A Phase 2 Study of Cediranib in Combination With Olaparib in Advanced Solid Tumors
Phase: PHASE2
Conditions: Advanced Malignant Solid Neoplasm, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Lung Small Cell Carcinoma, Metastatic Pancreatic Adenocarcinoma, Metastatic Triple-Negative Breast Carcinoma, Pancreatic Ductal Adenocarcinoma, Stage III Breast Cancer AJCC v7, Stage III Lung Non-Small Cell Cancer AJCC v7, Stage III Lung Small Cell Carcinoma AJCC v7, Stage III Pancreatic Cancer AJCC v6 and v7, Stage IIIA Breast Cancer AJCC v7, Stage IIIA Lung Non-Small Cell Cancer AJCC v7, Stage IIIA Lung Small Cell Carcinoma AJCC v7, Stage IIIB Breast Cancer AJCC v7, Stage IIIB Lung Non-Small Cell Cancer AJCC v7, Stage IIIB Lung Small Cell Carcinoma AJCC v7, Stage IIIC Breast Cancer AJCC v7, Stage IV Breast Cancer AJCC v6 and v7, Stage IV Lung Non-Small Cell Cancer AJCC v7, Stage IV Lung Small Cell Carcinoma AJCC v7, Stage IV Pancreatic Cancer AJCC v6 and v7, Triple-Negative Breast Carcinoma, Unresectable Lung Small Cell Carcinoma, Unresectable Pancreatic Adenocarcinoma, Unresectable Pancreatic Carcinoma, Unresectable Triple-Negative Breast Carcinoma
Sponsor: National Cancer Institute (NCI)

Page i 
Summary of Changes - Protocol 
NCI Protocol #: 9881 
Local Protocol #: 1604017576 
Protocol Version Date: September 7, 2021 
Informed Consent Version Date: September 7, 2021 
 
Protocol Title:  
NCI# 9881: A Phase 2 Study of Cediranib in Combination with Olaparib in Advanced Solid 
Tumors. 
 
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 69 
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 
 
 

Page ii 
x 
Modified Specific Protocol Exceptions to Expedited Reporting (SPEER) 
reporting requirements:  
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. 
TOC 
Table of Contents updated.  
 

NCI Protocol #:9881 
Version Date: September 7, 2021 
 
1 
NCI Protocol #: 
9881 
 
Local Protocol #: 
1604017576 
 
ClinicalTrials.gov Identifier:  NCT02498613 
 
TITLE:  A Phase 2 Study of Cediranib in Combination with Olaparib in Advanced Solid 
Tumors 
 
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 
Administrative Assistant:  Michele Messina: 203-737-6980 
 
Participating Organizations  
 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-NCI / National Cancer Institute 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 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
 
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 
 
 

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Vanderbilt University Medical Center 
2220 Pierce Ave. 
571 Preston Building 
Nashville, TN 37232-6848 
615-936-2572 
 
Translational Co-Principal Investigator: 
J. Paul Eder, MD 
Yale Cancer Center 
333 Cedar Street 
WWW 211, PO Box 208028 
New Haven, CT 06520-8028 
joseph.eder@yale.edu 
Office: 203-737-1906 
Imaging Co-Principal Investigator  
Ming-Kai Chen, MD, PhD 
Department of Radiology and Biomedical 
Imaging  
Yale University School of Medicine 
789 Howard Avenue  
New Haven, CT  06520 
ming-kai.chen@yale.edu 
Office: 203-737-3505 
 
Study Coordinator:  
Nora Autuori 
Yale Cancer Center 
333 Cedar Street | WWW218-A 
New Haven, CT 06520-8028 
Office: (203)737-1694 
Mobile: (203)361-4423  
Fax: (203)785-4116 
Email: nora.autuori@yale.edu 
Responsible Program Manager 
 
Nora Autuori 
Yale Cancer Center 
333 Cedar Street | WWW218-A 
New Haven, CT 06520-8028 
Office: (203)737-1694 
Mobile: (203)361-4423  
Fax: (203)785-4116 
Email: nora.autuori@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 / May 29, 2015 
 
 
 
 
Revision / Version 2 / October 09, 2015 
 
 
 
 
Revision / Version 3 / December 2, 2015 
 
 
 
 
Amendment / Version 1 / April 8, 2016 
 
 
 
 
Amendment / Version 2 / November 14, 2016 
 
 
 
 
Amendment / Version 3 / January 6, 2017 
 
 
 
 
Amendment / Version 4 / March 13, 2017 
 
 
 
 
Amendment / Version 5 / June 5, 2017 
 
 
 
 
Amendment / Version 6 / September 28, 2017 
 
 
 
 
Amendment / Version 7 / March 26, 2018 
 
 
 
 
Amendment / Version 8 / May 16, 2018 
 
 
 
 
Amendment / Version 9 / August 2, 2018 

NCI Protocol #:9881 
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Amendment / Version 10 / January 7, 2019 
 
 
 
 
Amendment / Version 11 / April 10, 2019 
 
 
 
 
Amendment / Version 12 / May 28, 2019 
 
 
 
 
Amendment / Version 13 / February 23, 2021 
 
 
 
 
Amendment / Version 14 / September 7, 2021 

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SCHEMA 
 
This is an open-label, multi-disease cohort, phase II study of cediranib plus olaparib for patients 
with advanced solid tumors. The study has a Simon 2-stage design to assess anti-tumor activity of 
the combination therapy in each of the disease cohorts running in parallel. These cohorts include:  
 
(a) Non-small cell lung cancer (NSCLC) 
(b) triple-negative breast cancer (TNBC)  
(c) pancreatic ductal adenocarcinoma (PDAC) and  
(d) small cell lung carcinoma (SCLC).   
 
The primary endpoint is the objective response rate in each of the cohorts, as defined by RECIST 
version 1.1.  The secondary endpoints are safety and tolerability and progression free survival in 
each of these cohorts.  
 
As shown in the Figure 1 below, patients in each cohort will be treated with cediranib 
monotherapy followed by the combinatorial therapy. During the cediranib monotherapy lead-in, 
several correlative studies will be performed, including FMISO-PET/CT scans, a tumor biopsy, 
serum angiogenesis markers and plasma circulating tumor DNA (ctDNA). Additional serum 
angiogenesis markers and plasma ctDNA will be collected throughout the study. 
 
FMISO-PET/CT will be performed in 6 evaluable patients with NSCLC at minimum. FMISO-
PET/CT scans are not required for other disease cohorts.   
  
 
One baseline tumor biopsy is required for all study patients for a BROCA test. This biopsy may 
be waived if a patient has a tumor biopsy sample collected within the past 3 months and has not 
received any systemic anti-cancer therapy in the interim.  
 
Serum angiogenesis markers and plasma ctDNA will be required in all patients.  
 
 

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Figure 1. Study Schema 
 
 

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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................4 
1. 
OBJECTIVES ......................................................................................................................9 
1.1 
Primary Objectives...................................................................................................9 
1.2 
Secondary Objectives...............................................................................................9 
1.3 
Exploratory Objectives ............................................................................................9 
2. 
BACKGROUND .................................................................................................................9 
2.1 
Study Diseases .........................................................................................................9 
2.2 
CTEP IND Agents .................................................................................................12 
2.3 
Rationale ................................................................................................................29 
2.4 
Correlative Studies Background ............................................................................32 
3. 
PATIENT SELECTION ....................................................................................................38 
3.1 
Eligibility Criteria ..................................................................................................38 
3.2 
Exclusion Criteria ..................................................................................................40 
3.3 
Inclusion of Women and Minorities ......................................................................43 
4. 
REGISTRATION PROCEDURES ...................................................................................43 
4.1 
Investigator and Research Associate Registration with CTEP ..............................43 
4.2 
Site Registration .....................................................................................................44 
4.3 
Patient Registration ................................................................................................47 
4.4 
General Guidelines.................................................................................................48 
5. 
TREATMENT AND/OR IMAGING PLAN .....................................................................48 
5.1 
Agent Administration.............................................................................................48 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................51 
5.3 
Duration of Therapy ...............................................................................................52 
5.4 
Duration of Follow Up ...........................................................................................53 
5.5 
Criteria for Removal from Study ...........................................................................53 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................53 
6.1 
Cediranib and Olaparib Dose Modification Tables ...............................................54 
6.2 
General Management of Adverse Events ..............................................................54 
6.3 
Hypertension ..........................................................................................................57 
6.4 
Proteinuria ..............................................................................................................60 
6.5 
Decrease in LVEF ..................................................................................................61 
6.6 
Diarrhea..................................................................................................................62 
6.7 
Fever and Neutropenia ...........................................................................................62 
6.8 
Nausea and Vomiting .............................................................................................63 
6.9 
Thyroid Toxicities ..................................................................................................63 
6.10 
Gastrointestinal Perforation ...................................................................................63 
6.11 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) ............................64 
6.12 
Rotator Cuff injury .................................................................................................64 

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7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................65 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................65 
7.2 
Adverse Event Characteristics ...............................................................................73 
7.3 
Expedited Adverse Event Reporting ......................................................................74 
7.4 
Routine Adverse Event Reporting .........................................................................75 
7.5 
Secondary Malignancy...........................................................................................76 
7.6 
Second Malignancy ................................................................................................76 
7.7 
Pregnancy ...............................................................................................................76 
7.8 
Pregnancy loss .......................................................................................................77 
7.9 
Neonatal death .......................................................................................................77 
8. 
PHARMACEUTICAL and IMAGING AGENT INFORMATION..................................77 
8.1 
CTEP and CIP IND Agents ...................................................................................77 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................89 
9.1 
Hypoxia Imaging Study (Required from 6 evaluable participants in the 
NSCLC cohort and optional for the other participants) .........................................89 
9.2 
Integral Correlative Study ......................................................................................91 
9.3 
Integrated Correlative Studies................................................................................91 
9.4 
Exploratory/Ancillary Correlative Studies ............................................................92 
10. 
STUDY CALENDAR .......................................................................................................96 
11. 
MEASUREMENT OF EFFECT........................................................................................99 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................99 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ...........................................................................................................105 
12.1 
Study Oversight ...................................................................................................106 
12.2 
Data Reporting .....................................................................................................106 
12.3 
CTEP Multicenter Guidelines ..............................................................................108 
12.4 
Collaborative Agreements Language ...................................................................108 
12.5 
Safety Monitoring ................................................................................................110 
12.6 
Data Safety Monitoring Plan ...............................................................................110 
13. 
STATISTICAL CONSIDERATIONS.............................................................................110 
13.1 
Study Design/Endpoints.......................................................................................110 
13.2 
Sample Size/Accrual Rate....................................................................................112 
13.3 
Stratification Factors ............................................................................................113 
13.4 
Analysis of Study Endpoints ................................................................................113 
13.5 
Reporting and Exclusions ....................................................................................114 
REFERENCES ............................................................................................................................114 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................124 
APPENDIX B:  NEW YORK HEART ASSOCIATION CLASSIFICATIONS ........................125 

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APPENDIX C LIST OF MEDICATIONS PROHIBITED ON STUDY ....................................126 
APPENDIX D  PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD ......127 
APPENDIX E: PILL DIARIES and Blood Pressure MONITORING for Cycle 1 .....................131 
APPENDIX F:    PILL DIARIES and Blood Pressure MONITORING for Cycle2 and After ...133 
APPENDIX G: Oral Antihypertensive Medications ...................................................................135 
APPENDIX H: Lab Manual ........................................................................................................137 
 
 

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1. OBJECTIVES 
1.1 
Primary Objectives 
1.1.1 To determine the objective response rate (ORR) of cediranib plus olaparib in combination 
in patients with advanced or metastatic solid tumors of the following tumor types: non-
small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), pancreatic ductal 
adenocarcinoma (PDAC), and small cell lung cancer (SCLC). The responses will be 
assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 
 
1.2 
Secondary Objectives 
1.2.1 To assess the safety and tolerability of oral administration of cediranib in combination with 
olaparib in patients with select advanced solid tumors.  
1.2.2 To estimate progression free survival (PFS) in each tumor cohort 
 
1.3 
Exploratory Objectives 
1.3.1 To estimate the prevalence of the mutations of DNA repair genes in tumors using the 
BROCA panel and to correlate tumor regression with mutations status (Integrated) 
1.3.2 To evaluate changes in tumor hypoxia on cediranib treatment compared to baseline by 
[F-18] fluoromisonidazole (FMISO) PET/CT in patients with NSCLC.  
1.3.3 To evaluate levels of angiogenesis/ inflammatory markers including VEGF at baseline 
and on treatment  
1.3.4 To evaluate levels of ctDNA at baseline and on treatment. 
 
 
 
2. BACKGROUND 
2.1 
Study Diseases  
Malignancies of lung, breast, prostate and pancreas are among the top 4 lethal cancers in 
the U.S., accounting for 50% of all cancer-related death in men and 48% in women. Despite 
recent advances in molecularly targeted therapies in lung and breast cancers, the benefits 
of these therapies are limited to a subset of patients whose tumor harbor sensitizing genetic 
aberrations. Treatment options for advanced NSCLC, TNBC, PDAC, and SCLC are 
limited when their disease progresses after first- or second-lines chemotherapies. The 
median overall survivals in these patients are in the range of 4 to 8 months. 
 

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2.1.1 Non-Small Cell Lung Cancer (NSCLC)  
NSCLC is the leading cause of cancer related death in the US [1]. The identification of 
mutations in lung cancer has led to the development of molecularly targeted therapies to 
improve the survival of subsets of patients with metastatic disease [2].The use of 
combination chemotherapy has shown objective responses and small improvement in 
survival patients with metastatic disease [3]. Patients with good performance status and 
symptomatic disease are often treated with the first-line platinum-based doublet 
chemotherapy. Bevacizumab added to paclitaxel and carboplatin, has shown to improve 
median OS (12.3 vs 10.3 mos) [4], and was approved in 2006, for the first-line systemic 
treatment of patients with advanced non-squamous, non-small cell lung cancer. 
 
Patients with NSCLC who have relapsed after front-line platinum-based doublet 
chemotherapy, can be considered for second-line therapies, such as docetaxel, pemetrexed 
and others. The median overall survival for these patients receiving second line 
chemotherapy is about 6-8 months [5-7]. In December 2014, ramucirumab, an IgG1 
monoclonal antibody that targets the extracellular domain of VEGFR-2, was approved by 
the US FDA, based on data from a randomized phase III trial demonstrating a survival 
difference of 1.4 months (10.5 vs 9.1 months in docetaxel plus ramucirumab vs docetaxel 
alone)[8]. 
 

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2.1.2 Triple-negative breast cancer (TNBC)  
Triple-negative breast cancer (TNBC), characterized by the absence or minimal expression 
of estrogen (ER) and progesterone receptors (PR) and human epidermal growth factor 
receptor 2 (HER2), accounts for 15% to 20% of invasive breast cancers diagnosed in the 
United States. It is more common in younger women, African Americans, Hispanics, and 
BRCA1-mutation carriers. With no targetable characteristic molecular mutations yet 
identified, standard treatment for TNBC remains chemotherapy. In early-stage TNBC, 
recurrence-free (RFS) and overall survival (OS) are improved significantly with adjuvant 
chemotherapy, including dose-dense treatment [9], but overall prognosis remains inferior 
to that of other breast cancer subtypes, with higher risk of early relapse, often involving 
viscera.   
 
The 5-year survival of patients with TNBC is less than 30%, and almost all patients will 
die because of the progression of their disease despite adjuvant chemotherapy [10]. Current 
systemic treatment options for metastatic TNBC patients are primarily represented by 
cytotoxic chemotherapy. Although chemotherapy remains the mainstay of treatment for 
metastatic TNBC, there are no standard chemotherapeutic schedules to date.  
 
2.1.3 Pancreatic adenocarcinoma (PDAC)  
Approximately, 48,960 new cases and 40,560 deaths of pancreatic cancer are estimated to 
occur in the United States in 2015 [1]. While it is 6th in rank in terms of incidence, it is the 
4th leading cause of cancer related death in the U.S. The incidence of carcinoma of the 
pancreas has markedly increased over the past several decades and ranks as the fourth 
leading cause of cancer death in the United States. Despite the high mortality rate 
associated with pancreatic cancer, its etiology is poorly understood.  
 
The front-line systemic chemotherapy options for stage IV disease include: gemcitabine-
based therapies[11-13] and 5-FU, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) 
[14]. However, the objective response rates are low, and the median survival for those 
undergoing the modern first line therapies remain less than a year [13, 14]. No standard 
second-line systemic therapy exists. The CONKO-003 trial suggested that a second line 5-
FU, oxaliplatin- based combination chemotherapy after progression on a gemcitabine-
based regimen may be beneficial compared with best supportive care [15].  Median 
survival on second-line chemotherapy was 4.82 months (95% CI, 4.29–5.35) for the OFF-
regimen treatment and 2.30 months (95% CI, 1.76–2.83) with BSC alone (HR = 0.45; 95% 
CI, 0.24–0.83).  
 

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2.1.4 Small cell lung cancer (SCLC)  
SCLC accounts for approximately 15% of bronchogenic carcinomas. Given its high 
tendency to proliferate and disseminate, approximately 70% of patients with SCLC present 
with extensive stage disease (ED), i.e., the disease outside of the hemithorax of origin, the 
mediastinum, or the supraclavicular lymph nodes [16]. While SCLC is more responsive to 
chemotherapy and radiation therapy than other cell types of lung cancer, a cure is 
impossible for extensive stage disease or relapsed disease. Chemotherapy for patients with 
ED-SCLC is commonly given as a two-drug combination of platinum and etoposide in 
doses associated with at least moderate toxic effects (as in limited-stage [LD] SCLC) [17]. 
Doses and schedules used in current programs yield overall response rates of 50% to 80% 
and complete response rates of 0% to 30% in patients with ED [18]. Unfortunately, the 
high initial responses seen with SCLC patients is short-lived, and most patients succumb 
to disease recurrence and progression within the first year after frontline therapy. 
Topotecan is the only agent with regulatory approval for treatment of relapsed SCLC. A 
randomized phase III study of IV topotecan vs CAV (cyclophosphamide, doxorubicin and 
vincristine) for relapsed SCLC showed comparable objective response rates (24.3% vs 
18.3%, p=0.285) and survival, but with more favorable quality of life and symptom control 
with topotecan. The median overall survival for these patients was about 25 weeks [19]. 
 
Another study of oral topotecan versus best supportive care (BSC) in 141 patients with 
relapsed SCLC also showed the benefit of topotecan on survival (13.9 weeks to 25.9 weeks, 
p=0.0104) and improved quality of life and symptom control [20].  
 
 
2.2 
CTEP IND Agents 
 
2.2.1 Cediranib (AZD2171) 
Cediranib (AZD2171) quinazoline maleate; AZD2171 maleate) is an orally (PO) 
administered small molecule vascular endothelial growth factor (VEGF) receptor tyrosine 
kinase (TK) inhibitor with activity against all 3 VEGFRs [21-23]  
 
Mechanism of Action 
VEGF is a key angiogenic factor, and has been implicated in tumor blood vessel formation 
and in disease progression in a range of solid tumor malignancies (Hicklin and Ellis, 2005).  
Two high-affinity VEGF transmembrane receptors (VEGFRs) with associated TK activity 
have been identified on human vascular endothelium, VEGFR-1 (also known as fms-like 
tyrosine kinase 1 or Flt-1) and VEGFR-2 (also known as kinase insert domain-containing 
receptor or KDR) [24].  VEGFR-1 and VEGFR-2 signaling help mediate tumor 
progression.   Cediranib has been developed as a potent inhibitor of VEGFR-1 and 
VEGFR-2 [22].  Cediranib also has activity against VEGFR-3 and c-Kit [23, 25].  
Cediranib is expected, with chronic oral dosing, to inhibit VEGF-driven angiogenesis and 
as a result, prevent the progression and metastasis of solid tumors.   
 
Nonclinical Efficacy 
The effect of cediranib was studied in athymic nu/nu mice bearing established 
subcutaneous human tumor xenografts of diverse histologies [SW620 (colon), PC-3 

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(prostate), Calu-6 (lung), SKOV-3 (ovarian), and MDA-MB-231 (breast)].  Animals were 
administered cediranib PO at doses from 0.75-6 mg/kg/day (2.25-18 mg/m2/day) in a 
constant volume of 0.1 mL/10 g body weight for 24-28 days.  Cediranib produced a 
statistically significant inhibition of tumor growth in all human tumor types examined 
when dosed at 1.5 mg/kg/day (4.5 mg/m2/day) or higher [22]. The broad anti-tumor activity 
of cediranib was confirmed alone and in combination with other anti-cancer agents in a 
wide range of models. Using a transgenic mouse model in which multiple mammary 
tumors spontaneously develop after two pregnancies, the temporal effects of cediranib 
administration was studied [26].  When dosed with cediranib (0.75- 6 mg/kg/day PO) at 
the time early lesions start to develop, the number of tumor foci was not affected, but their 
growth was inhibited.  When tumors were well-established before cediranib was given (at 
doses of 3 and 6 mg/kg/day), dose-dependent growth inhibition occurred as well as tumor 
regression. These data are in line with inhibition of angiogenesis rather than a direct effect 
on tumor cells.  
 
Nonclinical Pharmacology and Toxicology 
Protein binding of cediranib (90-95%) was relatively high across all species examined and 
was independent of concentration (range: 0.03-10 mcg/mL) and gender (Cediranib 
Investigator’s Brochure, 2014).  Cediranib was approximately 95% bound to human 
plasma proteins, with human serum albumin and Į1-acid glycoprotein accounting for most 
of this binding.   
 
VEGF has three major biological activities in endothelial cells of rats and primates of the 
age groups used in the nonclinical studies (Cediranib Investigator’s Brochure, 2014).  It is 
an important angiogenic factor, a potent physiological mediator of vascular tone 
(specifically of vasodilation), and a potent modulator of capillary permeability inducing 
endothelial cell fenestrations.  VEGF receptor inhibition was therefore considered to be the 
cause of many of the pathophysiological changes encountered.  Vascular (myocarditis, 
choroid plexus) and renal (glomerulosclerosis and tubular degeneration) pathologies have 
been seen in rat, dog, and primate dosed with cediranib which are considered to be 
consistent with lesions induced by hypertension, although a direct effect by cediranib on 
these tissues cannot be excluded.  Pathological findings were also seen in the adrenal glands 
(degenerative cortical changes), pancreas (acinar epithelial cell necrosis), thyroid 
(follicular epithelial cell atrophy), liver (hepatocyte necrosis), and biliary system 
(cholangitis and bile duct proliferation and bile duct cholangitis) of the rat.  In addition in 
the primate, changes were seen in the gallbladder (mucosal hypertrophy) and bile duct 
(hyperplasia/hypertrophy). 
 
Cediranib did not induce rat hepatic microsomal P450 activity but caused a 40-60% 
reduction in CYP1A activity at the 5 mg/kg dose level (cediranib Investigator’s Brochure, 
2014).  Inhibition studies in vitro using human hepatic microsomal protein gave IC50 values 
for cediranib against CYP2D6, CYP3A4 testosterone, and CYP3A4 midazolam of 32.9, 
16.2, and 21.4 mcg/mL, respectively.  For CYP1A2, CYP2A6, CYP2C8, CYP2C9, 
CYP2C19, and CYP2E1, the IC50 values were outside the concentration range of cediranib 
examined.  As the clinically relevant plasma concentration of cediranib has not yet been 
determined, any possible effect on compound clearance and drug interaction is currently 

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14 
unknown.  
 
Further details of the nonclinical pharmacology and toxicity of cediranib can be found in 
the cediranib Investigator’s Brochure (2014). 
 
Clinical Pharmacology (cediranib Investigator’s Brochure 2014) 
Following single and multiple oral doses, absorption is extended, with Cmax typically 
attained between 1 and 8 h post-dose. Although absolute bioavailability has not been 
determined, cediranib appears well absorbed with apparently linear PK for single and 
multiple doses ranging from 0.5 to 60 mg. After attaining Cmax, plasma concentrations 
decline in an apparent bi-exponential manner, with a tòȜz of 22.0 6.50 h. 
 
After multiple once-daily oral doses, steady-state plasma concentrations are attained after 
approximately 7 days. There is limited accumulation (3 fold), consistent with the tòȜz 
observed following single doses, and steady-state plasma concentrations are predicted by 
the single-dose PK, indicating no time-dependent changes in PK.  
 
Cediranib binds to human plasma proteins (95.4%), including serum albumin and Į1-acid 
glycoprotein, independent of concentration over the range 0.06 to 22 ȝM (30 to 1000 
ng/mL). 
 
