A Randomized Phase 2 Trial of Cediranib and Olaparib Compared to Bevacizumab in Patients With Recurrent Glioblastoma Who Have Not Received Prior VEGF Therapy
Phase: PHASE2
Conditions: Recurrent Glioblastoma
Sponsor: National Cancer Institute (NCI)

i 
 
 
SUMMARY OF CHANGES -- Protocol 
 
 
NCI Protocol #: 10067 
Local Protocol #: 17-735 
Protocol Version Date: 05/10/2019 
 
Protocol Title: A randomized phase 2 trial of cediranib and olaparib compared to bevacizumab 
in patients with recurrent glioblastoma who have not received prior VEGF therapy. 
 
I. Changes Requested by CTEP Request for Rapid Amendment (RRA) May 9, 2019 
# 
Section 
Comments 
1.  Title page and 
header 
Updated protocol version date 05/10/2019 
2.  
7.1.1.1 CAEPR 
for Olaparib 
• 
Increase in Risk Attribution: 
• 
Changed to Less Likely from Also Reported on Olaparib Trials But With 
Insufficient Evidence for Attribution: Platelet count decreased; White blood 
cell decreased 
 
• 
Provided Further Clarification: 
• 
A new note has been added to the CAEPR; “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.” 
 
PLEASE NOTE:  The specific detailed changes listed here compare the new 
revised CAEPR Version 2.4, and associated risk information for the ICD, to the 
most recent CAEPR Version 2.3.   If your trial contains an older CAEPR version 
(i.e., does NOT currently contain CAEPR Version 2.3), you MUST include a 
description of any additional changes resulting from migration from the older 
CAEPR version. 

 
1 
NCI Protocol #: 
10067 
 
Local Protocol #: 
17-735 
 
ClinicalTrials.gov Identifier:  NCT02974621 
 
 
TITLE:  A randomized phase 2 trial of cediranib and olaparib compared to bevacizumab in 
patients with recurrent glioblastoma who have not received prior VEGF therapy. 
 
Corresponding Organization: LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
 
Coordinating Center: 
Not Applicable 
 
Principal Investigator: 
Isabel Arrillaga-Romany, M.D., Ph.D. 
Stephen E. and Catherine Pappas Center for Neuro-Oncology
 
Massachusetts General Hospital  
Yawkey 9E 
55 Fruit Street 
Boston, MA 02114 
Phone: 617-724-8770 
Fax: 617-643-2591 
E-mail: iarrillaga@mgh.harvard.edu 
 
Co-investigators: 
Tracy Batchelor, M.D. 
Massachusetts General Hospital  
Yawkey 9E 
55 Fruit Street 
Boston, MA 02114 
Phone: 617-8770 
Fax: 617-643-8769 
E-mail: tbatchelor@partners.org 
 
Elizabeth R. Gerstner, M.D. 
Stephen E. and Catherine Pappas Center for Neuro-Oncology 
Massachusetts General Hospital 
55 Fruit Street 
Boston, Massachusetts 02114 
617-724-8770 (telephone) 
617-724-8769 (facsimile) 
E-mail:  egerstner@partners.org 
 
 
 
 
 

 
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Participating Organizations (Only the participating LAOs should be listed.) 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-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 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
Statistician: 
 
 
Alona Muzikansky 
50 Staniford Street 
Boston, MA 02114 
Telephone: 617-724-6985, Fax: 617-724-9878 
Email: amuzikansky@partners.org 
MGH Study Coordinator:  
Edwin Nunez 
326 Cambridge Street, Office 3-326 
Boston, MA 02114 
Telephone: 617-643-4395, Fax: 617-726-4319 
Email: ENUNEZ2@PARTNERS.ORG  
Responsible Research Nurse: 
Nicola Gribbin, RN 
Yawkey 9E, 55 Fruit Street 
Boston, MA 02114 
Telephone: 617-726-9579, Fax: 
ngribbin@partners.org 
Email: NGRIBBIN@mgh.harvard.edu 
LPO Coordinator: 
Katie Parks 
Program for Coordination and Oversight of 
Research Protocols (PCORP) 
101 Merrimac Street #410B 
Boston, MA 02114 
Telephone: 617-643-5993, Fax: 617-643-7715 
Email: kparks1@mgh.harvard.edu 
NCI-Supplied Agents: 
Cediranib (NSC 732208) 
Olaparib (NSC 747856) 
Other Agents: 
Bevacizumab (NSC 704865), commercially supplied 
IND Sponsor: DCTD, NCI 
 
Protocol Type / Version / Version Date: 
Original / 15 / May 10, 2019  

 
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SCHEMA 
 
 
 
 
 

 
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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Primary Objectives ...................................................................................................7 
1.2 
Secondary Objectives ...............................................................................................7 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Study Disease: Glioblastoma ...................................................................................7 
2.2 
CTEP  IND Agents ..................................................................................................9 
2.3 
Advanced Imaging .................................................................................................27 
2.4 
Bevacizumab ..........................................................................................................28 
2.5 
Rationale ................................................................................................................32 
2.6 
Correlative Studies Background ............................................................................32 
3. 
PATIENT SELECTION ....................................................................................................35 
3.1 
Eligibility Criteria ..................................................................................................35 
3.2 
Exclusion Criteria ..................................................................................................37 
3.3 
Inclusion of Women and Minorities ......................................................................40 
4. 
REGISTRATION PROCEDURES ...................................................................................40 
4.1 
Investigator and Research Associate Registration with CTEP  .............................40 
4.2 
Site Registration .....................................................................................................41 
4.3 
Patient Registration ................................................................................................43 
4.4 
General Guidelines .................................................................................................45 
5. 
TREATMENT PLAN ........................................................................................................45 
5.1 
Agent Administration .............................................................................................45 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................49 
5.3 
Duration of Therapy ...............................................................................................50 
5.4 
Duration of Follow Up ...........................................................................................50 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................51 
6.1 
Parameters for All Cycles ......................................................................................51 
6.2 
Olaparib and Cediranib ..........................................................................................52 
6.3 
Bevacizumab ..........................................................................................................62 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................67 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................67 
7.2 
Adverse Event Characteristics ...............................................................................79 
7.3 
Expedited Adverse Event Reporting ......................................................................80 
7.4 
Routine Adverse Event Reporting .........................................................................82 
7.5 
Secondary Malignancy ...........................................................................................82 
7.6 
Second Malignancy ................................................................................................82 

 
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8. 
PHARMACEUTICAL INFORMATION ..........................................................................82 
8.1 
CTEP IND Agent(s) ...............................................................................................83 
8.2 
Bevacizumab ..........................................................................................................89 
8.3 
Blood Pressure Cuffs .............................................................................................90 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................90 
9.1 
Specimen Requirements .........................................................................................91 
9.2 
Integrated Correlative Studies ................................................................................92 
9.3 
Imaging correlative studies (Tumor Perfusion and Oxygenation, and Brain 
Tumor Cellularity) .................................................................................................98 
10. 
STUDY CALENDAR .......................................................................................................99 
11. 
MEASUREMENT OF EFFECT......................................................................................101 
11.1 
Definition of Measurability of Disease (per Response Assessment in 
Neuro-Oncology (RANO) Criteria) .....................................................................101 
11.2 
Response Assessments .........................................................................................101 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ...........................................................................................................104 
12.1 
Study Oversight ...................................................................................................104 
12.2 
Data Reporting .....................................................................................................105 
12.3 
Collaborative Agreements Language ...................................................................106 
12.4 
Genomic Data Sharing Plan .................................................................................108 
12.5 
Incidental/Secondary Findings Disclosure Procedure .........................................108 
13. 
STATISTICAL CONSIDERATIONS.............................................................................110 
13.1 
Study Design/Endpoints.......................................................................................110 
13.2 
Sample Size/Accrual Rate ....................................................................................110 
13.3 
Stratification Factors ............................................................................................111 
13.4 
Interim Analysis ...................................................................................................111 
13.5 
Analysis of Primary and Secondary Endpoints ...................................................112 
13.6 
Reporting and Exclusions ....................................................................................113 
14. 
PUBLICATION PLAN ...................................................................................................114 
REFERENCES ............................................................................................................................115 
APPENDIX A: PERFORMANCE STATUS CRITERIA ...........................................................125 
APPENDIX B: CYP3A4 INDUCERS AND INHIBITORS .......................................................126 
APPENDIX C: PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARDs .............................................................................................................................128 
APPENDIX D: PATIENT PILL DIARY ....................................................................................133 

 
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APPENDIX E: PATIENT’S BLOOD PRESSURE DIARY .......................................................134 
APPENDIX F: MRI PROTOCOL ...............................................................................................135 
APPENDIX G: ORAL ANTIHYPERTENSIVE MEDICATIONS ............................................140 
APPENDIX H: NEW YORK HEART ASSOCIATION CLASSIFICATIONS .........................142 
APPENDIX I: PATIENT HANDOUT ........................................................................................143 
APPENDIX J: COLLECTION OF SPECIMENS .......................................................................144 
APPENDIX K: TRACKING OF SPECIMENS ..........................................................................145 
APPENDIX L: SHIPPING OF SPECIMENS TO THE ETCTN 
BIOREPOSITORY ..................................................................................147 
APPENDIX M: ASSAY INFORMATION .................................................................................151 
 
 
 

 
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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1. To compare the anitumor activity of cediranib/olaparib versus reference bevacizumab 
monotherapy, as measured by progression-free survival at 6 months (PF6), in patients 
with recurrent GBM.  
 
1.2 
Secondary Objectives 
 
1. To compare overall survival (OS), progression free survival (PFS) and objective 
response (ORR) in patients with recurrent GBM treated with cediranib/olaparib 
versus bevacizumab 
2. To assess the safety of the combination of olaparib and cediranib in patients with 
recurrent GBM 
3. To evaluate the association of blood based biomarkers involved with angiogenesis 
using the Biomarker Review Committee-approved Plasma Angiome Panel (bFGF, 
Ang-1, Ang-2, Tie-2, SDF1-α, Collagen IV, PlGF, sVEGFR1, sVEGFR2, VEGF, Il-
1β, Il-6, Il-8, TNF-α, CAIX) with the clinical activity of cediranib/olaparib.  
4. To evaluate the association of tissue biomarkers involved with DNA repair using the 
Biomarker Review Committee-approved BROCA panel with the clinical activity of 
cediranib/olaparib.  
5. To identify genomic alteration by whole exome sequencing in GBM tumor 
specimens that correlate with the clinical activity of cediranib/olaparib.  
6. To evaluate the association of MRI imaging parameters (tumor perfusion and 
oxygenation, brain tumor cellularity) with the biological response of 
cediranib/olaparib. 
7. To contribute genetic analysis data from de-identified biospecimens to Genomic 
Data Commons (GDC), a well annotated cancer molecular and clinical data 
repository, for current and future research; specimens will be annotated with key 
clinical data, including presentation, diagnosis, staging, summary treatment, and if 
possible, outcome 
8. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA 
analysis), and nucleic acids obtained from patients at the ETCTN Biorepository at 
Nationwide Children's Hospital 
 
 
 
2. BACKGROUND 
 
2.1 
Study Disease: Glioblastoma 
 
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with an 
incidence of two to three per 100,000 adults per year and accounts for 52% of all primary brain 
tumors. Despite recent advances in diagnosis and treatments, it typically results in death within 

 
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the first 15 months from diagnosis. Current standard of care for newly diagnosed GBM consists 
of maximal safe surgical resection followed by 60Gy radiotherapy with concurrent 
temozolomide, then 6 months of adjuvant temozolomide. Patients treated with this multi-
modality therapy have a median survival of 14.6 months and a median progression free survival 
of 6.9 months (Stupp et al 2005). At the time of disease recurrence treatment options are limited 
and of poor effectiveness. Prior to the era of anti-angiogenic agents, single-agent irinotecan or 
nitrosoureas were used with an objective response rate of less than 10%, 6-month progression-
free survival of 9-21% and median OS of 30 weeks or less (Friedman et al 2009, Batchelor  et al 
2013). More recently, bevacizumab, a monoclonal antibody that binds circulating vascular 
endothelial growth factor (VEGF) and prevents its interaction with VEGF receptors on cell 
surface, has been commonly used for recurrent GBM as its clinical activity was shown in phase 
II trials as a single agent or in combination with chemotherapy agents (Kreisl et al 2009, 
Friedman et al 2009, Taal et al 2014). In these trials, single-agent bevacizumab resulted in ORR 
of 28 - 38%, 6-month PFS of 16 - 57% and median OS of 31 - 36 weeks. These poor survival 
outcomes of recurrent GBM highlight urgent medical needs for new treatment strategies.  
 
Like most proliferating tumors, GBM relies heavily on the accurate repair of double stranded 
breaks (DSB) and maintenance of genome stability, attributed in part to an intact homologous 
recombination (HR) pathway that works as a precisely regulated DNA lesion-specific repair 
mechanism (Santivasi, 2013). Importantly, dysfunction in repair of both single stranded breaks 
(SSB) and DSB would be synthetically lethal, making disruption of these repair mechanisms 
targets for treatment. The enzyme poly (ADP-ribose) Polymerase 1 (PARP) plays a key role in 
the repair of SSB, and PARP inhibitors have been successful in the treatment of cancers known 
to have HR deficiency, such as ovarian cancers and breast cancers with BRCA 1/2 mutations 
(Fong 2013, Fong 2010, Audeh 2010, Tutt 2010). 
 
Recently, a significant extension of progression-free survival in patients with platinum-sensitive 
ovarian cancer was demonstrated with the combination treatment of an oral pan-VEGFR TKI, 
cediranib, with olaparib, an oral PARP inhibitor. Importantly, post hoc analysis suggested that 
cediranib plus olaparib could provide significant benefit even in the absence of BRCA 1/2 
mutation. In vitro, hypoxia has been shown to down-regulate expression of HR repair gene, 
including BRCA 1/2 in both normal and cancer cells (Bindra 2005, Bindra 2004, Meng 2012) 
and to decrease the synthesis of HR proteins to offset chemo- and radio-resistance (Chan 2008). 
Moreover, tumor cells in the hypoxic and post-hypoxic periods show increased sensitivity to 
PARP inhibition (Klein 2010). VEGFR3 inhibition also results in down regulation of both 
BRCA 1 and 2 in cancer cells (Lim 2014). This suggests that angiogenesis blockade, perhaps 
through resulting hypoxia, could promote disruptions in the HR pathway such that patients 
without known HR deficiencies would benefit from PARP inhibition.  
 
Loss of PTEN occurs in approximately 36% of GBMs. PTEN has nuclear functions including 
transcriptional regulation of the RAD51 gene, whose product is essential for HR (Shen 2007), 
and loss of PTEN has been shown to compromise HR-mediated repair in astrocytes (McEllin 
2010). In GBM and other tumor cell lines, HR deficiency caused by PTEN loss sensitized tumor 
cells to PARP inhibitors, though notably there were effects on PTEN wild-type cells (Majuelos-
Melguizo 2015, McEllin 2010). These data suggest that GBM may be sensitive to PARP 

 
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inhibition, but that induction of HR deficiency (by PTEN loss or hypoxia induction) may confer 
greater activity. It also suggests that patients with PTEN loss could have a greater response to the 
combination treatment with a PARP inhibitor and an anti-angiogenic agent.  
 
GBM is further characterized by angiogenesis and up-regulation of multiple pro-angiogenic 
signal transduction pathways. Several pro-angiogenic cytokines play a role in tumor-related 
angiogenesis with VEGF playing a prominent role. Anti-VEGF therapies in the form of 
antibodies (for example, bevacizumab) and tyrosine kinase inhibitors (for example, cediranib) 
result in radiographic responses and extended progression free survival but have no demonstrated 
impact on overall survival in GBM patients (Batchelor et al 2013, Chinot et al 2014, Gilbert et al 
2014). Bevacizumab received accelerated FDA approval as monotherapy for recurrent GBM in 
2009. Several resistance mechanisms to anti-angiogenic therapies have been described and 
contribute to the failure of anti-VEGF therapy (Bergers 2008, Carmeliet 2011, Jain 2014). 
Importantly, the combination of PARP and VEGF inhibition targets multiple tumor pathways 
that may contribute to resistance, suggesting an alternate mode by which the combination of 
proposed therapies might potentiate each other’s effects.  
 
To date, studies on GBM and PARP inhibitors have focused on using these agents as radio- or 
chemo-potentiators. Several studies in GBM are being conducted combining PARP inhibitors 
with temozolomide to augment the pro-apototic effect of this methylating agent (NCT00687765, 
NCT02152982, NCT01390571) but results are pending. In the current phase 2 trial we will 
exploit the potentially synergistic action of PARP inhibition with anti-angiogenesis on DNA 
repair.  
 
2.2 
CTEP  IND Agents  
 
2.2.1 Cediranib 
 
Cediranib (AZD2171, Recentin™; 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-
pyrrolidin-1-ylpropoxy) quinazoline maleate; AZD2171 maleate) is a member of an emerging 
class of novel orally (PO) -administered small molecule vascular endothelial growth factor 
(VEGF) receptor tyrosine kinase (TK) inhibitors with anti-angiogenic properties (Hennequin et 
al 1999; Wedge et al 2005). 
 
2.2.1.1 
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) 
(Ferrara et al 2003). VEGFR-1 and VEGFR-2 signaling help mediate tumor progression. 
Cediranib has been developed as a potent inhibitor of VEGFR-1 and VEGFR-2 (Wedge et al 
2005). Cediranib also has activity against VEGFR-3 and c-Kit (Jurgensmeier et al 2005). 
Cediranib is expected, with chronic oral dosing, to inhibit VEGF-driven angiogenesis and as a 

 
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result prevent the progression and metastasis of solid tumors, and may have broad-spectrum 
clinical utility. 
 
2.2.1.2 
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(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.  
 
The murine renal cell carcinoma (RENCA) model, which rapidly (generally within 10 days) 
metastasizes to the lung and abdominal lymph nodes, has also been used for cediranib efficacy 
studies (Drevs et al 2004). In experiments incorporating a vehicle control, cediranib (at a dose of 
6.3 mg/kg/day PO) reduced primary tumor growth, metastasis, and microvessel density more 
potently than any other previously-studied VEGF RTK inhibitor reported in the literature.  
 
Using a transgenic mouse model in which multiple mammary tumors spontaneously develop 
after two pregnancies, investigators studied the temporal effects of cediranib administration 
(Klinowska et al 2004). 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.  
 
Further details of the nonclinical efficacy of cediranib can be found in the Cediranib 
Investigator’s Brochure (2016). 
 
2.2.1.3 
Nonclinical Pharmacology and Toxicology 
 
Nonclinical pharmacology and toxicology company-sponsored studies have been conducted in 
rats, dogs, and cynomolgus monkeys (Cediranib Investigator’s Brochure, 2016). In rats and dogs, 
oral bioavailability is high, but absorption is relatively slow, with Cmax of the agent seen 4-6 
hours after PO dosing. Plasma concentrations and exposure are generally linear over the dose 
ranges studied in rats. Cediranib is excreted in the feces (>70% of the dose) of rats, dogs, and 
cynomolgus monkey after both PO andintravenous (IV) administration. Fecal excretion was the 
predominant route of elimination (>70% of the dose) in both rat, dog and cynomolgus monkey 
after both PO and IV administration. Elimination was rapid in rats and monkeys with over 75% 
of the dose being recovered in the first 48 hours; in dogs, excretion was slightly slower but again 
substantially complete by 7 days. Over the dose ranges examined in the rat, plasma 
concentrations and exposure generally increased in proportion to dose; however, in monkeys, 
plasma cediranib concentration-time profiles obtained following a single PO dose indicated that 
systemic exposure increased in a greater than dose-proportional manner over the dose range 
0.05-2.5 mg/kg.  
 

 
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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, 2016). Cediranib was approximately 95% bound to human plasma proteins, with 
human serum albumin and α1-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, 2016). 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 2.5 mg/kg dose level (Cediranib Investigator’s Brochure, 2011). 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 unknown.  
 
Further details of the nonclinical pharmacology and toxicity of cediranib can be found in the 
Cediranib Investigator’s Brochure (2016). 
 
2.2.1.4 
Clinical Pharmacology and Pharmacodynamics 
 
Preliminary pharmacokinetics (PK) information indicates a time to maximum serum 
concentration (Tmax) of 2 hours (range, 2-6 hours), a Cmax of 107.8 ± 29.8 ng/mL, and a t1/2 of 
12.1 ± 2.2 hours (Sridhar et al 2008). Preliminary information on blood biomarkers in 
glioblastoma patients indicates that plasma VEGF, placental growth factor (PLGF), and stromal 
cell-derived factor 1α (SDF1α) were increased after treatment, and plasma PIGF and VEGF 
decreased upon cediranib discontinuation. Plasma basic fibroblast growth factor (bFGF) and 
SDF1α and viable circulating endothelial cells (CECs) increased when tumors escaped treatment 
with cediranib (Batchelor et al 2010).  
 
Additional information on the relationship between clinical outcome and biomarkers has been 
reported for a DCTD-sponsored trial (Sorensen et al 2009). Changes in vascular 

 
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permeability/flow as measured by magnetic resonance imaging (MRI) methods (Ktrans), 
microvessel volume, and circulating collagen IV levels were determined. Of the 30 patients in 
the trial, all three parameters were reliably measured in 28. A greater reduction in Ktrans after one 
dose of cediranib was seen in patients with increased PFS (P=0.0015) and overall survival (OS) 
(P=0.0039). A greater increase in the calculated blood volume (CBV) of tumor microvessels 
after one dose of cediranib was seen in glioblastoma patients with extended OS (P=0.0056). A 
greater increase in collagen IV levels in plasma was detected in patients with extended PFS 
(P=0.0010). Peripheral blood was evaluated serially for VEGF concentration and CECs in 
another trial (Ramalingam et al 2008). A stark increase in CECs was noted at progression in 
several patients. 
 
Further details of the clinical pharmacology and toxicity of cediranib can be found in the 
Cediranib Investigator’s Brochure (2016). 
 
 
2.2.1.5 
Adverse Events and Recommended Dose 
 
The most frequently reported AEs for cediranib on company-sponsored trials were fatigue, 
diarrhea, nausea, vomiting, hoarseness, hand-foot syndrome, and hypertension (Cediranib 
Investigator’s Brochure, 2016). Hypertension is an expected pharmacologic effect of agents that 
inhibit VEGF, and is one of the most common adverse events (AEs) reported in trials of 
cediranib. Dose-related increases in thyroid stimulating hormone (TSH) and decreases in total 
thyroxine have been observed at doses of 30 mg and above, and are most marked at 60 mg. The 
recommended dose for cediranib monotherapy is 30 mg/day; the recommended dose in 
combination with chemotherapy agents is 20 mg/day, although exceptions to these doses may be 
appropriate in other studies, depending on age, patient population, tumor type, or agent(s) given 
in combination with cediranib. 
 
2.2.1.6 
Clinical Experience 
 
Cediranib is actively being investigated for use in patients with cancer. As of July 24, 2015, 
approximately 5800 patients have received cediranib through various phase 1-3 trials. There are 
no clinical studies with cediranib involving healthy volunteers. Details of the studies, responses, 
and safety assessments are summarized in the Cediranib Investigator’s Brochure (2016).  
 
Cediranib has been administered to patients in at least 38 DCTD, NCI-sponsored clinical trials. 
CRs and PRs have been reported in clinical trials of cediranib in solid tumors such as NSCLC 
(Gadgeel et al 2011), renal cell carcinoma (RCC) (Sridhar et al 2008), prostate (Dahut et al 
2013), mesothelioma (Garland et al 2011), and gynecologic tumors (Hirte et al 2008; Matulonis 
et al 2009).  
 
The MTD for cediranib in combination with 75 mg/m2 temozolomide and radiation was 
established at 30 mg/day in patients with newly-diagnosed glioblastoma, with no dose-limiting 
toxicities (DLTs) observed (Gerstner et al 2012). Cediranib was then administered at 45 mg/day 
in a post-radiation setting, and in addition to the expected AEs of hypertension, fatigue and 

 
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palmar/plantar erythema, one patient discontinued due to grade 3 transaminase elevation and one 
patient required dose reduction to 15 mg/day due to proteinuria. Median PFS was 288 days (95% 
CI 240–) and median OS was 786 days (95% CI 411–); these values were improvements over 
historical controls. Best radiographic response in patients who completed chemoradiotherapy 
was CR in two patients, PR in 20 patients, and SD in 15 patients. Patients with increased tumor 
perfusion during chemoradiotherapy survived nearly 1 year longer (mean OS 611 days) than 
patients with decreased perfusion (mean OS 269 days).  
 
Among 31 patients in a phase 2 trial of cediranib in recurrent glioblastoma, radiographic PRs 
(>50% volume reduction) were reported in 17 patients, and minor responses (25-50% volume 
reduction) in an additional 6 patients (Batchelor et al 2010). Median PFS was 117 days, and 
median OS was 227 days. Additionally, cediranib alleviated brain edema, a major cause of 
morbidity in glioblastoma patients (Batchelor et al 2007). DLTs were observed in 9 of the 16 
patients with hypertension; fatigue and diarrhea were seen most often.  
 
In a randomised phase 3 study (REGAL) conducted in patients with recurrent GBM, clinical 
efficacy of cediranib monotherapy or in combination with lomustine, was compared with 
lomustine alone (Batchelor et al 2013). No significant difference was observed on PFS for the 
comparison of cediranib 30 mg versus lomustine alone, or for the comprison of cediranib 20 mg 
+ lomustine versus lomustine alone. Furthermore, there was no differece in OS between the 3 
arms. The incidence of SAEs was comparable between all 3 treatment arms. The most common 
SAEs (>4% of patients in any arm) reported during this study were thrombocytopenia, 
pulmonary embolism, neutropenia and convulsion. SAEs that occurred more frequently (by 
≥2%) in the cediranib 20 mg + lomustine arm compared with the placebo + lomustine arm were 
thrombocytopenia, neutropenia, anaemia, pneumonia and convulsion. 
 
Two phase 2 trials of cediranib at two different dose levels (30 mg/day and 45 mg/day) in 
patients with unresectable locally advanced or metastatic hepatocellular carcinoma (HCC) 
yielded no objective responses (Zhu et al 2012; Alberts et al 2012). Grade 3 AEs were observed 
in 93% of patients receiving 45 mg/day (Alberts et al 2012). Fatigue, hypertension, and anorexia 
accounted for the majority of the AEs.  
 
Response information for 45 of 46 patients on a trial of cediranib in malignant pleural 
mesothelioma reported PR by RECIST in 4/47 patients (9%), including 2 patients with bulky 
disease who had 56% and 91% tumor shrinkage; and 16/47 (34%) had SD (Garland et al 2011). 
Median PFS was estimated at 2.56 months, median OS at 9.5 months. The most common non-
hematologic AEs were hypertension (70%), fatigue (64%), and diarrhea (64%).  
 
Among 47 evaluable patients receiving cediranib in a trial in ovarian, primary peritoneal serous, 
or fallopian tube cancer, the clinical benefit rate was 30%; eight patients had a PR and six had 
SD; there were no CRs (Matulonis et al 2009). Median PFS was 5.2 months, and median OS had 
not been reached after a median follow-up time of 10.7 months. Grade 4 AEs included CNS 
hemorrhage, lipase, and hypertriglyceridemia/hypercholesterolemia/elevated lipase, and 
dehydration/elevated creatinine. Grade 3 AEs include hypertension, fatigue, and diarrhea. 
Hypertension occurred in 87% of the patients by the end of the study; in 43%, it was grade ≥3 

 
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(Robinson et al 2010). Grade 2 hypothyroidism occurred in 43% of patients.  
 
ICON6 was a pivotal phase 3, multi-centre, 2-stage, randomised, 3-arm, double-blind, placebo-
controlled study to determine the efficacy and safety of cediranib given in combination with 
platinum-based chemotherapy for 6 cycles followed by maintenance cediranib monotherapy in 
women with PSR ovarian cancer (epithelial ovarian, fallopian tube or serous primary peritoneal). 
There was a statistically significant improvement in PFS for the cediranib concurrent / 
maintenance arm (median 11.0 months) compared with the chemotherapy + placebo arm 
(median 8.7 months) with a HR of 0.57 (Raja et al., 2011).  
 
Information on 59 patients in a trial of cediranib in metastatic androgen-independent prostate 
cancer has been reported (Dahut et al 2013). A total of 59 patients were enrolled, of whom 67% 
had received two or more previous chemotherapy regimens. Six of 39 patients with measurable 
disease had confirmed PRs and one had an unconfirmed PR. At 6 months, 43.9% of patients 
were progression-free; the median PFS and OS periods for all patients were 3.7 months and 10.1 
months, respectively. Decreases in lymph node metastases as well as in lung, liver, and bone 
lesions were observed. Grade 3 AEs included vomiting, prolonged QTc interval, muscle 
weakness, weight loss, dehydration, fatigue, hypoxia, renal failure, transaminitis, and anorexia.  
 
Thirty-two of 43 patients enrolled in a trial of cediranib in renal cell carcinoma (RCC) are 
evaluable for response (Sridhar et al 2008). PRs were observed in 12 patients, SD in 15, and PD 
in 5. Median PFS was 8.7 months and the 6-month progression-free proportion was 63%. 
Treatment-related grade 3 or higher AEs included hypertension, fatigue, joint pain, abdominal 
pain, and dyspnea.  
 
Cediranib was administered in a phase 2 trial in small cell lung cancer (SCLC), in which one 
unconfirmed PR and eight SD were noted (Ramalingam et al 2008). Salient AEs were fatigue 
(four grade 3, two grade 4), and grade 3 diarrhea, skin rash, proteinuria, transaminitis, muscle 
weakness, and hypertension. However, the original 45 mg/day dose was not tolerable in the 
patient population, and the modest activity seen at 30 mg/day did not support the use of cediranib 
as monotherapy for SCLC.  
 
A combination trial of cediranib plus docetaxel, doxorubicin, and cyclophosphamide in advanced 
breast cancer accrued only two patients, and was closed due to systolic dysfunction that occurred 
with concurrent cediranib and doxorubicin (Denduluri et al 2007).   
 
Another combination trial of cediranib plus pemetrexed in NSCLC divided patients into two 
arms—those who had not received bevacizumab in prior chemotherapy regimens (Cohort A), 
and those who had (Cohort B) (Gadgeel et al 2011). The confirmed response rate was 16% (10% 
Cohort A, 25% Cohort B), and the disease control rate (CR/PR/SD) was 71% (74% Cohort A, 
67% Cohort B). Grade 3/4 AEs included neutropenia, febrile neutropenia, fatigue, diarrhea, 
hypertension, anorexia, cardiac ischemia, bronchopleural fistula, and esophagitis. Of the 17 
patients who received cediranib for 4 cycles, 71% required dose reduction from 30 mg/day, and 
of the 18 patients who received pemetrexed for 4 cycles, 22% required dose reduction.  
Additional information on clinical trials conducted with cediranib is summarized in Lindsay et al 

 
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2009. 
 
