Conditions: Extensive Stage Lung Small Cell Carcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 9
Healthy volunteers: no

Brief summary:
This phase II trial studies how well olaparib, cediranib maleate, and standard chemotherapy work in treating patients with small cell lung cancer. Drugs used in chemotherapy, such as carboplatin, cisplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Olaparib and cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Olaparib, cediranib maleate, and standard chemotherapy may work better in treating patients with small cell lung cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine whether the addition of cediranib maleate (cediranib) plus olaparib as maintenance therapy, in patients with small cell lung cancer (SCLC) who have stable disease or better (non-progressive disease or non-PD) after initial therapy, leads to improved median progression-free survival (PFS), PFS is measured in months from the time of randomization to maintenance therapy (after completion of initial therapy), compared to standard therapy (no maintenance treatment.

SECONDARY OBJECTIVES:

I. To evaluate the impact of cediranib plus olaparib maintenance therapy on median overall survival (OS) in patients with SCLC who have non-PD after initial therapy.

II. To determine whether the addition of cediranib to cisplatin/carboplatin plus etoposide during initial therapy adds benefit to response rate, median PFS and median OS.

III. To assess safety and tolerability of the combination of cediranib plus olaparib during maintenance therapy.

IV. To evaluate potential biomarkers of clinical benefit to olaparib/cediranib combination, including tumor proteomic and genomic markers, and circulating levels of cytokines and angiogenic factors, that that may be associated with clinical benefit.

OUTLINE:

INITIAL THERAPY PHASE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive carboplatin intravenously (IV) over 60 minutes or cisplatin IV over 60 minutes on day 1 and etoposide IV over 60 minutes on days 1, 2, and 3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive treatment as in Arm I and also receive cediranib maleate orally (PO) once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

Patients in Arm I who have stable disease, partial, or a complete response are randomized to receive maintenance therapy or no maintenance therapy. Patients in Arm II are assigned to receive maintenance therapy.

MAINTENANCE THERAPY: Patients receive cediranib maleate PO QD and olaparib PO twice daily (BID) on days 1-28.

NO MAINTENANCE THERAPY: Patients are eligible to crossover to receive treatment with cediranib maleate and olaparib upon disease progression at the treating investigator's discretion.

After completion of study treatment, patients are followed up every 3-4 months for at least 1 year.

Arms:
arm 1: Patients receive carboplatin IV over 60 minutes or cisplatin IV over 60 minutes on day 1 and etoposide IV over 60 minutes on days 1, 2, and 3. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

Patients in Arm I who have stable disease, partial, or a complete response are randomized to receive maintenance therapy or no maintenance therapy. Patients in Arm II are assigned to receive maintenance therapy.

MAINTENANCE THERAPY: Patients receive cediranib maleate PO QD and olaparib PO BID on days 1-28.

NO MAINTENANCE THERAPY: Patients are eligible to crossover to receive treatment with cediranib maleate and olaparib upon disease progression at the treating investigator's discretion. arm 2: Patients receive treatment as in Arm I and also receive cediranib maleate PO QD on days 1-21. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive cediranib maleate PO QD and olaparib PO BID on days 1-28.

Interventions: intervention 1: Carboplatin intervention 2: Cediranib intervention 3: Cediranib Maleate intervention 4: Cisplatin intervention 5: Etoposide intervention 6: Olaparib
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO intervention 3: Given PO intervention 4: Given IV intervention 5: Given IV intervention 6: Given PO

Protocol document:
Prot_SAP_000.pdf: 
 
 
1 
 
SUMMARY OF CHANGES 
 
For Protocol Amendment #11 to: 9974  
 
NCI Protocol #: 9974 
Local Protocol #: 17-732 
 
NCI Version Date: 13 May 2019 
Protocol Date: 13 May 2019 
 
I. 
Protocol Changes following Request for Rapid Amendment  
 
# 
Section  
Page(s)  Change  
1 
ICD 
- 
The informed consent document was modified as a result of the 
CTEP RRA for Olaparib and latest version of the CAEPR.  
 
The protocol version date was also updated in the consent 
document.  
2 
Protocol 
document 
- 
The protocol version date was updated on the cover page and 
throughout the protocol document. Minor typographical revisions 
were made throughout the protocol document. These changes are 
tracked. 
3 
7.1 
69 
The Comprehensive Adverse Events and Potential Risks Lists 
(CAEPRs) were updated to reflect the latest CAEPR for Olaparib 
(Version 2.4, April 24, 2019). These changes are a result of the 
CTEP RRA for Olaparib. 
 
The following changes were made to the CAEPR:  
• Increase in Risk Attribution: 
• Changed to Rare but Serious from Also Reported on 
Cediranib 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.” 
 


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NCI Protocol #: 
9974 
 
Local Protocol #: 
17-732 
 
ClinicalTrials.gov Identifier:  NCT02899728 
 
TITLE:  A phase II study of olaparib plus cediranib in combination with standard therapy for 
small cell lung cancer 
 
Corresponding Organization: LAO-MA036 / Dana-Farber Harvard Cancer Center  
 
Principal Investigator: 
Jacob Sands, MD 
 
 
 
Dana-Farber Cancer Institute 
 
 
 
450 Brookline Avenue 
 
 
 
Boston, MA 02215 
 
 
 
 
Phone: 617-632-6049 
 
 
 
Fax: 617-632-6485 
 
 
 
Jacob_sands@dfci.harvard.edu  
 
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 
 
 
 


NCI Protocol #:9974 
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Study Coordinator: 
Sarah Clifford, MPH 
450 Brookline Avenue, LGGB 
Boston, MA 02215 
Phone: 617-632-5438 
Fax: 617-632-6485 
Sarahe_clifford@dfci.harvard.edu 
 
  
NCI-Supplied Agent(s):  Olaparib (AZD2281, NSC 747856), cediranib (AZD2171, NSC 
732208) 
 
Other Agent(s):  Cisplatin (Commercial), Carboplatin (Commercial), Etoposide (Commercial) 
 
IND Sponsor:  DCTD, NCI 
 
Protocol Type / Version # / Version Date: Original / Version 5 / 04 April 2017 
 
 
 
 
Amendment 3 / Version 6 / 03 October 2017 
 
 
 
 
Amendment 4 / Version 7 / 18 October 2017 
 
 
 
 
Amendment 6 / Version 8 / 21 May 2018 
 Amendment 7 / Version 9 / 31 Jul 2018 
Amendment 8  / Version 10 / 12 Oct 2018 
Amendment 9 / Version 11 / 11 Jan 2019 
Amendment 10 / Version 12 / 17 Jan 2019 
Amendment 11 / Version 13 / 13 May 2019 


NCI Protocol #:9974 
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SCHEMA 
 
 
 
OVERALL SCHEMA 
 
 
PLANNED OBJECTIVES 
        
 
  


NCI Protocol #:9974 
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TABLE OF CONTENTS 
 
SCHEMA ............................................................................................................................... 4 
1. 
OBJECTIVES .............................................................................................................. 8 
1.1 
Primary Objectives............................................................................................ 8 
1.2 
Secondary Objectives ........................................................................................ 8 
2. 
BACKGROUND ......................................................................................................... 8 
2.1 
Small Cell Lung Cancer .................................................................................... 8 
2.2 
CTEP IND Agents .......................................................................................... 11 
2.3 
Other Agents................................................................................................... 22 
2.4 
Correlative Studies Background....................................................................... 22 
3. 
PATIENT SELECTION ............................................................................................. 27 
3.1 
Eligibility Criteria ........................................................................................... 28 
3.2 
Exclusion Criteria ........................................................................................... 29 
3.3 
Inclusion of Women and Minorities ................................................................. 32 
4. 
REGISTRATION PROCEDURES ............................................................................. 32 
4.1 
Investigator and Research Associate Registration with CTEP ........................... 32 
4.2 
Site Registration.............................................................................................. 33 
4.3 
Patient Registration ......................................................................................... 35 
4.4 
General Guidelines.......................................................................................... 36 
5. 
TREATMENT PLAN ................................................................................................ 36 
5.1 
Agent Administration ...................................................................................... 36 
5.2 
General Concomitant Medication and Supportive Care Guidelines ................... 40 
5.3 
Duration of Therapy ........................................................................................ 45 
5.4 
Duration of Follow Up .................................................................................... 46 
6. 
DOSING DELAYS/DOSE MODIFICATIONS........................................................... 47 
6.1 
Dose Modification Guidelines ......................................................................... 47 
6.2 
Toxicity Management Guidelines .................................................................... 48 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS.......................... 63 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ............... 63 
7.2 
Adverse Event Characteristics ......................................................................... 71 
7.3 
Expedited Adverse Event Reporting ................................................................ 71 
7.4 
Routine Adverse Event Reporting.................................................................... 74 
7.5 
Reporting of Pregnancy and Overdose ............................................................. 74 
7.6 
Secondary Malignancy .................................................................................... 74 
7.7 
Second Malignancy......................................................................................... 74 
8. 
PHARMACEUTICAL INFORMATION .................................................................... 75 
8.1 
CTEP IND Agents .......................................................................................... 75 


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8.2 
Commercial Agents......................................................................................... 81 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ..................................... 84 
9.1 
Archival Tumor Tissue Collection - Exploratory/Ancillary Correlative 
Studies............................................................................................................ 84 
9.2 
Specimen requirements ................................................................................... 84 
9.3 
Blood-Based Exploratory/Ancillary Correlative Studies ................................... 92 
9.4 
Fresh Tumor Tissue Collection - Exploratory/Ancillary Correlative 
Studies............................................................................................................ 95 
10. 
STUDY CALENDAR ................................................................................................ 96 
11. 
MEASUREMENT OF EFFECT ............................................................................... 101 
11.1 
Antitumor Effect – Solid Tumors................................................................... 101 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ................................................................................................... 107 
12.1 
Study Oversight ............................................................................................ 107 
12.2 
Data Reporting.............................................................................................. 108 
12.3 
CTEP Multicenter Guidelines ........................................................................ 110 
12.4 
Collaborative Agreements Language ............................................................. 110 
12.5 
Genomic Data Sharing Plan........................................................................... 111 
13. 
STATISTICAL CONSIDERATIONS....................................................................... 111 
13.1 
Study Design/Endpoints ................................................................................ 112 
13.2 
Sample Size/Accrual Rate ............................................................................. 114 
13.3 
Stratification Factors ..................................................................................... 115 
13.4 
Analysis of Secondary Endpoints................................................................... 115 
13.5 
Reporting and Exclusions .............................................................................. 116 
REFERENCES.................................................................................................................... 118 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ............................................ 126 
APPENDIX B      PATIENT DRUG INFORMATION HANDOUT AND 
WALLET CARD ..................................................................................................... 127 
APPENDIX C 
OLAPARIB PATIENT DRUG INFORMATION 
HANDOUT AND WALLET CARD......................................................................... 129 
APPENDIX D  
CONCOMITANT MEDICATIONS ................................................... 131 
APPENDIX E 
CEDIRANIB AND OLAPARIB DRUG DIARY ................................ 133 
APPENDIX F 
CEDIRANIB DRUG DIARY............................................................. 135 
APPENDIX G 
ORAL ANTIHYPERTENSIVE MEDICATIONS............................... 136 


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APPENDIX H 
Blood pressure diary .......................................................................... 138 
Appendix I Diarrhea Management........................................................................................ 140 
 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
To determine whether the addition of cediranib plus olaparib as maintenance therapy, in patients 
with small cell lung cancer (SCLC) who have stable disease or better (non-progressive disease or 
non-PD) after initial therapy, leads to improved median progression-free survival (PFS).   PFS is 
measured in months from the time of randomization to maintenance therapy (after completion of 
initial therapy), compared to standard therapy (no maintenance treatment).   
 
1.2 
Secondary Objectives 
 
To evaluate the impact of cediranib plus olaparib maintenance therapy on median overall 
survival (OS) in patients with SCLC who have non-PD after initial therapy.  The groups 
compared are 1) those randomized to EP and subsequently randomized to OC 
maintenance and 2) those randomized to EP and subsequently randomized to no 
maintenance. 
 
To determine whether the addition of cediranib to cisplatin/carboplatin plus etoposide 
during initial therapy adds benefit to response rate, median PFS and median OS.  PFS and 
OS are measured in months from the time of randomization to initial therapy.  The groups 
compared are 1) those randomized to EPC followed by maintenance and 2) those 
randomized to EP initial therapy AND subsequently randomized to OC maintenance 
therapy. 
 
To assess safety and tolerability of the combination of cediranib plus olaparib during 
maintenance therapy. 
 
To evaluate potential biomarkers of clinical benefit to olaparib/cediranib combination, 
including tumor proteomic and genomic markers, and circulating levels of cytokines and 
angiogenic factors, that that may be associated with clinical benefit. 
 
2. BACKGROUND 
 
2.1 
Small Cell Lung Cancer 
 
Lung cancer is the leading cause of cancer-related death in the United States and more people die 
of lung cancer than from breast, colon, and prostate cancer combined(1). SCLC is an aggressive 
tumor that represents approximately 13 percent of all lung cancer in the US(2). This disease has 
a dismal outcome that has improved only marginally in the last 30 years(3). Although it is a 
chemotherapy- and radiotherapy-sensitive tumor, SCLC continues to show very high rates of 
relapse and metastasis, resulting in a very poor prognosis.  The high propensity for metastases 
and poor outcomes in this tumor type underscore the need to develop therapies with more 
durable benefit and that may block not only tumor growth, but also invasion and the 
development of distant metastases. 
 


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Angiogenesis inhibitors have been studied in SCLC with this goal in mind and have had 
encouraging hints of activity. Several angiogenesis inhibitors have shown a significant stable 
disease rate as later line therapy, including pazopanib (52% stable disease [SD] rate)(4), sunitinib 
(30% SD rate)(5), and cediranib (36% SD rate)(6). Tyrosine kinase inhibitors (TKIs) have also 
demonstrated promising activity in SCLC when given in combination with chemotherapy or in 
the maintenance setting. In a phase I study, we found that cediranib, a TKI targeting VEGFR, 
PDGFR, and c-KIT, was tolerable when given at a dose of 20 mg or 30 mg daily in combination 
with etoposide and cisplatin (EP). The combination was found to have an objective response rate 
(ORR) in excess of 70 percent and a PFS rate of 8.9 months in SCLC patients receiving 20 mg 
daily(7) (Heymach et al, in preparation). A similar TKI, sunitinib, was found to be safe and to 
significantly prolong PFS when used as maintenance therapy after EP chemotherapy with a 
median PFS of 3.7 months for sunitinib vs. 2.1 months for placebo (PFS HR 1.62, P=0.02)(8).   
A trend toward longer overall survival was also demonstrated in limited-stage SCLC patients in a 
trial of vandetanib maintenance after chemotherapy (HR 0.45, one sided P=0.07)(9). 
 
There are currently no validated biomarkers for VEGFR TKIs in routine clinical use, although 
several promising candidates have been identified.  We and others have shown that circulating 
levels of plasma cytokines and angiogenic factors (CAFs) as well as germline genetic variations 
in angiogenic and inflammatory genes may be predictive markers for benefit or the emergence of 
therapeutic resistance(10-14). Notably, through the testing and validation using samples from 
two randomized placebo controlled studies of the VEGFR TKI pazopanib, an agent with a 
similar spectrum as cediranib, we identified IL-6 as a predictive marker of benefit for 
pazopanib(10).  This included validation studied using CLIA-certified assays. We have also 
identified plasma HGF and bFGF as markers associated with the emergence of therapeutic 
resistance from patients treated with chemotherapy plus bevacizumab(11) and circulating VEGF 
as predictive marker of PFS benefit for the VEGFR TKI vandetanib(12).  Germline genetic 
variations have also been associated with response and toxicities after treatment with 
bevacizumab(13). 
 
Proteomic profiling was performed on a large panel of SCLC cell lines which led to the 
observation that PARP1 and several other DNA repair proteins are expressed at high levels in 
SCLC(15).  PARP1 over-expression was confirmed in patient tumors at the protein level by 
immunohistochemistry (IHC) and at the mRNA level.  Based on this finding, several PARP 
inhibitors were tested in pre-clinical models of SCLC.  Olaparib, rucaparib, and talazoparib 
(previously BMN-673) all demonstrated striking single agent activity in a majority of SCLC cell 
lines tested.  Furthermore, the addition of a PARP inhibitor to standard chemotherapies (e.g., 
cisplatin, etoposide and/or topotecan) and radiation further potentiated their effect(15, 16).  In 
animal models including xenografts and patient-derived xenografts (PDXs), talazoparib has 
demonstrated significant anti-tumor activity as a single agent, comparable or superior to 
cisplatin(17),(18).   Based on these observations, several clinical trials were initiated to 
investigate the effects of PARP inhibition in SCLC patients.  In the first study to complete 
enrollment, single-agent talazoparib (BMN-673) was tested in patients with platinum-sensitive 
SCLC relapse (NCT01286987).  Preliminary data demonstrated 2 out of 23 patients with 
RECIST confirmed partial responses (PRs) and 3 out of 23 with SD > 24 weeks (clinical benefit 
rate of 25%).  More than half of patients treated had some tumor volume reduction as their best 
response(19). Currently, there are two studies investigating the use of veliparib (ABT-888) in 


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combination with standard frontline chemotherapy (NCT01642251 and NCT02289690).  E2511 
(NCT01642251) is a phase I/II trial of cisplatin, etoposide, and veliparib in treatment naïve 
SCLC patients.  Phase I data from this study support the safety and tolerability of the 
combination, with partial or complete responses observed in 5 out of 7 evaluable patients(20).   
 
To date, the activity of PARP inhibitors is best established in cancers with mutations in 
BRCA1/2 and other DNA repair genes that result in synthetic lethality in the setting of PARP 
inhibition.  In fact, olaparib monotherapy was FDA approved last year for patients with advanced 
BRCA-mutated ovarian cancer. In SCLC, their mechanism of action and identification of 
potential PARP inhibitor biomarkers is an area of active investigation.  Likely the universal loss 
of RB1, with resulting dependence on E2F1, plays a role.  It has been demonstrated that 
expression levels of several DNA repair proteins – both individually and as a “DNA repair 
signature” – are associated with response in pre-clinical models of lung cancer(21).      
 
Rationale for combination of angiogenesis inhibition with PARP inhibition in SCLC 
 
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(22), 
resulting in p53 accumulation and eventual apoptosis; p53-deficient tumors suppressed the 
apoptotic effect, promoting tumor survival in spite of the hypoxic state(23).  However, despite 
the presence of DSB markers such as histone gH2AX, there is little evidence of DNA damage 
during the hypoxic state, and gH2AX staining is atypical (diffuse rather than punctate), though 
severe hypoxia may result in aberrant replication complexes, single-strand breaks, and regions of 
single-stranded DNA(24).  After re-oxygenation, double-strand breaks are noted to accumulate, 
and tumor survival is dependent upon intact DNA repair complexes(25).  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 
downregulation(26, 27).  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(28).  Exposure to PARP inhibitors or PARP-1 
RNAi downregulated BRCA1 and RAD51 expression in a dose-dependent manner, regardless of 
oxygenation, and the addition of hypoxic conditions to PARP inhibition enhanced the 
downregulatory 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, gH2AX 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 gH2AX foci(29).  Small interfering RNA (siRNA) 
knockdown of the replication stress-induced ataxia teleangiectasia mutated kinase (ATM)- and 


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Rad3-related kinase (ATR) pathway, but not the ATM pathway, inhibited gH2AX formation, 
and siRNA knockdown of gH2AX significantly decreased growth factor-induced proliferation 
and fetal calf serum-induced HUVEC proliferation under hypoxic conditions.  PARP inhibition 
(via the specific small-molecule inhibitor GPI 15427) inhibited angiogenesis in matrigel in vitro 
(30).  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 1a (HIF-1α) induction by the hypoxia mimetic agent CoCl2, 
indicating that PARP inhibition’s effects on migration were not exerted through influencing HIF-
1a function. 
 
Collectively, the evidence indicates that anti-angiogenic therapy may complement PARP 
inhibition, and 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. 
 
Given the striking clinical benefit of this combination seen in ovarian cancer, the known clinical 
activity of anti-angiogenic agents in SCLC as well as the potential activity of PARP inhibition in 
SCLC based on pre-clinical data and emerging clinical data, there is potential for improved 
efficacy with the combination of these two classes of drugs in SCLC as well.  The effect of 
combination olaparib plus cediranib as maintenance therapy following first-line chemotherapy (± 
cediranib) for extensive-stage SCLC will be evaluated to determine whether synergistic 
prolongation of PFS is possible in SCLC, a tumor type with 60-80 percent responses to first-line 
chemotherapy but PFS of only 3 months post-first line treatment. 
 
2.2 
CTEP IND Agents 
 
2.2.1 Cediranib (AZD2171) 
 
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 administered small molecule vascular endothelial growth 
factor (VEGF) receptor TKI with anti-angiogenic properties (31, 32). 
 
Investigators should be familiar with the current cediranib IB.  
 
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 (33). 
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) (34). VEGFR-1 and VEGFR-2 signaling help 
mediate tumor progression. Cediranib has been developed as a potent inhibitor of 
VEGFR-1 and VEGFR-232. Cediranib also has activity against VEGFR-3 and c-Kit. 


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Cediranib is expected, with chronic oral dosing, to inhibit VEGF-driven angiogenesis 
and as a result prevent the progression and metastasis of solid tumors, and may have 
broad-spectrum clinical utility. 
 
2.2.1.2 
Summary of Non-Clinical Efficacy Studies 
 
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 orally 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. 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 receptor 
TKI 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. 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. 
 
A full description of non-clinical efficacy studies can be found in the current version 
of the cediranib IB.   
 
2.2.1.3 
Summary of Non-Clinical Pharmacology and Toxicology 
 
Nonclinical pharmacology and toxicology company-sponsored studies have been 
conducted in rats, dogs, and cynomolgus monkeys. 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 and intravenous (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 


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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. 
 
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 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 non-clinical studies. 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. 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. 
 
A full description of non-clinical pharmacology and toxicology can be found in the 
current version of the cediranib IB. 
 
2.2.1.4 
Summary of Clinical Pharmacokinetics 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 half-life (t1/2) of 12.1 ± 2.2 hours. 
 
Preliminary information on blood biomarkers in glioblastoma patients indicates that 
plasma VEGF, placental growth factor (PLGF), and stromal cell-derived factor 1α 


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(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(35). 
 
Additional information on the relationship between clinical outcome and biomarkers 
has been reported for a DCTD-sponsored trial(36). Changes in vascular 
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 eduction in Ktrans after one dose of cediranib was seen in patients with 
increased PFS (P=0.0015) and 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(6). A 
stark increase in CECs was noted at progression in several patients. 
 
A full description of clinical pharmacokinetics and pharmacodynamics can be found 
in the current version of the cediranib IB. 
 
 
2.2.1.5 
Clinical Experience 
 
AstraZeneca has sponsored 15 phase I studies of cediranib (single-agent or in 
combination with gefitinib, either FOLFOX, irinotecan [±cetuximab], pemetrexed or 
docetaxel, etoposide/cisplatin, or lomustine), 8 phase 2 studies (single-agent, or in 
combination with fulvestran, FOLFOX, or paclitaxel/carboplatin), one phase 2/3 
study (cediranib plus bevacizumab), and two phase 3 studies (cediranib plus 
FOLFOX or XELOX and cediranib plus lomustine). Details of the studies, responses, 
and safety assessments are summarized in the Cediranib Investigator’s Brochure. 
 
Cediranib has been administered to patients in 38 DCTD, NCI-sponsored clinical 
trials. Complete responses (CRs) and partial responses (PRs) have been reported in 
clinical trials of cediranib in solid tumors such as NSCLC(37), renal cell carcinoma 
(RCC)(38), prostate(39), mesothelioma(40), and gynecologic tumors (41, 42). 
 
The maximum tolerated dose (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. Cediranib 
was then administered at 45 mg/day in a post-radiation setting, and in addition to the 
expected AEs of hypertension, fatigue and 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 


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chemoradiotherapy was CR in two patients, PR in 20 patients, and stable disease (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(35). Median PFS 
was 117 days, and median OS was 227 days. Additionally, cediranib alleviated brain 
edema, a major cause of morbidity in glioblastoma patients(35). DLTs were observed 
in 9 of the 16 patients with hypertension; fatigue and diarrhea were seen most often. 
 
Two phase II 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(43, 44). Grade 3 AEs were 
observed in 93% of patients receiving 45 mg/day. 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 
SD44. 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 (41). 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 ≥351. 
Grade 2 hypothyroidism occurred in 43% of patients. 
 
