Phase I/II Study of Cediranib and Olaparib in Combination for Treatment of Recurrent Papillary-Serous Ovarian, Fallopian Tube, or Peritoneal Cancer or for Treatment of Recurrent Triple-Negative Breast Cancer
Phase: PHASE1
Conditions: Fallopian Tube Carcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian High Grade Serous Adenocarcinoma, Ovarian Serous Adenocarcinoma, Ovarian Serous Surface Papillary Adenocarcinoma, Primary Peritoneal Serous Adenocarcinoma, Triple-Negative Breast Carcinoma
Sponsor: National Cancer Institute (NCI)

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SUMMARY OF CHANGES - Protocol 
 
 
NCI Protocol # 8348 
 
Local Protocol # 09-293 
 
Current Protocol Version Date:  January 03, 2019  
 
Previous Protocol Version Date:  July 30, 2018 
 
 
# 
Section 
Page(s) 
Change 
1.  
Header; 
Title Page 
All; 1 
The protocol version date has been updated from July 30, 2018 to January 
03, 2019. 
2.  
Title Page 
2 
The Site PIs for University of Michigan and Evanston Hospital/NorthShore 
University Health System have been updated.  
3.  
6.1.1 
40-43 
Revision of the Protocol CAEPR: 
  
• 
Added New Risk:  
• 
Rare but Serious: Hemolytic uremic syndrome; Thrombotic 
thrombocytopenic purpura 
 
• 
Increase in Risk Attribution: 
• 
Changed to Rare but Serious from Also Reported on Cediranib 
Trials But With Insufficient Evidence for Attribution: Heart 
failure; Hepatic failure; Nephrotic syndrome; Wound 
complication 
 
4.  
ICF – Ph 1 
12 
Revision of the ICD as Specified Below: 
The condensed risk profile has been modified 
 
• 
Added New Risk: 
• 
Rare:  Anemia, kidney problems which may cause tiredness, 
bruising, swelling, or may require dialysis 
• 
Increase in Risk Attribution 
• 
Changed to Rare from Also Reported on Cediranib Trials But 
With Insufficient Evidence for Attribution (i.e., added to Risk 
Profile):  Liver damage which may cause yellowing of eyes and 
skin, swelling; Non-healing surgical site 
 
• 
Provided Further Clarification: 
• 
Blood clot which may cause swelling, pain, shortness of breath 
(under Occasional) is now reported as Blood clot which may 
cause swelling, pain, shortness of breath, confusion, or paralysis 
(under Occasional) 
 

 
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# 
Section 
Page(s) 
Change 
5.  
ICF – Ph 2 
11 
Revision of the ICD as Specified Below: 
The condensed risk profile has been modified 
 
• 
Added New Risk: 
• 
Rare:  Anemia, kidney problems which may cause tiredness, 
bruising, swelling, or may require dialysis 
• 
Increase in Risk Attribution 
• 
Changed to Rare from Also Reported on Cediranib Trials But 
With Insufficient Evidence for Attribution (i.e., added to Risk 
Profile):  Liver damage which may cause yellowing of eyes and 
skin, swelling; Non-healing surgical site 
 
• 
Provided Further Clarification: 
• 
Blood clot which may cause swelling, pain, shortness of breath 
(under Occasional) is now reported as Blood clot which may 
cause swelling, pain, shortness of breath, confusion, or paralysis 
(under Occasional) 
 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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PROTOCOL VERSION DATE:  January 03, 2019 
 
NCI PROTOCOL # 8348 
 
 
DF/HCC PROTOCOL # 09-293 
 
TITLE: Phase I/II study of cediranib and olaparib in combination for treatment of recurrent 
papillary-serous ovarian, fallopian tube, or peritoneal cancer or for treatment of recurrent triple-
negative breast cancer.   
 
COORDINATING CENTER: 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215 
 
PRINCIPAL INVESTIGATOR: 
Joyce Liu, MD 
Dana-Farber Cancer-Institute 
450 Brookline Ave. 
Boston, MA 02215 
Phone: 617-632-5269 
Fax: 617-632-3749 
Email: joyce_liu@dfci.harvard.edu 
 
CO-INVESTIGATORS: 
 
Ursula Matulonis, M.D. 
Dana-Farber Cancer Institute  
 
 
 
 
450 Brookline Ave.  
 
 
Boston, MA 02215 
Telephone: 617-632-2334 
Fax: 617 632-3479 
email: ursula_matulonis@dfci.harvard.edu 
 
Richard Penson, MD 
Massachusetts General Hospital 
55 Fruit Street 
Boston, MA 02114 
Phone: 617-724-4800 
Fax: 617-724-6898 
Email: penson.richard@mgh.harvard.edu  
 
Mary Buss, MD, MPH 
Beth Israel Deaconess Medical Center 
330 Brookline Ave., SCC-9 
Boston, MA 02115 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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Phone: 617-667-1395 
Fax: 617-975-5665 
Email: mbuss@bidmc.havard.edu 
 
Gini F. Fleming, MD 
University of Chicago Medical Center 
5841 S Maryland Ave. MC 2115 
Chicago, IL 60637-1470 
Phone: 773-702-6712 
Fax: 773-702-0963 
Email: gfleming@medicine.bsd.uchicago.edu 
 
Bobbie Jo Rimel, MD 
Cedars Sinai Medical Center 
8700 Beverly Blvd., Suite 290W 
Los Angeles, CA 90048 
Phone: 310-423-1126 
Fax: 310-423-9753 
Email: bobbie.Rimel@cshs.org 
 
Deborah K. Armstrong, MD 
Johns Hopkins Kimmel Cancer Center 
1650 Orleans St. CRB-190 
Baltimore, MD 21231 
Phone: 410-614-2743 
Fax: 410-955-0125 
Email: darmstro@jhmi.edu 
 
Jean M. Hansen, DO 
University of Michigan  
L4000 Women’s Hospital 
1500 East Medical Center Drive 
Ann Arbor, MI 48109 
Phone: 734-936-6886 
Fax: 734-764-7261 
Email: jeamarie@med.umich.edu 
 
Mary Tilley Jenkins-Vogel, MD 
NorthShore University HealthSystem  
Evanston Hospital 
2650 Ridge Ave. 
Walgreen Building, Suite 1507 
Evanston, IL 60201 
Phone: 847-570-2639 
Fax: 847-733-5358 
Email: tjenkinsvogel@nothshore.org 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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Sreenivasa R. Nattam, MD 
Fort Wayne Oncology/Hematology 
11143 Park View Plaza Dr, Suite 100 
Fort Wayne, IN 46845 
Phone: 260-484-8830 
Fax: 260-483-2302 
 
Jung-min Lee, MD  
National Cancer Institute 
Building 10, Room 13N218 
Bethesda, MD 20892 
Phone: 301-443-7735 
Fax: 301-402-0172 
Email: leej6@mail.nih.gov  
 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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STATISTICIAN:  
William Barry, PhD 
Biostatistics & Computational Biology 
Dana-Farber Cancer Institute 
450 Brookline Ave., CLS11007 
Phone:  617-632-5134 
Fax:  617-632-2444 
Email: bbarry@jimmy.harvard.edu 
 
RESEARCH NURSE:  
Christin Whalen, RN 
Dana-Farber Cancer Institute 
450 Brookline Ave., LG1B 
Boston, MA 02215 
Phone: 617-582-7738 
Fax: 617-582-7921 
Email: christin_whalen@dfci.harvard.edu 
 
CLINICAL RESEARCH SPECIALIST: 
Jennifer Curtis, MS 
Dana-Farber Cancer Institute 
450 Brookline Ave., DA116 
Boston, MA 02215 
Phone: 617-582-7183 
Fax: 617-394-2662 
Email: jennifer_curtis@dfci.harvard.edu 
 
AGENTS:   
1. Cediranib (NSC 732208; IND124225), supplied by CTEP 
2. Olaparib (NSC 747856; IND 75918), supplied by CTEP 
 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer  
Protocol Version Date: January 03, 2019 
 
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1. 
SCHEMA 
 
Phase I Dose Escalation Scheme  
 
Dose escalation will proceed within each cohort according to the following scheme: 
Number of Participants with DLT 
at a Given Dose Level 
 
Escalation Decision Rule 
 
0 out of 3 
Enter 3 participants at the next dose level. 
> 2 
Dose escalation will be stopped. This dose 
level will be declared the maximally 
administered dose (highest dose 
administered). Three (3) additional 
participants will be entered at the next lowest 
dose level if only 3 participants were treated 
previously at that dose. 
1 out of 3 
Enter at least 3 more participants at this dose 
level. 
• If 0 of these 3 participants experience 
DLT, proceed to the next dose level. 
• If 1 or more of this group suffer DLT, 
then dose escalation is stopped, and this 
dose is declared the maximally 
administered dose. Three (3) additional 
participants will be entered at the next 
lowest dose level if only 3 participants 
were treated previously at that dose. 
<1 out of 6 at highest dose level below the 
maximally administered dose 
This is generally the recommended phase 
II dose. At least 6 participants must be 
entered at the recommended phase II 
dose. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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Phase II Component at Recommended Phase 2 Dose (RP2D) 
 
** prior to initiation of treatment, patients will be recruited to the Medical Oncology Branch of 
the Center for Cancer Research, National Cancer Institute for translational component of study, 
see schema below. 
 
 
 
 
 
 
Dx platinum-
sensitive 
recurrent 
ovarian cancer 
Randomize patient (1:1) 
to either olaparib 
monotherapy or 
cediranib/olaparib at 
RP2D 
50% patients: 
olaparib 
monotherapy 
50% patients: 
cediranib and 
olaparib at RP2D  
Disease 
progression 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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Translational Sample Acquisition Schema 
 
Schema for sample acquisition for translational objectives for patients at NCI participating in this 
component: 
 
 
 
 
 
At Progression 
 
 
 
 
 
Optional tumor 
core biopsy and/or 
malignant fluid 
sampling 
2-8 HOURS AFTER 
5TH OLAPARIB DOSE 
3RD CEDIRANIB DOSE 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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TABLE OF CONTENTS 
 
SCHEMA ....................................................................................................................................... 5 
 
1. OBJECTIVES ....................................................................................................................... 11 
1.1. Study Design .................................................................................................................. 11 
1.2. Primary Objectives......................................................................................................... 11 
1.3. Secondary Objectives..................................................................................................... 11 
 
2. BACKGROUND ................................................................................................................... 12 
2.1. Ovarian Cancer .............................................................................................................. 12 
2.2. Study Agents .................................................................................................................. 14 
2.2.1. Cediranib .............................................................................................................14 
2.2.2. Olaparib...............................................................................................................19 
2.3. Background for Correlative Studies............................................................................... 20 
2.4. Rationale ...................................................................................................................... 22 
 
3. PARTICIPANT SELECTION ............................................................................................ 24 
3.1. Inclusion Criteria ........................................................................................................... 24 
3.2. Exclusion Criteria .......................................................................................................... 27 
3.3. Inclusion of Women, Minorities and Other Underrepresented Populations .................. 29 
 
4. REGISTRATION PROCEDURES ..................................................................................... 30 
4.1. General Guidelines for DF/HCC and DF/PCC Institutions ........................................... 30 
4.2. Registration Process for DF/HCC and DF/PCC Institutions ......................................... 30 
4.3. Registration Process for non DF/HCC Institutions ........................................................ 31 
 
5. TREATMENT PLAN ........................................................................................................... 31 
5.1. Pre-treatment Criteria..................................................................................................... 33 
5.2. Agent Administration..................................................................................................... 35 
5.2.1. Cediranib .............................................................................................................35 
5.2.2. Olaparib...............................................................................................................35 
5.3. Definition of Dose-Limiting Toxicity ............................................................................ 36 
5.4. General Concomitant Medication and Supportive Care Guidelines .............................. 37 
5.5. Duration of Therapy ....................................................................................................... 38 
5.6. Duration of Follow Up ................................................................................................... 38 
5.7. Criteria for Removal from Study Treatment .................................................................. 38 
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ........ 39 
6.1. Anticipated Toxicities .................................................................................................... 39 
6.2. Dose Modifications/Delays ............................................................................................ 47 
6.3. Toxicity Management .................................................................................................... 50 
6.3.1. Dose Modifications and Management of Cediranib and Olaparib Toxicities ....50 
6.3.2. Hypertension .......................................................................................................52 
6.3.3. Proteinuria ...........................................................................................................56 
6.3.4. Decrease in LVEF ...............................................................................................57 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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6.3.5. Diarrhea...............................................................................................................58 
6.3.6. Fever and Neutropenia ........................................................................................58 
6.3.7. Thyroid Toxicities ...............................................................................................59 
6.3.8. RPLS ...................................................................................................................59 
 
 
 
6.3.9    Rotator Cuff Injury.............................................................................................59 
6.3.10 Additional Toxicities and Dose Adjustments .....................................................60 
 
7. DRUG FORMULATION AND ADMINISTRATION ...................................................... 61 
7.1. Cediranib (AZD2171, NSC 732208) ............................................................................. 61 
7.2. Olaparib (AZD2281, NSC 747856) ............................................................................... 63 
 
8. CORRELATIVE/SPECIAL STUDIES .............................................................................. 66 
8.1. Tissue and Sample Acquisition and Processing............................................................. 66 
8.2. Rationale for Selected Endpoints ................................................................................... 66 
8.3. Sample Acquisition ........................................................................................................ 66 
8.4. Functional Imaging ........................................................................................................ 67 
8.5. PAR Incorporation ......................................................................................................... 68 
8.6. Circulating Endothelial Cells (CEC) ............................................................................. 68 
8.7. Circulating Cytokines .................................................................................................... 68 
8.8. Pharmacogenomics, PARP and  XRCC1 Polymorphisms ............................................ 68 
8.9. IHC/IF 
...................................................................................................................... 69 
8.10. Proteomic Endpoints ...................................................................................................... 69 
8.11. BRCA Mutation Status .................................................................................................. 69 
8.12. Family Risk Assessment ................................................................................................ 69 
8.13. Post-progression Tissue Analysis .................................................................................. 70 
 
 8.14. Pharmacokinetic (PK) studies.........................................................................................70 
 
9. STUDY CALENDAR ........................................................................................................... 73 
9.1. Study Calendar:  Phase I and Phase I-T ......................................................................... 74 
9.2. Study Calendar:  Phase II ............................................................................................... 76 
 
10. MEASUREMENT OF EFFECT ......................................................................................... 78 
10.1. Measurable Disease Response Definition ...................................................................... 78 
10.2. CA-125 Response Definition ......................................................................................... 82 
10.3. Response Criteria ........................................................................................................... 83 
10.4. Confirmatory Measurement/Duration of Response ....................................................... 84 
10.5. Other Response Parameters ........................................................................................... 85 
 
11. ADVERSE EVENT REPORTING REQUIREMENTS ................................................... 86 
11.1. General 
...................................................................................................................... 86 
11.2. Definitions...................................................................................................................... 86 
11.3. Recording Adverse Events ............................................................................................. 88 
11.4. Reporting Adverse Events ............................................................................................. 88 
11.5. Sponsor Notification by Investigator ............................................................................. 88 
11.5.1. Expedited Reporting Guidelines .........................................................................88 
11.5.2. Non-Serious Adverse Event Reporting Requirements .......................................90 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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11.6. Institutional Review Board (IRB) Notification by Investigator .................................... 90 
11.7. Hospital Risk Management Notification by Investigator .............................................. 90 
12. DATA AND SAFETY MONITORING .............................................................................. 91 
12.1. Data Reporting ............................................................................................................... 91 
12.2. Safety Meetings ............................................................................................................. 92 
12.3. Monitoring ..................................................................................................................... 92 
 
13. REGULATORY CONSIDERATIONS .............................................................................. 93 
13.1. Protocol Review and Amendments ................................................................................ 93 
13.2. Informed Consent........................................................................................................... 93 
13.3. Ethics and Good Clinical Practice (GCP) ...................................................................... 93 
13.4. Study Documentation..................................................................................................... 94 
13.5. Records Retention .......................................................................................................... 94 
13.6. CRADA / Clinical Trials Agreement (CTA) ................................................................. 94 
 
14. STATISTICAL CONSIDERATIONS ................................................................................ 96 
14.1. Study Design/Endpoints................................................................................................. 96 
14.2. Sample Size and Data Analysis ..................................................................................... 98 
14.3. Reporting and Exclusions .............................................................................................. 99 
 
15. PUBLICATION PLAN ...................................................................................................... 100 
 
16. REFERENCES .................................................................................................................... 101 
 
17. APPENDICES ..................................................................................................................... 104 
APPENDIX A:  Performance Status Criteria ....................................................................... 105 
APPENDIX B:  Patient’s Pill Diary: Cediranib ................................................................. 106 
 
 
Patient’s Pill Diary: Olaparib (Capsule) .................................................. 107 
 
 
Patient’s Pill Diary: Olaparib (Tablet) .................................................... 108 
 
 
 
 
 
 
 
Patient's Pill Diary: PK Expansion Cohort..............................................109 
APPENDIX C:  Patient’s Blood Pressure Diary .................................................................. 111 
APPENDIX D:  List of Drugs that May Have Potential CYP3A4 Interactions ................... 112 
APPENDIX E:  New York Heart Association Classifications ............................................ 114 
APPENDIX F:   Medications that May Cause QTc Prolongation ........................................ 115 
APPENDIX G:  DF/HCC Multi-Center Data and Safety Monitoring Plan ......................... 120 
APPENDIX H: DF/HCC Tumor Metrics Submission Procedures for non-DF/HCC Sites 142 
APPENDIX I: Family History Questionnaire .................................................................... 143 
 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer  
Protocol Version Date: January 03, 2019 
 
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1. 
OBJECTIVES 
 
1.1. 
Study Design 
 
This is a Phase I/II trial of the combination of cediranib and olaparib in the treatment of recurrent 
ovarian, fallopian tube, or peritoneal cancer or in recurrent triple-negative breast cancer to define 
the safe dose of this combination, followed by a randomized two-arm Phase II study comparing 
the combination of cediranib and olaparib at the recommended Phase 2 dose (RP2D) as 
determined in the Phase I portion of the study compared to the control arm of olaparib alone in 
patients with recurrent platinum-sensitive papillary-serous or endometrioid ovarian, fallopian 
tube, or peritoneal cancer.  A total of up to 148 patients are planned for study enrollment, with up 
to 28 patients in the phase I dose escalation portion, up to 90 patients in the Phase II randomized 
portion, and up to 30 patients in the phase I (tablet) dose escalation portion. 
 
1.2. 
Primary Objectives 
 
1.2.1. Phase 1 Portion:  Assess the MTD of cediranib in combination with olaparib in 
the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer or 
metastatic triple-negative breast cancer. 
 
1.2.2. Phase 2 Portion:  Assess the efficacy (as measured by progression-free survival 
(PFS) ) of the combination of cediranib and olaparib compared to olaparib alone 
in recurrent grade 2 or 3 platinum-sensitive papillary-serous or endometrioid 
ovarian, fallopian tube, or peritoneal cancer. 
 