Clearance of cediranib is moderate (CL/F, 28.2 15.1 L/h, mean SD), approximating 64% 
of nominal hepatic plasma flow. In patients administered 45 mg radiolabelled cediranib, 
the majority of the radioactive material recovered was excreted in the faeces (58.8% 26.9) 
and urine (20.8% 7.1) within 7 days. Only a small fraction (<1% of the administered dose) 
of cediranib was excreted unchanged in the urine. 
 
Dose-proportional increases in Css,max and AUCss were observed for cediranib doses 
ranging from 0.5 to 60 mg; however, further PK data are needed to make a definitive 
statement about linearity or dose proportionality. 
 
Data obtained following a single 45-mg dose in the presence and absence of a 
standard high-fat meal, show that food decreases Cmax by 33% and AUC by 24%. 
Cediranib should be administered at least 1 h before or 2 h after food. 
 
Comparison of studies conducted in Japanese patients, with corresponding Western 
study data indicates similar PK between Western and Japanese patients. 
 
Safety Profile 
Hypertension is an expected AE with agents that inhibit VEGF signaling. In cediranib 
studies, increases in blood pressure have been observed and cases of hypertension have 
been reported, including CTC Grade 4 hypertension and end-organ damage related to 
hypertension, such as cerebrovascular events. 
 
Left ventricular dysfunction, in some cases leading to cardiac failure, has been observed in 
patients receiving cediranib with risk factors for left ventricular dysfunction (including 

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previous or concomitant anthracycline treatment). 
 
A number of events of bleeding and hemorrhage have occurred, they were mostly mild and 
the most common type of bleeding was mucocutaneous (epistaxis). However, 
gastrointestinal, central nervous system, pulmonary bleeding and hematuria have also been 
reported. Some reports of hemorrhage were fatal but causality could not be unequivocally 
assigned to cediranib.  
 
Gastrointestinal perforation, sometimes associated with fistula formation, has been 
observed in patients receiving cediranib. Some events of gastrointestinal perforation have 
been fatal but causality could not be unequivocally assigned to cediranib.  
 
Pancreatitis has been infrequently reported in patients receiving cediranib. 
 
Fatigue, hand and foot syndrome, diarrhea, headache, nausea, vomiting, anorexia and 
weight loss are commonly occurring AEs in cediranib studies. Dehydration has been 
observed in clinical studies as a consequence of cediranib-related or chemotherapy-related 
diarrhea, vomiting, anorexia, or reduced oral intake.  
 
Hoarseness (dysphonia) has been reported as common and dose-related. 
 
Muscle weakness, proteinuria, dry mouth and oral mucosal inflammation have been 
observed in cediranib studies. Impaired wound healing, generally low grade has been seen. 
Infections, generally low grade, have been reported. Arterial thromboembolism (including 
cerebrovascular accident, myocardial infarction and infrequent retinal arterial occlusion) 
and venous thromboembolic events (including pulmonary embolism and retinal vein 
occlusion) have been observed in patients receiving cediranib. 
 
Recommended Dose: 
Based on the totality of the safety, tolerability, efficacy, PK, and pharmacodynamic data 
that are currently available from both AZ-sponsored and collaborative group studies with 
cediranib, the following general recommendations regarding cediranib doses in clinical 
studies have been made: 
• Cediranib 30 mg is the recommended dose for monotherapy. 
• Cediranib 20 mg is the recommended dose in combination with chemotherapy agents. 
 
Clinical Experience  
The following summarizes a few key clinical trials of cediranib in the diseases that are 
being studied:  
 
1. NSCLC 
A phase I and pharmacokinetic study of daily oral cediranib in combination with cisplatin 
and gemcitabine in patients with advanced non-small cell lung cancer was led by the 
National Cancer Institute of Canada Clinical Trials Group [27].  Patients received cisplatin 
80 mg/m2 on day 1 and gemcitabine 1250 mg/m2 on days 1 and 8 of a 3-week cycle, and 
daily oral cediranib at either 30 mg or 45 mg.  Fifteen patients were enrolled. No dose-

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limiting toxicities were observed during cycle 1. Fatigue, nausea, diarrhea, anorexia and 
granulocytopenia were common; hypertension was manageable. No grade 3/4 bleeding 
occurred. At 45 mg/d, fatigue, diarrhea and thrombocytopenia were increased; and 
headache, hoarseness and grade 2 hand-foot syndrome were observed. Cediranib had no 
effect on cisplatin elimination, but clearance of gemcitabine is significantly reduced in the 
presence of cediranib (p>0.02). Central review confirmed responses in four of 15 enrolled 
patients (26.7%, 95% CI 7.8-55%) and four of 12 evaluable patients (33.3%, 95% CI 9.9-
65%). It was concluded that cediranib at 30 mg daily could be combined with standard 
doses of cisplatin/gemcitabine with encouraging anti-tumor activity, and was the 
recommended phase III dose.  Toxicity was higher, but was deemed predictable and 
manageable. 
 
The NCIC clinical trials group led another phase I pharmacokinetic study of daily oral 
AZD2171 in combination with carboplatin and paclitaxel in patients with advanced non-
small-cell lung cancer [28]. Patients received carboplatin targeted to an area under the 
concentration time curve of 6 and paclitaxel 200 mg/m2, both on day 1 of a 3-week cycle; 
daily oral AZD2171 at either 30 mg or 45 mg commenced day 2 of cycle 1.  Twenty 
patients were enrolled. No dose-limiting toxicities were observed during cycle 1 at either 
dose. Fatigue, diarrhea, anorexia, and granulocytopenia were common; hypertension was 
manageable with a treatment algorithm designed for this protocol. No clinically significant 
drug-related bleeding was observed. At 45 mg/d, fatigue and diarrhea were increased, and 
headache and hoarseness were observed. Paclitaxel clearance decreased during cycle 2, but 
no other significant pharmacokinetic interactions were observed. After radiology review, 
confirmed responses were observed in nine patients (response rate, 45%; 95% CI, 23% to 
68%); all but one enrolled patient showed evidence of tumor shrinkage, some with 
cavitation. Based on this data, a larger Phase II/III, BR24 study was undertaken. 
 
The BR24 study was a phase II/III double-blind study to assess efficacy and safety of 
cediranib at 30mg with standard chemotherapy as initial therapy for advanced non-small-
cell lung cancer (NSCLC) [29]. Paclitaxel (200 mg/ mg/m2) and carboplatin (area under 
the serum concentration-time curve 6) were given every 3 weeks, with daily oral cediranib 
or placebo at 30 mg (first 45 patients received 45 mg). Progression-free survival (PFS) was 
the primary outcome of the phase II interim analysis. A total of 296 patients were enrolled, 
251 to the 30-mg cohort. The phase II interim analysis demonstrated a significantly higher 
response rate (RR) for cediranib than for placebo, HR of 0.77 for PFS, no excess 
hemoptysis, and a similar number of deaths in each arm.  The study was halted to review 
imbalances in assigned causes of death. Approximately 13% of the deaths in the cediranib 
group was deemed related to protocol toxicity +/- NSCLC vs 0% protocol toxicity related 
death in the placebo.  In the primary phase II analysis (30-mg cohort), the adjusted HR for 
PFS was 0.77 (95% CI, 0.56 to 1.08) with a higher RR for cediranib than for placebo (38% 
v 16%; P < .0001). Cediranib patients had more hypertension, hypothyroidism, hand-foot 
syndrome, and GI toxicity. Hypoalbuminemia, age > or = 65 years, and female sex 
predicted increased toxicity. Survival update (N = 296) 10 months after study unblinding 
favored cediranib over placebo (median of 10.5 months v 10.1 months; HR, 0.78; 95% CI, 
0.57 to 1.06; P = .11).  Subsequently, it led to the BR29 study, randomized, double-blind, 
placebo-controlled trial of cediranib 20 mg with carboplatin and paclitaxel in advanced 

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NSCLC. 
 
The BR29 study was a randomized double-blind placebo-controlled study to evaluate the 
addition of cediranib 20mg to standard carboplatin/paclitaxel chemotherapy in advanced 
non-small cell lung cancer [30]. Eligible patients received paclitaxel (200mg/m2 and 
carboplatin (area under the concentration time curve 6) intravenously every 3 weeks. Daily 
oral cediranib/placebo 20mg was commenced day 1 of cycle 1 and continued as 
monotherapy after completion of 4-6 cycles of chemotherapy. The primary end-point of 
the study was overall survival (OS). The trial would continue to full accrual if an interim 
analysis (IA) for PFS, performed after 170 events of progression or death in the first 260 
randomized patients, revealed a hazard ratio (HR) for PFS of င 0.70.  The trial was halted 
for futility at the IA (HR for PFS 0.89, 95% confidence interval [CI] 0.66-1.20, p = 0.45). 
A final analysis was performed on all 306 enrolled patients. The addition of cediranib 
increased response rate ([RR] 52% versus 34%, p = 0.001) but did not significantly 
improve PFS (HR 0.91, 95% CI 0.71-1.18, p = 0.49) or OS (HR 0.94, 95% CI 0.69-1.30, 
p=0.72). Cediranib patients had more grade 3 hypertension, diarrhea and anorexia. It was 
concluded that the addition of cediranib 20mg daily to carboplatin/paclitaxel chemotherapy 
increased RR and toxicity, but not survival. 
 
The North Central Cancer Treatment Group Study led another randomized phase II study 
of gemcitabine and carboplatin with or without cediranib as first-line therapy in advanced 
non-small-cell lung cancer (N0528) [31]. This study was to assess the safety and efficacy 
of gemcitabine and carboplatin with (arm A) or without (arm B) daily oral cediranib as 
first-line therapy for advanced non-small-cell lung cancer.  A lead-in phase to determine 
the tolerability of gemcitabine 1000 mg/m on days 1 and 8, and carboplatin on day 1 at 
area under curve 5 administered every 21 days with cediranib 45 mg once daily was 
followed by a 2 (A):1 (B) randomized phase II study. The primary end point was confirmed 
overall response rate (ORR) with 6-month PFS (PFS6) rate in arm A as secondary end 
point. On the basis of the safety assessment, cediranib 30 mg daily was used in the phase 
II portion. A total of 58 and 29 evaluable patients were accrued to arms A and B. Patients 
in A experienced more grade 3+ nonhematologic adverse events, 71% versus 45% (p = 
0.01). The ORR was 19% (A) versus 20% (B) (p = 1.0). PFS6 in A was 48% (95% 
confidence interval: 35%-62%), thus meeting the protocol-specified threshold of at least 
40%. The median overall survival was 12.0 versus 9.9 months (p = 0.10).   
 
2. Triple Negative Breast Cancer (TNBC) 
A phase I trial of olaparib plus cediranib enrolled patients with triple negative breast cancer 
or with recurrent epithelial ovarian cancer. Twenty-eight patients (20 ovarian, 8 breast) 
enrolled to 4 dose levels. Two dose limiting toxicities (DLTs) (1 grade 4 neutropenia  4 
days; 1 grade 4 thrombocytopenia) occurred at the highest dose level (cediranib 30 mg 
daily; olaparib 400 mg twice daily [BID]). The RP2D was cediranib 30 mg daily and 
olaparib 200 mg BID. Grade 3 or higher toxicities occurred in 75% of patients, and 
included grade 3 hypertension (25%) and grade 3 fatigue (18%). One grade 3 bowel 
obstruction occurred. The overall response rate (ORR) in the 18 RECIST-evaluable ovarian 
cancer patients was 44%, with a clinical benefit rate (ORR plus stable disease (SD) > 24 
weeks) of 61%. None of the seven evaluable breast cancer patients achieved clinical 

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18 
response; two patients had stable disease for > 24 weeks. 
 
3. PDAC 
Cediranib has not been tested in patients with pancreatic cancer.  
 
4. SCLC 
NCI #7097 was a phase II trial of cediranib (AZD2171) for second-line therapy of small 
cell lung cancer [32]. The dose of cediranib was 45 mg PO once a day for the first 12 
patients and was reduced to 30 mg PO once a day for the subsequent patients because of 
intolerance of the higher dose. Treatment was given on a daily continuous schedule. The 
primary end point was determination of the response rate.  Twenty-five eligible patients 
were enrolled. A median of two cycles were administered. Salient grade 3/4 toxicities were 
fatigue, diarrhea, hypertension, proteinuria, and elevated liver enzymes. Tolerability was 
better with the 30 mg dose once a day. Nine patients had stable disease, but no patient had 
a confirmed PR. The median PFS and OS were 2 and 6 months, respectively. Response 
criteria to proceed to full accrual were not met.  
 
Another study assessed cediranib plus EP as first-line therapy for extensive 
stage/metastatic lung cancer [33]. Pts received up to six 21-day cycles of EP (E 100 mg/m2, 
days 1-3; P 80 mg/m2, day 1) with once-daily cediranib from day 4 of cycle 1 until disease 
progression or toxicity and were eligible for safety review if they completed the first 21 
days of cediranib or had a dose limiting toxicity (DLT). The primary objective was 
assessment of safety and tolerability. At data cut-off, 22 pts had received treatment. 
Recruitment to the 30 mg cohort was stopped at 4 pts (all SCLC) when 20 mg became the 
recommended dose with chemotherapy. As only 1/6 pts in the initial cediranib 20 mg 
cohort experienced a DLT (hemoptysis), this combination was considered suitable for 
cohort expansion. Adverse events (AEs) reported in  50% pts receiving cediranib 20 mg 
+ EP were nausea, vomiting, neutropenia and diarrhea. The incidences of hypertension and 
fatigue were both 39%. Five pts discontinued treatment due to an AE: anemia, duodenal 
ulcer bleeding, increased creatinine and hemoptysis. In a preliminary efficacy assessment 
(RECIST), 10/14 (71%) SCLC pts achieved a partial response (PR) (12/18 [67%] including 
30 mg cohort). In the 20 mg cohort, the mean best change from baseline in tumor size was 
-53.3%. Median PFS was 8 months and 5/8 ongoing pts had a PR. Cediranib 20 mg + EP 
was well tolerated and has shown evidence of activity in SCLC and lung NEC 
 

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19 
2.2.2 Olaparib (AZD2281; LynparzaTM) 
 
Olaparib (AZD2281, KU-0059436) is a potent oral inhibitor of PARP-1 and PARP-2. 
PARP inhibition is a novel approach to targeting tumours that have homologous 
recombination deoxyribonucleic acid (DNA) repair (HRR) pathway deficiencies (HRD). 
In HRD tumours, single agent treatment with olaparib can lead to tumour regression by a 
process known as synthetic lethality- a result of the accumulation of un-repaired DNA 
double-strand breaks (DSBs) and an unsupportable increase in genomic instability.  
 
Olaparib is the first PARP inhibitor approved by regulatory agencies for clinical indication. 
US Food and Drug Administration (FDA) approved its use for a monotherapy in patients 
with deleterious or suspected deleterious germline BRCA mutated, advanced ovarian 
cancer who have been treated with three or more prior lines of chemotherapy. The 
European Medicines Agency approved its use as a 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.  
 
Mechanism of Action 
Preclinically, olaparib displays antitumor activity against a variety of tumor cell lines and 
this sensitivity of the cells is believed to depend upon components of a defective HRR 
capability (Olaparib Investigator’s Brochure, 2014).  As a major example of this selective 
activity, both BRCA1- and 2-deficient (-/-) tumors are sensitive to PARP inhibition.  Early 
studies indicated that PARP inhibition in BRCA1/2 homozygous null cells, but not the 
isogenic BRCA heterozygous cells, led to cell death.  BRCA1 and 2 are proteins necessary 
for proper function of HRR, the high fidelity repair system that addresses DNA double-
strand breaks (DSBs).  The backup repair system to HRR is base-excision repair (BER), 
which requires PARP function and primarily addresses single-strand breaks (SSBs).  
However, the system works both ways in that repair of SSBs in BER can lead to stalled 
replication forks that strain the system and cause double strand breaks, resulting in a 
situation that requires intact HRR and BRCA1 or BRCA2.  Thus, HRR dysfunction 
sensitizes cells to PARP inhibition leading to further chromosomal instability, cell cycle 
arrest and apoptosis [34].  This sensitivity is suggested to result in a large therapeutic 
window for PARP inhibition in mutation carriers.  Pre-clinical studies support these 
findings showing that other BRCA mutant, but not wild-type, human cell lines are highly 
sensitive to olaparib [35]. 
 
Nonclinical Pharmacology and Efficacy 
Olaparib has demonstrated cellular activity in the low nM range with a cellular dose for 
50% inhibition (IC50) of 2 nM in HeLa cells (Olaparib Investigator’s Brochure, 2014).  The 
effective concentration for inhibiting cellular PARP activity in cancer cells by >90% is 
approximately 30 nM to 100 nM olaparib in several tumor cell lines including ovarian 
A2780, breast MCF-7, and colorectal SW620.  These concentrations led to significant 
ablation of PARP activity (based on the inhibition of PAR formation), with maximal 
PARP-1 inhibition occurring at around 100 nM.  Consistent with this, maximal potentiation 
of an appropriate DNA SSB-inducing chemotoxic agent (MMS) was also seen in vitro at 

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100 nM, which equates to 43.4 ng/mL. 
 
Following single oral doses, absorption was rapid (maximum plasma concentration [Cmax] 
<2 hours in mice, rats and dogs) while bioavailability was <60% in male and female mice, 
<20% in male and female rats and ~79% in male dogs (Olaparib Investigator’s Brochure, 
2013).  Low oral bioavailability in rat may have been due to poor absorption or rapid first 
pass metabolism.  Distribution of olaparib is in the gastrointestinal tract and in tissues 
associated with the metabolism and elimination of foreign compounds.  Further 
investigations are still ongoing.  Excretion is primarily via the feces and, to a lesser extent, 
the urine. 
 
Investigations in human in vitro systems indicated metabolism of olaparib was CYP 
mediated and that CYP3A4 and 3A5 were the dominant metabolic enzymes (Olaparib 
Investigator’s Brochure, 2013).  Similar studies indicated flavin mono-oxygenase-3 was 
not able to metabolize olaparib.  In in vitro direct inhibition assays, olaparib (100 ȝM) had 
only limited effect against CYP3A (up to 46% inhibition) and less effect against other 
CYPs tested. In time dependent inhibition assays, olaparib had only very minor effects 
against CYP3A and no effect against other CYPs.  Clinically significant direct inhibition 
of intestinal CYP3A is possible but significant effects against hepatic CYP3A are less 
likely.  The CYP induction potential of olaparib was investigated in cultures of human 
hepatocytes.  At the highest olaparib concentration (30 microM), minor induction of 
CYP2B6 activity was observed (<40% positive control) and smaller effects on CYPs 2C9 
and 2C19 activities were noted.  These changes were unlikely to be of clinical significance.  
A small decrease in CYP3A activity was noted, which may suggest time-dependent 
inhibition, however, this was not explored further. 
 
In studies using Madin-Darby Canine Kidney (MDCK) II cells transfected with multidrug 
resistance 1 (MDR1; Pgp), BCRP or MRP-2 drug efflux transporters, olaparib was shown 
to be a substrate of MDR1 but not BCRP or MRP-2 (Olaparib Investigator’s Brochure, 
2013).  In the same systems, olaparib was an inhibitor of BCRP and MRP-2 but had little 
or no inhibitory effect on MDR1. 
 
In isolated human hepatocytes, olaparib was a substrate for organic anion transport 
proteins.  In the same system, olaparib was shown to be an organic cation transporter 1 
(OCT1) inhibitor (IC50 11.9 ȝM) (Olaparib Investigator’s Brochure, 2013).  In HEK-293 
cells transfected with OATP1B1, olaparib functioned as an inhibitor and IC50 values of 
20.3 microM and 27.1 microM were derived (substrate dependent).  Using the criteria 
defined in the European Medicines Agency (EMA) guidelines on the investigations of drug 
interactions (EMA 2013), it is possible olaparib may precipitate an interaction via hepatic 
drug uptake transporters, particularly OCT1. 
 
SimCYP population PK simulations of the separate effect of co-administration of 
itraconazole and rifampicin (clinically relevant CYP3A inhibitor and inducer, respectively) 
on olaparib PK in humans, when administered at the recommended human dose, were 
performed (Olaparib Investigator’s Brochure, 2013).  The itraconazole (200 mg twice daily 
[BID] x 7 days) simulation indicated olaparib (400 mg bd x 7 days) steady state Cmax and 

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21 
area under the concentration-time curve (AUC) would increase by 2.8 and 3.5 fold, 
respectively. The rifampicin simulation (600 mg x 6 days) indicated olaparib (400 mg BID 
x 6 days) steady state Cmax and AUC in the presence of rifampicin would be reduced to 
33% and 29%, respectively, of the values in the absence of rifampicin. 
 
Nonclinical Toxicology 
Olaparib has been tested in dogs and rats (Olaparib Investigator’s Brochure, 2013).  There 
were no noted effects on the cardiovascular or respiratory parameters of an anesthesized 
dog or any behavioral, autonomic, or motor effects in the rat.  Toxicology studies indicate 
that the target organ of toxicity is the bone marrow.  Ex vivo work has confirmed that 
olaparib is also active against human marrow.  The cytotoxic effect becomes evident at a 
higher concentration than required to fully ablate PARP activity.  28-day dog and rat 
studies demonstrate a reversible myelotoxic effect that is mild to moderate.  Platelets are 
first affected, followed by white blood cells.  In 26-week repeat-dose studies in rats, doses 
were well-tolerated in male rats, with hematological effects and increased spleen weights 
observed at all dosages.  In female rats, doses of 15 mg/kg/day resulted in significant 
reduction in body weight.  Hematological effects and increased spleen weights were again 
observed at all dosages.  The difference between sexes was considered to be due to the fact 
that females had greater plasma exposure levels than males.  In 26-week repeat-dose 
studies in dogs, olaparib was well-tolerated.  Hematological changes were observed, 
characterized by pancytopenia. 
 
Clinical Pharmacology- Single dose Tablet Data (Olaparib Investigator’s Brochure, 
2014) 
 
Following administration of single oral doses of the tablet formulation at doses of 25, 50 
and 250 mg (n=6 per cohort), absorption was rapid and slightly more rapid than seen 
following the capsule dose. The Cmax was typically achieved between 0.5 hours and 2 
hours after dosing. Following the peak, plasma concentrations declined biphasically with 
a terminal t½, across all 3 dose levels, of between 5 hours and 9 hours (average=6.97 
hours1.06 Sd). Both Gmean Cmax and AUC increased approximately proportionally with 
dose (8-fold and 12-fold, respectively, for a 10-fold increase in dose). The mean volume 
of distribution of olaparib was 54.9 L30.1 Sd and the mean plasma clearance was 5.42 
L/h2.60 Sd.  
 
The relative bioavailabilities of the tablet formulation (compared to capsule) at the 3 dose 
levels studied are shown in Table 10. At the 2 lower tablet doses (25 and 50 mg), following 
normalisation for dose, although the Cmax achieved after dosing with the tablet 
formulation tended to be higher than that with the capsule, the AUC values for the 2 
formulations were actually very similar. However, at the highest tablet dose (250 mg), the 
exposure delivered by the tablet formulation (both dose-normalised Cmax and AUC) was 
higher than that delivered by the capsule. The tablet and the capsule formulations cannot 
therefore be considered to be bioequivalent. 
 
Table 1.2.1.3-1.  Systemic Exposure of Olaparib Tablet vs. Capsule Formulations 
Parameter 
25 mg tablet vs. 50 50 mg tablet vs. 100 250 mg tablet vs. 

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22 
mg capsule 
mg capsule 
400 mg capsule 
Cmax ratio 
1.29 
1.53 
2.49 
90% CI 
1.10, 1.52 
1.11, 2.11 
1.87, 3.31 
AUC ratio 
1.03 
0.99 
1.74 
90% CI 
0.85, 1.24 
0.69, 1.42 
1.36, 2.23 
Cmax = maximum plasma concentration, AUC = area under the concentration-time curve, 
CI = confidence interval 
 
Safety Profile: As of 02 October 2013, approximately 2103 patients with ovarian, breast, 
pancreatic, gastric and a variety of other solid tumors are estimated to have received 
treatment with olaparib across the dose range 10 mg od to 600 mg bd in AstraZeneca-
sponsored, investigator-sponsored and collaborative group studies. Olaparib has been 
given as either monotherapy (18 studies, an estimated 1214 patients) or in combination 
with other 
chemotherapy/anti-cancer agents (25 studies, an estimated 889 patients). Many of these 
combinations studies are ongoing. The majority of patients to date have received the 
capsule formulation of olaparib (an estimated 1635 patients). Approximately 468 patients 
have received the tablet formulation to date. Approximately 304 patients have received 
comparator or placebo across the olaparib development program.  
 