Preliminary information from 60 patients in a phase II trial of cediranib in persistent 
ovarian, peritoneal, or fallopian tube cancer has been reported(42). Patients were 
divided into those whose disease was found to be platinum-resistant and those whose 
disease was platinum-sensitive in a prior therapy regimen. Response and prolonged 
SD rate was 41% for platinum-sensitive and 29% for platinum-resistant patients, 
respectively. In the platinum-sensitive group, there were two confirmed PRs and one 
unconfirmed PR, while one unconfirmed PR was observed in the platinum resistant 
arm. Median time to progression (TTP) and median survival for all patients was 4.1 
months and 11.9 months, respectively, with no significant differences between the 
platinum-sensitive and -resistant groups. The most frequent AEs were fatigue, 
diarrhea, hypertension, and anorexia, while hypertension and fatigue were the most 


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frequent grade 3 or higher AEs. Sixteen patients required dose reduction to 30 mg and 
20 mg. 
 
Information on 59 patients in a trial of cediranib in metastatic androgen-independent 
prostate cancer has been reported(39). 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(38). 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 II trial in small cell lung cancer (SCLC), in 
which one unconfirmed PR and eight SD were noted(6). 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. 
 
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)(37). 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. 
 
2.2.1.6 
Adverse Events and Recommended Dosing 
 
The most frequently reported AEs for cediranib on company-sponsored trials were 
fatigue, diarrhea, nausea, vomiting, hoarseness, hand-foot syndrome, and 
hypertension. 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 


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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 (82). 
 
 
2.2.2 Olaparib (AZD2281) 
 
Olaparib is an inhibitor of the polyadenosine 5’ diphosphoribose [poly(ADP-ribose)] 
polymerase enzymes, PARP-1 (IC50 = 5nM), PARP-2 (IC50 = 1nM), and PARP-3 (IC50 
= 4nM), which is being developed as an oral monotherapy (including maintenance) as 
well as for combination therapy with chemotherapy, ionizing radiation and other anti-
cancer agents including novel agents and immunotherapy. 
 
Investigators should be familiar with the current olaparib IB.  
 
2.2.2.1 
Mechanism of Action 
 
PARP enzymes are involved in post-translational modification of histones and other 
nuclear proteins that contribute to the survival of cells following DNA damage and 
are essential for repairing DNA single strand breaks. PARP inhibition is a novel 
approach to targeting tumors with deficiencies in DNA repair mechanisms, as 
inhibition of PARPs leads to the persistence of single strand breaks, which can then 
be converted to the more serious DNA double strand breaks during the process of 
DNA replication. In normal cells, these double strand breaks can be efficiently 
repaired during cell division by homologous recombination repair (HR).  HR is a 
process involving ATM (a major DNA double strand break signaling kinase, the 
‘MRN’ nuclease protein complex; including Meiotic Recombination 11Homolog A 
[MRE11A], human RAD50 homolog [RAD50], and other homologous recombination 
DNA repair proteins such as RAD51, BRCA1 and BRCA2). Tumors exhibiting HR 
deficiencies (HRD), such as serous ovarian cancers and other tumor types with 
mutations in genes such as BRCA1/2, RAD51C, RAD51D, ATR, ATM, or Fanconi 
Anemia pathway members, cannot accurately repair the DNA damage, which may 
become lethal to cells as DNA damage accumulates. In these tumor types, olaparib 
may offer a potentially efficacious and less toxic cancer treatment compared with 
currently available chemotherapy regimens.  
 
2.2.2.2 
Summary of Non-Clinical Efficacy Studies 
 
Pre-clinical studies show cytotoxicity and anti-tumor activity following treatment 
with olaparib in cell lines and mouse tumor models with deficiencies in BRCA 53 as 
well as primary explant models and BRCA knock-out models, either as monotherapy 


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or in combination with established chemotherapies. Cytotoxicity of olaparib may 
involve inhibition of PARP enzymatic activity in addition to increased formation of 
PARP-DNA complexes, resulting in disruption of cellular homeostasis and cell death.  
PARP inhibitors such as olaparib may also enhance the DNA damaging effects of 
chemotherapy(45-47).  Non-clinical studies looking at combinations of olaparib with 
chemotherapies such as alkylating agents, topoisomerase I inhibitors, platinum agents 
and taxanes, have additive to synergistic effects. For example, attenuation of PARP 
activity by PARP inhibitors leads to the chemopotentiation of topotecan, irinotecan 
and cisplatin cytotoxicity in both in vitro and in vivo models(45, 48-52). These 
studies highlight the importance of olaparib both as monotherapy and as part of 
combination therapy.   
 
A full description of non-clinical efficacy studies can be found in the current version 
of the olaparib IB. 
 
 
2.2.2.3 
Summary of Non-Clinical Toxicology 
 
In repeat dose oral toxicity studies of up to six months duration in rats and dogs, the 
principal target organ for toxicity was the bone marrow, with associated changes in 
peripheral hematology parameters.  All changes showed full or partial recovery 
following withdrawal of olaparib. These effects of olaparib may be related to the 
pharmacology and mechanism of action of olaparib as an inhibitor of PARP-1 and 
PARP-2, as PARP-2 has been shown to play a role in hematopoietic stem/progenitor 
cell survival in both steady-state conditions and in response to stress(53). 
 
In an Ames bacterial mutation test, olaparib was not mutagenic, but was clastogenic 
in an in vitro CHO chromosome aberration test. Oral dosing of olaparib also induced 
micronuclei in bone marrow of rats. These findings are consistent with genomic 
instability resulting from the primary pharmacology of olaparib. 
 
In reproductive toxicology studies in rats, there were no adverse effects on male 
fertility following oral dosing of olaparib prior to mating.  In female rats, conception 
rates were unaffected by pre- and peri-conception dosing.  However, embryo-fetal 
survival was decreased and administration of olaparib during organogenesis had an 
adverse effect on embryo-fetal survival and increased major fetal malformations at 
dose levels that were not maternally toxic. These effects on embryo-fetal 
development are considered to be related to the pharmacology of olaparib.  Exposures 
in the both the repeat dose and reproductive toxicology studies were generally below 
those achieved at the clinically therapeutic doses of 400 mg BID olaparib (capsule) 
and 300 mg BID (tablet). 
 
Combination studies performed in rats suggest the potential for olaparib to exacerbate 
the effects of temozolomide and topotecan; however olaparib in combination with 
these anti-cancer agents did not induce any additional target organ toxicities 
compared to those seen with single agents. 


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A full description of non-clinical toxicology can be found in the current version of the 
olaparib IB. 
 
 
2.2.2.4 
Summary of Clinical Pharmacokinetics 
 
Oral absorption of olaparib is rapid with peak plasma concentrations typically 
achieved between one and three hours after dosing. No marked accumulation was 
found with multiple dosing (accumulation ratio of 1.4-1.5 for twice daily dosing), 
with steady state exposures achieved within three to four days. Limited data suggests 
that systemic exposure (AUC) of olaparib increases less than proportionally with 
doses over a range of 100 to 400 mg, though PK data were variable across clinical 
trials. Co-administration with a high fat meal slowed the rate of absorption (Tmax 
delayed by 2 hours), but did not significantly alter the extent of olaparib absorption 
(mean AUC increased by approximately 20%). 
 
Olaparib has a mean apparent volume of distribution at steady state of 167 ± 196 L 
after a single 400 mg dose. The in vitro protein binding at plasma concentrations 
achieved after 400 mg twice daily dosing is approximately 82%. Olaparib is 
metabolized primarily by CYP3A4. After a single 400 mg dose of olaparib, a mean 
terminal plasma t1/2 of 11.9 ± 4.8 hours and apparent plasma clearance of 8.6 ± 7.1 
L/h were observed. 
 
A full description of clinical pharmacokinetics can be found in the current version of 
the olaparib IB. 
 
 
2.2.2.5 
Summary of Clinical Experience 
 
Olaparib has undergone a number of Phase I, II, and III clinical trials in a variety of 
tumor types enriched for those with HR deficiency, including BRCA- mutated 
cancers.  Specifically, monotherapy studies have focused on BRCA1/2 associated 
ovarian cancer, BRCA1/2 associated breast cancer, a number of phase I studies in 
solid tumors, and phase II and III studies in BRCA mutated pancreatic cancer and 
MSI positive colorectal cancer.  A number of Phase I and II clinical trials of olaparib 
in combination with chemotherapy and targeted agents including cisplatin, topotecan, 
gemcitabine, paclitaxel, and bevacizumab are currently ongoing or completed.   
 
As of 15 December 2016, approximately 6558 patients are estimated to have received 
olaparib in the clinical programme including AstraZeneca-sponsored studies (3923 
patients), a MAP (676 patients), ISSs and collaborative group studies (1959 patients). 
An estimated 4475 patients with ovarian, breast, pancreatic, gastric and a variety of 
other solid tumours are estimated to have received treatment with olaparib in 
AstraZeneca-sponsored, interventional studies (3799 patients) and the MAP (676 
patients). Since 2012/2013, most new clinical studies have utilized the tablet 


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formulation which was designed to deliver the therapeutic dose of olaparib in fewer 
dose units than the capsule. Of the 4475 patients, 2109 received the capsule 
formulation, 2341 received the tablet formulation, and 25 received both capsule and 
tablet. In the AstraZeneca-sponsored, interventional studies, olaparib was given either 
as monotherapy (2618 patients) or in combination with chemotherapy or other anti-
cancer agents, including studies where patients received monotherapy and 
combination therapy sequentially (n=1181). 
 
Data from the available pre-clinical studies and subsequent clinical development 
programme demonstrate that olaparib appears to be active and generally well 
tolerated in patients with solid tumors including those with BRCA mutated cancers. 
In ovarian cancer, responses have been seen in all patient groups, including platinum 
resistant and refractory cancer. 
 
From the available data to date in patients with advanced cancer, there is no evidence 
of any unexpected toxicity following long-term olaparib (capsule) monotherapy 
exposure. 
 
Adverse laboratory findings and/or clinical diagnoses considered to be associated 
with administration of olaparib monotherapy include haematological effects 
(anaemia, neutropenia, lymphopenia, thrombocytopenia, MCV elevation and increase 
in blood creatinine), nausea and vomiting, decreased appetite, diarrhoea, dyspepsia, 
stomatitis, upper abdominal pain, dysgeusia, fatigue (including asthenia), headache 
and dizziness. Most of these events were generally mild or moderate in intensity. 
 
In a relatively small number of patients, pneumonitis, MDS/AML and new primary 
malignancies have been observed. Evidence from across the development programme 
for olaparib does not support a conclusion that there is a causal relationship between 
olaparib and these events. These are important potential risks for olaparib and are 
being kept under close surveillance. 
 
Data from studies of olaparib in combination with various chemotherapy agents 
indicate an increase in bone marrow toxicity (anaemia, neutropenia, 
thrombocytopenia) greater than expected if the agents had been administered alone. 
The effects are generally transient but treatment delays are common and alternative 
administration schedules/toxicity management processes are currently being 
evaluated within some of these studies. When this type of toxicity has occurred it has 
been managed by routine clinical practice including dose delays, dose reductions, 
intermittent dosing and/or the use of supportive care measures, including 
G-CSF. Currently, all ongoing olaparib combination studies are being closely 
monitored for myelotoxicity. Results of a Phase II study in combination with 
carboplatin/paclitaxel (Study D0810C00041) showed that addition of olaparib to 
carboplatin AUC 4 + paclitaxel in the chemotherapy phase had a generally similar 
tolerability profile to carboplatin AUC 6 + paclitaxel. The regimen of olaparib 
capsules 200 mg bd for 10 days out of 21, with carboplatin AUC 4 + paclitaxel had 
an acceptable and manageable tolerability profile in patients with recurrent serous 


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ovarian cancer. Olaparib tolerability during the monotherapy maintenance phase was 
consistent with the previously known safety and tolerability profile. 
 
In Study D0810C00039 and Study D081BC00004, olaparib 100 mg tablet bd in 
combination with weekly paclitaxel 80 mg/m2 was well tolerated, with no new 
unexpected safety findings. In both studies, the incidence of neutropenia was higher 
for the olaparib combination arm and this contributed to higher rates of dose 
modifications for patients on olaparib compared to placebo. In Study D081BC00004, 
there was also a higher incidence of anaemia on the olaparib + paclitaxel combination 
arm than on the placebo + paclitaxel arm and more dose interruptions, reductions and 
discontinuations (81). 
 
A full description of most recent IP clinical data can be found in the current version 
of the olaparib IB 
 
2.2.3 Combination Cediranib and Olaparib 
 
NCI protocol 8348 included a phase I component that established the recommended 
phase II dosing (RP2D) of cediranib in combination with olaparib in the capsule 
formulation. This phase I enrolled a total of 28 patients (20 ovarian, 8 breast)(54). 
 
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 RP2D was 
declared to be cediranib 30 mg QD and olaparib 200 mg BID64. 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 RECIST criteria, version 1.164. 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, 
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 


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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 I-T component. Six doses of 
cediranib and olaparib tablets were explored (number of patients on each dose level in 
parentheses): 
• Cediranib 20 mg daily / Olaparib 200 mg BID (3) 
• Cediranib 20 mg daily / Olaparib 250 mg BID (3) 
• Cediranib 20 mg daily / Olaparib 300 mg BID (6) 
• Cediranib 30 mg daily / Olaparib 150 mg BID (3) 
• Cediranib 30 mg daily / Olaparib 200 mg BID (6) 
• Cediranib 30 mg daily / Olaparib 250 mg BID (3) 
 
Three DLTs were observed across all patients enrolled to 8348 Phase 1-T; one DLT in 
the six patients on cediranib 30 mg/olaparib 200 mg, and two DLTs in the two patients on 
cediranib 30 mg/olaparib 250 mg. The RP2D was therefore concluded to be cediranib 20 
mg daily and olaparib tablets 300 mg BID or cediranib 30 mg daily and olaparib tablets 
200 mg 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 20 mg/olaparib 300 mg dosing 
and one CR and two PRs in the six patients on the cediranib 30 mg/olaparib 200 mg 
dosing. To preserve uniformity of cediranib dosing with prior clinical trial experience, the 
dose of cediranib 30 mg daily and olaparib tablet 200 mg BID will be further explored in 
this study. 
 
2.3 
Other Agents 
 
Please reference the individual FDA package inserts for carboplatin, cisplatin, and etoposide for 
background information. Agents will be administered per standard of care guidelines in 
accordance with institutional standards and the FDA prescribing information. 
 
2.4 
Correlative Studies Background 
 
2.4.1 Tumor PARP Immunohistochemistry 
 
Based on pre-clinical analysis of lung tumors and cell lines, it’s hypothesized that 
patients with elevated PARP1 protein expression by immunohistochemistry (IHC) will 
have greater susceptibility to PARP inhibitor therapy, and that patients whose tumors 
have high PARP1 expression will have superior outcome when treated with olaparib.  In 
a previous study of lung cancer, the greatest in vitro activity of PARP inhibitors was 
observed in SCLC models and this was associated with significantly higher PARP1 
protein levels in both pre-clinical models of SCLC and SCLC clinical specimens(3).   
 
It is predicted that high PARP1 expression levels by IHC may be a biomarker of PARP 
inhibitor sensitivity in lung cancer. It is expected that those patients with elevated PARP1 
protein levels will demonstrate a superior outcome when treated with olaparib. The 


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outcome data in patients with PARP1 H-scores above 200 (high PARP1) or below 200 
(low PARP1) in the olaparib-treated patients will be compared.  H-scores will be 
calculated based on the intensity of IHC staining (0-3) times the percentage of tumor cells 
staining positive (as previously described15). As there is not an established threshold for 
PARP1 positivity, an exploratory analysis looking at the association of PARP1 
expression (H-score) as a continuous variable and PARP1 expression intensity as a 
categorical variable based (0, 1+, 2+, 3+) with relevant clinical endpoints (e.g., response, 
PFS, OS) will also be performed.  As an alternative to IHC (depending on available 
tissue/profiling data), PARP1 levels could be assessed at the mRNA level, as correlation 
between protein and mRNA levels has previously been shown. 
 
More recently, SLFN11 has emerged as an important predictive biomarker of response to 
PARP inhibition including with olaparib in SCLC models, with loss of SLFN11 
conferring resistance to PARP inhibition (55, 56).  In patient-derived xenografts, high 
SLFN11 (by H-score) was associated with response to PARP inhibition and treatment 
with PARP inhibitors resulted in a decrease in SLFN11 levels suggesting regulation of 
SLFN11 expression by PARP (56).  
 
2.4.2 Plasma Angiome Analysis 
 
To date, the effort to identify candidate predictive blood-based markers for anti-
angiogenic inhibitors has been challenging for many reasons. These include biological 
complexity, limitations of available reagents, limited sample collection in most trials, and 
a lack of randomization, which is needed to deal with the potential confounding of 
prognostic and predictive markers. Many of these barriers have now been overcome.  
Compared to tissue-based biomarkers, blood-based biomarkers have the significant 
advantages of low cost, universal applicability, and the ability to be followed over the 
course of a patient’s treatment.   By focusing on soluble factors of known biological 
relevance, further scientific, diagnostic, and therapeutic efforts are greatly facilitated.   
 
Recently, a multiplex ELISA approach has identified several strong candidate predictors 
of benefit from bevacizumab(57-59).  This approach was also used to identify IL-6 as a 
strong candidate predictive biomarker for anti-VEGF therapy in renal cell carcinoma.  
This marker was found to be a predictive marker in two independent phase III studies, 
each of which used a different VEGF inhibitor(10). Numerous other inflammatory 
mediators have been shown to regulate tumor angiogenesis and sensitivity to anti-VEGF 
therapy(60, 61). Tumor angiogenesis, inflammation, and anti-tumor immunity have 
highly interconnected biologies, a topic that has been extensively reviewed(62-64). 
However, to date, these factors have not been systematically interrogated in most anti-
VEGF therapy trials. Analysis of the role of inflammation in mediating resistance to anti-
VEGF therapy is now highly clinically relevant, particularly since most of these factors 
are now targetable in the clinic with agents either FDA approved or in clinical trials.   
 
The application of multiplex ELISA approaches in clinical samples is rapidly evolving, 
having only recently shown positive results. Many of the analytes in the planned 
multiplex array were developed specifically for this use and have been carefully 


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optimized for performance in plasma and serum samples from cancer patients. The 
approach utilizes the Searchlight™ platform from Aushon BioSystems Incorporated. The 
specific panel design is depicted in Table 1 below.  All antibody pairs have been 
validated to limit cross-reactivity and optimal dilutions were identified for every panel.  
Specific blocking buffers were identified, cross-reactivity of antibodies was tested and 
non-specific binding was minimized. Preliminary testing and plate validation were 
performed by independent laboratory groups. Freeze/thaw stability tests were done for all 
individual analytes. Lastly, assay performance across the different tissue types (citrated 
plasma, EDTA plasma and serum) was evaluated. 
 
 
Table 1: Plasma-based marker identification 
Soluble 
Angiogenic 
Factors 
Matrix-
Derived  
Factors 
Markers of 
Vascular 
Activation and 
Inflammation 
ANG-2 
PDGF-BB 
sEndoglin 
CRP 
bFGF 
PlGF 
Osteopontin 
ICAM-1 
HGF 
VEGF-A 
TGFβ1 
IL-6 
IGFBP1 
VEGF-D 
TGFβ2 
PAI-1 Active 
IGFBP2 
sVEGFR1 
TGFβ RIII 
PAI-1 Total 
IGFBP3 
sVEGFR2 
TIMP1 
SDF-1 
PDGF-AA sVEGFR3 
TSP2 
VCAM-1 
 
This approach is technically robust and readily adaptable to clinical practice. As this data 
will be derived from patients, even preliminary data may significantly improve 
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 pre-
clinical models. It is anticipated that through collection of blood based biomarkers, 
candidate markers of benefit that are specific for anti-angiogenic agents will be identified 
and validated and will offer multiple prognostic factors.  
 
Baseline, post-1 cycle of therapy, post-1 cycle of maintenance therapy (or corollary time 
point for no maintenance cohort) and progression levels will be quantified and change 
from baseline will be determined for all analytes at the desired time points.  Blood 
analytes will be correlated with PFS and/or OS.   
 
2.4.3 Whole Exome Sequencing and Whole Transcriptome Sequencing 
 
The Broad Institute has, to date, generated a total of over 2,500 x 1012 bases (2,500 
Terabases) of sequence data using next-generation sequencing (NGS). The Broad 
Institute has substantial experience with whole exome sequencing (WES), and in fact 
invented one of the most commonly used approaches available today(65).  The protocol 
involves generating tens of thousands of 120-mer oligonucleotides on solid arrays, 
cleaving them from the array and converting them into single-stranded, biotin-labeled 


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RNA “baits” to drive hybridization through high concentration. This protocol has been 
licensed to Agilent, and this method has now been used in more than 500 publications. 
 
The sequencing platform of the Broad Institute boasts 50 Illumina HiSeq instruments and 
10 MiSeqs, for an average capacity of 2.1 Terabytes (spanning 6192 flow cells) per day. 
The whole-exome panel includes: 18,557 genes (selected from RefSeq CDS) comprising 
185,915 exons and 33 Mb of target.  These targets are covered by 277,944 oligo “baits.” 
A new exome-wide bait set is being adapted that allows more even sequence coverage 
per capture reaction; this innovation will allow the sequencing of clinical tumor samples 
to a sufficient overall mean coverage, while preserving the overall sensitivity and 
specificity of variant calling. 
 
To perform WES, nucleic acid (DNA and RNA) will be obtained from circulating free 
DNA or tumor tissue using standard operating procedures in common use at the Broad 
Institute. For clinical tumor specimens, a “high-coverage” sequencing approach will be 
utilized, which should yield an average coverage of 150-200 fold; paired normal DNA 
will be sequenced to a depth of approximately 80-100-fold. WES data will be analyzed 
for base mutations, small insertions/deletions, and copy number alterations. 
 
In parallel, the Broad Genomics Platform will perform whole transcriptome sequencing. 
The Broad Genomics Platform has extensive experience with whole transcriptome 
sequencing from both frozen and FFPE tumor samples. Regarding the latter, 
transcriptome capture is an alternative to traditional transcript enrichment methods 
(including polyA selection and ribosomal depletion) that is optimal for low-input and 
de¬graded samples including formalin-fixed paraffin-embedded (FFPE) tissues. The 
approach first prepares a stranded cDNA library from isolated RNA, then hybridizes the 
library to a set of DNA oligonucleotide probes to enrich the library for mRNA transcript 
fragments. Transcriptome Capture targets 21,415 genes, representing 98.3% of the 
RefSeq exome. In biological scenarios this assay has achieved expected results. For 
example, in one patient tumor at three time points, the third time point manifested robust 
KRAS amplification in the DNA that had concomitant over-expression of KRAS in the 
RNA from that same tumor.  
 
WES of tumor tissue (as available) and tumor-derived circulating free DNA (cfDNA) 
from blood will be used to evaluate whether there are genomic alterations that may be 
associated with improved PFS with the combination of olaparib plus cediranib 
maintenance therapy or with standard therapy.  The data gathered from comparisons of 
germline and tumor DNA will also permit single nucleotide polymorphism (SNP) 
profiling.  SNP analysis will be performed to identify germline SNPs in angiogenesis 
gene and DNA repair genes associated with improved PFS. 
 
2.4.4 Whole Exome Sequencing from Circulating Free DNA 
 
Dr. Love and colleagues in concert with the Broad Institute initiatives under Dr. 
Garraway have demonstrated that accurate and powered WES  of circulating tumor cells 
(CTCs) is both possible and likely useful clinically(66).   This was first established in 


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experimental and analytical workflows for census-based sequencing of single CTCs and 
then validated in patients with metastatic prostate cancer. The approach is currently being 
validated in other tumor types including SCLC.  This same approach is also being 
extended to the sequencing of tumor-derived cfDNA.   
 
Blood sample collections will occur at baseline, after cycle 1, after cycle 2, after cycle 1 
of maintenance therapy (or corollary time point in no maintenance cohort), cycle 3 day 1 
of maintenance therapy, and at the time of progression.  Each blood sample would be 
processed for CTCs, cfDNA, and germline DNA. The extraction of cfDNA and germline 
DNA will be performed from frozen aliquots of plasma and white blood cells, 
respectively. The yields and purities of cfDNA will be assessed prior to WES. It has been 
recently demonstrated that the yield and purity of cfDNA from a set of previously 
collected SCLC plasma samples is adequate for sequencing (25-30%) with variance in 
the quantity through the course of therapy.  DNA samples will be subjected to the same 
WES analysis at the Broad Institute described in Section 2.4.3.  In addition to evaluating 
genomic alterations in DNA extracted from blood, the findings will be compared to 
parallel sequencing analysis done on tissue biopsies from the same subjects to compare 
similarities and any potential differences.  This analysis will help us to determine whether 
cfDNA sequencing may be a possible substitute for tissue-based sequencing which would 
be critical particularly in this tumor type given the difficulty in obtaining adequate tissue 
for molecular analysis.  We will also evaluate quantitative changes in tumor-derived 
cfDNA through the course of therapy to determine correlation with tumor burden.   
 