1.2.3. Phase 1-T (olaparib tablet) Portion:  Assess the MTD of cediranib in 
combination with olaparib tablet formulation in the treatment of recurrent ovarian, 
fallopian tube, or peritoneal cancer. 
 
1.3. 
Secondary Objectives 
 
1.3.1. Phase 1 Portion:  Assess the toxicities of the combination of cediranib and 
olaparib in the treatment of recurrent ovarian, fallopian tube, or peritoneal cancer 
or metastatic triple-negative breast cancer.  Assess clinical benefit, progression-
free survival, and overall survival for patients treated with cediranib and olaparib. 
 
1.3.2. Phase 2 Portion:  Assess tumor response, clinical response benefit (response or 
stable disease as defined by RECIST response criteria x 16 weeks), and overall 
survival (OS) for patients treated with cediranib and olaparib at the RP2D as 
compared with patients receiving olaparib alone. 
 
1.3.3. Phase 2 Portion Translational Objectives:   
• To evaluate the prognostic and predictive role of measured changes in 
functional vascular imaging using DCE-MRI between pre-study and day 3. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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• To evaluate in an exploratory fashion the predictive or prognostic value of 
SNPs in key genes involved in angiogenesis and DNA repair. 
• To evaluate the predictive value of baseline PBMC PAR incorporation on 
response to therapy. 
• To measure early changes in vascular cytokine production and evaluate in an 
exploratory fashion that these changes may be predictive or prognostic, or 
differentially affected by the combination of agents. 
• To evaluate early changes to circulating endothelial cells and if these changes 
are predictive or prognostic. 
• To assess changes in measures of DNA damage and repair and angiogenesis 
in tumor cells (tissue and/or malignant effusions) and correlate to 
drug/drug/combination. 
 
1.3.4. Phase 1-T (olaparib tablet) Portion:  Assess the toxicities of the combination of 
cediranib and olaparib (tablet formulation) in the treatment of recurrent ovarian, 
fallopian tube, or peritoneal cancer.  Assess clinical benefit, progression-free 
survival, and overall survival for patients treated with cediranib and olaparib 
(tablet formulation).  Assess the pharmacokinetic profile of cediranib and olaparib 
(tablet formulation) when administered in combination. 
 
 
2. 
BACKGROUND 
 
2.1. 
Ovarian Cancer 
 
2.1.1. Background 
 
Epithelial ovarian cancer is the most lethal of the gynecologic malignancies, with an estimated 
22,000 new cases and 15,000 deaths in the United States in 2008 (Jemal et al., 2008).  Patients 
initially are diagnosed during exploratory laparotomy, during which time surgical staging is 
performed and gross disease is debulked.  Over 70% of patients present with advanced disease, 
with spread of disease to the upper abdomen (Stage III) or more widely metastatic disease such 
as malignant pleural effusions or liver/splenic intraparenchymal lesions (Stage IV).  Post-
operative adjuvant chemotherapy is indicated for all patients with advanced disease, and options 
include intraperitoneal chemotherapy with cisplatin and paclitaxel or intravenous chemotherapy 
with carboplatin and paclitaxel.  In over 70% of cases, platinum and taxane-based combination 
therapy results in a clinical complete remission, typically defined as having no evidence of 
residual tumor, based on a normal serum CA-125 level, normal exam, and normal radiographic 
study such as a CT scan. 
 
Unfortunately, despite achieving a complete remission, the majority of patients relapse and 
eventually die of disease, due to the persistence of chemoresistant cancer cells.  Despite 
aggressive surgical and chemotherapeutic approaches, the chance of achieving long-term 
disease-free survival for subjects with stage III and stage IV disease is only approximately 25% 
and <10%, respectively (McGuire et al., 1996).  Other less common Mullerian tumors such as 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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primary peritoneal serous cancers and fallopian tube cancers have similar clinical courses and 
behavior.  Thus, it is useful to group these three types of gynecologic cancers into one entity for 
the purpose of treatment and clinical investigation. 
 
Relapse in these three types of gynecologic cancers is generally incurable, and the goal of 
treatment changes to one of palliation.  The treatment of recurrent ovarian cancer with 
conventional cytotoxic agents is limited by the development of chemoresistance as well as 
intolerable side effects.  The combination of anti-angiogenic and PARP-inhibitor agents may 
prove synergistic and perhaps improve overall patient outcomes. 
 
2.1.2. Use of Anti-angiogenic Drugs in Ovarian Cancer 
 
The treatment of ovarian cancer with conventional cytotoxic agents is limited by the 
development of chemoresistance as well as intolerable side effects.  Novel agents that target the 
angiogenic pathway may improve clinical outcome.  Two groups have demonstrated that single 
agent bevacizumab in recurrent ovarian cancer has a response rate of approximately 18% 
(Burger et al., 2007; Cannistra et al., 2007).  Toxicities of single agent bevacizumab include 
hypertension, vascular events such as a DVT, pulmonary embolus or stroke, gastrointestinal 
perforation, and hoarseness.  In one study, there was an up to 11% chance of a gastrointestinal 
perforation, which resulted in early study closure (Cannistra et al., 2007).  Additionally, the 
GOG is currently performing an upfront randomized trial of carboplatin and paclitaxel given 
intravenously with or without bevacizumab during initial chemotherapy with a second 
randomization in the maintenance phase to either placebo or continued bevacizumab (GOG 218). 
 
Two studies have been conducted in the United States and Canada of single agent cediranib in 
women with recurrent ovarian, peritoneal, or fallopian tube cancer.  A CTEP-sponsored study 
within the Dana-Farber/Harvard Cancer Center has included 41 patients to date, and 
demonstrated an overall 31% clinical benefit response rate, with 19% of patients experiencing a 
PR and 12.5% with stable disease that lasted at least 16 weeks  (Matulonis et al., 2008).  
Toxicities observed in this study included hypertension, hypothyroidism, diarrhea, abdominal 
pain, fatigue, and nausea and vomiting.  No gastrointestinal perforations were observed.  A 
separate trial conducted through the California consortium also concluded similar results (Hirte 
et al., 2008). 
 
2.1.3. Use of PARP-inhibitors in Ovarian Cancer 
 
Studies in ovarian cancer have demonstrated a strong hereditary component.  Among the genes 
most commonly linked with a susceptibility to developing ovarian cancer are the BRCA1 and 
BRCA2 genes.  Germline mutations in BRCA1/2 genes have been detected in studies at rates 
ranging from 8-18% in ovarian cancer patients.  The frequency of these BRCA1/2 mutations is 
markedly increased in Jewish populations. 
 
In addition to germline BRCA1/2 mutations, there are many other mechanism that can affect 
BRCA1/2 function and thus affect homologous recombination.  Deleterious somatic mutations 
have been observed in both BRCA1 and BRCA2 in approximately 5% of ovarian cancers.  
Additionally, epigenetic mechanisms such as promoter hyper-methylation can result in aberrant 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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expression of BRCA1/2 and have been noted in 11-35% of ovarian cancer patients (Yang et al., 
2006; Press et al., 2008).  Other proteins involved in the homologous recombination pathway, 
including Fanconi anemia proteins, ATM, MRE-11, and EMSY, are also affected in a significant 
proportion of ovarian cancer patients, with an estimate between 17% and 60% (Taniguchi et al., 
2003; Hughes-Davies et al., 2003).  
 
A Phase I study with olaparib included an expansion phase in BRCA-deficient ovarian cancer at 
200mg BID (Fong et al., 2008).  32 patients with BRCA-deficient ovarian cancer were evaluable 
for response.  14 of the 32 patients achieved a partial response, while stable disease was seen in 
an additional 8 patients.  An international multicenter Phase II study enrolled two sequential 
cohorts of women with known germline BRCA2 or BRCA2 mutations and recurrent advanced 
ovarian cancer to receive olaparib continuously at a dose of 400mg BID (Cohort 1) or 100mg 
BID (Cohort 2) (Audeh et al., 2010).  Responses were observed in 33% (11 of 33) patients 
enrolled in the 400mg BID cohort and 13% (3 of 24) patients enrolled in the 100mg BID cohort.  
Preliminary data have also demonstrated activity of olaparib in sporadic ovarian cancers.  A 
Phase II study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer 
included a cohort of  46 ovarian cancer patients who were known not to carry a germline BRCA 
mutation, in which an overall response rate of 23.9% was observed (Gelmon et al., 2010).  
Additional studies of olaparib as monotherapy or in combination with a platinum reagent for 
treatment of metastatic BRCA-deficient ovarian cancer are ongoing.  Preliminary results from a 
Phase II trial investigating olaparib as maintenance therapy following platinum-based therapy for 
platinum-sensitive serous ovarian cancer demonstrated a significant progression-free survival 
benefit (8.4 vs. 4.8 months, p<0.00001), with subgroup analyses demonstrating evidence of 
benefit regardless of BRCA status (Ledermann et al., 2011).  A Phase I study of a different 
PARP inhibitor MK-4827, has also demonstrated preliminary evidence of single-agent activity in 
patients with ovarian cancer (Sandhu et al., 2010).   
 
2.2. 
Study Agents 
 
2.2.1. Cediranib 
 
Mechanism of Action 
   
Cediranib (NSC 732208) is an orally available small molecule that is a multitargeted kinase 
inhibitor of the VEGFR family and has significant activity against c-kit and PDGFR-beta 
signaling.  VEGF, the ligand to the VEGFR family of tyrosine receptor kinases, has been 
implicated in tumor blood vessel formation and in disease progression in a wide range of solid 
tumor malignancies.  Expression of this factor is increased by diverse stimuli which include 
proto-oncogene activation and hypoxia, with the hypoxic state frequently occurring in solid 
tumors because of inadequate perfusion.  In addition to its angiogenic role, VEGF also 
profoundly increases the permeability of the vasculature and thereby potentially contributes to 
tumor progression, as a leaky tumor endothelium can enhance nutrient and catabolite exchange 
and represent less of a barrier to tumor cell migration during metastasis.  Numerous 
antiangiogenic agents have been developed with the goal of suppressing neovascularization and 
inhibiting tumor growth and metastasis.  Unlike many of these intravenously-administered 

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antiangiogenic agents, cediranib is a member of an emerging class of novel orally-administered 
VEGF tyrosine kinase inhibitors (Hennequin et al., 1999; Wedge et al., 2000, 2002). 
 
Two high-affinity receptors for VEGF with associated tyrosine kinase activity have been 
identified on human vascular endothelium, KDR (kinase insert domain-containing receptor, also 
known as VEGFR2) and Flt-1 (fms-like tyrosine kinase 1, also known as VEGFR1).  Although 
the relative contributions of KDR and Flt-1 signaling in mediating tumor progression have not 
been elucidated, a number of studies suggest that KDR has a more predominant role.  Cediranib 
is a potent inhibitor of both KDR (IC50<0.002 µM) and Flt-1 (IC50=0.005 µM) and shows 
activity against c-kit, platelet-derived growth factor receptor beta (PDGFRβ), and Flt-4 at 
nanomolar concentrations.  It has been shown that cediranib potently and selectively inhibits 
VEGF-stimulated human umbilical cord vascular endothelial cell (HUVEC) proliferation with an 
IC50 of 4 nM (Ogilvie et al., 2004).  Cediranib was also found to have a profound inhibitor effect 
on vessel area, length, and branching at subnanomolar concentrations using a modified 
fibroblast/endothelial cell co-culture system.  Cediranib’s effects on hemodynamic parameters 
have been studied in an athymic rat xenograft model of human colorectal carcinoma (SW620) 
using perfusion-permeability dynamic contrast-enhanced magnetic resonance imaging, which 
demonstrated that in this model, cediranib significantly reduced vascular permeability by 80% 
(p<0.005) and vascular volume by 68% (p<0.05) (Bradley et al., 2004). 
 
Non-clinical Efficacy 
 
The effect of cediranib has been 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 
(PO) at doses from 0.75 to 6 mg/kg/day (2.25-18 mg/m2/day) in a constant volume of 0.1 
mL/10g body weight for 24 to 28 days.  Cediranib produced a statistically significant inhibition 
of tumor growth the xenograft models when dosed at 1.5 mg/kg/day (4.g mg/m2/day) or higher.  
In the murine renal cell carcinoma (RENCA) model, cediranib (at a dose of 6.3 mg/kg/day PO) 
reduced primary tumor growth, metastasis, and microvessel density more potently than any other 
previously-studied VEGF RTK inhibitor reported in the literature (Drevs et al., 2004).  The 
temporal effects of cediranib administration have been investigated in a transgenic mouse model 
in which multiple mammary tumors spontaneously develop after two pregnancies (Klinowska et 
al., 2004).  When dosed with cediranib (0.75 to 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 prior to cediranib administration (at doses of 3 and 6 mg/kg/day), 
dose-dependent growth inhibition occurred as well as tumor regression. 
 
Non-clinical Pharmacology and Toxicology 
 
Non-clinical pharmacology and toxicology company-sponsored cediranib studies have been 
conducted in rats, dogs, and cynomolgus monkeys.  In rats and dogs, oral bioavailability is high, 
but absorption is relatively slow, with peak plasma concentration (Cmax) of the agent seen 4-6 
hours after PO dosing.  Plasma concentrations and exposure are generally linear over the dose 
range studied in rats.  Fecal excretion was the predominant route of elimination (>70% of the 
dose) in rat, dog, and cynomolgus monkeys after both oral and intravenous administration.  

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Elimination was rapid in rats and monkeys with over 7% of the dose being recovered in the first 
48 hours; in dogs excretion was slightly slower but substantially complete by 7 days. 
 
In vitro data suggest that cediranib at a range of concentrations up to 101 µg/mL demonstrated 
no inhibition of CYP isozymes CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and 
CYP2E1.  There were very mild effects seen for CYP2D6, CYP3A4 testosterone and CYP3A4 
midazolam, with IC50 values estimated to be 32.9, 16.2, and 21.4 µg/mL, respectively.  These 
concentrations are greater than those currently observed in clinical studies, and therefore 
cediranib is not expected to cause clinically significant drug interactions through inhibition of 
P450-mediated metabolism of co-administered agents. 
 
VEGF is an important angiogenic factor, a potent physiological mediator of vascular tone, and a 
potent modulator of capillary permeability, and therefore VEGF receptor inhibition was 
considered to be the cause of many of the observed pathophysiologic changes.  Vascular 
(myocarditis, choroid plexus) and renal (glomerulosclerosis and tubular degeneration) pathology 
have been seen in rats, dogs, and primates dosed with cediranib and are considered to be 
consistent with lesions induced by hypertension, although a direct effect by cediranib on these 
tissues cannot be excluded.  Cediranib has also resulted in pathological findings 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 primates, changes were 
seen in the gallbladder (mucosal hypertrophy) and bile duct (hyperplasia/hypertrophy). 
 
Pharmacology and Pharmacokinetics in Humans 
 
The company reports that the pharmacokinetics of cediranib support once-daily oral dosing.  
Although the absolute bioavailability has not been determined, cediranib appears well-absorbed 
with apparently linear PK for single and multiple doses ranging from 0.5 to 60mg.  After 
multiple once-daily oral doses, steady-state plasma concentrations are attained after 
approximately 7 days.  There is limited accumulation, and steady-state plasma concentrations are 
predicted by the single-dose PK, indicating no time-dependent changes in PK.  Clearance of 
cediranib is moderate, approximating 64% of nominal hepatic plasma flow, and appears to be 
extensively through metabolism.  <1% of the administered dose of cediranib is excreted 
unchanged in the urine. 
 
Cediranib has been administered in combination with a number of chemotherapy regimens.  
Steady-state plasma concentrations of paclitaxel, carboplatin, oxaliplatin, 5-FU (given as 
mFOLFOX6), docetaxel, pemetrexed, irinotecan, +SN38, gefitinib, or gemcitabine displayed 
little or no apparent effect (<1.5-fold change) when given in the presence of cediranib.  Steady-
state PK parameters of cediranib in combination with the chemotherapy agents are comparable to 
those seen previously with cediranib monotherapy.  Additionally, comparison of studies suggests 
that Western and Japanese patients have similar PK. 
 
Data obtained following a single 45-mg cediranib dose in the presence and absence of a standard 
high-fat meal showed that food decreases the Cmax by 33% and AUC by 24%.  Cediranib should 
therefore be administered at least 1 hour before or 2 hours after food. 

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Safety and Tolerability in Humans   
 
Early clinical data demonstrated that the most common adverse events (AEs) with cediranib 
included fatigue, diarrhea, nausea, vomiting, hoarseness, hand-foot syndrome, and hypertension. 
 
Hypertension is an expected AE with agents that inhibit VEGF signaling, and is the major 
cardiovascular AE associated with cediranib treatment.  CTC grade 4 hypertension and end-
organ damage related to hypertension, such as cerebrovascular events, have been observed with 
cediranib.  Therefore, clinical trials include rigorous monitoring of BP and renal function 
(creatinine, creatinine clearance, and urinary protein).  A hypertension management protocol is 
incorporated into all clinical study protocols.  Patients with pre-existing hypertension may be at 
particularly high risk of developing moderate or severe hypertension on cediranib and may 
benefit from having their BP management optimized prior to starting the drug.  
 
Left ventricular dysfunction, in some cases leading to cardiac failure, has been observed in 
patients with risk factors for left ventricular dysfunction (including previous or concomitant 
anthracycline treatment).  Additional toxicities include bleeding and hemorrhagic episodes such 
as CNS bleeding that may also be a result of HTN.  Some hemorrhagic events were fatal, but 
causality could not be unequivocally assigned to cediranib.  Gastrointestinal perforation, 
sometimes associated with fistula formation, has been observed in patients receiving cediranib.  
Some events of gastrointestinal perforation have been fatal.  Fatigue, hoarseness, diarrhea, hand-
foot syndrome, nausea, and vomiting are commonly occurring adverse events in cediranib 
studies.  Dehydration has been observed in clinical studies as a consequence of cediranib- or 
chemotherapy-related diarrhea or vomiting; chemotherapy-associated anorexia or reduced oral 
intake may also be the cause.  Muscle weakness, proteinuria, dry mouth, and oral mucosal 
inflammation have been observed in cediranib studies.  Increases in transaminases, which are 
sometimes associated with increases in total bilirubin, have also been seen.  Thrombocytopenia, 
predominantly of CTC grade 1 or 2, has also been observed with cediranib monotherapy or in 
combination treatment.  Reversible posterior leukoencephalopathy syndrome has been observed 
rarely in patients receiving cediranib.  Additionally, cediranib has been associated with increases 
in TSH; in a small number of patients, clinical hypothyroidism has been reported and may 
require oral thyroid replacement. 
 
