A Randomized Phase 2 Study of Cediranib in Combination With Olaparib Versus Olaparib Alone in Men With Metastatic Castration Resistant Prostate Cancer
Phase: PHASE2
Conditions: Advanced Prostate Adenocarcinoma With Neuroendocrine Differentiation, Castration-Resistant Prostate Carcinoma, Metastatic Prostate Adenocarcinoma With Neuroendocrine Differentiation, Metastatic Prostate Carcinoma, Prostate Adenocarcinoma With Neuroendocrine Differentiation, Stage IV Prostate Adenocarcinoma AJCC v7
Sponsor: National Cancer Institute (NCI)

 
 
i 
 
SUMMARY OF CHANGES -- PROTOCOL 
 
 
NCI Protocol #: 9984 
Local Protocol #: 2000020461 
Protocol Version Date: September 7, 2021 
 
Background 
 
As part of Good Clinical Practice, CTEP reviews each CAEPR list on an annual basis. The review 
includes literature search, CTEP-AERS submission review, and comparison to the latest agent 
Investigator’s Brochure.  After review of all the available data, CTEP has identified new and/or modified 
risk information associated with olaparib. 
 
 
I. 
Request for Rapid Amendment Letter for Olaparib from CTEP on 8/27/21: 
Section 
Comments 
1. 
7.1.1.2 
for Insertion of 
Revised 
CAEPR 
(Version 2.5, 
July 1, 2021),  
Page 67 
 
 
x The SPEER grades have been updated. 
 
x 
Added New Risk:  
x 
Rare but Serious: Allergic reaction; Febrile neutropenia; Skin and 
subcutaneous tissue disorders - Other (angioedema); Skin and 
subcutaneous tissue disorders - Other (erythema nodosum) 
x 
Also Reported on Olaparib Trials But With Insufficient Evidence for 
Attribution: Arterial thromboembolism; Atrial fibrillation; Death 
NOS; Dermatitis radiation; Enterocolitis; Erythema multiforme; 
Esophageal stenosis; Hypoxia; Muscle weakness upper limb; 
Obstruction gastric; Peripheral ischemia; Reversible posterior 
leukoencephalopathy syndrome; Sinus bradycardia; Soft tissue 
necrosis lower limb; Treatment related secondary malignancy 
 
x 
Increase in Risk Attribution:  
x 
Changed to Likely from Less Likely: Abdominal pain 
x 
Changed to Less Likely from Also Reported on Olaparib Trials But 
With Insufficient Evidence for Attribution: Mucositis oral; Muscle 
cramp; Myalgia; Pain in extremity; Rash maculo-papular 
 
x 
Decrease in Risk Attribution:  
x 
Changed to Rare but Serious from Less Likely: Platelet count 
decreased 
x 
Changed to Also Reported on Olaparib Trials But With Insufficient 
Evidence for Attribution from Less Likely: Fever; Lymphocyte 
count decreased 
 
 
x 
Modified Specific Protocol Exceptions to Expedited Reporting (SPEER) 
reporting requirements:  

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
ii 
x 
Added to SPEER: Back pain; Neutrophil count decreased 
 
x 
Provided Further Clarification: 
x 
Infection listed under Less Likely is now captured as “Upper 
respiratory infection” and “Urinary tract infection” under Less 
Likely. 
 
PLEASE NOTE:  The specific detailed changes listed here compare the new 
revised CAEPR Version 2.5, and associated risk information for the ICD, to the 
most recent CAEPR Version 2.4.   If your trial contains an older CAEPR version 
(i.e., does NOT currently contain CAEPR Version 2.4), you MUST include a 
description of any additional changes resulting from migration from the older 
CAEPR version. 
 
 
II. 
Additional Changes  
 
 
Section 
Comments 
2. 
Header, all 
pages  
Version date updated 
3. 
Title Page 
Version date updated.  
4. 
Title Page, 
Project 
manager  
Project manager’s contact information updated  
5. 
TOC 
Table of Contents updated 
 
 

 
 
1 
 
Protocol #: 
9984 
 
Local Protocol #: 
2000020461 
 
ClinicalTrials.gov Identifier: NCT02893917 
 
TITLE: A Randomized Phase 2 Study of cediranib in Combination with olaparib versus olaparib 
alone in men with metastatic castration resistant prostate cancer 
 
 
Corresponding Organization: LAO-CT018 / Yale University Cancer Center LAO  
 
Principal Investigator: 
Joseph W. Kim, MD 
Yale Cancer Center 
333 Cedar Street, FMP 121 
New Haven, CT 06520 
joseph.w.kim@yale.edu 
Direct Office: 203-737-6467 
 
Translational Co-Investigators:  
 
Rana McKay, MD 
 
University of California, San Diego 
 
Moores Cancer Center  
 
3855 Health Sciences Drive, #0987 
 
La Jolla, CA 92093-0987 
 
rmckay@ucsd.edu 
 
Phone: 858-822-6185   
 
 
Eliezer Van Allen, MD, PhD 
 
Dana Farber Cancer Institute 
 
Boston, MA 
 
eliezerm_vanallen@dfci.harvard.edu  
 
 
Participating Organizations  
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
2 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
CATCHUP / Creating Access to Targeted Cancer Therapy for Underserved Populations 
 
Statistician: 
Yu Shyr, PhD 
Harold L. Moses Chair in Cancer Research 
Director, Vanderbilt Center for Quantitative Sciences; 
Director, Vanderbilt Technologies for 
Advanced Genomics Analysis and Research Design 
(VANGARD) 
Associate Director for Quantitative Sciences Integration, 
Vanderbilt-Ingram Cancer Center 
Professor of Biostatistics, Biomedical Informatics, and 
Cancer Biology Researcher 
 
 
Vanderbilt University Medical Center 
2220 Pierce Ave. 
571 Preston Building 
Nashville, TN 37232-6848 
615-936-2572 
yu.shyr@vanderbilt.edu 
 
 
 
Study Coordinator: 
Shelby DeCarlo BSN, RN 
Clinical Research Nurse 
Yale Cancer Center, Clinical 
Trials Office 
2 Church Street South Suite 507 
New Haven, CT 06519 
(203) 737-6299 
 
Project Manager:  
TBD 
Clinical Trials Office, Yale 
Cancer Center 
2 Church Street South, Suite 507 
New Haven, CT 06519 
cto-guendosarc@yale.edu; 
joseph.w.kim@yale.edu 
 
 
 
NCI-Supplied Agent(s):  AZD2171 (cediranib) #NSC 732208; Olaparib (AZD2281) NSC 
747856 
 
IND #:  
 
IND Sponsor: DCTD, NCI  
 
  
Protocol Type / Version # / Version Date:  
Original/ Version 1 / Version Date: July 25, 2016 
 
 
Revision/ Version 2 / Version Date: September 29, 2016 
Revision/ Version 3 / Version Date: November 29, 2016 
Amendment/ Version 1 / Version Date: January 23, 2017 
Amendment/ Version 2/ Version Date: March 23, 2017 
Amendment/ Version 3/ Version Date: September 14, 2017 
Amendment/ Version 4/ Version Date: April 03, 2018 
Amendment/ Version 5/ Version Date: May 17, 2018 
Amendment/ Version 6/ Version Date: August 02, 2018 
Amendment/ Version 7/ Version Date: January 7, 2019 
Amendment/ Version 8/ Version Date: April 2, 2019 (Withdrawn by CTEP)  

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
3 
Amendment/ Version 9/ Version Date: May 28, 2019 
Amendment/ Version 10/ Version Date: September 8, 2020 
Amendment/ Version 11/ Version Date: September 7, 2021 
 
 

NCI Protocol #: 9984 
 
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SCHEMA 
 
 
 

NCI Protocol #: 9984 
 
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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................4 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objectives ...................................................................................................8 
1.2 
Secondary Objectives ...............................................................................................8 
1.3 
Exploratory Objectives ............................................................................................8 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Study Disease: Prostate Cancer ...............................................................................9 
2.2 
CTEP IND Agents ...................................................................................................9 
2.3 
Rationale ................................................................................................................13 
2.4 
Correlative Studies Background ............................................................................17 
3. 
PATIENT SELECTION ....................................................................................................24 
3.1 
Eligibility Criteria ..................................................................................................24 
3.2 
Exclusion Criteria: .................................................................................................27 
3.3 
Inclusion of Women and Minorities ......................................................................30 
4. 
REGISTRATION PROCEDURES ...................................................................................31 
4.1 
Investigator and Research Associate Registration with CTEP ..............................31 
4.2 
Site Registration .....................................................................................................32 
4.3 
Patient Registration ................................................................................................34 
4.4 
General Guidelines .................................................................................................35 
5. 
TREATMENT PLAN ........................................................................................................35 
5.1 
Agent Administration .............................................................................................35 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................37 
5.3 
Criteria for Taking a participant OFF protocol therapy .........................................40 
5.4 
Duration of Follow Up ...........................................................................................40 
5.5 
Criteria to take a participant OFF study .................................................................41 
5.6 
Criteria for cross-over to cediranib/olaparib combination arm. .............................41 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................41 
6.1 
Arm A:  Management of Cediranib and Olaparib Related Adverse Events ..........41 
6.2 
Arm B: Olaparib Monotherapy ..............................................................................59 
6.3 
Interruptions for intercurrent non-toxicity related events ......................................61 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................62 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................62 
7.2 
Adverse Event Characteristics ...............................................................................70 
7.3 
Expedited Adverse Event Reporting ......................................................................70 
7.4 
Routine Adverse Event Reporting .........................................................................72 
7.5 
Secondary Malignancy ...........................................................................................72 
7.6 
Second Malignancy ................................................................................................73 
7.7 
Pregnancy ...............................................................................................................73 
7.8 
Pregnancy loss .......................................................................................................73 

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7.9 
Neonatal death .......................................................................................................73 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................73 
8.1 
CTEP IND Agent(s) ...............................................................................................73 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................79 
9.1 
Integrated Correlative Studies ................................................................................82 
10. 
STUDY CALENDAR .......................................................................................................91 
11. 
MEASUREMENT OF EFFECT........................................................................................95 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................95 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ...........................................................................................................103 
12.1 
Study Oversight ...................................................................................................103 
12.2 
Data Reporting .....................................................................................................103 
12.3 
Collaborative Agreements Language ...................................................................105 
13. 
STATISTICAL CONSIDERATIONS.............................................................................107 
13.1 
Study Design/Endpoints.......................................................................................107 
13.2 
Sample Size/Accrual Rate ....................................................................................107 
13.3 
Stratification Factors ............................................................................................110 
13.4 
Analysis of Primary and Secondary Endpoints ...................................................110 
13.5 
Reporting and Exclusions ....................................................................................113 
REFERENCES ............................................................................................................................115 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................122 
APPENDIX B 
NEW YORK HEART ASSOCIATION 
CLASSIFICATIONS .......................................................................................................123 
APPENDIX C-1 
PATIENT DRUG INFORMATION HANDOUT AND 
WALLET CARD –  OlAPARIB .....................................................................................124 
APPENDIX C-2 
PATIENT DRUG INFORMATION HANDOUT AND 
WALLET CARD – CEDIRANIB ...................................................................................126 
APPENDIX D 
LIST OF MEDICATIONS PROHIBITED ON STUDY ........................128 
APPENDIX E 
PILL Diary For Olaparib Monotherapy ARM .........................................126 
APPENDIX F 
PILL DIARY FOR CEDIRANIB / OLAPARIB 
COMBINATION ARM ...................................................................................................128 
APPENDIX F-1  
SYMPTOM DIARY FOR Cediranib and Olaparib 
Combination Arm ............................................................................................................131 

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APPENDIX G 
SUGGESTED ORAL ANTI-HYPERTENSIVE 
MEDICATIONS ..............................................................................................................134 
APPENDIX H RISK-BASED APPROACH FOR PATIENT MONITORING 
AND PROTOCOL DRIVEN MANAGEMENT .............................................................136 
APPENDIX I Standard Operating Procedure for Collection and Processing of 
Biopsy Tissue ...................................................................................................................138 
APPENDIX J 
Tissue Requsition Form ...........................................................................146 
Appendix K  Blood Requisition Form .......................................................................................147 
Appendix L  Research Lab data Table .........................................................................................148 
 
 
 

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8 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To assess the clinical activity of the combination of cediranib and olaparib, as measured 
by radiographic progression free survival (rPFS), as compared to olaparib monotherapy in 
patients with mCRPC.  See Section 11.1.7 for the definition of rPFS.  
 
1.2 
Secondary Objectives 
1.2.1 To assess the clinical activity of the combination of cediranib and olaparib, as measured 
by PSA response rate, radiographic response rate by RECIST v1.1, and overall survival 
(OS), as compared to olaparib monotherapy in patients with mCRPC.  
o PSA response is defined by PSA decline > 50% from the baseline, confirmed by a 
second value 3-4 weeks later  
 
1.2.2 To evaluate association of homologous recombination DNA repair deficiency (HRD) with 
the clinical activity of the combination of cediranib and olaparib or olaparib monotherapy, 
as measured by rPFS, in mCRPC patients.  
o HRD positive status is defined by presence of homozygous deletion or deleterious 
mutations in key homologous recombination genes of DNA repair genes as 
analyzed by BROCA-HR test.  
 
1.2.3 To evaluate the safety the combination of cediranib and olaparib and olaparib 
monotherapy in patients with metastatic prostate cancer. 
 
 
1.3 
Exploratory Objectives 
 
1.3.1 To characterize genomic alterations by whole exome sequencing in mCRPC patients and 
correlate that with clinical activity or resistance to olaparib with or without cediranib 
 
1.3.2 To characterize changes in RNA expression of DNA repair genes, angiogenesis markers, 
and immune markers, by whole transcriptome sequencing and correlate with clinical 
activity or resistance to olaparib with or without cediranib.  
 
1.3.3 To characterize changes in immune tumor microenvironment in mCRPC patients by 
profiling expression of co-stimulatory and co-inhibitory molecules and tumor infiltrating 
lymphocytes, and correlate with clinical activity or resistance to olaparib with or without 
cediranib.  
 
1.3.4 To identify baseline predictive biomarkers for rPFS or response and to identify on-
treatment markers of acquired resistance in men with mCRPC receiving either olaparib 
plus cediranib or olaparib alone. 
 

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9 
1.3.5 To explore biomarker signatures that correlate with the clinical activity or resistance to 
olaparib with or with cediranib, including changes in gene expression or acquired 
mutations in tumor biopsies. 
 
 
 
2. BACKGROUND 
 
2.1 
Study Disease: Prostate Cancer 
 
Metastatic castration resistant prostate cancer (mCRPC) is a disease that kills 
approximately 27,000 men each year in the United States (U.S.) alone [1]. It is the second 
leading cause of cancer-related death in the U.S. Approved therapies for mCRPC shown to 
confer survival benefit include sipuleucel-T, enzalutamide, abiraterone, docetaxel, radium-
223 and cabazitaxel. Despite advancement of these new agents, resistance to these 
therapies is inevitably seen.  Furthermore, the response to the subsequent hormonal therapy 
following abiraterone or enzalutamide, as an example, is only modest [2, 3]. One study 
suggests that the median overall survival among patients whose disease resistant to 
abiraterone or enzalutamide, via AR-V7 as an example, is in the range of 5.5 months to 
10.6 months [4] 
 
A systemic, multi-institutional study of clinical mCRPC tumors obtained from 150 men 
has provided genomic landscape data of mCRPC [5]. In that study, aberrations in AR, ETS 
genes, TP53 and PTEN were the most frequent (40 to 60%). Of note, aberrations of BRCA2, 
BRCA1 and ATM were observed in 19.3% overall, including 5.3% (8 of 150) harboring 
germline BRCA2 mutations with a subsequent somatic event resulting in bi-allelic loss. 
Other recurrent aberrations in DNA repair genes were identified in at least 34 of 150 
(22.7%). Recently, Prichard et al. also isolated germline DNA from 692 men with 
metastatic prostate cancer and reported that 82 men (11.8%) had deleterious germline 
DNA-repair gene mutations. The mutations were found in 16 genes, including BRCA2 
(5.3%), ATM (1.6%), CHEK2 (1.9%), BRCA1 (0.9%), RAD51D (0.4%) and PALB2 (0.4%) 
[6].  Additionally, the clinical samples from a single-center phase II study (TOPARP) study 
in United Kingdom, reported that 16 of 49 (33%) mCRPC were found to have homozygous 
deletion and/or deleterious mutations in the genes of DNA repair pathway [7].  Other 
groups have also reported 12% (7 of 60) of advanced prostate cancers are hyper-mutated 
and have mutations in MSH2 and MSH6 mismatch repair genes [8]. In summary, it is 
estimated that about 12 to 33% of mCRPCs have defective DNA repair pathway. These 
findings are of special interest because agents targeting DNA repair pathway, notably, poly 
(ADP-ribose) polymerase (PARP) inhibitors, have shown promising activities in several 
solid tumors with defective DNA repair pathways.  
 
2.2 
CTEP IND Agents 
 
2.2.1 Cediranib (AZD2171) (NSC 732208) 
 
Cediranib (AZD2171) is a potent small molecule vascular endothelial growth factor 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
10 
(VEGF) receptor tyrosine kinase (RTK) inhibitor of all three VEGF receptors (VEGFR-1, 
-2 and -3) at nanomolar concentrations.  Inhibition of VEGF signalling leads to the 
inhibition of angiogenesis, lymphangiogenesis, neovascular survival and vascular 
permeability.  Cediranib has additional activity against stem cell factor receptor (c-kit) 
tyrosine kinase inhibiting this kinase with a similar potency to that at which it inhibits 
VEGFRs.  Cediranib is less active versus platelet-derived growth factor receptor (PDGFR) 
tyrosine kinases, and inactive against other kinases tested.  
 
Cediranib inhibited the growth of tumours in preclinical models in a dose-dependent 
manner.  At doses that reduce tumour growth VEGFR-2 and c-kit were inhibited, but only 
partial inhibition of PDGFR was observed.  Anti-tumour activity was associated with a 
reduction in micro-vessel density and changes in vascular permeability.  Cediranib reduced 
ascites accumulation in pre-clinical models of ovarian cancer.  Cediranib also inhibited 
metastatic dissemination in pre-clinical models, and through inhibition of VEGFR-3 
inhibited lymphangiogenesis.  Collectively, these changes indicate that cediranib limits 
tumour growth, metastases and microvascular permeability.  Following once daily (od) 
dosing with 20 mg cediranib, the unbound minimum steady-state plasma concentration 
(Css,min) was approximately 5-fold greater than the human umbilical vein endothelial cell 
(HUVEC) proliferation inhibitory concentration 50% (IC50) reported in non-clinical 
studies.  At a clinical dose of 20 mg in patients, a small increase in diastolic blood pressure 
(DBP) and systolic blood pressure (SBP) is expected; a significant reduction in serum 
soluble VEGFR2 was observed; and a decrease in tumour vessel permeability and 
vascularity in liver lesions, as measured by dynamic contrast enhanced magnetic resonance 
imaging, was detected.  
 
Preclinical, toxicology and safety, pharmacology and clinical experience is fully described 
in the current version of the cediranib investigator’s brochure.  (Cediranib IB Ed. 19)  
 
 
2.2.1.1 
Pharmaceutical information.  
 
Refer to Section 8.1.1 
 
2.2.1.2 
 Clinical Activity of Cediranib in Prostate Cancer:  
Ryan et al reported the results of a phase I dose escalation and pharmacokinetic study of 
cediranib in patients with advanced prostate cancer [9]. Twenty-six patients received oral 
daily dosing of AZD2171 at 1, 2.5, 5, 10, 20, 30 mg. The maximum tolerated dose (MTD) 
was defined as the dose below that at which >or=33% of patients experienced a dose-
limiting toxicity (DLT) within 21 days of initiating therapy. Pharmacokinetic analysis was 
performed. DLTs occurred at the 30 mg dose and included grade 3 events in three patients: 
fatigue (n = 3) and muscle weakness (n = 2). The pharmacokinetic profile revealed an 
effective half-life of approximately 27 h. At steady state, the unbound drug concentration 
was 4.4 times above the concentration required to inhibit endothelial cell proliferation in 
vitro. Four patients experienced PSA reductions within 30 days following drug 
discontinuation (one on 2.5 mg, two on 20 mg and 1 on 30 mg). In two patients treated 
with 20 mg, post therapy PSA declines persisted for >17 months, despite a PSA increase 

NCI Protocol #: 9984 
 
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11 
on therapy. Resolution of adenopathy occurred in one patient persisting for >17 months. 
Plasma concentrations were maximum 2-8 h post dosing with an overall median value of 
2 h. The dose of 20 mg daily was declared as the MTD. One objective response and several 
PSA declines following the discontinuation of therapy for toxicity suggest that evidence of 
clinical efficacy may be delayed. While further study is indicated, careful attention must 
be paid to the novel toxicities of this agent with prolonged dosing. 
 
Dahut et al. reported the final data of a phase II study of cediranib in patients with 
docetaxel-pre-treated, castrate-resistant prostate cancer [11]. A total of 59 patients were 
enrolled, of whom 67% had received two or more previous chemotherapy regimens. 
Patients were treated with 20mg orally daily. Six of 39 patients with measurable disease 
had confirmed partial responses and one had an unconfirmed partial response. At 6 months, 
43.9% of patients were progression-free; the median PFS and OS periods for all patients 
were 3.7 months and 10.1 months, respectively. The DCE-MRI variables baseline transport 
constant (Ktrans) and rate constant at day 28 were significantly associated with PFS in 
univariate analyses, but only baseline Ktrans remained significant when considered jointly. 
The most frequent toxicities were hypertension, fatigue, anorexia and weight loss; the 
addition of prednisone reduced the incidence of constitutional toxicities.  
 
2.2.2 Olaparib (AZD2281) (NSC 747856) 
 
Olaparib 
(AZD2281, 
KU-0059436) 
is 
a 
potent 
inhibitor 
of 
polyadenosine 
5’diphosphoribose polymerase (PARP) developed as a monotherapy as well as for 
combination with chemotherapy, ionising radiation and other anti-cancer agents including 
novel agents and immunotherapy. The capsule formulation of olaparib was approved in 
December 2014 by the European Commission (EC) and United States (US) Food and Drug 
Administration (FDA), as follows: 
 
EU indication: Lynparza is indicated as monotherapy for the maintenance 
treatment of adult patients with platinum-sensitive relapsed BRCA-mutated 
(germline and/or somatic) high grade serous epithelial ovarian, fallopian tube, or 
primary peritoneal cancer who are in response (complete response or partial 
response) to platinum-based chemotherapy. 
 
US indication: Lynparza is indicated as monotherapy in patients with deleterious 
or suspected deleterious germline BRCA mutated (as detected by an FDA-approved 
test) advanced ovarian cancer who have been treated with three or more prior lines 
of chemotherapy. 
 
The approved tradename for olaparib is LYNPARZA™. 
 
The majority of completed studies were performed with the capsule formulation of 
olaparib.  Since 2012/2013 most new studies, including the Phase III registration studies, 
are being performed with the tablet formulation which was designed to deliver the 
therapeutic dose of olaparib in fewer dose units than the capsule.  
 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
12 
Preclinical, toxicology and safety, pharmacology and clinical experience is fully described 
in the current version of the olaparib investigator’s brochure. (Olaparib IB Ed. 14) 
 
2.2.2.1 
Pharmaceutical information  
 
Please refer to Section 8.1.2 
 
2.2.2.2 
Clinical Activity of Olaparib in Prostate Cancer  
Olaparib (LynparzaTM) is indicated as monotherapy in patients with deleterious or 
suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) 
advanced ovarian cancer who have been treated with three or more prior lines of 
chemotherapy. The indication is approved under accelerated approval based on objective 
response rate and duration of response. Continued approval for this indication may be 
contingent upon verification and description of clinical benefit in confirmatory trials.   
 
The efficacy of Lynparza was investigated in a single-arm study in patients with deleterious 
or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers (Study 1). 
A total of 137 patients with measurable, gBRCAm associated ovarian cancer treated with 
three or more prior lines of chemotherapy were enrolled. All patients received Lynparza at 
a dose of 400 mg twice daily as monotherapy until disease progression or intolerable 
toxicity. Objective response rate (ORR) and duration of response (DOR) were assessed by 
the investigator according to RECIST v1.1. The median age of the patients was 58 years, 
the majority were Caucasian (94%) and 93% had an ECOG PS of 0 or 1. Deleterious or 
suspected deleterious, germline BRCA mutation status was verified retrospectively in 97% 
(59/61) of the patients for whom blood samples were available by the companion 
diagnostic BRACAnalysis CDxTM, which is FDA approved for selection of patients for 
Lynparza treatment.  
 
Efficacy results from the Study 1 are summarized in the Table below. 
季
 
In January 2016, the US Food and Drug Administration (FDA) granted Breakthrough 
Therapy designation for olaparib for the monotherapy treatment of BRCA1/2 or ATM gene 
mutated metastatic Castration Resistant Prostate Cancer (mCRPC) in patients who have 
received a prior taxane-based chemotherapy and at least one newer hormonal agent 
(abiraterone or enzalutamide). 
 
This designation was based on the results of the TOPARP-A Phase II trial [7]. The study 
showed that sixteen of 49 patients who could be evaluated had a response (33%; 95% 
confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 
6 months. Next-generation sequencing identified homozygous deletions, deleterious 
mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
13 
genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 
patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 
with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM 
aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 
patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse 
events, findings that are consistent with previous studies of olaparib. 
 
2.3 
Rationale 
A systemic, multi-institutional study of clinical mCRPC tumors obtained from 150 men 
has provided genomic landscape data of mCRPC [5]. In that study, aberrations in AR, ETS 
genes, TP53 and PTEN were the most frequent (40 to 60%). Of note, aberrations of BRCA2, 
BRCA1 and ATM were observed in 19.3% overall, including 5.3% (8 of 150) harboring 
germline BRCA2 mutations with a subsequent somatic event resulting in bi-allelic loss. 
Other recurrent aberrations in DNA repair genes were identified in at least 34 of 150 
(22.7%). Recently, Prichard et al. also isolated germline DNA from 692 men with 
metastatic prostate cancer and reported that 82 men (11.8%) had deleterious germline 
DNA-repair gene mutations. The mutations were found in 16 genes, including BRCA2 
(5.3%), ATM (1.6%), CHEK2 (1.9%), BRCA1 (0.9%), RAD51D (0.4%) and PALB2 (0.4%) 
[6]. Additionally, the clinical samples from a single-center phase II study (TOPARP) study 
in United Kingdom, reported that 16 of 49 (33%) mCRPC were found to have homozygous 
deletion and/or deleterious mutations in the genes of DNA repair pathway [7].   
 
Other groups have also reported 12% (7 of 60) of advanced prostate cancers are hyper-
mutated and have mutations in MSH2 and MSH6 mismatch repair genes [8]. In summary, 
it is estimated that about 12 to 33% of mCRPCs have defective DNA repair pathway. These 
findings are of special interest because agents targeting DNA repair pathway, notably, poly 
(ADP-ribose) polymerase (PARP) inhibitors, have shown promising activities in several 
solid tumors with defective DNA repair pathways. 
 
PARP is a large family of proteins involved in multiple cellular process including DNA 
repair, chromatin regulation, transcription regulation, apoptosis and others [10]. As a 
regulator of transcription factor, PARP-1 elicits pro-tumorigenic effects in androgen 
receptor (AR)-positive prostate cancer cell lines, regardless of the genotoxic insult [11]. 
PARP1 is recruited to sites of AR function, therein promoting AR occupancy and 
supporting transcriptional function. In vivo, PARP inhibitor has shown anti-tumor 
activities both in, hormone sensitive and hormone resistant PC models [11]. Additionally, 
Brenner et al has demonstrated the role of PARP1 in ETS gene –mediated transcription 
and cell invasion in preclinical models of prostate cancer.  Inhibition of PARP has resulted 
in inhibition of ETS positive prostate cancer xenograft growth [12].  
 
Olaparib, PARP inhibitor, in prostate cancer: Recently, the data from a phase II trial of 
olaparib in 49 men with mCRPC (TOPARP study) were presented at the 2015 Annual 
Meeting of AACR by Mateo and his colleagues [13]. Olaparib 400mg twice a day was 
overall well tolerated without any unexpected side effects in this heavily pre-treated 
patients. The two most common toxicities were anemia (76%) and fatigue (58%). Twenty-
six percent of the patients required a dose reduction to 300mg bid. The response data 

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14 
indicated that olaparib is active as a monotherapy in a significant subgroup of patients. 
Sixteen of 49 (32.7%) unselected patients achieved response defined by PSA decline 
>50%, objective response and/or CTC conversion. A post hoc analysis to explore the 
biomarker of response from the tumor biopsy tissue suggested that the markers of DNA 
repair defect appear to be a potential biomarker of response. The biomarkers were defined 
by homozygous deletion and/or a putative deleterious mutation in a gene reported to be 
involved in DNA repair and /or sensitivity to PARP inhibition. In this study, 16 (32.7%) 
patients had biomarker positive and 33 (67.3%) patients were biomarker negative. Among 
the 16 responders, 14 of these patients were noted to have a biomarker and 2 responders 
did not have a biomarker. Homozygous deletion or deleterious mutation in BRCA2 and 
ATM were the most commonly observed events associated with response to olaparib. Other 
affected genes associated with response include FANCA, CHEK2, BRCA1, PALB2, 
HDAC2, RAD51, MLH3, ERCC3, MRE11, and NBN.   
 
