorders and administration site conditions - Other (failure to thrive); Hypothermia; Neck edema; 
Non-cardiac chest pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic hemorrhage 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (drug-induced liver injury); Immune 
system disorders - Other (Giany cell arteritis syndrome); Serum sickness 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning, and procedural 
complications - Other (radiation pneumonitis); Wound complication 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; CPK increased; Cardiac 
troponin I increased; Ejection fraction decreased; Electrocardiogram QT corrected interval prolonged; 
Electrocardiogram T wave abnormal; GGT increased; Lipase increased; Lymphocyte count decreased; 
Neutrophil count decreased; Serum amylase increased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypermagnesemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; 
Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Generalized muscle 
weakness; Musculoskeletal and connective tissue disorder - Other (polymyalgia rheumatica); Pain in 
extremity; Rhabdomyolysis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (brain metastasis swelling); Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (increase in tumor mass); Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (lung cyst); Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (tumor flare); Treatment related secondary 
malignancy; Tumor hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dizziness; Edema cerebral; 
Encephalopathy; Headache; Ischemia cerebrovascular; Nervous system disorders - Other (axonal 
neuropathy); Nervous system disorders - Other (hemiparesis); Nervous system disorders - Other 
(hypoesthesia); Nervous system disorders - Other (neuropathy peripheral); Paresthesia; Seizure; Stroke; 
Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Confusion; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Aspiration; Bronchopulmonary hemorrhage; Hypoxia; Laryngeal obstruction; Pleural effusion; 
Pneumothorax; Pulmonary edema; Pulmonary fistula; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (asphyxia); Respiratory, thoracic and mediastinal disorders - Other 
(granulomatous changes in the lung); Respiratory, thoracic and mediastinal disorders - Other (fungal 
pneumonia; Phialemonium spp.) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Dry skin 
VASCULAR DISORDERS - Hypertension; Thromboembolic event 
 
 
Note: Durvalumab (MEDI4736) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
 
 
 
 
 

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10.2 Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI CTCAE version 5.0 will be utilized for AE reporting.  All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0.  A copy of the 
CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 10.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
Section 10.3.7. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
10.3 Expedited Adverse Event Reporting 
 
10.3.1 Rave CTEP-AERS Integration 
 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS) 
integration enables evaluation of Adverse Events (AEs) entered in Rave to determine whether 
they require expedited reporting and facilitates entry in CTEP-AERS for those AEs requiring 
expedited reporting.  Sites must initiate all AEs for this study in Medidata Rave. 
 
Treatment-emergent AEs:  All AEs that occur after start of treatment are collected in Medidata 
Rave using the Adverse Event form, which is available for entry at each treatment course or 
reporting period and is used to collect AEs that start during the period or persist from the 
previous reporting period.  AEs that occur 30 days after the last administration of the 
investigational agent/intervention are collected using the Late Adverse 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/aeguidelin
es.pdf. 
 
10.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
10.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 

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10.3.4 Copanlisib Adverse Events of Special Safety Interest 
 
AESI are events of scientific and medical interest specific to the further understanding of 
copanlisib’s safety profile and require close monitoring and rapid communication by the 
investigators to CTEP.  An AESI may be serious or non-serious.  The AESI for copanlisib are 
the following: 
 
Non-infectious pneumonitis 
 
Non-infectious pneumonitis has been observed in studies with copanlisib.  As soon as there is a 
reasonable suspicion of a patient experiencing non-infectious pneumonitis, the investigator 
should report it within 24 hours via CTEP-AERS regardless of whether the event is assessed as 
causally related/not related to the study therapy, or as serious/non-serious by an investigator.   
 
10.3.5 Olaparib Adverse Events of Special Interest 
 
An AESI can be serious or non-serious. All AESIs will be recorded in the eCRF. Serious AESIs 
will be recorded and reported as per Section 10.3.3. 
 
AESIs for olaparib are the Important Identified Risk of MDS/AML and the Important Potential 
Risks of new primary malignancy (other than MDS/AML) and pneumonitis. 
 
Additional detailed information regarding the AESI will be requested from any investigator 
reporting an AESI. During the study, there may be other events identified as AESIs that require 
the investigators to provide additional detailed information to help characterize the event and 
gain a better understanding regarding the relationship between the event and the study 
intervention.  
 
10.3.6 Durvalumab (MEDI4736) Adverse Events of Special Interest 
 
An imAE is defined as an AESI that is associated with drug exposure and is consistent with an 
immune-mediated mechanism of action and where there is no clear alternate etiology.  Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis.  Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin, or other etiologic causes of the imAE.  
 
AESIs observed with durvalumab (MEDI4736) include, but are not limited to: 
• Diarrhea/Colitis and intestinal perforation 
• Pneumonitis / ILD 
• Hepatitis / transaminase increases 
• Endocrinopathies (i.e., events of hypophysitis/hypopituitarism, thyroiditis, adrenal 
insufficiency, hyper- and hypothyroidism and type I diabetes mellitus) 
• Rash/Dermatitis 
• Nephritis/Blood creatinine increases 
• Pancreatitis/serum lipase and amylase increases 

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• Myocarditis 
• Myositis/Polymyositis 
• Intestinal perforations 
• Other inflammatory responses that are rare/less frequent with a potential immune-
mediated etiology include, but are not limited to, pericarditis, neuromuscular toxicities 
(such as Guillain-Barré syndrome and myasthenia gravis), sarcoidosis, uveitis, other 
events involving the eye and skin, hematological events, rheumatological events, 
vasculitis, non-infectious meningitis, and non-infectious encephalitis 
 
AESIs observed with durvalumab (MEDI4736) requiring reporting through CTEP ARES 
include: 
 
• Pneumonitis / ILD any grade / ALT/AST increases / hepatitis / hepatotoxicity - Hy’s 
Law:  
o Cases where a patient shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 × ULN together with total 
bilirubin ≥2 × ULN may need to be reported as SAEs. Cases of potential DILI 
should be evaluated as described in Appendix H. 
• Neuropathy / neuromuscular toxicity (e.g., Guillain-Barré, and myasthenia gravis) 
• Endocrinopathies (i.e., events of hypophysitis, hypopituitarism, thyroiditis, adrenal 
insufficiency, diabetes insipidus, hyper- and hypothyroidism and type I diabetes mellitus) 
 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs. 
 
10.3.7 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting via CTEP-
AERS regardless of whether they are associated with ≥24-hour hospitalization or not.  However, 
they still must be reported through the routine reporting mechanism (Section 10.4).  These are:  
any grade alopecia, Grade 2 hypernatremia/hyponatremia, Grade 2 hyperkalemia/hypokalemia, 
Grade 2 hyperphosphatemia/hypophosphatemia, Grade 2 hypermagnesia/hypomagnesia, Grade 2 
anemia, Grade 2 hypoalbuminemia, Grade 2 INR, Grade 2 PTT, and Grade 2 hyperuricemia. 
 