A phase III study evaluated cediranib 20 mg/day in combination with carboplatin/paclitaxel vs 
placebo in combination with carboplatin/paclitaxel, as first-line treatment, in patients with 
advanced NSCLC (Laurie et al 2014).  
 
2.2.1.7 
Safety Profile 
 
As of August 2009, 582 patients on DCTD, NCI-sponsored clinical trials of cediranib had been 
evaluated for AEs. The most common grade 3/4 AEs were hypertension, fatigue, anorexia, 
diarrhea, and metabolic (ALT/SGPT and AST/SGOT).  
 
Hypothyroidism was observed in 14/21 pediatric patients with CNS tumors administered 
cediranib, including one with a prolonged elevated TSH and thyroxine (T4) that went untreated. 
Proteinuria has been seen in seven patients, including two grade 3 events in Cycle 1 and Cycle 2, 
respectively. Hypertension has been observed in 18/21 patients who received more than a few 
days of therapy. Of the 18 cases, 10 experienced grade 2 hypertension as the highest reported 
grade and 8 reported grade 3 hypertension. Reversible posterior leukoencephalopathy syndrome 
(RPLS) shortly after initiation of Cycle 2 of therapy was seen in one patient who had been 
appropriately managed for grade 3 hypertension  
 
In a phase 2 trial of cediranib in 46 patients with epithelial ovarian, fallopian tube, or peritoneal 
cancer, 31 patients (67%) developed hypertension by Day 3 of treatment, and 87% had 
developed hypertension by the end of the study (Robinson et al 2010). Fourteen women 
developed proteinuria, seven within the first 2 weeks of treatment. Only 7 of the 20 women who 
developed grade 3 hypertension developed proteinuria.  
 
In a phase 2 study of cediranib in patients with solid tumors, patients (n=126) were assigned to 
cediranib dose groups of either 45 or 30 mg/day with or without antihypertensive prophylaxis 
(Langenberg et al 2009). Severe hypertension occurred in one patient receiving prophylaxis 
versus 18 in the non-prophylaxis groups.  
 
Antihypertensive prophylaxis did not result in fewer dose reductions or interruptions. Increases 
in blood pressure, including moderate and severe readings of hypertension, were seen in all 
groups and successfully managed.  
 
Hypertension and kidney toxicity (i.e., proteinuria) are commonly observed AEs seen in the class 
of angiogenesis inhibitor agents (Izzedine et al 2007; Launay-Vacher and Deray, 2009). Indeed, 
many of the AEs observed in human clinical trials of cediranib have been described in studies of 
other angiogenesis inhibitors (Herbst, 2006; Kappers et al 2009). A number of mechanisms have 
been described that account for AEs such as impaired wound healing, gastrointestinal 
perforation, hemorrhage and thrombosis, cardiac impairment, endocrine dysfunction, and RPLS 
(Kamba et al 2007).  
 

 
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In a randomised double-blind phase III trial of cediranib (AZD2171) in relapsed platinum 
sensitive ovarian cancer (ICON6), diarrhea was one of the most commonly reported adverse 
reactions (93.0%). The majority of patients reported events of NCI CTCAE Grades 1 to 2 
(74.0%), whereas NCI CTCAE Grade 3 diarrhea was less frequent (19.0%). Hospitalisations 
were infrequent (2.5%) and diarrhea led to cediranib discontinuation in 10.8% of patients. 
Although diarrhea was shown to have an early onset (within the first cycle), it can occur at any 
time during the treatment with cediranib.  Dose pauses, and dose reduction, were frequently used 
to manage diarrhea (33.5% and 17.1%, respectively). In some patients dehydration (13.3%) and 
hypomagnesaemia (25.9%) were associated with diarrhea. Patients should be instructed to seek 
advice from their healthcare professional early. 
 
 
2.2.2 Olaparib (AZD2281) 
 
Olaparib (AZD2281, KU-0059436, CO-CE 42, 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-
yl]carbonyl}-4-fluorophenyl)methyl]phthalazin-1(2H)-one) is a potent and well-tolerated oral 
inhibitor of polyadenosine 5’-diphosphoribose [poly-(ADP-ribose)] polymerization (PARP)-1 
and PARP2. Olaparib is an active monotherapy in tumors with defective components of 
homologous recombination repair (HRR), which includes those with BRCA1/2 mutations. A 
first-in-man phase 1 dose escalation trial of single agent olaparib in a patient cohort enriched for 
patients with BRCA germline mutations indicated substantial PARP inhibition in surrogate 
tissues and anti-tumor activity in 40% of ovarian cancer patients with germline BRCA mutations, 
using combined RECIST and GCIG CA-125 criteria (Fong et al 2010). 
 
2.2.2.1 
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, 2013). 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 (Farmer et al 2005). 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 (Menear et al 2008). 
 
 

 
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2.2.2.2 
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, 2013). 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 lead 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 100 nM, which equates to 43.4 ng/mL.  
 
An analysis of the correlation of olaparib response with several standard-of-care (SOC) 
chemotherapies in a panel of breast cancer cell lines has demonstrated a strong correlation with 
both carboplatin (0.84, p=0.0006) and camptothecin (0.8, p=0.0018) (Olaparib Investigator’s 
Brochure, 2013). This is consistent with what is known about the types of DNA damage they 
induce (intra-strand and inter-strand cross-links for platinum and trapped topoisomerases-DNA 
adducts for camptothecins, both of which result in DNA DSB formation in replicating cells) and 
the DDR pathways that deal with them (primarily HRR in cells undergoing DNA replication). 
The same does not hold for a mechanistically unrelated chemotherapy, such as paclitaxel (-0.11) 
whose mechanism of action is unrelated to the induction of DNA damage.  
 
The analysis of olaparib and platinum response was extended to additional tumor indications 
where platinum treatment is SOC and included ovarian, non-small cell lung cancer (NSCLC) and 
head and neck squamous cell carcinoma cell lines (Olaparib Investigator’s Brochure, 2013). 
Consistent with the breast cancer cell line data, the strong correlation between platinum response 
and olaparib response was observed. These in vitro data have been extended further into in vivo 
patient-derived tumor explant (PTX) models of both breast and NSCLC and again the correlation 
is seen between platinum sensitivity and olaparib sensitivity.  
 
In vitro combination studies demonstrate that olaparib is able to potentiate the cytotoxicity of 
DNA-damaging agents, including the mono-methylating agent temozolomide (melanoma, 
glioblastoma, colorectal), topoisomerase-1 inhibitors such as camptothecin, irinotecan, and 
topotecan (ovarian, pancreatic, colorectal), and platinum-based agents such as cisplatin and 
carboplatin (breast) (Olaparib Investigator’s Brochure, 2013). Studies with BRCA1-deficient 
orthotopically-transplanted in vivo mouse mammary tumor models showed that, in addition to 
single agent activity of olaparib, sequential treatment of mice with olaparib following a single 
dose of platinum agent increased the time to progression on treatment and extended OS. These 
data support the idea that olaparib can extend the antitumor effect of platinum agents when given 
as a maintenance treatment.  
 
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 

 
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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 μM) 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 mcM), 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 μM) (Olaparib Investigator’s Brochure, 2013). In HEK-293 cells transfected with 
OATP1B1, olaparib functioned as an inhibitor and IC50 values of 20.3 mcM and 27.1 mcM 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 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. 
 
2.2.2.3 
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 

 
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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. 
 
2.2.2.4 
Clinical Pharmacology 
 
Olaparib is rapidly absorbed following capsule oral dosing in cancer patients (Olaparib 
Investigator’s Brochure, 2013). Mean volume of distribution was 40.3 L, mean plasma clearance 
was 4.55 L/h, and the estimated terminal half-life (t1/2) was between 5 and 12 hours. Exposure 
increased proportionally with dose at doses up to 100 mg but increased in a less than 
proportional fashion at higher doses. On multiple dosing, there was no evidence of time 
dependency of the PK and no marked accumulation. There was no evidence of ethnic difference 
in olaparib PK between Japanese and Caucasian patients. Recovery of administered radio-
labelled olaparib dose was >94% in four patients and approximately 60% in a further two with 
the lower recoveries apparently due to slower fecal excretion of dosed material by these two 
patients. Drug-related material was eliminated in the urine (35-50%) and in the feces (12-60%) 
with 6-20% of the dosed material recovered in the urine as unchanged drug. Plasma 
concentrations of olaparib were similar to those of total radioactivity up to 6 or 8 hours after 
dosing but the profiles diverged thereafter indicating the presence of circulating metabolites. 
Metabolite identification in plasma and the excreta is ongoing.  
 
Studies of the relative single-dose bioavailability of capsule vs. tablet formulations showed that 
at the two lower tablet doses, the Cmax with the tablet formulation tended to be slightly higher 
and the AUC was similar (Olaparib Investigator’s Brochure, 2013). However, at the highest 
tablet dose (250 mg), the exposure delivered by the tablet formulation (both Cmax and AUC) was 
higher than that delivered by the 400 mg capsule. The tablet and the capsule formulations cannot 
therefore be considered to be bioequivalent. Further details regarding PK comparisons between 
the capsule and tablet formulations may be found in the 2013 Olaparib Investigator’s Brochure. 
 

 
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Table 2-1. Systemic Exposure of Olaparib Tablet vs. Capsule Formulations 
Parameter 
25 mg tablet vs. 50 
mg capsule 
50 mg tablet vs. 100 
mg capsule 
250 mg tablet vs. 400 
mg capsule 
Cmax ratio 
90% CI 
1.29 
1.10 - 1.52 
1.53 
1.11 - 2.11 
2.49 
1.87 - 3.31 
AUC ratio 
90% CI 
1.03 
0.85 - 1.24 
0.99 
0.69 - 1.42 
1.74 
1.36 - 2.23 
Cmax = maximum plasma concentration, AUC = area under the concentration-time curve, CI = 
confidence interval 
 
2.2.2.5 
Clinical Efficacy 
 
The first clinical study in man of olaparib (KU-36-92) was a dose-escalation study in patients 
with advanced solid tumors (Olaparib Investigator’s Brochure, 2013). Preliminary data 
demonstrated that olaparib is generally well-tolerated at doses up to and including the MTD of 
400 mg BID in patients with various solid tumors. As of October 2, 2013, approximately 2103 
patients with ovarian, breast, pancreatic, melanoma, and other advanced solid tumors have 
received olaparib, either as monotherapy or in combination with other chemotherapy agents. AEs 
considered to be associated with olaparib included anemia (mild to moderate), neutropenia (mild 
to moderate), and thrombocytopenia (generally mild to moderate, sometimes severe), nausea and 
vomiting (mild to moderate), and fatigue (mild to moderate).  
 
Olaparib has also been studied in an expansion phase in BRCA-deficient ovarian cancer at a dose 
of 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 (Fong et al 
2010). 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 
olaparib continuously at a dose of 400 mg BID (Cohort 1) or 100 mg BID (Cohort 2) (Audeh et 
al 2010). 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 included a cohort of 46 ovarian 
cancer patients who were known not to carry a germline BRCA mutation, in which an overall 
response rate (ORR) of 23.9% was observed (Gelmon et al 2010).  
 
Additional studies of olaparib as monotherapy or in combination with a platinum reagent for 
treatment of metastatic BRCA-deficient ovarian cancer are ongoing. Results from a phase 2 trial 
investigating olaparib as maintenance therapy following platinum-based therapy for platinum-
sensitive serous ovarian cancer demonstrated a significant progression-free survival (PFS) 
benefit (8.4 vs. 4.8 months, P<0.001), with subgroup analyses demonstrating evidence of benefit 
regardless of BRCA status (Ledermann et al 2012). 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 (Lee et al 2011). They also 
see activity with over 80% of ovarian cancer patients attaining either SD or PR lasting up to 18+ 

 
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months. Additional phase 1 and 2 trials in both BRCA-deficient and BRCA-competent ovarian 
cancer are currently ongoing.  
 
Olaparib was granted accelerated approved by the FDA in the United States as monotherapy in 
women with advanced ovarian cancer associated with germline BRCA mutation in the 
companion diagnostic test BRACAnalysis CDx and who have received at least 3 prior lines of 
therapy for ovarian cancer on December 19, 2014. 
 
2.2.3 Pre-clinical rationale for combination of cediranib and olaparib 
 
Several lines of preclinical evidence support the combination of a PARP inhibitor and anti-
angiogenic therapy.  
 
While the role of DNA damage repair pathways in tumors treated with anti-angiogenic therapies 
is not well understood, the hypoxic state is known to result in genetic instability and 
mutagenesis. It is known that hypoxia triggers a DNA damage response, resulting in p53 
accumulation and eventual apoptosis; p53-deficient tumors suppressed the apoptotic effect, 
promoting tumor survival in spite of the hypoxic state (Graeber et al 1996). However, despite the 
presence of DSB markers such as histone H2AX, there is little evidence of DNA damage during 
the hypoxic state, and H2AX staining is atypical (diffuse rather than punctate), though severe 
hypoxia may result in aberrant replication complexes, SSBs, and regions of single-stranded DNA 
(Hammond et al 2002). After re-oxygenation, DSBs are noted to accumulate, and tumor survival 
is dependent upon intact DNA repair complexes (Hammond et al 2004). Thus, post-hypoxic 
tumor cells which rely upon angiogenic signaling may also be vulnerable to PARP inhibition.  
 
Human breast (MCF-7) and lung adenocarcinoma (A549) cell lines grown under hypoxic 
conditions exhibit severely reduced levels of BRCA1 and RAD51 due to transcriptional down-
regulation (Bindra et al 2004; Bindra et al 2005). Subsequent work determined that chemical 
PARP inhibitors displayed increased cytotoxicity against A549, RKO (colon), and H460 (lung) 
cell lines under hypoxic conditions, compared to normoxic conditions (Hegan et al 2010). 
Exposure to PARP inhibitors or PARP-1 RNAi down-regulated BRCA1 and RAD51 expression 
in a dose-dependent manner, regardless of oxygenation, and the addition of hypoxic conditions 
to PARP inhibition enhanced the down-regulatory effect.  
 
In addition, studies in primary human umbilical vein endothelial cells (HUVECs) and 
immortalized human endothelial cell lines demonstrate a connection between hypoxia driven 
angiogenesis and DNA repair, and show that inhibition of DNA repair pathways can inhibit 
endothelial cell proliferation. In HUVECs treated under a hypoxic state, H2AX foci are found 
primarily in proliferating endothelial cell populations (positive staining for proliferative cell 
nuclear antigen) where they co-localize with replication protein A, suggesting a replication 
stress-related origin of hypoxia-induced H2AX foci (Economopoulou et al 2009). Small 
interfering RNA (siRNA) knockdown of the replication stress-induced ataxia teleangiectasia 
mutated kinase (ATM)- and Rad3-related kinase (ATR) pathway, but not the ATM pathway, 
inhibited H2AX formation, and siRNA knockdown of H2AX significantly decreased growth 
factor-induced proliferation and fetal calf serum-induced HUVEC proliferation under hypoxic 

 
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conditions. PARP inhibition (via the specific small-molecule inhibitor GPI 15427) inhibited 
angiogenesis in matrigel in vitro (Tentori et al 2007). At drug levels that did not affect 
endothelial cell proliferation (0.1-1 mcM), PARP inhibition reduced the formation of tube-like 
structures and inhibited platelet-derived growth factor (PlGF)- and VEGF-induced endothelial 
cell migration. At 1 mcM, GPI 15427 did not inhibit hypoxia-inducible factor 1α (HIF-1α) 
induction by the hypoxia mimetic agent CoCl2, indicating that PARP inhibition’s effects on 
migration were not exerted through influencing HIF-1α function.  
Collectively, the evidence indicates that anti-angiogenic therapy may complement PARP 
inhibition, particularly in the context of DNA repair-deficient tumors. These results also suggest 
that the combination of cediranib and olaparib may synergize not only with regard to direct 
antitumor activity but also with regard to their anti-angiogenic effect on tumor vasculature. 
 
2.2.3.1 
Nonclinical Efficacy 
 
Limited nonclinical data exist regarding the specific combination of olaparib and cediranib. 
Olaparib (100 nM) and cediranib (5 nM) have potentially synergistic activity in in vitro 
microvascular cell tube growth assays (Figure 1), inhibiting cell tube growth and branching in a 
greater than additive fashion (Jung Min Lee, unpublished data) Olaparib (10 nM) and cediranib 
(50 nM) individually reduced tumor cell invasion, and the combination of both agents nearly 
completely abolished invasion compared to the control (Figure 2). 
 
 
Figure 1. Microvascular cell tube formation assay. 

 
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Figure 2. Tumor invasiveness assay. 
 
2.2.4 Clinical background for combination of cediranib and olaparib 
 
2.2.4.1 
Phase 1 experience with cediranib and olaparib 
 
NCI protocol 8348 included a Phase 1 component that established the recommended Phase 2 
dosing (RP2D) of cediranib in combination with olaparib in the capsule formulation. This Phase 
1 enrolled a total of 28 patients (20 ovarian, 8 breast). (Liu et al 2013)   
 
At the highest dosing level of cediranib 30 mg daily (QD) and olaparib 400 mg BID, two DLTs 
were observed (grade 4 neutropenia and thrombocytopenia), and the recommended phase 2 dose 
(RP2D) was declared to be cediranib 30 mg QD and olaparib 200 mg BID (Liu et al 2013). Only 
one additional grade 4 adverse event (AE) (neutropenia) was observed. Fatigue (93%), diarrhea 
(86%), nausea (57%), and hypertension (45%) were the most commonly observed AEs, 
consistent with previously reported toxicities of cediranib and olaparib. Fatigue, which has been 
observed with both cediranib and olaparib in single-agent studies, may have been more 
prominent due to overlapping toxicity. Diarrhea was generally controllable with loperamide, 
although several patients required dose reduction. Hypertension, a well-documented toxicity of 
cediranib, was manageable with aggressive anti-hypertensive therapy; of note, only one patient 
required dose reduction for hypertension. Although all three grade 4 AEs observed were 
hematologic, in general, the combination was well-tolerated with primarily grade 1/2 
hematologic toxicities.  
 
Twenty-five patients (18 ovarian, 7 breast) from the phase 1 portion were evaluable for response 
by Response Evaluation In Solid Tumors (RECIST) criteria, version 1.1 (Liu et al 2013). The 
two ovarian cancer patients not evaluable by RECIST 1.1 were followed by Gynecologic Cancer 
InterGroup (GCIG) CA125 criteria. The non-evaluable breast cancer patient experienced clinical 
progression within the first cycle of treatment and therefore did not undergo comparative 
imaging. There was one confirmed CR and seven confirmed PRs among the 18 evaluable 
ovarian patients, for an ORR of 44%. An additional three patients had SD for at least 24 weeks, 

 
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for an overall clinical benefit rate of 61%. Both ovarian patients followed by CA125 had SD, 
with one patient having SD for ≥24 weeks. In the 11 evaluable ovarian patients with known 
BRCA mutation, there was one CR and four PRs, for an ORR of 45%. None of the breast cancer 
patients met RECIST 1.1 criteria for clinical response. Two patients had SD for ≥24 weeks. The 
median PFS was 8.7 months for ovarian cancer patients and 3.7 months for breast cancer 
patients.  
 
Dose escalation of cediranib in combination with olaparib in the tablet formulation has been 
completed in NCI protocol 8348 through a Phase 1-T component. Six doses of cediranib and 
olaparib tablets were explored (number of patients on each dose level in parentheses):   
 
Cediranib 20mg daily / Olaparib 200mg BID (3) 
Cediranib 20mg daily / Olaparib 250mg BID (3) 
Cediranib 20mg daily / Olaparib 300mg BID (6) 
Cediranib 30mg daily / Olaparib 150mg BID (3) 
Cediranib 30mg daily / Olaparib 200mg BID (6) 
Cediranib 30mg daily / Olaparib 250mg BID (3) 
 
Three DLTs were observed across all patients enrolled to 8348 Phase 1-T; one DLT in the six 
patients on cediranib 30mg/olaparib 200mg, and two DLTs in the two patients on cediranib 
30mg/olaparib 250mg. The recommended phase 2/3 dosing was therefore concluded to be 
cediranib 20mg daily and olaparib tablets 300mg BID or cediranib 30mg daily and olaparib 
tablets 200mg BID. Six responses (CR or PR) were observed in the 24 patients on the study; 
these included one CR in the six patients on the cediranib 20mg/olaparib 300mg dosing and one 
CR and two PRs in the six patients on the cediranib 30mg/olaparib 200mg dosing. To preserve 
uniformity of cediranib dosing with prior clinical trial experience, the dose of cediranib 30mg 
daily and olaparib tablet 200mg BID will be further explored in this study. 
 
2.2.4.2 
Phase 2 experience with cediranib and olaparib combination 
 
A multi-center open-label randomized Phase 2 trial comparing the activity of the cediranib and 
olaparib combination to olaparib alone in platinum-sensitive recurrent ovarian cancer 
randomized 90 patients in a 1:1 ratio to either the combination or single agent olaparib (capsule 
formulation) (Liu et al 2014). Eligibility criteria for this trial included platinum-sensitive disease 
recurrence, with platinum-sensitivity defined as recurrence occurring greater than or equal to 6 
months after the last platinum-containing regimen. Patients were allowed to receive an unlimited 
number of platinum-based lines of therapy, and up to one non-platinum-based regimen in the 
recurrent setting. No anti-angiogenics in the recurrent setting were allowed; no prior PARP-
inhibitors were allowed. 
 
The combination of cediranib and olaparib significantly extended both PFS and overall response 
rate (ORR) compared to olaparib alone in this patient population, with a median PFS of 9.0 
months for olaparib alone and 17.7 months for cediranib/olaparib (HR 0.418, 95% CI 0.229-
0.763, p = 0.005) (Figure 3). There were 2 complete responses (CR) and 20 partial responses 
(PR) in patients on olaparib alone (48% ORR) and 5 CRs and 30 PRs in patients on 

 
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cediranib/olaparib (80% ORR, p = 0.002). 
 
 
Figure 3. Kaplan-Meier PFS curves in patients treated on olaparib and 
cediranib/olaparib in Phase 2 trial. 
 
Forty-seven of the 90 patients enrolled to the Phase 2 cediranib/olaparib vs. olaparib trial were 
known BRCA mutation carriers (25 olaparib; 23 cediranib/olaparib). A post-hoc subset analysis 
of PFS by BRCA mutation status (carrier vs. non-carrier/unknown) is shown in Figure 4. In 
BRCA mutation carriers, the median PFS was 16.5 months on the olaparib alone arm and 19.4 
months on the cediranib/olaparib arm (HR 0.55, 95% CI 0.24-1.27, p = 0.16). In BRCA non- 
carrier/unknown patients, the median PFS was 5.7 months on the olaparib alone arm, and 16.5 
months in the cediranib/olaparib arm (HR 0.32, 95% CI 0.14-0.74, p = 0.008). 
 
Differentially occurring grade 3 or 4 toxicities attributed to study treatment included fatigue 
(27% cediranib/olaparib vs 11% olaparib, p = 0.06), diarrhea (23% vs 0%, p = 0.0004), and 
hypertension (41% vs 0%, p < 0.0001). There were two Grade 4 events, both in the 
cediranib/olaparib arm: 1 grade 4 hypertension in a patient who was not fully compliant with 
blood pressure monitoring and 1 grade 4 myelodysplastic syndrome (MDS). The patient with 
MDS had two prior lines of therapy and had been on study for approximately 1 year when she 
was diagnosed with MDS. Four patients on the cediranib/olaparib arm withdrew from study 
treatment secondary to toxicity (1 each due to weight loss, MDS, recurrent avascular necrosis in 
the setting of prior history of avascular necrosis, and vaginal fistula formation). Otherwise, AEs 
were manageable with a combination of symptom management and dose holds and/or 
reductions, and removal from the study for reasons other than a PFS event was balanced between 
the arms (2 withdrawal of consent, 1 investigator decision, 5 clinical progressions on 
cediranib/olaparib vs. 3 withdrawal of consent, 1 investigator decision, and 6 clinical 
progressions on olaparib alone).    

 
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Figure 4. Kaplan-Meier PFS curves in BRCA mutation and BRCA non-
carrier/unknown patients. 
 
 
 
 

 
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2.3 
Advanced Imaging 
 
2.3.1 MRI 
 
Our goal is to explore changes in tumor vasculature resulting from treatment with 
Cediranib and olaparib and the impact these changes have on response to treatment. Results from 
this study will shed light on the potential mechanism of actions of cediranib and olaparib and 
how these agents may modulate tumor vasculature. This study will evaluate patients with 
recurrent glioblastoma with MRI to assess changes in tumor blood flow, blood volume, and 
vessel caliber, with advanced MRI.  
 
Of note, this study will be run through the ECTCN across various sites. We anticipate that not all 
sites will have the capacity to perform some of the more sophisticated/advanced MRI sequences 
and, thus, may not participate in this exploratory aim of the study. We will assess feasibility 
across sites and if there is insufficient participation to the advanced MR portions of the imaging 
study, we will proceed with the standard MRI imaging only. Please refer to Appendix F for 
advanced imaging and stadard imaging protocols.  
 
 
2.3.1.1 
Rationale for use MRI 
 
The dependence of tumor growth and metastasis on angiogenesis — which has been extensively 
demonstrated in animal models — has provided a powerful rationale for anti-angiogenic 
approaches to cancer therapy (van de Beek, 2007; Carmeliet & Jain, 2000; Kleihues et al 1993). 
Targeting blood vessels in brain tumors has been a particularly attractive strategy, given the 
characteristic high degree of endothelial proliferation, vascular permeability, and pro-angiogenic 
growth-factor expression (for example, VEGF) (Dvorak, 2002; Sundberg, 2001). The approval 
of bevacizumab, which neutralizes VEGF, in May 2009 for recurrent glioblastoma (rGBM) 
represented the first new therapy for this disease in many years. A strong antiedema effect is 
clearly seen with anti-VEGF therapy in many patients. Whether this conveys a survival benefit in 
subset of patients remains unknown; cediranib monotherapy did not improve survival over 
lomustine in rGBM in a recent phase III trial. 
 
Bevacizumab and other anti-VEGF inhibitors are not an effective monotherapy outside the brain, 
but it is effective when combined with other drugs. The mechanism of this clinical efficacy is 
still incompletely understood. Anti-VEGF therapies have been shown to promote vascular 
“normalization” (Batchelor et al 2007; Jain et al 2005; Willett et al 2004) in many patients, 
which could improve local tumor blood flow and therefore cytotoxic chemotherapy delivery to 
the tumor. We have shown that the ‘normalization window’ of the anti-VEGF agent cediranib 
can be detected using serial, non-invasive MRI techniques in rGBM (Batchelor et al 2007), and 
we have seen increases in blood flow (Sorensen et al 2012). Whether this effect is similar with 
the combination of olaparib plus cediranib is unknown, and how oxygenation is affected also 
remains an outstanding question. 
 

 
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The acquisition of MRI should allow us to assess both hypoxia and vascular changes to 
determine the time course and interplay between vascular physiology, tumor oxygenation and 
response to treatment.  
 
2.4 
Bevacizumab 
 
Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that binds all biologically active 
isoforms of human VEGF (or VEGF-A) with high affinity (kd = 1.1 nM ). The antibody consists 
of a human IgG1 framework and the antigen-binding complementarity-determining regions from 
the murine anti-VEGF MAb A.4.6.1.16-18. For this study, we will use the commercially 
available formulation of bevacizumab, Avastin. 
 
 
2.4.1 Clinical Trials 
 
Bevacizumab has been studied in multiple Phase I, II, and III clinical trials in more than 5000 
patients and in multiple tumor types. In addition, data are available from 3,863 patients enrolled 
in two postmarketing studies in metastatic colorectal cancer (CRC). Approximately 130,000 
patients have been exposed to bevacizumab as a marketed product or in clinical trials. The 
following discussion summarizes bevacizumab’s safety profile and presents some of the efficacy 
results pertinent to this particular trial. Please refer to the bevacizumab Investigator Brochure for 
descriptions of all completed Phase I, II, and III trials reported to date. The maximum tolerated 
dose of bevacizumab has not been determined; however, the dose level of 20 mg/kg was 
associated with severe headaches (Kim et al 1999). The dose schedule of either 10 mg/kg every 2 
weeks or 15 mg/kg every 3 weeks is used in most phase II or III trials with only a few exceptions 
(e.g., the pivotal phase III trial in colorectal cancer, in which bevacizumab was given at 5 mg/kg 
every 2 weeks). 
 
Clinical proof of principle for anti-VEGF therapy with bevacizumab has been provided by the 
pivotal phase III trial of bevacizumab (5 mg/kg every 2 weeks) in combination with bolus 
irinotecan/5-fluorouracil/leucovorin (IFL) in patients with untreated advanced colorectal cancer 
(AVF2107g) (Hurwitz et al 2004). In that study, the addition of bevacizumab to IFL was 
associated with an increase in objective responses (45% vs. 35%) and significant prolongations 
of both time to progression (10.6 vs. 6.2 months) and overall survival (20.3 vs. 15.6 months) 
compared with IFL. Based on the survival advantage, bevacizumab was approved in 2004 in the 
United States for first-line treatment in combination with IV 5-FU−based chemotherapy for 
subjects with metastatic colorectal cancer. 
 
Additional data from Phase III trials in metastatic CRC (E3200), non−small cell lung cancer 
(NSCLC; E4599), and metastatic breast cancer (E2100) have also demonstrated clinical benefit 
from bevacizumab when added to chemotherapy (see the Bevacizumab Investigator Brochure for 
additional details). Additional clinical trials are ongoing in a variety of solid tumors and 
hematologic malignancies using bevacizumab as monotherapy or in combination with 
chemotherapy, radiation, or other targeted/biologic agents. 
 

 
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2.4.2 Safety Profile 
 
In the initial Phase I and II clinical trials, four potential bevacizumab-associated safety signals 
were identified: hypertension, proteinuria, thromboembolic events, and hemorrhage. Additional 
completed Phase II and Phase III studies of bevacizumab as well as spontaneous reports have 
further defined the safety profile of this agent. Bevacizumab-associated adverse events identified 
in phase III trials include congestive heart failure (CHF) primarily in metastatic breast cancer, 
gastrointestinal perforations, wound healing complications, and arterial thromboembolic events 
(ATE). These and other safety signals are described in further detail as follows and in the 
bevacizumab Investigator Brochure. 
 