Data from these studies indicate that olaparib is generally well tolerated at monotherapy 
doses up to 400 mg bd (capsule formulation) and 300 mg bd (tablet formulation) in patients 
with solid tumours. Administration of olaparib monotherapy has been associated with 
reports of laboratory findings and/or clinical diagnoses of: 
 
寧 
Hematological toxicity: 
ʷ Anemia, generally mild or moderate (CTCAE Grade 1 or 2) 
ʷ Neutropenia, predominantly mild or moderate (CTCAE Grade 1 or 2) 
ʷ Lymphopenia, generally mild or moderate (CTCAE Grade 1 or 2) 
ʷ Thrombocytopenia, generally mild or moderate (CTCAE Grade 1 or 2) 
ʷ Mean corpuscular volume elevation 
ʷ Increase in blood creatinine, generally mild or moderate intensity (CTCAE 
Grade 1 or 2) 
寧 
Nausea and vomiting, generally mild or moderate (CTCAE Grade 1 or 2), intermittent 
and manageable on continued treatment 
寧 
Decreased appetite, generally mild or moderate intensity (CTCAE Grade 1 or 2) 
寧 
Diarrhea, generally mild or moderate intensity (CTCAE Grade 1 or 2) 
寧 
Dyspepsia and upper abdominal pain, generally mild or moderate intensity (CTCAE 
Grade 1 or 2) 
寧 
Stomatitis, generally mild or moderate intensity (CTCAE Grade 1 or 2)  
寧 
Dysgeusia, generally mild or moderate intensity (CTCAE Grade 1 or 2) 

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寧 
Fatigue, (including asthenia), generally mild or moderate intensity (CTCAE Grade 1 
or 2) 
寧 
Headache, generally mild or moderate intensity (CTCAE Grade 1 or 2) 
寧 
Dizziness, generally mild or moderate intensity (CTCAE Grade 1 or 2) 
 
Important potential risks 
MDS/AML have been reported in <1% of patients. The cases were typical of secondary 
MDS/therapy-related AML. The duration of therapy with olaparib in patients who 
developed secondary MDS/AML varied from <6 months to >2 years. All patients had 
potential contributing factors for the development of MDS/AML, having received 
extensive previous chemotherapy with platinum agents. Many had also received other 
DNA damaging agents. 
 
In the ovarian study, one patient who developed MDS had had two prior lines of therapy, 
and had been on combination cediranib/olaparib for ~1 year when she was diagnosed with 
MDS.  
 
Pneumonitis events have been reported in <1% of patients receiving olaparib 
(Investigator’s Brochure 2014. Section 5.2.7.1). The reports of pneumonitis had no 
consistent clinical pattern and were confounded by a number of pre-disposing factors 
(cancer and/or metastases in lungs, underlying pulmonary disease, smoking history, and/or 
previous chemotherapy and radiotherapy). 
 
New primary malignancies have been reported in a small number of patients (Investigator’s 
Brochure 2014 Section 5.2.7.1). There were other contributing factors/potential alternative 
explanations for the development of the new primary  
malignancy in all cases.  
 
Laboratory toxicities: 
From the completed studies, there are no safety concerns noted for the renal or hepatic 
parameters measured and no clinically significant changes of concern relating to 
coagulation parameters. Changes observed in the hematological parameters (decreased 
hemoglobin, neutrophils, thrombocytes and lymphocytes) are known to be associated with 
olaparib monotherapy and/or can be explained by co-existing conditions/previous 
chemotherapy. Mean corpuscular volume increases have also been observed with olaparib. 
The clinical significance of this laboratory finding is unknown. Data from Phase I and 
Phase II studies of olaparib in combination with various chemotherapy agents indicate an 
increase in neutropenia, thrombocytopenia and anemia compared to giving these agents 
alone. These findings are consistent with pre-clinical findings and are reflected in the more 
severe hematological events i.e., CTCAE Grade 4 neutropenia, febrile neutropenia and 
thrombocytopenia being reported as SAEs. 
 
Mild elevations in creatinine with no apparent sequelae have been observed in the absence 
of an elevation in urea or blood urea nitrogen or a reported abnormality on urinalysis. The 
clinical significance of these mild elevations in creatinine is unknown but inhibition of 

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24 
organic cation-transporter-2 by olaparib is considered a plausible mechanistic explanation.  
 
Clinical Efficacy: 
The regulatory approvals of olaparib were based on the study D0810C00019 (versus 
placebo in platinum sensitive serous ovarian cancer). This is a Phase II, randomized, double 
blind, multicenter study to assess the efficacy of olaparib (capsule formulation) in the 
treatment of patients with platinum sensitive serous ovarian cancer, following treatment 
with 2 or more platinum containing regimens [36].  Patients were randomly assigned to 
receive olaparib, at a dose of 400 mg twice daily, or placebo. The primary end point was 
progression-free survival according to the Response Evaluation Criteria in Solid Tumors 
guidelines. Of 265 patients who underwent randomization, 136 were assigned to the 
olaparib group and 129 to the placebo group. Progression-free survival was significantly 
longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from 
randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 
95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-
free survival showed that, regardless of subgroup, patients in the olaparib group had a lower 
risk of progression. The investigators concluded that olaparib as maintenance treatment 
significantly improved progression-free survival among patients with platinum-sensitive, 
relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival 
benefit. The toxicity profile of olaparib in this population was consistent with that in 
previous studies. 
 
Fong et al reported the result of a phase I study in a study population enriched in carriers 
of a BRCA1 or BRCA2 mutation [37]. The investigators enrolled and treated 60 patients; 
22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of 
BRCA-associated cancer but declined to undergo mutational testing. The olaparib dose and 
schedule were increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily 
continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 
400 mg twice daily (grade 3 mood alteration and fatigue) and two of five patients receiving 
600 mg twice daily (grade 4 thrombocytopenia and grade 3 somnolence). This led to 
enrolment of another cohort, consisting only of carriers of a BRCA1 or BRCA2 mutation, 
to receive olaparib at a dose of 200 mg twice daily. Other adverse effects included mild 
gastrointestinal symptoms. There was no obvious increase in adverse effects seen in the 
mutation carriers. Pharmacokinetic data indicated rapid absorption and elimination; 
pharmacodynamic studies confirmed PARP inhibition in surrogate samples (of peripheral-
blood mononuclear cells and plucked eyebrow-hair follicles) and tumor tissue. Objective 
antitumor activity was reported only in mutation carriers, all of whom had ovarian, breast, 
or prostate cancer and had received multiple treatment regimens. 
 
In an expansion phase in BRCA-deficient ovarian cancer at a dose of olaparib 200 mg BID, 
fifty patients were treated, including 48 with BRCA-deficient germline mutations and two 
patients of unknown status or significance.  Twenty (40%) patients achieved complete 
response (CR) or partial response (PR) by RECIST and/or GCIG-CA125 criteria.  An 
additional three patients experienced stable disease (SD) for more than four cycles  [38].  
A multicenter phase 2 study enrolled two sequential cohorts of women with known 
germline BRCA2 or BRCA2 mutations and recurrent advanced ovarian cancer to receive 

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olaparib continuously at a dose of 400 mg BID (Cohort 1) or 100 mg BID (Cohort 2) [39].  
Responses were observed in 33% (11 of 33) patients enrolled in the 400mg BID cohort and 
13% (3 of 24) patients enrolled in the 100 mg BID cohort.  A phase 2 study of olaparib in 
advanced serous ovarian cancer and triple-negative breast cancer showed ORR of 41% in 
ovarian patients with BRCA1 or BRCA2 mutations and 24% without mutations and no 
confirmed responses in patients with breast cancer [40].  
 
Kaufman et al reported the results from the phase 2 multiple phase 2 study of olaparib 
monotherapy in patients with advanced solid cancer and a germline BRCA1/2 
mutation[41]. Olaparib was given 400mg twice a day and the primary endpoint was tumor 
response rate. A total of 298 patients received treatment and were evaluable. The tumor 
response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (60 of 193; 
95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 23.9), 21.7% (five of 23; 95% 
CI, 7.5 to 43.7), and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in ovarian, breast, 
pancreatic, and prostate cancers, respectively. Stable disease  8 weeks was observed in 
42% of patients (95% CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% (95% 
CI, 34.0 to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with 
ovarian, breast, pancreatic, or prostate cancer, respectively.  
 
Lee and Kohn and colleagues have examined olaparib with carboplatin in two schedules in 
BRCA1/2 mutation carriers with breast and/or ovarian cancer and women with high grade 
serous ovarian cancers [42].  They also see activity with over 80% of ovarian cancer 
patients attaining either SD or PR lasting up to 18+ months.  Additional phase 1 and 2 trials 
in both BRCA-deficient and BRCA-competent ovarian cancer are currently ongoing. 

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2.2.3 FMISO  
[1H-1-(3-[18F]-fluoro-2-hydroxy-propyl)-2-nitro-imidazole, or [18F]-fluoromisonidazole 
has a molecular weight of 189.14 Daltons. [18F]FMISO is an azomycin-based hypoxic 
cell sensitizer that has a nearly ideal partition coefficient and, when reduced by hypoxia, 
binds covalently to cellular molecules at rates that are inversely proportional to 
intracellular oxygen concentration, rather than by any downstream biochemical 
interactions. The covalent binding of nitroimidazoles is due to bioreductive alkylation 
based on reduction of the molecule through a series of 1-electron steps in the absence of 
oxygen.  Products of the hydroxylamine, the 2-electron reduction product, bind stably in 
cells to macromolecules such as DNA, RNA, and proteins. In the presence of oxygen, a 
futile cycle results in which the first 1-electron reduction product, the nitro radical anion, 
is re-oxidized to the parent nitroimidazole, with simultaneous production of an oxygen 
radical anion.  FMISO is not trapped in necrotic tissue because mitochondrial electron 
transport is absent.  The normal route of elimination for FMISO is renal.  The LD50's in 
adult male Balb/C mice for MISO and FMISO are 1.8 mg/g (1.3-2.6) and 0.9 mg/g, 
respective. Clinical studies employing multiple dosing of MISO have also been reported 
and peripheral neuropathy (PN) was the manifestation of toxicity that became dose 
limiting with daily doses of 3-5 g/m2. ely.  ]  
Toxicity of FMISO in Humans:  
FMISO’s primary toxicity is likely to be peripheral neuropathy, which is dependent upon 
frequency and dose level.  There is no evidence to suggest that FMISO poses a 
risk for PN when administered as an imaging agent for PET as described herein.  
The risk for PN in fact appears to be minimized or absent even at therapeutic 
doses that far exceed those necessary for PET imaging. The maximum dose to 
humans reported in imaging protocols was 1 mg/kg or 70 mg for a 70 kg subject; 
no adverse events have been reported. This is about 0.1% of the projected LD50.  
Total patient imaging doses of the current radiopharmaceutical formulation 
contain  15 g of fluoromisonidazole and less than 35 g of other nitroimidazole 
derivatives.  This is <0.001% of the projected LD50. The drug is the only active 
ingredient and it is formulated in  10 mL of 5% ethanol in saline for intravenous 
injection   
Table: Radiation Absorbed Dose to Organs 

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Calculated total body dose for a 70 kg man injected with 3.7 MBq/kg was 0.013 
mGy/MBq; for a 57 Kg woman it was 0.016 mGy/MBq. Effective dose 
equivalents were 0.013 mSv/MBq for men and 0.014 mSv/MBq for women. The 
radiation exposure from [18F]FMISO is equal to or lower than that of other widely 
used nuclear medicine studies. Increasing the frequency of voiding can reduce 
radiation dose to the normal organ receiving the highest radiation absorbed dose, 
the bladder wall. Potential radiation risks associated with a typical PET study 
utilizing this agent are within generally accepted limits. 
 
Although each organ will receive a different dose, the maximum amount of radiation 
exposure subjects will receive from this study is equal to an effective dose equivalent 
of 2.9 rem for a total of up to 2 injections of 5mCi [18F]FMISO (10mCi total) plus up 
to 6 attenuation correction CT scans (3 CTs per PET scan). 

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Previous Human [F-18]FMISO Imaging Studies:  Positron emission scanning 
with [18F]FMISO has been studied for hypoxia in a variety of tumors, including 
brain cancer, head and neck cancer, lung cancer, sarcoma, rectal cancer, and etc. 
as well as ischemic stroke over the past 20 years in Australia, Switzerland, 
Denmark, Germany and in the United States under RDRC approval or its 
equivalent. Several published studies from the United States are from the 
University of Washington in Seattle since 1994. Please refer to FMISO IB 2013 
for detail)  
 
 

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2.3 
Rationale 
2.3.1 Hypoxia and Homologous Recombination DNA Repair  
Hypoxia is one of the characteristics of the microenvironment in growing tumors. 
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. Hypoxia is also induced when 
highly proliferative tumor cells distance themselves from an oxygen supply.[43]  The 
changes that a tumor cell must undergo to survive the metabolic challenges imposed by a 
low oxygen state are multiple. 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.[43-45]    
 
Dr. Peter Glazer’ group at Yale University and others have shown that hypoxia also induces 
genomic instability and gene silencing, especially of the genes that are involved in DNA 
repair mechanisms. Among others, his lab has shown that hypoxia can induce homologous 
recombination DNA repair defects by transcriptional repression of RAD51, BRCA1 and 
BRCA2 in numerous human cell lines derived from a wide range of tissues using 
quantitative PCR and Northern blotting, including MCF7 (breast), A549 (lung 
adenocarcinoma), RKO (colon), CaCo-2 (colon), PC3 (prostate) and DU145 (prostate) 
[46]. Subsequent work reported that, as expected, PARP inhibitors displayed increased 
cytotoxicity against A549 (lung adenocarcinoma), RKO (colon) and H460 (lung 
adenocarcinoma under hypoxic conditions, compared to normoxic conditions[47].  
Interestingly, they also reported that disruption of PARP function, either via chemical 
PARP inhibitors or siRNAs targeted to PARP-1, can inhibit HDR by suppressing 
expression of BRCA1 and RAD51 regardless of oxygenation status, and the addition of 
hypoxic conditions to PARP inhibition enhanced the down regulatory effect. In addition, 
transcription of RAD51 and MLH1 also decreased in response to hypoxia via a similar 
mechanism [46, 48-51]. Posttranslational modifications of histones have been described as 
an important epigenetic mechanism of gene regulation [52-54].  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 [55]. 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 [55], that is thought to trigger angiogenesis. 
 
The acquired homologous recombination defect (HRD) with downregulation of BRCA1/2 
is an important observation and may have therapeutic implications for the use of PARP 
inhibitors. 
 
2.3.2 Cediranib as an inducer of hypoxia   
Cediranib is a potent VEGFR tyrosine kinase inhibitor (VEGFR TKI) with activity against 
VEGFR-1, -2, -3 and c-Kit [22, 23, 25]. Cediranib has been shown to inhibit endothelial 
cell proliferation, survival and angiogenesis, and has shown activity against a broad range 
of tumor xenografts [22, 56, 57].  Cediranib as an inhibitor of VEGF signaling through its 

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action on VEGFRs, has been shown in preclinical models to inhibit vascular permeability 
and perfusion measured by dynamic contrast-enhanced magnetic resonance imaging 
(DCE-MRI) [58-60]. In the First-Trial-In-Man (FTIM) study in patients with advanced 
solid tumors, pharmacodynamic assessment demonstrated time-, dose- and exposure-
related decreases in initial area under the curve, defined over 60 seconds post-contrast 
arrival in the tissue (iAUC60) using DCE-MRI [61]. These data were confirmed in 
additional clinical studies [62, 63]. In subcutaneous xenografts combined carbogen USPIO 
MRI also revealed decreases in perfusion following cediranib treatment [64]. Hypoxia was 
measured in parallel by using pimonidazole and histologic assessment after sacrificing the 
animals. A significant 40% increase in tumor hypoxia was observed. 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 [65].  
 

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2.3.3
Clinical Studies of the combination of cediranib and olaparib
In a randomized open-label phase 2 study, patients with platinum-sensitive, 
relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary 
peritoneal cancer, or those with deleterious germline BRCA1/2 mutations, were 
randomized  to receive olaparib capsules 200 mg twice daily or the combination 
of cediranib 30 mg daily and olaparib capsules 400 mg twice daily [66]. The 
primary endpoint was PFS analyzed in the intent-to-treat population. Median PFS 
was 17.7 months (95% CI 14.7–not reached) for the women treated with cediranib 
plus olaparib compared with 9.0 months (95% CI 5.7–16.5) for those treated with 
olaparib monotherapy (hazard ratio 0.42, 95% CI 0.23–0.76; p=0.005). In a post-
hoc, subgroup analysis by germline BRCA mutation (gBRCAmt) status, the 
magnitude of the difference between the two arms was even more striking in 
those with wild-type BRCA or unknown status (wtBRCA/unk) than in those with 
gBRCAmt. Among the wtBRCA/unk, the hazard ratio (HR) of PFS for the 
combination versus olaparib monotherapy was 0.32 (95% CI 0.14–0.74, p=0.008) 
whereas among mtBRCA, the HR was 0.55 (95% CI 0.24-1.27, p=0.16). The 
difference in median PFS was 8.7 months (9 vs 17.7 months in olaparib vs 
cediranib plus olaparib, respectively) in the wtBRCA/unk, whereas the difference 
in median PFS was only 2.9 months (16.5 vs 19.4 months) in the mtBRCA. While 
data from a post-hoc analysis data must be interpreted with caution, nonetheless, 
this is hypothesis-generating and supports further investigation to elucidate the 
mechanism of the potential synergy especially in those with BRCA wild-type. 
2.3.4
Summary of Rationale
Cediranib, by inhibition of VEGF-signaling decreases vascular permeability and perfusion 
and induces hypoxia in tumors. Hypoxia as a consequence may downregulate BRCA1 
expression through multiple mechanisms, as well as at the same time upregulate VEGF 
expression. Downregulation of BRCA1 may lead to a BRCA loss phenotype and tumors 
via this mechanism may become more sensitive to olaparib, a PARP inhibitor. The 
hypothesis that cediranib may render tumors more sensitive to olaparib will be tested in 
this study and multiple correlative endpoints elucidate underlying mechanisms.
Figure 2: Summary of Rationale
y g

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2.4 
Correlative Studies Background 
 
2.4.1 Introduction 
 
The hypothesis that cediranib may render tumors sensitive to olaparib treatment via 
induction of hypoxia and downregulation of BRCA1, will be tested in this study. While 
evidence from multiple preclinical and clinical studies exists for each step of the 
hypothesis, this has not been tested in a single clinical study. However data exist showing 
increased efficacy of the combination over olaparib monotherapy in patients without 
germline BRCA mutation [66]. 
 
The correlative studies described below will focus on generating data to test the 
hypothesis. It is proposed to explore the induction of hypoxia in patient’s tumors after 
single agent cediranib treatment using FMISO PET imaging in the NSCLC cohort. From 
all patients, blood samples at multiple time points will be obtained to measure VEGF 
(and other vascular and angiogenic markers) as well as circulating tumor DNA (ctDNA). 
The markers will be correlated with each other and outcome. Tissue and blood markers 
will be exploratory.  
 
In addition, the use of the BROCA panel is planned as in integrated marker in the study 
for all study patients. In addition to testing the tumors, a blood sample will be obtained at 
baseline for germline BROCA testing.  
 
It is likely that the variants / mutations in the genes included in this panel will influence 
the response to olaparib therapy. The panel is currently studied in ovarian studies using 
the combination of cediranib and olaparib and this study will be the first to study the 
BROCA panel outside of ovarian cancer.  
 
2.4.2 [18F]FMISO imaging for tumor hypoxia (Drs. Ming-Kai Chen, Richard Carson, 
David Carlson, Yale University) 
 
Fluorine-18 labeled misonidazole, 1H-1-(3-[18F]-fluoro-2-hydroxy-propyl)-2-nitro-
imidazole, or [18F]FMISO, is a radiolabeled imaging agent that has been used for 
investigating tumor hypoxia with positron emission tomography (PET). An ideal hypoxia-
imaging agent should distribute independently of blood flow, which is best achieved when 
the partition coefficient of the tracer is close to unity. Under these circumstances, imaging 
can be done at a time when the intracellular tracer distribution has equilibrated with the 
tracer in plasma near the cells. [18F]FMISO is an azomycin-based hypoxic cell sensitizer 
that has a nearly ideal partition coefficient and, when reduced by hypoxia, binds covalently 
to cellular molecules at rates that are inversely proportional to intracellular oxygen 
concentration, rather than by any downstream biochemical interactions. [67] 

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Since its development [68], numerous studies, both pre-clinical and clinical, consider [18F]-
FMISO and PET imaging to be the most promising method for hypoxia quantification, 
since the tracer binds in hypoxic cells selectively [69-72]. As a result, it is a lead contender 
in the in vivo and clinical assessment of hypoxia and is the most extensively studied PET 
hypoxia tracer [73, 74]. Koh et al. [69] and Valk et al. [70] first demonstrated that [18F]-
FMISO could detect hypoxia in human tumors. Rasey et al. [71] further validated the tracer 
sensitivity as a hypoxic marker in 37 patients and confirmed the prevalence, presence, and 
variability of hypoxia in human tumors. Bruehlmeier et al. [75] also supported the use of 
[18F]FMISO for hypoxia quantification and showed the lack of influence of perfusion and 
the blood-brain-barrier on tracer hypoxia detection. This implies tracer differentiation and 
specificity. Only Bentzen et al. [76] has shown an inability for [18F]FMISO to detect 
hypoxia in human tumors. However, this discrepancy could be attributed to the trial 
protocol design, as [18F]-FMISO was used to characterize tumors, not to explicitly detect 
hypoxia. Most significantly, Gagel et al. [77] showed the tracer was representative of 
intracellular pO2 as [18F]-FMISO uptake correlated with Eppendorf pO2 probe 
measurements, while this was not the case for [18F]-FDG, a tracer for glucose metabolism 
[78]. Statistically significant correlations have also been found between [18F]FMISO 
uptake and immunohistochemistry staining [79-81] for HIF1-alpha hypoxic-inducible 
factor [76]. Okamoto et al. [82] showed that [18F]FMISO PET could provide reproducible 
hypoxic volumes in H&N cancer patients. In the clinic, [18F]FMISO has been shown to 
detect hypoxia in a variety of tumor types from soft-tissue sarcoma, H&N cancer, non-
small cell lung cancer, breast cancer, and brain tumors [71, 77, 83-86]. 
 
In this study, the PET/CT imaging of hypoxia with [18F]FMISO will be performed at 
baseline and following cediranib monotherapy in the NSCLC cohort. Please see Section 
5.1.3 for detail.  
 
2.4.3 Angiome Panel  (Dr. Andrew Nixon, Duke) 
 
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 

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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 
 bevacizumab, his group identified VEGF-D as a candidate predictor for benefit from 
bevacizumab [87].  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 [88] and CALGB90206 was a phase III study of IFN +/- 
bevacizumab in 1st line mRCC [89].   Both of these studies found that high levels of IL6 
predicted for greater benefit from these VEGF inhibitors [90, 91].  The CALGB study with 
bevacizumab also found a predictive role for HGF that was IL-6 dependent (i.e., a 3-way 
treatment interaction) [90]. 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 [92, 93]. Tumor angiogenesis, inflammation, and anti-tumor 
immunity have highly interconnected biologies, a topic that has been extensively reviewed 
[94-96]. 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 

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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 
 
2.4.4 Circulating Tumor DNA - Plasma (Dr. Abhijit Patel, Yale)  
 
For many types of cancer, serum protein biomarkers to monitor therapeutic efficacy 
either do not exist or are not very robust.  For example, there are currently no blood 
biomarkers that are in routine clinical use to track response to therapy in patients with 
non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).  In patients with 
advanced breast and pancreatic cancers, the blood markers CA 27.29, CEA, and CA 19-9 
can be used to monitor treatment response and to detect disease progression.  However, 
these markers suffer from lack of cancer specificity, as serum levels can be elevated in 
patients with other types of cancer and can also be elevated in non-malignant conditions 
such as cirrhosis, inflammatory bowel disease, hepatitis, and renal impairment, among 
others.  Moreover, serum levels of protein markers typically change gradually, making it 
difficult to obtain a rapid assessment of the effectiveness of a therapy.  Thus, new blood 
biomarkers with greater specificity and faster response kinetics could provide a more 
reliable and rapid assessment of treatment efficacy to guide therapeutic decision-making.   
 