10.4 Routine Adverse Event Reporting 
 
All AEs must be reported in routine study data submissions.  AEs reported expeditiously 
through CTEP-AERS must also be reported in routine study data submissions. 
 
AE data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents.  AEs are reported in a routine manner at scheduled times during the 
trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine AE reporting 
in Rave. 

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10.4.1 Reporting of deaths 
 
All deaths that occur during the study, or within the protocol-defined 90-day post-last dose of 
durvalumab (MEDI4736) safety follow-up period must be reported as follows: 
 
• Death that is clearly the result of disease progression should be documented but 
should not be reported as an SAE. 
• Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported as a SAE within 24 hours (For 
SAEs causal relationship will also be assessed for other medication and study 
procedures.  Note that for SAEs that could be associated with any study procedure, 
the causal relationship is implied as “yes.”)  The report should contain a comment 
regarding the co-involvement of progression of disease, if appropriate, and should 
assign main and contributory causes of death.  
 
• Deaths with an unknown cause should always be reported as a SAE. 
10.4.2 Reporting of overdoses 
 
There is currently no specific treatment in the event of overdose with olaparib and possible 
symptoms of overdose are not established.  Olaparib must only be used in accordance with the 
dosing recommendations in this protocol.  Any dose or frequency of dosing that exceeds the 
dosing regimen specified in this protocol should be reported as an overdose.  The MTD is 300 
mg twice daily (tablet).  Adverse reactions associated with overdose should be treated 
symptomatically and should be managed appropriately. 
 
Use of durvalumab (MEDI4736) in doses in excess of that specified in the protocol is considered 
to be an overdose.  There is currently no specific treatment in the event of overdose of durvalumab 
(MEDI4736) and possible symptoms of overdose are not established.  
 
• An overdose with associated AEs will be recorded as the AE diagnosis or symptoms 
in the relevant AE modules of the eCRF and in the Overdose eCRF module. 
• An overdose without associated symptoms will only be reported in the Overdose 
eCRF module. 
For overdoses associated with an SAE, the standard reporting timelines apply.  For other 
overdoses, reporting must occur within 30 days. 
 
10.4.3 Reporting of hepatic function abnormality 
 
Cases where a patient shows elevations in liver biochemistry may require further evaluation.  Cases 
of potential drug-induced liver injury (DILI) that include an elevated ALT or AST in combination 

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with either an elevated bilirubin or clinical jaundice, as defined by Hy’s Law and based on the 
following observations may need to be reported as SAEs:  
o Treatment-emergent ALT or AST >3×ULN (or >3× baseline value in disease 
states where LFTs may be elevated at baseline) in combination with total bilirubin 
>2×ULN (of which ≥35% is direct bilirubin).  
o Treatment-emergent ALT or AST >3×ULN (or >3× baseline value in disease 
states where LFTs may be elevated at baseline) in combination with clinical 
jaundice 
 
Cases of Hy’s Law should be evaluated as described in Appendix H. 
 
Please refer to Section 7.3, Dosing Modification and Toxicity Management Guidelines for 
Immune-Mediated, Infusion-Related, and Non-Immune Mediated Reactions durvalumab 
(MEDI4736) Monotherapy Table for further instruction on cases of increases in liver biochemistry 
and evaluation of Hy’s law.  
10.5 Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome.  Newborn infants should be followed until 30 days old.  Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) 
and DCP INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) 
for more details on how to report pregnancy and its outcome to CTEP.  
 
Additionally, all pregnancies and outcomes of pregnancy should be reported to CTEP via CTEP-
AERS except for: 
 
− Pregnancy discovered before the study patient has received any study drugs. 
− Pregnancy of a female partner of male patient, providing there is no restriction of male 
patient fathering a child. 
 
10.5.1 Maternal exposure 
 
If a patient becomes pregnant during the course of the study, the investigational products should 
be discontinued immediately.  
 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication.  
Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and 
handled as SAEs.  Elective abortions without complications should not be handled as AEs.  The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented using the 
Pregnancy Reporting Form as described in the NCI Guidelines for Investigators (at 

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http://ctep.cancer.gov/protocolDevelopment/adverse effects.htm) even if the patient was 
discontinued from the study.  
 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform CTEP within 1 day, i.e., immediately, but no later than 24 hours of when he or she 
becomes aware of it.  
 
The same timelines apply when outcome information is available. 
 
10.5.2 Paternal exposure 
 
Male patients should refrain from fathering a child or donating sperm during the study and for 
180 days after the last dose of copanlisib + olaparib + MEDI 4736 (durvalumab) combination 
therapy.  
 
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 180 days after the last dose 
of copanlisib + olaparib + durvalumab combination therapy should, if possible, be followed up 
and documented.  
 
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, the 
Investigator must obtain the consent of the patient’s partner.  Therefore, the local study team 
should adopt the generic informed consent form (ICF) template in line with local procedures and 
submit it to the relevant Ethics Committees (ECs)/ IRBs prior to use. 
 
10.6 Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., AML)  
• MDS  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
10.7 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 

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metastasis from the initial malignancy).  Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
 
 
11. 
STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans 
and x-rays must be done ≤4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.

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11.1 Laboratory Assessments 
 
Full hematology assessments for safety (hemoglobin, red blood cells [RBC], platelets, mean cell 
volume [MCV], mean cell hemoglobin concentration [MCHC], mean cell hemoglobin [MCH], 
white blood cells [WBC], absolute differential white cell count (neutrophils, lymphocytes, 
monocytes, eosinophils and basophils) and absolute neutrophil count or segmented neutrophil 
count and band forms should be performed at each visit and when clinically indicated.  If 
absolute differentials are not available, please provide % differentials.   
 
Serum biochemistry assessments for safety include sodium, potassium, calcium, magnesium, 
fasting glucose, creatinine, total bilirubin, alkaline phosphatase (ALP), aspartate transaminase 
(AST), alanine transaminase (ALT), urea or blood urea nitrogen (BUN), total protein, albumin, 
bicarbonate, chloride, phosphorus, amylase, lipase, and lactic dehydrogenase (LDH).  These 
assessments should be performed at every clinic visit and when clinically indicated.   
 
Coagulation (activated partial thromboplastin time [aPTT] and INR) will be performed at 
baseline and if clinically indicated unless the patient is receiving warfarin.  Patients taking 
warfarin may participate in this study; however, it is recommended that prothrombin time (INR 
and aPTT) be monitored carefully at least once per week for the first month, then monthly if the 
INR is stable. 
 
Gamma glutamyltransferase (GGT), will be conducted pre-study, C1D1 and D1 of every cycle 
thereafter. Free T3 and free T4 only need to be tested if TSH is abnormal. Testing can be added 
more frequently, if clinically indicated. 
 