Hypoxia-induced downregulation of DNA repair genes 
Hypoxia is one of the characteristics of the microenvironment in a growing tumor. 
Inadequate vascularization in tumors creates a microenvironment that is low in oxygen 
supply, rendering tumors hypoxic. Tumors respond to this condition by inducing 
angiogenesis, mainly through VEGF-dependent pathways [14].  Multiple are the changes 
that a tumor cell must undergo to survive the metabolic challenges imposed by a low 
oxygen state. Hypoxia-inducible factor 1alpha (HIF-1D) is primarily responsible for 
alterations in metabolism that support the survival of hypoxic tumor cells.  Among many 
others, hypoxia has been shown to confer cancer cells several adaptive survival 
mechanisms, including increased glycolysis, angiogenesis, metastasis, EMT, resistance to 
radiation therapy and chemotherapy.[14-16]    
 
Dr. Peter Glazer’s laboratory at Yale 
University tested a hypothesis that 
genomic instability is one of the 
tumor’s 
genomic 
adaptions 
to 
hypoxia. His lab and other groups 
demonstrated that hypoxia induces 
homologous recombination DNA 
repair defects by transcriptional 
repression of RAD51, BRCA1 and 
BRCA2 in multiple cancer cell lines 
including MCF7 (breast), A549 
(lung 
adenocarcinoma), 
RKO 
(colon), 
CaCo-2 
(colon), 
PC3 
(prostate) and DU145 (prostate) [17]. In addition, Dr. Robert Bristow’s laboratory at 
University of Toronto also demonstrated that hypoxia down-regulates DNA repair genes, 
including HR-related genes (Rad51, Rad52, Rad54, BRCA1, BRCA2) and NHEJ-related 
genes (Ku70, DNA-PKcs, DNA ligase IV, XRCC4) in prostate cancer cells [18].  
Subsequent work also reported that PARP inhibitors exerted increased cytotoxicity against 
multiple cancer cells under hypoxic conditions, compared to normoxic conditions [19].  
Posttranslational modifications of histones have been described as an important epigenetic 
Figure 1: Decreased homologous recombination 
(HR) in hypoxic and post-hypoxic cells (Bindra 
RS. 2005. Annals of the NYAS) 

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15 
mechanism of gene regulation [20-22].  Hypoxia also drives epigenetic modification of the 
BRCA1 promoter via decreases in methylation of H3K4 as well as combined decreases in 
acetylation/ increased methylation of H3K9 [23]. Similar modifications are seen during the 
downregulation of the RAD51 promoter in hypoxic conditions and the same epigenetic 
mechanism is involved in the upregulation of VEGF in hypoxia [23], that is thought to 
trigger angiogenesis. Taken together, hypoxia-induced downregulation of DNA repair 
genes may have therapeutic implications for the use of PARP inhibitors.  
 
Cediranib: 
a 
pan-VEGFR 
tyrosine kinase inhibitor and 
an inducer of tumor hypoxia  
Cediranib is a potent tyrosine 
kinase inhibitor of vascular 
endothelial 
growth 
factor 
receptor (VEGFR)-1, -2 and -3. 
Cediranib has been shown in 
preclinical models to inhibit 
vascular 
permeability 
and 
perfusion 
as 
measured 
by 
dynamic 
contrast-enhanced 
magnetic resonance imaging 
(DCE-MRI) [24-26]. An imaging biomarker study in a xenografts model demonstrated that 
cediranib treatment led to tumor hypoxia and decreased perfusion as shown in Figure 2 
above [27].  In another study using HT29 colorectal xenografts model, the tumor response 
to short-term treatment with cediranib (3 daily doses) was also studied using dynamic 
contrast-enhanced and diffusion weighted MRI as well as 18F-fluoromisonidazole (18F-
FMISO) (hypoxia imaging) positron emission tomography (PET) and histological markers. 
Rats bearing human tumor xenografts were imaged at baseline and 2 hours after the final 
dose of cediranib. DCE-MRI-derived parameters decreased significantly in cediranib 
treated animals compared to controls. The fraction of perfused blood vessels in the 
cediranib-treated group was lower than the control group. Treatment with cediranib 
showed decreased post-treatment 18F-FMISO uptake, suggesting that short-term treatment 
with cediranib caused decreases in tumor permeability and perfusion and induced hypoxia 
[28]. Histological assessments of tumor xenografts from animals, in which cediranib 
significantly delayed tumor growth, revealed reduced vessel density and perfusion as well 
as increased hypoxia on cediranib treatment, which was enhanced by concomitant radiation 
treatment [29].  
 
Cediranib in Prostate cancer 
The activity of cediranib has been demonstrated in two early phase clinical trials. A phase 
I dose escalation study of cediranib in 26 patients with hormone refractory prostate cancer 
indicated that the 20mg daily dose was the maximally tolerated dose (MTD) [9]. The most 
frequently occurring AEs were fatigue, dysphonia, headache, hypertension, diarrhea, and 
anorexia. In that study, favorable PSA changes and a durable objective response have been 
noted. In a phase II study, cediranib 20mg a day resulted in objective responses in 6 of 39 
patients (15%) with mCRPC who had prior docetaxel-based therapy [30]. The data 
Figure 2: Representative composite images of 
pimonidazole adduct (green, hypoxia) and Hoechst 
33342 (blue, perfusion) uptake in cediranib- or vehicle 
treated rat C6 gliomas (Burrell JS et al. IJC 2012)  

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indicated a lack correlation between objective responses and PSA changes. Additionally, 
the imaging biomarker study with DCE-MRI suggested that cediranib has a direct effect 
on the microcirculation and vasculature. PSA levels have not corresponded with imaging 
responses. 
 
Clinical Data on Combination of Cediranib and Olaparib 
A phase I study of the cediranib and olaparib was tested in 28 patients with recurrent 
ovarian or triple-negative breast cancer at 4 dose levels. Two dose limiting toxicities were 
observed (One grade 4 neutropenia > 4 days and the other grade 4 thrombocytopenia, 
occurred at the highest dose level (cediranib 30mg once daily and olaparib 400mg twice 
daily. The RP2D was cediranib 30mg once a day and olaparib 200mg twice a day [31]. A 
randomized phase II study of the combination versus olaparib in patients with platinum-
sensitive ovarian cancer showed a statistically significant improvement in median 
progression-free survival (17.7 vs 9.0 months; hazard ratio 0.42, 95% CI 0·23-0·76; 
p=0·005). Grade 3 and 4 adverse events were more common with combination therapy 
than with monotherapy, including fatigue, diarrhea, and hypertension.  
 
Rationale for Cediranib Olaparib Combination Dosing  
This study will use the recommended phase II dosing from phase I study by Joyce Liu et 
al: oral administration of cediranib 30mg once a day in combination with olaparib 200mg 
twice a day, continuously[31].  
 
Unlike the earlier safety studies, Liu’s Phase I study and the subsequent studies have 
implemented much more stringent guideline (See Section 6) on management of the 
toxicities related to the cediranib and olaparib combination, such as hypertension 
management with daily monitoring of blood pressure, and early initiation of anti-
hypertensive. Such strategies have significantly helped management of the toxicities and 
the doses of up to 30mg of cediranib and olaparib 200mg bid were well tolerated with 
manageable side effects.  
 
In addition, the study will use mobile application, eCediranib-Olaparib (eCO) Application, 
to monitor patients’ side effects, such as hypertension and diarrhea. This application will 
allow the investigators to allow therapeutic interventions and drug holidays to allow 
optimal management of the side effects.  
 
Rationale for Olaparib tablet monotherapy dose 
The current US FDA approval of olaparib in ovarian cancer is 400mg of olaparib capsules 
twice a day. Sixteen olaparib capsules per day are required the approved 400mg twice-
daily dose. To that end, a tablet formulation has been developed to reduce pill burden and 
has been studied in several clinical trials for optimal dose and administration scheduled of 
the tablet formulation.  
 
Specifically, in prostate cancer, Mateo et al reported the bioavailability study [32].  
Olaparib 200 mg tablets displayed similar Cmax,ss, but lower AUCss and Cmin,ss than 
400 mg capsules. Following multiple dosing, steady-state exposure with tablets ≥300 mg 
matched or exceeded that of 400 mg capsules. After dose escalation, while 400 mg twice 

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daily was the tablet maximum tolerated dose based on hematological toxicity, 65 % of 
patients in the randomized expansion phase eventually required dose reduction to 300 mg. 
Intermittent tablet administration did not significantly improve tolerability. Tumor 
shrinkage was similar for 300 and 400 mg tablet and 400 mg capsule cohorts. The authors 
concluded that they recommended that 300mg twice daily was the recommended 
monotherapy dose of olaparib tablet.  
 
Summary of rationale for the combination of cediranib and olaparib for prostate 
cancer 
1. A significant proportion of advanced mCRPCs harbor mutations in DNA repair 
pathways.  
2. Olaparib has shown anti-tumor activities in patients with mCRPC, mostly limited to 
patients with the tumors harboring mutations in DNA repair pathways.  
3. Cediranib, by inducing tumor hypoxia, may result in downregulation of the DNA repair 
genes leading to sensitization of the tumor to olaparib, a PARP inhibitor, in patients 
with mCRPC.  
4. Combination of cediranib 30mg once a day, and olaparib 200mg BID has well 
documented and manageable toxicity profile.  
5. The combination has demonstrated superior clinical outcome compared with olaparib 
monotherapy in patients with advanced ovarian cancer.  
 
Hypothesis: The combination of cediranib and olaparib has superior clinical activity, as measured 
by radiographic progression free survival, in patients with mCRPC, compared with olaparib 
monotherapy.  
 
2.4 
Correlative Studies Background 
2.4.1 BROCA-HR Panel (Dr Elizabeth Swisher, University of Washington, Seattle) 
(Integrated Biomarker) 
 
The BROCA-HR assay will be used in the study to assess correlation of homologous 
recombination deficiency (HRD) status, on the effectiveness of cediranib/olaparib 
combination and olaparib monotherapy. 
 
BRCA1 and BRCA2 (BRCA1/2) are tumor suppressor genes, in which inherited loss-of-
function mutations confer a high lifetime risk of breast and ovarian carcinoma. BRCA1/2 
are key components of the BRCA-Fanconi anemia (FA) pathway, which is critical to 
homologous combination-mediated DNA repair. Other genes in this pathway 
(BRIP1/FANCJ, PALB2/FANCN, RAD51C/FANCO, RAD51D) also contribute to 
hereditary breast and ovarian cancer [33-37]. The Cancer Genome Atlas Network (TCGA) 
recently suggested that up to half of serous ovarian carcinomas have homologous 
recombination defects (HRD), but that estimate was based on a variety of molecular 
findings, many with uncertain impact on DNA repair function [38]. PARP inhibitors 
(PARPi) demonstrate synthetic lethality in cells with HRD, including cells deficient in 
BRCA1/2 [39, 40]. Recurrent ovarian carcinomas in BRCA1/2 mutation carriers have an 
approximate 40% response rate to PARPi and also have an increased response to platinum 
based chemotherapy [41]. Importantly, approximately 25% of serous ovarian cancers that 

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are wildtype for BRCA1/2 also respond to PARPi [42]. 
 
Germline BRCA1/2 mutations (gBRCAm) are the prototype molecular alterations that 
confer HRD (Bryant et al., 2005; Farmer et al., 2005). BRCA1 and BRCA2 somatic 
mutation (sBRCAm) occur in approximately 6% of ovarian carcinomas [38, 43] and also 
appear to confer sensitivity to PARPi [44]. PARPi also selectively kill cells in vitro that 
are deficient in other (HR) genes including RAD51D, NBN, ATM, and CHEK2 [33, 45].  
Germline and somatic mutations in BRCA1/2 and other BRCA-FA genes in ovarian 
carcinomas are associated with improved response to primary platinum therapy and longer 
overall survival [43].  
 
In order to respond to a PARPi, cancer cells need to be deficient in HR but also proficient 
in the alternative error prone non-homologous end joining (NHEJ) DNA repair pathway 
[46, 47]. Thus, loss of HR is not, by itself, sufficient for PARPi sensitivity, and an accurate 
predictor of PARPi responsiveness could require assessment of many components of both 
the HR and NHEJ pathways. A more efficient assay, which would not require a prior 
knowledge of the critical elements in these DNA repair pathways, would instead measure 
DNA repair capacity. Recent evidence suggests that BRCA1/2 deficient cancers exhibit 
global DNA alterations termed “genomic scarring” that are consistent with their reliance 
on the NHEJ pathway [48-50]. This genomic scar could serve as a downstream measure of 
DNA repair capacity, indicative of both HR deficiency and NHEJ proficiency. Therefore, 
mutations in NHEJ and other pathways that could affect HR as well as genomic scarring 
will also be evaluated as exploratory biomarkers.   
 
 
The marked susceptibility of patients with gBRCAm-associated cancers has validated 
gBRCAm as a predictive biomarker for PARPi response [51]. Other mechanisms of HRD 
may be a functional biomarker for response to DNA damaging agents and PARPi. Thus, it 
may be important to identify which cancer patients have germline or somatic mutations in 
HRD genes and to examine their potential as predictive biomarkers. Additional exploratory 
biomarkers for HRD will include BRCA1 methylation, BRCA1 protein expression, and 
genomic scarring. We hypothesize that the BROCA test will identify subsets of cancer 
patients with HRD, and may yield biomarkers with potential to guide administration of this 
combination therapy. 
 
BROCA is a targeted capture and massively parallel sequencing assay that is capable of 
identify all classes of mutations including gene rearrangements [52, 53]. Using BROCA, 
Walsh et al demonstrated that nearly one-fourth of women with ovarian carcinoma have 
germline loss of function mutations in at least 12 genes [54]. Furthermore, most of these 
genes are in the BRCA-FA pathway. After BRCA1/2, the most common genes mutated in 
women with ovarian cancer are BRIP1 (FANCJ), RAD51D, RAD51C (FANCO), and 
PALB2 (FANCN) [54, 55].  Pennington et al. applied BROCA to detect somatic mutations 
in tumor DNA from 363 women with ovarian carcinoma. Combining germline and somatic 
mutations increased the fraction of cases identified with HRD to 31%, including 23% with 
germline and 9% with somatic mutations in FA/HR genes (and 1% with both somatic and 
germline mutations) [56]. The presence of either a germline or somatic FA/HR mutation is 
highly predictive of an improved primary response to platinum chemotherapy and longer 

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overall survival [56]. Germline and somatic loss of function mutations were identified in 
all of the 13 FA/HR genes evaluated.  
 
Dr. Swisher’s laboratory has designed a new version of BROCA (BROCA-HR) that 
includes many additional DNA repair genes (75 total genes) as well as 3000 single 
nucleotide polymorphisms (SNPs). Similar sequencing accuracy and sensitivity 
sequencing DNA is obtained from formalin fixed paraffin embedded (FFPE), fresh blood 
and flash frozen specimens. BROCA-HR includes genes that are targets of both somatic 
and germline mutations. The BROCA-HR includes genes that regulate HR or NHEJ that, 
if mutated, could mediate resistance to PARPi such as TP53BP1 [57-59]. The current 
design for BROCA-HR includes the following genes: 
 
BROCA-HR gene list (n=75) 
a. FA-BRCA HR pathway: ATM, ATR, BABAM1, BAP1, BARD1, BLM, BRCA1, BRCA2 
(FANCD1), BRIP1 (FANCJ), BRCC3, BRE, CHEK1, CHEK2, ERCC1, ERCC4 
(FANCQ), FAM175A (abraxas), FANCA, FANCB, FANCC, FANCD2,  FANCE, 
FANCF, FANCG (XRCCC9), FANCI, FANCL, FAMCM, GEN1, MRE11A, NBN, 
PALB2 (FANCO), RAD50, RAD51C (FANCO), RAD51D, RBBP8 (CtIP), SLX4 
(FANCP), UIMC1 (RAP80), XRCC2  
b. DNA mismatch repair MLH1, MSH2 (and EPCAM), MSH6, PMS2  
c. Other DNA repair, surveillance genes, or modifier genes : CDK12, CDH4, HELQ, 
NEIL1, PPM1D, POLD1, POLE, RIF1,TP53, ID4, PAXIP1, POLQ, RINT1, TP53BP1, 
USP28, WRN, XRCC3  
d. NER genes: ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, DDB1, XPA, XPC  
e. NHEJ genes: DCLRE1C, LIG4, PRKDC, TOBP1, XRCC4, XRCC5, XRCC6 
f. PI3K pathway: PTEN, PI3KCA 
 
A common characteristic of genomic scarring is large (>15Mb) but sub-chromosomal 
deletions. Therefore, fine mapping of LOH is not necessary to identify the HRD genomic 
scar. The theoretical ability of 3000 SNPs to define “genomic scarring” in existing TCGA 
data was tested by Dr. Swisher’s lab (unpublished data). Using only 3000 SNPs can define 
cases with high LOH which have better prognosis. Combining the BRCA mutational status 
and the LOH profile provides additional prognostic information.  
 
In this trial, 3000 SNPs will be assayed in the same BROCA-HR mutational assay at no 
additional cost which will provide an LOH profile to assess genomic scarring as an 
exploratory biomarker. The mutation information from BROCA sequencing will then be 
combined with the LOH profile to test performance of a combined biomarker, with the 
prediction that HR proficient cancers may achieve less benefit from the addition of PARPi. 
 
Cases will be identified as HR proficient or deficient based on sequencing data of known 
Fanconi anemia (FA)-BRCA genes. 
 
2.4.2 Whole Exome Sequencing (Dr. Eli Val Allen, Broad Institute / Dana Farber Cancer 
Institute), Integrated Biomarker  
 
The Sequencing Platform of the Broad Institute boasts 50 Illumina HiSeq instruments and 
10 MiSeqs, for an average capacity of 2.1 Terabytes (spanning 6192 flow cells) per day. 

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The Broad developed the leading commercial method for whole-exome solution-phase 
hybrid selection (now licensed to Agilent). This approach to hybrid selection has now been 
widely adopted by major companies and other centers and has been used in > 100 
publications. The whole-exome panel includes: 18,557 genes (selected from RefSeq CDS) 
comprising 185,915 exons and 33 Mb of target.  These targets are covered by 277,944 oligo 
“baits”. A new exome-wide bait set is being adapted that allows more even sequence 
coverage per capture reaction; this innovation will allow us to sequence clinical tumor 
samples to a sufficient overall mean coverage, while preserving the overall sensitivity and 
specificity of variant calling at a reduced cost. 
 
To perform WES, nucleic acid (DNA and RNA) will be obtained from tumor cellular 
material using SOPs in common use at the Broad Biological Samples Platform. Nucleic 
acid will be transferred to the Genetic Analysis Platform at the Broad Institute. DNA 
quality and quantity will be confirmed by gel electrophoresis and Picogreen, respectively. 
The tumor and normal exome will be selected using the solution-phase hybrid capture 
method, and sequencing will be performed using the Illumina HiSeq, HiSeq2500, or 
HiSeqX10 instrument (when the latter becomes available). For clinical tumor specimens, 
we will utilize a “high-coverage” sequencing approach, which should yield an average 
coverage of 150-200 fold; paired normal DNA will be sequenced to a depth of ~80-100-
fold. WES data will be analyzed for base mutations, small insertions/deletions, and copy 
number alterations using the Firehose pipeline. 
 
We evaluate our exome sequencing in a number of ways.  First, it is critical to obtain even 
and robust coverage across targets, avoiding inefficiencies due to targets being at very 
different concentrations, or missing in one sample to the next. In the course of our exome 
development, we have found the following to be the most useful parameters to inform our 
coverage model and the most critical to optimize around to increase efficiency: 

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Non-duplicate reads.  Observation of duplicate reads (reads with the same start and stop 
sites) indicates that the same molecule has been sequenced multiple times.  This can 
mislead SNP calling algorithms, since the same molecule-specific (PCR or other) error can 
erroneously be counted as independent observations.   
 
On-target sequence yield.   A major inefficiency of all massively parallel targeting 
approaches is the inability to precisely and uniquely capture (to the base pair) the target of 
interest. Optimization of our protocol has resulted in routine on-target proportion of ~ 85% 
of reads. 
 
Uniformity of coverage.   All target enrichment methods are non-uniform (compared to 
whole genome shotgun).   We measure non-uniformity using a metric - “fold-80 penalty”.  
This represents the fold difference between the mean coverage for all targets and the 
coverage achieved by 80% of targets.  That is, how much coverage must be increased so 
that 80% of targets achieve the mean coverage.  In our experience, an increase of 3-5 fold 
is required with current protocols to ensure that 80% of target bases are covered to 30X.   
 
Knowledge of these parameters is required to estimate the total sequence required in whole 
exome sequencing.  We base our estimate on (a) target size of 30 Mb, (b) on-target rate of 
80%, (c) desired coverage of 30X, and (d) a uniformity factor of 4 (80% of target achieves 
30X).  This model we estimate ~4.5 Gb of high quality, non-duplicate sequence per sample 
(30 Mb* 1.25 * 30 X * 4  = 4.5 Gb 
 
2.4.3 Whole Transcriptome Sequencing (Dr. Eli Val Allen, Broad Institute / Dana Farber Cancer 
Institute, Integrated Biomarker) 
 
In parallel with whole exome sequencing, the Broad Genomics Platform will perform 
whole transcriptome sequencing. The Broad Genomics Platform has extensive experience 
with whole transcriptome sequencing from both frozen and FFPE tumor samples. 
Regarding the latter, transcriptome capture is an alternative to traditional tran¬script 
enrichment methods (including polyA selection and ribosomal depletion) that is optimal 
for low-input and de-graded samples including formalin-fixed paraffin-embed¬ded (FFPE) 
tissues. The approach first prepares a stranded cDNA library from isolated RNA, then 
hybridizes the library to a set of DNA oligonucleotide probes to enrich the library for 
mRNA transcript fragments. Transcriptome Capture targets 21,415 genes, representing 
98.3% of the RefSeq exome. Specific details on the sequencing methodology follow: 
 
RNA samples and two positive controls (K-562) are assessed for quality using Agilent's 
Bioanalyzer 2100. The percentage of fragments with a size greater than 200nt (DV200) 
was calculated using the Agilent software.  Samples with a DV200 score less than 30% 
were not included, as the likelihood of success is dramatically reduced with these more 
fragmented 
samples 
(see 
Illumina 
tech 
note: 
http://www.illumina.com/documents/products/technotes/technote-truseq-rna-access.pdf). 
100ng of RNA is used as the input for first strand cDNA synthesis using Superscript III 
reverse transcriptase (Life Technologies, Cat. #18080044) and Illumina’s TruSeq Stranded 

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Total RNA Sample Prep Kit (Illumina, Cat. #RS-122-2201).  The fragmentation step prior 
to cDNA synthesis was omitted in the FFPE RNA samples, only the K-562 positive control 
samples were fragmented at 94°C for 8 minutes.  Synthesis of the second strand of cDNA 
was followed by indexed adapter ligation. Subsequent PCR amplification enriched for 
adapted fragments. The amplified libraries are quantified using a Qubit assay (Life 
Technologies, Cat. #Q3285) and assessed for quality on an Agilent Technologies 2100 
Bioanalyzer (DNA 1000 chip).  200ng of each cDNA library, not including controls, are 
combined into two 4-plex pools.  Illumina’s Coding Exome Oligos (Illumina, Part 
#15034575) that target the exome are added, and hybridized on a thermacycler with the 
following conditions: 95°C for 10 minutes, 18 cycles of 1 minute incubations starting at 
94°C, then decreasing 2°C per cycle, then 58°C for 90 minutes.  Following hybridization, 
streptavidin beads were used to capture the probes that were hybridized in the previous 
step.  Two wash steps effectively remove any non-specifically bound products.  These same 
hybridization, capture and wash steps are repeated to assure high specificity. A second 
round of amplification enriches the captured libraries.  qPCR (Kapa Biosystems, Cat. 
#KK4600) was performed on the pooled libraries and normalized to 2nM. The normalized, 
pooled libraries were loaded onto HiSeq2500 for a target of 50 million 2x76bp paired reads 
per sample.  
 
2.4.4 Plasma Angiome (Integrated Biomarker, Dr. Andrew Nixon at Duke University)  
 
The focus of the blood-borne biomarkers across all study arms will be VEGF-A (VEGF), 
as VEGF expression is directly regulated by hypoxia through similar mechanisms as 
BRCA1 expression, however VEGF is induced, while BRCA1 is repressed. VEGF 
increases have been observed on treatment with cediranib in multiple studies and it is now 
accepted as a well-established PD marker, as increases have also been observed with other 
VEGF signaling inhibitors. In this study, VEGF will serve as an internal control for the 
effects of cediranib and hypoxia induction, which will be correlated to imaging endpoints 
and other hypoxia markers, as well as clinical efficacy. 
 
In addition to VEGF, a panel of other co- and counter-regulated markers of angiogenesis 
and inflammation will be evaluated to identify potential prognostic and predictive 
biomarkers.  Additionally, markers will be correlated with one another to identify 
biologically important patterns of expression among the analytes tested. 
 
To date, the effort to identify candidate predictive blood-based markers for anti-angiogenic 
inhibitors has been challenging for many reasons. These include biological complexity, 
limitations of available reagents and validated assays, limited sample collection in most 
trials, in particular large randomized studies. Compared to tissue-based biomarkers, blood-
based biomarkers have the significant advantages of low cost, universal applicability, and 
the ability to be followed over the course of a patient’s treatment.   By focusing on soluble 
factors of known biological relevance, further scientific, diagnostic, and therapeutic efforts 
may be facilitated.   
 
Recently, Dr. Nixon’s multiplex ELISA approach has identified several strong candidate 
predictors of benefit from bevacizumab. In CALGB80303, a phase III study of gemcitabine 

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± bevacizumab, his group identified VEGF-D as a candidate predictor for benefit from 
bevacizumab [60].  Another recent and instructive success is the identification of IL-6 as a 
strong candidate predictive biomarker for anti-VEGF therapy in renal cell carcinoma.  This 
marker was found to be a predictive marker in two independent phase III studies, each of 
which used a different VEGF inhibitor.  VEG105192 was a phase III study of BSC +/- 
pazopanib in refractory mRCC [61] and CALGB90206 was a phase III study of IFN +/- 
bevacizumab in 1st line mRCC [62].   Both of these studies found that high levels of IL6 
predicted for greater benefit from these VEGF inhibitors [63, 64].  The CALGB study with 
bevacizumab also found a predictive role for HGF that was IL-6 dependent (i.e., a 3-way 
treatment interaction) [63]. The role of the IL6-Jak-Stat axis is particularly intriguing given 
its role in tumor associated inflammation and anti-tumor immunity. Numerous other 
inflammatory mediators have been shown to regulate tumor angiogenesis and sensitivity 
to anti-VEGF therapy [65, 66]. Tumor angiogenesis, inflammation, and anti-tumor 
immunity have highly interconnected biologies, a topic that has been extensively reviewed 
[67-69]. However, to date, these factors have not been systematically interrogated in most 
anti-VEGF therapy trials.   Analysis of the role of inflammation in mediating resistance to 
anti-VEGF therapy may be highly clinically relevant.   
 
The design of the Dr. Nixon’s multiplex panel array to interrogate diverse biologies related 
to angiogenesis is highly refined, technically robust and readily adaptable to clinical 
practice. Many of the analytes in the multiplex array were developed specifically for this 
use and have been carefully optimized for performance in plasma and serum samples from 
cancer patients. This approach utilizes the CiraScan™ platform from Aushon BioSystems 
Inc.  The Nixon lab has worked in tandem with the team at Aushon for over eight years to 
develop multiple new assays and optimize the performance of the specific panel design 
(see Table 2.3).  
 
While the markers listed below represent the most optimized panel to date, it is anticipated 
that new information and novel findings will be available at the time of analysis.  The final 
decision on the specific markers to be evaluated will made using the most up-to-date 
information and best science available at the time of analysis. 
 
Table 2.3  Plasma-based marker identification 
 
 
 
 
 
 
Soluble 
Angiogenic 
Factors 
Matrix-
Derived  
Factors 
Markers 
of 
Vascular 
Activation and 
Inflammation 
ANG-2 
PDGF-BB 
sEndoglin 
CRP 
bFGF 
PlGF 
Osteopontin 
ICAM-1 
HGF 
VEGF-A 
TGFE1 
IL-6 
IGFBP1 
VEGF-D 
TGFE2 
PAI-1 Active 
IGFBP2 
sVEGFR1 
TGFERIII 
PAI-1 Total 
IGFBP3 
sVEGFR2 
TIMP1 
SDF-1 
PDGF-AA sVEGFR3 
TSP2 
VCAM-1 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
24 
3. PATIENT SELECTION 
3.1 
Eligibility Criteria  
3.1.1 Patients must have histologically confirmed progressive, metastatic castration resistant 
prostate adenocarcinoma by meeting ALL the following:  
3.1.1.1 
Pathology of prostate gland or metastatic disease must confirm the diagnosis of prostate 
adenocarcinoma. Mixed histology with other variants including but not limited to small 
cell or neuroendocrine differentiation must be discussed with the Study PI.  
3.1.1.2 
Metastasis must be documented by radiographic evidence.  
3.1.1.3 
Castration resistance must be documented with surgical or medical castration with 
serum testosterone <50ng/dL (<2.0 nM). If the patient is being treated with LHRH 
agonists (patient who has not undergone orchiectomy), this therapy must have been 
initiated at least 4 weeks prior to Cycle 1, Day 1 and must be continued throughout 
the study.  
 
3.1.1.4 
Progression must be evidenced and documented by any of the following parameters. 
x 
Two consecutively rising PSA values, above the baseline, at a minimum of 
1-week intervals. The minimal value to enter the study is 1.0 ng/ml or 
greater. The reference value (#1) is the last PSA measured before increases 
are 
documented, 
with 
subsequent 
values 
obtained a minimum of 1 
week apart. If the PSA at 
time point 3 (value #3A) is 
greater than that at point 2, 
then eligibility has been 
met. If the PSA is not 
greater than point 2 (value 
#3B), but value #4 is, the 
patient 
is 
eligible 
assuming that other criteria are met, if values 3A or #4 are 1 ng/mL or 
higher (Prostate cancer Working Group 3. Scher HI et al. J Clin Oncol. 
2016), 
x 
Appearance of one or more new lesions on bone scan.  
x 
Progressive disease by RECIST 1.1 
 
 

NCI Protocol #: 9984 
 
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25 
3.1.2 Must have a tumor lesion safely accessible for biopsy per the investigator’s discretion. 
While a soft tissue metastasis preferred for a biopsy, a bone metastasis is allowed for biopsy 
as long as enough cores can be obtained.   A biopsied lesion cannot be used for target lesion 
for response assessment.  
 
3.1.3 Must be agreeable to the mandatory research tumor biopsies (pre-treatment and on-
treatment). Tumor biopsies are mandatory at pre-treatment and at on-treatment. There is 
an optional biopsy at post-progression.  
 
3.1.4 Must have received at least one prior line of therapy for mCRPC. A taxane chemotherapy 
administered for metastatic castration sensitive disease will not count, unless patient 
develops disease progression within 12 months from the last dose chemotherapy.  
 
3.1.5 Must have a life expectancy greater than or equal to 16 weeks. 
 
3.1.6 If patient is currently on prednisone or other corticosteroids for palliation, the dose must 
be less than or equal to 10mg a day or its equivalent dose and it must have been started at 
least 4 weeks prior to cycle 1 day 1. 
 