2.4.5 BROCA-HR 
 
In order to respond to a PARP inhibitor, cancer cells need to be deficient in homologous 
repair (HR) mechanisms but also proficient in the alternative error prone non-
homologous end joining (NHEJ) DNA repair pathway(67, 68). Loss of HR is not by itself 
sufficient for PARP inhibitor sensitivity, and an accurate predictor of PARP inhibitor 
responsiveness could require assessment of many components of both the HR and NHEJ 
pathways. A more efficient assay, which would not require a prior knowledge of the 
critical elements in these DNA repair pathways, would instead measure DNA repair 
capacity.  
 
BROCA is a targeted capture and massively parallel sequencing assay that is capable of 
identify all classes of mutations including gene rearrangements(69, 70). Using BROCA, 
Walsh et al demonstrated that nearly one-fourth of women with ovarian carcinoma have 
germline loss of function mutations in at least 12 genes(69).  Furthermore, most of these 
genes are in the BRCA-FA pathway. After BRCA1/2, the most common genes mutated 
in women with ovarian cancer are BRIP1 (FANCJ), RAD51D, RAD51C (FANCO), and 
PALB2 (FANCN)(69, 71).  Pennington et al applied BROCA to detect somatic mutations 
in tumor DNA from 363 women with ovarian carcinoma. Combining germline and 
somatic mutations increased the fraction of cases identified with HRD to 31%, including 
23% with germline and 9% with somatic mutations in FA/HR genes (and 1% with both 
somatic and germline mutations). The presence of either a germline or somatic FA/HR 
mutation is highly predictive of an improved primary response to platinum chemotherapy 


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(p<0.0005) and longer overall survival (p=.001)(72). Germline and somatic loss of 
function mutations were identified in all of the 13 FA/HR genes evaluated.  
 
Dr. Swisher’s laboratory has designed a new version of BROCA (BROCA-HR) that 
includes many additional DNA repair genes (75 total genes) as well as 3000 SNPs. 
Similar sequencing accuracy and sensitivity sequencing DNA is obtained from FFPE, 
fresh blood and flash frozen specimens. BROCA-HR includes genes that are targets of 
both somatic and germline mutations. The BROCA-HR includes genes that regulate HR 
or NHEJ that if mutated, could mediate resistance to PARP inhibitors such as 
TP53BP1(73-75).  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=75) 
a. FA-BRCA HR pathway: ATM, ATR, BABAM1, BAP1, BARD1, BLM, BRCA1, 
BRCA2 (FANCD1), BRIP1 (FANCJ), BRCC3, BRE, CHEK1, CHEK2, ERCC1, 
ERCC4 (FANCQ), FAM175A (abraxas), FANCA, FANCB, FANCC, FANCD2,  
FANCE, FANCF, FANCG (XRCCC9), FANCI, FANCL, FAMCM, GEN1, MRE11A, 
NBN, PALB2 (FANCO), RAD50, RAD51C (FANCO), RAD51D, RBBP8 (CtIP), SLX4 
(FANCP), UIMC1 (RAP80), XRCC2  
b. DNA mismatch repair: MLH1, MSH2 (and EPCAM), MSH6, PMS2  
c. Other DNA repair, surveillance genes, or modifier genes: CDK12, CDH4, HELQ, 
NEIL1, PPM1D, POLD1, POLE, RIF1, TP53, ID4, PAXIP1, POLQ, RINT1, 
TP53BP1, USP28, WRN, XRCC3 
d. NER genes: ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, DDB1, XPA, XPC  
e. NHEJ genes: DCLRE1C, LIG4, PRKDC, TOBP1, XRCC4, XRCC5, XRCC6  
f. PI3K pathway: PTEN, PI3KCA 
 
BROCA-HR analysis will be used to determine whether there are alterations in DNA 
repair genes that characterize a state of HR deficiency that is associated with improved 
PFS with olaparib plus cediranib combination maintenance therapy as compared with 
standard no maintenance therapy. 
 
2.4.6 Circulating Tumor Cells for Cell Derived Xenograft Models 
 
Participants enrolling to this trial will also be offered participation in a companion study 
from the NCI for blood collection to generate novel cell lines and cell-derived xenografts 
at the National Cancer Institute (NCI). This separate companion protocol (NCI 9846) will 
allow expeditious collection of samples that are essential to allow generation of patient-
derived models and cell lines, which must be derived from fresh, viable tissue for further 
study of SCLC. 
 
3.   PATIENT SELECTION 
 


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3.1 
Eligibility Criteria  
3.1.1 Histologically or cytologically confirmed diagnosis of extensive-stage small cell lung 
cancer with no prior systemic treatment. 
 
3.1.2 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for 
non-nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) with 
conventional techniques or as ≥10 mm (≥1 cm) with spiral CT scan, MRI, or calipers 
by clinical exam.  See Section 11 for the evaluation of measurable disease. 
 
3.1.3 Age ≥18 years. Because no dosing or adverse event data are currently available on the 
use of cediranib in combination with carboplatin/cisplatin plus etoposide or cediranib 
plus olaparib in patients <18 years of age, children are excluded from this study, but 
will be eligible for future pediatric trials. 
 
3.1.4 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.5 Patients must have normal organ and marrow function within 28 days prior to 
administration of therapy as defined below: 
 
− 
White blood cell count (WBC) 
≥ 3 × 109/L  
− 
No features suggestive of MDS/AML on peripheral blood smear 
− 
Absolute neutrophil count 
≥1,500/mcL 
− 
Platelets 
≥100,000/mcL 
− 
Hemoglobin 
≥ 10 g/dL with no blood transfusion within 28 days of 
initiation of therapy. 
− 
Total bilirubin 
≤ 1.5 × institutional upper limit of normal (ULN) 
− 
AST(SGOT)/ALT(SGPT) 
≤ 2.5 × institutional ULN, unless liver metastases are 
present and then ≤ 5 × institutional ULN is acceptable 
− 
Creatinine clearance 
≥ 50 mL/min  
- 
Proteinuria  
 
 
 
 
 Urine protein:creatinine ratio (UPC) of ≤ 1 OR ≤ 2+ 
proteinuria on two consecutive urinalysis/dipstick tests 
taken no less than 1 week apart. Patients with 2+ 
proteinuria on dipstick must also have a UPC of ≤ 0.5 
on 2 consecutive samples.  
 
3.1.6 Ability to swallow and retain oral medication. 
 


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29 
 
3.1.7 The effects of olaparib and cediranib on the developing human fetus are unknown.  
For this reason and because other therapeutic agents used in this trial are known to be 
teratogenic, women of child-bearing potential and male patients and their partners who 
are sexually active must agree to use two highly effective forms of contraception in 
combination (see olaparib IB page 161-162 for acceptable methods) for the duration of 
study participation and for 3 months after completion of olaparib and cediranib 
administration.  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.     
3.1.8 Postmenopausal or evidence of non-pregnant status for women of childbearing potential 
as confirmed by a negative urine or serum pregnancy test within 7 days prior to the start 
of therapy.  Postmenopausal status is defined as:  
 
--age ≥60 years, or 
--age <60 with any one or more of the conditions below: 
--amenorrheic for ≥1 year in the absence of chemotherapy and/or hormonal   
treatments, 
--luteinizing hormone and/or follicle stimulating hormone and/or estradiol levels in 
the post-menopausal range, 
--radiation-induced oophorectomy with last menses >1 year ago, 
--chemotherapy-induced menopause with >1 year interval since last menses, 
--surgical sterilization (bilateral oophorectomy or hysterectomy). 
 
3.1.9 Ability to understand and the willingness to sign a written informed consent document. 
 
3.1.10 Participants must have archival tumor tissue available for analysis (minimum 20 5 um 
slide) or be able to undergo a baseline fresh tumor tissue biopsy.  
3.1.11 Adequately controlled blood pressure.  (defined as systolic blood pressure [SBP] of < 
140mmHg and diastolic blood pressure [DBP] of < 90mmHg) on maximum of three 
antihypertensive medications.  Participants must have a blood pressure (BP) of < 
140/90 taken in the clinic or hospital setting by a medical professional within 2 weeks 
prior to starting on study.    It is strongly recommended that participants who are on 3 
antihypertensive medications be followed by a cardiologist or a primary care physician 
for management of BP while on study.  
 
3.1.12 Adequately controlled thyroid function, with no symptoms of thyroid dysfunction. 
 Patients can be on thyroid hormone replacement medication. Asymptomatic patients 
 with elevated TSH with normal T4/T3 are allowed to enroll, and recommended to 
 follow with routine thyroid function test. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who have had major surgery or trauma within 28 days prior to entering the 
study.  Patients must have recovered from any effects of any major surgery and 
surgical wound should have healed prior to starting treatment. 
 


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3.2.2 Patients who have had radiotherapy within 14 days prior to entering the study. 
 
3.2.3 Patients with a non-healing wound, fracture, or ulcer. 
 
3.2.4 Patients who have not recovered from adverse events due to prior anti-cancer therapy 
(i.e., have residual toxicities > CTCAE Grade 1 or baseline, with the exception of 
alopecia). 
 
3.2.5 Patients who are receiving any other investigational agents. 
 
3.2.6 Patients with symptomatic central nervous system (CNS) metastases or 
leptomeningeal carcinomatosis should be excluded from this clinical trial because of 
their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse 
events. Exceptions include patients with previously-treated CNS metastases or those 
with asymptomatic, subcentimeter metastases, and have no requirement for steroids or 
anti-seizure medication for at least one week prior to study entry. Screening with CNS 
imaging studies (CT scan or MRI) is required. 
 
3.2.7 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to olaparib, cediranib, carboplatin, cisplatin, or etoposide. 
 
3.2.8 Patients with a history of myelodysplastic syndrome (MDS). 
 
3.2.9 Patients with a history of acute myeloid leukemia (AML), or patients with a history of 
any other primary malignancy within 3 years prior to initiation of treatment on this 
study. Exceptions include: patients with a history of malignancies (other than AML) 
that were treated curatively and have not recurred within 3 years prior to study entry; 
resected basal and squamous cell carcinomas of the skin; and completely resected 
carcinoma in situ of any type. 
 
3.2.10 Patients with clinically significant gastrointestinal abnormalities including, but not 
limited to:  
• Clinically significant signs and/or symptoms of bowel obstruction within 3 
months prior to starting treatment. 
• History of intra-abdominal abscess within 3 months prior to starting treatment. 
• History of GI perforation within 6 months prior to starting treatment 
• Evidence of abdominal fistula within 6 months prior to starting treatment. 
History of abdominal fistula will be considered eligible if the fistula was 
surgically repaired, and there has been no evidence of fistula for at least 6 
months prior to starting treatment, and patient is deemed to be at low risk of 
recurrent fistula. 
 
 


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31 
 
3.2.11 Patients with a history of cerebrovascular accident including transient ischemic attack 
(TIA), pulmonary embolism or insufficiently treated deep venous thrombosis (DVT) 
within the past 3 months.  Note: Participants with recent DVT who have been treated 
with therapeutic anti-coagulants for at least 6 weeks are eligible, with the exception of 
participants being treated with warfarin, which is prohibited on this study.  Other oral 
anti-coagulants may be allowed after discussion with overall PI, but short half-life low 
molecular weight heparins are strongly preferred. 
 
3.2.12 Patients with evidence of active bleeding diathesis. 
 
3.2.13 Patients with hemoptysis in excess of 2.5 mL within 6 weeks prior to the first dose of 
study medication. 
 
3.2.14 Patients receiving any medications or substances that are potent inhibitors or inducers 
of CYP3A4 are ineligible.  The required washout period for strong inhibitors is 2 
weeks and at least one week for moderate inhibitors.  The required washout period 
prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 4 weeks for 
other agents, because the lists of these agents are constantly changing, it is important 
to regularly consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/; medical reference texts such as the 
Physicians’ Desk Reference may also provide this information.  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. 
Details regarding concomitant medication administration are located in Section 5.3. 
 
3.2.15 Patients requiring concomitant therapy with phenytoin, phenobarbital, carbamazepine, 
or valproic acid. 
 
3.2.16 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.  Specifically, patients with any of the following within 6 months 
prior to starting treatment are excluded: 
• Acute myocardial infarction 
• Unstable angina 
• New York Heart Association functional classification of III or IV. 
• Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) per 
institutional guidelines, or <55% 
• Prior allogeneic bone marrow transplant or double umbilical cord blood 
transplantation 
• Patients with active hepatitis (B or C) 
• Patients with active pneumonitis 
 


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32 
 
3.2.17 Pregnant women are excluded from this study because olaparib and cediranib are 
agents with the potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with olaparib or cediranib, breastfeeding should be 
discontinued if the mother is treated with olaparib or cediranib. These potential risks 
may also apply to other agents used in this study. 
3.2.18 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with olaparib and cediranib.  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. 
3.2.19 Patients must be willing and able to check and record daily blood pressure readings if 
 
receiving cediranib. 
 
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.   
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
4.1.1 CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
 
Registration requires the submission of: 
 
• a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• a current Curriculum Vitae (CV) 
• a completed and signed Supplemental Investigator Data Form (IDF) 
• a completed Financial Disclosure Form (FDF) with an original signature 
 


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33 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm. 
 
For questions about Investigator Registration, please contact the CTEP Investigator 
Registration Help Desk by email at pmbregpend@ctep.nci.nih.gov. 
 
4.1.2 CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only.  (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
 
An active CTEP-IAM user account is required to access all CTEP applications and, if 
applicable (e.g., all Network trials), all Cancer Trials Support Unit (CTSU) applications 
and websites. 
 
Additional information can be found on the CTEP website at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm. 
 
For questions about Associate Registration or CTEP-IAM Account Creation, please 
contact the CTEP Associate Registration Help Desk by email at 
ctepreghelp@ctep.nci.nih.gov. 
 
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: an active Federal Wide 
Assurance (FWA) number, an active roster affiliation with the Lead Network or a participating 
organization, a valid IRB approval, and compliance with all protocol specific requirements. 
 
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 


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34 
 
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 9974 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 folder to expand, then select LAO-MA036, 
and protocol # 9974. 
• 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 9974 Site Registration: 
 
• CTSU Transmittal Sheet (optional)  
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted) 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will 
be entered and tracked in the CTSU RSS.   


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35 
 
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 1100 
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 
 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
For trials with slot reservation requirements, OPEN will connect to IWRS at enrollment 
initiation to check slot availability.  Registration staff should ensure that a slot is 
available and secured for the patient before completing an enrollment. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  


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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 or request slot reservations:  Be on an ETCTN Corresponding 
or Participating Organization roster with the role of Registrar. 
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• 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 Patient Enrollment Instructions   
 
n/a 
 
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 Slot Reservations and Cohort Management User Guide, which 
is available on the Theradex website: 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11 This 
link to the Theradex website is also on the CTSU website OPEN tab. For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk at 609-619-7802 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 5 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.  Reported adverse events and potential 


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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. Bisphosphonate use is permitted. 
Participants receiving maintenance therapy may be permitted to have palliative radiation therapy 
on a case-by-case basis following discussion with the site investigator.  
 
Patients will be randomized prior to initial therapy to receive cisplatin/carboplatin and etoposide 
alone, or cisplatin/carboplatin and etoposide in combination with cediranib. The decision to use 
cisplatin or carboplatin will be left to the treating investigator; however the decision of which 
platinum agent to use should be made prior to the initial randomization. Randomization will 
occur in a 2:1 ratio such that two-thirds of the participants will be randomized to receive 
cisplatin/carboplatin and etoposide alone. 
 
Following completion of four cycles of initial therapy, participants who were randomized to 
receive cisplatin/carboplatin and etoposide alone and have stable disease, partial, or a complete 
response will be randomized equally to receive either no maintenance therapy or maintenance 
therapy with cediranib plus olaparib. Participants who received cediranib during the initial 
therapy phase will be directly assigned to receive maintenance therapy with cediranib and 
olaparib following initial therapy.  
 
Participants who do not receive maintenance therapy will be eligible to crossover to receive 
treatment with cediranib plus olaparib upon disease progression at the treating investigator’s 
discretion.  Because of the extremely limited efficacy of 2nd line regimens for SCLC, the 1st 
recommendation by NCCN guidelines is participation in a clinical trial. Response rates following 
disease progression after initial therapy for SCLC vary between 0-20% (i.e. 20% RR to 
topotecan for chemotherapy-sensitive patients, but < 5% RR for those who are chemotherapy-
resistant) with PFS to 2nd line therapy varying between 1-4 months.  Cediranib in the 
maintenance setting in a small trial conducted by Heymach and colleagues had an improved PFS 
compared to historical controls and the combination of cediranib + olaparib in other tumor types 
has been demonstrated to be synergistic in improving PFS (Liu et al., 2013).  Overall, given the 
preclinical rationale for the combination for efficacy (as detailed in the protocol) as well as 
clinical data from other tumor types, we feel this combination is a reasonable strategy to offer 
patients with progression on 1st line therapy in the context of this clinical trial (where response 
and outcomes may be systematically evaluated).  
 
 
Randomization to maintenance/no maintenance therapy should occur within two weeks of 
completion of initial therapy and follow-up radiation, which will include consolidation thoracic 
radiation ± prophylactic cranial irradiation as appropriate. If both thoracic and cranial irradiation 
are performed, they should be performed concurrently. Maintenance therapy should begin when 
radiation-associated toxicity has resolved to CTCAE ≤ grade 1 or baseline (with the exception of 
alopecia).   Treatment should start no sooner than 3 weeks and no later than 6 weeks after 
completion of radiation therapy. A new baseline scan should be obtained at the start of 
maintenance therapy. 
 


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Table 2: Regimen Description – Initial Therapy Phase 
Agent 
Premedications; Precautions 
Dose* Route Schedule 
Cycle 
Length 
Number of 
Cycles 
Cediranib§ 
Patients should fast for 2 
hours before and 1 hour after 
each dose.  
20 mg 
Oral 
Daily 
21 days 
(3 
weeks) 
4 
Cisplatin∂ 
As per institutional standards 
75 
mg/m2 
IV 
Day 1 
Carboplatin∂ As per institutional standards AUC 6 
IV 
Day 1 
Etoposide 
As per institutional standards 
100 
mg/m2 
IV 
Days 1, 2, 
3 
*: Body Surface Area (BSA) to be calculated per institutional standards 
§: Cediranib will only be given to patients randomized to the cediranib treatment arm 
∂: Either cisplatin or carboplatin may be given at the treating investigator’s discretion 
 
Table 3: Regimen Description – Maintenance Phase 
Agent 
Premedications; Precautions 
Dose Route Schedule 
Cycle 
Length 
Cediranib Patients should fast for 2 hours before and 1 
hour after each dose 
30 mg Oral 
Daily 
28 days 
(4 weeks) 
Olaparib 
Tablets can be taken by mouth with a light 
meal/snack 
200 
mg 
Oral 
Twice 
daily 
 
Participants will be requested to maintain a study medication diary that will indicate each dose of 
oral medication taken to illustrate treatment compliance. The medication diary should be 
returned to appropriate research staff for review at the end of each treatment cycle. 
5.1.1 Cediranib 
 
Cediranib is available as a beige film-coated tablet containing 20 mg or 15 mg of 
cediranib. Patients can be administered cediranib study treatment tablets orally at a dose 
of 30 mg or 20 mg once daily (od).  Subjects who are randomized to receive cediranib 
during the initial therapy phase will take cediranib at the dose of 20 mg by mouth daily 
each day of the 21 day cycle for four cycles. Following the initial therapy phase, patients 
receiving cediranib plus olaparib as maintenance therapy will receive cediranib at 30 mg 
(2 x 15mg tablets) by mouth daily each day of the 28 day maintenance cycles. Cediranib 
will be given each morning on an empty stomach, patients should be instructed to fast for 
a minimum of two hours before each dose and continue to fast for one hour after each 
dose. Cediranib should be taken with a glass of water. Doses should be taken 
approximately 24 hours apart. A missed dose may be taken up to two hours after the 
regularly scheduled dosing time. Doses outside of this time frame should be considered 
missed and should not be taken. Patients should be instructed to swallow cediranib 
whole; it should not be chewed, crushed, or dissolved. A vomited dose should not be 
retaken; instead participants should be instructed to continue with their next regularly 
scheduled dose as clinically appropriate. 


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One x 20 mg and 1 x 15 mg tablets is used to manage dose reductions 
 
Please see Section 5.2 for concomitant medication and supportive care guidelines. 
 
5.1.2 Olaparib 
 
Olaparib is available as a film-coated tablet containing 150 mg or 100 mg of olaparib. 
Patients can be administered olaparib study treatment tablets orally at a dose of 200 mg 
twice daily (bd).  Patients randomized to receive olaparib plus cediranib as maintenance 
therapy will take olaparib at 200 mg (2 x 100mg tablets) by mouth twice daily each day 
of the 28 day maintenance cycle. Patients should be instructed that they may take 
olaparib with a light meal or snack. Doses should be taken approximately 12 hours apart. 
A missed dose may be taken up to two hours after the regularly scheduled dosing time. 
Doses outside of this time frame should be considered missed and should not be taken. 
Patients should be instructed to swallow olaparib whole; it should not be chewed, 
crushed, or dissolved. A vomited dose should not be retaken; instead participants should 
be instructed to continue with their next regularly scheduled dose as clinically 
appropriate. As cediranib must be taken on an empty stomach, for participants 
randomized to combination therapy, they will be advised to take the Cediranib as soon as 
they wake up (fasting) and then 1 hour afterwards take the olaparib with breakfast or a 
snack.  Alternatively, if this is a difficult schedule, taking olaparib with breakfast/light 
snack followed by cediranib 2 hours later is also permitted to maintain fasting dosing of 
cediranib. At night (12 hours after olaparib morning dose) they would take the olaparib 
with a snack or light meal. 
 
One x 150 mg and 1 x 100 mg tablets is used to manage dose reductions. 
 
Participants should be instructed to avoid consuming grapefruit and grapefruit juice while 
on study. Please see Section 5.2 for concomitant medication and supportive care 
guidelines. 
 
5.1.3 Cisplatin 
 
Either cisplatin or carboplatin will be given to all participants during the initial therapy 
phase on day 1 of each 21 day cycle for four cycles. The decision to use cisplatin or 
carboplatin will be left to the treating investigator. Participants who receive cisplatin will 
receive it at a dose of 75 mg/m2 IV in 0.9% NaCl over 60 minutes. BSA calculations and 
recalculation of the dose at the start of each subsequent cycle due to changes in the 
participant’s weight should be performed per institutional standards. Cisplatin will be 
given as per institutional policies and the FDA prescribing information.  
 
Hypersensitivity reactions have been reported in patients who have received cisplatin. 
The reactions typically consist of facial edema, wheezing, tachycardia, and hypotension 
within a few minutes of drug administration. Reactions may be controlled by intravenous 
epinephrine with corticosteroids and/or antihistamines as indicated. Patients receiving 


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cisplatin should be observed carefully for possible anaphylactic-like reactions and 
supportive equipment and medication should be available to treat such a complication. 
 
5.1.4 Carboplatin 
 
Either cisplatin or carboplatin will be given to all participants during the initial therapy 
phase on day 1 of each 21 day cycle for four cycles. The decision to use cisplatin or 
carboplatin will be left to the treating investigator. Participants who receive carboplatin 
will receive it IV at a dose of AUC 6 in 0.9% NaCl over 60 minutes. All dosing 
calculations should be performed per institutional standards. Carboplatin will be given as 
per institutional policies and the FDA prescribing information.  
 
Hypersensitivity to carboplatin has been reported in 2 percent of patients. These allergic 
reactions have been similar in nature and severity to those reported with other platinum-
containing compounds, i.e., rash, urticaria, erythema, pruritus, and rarely bronchospasm 
and hypotension. Anaphylactic reactions have been reported as part of post-marketing 
surveillance. These reactions have been successfully managed with standard epinephrine, 
corticosteroid, and antihistamine therapy. Please see FDA prescribing information. 
 
5.1.5 Etoposide 
 
Etoposide will be given to all participants during the initial therapy phase on days 1, 2, 
and 3 of each 21 day cycle for four cycles. Participants will receive etoposide at a dose of 
100 mg/m2 IV in 0.9% NaCl over 60 minutes. BSA calculations and recalculation of the 
dose due to changes in the participant’s weight should be performed per institutional 
standards. Etoposide will be given as per institutional policies and the FDA prescribing 
information.  
 