HbA1C will be conducted pre-study, C1D1, D1 of every third cycle beginning at cycle 4 (C4D1, 
C7D1, C10D1, etc.). It is also required at end of treatment (EOT) [this testing is not required if 
the previous test was performed within 4 weeks preceding the EOT visit] and 3 months after the 
EOT visit. 
 
Thyroid testing (TSH) will be conducted pre-study, C1D1 and then every other cycle. Free T3 
and free T4 only need to be tested if TSH is abnormal. Testing can be added if clinically 
indicated. 
 
Urinalysis by dipstick should be performed at baseline and only if clinically indicated thereafter.  
Microscopic analysis should be performed by the hospital’s local laboratory if required. 
 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged 
hematological toxicities as defined in Section 7.2.3.3. 
Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic analysis 
and flow cytometry, and a core biopsy for bone marrow cellularity.  If it is not possible to 
conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then attempts 
should be made to carry out the tests on a blood sample.  Full reports must be provided by the 
investigator for documentation on the Patient Safety database.  These data are not required to be 
entered into CRF. 

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These tests will be performed by the hospital’s local laboratory.  Additional analyses may be 
performed if clinically indicated. 
 
Any clinically significant abnormal laboratory values should be repeated as clinically indicated 
and recorded on the eCRF. 
 
In case a patient shows an AST or ALT ≥3×ULN or total bilirubin ≥2×ULN, patients should be 
evaluated for potential DILI (please refer to Appendix H, “Actions required in cases of combined 
increase of Aminotransferase and Total Bilirubin – Hy’s Law”, for further instructions).  
 
11.2 ECG 
 
ECGs are required within 7 days prior to starting study treatment and when clinically indicated. 
 
Twelve-lead ECGs will be obtained after the patient has been rested in a supine position for at 
least 5 minutes in each case.  The investigator or designated physician will review the paper 
copies of each of the timed 12-lead ECGs on each of the study days when they are collected. 
ECGs will be recorded at 25 mm/sec.  All ECGs should be assessed by the investigator as to 
whether they are clinically significantly abnormal/not clinically significantly abnormal.  If there 
is a clinically significant abnormal finding, the Investigator will record it as an AE on the eCRF.  
The original ECG traces must be stored in the patient medical record as source data. 
 
 
12. 
MEASUREMENT OF EFFECT 
 
Although the clinical benefit of these drugs has not yet been established, the intent of offering 
this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully 
monitored for tumor response and symptom relief in addition to safety and tolerability.  Patients 
with measurable disease will be assessed by standard criteria.  For the purposes of this study, 
patients should be re-evaluated every 8 weeks.  In addition to a baseline scan, confirmatory scans 
will also be obtained at least 4 weeks following initial documentation of an objective response. 
 
12.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained at least 4 (not less than 4) 
weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 

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12.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with copanlisib, olaparib, and durvalumab (MEDI4736). 
 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy in accordance with evaluability criteria 
listed in section 6.2.1, and have had their disease re-evaluated will be considered evaluable for 
response.  These patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the end of cycle 1 will 
also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy in accordance with evaluability criteria listed in section 6.2.1, and have had their 
disease re-evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of the lesions.  
 
12.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  Tumor lesions that are situated in a previously irradiated area may be 
considered measurable if they have progressed by RECIST since being irradiated.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in follow-up, 
only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] 
short axis), are considered non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above.  However, if non-cystic lesions are 

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present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
12.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT scans have slice 
thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice 
the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 

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impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
 
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 
CR or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) 
and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J 
Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between PR and CR in rare 
cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual 
benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 

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during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and PD. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
d.  Since Copanlisib is a potent inhibitor of Glucose Transporter 1 (Glut1), it may inhibit 
cancer cell uptake of glucose or FDG.  This may cause decreased FDG uptake to be noted 
on scans and suggest an antitumor effect rather than just a pharmacodynamic effect.  
FDG-PET testing should be done at least one week after the last dose of copanlisib. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.1.4 Response Criteria 
 
12.1.4.1 
Evaluation of Target Lesions 
 
CR:  Disappearance of all target lesions.  Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to <10 mm (<1 cm). 
 
PR:  At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the 
baseline sum diameters. 
 
PD:  At least a 20% increase in the sum of the diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm (0.5 cm).  (Note:  the appearance of one or more new lesions is also considered 

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progressions). 
 
SD:  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
 
12.1.4.2 
Evaluation of Non-Target Lesions 
 
CR:  Disappearance of all non-target lesions and normalization of tumor marker level.  All 
lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
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. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or PI). 
 
12.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 

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Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
12.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or PD is objectively documented (taking as reference for PD 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 PD is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
12.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
 
12.2 Other Response Parameters 
 
The response to immunotherapy may differ from the typical responses observed with cytotoxic 

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chemotherapy including the following (Wolchok et al., 2009): 
• Response to immunotherapy may be delayed 
• Response to immunotherapy may occur after PD by conventional criteria 
• The appearance of new lesions may not represent PD with immunotherapy 
• SD while on immunotherapy may be durable and represent clinical benefit. 
 
Based on the above-described unique response to immunotherapy and based on guidelines from 
regulatory agencies, e.g., European Medicines Agency’s “Guideline on the evaluation of 
anticancer medicinal products in man” (EMA/CHMP/205/95/Rev.4) for immune modulating 
anticancer compounds, the study may wish to implement the following in addition to standard 
RECIST 1.1 criteria: 
 
• RECIST will be modified so that PD must be confirmed at the next scheduled visit, 
preferably, and no earlier than 4 weeks after the initial assessment of PD in the absence 
of clinically significant deterioration. Treatment with copanlisib + olaparib, or copanlib + 
olaparib + durvalumab (MEDI4736) would continue between the initial assessment of 
progression and confirmation for progression.  
 
Modification of RECIST as described may discourage the early discontinuation of copanlisib + 
olaparib + durvalumab (MEDI4736) and provide a more complete evaluation of its antitumor 
activity than would be seen with conventional response criteria.  Nonetheless, the efficacy 
analysis will be conducted by programmatically deriving each efficacy endpoint based on 
RECIST 1.1 criteria. 
 
Of note, clinically significant deterioration is considered to be a rapid tumor progression that 
necessitates treatment with anticancer therapy other than copanlisib + olaparib + durvalumab 
(MEDI4736) or with symptomatic progression that requires urgent medical intervention (e.g., 
CNS metastasis, respiratory failure due to tumor compression, spinal cord compression). 
 
12.2.1 Efficacy Variable 
 
Patients who have disease control following completion of 24 months of treatment or patients who 
are withdrawn from copanlisib + olaparib (+ durvalumab [MEDI4736]) treatment for reasons other 
than confirmed PD will continue to have objective tumor assessments. 
 