3.1.7 Patients must have measurable disease by RECIST v1.1, or evaluable disease with bone 
metastases demonstrated by Tc99 Bone Scan.  See Section 11 for the evaluation of 
measurable disease.  Patients with bone metastases only are allowed. (NOTE: Nodes > 
1.5cm (not >2cm) in the short axis are considered measurable, per PCWG3).  
 
3.1.8 Toxicities of prior therapy (except alopecia) should be resolved to ≤ grade 1 as per NCI-
CTCAE v5.0.  Patients with long-standing stable grade 2 neuropathy or others (e.g., adrenal 
insufficiency or hypothyroidism on stable doses of replacement therapy) may be allowed 
after discussion with the study Principal Investigator (PI). 
 
3.1.9 Age ≥18 years. There is no dosing or adverse event data currently available on the use of 
cediranib or olaparib in patients <18 years of age, thus excluding them from enrollment. 
 
3.1.10 ECOG performance status 0 or 1 (Karnofsky ≥70%, see Appendix A). 
 

NCI Protocol #: 9984 
 
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26 
3.1.11 Patients must have normal organ and marrow function within 28 days prior to 
administration of study treatment as defined below: 
3.1.11.1 
WBC >3x10^9/L 
3.1.11.2 
Absolute neutrophil count ≥ 1,500/mcL  
3.1.11.3 
Platelets > 100,000/mcL  
3.1.11.4 
Hemoglobin >10 g/dL with no pack red blood cell transfusion in the past 28 days 
3.1.11.5 
Creatinine Clearance > 51mL/min, calculated using Cockcroft-Gault formula as 
follows:  Cockcroft-Gault CrCl = (140-Age)* (Wt in Kg)/ (72*Cr) 
3.1.11.6 
Urine protein: creatinine ratio (UPC) of ≤ 1. 
3.1.11.7 
Total bilirubin ≤ 1.5x the institutional ULN  
3.1.11.8 
AST (SGOT) and ALT (SGPT) < 3 times institutional ULN unless liver metastases are 
present in which case they must be < 5 x ULN. 
3.1.11.9 
Coagulation parameters (INR and aPTT) within 1.25 × ULN institutional limits, except 
where a Lupus anti-coagulant has been confirmed, or except patients on 
anticoagulation. 
 
3.1.12 Patients must be able to swallow oral medications and not have gastrointestinal illnesses 
that would preclude absorption of cediranib or olaparib. 
 
3.1.13 Adequately controlled thyroid function, with no symptoms of thyroid dysfunction.  Patients 
can be on thyroid hormone replacement medication. Asymptomatic patients with elevated 
TSH with normal T4/T3 are allowed to enroll, and recommended to follow with routine 
thyroid function test especially if they are randomized to cediranib/olaparib arm.  
 
3.1.14 Adequately controlled blood pressure (BP) <140 mmHg (systolic) and <90 mmHg 
(diastolic) taken in the clinic setting by a medical professional within 2 weeks prior to 
starting study. Patients with hypertension may be managed with up to a maximum of 3 
antihypertensive medications.  Patients who are on 3 antihypertensive medications are 
highly recommended to be followed by a cardiologist or blood pressure specialist for 
management of BP while on protocol. 
 
3.1.15 Patients must be willing and able to check and record daily blood pressure readings when 
randomized to cediranib containing arm. 
 
3.1.16 Patients must have documented LVEF by echocardiogram greater than institution’s lower 
limit of normal (or 55% if threshold for normal not otherwise specified by institutional 
guidelines) obtained within 3 months prior to registration if they have any of the following 
risk factors for cardiac toxicities: 
x A New York Heart Association (NYHA) classification of II controlled with 
treatment (see Appendix B) 
x Prior central thoracic radiation therapy (RT), including RT to the heart 
x History of myocardial infarction within 12 months prior to registration.  
x Prior treatment with anthracyclines 
x Prior treatment with trastuzumab 
x Prior history of other significant impaired cardiac function 
 

NCI Protocol #: 9984 
 
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3.1.17 Male participants and their female partners, who are sexually active and of childbearing 
potential, must agree to the use of two highly effective forms of contraception in 
combination [see below for acceptable methods], and not to donate sperm, throughout the 
period of taking study treatment and for 3 months after last dose of study drug(s) to prevent 
pregnancy in a partner.  Acceptable methods of contraception to be used in this study 
include:   
 
x 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  
 
x Acceptable non-hormonal birth control methods include:  
o Total sexual abstinence.  Abstinence must be for the total duration of the study 
and the drug washout period. 
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 
x Acceptable hormonal methods: 
o 
Etonogestrel implants (eg, Implanon, Norplan) + male condom with 
spermicide 
o 
Normal and low dose combined oral pills + male condom with spermicide 
o 
Norelgestromin/ethinyl estradiol (EE) transdermal system + male condom 
with spermicide 
o 
Intravaginal device + male condom with spermicide (eg, EE and 
etonogestrel)  
o 
Cerazette (desogestrel) + male condom with spermicide.  Cerazette is 
currently the only highly efficacious progesterone based pill. 
 
3.1.18 Ability to understand and the willingness to sign a written informed consent document. 
 
 
3.2 
Exclusion Criteria: 
3.2.1 Patients who have had chemotherapy, hormonal therapy (except LHRH agonist or 
antagonist), immunotherapy, radioisotope therapy, or RT within 21 days prior to start of 
the study agents. 
 
3.2.2 Initiating bisphosphonate, or RANKL antibody therapy or adjusting the dose/regimen 
within 30 days prior to Cycle 1 Day 1 is prohibited. Patients on a stable bisphosphonate 
regimen are eligible and may continue. 
 

NCI Protocol #: 9984 
 
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28 
3.2.3 Patients who have received any other investigational agents within the past 28 days prior 
to Cycle 1 Day 1.   
 
3.2.4 Patients with untreated brain metastases, spinal cord compression, or evidence of 
symptomatic brain metastases or leptomeningeal disease as noted on computed 
tomography (CT) or magnetic resonance imaging (MRI) scans are excluded from this 
clinical trial, since neurologic dysfunction may confound the evaluation of neurologic and 
other AEs.  While screening Brain MRI is not required, it should be performed if clinically 
indicated at the discretion of the treating investigator. Should patient found to have brain 
metastasis, treatment of brain metastasis must precede the participation in this study.   
 
3.2.5 For patients with known and treated brain metastases is allowed in this study if they fulfill 
ALL of the following criteria: 
• The lesions have remained radiologically stable for at least six weeks after completion 
of brain irradiation or stereotactic brain radiosurgery, and must remain stable at the 
time of study entry.  
• There is no mass effect present radiologically and no steroids requirement for 
symptom control for more than 4 weeks. 
 
3.2.6 Patients who have received a prior inhibitor of VEGF signaling inhibitor, or a PARP 
inhibitor administered.  
3.2.7 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to cediranib or olaparib. 
 
3.2.8 Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir), moderate CYP3A inhibitors (eg. 
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil), strong CYP3A 
inducers (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, 
carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (eg. 
bosentan, efavirenz, modafinil)  (See Appendix D for updated list from FDA website).  
 
A minimum washout period of 2 weeks prior to cycle 1 day 1 is required for strong 
inhibitors, and at least one week for moderate inhibitors. A minimum washout 
period of 4 weeks prior to cycle 1 day 1 is required for CYP3A inducers. A 
minimum washout period of 5 weeks prior to cycle 1 day 1 is required for 
enzalutamide or phenobarbital.  Dihydropyridine calcium-channel blockers are 
permitted for management of hypertension.  
 
3.2.9 Current use of natural herbal products or other “folk remedies.” If using previously, 
patients must stop using natural herbal products while participating in this study. 
Multivitamin, Ca/Vit D and other vitamin complex supplements are allowed. 
 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
29 
3.2.10 Patients with concomitant or prior invasive malignancies within the past 5 years.  Subjects 
with limited stage basal cell or squamous cell carcinoma of the skin, carcinoma in situ of 
the breast, or non-muscle invasive bladder cancer, are eligible as long as they received 
curative intent therapy.  
 
3.2.11 Uncontrolled intercurrent illness including, but not limited to, uncontrolled seizures 
ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
3.2.12 Resting ECG with QTc > 470 msec on two or more time points within a 24 hour period, 
noted within 14 days of treatment, or family history of long QT syndrome. 
 
3.2.13 History of myocardial infarction within 6 months of the randomization. 
 
3.2.14 History of stroke or transient ischemic attack within 6 months of the randomization 
 
3.2.15 NYHA classification of III or IV. 
 
3.2.16 Current cardiac arrhythmic condition requiring concurrent use of anti-arrhythmic drug. 
Rate controlled atrial fibrillation is allows. 
 
3.2.17 History of hypertensive crisis or hypertensive encephalopathy within 3 years of the 
randomization 
 
3.2.18 Clinically significant peripheral vascular disease or known abdominal aortic aneurysm 
(>5cm in diameter) or history of aortic dissection.  Patients with known history of AAA 
with > 4cm in diameter, a repeat US within the last 6 months prior to randomization will 
be required to document that it is < 5cm, and patient must be asymptomatic from the 
aneurysm, and the blood pressure must be well controlled as required in this protocol.  
 
3.2.19 A major surgical procedure, open biopsy, or significant traumatic injury within 3 months 
prior to Cycle 1 Day 1 (percutaneous/endobronchial/endoscopic biopsies are allowed).   
 

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30 
3.2.20 History of bowel obstruction within 1 month prior to starting study drugs.  
 
3.2.21 History of hemoptysis within the last 1 month prior to randomization 
 
3.2.22 Presence of cavitation of central pulmonary lesion, or radiographic evidence of 
pneumonitis or other extensive bilateral lung disease such as interstitial lung disease.  
 
3.2.23 Any history of GI perforation, history of intra-abdominal abscess within 3 months prior to 
starting treatment, or history of abdominal fistula unless the fistula history meets all the 
following: (a) the fistula was surgically repaired, (b) there has been no evidence of fistula 
for at least 6 months prior to starting treatment, (c) patient is deemed to be at low risk of 
recurrent fistula, and (d) the case must be discussed with the study PI.  
 
3.2.24 Current dependency on IV hydration or total parenteral nutrition (TPN). 
 
3.2.25 Known coagulopathy or bleeding diathesis.  Those on therapeutic anticoagulation or anti-
platelet agent are permitted only after discussing with the study PI.  See Section 5.2 for 
monitoring of anticoagulation therapy.  
 
3.2.26 Patients with history of intra-abdominal bleeding or retroperitoneal bleeding within the last 
3 years are excluded 
 
3.2.27 Patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), 
or features suggestive of MDS/AML. 
 
3.2.28 Patients with known active human immunodeficiency virus (HIV), Hepatitis B or 
Hepatitis C infection. It is because of the potential requirement for anti-viral therapies 
that are prohibited on the study. Patients with a history of hepatitis B or hepatitis C, who 
are deemed cured and no longer require treatment may be allowed to enroll after 
consultation with the respective specialist and the Study PI.  
 
3.2.29 Previous allogenic bone marrow transplant or double umbilical cord blood transplantation 
(dUCBT) 
 
3.2.30 Whole blood transfusions in the last 120 days prior to entry to the study. 
 
3.2.31 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site) 
 
3.2.32 Previous enrollment in the present study  
  
3.3 
Inclusion of Women and Minorities 
 
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 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
31 
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 and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN or RAVE or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined 
in the table below. 
 
Documentation Required 
IVR 
NPIV
R 
AP 
A 
FDA Form 1572 
D 
D 
 
 
Financial Disclosure Form 
D 
D 
D 
NCI Biosketch (education, training, 
employment, license, and certification) 
D 
D 
D 
HSP/GCP training 
D 
D 
D 
Agent Shipment Form (if applicable) 
D 
CV (optional) 
D 
D 
D 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
32 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
x 
Added to a site roster 
x 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
x 
Act as the site-protocol PI on the IRB approval 
x 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
Additional information can be found on the CTEP website at < 
https://ctep.cancer.gov/investigatorResources/default.htm  >.  For questions, please contact the 
RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
If interested in participating in this study, an investigator or his/her team at the participating 
site must discuss with the Study PI via email:  joseph.w.kim@yale.edu 
 
Each investigator or group of investigators at a clinical site must obtain Institutional 
Review Board (IRB) approval for this protocol and submit all required regulatory 
documents (including any protocol specific documents) to the CTSU Regulatory Office 
before they can be approved to enroll patients. Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to the following:  
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site 
 
The CTSU Regulatory Office tracks receipt of these documents in the CTSU Regulatory 
Support System (RSS), reviews for compliance, and transmits site approval data to CTEP. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study 
are not required to submit IRB approval documentation to the CTSU Regulatory Office. 
For sites using the CIRB, IRB approval information is received from the CIRB and applied 
to the RSS in an automated process.  Signatory Institutions must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB via IRBManager to indicate their intent 
to open the study locally.  The CIRB’s approval of the SSW is then communicated to the 
CTSU Regulatory Office.  In order for the SSW approval to be processed, the Signatory 
Institution must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. 
 

NCI Protocol #: 9984 
 
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33 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the NCI Protocol #9984 protocol page 
located on the CTSU Web site.  Permission to view and download this protocol is restricted 
and is based on person and site roster data housed in the CTSU RSS.  To participate, 
Investigators and Associates must be associated with the Corresponding or Participating 
protocol organization in the RSS.  
 
x Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password. 
x Click on the Protocols tab in the upper left of your screen.  
x Either enter the protocol # in the search field at the top of the protocol tree, or 
x Click on the By Lead Organization folder to expand, then select LAO-CT018, and 
protocol #9984. 
x Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above.) 
 
4.2.2 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be 
entered and tracked in the CTSU RSS.   
Regulatory Submission Portal: www.ctsu.org  (members’ area) Æ Regulatory Tab 
ÆRegulatory Submission  
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction 
and support 
 
4.2.3 Requirements For Protocol #9984 Site Registration: 
 
x IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted)  
 
4.2.4 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU website.   
 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
34 
username and password 
• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. 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. 
 
4.2.5 Ordering Blood Pressure Cuffs  
 
As a part of site initiation, each participating site must order blood pressure cuffs for their 
expected number of accrual:  
 
x 
Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password. 
x 
Click on the Protocol tab at the top of your screen. 
x 
Click on the ETCTN subtab. 
x 
Click on the following folders: Phase 1 Grants / LAO-CT018 / 9984 / LPO 
Documents / Miscellaneous  
x 
Click Shipment Authorization Form for Blood Pressure Cuffs 
 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It is 
integrated with the CTSU Enterprise System for regulatory and roster data interchange and 
with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.2 OPEN/IWRS User Requirements 
OPEN/IWRS users must meet the following requirements: 
x Have a valid CTEP-IAM account (i.e., CTEP username and password). 
x To enroll patients or request slot reservations:  Be on an ETCTN Corresponding or 

NCI Protocol #: 9984 
 
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35 
Participating Organization roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type.  If a DTL is required for the study, the 
registrar(s) must also be assigned the OPEN Registrar task on the DTL. 
x Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
x All eligibility criteria have been met within the protocol stated timeframes.   
x If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 OPEN/IWRS Questions? 
 
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.  
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 7 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. TREATMENT PLAN 
 
Androgen deprivation therapy is a standard therapy for all patients with mCRPC. Patients 
in both Arms A and B, unless undergone bilateral orchiectomy, must continue with 
LHRH or GnRH agonists throughout the study as a standard of care.  The therapy must 
have been initiated at least 4 weeks prior to Cycle 1, Day 1.  
 
5.1 
Agent Administration 
The treatment assignment is done via randomization on a 1:1 basis to receive either 
cediranib and olaparib combination (Arm A) or olaparib monotherapy (Arm B) (See 
Section 4.3 for registration/randomization process). The study treatment is not blinded with 
regards to whether patients are receiving the combination therapy or olaparib monotherapy. 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 7.  Appropriate dose modifications are described in 
Section 6.  No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's malignancy. 
 
One cycle will be considered 28 days.   
 
5.1.1 Arm A:  Cediranib and Olaparib Combination 
 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
36 
Olaparib 200mg (two 100mg tablets) orally twice daily continuous dosing. Cediranib 
30mg in tablet formulation orally once daily. 
 
Patients randomized to Arm A will be required to maintain medication and blood pressure 
diaries (See Appendix F). Patients will be instructed in its use, and asked to bring it with 
them to each appointment. Patients should avoid grapefruit juice while on study, due to 
P450 interactions with olaparib.  
 
A blood pressure cuff will be provided to patients randomized to Arm A. See Section 4.2.5 
for the site to order blood pressure cuffs.  Patients on this arm must be counseled on the 
blood pressure monitoring and diarrhea management. It is highly advisable that patients 
should have an anti-hypertensive and an anti-diarrheal prescribed prior to starting 
cediranib. Please refer to Appendix G and Appendix H. 
 
5.1.1.1 
Cediranib 
Cediranib at the appropriate dose level will be given orally continuously each 
morning on an empty stomach, either 1 hour before or 2 hours after breakfast.  
Patients should not “make up” a missed dose or a dose that was vomited.  Patients 
should take cediranib with a glass of water.  Cediranib may be taken at the same time 
as the morning olaparib dose. 
 
5.1.1.2 
Olaparib 
Olaparib at the appropriate dose level will be given orally continuously twice daily, 
with doses taken at the same times each day approximately 12 hours apart.  The 
correct number of, 100 mg, or 150 mg tablets comprising the appropriate dose should 
be taken at the same times each day with approximately 240 mL of water.  The 
morning dose may be taken at the same time as the cediranib dosing.  The evening 
dose may be taken with a light meal/snack.  The olaparib tablets should be swallowed 
whole and not chewed, crushed, dissolved, or divided. 
 
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, 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 should not be 
taken, and the patient should take their allotted dose at the next scheduled time.  
 
5.1.2 Arm B: Olaparib monotherapy 
 
Olaparib 300 mg (two 150mg tablets) orally twice daily continuous dosing. Patients 
randomized to Arm B will be required to maintain a medication diary (See Appendix E). 
 
Olaparib at the appropriate dose level will be given orally continuously twice daily, with 
doses taken at the same times each day approximately 12 hours apart.  The correct number 
of, 100 mg, or 150 mg tablets comprising the appropriate dose should be taken at the same 
times each day with approximately 240 mL of water.  The evening dose may be taken with 

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37 
a light meal/snack.  The olaparib tablets should be swallowed whole and not chewed, 
crushed, dissolved, or divided. 
 
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, 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 should not be taken, and the patient should take their 
allotted dose at the next scheduled time.  
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Patient should receive general concomitant and supportive care medications based on best 
medical practice. All medications must be recorded in the case report form and be reviewed 
by the treating physician at each visit. 
 
5.2.1 Prostate Cancer Related Supportive Therapies 
o Luteinizing hormone-releasing hormone (LHRH) agonist or antagonist, to maintain 
a testosterone level <50g/dL should be administered in patients who have not 
undergone an orchiectomy as a standard of care.  
 
o The patient can receive a stable dose of corticosteroids before and during the study 
as long as these were commenced at least 4 weeks prior to treatment.  Higher doses 
of steroids are permitted if clinically indicated for acute medical conditions, such 
as prevention or treatment of contrast allergy.   
 
o Initiating bisphosphonate, or RANKL antibody therapy or adjusting the 
dose/regimen within 30 days prior to Cycle 1 Day 1 is prohibited.  Patients on a 
stable bisphosphonate or RANKL therapy regimen are allowed and may continue. 
 
o Conventional multi-vitamins and minerals, such as Calcium and Vitamin D 
supplements are allowed on study.  
 
5.2.2 Medications that may NOT be administered:  
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy (except 
androgen deprivation therapy), palliative radiotherapy (exception may be given), 
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 whilst the patient is 
receiving study medication and during the 30 day follow up period. An increased risk of 
infection by the administration of live virus and bacterial vaccines has been observed with 
conventional chemotherapy drugs and the effects with olaparib are unknown. 
 
Because the composition, PK, and metabolism of many herbal supplements are unknown, 
the concurrent use of herbal supplements, or other “folk remedies” is prohibited during 

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38 
the study (including, but not limited to, cannabis, St. John’s wort, kava, ephedra [ma 
huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or 
ginseng). 
 
5.2.3 Restricted concomitant medications (Olaparib IB Edition Number 14, 10 March 2017) 
 
Appendix D provides a list of drugs that are prohibited. Appendix C-1 and Appendix C-2 
(Patient Drug Information Handout and Wallet Card) should be provided to patients. 
 
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) MUST NOT be taken with olaparib. Treating investigator MUST check with 
the FDA website cited in Appendix D for the updated list.  
 
If there is no suitable alternative concomitant medication then the dose of olaparib should 
be reduced for the period of concomitant administration. The dose reduction of olaparib 
should be recorded in the CRF with the reason documented as concomitant CYP3A 
inhibitor use.  
 
• 
Strong CYP3A inhibitors – reduce the dose of olaparib to 100mg bd 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 150mg bd 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. 
 
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 (eg. 
bosentan, efavirenz, modafinil) of CYP3A MUST NOT be taken with olaparib. Treating 
investigator MUST check with the FDA website cited in Appendix D for the updated list 
 
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. 
 
P-gp inhibitors 
It is possible that co-administration of P-gp inhibitors (eg amiodarone, azithromycin) may 
increase exposure to olaparib. Caution should therefore be observed. 
 
Effect of olaparib on other drugs 

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39 
o Based on limited in vitro data, olaparib may increase the exposure to substrates of 
CYP3A4, P-gp, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K.  
 
o Based on limited in vitro data, olaparib may reduce the exposure to substrates of 
CYP3A4, CYP1A2, 2B6, 2C9, 2C19 and P-gp.  
 
o The efficacy of hormonal contraceptives may be reduced if co administered with 
olaparib.  
 
o Caution should therefore be observed if substrates of these isoenzymes or 
transporter proteins are co-administered. 
 
o Examples of substrates include: 
• 
CYP3A4 – hormonal contraceptive, simvastatin, cisapride, cyclosporine, 
ergot alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine 
• 
CYP1A2 – duloxetine, melatonin 
• 
CYP2B6 – bupropion, efavirenz 
• 
CYP2C9 – warfarin  
• 
CYP2C19 - lansoprazole, omeprazole, S-mephenytoin 
• 
P-gp - simvastatin, pravastatin, digoxin, dabigatran, colchicine 
• 
OATP1B1 - bosentan, glibenclamide, repaglinide, statins and valsartan 
• 
OCT1, MATE1, MATE2K – metformin 
• 
OCT2  - serum creatinine 
• 
OAT3  -furosemide, methotrexate 
 
5.2.4 Other supportive care guideline  
 
Anticoagulant Therapy 
Patients who are taking warfarin may participate in this trial; however, it is recommended 
that international normalized ratio (INR) be monitored carefully at least once per week for 
the first month, then monthly if the INR is stable. Subcutaneous heparin and low molecular 
weight heparin are permitted. Direct oral anticoagulants (DOACs) are also permitted.  
 
For the research tumor biopsy, the anticoagulant therapy should be held prior to the 
scheduled biopsy at the discretion of the treating investigator in accordance with the 
institution’s guideline.  
 
Anti-emetics/Anti-diarrheal 
If a patient develops nausea, vomiting and / or diarrhea, then these symptoms should be 
reported as AEs, and appropriate treatment of the event given. 
 
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 or radiographic progression during the study 
period.  Study treatment should be discontinued for a minimum of 3 days before a patient 

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40 
undergoes therapeutic palliative radiation treatment.  Study treatment should be restarted 
within 4 weeks as long as any bone marrow toxicity has recovered.  This must be discussed 
with overall Study PI.  
 
 
Administration of other anti-cancer agents 
Patients must not receive any other concurrent anti-cancer therapy, including 
investigational agents, while on study treatment. Patients may continue the use of 
bisphosphonates or denosumab for bone disease and corticosteroids provided the dose is 
stable before and during the study and they were started at least 4 weeks prior to beginning 
study treatment.  
 
Subsequent therapies for cancer  
Details of first and subsequent therapies for cancer and/or details of surgery for the 
treatment of the cancer, after discontinuation of treatment, will be collected.  Reasons for 
starting subsequent anti-cancer therapies including access to other PARP inhibitors or 
investigational drugs will be collected and included in the exploratory assessments of OS. 
 
 
 
5.3 
Criteria for Taking a participant OFF protocol therapy  
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies: 
 
x 
Disease progression 
x 
Intercurrent illness that prevents further administration of treatment 
x 
Unacceptable adverse event(s), or adverse event(s) requiring study medication(s) to be 
discontinued (See Important Safety Information of the section 6.1) 
x 
Patient decides to withdraw from treatment or the study 
x 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
x 
Patient’s non-compliance that render further treatment unacceptable in the judgment of 
the investigator 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
5.4 
Duration of Follow Up 
Patients who discontinue therapy due to reasons other than radiographic disease progression, will 
be followed until radiographic disease progression or initiation of the subsequent therapy is 
documented.  
 
Participants removed from protocol therapy for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event.  
 
All participants’ vital status may be followed after removal from the study treatment via a phone 

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41 
call or medical records review every 6 months and using publicly available databases. 
 
5.5 
Criteria to take a participant OFF study 
Participants will be removed from study when any of the following criteria apply: 
x 
Lost to follow-up 
x 
Withdrawal of consent for data submission 
x 
Death  
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
5.6 
Criteria for cross-over to cediranib/olaparib combination arm.  
For patients in Olaparib monotherapy arm will have an option to cross over to the combination 
upon documented radiographic progression as defined in the primary objective (Section 1.1), not 
by PSA progression.  
 
Before receiving the combination therapy, patient must meet all the Patient Section criteria in 
Section 3: except the following:  
- 
No washout is required from the last dose of olaparib therapy.  
- 
The biopsies before cross-over treatment and at on-treatment are highly encouraged if 
they have easily accessible tumor but not required. On-treatment biopsy may be done 
during the 4th week of the combination therapy.  
- 
Angiome panel blood draw will be required. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as indicated in the following table(s). The descriptions 
and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A copy of the 
CTCAE version 5.0 can be downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
6.1 
Arm A:  Management of Cediranib and Olaparib Related Adverse Events  
 
The dose levels and the general approach to dose modification of olaparib and cediranib 
combination therapy are shown below.  AEs should be treated with the appropriate maximum 
supportive care, and dose reductions should be clearly documented in the case report form. 
 
Table 1: Dose Modification of Cediranib  
 
Dose level 
Cediranib  
1 (starting dose) 
30 mg (two 15mg tablets) orally, once a day 
-1 
20 mg (one 20mg tablet) orally, once a day  
-2 
15 mg (one 15mg tablet) orally, once a day 
 
Table 2: Dose Modification of Olaparib 

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42 
  
Dose level 
Olaparib Tablet 
1 (starting dose) 
200 mg (two 100mg tablets) orally, every 12 hours 
-1 
150mg (one 150mg tablet) orally, every 12 hours 
-2 
100 mg (one 100mg tablet) orally, every 12 hours 
 
IMPORTANT SAFETY INFORMATION 
At the discretion of the investigator, the study drugs may be held or dose modified independently 
if the observed toxicity is attributed to only one of the drugs, while the patient continues to receive 
the drug not associated with the observed toxicity.  The time a given drug is held should not exceed 
3 weeks.  Once dose of study drug(s) have been reduced, no dose re-escalation is permitted. 
 
If treatment has to discontinue due to toxicity, both IPs (cediranib and olaparib) should be 
discontinued at the same time; patients are not allowed to remain in the study if they are taking 
either cediranib or olaparib as monotherapy. However, in rare circumstances, patients 
experiencing ongoing clinical benefit but who develop one of the toxicities listed below related 
to one of the IPs that prevents them to continue to take this IP, may be allowed to continue on 
the unrelated drug if in the opinion of the treating investigator the risk benefit remains favorable 
and only after discussion with the Principal Investigator. 
 
AEs requiring cediranib to be discontinued: 
 
x 
GI perforation 
 
x 
Arterial Thromboembolic Event 
 
x 
PRES 
 
x 
Severe hemorrhage 
 
x 
Severe persistent hypertension despite maximal anti-hypertensive treatment 
 
AEs requiring olaparib to be discontinued: 
 
x 
Bone marrow findings consistent with MDS/ AML 
 
x 
Severe persistent anemia 
 
x 
Pneumonitis 
 
Patients experiencing ongoing clinical benefit who experience a related AE where 
continuation of one of the drugs is considered, in the judgment of the treating Investigator 
AND the Principal Investigator, to be potentially life threatening or with the potential for 
long-term harm to the patient, may be allowed to continue on the unrelated drug after 
discussion with the Principal Investigator. 
 

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43 
6.1.1 Hematologic Toxicity  
 
6.1.1.1 
Management of neutropenia and thrombocytopenia 
 
 
Neutropenia and thrombocytopenia are recognized common adverse drug reactions reported 
for both olaparib and cediranib.  Treatment should be managed according to Table 3: 
 
 
Olaparib dose 
Cediranib Dose 
CTCAE Grade 1-2 
 
ANC >1.0 G/L 
or 
Platelet count >50 G/L 
Investigator judgement to 
continue treatment or allow 
dose interruption; dose 
interruptions should be for a 
maximum of 
3 weeks; appropriate 
supportive treatment and 
causality investigation 
 
Investigator judgement to 
continue treatment or allow 
dose interruption; dose 
interruptions should be for a 
maximum of 3 weeks; 
appropriate supportive 
treatment and causality 
investigation 
 
CTCAE grade 3-4 
ANC <1.0 G/L 
or 
Platelet count <50 G/L 
 
Dose interruption until 
recovered to 
CTCAE Grade ≤1 for a 
maximum of 3 weeks. 
Upon recovery, 
olaparib dose should be 
reduced by 
one dose level.  If repeat 
CTCAE Grade 3-4 
occurrence, further dose 
reduce one or both IPs 
Dose interruption until 
recovered to 
CTCAE Grade ≤1 for a 
maximum of 
3 weeks. Upon recovery, 
cediranib dose should be 
reduced by one dose level.  If 
repeat CTCAE Grade 3-4 
occurrence, further dose 
reduce one or both IPs 
Abbreviations: ANC absolute neutrophil count; CTCAE common terminology criteria for adverse events; 
IP  investigational product 
 
Use of hematopoietic agents 
Use erythropoietin-stimulating agents per standard of care National Comprehensive Cancer 
Network (NCCN) and/or institutional guidelines, iron supplements, and/or transfusions as 
clinically indicated for management of anemia.  Prescribing information for the erythropoiesis 
stimulating agents (including Aranesp, Epogen and Procrit) highlight that there is a potential risk 
of shortening the time to tumor progression or disease-free survival.  Primary prophylaxis with 
granulocyte colony-stimulating factor (G-CSF) is not recommended. They do not alleviate 
fatigue or increase energy.  They should not be used in patients with uncontrolled hypertension.  
The package inserts should be consulted. 
 