Recent technological advances have made it possible to detect and quantify small 
amounts of cell-free tumor-derived DNA fragments in the bloodstream of patients with 
various types of cancer [97-102].  Such circulating tumor DNA (ctDNA) is believed to be 
released from dying cancer cells, and is showing excellent promise as a cancer biomarker 
[103, 104].  Tumor-derived DNA can be distinguished from normal background cell-free 
DNA in plasma based on the presence of tumor-specific somatic mutations.  Because 
somatic mutations are a hallmark of cancer, circulating tumor DNA should in principle be 
identifiable in all types of malignancies.  False-positive results are expected to be 
extremely uncommon since cancer-associated mutations should rarely be found in plasma 
in the absence of malignancy.  Furthermore, because there is no physiologic background 
level, a small amount of mutant DNA released from a small tumor should be detectable if 
the technical background (error rate) of the assay can be minimized. It has also been 
observed (in our lab and by others) that ctDNA exhibits much more rapid posttreatment 
kinetics than protein markers.  Most protein markers typically show a decline with 
successful therapy over several months, whereas ctDNA can show a dramatic decline 
within ~2-3 weeks [102]. While most protein markers are secreted by living and growing 
cancer cells, ctDNA is a byproduct of dying cancer cells, and it is rapidly cleared from 
the blood with a half-life of ~2 hours [105]. Thus, ctDNA provides a real-time estimation 
of active tumor cell death, rather than simply a measure of tumor burden.  In several 
cases, we have observed an initial spike in ctDNA levels within the first few days after 
beginning treatment (likely due to tumor kill), followed by a substantial decline below 
pre-treatment levels after the initial wave of cell death has subsided.  This can lead to an 

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exaggerated difference between pre- and post-treatment levels, suggesting that ctDNA 
may be a more responsive marker of therapeutic efficacy.   
 
Patel laboratory has developed an ultrasensitive assay for measuring small amounts of cell-
free mutant DNA released into the blood from dying tumor cells[102, 106].  The assay uses 
next-generation sequencing combined with novel error suppression techniques to enable 
measurement of rare mutant ctDNA down to a fractional abundance of ~0.02%.  Coverage 
of a broad panel of mutation-prone genomic regions ensures that ctDNA can be detected 
in the majority of patients with common solid malignancies.  The assay has been tested on 
over 1500 clinical samples thus far.  Indeed, in patients receiving chemotherapy, targeted 
therapy, surgery, or radiation therapy, we have observed that ctDNA levels usually 
decrease substantially during successful treatment (sometimes with a transient spike due to 
tumor kill).  However, longitudinal testing of the assay has been performed mostly on 
heterogeneous populations of patients who were treated with a variety of regimens.  To 
more rigorously evaluate the performance of the assay, here we plan to obtain blood 
samples at well-defined intervals from a population of patients having 4 different types of 
cancer, all receiving uniform treatment in the setting of a clinical trial.  
 
2.4.5 BROCA Panel (Dr Elizabeth Swisher, University of Washington, Seattle) 
The BROCA-HR assay will be used in the study to assess correlation of response and effect 
of homologous recombination deficiency (HRD) status, on the effectiveness of targeted 
therapy with cediranib in combination with olaparib. BROCA testing will be performed on 
the tumor samples as well as a germline blood sample obtained at baseline.  
 
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 [107-111]. 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 [112]. PARP inhibitors 
(PARPi) demonstrate synthetic lethality in cells with HRD, including cells deficient in 
BRCA1/2 [34, 113]. 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 [114]. Importantly, approximately 25% of serous ovarian cancers that 
are wildtype for BRCA1/2 also respond to PARPi [40]. 
 
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 [112, 115] and also 
appear to confer sensitivity to PARPi [116]. PARPi also selectively kill cells in vitro that 
are deficient in other (HR) genes including RAD51D, NBN, ATM, and CHEK2 [107, 117].  
Germline and somatic mutations in BRCA1/2 and other BRCA-FA genes in ovarian 

NCI Protocol #:9881 
Version Date: September 7, 2021 
 
37 
carcinomas are associated with improved response to primary platinum therapy and longer 
overall survival [115].  
 
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 
[118, 119]. 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 [120-122]. 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 [37]. 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 [123, 124]. 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 [125]. 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) [125, 126].  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) [127]. The presence of either a germline or 
somatic FA/HR mutation is highly predictive of an improved primary response to platinum 
chemotherapy and longer overall survival (Pennington, Swisher et al. manuscript in 
progress). Germline and somatic loss of function mutations were identified in all of the 13 
FA/HR genes evaluated.  

NCI Protocol #:9881 
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38 
 
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 [128-130]. 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. 
 
 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 

NCI Protocol #:9881 
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39 
3.1.1 Patients must have histologically confirmed, metastatic or unresectable malignancy of the 
following types: (a) non-small cell lung cancer (NSCLC), (b) triple-negative breast 
cancer (TNBC; defined by ER<1%, PR<1% and HER2 1+ or less by IHC; if HER-2 
expression is 2+, a negative FISH testing is required) (c) pancreatic adenocarcinoma 
(PDAC), or (d) small cell lung cancer (SCLC). 
3.1.2 Must have received at least one line of standard systemic treatment for locally advanced 
or metastatic disease setting of the respective tumor type. For NSCLC, it is either PD-
1/PD-L1 inhibitor, or platinum-containing chemotherapy, or an EGFR tyrosine kinase 
inhibitor or an ALK inhibitor if sensitizing mutation present; TNBC: platinum-containing 
chemotherapy; PDAC: 5-FU-, gemcitabine-, or taxane-containing chemotherapy either 
with or without radiation therapy; SCLC: platinum-containing chemotherapy for limited 
or extensive stage disease. 
 
3.1.3 Patients must have measurable disease by RECIST v1.1. See Section 11 for the evaluation 
of measurable disease. 
 
3.1.4 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 prior grade 2 
treatment-related hypothyroidism requiring treatment, provided Free T4 within normal 
range, may be considered eligible after discussion with the study Principal Investigator 
(PI). 
 
3.1.5 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. 
 
3.1.6 ECOG performance status 0, 1 or 2 (Karnofsky 50%, see Appendix A). 
 
3.1.7 Life expectancy of >4 months.  
 
3.1.8 Patients must have normal organ and marrow function as defined below: 
 
 
leukocytes 
3,000/mcL 
 
absolute neutrophil count 
1,500/mcL 
 
platelets 
100,000/mcL 
 
hemoglobin  
>9 g/dL 
 
total bilirubin 
1.5 î the institutional upper limit of normal (ULN) 
 
AST(SGOT)/ALT(SGPT) 
2.5 î institutional ULN 
 
creatinine 
1.5x ULN  
 
 
 
 
OR 
 
creatinine clearance 
45 mL/min/1.73 m2 for patients with creatinine levels 
above institutional normal. The creatinine clearance is 
calculated using Cockcroft-Gault formula as follows:  
Cockcroft-Gault CrCl = (140-Age)* (Wt in Kg) * (0.85 
if female) / (72*Cr) 
 
Proteinuria  
 
 
a urine protein:creatinine ratio of <1, or <1 g protein on 
24-hour urine collection 

NCI Protocol #:9881 
Version Date: September 7, 2021 
 
40 
 
Coagulation parameters 
within 1.25 î ULN institutional limits, except where a 
(INR, aPTT)  
 
Lupus anti-coagulant has been confirmed 
 
3.1.9 Patients must be able to tolerate oral medications and not have gastrointestinal illnesses 
that would preclude absorption of cediranib or olaparib. 
 
3.1.10 Adequately controlled thyroid function defined by Free T4 within normal range, with no 
symptoms of thyroid dysfunction. 
 
3.1.11 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. 
 
3.1.12 Patients who have the following risk factors are considered to be at increased risk for 
cardiac toxicities, and 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.     
x Prior treatment with anthracyclines 
x Prior treatment with trastuzumab 
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 (patients with history of 
myocardial infarction within 6 months are excluded from the study) 
 
3.1.13 The effects of cediranib and olaparib on the developing human fetus are unknown.  For 
this reason, women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study entry 
and for the duration of study participation.  Should a woman become pregnant or suspect 
she is pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  Men treated or enrolled on this protocol must also agree 
to use adequate contraception prior to the study, for the duration of study participation, and 
for 4 months after completion of cediranib and olaparib administration. 
 
3.1.14 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 or RT within 3 weeks prior to start of the study 
agents, or those who have not recovered from adverse events due to agents administered 
more than 3 weeks earlier. 
 

NCI Protocol #:9881 
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41 
3.2.2 Patients should not have received any other investigational agents within the past 4 weeks.   
 
3.2.3 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 should be excluded from 
this clinical trial, since neurologic dysfunction may confound the evaluation of neurologic 
and other AEs. Screening Brain MRI (or CT if MRI contraindicated) will be required for 
patients with recurrent NSCLC, TNBC, or SCLC. Brain MRI (or CT if MRI 
contraindicated) is required for PDAC if clinically suspected by patient’s symptoms or 
neurological exam.  Should patient found to have brain metastasis, treatment of brain 
metastasis must precede the participation in this study.  For patients with known and treated 
brain metastases is allowed in this study if they fulfill the following criteria: 
• The lesions have improved or remained stable radiographically and clinically for at 
least 6 weeks after completion of brain irradiation or stereotactic brain 
radiosurgery and off steroids for at least 6 weeks. 
 
3.2.4 Patients who have received prior inhibitor of VEGF signaling and a PARP inhibitor 
administered in combination. Unless administered in combination, patients who received 
a prior PARP inhibitor or a prior VEGF-signaling inhibitor agent are allowed after 
discussing with the PI.   
 
3.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to cediranib or olaparib. 
 
3.2.6 Participants receiving any medications or substances that are strong inhibitors or inducers 
of CYP3A4 (See Appendix C) are ineligible. Dihydropyridine calcium-channel blockers 
are permitted for management of hypertension. 
 
3.2.7 Current use of natural herbal products or other complementary alternative medications 
(CAM) or “folk remedies.”  
 
3.2.8 Patients with concomitant or prior invasive malignancies within the past 3 years.  
Subjects with treated limited stage basal cell or squamous cell carcinoma of the skin or 
carcinoma in situ of the breast or cervix are eligible. 
 
 
3.2.9 Uncontrolled intercurrent illness including, but not limited to, 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. 
 

NCI Protocol #:9881 
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42 
3.2.10 History of myocardial infarction within 6 months prior to registration. 
 
3.2.11 History of stroke or transient ischemic attack within 6 months prior to registration. 
 
3.2.12 NYHA classification of III or IV. 
 
3.2.13 Current cardiac arrhythmia requiring concurrent use of anti-arrhythmic drugs  
 
3.2.14 History of hypertensive crisis or hypertensive encephalopathy within 3 years prior to 
registration. 
 
3.2.15 Clinically significant peripheral vascular disease or abdominal aortic aneurysm (>5cm) or 
aortic dissection.   If known history of abdominal aortic aneurysm with >4cm in diameter, 
all of the following must be met:  
x An US within the last 6 months prior to registration will be required to document 
that it is < 5cm 
x patient must be asymptomatic from the aneurysm 
x Blood pressure must be well controlled as defined in this protocol. 
 
3.2.16 A major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to starting cediranib (percutaneous/endobronchial biopsies are allowed).   
 
3.2.17 History of bowel obstruction within 1 month prior to starting study drugs.  
 
3.2.18 History of hemoptysis or any significant bleeding within the last 1 month prior to 
enrollment. 
 
3.2.19 Presence of cavitation of central pulmonary lesion 
 
3.2.20 History of abdominal fistula, intra-abdominal abscess, or gastrointestinal perforation 
within the 3 months prior to enrollment.  
 
3.2.21 Patients may not have current dependency on IV hydration or total parenteral nutrition 
(TPN). 
 
3.2.22 Patients may not have evidence of coagulopathy or bleeding diathesis.  Therapeutic 
anticoagulation for prior thromboembolic events is permitted. The clinical indication for 
therapeutic anticoagulation must be clearly documented prior to enrollment and must be 
discussed with the P.I.  Given the increased risk of serious bleeding from cediranib, 
patients who are on greater than or equal to 2 anti-thrombotic agents, including but not 
limited to anti-platelet agents (NSAIDs/aspirin, clopidogrel), heparin, LMWH, warfarin, 
and a direct thrombin inhibitor, will be excluded.   
 

NCI Protocol #:9881 
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43 
3.2.23 Patients may not have features suggestive of myelodysplastic syndrome (MDS) or acute 
myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if 
clinically indicated. 
 
3.2.24 Pregnant women are excluded from this study because olaparib and cediranib have the 
potential for teratogenic or abortifacient effects.  Due to the fact that there is an unknown 
but potential risk for adverse events in nursing infants secondary to treatment of the mother 
with olaparib and cediranib, breastfeeding should be discontinued if the mother is treated 
with cediranib and olaparib.   
 
 
3.2.25 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with cediranib or olaparib.  Appropriate studies 
will be undertaken in patients receiving combination antiretroviral therapy when 
indicated.  HIV-positive patients with undetectable viral loads and CD4 counts >300, and 
not on any antiretroviral therapy may be allowed after discussing with the principle 
investigator. 
 
3.2.26 Any condition that, in the opinion of the treating investigator would interfere with 
evaluation of the investigational product or interpretation of subject safety or study results. 
 
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 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 

NCI Protocol #:9881 
Version Date: September 7, 2021 
 
44 
in the table below. 
 
Documentation Required 
IVR 
NPIVR 
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 
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 a site is interested in participating in this study, it is highly recommended that an 
investigator or his/her team at the participating site reach out to the Study PI via email:  
joseph.w.kim@yale.edu to discuss their interest in the participation.  
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 

NCI Protocol #:9881 
Version Date: September 7, 2021 
 
45 
this protocol and submit IRB approval and supporting documentation 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:  
x An active Federal Wide Assurance (FWA) number 
x An active roster affiliation with the Lead Network or a participating organization 
x A valid IRB approval 
x Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
x Active registration status 
x The IRB number of the site IRB of record listed on their Form FDA 1572 
x An active status on a participating roster at the registering site  
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. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the 9881 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 #9881. 
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.) 

NCI Protocol #:9881 
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46 
 
4.2.2 Requirements For 9881 Site Registration: 
 
x Send an email to the Study PI: joseph.w.kim@yale.edu to obtain approval to participation 
in this study.  
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) (All sites) 
x Local informed consent document (All sites) 
x CTEP ISCG Approval of International Site Participation Site Participation (International 
sites only) 
x LPO Approval of International Site Participation (International sites only)  
x Clinical trial Site information Form (California sites only)  
x Qualified Investigator Undertaking (California sites only) 
x Research ethics Board Attestation (California sites only) 
 
 
4.2.3 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 Æ 
Regulatory 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. 
 
4.2.4 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 
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 

NCI Protocol #:9881 
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47 
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. 
 
 
4.3 
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. 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment 
initiation to check slot availability.  Registration staff should ensure that a slot is available 
and secured for the patient before completing an enrollment. 
 
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 
Participating Organization roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type.  
x To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
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? 
 

NCI Protocol #:9881 
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48 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is 
available 
on 
the 
Theradex 
website: 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. This link to 
the Theradex website is also on the CTSU website OPEN tab. For questions about the use 
of IWRS for slot reservations, contact the Theradex Helpdesk: 609-619-7802 or Theradex 
main number 609-619-7862; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 10 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 and the PI should be notified of cancellations as soon as possible. 
 
5. TREATMENT AND/OR IMAGING PLAN 
Cycle1 is 35 days long and remaining cycles are 28 days long. 
 
5.1 
Agent Administration 
 
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. 
 
Dose level 
Cediranib Tablet 
-2 
15 mg daily, orally 
-1 
20 mg daily, orally  
1 (starting dose) 
30 mg daily, orally 
 
Dose Level 
Olaparib Tablet 
-2 
100 mg twice daily, orally 
-1 
150 mg twice daily, orally 
1 (starting dose) 
200 mg twice daily, orally 
 
NOTE: Dose modification will be done independent of each other. 
 
5.1.1 Cediranib 
 
Cediranib dosing will start at 30mg orally on day 1 of each cycle (See Study Calendar for 
detail). 
 

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49 
Cediranib at the appropriate dose level will be given orally every 24 hours (+/- 2 hours) 
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 should be taken on an empty stomach 
approximately one hour (+/- 30 mins) before the morning dose of olaparib. 
 
Cediranib will be dispensed at the start of each cycle.  Patients will be provided with a pill 
diary for each drug (Appendix E (cycle 1) and Appendix F), instructed in its use, and asked 
to bring it with them to each appointment. 
 
5.1.2 Olaparib  
For those undergoing FMISO scans (NSCLC), olaparib 200mg twice a day, orally, is to 
start on the day after the second FMISO scans after the second set of research blood is 
collected. See Study Calendar for detail. 
For the rest of patients, olaparib 200mg twice a day, orally, is to start on Day 4 of cycle 1 
after the second set of research blood is collected. See Study Calendar for detail. In case of 
scheduling conflicts, olaparib may start on any day between 4 and 7. 
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 (+/- 2 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 
should be taken approximately 1 hour (+/- 30 mins) after the cediranib dose, with a light 
meal/snack.  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. 
Olaparib will be dispensed at the end of cediranib monotherapy of cycle 1 (to minimize the 
confusion for the patient during the monotherapy lead-in period), and at the start of the 
subsequent cycles. 
 
Patients will be provided with a pill diary (Appendix E (cycle 1 diary) and Appendix F), 
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.   
 
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. 
 
5.1.3 [18F]Fluoromisonidazole (FMISO) 
Schedule:  
Please refer to the Study Calendar for the schedule of the scans. 
 

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[F-18]FMISO Administered Dose: 
[F-18]FMISO will be administered to subjects over 1 minute by intravenous bolus 
injection. Doses will be pre-calibrated to 5 mCi, with a dose range of 4-5 mCi. The dose 
will not exceed 5 mCi total. 
[F-18]FMISO-PET Imaging: 
Imaging Acquisition: 
Up to imaging-evaluable twenty patients with NSCLC will undergo 2 [18F]-FMISO 
PET/CT scans of the thorax. The first baseline scan will be obtained after the biopsy, 
the second scan will be acquired after cediranib monotherapy. Each dynamic [18F]-
FMISO PET scan consists of 3 parts and a CT will be performed before each part for 
attenuation correction. PET scans will be acquired from 0-120mins, 150-180mins, and 
210-240 mins post IV automated injection of a 4-5 mCi bolus of [18F]-FMISO. 
Alternatively, a short protocol of dynamic FMISO PET scans could be acquired from 
0-60 min and 90-120 min. PET/CT scans will be performed on the Siemens Biograph 
mCT PET/CT scanner at Yale PET center or other similar PET scanners at other 
institutions. An intravenous line will be placed for venous blood sampling at pre-
determined times to provide an accurate value of the [18F]-FMISO activity input 
function. 
 
Imaging Analysis: 
Tumor regions will be defined from the CT and PET images. A number of quantification 
measures will be used to compare pre- and post-drug hypoxia levels, including 
standardized uptake values (SUV), hypoxic volumes (HV), as well as tracer 
compartment kinetic modeling measures. Tumor to blood ratio (TBR) is defined as the 
ratio of the [18F]-FMISO signal in each tumor voxel in the tumor region of interest 
(ROI) summed from 210-240 min or 90-120 min (from short protocol) to the average 
signal in heart over the same time frame post-injection. Threshold values used to define 
HVs by [18F]-FMISO imaging impact the reliability and robustness of hypoxia 
quantification. Using a defined TBR threshold >1.2, HV percentages (fraction of tumor 
that is hypoxic) will be calculated based on absolute tumor volume defined by CT 
[131]. (Cheng J. J Nucl Med. 2013) 
 
Image Interpretation: 
The summed [18F]-FMISO imaging will be interpreted by experienced nuclear medicine 
physician visually, using a scoring system according to Rischin et al. (J Clin Oncol. 
2006;24:2098–2104). This scoring system has 5 classes: 0=uptake less than background; 
1=no regions of focal uptake greater than background; 2 = focal uptake mildly greater than 
background; 3=focal uptake moderately greater than background; and 4=focal uptake 
markedly greater than background. In a second step, these 5 classes will be grouped into 2 
classes and a score  2 is considered positive for hypoxia.  
 
TBR and HV imaging (TBR>1.2) will be generated and reviewed as well. HV will be 
calculated based on absolute tumor volume defined by CT.  
 
 
The interpretation will be done centrally by Yale investigators. The FMISO imaging must 

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mailed to Dr. Ming-Kai Chen at the following address within 1 week of completing a 
pair of FMISO PET/CT scans:  
 
Positron Emission Tomography (PET) Center 
Yale University 
801 Howard Avenue 
PO Box 208048 
New Haven, CT 06520-8048 
Ph: (203) 737-YPET 
Fax: (203) 785-3107 
Email: ming-kai.chen@yale.edu 
 
The CT of the FMISO will not be used for disease assessment. 
               
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of AZD2171 (cediranib) and olaparib 
(AZD2281) with other concomitantly administered drugs, the case report form must 
capture the concurrent use of all other drugs, over-the-counter medications, or alternative 
therapies.  The Principal Investigator should be alerted if the patient is taking any agent 
known to affect or with the potential for drug interactions. In vitro studies demonstrate that 
olaparib (AZD2281) is primarily metabolized by CYP 3A4/5 enzymes. Potent inhibitors or 
inducers of CYP 3A4/5 may be prohibited or used with caution. The study team should check 
a frequently-updated medical reference for a list of drugs to avoid or use with caution. 
Appendix C provides a list of drugs that are prohibited. Appendix D (Patient Drug 
Information Handout and Wallet Card) should be provided to patients. 
 
 
Cediranib demonstrated minimal inhibitory effects on the activity of CYP3A4 (testosterone 
and midazolam) in vitro, although the IC50 was far in excess of the clinically relevant 
concentrations.  In vitro studies suggested that CYP enzymes were not significantly 
involved in the production of the principle human metabolites of cediranib, therefore co-
administration of known inhibitors or inducers of hepatic CYP enzymes would not be 
expected to have significant effects on the clearance of cediranib. 
 
Olaparib did not cause significant inhibition or induction of P450 isozymes. However, in 
vitro, cytochrome P450 (CYP) 3A4 (CYP3A4) and 3A5 (CYP3A5) were shown to be the 
major isozyme responsible for the metabolism of olaparib. Modelling and simulation 
suggests olaparib clearance may be increased by co-administration with rifampicin (a 
CYP3A4 inducer) and decreased by co-administration with itraconazole (a CYP3A4 
inhibitor).  Given these data, potent inhibitors or inducers of CYP3A4 (See Appendix C) 
must not be used during this study for patients receiving olaparib.  Dihydropyridine 
calcium-channel blockers are allowed for management of hypertension. 
 

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Patient should receive general concomitant and supportive care medications based on best 
medical practice.   
 
Primary prophylaxis with G-CSF or other bone marrow-supportive agents, including 
erythropoiesis-stimulating agents, is not allowed.  (See Section 6 for Management of 
Febrile Neutropenia) 
 
The use of any natural/herbal products or other “folk remedies” is not allowed on study.   
All medications must be recorded in the case report form and be reviewed by the treating 
physician at each visit. 
 
Frequent blood pressure monitoring is important in patients receiving cediranib.  
Experience to date suggests that increases in blood pressure may occur following dosing 
with cediranib for a number of weeks and that these increases may occur over a relatively 
short time frame.  It is imperative that the investigator institute appropriate measures to 
control BP.  This may necessitate changes to existing antihypertensive medication, addition 
of new medication(s), and/or interruption/withdrawal of cediranib.  Patients will be 
provided blood pressure cuffs and must be able and willing to monitor their blood pressure 
on a twice daily basis.  Section 6 includes specific guidelines on the management and, if 
appropriate, dose modifications for treatment-emergent hypertension.   
 
Diarrhea should be managed with loperamide:  4 mg at first onset, then 2 mg every 2-4 
hours until diarrhea is controlled (maximum = 16 mg loperamide per day).  Additional 
guidelines for management of diarrhea are presented in Section 6.  
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the 
following criteria applies: 
 
x 
Disease progression, 
 
x 
Intercurrent illness that prevents further administration of treatment, 
 
x 
Unacceptable adverse event(s), 
 
x 
Patient decides to withdraw from the study, or 
 
x 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
When a decision is made to discontinue study treatment, an evaluation listed under End of 
Treatment (EOT) will be performed (See Study Calendar), unless patients withdraws consent 
to undergo EOT evaluation.  
 