Confirmation of progression guidelines are set for the following reasons:  
• for patient management and treatment decisions; 
• in the absence of significant clinical deterioration, to promote the collection of additional 
scans after the first radiologic RECIST 1.1 assessment of PD in order to distinguish 
pseudoprogression from true radiologic progression, also known as RECIST 1.1 modified 
for confirmation of progression; and 
 
Confirmed objective disease progression refers to either of the following scenarios:  1) clinical 
progression/deterioration followed by a radiologic verification scan (PD by RECIST 1.1); or 2) in 
the absence of significant clinical deterioration, radiologic PD by RECIST 1.1 followed by a 
second radiologic confirmation scan with PD assessed according to the specific confirmation of 

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progression criteria listed below. (RECIST 1.1 modified for confirmation of progression refers to 
the second scenario above).  The confirmatory scan should occur preferably at the next scheduled 
imaging visit and no earlier than 4 weeks following the date of the immediate prior assessment of 
RECIST 1.1 PD. 
 
Immediate prior radiologic progression would be considered confirmed if any the following 
criteria are met in the confirmatory scan: 
• ≥20% increase in the sum diameters of target lesions (TLs) compared with the nadir at 2 
consecutive visits, with an absolute increase of at least 5 mm in sum of diameters compared 
to nadir, 
• and/or significant progression (worsening) of non-target lesions (NTLs) and/or of pre-
existing new lesions at the confirmatory scan time-point compared with the immediate 
prior time-point (Note:  Pre-existing new lesions are evaluated as NTLs at the confirmatory 
scan time-point), 
• and/or additional new unequivocal lesions at the confirmatory scan time-point. 
NOTE:  In order to have confirmed objective disease progression, there should be two 
consecutive PD’s, the first PD by RECIST 1.1 and the second PD using the confirmation of 
progression criteria (above). 
 
• In the absence of significant clinical deterioration, treatment with study drug may 
continue between the initial assessment of progression and the scan to confirm 
progression. 
• If progression is not confirmed, in the absence of significant clinical deterioration, then the 
patient should continue study drug and on-treatment assessments until the next PD which 
will also require a follow-up confirmation scan.   
If a patient discontinues treatment (and/or receives a subsequent anticancer therapy) prior to 
radiologic progression, then the patient should still continue to be followed until confirmed 
objective disease progression. 
 
 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
AE lists, guidelines, and instructions for AE reporting can be found in Section 10 (Adverse 
Events: List and Reporting Requirements). 
 
13.1 Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol PI is 
responsible for monitoring the conduct and progress of the clinical trial, including the ongoing 
review of accrual, patient-specific clinical and laboratory data, and routine and SAEs; reporting 
of expedited AEs; and accumulation of reported adverse events from other trials testing the same 
drug(s).  The Protocol PI and statistician have access to the data at all times through the CTMS 
web-based reporting portal.   
 

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For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de-
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS.  In 
addition, for the Phase 1 portion, the Protocol Principal Investigator will have at least monthly, 
or more frequently, conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and adverse events and unanticipated problems.  
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
13.2 Data Reporting 
 
Medidata Rave is the clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
  
Requirements to access Rave via iMedidata: 
 
•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: 
oRave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus 
(AP) registration type, 
oRave Investigator role must be registered as a Non-Physician Investigator (NPIVR) or 
Investigator (IVR), and 
oRave Read Only or Rave SLA role must have at a minimum an Associate (A) registration 
type. 
 
•Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in the Regulatory application, all persons 
with Rave roles assigned on the appropriate roster will be sent a study invitation email from 
iMedidata.  No action will be required; each study invitation will be automatically accepted and 
study access to the study 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.  

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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 invitation (previously sent but not accepted 
or declined by 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 Data Manaement 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. 
 
13.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-site 
audits will be conducted three times annually (one annual site visit and two data audits).  For 
CTMS monitored studies, after users have activated their accounts, please contact the Theradex 
Help Desk at (609) 619-7862 or by email at CTMSSupport@theradex.com for additional support 
with Rave and completion of CRFs. 
 
13.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks.  The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS.  Metrics for timeliness will be followed and assessed on a quarterly basis.  
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received.  Queries will be issued by CTMS directly within Rave.  The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  Monthly web-

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based reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm)  and 
CTSU websites. 
 
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will be 
included when appropriate to meet unique study requirements.  The PI is encouraged to review 
the eCRFs, working closely with CTMS to ensure prospectively that all required items are 
appropriately captured in the eCRFs prior to study activation.  CTMS will prepare the eCRFs 
with built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/adverse events.htm). 
 
13.2.3  Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered 
queries and form delinquencies, monitor data quality and timeliness, generate reports, and review 
metrics.  
 
The DQP is located on the CTSU members’ website under Data Management.  The Rave Home 
section displays a table providing summary counts of Total Delinquencies and Total Queries.  
DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, forms with 
current status, and timeliness reports.  Site staff should review the DQP modules on a regular 
basis to manage specified queries and delinquent forms. 
 
The DQP is accessible by site staff who are rostered to a site and have access to the 
CTSU website.  Staff who have Rave study access can access the Rave study data via 
direct links available on the DQP modules. 
 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice a 
month. These notifications serve as alerts that queries and/or delinquent forms require 
site review, providing a summary count of queries and delinquent forms for each Rave 
study that a site is participating in. Additional site staff can subscribe and unsubscribe to 

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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. 
 
 
13.3 CTEP Multicenter Guidelines 
 
N/A 
 
13.4 Collaborative Agreements Language 
 
The agents supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Companies 
(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. Agents may not be used for any purpose outside the scope of this protocol, nor can Agents be 
transferred or licensed to any party not participating in the clinical study.  Collaborators data 
for agents are confidential and proprietary to collaborators 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 other 
agents, 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 

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agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborators.  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
 
 

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14. 
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Di Giacomo, A.M., M. Biagioli, and M. Maio.  (2010).  The emerging toxicity profiles of anti-
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Domchek, S. Y-J Bang, G. Coukos, et al. (2016).  MEDIOLA: A phase I/II, open-label trial of 
olaparib in combination with durvalumab (MEDI4736) in patients (pts) with advanced solid 
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Farmer, H., N. McCabe, C.J. Lord, et al.  (2005). Targeting the DNA repair defect in BRCA 
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Food and Drug Administration.  Approval Letter for ALIQOPA™ for injection, 60mg.  (2017)  
 
IMFINZI® (durvalumab).  Package Insert. (2018) 
 
Gockeritz, E., S. Kerwien, M. Baumann, et al.  (2015).  Efficacy of phosphatidylinositol-3 kinase 
inhibitors with diverse isoform selectivity profiles for inhibiting the survival of chronic 
lymphocytic leukemia cells.  Int J Cancer.  137:2234-2242. 
 
Green, R.C., J.S. Berg, W.W. Grody, et al. (American College of Medical Genetics and 
Genomics).  (2013). ACMG recommendations for reporting of incidental findings in clinical 
exome and genome sequencing.  Genet Med.  15(7):565-574.  
 