Febrile Neutropenia 
If a patient develops febrile neutropenia, both cediranib and olaparib 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 of the last dose 
of olaparib unless absolutely necessary.   
 

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When ANC is >1.5x10^9/L and patient remains afebrile for >72 hours, the study drug (s) can 
be restarted at one dose level lower than the prior. Growth factor support should be stopped at 
least 24h before restarting study drug (7 days for pegylated G-CSF). 
 
Platelet transfusions, if indicated, should be done according to local hospital guidelines. 
 
Dose modifications for hematologic toxicity 
 
Patients who have IPs held for hematologic toxicities should have blood counts and differentials 
checked at least weekly until recovery; these data should be recorded in eCRF as extra 
laboratory examinations.  If counts do not improve to CTCAE Grade 1 or better despite drug 
cessation for 3 weeks, patients should be referred to a hematologist for further assessment.  A 
bone marrow analysis should be considered per hematology assessment. 
 
For AEs that are unrelated to the study drug, study drug may be withheld for up to 3 weeks at 
the discretion of the treating Investigator. 
 
6.1.1.2 
Management of anemia 
 
Anemia is a common adverse drug reaction related to olaparib.  Cediranib is not reported to 
increase the risk of anemia.  Management of anemia is in accordance with Table 4: 
 
Table 4: 
Management of anemia 
 
 
Olaparib dose  
Cediranib dose  
Hb <10 but ≥8 g/dL 
Give appropriate supportive 
treatment and investigate 
causality. 
Investigator judgement to 
continue olaparib or interrupt 
dose for a maximum of 3 
weeks. 
If repeat Hb <10 but ≥8 g/dL, 
dose interrupt until Hb 
≥10 g/dL for maximum of 3 
weeks and upon recovery 
dose reduce to 150 mg bd as a 
first step and to 100 mg bd 
as a second step. 
No change 
Hb < 8 g/dL 
Give appropriate supportive 
treatment and investigate 
causality.  
Interrupt olaparib until 
improved to Hb >10g/dL. 
Upon recovery dose reduce to 
150mg bd  
No change 
Abbreviations: bd twice daily; Hb hemoglobin 
 
Common treatable causes of anemia (e.g., iron, vitamin B12 or folate deficiencies and 

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hypothyroidism) should be investigated and appropriately managed.  In some cases 
management of anemia may require blood transfusions.  Any subsequently required dose 
interruptions, related to development of anemia, or coexistent with newly developed 
neutropenia, and/or thrombocytopenia, will require olaparib dose reductions to 150 mg twice 
daily as a first step and to 100 mg twice daily as a second step. 
 
If Hb drops to < 8 g/dL despite the dose reduction or more than one blood transfusion is 
required to recover Hb levels with no alternative explanation for the anemia, olaparib should 
be permanently discontinued. 
 
6.1.1.3 
Management of prolonged hematological toxicities while on study treatment 
 
If a patient develops prolonged hematological toxicity such as: 
 
x 
≥2 week interruption/delay in olaparib due to CTCAE Grade 3 or worse anemia 
and/or development of blood transfusion dependence 
 
x 
≥2 week interruption/delay in 1 or both IPs due to CTCAE Grade ≥3 neutropenia 
(ANC <1 x 109/L) 
 
x 
≥2 week interruption/delay in 1 or both IPs due to CTCAE Grade ≥3 
thrombocytopenia and/or development of platelet transfusion dependence (Platelets 
<50 x 109/L) 
 
Check weekly differential blood counts including reticulocytes and peripheral blood smear.  
If any blood parameters remain clinically abnormal after 3 weeks of dose interruption, the 
patient should be referred to hematologist for further investigations.  Bone marrow analysis 
and/or blood cytogenetic analysis should be considered at this stage according to standard 
hematological practice.  Both IPs should be discontinued if blood counts do not recover to 
CTCAE Grade ≤1 within 3 weeks of dose interruption. 
 
Bone marrow or blood cytogenetic analysis may be performed according to standard 
hematological practice for patients with prolonged hematological toxicities as defined 6.1.1.3 
above. Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic 
analysis and flow cytometry, and a core biopsy for bone marrow cellularity.  If it is not possible to 
conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then attempts should 
be made to carry out the tests on a blood sample.  If findings are consistent with MDS/AML, study 
drug should be discontinued and a full description of findings should be submitted with an SAE 
report by the investigator to CTEP.    Presence or absence of blood cytogenetic abnormalities and 
flow cytometry will be documented on the clinical database.  
 
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder should be 
reported as an SAE and full reports must be provided by the investigator to the CTEP. Olaparib 
treatment should be discontinued if patient’s diagnosis of MDS and/or AML is confirmed. 
 
6.1.2 General Management of Non-Hematologic Adverse Events 
 

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Cediranib should be discontinued should any of the following AEs occur:  GI perforation; 
arterial thromboembolic events; PRES (radiologically confirmed); severe or medically 
significant hemorrhage and severe persistent hypertension despite maximal anti-hypertensive 
treatment. 
 
Dose modifications for other non-hematologic events on IPs should be managed according to 
Table 5 below.  
Table 5:  General Management of Adverse Events (Non-Hematologic) 
 
Observation 
Action 
AE resolves promptly with supportive care  
Maintain dose level 
Any grade 2 non-hematologic AE (excluding 
hypertension or other AEs with specific 
management instructions outlined in the sections 
below, or easily correctable asymptomatic grade 2 
laboratory abnormalities) related to cediranib or 
olaparib that resolve within 72 hours with or 
without supportive care. 
Hold study drug(s) for up to 21 days until 
toxicity resolves to < 1 grade 1.  
Treatment may be restarted at the same 
dose without dose reduction if the 
nature of these toxicities are 
tachyphylaxes (e.g., headache or 
nausea) 
 
We expect toxicities, such as grade 2 
headache, and grade 2 nausea, to 
diminish or improve to grade 1 or less, 
by holding the drug(s) with or without 
supportive care, within 3 days. If so, the 
treatment may be restarted at the same 
dose without dose reduction at the 
discretion of the treating physician.  If, 
however, the AEs recur at grade 2 again 
upon restart, then it would require dose-
reduction of the suspected drug(s).  
  
If the initial grade 2 AE does not 
improve to grade 1 or less within 3 days, 
then the drug-hold will continue until the 
AE improves to grade1 or less. As long 
as it recovers within 14 days, the drug(s) 
can be resumed, but at a reduced dose 
level. 
 
Any grade 2 non-hematologic AE (excluding 
hypertension or other AEs with specific 
management instructions outlined in the sections 
below, or easily correctable asymptomatic grade 2 
laboratory abnormalities) related to cediranib or 
olaparib that persists despite maximal support.   
Hold study drug(s)1 for up to 21 days 
until toxicity resolves to d grade 1.  
Treatment may be restarted at one dose 
level lower for the drug(s) causing the 
toxicity, as per the dose reduction levels 
in section 6.1 (for Arm A) and section 

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6.2 (for Arm B), at the treating 
investigator’s discretion.2 The overall PI 
of the study should be informed regarding 
all dose modifications.  
Patients whose toxicity has not resolved 
after 21days will be removed from study.  
 
Patients experiencing persistent Grade 2 
fatigue that is felt to be acceptable by 
both patient and treating investigator may 
continue on study drug without dose hold 
or reduction at the treating investigator’s 
discretion. 
Any grade 3 non-hematologic (excluding grade 3 
hypertension or easily correctable asymptomatic 
grade 3 laboratory abnormalities) 
 
Hold study drug(s)1 for up to 21 days 
until toxicity resolves to d grade 1. 
Treatment may be restarted at one dose 
level lower for the drug(s) causing the 
toxicity, as per the dose reduction levels 
in section 6.1 (for Arm A) and section 
6.2 (for Arm B) at the treating 
investigator’s discretion.2 
The study PI of the study should be 
informed regarding all dose modifications.  
 
Grade 3 non-hematologic AE (excluding grade 3 
hypertension or easily correctable asymptomatic 
grade 3 laboratory abnormalities) related to 
cediranib and olaparib combination that does not 
resolve to grade 2 or less within 21 days despite 
maximum supportive care and treatment hold.3 
 
Grade 3 myocardial infarction or acute coronary 
syndrome  
Unless specified elsewhere, discontinue 
study drug(s) causing the toxicity 
permanently.  
Grade 4 non-hematologic AE (excluding easily 
correctable asymptomatic grade 4 laboratory 
abnormalities), related to cediranib or olaparib or 
both.  
 
Unless specified elsewhere, discontinue 
study drug(s) causing the toxicity 
permanently. 
1At the discretion of the investigator, the study drugs may be held or dose modified 
independently if the observed toxicity is attributed to only one of the drugs, while the patient 
continued to receive the drug not associated with the observed toxicity.  The time a given 
drug is held should not exceed 14 days.  For grade 3 fatigue, both cediranib and olaparib 
should be held and then dose-reduced.  
 
2 If a patient has a grade 3 or higher toxicity at the lowest dose level (excluding grade 3 
hypertension or easily correctable asymptomatic grade 3 laboratory abnormalities), the 

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suspected drug must be discontinued. 
 
3Excluding hypertension, for venous thromboembolic events, treatment may be resumed 
at the discretion of the investigator after discussing with the Study PI, once patient is 
asymptomatic. 
 
 
 
6.1.3 Management of cediranib-related toxicities  
6.1.3.1 
Hypertension (See APPENDIX G for suggested oral anti-hypertensives) 
 
Increases in BP and cases of hypertension have been associated with many drugs acting on the 
VEGF pathway.  The proposed mechanism for this increase is through inhibition of VEGF-induced 
peripheral vasodilation.  Hypertension following cediranib treatment has been seen in animal 
studies as well as clinical trials.   
 
Only doses of cediranib will be modified for hypertension; olaparib doses will not be reduced 
unless other toxicities are experienced.  Patients receiving cediranib should be provided with blood 
pressure monitors for home use and will check and record their blood pressures at least twice daily 
while on study treatment. When BP is stable for at least 8 weeks, then BP monitoring can be 
reduced to once daily. Should further hypertension arise, return to twice daily monitoring, until at 
least 8 weeks of stability then can return to daily. 
 
See the tables below for hypertension management and suggested antihypertensive medications 
by class.  
 
Note: 
x If patients require a delay of >1 week for management of hypertension, management should 
be discussed with the study PI. 
x If patients require a delay of >3 weeks for management of hypertension, discontinuation 
of cediranib may be considered after discussing with the Study PI. 
x Patients may have up to 4 drugs for management of hypertension prior to any dose 
reduction in cediranib. 
x Hypertension should be graded using the NCI CTCAE v5.0. Please note: patients may have 
baseline hypertension meeting CTCAE grading criteria on study entry provided this is 
adequately controlled on maximum of 3 antihypertensive medications. Patients with 
baseline hypertension who require the addition of new medications for hypertension 
management while on study drug may not have an increase in CTCAE grade, but a change 
in attribution should be noted. 
x While patients are receiving treatment with cediranib, the early initiation of 
antihypertensive treatment for grade 1 or 2 hypertension to minimize more severe or 
persistent hypertension is not considered a grade 3 AE. 
x Stopping or reducing the dose of cediranib is expected to cause a decrease in BP. Continue 
to monitor BP twice daily and decrease the monitoring to once a day once stability is 
achieved.  The treating physician should monitor the patient for hypotension and adjust the 
number and dose of antihypertensive medications accordingly. 

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Table 6.3: Hypertension Monitoring and Management 
• See Appendix G for suggested antihypertensive medications by class 
• Abbreviations: Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin II Receptor 
Blockers (ARB), selective beta blockers (BB), Dihydropyridine calcium channel blockers 
(DHP-CCP) 
Event 
Definition 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Cediranib Dose 
Modification 
Grade 1 
Asymptomatic 
transient (<24 
hours) increase 
by >20 mmHg 
diastolic or to > 
140/90 mmHg if 
previously WNL 
Consider early 
initiation of BP 
medication for 
BP > 140/90 
mmHg that is 
confirmed on a 
second reading.  
Cediranib can 
cause rapid 
escalation in BP, 
and early 
initiation of BP 
management can 
reduce likelihood 
of hypertension-
related 
complications 
Standard 
monitoring per 
treating MD 
none 
Grade 2 
Recurrent or 
persistent (>24 
hrs) or 
symptomatic 
increase by >20 
mmHg 
(diastolic) or to 
> 140/90 mmHg 
if previously 
WNL 
Monotherapy 
may be indicated 
Initiate BP 
medication for 
first-line 
treatment. 
Escalate dose of 
medication in 
stepwise 
fashion until 
BP is controlled 
or 
at a maximum 
dose 
If BP is not 
controlled to 
< 140/90 mmHg 
with one drug 
regimen, then add 
a 
second agent. 
Study drug does 
not need to be 
held 
Increase 
frequency of 
monitoring until 
stabilized to BP 
<140/90 mmHg. 
Do not hold 
cediranib unless 
otherwise 
clinically 
necessary 

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50 
unless otherwise 
clinically 
necessary 
 
Consider renal 
consult 
Grade 3 
Requiring more 
than one drug or 
more intensive 
therapy than 
previously. 
Maximize 2 drug 
regimen 
• Suggestions: 
ACE inhibitor + 
BB. 
Escalate doses of 
existing 
medication 
until BP is 
controlled or at a 
maximum dose. 
If BP is not 
controlled to 
< 140/90 mmHg 
with two drug 
regimen, then add 
a 
third agent. 
 
Study Drug will 
not be held 
during 
trial of two drug 
combinations. 
Additional 
antihypertensive 
drugs, up to a 
total 
of 4, may be 
maximized for 
blood pressure 
control. 
 
Consider consult 
with a BP 
management 
specialist if 
greater than 
3 drugs are 
required for 
BP control. 
Increase 
frequency of 
monitoring until 
stabilized to BP 
<140/90 mmHg. 
Do not hold 
cediranib unless 
BP 
is not decreased 
to 
less than 150/100 
mmHg 48 hours 
after multi-drug 
therapy is 
instituted or if 
clinical 
symptoms 
worsen 
(e.g. headache). 
 
If BP is not 
controlled to less 
than 150/100 
mmHg with 
maximal therapy 
or 
if clinical 
symptoms 
worsen, 
then hold drug 
(up 
to 14 days) until 
maximum effect 
of 
the 
antihypertensive 
agents 
is achieved. 
 
 
If BP is reduced 
to 
less than 140/90 
within 14 days, 
cediranib may be 

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51 
 
resumed at prior 
dose. 
Grade 4 
If threatening 
consequences 
OR 
SBP ≥ 
180mmHg 
OR 
DBP ≥ 
110mmHg 
Initiate treatment 
Hospitalize 
patient 
for ICU 
management, IV 
therapy as 
necessary 
14 days are 
allowed 
to maximize the 
full 
effect of 
antihypertensive 
agents. 
Intensive BP 
monitoring 
(hospitalization 
if 
necessary) 
Hold cediranib 
for up to 21 
days and repeat 
BP. 
 
If BP is reduced 
to 
less than 140/90 
within 7 days, 
cediranib may be 
resumed at a 
reduced dose 
after discussion 
with the Study PI 
and/or sponsor. 
 
6.1.3.2 
Proteinuria 
 
Proteinuria has been observed in cediranib studies.  Patients with a urine protein to creatinine 
ratio (UPC) of greater than 1.0 at entry are ineligible.   Increases in proteinuria may occur during 
treatment and should be managed as follows: 
 
Management of Proteinuria 
 
Proteinuria Value if 
following by U/A 
Monitoring 
Dose modification 
Greater than 2+ on 
urine dipstick or U/A  
AND 
Creatinine ≤1.5x ULN 
Perform UPC.  
Continue study drugs at 
planned dose. 
Greater than 2+ on 
urine dipstick or U/A 
AND 
Creatinine >1.5x ULN 
Perform UPC. 
HOLD cediranib until 
results of UPC are known, 
and see below 
Based on results of the UPC†: 
UPC ≤ 1.0 
Continue monitoring prior to each cycle 
as per previous. 
Continue study drugs at 
planned dose 
UPC > 1.0 and ≤ 3.5 
AND Creatinine ≤1.5x 
ULN 
Perform UPC prior to each cycle. 
Continue study drugs at 
planned dose. 

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52 
UPC > 3.5 OR 
Creatinine >1.5x ULN 
Perform UPC prior to each cycle. 
Hold cediranib for up to 
21 days and repeat UPC 
and Creatinine assessment.  
If UPC resolves to <3.5 
and Creatinine to ≤1.5x 
ULN, resume cediranib 
with reduction in cediranib 
by one dose level.  
Consider consultation with 
nephrologist. 
†If UPC is <1.0 and creatinine >1.5x ULN, AE management should be followed as per Section 
6.1.2 and 6.1.3.14. . 
 
 
6.1.3.3 
Decrease in LVEF  
Patients who have any of the following should undergo an echocardiogram (ECHO) at 
baseline and every 4 cycles while on cediranib/olaparib therapy and when clinically 
indicated: 
 
• 
Prior treatment with anthracyclines 
 
• 
Prior treatment with trastuzumab 
 
• 
Prior central thoracic RT, including RT to the heart 
 
• 
History of myocardial infarction within 6 to 12 months or history of other 
significant impaired cardiac function (Patients with history of myocardial infarction 
within 6 months are excluded from the study) 
 
The decision to continue or interrupt cediranib/olaparib is based on the LVEF as it relates to 
the institution’s LLN and change in ejection fraction from screening (LVEF as measured at 
enrollment) according to Table below. 
 
Relationship of 
LVEF to Institution’s 
LLN at baseline  
LVEF Decrease 
<10% 
LVEF Decrease  
10-15% 
LVEF Decrease 
>15% 
 
LVEF Normal  
 
Continue cediranib 
Continue and repeat 
ECHO within 
4-8 weeks 
Continue and repeat 
ECHO within 
4-8 weeks 
 
 
1-5% below LLN 
Continue and repeat 
ECHO within 
4-8 weeks 
Interrupt 
cediranib and 
repeat ECHO 
within 3 weeks.  
Initiate 
Cardiology 
Interrupt 
cediranib and 
repeat ECHO 
within 3 weeks 
Initiate 
Cardiology 

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Consult 
Consult 
 
 
>6% below LLN 
Continue and repeat 
ECHO within 
4-8 weeks 
Interrupt 
cediranib and 
repeat ECHO 
within 3 weeks 
Initiate 
Cardiology 
Consult 
 
Interrupt 
cediranib and 
repeat ECHO 
within 3 weeks 
Initiate 
Cardiology 
Consult 
 
Abbreviations: ECHO echocardiogram; LLN lower limit of normal; LVEF left ventricular ejection 
fraction; MUGA multigated acquisition. LVEF decreases in percentage points. 
 
The treating investigator may resume cediranib at one dose level lower than the prior 
after discussing with the study PI when all the following are met:  
- 
The repeat Echo shows LVEF>LLN, or LVEF is recovered back to baseline within 4 
weeks.   
- 
Patient must be free of clinical signs and symptoms of heart failure.  
  
Unless recovered within 4 weeks (i.e, cediranib held for >4 weeks), stop cediranib 
permanently. 
 
 
6.1.3.4 
Diarrhea 
 
Diarrhea is often observed with cediranib, and active and early management of diarrhea is 
recommended 
even 
with 
grade 
1 
diarrhea. 
 
Management 
as 
follows: 
 
Management of Diarrhea 
 
Toxicity 
Management/Modifications 
Initial grade 1 or 2 diarrhea: 
Patients can take loperamide (per standard 
practice) and continue to take loperamide until 
patients are free from diarrhea for at least 12 
hours.  The dose of loperamide should not 
exceed 16 mg in a 24-hour period. Patients 
should be also be counseled to start BRAT diet 
(Banana, Rice, Applesauce, and Toast). 
If diarrhea persists despite 24 hours of 
loperamide treatment, hold cediranib for a 
maximum of 7 days, continue loperamide, and 
maintain hydration.  Cediranib may be 
restarted at the same dose once patients have 
been free from diarrhea for 12 hours. 
 

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54 
Patients should be instructed to contact their 
study physician if mild or moderate (NCI 
CTCAE Grade 1 or 2) diarrhea persists for over 
48 hours despite treatment with loperamide 
and cediranib dose interruption. 
Persistent grade 2 diarrhea for >7 days of 
holding cediranib, or  
 
Initial grade 3 or 4 diarrhea 
Hold both cediranib and olaparib for up to 14 
days until toxicity resolves to d grade 1. 
Treatment may be restarted at one dose level 
lower, as per the dose reduction levels in 
Section 6.1  
Grade 3 or 4 diarrhea lasting >14 days despite 
maximum supportive care and treatment being 
held  
Discontinue study drugs permanently. 
Recurrent grade 3 or 4 diarrhea  
Hold both cediranib and olaparib for up to 7 
days until toxicity resolves to < grade 1.  
 
If the diarrhea last >7 days despite maximal 
supportive care and treatment being held, 
discontinue study drugs permanently.  
 
6.1.3.5 
Management of Thyroid Toxicities  
 
The use of cediranib has been associated with elevations of TSH and patients should be managed 
as per the following schema and chart: 
 
Monitoring and Management of Thyroid Toxicities 
 
Result of TSH, T4, and T3 
Action 
Increases of TSH with normal T4/T3:  
Monitor. 
Increases in TSH with normal T4/T3 and 
adverse 
events 
suggestive 
of 
incipient 
hypothyroidism: 
Consider replacement thyroxine.   
Increase in TSH with reductions in T4 and T3: Consider replacement thyroxine. 
 
In all of the above cases, study treatment should continue unless clinically contraindicated.  
Referral to an endocrinologist should also be considered if thyroid abnormalities occur.  Patients 
already on thyroid replacement hormone who require adjustment of their replacement regimen will 
be considered to have a drug-related toxicity. 
6.1.3.6 
Gastrointestinal Perforation 
 
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patients receiving cediranib.  Some events of gastrointestinal perforation have been fatal but 
causality could not be unequivocally assigned to cediranib. 
 
Cediranib should be permanently discontinued in those patients who experienced gastrointestinal 
perforation or fistula. All events of gastrointestinal perforation are followed up and an assessment 
should be made on their relationship to the underlying tumor.  
 
6.1.3.7 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS)  
 
Cases of MRI-documented posterior reversible encephalopathy syndrome (PRES), including 
RPLS, have been reported in patients receiving cediranib in clinical studies.  Cediranib should be 
held in patients with symptoms/signs suggestive of RPLS, pending work-up and management, 
including control of blood pressure, if hypertension is present.   Cediranib should be 
discontinued upon diagnosis of RPLS.  After consultation with the PI and the NCI, consideration 
of restarting the study may be evaluated in light of any clinical benefit.   
 
6.1.3.8 
Fatigue  
 
Fatigue is a common adverse drug reaction reported for both cediranib and olaparib.  
Fatigue experienced by patients taking cediranib may be rapid in onset.  During clinic visits, 
patients fatigue levels should be discussed.  Patients should seek medical advice early if 
Grade 2 fatigue develops (moderate fatigue causing difficulty performing some activities of 
daily living). 
 
Care should be taken to ensure that the nutritional status of the patients is optimized and 
patients should be encouraged to drink plenty of fluids. Patients should be encouraged to 
manage fatigue by alternating periods of rest with light aerobic exercise, which may improve 
the symptoms in some cases. 
 
Consideration should be given to other possible causes of fatigue (e.g., thyroid function, 
depression/insomnia and other concomitant medicinal products). Additionally, short interruption 
of cediranib dosing (initially 2-3 days-or longer-up to a maximum of 21 days) may help relieve 
fatigue.  When symptoms improve cediranib should be restarted with the same dose or, if 
necessary, a dose reduction can be considered. 
 
When Grade 3 or 4 fatigue develops, both cediranib and olaparib should be held for a 
maximum of 3 weeks or until it improves to grade 1 or baseline. Upon improvement, both drugs 
should be dose-reduced.  
 
6.1.3.9 
Fistula 
 
In patients treated with cediranib, fistula has been reported and reflected the location of the 
underling malignancy.  In the ovarian cancer population, vaginal fistula has been uncommonly 
reported in cediranib treated patients.  Cediranib should be used with caution in patients at risk of 
fistula and discontinuation of cediranib should be considered in patients who develop fistulae. 
 

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6.1.3.10 
Arterial thromboembolism 
 
Arterial thromboembolic events (including transient ischemic attack and ischemic stroke) have 
been reported in clinical studies with cediranib.  Cediranib should be used with caution in 
patients who are at an increased risk of thrombotic events or who have a history of thrombotic 
events.  Cediranib should be permanently discontinued in patients who develop an arterial 
thromboembolic event. 
 
6.1.3.11 
Venous thromboembolism 
 
Venous thromboembolic events including pulmonary embolism and deep vein thrombosis have 
been commonly reported in patients treated with cediranib.  Anticoagulant treatment should be 
started in accordance with clinical practice.  Discontinuation of cediranib may be considered. 
Cediranib should be used with caution in patients at risk of venous thromboembolism.  
 
6.1.3.12 
Wound healing 
 
Treatment with cediranib should be stopped at least 2 weeks prior to scheduled surgery.  The 
decision to resume cediranib therapy after surgery should be based on clinical judgment of 
adequate wound healing.  In patients who experience wound healing complications during 
therapy, treatment with cediranib should be interrupted until the wound is fully healed.  No 
formal studies of the effect of cediranib on wound healing have been conducted; however in the 
ICON6 pivotal study there was no evidence of an increase in wound healing complications in 
cediranib treated patients compared with placebo. 
 
6.1.3.13 
Elderly 
 
There is a limited amount of safety data available for cediranib use in patients aged 75 years and 
older.  Based on a population PK analysis, the clearance of cediranib decreased with age, 
however, no dose adjustment is needed given the small impact on exposure or variability. 
Caution should be taken when treating patients who are aged 75 years or older with cediranib. In 
case of toxicity dose pause or dose reduction may be considered. 
 
6.1.3.14 
Mild/moderate renally impaired patients 
 
Patients with mild and moderate renal impairment discontinued cediranib more often due to 
adverse events, particularly when cediranib was co-administered with chemotherapy. Population 
PK analysis showed that no adjustment of cediranib dose is required in this population as 
cediranib is minimally renally cleared; however, cediranib clearance may be decreased in 
patients with low body weight.  In the ICON6 pivotal study, patients with mild or moderate 
impairment had lower median body weight compared with patients with normal renal function.  
Caution should be exercised in patients with mild and moderate renal impairment and a cediranib 
dose adjustment should be considered in case of signs of toxicity. 
 
For information on use of olaparib in renally-impaired patients, please see Section 6.1.4.5 
 

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6.1.3.15 
Weight decreased 
 
In the ICON6 study, weight decreased was very commonly reported in cediranib treated patients.  
Weight loss (≥7%) in cediranib-treated patients was associated with higher incidence of 
decreased appetite, vomiting and stomatitis, although these events were also commonly reported 
in patients who did not lose weight. 
 
6.1.3.16 
Rotator Cuff injury  
 
A limited number of patients have experienced rotator cuff injuries while receiving the 
combination of cediranib and olaparib.  Patients should therefore be monitored closely for the 
development of any shoulder pain or weakness. 
 
Management of Rotator Cuff Symptoms 
Grade 
Symptoms/Findings 
Action 
Dose modifications 
1 
Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations 
only; intervention not 
indicated 
Limit heavy lifting or 
carrying of heavy 
objects, bags or 
backpacks.   
 
Consider shoulder MRI 
if symptoms warrant. 
None. 
2 
Moderate; minimal, local, 
or noninvasive 
intervention indicated; 
limiting age appropriate 
instrumental ADL 
Obtain shoulder MRI if 
not previously obtained. 
 
If rotator cuff injury 
present on MRI, refer 
for physical therapy.   
 
Consider referral to 
orthopedics for 
evaluation as 
appropriate. 
Hold cediranib and 
olaparib for up to 14 days 
until symptoms resolve to 
Grade 1 or less.  
Cediranib and olaparib 
may then be resumed at a 
reduced dose level of 
each study drug.  If 
patient is on the lowest 
dose level(s) of cediranib 
or olaparib, please contact 
the study PI to discuss 
dose modifications. 
3 
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated; 
disabling; limiting self 
care ADL 
Obtain shoulder MRI if 
not previously obtained. 
 
Refer to orthopedic 
surgeon for evaluation. 
Hold cediranib and 
olaparib for up to 14 days 
until symptoms resolve to 
Grade 1 or less.  
Cediranib and olaparib 
may then be resumed at a 
reduced dose level of 
each study drug after 
discussion with the 
overall PI. 
 

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6.1.4 Management of olaparib associated toxicity  
 
6.1.4.1 
Management of MDS/AML 
 
Patients who develop MDS/AML on treatment should be discontinued from olaparib 
treatment and managed appropriately. 
 
6.1.4.2 
Management of olaparib-related 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 1 or both 
IPs dosing is recommended and further diagnostic workup (including a HRCT scan) 
should be performed to exclude pneumonitis. 
 
Following investigation, if no evidence of abnormality is observed on CT imaging 
and symptoms resolve, then IP(s) can be restarted, if deemed appropriate by the 
investigator.  If significant pulmonary abnormalities are identified, these need to be 
discussed with the Study PI.  
 
6.1.4.3 
Febrile Neutropenia  
 
See 6.1.1.1 Management of Neutropenia and Thrombocytopenia 
 
6.1.4.4 
Management of Nausea and Vomiting 
 
Events of nausea and vomiting are known to be associated with olaparib treatment.  
In study D0810C00019 nausea was reported in 71% of the olaparib treated patients 
and 36% in the placebo treated patients and vomiting was reported in 34% of the 
olaparib treated patients and 14% in the placebo treated patients.  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 treatment with 
the IPs, 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. Taking olaparib tablets with food may help alleviate 
symptoms of nausea and vomiting. 
 
As per international guidance on anti-emetic use in cancer patients (European Society 
for Medical Oncology [ESMO], NCCN), generally a single agent antiemetic should be 
considered e.g. dopamine receptor antagonist, antihistamines or dexamethasone. 