Clinical Studies with Cediranib as Monotherapy 
 
Cediranib has been evaluated as monotherapy in patients with solid tumors and metastatic liver 
disease (Study D8480C00001), in relapsed or refractory AML (D8480C00002), and in advanced 
prostate adenocarcinoma (Study D8480C0003).  A detailed description of the preliminary data 
from these studies is provided in Section 5 of the investigator’s brochure (IB). 
 
The MTD of cediranib, as determined in Phase I studies detailed in the IB, was 45 mg.  
However, due to the toxicities observed cediranib 45 mg/day, 30 mg is now considered the 
starting single agent dose.  A number of Phase 2 clinical trials of single agent cediranib have 

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been conducted in multiple tumor types, with many run through the National Cancer Institute’s 
CTEP program. 
 
Two single-agent studies of cediranib have been conducted in ovarian cancer specifically.  The 
first is a CTEP-sponsored study conducted within the Dana-Farber/Harvard Cancer Center which 
has included 41 patients to date (Matulonis et al., 2008).  The study assessed cediranib 
monotherapy in women with recurrent ovarian, peritoneal or fallopian tube cancers.  Eligibility 
included prior platinum-based chemotherapy, up to 2 prior lines of chemotherapy in the recurrent 
setting, ECOG PS of 0 or 1, controlled BP, and normal organ function.  Patients could have 
either platinum-resistant or platinum-sensitive recurrence.  42 patients were enrolled by 
September 2008, and the study closed in November 2008.  The primary endpoint of the study 
was response rate measured either by RECIST or modified GCIG CA125 criteria, and secondary 
endpoints included toxicity and progression-free survival.  Response was measured after every 2 
28-day cycles.  After the first 11 patients were enrolled at the original dose of 45 mg/day PO, the 
protocol was amended to decrease the dose of cediranib to 30mg daily due to toxicities.  36 
patients received drug (1 patient never received drug), toxicity assessment was available on 33 
patients, and tumor response assessment was made in 32 patients (intention-to-treat population).  
There was an overall 31% clinical benefit response rate observed; 19% of patients had a PR and 
12.5% had stable disease that lasted at least 16 weeks.  Toxicities observed included 
hypertension, hypothyroidism, diarrhea, abdominal pain, fatigue, and nausea and vomiting.  A 
separate trial conducted through the California consortium demonstrated similar results (Hirte et 
al., 2008). 
 
Cediranib in Combination Therapy 
 
Cediranib was given in combination with one of five different standard chemotherapy regimens 
in a phase I trial in patients with advanced solid tumors.  A total of 46 patients had RECIST 
assessments performed both at screening/baseline and after Cycle 1 of study treatment, and the 
data suggested that there was preliminary evidence of some anti-tumor activity with all of the 
treatment combinations in this study (Shields et al., 2007).   Further details are available in 
Section 5 of the IB. 
 
There are ongoing studies of cediranib in combination with FOLFOX in metastatic colorectal 
cancer, and a phase 1 study has been conducted of cediranib in combination with carboplatin and 
paclitaxel in NSCLC (Laurie et al., 2008).  In ovarian cancer, ICON6 is a study being run in 
Europe under the guidance of Dr. Stan Kaye.  This is a double-blinded, placebo-controlled 
multicenter study of the safety and efficacy of concurrent cediranib with platinum-based 
chemotherapy and single-agent maintenance cediranib in patients with platinum-sensitive 
recurrent ovarian cancer.  Eligible patients include those with recurrent ovarian cancer whose 
cancer has relapsed more than 6 months following completion of first-line platinum-based 
treatment, and approximately 2000 patients will be enrolled.  Patients will be randomized to one 
of the three arms: (A) 6 cycles of standard carboplatin and docetaxel given every 3 weeks plus 
placebo during chemotherapy with placebo for up to 18 months from randomization as 
maintenance; (B) 6 cycles of carboplatin and docetaxel given every 3 weeks plus cediranib 
during chemotherapy followed by placebo in maintenance; (C) use of cediranib during both 
platinum-based chemotherapy as well as up to 18 months of maintenance. 

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2.2.2. Olaparib 
 
Mechanism of Action 
 
Polyadenosine 5’-diphosphoribose [poly-(ADP-ribose)] polymerization (PARP) is a unique post-
translational modification of histones and other nuclear proteins that contributes to the survival 
of cells following DNA damage.  PARP-1 is one of the enzymes that catalyzes this process, and 
has been shown to be immediately stimulated by DNA strand breaks.  PARP-1 activation leads 
to DNA repair through the base excision repair (BER) pathway, and cells deficient in PARP-1 
have been shown to have delayed DNA repair.  Loss of PARP-1 activity in cells or in knockout 
mice leads to both radio- and chemo-sensitization.  PARP-inhibitors can enhance the anti-tumor 
effects of radiation and DNA-damaging cytotoxic agents (Virag et al., 2002; Nguewa et al., 
2005). 
 
Olaparib is an orally-bioavailable inhibitor of PARP-1 and has demonstrated monotherapy 
activity in tumor cells with defects in the homologous recombination pathway, including cells 
with BRCA1-/- and BRCA2-/- genotype (Bryant et al., 2005; Farmer et al., 2005).  Recent 
studies have indicated that PARP inhibition in BRCA1 and BRCA2 homozygous null cells, but 
not the isogenic BRCA heterozygous cells, leads to selective cell death.   
 
Non-clinical Pharmacology and Toxicology 
 
Olaparib has demonstrated cellular activity in the low nM range with a cellular dose for 50% 
inhibition (IC50) of 2nM in HeLa cells.  Distribution of olaparib is in the gastrointestinal tract and 
in tissues associated with the metabolism and elimination of foreign compounds.  Further 
investigations are still ongoing.  Excretion is primarily via the feces and, to a lesser extent, the 
urine. 
 
Olaparib has been tested in dogs and rats.  There were no noted effects on the cardiovascular or 
respiratory parameters of an anesthesized dog or any behavioral, autonomic, or motor effects in 
the rat.  Toxicology studies indicate that the target organ of toxicity is the bone marrow.  Ex vivo 
work has confirmed that olaparib is also active against human marrow.  The cytotoxic effect 
becomes evident at a higher concentration than required to fully ablate PARP activity.  28-day 
dog and rat studies demonstrate a reversible myelotoxic effect that is mild to moderate.  Platelets 
are first affected, followed by white blood cells.  26-week repeat-dose studies in rats 
demonstrated doses to be well-tolerated in male rats, with hematological effects and increased 
spleen weights observed at all dosages.  In female rats, doses of 15/mg/kg/day resulted in 
significant reduction in body weight.  Hematological effects and increased spleen weights were 
again observed at all dosages.  The difference between sexes was considered to be due to the fact 
that females had greater plasma exposure levels than males.  In 26-week repeat-dose studies in 
dogs, olaparib was well-tolerated.  Hematological changes were observed, characterized by 
pancytopenia. 
 
 

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Clinical Experience 
 
The first clinical study in man of olaparib (KU-36-92) was a dose-escalation study in patients 
with advanced solid tumors.  Preliminary data demonstrated that olaparib is generally well-
tolerated at doses up to and including the MTD of 400mg BID in patients with various solid 
tumors.  As of December 5, 2008, >540 patients with ovarian, breast, pancreatic, melanoma, and 
other advanced solid tumors have received olaparib, either as monotherapy or in combination 
with other chemotherapy agents.  AEs considered to be associated with olaparib included anemia 
(mild to moderate), neutropenia (mild to moderate), and thrombocytopenia (generally mild to 
moderate, sometimes severe), nausea and vomiting (mild to moderate), and fatigue (mild to 
moderate). 
 
Olaparib has also been studied in an expansion phase in BRCA-deficient ovarian cancer at a dose 
of 200mg BID.  32 patients with BDOC, the majority of whom were platinum-
resistant/refractory were evaluable for response.  14 of 32 patients achieved partial response, 13 
meeting GCIG-CA125 criteria, and 10 meeting RECIST criteria.  Stable disease was seen in an 
additional 8 patients (Fong et al., 2008).  A multicenter Phase II study enrolled two sequential 
cohorts of women with known germline BRCA2 or BRCA2 mutations and recurrent advanced 
ovarian cancer to receive olaparib continuously at a dose of 400mg BID (Cohort 1) or 100mg 
BID (Cohort 2) (Audeh et al., 2010).  Responses were observed in 33% (11 of 33) patients 
enrolled in the 400mg BID cohort and 13% (3 of 24) patients enrolled in the 100mg BID cohort.  
A Phase II study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer 
included a cohort of  46 ovarian cancer patients who were known not to carry a germline BRCA 
mutation, in which an overall response rate of 23.9% was observed (Gelmon et al., 2010).  
Preliminary results from a Phase II trial investigating olaparib as maintenance therapy following 
platinum-based therapy for platinum-sensitive serous ovarian cancer demonstrated a significant 
progression-free survival benefit (8.4 vs. 4.8 months, p<0.00001), with subgroup analyses 
demonstrating evidence of benefit regardless of BRCA status (Ledermann et al., 2011).  Lee and 
Kohn and colleagues have examined olaparib with carboplatin in 2 schedules in BRCA1/2 
mutation carriers with breast and/or ovarian cancer and women with high grade serous ovarian 
cancers.  They also see activity with over 80% of ovarian cancer patients attaining either disease 
stabilization or partial response, lasting up to 18+ months (Lee et al, 2011).   Additional phase I 
and II trials in both BRCA-deficient and BRCA-competent ovarian cancer are currently ongoing. 
 
2.3. 
Background for Correlative Studies 
 
2.3.1. Functional Imaging 
 
Functional tumor imaging with dynamic contrast enhanced magnetic resonance imaging (DCE-
MRI) is capable of evaluating changes in vascularity and quality of index lesions.  This imaging 
modality takes advantage of the fact that angiogenic vessels are hyperpermeable to many 
macromolecules by assessing the kinetics of contrast inflow and egress from a tumor region of 
interest. Quantitative parameters such as the volume of transfer constant of contrast agent (Ktrans) 
or the blood plasma volume fraction (Vp) as well as semi-quantitative measures, such as area under 

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the contrast concentration versus time curve for 90 seconds after contrast injection (IAUC90) can 
be derived from DCE-MRI studies. This modality may provide early indications of treatment 
effect even before changes in size can be perceived on CT. The molecular imaging studies will 
be performed for research purposes and will not be used to assess clinical responses as defined 
by RECIST criteria.  
 
2.3.2. Cytokine Modulation  
 
Most of the inhibitors of angiogenesis, direct and indirect, are associated with altered regulation 
of proangiogenic and proinflammatory cytokines.  These pharmcodynamic changes are 
consistent across different modalities of angiogenesis inhibition and include induction of 
circulating VEGF, IL6, IL8, angiopoietin2, and others.  To date, these endpoints have not been 
validated as predictive or prognostic for ovarian cancer response to angiogenesis inhibitors.  
Economopoulou and colleagues demonstrated that functional H2AX is required for cell 
response to aggravated hypoxia indicating a need for DNA repair in angiogenesis NAT MED.  
Thus, it is posited that there will be greater differences in the pharmacodynamic cytokine 
response to the combination of cediranib and olaparib. 
 
2.3.3. PAR Incorporation 
 
Incorporation of polyADP ribose moieties at sites of double stranded DNA breaks is a signal to 
the repair machinery to initiate repair.  It is not a marker of repair, per se.  It was initially 
hypothesized that modulation of PAR incorporation by PARP inhibitors would be both proof of 
mechanism and could be used to predict outcome.  Proof of mechanism was shown in an early 
phase 0 study of ABT-888 (veliparib) by Kummar et al  (Kummar et al., 2009) but predictive or 
prognostic value has not been reported.  Preliminary analysis of PBMC PAR incorporation data 
from the NCI phase 1 study of olaparib and carboplatin suggests that initial PAR incorporation 
results may be predictive of response to the combination.  Those preliminary data using 
pretherapy results are provocative and form the basis for examining PBMC PAR concentrations 
as an exploratory endpoint in this study.   
 
 
 
 
 
 
 
 
 
 
 
 
Lee, Hays, and Kohn and colleagues evaluated the potential of incorporation of PAR at baseline 
into PBMC in BRCA1/2mut women accrued to a study of olaparib and carboplatin.  ROC analysis 
of initial PAR levels in each patient measured against her response (PR/CR vs. PD) indicated a 

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cutoff of 190.5pg PAR/1x107 PBMC would yield a sensitivity of 50% and specificity of 100%.  
This cutoff value was then applied to the evaluable patient cohort (N=29) for stratification prior 
to comparison with PFS and Wilcoxon analysis.  A trend toward increased PFS was observed for 
patients with initial levels of PAR incorporation in PBMCs less than the ROC-predetermined 
cutoff (p=0.08; HR 2.05). 
 
2.4. 
Rationale 
 
The treatment of recurrent ovarian cancer with conventional cytotoxic agents is unsatisfactory.  
Combinations of novel agents with demonstrated effects in ovarian cancer may improve clinical 
outcome.  Results from studies of cediranib and other anti-angiogenic agents have demonstrated 
single-agent activity in ovarian cancer.  Olaparib has demonstrated single-agent activity in 
BRCA-deficient ovarian cancer and other cells deficient in homologous recombination.  Studies 
have shown that BRCA wild-type ovarian cancers still demonstrate deficiencies in homologous 
recombination, and studies of olaparib as monotherapy in BRCA wild-type ovarian cancers are 
ongoing. 
 
2.4.1. Rationale for Selected Approach and Trial Design 
 
• Treatment of recurrent ovarian cancer with conventional cytotoxic agents is limited 
by development of chemoresistance and intolerable side effects.  New therapeutic 
approaches are needed to improve clinical outcomes. 
• Studies of cediranib and other anti-angiogenic agents have demonstrated single-agent 
activity in ovarian cancer. 
• Olaparib is a PARP-1 inhibitor that is active against BRCA-deficient ovarian cancer.  
It is also active against cells deficient in homologous recombination (HR) in the in 
vitro setting. 
• BRCA wild-type ovarian cancers still demonstrate deficiencies in the homologous 
recombination pathways.  PARP-1 inhibitors have also demonstrated activity in 
BRCA wild-type ovarian cancers, potentially due to other mechanisms conveying 
HR-deficiency. 
• BRCA-deficient and triple-negative breast cancers share a similar molecular profile in 
tissue microarrays (Sorlie et al., 2003, Lakhani et al., 2002).     
• PARP-inhibition has demonstrated anti-angiogenic effects in preclinical studies.  
Incubation of endothelial cells with PJ-34 (a PARP inhibitor) inhibited proliferation 
of the cells (Pyriochou et al., 2008).  GPI 15427 (a potent PARP-1 and PARP-2 
inhibitor) inhibits in vivo angiogenesis in a matrigel plug assay.  PARP-1 knockout 
mice also demonstrate decreased in vivo angiogenesis by matrigel plug assay when 
compared with control mice with wild-type PARP-1 activity (Tentori et al., 2007). 
• The combination of cediranib and olaparib has the potential for synergistic effect, 
given the anti-angiogenic effects of PARP-inhibition, while having minimal 
overlapping toxicities. 
 
As cediranib and olaparib have not been used in combination with one another before, a Phase I 
dose escalation study will first be completed to determine the MTD of these two agents in 

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combination.  The MTD would be considered the recommended Phase 2 dose (RP2D).  The 
study would then evaluate the effectiveness of the RP2D of the combination of cediranib and 
olaparib as compared to that of cediranib alone in platinum-sensitive recurrent papillary-serous 
ovarian, fallopian tube, and peritoneal cancers.  The single agent dose of cediranib has been 
determined to be 30mg daily, and olaparib has been studied in ovarian cancer at a dose of 400mg 
twice daily in a capsule formulation.  Due to concerns regarding the overlapping toxicity of 
fatigue or unexpected toxicities in setting of combining these two agents for the first time, the 
starting dose of cediranib will be 20mg daily and that of olaparib will be 100mg twice daily. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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3. 
Participant SELECTION 
 
3.1. 
Inclusion Criteria 
 
Potentially eligible patients will be screened by their gynecologic oncologist and/or medical 
oncologist.  Participants must meet the following criteria on screening examination to be eligible 
to participate in the study: 
 
3.1.1. For Phase I Portion:  Participants must have histologically or cytologically confirmed 
epithelial ovarian cancer, primary peritoneal serous cancer, fallopian tube cancer, or 
triple-negative breast cancer. 
 
For Phase II Portion:  Participants must have histologically or cytologically Grade 2 or 
3 (high-grade) papillary-serous or endometrioid epithelial ovarian cancer, primary 
peritoneal serous cancer, or fallopian tube cancer.  Participants with epithelial ovarian, 
primary peritoneal, or fallopian tube cancers of other high-grade histologies who carry a 
known deleterious BRCA germline mutation by standard clinical testing (Myriad 
BRACAnalysis) will also be considered eligible. 
 
For Phase I-T Portion:  Participants must have histologically or cytologically confirmed 
epithelial ovarian cancer, primary peritoneal serous cancer, or fallopian tube cancer. 
 
3.1.2. Ovarian cancer, primary peritoneal, and fallopian tube participants in the Phase 1 and 
Phase 1-T portions of this trial must have either measurable cancer by RECIST 1.1 
criteria or  an elevated CA125 level at least twice the upper limit of normal on two 
separate  occasions at least 1 day but not more than 3 months apart.  At least one of the 
samples should be within 1 week of starting treatment.  Patients with both an elevated 
CA125 and measurable cancer will be followed by RECIST 1.1 criteria.  Patients with 
only an elevated CA125 level will be followed by modified GCIG criteria, as detailed in 
Section 10.2. 
 
 
Participants in the Phase II portion of the trial must have measurable disease by RECIST 
1.1 criteria. 
 
 
Breast cancer participants must have measurable disease by RECIST criteria. 
 
3.1.3. Prior therapy: 
 
For Phase I and Phase I-T Portions: 
• Prior chemotherapy for ovarian cancer patients must have included a first-line 
platinum-based regimen with or without intravenous consolidation chemotherapy. 
• Breast cancer patients must have recurred post both an adriamycin- and taxane-
containing regimen. 
• Prior hormonal-based therapy for ovarian, primary peritoneal serous, fallopian tube 
cancer, or breast cancer is acceptable. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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• Patients may not have had a prior PARP-inhibitor in the recurrent or metastatic 
setting.  Prior treatment with BSI-201 is allowed. 
• Patients may not have had a prior anti-angiogenic agent in the recurrent or metastatic 
setting. 
 
For Phase II Portion: 
• Prior chemotherapy must have included a first-line platinum-based regimen with or 
without intravenous consolidation chemotherapy. 
• Prior hormonal-based therapy for ovarian, primary peritoneal serous, or fallopian tube 
cancer is acceptable. 
• Patients may not have previously received a PARP-inhibitor.  Prior treatment with 
BSI-201 is allowed. 
• Patients may not have had a prior anti-angiogenic agent in the recurrent setting. 
• Patients may have received up to 1 non-platinum-based line of therapy in the 
recurrent setting. 
• Patients may have received an unlimited number of platinum-based therapies in the 
recurrent setting. 
• Patients should have platinum-sensitive disease, where platinum-sensitive disease is 
defined as having had a > 6 month interval since last receiving platinum therapy prior 
to disease recurrence.  Patients must have had a prior response while on the platinum-
containing regimen and cannot have experienced disease progression while receiving 
platinum. 
 