Hypertension: An increased incidence of hypertension has been observed in patients treated 
with bevacizumab. Grade 4 and 5 hypertensive events are rare. Clinical sequelae of hypertension 
are rare but have included hypertensive crisis, hypertensive encephalopathy, and reversible 
posterior leukoencephalopathy syndrome (RPLS) (Ozcan et al 2006; Glusker 2006). There is no 
information on the effect of bevacizumab in patients with uncontrolled hypertension at the time 
of initiating bevacizumab therapy. Therefore, caution should be exercised before initiating 
bevacizumab therapy in these patients. Monitoring of blood pressure is recommended during 
bevacizumab therapy. Optimal control of blood pressure according to standard public health 
guidelines is recommended for patients on treatment with or without bevacizumab. 
 
Temporary interruption of bevacizumab therapy is recommended in patients with hypertension 
requiring medical therapy until adequate control is achieved. If hypertension cannot be 
controlled with medical therapy, bevacizumab therapy should be permanently discontinued. 
Bevacizumab should be permanently discontinued in patients who develop hypertensive crisis or 
hypertensive encephalopathy. 
 
Proteinuria: An increased incidence of proteinuria has been observed in patients treated with 
bevacizumab compared with control arm patients. In the bevacizumab-containing treatment arms 
of clinical trials (across all indications), the incidence of proteinuria (reported as an adverse 
event) was up to 38% (metastatic CRC Study AVF2192g). The severity of proteinuria has ranged 
from asymptomatic and transient events detected on routine dipstick urinalysis to nephrotic 
syndrome; the majority of proteinuria events have been grade 1. NCI-CTC Grade 3 proteinuria 
was reported in up to 3% of bevacizumab-treated patients, and Grade 4 in up to 1.4% of 
bevacizumab-treated patients. The proteinuria seen in bevacizumab clinical trials was not 
associated with renal impairment and rarely required permanent discontinuation of bevacizumab 
therapy. Bevacizumab should be discontinued in patients who develop Grade 4 proteinuria 
(nephrotic syndrome) Patients with a history of hypertension may be at increased risk for the 
development of proteinuria when treated with bevacizumab. There is evidence from the dose-
finding, Phase II trials (AVF0780g, AVF0809s, and AVF0757g) suggesting that Grade 1 
proteinuria may be related to bevacizumab dose. Proteinuria will be monitored by urine protein : 
creatinine (UPC) ratio or urine dipstick at least every 2 weeks. 
 
Thromboembolic Events: Both venous and arterial thromboembolic (TE) events, ranging in 
severity from catheter-associated phlebitis to fatal, have been reported in patients treated with 

 
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bevacizumab in the colorectal cancer trials, the recurrent glioblastoma trial and, to a lesser 
extent, in patients treated with bevacizumab in NSCLC and breast cancer trials. Venous 
thromboembolic events (VTE) have also been observed in trials with bevacizumab and 
glioblastoma. In clinical trials across all indications the overall incidence of VTE events was 
2.8%−17.3% in the bevacizumab-containing arms compared with 3.2%−15.6% in the 
chemotherapy control arms. Since VTE are very common in GBM independent of treatment 
(Stupp et al 2005), a relationship of VTE to bevacizumab in this population will be uncertain. 
 
The first incidence of VTE will therefore not constitute a DLT. An increased incidence of arterial 
thromboembolic events (ATE) was observed in patients treated with bevacizumab compared 
with those receiving control treatment. ATE include cerebrovascula accidents, myocardial 
infarction, transient ischemic attacks (TIAs), and other ATE. In a pooled analysis of data from 
five randomized Phase II and III trials (mCRC [AVF2107g, AVF2192g, AVF0780g]; locally 
advanced or metastatic NSCLC [AVF0757g]; metastatic breast cancer [AVF2119g]), the 
incidence rate of ATE was 3.8% (37 of 963) in patients who received chemotherapy + 
bevacizumab compared with 1.7% (13 of 782) in patients treated with chemotherapy alone. ATE 
led to a fatal outcome in 0.8% (8 of 963) of patients treated with chemotherapy + bevacizumab 
and 0.5% (4 of 782) of patients treated with chemotherapy alone. Cerebrovascular accidents 
(including TIAs) occurred in 2.3% of patients treated with chemotherapy + bevacizumab and 
0.5% of patients treated with chemotherapy alone. Myocardial infarction occurred in 1.4% of 
patients treated with chemotherapy + bevacizumab compared with 0.7% of patients treated with 
chemotherapy alone (see the Bevacizumab Investigator Brochure for additional details). 
 
Gastrointestinal perforation: Patients may be at increased risk for the development of 
gastrointestinal perforation and fistula when treated with bevacizumab and steroids or 
chemotherapy. Bevacizumab should be permanently discontinued in patients who develop 
gastrointestinal perforation. A causal association of intra-abdominal inflammatory processes and 
gastrointestinal perforation to bevacizumab treatment has not been established. Nevertheless, 
caution should be exercised when treating patients with intra-abdominal inflammatory processes 
with bevacizumab. Gastrointestinal perforation has been reported in other trials in non-colorectal 
cancer populations (e.g., ovarian, renal cell, pancreas, breast, and NSCLC) and may be higher in 
incidence in some tumor types. 
 
Fistula: Bevacizumab use has been associated with serious cases of fistulae including events 
resulting in death. Fistulae in the GI tract are common (1%–10% incidence) in patients with 
metastatic CRC, but uncommon (0.1%−1%) or rare (0.01%–0.1%) in other indications. In 
addition, fistulae that involve areas of the body other than the GI tract (e.g. tracheoesophageal, 
bronchopleural, urogenital, biliary) have been reported uncommonly (0.1%–1%) in patients 
receiving bevacizumab in clinical studies and postmarketing reports. Events were reported at 
various timepoints during treatment, ranging from 1 week to > 1 year following initiation of 
bevacizumab, with most events occurring within the first 6 months of therapy. 
 
Wound healing complications: Wound healing complications such as wound dehiscence have 
been reported in patients receiving bevacizumab. In an analysis of pooled data from two trials in 
metastatic colorectal cancer, patients undergoing surgery 28-60 days before study treatment with 

 
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5- FU/LV plus bevacizumab did not appear to have an increased risk of wound healing 
complications compared to those treated with chemotherapy alone. Surgery in patients currently 
receiving bevacizumab is not recommended. No definitive data are available to define a safe 
interval after bevacizumab exposure with respect to wound healing risk in patients receiving 
elective surgery; however, the estimated half life of bevacizumab is 21 days. Bevacizumab 
should be discontinued in patients with severe wound healing complications. 
 
If patients receiving treatment with bevacizumab require elective major surgery, it is 
recommended that bevacizumab be held for 4–8 weeks prior to the surgical procedure. Patients 
undergoing a major surgical procedure should not begin or restart bevacizumab until 4 weeks 
after that procedure (in the case of high-risk procedures such as liver resection, thoracotomy, or 
neurosurgery, it is recommended that bevacizumab be restarted no earlier than 4 weeks after 
surgery). 
 
Hemorrhage: Overall, grade 3 and 4 bleeding events were observed in 4.0% of 1132 patients 
treated with bevacizumab in a pooled database from eight phase I, II, and III clinical trials in 
multiple tumor types (Bevacizumab Investigator Brochure). The hemorrhagic events that have 
been observed in bevacizumab clinical studies were predominantly tumor-associated hemorrhage 
(see below) and minor mucocutaneous hemorrhage. 
 
Tumor-Associated Hemorrhage: Major hemorrhage has been observed primarily in patients 
with NSCLC. Life-threatening and fatal hemoptysis was identified as a bevacizumab-related 
adverse event in NSCLC trials. These events occurred suddenly and presented as major or 
massive hemoptysis. GI hemorrhages, including rectal bleeding and melena have been reported 
in patients with CRC, and have been assessed as tumor associated hemorrhages. Tumor-
associated hemorrhages were only very rarely seen in patients with high grade gliomas (1-2 %) 
(Cloughsey et al 2008). 
 
Mucocutaneous Hemorrhage: Across all bevacizumab clinical trials, mucocutaneous 
hemorrhage has been seen in 20%-40% of patients treated with bevacizumab. These were most 
commonly NCICTC Grade 1 epistaxis that lasted less than 5 minutes, resolved without medical 
intervention and did not require any changes in bevacizumab treatment regimen. There have also 
been less common events of minor mucocutaneous hemorrhage in other locations, such as 
gingival bleeding and vaginal bleeding. 
 
Reversible Posterior Leukoencephalopathy Syndrome: There have been rare reports of 
bevacizumab-treated patients developing signs and symptoms that are consistent with RPLS, a 
rare neurologic disorder that can present with the following signs and symptoms (among others): 
seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or 
without associated hypertension. Brain imaging is mandatory to confirm the diagnosis of RPLS. 
In patients who develop RPLS, treatment of specific symptoms, including control of 
hypertension, is recommended along with discontinuation of bevacizumab. The safety of 
reinitiating bevacizumab therapy in patients previously experiencing RPLS is not known. 
 

 
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Congestive heart failure: In clinical trials CHF was observed in all cancer indications studied to 
date, but predominantly in patients with metastatic breast cancer. In the Phase III clinical trial of 
metastatic breast cancer (AVF2119g), 7 (3%) bevacizumab-treated patients experienced CHF, 
compared with two (1%) control arm patients. These events varied in severity from 
asymptomatic declines in left ventricular ejection fraction (LVEF) to symptomatic CHF 
requiring hospitalization and treatment. All the patients treated with bevacizumab were 
previously treated with anthracyclines (doxorubicin cumulative dose of 240−360 mg/m2). Many 
of these patients also had prior radiotherapy to the left chest wall. Most of these patients showed 
improved symptoms and/or left ventricular function following appropriate medical therapy 
(Miller et al. 2005). No information is available on patients with preexisting CHF of New York 
Heart Association (NYHA) Class II−IV at the time of initiating bevacizumab therapy, as these 
patients were excluded from clinical trials. 
 
Additional Adverse Events: See the bevacizumab Investigator Brochure for additional details 
regarding the safety experience with bevacizumab. 
 
 
2.5 
Rationale 
 
The combination of cediranib and olaparib may offer a novel treatment regimen for patients with 
recurrent GBM whose current standard of care is single-agent bevacizumab. However, 
unanswered questions exist regarding the activity of the combination therapy in this clinical 
setting, and the biomarkers that may predict for tumor response to this regimen. 
 
In this phase 2 trial, the potentially synergistic action of PARP inhibition and anti-angiogenesis 
on DNA repair and biomarkers of angiogenesis and DNA repair will be evaluated. Patients with 
recurrent GBM will be randomized to either the combination of cediranib plus olaparib or singe-
agent bevacizumab. This will allow comparison of clinical anti-tumor activity of the combination 
therapy to that of bevacizumab.   
 
Cediranib and olaparib have been tolerated in human studies and have limited significant 
overlapping toxicities, particularly when proactively managed (Liu 2014). Safety profiles of the 
combination will be assessed in patients with recurrent GBM.  
 
2.6 
Correlative Studies Background 
 
2.6.1 Plasma Angiome 
 
Currently there is no known biomarker that might predict for a response to the cediranib plus 
olaparib combination. To identify blood-based markers of anti-angiogenic inhibition, the Duke 
multiplex ELISA-based plasma angiome panel will be tested. This panel consists of a number of 
angiogenic biomarkers (Table 2.2, including Ang-2, stromal cell-derived factor (SDF)-1, VEGF-
D, osteopontin (OPN), and interleukin (IL)-6. In order to develop the most optimal arrays, the 
Duke team leverages three multiplex protein array systems. Many analytes have been previously 
validated on the CiraScan platform, produced by Aushon Biosystems. Additional multiplex 

 
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systems that will be employed include the Meso Scale Discovery (MSD) and ProteinSimple 
platforms.  The ProteinSimple platform uses microcapillary flow cells for improved sensitivity 
and reproducibility versus traditional ELISA techniques.  
 
We have devoted considerable effort to the development and optimization of an appropriately 
designed panel for the evaluation key angiogenic and inflammatory markers.  Table 2.2 below 
lists the panel of markers currently optimized; however, modifications to this list may occur 
based on the needs for any given study. This “Angiome” multiplex array has recently been 
approved by the NCI Biomarker Review Committee (BRC) as an integrated biomarker for use in 
two Phase III studies of cediranib and olaparib in both platinum-sensitive and platinum-resistant 
ovarian cancer.  We worked closely with the NCI in developing our validation approach, 
establishing the key analytic features for protein multiplex array analyses. The Angiome 
multiplex array has gone through a rigorous evaluation to ensure data quality. 
 
Recently, the approach was used to identify several strong candidate predictors of benefit from 
bevacizumab, including VEGF-D in CALGB80303 (Nixon 2013) and IL-6 in CALGB90206 
(Nixon 2013). Studies are underway in ovarian cancer to investigate the utility of this plasma 
angiome panel in directing treatment with bevacizumab and with the cediranib/olaparib 
combination.  
 
Table 2-2. Plasma-based marker identification 
Soluble Angiogenic Factors 
Matrix-derived 
Factors 
Markers of 
Vascular Activation 
and Inflammation 
ANG-2 
VEGF-A 
BMP-9 
CD73 
bFGF 
VEGF-C 
OPN 
ICAM-1 
HGF 
VEGF-D 
TGF1 
IL-6 
PDGF-AA 
sVEGFR1 
TGF2 
IL-6R 
PDGF-BB 
sVEGFR2 
TGFR3 
IL-6ST (GP130) 
PlGF 
sVEGFR3 
TIMP1 
SDF-1 
 
 
TSP2 
VCAM-1 
 
 
This approach is technically robust and readily adaptable to clinical practice. Because this data 
will be derived from patients, even preliminary data may significantly improve our 
understanding of how angiogenesis and tumor growth factors are regulated in cancer patients. 
Promising findings can be followed up in future clinical studies and in preclinical models. 
Because the Duke angiome lab serves as the core lab for multiplex ELISA analyses within the 
Alliance, the current ovarian cancer profiling can be compared to the profiles seen in other phase 
III studies, helping to optimize future profiling approaches and provide the disease specific 
context needed for clinically meaningful companion diagnostics. Given the results of this prior 
work and the work of others, we anticipate being able to identify and validate or refute candidate 
markers of benefit that are specific for anti-angiogenic agents. 
 

 
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2.6.2 Biomarker Review Committee-approved BROCA panel  
 
BROCA is a targeted massively parallel sequencing assay that is capable of identifying all 
classes of mutations including gene rearrangements. This panel, performed at the University of 
Washington under the direction of Dr. Elizabeth Swisher, will be used to screen for 
abnormalities in a variety of genes that might be involved in DNA repair and may impact the 
activity of olaparib and cediranib in GBM. The goal of this assay is to determine if underling 
mutations in the tumor reflect a sensitivity or resistance to the olaparib/cediranib. Including it in 
the other arm will shed light on variations that may be treatment specific.  
 
The University of Washington group has previously published the methodology and validation 
experiments for targeted capture and massively parallel sequencing of cancer genes (Nord et al 
2011; Walsh et al 2011; Walsh et al 2010; Pritchard et al 2012; Pennington et al 2012).  
 
The new version of BROCA (BROCA-HR) 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 homologous 
recombination or NHEJ that, if mutated, could mediate resistance to PARPi such as TP53BP1 
(Johnson et al 2013; Bunting et al 2010; Bouwman et al 2010). The BROCA design is flexible 
and can be altered to include any genes of research interest. The current design for BROCA-HR 
includes the following genes: 
 
BROCA-HR gene list (n=82) 
a. BRCA-FA homologous recombination pathway: ATM, ATR, BABAM, BAP1, 
BARD1, BLM, BRCA1, BRCA2 (FANCD1), BRCC3, BRE, BRIP1 (FANCJ), CHEK1, CHEK2, 
ERCC1, ERCC4 (FANCQ), FAM175A (abraxas), FANCA,FANCB, FANCC, FANCD2, FANCE, 
FANCF, FANCG (XRCCC9), FANCI, FANCL, FANCM, GEN1, MRE11, NBN, PALB2 
(FANCO), RAD50, RAD51, RAD51C (FANCO), RAD51D, RBBP8 (CtIP), RECQL, SLX4 
(FANCP), UIMC1 (RAP80), XRCC2, 
b. DNA mismatch repair (Lynch syndrome) MLH1, MSH2 (and EPCAM), MSH6, 
PMS2 
c. Other DNA repair or surveillance genes : CDH4, CDK12, DDB1, HELQ, ID4, NEIL1, 
PPM1D, POLD1, POLE, RIF1, PARP1, PAXIP1, POLQ, RINT1, TP53, TP53BP1, USP28, 
WRN, XRCC3 
d. NER genes: ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, DDB1, XPA, XPC, 
e. NHEJ pathway genes: DCLRE1C, LIG4, PARP1, PRKDC, TOPBP1, XRCC4, 
XRCC5, XRCC6 
f. PI3K pathway: PTEN, PIK3CA 
 
 
2.6.3 Whole exome sequencing (WES) 
 
A goal of this study is to obtain archived tissue and blood specimens from patients enrolled to 

 
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ETCTN clinical trials for WES. Patient specimens will be analyzed to identify tumor mutations, 
amplifications, or translocations that may inform about the disease or about drug treatment 
mechanism of action, potential prediction of response, and interrogation of mechanisms of 
primary or secondary resistance to treatment in the early cancer drug development environment.  
Such profiling may also have predictive or prognostic import. 
 
Archived tumor specimes and blood draw will be obtained from patients who sign the informed 
consent document to enroll in this treatment trial.   
 
Whole exome sequencing of formalin-fixed paraffin embedded (FFPE) tissue will be performed 
at the Molecular Characterization Laboratory on the purified DNA and RNA aliquots provided 
by the Biorepository with the goal of correlating finding to treatment response.  
 
2.6.4 Imaging correlates 
 
Brain MRI scans will be performed to assess treatment response. MRI may also be performed to 
better understand the biological impact that the experimental treatment is having on the tumor. In 
addition to routine MRI sequences (T1, T2), we will perform perfusion, and diffusion tensor 
imaging to non-invasively and serially measure structural and functional changes in the tumor 
vasculature and tumor microenvironment. The advanced MRI techniques described above have 
successfully been incorporated into prior GBM clinical trials using cediranib and revealed useful 
insights into cediranib’s mechanisms of action.  
 
Of particular relevance to this study, these MRI techniques have successfully measured changes 
in tumor vasculature and perfusion so will shed light on the role hypoxia is hypothesized to play 
in promoting the synergistic effect of PARP inhibition and VEGF inhibition. Incorporation of the 
techniques to this trial should allow us to further optimize the development of these 
combinations of drugs (Batchelor 2013). 
 
Patients will undergo advanced MRI scans prior to initiation of treatment (baseline), prior to 
cycle 3 day 1 and then every 2 months thereafter during treatment. These physiological MRI 
studies will only be pursued if there is sufficient capability among sites to perform these studies. 
We hope to accure at least 20 patients for advanced MRI correlative study.  
 
 
3. PATIENT SELECTION 
3.1 
Eligibility Criteria  
1. Unequivocal evidence of progressive disease on contrast-enhanced brain CT or 
MRI as defined by RANO Criteria, or have documented recurrent glioblastoma on 
diagnostic biopsy. 
 
2. Previous therapy with at least radiotherapy and temozolomide. 
 
3. Must be 12 weeks from radiotherapy. If patients are within 12 weeks of 
radiotherapy, then the progressive lesion must be outside of the high-dose 

 
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radiation target volume or have unequivocal evidence of progressive tumor on a 
biopsy specimen. 
 
4. Only first and second recurrences of GBM are eligible 
 
5. From the projected start of scheduled study treatment, the following time periods 
must have elapsed: 5 half-lives from investigational agents, 4 weeks from 
cytotoxic therapy (except 23 days for temozolomide and 6 weeks from 
nitrosoureas), 6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever is 
shorter) from other systemic anti-tumor therapies. Treatment on study may start 
one day after discontinuation of the optune device.  
 
6. All adverse events Grade > 1 related to prior therapies (chemotherapy, 
radiotherapy, and/or surgery) must be resolved, except for alopecia. 
 
7. Willingness to release archival tissue sample for research purposes, if available. 
 
8. Age ≥ 18. Because no dosing or adverse event data are currently available on the 
use of olaparib in combination with cediranib in patients <18 years of age, 
children are excluded from this study, but may be eligible for future pediatric 
trials. 
 
9. Karnofsky performance status ≥ 60 (see Appendix A) 
 
10. Life expectancy of at least 3 months 
 
11. 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 
≥ 10.0 g/dL and no blood transfusions in the 28 days prior to 
entry/randomization 
• total bilirubin 
≤ 1.5 x institutional upper limit of normal (ULN) 
• AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional upper limit of normal 
• Creatinine should not exceed the institutional upper limit of normal  
OR creatinine clearance ≥60 mL/min/1.73 m2  
 
12. Urine protein:creatinine (UPC) ratio < 1 or urine dipstick for proteinuria ≤ 2+ 
(note: if the UPC ratio is ≥ 1 then a 24-hour urine collection should be performed 
and this must demonstrate ≤ 1g of protein in 24 hours) 
 
13. CT or MRI within 14 days prior to start of study drug. 
 

 
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14. Corticosteroid dose must be stable or decreasing for at least 5 days prior to the 
baseline MRI scan. 
 
15. The effects of olaparib and cediranib on the developing human fetus are 
unknown.  Female subjects must either be of non-reproductive potential, not 
breast-feeding or must have a negative urine or serum pregnancy test within 28 
days of study treatment, confirmed prior to treatment on day 1. 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 6 months after completion of olaparib + 
cediranib administration. 
 
16. Ability to understand and the willingness to sign a written informed consent 
document. 
 
 
3.2 
Exclusion Criteria 
 
1. Participants should not have received any other investigational agents nor have 
participated in an investigational drug trial within the past 4 weeks. 
 
2. Participants may not have had prior use of PARP inhibitors. Patients may not 
have received prior treatment affecting the VEGF pathway including but not 
limited to thalidomide, bevacizumab, sunitinib, or sorafenib. 
 
3. Patients who are receiving any other investigational agents. 
 
4. History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to olaparib, cediranib or bevicizumab. 
 
5. Participants may not have any evidence of ongoing inadequately controlled 
hypertension (defined as a systolic BP of >140 mmHg or a diastolic BP of >90 
mmHg). Patients with hypertension may not be on more than three 
antihypertensive medications for management of their blood pressure 
(medications that combine two anti-hypertensives into one are considered as two 
medications). It is strongly recommended that patients who require three 
antihypertensive medications for baseline management of pre-existing 
hypertension be actively followed by a cardiologist or blood pressure specialist 
for management of BP while on protocol. 
 
6. Participants may not have had any prior history of hypertensive crisis or 

 
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hypertensive encephalopathy. 
 
7. Participants may not have had history of abdominal fistula or gastrointestinal 
perforation within the past 6 months. 
 
8. Participants may not have had a history of intra-abdominal abscess within the past 
6 months. 
 
9. Patients may not have a known or confirmed history of pneumonitis. 
 
10. Participants may not have current signs and/or symptoms of bowel obstruction or 
signs and/or symptoms of bowel obstruction within 3 months prior to starting 
study drugs 
 
11. Participants may not have a dependency on IV hydration or TPN. 
 
12. Patients with myelodysplastic syndrome/acute myeloid leukemia   
 
13. Participants with any concomitant or prior invasive malignancies are ineligible 
with the following exceptions: 
• Treated limited-stage basal cell or squamous cell carcinoma of the skin 
• Carcinoma in situ of the breast or cervix 
• Prior cancer treated with curative intent with no evidence of recurrent disease 
3 years following diagnosis and judged by the investigator to be at low risk of 
recurrence. 
 
14. Participants with any of the following: 
• History of myocardial infarction within six months 
• Unstable angina 
• History of CVA within 6 months  
• New York heart association grade II or greater congestive heart failure  
• Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection) 
• Clinically significant peripheral vascular disease  
 
15. If cardiac function assessment is clinically indicated or performed: participants 
will be ineligible if left ventricular ejection fraction (LVEF) is less than normal 
per institutional guidelines, or <55%, if the threshold for normal is not otherwise 
specified by institutional guidelines. 
 
16. Participants may not have QTc >470msec or family history of long QT syndrome. 
 
17. Participants may not have a major surgical procedure, open biopsy, or significant 
traumatic injury within 28 days prior to starting cediranib. Anticipation of need 
for major surgical procedures during the course of the study also excludes patients 

 
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39 
 
from the trial.  
 
18. Participants should not have any 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. 
 
19. Participants receiving any medications or substances that are strong inhibitors or 
inducers of CYP3A4 or moderate inhibitors of CYP3A4 are ineligible (see 
Appendix B). The study team should check a frequently-updated medical 
reference for a list of drugs to avoid or minimize use of. As part of the 
enrollment/informed consent procedures, the patient will be counseled on the risk 
of interactions with other agents, and what to do if new medications need to be 
prescribed or if the patient is considering a new over-the-counter medicine or 
herbal product. Dihydropyridine calcium-channel blockers are permitted for 
management of hypertension. Appendix C (Patient Drug Information Handout 
and Wallet Card) should be provided to patients. 
 
20. Pregnant women are excluded from this study because cediranib and olaparib 
agent with the potential for teratogenic or abortifacient effects.  Because there is 
an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with cediranib and olaparib breastfeeding should be 
discontinued if the mother is treated with cediranib and olaparib. These potential 
risks may also apply to other agents used in this study 
 
21. HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with cediranib and olaparib. In 
addition, these patients are at increased risk of lethal infections when treated with 
marrow-suppressive therapy.  Appropriate studies will be undertaken in patients 
receiving combination antiretroviral therapy when indicated. 
 
22. Current use of a prohibited medication. The following medications or non-drug 
therapies are prohibited: 
• Other anti-cancer therapy while on study treatment 
• Concurrent treatment with bisphosphonates is permitted; however, treatment 
must be initiated prior to the first dose of study therapy. Prophylactic use of 
bisphosphonates in patients without bone disease is not permitted, except for 
the treatment of osteoporosis. 
• Because the composition, PK, and metabolism of many herbal supplements 
are unknown, the concurrent use of all herbal supplements is prohibited during 
the study (including, but not limited to, cannabis, S. John’s wort, kava, 
ephedra [ma huang], gingko biloba, dehydroepiandrosterone [DHEA], 
yohimbe, saw palmetto or ginseng). 
• Raloxifene is allowed for patients taking it for bone health.  
 

 
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23. Participants should not have evidence of coagulopathy or bleeding diathesis. 
Therapeutic anticoagulation for prior thromboembolic events is permitted. 
 
 
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. 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all individuals contributing to NCI-sponsored trials to register 
and to renew their registration annually.  To register, all individuals must obtain a 
Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, persons with a 
registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN or RAVE 
or acting as a primary site contact) must complete their annual registration using 
CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type 
are outlined in the table below. 
 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 

 
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41 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
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: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
 
For questions, please contact the RCR Help Desk by email at RCRHelpDesk@nih.gov 
 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. 
 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 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: 
• An active Federal Wide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 

 
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42 
 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
 
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 10067 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.  
 
• Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization to expand, and then select LAO-MA036 and 
protocol #10067.” 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will load to RSS as described above) 
 
4.2.2 Requirements For NCI protocol 10067 Site Registration: 
 
• 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 ) 
• ETCTN Specimen Tracking Training – please refer to the memo dated 
10/03/2017 posted on the CTSU website for further details 
• SIV Attestation for new participating sites 
• Pharmacy Training Attestation for new participating sites 
• Protocol Signature Page and Training Attestation 
 

 
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For protocol amendents, the following will be required: 
• 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) 
• Protocol Signature Page and Training Attestation 
• Pharmacy Training Attestation if the amendment significantly impacts study drug 
ordering, handling, storage or accountability. 
 
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) → Regulatory Tab →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 
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 
 

 
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4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN).  OPEN is a web-based registration system available to users on a 
24/7 basis.  It is integrated with the CTSU Enterprise System for regulatory and 
roster data interchange and with the Theradex Interactive Web Response System 
(IWRS) for retrieval of patient registration/randomization assignment.  Patient 
enrollment data entered by Registrars in OPEN / IWRS will automatically transfer 
to the NCI’s clinical data management system, Medidata Rave. 
 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients:  Be on an ETCTN Corresponding or Participating Organization 
roster with the role of Registrar.  Registrars must hold a minimum of an AP 
registration type.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.   
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 Special Instructions for Patient Enrollment 
 
For the ETCTN Biobanking and Molecular Characterization Initiative, the following 
information will be requested: 
• Protocol Number 
• Investigator Identification  
o Institution and affiliate name 
o Investigator’s name 
• Eligibility Verification:  Patients must meet all the eligibility requirements 
listed in Section 3. 
• Additional Requirements: 
•  Patients must provide a signed and dated, written informed 
consent form. 
 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate 
and unique identification numbers to the patient, a Universal patient ID (UPID) and a 

 
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45 
 
Treatment patient ID.  The UPID is associated with the patient and used each and every 
time the patient engages with the ETCTN Biobanking and Molecular Characterization 
portion of this protocol.  The UPID contains no information or link to the treatment 
protocol.  IWRS will maintain an association between the UPID for ETCTN biobanking 
and molecular characterization and any treatment protocols the patient participates in, 
thereby allowing analysis of the molecular characterization results with the clinical data.   
 
Immediately following enrollment, the institutional anatomical pathology report for the 
diagnosis under which the patient is being enrolled must be uploaded into Rave.  The 
report must include the surgical pathology ID (SPID) and the IWRS-assigned UPID for 
this trial.  Important:  Remove any personally identifying information, including, but 
not limited to, the patient’s name, initials, and patient ID# for this treatment trial, 
from the institutional pathology report prior to submission. 
 
 
4.3.4 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
Theradex has developed a 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.  
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 14 days days. Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  The cycle length is 28 days, and patients 
will undergo cancer assessment per RANO criteria after every 2 cycles of therapy. 
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. 
 

 
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5.1.1 Arm 1 (investigational) 
 
Agent 
Dosing Instructions 
Dose 
Route 
Schedule 
Cycle 
Length 
Olaparib 
Orally BID at the same 
times each day 
200 mg 
PO 
Twice daily and 
continuously 
28 days 
(4 weeks) 
Cediranib 
Orally each morning on an 
empty stomach, either 1 
hour before or 2 hours after 
breakfast 
30 mg 
PO 
Daily and 
continuously 
28 days 
(4 weeks) 
Patients will be required to maintain an accurate medication diary of each dose of medication. 
The medication diary will be returned to clinic staff at the end of each cycle. 
 