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6.1.4.5 
Management of renal impairment  
 
If subsequent to study entry and while still on study treatments, a patient’s estimated 
creatinine clearance (CrCL) falls below the threshold for study inclusion (<50 mL/min), 
retesting should be performed promptly.  A dose reduction of olaparib is recommended for 
patients who develop moderate renal impairment (calculated CrCL by Cockcroft-Gault 
equation of ≥31 mL/min and ≤50 mL/min) for any reason during the course of the study: the 
dose of olaparib should be reduced to 150 mg bd. 
 
Because the CrCL determination is only an estimate of renal function, in instances where the 
CrCL falls to between 31 mL/minutes and 50 mL/minutes, the Investigator should use his or 
her discretion in determining whether a dose change or discontinuation of therapy is 
warranted. 
 
Olaparib has not been studied in patients with severe renal impairment 
(CrCL ≤30 mL/minutes) or end-stage renal disease; if patients develop severe impairment or 
end stage disease is it recommended that olaparib be discontinued.  For information on use of 
cediranib in renally-impaired patients, please see Section 6.1.3.14. 
 
6.2 
Arm B: Olaparib Monotherapy  
 
Dose Modification Table 
Dose Level 
Olaparib Tablet 
1 (starting dose) 
300 mg (two 150mg tablets) orally, every 12 hours 
-1 
250 mg (one 150mg tablet and one 100mg tablet) orally, every 12 hours 
-2 
200 mg (two 100mg tablets) orally, every 12 hours 
 
IMPORTANT SAFETY INFORMATION: 
AEs requiring olaparib to be discontinued: 
 
x 
Bone marrow findings consistent with MDS/ AML 
 
x 
Severe persistent anemia 
 
x 
Pneumonitis 
 
Patients experiencing ongoing clinical benefit who experience a related AE where 
continuation of one of the drugs is considered, in the judgment of the treating Investigator 
AND the Principal Investigator, to be potentially life threatening or with the potential for 
long-term harm to the patient, may be allowed to continue on the unrelated drug after 
discussion with the Principal Investigator. 
 
 

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6.2.1 Management of Hematological Toxicity  
6.2.1.1 
Management of Anemia  
 
Table 6.2.1.1 Management of Anemia (Olaparib monotherapy Arm) 
Hemoglobin 
Action to be taken 
Hb < 10 but ≥ 8 g/dl 
(CTCAE Grade 2) 
Give appropriate supportive treatment and investigate causality.  
 
Investigator judgement to continue olaparib with supportive 
treatment  (eg transfusion) or interrupt dose for a maximum of 4 
weeks.  
 
If repeat Hb< 10 but ≥ 8 g/dl, dose interrupt (for max of 4 weeks) 
until Hb ≥ 10 g/dl and upon recovery dose reduction to 250 mg 
twice daily as a first step and to 200 mg twice daily as a second 
step may be considered. 
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 
≥ 10 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 CTC grade 3 or 
worse anemia and/or development of blood transfusion dependence), refer to Section 6.1.1.3 for 
the management of this.  
 
6.2.1.2 
Management of Neutropenia, leukopenia and thrombocytopenia  
 
Table 6.2.1.2: Management of Neutropenia, leukopenia and thrombocytopenia (Olaparib 
monotherapy Arm) 
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 

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Toxicity 
Study treatment dose adjustment 
CTCAE Grade 3-4 
Dose interruption until recovered to CTCAE gr 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 
 
Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by the 
investigator with close follow up and interruption of study drug if CTC 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 h (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 haematological toxicity (≥2 week interruption/delay 
in study treatment due to CTC grade 3 or worse), refer to Section 6.1.1.3.  
 
6.2.1.3 
Management of prolonged hematological toxicities while on study treatment 
 
See the section 6.1.1.3  
 
6.2.2 General Management of Non-Hematological Toxicities 
 
See section 6.1.2 Table 5 
 
6.2.3 Management of olaparib-associated toxicity 
 
See the Section 6.1.4 the management of olaparib associated toxicity and its subsections 
 
 
6.3 
Interruptions for intercurrent non-toxicity related events  
 
6.3.1 Arm A: Cediranib + Olaparib Arm 
 
Cediranib and olaparib dose interruption for conditions other than toxicity resolution should be 
kept as short as possible.  If a patient cannot restart the investigational products (IPs) within 3 
weeks for resolution of intercurrent conditions not related to disease progression or toxicity, the 
case should be discussed with the study PI. 
 
Both cediranib and olaparib should be stopped at least 2 weeks prior to planned surgery.  After 

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surgery both IPs can be restarted when the wound has healed.  No stoppage of IPs is required for 
any needle biopsy procedure. 
 
Both IPs should be discontinued for a minimum of 3 days before a patient undergoes radiation 
treatment.  Both IPs should be restarted within 3 weeks as long as any bone marrow toxicity has 
recovered. 
 
6.3.2 ARM B: olaparib monotherapy arm 
 
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 
intercurrent conditions not related to disease progression or toxicity, the case should be discussed 
with the Study PI. 
 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the 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. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following 
list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine 
whether the event requires expedited reporting via the CTEP Adverse Event Reporting System 
(CTEP-AERS) in addition to routine reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
The Comprehensive Adverse Event 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 of AEs, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text.  The 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/adverse_effects.htm for further clarification.  

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NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the SPEER.  
Report ONLY AEs higher than this grade expeditiously.  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. 
 
7.1.1 CAEPRs for CTEP IND Agents 
 
7.1.1.1 
CAEPR for cediranib  
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
 for 
Cediranib (AZD2171, NSC 732208) 
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 1608 patients. Below is the CAEPR for Cediranib 
(AZD2171). 
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 2.15, November 7, 20181   
 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Hemolytic uremic syndrome   
 
 
Thrombotic 
thrombocytopenic purpura 
  
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
ENDOCRINE DISORDERS 
  
 
Hyperthyroidism 
 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
  
 
Anal mucositis 
 
 Anal mucositis (Gr 2) 
 
Constipation 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
64 
 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
Dysphagia 
 
 Dysphagia (Gr 2) 
 
 
 Gastrointestinal fistula2 
  
 
 
 Gastrointestinal perforation3   
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
 
Pancreatitis 
  
 
Rectal mucositis 
 
 Rectal mucositis (Gr 2) 
 
Small intestinal mucositis 
 
 Small intestinal mucositis (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
 Infection4 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase increased  
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Lymphocyte count decreased 
 
  
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
  
 
Thyroid stimulating hormone 
increased 
 
 Thyroid stimulating hormone 
increased (Gr 2) 
 
Weight loss 
 
 Weight loss (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Generalized muscle weakness  
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
Lethargy 
 
  
 
 
Leukoencephalopathy 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
 
Nephrotic syndrome 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
65 
 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Laryngeal mucositis 
 
 Laryngeal mucositis (Gr 2) 
 
Pharyngeal mucositis 
 
 Pharyngeal mucositis (Gr 2) 
 
Tracheal mucositis 
 
 Tracheal mucositis (Gr 2) 
Voice alteration 
 
 
 Voice alteration (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Palmar-plantar 
erythrodysesthesia syndrome 
 
 Palmar-plantar 
erythrodysesthesia syndrome 
(Gr 2) 
VASCULAR DISORDERS 
  
 
 
Arterial thromboembolism 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event 
 
 Thromboembolic event (Gr 4) 
 
Vascular disorders - Other 
(hemorrhage)5 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Enterovesical fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS 
SOC. 
 
3Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
4Infections includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
5Hemorrhage is a known consequence of VEGF/VEGFR signaling inhibition. The majority of hemorrhage 
events reported were mild; however, serious events, defined as symptomatic bleeding in a critical area or 
organ system (e.g., eye, gastrointestinal tract, genitourinary [GU] tract, respiratory tract, and nervous 
system) have been reported. 
 
 
 
Adverse events reported on cediranib (AZD2171) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that cediranib (AZD2171) caused the adverse 
event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system disorders - 
Other (polycythemia); Bone marrow hypocellular; Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Cardiac disorders - Other 
(premature ventricular complexes); Cardiac disorders - Other (valvular heart disease); Chest pain - 
cardiac; Mobitz (type) II atrioventricular block; Myocardial infarction; Palpitations; Pericardial effusion; 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
66 
Pericarditis; Restrictive cardiomyopathy; Sinus bradycardia; Sinus tachycardia; Supraventricular 
tachycardia 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (ears feel full/plugged); Ear 
and labyrinth disorders - Other (viral labyrinthitis); Tinnitus; Vertigo 
EYE DISORDERS - Blurred vision; Eye disorders - Other (blindness); Eye disorders - Other (visual 
disturbance); Papilledema; Photophobia; Retinal vascular disorder 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal pain; Ascites; Bloating; Colitis; Colonic 
obstruction; Duodenal ulcer; Dyspepsia; Enterocolitis; Esophageal necrosis; Esophageal ulcer; 
Esophagitis; Flatulence; Gastric necrosis; Gastric ulcer; Gastroesophageal reflux disease; 
Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal disorders - Other (hydrops); 
Gastrointestinal disorders - Other (tongue sensitivity); Ileus; Oral pain; Periodontal disease; Peritoneal 
necrosis; Rectal pain; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Edema 
limbs; Fever; Gait disturbance; Hypothermia; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder obstruction; Hepatic pain; Hepatobiliary 
disorders - Other (bile duct obstruction); Hepatobiliary disorders - Other (jaundice cholestatic) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Immune system disorders - Other 
(systemic inflammatory response syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Dermatitis radiation; Fracture; 
Injury, poisoning and procedural complications - Other (tracheostomy malfunction); Intestinal stoma leak; 
Venous injury; Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; Blood 
lactate dehydrogenase increased; CPK increased; Cardiac troponin I increased; Cardiac troponin T 
increased; Cholesterol high; Creatinine increased; Ejection fraction decreased; Electrocardiogram QT 
corrected interval prolonged; GGT increased; Hemoglobin increased; INR increased; Investigations - 
Other (elevated ammonia level); Investigations - Other (increased blood erythropoietin); Lipase increased; 
White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypertriglyceridemia; Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; 
Hypomagnesemia; Hyponatremia; Metabolism and nutrition disorders - Other (failure to thrive) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Avascular necrosis; Back 
pain; Bone pain; Chest wall pain; Muscle cramp; Muscle weakness lower limb; Muscle weakness upper 
limb; Myalgia; Myositis; Neck pain; Pain in extremity; Rotator cuff injury 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Central nervous system necrosis; Cognitive disturbance; 
Depressed level of consciousness; Dysarthria; Dysgeusia; Dysphasia; Encephalopathy; Hydrocephalus; 
Ischemia cerebrovascular; Memory impairment; Muscle weakness left-sided; Nervous system disorders - 
Other (coma); Nervous system disorders - Other (right hemiparesis); Olfactory nerve disorder; Peripheral 
motor neuropathy; Peripheral sensory neuropathy; Seizure; Somnolence; Spinal cord compression; 
Stroke; Syncope; Transient ischemic attacks; Tremor 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Depression; Hallucinations; Insomnia; Suicide 
attempt 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Cystitis noninfective; 
Hematuria; Urinary retention; Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; Menorrhagia; Vaginal 
fistula 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Aspiration; Hypoxia; 
Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Pneumothorax; Pulmonary edema; Pulmonary 
fistula; Pulmonary hypertension; Sinus pain 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail loss; 
Pruritus; Purpura; Rash acneiform; Rash maculo-papular; Skin and subcutaneous tissue disorders - 
Other (petechiae); Skin and subcutaneous tissue disorders - Other (plantar warts); Skin ulceration; 
Urticaria 
VASCULAR DISORDERS - Capillary leak syndrome; Flushing; Hypotension; Vasculitis 
 
 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
67 
 
Note: Cediranib (AZD2171) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent.  
 
7.1.1.2 
CAEPR for olaparib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Olaparib (AZD2281, NSC 747856) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 3449 patients. Below is the CAEPR for Olaparib 
(AZD2281). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
 
Version 2.5, July 1, 20211 
 
 Adverse Events with Possible  
 Relationship to Olaparib (AZD2281) 
 (CTCAE 5.0 Term) 
[n= 3449] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 4)  
 
 
Febrile neutropenia 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
  
Abdominal pain 
 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
                                                    
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
68 
 
 Adverse Events with Possible  
 Relationship to Olaparib (AZD2281) 
 (CTCAE 5.0 Term) 
[n= 3449] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
INFECTIONS AND INFESTATIONS 
  
 
Upper respiratory infection 
 
  
 
Urinary tract infection 
 
  
INVESTIGATIONS 
  
 
Creatinine increased 
 
  
 
Neutrophil count decreased 
 
 Neutrophil count decreased 
(Gr 4) 
 
 
Platelet count decreased 
  
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
Muscle cramp 
 
  
 
Myalgia 
 
  
 
Pain in extremity 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)   
 
 
Leukemia secondary to 
oncology chemotherapy 
  
 
 
Myelodysplastic syndrome 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash maculo-papular 
 
  
 
 
Skin and subcutaneous tissue 
disorders - Other (angioedema) 
  
 
 
Skin and subcutaneous tissue 
disorders - Other (erythema 
nodosum) 
  
 
NOTE: New Primary Malignancies other than MDS/AML 
New primary malignancies have been reported in <1% of patients. There were other contributing 
factors/potential alternative explanations for the development of the new primary malignancy in all cases, 
including documented BRCA mutation, treatment with radiotherapy and extensive previous chemotherapy 
including carboplatin, taxanes, anthracyclines and other alkylating and DNA damaging agents. Most are 
not attributed to olaparib. 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
69 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
 
Adverse events reported on olaparib (AZD2281) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that olaparib (AZD2281) caused the adverse 
event: 
 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (nodal rhythm); Chest pain - cardiac; 
Sinus bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Hypothyroidism 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Colonic obstruction; Dry mouth; Dysphagia; 
Enterocolitis; Esophageal stenosis; Flatulence; Gastroesophageal reflux disease; Gastrointestinal 
disorders - Other (gastrointestinal hemorrhage); Gastrointestinal disorders - Other (intestinal obstruction); 
Gastrointestinal disorders - Other (intestinal perforation); Ileus; Jejunal perforation; Obstruction gastric; 
Pancreatitis; Periodontal disease; Rectal hemorrhage; Small intestinal obstruction; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Fever; Malaise; 
Non-cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (systemic inflammatory response 
syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Dermatitis radiation; Fracture; 
Gastrointestinal anastomotic leak; Injury, poisoning and procedural complications - Other (vena cava 
injury); Wound dehiscence 
INVESTIGATIONS - Alanine aminotransferase increased; Aspartate aminotransferase increased; Blood 
bilirubin increased; GGT increased; Hemoglobin increased; Lipase increased; Lymphocyte count 
decreased; Serum amylase increased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hypermagnesemia; 
Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Avascular necrosis; Bone pain; 
Generalized muscle weakness; Muscle weakness lower limb; Muscle weakness upper limb; Neck pain; 
Rotator cuff injury; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Treatment 
related secondary malignancy; Tumor pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Ataxia; Cognitive disturbance; Concentration impairment; 
Encephalopathy; Intracranial hemorrhage; Peripheral sensory neuropathy; Reversible posterior 
leukoencephalopathy syndrome; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Hallucinations; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other 
(decreased glomerular filtration rate); Renal and urinary disorders - Other (hydronephrosis); Urinary tract 
obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Hypoxia; Oropharyngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal 
disorders - Other (chronic obstructive pulmonary disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Pruritus 
VASCULAR DISORDERS - Arterial thromboembolism; Flushing; Hot flashes; Hypertension; Hypotension; 
Peripheral ischemia; Thromboembolic event 
 
 
 
 
Note: Olaparib (AZD2281) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
70 
 
7.2 
Adverse Event Characteristics  
 
x CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
will be utilized until March 31, 2018 for AE reporting. CTCAE version 5.0 will be utilized 
for AE reporting beginning April 1, 2018. 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. 
 
x 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 7.1.1) 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 7.3.4. 
 
x 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. 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting 
System), 
accessed 
via 
the 
CTEP 
Web 
site 
(https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP Web 
site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 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 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
71 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for other 
e-mail recipients.  
 
7.3.3 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 system organ class (SOC) “General disorders and administration site conditions.”  
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
Expedited Reporting Requirements for Adverse Events that Occur on Phase 1 and Early 
Phase 2 Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
(FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting 
in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not 
resulting 
in 
Hospitalization  
≥ 24 hrs 
Not required 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
72 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning of 
the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded 
UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this 
reporting period. 
Effective Date:  May 5, 2011 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times during 
the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine AE 
reporting in Rave. 
 
7.5 
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:  
 
x Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
x Myelodysplastic syndrome (MDS)  
x 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.  
 

NCI Protocol #: 9984 
 
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73 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE reporting 
unless otherwise specified. 
 
7.7 
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.  
 
7.8 
Pregnancy loss 
 
x Pregnancy loss is defined in CTCAE as “Death in utero.”   
x Any Pregnancy loss should be reported expeditiously, as Grade 4 “Pregnancy loss” under the 
Pregnancy, puerperium and perinatal conditions SOC. 
x A Pregnancy loss should NOT be reported as a Grade 5 event under the Pregnancy, 
puerperium and perinatal conditions SOC, as currently CTEPAERS recognizes this event as 
a patient death. 
 
7.9 
Neonatal death 
 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the General 
disorders and administration SOC. 
 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 7.1. 
 
8.1 
CTEP IND Agent(s) 
No starter supplies will be provided. Study agents must be ordered after the patient is 
enrolled on the assigned treatment arm. If expedited shipment is required, sites should 
provide an express courier account through the Online Agent Order Processing (OAOP) 
application. 
 

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74 
8.1.1 Cediranib (AZD2171) (NSC 732208) 
 
Chemical Name:  4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidin-1- 
yl)propoxy] quinazoline maleate 
 
Other Names: cediranib, AZD2171 maleate  
 
CAS Registry Number: 288383-20-0 (for the free base) 
 
Molecular Formula: C25H27FN4O3 · C4H4O4 
       M W: 566.59 (maleate salt), 450.52 
(free base) 
 
Approximate Solubility: The aqueous solubility of AZD2171 (cediranib) is 0.0006 mg/mL 
for the free base (distilled water, pH 8.1 at 25°C) and 1.76 mg/mL for the maleate salt (distilled 
water, at 25°C).  
 
Mode of Action: AZD2171 (cediranib) is a highly potent tyrosine kinase inhibitor of all three 
vascular endothelial growth factor receptors (VEGFR-1, -2 and -3). Inhibition of VEGF 
signaling leads to inhibition of angiogenesis, neovascular survival and vascular permeability. 
Pre-clinical tumor models show that AZD2171 (cediranib) reduces micro-vessel density and 
metastasis, indicating that it limits tumor growth. 
 
How Supplied:  Astra-Zeneca supplies and CTEP, NCI, DCTD distributes AZD2171 
(cediranib). The agent is available as beige, round, biconvex, film-coated tablets containing 
15 mg, and 20 mg of AZD2171 (cediranib) free base.  The 15 mg and 20 mg tablets are 7 mm 
and 8 mm in diameter, respectively.  Each high-density polyethylene bottle contains 35 
tablets. 
 
Tablet excipients include mannitol, dibasic calcium phosphate anhydrous, sodium starch 
glycolate, microcrystalline cellulose, and magnesium stearate with a film coat containing 
hypromellose 2910, polyethylene glycol 400, red iron oxide, yellow iron oxide, black iron 
oxide, and titanium dioxide.  
 
Storage: Store intact bottles at controlled room temperature below 30°C (86°F).  
 
Stability: Stability studies are ongoing. Dispense AZD2171 (cediranib) tablets in their 
original containers. Alternatively, if exact quantity is dispensed in a pharmacy bottle, the 
supply should be assigned a 30-day expiration. 
 
If a storage temperature excursion is identified, promptly return AZD2171 (cediranib) 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.   
 
Route and Method of Administration:  Oral.   AZD2171 (cediranib) tablets should be taken 
either one hour before or two hours after meals.  

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75 
 
 
Potential Drug Interactions: AZD2171 (cediranib) is primarily metabolized by flavin-
containing monooxygenase enzymes (FMO1 and FMO3) and UGT1A4. It is not a substrate 
of CYP450 enzymes. In vitro studies suggest that AZD2171 (cediranib) is a substrate for P-
glycoprotein (Pgp), but not breast cancer resistance protein (BCRP). Since clinically 
relevant induction or inhibition of FMO enzymes is uncommon, use caution in patients 
taking concomitant medications that are strong inhibitors (e.g. ketoconazole) or strong 
inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin and St. John’s Wort) 
of UGT1A4 or Pgp in particular. If chronic concomitant administration of strong inducers 
or inhibitors is unavoidable, consult the protocol document and/or the principal investigator 
before making any dose adjustments. 
 
In vitro studies show that AZD2171 (cediranib) did not inhibit CYP 1A2, 2A6, 2C8, 2C9, 
2C19 and 2E1 and showed no induction of CYP 1A2, 2B6 and 3A4/5. It did weakly inhibit 
CYP 2D6 and 3A4/5, but this inhibition not expected to cause any clinically relevant drug 
interactions. 
 
In vitro studies show that AZD2171 (cediranib) is a weak inhibitor of BCRP, but not Pgp. 
Use caution in patients who are taking concomitant medications that are sensitive 
substrates of  BCRP transporters since there is a potential for drug-drug interactions.  
 
AZD2171 (cediranib) is approximately 95% bound to human plasma proteins, with human 
serum albumin and α1-acid glycoprotein accounting for most of this binding. Use caution 
in patients taking concomitant medications with narrow therapeutic ranges that are also 
highly protein-bound. 
 
Oral anticoagulants are not absolutely contraindicated during treatment with AZD2171 
(cediranib); however, use AZD2171 (cediranib) with caution and increase monitoring in 
patients while on study. Patients who receive VEGF inhibitors are at increased risk of 
bleeding and hemorrhage. 
 
Patient Care Implications: Agents that inhibit VEGF signaling have the potential to affect 
wound healing. For patients already enrolled onto the protocol, the manufacturer 
recommends holding AZD2171 (cediranib) for 2 weeks prior to elective surgery and 
restarting when the surgical wound is healed. Protocol exclusion criteria should include 
patients who have had major thoracic or abdominal surgery within 2 weeks prior to start of 
study or patients with any surgical incision that is not fully healed.  
 
Availability: Cediranib is an investigational agent supplied to investigators by the Division 
of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Cediranib is provided to the NCI under a Clinical Trials Agreement (CTA) between   
AstraZeneca International (the Pharmaceutical Collaborator) and the DCTD, NCI (see 
Section 12.3). 
 
8.1.2 Olaparib (AZD2281) (NSC 747856) 
 

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76 
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 film-
coated tablets in 100 mg and 150 mg strengths.  
 
x 100 mg tablets are 14.5 mm x 7.25 mm oval-shaped 
x 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). 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. 
 
Stability:  Shelf-life studies are ongoing. 
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.   

NCI Protocol #: 9984 
 
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77 
 
Route and Method of Administration:  Tablets are taken by mouth and can be taken with a 
light meal/snack if needed to reduce stomach irritation. Olaparib tablets must be swallowed 
whole. Do not chew, dissolve, or crush the tablets. 
 
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-glycoprotein (P-gp), but not for organic anion-
transporting polypeptides (OATP1B1 and OATP1B3), organic cation transporter 1 (OCT1), 
multi-drug resistance protein 2 (MRP-2) efflux transporter or breast cancer resistance protein 
(BCRP). Administration of strong P-gp inhibitors and inducers should be avoided with 
concurrent olaparib.   
 
Based on in vitro data, olaparib inhibits CYP 3A4 and UGT1A1 enzyme systems and induces 
CYP 1A2, 2B6, and 3A4 and potentially induces CYP 2C9, 2C19 and P-gp. Therefore, avoid 
concomitant administration of sensitive substrates, particularly those with narrow therapeutic 
ranges.   
 
Olaparib is also an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, multi-drug and toxin 
extrusion proteins (MATE1 and MATE2K) and a weak inhibitor of BRCP, but not an 
inhibitor of OATP1B3 or MRP-2. In vitro studies suggest that olaparib may increase exposure 
of substrates of these transport systems, although the clinical relevance is not clear. The 
manufacturer recommends that statins, in particular, should be administered with caution 
when given concomitantly with olaparib. 
 
Patient Care Implications: Pre-clinical data indicate that olaparib adversely affects 
embryofetal survival and development. Therefore, women of child-bearing potential and their 
partners should agree to use two (2) highly effective forms of contraception throughout study 
participation and for at least one (1) month after the last dose of olaparib.  Male study 
participants should avoid fathering a child or donating sperm during the study and for three 
(3) months after the last dose of olaparib. The study investigator should discuss the most 
appropriate forms of highly effective contraceptive methods for each patient.  
 
Because the adverse events related to olaparib may include asthenia, fatigue and dizziness, 
patients should be advised to use caution while driving or using machinery. 
 
Availability: Olaparib is an investigational agent supplied to investigators by the Division 
of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Olaparib is provided to the NCI under a Clinical Trials Agreement (CTA) between   
AstraZeneca International (the Pharmaceutical Collaborator) and the DCTD, NCI (see 
Section 12.3) 

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78 
 
8.1.3 Agent Ordering and Agent Accountability 
8.1.3.1 
Agent Ordering - NCI-supplied agents (AZD2171 (cediranib) and olaparib 
(AZD2281)) may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch 
(PMB) policy requires that agent be shipped directly to the institution where the 
patient is to be treated.  PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained).  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational agents.  
The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution.  Active CTEP-registered 
investigators and investigator-designated shipping designees and ordering designees 
can 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 and a “current” password.  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.  
  
8.1.3.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Oral 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. 
 
8.1.3.3 
Investigator Brochure Availability 
 
The current versions of the IBs for PMB-supplied agents will be accessible to site 
investigators and research staff 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 
and a “current” password.  Questions about IB access may be directed to the PMB IB 
coordinator via email. 
 
8.1.3.4 
Useful Links and Contacts 
x CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
x NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
x PMB 
policies 
and 
guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  

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79 
x PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
x CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/ 
x CTEP 
Associate 
Registration 
and 
IAM 
account 
help:  
ctepreghelp@ctep.nci.nih.gov  
x PMB email:  PMBAfterHours@mail.nih.gov 
x PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
x PMB IB Coordinator: IBcoordinator@mail.nih.gov 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
This is a randomized phase II prospective, multicenter study of olaparib and cediranib versus 
olaparib in men with metastatic castration resistant prostate cancer (mCRPC).  This study 
incorporates several tissue-based and blood-based correlative studies to address the following 
objectives:   
 
x To evaluate association of homologous recombination DNA repair deficiency (HRD) with the 
clinical activity of the combination of cediranib and olaparib or olaparib monotherapy, as 
measured by rPFS, in mCRPC patients. (integrated) 
 
x To characterize genomic alterations by whole exome sequencing in mCRPC patients and 
correlate that with clinical activity or resistance to olaparib with or without cediranib. 
(integrated) 
 
x To characterize changes in RNA expression of DNA repair genes, angiogenesis markers, and 
immune markers, by whole transcriptome sequencing and correlate with clinical activity or 
resistance to olaparib with or without cediranib (integrated). 
 
x To identify baseline predictive biomarkers for rPFS or response and to identify on-treatment 
markers of acquired resistance in men with mCRPC receiving either olaparib plus cediranib 
or olaparib alone (exploratory). 
 
x To explore biomarker signatures that correlate with the clinical activity or resistance to olaparib 
with or with cediranib, including changes in gene expression or acquired mutations in tumor 
biopsies (exploratory). 
 
As shown in the flow diagram below, all the samples except plasma angiome panel, will be sent 
to the Lank Center for Genitourinary Oncology  at Dana-Farber Cancer Institute, as a central 
pathology processing for distribution of the biopsy tissue samples to appropriate destination.  
 

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The tumor tissue collections will occur via an image-guided (CT scan or US-guided) 
needle biopsy of a soft tissue or bone lesion. Biopsy of soft tissue is preferred when 
possible. Platelet count and coagulation profile will be checked prior to the biopsy as 
per institutional standard procedures. Heparin, low molecular weight heparin, aspirin, 
and other anti-platelet agents should be discontinued as per institutional standard 
procedures.   
 
The baseline biopsy will be performed after registration/randomization, and within a 
maximum of 1 week, prior to the start of the protocol therapy (i.e., cycle 1 day 1). The 
protocol therapy should begin within 7 days after the biopsy unless any concern by the 
treating investigator, in which case, it must be discussed with the overall Study PI, prior 
to starting the therapy.  
 
On-treatment biopsy will be done during the 4th week of the protocol therapy. While 
no stoppage of the study drug(s) is required for any needle biopsy, if any safety concern 
based on clinical factors the study drugs may be held pre and post biopsy, at the 
discretion of the treating investigator after discussing with the overall Study PI.   
 
Post-progression biopsy is optional.  Patients progressing on cediranib/olaparib or 
olaparib monotherapy may undergo a progression biopsy within 4 weeks from the last 
dose of the study treatment or prior to the starting the subsequent therapy, whichever 
comes first. 
 
NOTE: If feasible, the on-treatment biopsy and progression biopsy should be taken 
from the same tumor lesion as the baseline biopsy.  
 
Soft Tissue Biopsies: 
Participating Site's 
Laboratory: 
- Fresh BIOPSY 
SAMPES
- Blood Germline 
BROCA -HR
Lank Center for 
Genitourinary Oncology 
at Dana-Farber Cancer 
Institute 
1. University of 
Washington
-Tumor BROCA-HR 
- Blood Germline 
BROCA
2. The Broad Institute
-WES
-WTS

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81 
Soft tissue biopsies will be performed per institutional standards and/or operator 
preference. Preferred soft tissue biopsy sites include: lymph nodes, peripheral based 
liver lesions, exophytic soft tissue components associated with bone lesions, 
subcutaneous nodules, pleural-based lesions, and kidney lesions. An 18 gauge or larger 
is preferred for soft tissue biopsies. Cautionary Note: liver biopsy is allowed. Caution 
should be taken given the risk of post-procedural hemorrhage. 
 