Subjects may begin cediranib and olaparib at least 3 weeks after their last dose of 
chemotherapy or hormonal therapy, assuming they are otherwise eligible. 
 
3.1.4. Age ≥ 18 years.  Because no dosing or adverse event data are currently available on the 
use of cediranib or olaparib in participants < 18 years of age, children are excluded from 
this study but will be eligible for future pediatric trials.  
  
3.1.5. Estimated life expectancy of greater than 6 months. 
 
3.1.6. ECOG performance status 0 or 1 (Karnofsky > 60%, see Appendix A).  
 
3.1.7. Participants must have adequate organ and marrow function as defined below: 
• Absolute neutrophil count > 1,500/mcL 
• Platelets > 100,000/mcL 
• Hemoglobin > 9 g/dL 
• For patients enrolled to the Phase 1-T portion of the protocol, the 
Hemoglobin should be ≥ 10 g/dL 
• Total bilirubin within 1.5 times the upper limit of normal institutional limits 
• AST (SGOT)/ALT (SGPT) < 2.5 × institutional upper limit of normal 
• Creatinine < the institutional upper limit of normal or creatinine clearance > 60 
mL/min/1.73 m2 for subjects with creatinine levels above institutional normal 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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• Less than or equal to 1+ proteinuria on two consecutive dipsticks taken no less 
than 1 week apart, or < 1 gm protein on 24-hour urine collection or a urine 
protein:creatinine ratio of  < 1. 
• Troponin T or I within normal institutional limits 
• Coagulation parameters (INR, aPTT) within 1.25 × upper limit of normal 
institutional limits, except where a Lupus anti-coagulant has been confirmed 
 
3.1.8. Toxicities of prior therapy (excepting alopecia) should be resolved to less than or equal to 
Grade 1 as per NCI-CTCAE v4.0 (located on the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  Patients 
with long-standing stable grade 2 neuropathy may be considered after discussion with the 
overall PI. 
 
3.1.9. Subjects with treated limited stage basal cell or squamous cell carcinoma of the skin or 
carcinoma in situ of the breast or cervix are eligible.  Subjects with prior cancer treated 
with a curative intent with no evidence of recurrent disease 5 years following diagnosis 
and judged by the investigator to be at low risk of recurrence are eligible.  Subjects with 
any other concomitant or prior invasive malignancies are ineligible. 
 
3.1.10. Patients who have the following risk factors are considered to be at increased risk for 
cardiac toxicities.  These patients should have increased monitoring (see study calendar 
Section 9.0) 
• Prior treatment with anthracyclines 
• Prior treatment with trastuzumab 
• A New York Heart Association classification of II controlled with treatment (see 
Appendix E) 
• Prior central thoracic radiation therapy (RT), including RT to the heart 
• History of myocardial infarction within 12 months (Patients with history of 
myocardial infarction within 6 months are excluded from the study). 
 
3.1.11. The effects of cediranib and olaparib on the developing human fetus are unknown. For 
this reason, women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry, for the duration of study participation, and for 3 months following treatment 
discontinuation. Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately. 
 
3.1.12. Ability to understand and the willingness to sign a written informed consent. 
 
3.1.13. Patients must be able to tolerate oral medications and not have gastrointestinal illnesses 
that would preclude absorption of cediranib or olaparib. 
 
3.1.14. Patients must be willing and able to check and record daily blood pressure readings. 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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3.2. 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study. 
 
3.2.1. Participants who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered 
from adverse events due to agents administered more than 3 weeks earlier. 
 
3.2.2. Participants may not be receiving any other investigational agents nor have participated 
in an investigational trial within the past 4 weeks.  Subjects may not have received prior 
treatment affecting the VEGF pathway in the recurrent setting, including thalidomide, 
bevacizumab, sunitinib, or sorafenib.  In the Phase I portion of the trial, subjects may not 
have received prior treatment with oregovomab (OvaRex) or any other antibodies that 
may interfere with CA-125 measurements. 
 
3.2.3. Patients with untreated brain metastases, spinal cord compression, or evidence of 
symptomatic brain metastases or leptomeningeal disease as noted on CT or MRI scans 
should not be included on this study, since neurologic dysfunction may confound the 
evaluation of neurologic and other adverse events.  Screening imaging to rule out brain 
metastases is not required for screening, but should be performed prior to study 
enrollment if clinically indicated.  Patients with treated brain metastases and resolution of 
any associated symptoms must demonstrate stable post-therapeutic imaging for at least 6 
months following therapy prior to starting study drug. 
 
3.2.4. History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to cediranib or olaparib. 
 
3.2.5. Participants receiving any medications or substances that are strong inhibitors or inducers 
of CYP3A4 are ineligible.  A list of CYP3A4 inhibitors and inducers is provided in 
Appendix D.  Dihydropyridine calcium-channel blockers are permitted for management 
of hypertension. 
 
3.2.6. Patients with any of the following: 
• History of myocardial infarction within six months 
• Patients with QTc prolongation > 500 msec or other significant ECG 
abnormality noted within 14 days of treatment. 
o For patients enrolled in the Phase 1-T portion of the protocol, the QTc 
should not exceed 470 msec. 
• NYHA classification of III or IV 
• If cardiac function assessment is clinically indicated or performed: LVEF less 
than normal per institutional guidelines, or < 55%, if threshold for normal not 
otherwise specified by institutional guidelines. 
• Condition requiring concurrent use of drugs or biologics with pro-arrhythmic 
potential (see Appendix F). 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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3.2.7. History of stroke or transient ischemic attack within six months. 
 
3.2.8. Patients may not have any evidence of pre-existing inadequately controlled hypertension 
(defined as a systolic BP of >140 mmHg or a diastolic BP of >90 mmHg), and must have 
a normal blood pressure (≤140/90 mmHg) taken in the clinic setting by a medical 
professional within 2 weeks prior to starting study.  Patients with hypertension may be 
managed with up to a maximum of three antihypertensive medications.  Patients who are 
on three antihypertensive medications must be actively followed by a cardiologist or 
blood pressure specialist for management of blood pressure while on protocol.   
 
3.2.9. Any prior history of hypertensive crisis or hypertensive encephalopathy 
 
3.2.10. Clinical significant peripheral vascular disease or vascular disease (aortic aneurysm or 
aortic dissection) 
 
3.2.11. Unstable angina 
 
3.2.12. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days 
prior to starting cediranib. 
 
3.2.13. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess. 
 
3.2.14. Current signs and/or symptoms of bowel obstruction or signs and/or symptoms of bowel 
obstruction within 3 months prior to starting study drugs. 
 
3.2.15. Current dependency on IV hydration or TPN. 
 
3.2.16. Evidence of coagulopathy or bleeding diathesis.  Therapeutic anticoagulation for prior 
thromboembolic events is permitted.  
 
3.2.17. 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. 
 
3.2.18. Pregnant women are excluded from this study because cediranib and olaparib are agents 
with the potential for teratogenic or abortifacient effects. Because there is an unknown 
but potential risk of adverse events in nursing infants secondary to treatment of the 
mother with cediranib and olaparib, breastfeeding should be discontinued if the mother is 
treated with cediranib or olaparib. These potential risks may also apply to other agents 
used in this study. 
 
3.2.19. Known HIV-positive individuals are ineligible because of the potential for 
pharmacokinetic interactions with cediranib or olaparib. In addition, these individuals are 
at increased risk of lethal infections when treated with marrow-suppressive therapy. 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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3.2.20. Patients may not use natural herbal products or other “folk remedies” while participating 
in this study. 
 
3.2.21. No features suggestive of myelodysplastic syndrome (MDS) or acute myelogenous 
leukemia (AML) on peripheral blood smear or bone marrow biopsy, if clinically 
indicated. 
 
3.3. 
Inclusion of Women, Minorities and Other Underrepresented Populations 
Both genders and members of all races and ethnic groups are eligible for this trial. 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
9 
+ 
 
= 
 
Not Hispanic or Latino 
153 
+ 
 
= 
 
Ethnic Category: Total of all subjects 
162 (A1) 
+ 
0 (B1) 
= 
(C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
 
= 
 
Asian 
12 
+ 
 
= 
 
Black or African American 
5 
+ 
 
= 
 
Native Hawaiian or other Pacific Islander 
0 
+ 
 
= 
 
White 
145 
+ 
 
= 
 
Racial Category: Total of all subjects 
162 (A2) 
+ 
0 (B2) 
= 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
Accrual Rate: 
2-3 (Ph 1);   
5-6 (Ph 2) 
2-3 (Ph 1-T): 
pts/month 
Total Expected 
Accrual: 
127 
Min 
162 
Max 
Projected Start Date of Study: 
 
 
 
 
 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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4. 
REGISTRATION PROCEDURES 
 
4.1. 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Eligible patients will be entered on study centrally through the Quality Assurance Office for 
Clinical Trials (QACT) at the Dana-Farber Cancer Institute at the time of study enrollment.  
Completed QACT eligibility checklists and signed consent forms should be faxed to the QACT 
at 617-632-2295 prior to subjects starting protocol treatment.  The checklist will be reviewed at 
that time and the subject registered by the QACT Protocol Registrars (617-632-3761). 
 
Following registration, patients should begin protocol treatment within 5 days.  Other 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. 
 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP.  Agents may be ordered by a participating site only after initial IRB 
approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) except for Group studies.  
 
4.2. 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time. In emergency situations when a participant must begin treatment during 
off-hours or holidays, call the QACT registration line at 617-632-3761 and follow the 
instructions for registering participants after hours.   
 
Randomization can only be done between normal QACT business hours, 8:00 AM to 5:00 PM 
Eastern Standard Time.  
 
The registration procedures are as follows: 
 
1. Obtain written informed consent from the participant prior to the performance of 
any study related procedures or assessments. 
 
2. Complete the protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical/research record. To be 
eligible for registration to the study, the participant must meet each inclusion 
and exclusion criteria listed on the eligibility checklist.  
 
 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility 
for the treatment study. Registration to both treatment and ancillary studies will 
not be completed if eligibility requirements are not met for all studies.  
 
3. Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 
617-632-2295.  

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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Exception: DF/PCC Affiliate sites must fax the entire signed consent form 
including HIPAA Privacy Authorization and the eligibility checklist to the 
Network Affiliate Office. The Network Affiliate Office will register the 
participant with the QACT.  
 
4. The QACT Registrar will (a) validate eligibility, (b) register the participant on the 
study, and (c) randomize the participant when applicable.  
 
5. The QACT Registrar will send an email confirmation of the registration and/or 
randomization to the person initiating the registration immediately following the 
registration and/or randomization.  
 
4.3. 
Registration Process for non DF/HCC Institutions 
 
Registration for non-DF/HCC Institutions will be as detailed in the Data Safety Monitoring Plan 
(DSMP).  Please refer to the DSMP, Appendix G, Section 5.7 for specific procedures. 
 
 
5. 
TREATMENT PLAN  
 
Treatment will be administered on an outpatient basis.  Expected toxicities and potential risks as 
well as dose modifications for cediranib and olaparib are described in Section 6 (Expected 
Toxicities and Dosing Delays/Dose Modifications).  No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat the 
participant's malignancy. 
 
Phase I 
 
Each cycle will be 28 days (4 weeks).  For the Phase I component of this study, treatment cohorts 
will consist of 3 to 6 patients and the dose escalation schedule will be as follows. Participants 
enrolled to the Phase I portion of the study will continue treatment with olaparib capsule 
formulation. 
 
 
Dose Level 
Cediranib 
Olaparib (capsule) 
 
-1 
15mg PO daily 
100mg PO BID 
Starting dose → 
0 
20mg PO daily 
100mg PO BID 
 
1 
20mg PO daily 
200mg PO BID 
 
2 
30mg PO daily 
200mg PO BID 
 
3 
30mg PO daily 
400mg PO BID 
 
Phase I-T 
 
For the Phase I-T component of this study, treatment cohorts will consist of 3 to 6 patients.  Two 
separate cohorts of dose escalation will be accrued, one with a dosing of cediranib at 30mg daily 
(Phase I-TA) and a second at cediranib dosing of 20mg daily (Phase I-TB).  The two Phase I-T 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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dose escalation schemes will enroll in parallel. Participants enrolled to the Phase I-T portion of 
the study will receive treatment with the olaparib tablet formulation. The dose escalation 
schedule for the two cohorts will be per the following tables.  If the cohort of patients enrolled in 
a given dose level completes the DLT assessment window without experiencing a DLT in the 
first three patients or with 1 or fewer DLTs in six patients, the next higher dose level may be 
assessed. 
 
Phase 1-TA Dose Escalation:  Cediranib 30mg 
 
Dose Level 
Cediranib 
Olaparib (tablet) 
 
-1-TA 
30mg PO daily 
100mg PO BID 
Starting dose → 
0-TA 
30mg PO daily 
150mg PO BID 
 
1-TA 
30mg PO daily 
200mg PO BID 
 
2-TA 
30mg PO daily 
250mg PO BID 
 
3-TA 
30mg PO daily 
300mg PO BID 
 
Phase 1-TB Dose Escalation:  Cediranib 20mg 
 
Dose Level 
Cediranib 
Olaparib (tablet) 
 
-1-TB 
20mg PO daily 
150mg PO BID 
Starting dose → 
0-TB 
20mg PO daily 
200mg PO BID 
 
1-TB 
20mg PO daily 
250mg PO BID 
 
2-TB 
20mg PO daily 
300mg PO BID 
 
Toxicity assessments will be done using NCI Common Terminology Criteria for Adverse Events 
(CTCAE v4.0).  CTCAE v4.0 is identified and located on the CTEP website at 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).  Dose escalation 
to the next dose level will occur when the preceding cohort reaches the end of Cycle 1.  Patients 
who do not complete both treatments in cycle 1 for reasons other than cediranib or olaparib 
toxicity will be replaced.  Toxicity data for each cohort will be reviewed prior to dose escalation.  
Intra-patient dose escalation will be allowed at the discretion of the investigator and overall trial 
PI for patients following their completion of Cycle 2 if the following criteria are met:  the patient 
had no > grade 1 toxicities secondary to study treatment except for grade 2 or 3 HTN or nausea 
no greater than grade 1 after treatment with concurrent medications, the subsequent dose cohort 
has completed Cycle 1, and evaluation of DLTs has been completed for the subsequent dose 
cohort and the dose was deemed to be safe due to ≤ grade 2 toxicities.  Dose escalation will 
occur for both cediranib and olaparib according to the dose escalation schema.  Patients can be 
dose-escalated multiple times as long as they continue to meet criteria and do not exceed the 
final protocol-specified dose level (dose Level 3).  All intra-patient dose escalations must be 
discussed and approved by the overall trial PI.  If treatment-related toxicities related to one of the 
study drugs restricts further escalation of that drug, a modification to the dose escalation schema 
may be considered.  
 
Phase I-T PK expansion 
Once the MTD has been established during the Phase 1-T, two PK expansion cohorts of 6 
evaluable patients each will be enrolled for pharmacokinetic studies.  Participants in this 
expansion will receive a one week of either single-agent cediranib (Cohort 1-T PKced) or single-

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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agent olaparib (tablet formulation; Cohort 1-T PKolap) prior to starting cycle 1 of combination 
cediranib and olaparib (tablet formulation).  Full details of the PK evaluation schedule are 
outlined in Section 8.14.  Participants must be able to continue on study drug without any dose 
holds through Cycle 1 Day 16 of treatment to be considered fully evaluable for PK studies. 
 
Participants participating in the PK expansion cohorts will take their study drugs on the 
following schedule once combination dosing has started: 
1. Cediranib tablet(s) in the morning on an empty stomach (at least 2 hours after eating) 
2. Light meal ~1 hour after taking cediranib 
3. Morning olaparib tablet(s) after light meal 
4. Evening olaparib tablet(s) 12 hours after morning olaparib dose, taken after a light 
meal 
 
Phase II 
 
For the Phase 2 portion of this study, patients will be randomized in 1:1 ratio to one of the two 
following arms: 
1.   Olaparib 400mg BID (capsule) 
2.   Cediranib and olaparib at the RP2D (cediranib 30mg daily and olaparib 200mg BID 
(capsule)) derived from the Phase I portion of this study 
 
Participants enrolled to the Phase II portion of the study will continue treatment with olaparib 
capsule formulation. 
 
All patients must meet the eligibility criteria for the Phase II portion of the study, as outlined in 
Section 3.  Patient randomization will be stratified based upon: 
1.   Prior receipt of anti-angiogenic therapy. 
2.   BRCA mutation status (carrier, non-carrier, unknown). 
 
5.1. 
Pre-treatment Criteria 
 
5.1.1. Screening Visit: Patients must meet criteria at screening as outlined in Section 3.1. 
 
5.1.2. Hematologic Parameters for treatment: 
 
 
Absolute Neutrophil Count: 
• Cycle 1, Day 1:  ≥ 1500/mm3  
• Cycles 2 and Beyond, Day 1:  ≥ 1000/mm3 
For Phase 1-T patients:  
o Hemoglobin:  
• Cycle 1, Day 1: >=10g/dL  
• Cycles 2 and beyond, Day 1:  Per Table in Section 6.3.1 
o Platelets:  

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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• Cycle 1, Day 1: >=100,000/mcL  
• Cycles 2 and beyond, Day 1:  Per Table in Seciton 6.3.1 
 
5.1.3. All Cycles, Day 1:  Patients must have all of the following: 
• Adequate blood pressure control as detailed in Section 6.3.2. 
• Serum creatinine < 1.5 × the institutional upper limit of normal  
• Liver function test ≤ 2.5 × upper limit of normal. 
• ECOG performance status of 0 or 1. 
• No evidence of life-threatening medical problems. 
 
5.1.4. Pre-Cycle 1 Therapy: Translational Component 
• All patients will be strongly encouraged to participate in the translational 
component of the trial.  Travel to and from the NCI and all costs of imaging, 
blood draws, biopsy, or fluid sampling done at the NCI will be provided in kind.  
A stipend to assist with cost of the local stay during this aspect of the trial will be 
provided, or the patient can elect hospital admission at no cost. 
• Biopsiability will be determined prior to scheduling the NCI visit using most 
recent tumor imaging.  This will be followed by an on-study 
chest/abdominal/pelvic CT with oral and IV contrast obtained the day of 
evaluation at NCI.  A copy of this scan will be provided to the home institution 
for use in subsequent tumor measurements. 
• Patients will be seen at NCI with a copy of their signed protocol consent from 
their home institution. 
• Drug therapy will be initiated after acquisition of initial translational components 
and dispensed for the 28-day cycle. 
• Translational component sample acquisition will occur: 
o Prior to starting therapy 
o Prior to day 3: 2-8 hours after the 5th dose of olaparib (d1 will start with the 
am dose) and the 3rd dose of cediranib (the first dose of cediranib will be 
administered at the same time as the first dose of olaparib). 
 