5.1.2 Arm 2 (Reference) 
 
Agent 
Dosing Instructions 
Dose 
Route Schedule 
Cycle 
Length 
Bevacizumab 
Intravenously every two weeks 
(± 3 days) per institutional 
guidelines with associated pre-
medications.  
10mg/kg 
IV 
Day 1 
and 15 of 
28 day 
cycles 
28 days  
(4 weeks) 
Patient’s weight will be checked prior to each dose of bevacizumab. Dose will be adjusted if 
there is a >5% change in weight.  
 
5.1.3 Pre-treatment Criteria 
 
5.1.3.1 
Screening  
 
Patients must meet criteria at screening as outlined in Section 3.1 Inclusion Criteria and 3.2 
Exclusion Criteria. 
 
5.1.3.2 
 Hematologic parameters 
 
Patients must meet the following absolute neutrophil count (ANC) and hematologic parameters 
for treatment.  
 
For Arm 1 (olaparib and cediranib) 

 
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47 
 
For C1D1: ANC ≥ 1500 cells/μL, Platelets ≥ 100,000 cells/μL, Hemoglobin ≥ 9 g/dL 
For subsequent cycles: ANC ≥ 1000 cells/μL, Platelets ≥ 100,000 cells/μL, Hemoglobin ≥ 9 g/dL 
  
  
For Arm 2 (bevacizumab) 
For C1D1 should be: ANC ≥ 1500 cells/μL, Platelets ≥ 100,000 cells/μL, Hemoglobin ≥ 9 g/dL 
For C1D15 and subsequent cycles (including Day 15),  platelets must be ≥ 75K and ANC ≥ 1000 
cells/μL 
 
 
 
5.1.4 Treatment Administration 
 
5.1.4.1 
Cediranib 
 
Cediranib at the appropriate dose level will be given orally continuously each morning on an 
empty stomach, either 1 hour before or 2 hours after breakfast. Subjects have up to to 2 hours to 
make up any missed dose.  Subjects should not however “make up” a dose that was vomited. 
Subjects should take cediranib with a glass of water. The cediranib tablets should be swallowed 
whole and not chewed, crushed, dissolved, or divided. 
 
 
Cediranib will be dispensed at the start of each cycle. Patients will be provided with a pill diary 
for each drug (Appendix D), instructed in its use, and asked to bring it with them to each 
appointment. 
 
Frequent blood pressure monitoring is important in patients receiving cediranib. Clinical trials of 
cediranib demonstrate that increases in blood pressure may occur following dosing with 
cediranib for a number of weeks and that these increases may occur relatively quickly when 
starting the drug. Patients will be asked to record twice-daily blood pressure readings (Appendix 
E). If two successive systolic readings are >140 mmHg OR two successive diastolic readings are 
>90 mmHg OR any combination of elevated systolic and diastolic blood pressure are observed, 
patients will be instructed to contact their physician as soon as possible. Patients should seek 
medical advice if their BP exceeds 180 mmHg (systolic) or 105 mmHg (diastolic) at any time 
and should also be encouraged to contact their physician if they are concerned about any 
symptoms that may be associated with high blood pressure (e.g., headache). Section 7 includes 
specific guidelines on the management and, if appropriate, dose modifications for treatment-
emergent hypertension. Blood pressure cuffs will be provided to patients for blood pressure 
monitoring. 
 
5.1.4.2 
Olaparib 
 
Olaparib at the appropriate dose level will be given orally continuously twice daily, with doses 
taken at the same times each day approximately 12 hours apart. The correct number of 100mg or 
150mg tablets comprising the appropriate dose should be taken at the same times each day with 

 
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approximately 240 mL of water. The morning dose may be taken approximately 1 hour after the 
cediranib dose, following 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 start of each cycle. Patients will be provided with a pill diary 
(Appendix D), instructed in its use, and asked to bring it with them to each appointment. 
 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should not be “made 
up.” 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. 
 
5.1.4.3 
Bevacizumab 
 
Bevacizumab should be administered as a intravenous infusion using a rate–regulating device per 
institutional guidelines with associated pre-medications. Do not administer as an IV push or 
bolus. Anaphylaxis precautions should be observed during administration.  
 
If no institutional guidelines exist, follow below:  
 
Administer the initial dose over a minimum of 90 minutes. If no adverse reactions occur, 
administer the second dose over a minimum of 60 minutes. If no adverse reactions occur 
after the second dose, administer subsequent doses over a minimum of 30 minutes. If 
infusion-related adverse reactions occur, all subsequent infusions should be administered 
over the shortest period that was well tolerated.  
 
If a patient experiences an infusion-associated adverse reaction, he or she will be monitored 
according to institutional guidelines and may be pre-medicated for the next study drug infusion.  
 
 
5.1.4.4 
MRI Scan 
 
MR scans will be performed with the same sequences at baseline and after every two cycles of 
treatment. Sequences will include T1- and T2-weighted volumetric images, fluid attenuated 
inversion recovery (FLAIR), DWI/diffusion tensor imaging (DTI), and T2/T2*-weighted 
perfusion scans (Dynamic contrast susceptibility MRI) where available. The “Autoalign” 
package or similar available from the manufacturer will be used to achieve the same slice 
prescription in the same patient at each visit. Each MRI will last ~45 minutes vs. ~30-40 minutes 
for standard brain MRIs.  
 
Please refer to Appendix F for details on the imaging protocols.  
 

 
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5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
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. Based on in vitro and clinical exposure data, olaparib is considered unlikely to 
cause clinically significant drug interactions through inhibition or induction of cytochrome P450 
enzyme activity. However, in vitro data have also shown that the principal enzyme responsible 
for the formation of the 3 main metabolites of olaparib is CYP3A4. Given these data, potent 
inhibitors or inducers of CYP3A4 as outlined in Appendix B must not be used during this study 
for patients receiving olaparib. Moderate inhibitors of CYP3A4 should be avoided. If the 
inhibitor cannot be avoided, the olaparib tablet should be reduced by 50% during the duration 
that the patient remains on the moderate CYP3A4 inhibitor, as per below the table below. 
Dihydropyridine calcium-channel blockers are allowed for management of hypertension. 
 
Olaparib tablet dose 
Olaparib tablet dose on moderate CYP3A inhibitor 
200mg BID 
100mg BID 
150mg BID 
150mg daily (patient should take AM dose) 
100mg BID 
100mg daily (patient should take AM dose) 
 
Because of the potential for interaction of olaparib with other concomitantly administered drugs 
through the cytochrome P450 system, the case report form must capture the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies. Subjects should avoid 
grapefruit juice while on study, due to P450 interactions 
 
Patient should receive general concomitant and supportive care medications based on best 
medical practice. Neupogen and other bone marrow-supportive agents, including erythropoiesis 
stimulating agents, are not allowed during treatment. 
 
Caution should be taken with concomitant use of any medication that may markedly affect renal 
function.  Such medications may be used with caution if deemed essential for treatment or may 
be continued if already in use prior to entry in the study with no effect on renal function 
 
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 
instructed how to use them by each clinical site. Patients must be able and willing to monitor 
their blood pressure on a twice daily basis. Section 7 includes specific guidelines on the 
management and, if appropriate, dose modifications for treatment-emergent hypertension. 

 
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Because of the rapid changes in blood pressure that can occur and the potential for severe life 
threatening complications if hypertension is not appropriately managed, patients should check 
their blood pressure twice daily for at least the first 8 weeks after starting study drug, or, if 
antihypertensive management is required, until a stable anti-hypertensive regimen has been 
established, even if this requires more than 8 weeks. After 8 weeks or once a stable regimen has 
been achieved, blood pressure monitoring may be reduced to once daily. Twice daily monitoring 
should be re-implemented after any cediranib hold/dosing delay for two weeks or until the 
patient is re-established on a stable anti-hypertensive regimen, whichever takes longer. Patient 
blood pressures should be reviewed with the study team on a weekly basis for the first 8 weeks 
of study treatment to ensure that blood pressure guidelines are being correctly followed. 
 
Cediranib can impair healing. For this reason, cediranib should be held two weeks prior to any 
surgical procedures and may be restarted when the surgical wound is healed. Patients who have 
had major surgical procedure, open biopsy, or significant traumatic injury within 28 days of 
starting cediranib are not eligible for the study, as per Section 3.2. 
 
5.3 
Duration of Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue on 
until one of the following criteria applies:  
 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
• 
Clinical progression 
• 
Patient non-compliance 
• 
Pregnancy: 
o All women of child bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
• 
Termination of the study by sponsor 
• 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
5.4 
Duration of Follow Up 
 

 
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Patients will be followed for 30 days after removal from study or until death, whichever occurs 
first.  Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. All participants’ vital status may befollowed after 
removal from the study treatment using publically available databases. All patients who are 
removed from study treatment, regardless of rationale, will be followed for survival once off 
study for 3 years. Subjects will be followed for survival every 30 days after coming off study. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose modifications 
until March 31, 2018.  CTCAE version 5.0 will be utilized for AE reporting beginning April 1, 
2018. A copy of the CTCAE version 5.0 can be downloaded from the CTEP 
websitehttp://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
6.1 
Parameters for All Cycles 
 
Patients must meet the following parameters 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. Study 
drugs may be help for up to 28 days.  
 
For Arm 1 (olaparib and cediranib) 
For C1D1 
• ANC ≥ 1500 cells/μL 
• Platelets ≥ 100,000 cells/μl 
• Hemoglobin ≥ 9 g/dL 
• Creatinine ≤ 2.0 x ULN unless UPC is > 1.0 or urine dipstick is > 2+. Refer to section 
6.2.5 if UPC is > 1.0 or urine dipstick is > 2+. 
• Adequate blood pressure control, as detailed in Section 6.2.3.  
• Liver function tests (AST and ALT) ≤ 2.5 x the institutional upper limit of normal; note: 
patients can hold study treatment up to 28 days until liver function tests are within 
parameters to proceed with treatment. For grades ≥ 2 AST and/or ALT elevations, please 
follow instructions in Section 6.2.2 (General Management of Adverse Events). 
• Urine protein:creatinine ratio OR urine dipstick protein as detailed in Section 6.2.5 
For C1D15 and subsequent cycles (including all Day 15): Same as above except ANC ≥ 1000 
cells/μL 
 
For Arm 2 (bevacizumab) 
For C1D1:  
• ANC ≥ 1500 cells/μL  
• Platelets ≥ 100,000 cells/μL 

 
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• Hemoglobin ≥ 9 g/dL 
• Creatinine ≤ 2.0 x ULN 
• Adequate blood pressure control, as detailed in Section 6.3.1.  
• Proteniuria: < 2+ proteinuria as detailed in Section 6.3.1. 
For C1D15 and subsequent cycles (including all Day 15): same as above except platelets can be 
≥ 75,000 and ANC ≥ 1000 cells/μL 
 
 
6.2 
Olaparib and Cediranib  
 
6.2.1 Olaparib and Cediranib 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 
Olaparib tablets 
-2 
100 mg twice daily 
-1 
150 mg twice daily 
1 
200 mg twice daily 
 
Dose Level 
Cediranib tablets 
-2 
15 mg daily 
-1 
20 mg daily 
1 
30 mg daily 
 
6.2.2 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 6.2.3-6.2.13 
 

 
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Table 6.2.2A: General Management of Adverse Events (Non-hematologic)  
for cediranib / olaparib 
Observation 
Action 
AE resolves promptly with supportive care 
Maintain dose level 
Any grade 2 non-hematologic AE or for 
creatinine ≥ 2 x ULN (excluding hypertension 
or other AEs with specific management 
instructions outlined in the sections below, or 
easily correctable asymptomatic grade 2 
laboratory abnormalities) related to study 
drug(s) that persists despite maximal support. 
Hold study drug(s)1 for up to 14 days until 
toxicity resolves to ≤ grade 1 or: a) for 
AST/ALT until it resolves ≤ 2.5 ULN or b) 
for creatinine until it resolves < 2 x ULN1. 
Treatment may be restarted at one dose level 
lower for the drug(s) causing the toxicity, as 
per the dose reduction levels in Section 7.1, 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 ≥ grade 3 non-hematologic (excluding 
grade 3 hypertension or easily correctable  
symptomatic grade 3 laboratory 
abnormalities) 
Hold study drug(s)2 for up to 14 days until 
toxicity resolves to ≤ 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 7.1, at the treating 
investigator’s discretion.3 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.4  
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. 
1. 
Note: creatinine threshholds are different in the prescense of concurrent proteinuria. Please refer to section 
6.2.5 if urine dipstick is greater than 2+ or UPC > 1.0.  
2. 
At  the discretion of the investigator, the study drugs may be held or dose modified independently if the 
observed toxicity is attributed to only one of the drugs, while the patient continued to receive the drug not 
associated with the observed toxicity. The time a given drug is held should not exceed 14 days. 

 
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3. 
Patients who are at the lowest reduced dose level may have their drug resumed at that dose level after 
discussion with the overall PI. 
4. 
Excluding hypertension. For thromboembolic events, treatment may be resumed at the discretion of the 
investigator once patient is asymptomatic.  
 
Table 6.2.2B: General Management of Adverse Events (Hematologic)  
for cediranib / olaparib 
Observation 
Action 
Absolute neutrophil count ≥ 1000/µL 
AND 
Platelets ≥ 100,000/µL 
AND 
Hemoglobin ≥ 9 g/dL  
Maintain dose level 
Absolute neutrophil count < 1000/µL 
OR 
Platelets < 100,000/µL 
OR 
Hemoglobin < 9 g/dL 
Hold treatment for up to 14 days until 
absolute neutrophil count ≥1000/µL, platelets 
>100,000/µL, and hemoglobin ≥9 g/dL. 
Treatment may be restarted at one dose level 
lower for the drug(s) causing the toxicity, as 
perthe dose reduction levels in Section 
7.1, 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/µL, platelets 
≥100,000/µL, and hemoglobin ≥9 g/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/µL, platelets 
≥100,000/µL, and hemoglobin ≥9 g/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. 
 
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. 
 

 
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6.2.3 Hypertension  
 
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 will 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. 
 
See the table below for guidelines on hypertension management and Appendix G for suggested 
antihypertensive medications by class. 
 
Note: 
 
• If patients require a delay of >2 weeks for management of hypertension, management should 
be discussed with the overall PI and may require discontinuation from protocol therapy  
• Patients may have up to 4 drugs for management of hypertension prior to any dose reduction 
in cediranib.  
• Hypertension should be graded using the NCI CTCAE. 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.  
• Note: Stopping or reducing 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 6.2.3: 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, 
discontinuation of cediranib or protocol therapy may be considered after discussion 
with the Study PI.  
• Patients may have up to 4 drugs for management of hypertension prior to any dose 
reduction in cediranib  
• Hypertension should be graded using the NCI CTCAE. Please note: patients may 
have baseline hypertension meeting CTCAE grading criteria on study entry. Should 
patients require increase in dosing of BP medication or increased number of 
medications, they should then be noted to have hypertension related to study drug, 
with grading as per CTCAE criteria. Baseline grade of hypertension should also be 
recorded in the patient’s record.  

 
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• Note: 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. 
Toxicity 
Severity 
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 
within normal limit 
Consider early 
initiation of BP 
medication for BP > 
140/90 mmHg that is 
confirmed on a 
second reading. 
Cediranib can cause 
rapid escalation in 
BP, and early 
initiation of BP 
management can 
reduce likelihood of 
HTN-related 
complications. 
Continue 
standard BP 
monitoring per 
treating doctor 
and confirm 
resolution of 
BP to <140/90 
mmHg within 
24 hours 
 
 
None 
Grade 2 
Recurrent or 
persistent (>24 hrs) 
or symptomatic 
increase by >20 
mmHg (diastolic) or 
to > 140/90 mmHg 
if previously within 
normal limit. 
  
Monotherapy 
may be indicated 
Initiate BP 
medication for first 
line treatment. 
Suggestions:  ACE-
inhibitor. 
  
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. 
 
Increase 
frequency of 
monitoring 
until stabilized 
to BP <140/90 
mmHg. 
 
Do not hold 
cediranib unless 
otherwise 
clinically 
necessary. 

 
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Consider renal 
consult. 
Grade 3 
Requiring more 
than one drug or 
more intensive 
therapy than 
previously.  
Maximize 2 drug 
Regimen. 
• Suggestions: 
ACE-inhibitor 
+BB 
Escalate doses of 
existing medication 
until BP is controlled 
or at a maximum 
dose. 
 
If BP is not 
controlled to < 
140/90 mmHg with 
two drug regimen, 
then add a third 
agent. 
 
Study Drug will not 
be held during trial 
of two drug 
combinations. 
Additional 
antihypertensive 
drugs, up to a total 
of 4, may be 
maximized for 
blood pressure 
control. 
 
Consider consult 
with a blood 
pressure 
management 
specialist if more 
than 3 drugs are 
required for BP 
control. 
 
Increase 
frequency of 
monitoring 
until stabilized 
to BP <140/90 
mmHg. 
Do not hold 
cediranib or 
other study 
drugs unless BP 
is not decreased 
to < 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 
withhold 
cediranib (up to 
3 weeks) until 
maximum effect 
of the 
antihypertensive 
agents is 
achieved. 
If BP is reduced 
to Grade 1 
within 3 weeks, 
cediranib may 
be resumed at 
prior dose.  
 
 
Grade 4 
If threatening 
consequences 
Initiate treatment 
 
Intensive BP 
monitoring 
Hold 
cediranib. 

 
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OR 
SBP ≥ 180mmHg 
OR 
DBP ≥ 110mmHg 
Hospitalize patient 
for ICU 
management, IV 
therapy as necessary. 
 
14 days are allowed 
to maximize the full 
effect of anti-
hypertensive agents.  
(hospitalization 
if necessary) 
 
If BP is reduced 
to 
<140/90mmHg 
within 14 days, 
cediranib may 
be resumed at a 
reduced dose 
after discussion 
with the Study 
PI and/or 
sponsor. 
 
 
6.2.4 Diarrhea 
 
Diarrhea is often observed with cediranib and active and early management of diarrhea is 
recommended even with grade 1 diarrhea. Management as follows: 
 
Table 6.2.4: Management of Diarrhea 
Toxicity Severity 
Management / Modifications 
Initial grade 1 or 2 
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. 
Persistent grade 2 or grade 3 or 4 
Follow section 7.2 
 
6.2.5 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: 
 
Table 6.2.5: Management of Proteinuria 
Proteinuria Value if 
following by U/A 
Monitoring 
Dose modification 

 
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> 2+ on urine dipstick or U/A 
AND 
Creatinine ≤ 1.5 x ULN 
Perform UPC 
Continue study drugs at 
planned dose. 
> 2+ on urine dipstick or U/A 
AND 
Creatinine > 1.5 x ULN 
Perform UPC 
Hold cediranib until results 
of UPC are known and see 
below. 
Based on results of the UPC1: 
UPC ≤ 1.0 
AND 
Creatinine ≤ 2 x ULN 
Continue monitoring prior to 
each cycle as per previous.  
Continue study drugs at 
planned dose. 
UPC > 1.0 and ≤ 3.5  
AND 
Creatinine ≤ 1.5 x ULN 
Perform UPC prior to each 
cycle. 
Continue study drugs at 
planned dose. 
UPC > 3.5  
OR 
UPC > 1.0 AND Creatinine > 
1.5 x 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 ≤ 1.5 x ULN, 
resume cediranib with 
reduction in cediranib by one 
dose level. Consider 
consultation with 
nephrologist.  
1If creatinine is > 2x ULN regardless of UPC or urine dipstick then hold cediranib for up to 14 
days. Refer to section 6.2.2.   
 
6.2.6 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:  
 
1. Prior treatment with anthracyclines  
2. Prior treatment with trastuzumab  
3. A NYHA classification of II controlled with treatment (see Appendix H)  
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: 

 
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Table 6.2.6: Management and Monitoring of Decreased LVEF 
Relationship of 
LVEF to 
Institution’s LLN 
LVEF Decrease 
<10% 
LVEF Decrease 10-
15% 
LVEF Decrease ≥ 
16% 
Normal 
Continue 
Continue 
Continue and repeat 
MUGA/ECHO 
within 1-2 cycles. If 
LVEF decrease 
persists, remove from 
protocol therapy.  
 
Patients with symptomatic decrease in LVEF attributable to study drugs should be removed from 
protocol therapy.  
 
6.2.7 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. Patients will need to recover from fever and active infectious issues prior to 
resuming therapy. Growth factors such as Neupogen or Neulasta may not be used. 
 
6.2.8 Nausea and Vomiting 
 
Olaparib: 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. 
 
6.2.9 Thyroid Toxicities  
 
The use of cediranib has been associated with elevations of the TSH and patients should be 
managed as per the following schema and chart: 
 
Table 6.2.9: Management and Monitoring of Thyroid Toxicities 
Results of TSH, T4, and T3 
Action 
Increases in TSH with normal T4/T3 
Monitor 
Increase 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 
 

 
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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.  
 
6.2.10 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. 
 
6.2.11 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. 
 
6.2.12 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. 
 
Table 6.2.12: Management of Rotator Cuff Symtoms 
Severity 
Symptoms / Findings 
Action 
Dose modification 
Grade 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 
Grade 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.  
 
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 

 
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Consider referral to 
orthopedics for 
evaluation as appropriate. 
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. 
Grade 3 
Severe or medically 
significant but not 
immediately life 
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated; 
disabling; limiting self 
care ADL 
Obtain shoulder MRI if 
not previously obtained.  
 
Refer to orthopedic 
surgeon for evaluation. 
Hold cediranib and 
olaparib for up to 14 
days until symptoms 
resolve to Grade 1 or 
less. Cediranib and 
olaparib may then be 
resumed at a reduced 
dose level of each 
study drug after 
discussion with the 
overall PI.  
 
6.2.13 Myelodysplatic Syndrome 
 
Myelodysplastic syndrome (MDS) has been described in patients receiving olaparib. To monitor 
for any potential development of MDS, patients who have treatment held for hematologic 
toxicities should have blood counts and differentials checked at least weekly until recovery. If 
counts do not improve to CTCAE grade 1 or better despite drug cessation for 4 weeks, patients 
should be referred to a hematologist for further assessment. A bone marrow analysis should be 
considered per hematology assessment. 
 
6.3 
Bevacizumab 
 
6.3.1 Bevacizumab Dose Modifications 
 
Note 1:  There will be no dose reduction for bevacizumab.  Treatment should be interrupted 
or discontinued for certain adverse events, as described below 
Note 2:  If bevacizumab is interrupted for ANY reasons for >4 weeks (unless otherwise 
specified), the patient should discontinue bevacizumab therapy on protocol. 
 
 

 
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63 
 
Treatment Modification for Bevacizumab-Related Adverse Events 
Event 
CTCAE  Grade 
Action to be Taken 
Allergic reactions  
Or  
Infusion-related reactions 
Or  
Anaphylaxis 
Grade 1-2  
• Infusion of bevacizumab should be 
interrupted for subjects who develop 
dyspnea or clinically significant 
hypotension.  
• For infusion-associated symptoms not 
specified above, infusion should be 
slowed to 50% or less or interrupted.  
Upon complete resolution of the 
symptoms, infusion may be continued at 
no more than 50% of the rate prior to 
the reaction and increased in 50% 
increments every 30 minutes if well 
tolerated.  Infusions may be restarted at 
the full rate during the next cycle.  
• Subjects who experience bronchospasm 
(regardless of grade) should discontinue 
bevacizumab. 
Grade 3-4 
Discontinue bevacizumab 
Thromboembolic Event 
(Arterial), arterial  ischemia  
- Cardiac ischemia 
- Myocardial  infraction 
- CNS ischemia (TIA, CVA) 
- Any peripheral or visceral 
arterial ischemia/thrombosis 
Grade 2 (new or 
worsening since 
bevacizumab 
Discontinue bevacizumab. 
Grade 3-4 
Discontinue bevacizumab 
Thromboembolic Event 
(Venous) 
 
 
[Note:  Patients with primary lung cancer requiring 
therapeutic anticoagulation should discontinue bevacizumab] 
Grade 3 
OR 
asymptomatic 
Grade 4 
▪ Hold bevacizumab treatment.  If the 
planned duration of full-dose 
anticoagulation is <2 weeks, bevacizumab 
should be held until the full-dose 
anticoagulation period is over. 
▪ If the planned duration of full-dose 
anticoagulation is >2 weeks, bevacizumab 
may be resumed during full-dose 
anticoagulation IF all of the criteria below 
are met: 
- The subject must not have 
pathological conditions that carry 
high risk of bleeding (e.g. tumor 

 
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64 
 
Treatment Modification for Bevacizumab-Related Adverse Events 
Event 
CTCAE  Grade 
Action to be Taken 
involving major vessels or other 
conditions) 
- The subject must not have had 
hemorrhagic events while on study 
- The subject must be on stable dose of 
heparin or have an in-range INR 
(usually 2-3) on a stable dose of 
warfarin prior to restarting 
bevacizumab. 
▪ If thromboemboli worsen/recur upon 
resumption of study therapy, discontinue 
bevacizumab 
Grade 4 
(symptomatic) 
Discontinue bevacizumab 
Hypertension 
[Treat with anti-hypertensive medication as needed.  The goal 
of BP control should be consistent with general medical 
practice] 
Grade 1 
(SBP 120-139 
mmHg or DBP 
80-89 mmHg) 
Consider increased BP monitoring; start 
anti-hypertensive medication if appropriate 
Grade 2 
asymptomatic 
(SBP 140-159 
mmHg or DBP 
90-99 mmHg) 
Begin anti-hypertensive therapy and 
continue bevacizumab 
• Grade 2 
symptomatic 
(SBP 140-159 
mmHg or DBP 
90-99 mm Hg) 
 
• Grade 3 
(SBP >160 
mmHg or 
DBP >100 
mmHg) 
• Start or adjust anti-hypertensive 
medication 
• Hold bevacizumab until symptoms 
resolve AND BP < 160/90mmHg* 
• For hypertension that is refractory 
requiring delay of bevacizumab for > 4 
weeks, discontinue bevacizumab  
 
 
Grade 4  
(Hypertensive 
crisis or 
malignant 
hypertension) 
Discontinue bevacizumab 

 
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Treatment Modification for Bevacizumab-Related Adverse Events 
Event 
CTCAE  Grade 
Action to be Taken 
Heart Failure  
OR 
Left Ventricular (LV) 
dysfunction 
• Heart failure 
>Grade 2 
• LV 
dysfunction 
>Grade 3 
Discontinue bevacizumab 
Proteinuria 
Proteinuria will be monitored 
by urine analysis dipstick. If 
Dipstick >2+ proteinuria, 24-
hour urine protein should be 
obtained 
Dipstick > 2+ 
Hold bevacizumab and obtain 24 hour urine 
protein 
If 24-h urine 
protein <2g 
Continue bevacizumab 
If 24-h urine 
protein >2 g 
• Hold bevacizumab until 24-hour urine 
protein <2.0 g   
• Discontinue bevacizumab if urine protein 
does not recover to < 2.0 g after 8 
weeks of bevacizumab interruption 
Nephrotic 
syndrome 
Discontinue bevacizumab. 
Hemorrhage (intracranial or 
pulmonary)  
Grade 2-4 
• Discontinue bevacizumab 
Grade 1 
• Patients receiving full-dose 
anticoagulation should discontinue 
bevacizumab. 
• For patients not on full-dose 
anticoagulation, hold bevacizumab until 
ALL of the following criteria are met: 
- the bleeding has resolved and 
hemoglobin is stable 
- there is no bleeding diathesis that 
would increase the risk of therapy 
• there is no anatomic or pathologic 
condition that could increase the risk of 
hemorrhage recurrence 
Hemorrhage (not CNS or 
pulmonary) 
Grade 3  
 
• Patients receiving full-dose 
anticoagulation should discontinue 
bevacizumab. 
• For patients not on full-dose 
anticoagulation, hold bevacizumab until 
ALL of the following criteria are met: 
- the bleeding has resolved and 
hemoglobin is stable 

 
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Treatment Modification for Bevacizumab-Related Adverse Events 
Event 
CTCAE  Grade 
Action to be Taken 
- there is no bleeding diathesis that 
would increase the risk of therapy 
- there is no anatomic or pathologic 
condition that could increase the risk 
of hemorrhage recurrence. 
• Patients who experience recurrence of 
grade 3 hemorrhage should discontinue 
study therapy. 
Grade 4 
Discontinue bevacizumab 
RPLS (Reversible Posterior 
Leukoencephalopathy 
syndrome  
OR 
PRES (Posterior Reversible 
Encephalopathy Syndrome) 
Any Grade 
Discontinue bevacizumab upon diagnosis of 
RPLS.   
Wound dehiscence 
OR 
 Wound complications  
Grade 2 
Hold bevacizumab until healing  
Grade 3-4 
Discontinue bevacizumab 
Perforation (GI, or any other 
organ) 
Any Grade 
Discontinue bevacizumab 
Fistula (GI, pulmonary or any 
other organ) 
Any Grade 
Discontinue bevacizumab 
Obstruction of GI tract 
Grade 2 
requiring 
medical 
intervention 
Hold bevacizumab until complete resolution 
 
Grade 3-4 
• Hold bevacizumab until complete 
resolution 
• If surgery is required, patient may restart 
bevacizumab after 28 days and full 
recovery from surgery, and at 
investigator’s discretion 
Other Unspecified 
bevacizumab-related AEs 
(except controlled 
nausea/vomiting). 
Grade 3 
• Hold bevacizumab until symptoms 
resolve to<Grade 1 
Grade 4 
• Discontinue bevacizumab 
• Upon consultation with the study 
chair, resumption of bevacizumab may 
be considered if a patient is benefiting 
from therapy, and the Grade 4 toxicity is 
transient, has recovered to <Grade 1 and 
unlikely to recur with retreatment. 

 
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67 
 
 
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 and 
7.3) 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 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 2073 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 2.4, April 24, 20191 

 
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68 
 
 
 Adverse Events with Possible  
 Relationship to Olaparib (AZD2281) 
 (CTCAE 5.0 Term) 
[n= 2073] 
 
 
 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) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
  
INVESTIGATIONS 
  
 
Creatinine increased 
 
  
 
Lymphocyte count decreased 
 
  
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
  
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
  
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 
  
 
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, 

 
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69 
 
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. 
 
2Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATION SOC. 
 