Bone Biopsies:  
Bone biopsies will be performed per institutional standards and/or operator preference. 
Bone biopsies should not be performed on irradiated lesions. Preferred bone sites 
include the lumbar vertebrae, pelvic bones and long bones. Use of the OnControl® 
Biopsy System is preferred when safe and appropriate (pelvic bones). Given lower 
yield on bone biopsy special attention should be given to the following parameters 
which may correlate with tumor yield on bone biopsy: 
 
• 
Size  
• 
Degree of sclerosis  
• 
Distance from the skin to the lesion 
• 
Distance from the cortex to the lesion 
• 
Presence of a bone scan correlate  
• 
Area to target for biopsy (center versus periphery of the lesion) 
 
Important:  
For each tissue collection procedure, the intent is to acquire up to 6 needle cores for 
rapid freezing in OCT medium. Size of these biopsy cores can be variable (0.1-1.0 cm). 
While larger cores are preferable to optimize tumor capture, cores of any size should 
be processed. Long cores approximately > 2 cm can be split. A minimum of 3 cores 
is preferred. If feasible, the on-treatment biopsy and an optional progression biopsy 
should be taken from the same tumor lesion as the baseline biopsy. 
 
Refer to the Lab Manual for details of collection/processing of specimen/ shipping 
Information from Lank Center for Genitourinary Oncology at  DFCI  to the final 
destination (Appendices, I, J, K. and L)  
 
Specimen Requirement:  
 
Correlative 
Studies  
Required Specimen 
Collection Time Points 
 
 
BROCA-HR 
(integrated) 
Tumor biopsy specimen 
Pre-treatment  
 
Whole blood (germline)  
Pre-treatment  
Whole Exome 
Sequencing 
(integrated) 
Tumor biopsy specimen 
Pre-treatment 
On-treatment  
Optional Post-progression  
Whole 
Tumor biopsy specimen 
Pre-treatment 

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82 
Transcriptome 
Sequencing 
(integrated)  
On-treatment  
Optional Post-progression  
Plasma Angiome 
Panel (integrated)  
one 10ml lavender top 
(K2EDTA) tube of blood  
Pre-treatment  
Day 1 of each cycle.   
 
9.1 
Integrated Correlative Studies 
9.1.1 BROCA-HR – Integrated Laboratory Correlative Study  
9.1.1.1 
Collection of Specimen(s) 
 
Refer to the Specimen Requirement Table above and Appendices I, J and L.   
 
9.1.1.2 
Handling of Specimens(s) 
 
DNA will be extracted from PBMCs and FFPE tumor tissue containing at least 30% tumor 
nuclei. A targeted capture and massively parallel sequencing approach called BROCA will 
be applied to samples. For the proposed study, a more recent version of BROCA with 75 
genes (BROCA-HR) that serve as a single assay for germline and somatic mutations that 
influence response to therapy will be utilized. Library preparation has been fully automated 
to increase sample turnaround and lower cost. Paired-end libraries with 350bp inserts will 
be prepared from 1μg of constitutional or neoplastic DNA and hybridize to a custom pool 
of oligonucleotides targeting genomic regions as previously described using the 
SureSelectXT enrichment system on a Bravo liquid-handling instrument (Agilent)[71]. 
Following capture, samples will be barcoded with 48 different indexed primers. The pooled 
samples are sequenced on a single lane of a HiSeq flowcell (Illumina) with 2x101bp paired 
end reads and a 7bp index read to allow for de-multiplexing and binning of individual 
samples. Single nucleotide variants and insertions and deletions will be detected as 
previously described with some updates in the bioinformatics pipeline [72, 73]. Deletions 
and duplications of exons will be detected by a combination of depth of coverage and split 
read analysis as previously described, supplemented with additional alignments generated 
by SLOPE[73, 74]. All germline loss of function mutations in cancer susceptibility genes 
will be confirmed with PCR amplification and Sanger sequencing. Cases will be identified 
as HR proficient or deficient based on sequencing data of known Fanconi anemia (FA)-
BRCA genes and then correlate HR proficiency with response to platinum or PARPi on 
the trial. Later, in exploratory analyses, analyses of NHEJ and other modifying genes, 
genomic scarring, or other somatic tests by Dr. Swisher’s lab will be added to complement 
the determination of HR deficiency.  
 
9.1.1.3 
Shipping of Specimen(s) 
 
Refer to the Specimen Requirement Table above and Appendices I, J and L.  
 
 

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83 
9.1.1.4 
Site(s) Performing Correlative Study   
 
BROCA-HR will be performed by the laboratory of Dr. Elizabeth Swisher at the 
University of Washington (Seattle, WA). 
 
9.1.2 Whole exome sequencing (WES; Integrated) and Whole transcriptome sequencing (WTS; 
Integrated) 
 
9.1.2.1 
Collection of Specimens 
 
Refer to the Specimen Requirement Table above and Appendices I, J and L.  
 
9.1.2.2 
Handling of Specimens 
 
We will make use of our CLIA-certified whole exome sequencing process for this 
proposal. We will provide variant calls within three weeks from sample receipt. We 
describe data generation steps below: 
 
CLIA Portal. We have designed a portal through which information on patient samples 
can be directly entered and downstream results can be obtained. The following 
information is received securely through the portal:  
 
x Test Requisition Submission: All test requests for the Clinical Sequencing are 
received through the CRSP Client Portal. An authorized individual representing 
either a requisitioning physician or referring CLIA-certified laboratory may submit 
test requisitions via the CRSP Portal. Once the pertinent information for the 
requisitioning individual (i.e., NPI & medical license numbers) or entity (CLIA 
certificate number) has been verified, the client will be supplied with the 
information  (username/password) required to access the CRSP Client Portal. 
Submission of a test requisition through the CRSP Client Portal ensures that all 
required requisition elements (e.g. Patient and sample information and identifiers) 
are completed and are in an acceptable format. 
x Patient Information: Patient information will be de-identified to the sequencing 
center. We will store only the information provided and utilize IDs assigned by the 
clinical centers. We note that for our standard test requisitions we have made 
available a portal through which physicians can supply patient identifying 
information that will be stored securely in a compliant manner. This information is 
supplied in the form of a unique alphanumeric identifier (supplied by the 
requisitioning individual/entity) or the more standard collection of personal 
identifiers (e.g. first name, last name, date of birth, address, telephone number). The 
requisitioning individual/entity also completes an attestation that the patient or legal 
representative has been informed of the potential risks and benefits of undergoing 
genetic testing and has consented to such testing 
x Sample Information. The type of sample (DNA, EDTA-anticoagulated whole 
blood or Saliva) being submitted for testing will be supplied. If a unique 
alphanumeric patient identifier is being used, a distinct sample identifier will also 

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84 
be supplied. Finally, the sample collection date will also be noted on the test 
requisition form. 
 
Sample management and QC. Sample handling will be performed by the CLIA-certified 
lab within the Broad Institute’s Genomics Platform and includes an industry-grade high 
throughput registration, processing, and tracking system for biological samples. The 
system includes multiple points of quality control (i.e., sample quantitation, tracking, and 
genetic fingerprinting), allowing us to receive and process an average of 16,000 samples 
per month. On arrival, each sample is assigned a unique bar code and entered into a 
validated database for sample analysis coupled to a bar code tracking system that records 
sample information (e.g., source, histology, clinical data), nucleic acid quality control 
information (e.g., genotyping, PCR), location information (e.g., freezer, shelf, rack), and 
project information. The database is linked directly to the LIMS systems for array and 
sequencing analysis.  
For each DNA sample received, we will perform the following steps: Our optimized 
fingerprinting and WES processes require 50 to 100 ng input DNA. We will perform 
triplicate PicoGreen® DNA quantitation, and sample a subset of DNAs to verify high 
molecular weight DNA by a gel assay. By genotyping a panel of 127 highly polymorphic 
SNPs (including SNPs on chromosomes X and Y), a unique genetic ‘fingerprint’ is 
generated for each sample. These genotypes are stored in the sample-tracking database and 
compared to genotypes obtained from whole exome sequencing to ensure integrity of 
sample handling and tracking from sample receipt through library sequencing.  
 
Targeting the exome by hybrid selection. As described above, we will utilize whole exome 
targeting reagents from Illumina to prepare the sample libraries. The Illumina targeting 
process employs capture principles similar to those we developed and licensed to Agilent 
Technologies for the SureSelect® hybrid selection method but uses DNA instead of RNA 
oligonucleotides or baits for target capture. As discussed above the ‘Rapid Capture Exome’ 
content was co-developed with Illumina. Our own proprietary process enhancements to the 
‘Rapid Capture Exome’ protocol makes use of these capture reagents along with our 
OneWell ‘with-bead’ library construction protocol and a specialized dual-indexing step for 
an extra level of contamination control. Briefly, our fully automated LIMS-tracked process 
begins with 100ng of Picogreen-quantified genomic DNA (in special cases as little as 50 
ng of DNA). The genomic DNA is fragmented, using Covaris acoustic shearing, to the 
desired size of 150bp. Fragments are selectively bound to SPRI magnetic beads, followed 
by clean-up or washing steps, end repair, A-base addition, and indexed dual-adapter 
ligation. Following these steps the prepared DNA fragments are eluted from the SPRI 
beads and PCR amplified, generating 'pond' libraries ready for downstream hybrid capture. 
Pools of 12 indexed pond libraries then undergo two rounds of hybridization and ‘capture’ 
in which the pond pools are hybridized to the biotinylated exome baits, captured on 
streptavidin beads, washed at high stringency to remove off-target hybridizations, and then 
eluted from the SPRI beads. This process hybridization, washing, and elution is repeated 
once more and, following the second elution step, captured targets are PCR amplified, 
cleaned up one final time, and then submitted for sequencing.  
 

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Production Sequencing. Following targeting, libraries will be quantified (via Picogreen), 
normalized, and pooled. The resulting pool will be qPCR assayed and loaded onto flow 
cells for cluster amplification. All of these steps are part of Broad’s standard Illumina 
library construction process which includes numerous QC steps: verification of all liquid 
handling instrumentation prior to each run using fluorescent dyes, QC of all critical reagent 
lots, auditing of vendor issued QCs for all other reagents, regular training verification of 
personnel, and other in-process QCs including specifically designed qPCR assays to verify 
loading concentrations.  
We propose to use the HiSeq2500 for sequencing in this project. We have demonstrated 
failure rates of less than 10%, yields per flowcell of 130 Gb with run times of 27 hours for 
2x101 runs, and have already produced over forty (40) terabases of data with the 
HiSeq2500. The HiSeq2500 fits seamlessly into the Broad sequencing laboratory and 
analysis pipelines and greatly simplifies the workflow and time in the lab with on-board 
cluster generation and reduced chemistry and imaging cycle times. Four (4) exome libraries 
are mixed or multiplexed and loaded per flow cell lane. We generate 5 Gb of sequence for 
each library. Real-time monitoring of many quality metrics, including the following is used 
to ensure exquisite control of the production line: 
x On-target sequence yield. A major inefficiency of all massively parallel targeting 
approaches is the inability to precisely and uniquely capture (to the base pair) the 
target of interest. We have made a number of improvements to our production 
protocol (such as blocking agents against sequencing adaptors) which have resulted 
in routine on-target proportion of ~ 90% of reads.  
x Percent-target coverage ≥20X. We require the baseline coverage to be >80% of 
targets to be covered at over 20X across the target region. This level of coverage 
typically results in ~100X average coverage across the exome, though higher levels 
of coverage can be achieved with additional sequencing.  
x Non-duplicate reads. Observation of duplicate reads (reads with the same start and 
stop sites) indicates that the same molecule has been sequenced multiple times. This 
can mislead SNP calling algorithms, since the same molecule-specific (PCR or 
other) error can erroneously be counted as independent observations. We found that 
PCR upstream of selection can lead to a high degree of duplication, likely from 
bottlenecking of input material. Our current protocol is stable at 5-10% read 
duplication (duplicated reads are removed bioinformatically at BAM aggregation) 
and an increase in this measure signals issues with library preparation. 
x Contamination check. As an additional layer of process control and test accuracy, 
we routinely apply a set of algorithms called ‘verifyBamID’ to every sequencing 
dataset. VerifyBamID is a piece of software that detects possible sample mixture 
from population allele frequency only, which may be particularly useful when the 
genotype data is not available. Specically VerifyBamID verifies whether the reads 
in a particular file match previously known genotypes for an individual (or group 
of individuals), and checks whether the reads are contaminated as a mixture of two 
samples8. Using a mathematical model that relates observed sequence reads to a 
hypothetical true genotype, verifyBamID determines whether sequence reads 
obtained from the processing of a given sample match a particular individual or are 
more likely to be contaminated, derived from a closely related individual, or 
derived from a completely different individual.  

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In the rare instance when initial sequencing efforts fail to provide sufficient sequence 
coverage, additional sequence and coverage will be generated using the same rapid 
turn-around time exome express processes. 
 
Data analysis  
 
The CSRP’s analysis pipeline consists of a large number of tools designed to detect 
different types of genomic events (Figure 1): (i) Point mutations (MuTect – Cibulskis et 
al.,; (ii) small insertions and deletions (Indelocator – Sivachenko et al.); (iii) 
rearrangements (dRanger – Lawrence et al.) and their exact breakpoint (BreakPointer); (iv) 
Copy-number changes (CapSeg– Carter et al.,); (v) Purity and ploidy, absolute copy-
number and clonal/sub-clonal mutations (ABSOLUTE) (vi) Pathogen discovery (PathSeq); 
and finally (vii) we annotate all these genomic events with their effect on proteins, their 
relationship to disease, overlap with known cancer genes or pathways, potential functional 
effects using our tool Oncotator (Ramos et al., submitted; www.oncotator.org). The output 
of this pipeline is a set of VCF files (one per patient) and corresponding MAF file with all 
annotations. As of May 2014, MuTect and Indelocator have been validated in the CLIA 
process.  
 
The CSRP’s tools are of the highest quality 
in the field and were used to analyze a large 
number of cancer projects (references 
available upon request). For example, 
comparison of MuTect (CSRP’s mutation 
caller) to other commonly used tools 
demonstrated that it is vastly superior (much 
more sensitive for any given false-positive 
value) (Figure 1). Finally, the Broad Institute 
is developing tools to take all types of 
alterations in a patient’s tumor and prioritize 
the events with respect to clinical-relevance. 
These are then presented in a comprehensive 
report. Other tools that are being developed 
are aimed at analysis of sub-clonal 
composition of tumors and their evolution in 
multiple tumor samples (e.g. longitudinal 
samples, primary/metastases, primary/relapse etc.). These tools can estimate the number of 
macroscopic sub-clones and the fraction of cancer cells that they represent and when 
multiple tumors are analyzed the tools can also detect evolution of sub-clones (Landau, 
Carter, Stojanov et al.) 
 
Transcriptome Sequencing (RNA-seq)  
 
We will also generate transcriptome sequencing using tumor RNA obtained from biopsies. 
RNA-seq may provide insights into overexpressed genes, chimeric transcripts (possibly 
indicative of underlying structural genomic rearrangements), and/or alternatively spliced 
variants. Thus, application of RNA-seq to serially obtained biopsies may provide useful 
Figure 1 Receiver operating characteristic 
(ROC) curve for MuTect, for mutations at allele 
fraction of 0.2 and at 30x sequencing depth. 
Results are shown for Standard filtering (STD) 
and High-Confidence (HC). Results for two 
leading tools in the field, SomaticSniper and 
JointSVNMix are provided showing significant 
improved sensitivity for MuTect compared to the 
other tools. 

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information about dysregulated pathways or networks not evident from somatic genetic 
analysis, pharmacodynamic changes caused by drug action, adaptive cellular responses to 
drug target inhibition, and “non-genetic” resistance mechanisms. As with WES, the Broad 
Institute has developed considerable “production-scale” expertise in RNA-seq sequencing. 
As the production center for the Genotype Tissue Expression (GTEx) project 
(http://commonfund.nih.gov/GTEx/), the Broad Institute has developed many RNA-seq 
protocols. In addition to the GTEx project, the Broad also produced RNA-seq data for the 
entire Cancer Cell Line Encyclopedia (CCLE). Over the past two years, the Broad Institute 
generated RNA-seq data for over 3,000 samples. Through application of automated fluid- 
handling techniques and process optimization, they created an RNA-seq sample 
preparation pipeline that can handle 192 samples per week at current demand levels.  
Illumina’s TruSeq method affords robust performance in terms of RNA input and 
sequencing library complexity. This method allows for input RNA amounts as low as 250-
500 ng and is automated for high-throughput production. To generate RNA-seq data, 
polyA+ RNA will be isolated in the Genetic Analysis Platform at the Broad Institute. Next, 
strand-specific cDNA libraries will be generated. Each cDNA library will be sheared by 
sonication, paired-end adapters for Illumina sequencing will be added, and Illumina 
sequencing libraries will be prepared following established protocols. Each sample will be 
subjected to Illumina sequencing using an Illumina HiSeq instrument, producing ~101 bp 
paired-end reads. RNA-seq data will be analyzed by the Computational Biology Core.  
 
As with WES, the Broad Institute has developed considerable “production-scale” 
expertise in RNA sequencing. Illumina’s TruSeq method affords robust performance 
in terms of RNA input and sequencing library complexity. This method allows for input 
RNA amounts as low as 250-500ng and is automated for high-throughput production. 
Algorithms to identify RNA-based features including alternative splice variants, novel 
fusions and aggregate gene expression changes (CuffLinks/CuffDiff) will be applied 
to RNA-seq data. 
 
9.1.2.3 
Shipping of Specimens 
 
Refer to the Specimen Requirement Table above and Appendices I, J and L.  
 
9.1.2.4 
Site Performing Correlative Study 
WES and Transcriptome sequencing will be performed by the Center for Cancer 
Precision Medicine at the Broad Institute, Cambridge, MA.  
 
9.1.3 Plasma Angiome (Integrated)  
9.1.3.1 
Collection of Specimen 
 
Biomarker assays are time sensitive.  Samples must be processed within one hour of 
collection.  Complete the Blood Requisition Form (Appendix B of lab manual) and 
insert a copy of with shipment. 
 
Required material:   
x 10 mL purple/lavender-top EDTA-containing vacutainer tubes (BD Vacutainer, Catalog 
no. 366643)  

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x clear 15ml polypropylene tubes 
x 2ml cryovials  
x Labels designed for low temperatures (e.g., Cryo-Tag brand) 
 
Collection:  
1.Draw blood into one 10ml lavender top (K2EDTA) tube (BD Vacutainer, Catalog no. 
366643)  
2.Invert tubes 10 times to mix blood 
3.Centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge 
manufacturer’s instructions) 
4.Remove plasma from each tube and transfer equally into two separate clean 15ml 
polypropylene tubes 
5.Repeat centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge 
manufacturer’s instructions).  
6.Aliquot approximately 1.0ml of plasma from each tube into each 2.0ml cryovial. A total of 
5 capped cryovials are needed for EDTA plasma.   
7.Label tubes with the following information (using a Sharpie or Cryopen): 
x Protocol Name  
x Subject Study Number 
x Subject Initials 
x Sample Date and Time 
x Sample Type (EDTA plasma) 
x Cycle # 
 
8. Vials should be frozen at -80oC immediately in an upright position and kept at -
80oC until shipment. 
9. As plasma samples are analyzed in a retrospective manner, samples should be 
stored at the other sites outside Yale and shipped in batches at a later time to be 
agreed with the analyzing laboratory.  
10. Complete the Plasma Biomarker Sample Shipping Form (Angiogenesis and 
Inflammation Markers) (Appendix B of lab manual) and insert a copy of with 
shipment. 

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9.1.3.2 
Handling of Specimens 
 
Plasma samples will be analyzed by multiplex ELISA assays for plasma-based 
biomarkers utilizing the Aushon Cirascan Imaging System. The Aushon Cirascan 
Imaging System is used specifically for the imaging and analysis of chemiluminescent 
protein arrays in a 96-well plate. The protein arrays are created by spotting up to 16 
different capture antibodies per well in each well of the 96-well plate. The advantage 
of this system is that multiple target proteins of interest can be analyzed at the same 
time reducing the amount of sample required for analysis. In brief, a small volume of 
sample and/or standard is added to each well of the 96-well plate resulting in the capture 
of the target proteins by the arrayed antibodies. Biotinylated antibodies are then added 
that specifically bind the captured target proteins. Streptavidin conjugated to HRP 
(horseradish peroxidase) is then added followed by a chemiluminescent substrate. 
Imaging of the plate is performed using Aushon Cirascan Imaging System. Protein 
concentrations in the samples are quantified by comparing the intensity of the spots in 
the unknown wells to standard curves.  
 
Samples should be processed on site to obtain plasma and then shipped on dry ice. 
Biomarker assays are time sensitive, and samples should be stored on ice and processed 
within four hours of collection. Instructions for processing and labeling samples are 
below: 
 
9.1.3.3 
Shipping of Specimen 
Instructions for packing and notifications for shipment follow: 
x Agree to the timing of shipment with receiving laboratory. 
x Use at least 5 kg dry ice for overnight delivery. The amount of dry ice may have to 
be increased if a large number of samples are sent or for a large shipping container.  
x Samples should be placed upright in cryoboxes containing inserts.  
x Include a completed Plasma Biomarker Sample Shipping Form for Markers of 
Angiogenesis and Inflammation (see Appendix B of lab manual) itemizing the 
contents of the shipment. A photocopy should be maintained with study records at 
each site. 
x Place any paperwork in a plastic Ziploc bag.  
x Send an email notification to the receiving lab with tracking number, and attach 
electronic version of completed Biomarker Sample Shipping Form to 
andrew.nixon@duke.edu and the study coordinator (email tbd). 
x All samples must be shipped on dry ice by overnight delivery Monday through 
Wednesday (no holidays in the same week) to the following address: 
 
Phase I Biomarker Laboratory 
Dr. Andrew Nixon 
Duke University Medical Center 
395 MSRB, Research Drive 
Durham, NC 27710 
Phone: (919) 681-2239 
Email: andrew.nixon@duke.edu 

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9.1.3.4 
Site(s) Performing Correlative Study 
 
Plasma angiome will be performed by the laboratory of Dr. Andrew Nixon at Duke 
University Medical Center (Durham, NC) 
 
 
 
 

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10. STUDY CALENDAR 
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. 
 
 
 
Scre
enin
g 
Post  
Reg Cycle  (C ) 1 (=28 days) 
 
C 2 
 
 
C3 and 
later    
 
Off 
Study 
 
Day 
-27 
to 0 
D-6 
to 0 
D1  
D 15 
+/-3 
days 
 
D 22 
 - 28 
D 1 
+/- 
3 
day
s 
D15 
+/- 3 
days 
 
D 22 -28 
 
D 1 
+/- 3 days 
ARM A: Cediranib and 
Olaparib @X 
 
X  ---------------------------------------------------------------- >  
 
 
ARM B: Olaparib 
 
X  ----------------------------------------------------------------- > 
 
Home BP monitoring 
(Arm A only)1 
 
X  ---------------------------------------------------------------- > 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Registration 
and 
Randomization 
X 
 
 
 
 
 
 
 
 
 
Tumor Biopsies 2 
 
X2a 
 
 
X2b 
 
 
 
 
X2c 
Germline BROCA 
 
X 
 
 
 
 
 
 
 
 
Research 
Blood 
(Angiome) 
 
X 
 
 
X 
 
 
X 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical H&PE / VS / 
PS/ Con meds / Tox 
assessment / Weight  
X 
 
X 
X 
 
X 
X 
 
X 
 
Height  
X 
 
 
 
 
 
 
 
 
 
Hematology3 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Serum chemistry3 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Urine Protein/Creatinine 
Ratio3  
X 
 
X8 
X8 
 
X8 
X8 
 
X8 
X8 
INR and PTT 4 
X 
 
 
 
X 
 
 
 
 
 
TSH and free T4  
X 
 
 
 
 
 
 
 
X5 
 
PSA 
X 
 
 
 
 
X 
 
 
X 
 
Testosterone  
X 
 
 
 
 
 
 
 
 
 
Tc99 Bone Scan 
X 
 
 
 
 
 
 
X6 
 
 
CT/MRI Abdomen and  
CT Chest  
X 
 
 
 
 
 
 
X6 
 
 
CT Neck (if clinically 
indicated)  
X 
 
 
 
 
 
 
X6 
 
 
ECG3 
X 
 
 
 
 
 
 
 
 
 
Echo7 
X 
 
 
 
 
 
 
 
 
 
FOOT NOTE:  
1: patient must be advised to monitor home blood pressure twice a day for at least 8 weeks. Once deemed stable, 
then it may be reduced to once a day.  
2: Tumor biopsy is mandatory at pre-treatment and during the 4th week.  
2a: The baseline biopsy will be performed after registration/randomization, and within a maximum of 1 week, prior 
to the start of the protocol therapy (i.e., cycle 1 day 1). The protocol therapy should begin within 7 days after the 

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biopsy unless any concern by the treating investigator, in which case, the case must be discussed with the overall 
Study PI, prior to starting the therapy. 
2b:  On-treatment biopsy will be done during the 4th week of the study. While no stoppage of the study drug(s) is 
required for any needle biopsy, if any safety concern based on clinical factors, the study drugs may be held before 
and after the biopsy, at the discretion of the treating investigator after discussing with the overall Study PI. 
2c: Post-progression biopsy is optional. Patients progressing on cediranib/olaparib or olaparib monotherapy may 
undergo a progression biopsy within 4 weeks from the last dose of the study treatment, or prior to the starting the 
subsequent therapy, whichever comes first.  
  
Important Note:  
x 
liver metastasis biopsy is allowed. Caution must be taken given the risk of post-procedural hemorrhage. 
x 
If feasible, the on-treatment biopsy and progression biopsy should be taken from the same tumor lesion as 
the baseline biopsy. If not feasible, inform Study PI.  
 
3: See the relevant subsections of 10.1 below.  
4: Required within 7 days prior to the biopsy. See sections 10.1.2 and 5.2 for guidance for those on anticoagulation 
therapy.  
5: For patients on the combination arm only, monitor after every 2 cycles throughout the study or earlier if clinically 
indicated. 
6: See Section 11. Tumor reassessment will be time-based, and not cycle-based, with CT or MRI of Abdomen and 
Pelvis, CT scan of Chest, (CT neck if clinically indicated), and Tc99 Bone Scan, performed once every 8 weeks  
starting with the first restaging scan for the first 24 weeks of the study, then every 12 weeks (+/- 7 days) thereafter, 
and when clinically indicated. 
7: See section 10.1.7 below.  
@X: patients on olaparib monotherapy arm will have an option of cross-over. See the Section 5.6 Criteria for cross-
over. When crossed over, patients will follow the schedule as shown here beginning D1, post-cross-over cycle 1. 
Biopsies are highly encouraged, especially pre-cross-over, but this is optional.  
8: Only for patients on the combination arm. 
 
 
10.1 
Laboratory and Cardiac Safety Assessment 
 
Any clinically significant abnormal laboratory values should be reported as clinically indicated 
and recorded on the eCRF.  
  
10.1.1 Hematology test include the following and should be performed per study calendar and 
when clinically indicated.  
o hemoglobin,  
o red blood cells [RBC],  
o platelets,  
o mean cell volume [MCV],  
o mean cell hemoglobin concentration [MCHC],  
o mean cell hemoglobin [MCH],  
o white blood cells [WBC],  
o Absolute differential white cell count (neutrophils, lymphocytes, monocytes, 
eosinophils and basophils) and  
o Absolute neutrophil count or segmented neutrophil count and Band forms. 
  
If absolute differentials not available, please provide % differentials.  
 

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10.1.2 Coagulation test include the following and should be performed per study calendar and 
when clinically indicated.  
o Activated partial thromboplastin time (aPTT) 
o International normalized ratio (INR) 
 
o NOTE: 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. See the 
Section 5.2 for the guidance for patients on anticoagulation therapy.  
 
10.1.3 Biochemistry test include the following and should be performed per study calendar and 
when clinically indicated:  
o Na, K, Chloride, Bicarb, BUN, Cr, Glucose, Calcium, Magnesium, Phosphorus, 
Albumin, Total Protein, Alkaline Phosphatase, ALT, AST, Total Bilirubin, LDH. 
 
10.1.4 Urine Protein:Creatinine (UPC) Ratio should be performed in all patients for eligibility. 
Only those on the cediranib + olaparib arm are required to check UPC while they are on 
treatment.  
 
10.1.5 Bone Marrow and Blood Cytogenetic Analysis should be considered if a patient 
develops prolonged hematologic toxicities as defined in section 6.1.1.3.  These tests will 
be performed by the hospital’s local laboratory.  Additional analyses may be performed if 
clinically indicated. 
 
10.1.6 Resting 12-lead ECG:  
 
Two 12-lead ECGs within 24 hours are required within 14 days prior to registration per 
eligibility criteria 3.2.12, and when clinically indicated after registration/randomization.  
 
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. 
 

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10.1.7 Echocardiogram Assessment 
 
For eligibility purpose, echocardiogram is required if a potential candidate has the risk 
factors for developing potential cardiac toxicities from cediranib as defined in section 
3.1.16.   
 
For patients in combination arm only, echocardiogram is required after every 4 cycles if 
the subject has the cardiac risk factors as defined in section 6.1.3.3, or anytime if 
clinically indicated.  
 
 
 

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11. MEASUREMENT OF EFFECT 
 
Tumor reassessment will be time-based, and not cycle-based, with CT scan or MRI of Abdomen 
and Pelvis, CT scan of Chest, and Tc99 Bone Scan, performed once every 8 weeks (+/- 7 days) for 
the first 24 weeks, then every 12 weeks (+/- 7 days) thereafter, and at any other time if clinically 
indicated based on symptoms or physical signs suggestive of progressive disease.   
 
Imaging assessments can be discontinued if disease progression is confirmed according to RECIST 
version 1.1.  However, if a patient discontinues study treatment for any reason other than 
progression, imaging studies should continue every 8 weeks (+/- 7 days) on the protocol-outlined 
schedule until progression, or earlier if clinically indicated.  
 
11.1 
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 in 4 - 6 (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. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with cediranib and olaparib or olaparib.  
 
Evaluable for objective response.  All patients with measurable disease present at baseline 
who have started the study treatment 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, 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.  
 
11.1.2 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 

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

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11.1.3 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 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.   