Process 
Pre-treatment 
Day 3 
Blood for PBMCs, 
DNA, and CECs 
X 
X 
Plasma and serum for 
cytokines 
X 
X 
DCE-MRI imaging 
X 
X 
Biopsy:  core of 
tumor, involved skin, 
or malignant effusion 
sampling 
X 
X 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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5.2. 
Agent Administration  
 
5.2.1. Cediranib 
 
Cediranib at the appropriate dose level will be given orally continuously each morning on an 
empty stomach, either 1 hour before or 2 hours after breakfast.  Subjects should not “make up” a 
missed dose or a dose that was vomited.  Subjects should take cediranib with a glass of water.  
Subjects should avoid grapefruit juice while on study, due to P450 interactions.  Cediranib may 
be taken at the same time as the morning olaparib dose. 
   
Cediranib will be dispensed at the start of each cycle.  Patients will be provided with a pill diary 
for each drug (Appendix B), instructed in its use, and asked to bring it with them to each 
appointment. 
 
Frequent blood pressure monitoring is important in patients receiving cediranib.   Clinical trials 
of cediranib demonstrate that increases in blood pressure may occur following dosing with 
cediranib for a number of weeks and that these increases may occur relatively quickly when 
starting the drug.  Patients will be asked to record twice-daily blood pressure readings (Appendix 
C).  If two successive systolic readings are >140 mmHg OR two successive diastolic readings are 
>90 mmHg OR any combination of elevated systolic and diastolic blood pressure are observed, 
patients will be instructed to contact their physician as soon as possible.  Patients should seek 
medical advice if their BP exceeds 180 mmHg (systolic) or 105 mmHg (diastolic) at any time 
and should also be encouraged to contact their physician if they are concerned about any 
symptoms that may be associated with high blood pressure (e.g., headache).  Section 6 includes 
specific guidelines on the management and, if appropriate, dose modifications for treatment-
emergent hypertension. 
 
5.2.2. Olaparib 
 
Olaparib Capsules (Phase I and Phase II Participants) 
 
Olaparib at the appropriate dose level will be given orally continuously twice daily on an empty 
stomach.  The correct number of 50mg capsules comprising the appropriate dose should be taken 
at the same times each day with approximately 240 mL of water.  Patients should take olaparib 
on an empty stomach either 1 hour before or 2 hours after meals.  The olaparib capsules should 
be swallowed whole and not chewed, crushed, dissolved, or divided. 
 
Olaparib will be dispensed at the start of each cycle.  Patients will be provided with a pill diary 
(Appendix B), instructed in its use, and asked to bring it with them to each appointment. 
 
If vomiting occurs shortly after the olaparib capsules are swallowed, the dose should only be 
replaced if all of the intact capsules can be seen and counted.  Should any patient enrolled on the 
study miss a scheduled dose, the patient will be allowed to take the scheduled dose up to a 
maximum of 2 hours after that scheduled dose time.  If greater than 2 hours after the scheduled 
dose time, the missed dose should not be taken, and the patient should take their allotted dose at 
the next scheduled time. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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Olaparib Tablets (Phase I-T Participants) 
 
Olaparib at the appropriate dose level will be given orally continuously twice daily on an empty 
stomach.  The correct number of 25mg, 100mg, or 150mg tablets comprising the appropriate 
dose should be taken at the same times each day with approximately 240 mL of water.  Patients 
should take olaparib on an empty stomach either 1 hour before or 2 hours after meals.  The 
olaparib tablets should be swallowed whole and not chewed, crushed, dissolved, or divided. 
 
Olaparib will be dispensed at the start of each cycle.  Patients will be provided with a pill diary 
(Appendix B), instructed in its use, and asked to bring it with them to each appointment. 
 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted.  Should any patient enrolled on the 
study miss a scheduled dose, the patient will be allowed to take the scheduled dose up to a 
maximum of 2 hours after that scheduled dose time.  If greater than 2 hours after the scheduled 
dose time, the missed dose should not be taken, and the patient should take their allotted dose at 
the next scheduled time. 
 
5.3. 
Definition of Dose-Limiting Toxicity 
 
Toxicity assessments will be done using NCI Common Terminology Criteria for Adverse Events 
(CTCAE v4.0).  CTCAE v4.0 is identified and located on the CTEP website at 
(http://ctep.cancer/gov/protocolDevelopment/electronic_applications/ctc.htm).  Dose-limiting 
toxicity (DLT) refers to toxicities experienced during the first cycle of treatment.  A DLT is 
defined as any of the following:   
 
• Non-Hematologic Toxicity 
o Grade 3 or 4 events, excluding  
▪ Grade 3 fatigue 
▪ Grade 3 hypertension controlled with anti-hypertensive therapy. 
▪ Grade 3 hypophosphatemia 
▪ Grade 3 hyponatremia 
• Hematologic Toxicity 
o Grade 4 neutropenia of ≥ 4 days duration 
o Grade 4 neutropenia of any duration with fever or documented infection 
o All other hematologic toxicities of Grade 4 
o Inability to take 75% or more of the planned dose in Cycle 1 due to treatment-
related AEs 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6 (Expected Toxicities and Dosing Delays/Dose Modifications). 
 
Dose escalation will proceed within each cohort according to the following scheme. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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Number of Participants with DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 participants at the next dose level. 
> 2 
Dose escalation will be stopped. This dose 
level will be declared the maximally 
administered dose (highest dose 
administered). Three (3) additional 
participants will be entered at the next lowest 
dose level if only 3 participants were treated 
previously at that dose. 
1 out of 3 
Enter at least 3 more participants at this dose 
level. 
• If 0 of these 3 participants experience 
DLT, proceed to the next dose level. 
• If 1 or more of this group suffer DLT, 
then dose escalation is stopped, and this 
dose is declared the maximally 
administered dose. Three (3) additional 
participants will be entered at the next 
lowest dose level if only 3 participants 
were treated previously at that dose.  
< 1 out of 6 at highest dose level below the 
maximally administered dose 
This is generally the recommended 
phase II dose. At least 6 participants 
must be entered at the recommended 
phase II dose. 
 
If one patient develops a DLT, then the cohort will be expanded to include a total of 6 patients.  
If greater than or equal to two patients develop DLT, then that dose level will be considered the 
maximum administered dose (MAD), and further dose escalation will be terminated.  A total of 6 
patients will be treated at the next lower dose.  The maximum tolerated dose (MTD) will be the 
dose at which no more than 1 patient develops DLT when at least 6 patients have been treated. 
 
5.4. 
General Concomitant Medication and Supportive Care Guidelines 
 
The use of any natural/herbal products or other “folk remedies” are not allowed on study.  All 
medications must be recorded in the case report form and be reviewed by the treating physician 
at each visit. 
 
Cediranib demonstrated minimal inhibitor effects on the activity of CYP3A4 (testosterone and 
midazolam) in vitro, although the IC50 was far in excess of the clinically relevant 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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concentrations.  Based on in vitro and clinical exposure data, olaparib is considered unlikely to 
cause clinically significant drug interactions through inhibition or induction of cytochrome P450 
enzyme activity.  However, in vitro data have also shown that the principal enzyme responsible 
for the formation of the 3 main metabolites of olaparib is CYP3A4.  Given this data, potent 
inhibitors or inducers of CYP3A4 (as outlined in Appendix D) must not be used during this study 
for patients receiving olaparib.  Dihydropyridine calcium-channel blockers are allowed for 
management of hypertension. 
 
Patient should receive general concomitant and supportive care medications based on best 
medical practice.  Neupogen and other bone marrow-supportive agents, including 
erythropoiesis-stimulating agents, are not allowed during treatment. 
   
5.5. 
Duration of Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse events, treatment may continue 
indefinitely or until one of the following criteria applies: 
• Disease progression, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s), 
• Participant decides to withdraw from the study, or 
• General or specific changes in the participant’s condition render the 
participant unacceptable for further treatment in the opinion of the 
treating investigator. 
 
5.6. 
Duration of Follow Up  
 
Participants will be followed for 3 years after removal from study treatment or until death, 
whichever occurs first. Participants removed from study treatment for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse event. Participants’ vital 
status will be followed every 6 months following removal from the study treatment. Date and 
cause of death should be provided for participants who become deceased within the 3 year 
interval following removal from the study treatment. 
 
5.7. 
Criteria for Removal from Study Treatment  
Participants will be removed from study treatment when any of the criteria listed in Section 5.5 
applies. The reason for study treatment removal and the date the participant was removed must 
be documented in the study-specific case report form (CRF). Alternative care options will be 
discussed with the participant. 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator, Joyce Liu, MD at 617-632-3352 (pager). 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using NCI Common Terminology Criteria for Adverse Events (CTCAE 
v5.0).  CTCAE v 5.0 is identified and located on the CTEP website at 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate 
medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the 
toxicity has resolved or is deemed irreversible.  
 
6.1. 
Anticipated Toxicities  
 
A list of the adverse events and potential risks associated with the agents administered in this 
study appear below and will determine whether dose delays and modifications will be made or 
whether the event requires expedited reporting in addition to routine reporting.  
 
6.1.1. CAEPRs for CTEP-Supplied Investigational Agents 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single, 
complete 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 Agent Specific Adverse Event List (ASAEL), 
appears in a separate column and is identified with bold and italicized text. This subset of Aes (the 
ASAEL) contains events that are considered ‘expected’ for expedited reporting purposes only. 
Refer to the “CTEP, NCI Guidelines: Adverse Event Reporting Requirements” 
(http://ctep.cancer.gov/) for further clarification. The CAEPR may not provide frequency data; if 
not, refer to the Investigator’s Brochure for this information. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
40 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
CAEPR for cediranib 
 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
 for 
Cediranib (AZD2171, NSC 732208) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for further clarification. 
Frequency is provided based on 1608 patients. Below is the CAEPR for Cediranib (AZD2171). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
Version 2.15, November 7, 20181   
 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 5.0 Term) 
[n= 1608] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
 
Hemolytic uremic syndrome 
  
 
 
Thrombotic thrombocytopenic 
purpura 
  
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
ENDOCRINE DISORDERS 
  
 
Hyperthyroidism 
 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3)   
 
Anal mucositis 
 
 Anal mucositis (Gr 2) 
 
Constipation 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dysphagia 
 
 Dysphagia (Gr 2) 
 
 
 Gastrointestinal fistula2 
  
 
 
 Gastrointestinal perforation3 
  
 
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) 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
41 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 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%)  
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
 Infection4 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine aminotransferase increased 
(Gr 3) 
 
Alkaline phosphatase increased 
 
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Lymphocyte count decreased 
 
  
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
  
 
Thyroid stimulating hormone 
increased 
 
 Thyroid stimulating hormone 
increased (Gr 2) 
 
Weight loss 
 
 Weight loss (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Generalized muscle weakness 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
Lethargy 
 
  
 
 
Leukoencephalopathy 
  
 
 
Reversible posterior 
leukoencephalopathy syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
 
Nephrotic syndrome 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
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) 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
42 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 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%)  
  
VASCULAR DISORDERS 
  
 
 
Arterial thromboembolism 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event 
 
 Thromboembolic event (Gr 4) 
 
Vascular disorders - Other 
(hemorrhage)5 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, Enterovesical 
fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, Pancreatic fistula, 
Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS SOC. 
 
3Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric 
perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the 
GASTROINTESTINAL DISORDERS SOC. 
 
4Infections includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
5Hemorrhage is a known consequence of VEGF/VEGFR signaling inhibition. The majority of hemorrhage events 
reported were mild; however, serious events, defined as symptomatic bleeding in a critical area or organ system 
(e.g., eye, gastrointestinal tract, genitourinary [GU] tract, respiratory tract, and nervous system) have been reported. 
 
 
 
Adverse events reported on cediranib (AZD2171) trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that cediranib (AZD2171) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system disorders - Other 
(polycythemia); Bone marrow hypocellular; Febrile neutropenia 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Cardiac disorders - Other (premature 
ventricular complexes); Cardiac disorders - Other (valvular heart disease); Chest pain - cardiac; Mobitz (type) II 
atrioventricular block; Myocardial infarction; Palpitations; Pericardial effusion; Pericarditis; Restrictive 
cardiomyopathy; Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (ears feel full/plugged); Ear 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 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
43 
CONFIDENTIAL 
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HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder obstruction; Hepatic pain; Hepatobiliary disorders - 
Other (bile duct obstruction); Hepatobiliary disorders - Other (jaundice cholestatic) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Immune system disorders - Other (systemic 
inflammatory response syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Dermatitis radiation; Fracture; 
Injury, poisoning and procedural complications - Other (tracheostomy malfunction); Intestinal stoma leak; Venous 
injury; Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; Blood lactate 
dehydrogenase increased; CPK increased; Cardiac troponin I increased; Cardiac troponin T increased; Cholesterol 
high; Creatinine increased; Ejection fraction decreased; Electrocardiogram QT corrected interval prolonged; GGT 
increased; Hemoglobin increased; INR increased; Investigations - Other (elevated ammonia level); Investigations - 
Other (increased blood erythropoietin); Lipase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperglycemia; Hyperkalemia; 
Hypertriglyceridemia; Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Hypomagnesemia; 
Hyponatremia; Metabolism and nutrition disorders - Other (failure to thrive) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Avascular necrosis; Back 
pain; Bone pain; Chest wall pain; Muscle cramp; Muscle weakness lower limb; Muscle weakness upper limb; 
Myalgia; Myositis; Neck pain; Pain in extremity; Rotator cuff injury 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Central nervous system necrosis; Cognitive disturbance; Depressed 
level of consciousness; Dysarthria; Dysgeusia; Dysphasia; Encephalopathy; Hydrocephalus; Ischemia 
cerebrovascular; Memory impairment; Muscle weakness left-sided; Nervous system disorders - Other (coma); 
Nervous system disorders - Other (right hemiparesis); Olfactory nerve disorder; Peripheral motor neuropathy; 
Peripheral sensory neuropathy; Seizure; Somnolence; Spinal cord compression; Stroke; Syncope; Transient ischemic 
attacks; Tremor 
PSYCHIATRIC DISORDERS - Confusion; Delirium; Depression; Hallucinations; Insomnia; Suicide attempt 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Cystitis noninfective; 
Hematuria; Urinary retention; Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; Menorrhagia; Vaginal 
fistula 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Aspiration; Hypoxia; Pharyngolaryngeal 
pain; Pleural effusion; Pneumonitis; Pneumothorax; Pulmonary edema; Pulmonary fistula; Pulmonary hypertension; 
Sinus pain 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail loss; Pruritus; 
Purpura; Rash acneiform; Rash maculo-papular; Skin and subcutaneous tissue disorders - Other (petechiae); Skin 
and subcutaneous tissue disorders - Other (plantar warts); Skin ulceration; Urticaria 
VASCULAR DISORDERS - Capillary leak syndrome; Flushing; Hypotension; Vasculitis 
 
 
 
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. 
 
 
CAEPR for olaparib 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Olaparib (AZD2281, NSC 747856) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
44 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for further clarification. 
Frequency is provided based on 2073 patients. Below is the CAEPR for Olaparib (AZD2281). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in the 
SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
Version 2.3, June 18, 20181 
 
 Adverse Events with Possible  
 Relationship to Olaparib (AZD2281) 
 (CTCAE 5.0 Term) 
[n= 2073] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 4) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection2 
 
  
INVESTIGATIONS 
  
 
Creatinine increased 
 
  
 
Lymphocyte count decreased 
 
  
 
Neutrophil count decreased 
 
  
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 
  

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
45 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 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%) 
 
 
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
 
Pneumonitis 
  
 
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; Platelet count decreased; Serum amylase 
increased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hypermagnesemia; 
Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Avascular necrosis; Bone pain; 
Generalized muscle weakness; Muscle cramp; Muscle weakness lower limb; Myalgia; Neck pain; Pain in extremity; 
Rotator cuff injury 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Amnesia; Ataxia; Cognitive disturbance; Concentration impairment; 
Encephalopathy; Intracranial hemorrhage; Peripheral sensory neuropathy; Stroke; Syncope; Transient ischemic 
attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Hallucinations; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other (decreased 
glomerular filtration rate); Renal and urinary disorders - Other (hydronephrosis); Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Oropharyngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other 
(chronic obstructive pulmonary disease) 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Pruritus; Rash maculo-papular 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension; Hypotension; Thromboembolic event 
 
Note: Olaparib (AZD2281) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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6.1.2. Adverse Event Lists for olaparib  
 
Adverse events observed with olaparib are detailed in the Investigator’s Brochure (IB).  As of 
October 2, 2013, >2100 patients have received olaparib in doses ranging from 10mg daily to 
600mg BID, either as monotherapy or in combination with other chemotherapy agents 
(liposomal doxorubicin, cisplatin, dacarbazine, gemcitabine, gemcitabine+cisplatin, carboplatin, 
carboplatin+paclitaxel, paclitaxel, topotecan, irinotecan, or bevacizumab).  Preliminary 
unvalidated safety data are available for several studies and are detailed in the IB.  
 
Aes considered to be associated with administration of olaparib included laboratory findings 
and/or clinical diagnoses of anemia (generally mild to moderate, CTC grade 1 or 2), neutropenia 
(predominantly mild to moderate, CTC grade 1 or 2), thrombocytopenia (generally mild to 
moderate, CTC grade 1 or 2; sometimes severe, CTC grade 3 or 4), nausea and vomiting 
(generally mild to moderate, CTC grade 1 or 2, intermittent and manageable on continued 
treatment), and fatigue (generally intermittent, of mild to moderate intensity CTC grade 1 or 2).  
Pneumonitis events with no consistent clinical pattern have been reported in a small number of 
patients.  Rare hematologic malignancies, including myelodysplasia, have also been reported.  
Please see the table below, titled “Summary of Adverse Drug Reactions from Completed Clinical 
Trials of Olaparib,” for a summary of the adverse drug reactions from completed trials of 
olaparib. 
 
In the first clinical study in man, a total of 98 patients in the study were evaluable for safety.  As 
expected in patients with advanced cancer, all of the patients experienced at least one adverse 
event.  In total, 81 patients (82.7%) experienced at least one adverse event that the investigator 
attributed to study medication.  Most of the Aes were mild to moderate in intensity.  The number 
of patients with CTC grade ≥3 events attributed to study medication was low (24 patients, 
21.4%) and increased with increasing dose.  The observed Aes in each system are detailed 
below. 
 
• Gastrointestinal Disorders 
The most common gastrointestinal Aes were nausea (56 of 98 patients, 57%) and 
vomiting (44 of 98 patients, 45%).  Most were of mild to moderate intensity (CTC grade 
1 or 2), intermittent, and manageable on continued treatment.  Abdominal pain (24 of 98 
patients, 24.5%), constipation (18 of 98 patients, 18.4%), and diarrhea (25 of 98 patients, 
25.5%) were also observed. 
 