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 - Cardiac disorders - Other (nodal rhythm); Chest pain - cardiac; Sinus 
tachycardia 
EAR AND LABYRINTH DISORDERS - Tinnitus 
ENDOCRINE DISORDERS - Hypothyroidism 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Colonic obstruction; Dry mouth; Dysphagia; 
Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (gastrointestinal 
hemorrhage); Gastrointestinal disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other 
(intestinal perforation); Ileus; Jejunal perforation; Mucositis oral; Pancreatitis; Periodontal disease; Rectal 
hemorrhage; Small intestinal obstruction; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Malaise; Non-cardiac chest pain 
IMMUNE SYSTEM DISORDERS - Immune system disorders - Other (systemic inflammatory response 
syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - 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; 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 cramp; Muscle weakness lower limb; Myalgia; Neck pain; Pain in 
extremity; Rotator cuff injury 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Ataxia; Cognitive disturbance; Concentration impairment; 
Encephalopathy; Intracranial hemorrhage; Peripheral sensory neuropathy; 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; 
Oropharyngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal disorders 
- Other (chronic obstructive pulmonary disease) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Pruritus; Rash maculo-papular 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension; Hypotension; Thromboembolic event 
 
 
Note: Olaparib (AZD2281) in combination with other agents could cause an exacerbation of any adverse 

 
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70 
 
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 Cediranib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
 for 
Cediranib (AZD2171, NSC 732208) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  
for further clarification. Frequency is provided based on 1608 patients. Below is the CAEPR for Cediranib 
(AZD2171). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.15, November 7, 20181   
 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)   
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Hemolytic uremic syndrome   
 
 
Thrombotic 
thrombocytopenic purpura 
  
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
ENDOCRINE DISORDERS 
  
 
Hyperthyroidism 
 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
  
 
Anal mucositis 
 
 Anal mucositis (Gr 2) 
 
Constipation 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dysphagia 
 
 Dysphagia (Gr 2) 
 
 
 Gastrointestinal fistula2 
  
 
 
 Gastrointestinal perforation3   

 
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 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%)  
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
 
Pancreatitis 
  
 
Rectal mucositis 
 
 Rectal mucositis (Gr 2) 
 
Small intestinal mucositis 
 
 Small intestinal mucositis (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
 Infection4 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase increased  
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Lymphocyte count decreased 
 
  
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
  
 
Thyroid stimulating hormone 
increased 
 
 Thyroid stimulating hormone 
increased (Gr 2) 
 
Weight loss 
 
 Weight loss (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Generalized muscle weakness  
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
Lethargy 
 
  
 
 
Leukoencephalopathy 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
 
Nephrotic syndrome 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 

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

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

 
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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. 
 
 
7.1.1.3 
CAEPR for Bevacizumab  
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Bevacizumab (rhuMAb VEGF, NSC 704865) 
 
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 3540 patients. Below is the CAEPR for 
Bevacizumab (rhuMAb VEGF). 
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, May 2, 20181 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
 
 
Hemolytic uremic syndrome 
  
CARDIAC DISORDERS 
  
 
Cardiac disorders - Other 
(supraventricular arrhythmias)2  
 
 Cardiac disorders - Other 
(supraventricular arrhythmias)2 (Gr 3) 
 
 
Chest pain - cardiac3 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction3 
  
 
 
Ventricular arrhythmia 
  
 
 
Ventricular fibrillation 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3)  
 
Colitis 
 
 Colitis (Gr 3) 
 
Constipation 
 
 Constipation (Gr 3) 
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 

 
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 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
 
 
Gastrointestinal fistula4 
  
 
Gastrointestinal hemorrhage5 
 
 Gastrointestinal hemorrhage5 (Gr 2) 
 
Gastrointestinal obstruction6 
 
  
 
 
Gastrointestinal perforation7 
  
 
 
Gastrointestinal ulcer8 
  
 
Ileus 
 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
 
Nausea 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Fatigue 
 
 Fatigue (Gr 3) 
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 3) 
 
Pain 
 
 Pain (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Gallbladder perforation 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
 Allergic reaction (Gr 2) 
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection9 
 
 Infection9 (Gr 3) 
 
 
Infections and infestations - 
Other (necrotizing fascitis) 
  
 
Infections and infestations - Other 
(peri-rectal abscess) 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Infusion related reaction 
 
 Infusion related reaction (Gr 2) 
 
 
Injury, poisoning and 
procedural complications - 
Other (anastomotic leak)10 
  
 
Wound complication 
 
 Wound complication (Gr 2) 
 
Wound dehiscence 
 
 Wound dehiscence (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase increased 
(Gr 3) 
 
Alkaline phosphatase increased  
 Alkaline phosphatase increased (Gr 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased 
(Gr 3) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased  
(Gr 2) 
 
Creatinine increased 
 
  
Neutrophil count decreased  
 
 Neutrophil count decreased (Gr 3) 
 
Platelet count decreased 
 
 Platelet count decreased  
(Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 3) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 

 
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 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hyperglycemia 
 
  
 
Hypokalemia 
 
  
 
Hyponatremia 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 3) 
 
 
Avascular necrosis11 
  
 
Generalized muscle weakness 
 
  
 
Musculoskeletal and connective 
tissue disorder - Other (bone 
metaphyseal dysplasia)12 
 
  
 
Myalgia 
 
 Myalgia (Gr 3) 
 
Osteonecrosis of jaw13 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
 
Intracranial hemorrhage 
  
 
 
Ischemia cerebrovascular 
  
 
Peripheral sensory neuropathy14  
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
 
Syncope 
 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
 
Hematuria 
 
 Hematuria (Gr 3) 
 
 
Nephrotic syndrome 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
 
 
Urinary fistula 
  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
Reproductive system and 
breast disorders - Other 
(ovarian failure)15 
 
 
  
 
 
Vaginal fistula 
  
 
Vaginal hemorrhage 
 
 Vaginal hemorrhage (Gr 3) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Allergic rhinitis 
 
 Allergic rhinitis (Gr 2) 
 
 
Bronchopleural fistula 
  
 
 
Bronchopulmonary 
hemorrhage 
  
 
Cough 
 
 Cough (Gr 3) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Epistaxis 
 
 Epistaxis (Gr 3) 
 
Hoarseness 
 
 Hoarseness (Gr 3) 
 
 
Pulmonary hypertension 
  

 
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 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 5.0 Term) 
[n= 3540] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)   
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(nasal-septal perforation) 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(tracheo-esophageal fistula) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
  
 
Erythroderma 
 
  
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
Urticaria 
 
 Urticaria (Gr 2) 
VASCULAR DISORDERS 
  
 
 
Arterial thromboembolism3,16   
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event 
 
 Thromboembolic event (Gr 3) 
 
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. 
 
2Supraventricular arrhythmias may include supraventricular tachycardia, atrial fibrillation, and atrial flutter. 
 
3The risks of arterial thrombosis such as cardiac or CNS ischemia are increased in elderly patients and in 
patients with a history of diabetes. 
 
4Gastrointestinal fistula may include: Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Gastric fistula, Gastrointestinal fistula, Rectal fistula, and other sites under the GASTROINTESTINAL 
DISORDERS SOC. 
 
5Gastrointestinal hemorrhage may include: Colonic hemorrhage, Duodenal hemorrhage, Esophageal 
hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Intra-
abdominal hemorrhage, Oral hemorrhage, Rectal hemorrhage, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
6Gastrointestinal obstruction may include: Colonic obstruction, Duodenal obstruction, Esophageal 
obstruction, Ileal obstruction, Jejunal obstruction, Rectal obstruction, Small intestinal obstruction, and 
other sites under the GASTROINTESTINAL DISORDERS SOC. 
 
7Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation. 
 
8Gastrointestinal ulcer may include: Duodenal ulcer, Esophageal ulcer, Gastric ulcer, and other sites 
under the GASTROINTESTINAL DISORDERS SOC. 
 

 
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9Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
10Anastomotic leak may include Gastric anastomotic leak; Gastrointestinal anastomotic leak; Large 
intestinal anastomotic leak; Rectal anastomotic leak; Small intestinal anastomotic leak; Urostomy leak; 
Vaginal anastomotic leak. 
 
11There have been reports of non-mandibular osteonecrosis (avascular necrosis) in patients under the 
age of 18 treated with bevacizumab. 
 
12Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth plates. 
 
13Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients in association with 
bevacizumab treatment, the majority of whom had received prior or concomitant treatment with i.v. 
bisphosphonates. 
 
14Increased rate of peripheral sensory neuropathy has been observed in trials combining bevacizumab 
and chemotherapy compared to chemotherapy alone.  
 
15Ovarian failure, defined as amenorrhea lasting 3 or more months with follicle-stimulating hormone (FSH) 
elevation (≥30 mIU/mL), was increased in patients receiving adjuvant bevacizumab plus mFOLFOX 
compared to mFOLFOX alone (34% vs. 2%).  After discontinuation of bevacizumab, resumption of 
menses and an FSH level <30 mIU/mL was demonstrated in 22% (7/32) of these women.  Long term 
effects of bevacizumab exposure on fertility are unknown. 
 
16Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, heart 
attack, and stroke. 
 
 
Adverse events reported on bevacizumab (rhuMAb VEGF) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that bevacizumab (rhuMAb VEGF) 
caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Bone marrow hypocellular; Disseminated 
intravascular coagulation; Hemolysis; Thrombotic thrombocytopenic purpura 
CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block first degree; Cardiac 
arrest; Myocarditis; Pericardial effusion; Restrictive cardiomyopathy; Right ventricular dysfunction 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (tympanic membrane 
perforation); Hearing impaired; Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye disorders - Other 
(blindness); Eye disorders - Other (conjunctival hemorrhage); Eye disorders - Other (corneal epithelial 
defect); Eye disorders - Other (ischemic CRVO); Eye disorders - Other (macular pucker); Eye disorders - 
Other (transient increased IOP > or =30 mm Hg); Eye pain; Floaters; Keratitis; Optic nerve disorder; 
Photophobia; Retinal detachment; Retinal tear; Retinopathy; Vitreous hemorrhage; Watering eyes 
GASTROINTESTINAL DISORDERS - Ascites; Cheilitis; Colonic stenosis; Dry mouth; Dysphagia; 
Enterocolitis; Esophageal pain; Esophageal stenosis; Flatulence; Gastrointestinal disorders - Other 
(peritonitis); Oral pain; Pancreatitis; Proctitis; Rectal mucositis; Rectal stenosis; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema face; 
Edema limbs; Edema trunk; Facial pain; Fever; Flu like symptoms; Gait disturbance; Injection site 
reaction; Localized edema; Multi-organ failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder necrosis; Gallbladder obstruction; Hepatic 
failure; Hepatic necrosis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Bruising; Burn; 
Dermatitis radiation; Fracture 

 
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INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood antidiuretic hormone 
abnormal; CD4 lymphocytes decreased; CPK increased; Carbon monoxide diffusing capacity decreased; 
Electrocardiogram QT corrected interval prolonged; Forced expiratory volume decreased; GGT 
increased; INR increased; Lipase increased; Lymphocyte count decreased; Serum amylase increased; 
Weight gain 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; 
Hypocalcemia; Hypomagnesemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone pain; 
Chest wall pain; Fibrosis deep connective tissue; Head soft tissue necrosis; Joint effusion; Muscle 
weakness lower limb; Muscle weakness upper limb; Musculoskeletal and connective tissue disorder - 
Other (polymyalgia rheumatica); Neck pain; Osteonecrosis; Pain in extremity; Pelvic soft tissue necrosis; 
Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Arachnoiditis; Ataxia; Central nervous system necrosis; 
Cerebrospinal fluid leakage; Cognitive disturbance; Depressed level of consciousness; Dysesthesia; 
Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; Facial nerve disorder; Hydrocephalus; 
Leukoencephalopathy; Memory impairment; Myasthenia gravis; Nervous system disorders - Other 
(increased intracranial pressure); Paresthesia; Peripheral motor neuropathy; Pyramidal tract syndrome; 
Seizure; Somnolence; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Libido decreased; 
Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis noninfective; 
Dysuria; Renal and urinary disorders - Other (ureterolithiasis); Renal hemorrhage; Urinary frequency; 
Urinary incontinence; Urinary retention; Urinary tract obstruction; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Erectile dysfunction; Irregular 
menstruation; Pelvic pain; Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Atelectasis; Hypoxia; Nasal congestion; Pulmonary fibrosis; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (dry nares); Respiratory, thoracic and mediastinal disorders - Other 
(pulmonary infarction) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; Nail loss; Pain of skin; 
Photosensitivity; Purpura; Rash acneiform; Skin and subcutaneous tissue disorders - Other (diabetic foot 
ulcer); Skin and subcutaneous tissue disorders - Other (skin breakdown/ decubitus ulcer); Skin 
hyperpigmentation; Skin induration; Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Lymphocele; Phlebitis; Vasculitis 
 
Note: Bevacizumab (rhuMAb VEGF) 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  
 
• CTCAE term (AE description) and grade:   
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized until March 31, 2018 
for AE reporting.  CTCAE version 5.0 will be utilized for AE reporting beginning April 
1, 2018. All appropriate treatment areas should have access to a copy of the CTCAE 
version 5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 

 
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• 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. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in 
the “NCI Guidelines for Investigators: Adverse Event Reporting Requirements for 
DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from 
the CTEP Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events
.htm).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
 
7.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Principal Investigator and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the Reporter 
and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. Expedited reporting is required for any serious adverse event (SAE) 
that occurs after the initial dose of treatment, during treatment or within 30 days of the last 
administration of treatment in accordance with below.  

 
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Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions. Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 
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. 

 
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1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
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:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
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. 
 
 
8. PHARMACEUTICAL INFORMATION 
 

 
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A list of the adverse events and potential risks associated with the investigational agents 
administered in this study can be found in Section 8.1. 
 
8.1 
CTEP IND Agent(s) 
 
8.1.1 Olaparib (AZD2281) (NSC 747856) 
 
Chemical Name:  4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-
fluorophenyl)methyl]phthalazin-1(2H)-one 
 
Other Names: AZD2281; KU-0059436; CO-CE 42 
Classification: PARP inhibitor 
 
CAS Registry Number: 763113-22-0 
 
Molecular Formula:  C24H23FN4O3 
 
M.W.: 434.46 
 
Approximate Solubility: 0.1 mg/mL pH independent solubility across physiologic range 
 
Mode of Action: Olaparib is an inhibitor of subclasses 1, 2, and 3 of polyadenosine 5’ 
diphosphoribose polymerase (PARP-1, PARP-2, and PARP-3). In tumors that are deficient 
in the homologous recombination DNA repair pathway (example, BRCA mutants), 
inhibition of PARP by olaparib causes accumulation of DNA double-strand breaks and 
genomic instability. Olaparib may also enhance the effects of DNA damage caused by 
ionizing radiation and chemotherapy.  
 
Description: crystalline solid 
 
How Supplied: AstraZeneca supplies and the CTEP, DCTD distributes olaparib as green, film-
coated tablets in 100 mg and 150 mg strengths.  
 
• 100 mg tablets are 14.5 mm x 7.25 mm oval-shaped 
• 150 mg are 14.5 mm x 7.25 mm oval-shaped 
 
Tablets are packaged in induction-sealed high-density polyethylene (HDPE) 
bottles with child-resistant closures. Each bottle contains 32 tablets with 
desiccant.  
 
Tablet core components include active drug substance, copovidone, colloidal silicon 
dioxide, mannitol and sodium stearyl fumarate. Film coating contains hydroxypropyl 
methylcellulose (hypromellose), macrogol 400 (polyethylene glycol 400), titanium dioxide, 
iron oxide yellow and iron oxide black. 
 
Storage: Store in a secure location below 30° C (86° F). Sites are not permitted to re-package 
tablets. Once the bottle is opened, olaparib tablets must be used within 3 months of the 

 
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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. 
 
Potential Drug Interactions:  In vivo data indicate that CYP3A4/5 is important for olaparib 
metabolism and clearance in humans. For this reason, avoid concomitant administration of 
strong and moderate CYP 3A4/5 inducers and inhibitors.  Consult the protocol document 
or study investigator prior to making any dose adjustments related to potential drug-drug 
interactions. 
 
In vitro data shows olaparib is a substrate for P-glycoprotein (P-gp), but not for organic 
anion-transporting polypeptides (OATP1B1 and OATP1B3), organic cation transporter 1 
(OCT1), multi-drug resistance protein 2 (MRP-2) efflux transporter or breast cancer 
resistance protein (BCRP). Administration of strong P-gp inhibitors and inducers should be 
avoided with concurrent olaparib.   
 
Based on in vitro data, olaparib inhibits CYP 3A4 and UGT1A1 enzyme systems and 
induces CYP 1A2, 2B6, and 3A4 and potentially induces CYP 2C9, 2C19 and P-gp. 
Therefore, avoid concomitant administration of sensitive substrates, particularly those with 
narrow therapeutic ranges.   
 
Olaparib is also an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, multi-drug and toxin 
extrusion proteins (MATE1 and MATE2K) and a weak inhibitor of BRCP, but not an 
inhibitor of OATP1B3 or MRP-2. In vitro studies suggest that olaparib may increase 
exposure of substrates of these transport systems, although the clinical relevance is not clear. 
The manufacturer recommends that statins, in particular, should be administered with 
caution when given concomitantly with olaparib. 
 
Patient Care Implications: Pre-clinical data indicate that olaparib adversely affects embryofetal 
survival and development. Therefore, women of child-bearing potential and their partners 
should agree to use two (2) highly effective forms of contraception throughout study 
participation and for at least one (1) month after the last dose of olaparib. It is not known 
whether olaparib is found in seminal fluid, so as a precaution, male study participants must 
use a condom during treatment and for three (3) months after the last dose and should avoid 
fathering a child or donating sperm during this same time period. The study investigator 
should discuss the most appropriate forms of highly effective contraceptive methods for 
each patient.  

 
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Lactation is a protocol exclusion criterion and not advised since there is potential for serious 
adverse reactions in breastfed infants. Advise lactating women to not breastfeed during 
study treatment and for one (1) month after receiving the last dose of olaparib.  
 
Because the adverse events related to olaparib may include asthenia, fatigue and dizziness, 
patients should be advised to use caution while driving or using machinery.  
 
There are no data on the effect of olaparib on wound healing, therefore as a precaution, 
olaparib treatment should be stopped at least 3 days prior to planned surgery. After surgery 
olaparib can be restarted when the wound has healed. No stoppage of olaparib is required 
for any needle biopsy procedure.  
 
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
therapeutic or palliative radiation treatment. Study treatment should be restarted within 4 
weeks as long as any bone marrow toxicity has recovered.  
 
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 Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.2 Cediranib (AZD2171) (NSC 732208) 
 
Chemical Name: 4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin 1-
ylpropoxy) quinazoline maleate 
 
Other Names: Cediranib, AZD2171 maleate, Recentin™ 
 
CAS Registry Number: 288383-20-0 (for the free base) 
 
Molecular Formula: C25H27FN4O3 · C4H4O4 
 
Molecular Weight: 566.59 as maleate salt (450.52 as free base) 
Approximate Solubility: The aqueous solubility of AZD2171 is 0.0006 mg/mL for the free base 
(distilled water, pH 8.1 at 25°C) and 1.9 mg/mL for the maleate salt (distilled water, pH 4.4 at 
25°C). 
 
Mode of Action: Cediranib is a highly potent inhibitor of vascular endothelial growth factor 
receptor (VEGFR) tyrosine kinase activity, which inhibits VEGF-dependent angiogenesis, 
neovascular survival and vascular permeability. 
 
How Supplied: Astra-Zeneca supplies and CTEP, NCI, DCTD distributes Cediranib. The agent 

 
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is available as beige film-coated tablets containing, 15 mg and 20 mg of AZD2171 free base. 
The,15 mg and 20 mg tablets are,7 mm and 8 mm in diameter, respectively. Each bottle contains 
35 tablets. 
 
Tablet excipients include mannitol, dibasic calcium phosphate anhydrous, sodium starch 
glycolate, microcrystalline cellulose, and magnesium stearate with a film coat containing 
hypromellose 2910, polyethylene glycol 400, red iron oxide, yellow iron oxide, black iron oxide, 
and titanium dioxide. 
 
Storage: Store intact bottles at controlled room temperature [20°C-25°C, (68-77°F)] and protect 
from light and moisture. 
 
Stability: Stability studies are ongoing. Dispense 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 cediranib to controlled 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 of Administration: Oral. Cediranib tablets should be taken either one hour before or two 
hours after meals. 
 
Potential Drug Interactions: Cediranib (AZD2171) clearance is primarily mediated by flavin-
containing monooxygenase enzymes (FMO1 and FMO3) and UGT1A4. It is not a substrate of 
CYP450 enzymes. In vitro studies suggest that cediranib (AZD2171) 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 cediranib (AZD2171) is a weak inhibitor of BCRP, Pgp, OATP1B1, 
OATP1B3, OCT2 and MATE1. Use caution in patients who are taking concomitant medications 
that are sensitive substrates of these transporters since there is a low potential for drug-drug 
interactions. In vivo studies show that cediranib (AZD2171) could increase exposure of drugs 
like metformin by inhibiting renal tubular transporter MATE2-K, but this is thought to be 
infrequent and mild in severity. Cediranib is not an inhibitor of OAT1 or OAT3. 
 
In vitro studies using hepatic cultures show that cediranib (AZD2171) did not inhibit CYP 1A2, 
2A6, 2C8, 2C9, 2C19 and 2E1 and showed no induction of CYP 1A2, 2B6 and 3A4/5. It did 

 
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weakly inhibit CYP 2D6 and 3A4/5, but this inhibition not expected to cause any clinically 
relevant drug interactions.  The possibility that cediranib (AZD2171) may induce gastrointestinal 
CYP3A and UGT enzymes cannot be excluded; therefore, the efficacy of hormonal 
contraceptives may be reduced. Advise women study participants to use an additional non-
hormonal contraceptive method. 
 
Cediranib is approximately 95% bound to human plasma proteins, with human serum albumin 
and α1-acid glycoprotein accounting for most of this binding. Use caution in patients taking 
concomitant medications with narrow therapeutic ranges that are also highly protein-bound. 
 
Oral anticoagulants are not absolutely contraindicated during treatment with cediranib; however, 
use 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; therefore, it is recommended that cediranib is stopped two weeks prior to 
elective surgery and restarted when the surgical wound has healed. Patients should be excluded 
from participating in clinical studies with cediranib if they have had recent (at least two weeks, 
or until any wound has completely healed) major thoracic or abdominal surgery prior to study 
start, or a surgical incision that is not fully healed. 
 
Pre-clinical data indicate that cediranib adversely affects embryofetal survival and development. 
Therefore, women of child-bearing potential and their partners should agree to use two (2) highly 
effective forms of contraception throughout study participation and for at least six (6) months after 
the last dose of cediranib.  Male study participants should avoid fathering a child or donating sperm 
during the study and for six (6) months after the last dose of cediranib. The study investigator 
should discuss the most appropriate forms of highly effective contraceptive methods for each 
patient. Refer to the protocol document for specific guidance. 
 
 
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 Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 12.3) 
 
 
8.1.3 Agent Ordering and Agent Accountability 
 

 
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8.1.3.1 
NCI-supplied agents 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. 
 
Study agent must be ordered after patient is registered to the treatment arm as no 
starter supplies are available for this 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.   
 
8.1.3.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this 
protocol. 
 
8.1.3.3 
Investigator Brochure Availability - The current versions of the IBs for PMB-
supplied agents will be accessible to site investigators and research staff through the 
PMB Online Agent Order Processing (OAOP) application. Access to OAOP requires 
the establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status, a “current” password and “active” person 
registration status. Questions about IB access may be directed to the PMB IB 
coordinator via email.   
 
 
8.1.3.4 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 

 
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http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP/  
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.ci.nih.gov/iam/index.jsp 
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240)276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
• PMB IB Coordinator: IBcoordinator@mail.nih.gov 
 
8.2 
Bevacizumab 
 
Chemical Name: Immunoglobulin G1 (human-mouse monoclonal rhuMAb-VEGF -chain anti-
human vascular endothelial growth factor), disulfide with human-mouse monoclonal rhuMAb-
VEGF light chain, dimer 
 
Other Names: Avastin™, anti-VEGF monoclonal antibody, Anti-VEGF rhuMAb, rhuMAb-
VEGF 
 
CAS Registry Number: 216974-75-3 
 
Molecular Formula: C6538H10034N1716O2033S44 
 
Molecular Mass: 149,196.82 g/mol  
 
Dilution:  Withdraw appropriate dose of bevacizumab and dilute in 100mL of 0.9% sodium 
chloride. Bevacizumab is incompatible with dextrose solutions.  
 
Mode of Action: Bevacizumab binds and inhibits the biologic activity of human vascular 
endothelial growth factor (VEGF), thereby inhibiting VEGF-dependent angiogenesis, 
neovascular survival and vascular permeability. 
 
How Supplied: Commercially available. Please refer to the FDA-approved package labeling for 
additional information.  
 
The solution also contains α,α-trehalose dihydrate, monobasic monohydrate sodium phosphate, 
dibasic sodium phosphate, polysorbate 20 and water for injections. 
 
Storage: Injection concentrate – store at 2 – 8 C (36 – 46 F) and protect from light and 
moisture. Do not freeze. Store diluted solution at 2 – 8 C (36 – 46 F) for up to 8 hours.  
 
Route of Administration: IV infusion via a rate-regulating device per institutional guideline 
with associated pre-medications. Do not administer as an IV push or bolus. If no institutional 

 
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guidelines exist, follow below: 
 
Administer the initial dose over a minimum of 90 minutes. If no adverse reactions occur, 
administer the second dose over a minimum of 60 minutes. If no adverse reactions occur 
after the second dose, administer subsequent doses over a minimum of 30 minutes. If 
infusion-related adverse reactions occur, all subsequent infusions should be administered 
over the shortest period that was well tolerated.  
 
Potential Drug Interactions: Oral anticoagulants are not absolutely contraindicated during 
treatment with bevacizumab; however, use bevacizumab 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; therefore, it is recommended that bevacizumab is stopped four weeks prior to 
elective surgery and restarted when the surgical wound has healed. Patients should be excluded 
from participating in clinical studies with bevacizumab if they have had recent (at least four 
weeks, or until any wound has completely healed) major thoracic or abdominal surgery prior to 
study start, or a surgical incision that is not fully healed. 
 
Availability 
Bevacizumab is commercially available. 
 
Agent Ordering  
Bevacizumab will be ordered commercially. 
 
8.3 
Blood Pressure Cuffs 
 
A patient who is randomized to the olaparib and cediranib treatment arm (Arm 1) will be given a 
blood pressure cuff.  Blood pressure cuffs that are supplied for this study, are only to be used for 
this study.   
 
Supply and Distribution: Blood pressure cuffs will be supplied by VWR and distributed by 
Biologics.  Each kit contains a blood pressure monitor (which includes standard size cuff), an 
adaptor and a large size cuff.  Kits will be shipped in the original manufacturer’s packaging. 
 
Ordering Instructions:  No starter supplies are available.  Sites are permitted to order a 
maximum of 10 Blood Pressure kits at a time for enrolled patients.  To obtain the kits, please 
complete the “Shipment Authorization Form” and email to lisa.rutter@vwr.com.  The form is 
available on the CTSU website. Please allow for 3 business days from requesting blood pressure 
kits until expected receipt. All orders will be shipped via FedEx Priority Overnight. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 

 
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9.1 
Specimen Requirements 
 
Study 
Assay 
Required 
Specimen 
Collection  
Time Points 
Collection 
Details 
Plasma  
 Panel  
(Nixon 
Laboratory, 
Duke 
University) 
Multiplex ELISA 
assay utilizing the 
Aushon Cirascan 
Imaging System 
Two 4 mL 
tubes of 
blood 
1.1.1.1.1 Baseline,  
day 1 of 
cycle 2, 
and at the 
time of 
progression 
or end of 
study 
Collect in 
purple top 
tubes. 
Specimens 
should be 
processed on 
site to obtain 
plasma and then 
shipped on dry 
ice.  
BROCA- HR  
(Dr Elizabeth 
Swisher, 
University of 
Washington) 
BROCA Panel 
sequencing – a 
targeted capture 
and parallel 
sequencing 
approach using the 
SureSelectXT 
enrichment system 
on a Bravo liquid-
handling 
instrument 
(Agilent) 
7 mL 
whole 
blood 
Baseline 
Collect in 
yellow top 
(ACD solution 
A) tube. 
Specimen to be 
shipped at 
ambient 
temperature for 
overnight 
delivery. 
Archival 
FFPE 
slides 
(primary 
tumor) 
Baseline 
2 consecutive 
unstained 10 
µm slides 
should be 
provided. 
Whole Exome 
Sequencing 
(WES)  
 
PicoGree®DNA 
quantitation 
(qPCR) 
Archival 
FFPE 
slides 
(primary 
tumor),  
blood, 
and/or 
plasma 
Baseline 
One (1) H&E 
slide and 
twenty (20), 4 
µm unstained 
air-dried plus 
slides 
OR 
One (1) or more 
core punches 
(minimum of 4 
mm diameter) 
from tumor 
block 
 
Also, two 10 
mL Streck 

 
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tubes and one 
10 mL EDTA 
tube of blood 
Tumor 
Perfusion, pH 
and 
Oxygenation 
(Dr Elizabeth 
Gerstner, MGH) 
Dynamic 
susceptibility MRI, 
ME-aCEST-
SAGE-EPI 
 
Baseline,  prior to 
cycle 3 day 1 and 
then every 2 months 
 
Brain Tumor 
Cellularity  
(Dr Elizabeth 
Gerstner, MGH) 
Diffusion MR 
imaging 
 
Baseline, prior to 
cycle 3 day 1 and 
then every 2 months 
 
 
 
9.2 
Integrated Correlative Studies 
 
9.2.1 Plasma Angiome Panel 
 
9.2.1.1 
Collection of Specimens 
 
Please refer to the Specimen Requirements table in Section 9.1. for details regarding specimen 
collection. 
 
9.2.1.2 
Handling of Specimens 
 
Plasma samples will be analyzed by multiplex ELISA assays for plasma-based biomarkers 
utilizing the Aushon Cirascan Imaging System. The Aushon Cirascan Imaging System is used 
specifically for the imaging and analysis of chemiluminescent protein arrays in a 96-well plate. 
The protein arrays are created by spotting up to 16 different capture antibodies per well in each 
well of the 96-well plate. The advantage of this system is that multiple target proteins of interest 
can be analyzed at the same time reducing the amount of sample required for analysis. In brief, a 
small volume of sample and/or standard is added to each well of the 96-well plate resulting in the 
capture of the target proteins by the arrayed antibodies. Biotinylated antibodies are then added 
that specifically bind the captured target proteins. Streptavidin conjugated to HRP (horseradish 
peroxidase) is then added followed by a chemiluminescent substrate. Imaging of the plate is 
performed using Aushon Cirascan Imaging System. Protein concentrations in the samples are 
quantified by comparing the intensity of the spots in the unknown wells to standard curves. 
Samples should be processed on site to obtain plasma and then shipped on dry ice. Biomarker 
assays are time sensitive, and samples should be stored on ice and processed within four hours of 
collection. Instructions for processing and labeling samples are below: 
 
1. Draw two 4ml purple top (K2EDTA) tubes (BD Vacutainer, Catalog no. 367861) 
2. Invert tubes 10 times to mix blood 
3. Centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge 

 
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manufacturer’s instructions) 
4. Remove plasma from each tube and transfer equally into two separate clean 15ml 
polypropylene tubes 
5. Repeat centrifuge at 4°C at 2500 x g for 15 minutes (or in accordance with centrifuge 
manufacturer’s instructions) 
6. Aliquot approximately 1.0ml of plasma from each tube into each 2.0ml cryovial. For the 
EDTA, aliquot into pink capped cryovial. Total of 4 pink capped cryovials needed for 
EDTA plasma. 
7. Label and freeze at -80°C* (see labeling instructions below) 
 
*Please note: If your site does not have a -80°C freezer, samples should be shipped on dry ice on 
the day of collection. If unable to ship samples on the day of collection, please place the samples 
on dry ice until they can be shipped. Samples can be stored on dry ice for no more than 48 hours 
prior to shipping. Please replenish dry ice as needed to ensure samples stay frozen and there is 
enough to last throughout shipment. 
 