Ibrahim, Y.H., C. Garcia-Garcia, V. Sera. et al. (2012). PI3K Inhibition Impairs BRCA1/2 
Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition. 
Cancer Discov. doi: 2159-8290. 
 
Izzedine, H., V. Gueutin, C. Gharbi, et al.  (2014). Kidney injuries related to ipilimumab.  Invest 
New Drugs.  32:769-773. 
 
Jiao, S. W. Xia, H. Yamagichi, et al. (2017). PARP Inhibitor Upregulates PD-L1 Expression and 
Enhances Cancer-Associated Immunosuppression. Clin Cancer Res. 14:3711-3720. 
 
Johnson, D.B., J.M. Balko, M.L. Compton, et al.  (2016). Fulminant Myocarditis with 
Combination Immune Checkpoint Blockade.  N Engl J Med.  375:1749-1755. 

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Juvekar, A. L.N. Burga, E.P. Lunsford. et al. (2012). Combining a PI3K Inhibitor with a PARP 
Inhibitor Provides an Effective Therapy for BRCA1-Related Breast Cancer. Cancer Discov.  
11:1048-1063. 
 
Kalia, S.S., K. Adelman, S.J. Bale, et al.  (2016).  Recommendations for reporting of secondary 
findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy 
statement of the American College of Medical Genetics and Genomics.  Genet Med.  19:249-
255. 
 
Kaehler, K.C., S. Piel, E. Livingston, et al.  (2010).  Update on Immunologic Therapy With 
Anti–CTLA-4 Antibodies in Melanoma: Identification of Clinical and Biological Response 
Patterns, Immune-Related Adverse Events, and Their Management.  Seminars in Oncology.  
27:485-498. 
 
 
Kim, K.W., N.H. Ramaiya, K.M. Krajewski, et al.  (2013).  Ipilimumab associated hepatitis: 
imaging and clinicopathologic findings.  Invest New Drugs.  31:1071-1077. 
 
Lacouture, M.E., J.D. Wolchok, G. Yosipovitch, et al.  (2014). Ipilimumab in patients with 
cancer and the management of dermatologic adverse events.  J Am Acad Dermatol.  71:161-169. 
 
Liu, N., B.R. Rowley, C.O. Bull, et al.  (2013). BAY 80-6946 is a highly selective intravenous 
PI3K inhibitor with potent p110alpha and p110delta activities in tumor cell lines and xenograft 
models.  Mol Cancer Ther.  12:2319-2330. 
 
Liu S. and Yuan, Y. (2015).  Bayesian Optimal Interval Designs for Phase I Clinical Trials. 
Journal of the Royal Statistical Society: Series C, 64, 507-523. 
 
Matulonis, U. A., G.M. Wulf, W.T. Barry, et al. (2017).  Phase I dose escalation study of the 
PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) 
inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer.  Ann Oncol. 
28:512-518. 
MEDI4736 (durvalumab) Investigator’s Brochure.  (2017).  Durvalumab (MEDI4736).  
AstraZeneca, Wilmington, DE.  Edition 12.  November 3, 2017. 
 
Meghani, K., E. Gogola, S. Rottenberg, et al. (2017).  MicroRNA profiling to identify novel 
determinants of platinum resistance in BRCA1/2- mutated high-grade serous ovarian cancer.  
Can Res.  Abstract 77 (LB-329). 
 
Michalarea, V., D. Roda, Y. Drew, et al. (2016).  Phase I trial combining the PARP inhibitor 
olaparib (Ola) and AKT inhibitor AZD5363 (AZD) in germline (g)BRCA and non-BRCA 
mutant (m) advanced cancer patients (pts) incorporating noninvasive monitoring of cancer 
mutations.  Cancer Res.  Abstract CT010. 
 
Ng, C.M., B.L. Lum, V. Gimenez, et al. (2006).  Rationale for fixed dosing of pertuzumab in 
cancer patients based on population pharmacokinetic analysis. Pharm Res. 23:1275–1284. 

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Okkenhaug, K., and J.A. Burger.  (2016).  PI3K signaling in normal B cells and chronic 
lymphocytic leukemia (CLL).  Curr Top Microbiol Immunol.  393:123-142. 
 
Okkenhaug, K., M. Graupera, and B. Vanhaesebroeck.  (2016). Targeting PI3K in cancer: 
Impact on tumor cells, their protective stroma, angiogenesis, and immunotherapy.  Cancer 
Discov.  6:1-16. 
 
Olaparib Investigator’s Brochure.  (2018). Olaparib (AZD2281, KU-0059436).  Edition 15, 
March 8, 2018.  AstraZeneca Pharmaceuticals, Wilmington, Delaware. 
 
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copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in 
patients with advanced solid tumors and non-Hodgkin's lymphomas.  Ann Oncol.  27:1928-1940. 
 
Parkes, E. E., S.M. Walker, L.E. Taggart et al.  (2017). Activation of STING-Dependent Innate 
Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer.  J Natl Cancer Inst. 
109:199-210. 
 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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APPENDIX B 
LIST OF PROHIBITED MEDICATIONS WHILE ON COPANLISIB 
TREATMENT 
 
This list is not comprehensive.  Because the lists of these agents are constantly changing, it is 
important to regularly consult a frequently-updated medical reference for a list of drugs to avoid 
or minimize use of. 
 
Category 
Drug name 
Strong Cytochrome P450 3A 
(CYP3A) Inhibitors 
Voriconazole, Boceprevir, clarithromycin, 
cobicistat, conivaptan, danoprevir/ritonavir, 
eltegravir/ritonavir, grapefruit juice, 
indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, 
saquinavir/ritonavir, telaprevir, telithromycin, 
tipranavir/ritonavir, troleandomycin, 
Strong CYP3A Inducers 
Avasimibe, carbamazepine, mitotane, 
phenobarbital, phenytoin, rifabutin, rifampin 
(rifampicin), St. John's wort (hypericum 
perforatum) 
Herbal Preparations/ 
Medications 
Herbal preparations/medications are prohibited 
throughout the study.  These herbal medications 
include, but are not limited to:  St. John’s Wort, 
Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, and ginseng.  Patients should stop 
using these herbal medications 7 days prior to 
first dose of study drug 
 
 
 

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➢  
➢  

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APPENDIX D 
THE AVERAGE GLYCEMIC INDEX OF COMMON FOODS 
DERIVED FROM MULTIPLE STUDIES BY DIFFERENT LABORAORIES 
 
Foods are categorized as having a low-glycemic index if the glucose reference index is ≤55.  
High-Glycemic Index foods have a glucose reference index >55.  The summary table below 
contains glucose reference for common foods. 
 
 
 
 

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APPENDIX E 
FROZEN BIOPSY SPECIMEN BATCH RECORD 
 
Batch Record 
 
A separate Batch Record should be started for each patient sample.  
 