• General Disorders 
The most common general AE reported was fatigue, which was observed in 52 patients 
(53%).  Cases of fatigue were generally intermittent and of mild to moderate intensity 
(CTC grade 1 or 2).  Other Aes included pyrexia (10 patients, 10%) and peripheral  
edema (16 patients, 16%). 
 
• Cardiac Disorders 

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Protocol Version Date: January 03, 2019 
 
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29 patients reported mild (CTC grade 1), asymptomatic tachycardia.  None of these cases 
required treatment, and all events were considered to be unrelated to study drug. 
 
• Nervous System Disorders 
The most common nervous system Aes reported were headache (15%), dizziness (11%), 
and dysgeusia (13%).  Other reported Aes included somnolence, attention or mental 
impairment, cognitive disorder, dizziness, depression, and memory impairment. 
 
• Hematologic Disorders 
Laboratory findings and/or clinical diagnoses of anemia (generally mild to moderate, 
CTC grade 1 or 2), neutropenia (predominantly mild to moderate, CTC grade 1 or 2), and 
thrombocytopenia (generally mild to moderate, CTC grade 1 or 2, sometimes severe) 
were observed.  The incidence of anemia was 26%, neutropenia was 1%, and 
thrombocytopenia was 5%.  A few cases of myelodysplasia have been reported on studies 
including olaparib.  Additionally, data from study D0810C00002 have demonstrated 
increases in MCV in approximately 30% of patients, especially in those receiving greater 
than 6 cycles of treatment, mild and moderate in intensity, and asymptomatic in nature.  
No clinical consequences have been associated with this finding. 
 
 
MDS/AML have been reported in <1% of patients exposed to olaparib. The cases were typical of 
secondary MDS/therapy-related AML. The duration of therapy with olaparib in patients who 
developed secondary MDS/AML varied from <6 months to >2 years. All patients had potential 
contributing factors for the development of MDS/AML, having received extensive previous 
chemotherapy with platinum agents. Many had also received other DNA damaging agents. 
 
New primary malignancies have been reported in a small number of patients. There were other 
contributing factors/potential alternative explanations for the development of the new primary 
malignancy in all cases. 
 
Pneumonitis events have been reported in <1% of patients receiving olaparib. The reports of 
pneumonitis had no consistent clinical pattern and were confounded by a number of pre-
disposing factors (cancer and/or metastases in lungs, underlying pulmonary disease, smoking 
history, and/or previous chemotherapy and radiotherapy). 
 
6.2. 
Dose Modifications/Delays 
 
In the phase 1 and phase 1-T components of this study, doses of cediranib and olaparib will be 
administered at the same dose level throughout a cycle if no DLTs occur.  In cycle 1, patients 
experiencing non-hematologic Grade 2 Aes (or Grade 3 fatigue or hypertension) may have 
treatment held for up to 7 days for toxicity management.  Treatment may then be resumed at the 
same dose level.  Inability to take at least 75% of the planned dose of cediranib and olaparib in 
Cycle 1 due to drug-related toxicity is considered a DLT.  If any individual patient develops a 
DLT, treatment for this patient will be stopped.  If the toxicity is not resolved within 14 days, the 
patient will be removed from the study.  Patients who experienced a DLT whose toxicity has 

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resolved to baseline or Grade 1 and whose therapy has been discontinued for less than 14 days 
may resume therapy at the previous (next lower) dose level if necessary.  For patients who 
experience a DLT in the first cycle of the first cohort (cediranib 20mg daily and olaparib 100mg 
BID) whose toxicity has resolved to baseline or Grade 1 and whose therapy has been 
discontinued for less than 14 days, the dose may be reduced to cediranib 15mg daily and olaparib 
100mg BID.  During the DLT assessment period, both drugs must be held if there is an 
indication for either drug to be held. 
 
For patients experiencing non-hematologic Grade 2 Aes (or Grade 3 fatigue or hypertension) in 
cycles 2 or greater, treatment may be held for up to 14 days for toxicity management if 
necessary.  The treating physician may decide to hold treatment to ensure patient safety when 
grading and/or attribution is unclear. Patients whose treatment has been held for ≤7 days may 
then resume treatment at the same dose level.  If treatment is held for >7 days, please see Section 
6.3.1 regarding dose modifications.  For patients in the phase 1 and  1-T portions of the study in 
cycles 2 and beyond, dose modifications/delays should be managed as per Section 6.3.1.  Tables 
for cediranib and olaparib dosing levels are provided in Sections 6.2.1 and 6.2.2. 
 
In the phase 2 component of this study, dose modifications, and general management of 
Aes will be outlined as in Section 6.3.1.  Dose modifications and delays for specific toxicities 
of hypertension, proteinuria, decrease in LVEF, diarrhea, fever and neutropenia, thyroid 
toxicities, and RPLS will be as further outlined in specific subsections in Section 6.3. 
 
6.2.1. Table for Cediranib Dose Modification* 
 
Dose Level 
Cediranib 
-2 
15mg daily 
-1 
20mg daily 
1 
30mg daily 
* Presuming patients are being dosed at the maximum Phase 1 dose level of cediranib 
30mg daily or being dosed as the starting phase 2 dose level of cediranib 30mg daily.  
Patients who are being treated at a different dose level on the Phase 1 or Phase 1-T 
portions of this trial may be dose-reduced per this table but may not be dose-escalated 
except as detailed in Section 5. 
 
 
6.2.2. Tables for Olaparib Dose Modification 
 
 
Phase I: 
Dose Level 
Olaparib (capsule) 
-2 
100mg twice daily 
-1 
200mg twice daily 
1* 
400mg twice daily 
* This dose level is applicable only for patients who were dosed at the maximum Phase 
1 dose level of olaparib 400mg twice daily.  Patients who are being treated at a 
different dose level on the Phase 1 portion of this trial may be dose-reduced per this 
table but may not be dose-escalated except as detailed in Section 5. 

NCI Protocol: 8348 
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Protocol Version Date: January 03, 2019 
 
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Phase I-TA: 
Dose Level 
Olaparib (tablet) 
-2 
100mg twice daily 
-1 
150mg twice daily 
1 
200mg twice daily 
2 
250mg twice daily 
3 
300mg twice daily 
*   Patients may be dose-reduced per this table but may not be dose-escalated except as 
detailed in Section 5. 
 
Phase I-TB: 
Dose Level 
Olaparib (tablet) 
-3 
150mg twice daily 
-2 
200mg twice daily 
-1 
250mg twice daily 
1 
300mg twice daily 
*   Patients may be dose-reduced per this table but may not be dose-escalated except as 
detailed in Section 5. 
 
 
Phase II: 
 
 
 
For patients receiving olaparib monotherapy: 
Dose Level 
Olaparib (capsule) 
-2 
100mg twice daily 
-1 
200mg twice daily 
1 
400mg twice daily 
 
 
For patients receiving olaparib and cediranib combination therapy: 
Dose Level 
Olaparib (capsule) 
-2 
100mg twice daily 
-1 
150mg twice daily 
1 
200mg twice daily 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
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Protocol Version Date: January 03, 2019 
 
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6.3. 
Toxicity Management 
 
The management of general adverse events not otherwise specified will be as per the table in 
Section 6.3.1.  Management of specific toxicities, including hypertension, proteinuria, decreased 
in LVEF, diarrhea, fever and neutropenia, thyroid toxicities, and RPLS will be as further outlined 
in specific subsections in Section 6.3. 
 
6.3.1. Dose Modifications and Management of Cediranib and Olaparib Toxicities  
 
General Management of Adverse Events (Non-Hematologic) 
Observation 
Action 
AE resolves promptly with supportive care  
Maintain dose level 
Any grade 2 non-hematologic AE or grade 3 
fatigue related to cediranib or olaparib that 
persists despite maximal support.  
Hold study drug(s)1 for up to 14 days 
until toxicity resolves to  grade 1.3  
Treatment may be restarted at one dose 
level lower for the drug(s) causing the 
toxicity, as per the dose reduction levels 
in Sections 6.2.1 and 6.2.2, at the 
treating investigator’s discretion.  The 
overall PI of the study should be 
informed regarding all dose 
modifications.  Patients whose toxicity 
has not resolved after 14 days will be 
removed from study. 
Any   grade 3 non-hematologic (excluding grade 
3 fatigue or hypertension or easily correctable 
asymptomatic grade 3 laboratory abnormalities) 
Hold study drug(s)1 for up to 14 days 
until toxicity resolves to  grade 1.3 
Treatment may be restarted at one dose 
level lower for the drug(s) causing the 
toxicity, as per the dose reduction levels 
in Sections 6.2.1 and 6.2.2, at the 
treating investigator’s discretion.  The 
overall PI of the study should be 
informed regarding all dose 
modifications. 
1. Grade 3 or 4 non-hematologic AE related to 
cediranib and olaparib combination that does 
not resolve to grade 0-2 within 14 days despite 
maximum supportive care after treating patient 
at the lowest reduced dose level.2 
2. Grade 3 or 4 non-hematologic AE related to 
cediranib/olaparib lasting > 14 days despite 
maximum supportive care and treatment being 
held. 
Remove patient from study. 

NCI Protocol: 8348 
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Protocol Version Date: January 03, 2019 
 
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1 
For patients receiving both cediranib and olaparib after the DLT assessment period has 
completed in the Phase 1 or Phase 1-T or for patients enrolled to the cediranib/olaparib 
arm in the Phase 2 -- if the observed AE is specifically attributed to only one of the drugs, 
that drug may be held while the patient continues to receive the drug not associated with 
the observed AE.  The time a given drug is held should not exceed 14 days. 
2 
Excluding hypertension, see below 6.3.2 
3 
For thromboembolic events, treatment may be resumed at the discretion of the investigator 
once patient is asymptomatic. For weight loss events, treatment may be resumed at the 
discretion of the investigator once weight has stabilized.  
 
 
Dose Modification and Management of Hematologic Adverse Events 
Observation 
Action 
Absolute neutrophil count ≥ 1000/mcL 
AND  
Platelets ≥ 75,000/mcL 
AND 
Hemoglobin ≥ 8 mg/dL  
Maintain dose level 
Absolute neutrophil count < 1000/mcL 
OR 
Platelets < 75,000/mcL 
OR 
Hemoglobin < 8 mg/dL 
Hold treatment for up to 14 days until 
absolute neutrophil count ≥ 1000/mcL, 
platelets ≥ 75,000/mcL, and 
hemoglobin ≥ 8 mg/dL. Treatment may 
be restarted at one dose level lower for 
the drug(s) causing the toxicity, as per 
the dose reduction levels in Sections 
6.2.1 and 6.2.2, at the treating 
investigator’s discretion.  The overall PI 
of the study should be informed 
regarding all dose modifications.  
 
Patients whose counts have not 
recovered to absolute neutrophil count  
≥ 1000/mcL, platelets ≥ 75,000/mcL, 
and hemoglobin ≥ 8 mg/dL after 14 
days should be removed from study. 
Grade 4 hematologic AE related to cediranib or olaparib that 
does not resolve to absolute neutrophil count ≥ 1000/mcL, 
platelets ≥ 75,000/mcL, and hemoglobin ≥ 8 mg/dL despite 
maximum supportive care after 14 days. 
Remove patient from study. 
 
For AEs that are unrelated to the study drugs, study drug may be held for up to 14 days at the 
discretion of the treating investigator.  Drug holds of greater than 14 days for unrelated AEs 
where the patient is experiencing ongoing clinical benefit may be considered after discussion 
with the overall PI. 
 
Patients in the dual therapy arm, experiencing ongoing clinical benefit, who experience a related 
AE where continuation of one of the drugs is considered, in the judgment of the treating 

NCI Protocol: 8348 
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investigator AND overall PI, to be potentially life-threatening or with the potential for long-term 
harm to the patient, may be allowed to continue on the unrelated drug after discussion with the 
overall PI. 
 
6.3.2. 
 Hypertension Management 
 
Only doses of cediranib will be modified for hypertension; olaparib doses will not be reduced 
unless other toxicities are experienced.  Patients receiving cediranib should be provided with 
blood pressure monitors for home use and will check and record their blood pressures at least 
twice daily while on study treatment (see Appendix C). See Table 1 for hypertension 
management. 
 
Of note, hypertension onset can be acute and significant when cediranib treatment is initiated.  
For this reason, patients must have their blood pressure diaries reviewed by the study team 
weekly during the first 8 weeks of treatment.  
 
Table 1: Hypertension Monitoring and Management 
• 
See table for suggested antihypertensive medications by class (Table 2) 
• 
Abbreviations: Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin II Receptor Blockers 
(ARB), selective beta blockers (BB), Dihydropyridine calcium channel blockers (DHP-CCP) 
• 
If patients require a delay of >2 weeks for management of hypertension, discontinue protocol therapy 
• 
Patients may have up to 4 drugs for management of hypertension prior to any dose reduction in cediranib 
• 
Hypertension should be graded using the NCI CTCAE v5.0 
Event 
Definition 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Cediranib Dose 
Modification 
 
Grade 1 
 
 
Asymptomatic 
transient (<24 
hours) increase by 
>20 mmHg 
diastolic or to > 
140/90 mmHg if 
previously WNL 
None 
Standard monitoring 
per treating MD 
None 
 
Grade 2 
 
Recurrent or 
persistent (>24 
hrs) or 
symptomatic 
increase by >20 
mmHg (diastolic) 
or to > 140/90 
mmHg if 
previously WNL 
 
Monotherapy may 
be indicated 
Initiate BP medication 
for first line treatment: 
• Suggestion: 
Calcium-channel 
blocker 
 
Escalate dose of 
medication 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: 
• Suggestion: ACE-
Increase frequency 
of monitoring until 
stabilized 
Do not hold 
cediranib unless 
otherwise clinically 
necessary 

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inhibitor 
 
Study drug does not 
need to be held unless 
otherwise clinically 
necessary 
 
Consider renal consult 
 
Notes: 
• While patients are receiving treatment with cediranib, the early initiation of 
antihypertensive treatment for grade 1 or 2 hypertension to minimize more severe or 
persistent hypertension is not considered a grade 3 adverse event. 
• Decisions to hold or decrease the cediranib dose during treatment must be based on BP 
 
Grade 3 
Requiring more 
than one drug or 
more intensive 
therapy than 
previously.     
Maximize 2 drug 
regimen 
• Suggestions: 
Calcium channel 
blocker + ACE-
inhibitor  
 
Escalate doses of 
existing medication 
until BP is controlled 
or at a maximum dose. 
 
Study Drug will not 
be held during trial of 
two drug 
combinations.  
Additional anti-
hypertensive drugs, 
up to a total of 4, may 
be maximized for 
blood pressure 
control. 
 
Increased frequency 
of monitoring until 
stabilized 
Do not hold 
cediranib unless BP 
is not decreased to 
less than 150/100 
mmHg 48 hours 
after multi-drug 
therapy is instituted 
or if clinical 
symptoms worsen 
(e.g. headache). 
 
If BP is not 
controlled to less 
than 150/100 
mmHg with 
maximal therapy or 
if clinical symptoms 
worsen, then hold 
drug (up to 14 days) 
until maximum 
effect of the anti-
hypertensive agents 
is achieved. 
 
If BP is reduced to 
Grade 1 within 14 
days, cediranib may 
be resumed at prior 
dose. 
 
Grade 4 
If threatening 
consequences 
 
OR 
 
SBP ≥ 180mmHg 
 
OR 
 
DBP ≥ 110mmHg 
Initiate treatment 
 
Hospitalize patient for 
ICU management, IV 
therapy as necessary 
 
14 days are allowed to 
maximize the full 
effect of anti-
hypertensive agents. 
Intensive BP 
monitoring 
(hospitalization if 
necessary) 
Hold cediranib. 
 
If BP is reduced to 
Grade 1 within 14 
days, cediranib may 
be resumed at a 
reduced dose. 

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readings taken in the clinic by a medical professional. 
 
Table 2 provides a suggested management guide to cediranib-induced hypertension as well as 
recommended anti-hypertensive medications depending on hepatic metabolism.   
 
 
 
Table 2:   Suggested Anti-hypertensive Medications, Starting Doses and Hepatic 
Metabolism 
Dihydropyridine calcium-channel blockers (DHP CCB) (recommended as a first line agent 
for the management of HTN associated with cediranib unless contraindicated): 
Agent 
Initial Dose 
Intermediate 
Dose 
Maximum Dose 
Hepatic 
Metabolism 
 
Nifedipine XL 
 
 
Amlodipine 
 
 
Felodipine 
 
30 mg po qd 
 
 
2.5 mg po qd 
 
 
2.5 mg po qd 
 
 
60 mg po qd 
 
 
5 mg po qd 
 
 
5 mg po qd 
 
90 mg po qd 
 
 
10 mg po qd 
 
 
10 mg po qd 
 
 
CYP 3A4 
substrate 
 
CYP 3A4 
substrate 
 
CYP 3A4 
substrate + 
inhibitor 
 
Selective  blockers (BB): 
Agent 
Initial Dose 
Intermediate 
Dose 
Maximum Dose 
Hepatic 
Metabolism 
 
Metoprolol 
 
 
Atenolol 
 
Acebutolol 
 
 
Bisoprolol 
 
 
25 mg po bid 
 
 
25 mg po qd 
 
100 mg po bid 
 
 
2.5 mg po qd 
 
50 mg po bid 
 
 
50 mg po qd 
 
200mg-300 mg 
po bid 
 
5-10 mg po bid 
 
100 mg po bid 
 
 
100 mg po qd 
 
400 mg po bid 
 
 
20 mg po qd 
 
CYP 2D6 
substrate 
 
No 
 
Yes (CYP450 
unknown) 
 
Yes(CYP450 
unknown) 
Angiotensin Converting Enzyme Inhibitors (ACEIs): 
Agent 
Initial Dose 
Intermediate 
Dose 
Maximum Dose 
Hepatic  
Metabolism 
 
Captopril 
 
12.5 po tid 
 
25 mg po tid 
 
50 mg po tid 
 
CYP 2D6 

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Enalapril 
 
 
Ramipril 
 
 
Lisinopril 
 
Fosinopril 
 
Rarely used: 
Perindopril  
 
 
Quinapril 
 
 
5 mg po qd 
 
 
2.5 mg po qd 
 
 
5 mg po qd 
 
10 mg po qd 
 
 
4mg po qd 
 
 
10mg po qd 
 
 
10-20 mg po qd 
 
 
5 mg po qd 
 
 
10-20 mg po qd 
 
20 mg po qd 
 
 
none 
 
 
20 mg po qd 
 
 
40 mg po qd 
 
 
10 mg po qd 
 
 
40 mg po qd 
 
40 mg po qd 
 
 
8mg po qd 
 
 
40 mg po /qd 
 
substrate 
 
CYP 3A4 
substrate 
 
Yes (CYP450 
unknown) 
 
No  
 
Yes (CYP450 
unknown) 
 
Yes but not 
CYP450 
 
No 
Angiotensin II Receptor Blockers (ARB’s): 
Agent 
Initial Dose 
Intermediate 
Dose 
Maximum Dose 
Hepatic 
Metabolism 
 
Losartan 
 
 
Candesartan 
 
 
Irbesartan 
 
 
Telmisartan 
 
 
Valsartan 
 
25mg po qd 
 
 
4mg po qd 
 
 
75mg po qd 
 
 
40 mg po qd 
 
 
80 mg po qd 
 
50 mg po qd 
 
 
8-16 mg po qd 
 
 
150 mg po qd 
 
 
none 
 
 
none 
 
100 mg po qd 
 
 
32mg po qd 
 
 
300 mg po qd 
 
 
80 mg po qd 
 
 
160mg po qd 
 
 
CYP 3A4 
substrate 
 
CYP 2C9 
substrate  
 
CYP 2C9 
substrate 
 
Yes but not 
CYP450 
 
Yes but not 
CYP450 
 
 and  blockers:    
Agent 
Initial Dose 
Intermediate 
Dose 
Maximum Dose 
Hepatic 
Metabolism 
 
Labetolol 
 
 
100 mg po bid 
 
200 mg po bid 
 
400 mg po bid 
 
CYP 2D6 
substrate and 
inhibitor 

NCI Protocol: 8348 
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Agents in bold characters are suggested as optimal choices to avoid or minimize potential drug-
interactions with cediranib through CYP450. 
** Calcium channel blockers are the recommended first line agent, unless contraindicated, for 
the management of hypertension associated with cediranib. 
 