Plasma-containing tubes should be labeled with the following information (using a Sharpie or 
Cryopen): 
 
• Protocol Name 
• Subject Study Number 
• Subject Initials 
• Sample Date and Time 
• Sample Type (ie. whole blood, EDTA plasma, citrate plasma, serum, urine) 
 
9.2.1.3 
Shipping of Specimens 
 
Please refer to the Specimen Requirements table in Section 10.1 for specific shipping 
requirements. Samples should be shipped within 48 to 72 hours of completed processing. All 
biomarker samples must be shipped on dry ice by overnight delivery Monday through Thursday 
(no holidays) to the following address: 
 
Attention:  Phase I Biomarker Laboratory 
ATTN: Andrew Nixon, PhD 
Duke University Medical Center 
395 MSRB, Research Drive 
Durham, NC 27710 
 
9.2.1.4 
Site Performing Correlative Study 
 
Plasma angiome will be performed by the laboratory of Dr. Andrew Nixon at Duke University 
Medical Center (Durham, NC). 
 
9.2.2 BROCA testing 
 

 
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9.2.2.1 
Collection of Specimens 
 
Please refer to the Specimen Requirement table in Section 9.1. 
 
9.2.2.2 
Handling of Specimens 
 
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 BROCA1 
will be applied to samples. For the proposed study, a more recent version of BROCA with 55 
genes (BROCA-HR) that serve as a single assay to test for germline and somatic mutations that 
influence response to therapy will be utilized. Library preparation has been fully automated to 
increase sample turnaround and lower cost. Paired-end libraries with 350bp inserts will be 
prepared from 1µg of constitutional or neoplastic DNA and hybridize to a custom pool of 
oligonucleotides targeting genomic regions as previously described using the SureSelectXT 
enrichment system on a Bravo liquid-handling instrument (Agilent). 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 pipleline. 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. 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 treatment on the 
trial.  
 
9.2.2.3 
Shipping of Specimens 
 
Please refer to the Specimen Requirements table in Section 9.1. for specific shipping 
requirements. 
 
Please ship to: 
 
Mark Radke  
University of Washington 
1959 NE Pacific ST, HSB BB632 
Seattle WA 98195 
206-685-7927 
 
 
9.2.2.4 
Site Performing Correlative Study   
 
BRCA-HR will be performed by the laboratory of Dr. Elizabeth Swisher at the University of 
Washington (Seattle, WA). 

 
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9.2.3 Whole Exome Sequencing (WES) 
 
9.2.3.1 
Collection of Specimens 
 
Please refer to the Specimen Requirement table in Section 9.1. 
 
Tissue collected within 6 months prior to registration is preferred.  Older specimens may be 
submitted, but the yield of nucleic acids may be lower, and characterization and analysis may be 
compromised.   
 
Two 10 mL Streck tubes and one 10 mL EDTA tube of blood will be collected for analysis of 
germline DNA and banking of plasma for future cell free DNA (cfDNA) studies.  Blood 
collections will be performed according to standard procedures and will be shipped to the 
ETCTN Biorepository with the tumor specimen 
 
 
9.2.3.2 
Oversight of Tumor Specimen Collection 
 
For biospecimen collection, it is suggested, but not required, that a pathologist or qualified 
designee at the submitting institution assure the presence of tumor in solid tissue specimens and 
deem the biospecimen suitable for research with minimally 30% non-necrotic tumor content.  If 
a pathologist or designee is not available at the submitting institution, the pathologist at the 
ETCTN Biorepository will assess tumor quantity and quality. 
 
Alternatively, the pathologist of the submitting institution may confirm histopathology and 
histological characteristics of the biospecimen. 
 
It is the responsibility of the submitting institution to provide only those biospecimens that are 
not necessary for diagnostic purposes.   
 
9.2.3.3 
Procedure to Recall Biospecimens for Diagnostic/Patient Care Purposes 
 
If needed, residual tissue or blood that is currently stored in the biobank can be reclaimed.  If 
DNA or RNA analysis is required, some or all specimens may be returned for documented 
diagnostic/patient care or medically necessary events, including a request by or on behalf of the 
patient for tissue to determine eligibility for enrollment in a research protocol/clinical trial.  
Accessioned specimens, extracted nucleic acids, or slides sent to a reference laboratory cannot 
be reclaimed. 
 
The ETCTN Biorepository will need to be notified in writing of the specific reason for recalling 
the specimens as well as of what specimen types (e.g., FFPE blocks) need to be returned.  
Investigators should use their local records to retrieve and provide the number of the specimen 
that needs to be returned.  
 

 
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A description of the extenuating circumstance(s) will be required to accommodate the recall 
request.  Every effort will be made to facilitate medically necessary events or procedures to 
assure appropriate medical care for a patient with a serious or life-threatening illness.  This does 
not cover patient issues related to needing or wanting genetic information or specimens for 
genetic testing for personal risk from germline or somatic findings. 
 
 
9.2.3.4 
Handling of Specimens 
 
Processing of Biospecimens 
 
Specimens received at the ETCTN Biorepository for molecular characterization analyses, such as 
WES, will be processed for DNA/RNA extraction as follows: 
 
Tumor tissue received in formalin will be paraffin-embedded.  All FFPE blocks will be sectioned 
to generate an initial hematoxylin and eosin (H&E)-stained slide, and for nucleic acid 
extractions, additional RNase-free slides. 
 
Whole blood collected in Streck tubes will be centrifuged to separate PBMCs and plasma, and 
will be stored in a -80°C freezer.  
 
DNA and RNA will be co-extracted from tumor tissue.   DNA will be extracted from the whole 
blood collected in the EDTA tube.  The nucleic acids will be analyzed to determine 
concentration and quality.  Aliquots of DNA and RNA will be shipped to the central sequencing 
laboratory for analysis. 
 
Next Generation Sequencing  
 
DNA and RNA libraries for WES and RNA-Seq will be generated at the central sequencing 
laboratories by standard procedures.  Sequencing will be carried out on an Illumina 2500 
sequencer, and these results will have variant calling through the procedures associated with the 
GDC.  Results from these assays, annotated with limited clinical data (presentation, diagnosis, 
staging, summary treatment, outcome, etc.), will be stored in the Database of Genomes and 
Phenotypes (dbGaP) and in the GDC. 
 
 
Banking and Use of Specimens in Future Research 
 
Any biospecimens remaining after processing will be retained indefinitely at the ETCTN 
Biorepository under appropriate storage conditions.  Specimen types may include: 
• 
FFPE block 
• 
PBMCs 
• 
Plasma from Streck tubes (for future cfDNA analysis) 
• 
Isolated nucleic acids 
 

 
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Specimens from patients who consented to allow their specimens to be used for future approved 
research studies, including residuals from the currently defined research studies, will be retained 
at the ETCTN Biorepository.  Protocol-specified studies should be clearly described and 
prioritized in the protocol, and in general, should not require additional review and approval.  
Investigators are encouraged to consult with the ETCTN Biorepository for the evaluation of 
residual tissue specimens approaching depletion for protocol-specified studies. 
 
Banked specimens may be distributed to investigators for laboratory research studies as specified 
in the protocol or after appropriate review of the proposed research studies by CTEP.  In cases 
where additional clarification about laboratory research studies is needed, review and approval of 
a submitted analysis and data sharing plan by the NCI, ETCTN, CIRB, and if appropriate, the 
NCI Collaborator, may be needed. 
 
If future use is denied or withdrawn by the patient, the samples will be destroyed and not used in 
any future study.  Biospecimen recalls for patient issues related to needing/wanting genetic 
testing to determine personal risk from germline/somatic findings is not permitted (see Procedure 
to Recall Biospecimens). 
 
The ETCTN Biorepository will not deplete a biospecimen unless written permission is received 
from the ETCTN Program Directors or designee.  The investigator must provide a written 
proposal describing the nature of the research to be performed, the technical and analytical 
validation of the assays being used, the goals, objectives and statistical analysis plan for the 
research being performed.  The investigators should submit this concept/proposal through the 
CTEP Protocol and Information Office (PIO).  The proposal will be reviewed by the Medical 
Officer assigned to the protocol and will be reviewed by the CTEP Protocol Review Committee 
(PRC) for approval or disapproval for use of biospecimens that may be depleted. 
 
Manual checks of minimal biospecimens may occur at the time of distribution to confirm the 
amount available in relationship to the amount requested by the researcher.  Once minimal 
amounts are reached, the ETCTN Program Directors of the biospecimen resource is notified 
before specimens are distributed. 
 
9.2.3.5 
Shipping of specimens 
 
Please refer to Appendix J for additional information on shipping of specimens. 
 
Shipping Address 
 
Ship the specimen collection to the address below using overnight courier (FedEx), early 
morning delivery option. 
 
ETCTN Biorepository  
Nationwide Children’s Hospital 
700 Children’s Dr., WA1340 
Columbus, OH 43205 

 
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Phone: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred.  There is no central Courier 
account for this study.  Sites are responsible for all costs for overnight shipment per sample 
shipment to the ETCTN Biorepository, utilizing the site screening and base intervention 
payments.  
 
NOTE:  The ETCTN Biorepository FedEx Account will not be provided to submitting 
institutions. 
 
Contact Information for Assistance 
 
For all queries, please use the contact information below: 
 
ETCTN Biorepository  
Toll-free Phone:  (800) 347-2486 
E-mail:  BPCBank@nationwidechildrens.org 
 
 
9.3 
Imaging correlative studies (Tumor Perfusion and Oxygenation, and Brain 
Tumor Cellularity) 
 
9.3.1 MRI Sequence Acquisition 
 
For sites acquiring the advanced MRI scans will be performed with the same sequences during 
each visit, including T1- and T2-weighted volumetric images, fluid attenuated inversion recovery 
(FLAIR), diffusion imaging, perfusion scans, and a ME-aCEST-SAGE-EPI. The advanced scans 
will be done at sites capable of acquiring these sequences. All other sites should acquire the 
standard brain tumor protocol even if not participating in the advanced imaging. See Appendix F 
for aquisition parameters and scan transfer/shipment details.  
 
 
 

 
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10. STUDY CALENDAR 
 
Screening assessments must be completed after consent and within 4 weeks of starting treatment, 
unless otherwise specified. On treatment days, assessments must be performed prior to 
administration of any study agent. Study assessments and agents should be administered within ± 
3 days of the protocol-specified date, unless otherwise noted. 
 
 
Pre-
Studya 
Each cycle 
Cycles 1 
& 2 
Weeklyb 
Cycle 2 
D1 
Odd 
numbered  
Cycles 
Every 4 
Cycles 
Off 
Treatmento 
D1 
D15 
Informed 
Consenta 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Concomitant 
Medicationsc 
X 
X 
 
X 
 
 
 
X 
AE Assessment 
 
X 
X 
X 
 
 
 
X 
Vital Signsd 
X 
X 
X 
 
 
 
 
X 
BP measurement 
at Homee 
 
 
Twice a day, or as directed by your doctor 
 
Physical Exam 
X 
Xa 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
 
 
 
X 
Performance 
Status (KPS) f 
X 
Xa 
 
 
 
 
 
X 
CBC with 
differential 
X 
Xa 
X 
 
 
 
 
X 
Serum 
Chemistryg 
X 
Xa 
X 
 
 
 
 
X 
INR and PTT 
X 
 
 
 
 
 
 
 
TSH and Free 
T4h 
X 
Xa 
 
 
 
 
 
X 
Urine protein: 
creatinine ratioi 
X 
Xa 
X 
 
 
 
 
X 
EKG 
X 
 
 
 
 
 
 
 
MUGA or 
ECHOj 
X 
 
 
 
 
 
X 
 
Pregnancy testk 
X 
 
 
 
 
 
 
 
Tumor 
Measurementsl 
X 
 
 
 
 
X 
 
 
Translational 
bloodworkm 
X 
 
 
 
X 
 
X 
Archival Tissuen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Informed consent will be obtained prior to any study-related screening tests and within 4 weeks 
of starting study drug. For Cycle 1 Day 1, physical examination and laboratory evaluations do 

 
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not have to be repeated if they have been performed at screening within 7 days of Cycle 1 Day 1.   
b Patients should be contacted at least once weekly over the phone or be assessed in person for 
the first two cycles on study to assess for AEs and concomitant medications.  
c Because of a potential for interaction of cediranib and olaparib with other drugs through the 
cytochrome P450 system, special attention should be paid to other medications known to affect 
P450 isoenzymes, in particular CYP3A4. 
d Temperature, pulse rate, blood pressure 
e Relevant only for participants in Arm 1. Please refer to section 5.3 for information on blood 
pressure monitoring  
f See Appendix A for KPS performance status 
g Sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, albumin, calcium, 
phosphorus, AST (SGOT), ALT (SGPT), alkaline phosphatase, total bilirubin. 
h Pre-study, prior to the first 2 cycles, and at off-study visit for all participants. Otherwise, should 
be checked prior to each cycle if clinically indicated. 
i Urinanalysis may be used instead. See Section 6.2.5 for Management of Proteinuria.  
j MUGA or echocardiogram should be done at baseline and every 4 cycles for those patients at 
increased risk for compromised LVEF. Increased risk patients have had one or more of the 
following: (1) prior treatment with anthracyclines, (2) prior treatment with trastuzumab, (3) NY 
Heart Association classification of II, (4) prior central thoracic RT, (5) history of myocardial 
infarction within the 12 months prior. 
k beta-HCG for women of childbearing potential.  
l Tumor measurements by MRI will be performed within the 2 weeks prior to starting study 
treatment, prior to cycle 3 day 1 (- 1 week), and every 8 weeks (+/- 1 week) thereafter of 
treatment. If a partial or complete response is noted, a confirmatory CT scan or MRI should be 
performed. The next planned restaging MRI may be used as the confirmatory scan. All standard 
MRIs should be performed according to Appendix F.  
m Bloodwork will be drawn for translational studies of plasma angiome at baseline (pre-
treatment), at Cycle 2 day 1 of treatment and at the time of progression/end of study. Bloodwork 
will be drawn for BROCA-HR study at baseline only. Participation in these translational studies 
is required for study participation. Details on the required specimens are found in Section 9. 
Patients may choose to opt out of translational bloodwork at the time of progression. 
n Archival tissue – Please refer to section 9.1 for specimen requirenments. Please refer to section 
9.2.2 for information regarding handling and shipping of specimens. Archival tissue may be 
collected and shipped after study initiation.  
o Off-treatment assessments should be performed within 30 days of stopping study treatment. 
 
 
 

 
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11. MEASUREMENT OF EFFECT 
 
11.1 
Definition of Measurability of Disease (per Response Assessment in Neuro-
Oncology (RANO) Criteria) 
 
All lesions are to be measured at each evaluation; however, if there are too many measurable 
lesions, choose the largest two to be followed before a patient is entered on study.  
 
Evaluable for objective response: only those patients who have measurable disease present at 
baseline and have received at least one dose of therapy will be considered evaluable for response. 
These patients will have their response classified according to the definitions stated below.  
 
Measurable disease: Bidimensionally, contrast-enhancing, measurable lesions with clearly 
defined margins by MRI scan, with a minimal diameter of 1 cm, and visible on 2 axial slices 
which are at least 5 mm apart with 0 mm skip. Measurement of tumor around a cyst or surgical 
cavity, if necessary, requires a minimum thickness of 3 mm.  
 
Non-measurable evaluable disease: Unidimensionally measurable lesions, masses with 
margins not clearly defined, lesions with maximal diameter < 1 cm. 
 
11.2 
Response Assessments 
 
Response assessments will be performed every two months on treatment using the objective 
status categories per RANO criteria, which, in addition to radiographic scans, comprise elements 
of the neurological exam, KPS, and steroid use. Response assessments are to be derived from 
baseline or Best Response (see below). If a partial or complete response is noted, a follow up 
confirmatory CT scan or MRI should be performed. 
 
11.2.1 Best Response 
 
This will be calculated from the sequence of objective status. For patients who are having all 
disease sites assessed at every evaluation period, the best response will be defined as the best 
objective status, measured according to Section 12.2.2. If the response does not persist at the 
next routinely scheduled scan, the response will still be recorded based on the prior scan, but will 
be designated as a non-sustained response. If the response is sustained, e.g. still present on the 
subsequent scan, it will be recorded as a sustained response, lasting until the time of tumor 
progression. Best response is unknown if the subject does not qualify for a best response or 
increasing disease and if all objective status determinations before progression are unknown.  
 
11.2.2 Objective Status (per RANO Criteria) 
 
11.2.2.1 
Complete Response (CR). All of the following criteria must be met: 
 
a. Complete disappearance of all enhancing measurable and non-measurable disease 

 
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sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, 
this scan will be considered only stable disease.  
b. No new lesions 
c. All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline. 
d. Patients must be on no steroids or on physiologic replacement doses only. 
e. Stable or improved non-enhancing (T2/FLAIR) lesions 
f. Stable or improved clinically, for clinical signs and symptoms present at baseline 
and recorded to be disease related.  
 
11.2.2.2 
Partial Response (PR). All of the following criteria must be met: 
 
a. ≥ 50% decrease compared to baseline in the sum of products of perpendicular 
diameters of all measurable enhancing lesions sustained for at least 4 weeks. In 
the absence of a confirming scan 4 weeks later, this scan will be considered only 
stable disease. 
b. No progression of non-measurable disease. 
c. No new lesions. 
d. All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline.  
e. The steroid dose at the time of the scan evaluation should be no greater than the 
dose at time of baseline scan. 
f. Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
steroid compared to baseline scan. 
g. Stable or improved clinically, for clinical signs and symptoms present at baseline 
and recorded to be disease related. 
 
11.2.2.3 
Progressive Disease (PD). The following criteria must be met: 
 
a. 25% increase in sum of the products of perpendicular diameters of enhancing 
lesions (over best response or baseline if no decrease) on stable or increasing 
doses of steroids 
and/or one or more of the following: 
b. Significant increase in T2/FLAIR non-enhancing lesion on stable or incrasing 
doses of steroids compared to baseline scan or best response following initiation 
of therapy, not due to co-morbid events (radiation therapy, demylination, 
ischemic injury, infection, seizures, post-operative changes, or other treatment 
effects). 
c. Any new lesions 
d. Clear clinical deterioration not attributable to other causes apart from the tumor 
(e.g. seizures, medication side effects, complications of therapy, cerebrovascular 
events, infection etc.). The definition of clinical deterioration is left to the 
discresion of the investigator but it is recommended that a decline in the KPS 
from 100 or 90 to 70 or less, a decline in KPS of at least 20 from 80 or less, or a 
decline in KPS from any baseline to 50 or less, for at least 7 days, be considered 

 
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neurologic deterioraton, unless attributable to co-morbid events or changes in 
steroid dose.  
e. Failure to return for evaluation due to death or deteriorating condition.  
 
11.2.2.4 
Stable Disease (SD). All of the following criteria must be met: 
 
a. Does not qualify for CR, PR, or PD. 
b. All measurable and non-measurable sites must be assessed using the same 
techniques as baseline. 
c. Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of steroids 
compared to baseline scan. In the event that the steroid dose has been increased, 
the last scan considered to show stable disease will be the scan obtained when the 
steroid dose was equivalent to the baseline dose. 
d. Stable clinically. 
 
11.2.2.5 
Unknown Response Status. Progressive disease has not been documented and one or 
more measurable or non-measurable lesions have not been assessed.  
 
These RANO Response Criteria are also summarized in the following table.  
 
Table 11-1: Summary of the RANO Response Criteria 
 
CR 
PR 
SD 
PD# 
T1-Gd+ 
None 
≥ 50% decrease 
< 50% decrease 
- < 25% increase 
≥25% increase* 
T2/FLAIR 
Stable or 
decrease 
Stable or 
decrease 
Stable or 
decrease 
Increase* 
New lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or 
decrease 
Stable or 
decrease 
NA 
Clinical Status 
Stable or 
increase 
Stable or 
increase 
Stable or 
increase 
Decrease* 
Requirement 
for Response 
All 
All 
All 
Any* 
# Progression occurs when any of the criteria with * is present.  
NA:   Increase in corticosteroids alone will not be taken into account in determining 
progression in the absence of persistent clinical deterioration 
 
 
11.2.3 Efficacy Assessments  
 

 
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11.2.3.1 
Progression-Free Survival (PFS) is defined as the time from randomization to the 
earlier of progression or death due to any cause. Patients alive without disease 
progression are censored at date of last disease evaluation.  
 
11.2.3.2 
Overall Survival (OS) is defined as the time from randomization to death due to any 
cause or censored at date last known alive.  
 
 
11.2.4 Response Review 
 
Radiographic response to treatment will be determied locally by the treating physician. All brain 
MRI images may be collected in the future for consideration of central review at a later time 
point.  
 
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
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. 
 

 
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12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (check at < https://ctepcore.nci.nih.gov/iam  >) and 
the appropriate Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site Investigator) 
on either the LPO or participating organization roster at the enrolling site. To the hold Rave CRA 
role 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 
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 
 

 
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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 and Repository (caDSR) 
compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-
semantics/metadata-and-models).  Customized eCRFs will be included when appropriate to meet 
unique study requirements.  The PI is encouraged to review the eCRFs, working closely with 
CTMS to ensure prospectively that all required items are appropriately captured in the eCRFs 
prior to study activation.  CTMS will prepare the eCRFs with built-in edit checks to the extent 
possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex on a monthly 
basis.  The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 
 
 
12.3 
Collaborative Agreements Language 
 

 
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The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 

 
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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. 
 
12.4 
Genomic Data Sharing Plan 
 
The investigators and statistician and/or bioinformaticians for a study will have access to all data 
on mutations and variants stored in the Theradex Data Base and the GDC.  This information will 
be sequestered from access throughout the study until it is analyzed for purposes of reporting and 
publishing of the study results.  As specified in the CRADA for the agents used in the clinical 
study, the pharmaceutical collaborator will have at least 6 months, longer if needed for a 
regulatory filing, to review the data and or receive copies of the data once the study is completed 
and analyzed, or sooner, if specified for purposes of generating Intellectual Property.  Once these 
timeframes have been exceeded, the data will be available through a Data Access Committee 
(DAC) in the GDC following NCI and Collaborator review of the proposals.  
 
 
12.5 
Incidental/Secondary Findings Disclosure Procedure 
 
Given the potential clinical implications conferred by detecting a germline and/or somatic 
mutation in one of the proven cancer susceptibility genes, this protocol will use the following 
disclosure procedure, consistent with the recommendations of the American College of Medical 

 
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and Genomics (ACMG) (Green et al., 2013 and Kalia et al., 2016): 
 
The NCI Molecular Characterization Laboratory will review the mutations/variants once at the 
time of initial specimen evaluation according to the most recent version of the ACMG guidance 
on variants.  The NCI Molecular Characterization Laboratory will not re-review all specimens 
received if a new version of the ACMG guidance is published after the initial review. 
 
For each participant with a pathogenic or likely pathogenic germline and/or somatic variant 
detected in the WES of blood (as defined in the ACMG guidance), the NCI Molecular 
Characterization Laboratory will report to the Program Director or Scientific Officer the UPID 
and variant(s) identified.  The Program Director or Scientific Officer will contact Theradex to 
obtain the name of the protocol, investigator treating the patient, and the Principal Investigator of 
the grant.  The treating physician will be contacted by phone and in writing to ask the patient 
whether he or she is interested in learning more about the finding. 
 
If the patient wants to know more, the physician should contact the Program Director for more 
information about the mutation/variant.  The treating physician and a medical genetics counselor 
should meet with the patient to discuss the importance and meaning of the finding, but not the 
finding itself, and notify the patient that this research finding must be confirmed by Sanger 
sequencing at the patient’s/patient insurer’s expense in a Clinical Laboratory Improvement 
Amendments (CLIA)-approved laboratory.  The treating physician and genetic counselor should 
inform the patient of the confirmed result and its meaning and significance to the patient.  If 
desired, the patient may elect to undergo genetic counseling and confirmatory CLIA-approved 
clinical testing on his or her own.  Neither the research laboratory nor the National Cancer 
Institute will be responsible for the costs incurred for any confirmatory genetic testing or 
counseling.  
 
 
 
 

 
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13. STATISTICAL CONSIDERATIONS 
 
The purpose of this study is to compare the efficacy and safety of the combination of olaparib 
and cediranib with bevacizumab in patients with recurrent glioblastoma (GBM) and to evaluate 
integrated biomarkers and imaging correlates as predictors of tumor response to this combination 
regimen. 
 
13.1 
Study Design/Endpoints 
 
The primary objective of this study is to determine whether cediranib/olaparib combination 
(experimental arm) will improve the progression-free survival at 6 months (PFS6) compared to 
bevacizumab alone (control arm) in patients with recurrent GBM.    
 
In this randomized phase 2 trial, patients with recurrent GBM who meet inclusion criteria will be 
randomized to Arm 1 (cediranib / olaparib combination) or Arm 2 (bevacizumab) in a 1:1 ratio.  
 
The doses of cediranib and olaparib are as determined in a phase I trial by Liu et al.  
 
Information about known prognostic molecular markers of the disease, such as MGMT 
methylation and IDH mutation, will be collected from each participating site as these studies are 
now routinely performed at the time of the initial diagnosis. It is not planned to repeat these tests, 
unless indicated. Age, KPS, and resection type also have prognostic value in overall survival. 
 
Analysis population will be based on the modified ITT population. Patients who did not receive 
any study treatment will be excluded from analysis  
 
Primary endpoint is PFS6, defined as the proportion of subjects in the analysis population who 
remain progression-free for at least six months from randomization. 
 
Secondary endpoints include: 
• Overall survival (OS) and treatment adverse events. 
• Circulating cytokines involved with angiogenesis (bFGF, Ang-1, Ang-2, Tie-2, 
SDF1-α, Collagen IV, PlGF, sVEGFR1, sVEGFR2, VEGF, Il-1β, Il-6, Il-8, TNF-α, 
CAIX) 
• Serial circulating biomarkers involved with DNA repair  
• Tumor genomic alteration by whole exome sequencing 
• Imaging correlates (vascular permeability, tumor perfusion and oxygenation, brain 
tumor cellularity) 
13.2 
Sample Size/Accrual Rate 
 
On the basis of data reported by Friedman et al the progression-free survival at 6 months with 
bevacizumab alone was assumed to be approximately 40%. With 35 patients in each arm, there 
will be at least 85% power to detect an increase in PFS6 rate from 40% to 63% at a one-sided 

 
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significance level of 0.1 using the Log-Rank test and assuming a total study duration of 20 
months.  
 
We anticipate a monthly accrual rate of 5-7 patients therefore an estimated total study duration of 
20 months. A minimum of 52 events will be required in order to conduct the final analysis. In 
accordance with NIH policy, both men and women of all races and ethnic groups are eligible for 
this study. We will also analyze treatment differences by gender, race, and ethnicity. The 
following table lists the projected accrual for each racial and ethnic group based upon previous 
NCI recurrent GBM trials 
  
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
1 
0 
0 
1 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
4 
7 
1 
2 
14 
White 
15 
28 
2 
7 
52 
More Than One Race 
0 
0 
1 
2 
3 
Total 
19 
36 
4 
11 
70 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
 
13.3 
Stratification Factors 
 
No stratification factors will be applied to randomized patients. 
 
13.4 
Interim Analysis 
An early futility monitoring will be conducted when 50% of total information is collected. If at 
this stage the observed HR favors the control arm, the study will be stopped for futility. 

 
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13.5 
Analysis of Primary and Secondary Endpoints  
 
For the primary endpoint, PFS6 will be calculated with the Kaplan-Meier method and the Log-
Rank test will be conducted to compare between the study arms. 95% CI will be provided for 
proportion outcomes 
 
Time to event analysis such as OS and PFS will be calculated with the Kaplan-Meier method and 
the Log-Rank test will be conducted to compare between the study arms. Time to event will be 
calculated from start of treatment until documentation of event. For OS analysis, patients still 
alive will be censored at their last date of follow-up. For PFS analysis, patients without 
progression will be censored at their last date known to be progression free. OS analysis will be 
conducted within 2 years from start of study. It is expected that at least 80% of the study 
population have died within this time frame. 95% CI will be provided for all rate and proportion 
outcomes (such as response rate). ORR will be calculated as the proportion of patients that are 
determined to be CR, PR or SD at 2, 4, 6 and 12 months out of the total enrolled. Exact binomial 
95% CI will be provided for this rate. 
 
Descriptive statistics will be provided for all continuous Biomarkers outcomes, Contingency 
tables will be provided for categorical data. All comparisons between study arms will be adjusted 
for multiplicity and in particular FDR (Hochberg and Binaymini) will be used for genome data.  
Binary endpoints, including maximum grade AE during treatment, will be reported using 95% 
binomial confidence intervals.  
 
Sequential boundaries will be used to monitor dose-limiting toxicity rate. The accrual will be 
halted if excessive numbers of dose-limiting toxicities are seen, that is, if the number of dose-
limiting toxicities is equal to or exceeds bn out of n patients with full follow-up (see table). This 
is a Pocock-type stopping boundary that yields the probability of crossing the boundary at most 
0.05 when the rate of dose-limiting toxicity is equal to the acceptable rate 0.4. 
 
Number of Patients, n 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 
Boundary, bn 
- - - - 5 6 7 7 8 8 9 10 10 11 11 12 12 13 13 14 
Number of Patients, n 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 
Boundary, bn 
14 15 15 16 16 17 17 18 18 19 19 20 20 21 21  
 
 
 
 
 
 
This boundary is equivalent to testing the null hypothesis, after each patient, that the event rate is 
equal to 0.4, using a one-sided level 0.015602 test. 
 
 
13.5.1 Advanced Imaging Analysis 
 
Date will be analysed as per the methods of Gerstner et al, 2016.  
 