Anaphylactic-type reactions characterized by chills, rigors, tachycardia, bronchospasm, 
dyspnea, diaphoresis, fever, pruritus, hypertension or hypotension, loss of consciousness, 
nausea, and vomiting have been reported to occur in approximately 3 percent of all 
patients treated with etoposide. Facial flushing was reported in 2 percent and skin rashes 
in 3 percent of patients receiving etoposide. These reactions have usually responded 
promptly to the cessation of the infusion and administration of vasopressor agents, 
corticosteroids, antihistamines, or volume expanders as appropriate; however, the 
reactions can be fatal. Hypertension and/or flushing have also been reported. Blood 
pressure usually normalizes within a few hours after cessation of the initial infusion. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of cediranib and olaparib with other concomitantly 
administered drugs, the case report form (CRF) must capture the concurrent use of all other 
drugs, over-the-counter medications, or alternative therapies.  The Principal Investigator should 
be alerted if the patient is taking any agent known to affect or with the potential for drug 
interactions. The study team should check a frequently-updated medical reference for a list of 
drugs to avoid or minimize use of. Patient Drug Information Handout and Wallet Cards 


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(APPENDIX B and APPENDIX C) should be provided to patients if available and applicable. 
 
All participants receiving protocol therapy may receive antiemetics, antidiarrheals, and blood 
product transfusion support as necessary and per local guidelines. Use of granulocyte colony 
stimulating factors (G-CSF) will be at the treating investigator’s discretion. Use of other 
concomitant medications are allowed with the exception of the medications detailed in the below 
Sections 5.2.2, 5.2.3, 5.2.4, 5.2.5, and 5.2.6. Specific toxicity management guidelines are located 
in Section 6. 
 
Cediranib may impair wound healing. For this reason, cediranib should be held for two weeks 
prior to any surgical procedures and may be restarted when the surgical wound is healed. 
 
5.2.1 Blood Pressure Monitoring with Cediranib 
 
Frequent blood pressure monitoring is important in patients receiving cediranib. Clinical 
trials of cediranib have demonstrated 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. Anti-hypertensives should be utilized as 
needed to control blood pressure, please see APPENDIX G for suggested 
antihypertensive medications.  
Blood pressure monitoring cuffs are provided by Astra Zeneca and should be ordered 
once an eligible subject has been registered within the OPEN IWRS. The Blood Pressure 
Cuff Request Form can be found on the CTSU portal.  
 
All patients receiving cediranib will be asked to record twice daily blood pressure 
readings during the first 9 weeks of cediranib therapy (APPENDIX H). If anti-
hypertensive management is required, twice daily blood pressure monitoring must 
continue until a stable anti-hypertensive regimen has been established, even if this 
requires more than 9 weeks of monitoring. Following 9 weeks or once a stable anti-
hypertensive 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. 
 
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 study physician as soon as possible. 
Patients should seek immediate medical advice if their blood pressure exceeds 180 
mmHg (systolic) or 105 mmHg (diastolic) at any time and should also be encouraged to 
contact their study physician if they are concerned about any symptoms that may be 
associated with high blood pressure (e.g., headache). Section 6 includes specific 
guidelines on the management and, if appropriate, dose modifications for treatment-
emergent hypertension. 
 
5.2.2 Cediranib Concomitant Medication Guidelines 
 


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Cediranib (AZD2171) is primarily metabolized by flavin-containing monooxygenase 
enzymes (FMO1 and FMO3) and UGT1A4. It is not a substrate of CYP450 enzymes. In 
vitro studies suggest that cediranib is a substrate for P-glycoprotein (Pgp), but not breast 
cancer resistance protein (BCRP). Since clinically relevant induction or inhibition of 
FMO enzymes is uncommon, use caution in patients taking concomitant medications that 
are strong inhibitors (e.g. ketoconazole) or strong inducers (e.g. rifampicin, 
carbamazepine, phenobarbital, phenytoin and St. John’s Wort) of UGT1A4 or Pgp in 
particular. If chronic concomitant administration of strong inducers or inhibitors is 
unavoidable, consult the principal investigator before proceeding with screening.  Ideally, 
the use of strong inhibitors of UGT1A4 should be avoided at least one week prior to 
administration of cediranib. 
 
In vitro studies show that cediranib did not inhibit CYP 1A2, 2A6, 2C8, 2C9, 2C19 and 
2E1 and showed no induction of CYP 1A2, 2B6 and 3A4/5. It did weakly inhibit CYP 
2D6 and 3A4/5, but this inhibition is not expected to cause any clinically relevant drug 
interactions. 
 
In vitro studies show that cediranib is a weak inhibitor of BCRP, but not Pgp. Use caution 
in patients who are taking concomitant medications that are sensitive substrates of BCRP 
transporters since there is a potential for drug-drug interactions.  
 
Cediranib is approximately 95 percent 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. 
 
Patients receiving cediranib are at increased risk of bleeding and hemorrhage. For this 
reason, warfarin use is prohibited on trial. Low-molecular weight heparin is allowed but 
should be used with caution. Participants taking low-molecular weight heparins should be 
closely monitored for signs and symptoms of bleeding.  
 
5.2.3 Olaparib Concomitant Medication Guidelines 
 
Contraception 
Female patients of child bearing potential and male patients with partners of child 
bearing potential, who are sexually active, must agree to the use of two highly 
effective forms of contraception. This should be started from the signing of the 
informed consent and continue throughout period of taking study treatment and for 1 
month (female patients)/3 months (male patients) after last dose of study drug. 
Acceptable non-hormonal and hormonal birth control methods may be found in the 
Olaparib IB.  
 
Use of Natural/Herbal Products 
The use of any natural/herbal products or other traditional remedies should be 
discouraged, but use of these products, as well as use of all vitamins, nutritional 
supplements, and all other concomitant medications must be recorded in the case 


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report form (CRF). 
 
Live Virus/Bacterial Vaccines 
Live virus and live bacterial vaccines should not be administered whilst the patient is 
receiving study medication and during the 30 day follow up period. An increased risk 
of infection by the administration of live virus and bacterial vaccines has been 
observed with conventional chemotherapy drugs and the effects with olaparib are 
unknown. 
 
P-gp Inhibitors 
It is possible that co-administration of P-gp inhibitors (eg amiodarone, azithromycin) 
may increase exposure to olaparib. Caution should therefore be observed. 
 
Effect of olaparib on other drugs 
Based on limited in vitro data, olaparib may increase the exposure to substrates of 
CYP3A4, P-gp, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K.  
 
Based on limited in vitro data, olaparib may reduce the exposure to substrates of 
CYP3A4, CYP1A2, 2B6, 2C9, 2C19 and P-gp.  
 
The efficacy of hormonal contraceptives may be reduced if co administered with 
olaparib.  
Caution should therefore be observed if substrates of these isoenzymes or transporter 
proteins are co-administered. 
Examples of substrates include: 
• CYP3A4 – hormonal contraceptive, simvastatin, cisapride, cyclosporine, ergot 
alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine 
• CYP1A2 – duloxetine, melatonin 
• CYP2B6 – bupropion, efavirenz 
• CYP2C9 – warfarin  
• CYP2C19 - lansoprazole, omeprazole, S-mephenytoin 
• P-gp - simvastatin, pravastatin, digoxin, dabigatran, colchicine 
• OATP1B1 - bosentan, glibenclamide, repaglinide, statins and valsartan 
 The required washout period prior to starting study treatments is 2 weeks 
for strong inhibitors listed above, and at least 1 week for moderate 
inhibitors listed above. 
 The required washout period prior to starting study treatments is 5 weeks 
for enzalutamide or phenobarbital and 4 weeks for other agents. 
Based on in vitro data and clinical exposure data, animal in vivo data, and clinical 
exposure data, olaparib is primarily metabolized vis CYP3A4/5 (direct inhibitor of 
CYP3A in vitro).  Therefore, the following potent inhibitors of CYP3A4 must not be 
used during this study for any patient receiving olaparib. 
 
While this is not an exhaustive list, it covers the known potent inhibitors, which have 
most often previously been reported to be associated with clinically significant drug 


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interactions: 
 
Ketoconazole, itraconazole, ritonavir, idinavir, saquinavir, telithromycin, 
clarithromycin and nelfinavir  
 
For patients taking any of the above, the required wash-out period prior to starting 
olaparib is one week. In addition, to avoid potential reductions in exposure due to drug 
interactions and therefore a potential reduction in efficacy, the following CYP3A4 
inducers should be avoided: 
 
Phenytoin, rifampicin, rifapentine, rifabutin, carbamazepine, phenobarbitone, 
nevirapine, modafinil and St John’s Wort (Hypericum perforatum)  
 
For patients taking any of the above, the required wash-out periods prior to starting 
olaparib are 3 weeks (5 weeks for phenobarbitone). 
 
 
After randomization if the use of any potent inducers or inhibitors of CYP3A4 are 
considered necessary for the patient’s safety and welfare, the investigator must contact 
the Overall Principal Investigator.  A decision to allow the patient to continue in the study 
will be made on a case-by-case basis. Additionally please refer to APPENDIX D. 
 
Anti-emetics/Anti-diarrheals 
If a patient develops nausea, vomiting and / or diarrhea, then these symptoms should 
be reported as AEs (see section 7) and appropriate treatment of the event given. 
Anticoagulant Therapy  
Patients who are taking warfarin may participate in this trial; however, it is 
recommended that international normalised ratio (INR) be monitored carefully at 
least once per week for the first month, then monthly if the INR is stable. 
Subcutaneous heparin and low molecular weight heparin are permitted. 
Palliative radiotherapy  
Palliative radiotherapy may be used for the treatment of pain at the site of bony 
metastases that were present at baseline, provided the investigator does not feel that 
these are indicative of clinical disease progression during the study period.  Study 
treatment should be discontinued for a minimum of 3 days before a patient undergoes 
therapeutic palliative radiation treatment.  Study treatment should be restarted within 
4 weeks as long as any bone marrow toxicity has recovered.   
Patients may continue the use of bisphosphonates or denosumab for bone disease and 
corticosteroids for the symptomatic control of brain metastases provided the dose is 


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stable before and during the study and they were started at least 4 weeks prior to 
beginning study treatment.  
Subsequent therapies for cancer  
Details of first and subsequent therapies for cancer and/or details of surgery for the 
treatment of the cancer, after discontinuation of treatment, will be collected.  Reasons 
for starting subsequent anti-cancer therapies including access to other PARP 
inhibitors or investigational drugs will be collected and included in the exploratory 
assessments of OS. 
Medications that may NOT be administered with Olaparib 
• No other immunotherapy, hormonal therapy or other novel agent is to be 
permitted while the patient is receiving study medication. 
It is not recommended to consume grapefruit juice while on olaparib therapy. 
 
 
5.2.4 Cisplatin Concomitant Medication Guidelines 
 
Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin 
therapy. Participants should be monitored closely and dosages adjusted accordingly. See 
FDA prescribing information. 
 
5.2.5 Carboplatin Concomitant Medication Guidelines 
 
The renal effects of nephrotoxic compounds may be potentiated by carboplatin. See FDA 
prescribing information. 
 
5.2.6 Etoposide Concomitant Medication Guidelines 
 
Caution should be exercised when administering etoposide with drugs that are known to 
inhibit phosphatase activities (e.g., levamisole hydrochloride). See FDA prescribing 
information. Concomitant use of antiepileptic medications including phenytoin, 
phenobarbital, carbamazepine, and valproic acid is associated with increased etoposide 
clearance and reduced efficacy of etoposide. For this reason, concomitant use of 
phenytoin, phenobarbital, carbamazepine, and valproic acid is prohibited during the 
initial therapy phase of the study. 
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s) or progressive disease, treatment will 
consist of 4 cycles of chemotherapy at minimum.  For those randomized to the arm using 
cediranib or randomized to maintenance olaparib + cediranib, treatment on maintenance olaparib 
+ cediranib will continue indefinitely until one of the following criteria applies: 
 


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• 
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 
 
• 
Bone marrow findings consistent with MDS and/or acute myeloid leukemia. 
 
Participants who were randomized to receive no maintenance therapy may crossover to receive 
cediranib plus olaparib therapy upon disease progression at the treating investigator’s discretion. 
If crossover occurs, treatment with olaparib + cediranib will continue indefinitely as above until 
one of the criteria note above applies.  The first re-assessment after initiating crossover therapy 
will happen at 6 weeks after starting therapy. 
 
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 
 
Participants will be followed until death after removal from protocol therapy. This follow up will 
be performed by review of the medical record, contact with care providers, and/or telephone 
contact as needed every 3-4 months. 
 


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6. DOSING DELAYS/DOSE MODIFICATIONS 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
For adverse events that are unrelated to the study drugs, study treatment may be held for up to 14 
days at the discretion of the treating investigator. Drug holds of greater than 14 days for 
unrelated adverse events where the patient is experiencing ongoing clinical benefit may be 
considered after discussion with the overall PI. 
 
6.1 
Dose Modification Guidelines 
 
The dose levels and the general approach to dose modifications are shown below. AEs should be 
treated with the appropriate maximum supportive care, and dose reductions should be clearly 
documented in the CRFs. 
 
Dose reductions will be based on the offending medication(s). In the event the treating 
investigator feels all medications are responsible for the toxicity, all medications can be reduced. 
Cediranib and olaparib dose modifications should be made according to the schedules outlined in 
Table 4 and Table 5. Dose reductions of cisplatin, carboplatin, and etoposide should be made 
according to standard of care guidelines. Participants undergoing dose reductions for toxicities 
may not be re-escalated to a prior dose.  
 
Participants who do not tolerate initial cisplatin treatment despite maximal supportive care may 
be changed to receive carboplatin at the treating investigator’s discretion for the remainder of the 
initial therapy cycles. Similarly, participants who do not tolerate initial carboplatin treatment 
despite maximal supportive care may be changed to receive cisplatin at the treating investigator’s 
discretion for the remainder of the initial therapy cycles. Participants may receive a maximum of 
four cycles of platinum therapy during the initial therapy period.  
 
In rare circumstances, patients experiencing ongoing clinical benefit but who develop one of the 
toxicities listed below related to one of the IPs that prevents them to continue to take this IP, may 
be allowed to continue on the unrelated drug if in the opinion of the treating investigator the risk 
benefit remains favorable and only after discussion with the Principal Investigator.  
 
AEs requiring cediranib to be discontinued: 
 
· 
GI perforation 
 
· 
Arterial Thromboembolic Event 
 
· 
PRES 
 
· 
Severe hemorrhage 


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· 
Severe persistent hypertension despite maximal anti-hypertensive treatment 
 
AEs requiring olaparib to be discontinued: 
 
· 
Bone marrow findings consistent with MDS/ AML 
 
· 
Severe persistent anemia 
 
· 
Pneumonitis 
 
 
Patients experiencing ongoing clinical benefit who experience a related AE where continuation 
of one of the drugs is considered, in the judgment of the treating Investigator 
and the Principal Investigator, to be potentially life threatening or with the potential for long-
term harm to the patient, may be allowed to continue on the unrelated drug after discussion with 
the Principal Investigator. 
 
Table 4: Cediranib Dose Modifications 
Original Cediranib Dose 
Cediranib Dose Reduction 
20 mg daily 
15 mg daily 
30 mg daily 
1st Reduction: 20 mg daily 
2nd Reduction: 15 mg daily 
Dose reductions below 15 mg daily will not be allowed, if a participant requires reduction below 
15 mg daily they should be discontinued from cediranib therapy 
 
Table 5: Olaparib Dose Modifications 
Original Olaparib Dose 
Olaparib Dose Reduction 
200 mg twice daily 
1st Reduction: 150 mg twice daily 
2nd Reduction: 100 mg twice daily 
Dose reductions below 100 mg twice daily will not be allowed, if a participant requires 
reduction below 100 mg twice daily they should be discontinued from olaparib therapy 
 
6.2 
Toxicity Management Guidelines 
Management of hypertension (associated with cediranib) and diarrhea (associated with cediranib 
and/or olaparib is of particular concern.  All participants will be asked to record twice-daily 
blood pressure measurements as well as log any diarrhea events in patient diaries .  Guidelines 
for management are as per the tables below.  Patient information regarding diarrhea management 
in also in appendix I. 
 
 
6.2.1 Initial Therapy Phase 
 
Dose delays and modifications of cisplatin or carboplatin and etoposide should follow 
institutional standards (namely, participants must meet re-treatment criteria prior to re-initiation 
of therapy and may be dose-reduced per institutional standards). However, if dosing of 


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chemotherapy that occurs concurrently with cediranib is held, then that day’s dosing of cediranib 
should also be held. If dose –delay of chemotherapy for hematologic or other laboratory toxicity 
results in a > 3 week delay in therapy, protocol therapy should be discontinued. Exceptions to 
this may be reviewed on a case-by-case basis with the Overall Principal Investigator. 
 
Participants receiving cediranib during the initial therapy phase should also meet treatment 
guidelines relating to cediranib therapy as outlined in Table 6, Table 8, Table 9, Table 10, 
Table 11, Table 12, Table 13, Table 14, and Table 15. 
 
6.2.2 Maintenance Phase 
 
Study treatment may be held for a maximum of 21 days to allow recovery from toxicity 
associated with treatment during the maintenance phase of therapy. Participants requiring longer 
delays should be discontinued from protocol therapy. Exceptions are possible for participants 
who are deriving clinical benefit in the opinion of the treating investigator after discussion with 
the overall principal investigator. 
 
6.2.3 Cediranib Toxicity Management   
 
6.2.3.1 
Fatigue  
Fatigue is a common adverse drug reaction reported for both cediranib and olaparib.  Fatigue 
experienced by patients taking cediranib may be rapid in onset.  During clinic visits, patients 
fatigue levels should be discussed.  Patients should seek medical advice early if Grade 2 fatigue 
develops (moderate fatigue causing difficulty performing some activities of daily living). 
 
Care should be taken to ensure that the nutritional status of the patients is optimized and patients 
should be encouraged to drink plenty of fluids. Patients should be encouraged to manage fatigue 
by alternating periods of rest with light aerobic exercise, which may improve the symptoms in 
some cases. 
 
Consideration should be given to other possible causes of fatigue (e.g., thyroid function, 
depression/insomnia and other concomitant medicinal products). Additionally, short interruption 
of cediranib dosing (initially 2-3 days-or longer-up to a maximum of 21 days) may help relieve 
fatigue.  When symptoms improve cediranib should be restarted with the same dose or, if 
necessary, a dose reduction can be considered. 
 
6.2.3.2 
Fistula 
In patients treated with cediranib, fistula has been reported and reflected the location of the 
underling malignancy.  In the ovarian cancer population, vaginal fistula has been uncommonly 
reported in cediranib treated patients.  Cediranib should be used with caution in patients at risk of 
fistula and discontinuation of cediranib should be considered in patients who develop fistulae. 
 
6.2.3.3 
Arterial thromboembolism  
Arterial thromboembolic events (including transient ischemic attack and ischemic stroke) have 
been reported in clinical studies with cediranib.  Cediranib should be used with caution in 
patients who are at an increased risk of thrombotic events or who have a history of thrombotic 


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events.  Cediranib should be permanently discontinued in patients who develop an arterial 
thromboembolic event. 
 
6.2.3.4 
Venous thromboembolism 
Venous thromboembolic events including pulmonary embolism and deep vein thrombosis have 
been commonly reported in patients treated with cediranib.  Anticoagulant treatment should be 
started in accordance with clinical practice.  Discontinuation of cediranib may be considered.  
Cediranib should be used with caution in patients at risk of venous thromboembolism. 
 
6.2.3.5 
Wound healing 
Treatment with cediranib should be stopped at least 2 weeks prior to scheduled surgery.  The 
decision to resume cediranib therapy after surgery should be based on clinical judgment of 
adequate wound healing.  In patients who experience wound healing complications during 
therapy, treatment with cediranib should be interrupted until the wound is fully healed.  No 
formal studies of the effect of cediranib on wound healing have been conducted. 
 
6.2.3.6 
Elderly  
There is a limited amount of safety data available for cediranib use in patients aged 75 years and 
older.  Based on a population PK analysis, the clearance of cediranib decreased with age, 
however, no dose adjustment is needed given the small impact on exposure or variability. 
Caution should be taken when treating patients who are aged 75 years or older with cediranib. In 
case of toxicity dose pause or dose reduction may be considered.  
 
6.2.3.7 
Mild/moderate renally impaired patients 
Patients with mild and moderate renal impairment discontinued cediranib more often due to 
adverse events, particularly when cediranib was co-administered with chemotherapy. Population 
PK analysis showed that no adjustment of cediranib dose is required in this population as 
cediranib is minimally renally cleared; however, cediranib clearance may be decreased in 
patients with low body weight.  In the ICON6 pivotal study, patients with mild or moderate 
impairment had lower median body weight compared with patients with normal renal function.  
Caution should be exercised in patients with mild and moderate renal impairment and a cediranib 
dose adjustment should be considered in case of signs of toxicity. 
 
6.2.3.8 
Decreased weight  
In the ICON6 study, weight decreased was very commonly reported in cediranib treated patients.  
Weight loss (≥7%) in cediranib-treated patients was associated with higher incidence of 
decreased appetite, vomiting and stomatitis, although these events were also commonly reported 
in patients who did not lose weight. 
 
6.2.4 Olaparib Toxicity Management  
 
6.2.4.1 
Pulmonary symptoms 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormalities occur in 
the absence of a clear diagnosis, an interruption in 1 or both IPs dosing is recommended and 
further diagnostic workup (including a HRCT scan) should be performed to exclude 
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Following investigation, if no evidence of abnormality is observed on CT imaging and symptoms 
resolve, then IP(s) can be restarted, if deemed appropriate by the investigator.  If significant 
pulmonary abnormalities are identified, these need to be discussed with the Study Physician. 
 
6.2.4.2 
Nausea and vomiting  
Events of nausea and vomiting are known to be associated with olaparib treatment.  In study 
D0810C00019 nausea was reported in 71% of the olaparib treated patients and 36% in the 
placebo treated patients and vomiting was reported in 34% of the olaparib treated patients and 
14% in the placebo treated patients.  These events are generally mild to moderate (CTCAE 
Grade 1 or 2) severity, intermittent and manageable on continued treatment.  The first onset 
generally occurs in the first month of treatment for nausea and within the first 6 months of 
treatment for vomiting.  For nausea, the incidence generally plateaus at around 9 months, and for 
vomiting at around 6 to 7 months. 
 
No routine prophylactic anti-emetic treatment is required at the start of treatment with the IPs, 
however, patients should receive appropriate anti-emetic treatment at the first onset of nausea or 
vomiting and as required thereafter, in accordance with local treatment practice guidelines. 
Taking olaparib tablets with food may help alleviate symptoms of nausea and vomiting. 
 
6.2.4.3 
Renal impairment  
Olaparib has not been studied in patients with severe renal impairment (CrCL ≤30 mL/minutes) 
or end-stage renal disease; if patients develop severe impairment or end stage disease is it 
recommended that olaparib be discontinued.   
 
6.2.5 Interruptions for intercurrent non-toxicity related events 
 
Cediranib and Olaparib dose interruption conditions other than toxicity resolution should be 
kept as short as possible. If a patient cannot restart IP(s) within 3 weeks for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be 
discussed with study physician. 
 
Both IPs should be stopped at least 2 weeks prior to planned surgery.  After surgery both IPs 
can be restarted when the wound has healed.  No stoppage of IPs is required for any needle 
biopsy procedure. 
 
Both IPs should be discontinued for a minimum of 3 days before a patient undergoes radiation 
treatment.  Both IPs should be restarted within 3 weeks as long as any bone marrow toxicity 
has recovered. 
 
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, patients 
should be advised to use caution while driving or using machinery if these symptoms occur. 
 
6.2.6 Non-Hematologic Toxicities and Management  
Cediranib should be discontinued should any of the following AEs occur:  GI perforation; 
arterial thromboembolic events; PRES (radiologically confirmed); severe or medically 


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significant hemorrhage and severe persistent hypertension despite maximal anti-hypertensive 
treatment. 
 
Dose modifications for other non-hematologic events while on cediranib and/or olaparib should 
be managed according to Table 6. 
 
Table 6: Management of Non-Hematologic Adverse Events Not Otherwise Specified 
(Related to Cediranib and/or Olaparib) 
Non-Hematologic CTCAE Event Grade 
Management Guidelines 
 
Grade 1; or any AE that resolves promptly 
with supportive care 
 
Maintain dose level. 
 
Grade 2 non-hematologic AE or grade 3 
fatigue considered at least possibly related to 
study treatment that persists despite maximal 
supportive care.* 
 
Exceptions include:  
• Hypertension or other AEs with 
specific management instructions 
outlined in the tables below. 
• Non-clinically significant, 
asymptomatic, or easily correctable 
laboratory abnormalities. 
• Grade 3 fatigue that does not persist  
 
 
Hold study drug(s) for up to 21 days until 
toxicity resolves to ≤ grade 1 or baseline. 
  
Treatment may be restarted at investigator 
discretion at one dose level lower for the 
drug(s) causing the toxicity, as per the dose 
reduction levels in Section 6.2. 
 
Recurrence of Grade 3 or 4 toxicity would 
require dose reduction of both IPs. 
 