Facility / Clinic Collecting Specimens: ____________________________ 
 
NCI Protocol Number:  10217 
Patient ID:_________ 
 
 
• Biopsy Collection 
 
 
 
• Biopsy Procedure Details 
 
  

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• Biopsy Storage 
 
 
 
• Notes, including any deviations from this protocol 
 
______________________________________________________________________________ 
 
______________________________________________________________________________ 
 
______________________________________________________________________________ 
 
 
• Review of Batch Record 
 
 
 
Laboratory Personnel:  ______________________________ (Print) 
 
Laboratory Personnel:  ______________________________ (Sign) 
 
Date:  ___________________________________________ 
 
 
 

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APPENDIX F 
PATIENT MEDICATION DIARY 
 
 
 
PATIENT’S MEDICATION DIARY 
 
Today’s date _________________________ 
Agent ________Olaparib_________ 
Patient Name_________________________ (initials acceptable) Patient Study ID 
_____________________________________ 
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each month. 
2. You will take ___ tablets each day, ___ in the morning and ___ in the evening.  You should take the tablets with 8 oz. 
water, with or without any moderate fat or low-fat food. 
3. The olaparib tablet s should be swallowed whole and not chewed, crushed, dissolved, or divided.  Do not take with 
grapefruit juice or Seville oranges. 
4. If a dose is vomited shortly after being taken, retake the dose only if the intake tablets can be seen and counted. 
5. If a dose is missed, the dose can be taken within 2 hours of the scheduled time.  Otherwise, skip the dose and take the next 
dose at the scheduled time.  Note this in the Comments column.  
6. Record the date, the number of tablets you took, and when you took them.   
7. If you have any comments or notice any side effects, please record them in the Comments column. 
8.  Please return the forms to your physician when you go for your next appointment. 
 
Day 
 
Date 
Time of 
morning dose 
# of tablets 
taken   
Time of evening 
dose 
# of tablets 
taken  
Comments 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
CTEP-assigned Protocol #__10217__ 
 
Local Protocol # ___________________ 

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23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
Patient’s 
Signature_____________________________________________________________________________________
______ 
Physician’s Office will complete this section: 
1. 
Date patient started protocol treatment___________________________________________________________________ 
2. 
Date patient was removed from study____________________________________________________________________ 
3. 
Patient’s planned total daily dose________________________________________________________________________ 
4. 
Total number of tablets taken this month ___________________________________________________________________ 
5. 
Physician/Nurse/Coordinator/ or Data Manager’s Signature ___________________________________________________ 
 
 

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APPENDIX G 
 ACCEPTABLE BIRTH CONTROL METHODS  
 
Olaparib is regarded as a compound with medium/high fetal risk. 
 
Patients of child bearing potential and their partners, who are sexually active, must agree to the 
use of TWO highly effective forms of contraception in combination (as listed below) throughout 
their participation in the study.  Moreover, women study participants are expected to use highly 
effective contraception for 6 months after the last dose of study drug and men are expected to use 
highly effective contraception for 3 months.  
Male patients should not donate sperm throughout the period of taking olaparib and for 3 months 
following the last dose of olaparib.  Acceptable birth control methods are listed below.  
 
Condom with spermicide and one of the following: 
o Oral contraceptive or hormonal therapy (e.g. hormone implants) 
o Placement of an intra-uterine device 
 
Acceptable non-hormonal birth control methods include: 
o Total sexual abstinence.  When the patient refrains from any form of sexual intercourse 
and this is in line with their usual and/or preferred lifestyle; this must continue for the 
total duration of the trial and for at least 6 months after the last dose of study drug for 
female patients, and for 3 months after last dose for male patients.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods, or declaration of 
abstinence solely for the duration of a trial) and withdrawal are not acceptable methods 
of contraception. 
o Vasectomised sexual partner plus male condom.  With participant assurance that 
partner received post-vasectomy confirmation of azoospermia. 
o Tubal occlusion plus male condom with spermicide. 
o Intrauterine Device (IUD) plus male condom+spermicide.  Provided coils are copper-
banded. 
 
Acceptable hormonal methods: 
• Etonogestrel implants (e.g., Implanon, Norplan)+male condom with spermicide 
• Normal and low dose combined oral pills+male condom with spermicide 
• Norelgestromin/ethinyl estradiol (EE) transdermal system+male condom with spermicide 
• Intravaginal device+male condom with spermicide (e.g., EE and etonogestrel) 
• Cerazette (desogestrel)+male condom with spermicide.  Cerazette is currently the only 
highly efficacious progesterone-based pill.  
• Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom 
• Intrauterine system (IUS) device (e.g., levonorgestrel releasing IUS -Mirena®) PLUS 
male condom  
• Intravaginal device (e.g., EE and etonogestrel) PLUS male condom 

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

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

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injury. Although there is no published consensus on exactly when to stop a drug in the face of 
laboratory abnormalities and the decision will be affected by information on related drugs, the 
accumulating clinical experience, the clinical status of the patient, and many other factors, the 
following can be considered a basic guide. Discontinuation of treatment should be considered if: 
 
ALT or AST >8xULN 
ALT or AST >5xULN for more than 2 weeks 
ALT or AST >3xULN and (TBL >2xULN or INR >1.5) 
ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
 
It should be noted that although these guidelines have not been evaluated systematically in a 
prospective fashion, they represent an approach that is similar to current practice. 
 
2. Evaluating Data for Alternative Causes 
 
An important purpose of close observation is to gather additional clinical information to seek 
other possible causes of the observed liver test abnormalities, such as one of the following 
common causes: 
 
Acute viral hepatitis. The usual onset of hepatocellular DILI is indistinguishable from acute viral 
hepatitis A or B. Hepatitis C is much less often acute in its onset and tends to be insidious, but it 
sometimes can resemble acute DILI. The presence of acute viral hepatitis A, B, and C should be 
evaluated by serological markers. Viral hepatitis D (requires concomitant hepatitis B infection) 
and E are relatively rare in the United States. Hepatitis E is more common in developing 
countries, including Southeast Asia, and should be considered in recent travelers to those 
countries and in patients in trials conducted in those countries. Also rare are hepatocellular liver 
injuries caused by Epstein-Barr virus, cytomegalovirus, herpes simplex virus, toxoplasmosis, 
varicella, and parvovirus, although these infections are seen more typically in immuno- 
suppressed individuals. Adolescent and young adult patients with possible DILI should be tested 
for Epstein-Barr virus. Hepatitis is common among transplant patients with cytomegalovirus 
disease. 
 