 
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The DSC data will be analyzed using NordicIce or a similar program to generate values for 
rCBV and rCBF. 
 
Our goal is to explore the association of changes from baseline vascular MRI parameters at one 
month from initiation of treatment, with PFS in participants of this trial. Correlation between 
parameters will be assessed using Pearson correlation. Kaplan–Meier survival estimates for PFS 
time will be generated with its 95% confidence interval (CI). The ROC curves for the imaging 
markers will be constructed for PFS-6.  The areas under the ROC curves (AUC) will be 
estimated empirically with the trapezoid rule. The 95% CI of the AUCs will be calculated using 
Delong method (Delong et al, 1988).  
 
13.6 
Reporting and Exclusions 
 
13.6.1 Evaluation of Toxicity 
 
All participants who receive at least one dose of cediranib, olaparib or bevacizumab will 
be evaluable for toxicity from the time of their first treatment. Toxicities will be graded 
via CTCAE 4.0 until March 31, 2018.  CTCAE version 5.0 will be utilized for AE 
reporting beginning April 1, 2018  
 
 
13.6.2 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 

 
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reported.  The 95% confidence intervals should also be provided.  
 
14. PUBLICATION PLAN 
 
The results should be made public within 12 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 
 

 
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REFERENCES  
 
Agboola S, Flanagan C, Searl M, et al. (2014). Improving outcomes in cancer patients on oral 
anti-cancer medications using a novel mobile phone-based intervention: Study design of a RCT. 
JMIR Res Protoc. 3(4):e79. 
 
Alberts, S.R., T.R. Fitch, G.P. Kim, et al. (2012). Cediranib (AZD2171) in patients with 
advanced hepatocellular carcinoma: A phase II North Central Cancer Treatment Group clinical 
trial. Am J Clin Oncol. 35:329-333. 
 
Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, Scott C, 
Weitzel JN, Oaknin A, Loman N, Lu K, Schmutzler RK, Matulonis U, Wickens M, Tutt A. Oral 
poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations 
and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010 Jul 24;376(9737):245-51. 
 
Batchelor, T.T., A.G. Sorensen, E. di Tomaso, et al. (2007). AZD2171, a pan-VEGF tyrosine 
kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. 
Cancer Cell. 11:83-95. 
 
Batchelor, T.T., D.G. Duda, E. di Tomaso, et al. (2010). Phase II study of cediranib, an oral pan-
vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent 
glioblastoma. J Clin Oncol. 28:2817-2823. 
 
Batchelor TT, Gerstner ER, Emblem KE, Duda DG, Kalpathy-Cramer J, Snuderl M, 
Ancukiewicz M, Polaskova P, Pinho MC, Jennings D, Plotkin SR, Chi AS, Eichler AF, Dietrich  
J, Hochberg FH, Lu-Emerson C, Iafrate AJ, Ivy SP, Rosen BR, Loeffler JS, Wen PY, Sorensen 
AG, Jain RK. Improved tumor oxygenation and survival in glioblastoma patients who show 
increased blood perfusion after cediranib and chemoradiation. Proc Natl Acad Sci U S A. 2013 
Nov 19;110(47):19059-64. 
 
Batchelor TT, Mulholland P, Neyns B, et al. Phase III Randomized Trial Comparing the Efficacy 
of Cediranib As Monotherapy, and in Combination With Lomustine, Versus Lomustine Alone in 
Patients With Recurrent Glioblastoma. Journal of Clinical Oncology. Aug 12 2013. 
 
Bernsen HJ, Rijken PF, Peters H, et al. Hypoxia in a human intracerebral glioma model. J 
Neurosurg. 2000; 93:449-454. 
 
Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008 
Aug;8(8):592-603. 
 
Bindra RS, Gibson SL, Meng A, Westermark U, Jasin M, Pierce AJ, Bristow RG, Classon MK, 
Glazer PM. Hypoxia-induced down-regulation of BRCA1 expression by E2Fs. Cancer Res. 2005 
Dec 15;65(24):11597-604. 
 

 
NCI Protocol #:10067 
Version Date:   05/10/19 
 
116 
 
Bindra RS, Schaffer PJ, Meng A, Woo J, Måseide K, Roth ME, Lizardi P, Hedley DW, Bristow 
RG, Glazer PM. Down-regulation of Rad51 and decreased homologous recombination in 
hypoxic cancer cells. Mol Cell Biol. 2004 Oct;24(19):8504-18. 
 
Bindra, R.S., P.J. Shaffer, A. Meng, et al. (2005). Down-regulation of Rad51 and decreased 
homologous recombination in hypoxic cancer cells. Mol Cell Biol. 24:8504-8518. 
 
Bouwman P, Aly A, Escandell JM, et al. (2010). 53BP1 loss rescues BRCA1 deficiency and is 
associated with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol 17:688- 
95. 
 
Bunting SF, Callen E, Wong N, et al. (2010). 53BP1 inhibits homologous recombination in 
Brca1-deficient cells by blocking resection of DNA breaks. Cell 141:243-54. 
 
Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 
2011 May 19;473(7347):298-307. 
 
Chae SS, Kamoun WS, Farrar CT, Kirkpatrick ND, Niemeyer E, de Graaf AM, Sorensen AG, 
Munn LL, Jain RK, Fukumura D. Angiopoietin-2 interferes with anti-VEGFR2-induced vessel 
normalization and survival benefit in mice bearing gliomas. Clin Cancer Res. 2010 Jul 
15;16(14):3618-27. 
 
Chan N, Koritzinsky M, Zhao H, Bindra R, Glazer PM, Powell S, Belmaaza A, Wouters B, 
Bristow RG. Chronic hypoxia decreases synthesis of homologous recombination proteins to 
offset chemoresistance and radioresistance. Cancer Res. 2008 Jan 15;68(2):605-14. 
 
Cher LM, Murone C, Lawrentschuk N, et al. Correlation of hypoxic cell fraction and 
angiogenesis with glucose metabolic rate in gliomas using 18F-fluoromisonidazole, 18F-FDG 
PET, and immunohistochemical studies. J Nucl Med. 2006; 47:410-418. 
 
Chinot OL, Nishikawa R, Mason W, Henriksson R, Saran F, Cloughesy T, Garcia J, Revil C, 
Abrey L, Wick W. Upfront bevacizumab may extend survival for glioblastoma patients who do 
not receive second-line therapy: an exploratory analysis of AVAglio. Neuro Oncol. 2016 
Sep;18(9):1313-8. 
 
Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-
Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus 
radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 
20;370(8):709-22. 
 
Cloughesy T, Prados M, Wen P, et al. A phase II, randomized, non-comparative clinical trial of 
the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month 
progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM). J Clin 
Oncol 2008;26:abstr 2010b. 
 

 
NCI Protocol #:10067 
Version Date:   05/10/19 
 
117 
 
Dahut, W.L., R.A. Madan, J.J. Karakunnel, et al. (2013). Phase II clinical trial of cediranib in 
patients with metastatic castration-resistant prostate cancer. BJU Int. 111:1269-1280. 
 
DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more 
correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 
1988;44:837–45. 
 
Denduluri, N., A.W. Berman, U. Vatas, et al. (2007). Cardiotoxicity after doxorubicin and 
AZD2171, an oral vascular endothelial growth factor receptor (VEGFR) inhibitor, in patients 
(pts) with breast cancer. Proc Am Soc Clin Oncol. 25:A554. 
 
Drevs, J., J. Esser, S.R. Wedge, et al. (2004) Effect of AZD2171, a highly potent VEGF receptor 
tyrosine kinase inhibitor, on primary tumor growth, metastasis and vessel density in murine renal 
cell carcinoma. Proc Am Assoc Cancer Res: A4554. 
 
Dubois L, Landuyt W, Haustermans K, et al. Evaluation of hypoxia in an experimental rat 
tumour model by [(18)F]fluoromisonidazole PET and immunohistochemistry. Br J Cancer. 2004 
Nov 29; 91(11): 1947-54. 
 
Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine 
in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol. 2002 Nov 1; 
20 (21): 4368-80. 
 
Economopoulou, M., H.F. Langer, A. Celeste, et al. (2009). Histone H2AX is integral to 
hypoxia-driven neovascularization. Nat Med. 15:553-558. 
 
Farmer, H., N. McCabe, C.J. Lord, et al. (2005). Targeting the DNA repair defect in BRCA 
mutant cells as a therapeutic strategy. Nature 434(7035):917-921. 
 
Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, De Greve J, Lubinski 
J, Shanley S, Messiou C, A'Hern R, Tutt A, Ashworth A, Stone J, Carmichael J, Schellens JH, de 
Bono JS, Kaye SB. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in 
BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010 May 
20;28(15):2512-9. 
 
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau 
A, O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS. Inhibition of 
poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009 Jul 
9;361(2):123-34. 
 
Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with 
irinotecan in recurrent glioblastoma. Journal of Clinical Oncology. Oct 1 2009;27(28):4733-
4740. 
 

 
NCI Protocol #:10067 
Version Date:   05/10/19 
 
118 
 
Gadgeel, S.M., A. Wozniak, M.J. Edelman, et al. (2009). Cediranib, a VEGF receptor 1, 2, and 3 
inhibitor, and pemetrexed in patients (pts) with recurrent non-small cell lung cancer (NSCLC). J 
Clin Oncol. 27(suppl):Ae19007. 
 
Garland, L.L., K. Chansky, A.J. Wozniak, et al. (2011). Phase II study of cediranib in patients 
with malignant pleural mesothelioma. J Thoracic Oncol. 6:1938-1945. 
 
Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, 
Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, 
Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, 
Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J 
Med. 2014 Feb 20;370(8):699-708. 
 
Gelmon, K.A., M. Tischkowitz, H. Mackay, et al. (2011). Olaparib in patients with recurrent 
high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A 
phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 12(9):852-861. 
 
Gerstner, E.R., K.E. Emblem, A.S. Chi, et al. (2012). Effects of cediranib, a VEGF signaling 
inhibitor, in combination with chemoradiation on tumor blood flow and survival in newly 
diagnosed glioblastoma. J Clin Oncol. 30(Suppl):A2009. 
 
Gerstner ER, Zhang Z, Fink JR, Muzi M, Hanna L, Greco E, Prah M, Schmainda KM, Mintz A, 
Kostakoglu L, Eikman EA, Ellingson BM, Ratai E, Sorensen G, Barboriak DP, Mankoff D 
(2016). ACRIN 6684: Assessment of tumor hypoxia in newly diagnosed GBM using 18F-
FMISO PET and MRI. Clin Cancer Res. 2016 May 16. 
 
Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. N Engl J Med 
2006;354:980-982; discussion 980-982. 
 
Graeber, T.G., C. Osmanian, T. Jacks, et al. (1996). Hypoxia-mediated selection of cells with 
diminished apoptotic potential in solid tumours. Nature 379(6560):88-91. 
 
Gross MW, Karbach U, Groebe K, et al. Calibration of misonidazole labeling by simultaneous 
measurement of oxygen tension and labeling density in multicellular spheroids. Int J Cancer. 
1995; 61:567-573. 
 
Hammond, E.M., N.C. Denko, M.J. Dorie, et al. (2002). Hypoxia links ATR and p53 through 
replication arrest. Mol Cell Biol. 22(6):1834-1843. 
 
Hammond, E.M., M.J. Dorie, and A.J. Giaccia. (2004). Inhibition of ATR leads to increased 
sensitivity to hypoxia/reoxygenation. Cancer Res. 64(18):6556-6562. 
 

 
NCI Protocol #:10067 
Version Date:   05/10/19 
 
119 
 
Hegan, D.C., Y. Lu, G.C. Stachelek, M.E. Crosby, et al. (2010). Inhibition of poly(ADP-ribose) 
polymerase downregulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc 
Nat Acad Sci USA. 107:2201-2206. 
 
Herbst, R.S. (2006). Toxicities of antiangiogenic therapy in non-small cell lung cancer. Clin 
Lung Cancer. 8(suppl 1): S23-S30. 
 
Hennequin, L.F., A.P. Thomas, C. Johnstone, et al. (1999). Design and structure-activity 
relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors. J Med Chem. 
42:5369-5389. 
 
Hirte, H.W., L.Vidal, G.F. Fleming, et al. (2008). A phase II study of cediranib (AZD2171) in 
recurrent or persistent ovarian, peritoneal or fallopian tube cancer: Final results of a PMH, 
Chicago and California consortia trial. Proc Am Soc Clin Oncol. 26:A5521. 
 
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and 
leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-2342. 
 
Izzedine, H., O. Rixe, B. Billemont, et al. (2007). Angiogenesis inhibitor therapies: Focus on 
kidney toxicity and hypertension. Am J Kidney Dis. 50:203-218. 
 
Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. 
Science. 2005 Jan 7; 307 (5706): 58-62. 
 
Johnson N, Johnson SF, Yao W, et al. (2013). Stabilization of mutant BRCA1 protein confers 
PARP inhibitor and platinum resistance. Proc Natl Acad Sci U S A 110:17041-6. 
 
Jurgensmeier, J.M., S.R. Brave, N.H. James, et al. (2005). AZD2171, a highly potent inhibitor of 
VEGF receptor signaling, has additional activity versus the c-Kit receptor tyrosine kinase. Proc 
Am Assoc Cancer Res. 46:A5834. 
 
Kamba, T.,and D.M. McDonald, (2007). Mechanisms of adverse effects of anti-VEGF therapy 
for cancer. Br J Cancer. 96:1788-1795. Kappers,M.H.W., J.H.M. van Esch, S. Sleijfer, et al. 
(2009). Cardiovascular and renal toxicity during angiogenesis inhibition: Clinical and 
mechanistic aspects. J Hypertens. 27:2297-2309. 
 
Kearney N, McCann L, Norrie J, et al. (2009). Evaluation of a mobile phone-based advanced 
symptom management system (ASySM) in the management of chemotherapy-related toxicity. 
Support Care Cancer. 17(4):437-44. 
 
Kim YB, Yoshida M, Horinouchi S. Selective induction of cyclin-dependent kinase inhibitors 
and their roles in cell cycle arrest caused by trichostatin A, an inhibitor of histone deacetylase. 
Ann N Y Acad Sci 1999;886:200-203. 
 

 
NCI Protocol #:10067 
Version Date:   05/10/19 
 
120 
 
Kleihues P, Burger PC, Scheithauer BW. Histological typing of tumours of the central nervous 
system. 2nd ed. 1993, New York: Springer-Verlag. 11-30. 
 
Klein TJ, Glazer PM. The tumor microenvironment and DNA repair. Semin Radiat Oncol. 2010 
Oct;20(4):282-7. 
 
Klinowska, T.C., J.A. Jackson, P.M. Farrington, et al. (2004) AZD2171, a highly potent inhibitor 
of VEGF receptor tyrosine kinase activity, inhibits the growth of spontaneous mammary tumors 
in the MMTV-neu transgenic mouse. Proc Am Assoc Cancer Res: A4540. 
 
Koh WJ, Rasey JS, Evans ML, et al. Imaging of hypoxia in human tumors with [F- 
18]fluoromisonidazole. Int J Radiat Oncol Biol Phys. 1992; 22:199-212. 
 
Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by 
bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. Journal of clinical 
oncology.  Feb 10 2009;27(5):740-745. 
 
Kroenke K, Theobald D, Wu J, et al. (2010). Effect of telecare management on pain and 
depression in patients with cancer: a randomized trial. JAMA. 304(2): 163-71. 
 
Langenberg, M.H.G., C.M.L. van Herpen, J. de Bono, et al. (2009). Effective strategies for 
management of hypertension after vascular endothelial growth factor signaling inhibition 
therapy: Results from a phase II randomized, factorial, double-blind study of cediranib in 
patients with advanced solid tumors. J Clin Oncol. 36:6152-6159. 
 
Launay-Vacher, V., and G. Deray. (2009). Hypertension and proteinuria: A class-effect of 
antiangiogenic therapies. Anticancer Drugs. 20:81-82. 
 
Laurie SA, Solomon BJ, Seymour L, Ellis PM, Goss GD, Shepherd FA, et al. Randomised, 
double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients 
with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29. Eur J 
Cancer 2014;50(4):706-12. 
 
Laurie SA, Gauthier I, Arnold A, Shepherd FA, Ellis PM, Chen E, et al. Phase I and 
pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor 
tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-
small-cell lung cancer: The National Cancer Institute of Canada Clinical Trials Group. J Clin 
Oncol 2008;26:1871–1878. 
 
Ledermann, J.A., P. Harter, C. Gourley, et al. (2012). Olaparib maintenance therapy in platinum-
sensitive relapsed ovarian cancer. N Engl J Med. 366 (15):1382-1392. 
 
Lee, J.M., J. Squires, J.L. Hays, et al. (2011). A pharmacokinetics/pharmacodynamics study of 
sequence specificity of the PARP inhibitor olaparib with carboplatin in refractory/recurrent 
women’s cancers: NCT01237067. J Clin Oncol. (ASCO Annual Meeting Proceedings) 29s: 

 
NCI Protocol #:10067 
Version Date:   05/10/19 
 
121 
 
 
Lim JJ, Yang K, Taylor-Harding B, Wiedemeyer WR, Buckanovich RJ. VEGFR3 inhibition 
chemosensitizes ovarian cancer stemlike cells through down-regulation of BRCA1 and BRCA2. 
Neoplasia. 2014 Apr;16(4):343-53. 
 
Lindsay, C.R., I.R.J. MacPherson, and J. Cassidy. (2009). Current status of cediranib: The rapid 
development of a novel anti-angiogenic therapy. Future Oncol. 5:421-432. 
 
Liu, J.F., S. M. Tolaney, M. Birrer, et al. (2013). A Phase 1 trial of the poly(ADP-ribose) 
polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib 
(AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer. 
49:2972-2978. 
 
Liu JF, Barry WT, Birrer M, et al. (2014) Combination cediranib and olaparib versus olaparib 
alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. 
Lancet Oncol. Oct;15(11):1207-14. 
 
Liu J and Matulonis UA. New strategies in ovarian cancer: Translating the Molecular 
Complexity of Ovarian Cancer into Treatment Advances. (2014) Clin Cancer Res. 20:5150-6. 
 
Majuelos-Melguizo J, Rodríguez MI, López-Jiménez L, Rodríguez-Vargas JM, Martí Martín-
Consuegra JM, Serrano-Sáenz S, Gavard J, de Almodóvar JM, Oliver FJ. PARP targeting 
counteracts gliomagenesis through induction of mitotic catastrophe and aggravation of 
deficiency in homologous recombination in PTEN-mutant glioma. Oncotarget. 2015 Mar 
10;6(7):4790-803. 
 
Matulonis, U.A., S. Berlin, P. Ivy, et al. (2009). Cediranib, an oral inhibitor of vascular 
endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, 
fallopian tube, and peritoneal cancer. J Clin Oncol. 27:5601-5606. 
 
McCann L, Maguire R, Miller M, et al. (2009). Patients’ perceptions and experiences of 
using a mobile-phone based Advanced Symptom Management System (ASySM©) to monitor 
and manage chemotherapy related toxicity. Eur J Cancer Care (Engl). 18(2):156-64. 
 
McEllin B, Camacho CV, Mukherjee B, Hahm B, Tomimatsu N, Bachoo RM, Burma S. PTEN 
loss compromises homologous recombination repair in astrocytes: implications for glioblastoma 
therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res. 2010 Jul 
1;70(13):5457-64. 
 
McGuire WP, Hoskins WJ, Brady MF et al. (1996) Cyclophosphamide and cisplatin compared 
with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. New Engl 
Journal of Medicine 334:1-6. 
 

 
NCI Protocol #:10067 
Version Date:   05/10/19 
 
122 
 
Menear, K.A., C. Adcock, R. Boulter, et al. (2008). 4-[3-(4-cyclopropanecarbonylpiperazine-1- 
carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of 
poly(ADPribose) polymerase-1. J Med Chem. 51(20):6581-6591. 
 
Meng AX, Jalali F, Cuddihy A, Chan N, Bindra RS, Glazer PM, Bristow RG. Hypoxia down-
regulates DNA double strand break repair gene expression in prostate cancer cells. Radiother 
Oncol. 2005 Aug;76(2):168-76. 
 
Mengden T, Hernandez Medina RM, Beltran B, et al. (1998) Reliability of reporting self 
measured blood pressure values by hypertensive patients. Am J Hypertens. 11(12):1413-7. 
Nord AS, Lee M, King MC, et al. (2011). Accurate and exact CNV identification from targeted 
high-throughput sequence data. BMC Genomics 12:184. 
 
Mooney KH, Beck Sl, Friedman RH, et al. (2014). Automated monitoring of symptoms during 
ambulatory chemotherapy and oncology providers’ use of the information: a randomized clinical 
trial. Support Care Cancer. 22(9):2343-50. 
 
Ozcan C, Wong SJ, Hari P. Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. N Engl J Med 2006;354:980-982; discussion 980-982. 
 
Pennington KP, Walsh T, Harrell MI, et al. (2014). Germline and somatic mutations in 
homologous recombination genes predict platinum response and survival in ovarian, fallopian 
tube, and peritoneal carcinomas. Clin Cancer Res, 20(3):764-75. 
 
Pritchard CC, et al. (2012) ColoSeq Provides Comprehensive Lynch and Polyposis Syndrome 
Mutational Analysis Using Massively Parallel Sequencing. J Mol Diagn 14:357-366. 
 
Raja, FA, Griffin Cl, Qian W, et al. (2011). Initial toxicity assessment of ICON6: a randomized 
trial of cediranib plus chemotherapy in platinum-sensitive relapsed ovarian cancer. Br J Cancer. 
105(7):884-9. 
 
Rasey JS, Grunbaum Z, Magee S, et al. Characterization of radiolabeled fluoromisonidazole as a 
probe for hypoxic cells. Radiat Res. 1987; 111:292-304. 
 
Rasey JS, Nelson NJ, Chin L, et al. Characteristics of the binding of labeled fluoromisonidazole 
in cells in vitro. Radiat Res. 1990; 122:301-308. 
 
Rasey JS, Koh WJ, Evans ML, et al. Quantifying regional hypoxia in human tumors with 
positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients. Int 
J Radiat Oncol Biol Phys. 1996; 36:417-428. 
 
Raja FA, Griffin CL, Qian W, Hirte H, Parmar MK, Swart AM, et al. Initial toxicity assessment 
of ICON6: a randomised trial of cediranib plus chemotherapy in platinumsensitive relapsed 
ovarian cancer. Br J Cancer 2011;105(7):884-9. 
 

 
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Rajendran JG, Schwartz DL,O'Sullivan J, Peterson LM, Ng P, Scharnhorst J, et al. Tumor 
hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head 
and neck cancer. Clin Cancer Res 2006; 12:5435–41. 
 
Ramalingam, S.S., P.C. Mack, E.E. Vokes, et al. (2008). Cediranib (AZD2171) for the 
treatment of recurrent small cell lung cancer (SCLC): A California Consortium phase II study 
(NCI #7097A). Proc Am Soc Clin Oncol. 26:A8078. 
 
Robinson, E.S., U.A. Matulonis, P. Ivy, et al. (2010). Rapid development of hypertension and 
proteinuria with cediranib, an oral vascular endothelial growth factor receptor inhibitor. Clin J 
Am Soc Nephrol 5:477-483. 
 
Santivasi WL, Xia F. The role and clinical significance of DNA damage response and repair 
pathways in primary brain tumors. Cell Biosci. 2013 Feb 6;3(1):10. 
 
Shen WH, Balajee AS, Wang J, Wu H, Eng C, Pandolfi PP, Yin Y. Essential role for nuclear 
PTEN in maintaining chromosomal integrity. Cell. 2007 Jan 12;128(1):157-70. 
 
Sridhar, S.S., M.J. Mackenzie, S.J. Hotte, et al. (2008). Activity of cediranib (AZD2171) in 
patients (pts) with previously untreated metastatic renal cell cancer (RCC). A phase II trial of the 
PMH Consortium. Proc Am Soc Clin Oncol. 26:A5047. 
 
Sorensen AG, Emblem KE, Polaskova P, et al. Increased Survival of Glioblastoma Patients Who 
Respond to Antiangiogenic Therapy with Elevated Blood Perfusion. Cancer Res 2012;72:402-7 
 
Sorensen, A.G., T.T. Batchelor, W.-T. Zhang, et al. (2009). A “vascular normalization index” as 
potential mechanistic biomarker to predict survival after a single dose of cediranib in recurrent 
glioblastoma patients. Cancer Res. 69:5296-5300. 
 
Spence AM, Muzi M, Swanson KR, et al. Regional hypoxia in glioblastoma multiforme 
quantified with [18F]fluoromisonidazole positron emission tomography before radiotherapy: 
Correlation with time to progression and survival. Clin Cancer Res. 2008; 14:2623-2630. 
 
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant 
temozolomide for glioblastoma. N Engl J Med 2005;352:987-996. 
 
Sundberg C, Nagy JA, Brown LF, Feng D, Eckelhoefer IA, Manseau EJ, Dvorak AM, Dvorak 
HF. Glomeruloid microvascular proliferation follows adenoviral vascular permeability 
factor/vascular endothelial growth factor-164 gene delivery. Am J Pathol. 2001 Mar; 158 (3): 
1145-60. 
 
Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, 
Honkoop AH, Boerman D, de Vos FY, Dinjens WN, Enting RH, Taphoorn MJ, van den 
Berkmortel FW, Jansen RL, Brandsma D, Bromberg JE, van Heuvel I, Vernhout RM, van der 
Holt B, van den Bent MJ. Single-agent bevacizumab or lomustine versus a combination of 

 
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bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a 
randomised controlled phase 2 trial. Lancet Oncol. 2014 Aug;15(9):943-53. 
 
Tentori, L., P.M. Lacal, A. Muzi. (2007). Poly(ADP-ribose) polymerase (PARP) inhibition or 
PARP-1 gene deletion reduces angiogenesis. Eur J Cancer. 43:2124-2133. 
 
Tochon-Danguy HJ, Sachinidis JI, Chan F, et al. Imaging and quantitation of the hypoxic cell 
fraction of viable tumor in an animal model of intracerebral high-grade glioma using 
[18F]fluoromisonidazole (FMISO). Nucl Med Biol. 2002;29:191-197. 
 
Troost EG, Laverman P, Kaanders JH, et al. Imaging hypoxia after oxygenation-modification: 
comparing [18F]FMISO autoradiography with pimonidazole immunohistochemistry in human 
xenograft tumors. Radiother Oncol. 2006 Aug; 80(2): 157-64. 
 
Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, 
Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, Carmichael J. Oral 
poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations 
and advanced breast cancer: a proof-of-concept trial. Lancet. 2010 Jul 24;376(9737):235-44. 
 
Valk PE, Mathis CA, Prados MD, et al. Hypoxia in human gliomas: demonstration by PET with 
fluorine-18-fluoromisonidazole. J Nucl Med. 1992; 33:2133-2137. 
 
van de Beek D. Brain teasing effect of dexamethasone. Lancet Neurol. 2007 Mar; 6 (3): 203-4. 
 
Walsh T, Lee MK, Casadei S, et al. (2010) Detection of inherited mutations for breast and 
ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U 
S A 107:12629-33. 
 
Weaver A, Young Am, Rowntree J, et al. (2007). Application of mobile phone technology for 
managing chemotherapy-associated side effect. Ann Oncol. 18(11):1887-92. 
 
Wedge, S.R., J. Kendrew, L.F. Hennequin, et al. (2005). AZD2171: A highly potent, orally 
bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the 
treatment of cancer. Cancer Res. 65:4389-4400. 
 
Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, Chung DC, Sahani DV, 
Kalva SP, Kozin SV, Mino M, Cohen KS, Scadden DT, Hartford AC, Fischman AJ, Clark JW, 
Ryan DP, Zhu AX, Blaszkowsky LS, Chen HX, Shellito PC, Lauwers GY, Jain RK. Direct 
evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal 
cancer. Nat Med. 2004 Feb; 10 (2): 145-7. 
 
Zhu, A.X., M. Ancukiewicz, J.G. Supko, et al. (2012). Clinical, pharmacodynamic (PD), and 
pharmacokinetic (PK) evaluation of cediranib in advanced hepatocellular carcinoma (HCC): A 
phase II study (CTEP 7147). J Clin Oncol. 30(Suppl):A4112. 
 

 
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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: CYP3A4 INDUCERS AND INHIBITORS 
 
NOTE: The displayed lists are for reference only and  reviewers should consult a frequently 
updated medical reference for the most current list of agents with CYP interactions. 
 
CYP3A4 Inducers (prohibited) 
Armodafenil1 
Barbiturates2 
Bosentan1 
Carbamazepine 
Efavirenz 
Fosphenytoin1 
 
Modafinil2 
Nafcillin1 
Nevirapine 
Oxcarbazepine 
Pentobarbital1 
Phenobarbital 
Phenytoin 
Pioglitazone2 
Primidone1 
Rifabutin 
Rifampin 
Rifapentine1 
St. John’s wort2 
Troglitazone3 
1 Cited in Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong LL, 
Goldman MP, Lance LL, eds. Drug Information Handbook 20th ed. Hudson, OH; LexiComp Inc. 2011-
2012: 1810-1818 
2 Cited in Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University 
School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/table.asp. Accessed Nov 2011. 
3 Weak inhibitor per Lacy et al. May be used with caution. 
Note: Drugs without a superscript are cited in both the Lacy and Flockhart references. 
 
CYP3A4 Inhibitors  
Strong Inhibitors 
(prohibited) 
Moderate Inhibitors  
(avoid if possible; reduce 
olaparib dose if use 
unavoidable) 
Weak Inhibitors 
(use with caution, avoid if 
possible) 
Amprenavir1 
Atazanavir1 
Clarithromycin 
Conivaptan1 
Delavirdine1 
Fosamprenavir1 
Fospropofol1 
Imatinib1 
Indinavir 
Isoniazid1 
Itraconazole 
Ketoconazole 
Miconazole1 
Nefazodone 
Nelfinavir 
Amiodarone1 
Aprepitant 
Cimetidine1 
Clotrimazole1 
Cyclosporine1 
Desipramine1 
Doxycycline1 
Efavirenz1 
Erythromycin 
Fluconazole 
Fosaprepitant1 
Grapefruit juice 
Haloperidol1 
Lidocaine1 
Metronidazole1 
Chloramphenicol2 
Ciprofloxacin2 
Diethyldithiocarbamate2 
Fluvoxamine2 
Gestodene2 
Mibefradil2 
Mifepristone 
Norfluoxetine2 
Star fruit2 
Troleandomycin2 

 
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Nicardipine1 
Posaconazole1 
Propofol1 
Quinidine1 
Ritonavir 
Saquinavir2 
Telithromycin 
Norfloxacin1 
Sertraline1 
Tetracycline1 
Verapamil 
Voriconazole1 
1 Cited in Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong LL, 
Goldman MP, Lance LL, eds. Drug Information Handbook 20th ed. Hudson, OH; LexiComp Inc. 2011-
2012: 1810-1818 
2 Cited in Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University 
School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/table.asp. Accessed Nov 2011. 
Note: Drugs without a superscript are cited in both the Lacy and Flockhart references. 
 