Patients whose toxicity has not resolved after 
21 days will be removed from study. 
• At the discretion of the investigator, 
one IP may be held or dose modified or 
discontinued independently if the 
observed toxicity is attributed to only 
one of the drugs, while the patient 
continued to receive the second drug 
not associated with the observed 
toxicity. The time a given drug is held 
should not exceed 3 weeks. 
• Patients who are at the lowest 
reduced dose level may have their 
drug resumed at that dose level after 
discussion 
with 
the 
Principal 
Investigator if evidence of clinical 
benefit. 
 
 
Grade 3 or 4 non-hematologic AE related to 
 
Remove patient from protocol-specified 


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Table 6: Management of Non-Hematologic Adverse Events Not Otherwise Specified 
(Related to Cediranib and/or Olaparib) 
Non-Hematologic CTCAE Event Grade 
Management Guidelines 
cediranib and olaparib combination that does 
not resolve to Grade 0-2 within 3 weeks 
despite maximum supportive care after treating 
patient at the lowest reduced dose level 
 
Exceptions include:  
• Hypertension or other AEs with 
specific management instructions 
outlined in the tables below. 
• Non-clinically significant, 
asymptomatic, or easily correctable 
laboratory abnormalities. 
 
treatment. 
*: For thromboembolic events, treatment may be resumed at the discretion of the treating 
investigator once patient is asymptomatic. 
 
6.2.7 Hematologic Toxicities and Management 
 
6.2.7.1 
Management of neutropenia and thrombocytopenia 
Neutropenia and thrombocytopenia are recognized common adverse drug reactions reported for 
both olaparib and cediranib.   
 
6.2.7.2 
Management of anemia 
 
Anemia is a common adverse drug reaction related to olaparib.  Cediranib is not reported to 
increase the risk of anemia.   
 
Common treatable causes of anemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed.  In some cases management 
of anemia may require blood transfusions.  Any subsequently required dose interruptions, related 
to development of anemia, or coexistent with newly developed neutropenia, and/or 
thrombocytopenia, will require olaparib dose reductions to 150 mg twice daily as a first step and 
to 100 mg twice daily as a second step. 
 
If Hb drops to < 8 g/dL despite the dose reduction or more than one blood transfusion is required 
to recover Hb levels with no alternative explanation for the anemia, olaparib should be 
permanently discontinued. 
 
6.2.7.3 
Use of hematopoietic agents 
 
Use iron supplements, and/or transfusions as clinically indicated for management of anemia. 
Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is not recommended. 
They do not alleviate fatigue or increase energy.  They should not be used in patients with 


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uncontrolled hypertension.  The package inserts should be consulted. 
 
If a patient develops febrile neutropenia, IPs should be stopped and appropriate management 
including G-CSF should be given according to local hospital guidelines.  Please note that G-CSF 
should not be used within at least 24 hours of the last dose of olaparib unless absolutely 
necessary. 
 
Platelet transfusions, if indicated, should be done according to local hospital guideline 
 
6.2.7.4 
Dose modifications for hematologic toxicity 
 
Patients who have IPs held for hematologic toxicities should have blood counts and differentials 
checked at least weekly until recovery; these data should be recorded in eCRF as extra laboratory 
examinations.  If counts do not improve to CTCAE Grade 1 or better despite drug cessation for 3 
weeks, patients should be referred to a hematologist for further assessment.  A bone marrow 
analysis should be considered per hematology assessment. 
 
For AEs that are unrelated to the study drug, study drug may be withheld for up to 3 weeks at the 
discretion of the treating Investigator. 
 
6.2.7.5 
Management of prolonged hematological toxicities while on study treatment 
 
If a patient develops prolonged hematological toxicity such as: 
 
• ≥2 week interruption/delay in olaparib due to CTCAE Grade 3 or worse anemia and/or 
development of blood transfusion dependence 
 
• ≥2 week interruption/delay in 1 or both IPs due to CTCAE Grade ≥3 neutropenia (ANC 
<1 x 109/L) 
 
• ≥2 week interruption/delay in 1 or both IPs due to CTCAE Grade ≥3 thrombocytopenia 
and/or development of platelet transfusion dependence (Platelets <50 x 109/L) 
 
Check weekly differential blood counts including reticulocytes and peripheral blood smear.  If 
any blood parameters remain clinically abnormal after 3 weeks of dose interruption, the patient 
should be referred to hematologist for further investigations.  Bone marrow analysis and/or blood 
cytogenetic analysis should be considered at this stage according to standard hematological 
practice.  Both IPs should be discontinued if blood counts do not recover to CTCAE Grade ≤1 
within 3 weeks of dose interruption. 
  
 
Table 7: Management of Hematologic Adverse Events during Maintenance Therapy 
Hematologic Event 
Management Guidelines 
Absolute neutrophil count ≥ 1000/mcL 
AND 
Platelets ≥ 100,000/mcL 
Olaparib dose: Investigator judgement to 
continue treatment or allow dose interruption; 
dose interruptions should be for a maximum of 


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Table 7: Management of Hematologic Adverse Events during Maintenance Therapy 
Hematologic Event 
Management Guidelines 
 
3 weeks; appropriate supportive treatment and 
causality investigation. 
 
Cediranib dose: Investigator judgement to 
continue treatment or allow dose interruption; 
dose interruptions should be for a maximum of 
3 weeks; appropriate supportive treatment and 
causality investigation 
Absolute neutrophil count < 1000/mcL 
OR 
Platelets <100,000/mcL 
 
Olaparib dose: Dose interruption until 
recovered to CTCAE Grade ≤1 for a maximum 
of 3 weeks. Upon recovery, olaparib dose 
should be reduced by one dose level.  If repeat 
CTCAE Grade 3-4 occurrence, further dose 
reduce one or both IPs 
 
Cediranib dose: Dose interruption until 
recovered to CTCAE Grade ≤1 for a maximum 
of 3 weeks. Upon recovery, cediranib dose 
should be reduced by one dose level.  If repeat 
CTCAE Grade 3-4 occurrence, further dose 
reduce one or both IPs 
Hb < 10 but > 8 g/dL  
Olaparib dose: Give appropriate supportive 
treatment and investigate causality.  
Investigator judgement to continue olaparib or 
interrupt dose for a maximum of 3 weeks. 
If repeat Hb <10 but ≥8 g/dL, dose interrupt 
until Hb ≥10 g/dL for maximum of 3 weeks 
and upon recovery dose reduce to 150 mg bd 
as a first step and to 100 mg bd as a second 
step 
 
Cediranib dose: No change 
Hb < 8 g/d 
Olaparib dose: Give appropriate supportive 
treatment and investigate causality. 
Interrupt olaparib until improved to Hb ≥10 
g/dL. Upon recovery dose reduce olaparib to 
150 mg bd 
 
Cediranib dose: No change 
 
Table 8: Management of Hypertension (Associated with Cediranib) 
CTCAE Event Grade 
Blood Pressure 
Monitoring 
Management Guidelines 
See APPENDIX G for suggested antihypertensive medications by class. 


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Table 8: Management of Hypertension (Associated with Cediranib) 
CTCAE Event Grade 
Blood Pressure 
Monitoring 
Management Guidelines 
 
Abbreviations: Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin II Receptor 
Blockers (ARB), selective beta blockers (BB), Dihydropyridine calcium channel blockers (DHP-
CCP) 
 
All participants will be given blood-pressure monitors and asked to take their blood pressure 
twice-daily at home and record in a log.  Any blood pressure measurement over 140/90 should 
prompt a call to the treating team so that expeditious blood pressure management can occur. 
Patient BP will also be measured during routine study visits to ensure that BP guidelines are 
being correctly followed.  Increase in BP should be treated promptly with standard 
antihypertensive therapy, ensuring that the maximum recommended dose and number of 
antihypertensive medicinal products is reached before considering cediranib dose adjustment.   
 
If patients require a delay of >3 weeks for management of hypertension, discontinuation of 
cediranib therapy may be considered after discussion with the Overall Principal Investigator.  In 
case of persistent or severe hypertension, despite the optimal use of antihypertensive medicinal 
products and cediranib dose reduction, cediranib should be permanently discontinued. 
 
Patients may have up to 4 drugs for management of hypertension prior to any dose reduction in 
cediranib 
 
Only doses of cediranib will be modified for hypertension; olaparib doses will not be reduced 
unless other toxicities are experienced. 
 
Please note: patients may have baseline hypertension meeting CTCAE grading criteria on study 
entry provided this is adequately controlled on a maximum of 3 antihypertensive medications. 
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 v5.0 criteria. Patients already taking antihypertensive therapy at baseline or those aged 
75 years or older are at a higher risk of having elevated BP or may require more than one 
medicinal product or more intensive therapy. Pre-existing cardiovascular risks should be 
assessed and managed, and pre-existing hypertension should be adequately controlled before 
starting treatment with cediranib 
 
Baseline grade of hypertension should also be recorded in the patient’s record. 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. 
 
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 
Grade 1 
Continue standard BP 
 


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Table 8: Management of Hypertension (Associated with Cediranib) 
CTCAE Event Grade 
Blood Pressure 
Monitoring 
Management Guidelines 
monitoring per treating 
MD and confirm 
resolution of BP <140/90 
mmHg or baseline within 
24 hours. 
Maintain study drug dosing 
unless hold is otherwise 
clinically indicated. 
 
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. 
 
 
 
Grade 2 
Increase frequency of 
monitoring until 
stabilized to BP <140/90 
mmHg, 
 
Maintain study drug dosing 
unless hold is otherwise 
clinically indicated. 
 
Initiate BP medication for first 
line treatment. Suggestions: 
ACE-inhibitor. 
 
Escalate dose of medication in 
step-wise 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. 
 
Consider renal consult. 
 
 
Grade 3 
Increase frequency of 
monitoring until 
stabilized to BP < 140/90 
mmHg. 
Do not hold cediranib unless BP 
is not decreased to less than 
150/100 mmHg 48 hours after 
multi-drug therapy is instituted 
or if clinical symptoms worsen 


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Table 8: Management of Hypertension (Associated with Cediranib) 
CTCAE Event Grade 
Blood Pressure 
Monitoring 
Management Guidelines 
(e.g. headache). 
 
Maximize 2 drug regimen. 
Suggestions: ACE-inhibitor plus 
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. 
 
Additional anti-hypertensive 
drugs, up to a total of 4, may be 
maximized for blood pressure 
control. 
 
If BP is not controlled to less 
than 150/100 mmHg with 
maximal therapy or if clinical 
symptoms worsen, then hold 
cediranib (up to 14 days) until 
maximum effect of the anti-
hypertensive agents is achieved. 
 
If BP is reduced to < 140/90 
within 14 days, cediranib may be 
resumed at the prior dose level. 
 
Consider consult with a blood 
pressure management specialist 
if greater than 3 drugs are 
required for BP control. 
Grade 4 
Intensive BP monitoring 
(hospitalization if 
necessary) 
Hold cediranib. 
 
Initiate treatment. Hospitalize 
patient for ICU management, IV 
therapy as necessary. 
 
If BP is reduced to less than 
140/90 within 14 days, cediranib 


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Table 8: Management of Hypertension (Associated with Cediranib) 
CTCAE Event Grade 
Blood Pressure 
Monitoring 
Management Guidelines 
may be resumed at a reduced 
dose after discussion with the 
Overall Principal Investigator. 
 
Table 9: Management of Diarrhea (Associated with Cediranib and/or Olaparib or 
Etoposide) 
Non-Hematologic CTCAE Event Grade 
Management Guidelines 
 
Grade 1 or 2 (lasting ≤ 24 hours) 
Maintain study drug dosing unless hold is 
otherwise clinically indicated. 
 
Patients can take loperamide per standard 
practice (guidelines in Appendix I) and 
continue to take loperamide until patients are 
free from diarrhea for at least 12 hours. 
Patients should also be counseled to start a 
bananas, rice, applesauce, toast (BRAT) diet. 
 
Grade 1 or 2 (lasting ≥ 24 hours) 
If diarrhea persists despite 24 hours of 
loperamide treatment, hold study medication 
for a maximum of 14 days, continue treatment 
with antidiarrheals, and maintain hydration. 
Study medication may be resumed at the same 
dose once patients have returned to baseline or 
have been free from diarrhea for 12 hours. 
 
Persistent Grade 2, or Grade 3 or 4 
 
 
Hold study drug(s) for up to 14 days until 
diarrhea resolves to ≤ grade 1 or baseline. 
  
Treatment may be restarted at one dose level 
lower for the drug(s) causing the toxicity, as 
per the dose reduction levels in Section 6.2.  
 
Patients whose toxicity has not resolved after 
14 days will be removed from study. 
 
Diarrhea is often observed with cediranib.  Diarrhea usually starts early (within the first 4 weeks 
of treatment), however, it can occur at any time during treatment.  Management of diarrhea 
should start at the first sign of diarrhea. Loperamide and advice on how to manage diarrhea 
should be readily available to patients from the start of cediranib treatment so that they can be 
applied at first episode of diarrhea.  Active and early management of diarrhea is recommended 
even with Grade 1 diarrhea.   
 


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Table 10: Management of Proteinuria (Associated with Cediranib) 
Proteinuria if following by U/A 
Management Guidelines 
 
Greater than 2+ on urine dipstick or U/A 
AND 
Creatinine ≤ 1.5 × institutional ULN 
Perform urine protein: creatinine ratio (UPC). 
 
Maintain study drug dosing unless hold is 
otherwise clinically indicated. See below 
management of UPC results. 
 
Greater than 2+ on urine dipstick or U/A  
AND 
Creatinine > 1.5 × institutional ULN 
Hold cediranib until results of UPC are known. 
See below management of UPC results. 
 
Based on results of the UPC*: 
 
UPC ≤ 1 
Continue routine monitoring prior to each 
cycle. 
 
Continue study drug dosing at planned dose. 
UPC > 1 and ≤ 3.5  
AND 
Creatinine ≤ 1.5 × institutional ULN 
Perform UPC prior to each cycle. 
 
Continue study drug dosing at planned dose. 
UPC > 3.5 
OR 
Creatinine > 1.5 × institutional 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 × 
institutional ULN, resume cediranib with 
reduction in cediranib by one dose level. 
 
Consider consultation with nephrologist. 
*: If UPC is < 1 and creatinine > 1.5 × institutional ULN, AE management should be followed 
as per Table 6. 
 
Table 11: Management of Thyroid Toxicities (Associated with Cediranib) 
Result of TSH, T4, and T3 
Management Guidelines 
Referral to an endocrinologist should 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. 
 
Increase in TSH with normal T4/T3 
Maintain study drug dosing unless hold is 
otherwise clinically indicated. 
 
Continue to monitor. 
 
Increase in TSH with normal T4/T3 and 
adverse events suggestive of incipient 
Consider replacement thyroxine. 
 


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Table 11: Management of Thyroid Toxicities (Associated with Cediranib) 
Result of TSH, T4, and T3 
Management Guidelines 
hypothyroidism 
Maintain study drug dosing unless hold is 
otherwise clinically indicated. 
 
 
Increase in TSH with reductions in T4 and T3 
 
Consider replacement thyroxine. 
 
Maintain study drug dosing unless hold is 
otherwise clinically indicated. 
 
 
Table 12: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) 
Posterior reversible encephalopathy syndrome (PRES) has been uncommonly reported 
in clinical studies with cediranib. PRES is a neurological disorder which can present 
with headache, seizure, lethargy, confusion, blindness and other visual and neurologic 
disturbances, and can be fatal. Mild to severe hypertension may be present.  In patients 
developing PRES, treatment of specific symptoms including control of BP is 
recommended. Confirmation of PRES requires brain imaging, preferably MRI.  
Cediranib should be discontinued following confirmation of PRES.  The safety of 
reinitiating cediranib in patients previously experiencing PRES is not known. 
After consultation with the Overall PI and the NCI, consideration of restarting the study drugs 
may be evaluated in light of any clinical benefit. 
 
 
Table 13: 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 used with caution in patients at risk and 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. 
 
Table 14: Decreased LVEF 
Relationship to 
Institution’s LLN 
LVEF Decrease < 
10% from 
screening value 
LVEF Decrease 10 – 
15% from screening 
value 
LVEF Decrease ≥ 
16% from 
screening value 
Patients who have any of the following should undergo an echocardiogram (ECHO) or MUGA at 
baseline and every four cycles while on study: 
 
• Prior treatment with anthracyclines 
• Prior treatment with trastuzumab 
• Prior central thoracic radiation therapy (RT), including RT to the heart 


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Table 14: Decreased LVEF 
Relationship to 
Institution’s LLN 
LVEF Decrease < 
10% from 
screening value 
LVEF Decrease 10 – 
15% from screening 
value 
LVEF Decrease ≥ 
16% from 
screening value 
• History of myocardial infarction within 12 months prior to study entry 
 
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 this table. If the institution’s LLN is not specified, an 
LVEF of 50% should be considered the LLN threshold. 
Normal 
Maintain study drug 
dosing unless hold 
is otherwise 
clinically indicated. 
 
Maintain study drug 
dosing unless hold is 
otherwise clinically 
indicated. 
Maintain study 
drug dosing unless 
hold is otherwise 
clinically indicated. 
 
Repeat 
MUGA/ECHO 
within 3 cycles. 
1-5% below LLN 
Maintain study drug 
dosing unless hold 
is otherwise 
clinically indicated. 
 
Repeat 
MUGA/ECHO 
within 3 weeks. 
 
 
Maintain study drug 
dosing unless hold is 
otherwise clinically 
indicated. 
 
Repeat MUGA/ECHO 
within 3 weeks. 
 
Hold study 
medications and 
repeat 
MUGA/ECHO 
within 3 weeks. 
≥ 6% below LLN 
Maintain study drug 
dosing unless hold 
is otherwise 
clinically indicated. 
 
Repeat 
MUGA/ECHO 
within 3 weeks.  
 
Hold study medications 
and repeat 
MUGA/ECHO within 3 
weeks. 
 
Hold study 
medications and 
repeat 
MUGA/ECHO 
within 3 weeks. 
 
Table 15: Rotator Cuff Injury (Associated with Cediranib and Olaparib) 
Event Description 
Management Guidelines 
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. 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated  
Maintain study drug dosing unless hold is 
otherwise clinically indicated. 
 


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63 
 
Table 15: Rotator Cuff Injury (Associated with Cediranib and Olaparib) 
Event Description 
Management Guidelines 
Limit heavy lifting or carrying of heavy 
objects, bags, or backpacks. 
 
Consider shoulder MRI if symptoms warrant. 
 
Moderate; minimal, local, or noninvasive 
intervention indicated; limiting age appropriate 
instrumental ADL 
Hold cediranib and olaparib for up to 14 days 
until symptoms resolve to ≤ Grade 1 or 
baseline. Cediranib and olaparib may then be 
resumed at a reduced dose level of both study 
drugs. 
 
Obtain shoulder MRI if not previously 
obtained. 
 
If rotator cuff injury present on MRI, refer for 
physical therapy as clinically indicated. 
Severe or medically significant but not 
immediately life-threatening; hospitalization or 
prolongation of existing hospitalization 
indicated; disabling; limiting self care ADL. 
 
Hold cediranib and olaparib for up to 14 days 
until symptoms resolve to ≤ Grade 1 or 
baseline. Cediranib and olaparib may then be 
resumed at a reduced dose level of both study 
drugs after discussion with the overall PI. 
 
Table 16: Myelodysplastic Syndrome (Associated with Olaparib) 
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. Patients who develop MDS/AML on treatment should be 
discontinued from olaparib treatment and managed appropriately. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting via the CTEP Adverse Event Reporting 
System (CTEP-AERS) in addition to routine reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  In addition to the comprehensive list, a subset of AEs, 


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64 
 
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. 
 
7.1.1.1 
CAEPR for Cediranib 
 
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/aeguideline
s.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 


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65 
 
 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
Hyperthyroidism 
Hypothyroidism 
Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
Abdominal pain (Gr 3) 
Anal mucositis 
Anal mucositis (Gr 2) 
Constipation 
Constipation (Gr 3) 
Diarrhea 
Diarrhea (Gr 3) 
Dry mouth 
Dry mouth (Gr 2) 
Dysphagia 
Dysphagia (Gr 2) 
 
Gastrointestinal fistula2 
 
Gastrointestinal perforation3
Mucositis oral 
Mucositis oral (Gr 3) 
Nausea 
Nausea (Gr 3) 
 
Pancreatitis  
Rectal mucositis 
Rectal mucositis (Gr 2) 
Small intestinal mucositis 
Small intestinal mucositis (Gr 2) 
Vomiting 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue 
Fatigue (Gr 3) 
HEPATOBILIARY DISORDERS 
 
Hepatic failure 
INFECTIONS AND INFESTATIONS 
Infection4 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
Wound complication 
INVESTIGATIONS 
Alanine aminotransferase 
increased 
Alanine aminotransferase 
increased (Gr 3) 
Alkaline phosphatase 
increased 
Aspartate aminotransferase 
increased 
Aspartate aminotransferase 
increased (Gr 3) 
Lymphocyte count decreased 
Neutrophil count decreased 
Platelet count decreased 
Thyroid stimulating hormone 
increased 
Thyroid stimulating hormone 
increased (Gr 2) 
Weight loss 
Weight loss (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
Anorexia (Gr 3) 
Dehydration 
Dehydration (Gr 3) 
Hypophosphatemia 
Hypophosphatemia (Gr 3) 


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66 
 
 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
Generalized muscle weakness 
NERVOUS SYSTEM DISORDERS 
Dizziness 
Dizziness (Gr 2) 
Headache 
Headache (Gr 3) 
Lethargy 
 
Leukoencephalopathy 
Reversible posterior 
leukoencephalopathy 
syndrome 
RENAL AND URINARY DISORDERS 
 
Nephrotic syndrome 
Proteinuria 
Proteinuria (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Cough 
Cough (Gr 2) 
Dyspnea 
Dyspnea (Gr 3) 
Laryngeal mucositis 
Laryngeal mucositis (Gr 2) 
Pharyngeal mucositis 
Pharyngeal mucositis (Gr 2) 
Tracheal mucositis 
Tracheal mucositis (Gr 2) 
Voice alteration 
Voice alteration (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Palmar-plantar 
erythrodysesthesia syndrome 
Palmar-plantar 
erythrodysesthesia syndrome 
(Gr 2) 
VASCULAR DISORDERS 
 
Arterial thromboembolism 
Hypertension 
Hypertension (Gr 3) 
Thromboembolic event 
Thromboembolic event (Gr 4) 
Vascular disorders - Other 
(hemorrhage)5 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will 
be distributed to all Principal Investigators at the time of revision.  The current 
version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the 
name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2 Gastrointestinal 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, 


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67 
 
Esophageal perforation, Gastric perforation, Ileal perforation, Jejunal perforation, 
Rectal perforation, and Small intestinal perforation under the GASTROINTESTINAL 
DISORDERS SOC. 
 
4Infection 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 
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 


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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 
 
Note: Cediranib (AZD2171) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
 
7.1.1.2 
CAEPR for Olaparib 
 
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/aeguideline
s.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. 
 
 


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Version 2.4, April 24, 2019 1 
 
 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 2) 
GASTROINTESTINAL DISORDERS 
 
Abdominal distension 
 
Abdominal pain 
Abdominal pain (Gr 2) 
Constipation 
Constipation (Gr 2) 
Diarrhea 
Diarrhea (Gr 2) 
Dyspepsia 
Dyspepsia (Gr 2) 
Nausea 
Nausea (Gr3) 
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 


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malignancy in all cases, including documented BRCA mutation, treatment with radiotherapy and 
extensive previous chemotherapy including carboplatin, taxanes, anthracyclines and other 
alkylating and DNA damaging agents. Most are not attributed to olaparib. 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
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; 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; Pruritis; 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 event currently known to be caused by the other agent, or the combination may result in 


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events never previously associated with either agent. 
 
 
7.1.1.3 
Adverse Event List(s) for Cisplatin, Carboplatin, and Etoposide 
 
For risks associated with cisplatin, carboplatin, or etoposide, please refer to the 
respective package inserts. 
 
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 
5.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 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.h
tm).  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. 


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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. 
 
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 “Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” 
under the system organ class (SOC) of the same name.  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.  
 
Phase 1 and Early Phase 2 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/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) 
Death 
2) 
A life-threatening adverse event 
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization  
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
AdEERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 


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Resulting in 
Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
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 reported via AdEERS 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 within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For 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 
 
 
7.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS.  However, they still must be reported through the routine reporting 
mechanism (Section 7.4): 
 
CTCAE 
SOC 
Adverse 
Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 
5.0 
Grade 3-4 
hematologic 
toxicities not 
requiring 
hospitalization 
that last < 7 
days 
3-4 
n/a 
chemotherap
y 
 
5.0 
Alopecia 
any 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
 
7.5 
Reporting of Pregnancy and Overdose  
In the event of subject overdose with olaparib and/or cediranib, the trial Principal Investigator, 
Dr. Jacob Sands, must be notified within 24 hours regardless if the event presents an adverse 
event of any grade. The trial Principal Investigator will be responsible for collecting and 
reporting all event data to the NCI.  
 