 

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53 
5.4 
Duration of Follow Up 
x 
Patients will be followed for 4 weeks after discontinuing study treatment or until death, 
whichever occurs first, for a clinical assessment of any significant treatment related AE.  
x Patients who discontinue the study treatment for reasons other than disease progression or 
withdrawal of consent, will be followed via a clinic visit, a phone call by a study team, or 
obtaining medical records, every 4 weeks until disease progression, start of new therapy, 
or death, whichever occurs first. 
x Patients who discontinue the study treatment for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event, or until radiographic 
documentation of disease progression as noted above, start of new therapy, or death, 
whichever occurs first.  
x If patients discontinue study treatment due to withdrawing consent, no further follow-up 
will be performed. 
 
5.5 
Criteria for Removal from Study 
 
Patients will be removed from the study when any of the following happens, whichever occurs 
first:  
o Completion of study Follow Up as outlined in Section 5.4  
o Death  
o Lost to follow-up 
o Withdrawal of consent 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Hematologic Parameters for Treatment 
Patients must meet the following absolute neutrophil count (ANC) and hematologic parameters 
for treatment.  Additionally, dosing parameters for hematologic AEs in Section 6.2 should be 
observed. 
x Cycle 1, Day 1:   
o ANC  1500/mm3  
o Platelets > 100,000/mcL 
o Hemoglobin > 9 mg/dL 
 
x Cycles 2 and beyond, Day 1:   
o ANC  1000/mm3 
o Platelets > 100,000/mcL 
o Hemoglobin > 8 mg/dL 
 
All Cycles, Day 1 
Patients must meet the following parameters on day 1 of each cycle to proceed with treatment.  
Patients who do not meet these criteria may resume treatment later in the cycle once criteria are 
met.  Cycles and days are numbered continuously regardless of any dose holds or delays in 
resumption of treatment. 
 
x Adequate blood pressure control, as detailed in Section 6.3 

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54 
x Serum creatinine  1.5 x the institutional upper limit of normal 
x Liver function tests (AST and ALT)  2.5 x the institutional upper limit of normal 
x ECOG performance status of 0, 1 , or 2 
x No evidence of life-threatening medical problems 
x Urine protein:creatinine ratio OR urine dipstick protein as detailed in Section 6.4 
 
6.1 
Cediranib and Olaparib Dose Modification Tables 
 
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. 
 
Dose level 
Cediranib  
-2 
15 mg daily, orally 
-1 
20 mg daily, orally  
1 (starting dose) 
30 mg daily, orally 
 
Dose Level 
Olaparib Tablet 
-2 
100 mg twice daily, orally 
-1 
150 mg twice daily, orally 
1 (starting dose) 
200 mg twice daily, orally 
 
Dose modification will be done independent of each other. 
 
6.2 
General Management of Adverse Events 
 
The management of general adverse events not otherwise specified will be as per the table below.  
Management of specific toxicities, including hypertension, proteinuria, decreased in LVEF, 
diarrhea, fever and neutropenia, nausea and vomiting, thyroid toxicities, reversible posterior 
leukoencephalopathy syndrome (RPLS), and gastrointestinal perforation will be as further outlined 
in specific sections 6.3-6.11. 
 
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 study PI, 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 study 
PI. 
 
 
General Management of Adverse Events (Non-Hematologic) 
 
General Management of Adverse Events (Non-Hematologic) 
 
Observation 
Action 

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55 
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) 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) 
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 14 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, 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 14 days 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  tgrade 3 non-hematologic (excluding grade 
3 hypertension or easily correctable asymptomatic 
grade 3 laboratory abnormalities) 
Hold study drug(s)1 for up to 14 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, at the treating 
investigator’s discretion.2  The study PI 
of the study should be informed 
regarding all dose modifications. 
1. Grade 3 or 4 non-hematologic AE related to 
cediranib and olaparib combination that does not 
resolve to grade 0-2 within 14 days despite 
maximum supportive care after treating patient 
at the lowest reduced dose level.3 
2. Grade 3 or 4 non-hematologic AE related to 
cediranib/olaparib lasting >14 days despite 
maximum supportive care and treatment being 
held. 
Remove patient from study. 

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56 
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. 
2Patients who are at the lowest reduced dose level may have their drug resumed at that dose 
level after discussion with the overall PI. 
3Excluding hypertension.  For thromboembolic events, treatment may be resumed at the 
discretion of the investigator once patient is asymptomatic. 
 
General Management of Adverse Events (Hematologic) 
Observation 
Action 
Absolute neutrophil count 1000/mcL 
AND  
Platelets 100,000/mcL 
AND 
Hemoglobin 8 mg/dL  
Maintain dose level. 
Absolute neutrophil count <1000/mcL 
OR 
Platelets <100,000/mcL 
OR 
Hemoglobin <8 mg/dL 
Hold treatment for up to 14 days 
until absolute neutrophil count 
1000/mcL, platelets 
100,000/mcL, and hemoglobin 8 
mg/dL. 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, at the treating investigator’s 
discretion.  The study PI of the 
study should be informed regarding 
all dose modifications.  
 
Patients whose counts have not 
recovered to absolute neutrophil 
count 1000/mcL, platelets 
100,000/mcL, and hemoglobin 8 
mg/dL after 14 days should be 
removed from study. 
Grade 4 hematologic AE related to cediranib or olaparib 
that does not resolve to absolute neutrophil count 
1000/mcL, platelets 100,000/mcL, and hemoglobin 
8 mg/dL despite maximum supportive care after 14 
days. 
Remove patient from study. 
 
For AEs that are unrelated to the study drugs, study drug may be held for up to 14 days at the 
discretion of the treating investigator.  Drug holds of greater than 14 days for unrelated AEs 
where the patient is experiencing ongoing clinical benefit may be considered after discussion 
with the overall PI. 
 

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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 overall PI, 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 overall PI.  
6.3 
Hypertension  (SEE APPENDIX G for Suggested 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 one week, then BP monitoring can be 
reduced to once daily. Should further hypertension arise, return to twice daily monitoring, until at 
least one week 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 >2 weeks for management of hypertension, management 
should be discussed with the study PI and may require discontinuation of protocol therapy. 
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.  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 reduce the dose of cediranib is expected to cause a decrease in BP.  The treating 
physician should monitor the patient for hypotension and adjust the number and dose of 
antihypertensive medications accordingly. 
 
 
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) 
• If patients require a delay of >2 weeks for management of hypertension, discontinue protocol 
therapy 
• Patients may have up to 4 drugs for management of hypertension prior to any dose reduction 

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in cediranib 
• Hypertension should be graded using the NCI CTCAE v5.0 
• Note: Stopping or reducing the dose of cediranib is expected to cause a decrease in BP over 
several days. Continue to monitor BP twice daily.  
 
The treating physician and patient should monitor BP for hypotension and adjust the number 
and dose 
of antihypertensive medications accordingly. 
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 
none 
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 
unless otherwise 
clinically 
necessary 
Consider renal 
consult 
Increase 
frequency of 
monitoring until 
stabilized 
Do not hold 
cediranib unless 
otherwise 
clinically 
necessary 
Grade 3 
Requiring more 
than one drug or 
Maximize 2 drug 
regimen 
Increase 
frequency of 
Do not hold 
cediranib unless 

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more intensive 
therapy than 
previously. 
• 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. 
monitoring until 
stabilized 
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 
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 
Intensive BP 
monitoring 
(hospitalization 
if 
necessary) 
Hold cediranib. 
If BP is reduced 
to 
less than 140/90 
within 7 days, 
cediranib may be 
resumed at a 
reduced dose 
after discussion 

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to maximize the 
full 
effect of 
antihypertensive 
agents. 
with the Study PI 
and/or sponsor. 
 
 
6.4 
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. 
UPC > 3.5 OR 
Creatinine >1.5x ULN Perform UPC prior to each cycle. 
Hold cediranib for up to 7 
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 Table 
6.2. 

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61 
 
 
6.5 
Decrease in LVEF  
Patients who have any of the following should undergo an echocardiogram (ECHO) or multi-gated 
acquisition (MUGA) scan at baseline and every four cycles while on study, or whenever clinically 
indicated: 
1. Prior treatment with anthracyclines 
2. Prior treatment with trastuzumab 
3. A NYHA classification of II controlled with treatment (see Appendix B)  
4. Prior central thoracic RT, including RT to the heart 
5. History of myocardial infarction within the prior 12 months 
 
The decision to continue or hold cediranib/olaparib is based on the LVEF as it relates to the 
institution’s lower limit of normal (LLN) and change in ejection fraction from screening (LVEF 
as measured at registration) according to the following table. If the institution’s LLN is not 
specified, 
an 
LVEF 
of 
55% 
should 
be 
considered 
the 
LLN 
threshold: 
 
Management and Monitoring of Decreased LVEF 
 
Relationship of 
LVEF to 
Institution’s LLN 
LVEF 
Decrease 
from screening 
<10% 
LVEF 
Decrease 
from screening 
10-15% 
LVEF 
Decrease 
from screening 
>16% 
Normal 
Continue 
Continue 
Continue and 
repeat1 
MUGA/ECHO within 
1-2 cycles 
1-5% below LLN 
 
Continue and 
repeat1 
MUGA/ECHO within 
1-2 cycles 
Continue and 
repeat1 
MUGA/ECHO within 
1-2 cycles 
HOLD and 
repeat MUGA/ECHO 
within 1-2 cycles 
>6% below LLN 
 
Continue and 
repeat1 
MUGA/ECHO within 
1-2 cycles 
HOLD and 
repeat1 
MUGA/ECHO within 
1-2 cycles 
HOLD and 
repeat MUGA/ECHO 
within 1-2 cycles 
1: Repeating ECHO will be at the discretion of the treating physician 

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6.6 
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. 
 
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. 
 
For either persistent grade 2 diarrhea or grade 
3 or 4 diarrhea:   
Follow General Management of Adverse 
Events (Non-Hematologic) guidelines in 
Section 6.2.  
 
6.7 
Fever and Neutropenia  
 
Patients who develop fever and neutropenia will be managed via standard medical practice and 
American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network 
(NCCN) guidelines.   
For uncomplicated infections (e.g., community acquired-pneumonia, UTI, cellulitis etc) on oral 
antibiotic as an outpatient, patient may resume study therapy upon recovery of ANC to 1500 and 
afebrile for at least 48 hrs, while continuing antibiotics 
For complicated infections (sepsis, bacteremia), patients will need to recover from fever and active 
infectious issues prior to resuming therapy.  
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 of the last dose of study treatment. 
Study treatment can be restarted at the same dose if an AE of neutropenia or leucopenia have been 
recovered up to CTCAE Grade 1 (ANC 1.5 x 109/L). Growth factor support should be stopped 
at least 24h before restarting study drug (7 days for pegylated G-CSF). Any subsequent 
interruptions 
will 
require 
study 
treatment 
dose 
reductions. 

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63 
 
6.8 
Nausea and Vomiting 
 
Events of nausea and vomiting are known to be associated with olaparib treatment.  They are 
generally mild to moderate (CTCAE Grade 1 or 2) severity, intermittent and manageable on 
continued treatment.  No routine prophylactic anti-emetic treatment is required at the start of study 
treatment; however, patients should receive appropriate anti-emetic treatment at the first onset of 
nausea or vomiting and as required thereafter, in accordance with local treatment practice 
guidelines. 
 
If a continued anti-emetic is regimen is required, a dose reduction may be considered.  
 
6.9 
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. 
 
6.10 
Gastrointestinal Perforation 
 
Gastrointestinal perforation, sometimes associated with fistula formation, has been observed in 
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.  
 

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64 
6.11 
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.   
 
6.12 
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 

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65 
overall PI. 
 
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.  
 
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   

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66 
 
 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) 
 
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 
  

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67 
 
 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%)  
  
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 
  
 
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 

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68 
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; 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 

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69 
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 
 
 
 
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) 

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70 
 
 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%) 
 
 
                                                    
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
IMMUNE SYSTEM DISORDERS 
  
 
 
Allergic reaction 
  
INFECTIONS AND INFESTATIONS 
  
 
Upper respiratory infection 
 
  
 
Urinary tract infection 
 
  
INVESTIGATIONS 
  
 
Creatinine increased 
 
  
 
Neutrophil count decreased 
 
 Neutrophil count decreased 
(Gr 4) 
 
 
Platelet count decreased 
  
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
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) 
  

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71 
 
 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%) 
 
 
 
Skin and subcutaneous tissue 
disorders - Other (erythema 
nodosum) 
  
 
NOTE: New Primary Malignancies other than MDS/AML 
New primary malignancies have been reported in <1% of patients. There were other contributing 
factors/potential alternative explanations for the development of the new primary malignancy in all cases, 
including documented BRCA mutation, treatment with radiotherapy and extensive previous chemotherapy 
including carboplatin, taxanes, anthracyclines and other alkylating and DNA damaging agents. Most are 
not attributed to olaparib. 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
 
Adverse events reported on olaparib (AZD2281) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that olaparib (AZD2281) caused the adverse 
event: 
 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (nodal rhythm); Chest pain - cardiac; 
Sinus 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 

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72 
leukoencephalopathy syndrome; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Hallucinations; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other 
(decreased glomerular filtration rate); Renal and urinary disorders - Other (hydronephrosis); Urinary tract 
obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Hypoxia; Oropharyngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal 
disorders - Other (chronic obstructive pulmonary disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Pruritus 
VASCULAR DISORDERS - Arterial thromboembolism; Flushing; Hot flashes; Hypertension; Hypotension; 
Peripheral ischemia; Thromboembolic event 
 
 
 
 
Note: Olaparib (AZD2281) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
7.1.1.3 
CAEPR for [18F]Fluoromisonidazole (FMISO, NSC 742,836) 
 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
for 
Fluorine-18 Fluoromisonidazole (18F-FMISO, NSC 742836) 
 
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, 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 via AdEERS (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.  Below is the CAEPR for Fluorine-18 Fluoromisonidazole (18F-FMISO). 
 
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 1.1, July 11, 20181 
 
Adverse Events2 with Possible 
Relationship to Fluorine-18 Fluoromisonidazole 
(CTCAE v5.0 Term) 
 
Specific Protocol Exceptions to Expedited 
Reporting (SPEER) 
 
 
 
No AEs reported in human studies. 
 
 
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. 
 

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73 
Note:   No adverse events have been attributed to Positron-Emission Tomography (PET) 
imaging/diagnostic administration of Fluorine-18 Fluoromisonidazole (18F-FMISO) at the levels described 
in the Investigators Brochure.  Therefore, no adverse events are expected as a result of the intravenous 
(IV) administration of Fluorine-18 Fluoromisonidazole (18F-FMISO) for typical PET imaging applications 
such as tumor hypoxia.   
 
Note:  As with many IV administered agents, Fluorine-18 Fluoromisonidazole (18F-FMISO) could cause 
an allergic reaction that could potentially pose a threat to life (anaphylaxis).  This has not been observed 
in limited human exposure to date.  Reasonable precautions should be taken, consistent with normal 
radiologic and clinical facility practice.  The patient should be monitored until the PET procedure is 
completed, and trained personnel and emergency equipment should be available per facility standards. 
  
For purposes of informed consent regarding reasonably foreseeable risks to subjects in trials 
utilizing Fluorine-18 Fluoromisonidazole (18F-FMISO), the following potential adverse events are 
considered extremely rare: 
 
 
Injection-related risks that may include infection, or accidental extravasation of the dose that 
may lead to discomfort, localized pain, or infection.  
 
Risks related to allergic reaction/anaphylaxis that may be life threatening. 
 
Note: As with all PET imaging agents, Fluorine-18 Fluoromisonidazole (18F-FMISO) is a 
radiopharmaceutical that decays with positron emission.  As such, it poses an intrinsic radiation exposure 
risk.  However, when administered in accordance with the Investigator’s Brochure as a PET imaging 
agent, this risk is felt to be extremely small.  The organ and total body doses associated with Fluorine-18 
Fluoromisonidazole (18F-FMISO) PET imaging are comparable to or lower than those associated with 
other widely used clinical nuclear medicine procedures.  
  
Note: Fluorine-18 Fluoromisonidazole (18F-FMISO) 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. 
 
 
 
7.2 
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 
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. 

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74 
- 
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 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for other 
e-mail recipients.  
 
The Coordinating Center of the Corresponding Organization is responsible for submitting 
to the CTSU documentation of AEs that they deem reportable for posting on the CTSU 
protocol web page and inclusion on the CTSU bi-monthly broadcast. 
 
 
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 

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75 
disease process) should be submitted.   
 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention1, 2 
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 
Timeframes 
Grade 
2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting 
in 
Hospitalization  
 24 hrs 
10 Calendar Days 
24-Hour 
5 
Calendar Days 
Not resulting in 
Hospitalization  
 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be 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 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
x 
Grade 3 adverse events 
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 
 

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76 
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.  
 
Indicate form for reporting in Rave, timeframes, and if loading of the pathology report is required. 
 
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.  

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77 
 
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 AND IMAGING AGENT INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
8.1 
CTEP and CIP IND Agents 
 
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 

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78 
(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. The bottles are child-resistant. 
 
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 20°C to 25°C (68 to 77°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.  
 
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 Į1-acid glycoprotein accounting for most of this binding. Use caution 
in patients taking concomitant medications with narrow therapeutic ranges that are also 

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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) 
 
Chemical 
Name: 
 
4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-
fluorophenyl)methyl]phthalazin-1(2H)-one 
 
Other Names: AZD2281; KU-0059436; CO-CE 42 
 
Classification: PARP inhibitor 
 
CAS Registry Number: 763113-22-0 
 
Molecular Formula: 
 C24H23FN4O3 
 
M.W.: 434.46 
 
Approximate Solubility: 0.1 mg/mL pH independent solubility across physiologic range 
 
Mode of Action: Olaparib is an inhibitor of subclasses 1, 2, and 3 of polyadenosine 5’ 
diphosphoribose polymerase (PARP-1, PARP-2, and PARP-3). In tumors that are deficient in 
the homologous recombination DNA repair pathway (example, BRCA mutants), inhibition 
of PARP by olaparib causes accumulation of DNA double-strand breaks and genomic 
instability. Olaparib may also enhance the effects of DNA damage caused by ionizing 
radiation and chemotherapy.  
 
Description: crystalline solid 
 
How Supplied: AstraZeneca supplies and the CTEP, DCTD distributes olaparib as green, 

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80 
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.   
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.  In this study, the morning dose 
should be taken approximately 1 hour after the cediranib dose, with a light meal/snack. The 
evening dose can be taken with a light meal/snack. 
 
 
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.   
 

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81 
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). 
 
8.1.3 [18F]FMISO (Yale DMF) 
 
The FMISO will be under NCI’s IND but using the Yale DMF. 
 
Chemical name 
 
CAS: 
 
1H-Imidazole-1-ethanol, Į-(fluoro-18F-methyl)-2-nitro- 
 
IUPAC:  
1-([18F]Fluoro)-3-(2-nitro-imidazol-1-yl)propan-2-ol 
 
 
Chemical structure, chemical formula, and molecular weight 
 
 
 
N
N
HO
18F
NO2
 
 
 
Formula: C6H8FN3O3 
 
 Molecular Weight: 189.14 
 

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82 
CAS registry number 
 
[F-18]: 
104613-87-8 
[F-19]: 
13551-89-8 
 
Synonyms 
 
[F-18]FMISO 
Fluoromisonidazole 
1-(2-Hydroxy-3-fluoropropyl)-2-nitroimidazole 
1-(2-Nitro-1-imidazolyl)-3-fluoro-2-propanol 
 
Abbreviation/Code name 
 
FMISO 
 
Formulary composition   
 
The final product is formulated in  about 0.1 mL of absolute ethanol, 10.9 mL of sterile 
saline, with a final ethanol concentration of <1%.  Table X is a summary of the components 
contained in each batch of the formulated drug product. 
 
Final dosage form 
 
Sterile, apyrogenic solution. 
Table X. Typical Qualitative and Quantitative Components and Composition for Each 
Batch of [F-18]FMISO for Injection. 
 
Component 
Total Quantity 
Unit Quantity 
Volume 
11 mL 
N/A 
[F-18]FMISO 
 5 mCi 
 0.45 mCi/mL 
0.9% 
NaCl 
Injection, USP 
10.9 mL 
0.99 mL/mL 
Ethanol, absolute, 
USP 
0.1 mL 
0.01 mL/mL 
 
Route of administration 
 
Intravenous injection. 
 
Fluorine-18 
labeled 
misonidazole, 
1H-1-(3-[18F]-fluoro-2-hydroxy-propyl)-2-nitro-
imidazole, or [18F]FMISO, is a radiolabeled imaging agent that has been used for 
investigating tumor hypoxia with positron emission tomography (PET).   
 
Radiation Dose to Human Subjects 
Dosimetry and absorbed dose calculations: 

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18F is a positron emitter with a half-life of 110 minutes. Intravenously injected [18F]-
FMISO distributes throughout the total body water space, crossing cell membranes, 
including the blood-brain-barrier, by passive diffusion.  [18F]FMISO is bound and retained 
within viable hypoxic cells in an inverse relationship to the O2 concentration.  The uptake 
of [18F]FMISO in normal human tissues has been measured and used to estimate the 
radiation absorbed dose associated with the imaging procedure.  Dosimetry studies were 
performed at the University of Washington and have been published in the peer-reviewed 
Journal of Nuclear Medicine [136]. Briefly, absorbed dose calculations were based on the 
biodistribution data for [F-18]FMISO in 60 patients (55 males, and 5 females), and were 
calculated from S values obtained from MIRDOSE 2 according to MIRD.  The radiation 
dose estimates indicate that the maximum permissible single study dosage of [F-
18]FMISO, to remain below the 21 CFR 361.1 dose limit, is 64.4 mCi to a 70 kg human 
subject, (i.e., calculations based upon the urinary bladder wall as the critical organ; 5 rem 
per single study limit and 0.0777 rem/mCi of [F-18]FMISO to the urinary bladder wall 
with 2-h voiding intervals. 
 
 
Table: Radiation Absorbed Dose to Organs 
 

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84 
 
 
 
 
 
 
 
 
 
Availability: 
[F-18]FMISO is an investigational imaging agent and will be manufactured at the Yale 
PET Center under the NCI IND and conforms to the specifications of the NCI IND. [F-
18]FMISO has been produced regularly at The Yale PET Center for research use under 
RDRC.  
 
Single study dose limit 
 
The proposed radioactivity dose is 5 mCi per single study, which is below the permissible 
single study of 64 mCi based on dosimetry calculations. 
 
Method of radioassay 
 
Each dosage of [F-18]FMISO for injection will be assayed in the dose syringe using the F-
18 setting of a calibrated Capintec dose calibrator in the dispensing room prior to human 
subject administration.  
 
Mass Dosage of Active Ingredient 
The amount of injected drug is  15 ȝg ( 79.3 nmol) of FMISO. The use of FMISO at this 
mass dose is not expected to cause any clinically detectable pharmacological effects nor 
affect its accumulation in tumor cells in humans. [18F]FMISO has been used in healthy 
human subjects and patients with different cancers for many years all over the world. There 
is no evidence that nonradioactive and radioactive FMISO molecules display different 
biochemical behavior.   
 
Manufacturing of the Radioactive Drug Product 
Synthesis of the radioactive drug product is depicted in Scheme 1.  Briefly, [F-18]FMISO 
is synthesized from its O-THP- protected tosylate precursor (NITTP) via a bimolecular 
nucleophilic substitution reaction (SN2) with [F-18]fluoride in the presence of Kryptofix® 
222 followed by cleavage of the protecting group under acidic conditions. Purification with 
semi-preparative HPLC and formulation of the product with saline followed by terminal 
sterilization through filtration affords [F-18]FMISO for injection. Detailed manufacturing 
process and specifications for materials and reagents used in the manufacturing processes 
are described in the Master Batch Record. 
 

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85 
 
 
 
 
 
 
 
     
  
Scheme 1. Radiosynthesis of [F-18]FMISO 
 
           Quality Specifications of the Radioactive Drug Product 
 
The radioactive drug product [F-18]FMISO for Injection will meet the following minimum 
quality specifications.  
 
 
Visual appearance 
 
The final [F-18]FMISO for Injection shall be clear and colorless with no visual evidence 
of cloudiness or particulate matter.  In addition, there shall be no evidence of breach of 
integrity of the glass container and respective septum seal. 
 
 
 
pH 
The pH of the final [F-18]FMISO for Injection shall be between 4.6 and 8.  
 