 
 
6.3.3. Management of Proteinuria 
 
Proteinuria has been observed in cediranib studies.  Increases in proteinuria may occur during 
treatment and should be managed as follows: 
 
Proteinuria Value if 
following by U/A 
Monitoring 
Dose modification 
Greater than 1+ on 
urine dipstick or U/A  
Perform UPC. 
HOLD cediranib until 
results of UPC are known, 
and see below 
Based on results of the UPC†: 
UPC ≤ 1.0 
Continue monitoring prior to each cycle 
as per previous. 
Continue study drugs at 
planned dose 
UPC > 1.0 and ≤ 2.0  
Perform UPC prior to each cycle. 
Hold cediranib for up to 7 
days and repeat UPC.  If 
UPC resolves to ≤1.0, 
cediranib may be resumed 
at prior dose level.  If UPC 
remains ≥1.0 g but ≤2.0 on 
repeat collection at least 7 
days later, then resume 
treatment with reduction in 
cediranib by one dose 
level as per Table 6.2.1.  
Consider consultation with 
nephrologist. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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UPC > 2.0 
Perform UPC weekly until UPC is ≤2.0.  
Perform UPC prior to each cycle. 
Hold cediranib.  Consider 
consultation with 
nephrologist. 
 
When UPC is ≤2.0, 
resume treatment at one 
lower dose level for 
cediranib. 
 
6.3.4. Decrease in LVEF 
 
Patients who have any of the following should undergo an echocardiogram or MUGA at baseline 
and every four cycles while on study: 
1. Prior treatment with anthracyclines 
2. Prior treatment with trastuzumab 
3. A New York Heart Association classification of II controlled with treatment (see 
Appendix E)  
4. Prior central thoracic radiation therapy (RT), including RT to the heart 
5. History of myocardial infarction within the prior 12 months. 
 
The decision to continue or hold cediranib/olaparib is based on the LVEF as it relates to the 
institution’s lower limit of normal (LLN) and change in ejection fraction from screening (LVEF 
as measured at registration) according to the following table:    
 
Management and Monitoring of Decreased LVEF 
Relationship of 
LVEF to 
Institution’s LLN 
LVEF Decrease 
< 10% 
LVEF Decrease 
10-15% 
LVEF Decrease 
> 16% 
Normal 
Continue 
Continue 
Continue and 
repeat MUGA/ECHO 
within 1-2 cycles 
1-5% below LLN 
 
Continue and 
repeat MUGA/ECHO 
within 1-2 cycles 
Continue and 
repeat MUGA/ECHO 
within 1-2 cycles 
HOLD and 
repeat MUGA/ECHO 
within 1-2 cycles 
> 6% below LLN 
 
Continue and 
repeat MUGA/ECHO 
within 1-2 cycles 
HOLD and 
repeat MUGA/ECHO 
within 1-2 cycles 
HOLD and 
repeat MUGA/ECHO 
within 1-2 cycles 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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6.3.5. Diarrhea 
 
Diarrhea is often observed with cediranib, and active and early management of diarrhea is 
recommended even with grade 1 diarrhea.  Management as follows: 
 
 
Management of Diarrhea 
Toxicity 
Management/Modifications 
Initial grade 1 or 2 diarrhea: 
Patients can take loperamide (per standard 
practice) and continue to take loperamide 
until patients are free from diarrhea for at 
least 12 hours.  The dose of loperamide 
should not exceed 16mg in a 24-hour period. 
 
If diarrhea persists despite 24 hours of 
loperamide treatment, hold cediranib for a 
maximum of 7 days, continue loperamide, and 
maintain hydration.  Cediranib may be 
restarted at the same dose once patients have 
been free from diarrhea for 12 hours. 
 
For either persistent grade 2 diarrhea or grade 
3 or 4 diarrhea:   
Follow 6.3.1  
 
 
 
6.3.6. Management of Fever and Neutropenia  
 
Patients who develop fever and neutropenia will be managed via standard medical practice and 
American Society of Clinical Oncology and NCCN guidelines. Patients will need to recover 
from fever and active infectious issues prior to resuming therapy.  Growth factors such as 
Neupogen or Neulasta may not be used.  
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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6.3.7. Thyroid Toxicities 
 
The use of cediranib has been associated with elevations of the thyroid stimulating hormone 
(TSH) and patients should be managed as per the following schema and chart: 
 
Monitoring and Management of Thyroid Toxicities 
Result of TSH, T4, and T3 
Action 
Increases of TSH with normal T4/T3:  
Monitor 
Increases in TSH with normal T4/T3 and 
adverse events suggestive of incipient 
hypothyroidism: 
Consider replacement thyroxine.   
Increase in TSH with reductions in T4 and 
T3: 
Consider replacement thyroxine 
 
In all of the above cases, study treatment should continue unless clinically contraindicated.  
Referral to an endocrinologist should also be considered if thyroid abnormalities occur. 
 
6.3.8. Dose Modifications for Reversible Posterior Leukoencephalopathy Syndrome 
(RPLS) 
 
Cediranib should be held in patients with symptoms/signs suggestive of RPLS, pending work-up 
and management, including control of blood pressure.  Cediranib should be discontinued upon 
diagnosis of RPLS.  After consultation with the Principal Investigator and the NCI, consideration 
of restarting the study may be evaluated in light of any clinical benefit.   
 
6.3.9. Rotator Cuff Injury 
 
A limited number of patients have experienced rotator cuff injuries while receiving the 
combination of cediranib and olaparib.  Patients should therefore be monitored closely for the 
development of any shoulder pain or weakness. 
 
Management of Rotator Cuff Symptoms 
Grade 
Symptoms/Findings 
Action 
Dose modifications 
1 
Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations 
only; intervention not 
indicated 
Limit heavy lifting or 
carrying of heavy 
objects, bags or 
backpacks.   
 
Consider shoulder MRI if 
symptoms warrant. 
None. 
2 
Moderate; minimal, local, 
or noninvasive 
Obtain shoulder MRI if 
not previously obtained. 
Hold cediranib and 
olaparib for up to 14 days 

NCI Protocol: 8348 
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Protocol Version Date: January 03, 2019 
 
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intervention indicated; 
limiting age appropriate 
instrumental ADL 
 
If rotator cuff injury 
present on MRI, refer for 
physical therapy.   
 
Consider referral to 
orthopedics for 
evaluation as appropriate. 
until symptoms resolve to 
Grade 1 or less.  Cediranib 
and olaparib may then be 
resumed at a reduced dose 
level of each study drug.  
If patient is on the lowest 
dose level(s) of cediranib 
or olaparib, please contact 
the study PI to discuss 
dose modifications. 
3 
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of existing 
hospitalization indicated; 
disabling; limiting self 
care ADL 
Obtain shoulder MRI if 
not previously obtained. 
 
Refer to orthopedic 
surgeon for evaluation. 
Hold cediranib and 
olaparib for up to 14 days 
until symptoms resolve to 
Grade 1 or less.  Cediranib 
and olaparib may then be 
resumed at a reduced dose 
level of each study drug 
after discussion with the 
overall PI. 
 
6.3.10. Additional Toxicities and Dose Adjustments 
 
Other toxicities are possible on this trial.  In the phase 2 component, patients developing drug 
associated grade 3 or 4 non-hematological or non-mucosal toxicities that do not resolve or 
improve to grade 1 within 14 days will be removed from protocol.  Dose modifications should be 
made as outlined in Section 6.3.1 of the protocol.  
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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7. 
DRUG FORMULATION AND ADMINISTRATION  
 
7.1. 
Cediranib (AZD2171, NSC 732208) 
 
Please refer to the Investigator’s Brochure for cediranib information in addition to the 
information below 
 
7.1.1. Description 
 
Chemical Name:  
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-
pyrrolidin-1- ylpropoxy) quinazoline maleate 
 
Other Names: 
AZD2171 maleate, cediranib, Recentin™ 
 
CAS Registry Number: 
288383-20-0 (for the free base) 
 
Molecular Formula: 
C25H27FN4O3 · C4H4O4 
 
 
 
Molecular Weight:   
566.59 as maleate salt (450.52 as free base) 
 
Approximate Solubility: 
The aqueous solubility of cediranib has been measured as 0.0006 
mg/mL for the free base (distilled water, pH 8.1 at 25°C) and 1.9 
mg/mL for the maleate salt (distilled water, pH 4.4 at 25°C). 
 
7.1.2. Form 
 
How Supplied:  Astra-Zeneca supplies and CTEP, NCI, DCTD distributes AZD2171 
(cediranib).  The agent is available as beige film-coated tablets containing 15 mg and 20 mg of 
AZD2171 free base.  The 15 mg and 20mg tablets are 7 mm and 8 mm in diameter, respectively.  
Each bottle contains 35 tablets. 
 
In addition to the active ingredient, the tablets contain mannitol, dibasic calcium phosphate 
anhydrous, sodium starch glycolate, microcrystalline cellulose, and magnesium stearate with a 
film coat coating hypromellose 606, polyethylene glycol 400, red iron oxide, yellow iron oxide, 
black iron oxide, and titanium dioxide. 
  
7.1.3. Route of Administration 
 
Oral.  Cediranib tablets should be taken either 1 hour before or 2 hours after meals. 
 
7.1.4. Storage and Stability 
 
Storage: 
Store intact bottles at controlled room temperature [20°C-25°C, (68-77°F)] and 
protect from light.  
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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Stability:  Stability studies are ongoing.  
 
7.1.5. Compatibility 
 
From available preclinical data, there are no data suggesting clinically relevant pharmacokinetic 
interactions between cediranib and olaparib. 
 
7.1.6. Availability 
 
Cediranib is an investigational agent and will be supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI.  
 
Cediranib is provided to the NCI under a Collaborative Agreement between AstraZeneca 
International and the DCTD, NCI (see Section 13). 
 
7.1.7. Ordering 
 
NCI supplied agents may be requested by the Principal Investigators (or their authorized 
designee) at each participating institution. Pharmaceutical Management Branch (PMB) policy 
requires that agent be shipped directly to the institution where the participant 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 < https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx >.  Access to 
OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account < 
https://eapps-ctep.nci.nih.gov/iam/ > and the maintenance of an “active” account status and a 
“current” password.  For questions about drug orders, transfers, returns, or accountability, call 
(240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
 
7.1.8. Accountability 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of the agent (investigational or free of charge) using the 
NCI Drug Accountability Record Form (DARF). (See the CTEP home page at 
http://ctep.cancer.gov for the Procedures for Drug Accountability and Storage or to obtain a copy 
of the DARF.) 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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7.1.9. 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 at IBCoordinator@mail.nih.gov. 
 
7.1.10. Destruction and Return 
 
Standard NCI return procedures will be followed.  
 
7.2. 
Olaparib (AZD2281, NSC 747856) 
 
Please refer to the Investigator’s Brochure for olaparib information in addition to the information 
below.  The Investigator’s Brochure and all updates for olaparib will be provided to the overall 
Principal Investigator by AstraZeneca.  Co-investigators may obtain a copy of the Investigator’s 
Brochure for olaparib by contacting the overall Principal Investigator. 
 
7.2.1. Description 
 
Chemical Name:  
4-[3-(Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluro-
benzyl]-2-H-phthalazin-1-one 
 
Other Names: 
AZD2281, KU-0059436; CO-CE 42; PARPi; olaparib 
 
CAS Registry Number:  
763113-22-0 
 
Molecular Formula:   
C24H23FN4O3 
 
Molecular Weight:   
434.47 
 
Approximate Solubility:   
Olaparib is freely soluble in dimethylsulphoxide (DMSO) and 1-
methyl-2-pyrrolidinone (NMP), sparingly soluble in ethanol and 
methanol, and only very slightly soluble in water (<0.25 mg/mL). 
 
7.2.2. Form 
 
Olaparib capsules will be supplied as 50mg capsules.  Each bottle contains 120 capsules.  The 
capsules are Vcaps®Hydroxylpropyl Methylcellulose (HPMC) Capsugel® Capsules, not band-
sealed or enteric-coated.  Capsules may or may not be printed with a black ink radial logo (band) 
on the cap and body. 
 
In addition to the active ingredient, the capsules contain Gelucire® 44/14 and Lauroyl 
macrogolglycerides.  Olaparib capsules will be provided in white, high density polyethylene 
(HDPE) containers with child-resistant and tamper-evidence closure. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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Olaparib tablets are green, film-coated tablets available in 25 mg, 100 mg, and 150 mg strengths. 
Tablets are packaged in induction-sealed high-density polyethylene (HDPE) bottles with child-
resistant closures. Each bottle contains 32 tablets with dessicant.  
 
Tablet core consists of olaparib, copovidone, colloidal silicon dioxide, mannitol and sodium 
stearyl fumarate. Tablet film-coating consists of hydroxypropyl methylcellulose (hypromellose), 
macrogol 400 (polyethylene glycol 400), titanium dioxide, iron oxide yellow and iron oxide 
black.  
 
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.  
 
7.2.3. Route of Administration 
 
Oral.  Olaparib capsules or tablets should be taken either 1 hour before or 2 hours after meals. 
 
7.2.4. Storage and Stability 
 
Storage: Store the olaparib capsules and tablets below 30°C.  
 
Stability:  Stability studies are ongoing.  
 
7.2.5. Compatibility 
 
From available preclinical data, there are no data suggesting clinically relevant pharmacokinetic 
interactions between cediranib and olaparib. 
 
7.2.6. Availability and Ordering 
 
AZD2281 (NSC 747856) 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 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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(OAOP) application < https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx >.  Access to 
OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account < 
https://eapps-ctep.nci.nih.gov/iam/ > and the maintenance of an “active” account status and a 
“current” password.  For questions about drug orders, transfers, returns, or accountability, call 
(240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
 
7.2.7. Accountability 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of the agent (investigational or free of charge) using the 
NCI Drug Accountability Record Form (DARF). (See the CTEP home page at 
http://ctep.cancer.gov for the Procedures for Drug Accountability and Storage or to obtain a copy 
of the DARF.) 
 
7.2.8. 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 at IBCoordinator@mail.nih.gov. 
 
7.2.9. Destruction and Return 
 
Standard NCI return procedures will be followed. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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8. 
CORRELATIVE/SPECIAL STUDIES 
 
8.1. 
Tissue and Sample Acquisition and Processing 
 
PBMC 
Whole Blood 
Plasma 
Tumor/Effusion 
Cells 
Imaging 
PAR incorporation 
CEC 
Cytokines 
IHC for H2AX, 
RAD51, VEGF 
Ktrans and Kep 
SNP analysis 
 
 
Tissue lysate array 
for angiogenesis and 
DNA repair 
endpoints 
 
 
All samples will be prioritized for the outlined translational endpoints.  Should additional tissue 
or samples be available after completion of the stated endpoints, it may be used for additional 
research analysis with appropriate IRB approval or released at the patient’s request for patient-
requested assays. 
 
8.2. 
Rationale for Selected Endpoints 
 
These endpoints were selected to allow illustration of mechanism of the agents and potential 
interaction between the agents.  They were also selected to investigate, in an exploratory fashion, 
whether any measures were predictive or prognostic, with the former being of greater interest.   
 
8.3. 
Sample Acquisition 
 
Patient Protections  
• Each patient sample set will be coded with a unique patient identifier. No patient specific 
information is encoded in this ID.  The protocol scientific investigator(s) handling the 
samples will be blinded as to the patient identification, patient data and outcome.   
• Blood samples obtained by and stored through the Clinical Pharmacology Core will be 
labeled with unique barcodes. 
 
Tumor Samples  
• Biopsies:  At least two core biopsies representing 18-gauge x at least 1cm in length, will 
be obtained.  Inability to get tissue with a reasonable attempt will not preclude treatment 
and the patient will remain eligible for all other translational endpoints. Should CT scans 
be needed for safe core biopsy, a limit of 10 slices for each procedure will be observed to 
minimize radiation exposure to the patient. 
• Skin:  Where subcutaneous or skin is involved, two 2-3mm full thickness punch biopsies 
may be obtained. 
• Malignant effusions:  Known malignant effusions (pleural or peritoneal) may be 
acquired as the tissue sample in lieu of core tissue biopsies.  Where both are present, the 
decision as to which sample to obtain will be made jointly between the patient, 
interventional radiology, and the research team. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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Tumor Sample Handling 
• Core needles biopsy samples are to be immediately embedded and frozen in OCT on dry 
ice on site and stored in liquid nitrogen until use.  Biopsy scheduling and acquisition of 
research samples will follow the standard procedures for Special 
Procedures/Interventional Radiology and research sampling subjects protection. Members 
of the Kohn lab will be on call to receive, label, embed, and store biopsies Phone:  beeper 
102-11155.  
• Skin biopsies will be embedded in OCT on site upon receipt, frozen in dry ice, and 
stored in liquid nitrogen until use. Members of the Kohn lab will be on call to receive, 
label, embed, and store biopsies Phone:  beeper 102-11155. 
• Malignant Effusions:  A minimum of 50ml of non-heparanized effusion will be picked 
up by the Kohn laboratory.  Ten aliquots of supernatant and 10 viably frozen cell pellets 
will be stored in liquid nitrogen until use. 
 