In the event of subject pregnancy while on trial, the trial Principal Investigator, Dr. Jacob Sands, 
must be notified within 24 hours of learning of the event, whether or not it meets criteria for the 
reporting of an adverse event. The site should follow the pregnancy until the completion or the 
pregnancy is terminated.  The trial Principal Investigator will be responsible for collecting and 
reporting all event data to the NCI.  
 
7.6 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., 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.  
 
7.7 
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 


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reporting unless otherwise specified. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
8.1 
CTEP IND Agents 
No starter supplies will be provided. Study agents must be ordered after the patient is 
enrolled on the assigned treatment arm. If expedited shipment is required, sites should 
provide an express courier account through the Online Agent Order Processing (OAOP) 
application. 
8.1.1 Cediranib (AZD2171, NSC # 732208) 
 
Chemical Name:  4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-
(pyrrolidin-1- yl)propoxy] quinazoline maleate 
 
Other Names: Cediranib, AZD2171 maleate  
 
CAS Registry Number: 288383-20-0 (for the free base) 
 
Molecular Formula: C25H27FN4O3 • C4H4O4 
 
        
Molecular Weight: 566.59 (maleate salt), 450.52 (free base) 
 
Approximate Solubility: The aqueous solubility of AZD2171 (cediranib) is 0.0006 
mg/mL for the free base (distilled water, pH 8.1 at 25°C) and 1.76 mg/mL for the maleate 
salt (distilled water, at 25°C).  
 
Mode of Action: AZD2171 (cediranib) is a highly potent tyrosine kinase inhibitor of all 
three vascular endothelial growth factor receptors (VEGFR-1, -2 and -3). Inhibition of 
VEGF signaling leads to inhibition of angiogenesis, neovascular survival and vascular 
permeability. Pre-clinical tumor models show that AZD2171 (cediranib) reduces micro-
vessel density and metastasis, indicating that it limits tumor growth. 
 
How Supplied: Astra-Zeneca supplies and CTEP, NCI, DCTD distributes AZD2171 
(cediranib). The agent is available as beige, round, biconvex, film-coated tablets 
containing 15 mg, and 20 mg of AZD2171 (cediranib) free base.  The 15 mg and 20 mg 
tablets are 7 mm and 8 mm in diameter, respectively.  Each high-density polyethylene 
bottle contains 35 tablets. 
 
Tablet excipients include mannitol, dibasic calcium phosphate anhydrous, sodium starch 
glycolate, microcrystalline cellulose, and magnesium stearate with a film coat containing 
hypromellose 2910, polyethylene glycol 400, red iron oxide, yellow iron oxide, black 


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iron oxide, and titanium dioxide.  
 
Storage: Store intact bottles at controlled room temperature 20°C to 25°C (68 to 77°F) 
and protect from light and moisture.  
 
Stability: Stability studies are ongoing. Dispense AZD2171 (cediranib) tablets in their 
original containers. Alternatively, if exact quantity is dispensed in a pharmacy bottle, the 
supply should be assigned a 30-day expiration. 
 
If a storage temperature excursion is identified, promptly return AZD2171 (cediranib) to 
room temperature and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability.   
 
Route and Method of Administration: Oral. AZD2171 (cediranib) tablets should be 
taken either one hour before or two hours after meals.  
 
Potential Drug Interactions: AZD2171 (cediranib) is primarily metabolized by flavin-
containing monooxygenase enzymes (FMO1 and FMO3) and UGT1A4. It is not a 
substrate of CYP450 enzymes. In vitro studies suggest that AZD2171 (cediranib) is a 
substrate for P-glycoprotein (Pgp), but not breast cancer resistance protein (BCRP). Since 
clinically relevant induction or inhibition of FMO enzymes is uncommon, use caution in 
patients taking concomitant medications that are strong inhibitors (e.g. ketoconazole) or 
strong inducers (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin and St. John’s 
Wort) of UGT1A4 or Pgp in particular. If chronic concomitant administration of strong 
inducers or inhibitors is unavoidable, consult the protocol document and/or the principal 
investigator before making any dose adjustments. 
 
In vitro studies show that AZD2171 (cediranib) did not inhibit CYP 1A2, 2A6, 2C8, 2C9, 
2C19 and 2E1 and showed no induction of CYP 1A2, 2B6 and 3A4/5. It did weakly 
inhibit CYP 2D6 and 3A4/5, but this inhibition not expected to cause any clinically 
relevant drug interactions. 
 
In vitro studies show that AZD2171 (cediranib) is a weak inhibitor of BCRP, but not Pgp. 
Use caution in patients who are taking concomitant medications that are sensitive 
substrates of  BCRP transporters since there is a potential for drug-drug interactions.  
 
AZD2171 (cediranib) is approximately 95% bound to human plasma proteins, with 
human serum albumin and 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. 
 
Anticoagulants are not absolutely contraindicated during treatment with AZD2171 
(cediranib); however, use AZD2171 (cediranib) with caution and increase monitoring in 
patients while on study. Please see Section 5.2. Patients who receive VEGF inhibitors are 
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Patient Care Implications: Agents that inhibit VEGF signaling have the potential to 
affect wound healing. For patients already enrolled onto the protocol, the manufacturer 
recommends holding AZD2171 (cediranib) for 2 weeks prior to elective surgery and 
restarting when the surgical wound is healed. Protocol exclusion criteria include patients 
who have had major thoracic or abdominal surgery within 4 weeks prior to start of study 
or patients with any surgical incision that is not fully healed. 
Advise women study participants of reproductive potential to use effective contraception 
while receiving study treatment and for at least 6 weeks after the last dose of cediranib 
(AZD2171). Refer to the protocol document for specific guidance. 
Availability: Cediranib is provided to the NCI under a Collaborative Agreement between 
AstraZeneca (the Pharmaceutical Collaborator) and the DCTD, NCI (see Section 12.4). 
 
Agent Ordering and Agent Accountability: 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. 
 
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.   
 
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. 
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 


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establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status and a “current” password.  Questions about IB 
access may be directed to the PMB IB coordinator via email. 
Useful Links and Contacts: 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and 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 
 
8.1.2 Olaparib (AZD2281, NSC 747856)  
 
Chemical Name: 4-(3-4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl-4-
fluorophenyl)methyl phthalazin-1(2H)-one 
 
Other Names: AZD2281; KU-0059436; CO-CE 
 
Classification: PARP inhibitor 
 
CAS Registry Number: 763113-22-0 
 
Molecular Formula: C24H23FN4O3 
 
Molecular Weight: 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 


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How Supplied: AstraZeneca supplies and the CTEP, DCTD distributes olaparib as 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 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 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 of Administration: Tablets can be taken by mouth with a light meal/snack. 
Potential Drug Interactions:  In vivo data indicate that CYP3A4/5 is important for olaparib 
metabolism and clearance in humans. For this reason, avoid concomitant administration of 
strong and moderate CYP 3A4/5 inducers and inhibitors.  Consult the protocol document 
or study investigator prior to making any dose adjustments related to potential drug-drug 
interactions. 
In vitro data shows olaparib is a substrate for P-glycoprotein (P-gp), but not for organic 
anion-transporting polypeptides (OATP1B1 and OATP1B3), organic cation transporter 1 
(OCT1), multi-drug resistance protein 2 (MRP-2) efflux transporter or breast cancer 
resistance protein (BCRP). Administration of strong P-gp inhibitors and inducers should be 
avoided with concurrent olaparib. 
Based on in vitro data, olaparib inhibits CYP 3A4 and UGT1A1 enzyme systems and 
induces CYP 1A2, 2B6, and 3A4 and potentially induces CYP 2C9, 2C19 and P-gp. 
Therefore, avoid concomitant administration of sensitive substrates, particularly those with 
narrow therapeutic ranges. 
Olaparib is also an inhibitor of P-gp, OATP1B1, OCT1, OCT2, OAT3, multi-drug and toxin 


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extrusion proteins (MATE1 and MATE2K) and a weak inhibitor of BRCP, but not an 
inhibitor of OATP1B3 or MRP-2. In vitro studies suggest that olaparib may increase 
exposure of substrates of these transport systems, although the clinical relevance is not clear. 
The manufacturer recommends that statins, in particular, should be administered with 
caution when given concomitantly with olaparib. 
Patient Care Implications: Pre-clinical data indicate that olaparib adversely affects 
embryofetal survival and development. Therefore, women of child-bearing potential and 
their partners should agree to use two (2) highly effective forms of contraception throughout 
study participation and for at least one (1) month after the last dose of olaparib.  Male study 
participants should avoid fathering a child or donating sperm during the study and for three 
(3) months after the last dose of olaparib. The study investigator should discuss the most 
appropriate forms of highly effective contraceptive methods for each patient. 
Because the adverse events related to olaparib may include asthenia, fatigue and 
dizziness, patients should be advised to use caution while driving or using machinery. 
Availability: Olaparib is provided to the NCI under a Collaborative Agreement between 
AstraZeneca (the Pharmaceutical Collaborator) and the DCTD, NCI (see Section 12.4). 
 
Agent Ordering and Agent Accountability: 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. 
 
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.   
 
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 


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Records for each agent, strength, formulation and ordering investigator on this protocol. 
 
Investigator Brochure Availability: The current versions of the IBs for PMB-supplied 
agents will be accessible to site investigators and research staff through the PMB Online 
Agent Order Processing (OAOP) application.  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status and a “current” password.  Questions about IB 
access may be directed to the PMB IB coordinator via email. 
Useful Links and Contacts: 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account: https://eapps-
ctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and 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 
Commercial Agents 
 
8.2.1 Carboplatin 
 
Product description: A commercially available agent supplied as a sterile, pyrogen-free, 
10 mg/mL aqueous solution of carboplatin. Carboplatin is a platinum coordination 
compound. The chemical name for carboplatin is platinum, diammine [1,1-cyclobutane-
dicarboxylato(2-)-0,0í]-,(SP-4-2), and carboplatin has the following structural formula: 
 
 
Carboplatin is a crystalline powder with the molecular formula of C6H12N2O4Pt and a 
molecular weight of 371.25. It is soluble in water at a rate of approximately 14 mg/mL, 
and the pH of a 1% solution is 5-7. It is virtually insoluble in ethanol, acetone, and 


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dimethylacetamide. Please see FDA package insert. 
 
Solution preparation: Please see FDA package insert. Supplied as a premixed aqueous 
solution of 10 mg/mL carboplatin. 
 
Carboplatin can be further diluted to concentrations as low as 0.5 mg/mL with 5% 
dextrose in water (D5W) or 0.9% sodium chloride injection, USP. 
 
Route of administration: Intravenous, administer as per institutional standards. 
 
Agent Ordering: Commercially available agent 
 
8.2.2 Cisplatin 
 
Product Description: A commercially available clear, colorless, sterile aqueous solution 
available in amber vials. Each 50 mL amber vial of infusion concentrate contains: 1 
mg/mL cisplatin, 9 mg/mL Sodium Chloride, hydrochloric acid and sodium hydroxide to 
approximate pH of 4.0, and water for injection to a final volume of 50 mL.  
 
The active ingredient, cisplatin, is a yellow to orange crystalline powder with the 
molecular formula PtCl2H6N2, and a molecular weight of 300.1. Cisplatin is a heavy 
metal complex containing a central atom of platinum surrounded by two chloride atoms 
and two ammonia molecules in the cis position. It is soluble in water or saline at 1 
mg/mL and in dimethylformamide at 24 mg/mL. It has a melting point of 207°C. See 
FDA package insert. 
 
 
 
Solution Preparation: Please see FDA package insert. 50 mg vials should be 
reconstituted with 50 mL of sterile water for injection. Caution should be exercised in 
handling the powder and preparing the solution of cisplatin. Procedures for proper 
handling and disposal of anticancer drugs should be utilized. To minimize the risk of 
dermal exposure, always wear impervious gloves when handling vials and IV sets 
containing cisplatin for injection.  
 
Route of Administration: Intravenous, administer as per institutional standards in 0.9% 
NaCl, over 60 minutes. 
 
Agent Ordering: Commercially available agent 
 


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8.2.3 Etoposide 
 
Product description: Etoposide for Injection (VP-16) is a commercially available 
antineoplastic agent which is available for intravenous infusion as a 20 mg/ml solution in 
100 mg (5 ml), 500 mg (25 ml), or 1 gram (50 ml) sterile, multiple dose vials.  
 
  Etoposide (also commonly known as VP-16) is a semisynthetic derivative of 
podophyllotoxin used in the treatment of certain neoplastic diseases.  It is very soluble in 
methanol and chloroform, slightly soluble in ethanol, and sparingly soluble in water and 
ether.  It is made more miscible with water by means of organic solvents.Please see FDA 
package insert. 
 
The chemical name for etoposide is: It is 4’-demethylepipodophyllotoxin 9-[4,6-O-(R)-
ethylidene-β-D-glucopyranoside].  
 
Etoposide has the following structure: 
 
Solution Preparation: Please see FDA package insert. Etoposide Injection, USP must be diluted 
prior to use with either 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, to 
give a final concentration of 0.2 to 0.4 mg/mL.  If solutions are prepared at concentrations above 
0.4 mg/mL, precipitation may occur.   
 
Solutions of etoposide should be prepared in an aseptic manner. Parenteral drug products 
should be inspected visually for particulate matter and discoloration prior to 
administration whenever solution and container permit. 
 
Route of Administration: Intravenous, administer as per institutional standards in 0.9% 
NaCl over 60 minutes.  Shorter administration times are not recommended as 
hypotension can occur with infusion times shorter than 30 minutes. 


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Solutions of etoposide should be prepared in an aseptic manner. Parenteral drug products 
should be inspected visually for particulate matter and discoloration prior to 
administration whenever solution and container permit. 
 
Route of Administration: Intravenous, administer as per institutional standards in 0.9% 
NaCl over 60 minutes. Shorter administration times are not recommended as hypotension 
can occur with infusion times shorter than 30 minutes. 
 
 
Agent Ordering: Commercially available agent 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Please see Section 2.4 for detailed background information for all correlative studies. 
 
9.1 
Archival Tumor Tissue Collection - Exploratory/Ancillary Correlative Studies 
 
Archival tumor tissue collection is required for all participants enrolling to the trial, 
ideally 20 5 micron slides. Confirmation that archival tissue is available is required for 
trial eligibility. Participants who do not have archival tissue available may undergo a 
fresh tumor biopsy if clinically feasible.  
 
In the event that a participant has archival tissue available but does not have the 
minimum requested amount for every correlative study, priority should be as follows: 
1. Whole exome sequencing and RNA seq (10 5 micron slides minimum, 15 
preferred) 
2. PARP/SLFN11 immunohistochemistry (4-5 5 micron slides) 
3. BROCA-HR (2 consecutive unstained 10 micron slides or 4 consecutive 5 micron 
slides) 
 
If there is remaining tumor tissue that can be sent to the ECTCN biorepository for storage 
and DNA/RNA extraction, this should be done.  Otherwise, any remaining DNA/RNA 
after planned analyses at the Broad or University of Washington will be sent to this 
ECTCN biorepository. 
 
9.2 
Specimen requirements 
Overview of sample requirements 
Study 
Required Specimen 
Collection Time Points 
Collection Details 
BROCA-HR 
7 mL whole blood 
Baseline 
Collect in yellow top (ACD 
solution A) tube. Specimen to 
be shipped at ambient 
temperature for overnight 


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FFPE slides (from 
primary tumor 
and/or metastatic 
sites) 
Archival 
4-5 consecutive 
unstained 10 μm slides should 
be provided and shipped at 
ambient temperature overnight 
Plasma Angiome 
Two 4mL tubes of 
blood 
Baseline, Cycle 2 
Day 1 of treatment, at 
time of progression 
Collect in purple top tubes. 
Specimens should be 
processed on site to obtain 
plasma and then shipped on 
dry ice overnight. 
Whole exome 
sequencing (WES) 
and RNAseq 
FFPE slides 
Archival 
10 unstained slides of 5-10 
micron thickness should be 
provided and shipped at 
ambient temperature 
overnight
 
Whole exome 
sequencing (WES) 
and RNAseq 
Biopsy specimen (if 
obtained) 
Pre-treatment; 
Post-progression 
(optional) 
2 fresh frozen cores. Samples 
should be shipped by courier 
on dry ice for overnight 
delivery. 
Sequencing (ultra-
low pass +/-WES) 
10 ml whole blood 
Baseline, Cycle 2 Day1, 
cycle 3 Day1, then cycle 
2 and 3 day 1 during 
maintenance and at end 
of study 
Blood will be collected in 10 
cc EDTA tubes, processed on 
site (spun with plasma then 
aliquotted) and then shipped 
on dry ice. 
 
9.2.1 Tumor PARP Immunohistochemistry – Exploratory/Ancillary Laboratory Correlative 
Study #1  
 
Collection of Specimen: A minimum of 3 5 micron unstained slides should be obtained 
for analysis. 
 
Handling of Specimens: Specimens should be labeled with the NCI protocol number, 
study subject number, and “PARP IHC.”  
 
Samples will be subjected to immunohistochemistry (IHC) using total PARP1 antibody 
(Thermo Fisher, Freemont, CA) (used in prior studies, fresh Ab will be ordered when 
ready to perform IHC on study samples) (Byers, Cancer Discovery 2012).  Antigen 
retrieval will be performed using a decloaker with Dako Target Retrieval pH 6.0. 
 
SLFN11 IHC will be performed on FFPE specimens using fresh antibody as above 
against SLFN11 (HPA0203030, Sigma Aldrich) 
 


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Shipping of Specimens: Specimens should be shipped at room temperature.  Samples 
may be shipped to:  
Center for Biospecimen Research & Development (CBRD) 
Attn: Kelsey Weren 
NYU Langone Medical Center: Medical Science Building 
550 First Avenue, Berg 3rd Fl., Rm. 381 
New York, NY 10016 
Lab: 212-263-0135 
CBRD Main line: 646-501-4268 
CBRD Fax: 646-501-4579 
 
Sites Performing Correlative Study: PARP IHC will be performed in the laboratory of 
Dr. Lauren Byers at MD Anderson Cancer Center. 
 
 
 
9.2.2 Whole Exome Sequencing and Whole Transcriptome Sequencing from Tissue  – 
Exploratory/Ancillary Laboratory Correlative Study #2 
 
Collection of Specimens: A minimum of 10 unstained slides of 5 micron thickness 
should be obtained for analysis. 15 slides strongly preferred. 
 
Concomitant blood for germline DNA will be collected in 10 cc EDTA tube.  1mL of 
whole blood from this same tube will be banked from each tube at BASELINE ONLY. 
 
Handling of Specimens: The Broad Institute has designed a portal through which 
information on patient samples can be directly entered and downstream results can be 
obtained. The following information is received securely through the portal: 
 
Test Requisition Submission: All test requests for the Clinical Sequencing are received 
through the CRSP Client Portal. An authorized individual representing either a 
requisitioning physician or referring CLIA-certified laboratory may submit test 
requisitions via the CRSP Portal. Once the pertinent information for the requisitioning 
individual (i.e., NPI & medical license numbers) or entity (CLIA certificate number) has 
been verified, the client will be supplied with the information (username/password) 
required to access the CRSP Client Portal. Submission of a test requisition through the 
CRSP Client Portal ensures that all required requisition elements (e.g. Patient and sample 
information and identifiers) are completed and are in an acceptable format. 
 
Patient Information: Patient information will be de-identified to the sequencing center. 
We will store only the information provided and utilize IDs assigned by the clinical 
centers. We note that for our standard test requisitions we have made available a portal 
through which physicians can supply patient identifying information that will be stored 
securely in a compliant manner. This information is supplied in the form of a unique 
alphanumeric identifier (supplied by the requisitioning individual/entity) or the more 
standard collection of personal identifiers (e.g. first name, last name, date of birth, 
address, telephone number). The requisitioning individual/entity also completes an 


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


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hybridization and ‘capture’ in which the pond pools are hybridized to the biotinylated 
exome baits, captured on streptavidin beads, washed at high stringency to remove off- 
target hybridizations, and then eluted from the SPRI beads. This process hybridization, 
washing, and elution is repeated once more and, following the second elution step, 
captured targets are PCR amplified, cleaned up one final time, and then submitted for 
sequencing. 
 
Production Sequencing: Following targeting, libraries will be quantified (via Picogreen), 
normalized, and pooled. The resulting pool will be qPCR assayed and loaded onto 
flowcells for cluster amplification. All of these steps are part of Broad’s standard 
Illumina library construction process which includes numerous QC steps: verification of 
all liquid handling instrumentation prior to each run using fluorescent dyes, QC of all 
critical reagent lots, auditing of vendor issued QCs for all other reagents, regular training 
verification of personnel, and other in-process QCs including specifically designed qPCR 
assays to verify loading concentrations. 
 
We propose to use the HiSeq2500 for sequencing in this project. We have demonstrated 
failure rates of less than 10%, yields per flowcell of 130 Gb with run times of 27 hours 
for 2x101 runs, and have already produced over forty (40) terabases of data with the 
HiSeq2500. The HiSeq2500 fits seamlessly into the Broad sequencing laboratory and 
analysis pipelines and greatly simplifies the workflow and time in the lab with on-board 
cluster generation and reduced chemistry and imaging cycle times. Four (4) exome 
libraries are mixed or multiplexed and loaded per flow cell lane. We generate 5 Gb of 
sequence for each library. Real-time monitoring of many quality metrics, including the 
following is used to ensure exquisite control of the production line: 
 
On-target sequence yield. A major inefficiency of all massively parallel targeting 
approaches is the inability to precisely and uniquely capture (to the base pair) the target 
of interest. We have made a number of improvements to our production protocol (such as 
blocking agents against sequencing adaptors) which have resulted in routine on-target 
proportion of ~ 90% of reads. 
 
Percent-target coverage ≥20X. We require the baseline coverage to be >80% of targets to 
be covered at over 20X across the target region.  This level of coverage typically results 
in ~100X average coverage across the exome, though higher levels of coverage can be 
achieved with additional sequencing. 
 
Non-duplicate reads. Observation of duplicate reads (reads with the same start and stop 
sites) indicates that the same molecule has been sequenced multiple times. This can 
mislead SNP calling algorithms, since the same molecule-specific (PCR or other) error 
can erroneously be counted as independent observations. We found that PCR upstream of 
selection can lead to a high degree of duplication, likely from bottlenecking of input 
material. Our current protocol is stable at 5-10% read duplication (duplicated reads are 
removed bioinformatically at BAM aggregation) and an increase in this measure signals 
issues with library preparation. 
 


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Contamination check. As an additional layer of process control and test accuracy, we 
routinely apply a set of algorithms called ‘verifyBamID’ to every sequencing dataset. 
VerifyBamID is a piece of software that detects possible sample mixture from population 
allele frequency only, which may be particularly useful when the genotype data is not 
available. Specifically VerifyBamID verifies whether the reads in a particular file match 
previously known genotypes for an individual (or group of individuals), and checks 
whether the reads are contaminated as a mixture of two samples8. Using a mathematical 
model that relates observed sequence reads to a hypothetical true genotype, verifyBamID 
determines whether sequence reads obtained from the processing of a given sample 
match a particular individual or are more likely to be contaminated, derived from a 
closely related individual, or derived from a completely different individual. 
 
In the rare instance when initial sequencing efforts fail to provide sufficient sequence 
coverage, additional sequence and coverage will be generated using the same rapid turn-
around time exome express processes. 
 
Data analysis: The CSRP’s analysis pipeline consists of a large number of tools 
designed to detect different types of genomic events (Figure 1): (i) Point mutations 
(MuTect – Cibulskis et al.,; (ii) small insertions and deletions (Indelocator – Sivachenko 
et al.); (iii) rearrangements (dRanger – Lawrence et al.) and their exact breakpoint 
(BreakPointer); (iv) Copy-number changes (CapSeg– Carter et al.,); (v) Purity and 
ploidy, absolute copy-number and clonal/sub- clonal mutations (ABSOLUTE) (vi) 
Pathogen discovery (PathSeq); and finally (vii) we annotate all these genomic events with 
their effect on proteins, their relationship to disease, overlap with known cancer genes or 
pathways, potential functional effects using our tool Oncotator (Ramos et al., submitted; 
www.oncotator.org). The output of this pipeline is a set of VCF files (one per patient) and 
corresponding MAF file with all annotations. As of May 2014, MuTect and Indelocator 
have been validated in the CLIA process. 
 