 

 
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APPENDIX C: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARDS 
 
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. 
 
• 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.  
• Cediranib (AZD2171) may induce gastrointestinal CYP3A and UGT enzymes, therefore 
potentially reducing the effectiveness of hormonal contraceptives.  
• 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.  
• 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. 
• 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. 
 
• 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.  
• 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.  
• 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: 
➢ Tell your doctors if you stop taking regular medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistant, 
nurse practitioners, pharmacists) that you are taking part in a clinical 
trial. 
➢ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
➢ 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.  
➢ 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. 
➢ 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.   
➢ 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 SupplementsThe 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. 
 
• 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.  
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 

 
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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: 
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. 
• 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.  
• Avoid ingesting grapefruit, grapefruit juiceand Seville oranges while taking olaparib. 
• You may need to be monitored more frequently if you are taking any drugs that have 
narrow therapeutic ranges. 
• 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 

 
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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: 
➢ Tell your doctors if you stop taking regular medicines or if you start 
taking any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, pharmacists) that you are taking part in a clinical 
trial. 
➢ Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
➢ 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.   
 
➢ Olaparib must be used very carefully with other medicines that 
interact with these enzymes and proteins.  
➢ 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. 
➢ 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.  
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

 
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133 
 
APPENDIX D: PATIENT PILL DIARY 
 
Today’s Date  
 
 
 
Cycle Number  
______ 
 
 
Patient Name 
 
 
 
Patient Study ID 
 
 
 
1. Complete one form for each cycle (28 days). 
2. Record the date, the number of tablets you took, and when you took them. 
3. Bring your pill bottles (including empty bottles) and this form to every appointment. 
4. Do not chew, dissolve, or crush medications. DO NOT make up vomited 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. 
6. The first row in the table below is a EXAMPLE ROW for how to complete this diary. 
CEDIRANIB 
Take _____ (number) ____ mg tablets once 
a day. Take on an empty stomach 1 hour 
before taking the morning dose of olaparib. 
OLAPARIB 
Take ____ (number) ____ mg and ____ (number) 
____ mg tablets twice a day 12 hours apart after a 
light meal. Tablets should be taken with 8 ounces of 
water. 
Day 
Date 
15 mg 
20 mg 
AM 
Day 
Date 
100mg 
150mg 
AM 
PM 
1 
1/1/16 
2 
0 
7:00 
1 
1/1/16 
2 
0 
8:00 
8:00 
1 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
 
Patient’s Signature: ____________________________________________   Date:_________________ 
Physician/Nurse/Data Manager’s Signature: _________________________________  Date: _______________ 

 
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134 
 
APPENDIX E: PATIENT’S BLOOD PRESSURE DIARY 
 
Today’s Date  
 
 
 
Cycle Number  
 
 
 
Patient Name 
 
 
 
Patient Study ID 
 
 
 
1. Your blood pressure readings have two numbers. The first number is the pressure in your blood 
vessels during a heart beat (systolic), and the second number is the pressure in the vessels when the 
heart rests in between beats (diastolic). These numbers are usually written with a slash in between 
them (for example, normal blood pressure is 120/80). 
2. Record the date, then record your blood pressure twice each day using a home blood pressure 
monitor. 
• 
Each morning while you are resting (not while you are active: dressing, making breakfast etc.) 
• 
Each evening at bedtime or while you are relaxing during the evening.  
3. If you take your blood pressure at other times, record the numbers and time under “Other Readings”. 
4. If your systolic pressure is greater than 140 or your diastolic blood pressure is greater than 90, please 
contact your local doctor’s office at __________________________ for instructions. 
5. Please bring this form to every clinic visit or appointment.  
Day 
Date 
AM 
Readings 
PM 
Readings 
Other 
Readings 
(include 
time) 
Day 
Date 
AM 
Readings 
PM 
Readings 
Other 
Readings 
(include 
time) 
1 
 
/ 
/ 
 
15 
 
/ 
/ 
 
2 
 
/ 
/ 
 
16 
 
/ 
/ 
 
3 
 
/ 
/ 
 
17 
 
/ 
/ 
 
4 
 
/ 
/ 
 
18 
 
/ 
/ 
 
5 
 
/ 
/ 
 
19 
 
/ 
/ 
 
6 
 
/ 
/ 
 
20 
 
/ 
/ 
 
7 
 
/ 
/ 
 
21 
 
/ 
/ 
 
8 
 
/ 
/ 
 
22 
 
/ 
/ 
 
9 
 
/ 
/ 
 
23 
 
/ 
/ 
 
10 
 
/ 
/ 
 
24 
 
/ 
/ 
 
11 
 
/ 
/ 
 
25 
 
/ 
/ 
 
12 
 
/ 
/ 
 
26 
 
/ 
/ 
 
13 
 
/ 
/ 
 
27 
 
/ 
/ 
 
14 
 
/ 
/ 
 
28 
 
/ 
/ 
 
Patient’s Signature: ____________________________________________   Date:_________________ 
Date of this clinic visit:______________________ 
Physician/Nurse/Data Manager’s Signature: _________________________________  Date: _______________ 

 
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APPENDIX F: MRI PROTOCOL 
 
REQUIRED CONSENSUS MRI AQUISITION PARAMETERS (STANDARD IMAGING 
PROTOCOL) For sites that do NOT have advanced imaging available: (FDA/NBTS/NCI 
Standardized MRI Protocol).  
 
The MRI acquisition protocols defined in the following table have been defined by an 
international consensus panel. These parameters have been reviewed and adopted by the 
National Cancer Institute (NCI) and the Federal Drug Administration (FDA), and these 
acquisition parameters are required for all national and FDA drug-registration trials. The specific 
acquisition parameters, the sequence of imaging acquisition, and the plane of imaging are all 
required as explicitly stated in these protocols. Additionally, individual patients must be 
consistently imaged at the same field strength as their baseline registration scan. Additional 
sequences that the site wants can be added prior to injection or after the 3DT1 post but the time 
between injection and the 3DT1 post must be the same for each scan.  For example, 
susceptibility weighted imaging or T1 post with thicker sections are often included in brain 
tumor MRIs and those can be added. 
 
All MRI scans for every patient for the duration of the study, regardless if site is participating in 
the advanced MRI protocol, should be sent to Dr. Ben Ellingson. To ensure that the MRI 
protocol is being followed, Site Qualification will be performed by UCLA. New sites ideally will 
send a phantom scan prior to their first patient. Alternately, he first patient scan should be 
submitted for review within 2 weeks of the scan, and before the patient receives their second 
protocol scan. Sites will receive a notification of approval with the qualification results once 
complete. 
 
Future scans may be batched shipped every 3 months or sent as they are acquired to ensure no 
scans are missed. The preferred method for submitting scans is through a secure FTP. To set up 
an image transfer account, please contact Dr. Ellingson and Catalina Raymond. Please see 
Imaging transfer manual for additional details.  
 
▪ Ben Ellingson: Bellingson@mednet.ucla.edu  
▪ Catalina Raymond: CRaymond@mednet.ucla.edu  
 
If unable to submit via FTP, sites may send MRIs on CD/DVD. Please anonymize scans and label 
with patient’s study ID and date of the scan. Send to: 
 
UCLA brain tumor imaging laboratory 
Center for computer vision and imaging biomarkers 
924 Westwood Blvd 
Suite 615 
Los Angeles CA 90024 
310-482-7572 
 
MRIs should include all sequences acquired (ex. SWI or thicker T1 post images), be anonymised 

 
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prior to sending and labeled with the patient’s study ID and date of scan. Even unscheduled, 
emergently aquired MRIs should be sent particularly if the scan indicates progressive disease. 
 
3T Protocol: 
 
 
Ax FLAIR 
Ax DWI 
3D T1 Pre 
Contrast Injection a 
Ax T2 
3D T1 Postb 
Sequence 
TSEc – 
(turbo dark 
fluid) 
EPIf 
MPRAGEd,e 
TSEc 
MPRAGEd,e 
 
 
 
 
 
 
Plane 
Axial 
Axial 
Axial/Sagittal 
Axial 
Axial/Sagittal 
Mode 
2D 
2D 
3D 
2D 
3D 
TR [ms] 
>6000 
>5000 
2100g 
>2500 
2100g 
TE [ms] 
100-140 
Min 
Min 
80-120 
Min 
TI [ms] 
2500 
 
1100h 
 
1100h 
Flip Angle 
90/160 
90/180 
10-15 
90/160 
10-15 
Frequency 
256 
128 
256 
256 
256 
Phase 
256 
128 
256 
256 
256 
NEX 
1 
1 
1 
1 
1 
Frequency 
Direction 
A/P 
R/L 
A/P 
A/P 
A/P 
FOV 
240mm 
240mm 
256mm (for 1mm 
isotropic)i 
240mm 
256mm (for 
1mm isotropic)i 
Slice 
Thickness 
3mm 
3mm 
1mmi 
3mm 
1mmi 
Gap/Spacing 
0 
0 
0 
0 
0 
Diffusion 
Options 
 
b = 0, 500, 
and 1000 
s/mm2 
 
 
 
Parallel 
Imaging 
Up to 2x 
Up to 2x 
Up to 2x 
Up to 2x 
Up to 2x 
Scan Time 
(Approx) 
4-5 min 
3-5 min 
5-8 min 
3-5 min 
5-8 min 
 
a 0.1 mmol/kg or up to 20cc (single, full dose) of MR contrast. 
b Post-contrast 3D axial T1-weighted images should be collected with identical parameters to pre-
contrast 3D axial T1-weighted images 
c TSE = turbo spin echo (Siemens & Philips) is equivalent to FSE (fast spin echo; GE, Hitachi, 
Toshiba) 
d MPRAGE = magnetization prepared rapid gradient-echo (Siemens & Hitachi) is equivalent to 
the inversion recovery SPGR (IR-SPGR or Fast SPGR with inversion activated; GE), 3D turbo 
field echo (TFE; Philips), or 3D fast field echo (3D Fast FE; Toshiba). 
e A 3D acquisition without inversion preparation will result in different contrast compared with 
MPRAGE or another IR-prepped 3D T1-weighted sequences and therefore should be avoided. 
f In the event of significant patient motion, a radial acquisition scheme may be used (e.g. BLADE 
[Siemens], PROPELLER [GE], MultiVane [Philips], RADAR [Hitachi], or JET [Toshiba]); 
however, this acquisition scheme is can cause significant differences in ADC quantification and 

 
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137 
 
therefore should be used only if EPI is not an option. 
g For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TR = 5-15ms 
for similar contrast. 
h For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TI = 400-
450ms for similar contrast. 
i FOV and matrix size should be chosen to keep resolution at 1mm isotropic voxel size. Note that 
all voxel measurements should be equal in x, y, and z dimensions.  
 
 
Acronyms: 
Ax = Axial; ADC = apparent diffusion coefficient. FLAIR = fluid attenuated inversion recovery; 
DWI = diffusion-weighted imaging; 3D = three dimensional; TSE = turbo spin echo; EPI = echo 
planar imaging; MPRAGE = magnetization prepared rapid gradient-echo; A/P = anterior to 
posterior; R/L = right to left; NEX = number of excitations or averages; FOV = field of view 
 
1.5T Protocol: 
 
Ax FLAIR 
Ax DWI 
3D T1 Pre 
Contrast Injection a 
Ax T2 
3D T1 Postb 
Sequence 
TSEc – 
(turbo dark 
fluid) 
EPIf 
MPRAGEd,e 
TSEc 
MPRAGEd,e 
 
 
 
 
 
 
Plane 
Axial 
Axial 
Sagittal/Axial 
Axial 
Sagittal/Axial 
Mode 
2D 
2D 
3D 
2D 
3D 
TR [ms] 
>6000 
>5000 
2100g 
>3500 
2100g 
TE [ms] 
100-140 
Min 
Min 
100-120 
Min 
TI [ms] 
2200 
 
1100h 
 
1100h 
Flip Angle 
90/160 
90/180 
10-15 
90/180 
10-15 
Frequency 
256 
128 
172 
256 
172 
Phase 
256 
128 
172 
256 
172 
NEX 
1 
1 
1 
1 
1 
Frequency 
Direction 
A/P 
R/L 
A/P 
A/P 
A/P 
FOV 
240mm 
240mm 
256mm 
(for ≤1.5mm 
isotropic)j 
240mm 
256mm 
(for ≤1.5mm 
isotropic)j 
Slice 
Thickness 
4mm 
4mm 
1.5mmj 
4mm 
1.5mmj 
Gap/Spacing 
0 
0 
0 
0 
0 
Diffusion 
Optionsi 
 
b = 0, 500, 
and 1000 
s/mm2 
 
 
 
Parallel 
Imaging 
Up to 2x 
Up to 2x 
Up to 2x 
Up to 2x 
Up to 2x 
Scan Time 
(Approx) 
4-5 min 
3-5 min 
5-8 min 
3-5 min 
5-8 min 
a 0.1 mmol/kg or up to 20cc (single, full dose) of MR contrast. 
b Post-contrast 2D axial T1-weighted images should be collected with identical parameters to pre-

 
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138 
 
contrast 2D axial T1-weighted images 
c TSE = turbo spin echo (Siemens & Philips) is equivalent to FSE (fast spin echo; GE, Hitachi, 
Toshiba) 
d MPRAGE = magnetization prepared rapid gradient-echo (Siemens & Hitachi) is equivalent to 
the inversion recovery SPGR (IR-SPGR or Fast SPGR with inversion activated; GE), 3D turbo 
field echo (TFE; Philips), or 3D fast field echo (3D Fast FE; Toshiba). 
e A 3D acquisition without inversion preparation will result in different contrast compared with 
MPRAGE or another IR-prepped 3D T1-weighted sequences and therefore should be avoided. 
f In the event of significant patient motion, a radial acquisition scheme may be used (e.g. BLADE 
[Siemens], PROPELLER [GE], MultiVane [Philips], RADAR [Hitachi], or JET [Toshiba]); 
however, this acquisition scheme is can cause significant differences in ADC quantification and 
therefore should be used only if EPI is not an option. 
g For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TR = 5-15ms 
for similar contrast. 
h For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TI = 400-
450ms for similar contrast. 
i Older model MR scanners that are not capable of >2 b-values should use b = 0 and 1000 s/mm2. 
j FOV and matrix size should be chosen to keep resolution less than 1.5mm isotropic voxel size. 
Note that all voxel measurements should be equal in x, y, and z dimensions.  
 
Acronyms: 
Ax = Axial; ADC = apparent diffusion coefficient. FLAIR = fluid attenuated inversion recovery; 
DWI = diffusion-weighted imaging; 3D = three dimensional; TSE = turbo spin echo; EPI = echo 
planar imaging; MPRAGE = magnetization prepared rapid gradient-echo; A/P = anterior to 
posterior; R/L = right to left; NEX = number of excitations or averages; FOV = field of view 
 
ADVANCED MRI PROTOCOL: ANATOMIC + PERFUSION  
 
3D T1w Pre 
Ax 2D 
FLAIR 
Ax 2D DWI 
Pre-Load Contrast Injection a 
DSC Perfusionh 
Ax 2D T2w 
3D T1w Postb 
Sequence 
IR-GREd,e 
TSEc 
EPIf 
GE-EPI 
TSEc 
IR-GREd,e 
Plane 
Sagittal/Axial 
Axial 
Axial 
Axial 
Axial 
Axial/Sagittal 
Mode 
3D 
2D 
2D 
2D 
2D 
3D 
TR [ms] 
2100g 
>6000 
>5000 
1500 
>2500 
2100g 
TE [ms] 
Min 
100-140 
Min 
25-35 
80-120 
Min 
TI [ms] 
1100h 
2500 
 
 
 
1100h 
Flip Angle 
10º-15º 
90º/160
º 
90º/180º 
60º 
90º/160º 
10º-15º 
Frequency 
256 
256 
128 
128 
256 
256 
Phase 
256 
256 
128 
128 
256 
256 
NEX 
1 
1 
1 
>120 Reps; 
Inject after 45s 
of baseline data  
(>30 time 
points) 
1 
1 
FOV 
256mm 
240mm 
240mm 
240mm 
240mm 
256mm 
Slice 
Thickness 
1mm 
3mm 
3mm 
5mm 
3mm 
1mm 

 
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139 
 
Gap/Spacin
g 
0 
0 
0 
0-5mm 
0 
0 
Options/No
tes 
 
 
b = 0, 500, and 
1000 s/mm2 
3 directions 
 Cover tumor; 
18-20 Ga IV,  
right arm; 
3-5 mL/sec inj. 
rate 
 
 
Parallel 
Imaging 
Up to 2x 
Up to 2x 
Up to 2x 
Up to 2x 
Up to 2x 
Up to 2x 
Scan Time 
(Approx) 
5-8 min 
4-5 min 
3-5 min 
3 min 
7 min 
5-8 min 
 
a 0.05 mmol/kg (1/2 dose) preload should be injected 1-2 minutes prior to DSC MRI acquisition.  
b Post-contrast 3D T1-weighted images should be collected with equivalent parameters to pre-contrast 3D 
T1-weighted images 
c TSE = turbo spin echo (Siemens & Philips) is equivalent to FSE (fast spin echo; GE, Hitachi, Toshiba) 
d FL2D = two-dimensional fast low angle shot (FLASH; Siemens) is equivalent to the spoil gradient recalled 
echo (SPGR; GE) or T1- fast field echo (FFE; Philips), fast field echo (FastFE; Toshiba), or the 
radiofrequency spoiled steady state acquisition rewound gradient echo (RSSG; Hitachi). A fast gradient 
echo sequence without inversion preparation is desired.  
e MPRAGE = magnetization prepared rapid gradient-echo (Siemens & Hitachi) is equivalent to the 
inversion recovery SPGR (IR-SPGR or Fast SPGR with inversion activated; GE), 3D turbo field echo 
(TFE; Philips), or 3D fast field echo (3D Fast FE; Toshiba). 
f A 3D acquisition without inversion preparation will result in different contrast compared with MPRAGE 
or another IR-prepped 3D T1-weighted sequences and therefore should be avoided. 
g In the event of significant patient motion, a radial acquisition scheme may be used (e.g. BLADE 
[Siemens], PROPELLER [GE], MultiVane [Philips], RADAR [Hitachi], or JET [Toshiba]); however, 
this acquisition scheme is can cause significant differences in ADC quantification and therefore should 
be used only if EPI is not an option. Further, this type of acquisition takes considerable more time. 
h 0.05 mmol/kg dose injection at a rate of 3-5cc/sec. Maximize slice coverage to include the entire lesion 
as well as normal brain to the skull vertex.  The posterior fossa can be excluded from coverage if there 
are not enough slices to cover the entire brain. 
 
Acronyms: 
Ax = Axial; ADC = apparent diffusion coefficient. FLAIR = fluid attenuated inversion recovery; DWI = diffusion-weighted 
imaging; 3D = three dimensional; TSE = turbo spin echo; EPI = echo planar imaging; SS-EPI = single-shot echo planar imaging; 
GE-EPI = gradient echo echo planar imaging; 2DFL = two-dimensional FLASH (fast low angle shot) gradient recalled echo; 
MPRAGE = magnetization prepared rapid gradient-echo; A/P = anterior to posterior; R/L = right to left; NEX = number of 
excitations or averages; FOV = field of view; TE = echo time; TR = repetition time; TI = inversion time; PD = proton density; 
DSC = dynamic susceptibility contrast 
 
 
 
 
 
 

 
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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 
Intermediate 
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 
5 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 

 
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Valsartan 
80 mg daily 
None 
160 mg daily 
Yes, but not 
CYP450 
Selective  
β Blockers  
(BB) 
Metoprolol 
25 mg twice 
daily 
50 mg twice 
daily 
100 mg twice 
daily 
CYP 2D6 
substrate 
Atenolol 
25 mg daily 
50 mg daily 
100 mg daily 
No 
Acebutolol 
100 mg 
twice daily 
200-300 mg 
twice daily 
400 mg twice 
daily 
Yes (CYP450 
unknown) 
Bisoprolol 
2.5 mg daily 
5-10 mg daily 
20 mg daily 
CYP 3A4 
substrate 
α and β 
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 
Amolodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate 
Felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate 

 
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142 
 
 
APPENDIX H: 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 I: PATIENT HANDOUT 
 
 
 
 
 
 

 
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APPENDIX J: COLLECTION OF SPECIMENS 
 
Collection procedures described in this Appendix J apply to the ETCTN Biobanking and 
Molecular Characterization Initiative (WES) only 
 
Blood Sample Collection 
 
Whole blood samples will also be collected into 1 EDTA (purple-top) tube (10 mL) and 2 cell-
free DNA (cfDNA) Streck tubes (2 × 10 mL) to obtain plasma/peripheral blood mononuclear 
cells (PBMCs). 
 
Collection in EDTA (purple top) Tubes 
 
Collect blood in EDTA tube, and gently invert 5-10 times to mix.  Maintain specimens at 
ambient temperature (room temperature) during collection and transport.  Blood (10 mL) 
collected in an EDTA (purple top) tube will be processed for plasma and DNA per the 
standard operating procedure (SOP). 
 
Collection in Streck Tubes 
 
Collect blood in two cfDNA Streck tubes (10 mL), Cat No. 218992, and invert to mix.  
Note: blood must be thoroughly mixed to ensure preservation of specimen.  After 
collection, blood in cfDNA Streck tubes should never be refrigerated, as this will 
compromise the specimen.  Blood in cfDNA Streck tubes is stable at room temperature.  
These tubes will be shipped to the ETCTN Biorepository for further processing. Upon 
receipt at the ETCTN Biorepository, blood in cfDNA Streck tubes will be processed for 
plasma and DNA per the SOP. 
 
 
 
 

 
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APPENDIX K: TRACKING OF SPECIMENS 
 
Tracking procedures described in this Appendix K apply to the ETCTN Biobanking and 
Molecular Characterization Initiative (WES) 
 
Tracking of Specimens 
 
All biospecimens collected for this trial must be submitted using the ETCTN Rave Specimen 
Tracking System (STS) unless otherwise noted.  The system is accessed through special Rave 
user roles: “CRA Specimen Tracking” for data entry at the treating institutions and 
“Biorepository” for users receiving the specimens for processing and storage at reference labs 
and the Biorepository.  Please refer to the Medidata Account Activation and Study Invitation 
Acceptance link on the CTSU website under the Rave/DQP tab. 
 
Important:  Failure to complete required fields in STS may result in a delay in sample 
processing.  Any case reimbursements associated with sample submissions will not be credited 
if samples requiring STS submission are not logged into STS. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the software.   
 
For questions regarding the Specimen Tracking System, please contact the Theradex Help Desk 
at CTMSSupport@theradex.com. 
 
A shipping manifest must be included with all sample submissions. 
 
Overview of Process at Treating Site 
 
OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network (OPEN) 
system. OPEN communicates automatically with the Interactive Web Response System (IWRS) 
which handles identifier assignments, any study randomization and any prescribed slot 
assignments. If specimen analysis is required to determine eligibility, the protocol will be setup 
with multi-step registration. 
 
Registration without eligibility specimen analysis:  
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal 
Patient ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 
 
Any data entry errors made during enrollment should be corrected in Rave. 
 

 
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Rave Specimen Tracking Process Steps 
 
Step 1:  Complete the Histology and Disease form (but do not upload reports until a 
specimen label can be applied to them) and the Baseline forms regarding Prior 
Therapies. Enter the initial clinical specimen data:  
• Specimen Tracking Enrollment CRF:  Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, number of labels 
needed (include extra labels to apply to reports to be uploaded). CRF generates 
unique Specimen ID.  
 
Step 2:  Print labels using report in EDC and collect specimen. 
• Label specimen containers and write collection date on each label. 
• After collection, store labeled specimens as described in Section 9.  
• Apply an extra specimen label to each report before scanning. Return to the 
Histology and Disease form to upload any initial Pathology, Radiology, 
Molecular Reports (up to 4), Surgical reports and Pathology Verification form 
(when applicable). Return to Specimen Tracking Enrollment CRF to upload any 
molecular report (one per specimen) and/or specimen specific pathology or 
related report (one per specimen).   Uploaded reports should have PHI data like 
name, mailing address, medical record number or SSN redacted. Do not redact 
SPID, block number or relevant dates.  
 
Step 3:  Complete specimen data entry. 
• Specimen Transmittal Form: Enter Collection date and time and other required 
specimen details. 
 
Step 4:  When ready to ship, enter shipment information. 
• Shipping Status CRF:  Enter tracking number, your contact information, 
recipient, number of containers and ship date once for the 1st specimen in a 
shipment. 
• Copy Shipping CRF:  Select additional specimens to add to an existing shipment 
referenced by the tracking number. 
 
Step 5:  Print shipping list report and prepare to ship.  
• Print two copies of the shipping list, one to provide in the box, the other for your 
own records. 
• Print pathology or other required reports to include in the box. Be sure the printed 
copy includes the specimen label. 
 
Step 6:  Send email notification.  
• For only one of the specimens in the shipment, click “Send Email Alert” 
checkbox on the Shipping Status CRF to email recipient. 
 
Step 7:  Ship the specimen(s). 

 
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APPENDIX L: SHIPPING OF SPECIMENS TO THE ETCTN BIOREPOSITORY 
 
Shipping procedures described in this Appendix L apply to the ETCTN Biobanking and 
Molecular Characterization Initiative (WES) 
 
Shipping to the Biobank 
 
Tissue may be shipped in batches Monday through Wednesday, since the ETCTN Biorepository 
does not need to perform additional time-sensitive pre-analytic processing on them. 
 
Labeling of Specimens 
 
Tissue samples are to be labeled with: 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., FFPE Block, Formalin Fixed Tissue, Fresh Tissue in Media, 
etc.) 
• Tissue type (P for primary, M for metastatic or N for normal) 
• Surgical pathology ID (SPID) number   
• Block number from the corresponding pathology report (archival only) 
• Collection date (to be added by hand) 
 
Blood samples are to be labeled with: 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., blood, serum) 
• Collection date (to be added by hand) 
 
Example of Specimen Label 
 
The following image is an example of a tissue specimen label printed on a standard Avery label 
that is 1” high and 2.625” wide. 
 

 
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The QR code in the above example is for the Specimen ID shown on the second line.   
NOTE:  The QR code label is currently under development at Theradex as of 31-Aug-2018; 
therefore, labels generated by the STS for this study may not include a QR code. 
 
The second line item from the end includes four data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. The last alpha-numeric code is protocol specific and is only included if the protocol 
requires an additional special code classification 
 
The last line on the example label is for the handwritten date and optional time. 
 
Packing Instructions 
 
The shipment of all human tissue samples must comply with appropriate regulations as specified 
by the carrier.  Frozen samples should be sent on dry ice.  At a minimum, all samples must be 
packaged within two containers with absorbent material between containers to control any spill 
or leakage.  The outer container must be puncture resistant (e.g., cardboard mail tube, corrugated 
cardboard box).  A biohazard sticker must be affixed to both the inner and outer containers. 
 
1. Before packaging specimens verify that each specimen is labeled according to the 
instructions above and that the lids of all primary receptacles containing liquid are tightly 
sealed and wrapped in parafilm.  
2. Place samples into a biohazard envelope with absorbent material and seal the envelope 
securely.  
3. Place the biohazard envelope into a Tyvek envelope and seal securely.  
4. Place the sample(s) and a copy of the shipping manifest and corresponding pathology 
report (when applicable) into the insulated shipping container. 
5. Place the lid on top of the container. Close the outer flaps and tape shut. 
6. Attach a shipping label to the top of the shipping container. 
7. Place an Exempt Human Specimen sticker to the side of the container. 
8. Ship samples via overnight courier (FedEx preferred) to the address listed below. 
 

 
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Additional notes for specimen shipping 
 
Include a cold (not frozen) pack when shipping specimens during hot weather.  In winter months, 
please include extra insulation, such as bubble wrap inside the shipping container, to prevent 
specimens from freezing. 
 
When shipping slides, first place them in a plastic slide holder and stabilize by placing cotton or 
soft paper under the lid. Tape the lid so that is does not pop open during shipment (one piece of 
tape is sufficient). 
 
Forms to be Included in specimen shipping 
 
Copies of the following forms and reports are required to be included with all submissions of 
pathology materials: 
• The pathology report(s) on tumor from the most recent pre-diagnostic biopsy or surgery 
specimen(s). 
 
IMPORTANT NOTE:  Corresponding anatomical clinical pathology report MUST be 
submitted with the specimen for central confirmation of histology, or the sample will not be 
processed. This can be a prior pathology report on the same malignancy. 
• Reports on immunologic, immunohistochemical, or molecular studies, if performed on 
the pre-trial materials 
• A completed Sample Submission Form.  This form is to be submitted with tissue 
collected for research only  
• The Sample Tracking System (STS) generated shipping manifest 
NOTE:  The pathology report for the submitted biopsy material, if pathology review was 
performed locally, is required to be uploaded into Rave as soon as it is available. 
 
Shipping Address 
 
Ship the specimen collection to the address below using overnight courier (FedEx), early 
morning delivery option. 
 
ETCTN Biorepository  
Nationwide Children’s Hospital 
700 Children’s Dr., WA1340 
Columbus, OH 43205 
Phone: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred.  There is no central Courier 
account for this study.  Sites are responsible for all costs for overnight shipment per sample 
shipment to the ETCTN Biorepository, utilizing the site screening and base intervention 
payments.  

 
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NOTE:  The ETCTN Biorepository FedEx Account will not be provided to submitting 
institutions. 
 
Contact Information for Assistance 
 
For all queries, please use the contact information below: 
 
ETCTN Biorepository  
Toll-free Phone: (800) 347-2486 
E-mail:  BPCBank@nationwidechildrens.org  
 
 
 
 
 

 
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APPENDIX M: ASSAY INFORMATION 
 
Assays described in this Appendix M apply to the ETCTN Biobanking and Molecular 
Characterization Initiative. 
 
Next-generation sequencing assays (whole exome sequencing [WES] will be performed at the 
Molecular Characterization Laboratory on the purified DNA and RNA aliquots provided by the 
ETCTN Biorepository. 
 
DNA libraries will be generated using the Agilent SureSelect XT Target Enrichment System, and 
quantitated via digital droplet PCR (ddPCR).  Library samples are denatured, diluted and 
clustered on the cBot clonal amplification system in preparation for sequencing on the Illumina 
HiSeq 2500.