Radiochemical purity 
The radiochemical purity shall be > 95% of the sum of all radioactive peaks.  
 
Chemical purity 
The maximum mass dose of FMISO shall be  15 Pg per injection, and  35 g of other 
UV absorbing impurities eluting >3 min at 327, 280 or 254 nm (specific impurity at ~4 
min 3g/ml; Specific impurity at ~6 min 4g/ml). To maintain this chemical purity 
specification, the final dose of [F-18]FMISO for Injection administered to a human  
subject, defined by the maximum carrier mass dose of 15 g and specific activity at the 
time of injection, will be further adjusted in order to contain no more than 35 g of 
non-carrier mass in its impurity content, or 5 mCi, whichever is less, in the final dose 
administered to a human subject. 
 
Radiochemical identity 
The HPLC retention time of [F-18]FMISO shall correspond, within  10% variation, 
to that of the retention time of FMISO, chromatographed under identical conditions. 
 
Specific activity 
The specific activity of [F-18]FMISO shall be measured and used to determine the 
maximum radioactivity dose to be administered that would result in no more than 15 
Pg of FMISO in a single injection.  
 
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    M
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,
,
 ''

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86 
Radionuclide identity 
Repeat assay of the final [F-18]FMISO for Injection, performed using a Capintec dose 
calibrator of established accuracy, shall result in a calculated T1/2 physical between 
100 and 120 minutes (T1/2 physical of F-18 = 109.8 minutes). 
 
Bacterial endotoxin level 
The final [F-18]FMISO for Injection shall contain no more than 175 EU/V of 
endotoxin level at the expiration time (EU is USP Endotoxin Unit and V is the 
maximum volume of injection, in mL).  
 
Residual Kryptofix K222 level 
The final [F-18]FMISO for injection shall contain no more than 0.05 mg/mL of 
Kryptofix K222, according to the FDA limit. 
 
Volatile organic impurities 
The final [F-18]FMISO for Injection shall contain no more than 0.41 mg/mL (i.e., no 
more than 0.041%, or 410 ppm) of acetonitrile. Acetonitrile is used in the synthesis 
process and is removed during the evaporation and the semi-preparative HPLC 
purification procedure. The validation studies and the QC analysis will confirm that the 
levels of acetonitrile is below the limits in the final [F-18]FMISO for Injection.  
 
Sterility 
The final [F-18]FMISO for Injection shall be sterile. Due to the time constraint 
imposed by its 109.8 minute radionuclidic half-life, [F-18]FMISO for Injection will be 
dispensed for administration prior to the completion of sterility testing; the latter being 
initiated as soon as possible after tracer preparation.Note that a final step in the 
preparation of [F-18]FMISO for Injection involves its passage through a sterile, 0.22 
Pm membrane filter for terminal sterilization, into a commercially available sterile, 
apyrogenic collection vial. 
 
                              Routine Quality Control Tests of the Radioactive Drug Product 
 
All QC procedures will be performed on the same portion of sample taken from the final 
  formulation of [F-18]FMISO for Injection.   
 
Expiration Dating/Product Stability 
 
The expiration period applied to the [F-18]FMISO for Injection will be dependent on the 
requirement to maintain a radiochemical purity of > 95%.  Based on radiochemical stability 
testing, a maximum expiration period of eight (8) hour post the final formulation of [F-
18]FMISO for Injection will be applied to the product.  
 
Reprocessing of the Final Product 
 
In accordance with GMP Guidelines § 212.71(d), the final PET drug product may be 
reprocessed according to written procedures if a batch is rejected for failure to conform or 

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87 
meet established specifications. For example, reprocessing includes pH adjustment; a 
second passage through a membrane filter in the event that the membrane failed the 
integrity test; and re-purification by solid-phase extraction or by HPLC to remove 
impurities. 
 
Labeling of the Radioactive Drug 
 
The final product vial will be stored in a lead shield.  The lead shield will be labeled to 
include the identity of the product ("[F-18]FMISO Injection") and the statements, 
"Caution: New Drug-Limited by federal law to investigational use", “Caution - Radioactive 
material”, “Do not use if cloudy or if it contains particulate matter”.  A sample of the label 
is shown below.  A copy of the same label will also be affixed to the batch production 
record. 
 
 
8.1.4 Agent Ordering and Agent Accountability 
 

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88 
8.1.4.1 
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.  In general, sites may order initial 
agent supplies when a subject is being screened for enrollment onto the study.  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.   
 
Sites may order agent supplies in OAOP when a patient is enrolled. Orders can be 
expedited overnight Monday-Thursday when the site provides courier information 
 
8.1.4.2 
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. 
8.1.4.3 
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. 
8.1.4.4 
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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89 
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 IB Coordinator: IBCoordinator@mail.nih.gov 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Details for specimen collection, preparation and shipping will be outlined in lab manuals 
that will be provided to the sites. 
 
9.1 
Hypoxia Imaging Study (Required from 6 evaluable participants in the NSCLC cohort 
and optional for the other participants) 
 
The hypothesis is that cediranib treatment induces tumor hypoxia detected by [18F]-FMISO 
PET/CT imaging and that the changes in tumor hypoxia correlate with response to the 
combination of cediranib and olaparib.   
 
FMISO, is a radiolabeled imaging agent that has been used for investigating tumor hypoxia 
with positron emission tomography (PET). An ideal hypoxia-imaging agent should 
distribute independently of blood flow, which is best achieved when the partition 
coefficient of the tracer is close to unity. Under these circumstances, imaging can be done 
at a time when the intracellular tracer distribution has equilibrated with the tracer in plasma 
near the cells. FMISO is an azomycin-based hypoxic cell sensitizer that has a nearly ideal 
partition coefficient and, when reduced by hypoxia, binds covalently to cellular molecules 
at rates that are inversely proportional to intracellular oxygen concentration, rather than by 
any downstream biochemical interactions. 
 
In the clinic, [18F]-FMISO has been shown to detect hypoxia in a variety of tumor types 
from soft-tissue sarcoma, H&N cancer, non-small cell lung cancer, breast cancer, and brain 
tumors [71, 77, 83-86]. For more detail, please see Section 2.4 of this protocol. 
 
In our study, [18F]-FMISO PET/CT scans will be performed at baseline and following 
cediranib monotherapy in the NSCLC cohort. Six evaluable patients with NSCLC will 
undergo 2 [18F]-FMISO PET/CT scans of the thorax. The first baseline scan will be 
obtained after the biopsy, the second scan will be acquired after cediranib monotherapy.  
 
See the Study Calendar for the timing of FMISO scans and biopsies. The interval between 
the first baseline biopsy and the baseline scan will be less than 48 hours. The interval 

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90 
between the second scan and the second biopsy will be also less than 48 hours. The 
cediranib exposure will be 3 once-daily doses of cediranib 30mg. In a case of major 
scheduling conflict an exception may be given after consulting with a P.I. that the second 
FMISO scan may be done on Study Day 4 after 4 once-daily doses of cediranib 30mg.  
 
Each dynamic [18F]FMISO PET scan consists of 3 parts and a CT will be performed before 
each part for attenuation correction. PET scans will be acquired from 0-120mins, 150-
180mins, and 210-240 mins post IV automated injection of a 4-5 mCi bolus of [18F]FMISO. 
Alternatively, a short protocol of dynamic FMISO PET scans could be acquired from 0-60 
min and 90-120 min.  PET/CT scans will be performed on the Siemens Biograph mCT 
PET/CT scanner at Yale PET center or other similar PET scanners at other institutions. An 
intravenous line will be placed for venous blood sampling at pre-determined times to 
provide an accurate value of the [18F]FMISO activity input function. 
 
Imaging Analysis: Tumor regions will be defined from the CT and PET images. A number 
of quantification measures will be used to compare pre- and post-drug hypoxia levels, 
including standardized uptake values (SUV), hypoxic volumes (HV), as well as tracer 
compartment kinetic modeling measures. Tumor to blood ratio (TBR) is defined as the 
ratio of the [18F]FMISO signal in each tumor voxel in the tumor region of interest (ROI) 
summed from 210-240 min or 90-120 min (from short protocol) to the average signal in 
heart over the same time frame post-injection. Threshold values used to define HVs by 
[18F]FMISO imaging impact the reliability and robustness of hypoxia quantification. Using 
a defined TBR threshold >1.2, HV percentages (fraction of tumor that is hypoxic) will be 
calculated based on absolute tumor volume defined by CT [131]. (Cheng J. J Nucl Med. 
2013) 
 
Image Interpretation: 
The summed [18F]FMISO imaging will be interpreted by experienced nuclear medicine 
physician visually, using a scoring system according to Rischin et al. (J Clin Oncol. 
2006;24:2098–2104). This scoring system has 5 classes: 0=uptake less than background; 
1=no regions of focal uptake greater than background; 2 = focal uptake mildly greater than 
background; 3=focal uptake moderately greater than background; and 4=focal uptake 
markedly greater than background. In a second step, these 5 classes will be grouped into 2 
classes and a score  2 is considered positive for hypoxia.  
 
TBR and HV imaging (TBR>1.2) will be generated and reviewed as well. HV will be 
calculated based on absolute tumor volume defined by CT.   
 
 
The interpretation will be done centrally by Yale investigators. The FMISO imaging must 
mailed to Dr. Ming-Kai Chen at the following address within 1 week of completing a 
pair of FMISO PET/CT scans:  
 
Positron Emission Tomography (PET) Center 
Yale University 
801 Howard Avenue 
PO Box 208048 

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91 
New Haven, CT 06520-8048 
Ph: (203) 737-YPET 
Fax: (203) 785-3107 
Email: ming-kai.chen@yale.edu 
 
The CT of the FMISO will not be used for disease assessment.  
 
9.2 
Integral Correlative Study 
None  
 
9.3 
Integrated Correlative Studies 
 
9.3.1 BROCA Panel – Integrated Laboratory Correlative Study 
 
9.3.1.1 
Introduction 
To assess correlation of response and effect of homologous recombination deficiency 
(HRD) status, the BROCA-HR assay, established by the Swisher laboratory will be 
applied. In addition to testing the tumors, a blood sample will be obtained at baseline for 
germline BROCA testing. Somatic BROCA testing will be done using the baseline tumor 
biopsy tissue in all the disease  cohorts.  
 
One hypothesis for responses to a PARP inhibitors, is that cancer cells need to be deficient 
in Homologous Repair (HR) but also proficient in the alternative error prone non-
homologous end joining (NHEJ) DNA repair pathway [118, 119]. Thus, loss of HR is not, 
by itself, sufficient for sensitivity to a PARP inhibitor, and an accurate predictor of 
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 
[120-122]. This genomic scar could serve as a downstream functional output to measure 
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 BROCA-HR panel will be applied 
to the tumor samples from all the disease cohorts as integrated biomarker to evaluate if 
“genomic scaring” can potentially predict outcome of the combination therapy cediranib/ 
olaparib, and if a correlation to the hypoxia markers that are the focus of the study, can be 
observed.  For more detail, please see Section 2.4 of this protocol. 
 
9.3.1.2 
Laboratory Testing BROCA-HR 
DNA will be extracted from PBMCs and FFPE archived 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 

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92 
350bp inserts will be prepared from 1g 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)[137]. 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 [138, 
139]. 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[139, 140]. 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.  
 
9.3.1.3 
Collection, Handling and Shipping  of Specimens 
 
Details for specimen collection, preparation and shipping will be outlined in a lab 
manual that will be provided to the sites. 
 
In short, tumor samples will be collected at each study site. Slides with cut tumor 
sections will be shipped from the participating site to Dr. Swisher’s lab at University 
of Washington for the analyses described in this section. In addition, a 7ml blood 
sample is required for the germline sequencing, which will be shipped to Dr. Swisher’s 
lab directly. 
 
9.3.1.4 
Site Performing Correlative Study 
Dr. Elizabeth M. Swisher, MD 
University of Washington 
1959 NE Pacific St 
Health Sciences Building K154 
Seattle, Washington 98195-6460 
Phone: 206-543-3669  
swishere@uw.edu   
 
 
9.4 
Exploratory/Ancillary Correlative Studies 
 
9.4.1 Angiome Panel (Required in all study participants) 
 

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93 
9.4.1.1 Introduction 
VEGF increases on treatment with VEGF signaling inhibitors have been observed across 
multiple studies with cediranib and other VEGF signaling inhibitors. VEGF is regulated 
by hypoxia and will serve as a well established marker for hypoxia [61, 141-143]. VEGF  
levels will be measured at multiple timepoints, baseline, on cediranib monotherapy, on 
combination therapy, and at the end of the study. Additional biomarkers for angiogenesis 
will be measured in parrallel. The laboratory of Dr. Andrew Nixon has established a panel 
of angiogenic and inflammatory markers that can be measured in plasma from patients in 
a multiplexed ELISA format. All samples will be assessed at Duke University Medical 
Center.  All but one of the markers will be analyzed using the CiraScan system, produced 
by Aushon Biosystems.  The remaining marker, TGFERIII, will be analyzed using standard 
ELISA reagents from R&D Biosystems (Minneapolis, MN). The assays are designed as 
sandwich ELISAs and samples (patient plasma) or standards are added which bind to the 
specific capture antibodies and are detected using various outputs.  Each commercial 
vendor provides calibrators or standards.  Soluble TGFERIII will be detected using a 
Biotek ELx808IU-PC Absorbance Microplate Reader, while all other markers will be 
detected using the Aushon CiraScan Imaging and Analysis system.  All data collected will 
be quantitative with a continuous distribution of data across the range tested.  For more 
detail, please see Section 2.4 of this protocol. 
 
9.4.1.2 Collection, Handling and Shipping of Specimens 
 
 
Details for specimen collection, preparation and shipping will be outlined in a lab manual 
that will be provided to the sites. 
In brief, blood samples will be collected at each site, and samples must be processed within 
one hour of collection. For plasma samples, blood will be drawn into 10 ml purple top 
(K2EDTA) tubes and processed to obtain plasma as per lab manual. Plasma should be 
dispensed into cryovials in 1mL aliquots, and frozen at -80oC until shipping. As plasma 
samples are analyzed in a retrospective manner, samples should be stored at the sites at -
80°C and shipped in batches at a later time to be agreed with the analyzing laboratory.  
 
 
9.4.1.3 Site Performing Correlative Study 
  
Phase I Biomarker Laboratory 
 
Andrew Nixon, PhD 
Duke University Medical Center 
395 MSRB, Research Drive 
Durham, NC 27710 
 
Phone: (919) 681-2239 
andrew.nixon@duke.edu 
 
 
 

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94 
9.4.2 Plasma circulating tumor DNA (Required in all study participants) 
  
9.4.2.1 Introduction 
 
For many types of cancer, serum protein biomarkers to monitor therapeutic efficacy 
either do not exist or are not very robust.  For example, there are currently no blood 
biomarkers that are in routine clinical use to track response to therapy in patients with 
non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).  In patients with 
advanced breast and pancreatic cancers, the blood markers CA 27.29, CEA, and CA 19-9 
can be used to monitor treatment response and to detect disease progression.  However, 
these markers suffer from lack of cancer specificity, as serum levels can be elevated in 
patients with other types of cancer and can also be elevated in non-malignant conditions 
such as cirrhosis, inflammatory bowel disease, hepatitis, and renal impairment, among 
others.  Moreover, serum levels of protein markers typically change gradually, making it 
difficult to obtain a rapid assessment of the effectiveness of a therapy.  Thus, new blood 
biomarkers with greater specificity and faster response kinetics could provide a more 
reliable and rapid assessment of treatment efficacy to guide therapeutic decision-making.   
 
Recent technological advances have made it possible to detect and quantify small 
amounts of cell-free tumor-derived DNA fragments in the bloodstream of patients with 
various types of cancer [97-102].  Such circulating tumor DNA (ctDNA) is believed to be 
released from dying cancer cells, and is showing excellent promise as a cancer biomarker 
[103, 104].  Tumor-derived DNA can be distinguished from normal background cell-free 
DNA in plasma based on the presence of tumor-specific somatic mutations.  Because 
somatic mutations are a hallmark of cancer, circulating tumor DNA should in principle be 
identifiable in all types of malignancies.  False-positive results are expected to be 
extremely uncommon since cancer-associated mutations should rarely be found in plasma 
in the absence of malignancy.  Furthermore, because there is no physiologic background 
level, a small amount of mutant DNA released from a small tumor should be detectable if 
the technical background (error rate) of the assay can be minimized. It has also been 
observed (in our lab and by others) that ctDNA exhibits much more rapid posttreatment 
kinetics than protein markers.  Most protein markers typically show a decline with 
successful therapy over several months, whereas ctDNA can show a dramatic decline 
within ~2-3 weeks [102]. While most protein markers are secreted by living and growing 
cancer cells, ctDNA is a byproduct of dying cancer cells, and it is rapidly cleared from 
the blood with a half-life of ~2 hours [105]. Thus, ctDNA provides a real-time estimation 
of active tumor cell death, rather than simply a measure of tumor burden.  In several 
cases, we have observed an initial spike in ctDNA levels within the first few days after 
beginning treatment (likely due to tumor kill), followed by a substantial decline below 
pre-treatment levels after the initial wave of cell death has subsided.  This can lead to an 
exaggerated difference between pre- and post-treatment levels, suggesting that ctDNA 
may be a more responsive marker of therapeutic efficacy.   
 
Patel laboratory has developed an ultrasensitive assay for measuring small amounts of 
cell-free mutant DNA released into the blood from dying tumor cells[102, 106].  The 
assay uses next-generation sequencing combined with novel error suppression techniques 

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95 
to enable measurement of rare mutant ctDNA down to a fractional abundance of ~0.02%.  
Coverage of a broad panel of mutation-prone genomic regions ensures that ctDNA can be 
detected in the majority of patients with common solid malignancies.  The assay has been 
tested on over 1500 clinical samples thus far.  Indeed, in patients receiving 
chemotherapy, targeted therapy, surgery, or radiation therapy, we have observed that 
ctDNA levels usually decrease substantially during successful treatment (sometimes with 
a transient spike due to tumor kill).  However, longitudinal testing of the assay has been 
performed mostly on heterogeneous populations of patients who were treated with a 
variety of regimens.  To more rigorously evaluate the performance of the assay, here we 
plan to obtain blood samples at well-defined intervals from a population of patients 
having 4 different types of cancer, all receiving uniform treatment in the setting of a 
clinical trial. For more detail, please see Section 2.4 of this protocol. 
 
9.4.2.2 Collection, Handling and Shipping of Specimens 
 
Details for specimen collection, preparation and shipping will be outlined in a lab manual 
that will be provided to the sites. 
In brief, plasma should be collected in 10 mL purple-top EDTA-containing vacutainer 
tubes and gently turned end over end 3-4 times upon collection to dissolve the EDTA and 
prevent coagulation.  Tubes can then be kept at room temperature, and should be 
centrifuged at 1000 x g for 10 minutes in a clinical centrifuge within 4 hours of collection 
(sooner is better).  Tubes should be carefully balanced in the centrifuge to avoid vibrations 
which might disrupt WBCs.  The centrifuge should be stopped in "brake off" mode. 
 
Plasma should be dispensed into cryovials in 1mL aliquots, and frozen at -
80oC.  Care should be taken to avoid the buffy coat by not pipetting the last 5mm of plasma 
above the buffy coat layer.  Once the plasma is frozen, it should not be thawed until it 
is ready to be processed for sequencing.  
 
As plasma samples are analyzed in a retrospective manner, samples should be stored at 
collection sites shipped in batches at a later time to be agreed upon with the analyzing 
laboratory.  
 
9.4.2.3 Site Performing Correlative Study   
 
 
 
 
Laboratory of Dr. Abhijit Patel 
 
 
Department of Therapeutic Radiology 
 
Yale School of Medicine 
 
15 York Street 
 
Room HRT 213C 
New Haven, CT 06510 
Abhijit.Patel@yale.edu

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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. Holding the study medication(s) or not taking the study medications prior to research samples collection or 
safety assessment is not considered a study deviation. The study Day continues to roll along with calendar day even in the days of 
dose interruptions.  
 
 
 
Cycle  (C) 1 (D1-35) 
Cycle 2 
(D1-28) 
 
C3 and later 
(D1-28) 
End 
of 
Treat
ment 
 
Day (D)  
-30 to -1 
D 
-2 to 0  
D1 
D2 
D3 
D 4 
to 7 
D8 
+/- 3 ds  
D15 
+/- 3 ds 
D1 
+/- 3 ds 
D15 
+/- 3 ds 
D1 +/-
3 ds 
D15+
/- 3 ds 
 
Cediranib 
 
 
X 
X 
X 
X 
X------------------------------------------------------- > 
 
Olaparib 
 
 
 
 
 
X1 
X ------------------------------------------------------- > 
 
Home BP  monitoring 2 
 
 
X -------------------------------------------------------------------------------------------------- > 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Registration 
           X 
 
 
 
 
 
 
 
 
 
 
 
 
Biopsies3  
 
  X4 
 
 
 
 
 
 
 
 
 
 
 
FMISO5 
 
          X6 
 
 
X6 
 
 
 
 
 
 
 
 
Archival Tissue submission 
(optional)3A  
                                                                                    
                                                                                           X 
Research blood for germline 
BROCA testing7 
                        X 
Research Blood (Angiome 
panel)8 
 
X9 
 
 
 
X10 
 
X11 
X11 
 
X11 
 
X 
Research blood (ctDNA) 8 
 
X9 
 
 
 
X10 
 
X11 
X11 
 
X11 
 
 
X 
RECIST v1.1 Tumor 
Assessment 
X 
 
 
 
 
 
 
 
 
 
X12 
 
X16 
Brain MRI 13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
H&PE, VS, PS, Conc Meds,  
Toxicity Assessment 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 

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97 
Serum Chemistry14,  CBC 
w/diff, Urine Protein/Creatinine 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Cycle  (C) 1 (D1-35) 
Cycle 2 (D1-28) 
 
C3 and later 
End 
of 
Treat
ment 
 
Day (D)  
-30 to -2 
D 
-2 to 018  
D1 
D2 
D3 
D 4 
to 7 
D8 
+/- 3 ds  
D15 
+/- 3 ds 
D1 
+/- 3 ds 
D15 
+/- 3 ds 
D1+/- 
3 d 
D15+/
- 3 ds 
 
INR and PTT 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
TSH and free T415 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO and abdominal US (if 
indicated) 17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 15 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
FOOTNOTES: *** NOTE Cycle 1 has 35 days. Cycle 2 and subsequent cycles have 28 days *** 
1: For patients undergoing FMISO scans, olaparib starts after the pre-dose research labs are collected, on the day after the second FMISO scan. 
For the rest of the study patients, olaparib dosing starts on Day 4 (preferred) after the pre-dose research labs are collected. In case of scheduling conflicts, 
olaparib may start on any day between 4 and 7. 
2: Patients must be advised to monitor home blood pressure twice a day for at least one week. Once deemed stable, then it may be reduced to once a day. 
Should further hypertension arise, return to twice daily monitoring, until at least one week of stability then can return to daily. 
3: Mandatory for all study patients except those who can provide an archival tissue collected within the 3 months prior to the registration with no interval 
systemic therapy. The exception must be discussed with the study PI. 
3A: If a subject is not undergoing a research baseline biopsy, archival tissue submission should be done within the first 8 weeks of the study. For the subjects 
who are opting in to provide additional archival tissue submission, it may be done at any time after discussing with the study PI. 
4: The baseline biopsy should be obtained on either Day -2 or Day -1 before the baseline FMISO PET/CT scan (Day 0). For those not getting FMISO scans, the 
baseline biopsy should be obtained on either Day -2 or Day -1. At least one day (Day 0) must pass after the biopsy before the start of C1D1 cediranib.  
5: Mandatory for 6 evaluable NSCLC patients. For the rest of NSLCL patients, it would be optional and highly encouraged when a participating site has 
funding. 
6: Baseline FMISO scan should be done on Day 0 after the baseline biopsy (Day -1 or Day -2). The second FMISO scan should be done after 3 daily doses of 
cediranib on Day 3.  In case of a major scheduling conflict, the second FMISO scan may be done on Day 4 after the 4th daily dose after discussing with the 
Study P.I.  
7: Research blood for germline BROCA testing is necessary complete BROCA testing.  Therefore, it is mandatory for those who are getting biopsy or those 
submitting archival tissue for somatic BROCA testing. Preferably, it should be collected along with the baseline research labs.  
8: Mandatory for all study patients.  
9: Baseline research blood samples should be collected on the day of, prior to the biopsy.  
10: The second research blood samples should be collected on the day of olaparib add-in before the dosing of the study drugs (cediranib and olaparib) (See 
footnote 1 above).   
11: All the subsequent blood samples should be collected before the dosing of the study drugs. 
12: Restaging scans should be done within 7 days before or on Day 1 of cycles 3, 5, 7, 10 and every 3rd cycle thereafter, or earlier if clinically indicated. 