The CSRP’s tools are of the highest quality in the field and were used to analyze a large 
number of cancer projects (references available upon request). For example, comparison 
of MuTect (CSRP’s mutation caller) to other commonly used tools demonstrated that it is 
vastly superior (much more sensitive for any given false-positive value) (Figure 2). 
Finally, the Broad Institute is developing tools to take all types of alterations in a 
patient’s tumor and prioritize the events with respect to clinical-relevance. These are then 
presented in a comprehensive report. Other tools that are being developed are aimed at 
analysis of sub-clonal composition of tumors and their evolution in multiple tumor 
samples (e.g. longitudinal samples, primary/metastases, primary/relapse etc.). These tools 
can estimate the number of macroscopic sub-clones and the fraction of cancer cells that 
they represent and when multiple tumors are analyzed the tools can also detect evolution 
of sub-clones (Landau, Carter, Stojanov et al.) 
 


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Figure 2: Receiver operating characteristic (ROC) curve for MuTect, for mutations at allele 
fraction of 0.2 and at 30x sequencing depth. Results are shown for Standard filtering (STD) 
and High-Confidence (HC). Results for two leading tools in the field, SomaticSniper and 
JointSVNMix are provided showing significant improved sensitivity for MuTect compared 
to the other tools. 
 
Transcriptome sequencing (RNA-seq): We will also generate transcriptome sequencing 
using tumor RNA obtained from biopsies. RNA- seq may provide insights into 
overexpressed genes, chimeric transcripts (possibly indicative of underlying structural 
genomic rearrangements), and/or alternatively spliced variants. Thus, application of 
RNA-seq to serially obtained biopsies may provide useful information about dysregulated 
pathways or networks not evident from somatic genetic analysis, pharmacodynamic 
changes caused by drug action, adaptive cellular responses to drug target inhibition, and 
“non- genetic” resistance mechanisms. As with WES, the Broad Institute has developed 
considerable “production-scale” expertise in RNA-seq sequencing. As the production 
center for the Genotype Tissue Expression (GTEx) project 
(http://commonfund.nih.gov/GTEx/), the Broad Institute has developed many RNA-seq 
protocols. In addition to the GTEx project, the Broad also produced RNA-seq data for the 
entire Cancer Cell Line Encyclopedia (CCLE). Over the past two years, the Broad 
Institute generated RNA-seq data for over 3,000 samples. Through application of 
automated fluid- handling techniques and process optimization, they created an RNA-seq 
sample preparation pipeline that can handle 192 samples per week at current demand 
levels. 
 
Illumina’s TruSeq method affords robust performance in terms of RNA input and 
sequencing library complexity. This method allows for input RNA amounts as low as 
250-500 ng and is automated for high-throughput production. To generate RNA-seq data, 
polyA+ RNA will be isolated in the Genetic Analysis Platform at the Broad Institute. 
Next, strand-specific cDNA libraries will be generated. Each cDNA library will be 
sheared by sonication, paired-end adapters for Illumina sequencing will be added, and 
Illumina sequencing libraries will be prepared following established protocols. Each 
sample will be subjected to Illumina sequencing using an Illumina HiSeq instrument, 
producing ~101 bp paired-end reads. RNA-seq data will be analyzed by the 
Computational Biology Core. 
 
As with WES, the Broad Institute has developed considerable “production-scale” 
expertise in RNA sequencing. Illumina’s TruSeq method affords robust performance in 


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terms of RNA input and sequencing library complexity. This method allows for input 
RNA amounts as low as 250- 500ng and is automated for high-throughput production. 
Algorithms to identify RNA-based features including alternative splice variants, novel 
fusions and aggregate gene expression changes (CuffLinks/CuffDiff) will be applied to 
RNA-seq data. 
 
Shipping of Specimens: Please refer to the Specimen Requirements table in section 9.2 
for specific shipping requirements.  Samples should be shipped to: 
 
Broad Institute 
 
Attn: Genomics Platform—Samples Lab 
 
320 Charles Street—Lab 181 
 
Cambridge, MA 02141 
 
Phone (617) 714-8952 
 
Site(s) Performing Correlative Study: WES and RNASeq will be performed by the 
Center for Cancer Precision Medicine at the Broad Institute (Cambridge, MA). 
 
9.2.3 BROCA-HR – Exploratory/Ancillary Laboratory Correlative Study #3 
 
Collection of Specimen: A minimum of 2 consecutive unstained 10 µm slides should be 
obtained for analysis. 
 
Handling of Specimens: Specimens should be labeled with the NCI protocol number, 
study subject number, and “BROCA-HR.”  
 
DNA will be extracted from PBMCs and FFPE archived tumor tissue containing at least 
30% tumor nuclei. A targeted capture and massively parallel sequencing approach called 
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 inherited risk 
of ovarian carcinoma and 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 1ug of constitutional 
or neoplastic DNA and hybridize to a custom pool of oligonucleotides targeting genomic 
regions as previously described (27) 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 pipeline (27). Deletions and duplications of exons will be detected by a 
combination of depth of coverage and split read analysis as previously described (39), 
supplemented with additional alignments generated by SLOPE (40). 
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 


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then correlate HR proficiency with response to platinum or PARPi on the trial. Later, in 
exploratory analyses, we will add in analyses of NHEJ and other modifying genes, 
genomic scarring, or other somatic tests by our lab or others to complement the 
determination of HR deficiency. 
 
Shipping of Specimens: Please refer to the Specimen Requirements table in Section 9.2 
for specific shipping requirements. 
 
Sites Performing Correlative Study: BROCA-HR will be performed by the laboratory 
of Dr. Elizabeth Swisher at the University of Washington (Seattle, WA).  Samples should 
be shipped to:  
 
Swisher Lab 
 
ATTN: Kathy Agnew 
 
University of Washington 
 
1959 NE Pacific Street  
 
 
HSB BB632 
 
Seattle, WA 98195 
 
Phone (206) 685-7927 
 
Kagnew@uw.edu 
 
9.3 
Blood-Based Exploratory/Ancillary Correlative Studies 
 
9.3.1 Plasma Angiome Analysis – Exploratory/Ancillary Laboratory Correlative Study #4 
 
Collection of Specimens: Blood samples to be collected at the following time points: 
 
Table 17: Plasma Angiome Collection Schedule 
Trial Phase 
Visit Day 
Time Point 
Sample 
Number 
Initial therapy 
Cycle 1 Day 1 
Any time prior to 
dosing with any of the 
agents 
1 
Initial therapy 
Cycle 2 Day 1 
Any time prior to 
dosing with any of the 
agents 
2 
Maintenance 
Cycle 2 Day 1* 
Any time prior to 
dosing with any of the 
agents 
3 
Initial therapy OR 
maintenance 
Time of Disease 
Progression 
Any time during the 
visit 
4 
*: In participants not receiving maintenance therapy, “Cycle 2 Day 1” sample to be 
collected 6 weeks after the completion of the initial therapy phase of the trial. 
 
Blood for each time point should be collected in two 4 mL purple top tubes as described 
below. 
 


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Handling of Specimens: 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 
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 (e.g. EDTA plasma, whole blood, citrate plasma, etc.) 
 
Shipping of Specimens: 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 1,  
203 Research Drive 
Durham, NC 27710 
Phone (919) 681-2239 
Email contact: Chris Brady: jchris.brady@duke.edu  
 


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Sites Performing Correlative Study: This correlative analysis will be performed in the 
laboratory of Dr. Andrew Nixon at Duke University Medical Center. 
 
9.3.2 Circulating Free DNA (cfDNA) – Exploratory/Ancillary Laboratory Correlative Study 
#5 
 
Collection and Handling of Specimens: Blood samples to be collected at the following 
time points: 
 
Table 18: cfDNA Collection Schedule 
Trial Phase 
Visit Day 
Time Point 
Sample 
Number 
Initial therapy 
Cycle 1 Day 1 
Any time prior to 
dosing with any of the 
agents 
1 
Initial therapy 
Cycle 2 Day 1 
Any time prior to 
dosing with any of the 
agents 
2 
Initial Therapy 
Cycle 3 Day 1 
Any time prior to 
dosing with any of the 
agents 
3 
Maintenance 
Cycle 2 Day 1* 
Any time prior to 
dosing with any of the 
agents 
4 
Maintenance 
Cycle 3 Day 1 
Any time prior to 
dosing with any of the 
agents 
5 
Initial therapy OR 
maintenance 
Time of Disease 
Progression 
Any time during the 
visit 
6 
*: In participants not receiving maintenance therapy, a “Cycle 2 Day 1” sample is to 
be collected within 6 weeks of the completion of the initial therapy phase of the trial. 
 
NOTE: Time period from draw to freezing of plasma must be less than 3 hours. Blood 
will be collected in 10 cc EDTA tubes, barcoded, and processed within 3 hours of blood 
draw. We have previously confirmed that white blood cells remain stable during this 
period of time and thus, do not affect the purity of tumor-derived cell-free DNA. 1mL of 
whole blood will be banked from each tube and frozen at -80C in a 2d-barcoded tube 
until further processing. The remaining blood will be subjected to two rounds of 
centrifugation (2,000 x g for 10 min followed by 15,000 x g for 10min). Plasma will be 
removed and frozen at -80C in another 2d-barcoded tube until further processing. All 
samples are registered in our laboratory information management system and tracked 
throughout the process. Extractions of cell-free DNA and germline DNA will be 
performed from banked plasma and whole blood, respectively, using an automated liquid 
handler. Liquid handling systems will also be used for the subsequent steps of 
quantification, normalization, and library construction. Sequencing on the Illumina HiSeq 
will be used to assess the purity of tumor-derived cell-free DNA. Samples with sufficient 


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purity of tumor-derived cell-free DNA will be nominated for hybrid capture of the entire 
human exome and sequenced on the Illumina HiSeq.  
 
Shipping of Specimens: Specimens should be shipped at -70°C or colder 
 
Sites Performing Correlative Study: Circulating free DNA processing and assessment 
of tumor DNA purity as well as subsequent whole exome sequencing will be performed 
by the Center for Cancer Precision Medicine at the Broad Institute (Cambridge, MA). 
 
Shipping of Specimens: Please refer to the Specimen Requirements table in section 9.2 
for specific shipping requirements.  Samples should be shipped to: 
 
Broad Institute 
 
Attn: Genomics Platform—Samples Lab 
 
320 Charles Street—Lab 181 
 
Cambridge, MA 02141 
 
 
9.3.3 Circulating Tumor Cells for Cell Derived Xenograft Models – Exploratory/Ancillary 
Laboratory Correlative Study #5 
 
Collection of circulating tumor cells (CTCs) will be optional for all participants enrolled 
to the trial as part of a companion study NCI 9846. Patients will be asked to sign the 
protocol informed consent form to allow collection and use of samples to generate 
patient-derived models (cell lines) and the collection of associated limited medical 
information. Patients will not be able revoke their consent for research use of these 
samples once collected; this is specified in the informed consent form. 
 
Samples will be collected on the SAME schedule as described in table 19 (section 9.3.2) 
 
9.4 
Fresh Tumor Tissue Collection - Exploratory/Ancillary Correlative Studies 
  
9.4.1 Tumor PARP Immunohistochemistry, BROCA-HR, and WES 
 
Participants able and willing to undergo optional fresh tumor biopsies may have the fresh 
samples sent for Tumor PARP immunohistochemistry, BROCA-HR, and WES analysis 
as previously described. 
 
Collection of Specimens: Optional fresh biopsies will be obtained prior to entry on 
study, anytime between cycle 1 day 8 and cycle 2 day 1, and at the time of disease 
progression when clinically feasible. Time of progression biopsy should be obtained prior 
to the initiation of another anti-cancer therapy. In the event that it is not clinically 
possible to obtain a biopsy before the initiation of another treatment, the time of 
progression biopsy may be obtained any time up to 14 days after the last dose of study 
medication. 
 


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Collection of fresh tumor tissue by core biopsy, surgical resection, fine needle aspiration 
(FNA), or drainage of effusions should be performed according to local standards at each 
participating site. Whenever possible, core biopsy samples should be collected for 
analysis. Four biopsy passes utilizing a 16-18 gauge needle are preferable, but 20 gauge 
core needle biopsies are also acceptable at the discretion of the interventionalist 
performing the biopsy procedure.  
 
If a core biopsy is judged to be too unsafe or difficult for the participant in the opinion of 
the treating investigator or interventionalist performing the procedure, an FNA or 
cytology sample can also be collected. The goal for a thoracentesis or paracentesis 
procedure will be 500 – 1000 mL collected in a standard collection tube. The goal for an 
FNA will be three distinct passes. Less than the goal amount of tissue is acceptable for 
any of the biopsy collection methods, and should be based upon the clinical judgment of 
the treating investigator and the clinician performing the procedure. 
 
Handling of Specimens: Cytology samples should be made into blocks per routine local 
procedures. 
 
Research cores should be allocated in the following order: 
1. Core #1 and 2: Placed in neutral buffered formalin and then embedded in FFPE 
(Formalin Fixed Paraffin Embedded) no more than 16 hours after exposure to neutral 
buffered formalin.  
2. Cores #3 and 4: embedded in frozen OCT medium, transported and frozen on dry ice, 
stored at -80°C.  
 
Shipping of Specimens: Please see section 9.2 for details on shipping requirements. 
 
Samples should be shipped to: 
Center for Biospecimen Research & Development (CBRD) 
Attn: Kelsey Weren 
NYU Langone Medical Center: Medical Science Building 
550 First Avenue, Berg 3rd Fl., Rm. 381 
New York, NY 10016 
Lab: 212-263-0135 
CBRD Main line: 646-501-4268 
CBRD Fax: 646-501-4579 
 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  
Informed consent, scans, and x-rays must be done <4 weeks prior to the start of therapy.  In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy. 
 


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Table 19: Study Calendar – Initial Therapy Phase 
 
Pre- 
Study 
Cycle 1 
Day 1 
Cycle 1 
Day 8t 
Cycle 1 
Day 15t 
Cycle 2 
Day 1u 
Cycle 3 
Day 1u 
Cycle 4 
Day 1u 
Within 2 Weeks of 
Completion of Initial 
Therapy 
Off 
Treatmentv 
CediranibA 
 
As described in Section5.1.1 
 
 
Cisplatin/CarboplatinB 
 
As described in Section 5.1.3 
 
 
EtoposideB 
 
As described in Section 5.1.5 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------- 
 
X 
Physical exam 
X 
X 
 
 
X 
 
 
 
X 
Vital signsa 
Xb 
Xc 
X 
X 
X 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
 
 
X 
Performance status 
(ECOG) 
X 
X 
 
 
X 
X 
X 
 
X 
CBC w/diff, pltsd 
X 
X 
X 
X 
X 
X 
X 
 
X 
Serum chemistrye 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysisf 
X 
 
 
 
X 
X 
X 
 
X 
TSH and Free T4g 
X 
 
 
 
X 
X 
X 
 
X 
Coagulation Panelh 
X 
 
 
 
 
 
 
 
 
EKGi 
X 
 
 
 
 
 
 
 
 
Adverse event evaluation 
X 
X---------------------------------------------------------------------X 
 
X 
Initial Treatment 
Randomizationj 
X 
 
 
 
Tumor measurements 
X 
Tumor measurements are repeated every 6 weeks.  Documentation (radiologic) must be 
provided for patients removed from study for progressive disease. There is a ± 3 day 
scheduling window for obtaining tumor measurements. 
X 
Radiologic evaluation 
X 
CT or MRI imaging of every disease-involved site. Radiologic measurements should be 
performed every 6 weeks. There is a ±3 day scheduling window for obtaining scans. 
X 
β-HCGk 
X 
 
 
 
 
 
 
 
 
Echocardiogram or 
MUGAl 
X 
 
 
 
 
 
X 
 
 
Home Blood Pressure 
Monitoringm 
 
As described in Section5.2.1. 
 
 
Archival Tumor Tissue 
Collectionn 
X 
 
 
 
 
 
 
 
 
cfDNA Collectiono 
 
X 
 
 
X 
X 
 
 
X 
Plasma Angiome 
Analysisp 
 
X 
 
 
X 
 
 
 
X 
CTC Blood Collectionq 
 
X 
 
 
 
 
 
 
X 
Randomization to 
Maintenance Armr 
 
 
 
 
 
 
 
X 
 


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Table 19: Study Calendar – Initial Therapy Phase 
 
Pre- 
Study 
Cycle 1 
Day 1 
Cycle 1 
Day 8t 
Cycle 1 
Day 15t 
Cycle 2 
Day 1u 
Cycle 3 
Day 1u 
Cycle 4 
Day 1u 
Within 2 Weeks of 
Completion of Initial 
Therapy 
Off 
Treatmentv 
Tumor Tissue Biopsys 
X 
 
 
 
X 
 
 
 
X 
A: 
Cediranib: Dose as assigned; please see Section 2.2.1for treatment details. 
B: 
Chemotherapy agents to be administered per standard of care guidelines, please see Section  5.1.3 for treatment details. 
a. 
Vital signs to include heart rate, respiratory rate, blood pressure, temperature, and oxygen saturation (O2 sat). 
b. 
Screening blood pressure must be re-assessed on two occasions that are separated by a minimum of 1 hour.   
c. 
For participants receiving cediranib: blood pressure on cycle 1 day 1 must be < 140/90 mmHg prior to dosing. 
d. 
Additional time points as clinically indicated or as per standard of care. 
e. 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium, magnesium. Additional tests and time points as clinically indicated or as per standard 
of care. 
f. 
Urine protein:creatinine (UPC) ratio may be used instead. If urinalysis is performed for screening, test must be repeated with tests no less 
than 1 week apart. Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 and off study urinalyses/UPC only required for patients receiving 
cediranib. Additional tests may be performed as clinically indicated.   
g. 
Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, and off study TSH/Free T4 only required in patients receiving cediranib.  
h. 
Coagulation panel to consist of aPTT, PT, and PT-INR. 
i. 
Single EKG to be performed. EKG should be collected after the participant has been resting for at least 5 minutes. 
j. 
Initial randomization to be performed after participant has satisfied eligibility requirements. Please see Section 4.3for further detail.  
k. 
Serum pregnancy test (women of childbearing potential). 
l. 
Echocardiogram (echo) or MUGA required for all participants during screening. Repeat echo or MUGA required in participants with a 
prior history of treatment with anthracyclines, trastuzumab, central thoracic radiation therapy, or a history of myocardial infarction within 
12 months prior to study entry. 
m. 
Home blood pressure monitoring only required for participants randomized to receive cediranib. 
n. 
Archival tumor tissue collection as described in Section 9.1 
o. 
cfDNA to be collected any time prior to dosing with any of the agents on Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 3 Day 1 as described 
in Section 1Additional sample to be collected at the time of disease progression. 
p. 
Plasma angiome analysis to be collected any time prior to dosing with any of the agents on Cycle 1 Day 1 and Cycle 2 Day 1 as described 
in Section 9.3.1Additional sample to be collected at the time of disease progression. 
q. 
CTC blood collection only required for participants who agreed to this optional additional research study. Samples to be collected any 
time prior to dosing with any of the agents on Cycle 1 Day 1 and again at the off study visit as described in Section 9 
r. 
Participants who did not receive cediranib during the initial therapy phase who present with stable disease or better upon completion of 
initial therapy will be randomized to receive cediranib plus olaparib as maintenance therapy or no maintenance therapy, as discussed in 
Section 5.1Randomization to maintenance arm to occur within 2 weeks of completion of initial therapy.  
s. 
Optional fresh tumor biopsy when clinically feasible as described in Section 9 
t. 
A ± 2 day scheduling window exists for Cycle 1 Day 8 and Cycle 1 Day 15 to accommodate adverse weather, holidays, or other 
scheduling issues.  
u. 
A ± 3 day scheduling window exists for the start of a subsequent cycle to accommodate adverse weather, holidays, or other scheduling 
issues.  
v. 
Off treatment evaluation to be completed within 30 days of the last dose of study medication. Note: follow-up visits or other contact is 
required in order to identify SAEs during the 30 days following treatment.   
 
 
Table 20: Study Calendar – Maintenance Phase 
 
 
Within 2 
Weeks of 
Completion 
of Initial 
Therapy 
Cycle 
1 Day 
1 
Cycle 
1 Day 
8m 
Cycle 
1 Day 
15m 
Cycle 
1 Day 
22m 
Cycle 
2 Day 
1n 
Cycle 
2 Day 
15m 
Cycle 
3+ Day 
1n 
Off 
Treatmento 
Every 3 
months after 
discontinuingp 
CediranibA§ 
 
As described in Section 5.1.1 
 
 
OlaparibA§ 
 
As described in Section 5.1.2 
 
 
Randomization 
to Maintenance 
Therapya 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
X---------------------------------------------------------------------X 
X 
 
Adverse Event 
Assessment§ 
X---------------------------------------------------------------------X 
X 
 
Vital Signsb§ 
 
Xc 
X 
X 
X 
X 
X 
X 
X 
 


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Table 20: Study Calendar – Maintenance Phase 
 
 
Within 2 
Weeks of 
Completion 
of Initial 
Therapy 
Cycle 
1 Day 
1 
Cycle 
1 Day 
8m 
Cycle 
1 Day 
15m 
Cycle 
1 Day 
22m 
Cycle 
2 Day 
1n 
Cycle 
2 Day 
15m 
Cycle 
3+ Day 
1n 
Off 
Treatmento 
Every 3 
months after 
discontinuingp 
Physical Exam§ 
 
X 
 
X 
 
X 
 
X 
X 
 
Performance 
Status (ECOG)§ 
 
X 
 
 
 
X 
 
X 
 
 
Weight§ 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC w/Diff, 
Platelets§ 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum 
Chemistryd§ 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
TSH and Free 
T4§ 
 
X 
 
 
 
X 
 
X 
X 
 
Urinalysise§ 
 
X 
 
 
 
X 
 
X 
X 
 
EKGf§ 
 
X 
 
 
 
 
 
Xg 
 
 
Echocardiogram 
or MUGA§ 
 
 
 
 
 
 
 
Xh 
 
 
Home blood 
pressure 
monitoring§ 
 
As described in Section 5.2.1 
 
 
Tumor 
Measurements 
 
Initial measurements for the maintenance phase to be conducted at the 
end of cycle 4 of the initial therapy phase. Subsequent tumor 
measurements are repeated every 8 weeks.  Documentation (radiologic) 
must be provided for patients removed from study for progressive 
disease. There is a ± 7 day scheduling window for obtaining tumor 
measurements. 
X 
 
Radiologic 
Evaluation 
 
CT or MRI imaging of every disease-involved site. Participants should 
have imaging repeated prior to the initiation of maintenance therapy. 
Subsequent radiologic measurements during the maintenance phase 
should be performed every 8 weeks. After 6 months on maintenance 
therapy, scans may be performed every 12 weeks. There is a ±7 day 
scheduling window for obtaining scans. 
X 
 
cfDNA 
Collectioni 
 
 
 
 
 
X 
 
Xi 
X 
 
Plasma Angiome 
Analysisj 
 
 
 
 
 
X 
 
 
X 
 
CTC Blood 
Collectionk 
 
 
 
 
 
 
 
 
X 
 
Tumor Tissue 
Biopsyl 
 
 
 
 
 
 
 
 
X 
 
Telephone or 
care provider 
contact 
 
 
 
 
 
 
 
 
 
X 
§: 
Denotes an assessment that is only required in participants who are receiving cediranib and olaparib. 
A: 
Cediranib and Olaparib: Doses as assigned; please see Section 5.1.1 for treatment details. 
a. 
Randomization to maintenance therapy to be completed within 2 weeks of completion of initial therapy, please see Section 5.1for detail. 
b. 
Vital signs to include heart rate, respiratory rate, blood pressure, temperature, and O2 sat. 
c. 
Blood pressure on cycle 1 day 1 must be < 140/90 mmHg prior to dosing with cediranib. 
d. 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium. Additional tests and time points as clinically indicated. 
e. 
Urine protein:creatinine (UPC) ratio may be used instead. 
f. 
Single EKG to be performed at each time point. EKG should be collected after the participant has been resting for at least 5 minutes. 
g. 
EKG required on Cycle 3 Day 1 only. Additional EKGs to be collected as clinically indicated. 
h. 
Echocardiogram or MUGA required once every four cycles (e.g., Cycle 4 Day 1, Cycle 8 Day 1, and so on) in participants with a prior 
history of treatment with anthracyclines, trastuzumab, central thoracic radiation therapy, or a history of myocardial infarction within 12 
months prior to study entry. 
i. 
cfDNA to be collected any time prior to dosing with any of the agents on Cycle 2 Day 1, on cycle 3 day 1, and at the off study visit as 
described in Section 9In participants not receiving maintenance therapy, a “Cycle 2 Day 1” sample should be collected within 6 weeks 
following the completion of the initial therapy phase of the study. 
j. 
Plasma angiome analysis sample to be collected any time prior to dosing with any of the agents on Cycle 2 Day 1 and at the off study visit 
as described in Section 9.3. In participants not receiving maintenance therapy, the “Cycle 2 Day 1” sample should be collected 6 weeks 
following the completion of the initial therapy phase of the study. 