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

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Version Date: September 7, 2021 
99 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm (<1 
cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm (0.5 cm).  (Note:  the appearance 
of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm [<1 
cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status 

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100 
change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
11.1.4.3 
Evaluation of Bone Metastasis on Tc99 Bone Scan 
 
Per PCWG2 [75]and PCWG3 [76] guideline, progression by bone scan is determined if any of 
the following is met:  
(a) The first bone scan with greater than or equal to (>=) 2 new lesions compared 
to baseline is observed in less than (<) 12 weeks from randomization and was 
confirmed by a second bone scan taken >=6 weeks later showing >=2 additional 
new lesions (a total of >=4 new lesions compared to baseline), OR 
 
(b) The first bone scan with >=2 new lesions compared to baseline was observed 
in >=12 weeks from randomization and the new lesions were verified on the 
next bone scan >=6 weeks later (a total of >=2 new lesions compared to 
baseline);  
 
11.1.4.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 

NCI Protocol #: 9984 
 
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101 
**    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 
 
11.1.5 PSA response  
 
PSA response will be defined by PSA decline > 50% from baseline at any point, confirmed 
by a second value obtained 3 or 4 weeks later.  
 
11.1.6 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements.  
 

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102 
11.1.7 Radiographic Progression-Free Survival (rPFS):  
The time interval from randomization to the first occurrence of any one of the following:  
A. Progression by bone scan if  
(a) the first bone scan with greater than or equal to (>=) 2 new lesions compared to 
baseline was observed in less than (<) 12 weeks from randomization and was 
confirmed by a second bone scan taken >=6 weeks later showing >=2 additional new 
lesions (a total of >=4 new lesions compared to baseline), OR 
(b) the first bone scan with >=2 new lesions compared to baseline was observed in 
>=12 weeks from randomization and the new lesions were verified on the next bone 
scan >=6 weeks later (a total of >=2 new lesions compared to baseline);  
 
B. Progression of soft tissue lesions measured by computerized tomography (CT) or 
magnetic resonance imaging (MRI), progression defined by RECIST v1.1  
 
C. Death from any cause. 
 
Participants alive without disease progression are censored at date of last disease evaluation.  
 
11.1.8 Overall Survival 
Overall survival is the time interval from randomization to the date of death due to any 
cause, or censored, at date last known alive.  
 
11.1.9 PSA Response Rate:  
Proportion of patients with a PSA response among those who are evaluable for 
response to an assigned therapy. The patients who were registered with a baseline 
PSA of 1.0ng/mg or greater and with rising PSA as defined in section 3.1.1.4, will be 
considered for evaluable for PSA response.  
 
11.1.10  Objective response rate:  
Proportion of patients with an objective response as defined by RECIST v1.1 among 
those who are evaluable for response to an assigned therapy. An objective response is 
defined by either PR or CR by RECIST v1.1.  
 
11.1.11 Response Review 
 
All objective responses will be reviewed by exert radiologists of the participating sites. No 
independent review is planned.  
 
11.1.12  rPFS cross-over 
 
The time interval from the start of the combination therapy at cross-over to the first 
occurrence of radiographic progression, defined in 11.1.7, or death from any cause 
 

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103 
11.1.13 PSA response rate (cross-over) 
  
A proportion of crossed-over patients with a PSA response (greater than or equal to 50% 
decline from the PSA at pre-cross-over 
 
11.1.14 Objective response rate (cross-over) 
 
Proportion of patients with measurable disease at pre-cross-over, who achieved an objective 
response (PR or CR) as defined by RECIST v1.1.  
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and serious 
adverse events; reporting of expedited adverse events; and accumulation of reported adverse 
events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
For this Phase 2 portion of the study, the Protocol Principal Investigator will have, at a minimum, 
quarterly conference calls with the Study Investigators and the CTEP Medical Officer(s) to review 
accrual, progress, and pharmacovigilance.  Decisions to proceed to the second stage of a Phase 2 
trial will require sign-off by the Protocol Principal Investigator and the Protocol Statistician 
through IWRS and Medidata Rave. 
 
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. 
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the trial 
in Rave is granted through the iMedidata application to all persons with the appropriate roles 
assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site user 
must have an active CTEP IAM account (check at < https://ctepcore.nci.nih.gov/iam  >) and the 
appropriate Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site Investigator) on 
either the LPO or participating organization roster at the enrolling site. To the hold Rave CRA role 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
104 
or CRA Lab Admin role, the user must hold a minimum of an AP registration type.  To hold the 
Rave Site Investigator role, the individual must be registered as an NPIVR or IVR.  Associates can 
hold read-only roles in Rave.  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 RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) using 
their CTEP-IAM user name and password, and click on the “accept” link in the upper right-corner 
of the iMedidata page.  Please note, site users 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 link in the upper right pane 
of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website, Rave tab 
under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail 
at ctsucontact@westat.com. 
 
12.2.1 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 on an 18-36 month basis as part of routine cancer center site 
visits. For CTMS monitored studies, after users have activated their accounts, please 
contact 
the 
Theradex 
Help 
Desk 
at 
(609) 
799-7580 
or 
by 
email 
at 
CTMSSupport@theradex.com for additional support with Rave and completion of CRFs. 
 
 
12.2.2 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. 

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105 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis 
as data is received.  Queries will be issued by CTMS directly within Rave.  The queries 
will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve.  
Monthly web-based reports are posted for review by the Drug Monitors in the IDB, CTEP.  
Onsite audits will be conducted by the CTMS to ensure compliance with regulatory 
requirements, GCP, and NCI policies and procedures with the overarching goal of ensuring 
the integrity of data generated from NCI-sponsored clinical trials, as described in the 
ETCTN 
Program 
Guidelines, 
which 
may 
be 
found 
on 
the 
CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials) the 
recommended phase 2 dose (RP2D), and a description of any dose-limiting toxicities 
(DLTs).  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
). 
 
12.3 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) 
be transferred or licensed to any party not participating in the clinical study.  Collaborator(s) 
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
106 
as such by the investigators.  The protocol documents for studies utilizing Agents contain 
confidential information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement.  A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree 
in writing prior to the commencement of the trials that it will use the Multi-Party Data 
solely for development, regulatory approval, and commercialization of its own Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will 
be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
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 

NCI Protocol #: 9984 
 
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107 
for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in any 
case, prior to presentation at the meeting or publication in the proceedings.  Press releases and 
other media presentations must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is an open label randomized phase II study for patients with metastatic castration resistant 
prostate cancer, comparing the combination of cediranib and olaparib to olaparib monotherapy.  
 
The primary objective of the study is to assess the clinical activity of the combination of 
cediranib and olaparib, as measured by radiographic progression free survival (rPFS), as 
compared to olaparib monotherapy in patients with mCRPC.  Radiographic Progression Free 
Survival (rPFS) is the time interval from random assignment to the date of the first occurrence of 
disease progression or death, whichever occurs first.  See section 11.1.7 for the definition for this 
study.  Patients will be randomized in 1:1 ratio to either of the two arms. Patients randomized to 
the olaparib monotherapy arm will have the opportunity to receive the combination of cediranib 
and olaparib upon progression. 
  
 
13.2 
Sample Size/Accrual Rate 
 
We consider a median rPFS of at least 8.8 months for patients treated with the combination of 
cediranib and olaparib as clinically promising (Ha: rPFS of the combination arm is superior to that 
of the olaparib monotherapy arm), relative to the expected median rPFS of 4.8 months associated 
with olaparib monotherapy (Ho: rPFS for the combination arm is at best, equivalent to that of the 
olaparib monotherapy arm). This corresponds to observing a hazard ratio of 0.55 (combination 
arm: olaparib monotherapy arm). The sample size estimation was completed using the log-rank 
test. With the proposed sample size of 84 (42 patients per arm), it provides at least 90% power to 
detect a 4-month improvement of rPFS for the combination arm with one-sided type I error = 10%. 
The assumptions of this calculation are the estimated accrual time = 12 months, the additional 
follow-up time = 14 months, and the accrual rate = 7 patients per month. Assuming the drop-out 
rate is about 5% - 7%, a total sample size of 90 (45 per group) has excellent power to detect a 
clinically 
 

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109 
The expected median rPFS 4.8 months in the olaparib is based on the weighted average rPFS data 
from the TOPARP trial (Mateo et al. NEJM 2015). The authors did not report the overall rPFS of 
the study patients. Instead, they reported the rPFS of 2.7 months in biomarker negative patients 
(~70%) and 9.8 months in the biomarker positive patients (~30%). Based on these, we estimated 
that the average rPFS would be approximately 4.8 months. In our study, we will consider 4-month 
improvement in rPFS as clinically significant, which corresponds to HR0.55.  We feel that, based 
on the results of contemporary positive and negative mCRPC trials (Morris M. et al. JCO 2015; 
Sternberg C. JCO 2016; Saad F. Lancet Oncol. 2015), rPFS of 0.55 is an acceptable measure to 
determine if the combination warrants further clinical development or not.  Furthermore, a 4-month 
improvement in rPFS would indicate that there would be in average 2 staging scans to substantiate 
a radiographic response or progression. 
 
The primary analysis is based on comparing rPFS between the arms (in the overall study 
population, regardless of mutation status):  The final analysis is scheduled when 74 
progressions/deaths are observed, and the suggested futility analysis would happen when 37 
progressions/deaths are observed (half of the total required); at that point, if the control arm is 
doing better than the experimental arm (in terms of rPFS), the study would stop. It is expected that 
we will enroll at least 7 patients per month, based on accrual rate in each participating institution.  
This study will further be open to enrollment, ETCTN-wide 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
3 
0 
5 
8 
Asian 
0 
6 
0 
3 
9 
Native 
Hawaiian 
or 
Other Pacific Islander 
0 
3 
0 
1 
4 
Black 
or 
African 
American 
0 
26 
0 
6 
32 
White 
0 
25 
0 
7 
32 
More Than One Race 
0 
2 
0 
3 
5 
Total 
0 
65 
0 
25 
90 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
110 
 
13.3 
Stratification Factors 
 
None    
 
13.4 
Analysis of Primary and Secondary Endpoints 
 
13.4.1 Primary Analysis: 
 
We will use intension to treat (ITT) analysis for the primary and secondary endpoints.  The 
primary endpoint is radiographic progression free survival (rPFS). Radiographic Progression 
Free Survival (rPFS) is the time interval from random assignment to the date of the first 
occurrence of radiographic disease progression or death, whichever occurs first. See section 
11.1.7 for the definition for this study. The primary analysis will be based on “intent-to-treat.” 
All patients who are enrolled and randomly assigned to treatment will be included in the analysis 
and will be analyzed in the arms to which they were randomized.  
 
For the primary endpoint data analysis, i.e., rPFS, the two study arms will be compared for rPFS 
survival with Kaplan-Meier estimates and log-rank tests. The Rothman confidence interval (CI), 
which is based on Greenwood’s variance, Thomas and Grunkemeier CI, and the simultaneous 
confidence bands by Nair and Hall and Wellner, will be reported. In addition, the possible  
confounding variables will be compared for survival with log-rank test.  
 
13.4.2 Secondary Analyses 
 
The primary objective of the secondary analysis is for hypothesis generating instead of hypothesis 
testing.  No formal power analysis and sample size estimation was conducted. 
 
Overall Survival (OS) 
OS is defined at the time between randomization and death due to any cause (or last contact for 
surviving patients and those lost to follow-up). We will use the rank preserving structure failure 
time model for the OS analysis. 
 
Objective Response Rate (ORR) 
ORR will be based a subset of patients with RECISTv1.1- measurable disease. The exact 95% 
confidence interval of ORR will be reported based on the binomial distribution. The multivariate 
data analysis will be completed using the logistic regression model. The adjusted p-value and 
adjusted 95% confidence interval will also be reported.    
 
PSA Response Rate 
PSA response will be defined by PSA decline from baseline > 50%, confirmed by a second value 
at 3-4 weeks later.  PSA response rate analysis will be based on a subset of patients who had PSA 
progression prior to enrollment. The similar data analysis plan, as described for ORR, will be 
applied to PSA Response Rate.  
 
Analysis Plan for Safety Data: 

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Safety will be measured by the risk of adverse events per NCI CTCAE v4.0 until March 31, 2018 
and per CTCAE v5.0 beginning April 1, 2018.  All subjects who received at least a dose of study 
medications will be included for safety analysis. Descriptive statistics, including means, standard 
deviations, and ranges for continuous parameters, as well as percentages and frequencies for 
categorical parameters, will be presented.  Adverse medical events will be tabulated.  NCI toxicity 
Grade 3 and Grade 4 laboratory abnormalities will be listed and tabled.   
 
BROCA-HR  
A secondary objective is to evaluate association of homologous recombination DNA repair 
deficiency (HRD) with the clinical activity of the combination of cediranib and olaparib or olaparib 
monotherapy, as measured by rPFS, in mCRPC patients.  HRD positive status is defined by 
presence of homozygous deletion or deleterious mutations inkey homologous recombination genes 
of DNA repair genes as analyzed by BROCA-HR test. We estimate the frequency of the positive 
biomarker (HRD positive) would be approximately 25% (Prichard CC et al. NEJM 2016; 
Robinson et al. Cell 2015; Mateo J et al. NEJM 2015).  
 
The data analysis will be completed using log rank Test. The multivariate data analysis will be 
completed using the Cox PH model. 
 
Whole Exome Sequencing and Transcriptome Sequencing  
A secondary objective is to characterize genomic alterations by whole exome sequencing and 
transcriptome sequencing in mCRPC patients. This is an exploratory study and there are multiple 
potential outcomes we would want to derive from this analysis. This includes identification of 
biallelic loss of key DNA repair gene mutations (as determined by integrative mutation and copy 
number data that requires WES analysis), and mutational signatures for HR or NER that may 
impact response to therapy. In addition, we will study copy number variation, small indels, and 
structural variation. The biomarker data, e.g., whole exome sequencing and transcriptome 
sequencing, analysis will be completed using Lasso-based elastic net method. The elastic net 
method is a variable selection procedure by L1 and L2 penalized estimation that enforces variable 
selection and shrinkage simultaneously. The penalty parameter that controls the shrinkage of fixed 
terms and the variable selection will be determined by k-fold cross validation.  Because of the 
limited sample size, the biomarker data analysis is for exploratory research only. The statistical 
analyses will be completed by either R 3.2.1 or SAS 9.4 statistical program in this project.  
 
Plasma Angiome  
An exploratory objective is to identify baseline predictive biomarkers for rPFS or response and to 
identify on-treatment markers of acquired resistance in men with mCRPC receiving either olaparib 
plus cediranib or olaparib alone.  The data analysis will be completed using Lasso-based elastic 
net method. The elastic net method is a variable selection procedure by L1 and L2 penalized 
estimation that enforces variable selection and shrinkage simultaneously. The penalty parameter 
that controls the shrinkage of fixed terms and the variable selection will be determined by k-fold 
cross validation. 
 
13.4.3 Rationale for biopsies 
 
Paired biopsies will be required for all participants. The goal of the paired biopsies is to assess 

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interval changes in the biomarkers that will be critical for understanding the mechanisms of 
response and resistance to the cediranib and olaparib combination, compared with those to 
olaparib monotherapy.  
 
Within the combination arm, we hypothesize that cediranib work in synergy with olaparib by 
downregulating the expression of DNA repair genes, leading to homologous repair (HR) 
deficient state, thus sensitizing the tumor to a PARP inhibition. The whole exome and 
transcriptomes sequencing will be performed in baseline tumor biopsies and on-treatment 
biopsies to see if there is down-regulation of mRNA transcripts in DNA repair genes after 
initiation of cediranib and olaparib combination therapy, and to see if this change correlates with 
response to the therapy. The comparison between the arms will be done by the subgroup analysis 
of their HR biomarker status.  
 
For HR proficient patients (patients without germline or somatic mutations in DNA repair genes, 
determined by BROCA test), we expect to see significant difference in mRNA transcripts in 
DNA repair genes in the combination arm compared with olaparib monotherapy arm. In other 
words, there will be significant decrease seen in the combination arm from pre- vs on-treatment, 
but no significant decrease in the olaparib monotherapy arm. We assumed that 25% of the 
patients will have HR deficient (HRD) mCRPC and 75% HR proficient (HRP) mCRPC. Given 
our total sample size of 84 patients (See Section 13.2), we estimate that there will be 
approximately 63 HRP patients. With 1:1 randomization, we estimate that there will be 
approximately 31 and 32 HRP patients in the combination arm and olaparib monotherapy arm. 
Although there was no formal power analysis and sample size estimation conducted for this 
comparison, with the sample size of 30 per group, it provides at least 80% power to detect an 
odds ratio (OR) of 2.0 with one-sided type I error = 10%. 
 
For HR deficient patients (patients with germline or somatic mutations in DNA repair genes, 
determined by BROCA test), we expect to see no significant difference in mRNA transcript in 
DNA repair genes between the two arms. As above, we assumed that 25% of the patients will have 
HRD and 75% HRP. Given our total sample size of 84 patients (See Section 13.2), we estimate 
that there will be approximately 21 HRD patients. With 1:1 randomization, we estimate that there 
will be approximately 11 and 10 HRD patients in the combination arm and olaparib monotherapy 
arm. This analysis is for hypothesis generating instead of hypothesis testing. 
 
13.4.4 Futility Analysis for Early Stopping  
 
The futility analysis will be based on the method proposed by Wieand et al. (Stat in Med 1994, p 
1453). If after half events (50% of the targeted information) are observed and the observed hazard 
ratio for combination arm vs. single agent arm comparison favor the single agent arm, then the 
study will be closed to accrual. 
 
Wieand’s method is to analyze the data when half the required events have been observed.  At that 
time, if the ratio of the observe event rate of the experimental regimen divided by the observed 
event rate of the standard regimen equals or exceeds 1, we would consider terminating the trial 
and concluding that an advantage for the experimental regimen has not been established. The 
advantages associated with this method including the following: 

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(1) It is “intuitively reasonable”. Most investigators are ready to stop accruing patients to the 
regimen when a study is half over and there is no apparent (experimental) treatment benefit. 
(2) The fact that there is only one early look is not a serious detriment, since early reporting of 
results is generally not as important as early termination of accrual. 
(3) For any alternative satisfying the proportional hazards assumption, the loss of power associated 
with this design is minimal. 
 
13.4.5 Safety Analysis for Biopsies  
 
We will pilot a cohort of the first 6 patients assigned to either treatment arm, to make sure that 
the biopsies are performed safely and that adequate tissues are being obtained for the biomarker 
analysis. To this end, there will be an enrollment hold after the 6th patient gets enrolled. The 
enrollment will be held until the 6th patient undergoes the second biopsy, and is monitored for at 
least one week after the biopsy.  At that point, the overall study principal investigator, 
translational co-principal investigators and the investigators from the participating sites will 
review the biopsies of the first 6 participants to discuss and confirm the safety and feasibility of 
these biopsies, and to obtain approval to continue with enrollment. If participating investigators 
are not available for this discussion, we will email them the relevant information and ask them to 
respond.  
 
Examples of the significant adverse events related to the biopsy include:  
- 
Grade 3 or 4, significant bleeding complication requiring transfusion or hospitalization. 
- 
Grade 3 or 4 wound complication, such as poor healing limiting or delaying initiation of the 
study medication. 
- 
Grade 3 or 4 wound infection/abscess formation requiring hospitalization and IV antibiotics.  
- 
Grade 3 or 4 fistula formation.  
Other grade 3 or 4 adverse events deemed related to the biopsy that compromises the safety of 
the participants. 
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
cediranib/olaparib combination or olaparib monotherapy.   
 
13.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death 
from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 

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All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result 
in exclusion from the analysis of the response rate.  Precise definitions for categories 4-9 
will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Sub-analyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early discontinuation 
of treatment, major protocol violations, etc.).  However, these subanalyses may not serve 
as the basis for drawing conclusions concerning treatment efficacy, and the reasons for 
excluding patients from the analysis should be clearly reported.  The 95% confidence 
intervals should also be provided. 
13.5.3 Evaluation of radiographic progression free survival  
 
The analysis of the primary endpoint, radiographic progression free survival, will be based 
on an intent-to-treat basis. All patients who are enrolled and randomly assigned to 
treatment will be included in the analysis and will be analyzed in the arms to which they 
were randomized, even if there are major protocol treatment deviations or if they are 
ineligible. 
 
The definition of rPFS is provided in 11.1.7. Participants alive without disease progression 
are censored at date of last disease evaluation. The statistical analysis plan is provided in 13.4.1  
13.5.4 Evaluation of clinical activity to the combination therapy among those who have crossed 
over to the combination arm after progressing on olaparib monotherapy.  
 
Patients who cross-over to the cediranib and olaparib combination will be followed per 
the study calendar, section 10. The following data will be collected and assessed.  
o rPFS (cross-over): See section 11.1.12 for definition.  
o PSA response rate (cross-over): See section 11.1.13 for definition. 
o Object response rate (cross-over): See section 11.1.14 for definition. 
 
 
 

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107(28):12629-12633. 
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Pritchard CC, Salipante SJ, Koehler K, Smith C, Scroggins S, Wood B, Wu D, Lee 
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Mutational Analysis Using Massively Parallel Sequencing. J Mol Diagn. 2012; 14(4):357-366. 
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Small EJ, et al. Design and end points of clinical trials for patients with progressive prostate 
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Hussain M, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated 
Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 
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122 
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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123 
APPENDIX B 
NEW YORK HEART ASSOCIATION CLASSIFICATIONS 
 
Clinical Evaluation of Functional Capacity of Patients With Heart Disease in Relation to Ordinary 
Physical Activity 
 
Class 
Cardiac 
Symptoms 
Limitations 
Need 
for 
Additional Rest* 
Physical Ability 
to Work** 
 
 
 
 
 
I 
None 
None 
None 
Full Time 
 
 
 
 
 
II 
Only moderate 
Slight 
Usually 
only 
slight 
or 
occasional 
Usually full time 
 
 
 
 
 
III 
Defined, 
with 
less than ordinary 
activity 
Marked 
Usually 
moderate 
Usually part time 
 
 
 
 
 
IV 
May be present 
even at rest, and 
any 
activity 
increases 
discomfort 
Extreme 
Marked 
Unable to work 
 
*  To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician 
**  At accustomed occupation or usual tasks  
 
 

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124 
APPENDIX C-1 
PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD –  OLAPARIB 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, olaparib (AZD2281).  This clinical trial is sponsored by the National 
Cancer Institute (NCI).  This form is addressed to the patient, but includes important information 
for others who care for this patient.  
 
These are the things that you as a prescriber need to know: 
 
Olaparib interacts with certain specific enzymes in the liver and certain transport proteins that 
help move drugs in and out of cells. 
 
x The enzymes in question are CYP 3A4/5, 1A2, 2B6, 2C9, 2C19 and UGT1A1. Olaparib is 
cleared by CYP3A4/5 and is affected by strong and moderate inhibitors and inducers of 
CYP3A4/5. Olaparib inhibits CYP3A4 and UGT1A1enzymes and may increase levels of 
other drugs that are cleared by these enzymes. Olaparib induces CYP 1A2, 2B6 and 3A4 
enzymes and has the possibility of inducing CYP 2C9, 2C19 enzymes that may result in 
decreased levels of other drugs that are cleared by these enzymes.   
x The transport proteins in question are P-glycoprotein (P-gp), organic anion-transporting 
polypeptides (OATP1B1 and OAT3), organic cation transporters (OCT1 and OCT2), 
multi-drug and toxin extrusion proteins (MATE1 and MATE2K) and breast cancer 
resistance protein (BCRP). Olaparib requires P-gp to move in and out of cells and 
concomitant administration of strong P-gp inhibitors and inducers should be avoided. 
Olaparib inhibits P-gp, BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K 
transporters and has the possibility of inducing P-gp and that may affect the transport of 
other drugs that depend on these proteins to move in and out of cells. Use caution when 
taking substrates of these transporters, such as statins. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
November 2015 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Olaparib may interact with many drugs which can cause side effects. Because of this, it is very 
important to tell your study doctors about all of your medicines before you enroll on this clinical 
trial.  It is also very important to tell them if you stop taking any regular medicines, or if you start 
taking a new medicine while you take part in this study.  When you talk about your medications 
with your doctors, include medicine you buy without a prescription (over-the-counter remedy), 
or any herbal supplements such as St. John’s Wort. It is helpful to bring your medication bottles 
or an updated medication list with you. 
 
Many health care prescribers can write prescriptions.  You must also tell your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  

NCI Protocol #: 9984 
 
Version Date: September 7, 2021 
125 
These are the things that you and they need to know: 
 
Olaparib must be used very carefully with other medicines that need certain liver enzymes and 
transport proteins to be effective or to be cleared from your system.  Before you enroll onto the 
clinical trial, your study doctor will work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong inducers/inhibitors of CYP3A4/5 
and P-gp.” Olaparib inhibits enzymes “CYP3A4, UGT1A1, P-gp, OATP1B1, OCT1, OCT2, 
OAT3, MATE1, MATE2K and BCRP.” Olaparib possibly induces “CYP 1A2, 2B6, 3A4, 2C9, 
2C19 and P-gp.” These characteristics may change how other medicine works in your body. 
 
x Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctor or 
pharmacist to determine if there could be any side effects.  
x Avoid ingesting grapefruit, grapefruit juice and Seville oranges while taking olaparib. 
x You may need to be monitored more frequently if you are taking any drugs that have 
narrow therapeutic ranges. 
x Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is  
__________________________________________                and he or she can be contacted at  
 
________________________________. 
 
 
 
  
November 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD 
You are enrolled on a clinical trial using the experimental drug 
olaparib (AZD2281).  This clinical trial is sponsored by the NCI.  
Olaparib interacts with drugs that are processed by your liver, or use 
certain transport proteins in your body.  Because of this, it is very 
important to: 
¾ Tell your doctors if you stop taking regular medicines or if you start 
taking any new medicines. 
¾ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, pharmacists) that you are taking part in a clinical 
trial. 
¾ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
¾ Olaparib interacts with liver enzymes, CYP3A4/5, 1A2, 2B6, 2C9, 
2C19, UGT1A1, and transport proteins, P-gp, OATP1B1, OCT1, OCT2, 
OAT3, MATE1, MATE2K and BCRP.    
¾ Olaparib must be used very carefully with other medicines that 
interact with these enzymes and proteins.  
¾ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines that are considered ““strong or moderate 
inducers/inhibitors of CYP3A4/5 and P-gp.” Olaparib inhibits “CYP 
3A4, UGT1A1 and transport proteins P-gp, OATP1B1, OCT1, OCT2, 
OAT3, MATE1, MATE2K and BCRP and induces CYP 1A2, 2B6, 3A4, 
2C9, 2C19 and transport protein P-gp.” It may change how other 
medicine works in your body. 
¾ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for 
a list of drugs to avoid, or contact your study doctor.   
¾ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

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126 
APPENDIX C-2 
PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARD – CEDIRANIB  
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, cediranib (AZD2171).  This clinical trial is sponsored by the National 
Cancer Institute (NCI).  This form is addressed to the patient, but includes important information 
for others who care for this patient.  
 
These are the things that you as a prescriber need to know: 
  
Cediranib (AZD2171) interacts with certain specific enzymes in the liver and certain transport 
proteins that help move drugs in and out of cells. 
 
x The enzymes in question are CYP 3A4, 2D6, flavin-containing monooxygenase (FMO) 
and UGT1A4. Cediranib (AZD2171) is metabolized by FMO1, FMO3 and UGT1A4 and 
may be affected by other drugs that strongly inhibit or induce these enzymes.  Cediranib 
(AZD2171) weakly inhibits CYP 2D6 and 3A4 and may increase levels of affected 
substrates.  
x Cediranib (AZD2171) may induce gastrointestinal CYP3A and UGT enzymes, therefore 
potentially reducing the effectiveness of hormonal contraceptives.  
x The transport proteins in question are P-glycoprotein (P-gp) and breast cancer resistance 
protein (BCRP). Cediranib (AZD2171) requires P-gp to move in and out of cells. 
Cediranib (AZD2171) inhibits BCRP, P-gp, OATP1B1, OATP1B3, OCT2, MATE1 and 
MATE2-K and this may affect the clearance of other drugs that are dependent on these 
transport proteins.  
x Cediranib (AZD2171) is 95% protein bound (human serum albumin and alpha-1-acid 
glycoprotein) and may displace other highly protein-bound drugs. Use caution in patients 
taking concomitant medications with narrow therapeutic ranges. 
x Patients receiving Cediranib (AZD2171) are at increased risk of bleeding and hemorrhage. 
Increase monitoring in patients who also receive anticoagulation therapy. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 June 2016 
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
Cediranib (AZD2171) interacts with many drugs which can cause side effects. Because of this, it 
is very important to tell your study doctors about all of your medicines before you enroll on this 
clinical trial.  It is also very important to tell them if you stop taking any regular medicines, or if 
you start taking a new medicine while you take part in this study.  When you talk about your 
medications with your doctors, include medicine you buy without a prescription (over-the-
counter remedy), or any herbal supplements such as St. John’s Wort. It is helpful to bring your 
medication bottles or an updated medication list with you. 
 

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127 
Many health care prescribers can write prescriptions.  You must also tell your health care 
providers (doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a 
clinical trial.  
 
These are the things that you and they need to know: 
 
Cediranib (AZD2171) must be used very carefully with other medicines that need certain liver 
enzymes and transport proteins to be effective or to be cleared from your system.  Before you 
enroll onto the clinical trial, your study doctor will work with your regular health care providers 
to review any medicines and herbal supplements that are considered “strong inducers/inhibitors 
of FMO1, FMO3, UGT1A4 and P-gp.” Cediranib  
 
(AZD2171) inhibits enzymes “CYP 2D6 and 3A4, transport proteins BCRP, P-gp, OATP1B1, 
OATP1B3, OCT2, MATE1 and MATE2-K and is highly protein-bound.” These characteristics 
may change how other medicine works in your body. 
 
x Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctor or 
pharmacist to determine if there could be any side effects.  
x Cediranib (AZD2171) can increase the risk of bleeding and interferes with wound healing. 
Let your doctor know if you recently had or are planning to have any surgery.  
x Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any 
medicine.  Your study doctor’s name is  
__________________________________________                and he or she can be contacted at  
 
_________________________________. 
 
 
 
  
June 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD 
You are enrolled on a clinical trial using the experimental drug 
AZD2171 (cediranib).  This clinical trial is sponsored by the NCI.  
Cediranib (AZD2171) interacts with drugs that are processed by your 
liver, or use certain transport proteins in your body.  Because of this, it 
is very important to: 
¾ Tell your doctors if you stop taking regular medicines or if you start 
taking any new medicines. 
¾ Tell all of your health care providers (doctors, physician assistant, 
nurse practitioners, pharmacists) that you are taking part in a clinical 
trial. 
¾ Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
¾ Cediranib (AZD2171) interacts with CYP3A4, 2D6, FMO1, 
FMO3, UGT1A4 and transport proteins, P-gp and BCRP 
 
and must be used very carefully with other medicines that interact 
with these enzymes and proteins.  
¾ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines that are considered ““strong inducers/inhibitors of 
FMO1, FMO3, UGT1A4 and P-gp.” Cediranib (AZD2171) inhibits 
“CYP 2D6 and 3A4 and transport proteins BCRP, P-gp, 
OATP1B1, OATP1B3, OCT2, MATE1 and MATE2-K and is 
highly protein-bound.” It may change how other medicine works in 
your body. 
¾ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.   
¾ Your study doctor’s name is _____________________________ 
and can be contacted at __________________________________.  