Alcoholic and autoimmune hepatitis. Acute alcoholic hepatitis usually is recurrent, with a history 
of binging exposure to alcohol preceding episodes, and it has some characteristic features, such 
as associated fever, leukocytosis, right upper quadrant pain and tenderness, hepatomegaly, and 
AST >ALT, that may help distinguish it from other causes of liver injury. Other features of the 
physical examination may include the presence of stigmata of cirrhosis, such as spider nevi, 
palmar erythema, estrogenic changes in males, and Dupuytren’s contractures. Alcoholic and 
autoimmune hepatitis should be assessed by history, physical examination, and laboratory 
testing, including serologic testing (e.g., antinuclear or other antibodies). 
 
Hepatobiliary disorders. Biliary tract disease, such as migration of gallstones or intrahepatic 
lesions, more often causes cholestatic injury initially and should be investigated with gall bladder 
and ductal imaging studies, especially if ALP is increased. Malignant interruption of the biliary 
tract also should be considered. 

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

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212 
be considered if the subject has shown important benefit from the drug and other options are not 
available or if substantial accumulated data with the test drug do not show a potential for severe 
injury. The subject should be made aware of the potential risk, and consent to the re-challenge, 
and the PI consulted. 
 
 
 

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APPENDIX I 
PHARMACOKINETICS SHEET BASELINE ( STEP 2 TRIPLET 
ONLY) 
 
 
 
Study Sample Collection Log
Date:
BSA:
(m2)
Pharmacokinetic (PK) Sample Collection
Protocol Sample and Time 
Point
Projected Sample Due Time
(24 hr clock)
Actual Time
(24 hr clock)
Cycle 1 Day 1 or before
pre sample
C infusion start
=O dosing
Olaparib (O), Copanlisib (C)  
Comments
Collect 3-4 mL red-top tube; Clot upright at RT 30-60 min max; centrifuge 10 min 
1,200 x g RT; store serum at -70°C until shipment. 
Copanlisib (C) infusion (nominal 60 min)  Copanlisib Dose (mg):__________________________  Olaparib Dose (mg):__________________________
ONLY IN PATIENTS WITH TRIPLE COMBINATION (DURVALUMAB)
Note the start and stop times of infusions / administering of oral dose, in this form. Whenever the timing of drawing samples is dependent on the recent start or end of an 
infusion, a green arrow indicates which time-point starts the clock on subsequent blood draws.
NCI 10217 A Phase 1b Biomarker-Driven Combination Trial of Copanlisib, Olaparib, and MEDI4736 (Durvalumab) in Patients with Advanced Solid Tumors
Subject Initials:
(First_Middle_Last)  
Subject ID:  
Site Name:
At each PK time point, ~3-4 mL of peripheral blood will be collected. After sample processing, store plasma or serum samples at -70°C or below until shipment. See Section 5 of 
the protocol for more specific processing instructions and shipping instructions. At the time of sample transfer, a copy of this completed PK form must be transferred also.

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APPENDIX J  
TISSUE BIOPSY VERIFICATION FORM 
A copy of the diagnostic pathology report must be shipped with all tissue specimens sent 
to the 
EET Biobank. 
If the corresponding pathology report is not available for the biopsy, then a copy 
of the radiology report or operative report from the biopsy procedure and the 
diagnostic pathology report must be sent to the EET Biobank. A completed copy 
of this appendix (i.e., Tissue Biopsy Verification) must also be submitted to the 
EET Biobank. 
Note: If this information is not provided with the biopsy specimen, then it will not be 
accepted by the EET Biobank. 
 
 
Please have the Clinician* responsible for signing out this patient’s case complete the 
following: 
ETCTN Universal Patient ID:  
 
ETCTN Patient Study ID:   
 
Date of Procedure (mm/dd/yyyy):   
 
Tissue Type (circle one): 
Primary 
Metastatic 
Time point (circle one):  Baseline C1D15 C2D15 Progression   
Site Tissue Taken From:   
 
Diagnosis:   
 
I agree that this tissue may be released for research purposes only and that the release 
of this tissue will not have any impact on the patient’s care. 
 
Clinician Signature 
Date 
 
Clinician Printed Name 
*Note: For the purposes of this form, Clinician could include the Nurse Practitioner, Registered 
Nurse, Pathologist, Radiologist, Interventional Radiologist, Surgeon, Oncologist, Internist, or 
other medical professional responsible for the patient’s care.  
Version: 1 
Effective Date: 9/2019 
 
 
 
 
 
 

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APPENDIX K 
INTERVENTION GUIDELINES FOR COMMON TREATMENT 
RELATED ADVERSE EVENTS (AE) 
 
This section is meant to provide additional intervention guidelines for common treatment 
related AEs. 
 
Management of Copanlisib-related rash maculo-papular 
 
Rash 
maculo-
papular  
(CTCAE v5) 
Management 
Additional 
recommended 
intervention 
Grade 1 
Hold copanlisib until rash resolves 
Apply 
emollients/creams 
liberally as needed until rash 
resolves. 
 
Face: Desonide 0.05% cream 
Body: Triamcinolone 0.1% cream 
Grade 2 
• Hold copanlisib and olaparib until 
rash resolves. 
 
• Can restart olaparib if rash recovers 
to Grade 1 or completely resolves. 
 
• Can restart copanlisib when rash 
completely resolves 
 
• Apply 
emollients/creams 
liberally as needed until rash 
resolves. 
 
o Face: 
Desonide 
0.05% 
cream 
o Body: 
Triamcinolone 
0.1% cream 
 
• Short-term steroid taper 
 
o Medrol dose pack 
Grade ≥3 
• Hold copanlisib and olaparib until 
rash resolves. 
 
• Can restart olaparib if rash recovers 
to Grade 1 or completely resolves. 
 
 
•  Can restart copanlisib when rash 
completely resolves 
 
 
• Apply 
emollients/creams 
liberally as needed until rash 
resolves. 
 
o Face: 
Desonide 
0.05% 
cream 
o Body: 
Triamcinolone 
0.1% cream 
 
• Short-term steroid taper 
 
o Medrol dose pack 
 
• Hospital 
admission 
and 
IV 
steroid administration. 
 
 
 
 
 
 

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Management of transient glucose increase prior to copanlisib infusion 
 
Criteria  
Management 
Additional recommended 
intervention 
Asymptomatic glucose 
increase ≥200-250 mg/dL 
Patients who develop transient 
post-infusion glucose ≥200-250 
mg/dL after study drug 
administration may continue 
treatment; however, the 
subsequent infusion can only 
take place as long as glucose 
levels return to pre-infusion 
levels of <160 mg/dL (fasting) or 
<200 mg/dL (non-fasting) 
Does not generally require 
intervention with glucose 
lowering medication. 
Asymptomatic glucose 
increase to 
˃250 mg/dL 
• Patients who develop 
transient post-infusion 
glucose ˃250 mg/dL after 
study drug administration 
may continue treatment; 
however, the subsequent 
infusion can only take place 
as long as glucose levels 
return to pre-infusion levels 
of <160 mg/dL (fasting) or 
<200 mg/dL (non-fasting) 
 
• Should have repeated 
laboratory glucose 
determination.  
 