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Table 20: Study Calendar – Maintenance Phase 
 
 
Within 2 
Weeks of 
Completion 
of Initial 
Therapy 
Cycle 
1 Day 
1 
Cycle 
1 Day 
8m 
Cycle 
1 Day 
15m 
Cycle 
1 Day 
22m 
Cycle 
2 Day 
1n 
Cycle 
2 Day 
15m 
Cycle 
3+ Day 
1n 
Off 
Treatmento 
Every 3 
months after 
discontinuingp 
k. 
CTC blood collection only required for participants who agreed to this optional additional research study. Sample to be collected at the off 
study visit. Please see details in Section 9.3.1  
l. 
Optional fresh tumor biopsy when clinically feasible as described in Section 9.4 
m. 
A ± 3 day scheduling window exists to accommodate adverse weather, holidays, or other scheduling issues. 
n. 
Beginning with Cycle 2 Day 1, the start of a subsequent cycle may be delayed by up to 7 days to accommodate vacations, holidays, or other 
scheduling issues. Enough study medication supply should be dispensed to participants to allow for any pre-planned scheduling delays. 
o. 
Off treatment evaluation to be completed within 30 days of the last dose of study medication. Note: follow-up visits or other contact is 
required in order to identify SAEs during the 30 days following treatment. 
p. 
Participants will be followed until death or withdrawal of consent after removal from protocol therapy. This follow up will be performed by 
review of the medical record, contact with care providers, and/or telephone contact as needed every 3-4 months. 
 
 
 
 
 


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11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 6 weeks during 
the initial therapy phase of the trial, and then every 8 weeks thereafter.  In addition to a baseline 
scan, confirmatory scans should also be obtained not less than 4 weeks following initial 
documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with any of the protocol agents. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam.  
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area may not be 
considered measurable unless there has been demonstrated progression in the lesion. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 


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slice thickness recommended to be no greater than 5 mm [0.5 cm]).  At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 


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103 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT 
scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 


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104 
 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 


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105 
 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm).  
(Note:  the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 


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106 
 
Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Table 22: For Patient with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
 
Table 23: For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 


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107 
 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from randomization to time of progression or 
death, whichever occurs first. For the primary comparison regarding maintenance 
therapy, PFS is defined as the duration of time from the second randomization (to CO 
maintenance or no further therapy) for the subset of patients initially randomized to EP 
initial therapy who do not experience progressive disease.  For the secondary 
comparisons regarding initial therapy, PFS is defined as the duration of time from the 
first randomization (to EP initial therapy or EPC initial therapy). 
 
 
 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Study Oversight 
 
This protocol is monitored at several levels, as described in this section.  The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 


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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.  In addition, a conference call will be held after the first 10 participants are 
enrolled in the EPC arm to specifically review toxicity of the combination and determine 
whether there are unexpected adverse effects that should affect continued enrollment 
(specifically, if there are >4 grade 3 or above events, this should prompt re-evaluation of dosing 
for the combination.  Following the interim analysis, a decision to proceed will require sign-off 
by the Protocol Principal Investigator and the Protocol Statistician. 
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate 
roles assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site 
user must have an active CTEP IAM account (https://eapps-ctep.nci.nih.gov/iam) and the 
appropriate Rave role (Rave CRA, Read-Only, or Site Investigator) on either the Corresponding 
Organization or Participating Organization roster at the enrolling site.   
 
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 


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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-
11CTMSSupport@theradex.com.  On-site audits will be conducted three times annually (one 
annual site visit and two data audits).  For CTMS monitored studies, after users have activated 
their accounts, please contact the Theradex Help Desk at (609) 799-7580 or by email at 
ctms@theradex.com for additional support with Rave and completion of CRFs. 
 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching 
goal of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
)  and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include 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 


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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 
CTEP Multicenter Guidelines 
 
n/a 
 
12.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained 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 


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agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
12.5 
Genomic Data Sharing Plan 
 
n/a 
 
13. STATISTICAL CONSIDERATIONS 
 


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13.1 
Study Design/Endpoints 
 
This is a phase II randomized study of cisplatin/carboplatin plus etoposide (EP) ± 
cediranib followed by maintenance therapy with cediranib plus olaparib or no 
maintenance therapy. Patients will be randomized 2:1 to cisplatin/etoposide (EP) with or 
without cediranib (EPC) in initial therapy, with 2/3 of the patients randomized to initial 
therapy with EP alone. After initial therapy, patients with stable disease or better by 
RECIST version 1.1 criteria on EP alone will be randomized equally to no maintenance 
therapy or maintenance therapy with cediranib/olaparib (CO). Patients randomized to 
EPC as initial therapy will be directly assigned to receive maintenance therapy with 
cediranib/olaparib (CO).  
 
The primary objective of the trial is to assess the median PFS (in months) in participants 
who receive CO as maintenance therapy compared to those receiving standard therapy 
(no maintenance treatment); this comparison will involve the subset of patients assigned 
to initial therapy with EP alone who do not experience progressive disease and are 
randomized to no maintenance therapy or CO maintenance therapy. PFS will be defined 
as the time from second randomization to documented disease progression or death from 
any cause, whichever occurs first. Patients who have not experienced an event of interest 
by the time of analysis will be censored at the date of the last disease assessment without 
progression.  This analysis will use the intention-to-treat framework in which all patients 
randomized are considered recipients of their randomized assignment, regardless of 
treatment actually received.   
 
The sample size for this study is driven so that there would be adequate power to address 
the primary question of randomized therapy in maintenance. We will randomize 120 
eligible patients in a 2:1 ratio to EP and EPC initial therapy, resulting in 80 randomized 
to EP and 40 randomized to EPC.  Assuming that 80% of all patients randomized to EP 
initial therapy will achieve a response or stable disease and thus be randomized to the 
maintenance therapy comparison, we expect 64 patients to undergo the second 
randomization.  A total of 48 PFS events among these 64 patients will provide 87% 
power to detect a PFS hazard ratio of 0.5 with testing at the one-sided 0.10-level using a 
logrank test. Assuming exponential event times, this corresponds to an improvement in 
median PFS from 3 months to 6 months in the maintenance phase of therapy. It is 
possible that fewer than 80% of patients will be randomized in the maintenance (second) 
randomization, e.g., if fewer patients achieve a response or stable disease to the EP initial 
therapy.  To avoid an extended time period for completion of this trial but minimize 
power loss, the definitive analysis will be performed when 48 PFS events have occurred 
or when 90% of the patients who participate in the maintenance (second) randomization 
have PFS events, whichever comes first.  For example, if only 60% of patients registered 
to initial therapy are achieve PR/SD and are randomized to maintenance therapy (48 
patients), then the analysis would be performed when there were 43 PFS events.  This 
would provide power of 84% power to detect the hazard ratio of 0.5.   Because we expect 
that approximately 10% of patients of enrolled patients will be ultimately ineligible or 
will not start assigned therapy, we will enroll 132 patients in order to randomize 120 in 
the first step. 


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As secondary analyses, it is also of interest assess the effect of EP vs EPC initial therapy.  
Two secondary comparisons are of interest, which will be include all participants 
randomized to initial therapy.  The first compares those randomized to EP alone in the 
first randomization and no maintenance in the second randomization to those randomized 
to EPC in the first randomization followed by OC maintenance.  That is, this comparison 
compares the standard of care to the maximal regimen.    We anticipate that 120 eligible 
and treated patients will be randomized to EP vs EPC initial therapy, with 80 randomized 
to EP induction and 40 randomized to EPC initial therapy. The analysis will be done 
when there are 35 PFS events among the 40 patients randomized to EPC during initial 
therapy.  (PFS here is measured from the first randomization)  To account for the 
potential confounding effect of maintenance therapy in the analyses and comparisons of 
initial therapies, we will employ inverse-probability weighted Cox regression, (81-83) 
which will weight the information contributed by those randomized to maintenance 
observation after EP induction by approximately a factor of 2. This will maintain proper 
representation of patients who do and do not undergo the second randomization to 
maintenance therapy.  The second randomization is used to determine the weighting 
factor in the proposed analysis methods.  If the median PFS (from first randomization) is 
improved from 5.5 months in the EP initial therapy arm and no maintenance arm to 8.5 
months with the EPC induction followed by OC arm, we would expect approximately 30 
PFS events (among 32 patients randomized) in the EP initial therapy followed by no 
maintenance arm at the time of analysis (35 PFS events in the EPC initial therapy arm).  
This should provide roughly 70% power for this secondary comparison.  We will plan to 
conduct sensitivity analyses to assess the impact of the weighting factor at the time of 
interim and final analysis. 
  
The other secondary comparison compares those randomized to EP alone in the first 
randomization and OC maintenance in the second randomization to those randomized to 
EPC in the first randomization followed by OC maintenance.  That is, this comparison 
isolates the effect of EPC vs EP initial therapy when followed by OC maintenance.  The 
analysis will be performed analogously to the first secondary comparison.  These 
secondary analyses assume a one-sided 10% level test. 
 
Response rate will be analyzed as an additional secondary outcome.  Rates in each arm 
will be provided with exact 95% confidence intervals, and compared using the chi-
squared test (or Fisher’s exact test, as needed).  In addition, we will conduct exploratory 
analyses using biopsy tissue (see below) of predictive markers of response using logistic 
regression.  In addition, we will conduct exploratory analyses using biopsy tissue (see 
below) of predictive markers of response using logistic regression. 
 
 
Interim Analysis 
This study will also be monitored for futility(84).  For the primary maintenance question, 
an interim analysis at roughly 50% information (24 PFS events [measured from second 
randomization] for the primary maintenance question) is planned. At that time, if the 
point estimate of the PFS hazard ratio is consistent with detriment (HR > 1.0), then the 


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data monitoring committee may consider terminating the study early for overall lack of 
treatment difference between the two maintenance therapies.  For the secondary induction 
questions, an interim analysis at roughly 50% information (16 PFS events observed in the 
EPC initial therapy arm [measured from first randomization] is planned. At that time, if 
the (weighted) point estimate of the PFS hazard ratio for either comparison is consistent 
with detriment (HR > 1.0) of the EPC initial therapy arm, then the data monitoring 
committee may consider terminating accrual to the EPC initial therapy arm.   
 
 
13.2 
Sample Size/Accrual Rate 
 
Assuming roughly 10% of patients will not be eligible or start assigned therapy, a total of 132 
patients would constitute the total sample size. Accrual time is estimated to be a total of 24 
months, enrolling 2-4 patients per month across multiple sites.  Participants will be followed for 
at least one year post therapy completion. The total study duration will be 36 months. 
 
 
PLANNED ENROLLMENT REPORT 
Table 24: 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 
6 
8 
0 
0 
14 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
4 
5 
1 
2 
12 
White 
43 
51 
4 
6 
104 
More Than One Race 
1 
1 
0 
0 
2 
Total 
54 
65 
5 
8 
132 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 


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13.3 
Stratification Factors 
 
n/a 
 
13.4 
Analysis of Secondary Endpoints 
 
Secondary efficacy measures will include analysis of cediranib plus olaparib on the OS 
rate in patients with SCLC. OS will be defined as the time from initial randomization to 
death from any cause. Patients who are thought to be alive at the time of final analysis 
will be censored at the date of last contact.   Additional sensitivity analyses will be 
conducted on OS to address the effect of potential crossover to olaparib/cediranib on 
overall survival estimates.  These will include rank preserving structural failure time 
models. 
 
Safety and tolerability will be assessed using CTCAE version 5.0. 
 
Exploratory evaluation of blood-based angiogenic and DNA repair biomarkers will be 
conducted from samples collected at time points specified in Section 9. WES will be 
performed on diagnostic biopsy samples and tumor-derived circulating free DNA 
(cfDNA) will be collected for WES as well. Data from correlative studies will be 
summarized using descriptive statistics.  
 
Initial analyses of these data will utilize tests for association comparing the frequency of 
a particular genomic aberration at baseline and at progression (for example, using 
McNemar’s test) and association between alterations and baseline characteristics (for 
example, using Fisher’s exact test). More sophisticated analyses may include 
multivariable logistic regression modeling and/or competing risks analysis, however it is 
expected that analyzable results will not be obtained from 100% of patients (either due to 
things like assay failure, inability to biopsy at progression due to poor patient health, etc).   
 
For the aims related to plasma genotyping and serial plasma collection, we may employ a 
variety of statistical techniques for the analyses of these data. The rate of change at a 
particular time point may be compared to baseline measures of cfDNA and that measure 
will be analyzed for association with patient demographics and/or disease characteristics 
using the Kruskal Wallis test. Landmark analyses of PFS and OS in which the landmark 
time is defined by the cfDNA measurements at a particular time point, may be used as 
well. Presence or absence of mutations in plasma will be analyzed for association with 
other variables using Fisher’s exact test. To account for the repeated measures of plasma 
over time, we may potentially use these data as time varying covariates in multivariable 
Cox models to study their impact on outcomes like PFS and OS. 
 
We anticipate 75% of patients to have archival/diagnostic tissue available and 50% to 
have adequate tissue for all planned analyses which are primarily to evaluate predictive 
markers of response (i.e. DNA repair score, PARP expression, blood-based cytokine 
profile, etc).  We anticipate that we will obtain very few post-treatment optional biopsies 
for comparison to archival tissue (20% or less) but would be looking for changes in 


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PARP expression, levels of individual circulating cytokines (i.e. VEGF), or changes in 
genomic profile or gene expression profile that may identify a resistance mechanism.  For 
these evaluations, descriptive statistics would be employed.   
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first dose of study medication.  
As noted in section 12.1 The Overall 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.  In addition, a conference call will be held after the first 10 
participants are enrolled in the EPC arm to specifically review toxicity of the combination and 
determine whether there are unexpected adverse effects that should affect continued enrollment 
(specifically, if there are >4 grade 3 or above events, this should prompt re-evaluation of dosing 
for the combination.  All adverse events will be reported as in section 7.3.   
 
 
13.5.2 Evaluation of Response 
 
All participants included in the study who are randomized to a treatment arm must be 
assessed for response to treatment, even if there are major protocol treatment deviations 
or if they are ineligible.  Each participant will be assigned one of the following 
categories:  1) complete response, 2) partial response, 3) stable disease, 4) progressive 
disease, 5) early death from disease progression, 6) early death from toxicity, early death 
from 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 participants who proceed to the second randomization (those who have partial 
response or stable disease after completion of initial therapy) should be included in the 
primary analysis of PFS from the time of second randomization.  Participants who are 
randomized to initial therapy will also be included in the analysis of the secondary 
endpoints (comparing EP to EPC initial therapy (with or without maintenance)) as the 
intention-to-treat population.  Participants 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.  
 
All conclusions will be based on all eligible participants (those who are able to be 
randomized to treatment).  Subanalyses may then be performed on the basis of a subset of 
participants, 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 will not serve as the basis for drawing 
conclusions concerning treatment efficacy  
 


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Hemorrhage is a known consequence of VEGF/VEGFR signaling inhibition. The 
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78. 
Infection includes all 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC. 
79. 
This table will be updated as the toxicity profile of the agent is revised.  Updates will 
be distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
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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      PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, cediranib (AZD2171).  This clinical trial is sponsored by the National 
Cancer Institute (NCI).  This form is addressed to the patient, but includes important information 
for others who care for this patient.  
 
These are the things that you as a prescriber need to know: 
  
Cediranib (AZD2171) interacts with certain specific enzymes in the liver and certain transport 
proteins that help move drugs in and out of cells. 
 
• 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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APPENDIX C 
OLAPARIB PATIENT DRUG INFORMATION HANDOUT AND 
WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug, 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 
 
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. 
 


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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: 
 
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 juice and 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 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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APPENDIX D  
CONCOMITANT MEDICATIONS 
 
The following tables list CYP3A4 inducers (Table 25) and inhibitors (Table 26).  Investigators 
should consult a frequently updated drug information reference for a list of strong inducers and 
inhibitors. Please refer to Section 5.3 for further detail on concomitant medications. 
 
Table 21: CYP3A4 Inducers (Prohibited) 
Armodafenil1 
Barbiturates2 
Bosentan1 
Carbamazepine 
Dexamethasone1 
Efavirenz 
Fosphenytoin1 
Glucocorticoids2 (see note) 
Modafinil2 
Nafcillin1 
Nevirapine 
Oxcarbazepine 
Pentobarbital1 
Phenobarbital 
Phenytoin 
Pioglitazone2 
Primidone1 
Rifabutin 
Rifampin (Rifampicin) 
Rifapentine 
Rifepentine1 
St. John’s wort2 
Troglitazone3 
 
Note:  Topical steroids are permitted. Please contact overall PI if systemic steroids are clinically 
indicated while on trial. 
1Cited 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 
2Cited 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 22: CYP3A4 Inhibitors 
Strong Inhibitors 
(Prohibited) 
Moderate Inhibitors (use 
with caution, avoid if 
possible) 
Weak Inhibitors (use with 
caution, avoid if possible) 
Amprenavir1 
Atazanavir1 
Clarithromycin 
Conivaptan1 
Delavirdine1 
Fosamprenavir1 
Fospropofol1 
Imatinib1 
Indinavir 
Isoniazid1 
Itraconazole 
Ketoconazole 
Miconazole1 
Nefazodone 
Nelfinavir 
Nicardipine1 
Posaconazole1 
Propofol1 
Quinidine1 
Ritonavir 
Saquinavir2 
Telithromycin
Amiodarone1 
Aprepitant 
Cimetidine1 
Clotrimazole1 
Cyclosporine1 
Desipramine1 
Doxycycline1 
Efavirenz1 
Erythromycin 
Fluconazole 
Fosaprepitant1 
Grapefruit juice 
Haloperidol1 
Lidocaine1 
Metronidazole1 
Norfloxacin1 
Sertraline1 
Tetracycline1 
Verapamil 
Voriconazole1 
Chloramphenicol2 
Ciprofloxacin2 
Diethyldithiocarbamate2 
Fluvoxamine2 
Gestodene2 
Mibefradil2 
Mifepristone 
Norfluoxetine2 
Star fruit2 
Troleandomycin2 
 
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 E 
CEDIRANIB AND OLAPARIB DRUG DIARY 
Today’s Date: ________________________  
Cycle #: ______________ 
Patient Name:_________________________  
Patient Study ID: _____________ 
1.   Complete one form for each cycle (28 days). 
2.   Record the date, the number of tablets you took, and when you took them. 
3.   Bring your pill bottles (including empty bottles) and this form to every appointment. 
4.   Do not chew, dissolve, or crush medications. DO NOT make up vomited 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 an 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. 
Day 
Date 
15mg 
20mg 
AM 
Day 
Date 100mg 150mg 
AM 
PM 
1 
1/1/15 
2 
0 
7:00 
1 
1/1/15 
2 
0 
8:00 
8:00 
1 
1 
2 
2 
3 
3 
4 
4 
5 
5 
6 
6 
7 
7 
8 
8 
9 
9 
10 
10 
11 
11 
12 
12 
13 
13 
14 
14 
15 
15 
16 
16 
17 
17 
18 
18 
19 
19 
20 
20 
21 
21 
22 
22 
23 
23 
24 
24 
25 
25 
26 
26 
27 
27 
28 
28 


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Patient’s Signature:   
 
Date:   
 
 
Physician/Nurse/Data Manager’s Signature   
  Date  
 
 
 


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APPENDIX F 
CEDIRANIB DRUG DIARY 
Today’s Date: ________________________  Cycle #: ______________ 
Patient Name:_________________________  Patient Study ID: _____________ 
 
1.   Complete one form for each cycle (21 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 an EXAMPLE ROW for how to complete this diary. 
CEDIRANIB 
Take____ (number) ____mg tablets once a day. Take on an empty stomach (fast at least 2 hours before each dose 
and for 1 hour after each dose). 
Day 
Date 
15mg 
20mg 
AM 
1 
1/1/15 
0 
1 
7:00 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Patient’s Signature:   
 
Date:   
 
 
Physician/Nurse/Data Manager’s Signature   
  Date  
 
 
 
 


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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 
Intermediat
e dose 
Maximum 
dose 
Hepatic 
metabolism 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
 
captopril 
12.5 mg 3x 
daily 
25 mg 3x 
daily 
50 mg 3x 
daily 
CYP 2D6 
substrate 
enalapril 
5 mg daily 
10-20 mg 
daily 
40 mg daily Yes (CYP450 
unknown) 
ramipril 
2.5 mg 
daily 
5 mg daily 
10 mg daily Yes (CYP450 
unknown) 
lisinopril 
5 mg daily 
10-20 mg 
daily 
40 mg daily 
No 
fosinopril 
10 mg daily 20 mg daily 40 mg daily 
Yes, but not 
CYP450 
Rarely 
used: 
perindopril 
 
4 mg daily 
 
none 
 
8 mg daily 
 
Yes, but not 
CYP450 
Rarely 
used: 
quinapril 
10 mg daily 20 mg daily 40 mg daily 
No 
Angiotensin 
II Receptor 
Blockers 
(ARBs) 
losartan 
25 mg daily 50 mg daily 
100 mg 
daily 
CYP 3A4 and 
2C9 substrate 
candesartan 4 mg daily 
8-16 mg 
daily 
32 mg daily 
CYP 2C9 
substrate 
irbesartan 
75 mg daily 150 mg daily 
300 mg 
daily 
CYP 2C9 
substrate 
telmisartan 40 mg daily 
none 
80 mg daily 
Yes, but not 
CYP450 
valsartan 80 mg daily 
none 
160 mg 
daily 
Yes, but not 
CYP450 
Selective 
metoprolol 
25 mg 
50 mg 
100 mg 
CYP 2D6 


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β Blockers 
(BB) 
twice daily 
twice daily 
twice daily 
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) 
amlodipine 
2.5 mg 
daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate 
felodipine 
2.5 mg 
daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate 
 
 
 


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APPENDIX H 
BLOOD PRESSURE DIARY 
Today’s Date: ________________________  
Cycle #: ______________ 
Patient Name:_________________________  
Patient Study ID: _____________ 
 
Instructions to the Patient: 
1.   Your blood pressure readings have two numbers. The first (top) number is called the systolic pressure and the second 
(bottom) number is called the diastolic pressure. 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 (top number) is greater than 140  OR your diastolic blood pressure (bottom number) 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:   
 
Physician’s office will complete this section: 
Date of this clinic visit   
 
Physician/Nurse/Data Manager’s Signature   
 Date   
 


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APPENDIX I DIARRHEA MANAGEMENT  
 
Diarrhea is a common problem experienced by many patients and is a risk with olaparib, 
cediranib, and chemotherapy.  If it is not controlled quickly, it can lead to dehydration. 
 
WHEN TO REPORT YOUR DIARRHEA 
• 
Fever 100.5° or higher with diarrhea. 
• 
If you are experiencing diarrhea for the first time after starting therapy.  Based on questions 
answered during that phone call, we will advise starting Imodium AD if it seems the symptoms 
are treatment-related 
• 
are still have diarrhea 24 hours after starting Imodium AD—at this point, your doctor may 
advise additional prescription medications or want to evaluate you in person if there is a 
concern that you are becoming dehydrated 
OVER THE COUNTER MEDICATION MANAGEMENT OF DIARRHEA: 
• 
For diarrhea that occurs more than 2 episodes/day or more than one day continuously, use 
Imodium AD (maximum of 8 caplets per day) We recommend that you have Imodium 
AD on hand at home prior to starting therapy. 
o 1st dose: Take 2 caplets (4mg) 
o During the day: Take 1 caplet (2mg) every 2 hours after each loose stool 
o During the night: Take 2 caplets (4mg) at bedtime and every 4 hours as needed 
DRINK PLENTY OF FLUIDS 
• 
Drink 8 to 10 large glasses of liquids a day to replace those lost by diarrhea. Drink small 
quantities at a time slowly. 
o Water should only be part of the 8 to 10 glasses a day; it does not replace lost 
minerals 
o Jello is a good source of fluids 
o Gatorade replaces lost salt and 
potassium 
o Clear soup or broth replaces lost salt o AVOID caffeinated, very hot, or 
very cold drinks 
EAT SMALL MEALS OFTEN 
• 
A good choice of foods for diarrhea is the BRAT diet: 
o B- bananas- help replace lost nutrients 
o R- rice- easily digested and binding because it is a starch 
o A- apple sauce- provides sugars for energy 
o T- toast- easy to tolerate and binding because it is a starch 
• 
When these foods are being well tolerated, then you can add other bland low fiber foods 
such as: 
o Foods easy to digest: chicken- white meat without the skin, steamed rice, crackers, 
white bread, pasta noodles without sauce, and canned or cooked fruits without skins 
o Foods high in potassium: bananas, apricots without skin, peach nectar, potatoes 


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without skin, broccoli, halibut, mushrooms, asparagus, non-fat milk 
• 
Foods that can make diarrhea and cramping worse: 
o Fatty, fried, greasy, or spicy foods can cause more problems and discomfort 
o High-fiber foods: bran, whole grain cereals, dried fruit, fruit skins, popcorn, nuts and 
vegetables 
o Foods that cause gas: Beer, beans, cabbage, carbonated drinks