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98 
13: Screening Brain MRI is required for NSCLC, TNBC and SCLC. For PDAC, Brain MRI is required only if clinically indicated. CT Head/Brain is acceptable 
if MRI is contraindicated. 
14: Na, K, Chloride, Bicarbonate, BUN, Cr, Glucose, Calcium, Phosphorus, Magnesium, Albumin, Total Protein, Alkaline Phos, ALT, AST, Total Bilirubin. 
15: Mandatory at baseline. Encouraged to monitor during treatment at the discretion of the treating physician.  
16: The restaging scans at the EOT should be done only if clinically indicated especially for the subjects who are coming off treatment due to reasons other than 
disease progression.  
17: Echocardiogram is indicated at screening only if inclusion 3.1.12 is applicable, and after every 4 cycles while on study if Section 6.5 is applicable, and 
anytime during the study if clinically indicated.  Abdominal US is indicated only if exclusion 3.2.15 is applicable and anytime during the study if clinically 
indicated. 

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99 
11. MEASUREMENT OF EFFECT 
 
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 6-8 (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 monotherapy-lead-in, cediranib in combination with 
olaparib, or FMISO infusion.  
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression, or unequivocal clinical progression prior to the end of 
cycle 1 will also be considered evaluable. Patients who failed to start the cycle 1 day 1 
treatment will be considered not 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 tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area are not be 
considered measurable unless the irradiated demonstrated showed radiographic 
progression on previous scans. 
 

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100 
 
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.  
 
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 

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101 
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.   
 
The investigators should use CT scans at diagnostic quality for restaging. In order to use 

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102 
PET/CT for staging, CT has to be in diagnostic quality (with oral and intravenous 
contrast).It will only be used for restaging only if it was used for the baseline screening.  
 
In the setting of CT contrast is contraindicated (e.g., steroid refractory of contrast allergy, 
or renal insufficiency).  MR of abdomen and pelvis with gadolinium, and CT Chest 
without contrast will be acceptable. 
 
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 

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103 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
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. 

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104 
 
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 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 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. 
**    Confirmation is required for response. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may 
beaccepted 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 

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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 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.  
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
11.1.7 Response Review 
Radiology assessments for Yale site will be provided by the Yale tumor metric core. 
Assessment for other participating sites should be performed per the site’s own tumor 
metric core. 
 
 
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). 
 

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106 
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. 
During the Phase 2 portion of the study, the Protocol Principal Investigator will have, at a 
minimum, quarterly conference calls with the Study Investigators and the CTEP Medical 
Officer(s) to review accrual, progress, and pharmacovigilance.  Decisions to proceed to the 
second stage of a Phase 2 trial will require sign-off by the Protocol Principal Investigator and the 
Protocol Statistician. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
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 (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 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. 
 
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 

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107 
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. More frequent audits may be conducted if warranted by accrual or due to concerns 
regarding data quality or timely submission. For CTMS monitored studies, after users 
have activated their accounts, please contact the Theradex Help Desk at (609) 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. 
 
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 

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108 
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. 
 
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 
CTEP Multicenter Guidelines 
 
Not Applicable  
 
12.4 
Collaborative Agreements Language 
 
The agents supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company 
(hereinafter referred to as “Collaborator”) and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 

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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 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 
 

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110 
12.5 
Safety Monitoring 
The site investigators will meet by teleconference at a monthly frequency for approximately 30 
minutes. The site investigator(s) and research staff involved with the conduct of the protocol are 
required to attend. During the monthly teleconference, the investigators will discuss: 
• 
Safety of protocol participants (AEs and reporting).  
• 
Validity and integrity of the data (data completeness on case report forms and 
complete source documentation) 
• 
Enrollment rate relative to expectation of target accrual (eligible and ineligible 
participants) 
• 
Retention of participants, adherence to the protocol, and protocol violations 
• 
Protocol amendments 
 
12.6 
Data Safety Monitoring Plan  
 
Each participating site will provide the primary oversight of data and safety monitoring in 
accordance with the enrolling institution’s data safety monitoring plan.  The summary DSMC 
report from each site should be provided to the Study PI whenever it is generated. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
This is an open-label, multi-cohort, phase II trial of cediranib plus olaparib in patients with 
advanced solid tumors of the following histopathology: NSCLC, TNBC, PDAC and SCLC.  The 
study utilizes a Simon 2-stage design to assess anti-tumor activity of the combination therapy in 
each of these disease cohorts running in parallel.  
Of note, the NSCLC, PDAC and SCLC cohorts uses the minimax design whereas basaloid TNBC 
and non-basaloid TNBC cohorts use the optimal design. The rationale for the minimax design for 
the NSCLC, PDAC and SCLC is because the combination therapy has never been tested in these 
tumor types. The minimax design allows the maximal number of patients during the stage 1 before 
the study may get terminated for futility. The optimal design was chosen for TNBC because the 
combination has been previously tested in TNBC patients in a small phase I study by Joyce Liu et 
al. (Eur J. Cancer 2013.)  While not definitive conclusion, the study suggested rather inactivity of 
the combination regimen in patients with TNBC. Therefore, optimal design was chosen to keep 
the exposure of the investigational regimen at minimum for TNBC patients during the stage 1 
before terminating the study for futility.   
Primary endpoint  
x The objective response rate (ORR) in each of the cohorts.  The responses will be assessed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The ORR is 
defined by the total number of patients with either complete response or partial response 
divided by the total number of patients evaluable per response assessment.  For best overall 
response, confirmation of response is required by the subsequent scans > 4 weeks apart.  
 
Secondary endpoints 
x Safety as measured by the risk of adverse events per NCI CTCAE v5.0.  All subjects who 
receive at least a dose of study medications will be included for safety analysis. 

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x Progression free survival (PFS): PFS is defined as the duration of time from start of 
treatment to time of disease progression or death, whichever occurs first. Subjects who 
remain alive and have not progressed or received new therapy will be censored on the date 
of last protocol specified tumor assessment. 
 
Exploratory endpoints:  
x Prevalence of the mutations of DNA repair genes in each tumor cohort.  
x Changes in tumor hypoxia by imaging, as measured by FMISO PET/CT scans at pre- and 
post-cediranib monotherapy. (NSCLC cohort) 
a) clinically relevant Hypoxic volume (HV) post cediranib based on tumor-blood ratio 
(TBR) > 1.2.  
b) score  2 post cediranib based on visual interpretation with 5-point scoring system. 
x Changes in level of circulating tumor DNA at pre- and post cediranib monotherapy and on 
combination therapy. (All cohorts) 
x Changes in levels of angiogenesis/ inflammatory markers (angiome panel) at pre- and post 
cediranib monotherapy and on combination therapy. (All cohorts) 
 
NSCLC and PDAC cohorts:  
A Simon (Minimax) two-stage design is utilized to develop interim analysis guidelines to evaluate 
if there is “minimal activity” to fully enroll the current study and to consider cediranib plus olaparib 
in combination for study in future trials. If there is evidence that the true underlying overall ORR 
is at least 20%, consideration will be given for further testing of cediranib plus olaparib in 
combination. However, if cediranib plus olaparib in combination is inactive in NSCLC, PDAC or 
TNBC patients, then the study should be terminated early. Initially, 18 eligible patients will be 
entered into the study.  If there is less than 1 response in these first 18 patients, the trial will be 
terminated. If there are at least one or more than one responses in these first 18 patients, the trial 
will continue until 32 patients have been treated. If there are less than 4 responses in these 32 
patients then the study will be terminated, otherwise a phase III study will be conducted in the 
future. This design provides 90% statistical power to detect a difference of 15% (20% vs. 5%) with 
a significance level less than 0.1 (type I error). 
 
TNBC cohort:  
A Simon (Optimal) two-stage design is utilized to develop interim analysis guidelines to evaluate 
if there is “minimal activity” to fully enroll the current study and to consider cediranib plus olaparib 
in combination for study in future trials. If there is evidence that the true underlying overall ORR 
is at least 20%, consideration will be given for further testing of cediranib plus olaparib in 
combination. However, if cediranib plus olaparib in combination is inactive in TNBC patients, 
then the study should be terminated early. Initially, 12 eligible patients will be entered into the 
study.  If there is less than 1 response in these first 12 patients, the trial will be terminated. If there 
are at least one or more than one responses in these first 12 patients, the trial will continue until 37 
patients have been treated. If there are less than 4 responses in these 37 patients then the study will 
be terminated, otherwise a phase III study will be conducted in the future. This design provides 
90% statistical power to detect a difference of 15% (20% vs. 5%) with a significance level less 
than 0.1 (type I error). 

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112 
 
SCLC Cohort: 
A Simon (Minimax) two-stage design described above is applied to the sample size estimation for 
this cohort. If there is evidence that the true underlying overall ORR is at least 30%, consideration 
will be given for further testing of cediranib plus olaparib in combination. However, if cediranib 
plus olaparib in combination is inactive in SCLC patients, then the study should be terminated 
early. Initially, 16 eligible patients will be entered into the study.  If there are less than 2 responses 
in these first 16 patients, the trial will be terminated. If there are two or more responses in these 
first 16 patients, the trial will continue until 25 patients have been treated. If there are less than 5 
responses in these 25 patients then the study will be terminated, otherwise a phase III study will 
be conducted in the future. This design provides 90% statistical power to detect a difference of 
20% (30% vs. 10%) with a significance level less than 0.1 (type I error). 
 
NOTE: Subjects who are not considered evaluable for objective response as defined in 11.1.1 
will be replaced.  
 
13.2 
Sample Size/Accrual Rate 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
2 
1 
2 
1 
6 
Asian 
3 
3 
3 
3 
12 
Native Hawaiian or 
Other Pacific Islander 
2 
2 
2 
1 
7 
Black or African 
American 
13 
4 
8 
4 
29 
White 
11 
7 
11 
7 
36 
More Than One Race 
11 
7 
11 
7 
36 
Total 
42 
24 
37 
23 
126 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
 

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113 
13.3 
Stratification Factors 
 
Not applicable  
 
13.4 
Analysis of Study Endpoints 
 
Statistical Analysis Plan:  
The effectiveness of the cediranib plus olaparib in combination in patients will be assessed by 
overall response rate (ORR). The exact two-sided 95% confidence interval for the ORR will be 
reported. 
For lifetime data analyses, e.g., PFS, the study progression free survival will be estimated using 
the Kaplan-Meier method with the 95% confidence intervals (CIs).  Thomas and Grunkemeier CI 
which was derived by minimizing the likelihood function under certain constraints will be 
reported. In addition, the possible risk factors such as stage and performance status, will be 
compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox 
model will be applied to investigate potential prognostic factors, such as age and stage of disease 
on the survival data.  The adjusted p-values of the hazard ratios and the adjusted 95% confidence 
interval will be reported.  
 
Statistical Plan for the Imaging Endpoint:  
With our 6 FMISO-evaluable patients with NSCLC, we will use descriptive statistical analyses 
such as paired t-test and Wilcoxon Sign Rank test, to compare [18F]-FMISO binding for the 
primary measure of tumor to blood ratio (TBR) and hypoxia volume (HV) for differences in 
tumor hypoxia within subjects and individual target tumors (up to 5 targets per subject) before 
and after cediranib treatment. We will use McNemar’s test to evaluate the categorical scores 
before and after cediranib within subjects. 
 
Other Exploratory Endpoints:  
In our first 20 endpoint-evaluable patients with NSCLC and 20 endpoint-evaluable patients with 
TNBC, the exploratory analyses will be done using Fisher’s exact tests, Mann-Whitney U tests 
or McNemar’s test will be applied depending the type of data we observe.  For the pre- and post-
cediranib therapy outcome analysis, paired t- test or Wilcoxon signed-rank will be applied for the 
continuous variables. McNemar’s test will be applied for categorical variables. Fisher’s exact test 
will be applied for the association between hypoxia positivity and objective response. We will 
use these information from to estimate the 95% confidence intervals for future pivotal trials. 
 
Analysis Plan for Safety Data: 
Safety will be measured by the risk of adverse events per NCI CTCAE v5.0.  All subjects who 
receive 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.  The PK parameters will be presented in the table and figure format.     
 
Sensitivity Analysis for Protocol Violations: 

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The sensitivity analyses will be performed to evaluate the study results excluding patients having 
a major protocol violation. 
 
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 monotherapy-lead-in, cediranib in combination with olaparib, or FMISO 
infusion.  
 
The following AEs categories will be reported separately: 
x The AEs observed with cediranib monotherapy. 
x The AEs observed with FMISO infusion during the study.  
x The AEs observed with cediranib in combination with olaparib.  
 
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.] 
 
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.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided. 
 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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APPENDIX B:  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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APPENDIX C 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 inhibitors or inducers of CYP3A4/5 are prohibited during the study.  
 
1. 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/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 Inhibitors of CYP3A are prohibited 
 
2. 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/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 Inducers of CYP3A are prohibited. 
 
 
 
 

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APPENDIX D  PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD  
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study 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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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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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.  
These are the things that you and they need to know: 

NCI Protocol #:9881 
Version Date: September 7, 2021 
 
130 
 
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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131 
APPENDIX E:    PILL DIARIES AND BLOOD PRESSURE MONITORING FOR CYCLE 1 (DAYS 1 THRU 35) 
Today’s Date ______________________________ 
Cycle #   1 
Patient Name ______________________________ 
Patient Study ID _________________ 
1. Complete one form for each cycle. 
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 doses. 
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 every 24 hours. Take on an 
empty stomach 1 hour before taking the 
morning dose of olaparib. 
 
OLAPARIB 
Take _____ (number) ______ mg tablets twice a day 
12 hours apart with a light meal. You should avoid 
grapefruit juice while on study because grapefruit 
juice affects the metabolism of olaparib. The 
morning dose should be taken approximately 1 hour 
after cediranib, with a light meal.  
Blood Pressures  
 
Call your study 
team if your BP is 
greater than 
140/90 !! 
BP 
Medica
tions 
Day 
Date 
15mg 
20mg 
AM 
Day 
Date 
100mg 
150mg 
AM 
PM 
AM 
PM 
 
1 
1/1/15 
2 
0 
7:00 
1 
1/1/15 
2 
0 
7:00 
7:00 
112/62 
121/68 
 
1 
 
 
 
 
1 
 
 
 
 
 
/ 
/ 
 
2 
 
 
 
 
2 
 
 
 
 
 
/ 
/ 
 
3 
 
 
 
 
3 
 
 
 
 
 
/ 
/ 
 
4 
 
 
 
 
4 
 
 
 
 
 
/ 
/ 
 
5 
 
 
 
 
5 
 
 
 
 
 
/ 
/ 
 
6 
 
 
 
 
6 
 
 
 
 
 
/ 
/ 
 
7 
 
 
 
 
7 
 
 
 
 
 
/ 
/ 
 
8 
 
 
 
 
8 
 
 
 
 
 
/ 
/ 
 
9 
 
 
 
 
9 
 
 
 
 
 
/ 
/ 
 
10 
 
 
 
 
10 
 
 
 
 
 
/ 
/ 
 
11 
 
 
 
 
11 
 
 
 
 
 
/ 
/ 
 
12 
 
 
 
 
12 
 
 
 
 
 
/ 
/ 
 
13 
 
 
 
 
13 
 
 
 
 
 
/ 
/ 
 

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132 
14 
 
 
 
 
14 
 
 
 
 
 
/ 
/ 
 
15 
 
 
 
 
15 
 
 
 
 
 
/ 
/ 
 
16 
 
 
 
 
16 
 
 
 
 
 
/ 
/ 
 
17 
 
 
 
 
17 
 
 
 
 
 
/ 
/ 
 
18 
 
 
 
 
18 
 
 
 
 
 
/ 
/ 
 
19 
 
 
 
 
19 
 
 
 
 
 
/ 
/ 
 
20 
 
 
 
 
20 
 
 
 
 
 
/ 
/ 
 
21 
 
 
 
 
21 
 
 
 
 
 
/ 
/ 
 
22 
 
 
 
 
22 
 
 
 
 
 
/ 
/ 
 
23 
 
 
 
 
23 
 
 
 
 
 
/ 
/ 
 
24 
 
 
 
 
24 
 
 
 
 
 
/ 
/ 
 
25 
 
 
 
 
25 
 
 
 
 
 
/ 
/ 
 
26 
 
 
 
 
26 
 
 
 
 
 
/ 
/ 
 
27 
 
 
 
 
27 
 
 
 
 
 
/ 
/ 
 
28 
 
 
 
 
28 
 
 
 
 
 
/ 
/ 
 
29 
 
 
 
 
29 
 
 
 
 
 
 
 
 
30 
 
 
 
 
30 
 
 
 
 
 
 
 
 
31 
 
 
 
 
31 
 
 
 
 
 
 
 
 
32 
 
 
 
 
32 
 
 
 
 
 
 
 
 
33 
 
 
 
 
33 
 
 
 
 
 
 
 
 
34 
 
 
 
 
34 
 
 
 
 
 
 
 
 
35 
 
 
 
 
35 
 
 
 
 
 
 
 
 
Patient’s Signature: _______________________________        Date: ___________________ 
Physician/Nurse/Data Manager’s Signature _____________________  Date______________ 
 
 
 

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133 
APPENDIX F:    PILL DIARIES AND BLOOD PRESSURE MONITORING FOR CYCLE 2 AND LATER (DAY 1 THRU 28) 
Today’s Date ______________________________ 
Cycle # ______ 
Patient Name ______________________________ 
Patient Study ID _________________ 
1.Complete one form for each cycle. 
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 doses. 
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 every 24 hours. Take on an 
empty stomach 1 hour before taking the 
morning dose of olaparib. 
OLAPARIB 
Take _____ (number) ______ mg tablets twice a day 
12 hours apart with a light meal. You should avoid 
grapefruit juice while on study because grapefruit 
juice affects the metabolism of olaparib.  The 
morning dose should be taken approximately 1 hour 
after cediranib, with a light meal. 
Blood Pressures  
 
Call your study 
team if your BP is 
greater than 
140/90 !! 
BP 
Medica
tions 
Day 
Date 
15mg 
20mg 
AM 
Day 
Date 
100mg 
150mg 
AM 
PM 
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 
 
 
 
 
5 
 
 
 
 
 
/ 
/ 
 
6 
 
 
 
 
6 
 
 
 
 
 
/ 
/ 
 
7 
 
 
 
 
7 
 
 
 
 
 
/ 
/ 
 
8 
 
 
 
 
8 
 
 
 
 
 
/ 
/ 
 
9 
 
 
 
 
9 
 
 
 
 
 
/ 
/ 
 
10 
 
 
 
 
10 
 
 
 
 
 
/ 
/ 
 
11 
 
 
 
 
11 
 
 
 
 
 
/ 
/ 
 
12 
 
 
 
 
12 
 
 
 
 
 
/ 
/ 
 
13 
 
 
 
 
13 
 
 
 
 
 
/ 
/ 
 

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134 
14 
 
 
 
 
14 
 
 
 
 
 
/ 
/ 
 
15 
 
 
 
 
15 
 
 
 
 
 
/ 
/ 
 
16 
 
 
 
 
16 
 
 
 
 
 
/ 
/ 
 
17 
 
 
 
 
17 
 
 
 
 
 
/ 
/ 
 
18 
 
 
 
 
18 
 
 
 
 
 
/ 
/ 
 
19 
 
 
 
 
19 
 
 
 
 
 
/ 
/ 
 
20 
 
 
 
 
20 
 
 
 
 
 
/ 
/ 
 
21 
 
 
 
 
21 
 
 
 
 
 
/ 
/ 
 
22 
 
 
 
 
22 
 
 
 
 
 
/ 
/ 
 
23 
 
 
 
 
23 
 
 
 
 
 
/ 
/ 
 
24 
 
 
 
 
24 
 
 
 
 
 
/ 
/ 
 
25 
 
 
 
 
25 
 
 
 
 
 
/ 
/ 
 
26 
 
 
 
 
26 
 
 
 
 
 
/ 
/ 
 
27 
 
 
 
 
27 
 
 
 
 
 
/ 
/ 
 
28 
 
 
 
 
28 
 
 
 
 
 
/ 
/ 
 
Patient’s Signature: _______________________________        Date: ___________________ 
Physician/Nurse/Data Manager’s Signature _____________________  Date______________ 
 

NCI Protocol #:9881 
Version Date: September 7, 2021 
 
 
APPENDIX G: ORAL ANTIHYPERTENSIVE 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. Note that each agent’s dosing 
should be maximized before being replaced or adding another agent class. 
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 
Selective 
metoprolol 
25 mg 
twice daily 
50 mg 
twice daily 
100 mg 
twice daily 
CYP 2D6 
substrate 

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136 
E Blockers 
(BB) 
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  
 
 
 

NCI Protocol #:9881
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137
APPENDIX H: LAB MANUAL 
NCI Protocol 9881 LABORATORY MANUAL
Inserted into the Protocol
A Phase 2 Study of Cediranib in Combination with Olaparib in Advanced 
Solid Tumors
Study Sponsor:
NCI
PI: 
Joseph W. Kim, MD, Yale University
Translational Lead: J. Paul Eder, MD Yale University

NCI Protocol #:9881 
Version Date: September 7, 2021 
 
138 
1. INTRODUCTION 
 
This manual covers the procedures associated with acquisition of patient samples for biomarker 
analysis, processing, storage and shipment of these samples to central laboratories as required 
by the protocol.   
 
 
2. SAMPLE FLOW OVERVIEW  
Tumor tissue, blood and plasma biomarker samples will be collected and sent to central 
laboratories for storage and analysis. The diagram below highlights the flow process for all lab 
samples.   
 
 
 
 
3.  SAMPLING TIME POINTS 
3.1 Tumor Tissue Samples 
 
Baseline tumor tissue samples will be obtained from all study patients. Samples will be used to 
determine the molecular profile (deoxyribonucleic acid; DNA) of patient’s tumor and in particular 
the homologues recombination deficiency (HRD)-status of the tumors, compared to the normal 
cells (see blood sample below).   
 
Cycle and Day 
Time 
Day -2 to 0 
 
The baseline biopsy will be done after the research 
blood draws are collected.  
 
(See section 4.1 for submission of FFPE blocks from 
biopsy)  

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Version Date: September 7, 2021 
 
139 
Any day on study  
 
Archival tumor tissue submission (optional)  
 
(See section 4.5 for submission of archival tumor 
tissue)  
 
 
3.2 Blood samples   
 
Blood samples will be obtained from all study patients who are undergoing biopsies or 
submitting an archival tissue for BROCA testing. Samples will be used to determine the 
germline molecular profile of patients, compared to the tumor (see tumor sample above).  
 
 
Cycle and Day 
NOTE 
See the 3.1 
(same time as the tumor tissue 
submission) 
Any patients who are undergoing biopsy or submitting 
archival tissue for BROCA testing, must be 
accompanied by this germline testing by submitting a 
blood sample.  
 
 
3.3 Plasma (for markers of angiogenesis and inflammation) Collection Time Points 
 
Plasma samples to assess markers of angiogenesis and inflammation will be collected at the 
following time points: 
 
Cycle and Day 
Time 
Baseline, Day -2 to 0 
On the day of the biopsy, before the biopsy is 
performed.  
Cycle 1, Day 4-7 
On the day of the biopsy. The sample will be drawn 
before the first dose of olaparib. 
 
Cycle 1 Day 15 +/- 3 days 
before dosing 
Cycle 2 and the subsequent cycles, 
Day 1 +/- 3 days 
before dosing 
End of treatment: Discontinuation 
After discontinuation of the therapy.  
 
 
3.4 Plasma (for ctDNA) Collection Time Points 
 
Plasma samples will be collected to isolate ctDNAs as markers of hypoxia: 
 
 
Cycle and Day 
Time 

NCI Protocol #:9881 
Version Date: September 7, 2021 
 
140 
Baseline, Day -2 to 0 
On the day of the biopsy, before the biopsy is 
performed.  
Cycle 1, Day 4-7 
On the day of the biopsy. The sample will be drawn 
before the first dose of olaparib. 
 
Cycle 1 Day 15 +/- 3 days 
before dosing 
Cycle 2 and the subsequent cycles, 
Day 1 +/- 3 days 
before dosing 
End of treatment: Discontinuation 
After discontinuation of the therapy.  
 