• If the repeated glucose value 
is decreasing, the glucose 
may be followed without 
glucose lowering medication 
treatment if hydration status 
is normal as clinically 
assessed.  
 
• Consultation with 
endocrinologist is 
recommended. 
• Hydration if appropriate.  
 
• Consider prophylaxis 
with oral glucose 
lowering medication 
when planning next 
infusion. 
Symptomatic or persisting 
glucose increases to a value 
>250 mg/dL 
• Patients who develop 
transient post-infusion 
glucose ˃250 mg/dL after 
study drug administration 
• Rapid/ short acting 
insulin may be given for 
glucose persisting at 
>250 mg/dL, or if the 

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may continue treatment; 
however, the subsequent 
infusion can only take place 
as long as glucose levels 
return to pre-infusion levels 
of <160 mg/dL (fasting) or 
<200 mg/dL (non-fasting) 
 
• Hydration status should be 
clinically assessed. If clinical 
assessment is consistent 
with dehydration, fluids 
should be given as clinically 
appropriate (orally or IV).  
 
• Laboratory test confirming 
increase should be repeated. 
If the repeated glucose value 
is persistent and/or patient 
is symptomatic and/or the 
hydration status indicates 
the need for hydration, 
glucose lowering medication 
should be administered.  
 
• Prompt input from a 
diabetes specialist should be 
obtained. 
patient is symptomatic 
during the infusion day.  
 
• Rapid/short acting 
insulin.  
 
• According to the 
institution sliding scale 
coverage of glucose 
persisting at >250 mg/dL 
is recommended, with 
oral or IV hydration as 
clinically appropriate. 
When planning next 
infusion, consider 
prophylaxis with oral 
glucose lowering 
medication. 
 
         Management of glucose increases post-copanlisib infusion 
 
Hyperglycemia  
(CTCAE v5) 
Management 
Additional 
recommended 
intervention and/or action 
Grade 1 
Continue study treatment 
 
None.  
 
Grade 2 
• Hydration as clinically indicated 
 
• When 
planning 
next 
infusion 
prophylaxis with oral glucose lowering 
medication 
per 
local 
SOC 
is 
recommended. 
 
• Consultation 
with 
endocrinologist 
for 
diabetic patients is recommended 
• Continuing 
occurrence 
of 
post-infusion 
blood 
glucose 
>500 
mg/dL, 
based 
on 
repeated 
laboratory 
analysis 
despite 
optimal 
glucose 
lowering 
therapy 
after 
2 
infusions of copanlisib, and 
will 
require 
dose 
reduction 
by one dose level. 
Grade ≥3 
• Hydration as clinically indicated (orally, 
IV) 
 
• Insulin therapy per local SOC 
 
 
• Requires 
permanent 
discontinuation of the study 
drug if persistent occurrence 
of 
post-infusion 
blood 
glucose >500 mg/dL based on 

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• When planning next infusion consider 
prophylaxis with oral glucose lowering 
medication per local SOC 
 
• Consultation 
with 
endocrinologist 
is 
recommended 
laboratory 
analysis, 
which 
occurred at the lowest dose 
level despite optimal glucose 
lowering 
therapy 
(after 
at 
least one cycle of treatment) 
and with consultation of a 
diabetes specialist. 
 
   
 
 
 
 
 
Management of glucose increases on subsequent days post-copanlisib 
infusion 
 
Criteria 
Management 
Additional 
recommended 
intervention 
Grade 2 
 
Max 
post-infusion 
glucose level of ˃200 
mg/dL 
• Oral 
glucose 
lowering 
medication 
recommended 
on 
subsequent days. 
 
• Consultation 
with 
endocrinologist 
is 
recommended 
• Use 
of 
sulfonylurea/metaglinides, 
insulin 
secretagogues 
medications 
to 
manage 
increased glucose levels post- 
infusions 
are 
not 
recommended.  
 
• Treatment 
with 
glucose 
lowering 
medication 
suggested 
according to the local standard 
practice.  
 
• Based on the mechanisms of 
action and decreased risk of 
hypoglycemia; 
metformin, 
sodium-glucose 
co-
transporter-2 
(SGLT-2) 
inhibitor 
or 
dipeptidyl 
peptidase-4 
(DPP-4) 
inhibitor 
might 
be 
useful 
treatment 
options. 
 
              
 
 
 
 
 

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   Management of copanlisib-related arterial hypertension 
 
Hypertension 
(CTCAE v5) 
Management 
Additional recommended 
intervention and/or action 
Pre-dose 
measurements 
BP ≥150/90 mmHg 
No dose should be given until 
recovery to <150/90 mmHg 
• Consider BP lowering 
medication. 
 
• Dosing can proceed on the 
scheduled day if after at least 
2 consecutive measurements 
BP returns to <150/90 mmHg. 
If BP doesn’t return to 
<150/90 mmHg, delay dosing 
until next visit. 
During infusion 
Grade 3 or ≥160/100 
mmHg 
Infusion can be interrupted or 
slowed down and administration 
of BP lowering therapy should be 
initiated 
• Infusion may be resumed 
when BP has returned to 
<150/90 mmHg at the 
investigator’s discretion or 
skipped.  
 
• Subsequent study drug 
administrations may be 
reduced by 1 dose level at the 
investigator’s discretion 
Post-dose 
Drug-related grade 3 or 
≥160/100 mmHg" 
None 
• Administration of BP lowering 
therapy should be initiated 
according to local standard of 
care. 
 
• Additional measurements to 
be performed as clinically 

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indicated until recovery to 
<150/90 mmHg. 
 
• Subsequent study drug 
administrations may be 
reduced by 1 dose level at the 
investigator’s discretion 
Grade 4 
Permanent discontinuation. 
 
 
               
 
 
 
 
 
 
 
 
 
 
 
 
 
Recommended meal timing on days of copanlisib infusion 
 
Consumption of meals in close proximity to copanlisib infusion may exacerbate a glucose 
level increase. Therefore, caloric restriction is recommended on infusion days. The timing 
and content of meal intake and additional glucose testing (if clinically indicated) is 
managed and monitored by the investigators based on glucose response patterns during 
prior treatment days. 
 
Scenario 1: 
• Study labs drawn 
• Meal after labs drawn but before copanlisib infusion 
• Repeat glucose measurement prior to copanlisib infusion 
o 1 hour post-meal – repeat glucose measurement (point of care 
measurement is acceptable) 
o 2 hours post-meal – repeat glucose measurement (point of care 
measurement is acceptable) 
 
Scenario 2: 
• Meal before study labs drawn 
• Study labs drawn within 1-2 hours of meal 
• If labs are drawn 1-2 hours after meal, repeat glucose prior to copanlisib infusion 
(point of care measurement is acceptable) 

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