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128 
APPENDIX D 
LIST OF MEDICATIONS PROHIBITED ON STUDY 
 
The investigators must utilize the following frequently updated drug information references.  All 
the patient’s concomitant medications should be recorded and checked for potential drug 
interactions against the investigational agents.  
 
Strong or moderate inhibitors or inducers of CYP3A4/5 are prohibited during the study.  
 
1. 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Drug
InteractionsLabeling/ucm093664.htm#table3-2 
See the examples of clinical inhibitors for P450-mediated metabolism (for concomitant use 
clinical DDI studies and/or drug labeling). The drugs listed under Strong or Moderate 
Inhibitors of CYP3A are prohibited. 
 
Plus, unless indicated in the website, the following medications are considered Strong or 
Moderate inhibitors of CYP3A:  
x Strong CYP3A inhibitors: itraconazole, telithromycin, clarithromycin, protease 
inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, 
boceprevir, telaprevir.  
x Moderate CYP3A inhibitors: ciprofloxacin, erythromycin, diltiazem, 
fluconazole, verapamil.   
A minimum washout period of 2 weeks prior to cycle 1 day 1 is required for strong 
inhibitors, and at least one week for moderate inhibitors.  
 
2. 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Drug
InteractionsLabeling/ucm093664.htm#table3-3 
See the examples of clinical inducers for P450-mediated metabolism (for concomitant use 
clinical DDI studies and/or drug labeling).  The drugs listed under Strong or Moderate 
Inducers of CYP3A are prohibited 
 
Plus, unless indicated in the website, the following medications are considered Strong or 
Moderate inducers of CYP3A:  
x Strong CYP3A inducers: phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s 
Wort  
x Moderate CYP3A inducers: bosentan, efavirenz, modafinil. 
A minimum washout period of 4 weeks prior to cycle 1 day 1 is required for CYP3A 
inducers. A minimum washout period of 5 weeks prior to cycle 1 day 1 is required for 
enzalutamide or phenobarbital.  Dihydropyridine calcium-channel blockers are 
permitted for management of hypertension.  
 
 

 
 
126 
 
APPENDIX E 
PILL DIARY FOR OLAPARIB MONOTHERAPY ARM 
Today’s Date ______________________________ 
Cycle #   _____ 
Patient Name ______________________________ 
Patient Study ID _________________ 
 
1. Complete one form for each cycle (28 days). 
2. Record the date, the number of tablets you took, and when you took them. 
3. Bring your pill bottles (including empty bottles) and this form to every appointment. 
4. Do not chew, dissolve, or crush medications.  
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. Otherwise, do not make up the dose.  
5. If you miss a dose, you have up to 2 hours to make this dose up. Otherwise, write “missed” where you would normally write 
the time of your dose. 
The first row in the table below is an EXAMPLE ROW for how to complete this diary. 
OLAPARIB  
Take _____ (number) ______ mg and _____ (number) _____ 
mg tablets twice a day 12 hours apart after a light meal. You 
should avoid grapefruit juice while on study because grapefruit 
juice affects the metabolism of olaparib. 
NOTE  
Day Date 
100mg 
150mg 
AM 
PM 
 
1 
1/1/15 
0 
2 
7:00 
7:00 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 

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127 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
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Patient’s Signature: _______________________________        Date: ___________________ 
 
Physician/Nurse/Data Manager’s Signature _____________________  Date______________ 

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APPENDIX F 
PILL DIARY FOR CEDIRANIB / OLAPARIB COMBINATION ARM  
Today’s Date ______________________________ 
Cycle # ______ 
Patient Name ______________________________ 
Patient Study ID _________________ 
1. Complete one form for each cycle (28 days). 
2. Record the date, the number of tablets you took, and when you took them. 
3. Bring your pill bottles (including empty bottles) and this form to every appointment. 
4. Do not chew, dissolve, or crush medications. DO NOT make up vomited cediranib doses. 
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. Otherwise, do not make up the olaparib dose. 
5. If you miss a dose, you have up to 2 hours to make this dose up. Otherwise, write “missed” where you would normally 
write the time of your dose. 
The first row in the table below is an EXAMPLE ROW for how to complete this diary. 
CEDIRANIB 
Take ____ (number) _____ mg 
tablets once a day. Take on an 
empty stomach. Olaparib may be 
taken together in the AM. 
OLAPARIB 
Take _____ (number) ______ mg and _____ 
(number) _____ mg tablets twice a day 12 hours 
apart after a light meal. You should avoid grapefruit 
juice while on study because grapefruit juice affects 
the metabolism of olaparib.  
NOTE  
Da
y 
Date 
15mg 20m
g 
AM 
Day 
Date 
100mg 
150mg 
AM 
PM 
 
1 
1/1/15 
2 
0 
7:00 
1 
1/1/15 
2 
0 
7:00 
7:00 
 
 
1 
 
 
 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
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7 
 
 
 
 
 
 

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Patient’s Signature: _______________________________        Date: ___________________ 
Physician/Nurse/Data Manager’s Signature _____________________  Date______________ 
 
 
 

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APPENDIX F-1  
SYMPTOM DIARY FOR CEDIRANIB AND OLAPARIB COMBINATION ARM 
Today’s Date _______________________________ 
 
Cycle # ______ 
Patient Name ______________________________ 
 
Patient Study ID _________________ 
Study doctor’s name is _______________________  
 
The 24-hour number to call is _____________ 
TWO most common side effects of cediranib and olaparib combination treatment are elevated blood pressure and diarrhea. In 
order to effectively manage your side effects, please watch for these side effects and complete this diary as below.   
1. You must monitor and record your blood pressure at least twice a day.  CALL your study doctor when your blood pressure 
is greater than or equal to 140/90.  If so, you will need to take medication(s) to lower your blood pressure to below 140/90.  
2. Diarrhea is bowel movements occurring more often than normal, or bowel movements that are soft, loose, or watery.  
3. When you begin to have diarrhea, CALL your study doctor and TAKE loperamide (Imodium®) 2mg with every bowel 
movement until diarrhea stops, or 4mg initially if your diarrhea is more than 4 times than usual, and 2mg thereafter, with every 
bowel movement, until diarrhea stops. You are advised to start “BRAT” diet, made up of banana, rice, applesauce and toast, 
or the like). You will be given a patient information handout on diarrhea. https://www.cancer.gov/publications/patient-
education/diarrhea.pdf.  
4. If your diarrhea does not improve after 24 hours of loperamide and BRAT diet, or if you develop any associated symptoms, 
CALL your study doctor team again! 
 
 
Your 
GOAL 
blood 
pressure is <140/90 
 
Blood 
Pressures 
medications 
Write down your usual frequency of bowel 
movement before you begin this treatment:  
______time(s) a day.  
Any associated symptoms: feeling dizzy, 
fever Temperature > 100.5O, belly pain, 
blood in stool, or sore in rectal area?  
Other 
notable 
findings.   
Day  Date 
Morning BP  Evening BP 
Number of 
bowel movement 
Associated 
Symptoms?  
 
1 
02/01/2017 
  120   /   62 
112 / 60 
e.g.) Lisinopril 
40mg 
Atenolol 100mg 
Call if you begin 
to develop 
diarrhea  
Call if you develop any 
associated symptoms 
 
1 
 
         / 
       / 
 
 
 
 
2 
 
         / 
       / 
 
 
 
 

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Patient’s Signature: _______________________________        Date: ___________________ 
 
Physician/Nurse/Data Manager’s Signature _____________________   Date______________ 
 
 
 

 
 
134 
 
APPENDIX G 
SUGGESTED ORAL ANTI-HYPERTENSIVE MEDICATIONS 
Agents in bold characters are suggested as optimal choices to avoid or minimize 
potential drug-interactions with cediranib through CYP450. Agent classes are listed in 
order of preference in the absence of any other compelling indication, such as impaired 
renal function, proteinuria, etc. It is suggested that each agent’s dosing should be 
maximized before being replaced or adding another agent class. Additional agent may 
be used prior to the maximal dose of the current agent if clinically deemed necessary. 
 
Agent 
class 
 
Agent 
Initial 
dose 
Intermediat
e dose 
Maximum 
dose 
Hepatic 
metabolism 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
 
captopril 
12.5 mg 3x 
daily 
25 mg 3x 
daily 
50 mg 3x 
daily 
CYP 2D6 
substrate 
enalapril 
5 mg daily 
10-20 mg 
daily 
40 mg daily Yes (CYP450 
unknown) 
ramipril 
2.5 mg 
daily 
5 mg daily 
10 mg daily Yes (CYP450 
unknown) 
lisinopril 
5 mg daily 
10-20 mg 
daily 
40 mg daily 
No 
fosinopril 
10 mg daily 20 mg daily 40 mg daily 
Yes, but not 
CYP450 
Rarely 
used: 
perindopril 
 
4 mg daily 
 
none 
 
8 mg daily 
 
Yes, but not 
CYP450 
Rarely 
used: 
quinapril 
10 mg daily 20 mg daily 40 mg daily 
No 
Angiotensin 
II Receptor 
Blockers 
(ARBs) 
losartan 
25 mg daily 50 mg daily 
100 mg 
daily 
CYP 3A4 and 
2C9 substrate 
candesartan 
4 mg daily 
8-16 mg 
daily 
32 mg daily 
CYP 2C9 
substrate 
irbesartan 
75 mg daily 150 mg daily 
300 mg 
daily 
CYP 2C9 
substrate 
telmisartan 40 mg daily 
none 
80 mg daily 
Yes, but not 
CYP450 
valsartan 
80 mg daily 
none 
160 mg 
daily 
Yes, but not 
CYP450 

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Selective 
E Blockers 
(BB) 
metoprolol 
25 mg 
twice daily 
50 mg 
twice daily 
100 mg 
twice daily 
CYP 2D6 
substrate 
atenolol 
25 mg daily 50 mg daily 
100 mg 
daily 
No 
acebutolol 
100 mg 
twice daily 
200-300 mg 
twice daily 
400 mg 
twice daily 
Yes (CYP450 
unknown) 
bisoprolol 
2.5 mg 
daily 
5-10 mg 
daily 
20 mg daily 
CYP 3A4 
substrate 
D and E 
Blocker 
labetalol 
100 mg 
twice daily 
200 mg 
twice daily 
400 mg 
twice daily 
Yes, but not 
CYP450 
Diuretics 
Hydralazine 10 mg four 
times daily 
25 mg four 
times daily 
50 mg four 
times daily 
no 
Hydrochlor
othiazide 
12.5 mg 
AM daily 
25 mg AM 
daily 
50 mg AM 
daily 
no 
Furosemide  20 mg daily 20 mg twice 
daily 
40 mg twice 
daily 
no 
Nitrates 
Isosorbide 
dinitrate ER 
40 mg daily 40 mg twice 
daily 
80 mg twice 
daily 
CYP 3A4 
substrate 
Isosorbide 
mononitrate 
ER 
30 mg AM 
daily 
60 mg AM 
daily 
90 mg AM 
daily 
CYP 3A4 
substrate 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine 
XL 
30 mg daily 60 mg daily 90 mg daily 
CYP 3A4 
substrate 
amlodipine 
2.5 mg 
daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate 
felodipine 
2.5 mg 
daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate  
 
 
 

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APPENDIX H RISK-BASED APPROACH FOR PATIENT MONITORING AND 
PROTOCOL DRIVEN MANAGEMENT  
 
 

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APPENDIX I STANDARD OPERATING PROCEDURE FOR COLLECTION AND 
PROCESSING OF BIOPSY TISSUE  
 
1. 
TISSUE PROCESSING  
 
Tissue Laboratory Flow: 
 
 
 
 
 
 
 
 
 
 
 
The tissue/tumor collections will occur via an image-guided (CT scan or US-
guided) needle biopsy of a soft tissue or bone lesion. Biopsy of soft tissue is 
preferred when possible. Blood samples will be drawn within 2 weeks of the 
biopsy to document an acceptable coagulation profile (INR ≤ 1.5, PTT ≤ 60, 
platelets > 50,000) as per institutional standard procedures. Heparin, low 
molecular weight heparin, aspirin, and other anti-platelet agents should be 
discontinued as per institutional standard procedures.   
 
The baseline biopsy will be performed after registration/randomization, and within 
a maximum of 1 week, prior to the start of the protocol therapy (i.e., cycle 1 day 1). 
The protocol therapy should begin within 7 days after the biopsy unless any 
concern by the treating investigator, in which case, it must be discussed with the 
overall Study PI, prior to starting the therapy.  
 
Participating SIte's 
Laboratory: 
- Fresh BIOPSY SAMPES
- Blood Germline 
BROCA -HR
Department of Pathology 
at Dana-Farber Cancer 
Institute 
1. University of 
Washington
-Tumor BROCA-HR 
- Blood Germline 
BROCA
2. The Broad Institute
-WES
-WTS
Central Pathology 
Processing 
Final Destination 
HRD = Homologous recombination deficiency, WES=Whole exome sequencing, 
WTS=Whole transcriptome Sequencing, TILs=Tumor infiltrating lymphocytes, 
QIF=Quantitative Immunofluorescence.  

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139 
On-treatment biopsy will be done during the 4th week of the protocol therapy. 
While no stoppage of the study drug(s) is required for any needle biopsy, if any 
safety concern based on clinical factors the study drugs may be held pre and post 
biopsy, at the discretion of the treating investigator after discussing with the overall 
Study PI.   
 
Post-progression biopsy is optional.  Patients progressing on cediranib/olaparib 
may undergo a progression biopsy within 4 weeks from the last dose of the study 
treatment or prior to the starting the subsequent therapy, whichever comes first. 
  
 
Soft Tissue Biopsies: 
Soft tissue biopsies will be performed per institutional standards and/or operator 
preference. Preferred soft tissue biopsy sites include: lymph nodes, peripheral 
based liver lesions, exophytic soft tissue components associated with bone 
lesions, subcutaneous nodules, pleural-based lesions, and kidney lesions. An 18 
gauge or larger is preferred for soft tissue biopsies. Cautionary Note: liver biopsy 
is allowed. Caution should be taken given the risk of post-procedural 
hemorrhage. 
 
Bone Biopsies:  
Bone biopsies will be performed per institutional standards and/or operator 
preference. Bone biopsies should not be performed on irradiated lesions. 
Preferred bone sites include the lumbar vertebrae, pelvic bones and long bones. 
Use of the OnControl® Biopsy System is preferred when safe and appropriate 
(pelvic bones). Given lower yield on bone biopsy special attention should be 
given to the following parameters which may correlate with tumor yield on bone 
biopsy: 
• 
Size  
• 
Degree of sclerosis  
• 
Distance from the skin to the lesion 
• 
Distance from the cortex to the lesion 
• 
Presence of a bone scan correlate  
• 
Area to target for biopsy (center versus periphery of the lesion) 
 
Important:  
For each tissue collection procedure, the intent is to acquire up to 6 needle cores 
for rapid freezing in OCT medium. Size of these biopsy cores can be variable 
(0.1-1.0 cm). While larger cores are preferable to optimize tumor capture, cores 
of any size should be processed. Long cores approximately >2cm can be split.  A 
minimum of 3 cores is preferred. If feasible, the optional progression biopsy 
should be taken from the same tumor lesion as the baseline biopsy. 
 
A. Pre-Biopsy Labeling of Tubes and Cryomolds  
Research staff should communicate with the interventional radiology team in 
advance of the biopsy to ensure that requested specimens are collected 

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according to the laboratory manual. Coordination efforts with the 
interventional radiology and pathology teams will vary depending on the 
institution. It is advised to arrive at the biopsy collection site at least 15 
minutes ahead of the scheduled time to allow sufficient time to set up 
laboratory supplies and ensure rapid transport of specimens to the laboratory 
after collection. 
 
1. Label the metal molds or the plastic Tissue Tek™ standard-size 
cryomolds 1-8. This will identify which biopsy core was taken 1st, 2nd, 3rd, 
and etc.  
2. Using pre-printed or hand-written labels, label plastic tissue cassettes 
(mega sized) with the following information on the front of the cassette 
(see Figure 1): 
x Biopsy date  
x Institution site  
x Patient ID 
x Biopsy core number (refers to the order in which cores were 
collected) 
x Clinical protocol number  
x Pre, 4-week, or post-tx  
 
B. Collection of Biopsies 
This procedure should be performed within 20-30 minutes of biopsy 
collection and tissue out of body. Please complete tissue requisition form 
(Appendix J). Record times using military time (24-h designation), for example 
specify 16:15 to indicate 4:15 PM. Please record the time from biopsy to 
freezing. Please try to stay close to 30 minutes.  Procedures may vary 
depending on the institution. Bone and soft tissue biopsies will be processed 
by the same procedure as detailed below.  
 
1. Place a thin layer of prechilled OCT into a metal mold (or plastic 
cryomold).  
2. Transfer freshly collected needle biopsy with the sterile needle or 
tweezers at one end and place the core on the bottom of the metal mold 
as flat as possible. 
3. Fill a metal mold with a thin layer of prechilled OCT ensuring no air 
bubbles are present near the tissue. 
4. Immediately transfer the mold to the prechilled metal plate on dry ice and 
wait for complete freezing.  
5. Record time of collection and OCT frozen for each pass on the Image-
Guided Needle Biopsy requisition form. 
6. Repeat procedure for each separate biopsy (sequentially from #1 to #5). 
7. After the OCT solidified, cut the edge of the cryomold to fit into the pre-
labeled cassette before storage, if needed. Add a drop or two of OCT to 
cover any tissue exposed to air, and place on metal plate to freeze.Make 
sure to match the # on the mold with the pre-labeled cassette.  

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C. Storing of Biopsy Specimens   
Return to the sample processing laboratory with the specimens, transfer 
cryopreserved biopsy specimens to a -80°C freezer. Complete the tissue 
requisition form and store until shipping. Note any deviations from the 
laboratory manual on the requisition form. Please ship frozen tissue on 
dry ice. 
 
D. Shipping of Biopsy Specimens  
Samples can be shipped within 24 hours of collection, on dry ice by express 
overnight courier. Shipping reservations must be made to allow delivery within 
24hr prior to 2:00 PM next day. Call the receiving laboratory the day prior to 
shipping to confirm plan for receipt. Do not ship on Thursday or Friday (NO 
WEEKEND DELIVERY). Please make sure that blood for germline DNA/RNA 
be shipped with biopsies on dry ice. Lank Center of Genitourinary Oncology 
at Dana-Farber Cancer Institute will receive the “Blood for Germline 
DNA/RNA” and store it at received labeled conditions (i.e refrigeration at 4⁰ 
Celsius, etc) ‘as is’ (package intact and unopened), and will ship this package 
together with tissue nucleic acid to The University of Washington and The 
Broad Institute. 
 
Dana-Farber Cancer Institute 
Lank Center for Genitourinary Oncology 
Attention: Tissue Biopsy for Olaparib/Cedirinib, Dr. Rosina Lis or 
Zhenwei Zhang 
450 Brookline Avenue, DA1230 
Boston, MA 02215 
617-582-8757 
Pager from outside DF/HCC: 617-632-3352 
Pager #: 49274 
 
Please send an e-mail notification 1 week prior to shipment with the delivery 
plan and again on the day of shipment with the tracking information to the 
following: 
Zhenwei Zhang: Zhenwei_Zhang@dfci.harvard.edu  
 
E. Processing of Specimens at Central Laboratory (Lank Center for 
Genitourinary Oncology at Dana-Farber Cancer Institute)  
 
The central pathology processing laboratory will collect, process and prioritize 
specimens for further processing. Once tissue specimens are received to the 
laboratory, each core will be sectioned to generate an H and E slide to assess 
the tumor cellularity of the individual core. This will be documented on the 
Tissue Requisition Form (Appendix J).  
 
The cores with the most tumor cellularity (whether >30% or 10-30%) will be 

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utilized to isolate DNA/RNA. A minimum of 300 ng of DNA will be sent to 
University of Washington for BROCA-HR and HRD score. Additionally 1 
cryovial containing 1mL of whole blood for germline DNA analysis will be sent 
to the University of Washington with isolated nucleic acid. A minimum of 400 
ng of DNA and 400 ng RNA will be sent to The Broad Institute for whole 
exome and transcriptome sequencing. Additionally 1 cryovial containing 1mL 
of whole blood for germline DNA analysis will be sent to The Broad Institute 
with isolated nucleic acid. 
 
Any remaining cores will be stored for future use.  
 
 
Given necessity of ≥10% tumor cellularity of BROCA-HR analysis, cores with 
<10% tumor cellularity will not be processed for BROCA-HD or HRD scores 
and these patients will be counted as unevaluable.  
 
F. Shipping of Specimens from the Lank Center of Genitourinary Oncology 
at Dana-Farber Cancer Institute to Final Destination 
 
University of Washington  
Samples can be shipped in batches once every month on dry ice by express 
overnight courier. Shipping reservations must be made to allow delivery within 
24hr prior to 2:00 PM next day. Call the receiving laboratory the day prior to 
shipping to confirm plan for receipt. Do not ship on Thursday or Friday (NO 
WEEKEND DELIVERY). 
 
Dr. Elizabeth M. Swisher Lab  
University of Washington 
1959 NE Pacific St 
Health Sciences Building K154 
Seattle, Washington 98195-6460 
Phone: 206-616-4296 
Please send an e-mail notification 1 week prior to shipment with the delivery 
plan and again on the day of shipment with the tracking information to the 
following: 
 
swishere@uw.edu 
 
 
2. Procedure for Collection and Processing of Blood Specimens  
 
A. Blood for Germline DNA Collection 
 
Supplies: 
x 21g ¾ inch Safety-Lok Blood Collection set (butterfly needle) with 12 inch tubing  
x EDTA purple-top plasma tube 

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x Cryovials for transfer of samples from EDTA tubes 
x 
Disposable transfer pipettes 
Processing:  
1. Fill the EDTA tube with 5 mL of blood. Gently invert tubes 8-10 times 
immediately.  
2. Place EDTA tube on ice or 4 ⁰C and process IMMEDIATELY. 
3. Transfer 5 mL of blood into cryovials, 1.0 mL per cryovial. Freeze these vials 
immediately in -80 °C. 
 
 
B. Blood for Germline DNA Shipment  
Samples should be shipped with baseline biopsies, on dry ice. Shipping 
reservations must be made to allow delivery within 24hr, prior to 2:00 PM next 
day. Call the receiving laboratory the day prior to shipping to confirm plan for 
receipt. Do not ship on Thursday or Friday. 
 
Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute will 
receive the “Blood for Germline DNA/RNA” and store it at received conditions 
‘as is’ (package intact and unopened), and will ship this package together with 
nucleic acid to The University of Washington and The Broad Institute. 
 
Dana-Farber Cancer Institute 
Lank Center for Genitourinary Oncology 
Attention: Germline DNA/RNA for Olaparib/Cedirinib, Dr. Rosina Lis or 
Zhenwei Zhang 
450 Brookline Avenue, DA1230 
Boston, MA 02215 
617-582-8757 
Pager from outside DF/HCC: 617-632-3352 
Pager #: 49274 
 
Please send an e-mail notification with the shipment tracking information to 
the following: 
Zhenwei Zhang: Zhenwei_Zhang@dfci.harvard.edu  
 
C. Blood for Angiome Collection 
Biomarker assays are time sensitive.  Samples must be processed within one 
hour of collection.  Complete the Blood Requisition Form (Appendix K) and 
insert a copy of with shipment. 
 
Supplies:   
x 10 mL purple/lavender-top EDTA-containing vacutainer tubes (BD Vacutainer, 
Catalog no. 366643)  
x clear 15ml polypropylene tubes 

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x 2ml cryovials  
x Labels designed for low temperatures (e.g., Cryo-Tag brand) 
 
Processing:  
1 Draw blood into one 10ml lavender top (K2EDTA) tube (BD Vacutainer, Catalog no. 
366643)  
2 Invert tubes 10 times to mix blood 
3 Centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge 
manufacturer’s instructions) 
4 Remove plasma from each tube and transfer equally into two separate clean 15ml 
polypropylene tubes 
5 Repeat centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge 
manufacturer’s instructions).  
6 Aliquot approximately 1.0ml of plasma from each tube into each 2.0ml cryovial. A total 
of 5 capped cryovials are needed for EDTA plasma.   
7 Label tubes with the following information (using a Sharpie or Cryopen): 
x Protocol Name  
x Subject Study Number 
x Subject Initials 
x Sample Date and Time 
x Sample Type (EDTA plasma) 
x Cycle # 
 
8 Vials should be frozen at -80oC immediately in an upright position and kept at -
80oC until shipment. 
9 As plasma samples are analyzed in a retrospective manner, samples should be 
stored at the other sites outside Yale and shipped in batches at a later time to be 
agreed with the analyzing laboratory.  
10 Complete the Plasma Biomarker Sample Shipping Form (Angiogenesis and 
Inflammation Markers) (Appendix K) and insert a copy of with shipment. 
 
D. Blood for Angiome Shipment:   
 
Instructions for packing and notifications for shipment follow: 
x Agree to the timing of shipment with receiving laboratory. 
x Use at least 5 kg dry ice for overnight delivery. The amount of dry ice may 
have to be increased if a large number of samples are sent or for a large 
shipping container.  
x Samples should be placed upright in cryoboxes containing inserts.  
x Include a completed Plasma Biomarker Sample Shipping Form for 
Markers of Angiogenesis and Inflammation (see Form 3) itemizing the 

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contents of the shipment. A photocopy should be maintained with study 
records at each site. 
x Place any paperwork in a plastic Ziploc bag.  
x Send an email notification to the receiving lab with tracking number, and 
attach electronic version of completed Biomarker Sample Shipping Form 
to andrew.nixon@duke.edu and the study coordinator (email tbd). 
x All samples must be shipped on dry ice by overnight delivery Monday 
through Wednesday (no holidays in the same week) to the following 
address: 
 
Phase I Biomarker Laboratory 
Dr. Andrew Nixon 
Duke University Medical Center 
395 MSRB, Research Drive 
Durham, NC 27710 
Phone: (919) 681-2239 
Email: andrew.nixon@duke.edu 
 
 
 
 
 

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APPENDIX J 
TISSUE REQUSITION FORM 
 
 
A Randomized Phase II Trial of Olaparib and Cediranib versus Olaparib in men 
with Metastatic Castration Resistant Prostate Cancer  
 
 
Date:  
 
Protocol Number:  
Site Contact Name: 
 
Phone Number: 
 
Fax Number: 
 
Email Address: 
 
Institution: 
 
Site PI Name: 
 
Patient ID: 
 
Imaging-Guided Biopsy 
Date of Collection: 
 
Collection: 
□ Pre-treatment                □ On-treatment                   □ Off-treatment        
Site of Collection: □ Bone                              □ Liver                                □ Lymph Node     
□ Other (specify)            
Tissue Specimen Information  
Please complete for up to 6 cores. 
 
Specimen #1: 
 
Specimen #2: 
 
Time of Collection:  
(HH:MM) 
Time of Collection:   
Time of OCT Frozen: 
 
Time of OCT Frozen:  
Length of core: 
 
Length of core: 
 
Specimen #3: 
 
Specimen #4: 
 
Time of Collection:  
 
Time of Collection:   
Time of OCT Frozen: 
 
Time of OCT Frozen:  
Length of core: 
 
Length of core: 
 
Specimen #5: 
 
Specimen #6: 
 
Time of Collection:  
 
Time of Collection:   
Time of OCT Frozen: 
 
Time of OCT Frozen:  
Length of core: 
 
Length of core: 
 
Time transferred to -80: 
 
 
Comments/Deviations from Laboratory Manual: 
 
 
 
 
 
 
 
 
 
 

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APPENDIX K  BLOOD REQUISITION FORM 
 
A Randomized Phase II Trial of Olaparib and Cediranib versus Olaparib in men 
with Metastatic Castration Resistant Prostate Cancer 
 
Date:  
 
Protocol Number: 
 
Site Contact Name: 
 
Phone Number: 
 
Fax Number: 
 
Email Address: 
 
Institution: 
 
Site PI Name: 
 
Patient ID: 
 
Date of Collection: 
 
Time of Collection: 
(HH:MM) 
Whole Blood for Germline DNA/RNA □ 
Whole Blood: Specimen ID: 
# of Vials: 
 Time Frozen:  
(HH:MM) 
Blood for Angiome □ 
Blood Specimen ID: 
 # of Vials: 
Time Frozen:  
(HH:MM) 
Comments/Deviations from Laboratory Manual: 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
148 
 
APPENDIX L  RESEARCH LAB DATA TABLE 
 
 
 
Day-6 
to 0  
 
C1  
Day 1 
C 1  
Week 4 
Day 1 
Subseq
. cycles  
Off-
Treatme
nt Visit 
Shipping 
Frequency/Type 
Shipping 
Destination 
Tissue Specimens 
Metastatic 
Biopsy 
X1 
 
X1 
 
X1 
Same-Day, 24-hour Ship, 
Dry Ice (-80°)  
Lank Center for GU 
Oncology at DFCI (→  
University of 
Washington, The Broad 
Institute) 
Blood Specimens 
Germline 
DNA 
X 
 
 
 
 
Same-Day, 24-hour Ship,  
Dry Ice (-80°),  
with Biopsy Sample 
Lank Center for GU 
Oncology at DFCI (→  
University of 
Washington, The Broad 
Institute) 
Angiome 
 
X2 
 
X 
X 
 
Duke University  
 
1: Biopsy tissue prioritization: (in the order of importance)  
a. BROCA-HR panel (UW)  
b. WES & WTS (Broad) 
 
2: baseline; to be collected before taking the first dose of study drugs.