 
 
4 SAMPLE COLLECTION AND PROCESSING PROCEDURES 
All lab supplies, including collection tubes and cryovials, labels, and shipping containers, will 
need to be provided by each site. 
 
4.1 Tumor biopsy tissue samples  
 
x 
Samples should be taken either by incisional biopsy or by core needle biopsy (14 
gauge) according to each institution’s standards. If possible 3 to 5 samples per patient 
and time point should be acquired. (The samples not meeting this requirement may 
be acceptable, but MUST be discussed with the Study PI or Swisher Lab).   
x 
The size of each tissue sample should be in the range of 3 to 5 mm.  
x 
In order to keep time from tissue acquisition to fixation as short as possible, these 
samples should be placed in 10% neutral buffered formalin (NBF) within 15 minutes of 
the procedure. 
x 
The samples should be kept in 10% NBF for a duration of at least 6 hours and no 
longer than 72 hours. 
x 
Following formalin fixation, tissue samples should be paraffin embedded according to 
established in house protocols at the sites. 
x 
Paraffin embedded samples should be placed into cassettes and labeled on the 
cassette with a normal pencil with the following information: 
1. Protocol Name  
2. Subject Study Number 
3. Sample Date and Time 
 
x 
Each tissue core should be placed in a separate block resulting in 3-5 paraffin blocks 
per initial biopsy per patient. 
x 
Paraffin embedded tissue blocks should be stored at room temperature until shipped. 
x 
Paraffin block should be wrapped in bubble wrap and shipped in one box together to 
the address provided below.  
x 
Complete the Tumor Tissue Shipping Form (Form 1) and insert a copy of it with 
shipment. 

NCI Protocol #:9881 
Version Date: September 7, 2021 
 
141 
x 
Samples should be shipped Monday through Thursday to the following laboratory: 
Swisher Lab 
University of Washington 
1959 NE Pacific St 
Health Sciences Building BB632 
Seattle, Washington 98195-6460 
Phone: 206-685-7927  
Email: ovcalab@uw.edu 
 
4.2 Blood Samples for germline BROCA panel  
 
x 
Required material:   
o 8.5 ml Acid Citrate Dextrose (ACD) tubes: ACD Solution A tubes: Fisher Scientific catalog 
# 02-684-26 for pk of 100 
o Tubes with cap (items ordered separately) to hold blood tubes: Sarstedt cat # 78.898  for 
30 X 126 tube with absorbent, case of 250; and  Sarstedt cat # 65.679 for cap, case of 250 
o Cardboard shipping box to hold 3 tubes: U-line cat # S-463 for 5X4X2 box, pack of 100 
(tbc). If using this box for 1 sample, 2 empty plastic tubes need to be added to the plastic 
tube containing the blood sample.  
o Avery labels  # 5160 for labelling tubes- can purchase from any office supply  
 
x 
Draw 7ml of blood into one 8.5ml ml yellow top Acid Citrate Dextrose (ACD Solution A) tube on 
any weekday except Friday.  
x 
Invert tube 10 times to mix blood 
x 
Label the tubes after blood collection with the following information: 
 
1. 
Protocol Name  
2. 
Subject Study Number (the lab should NOT receive any patient identifiers, e.g., 
subject initials or date of birth) 
3. 
Sample Date and Time 
4. 
Sample Type (whole blood) 
 
x 
Complete the Blood Sample Shipping Form (germline control for BROCA panel) (Form 2)  and 
insert a copy of with shipment. 
x 
Samples should be shipped at ambient temperature for overnight delivery to the 
following laboratory: 
 
Swisher Laboratory 
University of Washington 
1959 NE Pacific St 
Health Sciences Building BB632 
Seattle, Washington 98195-6460 
Phone: 206-685-7927 
ovcalab@uw.edu 
 
 

NCI Protocol #:9881 
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142 
4.3 Plasma samples for Markers of Angiogenesis and Inflammation 
 
Biomarker assays are time sensitive.  Samples must be processed within one hour of collection.  
Complete the Biomarker shipping Form Plasma for  Angiogenesis and Inflammation Markers (Form 3)  
and insert a copy of with shipment. 
 
 
x 
Required material:   
o 10 mL purple/lavender-top EDTA-containing vacutainer tubes (BD Vacutainer, Catalog no. 
366643)  
o clear 15ml polypropylene tubes 
o 2ml cryovials  
o Labels designed for low temperatures (e.g., Cryo-Tag brand) 
 
 
x 
Draw blood into one 10ml lavender top (K2EDTA) tube (BD Vacutainer, Catalog no. 366643)  
x 
Invert tubes 10 times to mix blood 
x 
Centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge manufacturer’s 
instructions) 
x 
Remove plasma from each tube and transfer equally into two separate clean 15ml 
polypropylene tubes 
x 
Repeat centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge 
manufacturer’s instructions) 
x 
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.   
x 
Label tubes with the following information (using a Sharpie or Cryopen): 
 
1. Protocol Name  
2. Subject Study Number 
3. Subject Initials 
4. Sample Date and Time 
5. Sample Type (EDTA plasma) 
 
x 
Vials should be frozen at -80oC immediately in an upright position and kept at -80oC until 
shipment. 
x 
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.  
x 
Complete the Plasma Biomarker Sample Shipping Form (Angiogenesis and Inflammation 
Markers) (Form 3) and insert a copy of with shipment. 
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 
ATTN:  Andrew Nixon, PhD 

NCI Protocol #:9881 
Version Date: September 7, 2021 
 
143 
Duke University Medical Center 
395 MSRB, Research Drive 
Durham, NC 27710 
Phone: (919) 681-2239 
Email: andrew.nixon@duke.edu 
 
 
4.4 Plasma Biomarker Samples for ctDNA analysis 
 
x 
Required material:   
o 10 mL purple/lavender-top EDTA-containing vacutainer tubes tubes (BD Vacutainer, 
Catalog no. 366643)   
o Cryovials or microfuge tubes capable of storing at least 1 mL of plasma 
o Labels designed for low temperatures (e.g., Cryo-Tag brand) 
 
x 
Blood should be collected in 10 mL purple-top EDTA-containing vacutainer tubes and 
shipped in cryovials. 
x 
Prepare a label with the required information (see below) using a fine point permanent 
marker.  Apply completed labels to the K2EDTA Vacutainer tubes and cryovials. 
x 
Collect the maximum amount of whole blood into a single 10.0 mL lavender top K2 EDTA 
Vacutainer tubes using standard venipuncture technique.  Ensure that the tube is filled 
as much as possible.  If blood is collected from a port-a-cath, standard precautions 
should be used to avoid sampling blood that is diluted with saline or heparin from the 
port line (an appropriate volume should be discarded as waste before collecting the 
blood).  
x 
Gently invert the tubes, 3-4 times upon collection to dissolve the EDTA and prevent 
coagulation. 
x 
Tubes can then be kept at room temperature up to 4 hours, but processing them sooner 
is better. 
x 
Tubes should be centrifuged at 1000 x g for 10 minutes in a clinical centrifuge with a 
swinging bucket rotor. Tubes should be carefully balanced in the centrifuge to avoid 
vibrations which might disrupt WBCs.  The centrifuge should be stopped in "brake off" 
mode. 
x 
After centrifugation, use a new pipette to remove the plasma without disturbing the cell 
layer.   Care should be taken to avoid the buffy coat by not pipetting the last 5 mm of 
plasma above the buffy coat layer.   
x 
Plasma should be dispensed into cryovials in 1mL aliquots. Cap the cryovials tightly. 
x 
Label tubes with the following information (using a Sharpie or Cryopen): 
 
1. Protocol Name  
2. Subject Study Number 
3. Subject initials 
4. Sample Date and Time 
5. Sample Type (EDTA plasma) 
 

NCI Protocol #:9881 
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144 
x 
Vials should be frozen at -80oC immediately in an upright position and kept at -80oC until 
shipment. 
x 
As plasma samples are analyzed for ctDNAs 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.  
x 
Samples collected at Yale will be hand-delivered to the analyzing laboratory in batches. 
x 
Complete the Plasma Biomarker Sample Shipping Form (ctDNA samples) (Form 4)  and 
insert a copy of with shipment. 
x 
Samples should be shipped to the following laboratory on dry ice overnight: 
Attn:  Azeet Narayan 
Laboratory of Dr. Abhijit Patel 
Department of Therapeutic Radiology 
Yale School of Medicine 
15 York Street 
Room HRT 213C 
New Haven, CT 06510 
Phone:  203-737-6252 
Fax: 203-785-7482 
Email:  abhijit.patel@yale.edu 
 
4.5 Archival tumor sample submission (OPTIONAL)  
 
x 
Submit three unstained, charged slides; Two slides cut at 10 microns and one slide cut at 
4 microns. 
  
x 
The slides should be wrapped in bubble wrap and shipped in one box together to the 
address provided below.  
x 
Complete the Tumor Tissue Shipping Form (Form 1) and insert a copy of it with 
shipment. 
x 
Samples should be shipped Monday through Thursday to the following laboratory: 
Swisher Lab 
University of Washington 
1959 NE Pacific St 
Health Sciences Building BB632 
Seattle, Washington 98195-6460 
Phone: 206-685-7927  
Email: ovcalab@uw.edu 
 
 
5 SAMPLE SHIPMENT PROCEDURES 
5.1 Tumor Tissue Shipping 
Tumor biopsies are formalin-fixed and paraffin-embedded.  
 
x 
Ship Monday through Thursday. Do not ship on Friday as receiving lab cannot receive 
weekend samples. Agree timing of shipment with receiving laboratory. 

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145 
x 
For every shipment, send an email notification to the receiving lab with tracking number, 
and attach electronic version of completed Tumor Tissue Shipping Form (see Form 1) to  
ovcalab@uw.edu and the study coordinator (NCI9881Specimen@yale.edu). 
x 
Samples should be packaged carefully. Tissue blocks can be wrapped in tissue paper or 
bubble wrap and placed into one box for shipping. 
x 
Blocks should be shipped at ambient temperature. 
x 
Include a completed Tumor Tissue Shipping Form (Form 1) itemizing the contents of the 
shipment. A photocopy should be maintained with study records at each site. 
x 
All samples should be shipped at ambient temperatures to the following address: 
 
Swisher Laboratory 
University of Washington 
1959 NE Pacific St 
Health Sciences Building BB632 
Seattle, Washington 98195-6460 
Phone: 206-685-7927 
ovcalab@uw.edu 
 
 
5.2 Blood Sample Shipping  
 
Blood samples to determine the germline BROCA panel, need to be shipped to ensure delivery 
within 24 hours of collection. Instructions for packing and notifications for shipment follow: 
 
x 
Specimens must be packaged according to IATA regulations for shipping UN3373, 
Biologic specimen category B. Each Blood tube should be placed inside a plastic Sarsted 
tube with absorbent. Place the Sarsted tube, including ACD blood tube in the cardboard 
inner box and add 2 empty Sarsted  tubes as spacers. The cardboard inner box should be 
placed inside a Fedex UN3373 envelope (order direct from Fedex).  
x 
Include a completed Blood Sample Shipping Form (germline control for BROCA panel) 
(Form 2) itemizing the contents of the shipment. A photocopy should be maintained with 
study records at each site. Confirm that the identifies (subject number and initials) are in 
agreement.  
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 Blood Sample Shipping Form (germline control for BROCA panel) (Form 
2)  to ovcalab@uw.edu and the study coordinator (NCI9881Specimen@yale.edu). 
x 
All samples must be shipped Monday through Thursday at ambient temperatures for overnight 
delivery to the following address: 
 
Swisher Laboratory 
University of Washington 
1959 NE Pacific St 
Health Sciences Building BB632 

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Seattle, Washington 98195-6460 
Phone: 206-685-7927 
Email: ovcalab@uw.edu 
 
 
 
5.3 Plasma Sample Shipping (Markers of Angiogenesis and Inflammation) 
 
Plasma samples should be batch shipped at times agreed with the receiving laboratory (Dr. 
Andrew Nixon). 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 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 (NCI9881Specimen@yale.edu). 
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 
 
 
5.4 Plasma Sample Shipping (ctDNA) 
 
Plasma samples should be batch shipped at times agreed with the receiving laboratory (Dr. 
Abhijit Patel, Yale). Instructions for packing and notifications for shipment follow: 
 
x 
Agree 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.  

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147 
x 
Include a completed Plasma Biomarker Sample Shipping Form (see Form 4) 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 
Transmittal 
Form 
(Form 
4) 
to 
abhijit.patel@yale.edu and the study coordinator (NCI9881Specimen@yale.edu). 
x 
Samples collected at Yale should be hand-delivered in batches to the analyzing lab, using 
the same forms. 
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: 
 
Attn: Azeet Narayan  
Laboratory of Dr. Abhijit Patel  
Department of Therapeutic Radiology  
Yale School of Medicine  
15 York Street  
Room HRT 213C  
New Haven, CT 06510 
Phone: 203-737-6252 
Email:  abhijit.patel@yale.edu 
 
 
5.5 General Shipping Instructions 
 
As biomarker analyses will be performed at the end of the study, biomarker samples with the 
exception of the whole blood sample, that needs to be shipped freshly, should be stored at the 
site and shipped in batches at a time agreed with the receiving lab. All courier shipments must 
be made Monday to Wednesday. Do not ship samples the day before a national holiday. 
Shipping addresses for samples follow: 
 
 
Archival tumor tissue  
&  
Blood samples for germline 
BROCA testing 
Swisher Laboratory 
University of Washington 
1959 NE Pacific St 
Health Sciences Building BB632 
Seattle, Washington 98195-6460 
Phone: 206-685-7927 
Email: ovcalab@uw.edu  
Plasma for markers of 
angiogenesis and inflammation 
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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148 
Plasma for ctDNA analyses 
Attn: Azeet Narayan  
Laboratory of Dr. Abhijit Patel  
Department of Therapeutic Radiology  
Yale School of Medicine  
15 York Street  
Room HRT 213C  
New Haven, CT 06510 
Phone: 203-737-6252 
Email:  abhijit.patel@yale.edu 
 
 

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6 CONTACT INFORMATION  
For any questions on sample collection, processing, storage and shipment, please contact the 
team members listed below.  
 
Coordinator 
Yale 
University 
Nora Autuori 
Office: (203)737-1694 
Mobile: (203)361-4423  
Fax: (203)785-4116 
Email: nora.autuori@yale.edu 
Study PI 
Yale 
University 
Joseph W. Kim, MD 
Yale Cancer Center 
333 Cedar Street, FMP 121 
New Haven, CT 06520 
Direct Office: 203-737-6467 
Cell: 203-494-3287 
Email: joseph.w.kim@yale.edu  
Translational Science Leader 
Yale 
University 
J. Paul Eder, MD 
Yale Cancer Center 
333 Cedar Street 
WWW 211, PO Box 208028 
New Haven, CT 06520 
Office: 203-737-1906 
Email joseph.eder@yale.edu 
BROCA Analyses 
University 
of 
Washington 
Swisher Laboratory 
University of Washington 
1959 NE Pacific St 
Health Sciences Building BB632 
Seattle, Washington 98195-6460 
Phone: 206-685-7927 
Email: ovcalab@uw.edu  
Angiogenesis/ Inflammation 
Biomarker analyses (plasma) 
Duke 
University 
Phase I Biomarker Laboratory 
Andrew Nixon, PhD 
Duke University Medical Center 
395 MSRB, Research Drive 
Durham, NC 27710 
Phone: (919) 681-2239 
Email: andrew.nixon@duke.edu 
ctDNA analysis lab (plasma 
 
Yale 
University 
Abhijit Patel, MD, PhD 
Department of Therapeutic Radiology  
Yale School of Medicine  
15 York Street  
Room HRT 213C  
New Haven, CT 06510 
Phone: 203-737-6252 
Email: abhijit.patel@yale.edu 
 
 
 
 

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7 FORMS 
 
Form 1 
Tumor Tissue Shipping Form 
Form 2  
Blood Sample Shipping Form  (germline control for BROCA panel) 
Form 3 
Plasma Biomarker Sample Shipping form Angiogenesis and Inflammation 
Markers 
Form 4 
Plasma Biomarker Sample Shipping Form ctDNA 
 
 
 
 
 

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151 
 
 
 
 
 
 
FORM 1 
 
 
 
Tumor Tissue Shipping Form 
 
 
Please copy this form for multiple shipments 

NCI Protocol #:9881 
Version Date: September 7, 2021 
 
 
Form 1: Tumor Tissue Shipping Form 
Protocol   CTEP/ETCTN# 9881 
 
 
 
 
 
 
 
 
Shipping instructions: 
Record the shipping date and total # of samples in shipment below. Photocopy the Tumor Tissue Shipping Form. The original form should accompany the shipment. Retain a copy of the 
form with the study documents. Email to agree shipment times in advance of shipment, then email shipment tracking number and an electronic version form of the shipment to the Swisher 
Lab (ovcalab@uw.edu) and the study coordinator (NCI9881Specimen@yale.edu). For details please see section 5.1 of this Laboratory Manual. 
 
Patient ID 
Tissue 
Type 
Diagnosis 
Date 
Collected 
Sample 
Number of 
samples per 
timepoint 
Record time of 
collection for 
each specimen 
Record time of 
immersion of the 
sample into 
formalin 
Record duration 
of formalin 
fixation of the 
sample  
Record 
storage 
condition of 
the FFPE block 
 
 
 
 
[] FFPE fresh biopsy 
 
[] archival tumor slide  
 
 
 
 
 
 
 
 
 
 
 
 [] FFPE fresh biopsy 
 
[] archival tumor slide  
 
 
 
 
 
 
 
 
 
 
 
[] FFPE fresh biopsy 
 
[] archival tumor slide  
 
 
 
 
 
 
Shipment prepared by: 
 
(Print Name) 
Site contact Phone number: 
 
Site email:  
Page _______ of ________ 
Site:  
PI:  
Shipping Date: 
 
Ship to:   Swisher Laboratory 
University of Washington 
1959 NE Pacific St 
Health Sciences BuildingBB632 
Seattle, Washington 98195-6460 
Phone: 206-685-7927 
Email: ovcalab@uw.edu 
 
Tracking number: 
Number of samples in shipment:  

NCI Protocol #:9881 
Version Date: September 7, 2021 
 
 
 
 
 
 
FORM 2 
 
 
 
Blood Sample Shipping Form 
(germline control for BROCA) 
 
 
 
Please copy this form for multiple shipments 
 
 

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Form 2: Blood Sample Shipping Form (germline control for BROCA panel) 
 
 
Patient ID 
Date 
Collected 
 
Sample 
Number of aliquots 
per timepoint 
Record time collected 
for each specimen 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
Shipping instructions: 
Record the shipping date and total # of samples in shipment below. Photocopy the Blood Sample Shipping Form. The original form 
should accompany the shipment. Retain a copy of the form with the study documents. Email swishere@uw.edu to agree shipment 
times in advance of shipment, then email shipment tracking number and an electronic version form of the shipment to Dr. Swisher 
and the study coordinator (NCI9881Specimen@yale.edu). For details please see section 5.2 of this Laboratory Manual. 
 
 
 
 
Shipment prepared by: 
 
(Print Name) 
Site contact Phone number: 
 
Site email:  
Page _______ of ________ 
Confirm subject number and 
initials for each patients are 
in agreement  (sign):  
 
 
Site:  
 
PI: 
Results of the blood BROCA test will be returned to the site PI. Please add name, address, email address, phone and fax 
number below: 
 
 
 
 
 
 
 
Shipping Date: 
Number of samples in shipment:  
Tracking number: 
Ship to: 
 
Swisher Laboratory 
University of Washington 
1959 NE Pacific St 
Health Sciences Building BB632 
Seattle, Washington 98195-6460 
Phone: 206-685-7927 
Email: ovcalab@uw.edu 
 

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FORM 3 
 
 
 
Plasma Biomarker Sample Shipping Form 
(Angiogenesis and Inflammation Markers) 
 
Please copy this form for multiple shipments 
 

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Form 3: Plasma Biomarker Sample Shipping Form 
(Angiogenesis and Inflammation Markers) 
 
Shipping instructions:  
All samples must be shipped overnight on dry ice. For details please see section 5.3 of this Laboratory Manual. 
 
 
 
 
 
 
 
 
 
 
Shipment prepared by: 
 
(Print Name) 
Site contact Phone number: 
 
Site email:  
Page _______ of ________ 
Site:  
 
PI: 
Patient ID 
Patient 
Initials 
Date 
Collected 
Sample 
Number of aliquots 
per timepoint 
Record time collected 
for each specimen 
 
 
 
Baseline 
 
 
 
Cycle 1Day 4-7 
 
 
 
Cycle 1 Day 15 +/- 3 days 
 
 
 
Cycle 2 Day 1 +/- 3 days 
 
 
 
Cycle  __ Day 1 +/- 3 days 
 
 
 
EOT:  Discontinuation 
 
 
Patient ID 
Patient 
Initials 
Date 
Collected 
Sample 
Number of aliqots 
per timepoint 
Record time collected 
for each specimen 
 
 
 
Baseline 
 
 
 
Cycle 1Day 4-7 
 
 
 
Cycle 1 Day 15 +/- 3 days 
 
 
 
Cycle 2 Day 1 +/- 3 days 
 
 
 
Cycle  __ Day 1 +/- 3 days 
 
 
 
EOT:  Discontinuation 
 
 
Patient ID 
Patient 
Initials 
Date 
Collected 
Sample 
Number of aliqots 
per timepoint 
Record time collected 
for each specimen 
 
 
 
Baseline 
 
 
 
Cycle 1Day 4-7 
 
 
 
Cycle 1 Day 15 +/- 3 days 
 
 
 
Cycle 2 Day 1 +/- 3 days 
 
 
 
Cycle  __ Day 1 +/- 3 days 
 
 
 
EOT:  Discontinuation 
 
 
Shipping Date: 
Number of samples in shipment:  
Tracking number: 
Ship to: 
Phase I Biomarker Laboratory 
Andrew Nixon, PhD 
Duke University Medical Center 
395 MSRB, Research Drive 
Durham, NC 27710 
Phone: (919) 681-2239 
Email: andrew.nixon@duke.edu 

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157 
FORM 4 
 
 
 
Plasma Biomarker Sample Shipping Form 
(ctDNA samples) 
 
Please copy this form for multiple shipments 
 

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Version Date: September 7, 2021 
 
158 
Form 4: Plasma Biomarker Sample Shipping Form (ctDNA samples) 
 
 
 
Shipping instructions: 
 All samples must be shipped overnight on dry ice. For details please see section 5.4 of this Laboratory Manual.  
 
 
 
Shipment prepared by: 
 
(Print Name) 
Site contact Phone number: 
 
Site email:  
Page _______ of _______ 
Site:  
 
PI: 
Shipping Date: 
Number of samples in shipment:  
Tracking number:  
Ship to: 
Attn: Azeet Narayan 
Laboratory of Abhijit Patel 
Department of Therapeutic Radiology 
Yale School of Medicine 
15 York Street 
Room HRT 213C 
New Haven, CT 06510 
Phone:  203-737-6252 
Email:  abhijit.patel@yale.edu 
Patient ID 
Patient 
Initials 
Date 
Collected 
Sample 
Number of aliquots 
per timepoint 
Record time collected 
for each specimen 
 
 
 
Baseline 
 
 
 
Cycle 1Day 4-7 
 
 
 
Cycle 1 Day 15 +/- 3 days 
 
 
 
Cycle 2 Day 1 +/- 3 days 
 
 
 
Cycle  __ Day 1 +/- 3 days 
 
 
 
EOT:  Discontinuation 
 
 
Patient ID 
Patient 
Initials 
Date 
Collected 
Sample 
Number of aliqots 
per timepoint 
Record time collected 
for each specimen 
 
 
 
Baseline 
 
 
 
Cycle 1Day 4-7 
 
 
 
Cycle 1 Day 15 +/- 3 days 
 
 
 
Cycle 2 Day 1 +/- 3 days 
 
 
 
Cycle  __ Day 1 +/- 3 days 
 
 
 
EOT:  Discontinuation 
 
 
Patient ID 
Patient 
Initials 
Date 
Collected 
Sample 
Number of aliqots 
per timepoint 
Record time collected 
for each specimen 
 
 
 
Baseline 
 
 
 
Cycle 1 Day 4-7 
 
 
 
Cycle 1 Day 15 +/- 3 days 
 
 
 
Cycle 2 Day 1 +/- 3 days 
 
 
 
Cycle  __ Day 1 +/- 3 days 
 
 
 
EOT:  Discontinuation