Blood Sample Requirements 
• Circulating Endothelial Cells (CEC):  Three 8 cc CPT-citrate tubes (Tiger top: blue 
and black top) will be drawn pretreatment and the day of repeat imaging and biopsy.  The 
Trepel laboratory (Dr. Min-Jung Lee, leemin@mail.nih.gov) will be contacted to confirm 
scheduling and will be called 301-496-1547 when the sample is ready.  The sample is to 
be kept at room temperature until pick up. 
• Circulating Cytokines:  An approx 8-10ml clot tube and an 7 ml green top (heparin) 
tube (or volume equivalents) will be obtained prior to treatment and the day of repeat 
imaging and biopsy.  The tubes will be packed on wet ice and picked up by the Clinical 
Pharmacology Core (102-11964 (Call 301-402-3622 – Kathy Compton with any 
questions).  Serum and plasma will be separated and aliquoted according to the CPC 
SOPs and stored, barcoded, in the CPC repository until use.   
• PBMC PAR Incorporation:  Three 8 ml CPT-citrate tubes (Tiger top) will be obtained 
prior to treatment and the day of repeat imaging and biopsy.  PBMCs will be isolated 
according to CPC SOP, aliquoted and stored, barcoded, in the CPC repository until use 
(102-11964 (Call 301-402-3622 – Kathy Compton with any questions).  
• Pharmacogenomics:  A single purple top tube (EDTA – minimum of 7 cc) will be 
collected prior to initiation of therapy. Sample will be placed on wet ice and refrigerated. 
The CPC will be paged for pickup at 102-11964 (Call 301-402-3622 – Kathy Compton 
with any questions). DNA extraction and analysis will follow the CPC 
pharmacogenomics SOPs. 
 
8.4. 
Functional Imaging   
 
• Patients will be scheduled with the Molecular Imaging Program of the Center for Cancer 
Research, NCI.  No special preparation is required with the exception of recent 
electrolyte results and placement of a venous access device. 
• Index lesions will be selected for serial measurement based on size (preferably at least 2 
cm in largest diameter) and relative immobility.  Scans will be obtained on the same 
schedule as the tumor biopsies.   

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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• Conventional T1 and T2 weighted images of the target lesion will be obtained and a T1 
map will be generated.  This will be followed by a series of 3D gradient echo T1 
weighted dynamic sequence which will be acquired before, during and after the 
administration of 0.1mmol/kg of a gadolinium chelate.  Approximately 6 images are 
obtained prior to the administration of contrast media and the data collection continues of 
5 minutes after injection.  Data is transferred to an independent workstation and will be 
analyzed using a modified general kinetic model.  This model generates two parameters 
Ktrans and kep (permeability terms) which will be used as continuous outcome variables in 
the analysis.  Vascular fraction may also be assessed.  Color maps based on these 
parameters will also be generated.  Data obtained before and on therapy will be compared 
for changes as a result of decreases in angiogenesis. 
 
8.5. 
PAR Incorporation  
 
A validated commercial PAR ELISA (Trevigen) will be used to quantitate PAR labeling in 
batched PBMC aliquots.   
 
8.6. 
Circulating Endothelial Cells (CEC) 
 
CEC and circulating endothelial precursors (CEP) will be analyzed by multi-parameter flow 
cytometry. Cells will be analyzed for forward and side scatter, and a dump channel will be 
created to exclude cells expressing hematopoietic markers, such as CD45.  Endothelial cells will 
be identified using co-expression of markers, such as CD31 and CD146 for mature endothelial 
cells, and CD133 for CEP cells. The cell populations will also be analyzed for viability using 
scatter profiles and a vital stain, such as Hoechst 33258.  Percentages of stained cells will be 
determined and compared with appropriate negative controls. Multi-parameter flow analysis will 
be performed with a BD LSR II equipped with FlowJo software, using a minimum of 500,000 
events per analysis in the Trepel Laboratory. 
 
8.7. 
Circulating Cytokines  
 
VEGF, IL6, and IL8, among other pro-angiogenic cytokines have been shown to be induced 
during anti-angiogenic therapy as a pharmacodynamic measure of angiogenesis inhibition, 
including in cediranib in several cancers.  Plasma will be collected and rapidly separated and 
stored.  Samples will be batched and cytokines measured in at least duplicate using commercially 
available ELISA kits (most are available from R&D).  A minimum of the following cytokines 
will be examined:  VEGF, IL6, IL8.  Others that may be considered include but are not limited 
to:  sVEGFR2, Ang2, PIGF. 
 
8.8. 
Pharmacogenomics, PARP and  XRCC1 Polymorphisms 
 
Multiple polymorphisms of the PARP-1 protein have been described (Cottet et al., 2000; Hur et 
al., 2006) and are listed in the SNP database of the NCBI (National Center for Biotechnology 
Information).  Peripheral leukocytes will be genotyped for PARP polymorphisms in the CPC 
with Dr. W. D. Figg’s laboratory. Particular attention will be given to the SNP, PARP1 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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Val762Ala, in which the variant allele contributes to dramatically lower PARP1 activity (Zhang 
et al. 2005).  In addition, polymorphisms in XRCC1 will be assessed, as over-expression of 
XRCC1 decreases PARP1 activity.  The SNP XRCC1 Arg399Glu resides in PARP1-interaction 
region (amino acid 314-402) in XRCC1 gene and Arg194Trp and Arg280Ile are correlated to 
altered risks to cancers and/or platinum sensitivity (Yuan et al., 2006; Skjelbred et al. 2006; Hao 
et al., 2004), though with inconsistent results (Zhai et al. 2006; Miao et al. 2006).  
 
8.9. 
IHC/IF 
 
Tumor samples (core biopsy recuts and/or effusion cell pellets) will be used for IHC or 
immunofluorescence (IF) to examine both vascular and DNA repair endpoints using validated 
SOPs.  Scoring will be based upon number of positive cells and/or number of foci as pertinent to 
the endpoint.  The following endpoints will be examined, with the following prioritization: 
• RAD51 (foci per cell) 
• H2AX (foci per cell) 
• VEGF 
• CD31 or other measure of microvessels 
• Pending tissue, some or all of the following may be examined:  PARP1, BRCA1, 
ERCC1, XRCC1, other related endpoints. 
 
8.10. Proteomic Endpoints 
 
Core biopsy or effusion cell pellets will be examined in a blinded fashion in the fee-for-service 
MD Anderson Reverse Phase Protein Array Core.  This provides a comprehensive analysis of 
total and phosphorylated proteins involved in invasion, cell cycle, proliferation, DNA repair.  
Data will be analyzed for change over time trends, as well as patterns of protein expression.  
These endpoints coupled with the IHC/IF results are aimed to evaluate HR competence 
(RAD51+) and changes in vascular signaling. 
 
8.11. BRCA Mutation Status 
 
No testing of BRCA mutation status is currently planned; however, research assessment of 
homologous recombination competence and endpoints in DNA damage repair pathways may be 
performed on available  samples pending funding either within the NCI or with a collaborative 
partner outside of the NCI. 
 
8.12. Family Risk Assessment 
 
All patients will be asked to fill out the family risk assessment form (Appendix I). Where 
mutation is unknown, BRCAPro score will be calculated.  This will be examined as a variable 
against outcome and HRD status in the translational endpoints. 
 
 
 

NCI Protocol: 8348 
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Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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8.13. Post-progression Tissue Analysis 
 
At the time of progression, where possible, core needle biopsies from a new lesion or site of 
progression will be obtained. The biopsy will be taken at the time of drug discontinuation or 
within the 30d follow up period pending patient consent. This research biopsy will be optional 
and performed only if there is minimal risk.  In BRCA mutation carriers, research sequencing of 
BRCA will be performed from the tissue to test for the presence of secondary mutations that can 
restore BRCA function, as well as the presence of other proteins (e.g. 53BP1), identified as 
potentially mediating PARP-inhibitor resistance.  Pending tissue availability, other markers of 
DNA repair and vascular endpoints such (e.g. RAD51, H2AX, VEGFR, CD31) will also be 
examined. 
 
8.14. Pharmacokinetic (PK) studies 
 
The steady-state plasma pharmacokinetics of cediranib and olaparib will be defined in a group of 
12 patients in the safety expansion cohort treated with the recommended phase II doses of the 
combination, cediranib 30 mg QD and olaparib 200 mg BID, to assess whether or not the 
pharmacokinetic behavior of the two drugs is altered by their concurrent administration.  
Pharmacokinetic sampling will be performed during a single 24 h dosing interval after steady-
state pharmacokinetic conditions for the repeated oral dosing schedules have been achieved 
when each agent is given alone (cycle 0) and again when given together in the same patient 
(cycle 1).  In cycle 0, one group of six patients will receive single agent cediranib p.o. once daily 
for 7 days and the other group of six patients will receive single agent olaparib p.o. twice daily 
for 7 days.  Pharmacokinetic samples will be collected on day 7 before and for 8 h after the dose 
is taken in the morning and before dosing on day 8.  Combination therapy will begin on day 8 
which is formally day 1 of cycle 1.  Pharmacokinetic samples will again be collected before and 
for 8 hr after dosing on days 15-16 after the patients have received 14 days of combined therapy, 
as per the timepoints outlined below.   
 
The sampling schedule has been devised to accommodate treatment on an outpatient basis.  
Patients will be instructed to take the doses of the two drugs as per outlined in the protocol at the 
same time every day during the pharmacokinetic study.  Cediranib will be taken first thing in the 
morning on an empty stomach.  One hour later, the patient may have a light meal, followed by the 
morning dose of olaparib.  Dosing should be scheduled for times that will allow the patient to arrive 
at the clinic to obtain pharmacokinetic samples before dosing and to remain for an additional 8 
hours after the morning dose of olaparib.  The second daily dose of olaparib should be taken 12.0 
± 0.25 h after the morning dose.  It is very important that the patient is aware that the morning 
doses of the two drugs on day 8 and day 16 must not be taken before arriving at the clinic and the 
24.0 h pharmacokinetic sample has been collected.  The first set of blood samples (6 mL) will be 
obtained during cycle 0 shortly before taking the day 7 dose of the single agent drug and at 0.5, 
1.0, 2.0, 3.0, 4.0, 6.0, 8.0, and 24.0 h after dosing.   
 
The second set of blood samples (6 mL) will be obtained during cycle 1 starting on day 15 with 
the following schedule, to accommodate the sequential dosing schedule of the two drugs: 
 

NCI Protocol: 8348 
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Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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PK specimen 
Day 
Timing 
#1 
Cycle 1 Day 15 
Just prior to cediranib dose 
#2 
Cycle 1 Day 15 
0.5 hrs after cediranib dose 
#3 
Cycle 1 Day 15 
1.0 hrs after cediranib dose 
#4 
Cycle 1 Day 15 
2.0 hrs after cediranib dose, just prior to olaparib dose 
#5 
Cycle 1 Day 15 
2.5 hrs after cediranib dose (= 0.5 hrs after olaparib dose) 
#6 
Cycle 1 Day 15 
3.0 hrs after cediranib dose (= 1.0 hrs after olaparib dose) 
#7 
Cycle 1 Day 15 
4.0 hrs after cediranib dose (= 2.0 hrs after olaparib dose) 
#8 
Cycle 1 Day 15 
5.0 hrs after cediranib dose (= 3.0 hrs after olaparib dose) 
#9 
Cycle 1 Day 15 
6.0 hrs after cediranib dose (= 4.0 hrs after olaparib dose) 
#10 
Cycle 1 Day 15 
8.0 hrs after cediranib dose (= 6.0 hrs after olaparib dose) 
#11 
Cycle 1 Day 16 
24.0 hrs after C1D15 cediranib dose, just prior to C1D16 
cediranib dose 
#12 
Cycle 1 Day 16 
24.0 hrs after C1D15 morning olaparib odse, just prior to 
C1D16 morning olaparib dose 
 
Samples will be collected in plastic green stoppered Vacutainer 6.0 mL plasma collection tubes 
with spray-coated sodium heparin, gently inverted 5-times to thoroughly mix the blood with the 
anticoagulant, and placed on wet ice until centrifuged (1,300 x g, 10 min, 4°C) within 15 min 
after collection.  Separate the plasma from the blood cells using a disposable pipette and transfer 
the plasma into a 4.5 mL self-standing polypropylene cryogenic storage vial with external 
threads (Fisher Scientific, cat. no. 12-565-291).  Affix a pre-printed label, with the protocol 
number, patient accession number, and sample number onto the cryovial, oriented crosswise 
toward the upper part of the tube, without overlapping the vial cap.  Completely cover the label 
with polyester protective label tape (Fisher Scientific, cat. no. 11-867B) to prevent the label from 
detaching from the vial when stored frozen.  Store the plasma samples in a freezer at <-70°C 
until packaged for shipment to the analytical laboratory.   
 
Send complete sets of samples from one or more patients by next day delivery to the address 
listed below.  Place the sample tubes in a zip lock plastic bag.  Package samples in a seamless 
styrofoam container.  Place the sample bag over at least 3-4 inches of dry ice on the bottom of 
the container and completely cover with an additional 3-4 inches or more of dry-ice.  Seal the 
styrofoam container within a tight-fitting cardboard shipping box.  Insert copies of the 
Pharmacokinetic Data Form for each set of samples into a separate zip-lock plastic bag placed on 
top of the styrofoam container before the external shipping box is sealed.  Send the samples from 
Monday to Wednesday by overnight courier for delivery by 10 a.m. on the following day.  
Samples should not be shipped on a Thursday or Friday.  Please provide notification of the 
sample shipment by e-mail to shipping to jsupko@partners.org and slhilderbrand@partners.org.  
 
 Dr. Jeffrey G. Supko 
 Massachusetts General Hospital 
 55 Fruit St., GRJ 1025 
 Boston, MA 02114 
 Tel: 617-724-1970 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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The concentration of cediranib and olaparib in the plasma samples will be determined by the 
DF/HCC Cancer Pharmacology Core laboratory located on the main campus of the 
Massachusetts General Hospital (Boston, MA).  An analytical method facilitating the concurrent 
determination of the two drugs based upon for both compounds based upon high performance 
liquid chromatography with tandem mass spectrometric detection has been developed.  The 
analytical methods will be validated and applied to the analysis of study samples as 
recommended by the FDA Guidance for Industry:  Bioanalytical Method Validation, May 2001 
(http://www.fda.gov/-downloads/Drugs/Guidances/ucm070107.pdf).   
 
Individual patient plasma concentration-time curves will be analyzed by noncompartmental 
methods using routines supplied in the WinNonlin Professional Version 5.0.1 software package 
(Pharsight Corp., Cary, NC).  Pharmacokinetic parameters and variables will be calculated 
according to standard equations. Mean values of pharmacokinetic parameters will be statistically 
compared using the paired two-tailed t-test of the log-transformed data.   
 
 
 

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Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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9. 
STUDY CALENDAR 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy. 
Scans and assessment of cardiac function must be done < 4 weeks prior to the start of therapy. 
In the event that the participant's condition is deteriorating, laboratory evaluations should be 
repeated within 48 hours prior to initiation of the next cycle of therapy. 
All assessments must be performed prior to administration of any study medication. All study 
assessments and medications should be administered within + 3 days of the protocol-specified 
date, unless otherwise noted.  After completion of the first two cycles, cycle visits and associated 
studies can be performed within + 7 days of the protocol-specified date, unless otherwise noted.  
The study calendar for the Phase I and II portions of the study are as per the following pages: 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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9.1. 
Study Calendar:  Phase I and Phase I-T 
 
 
Pre-Study 
Prior to 
Each 
Cyclea,o 
Cycles 1 & 2 
Day 8, 15, 22 
(+/- 3 days) 
Every 2 
Cycles 
Off 
Treatment 
Informed Consenta 
Xa 
 
 
 
 
Medical History 
X 
 
 
 
 
Concomitant Medicationsb 
Xb 
Xb 
Xb 
 
Xb 
Adverse Event Assessment 
 
X 
X 
 
X 
Vital Signsc 
Xc 
Xc 
Xc 
 
Xc 
BP Measurement at Home 
(See Appendix C) 
 
Twice a day while on study 
 
Physical Exam 
X 
X 
X 
 
X 
Height 
X 
 
 
 
X 
Weight 
X 
X 
 
 
 
ECOG Performance Statusd 
Xd 
Xd 
 
 
Xd 
CBC with Differential 
X 
X 
X 
 
X 
Serum Chemistrye 
Xe 
Xe 
Xe 
 
Xe 
INR and PTT 
X 
 
 
 
 
Troponin T or I 
TSH and Free T4f 
Xf 
Xf 
 
 
Xf 
Urinalysisg 
Xg 
Xg 
Xg 
 
Xg 
Electrocardiogram 
X 
Xh 
 
 
 
MUGA or Echocardiogrami 
X 
 
 
X 
 
Pregnancy Testj 
Xj 
 
 
 
 
CA-125 Measurementsk 
Xk 
Xk 
 
 
 
Tumor Measurementsl,m 
Xl 
 
 
Xl,m 
 
Review of BP diary by study 
team 
 
X 
X 
 
 
Pharmacokinetics p 
 
X 
X 
 
 
a:   Informed consent will be obtained prior to any study-related screening tests.  For Cycle 1 
Day 1, physical examination and laboratory evaluations do not have to be repeated if they 
have been performed at screening within 7 days of Cycle 1 Day 1. 
b:  Because of a potential for interaction of cediranib and olaparib with other drugs through the 
cytochrome P450 system, the Principal Investigator should be alerted if the patient is taking 
any other medications known to affect P450 isoenzymes. 
c:   Temperature, pulse, blood pressure 
d:   See Appendix A for ECOG performance status 
e:   Sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, albumin, calcium, 
phosphorus, AST (SGOT), ALT (SGPT), alkaline phosphatase, total bilirubin, LDH. 
f:   Pre-study and prior to the first 2 cycles, then as clinically indicated, and at off-study visit. 
g:   A urine protein:creatinine ratio may be used instead.  See Section 6.3.3 Management of 
Proteinuria if dipstick at least 1+ on study. 
h:  ECG done prior to Cycle 1 and 2, and then prior to every cycle if clinically indicated. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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i:   MUGA or echocardiogram should be done at baseline and every other cycle for those 
patients at increased risk for compromised LVEF.  Increased risk patients have had one or 
more of the following:  (1) prior treatment with anthracyclines, (2) prior treatment with 
trastuzumab, (3) NY Heart Association classification of II, (4) prior central thoracic RT, (5) 
history of myocardial infarction within the 12 months prior. 
j:   beta-HCG for women of childbearing potential. 
k:  If patients have no measurable cancer for RECIST assessment, the patient must have two 
pretreatment CA-125 samples that are at least twice the upper limit of normal (at least 1 day 
but not more than 3 months apart; at least one of the samples should be within 1 week of 
starting treatment).  A CA-125 level drawn just prior (within 1 week of) to Cycle 1 Day 1 of 
cediranib/olaparib dosing will be used as the BASELINE CA-125.  CA-125 will be drawn at 
the start of each cycle. 
l:   Tumor measurements by CT scans or MRI will be performed within the 4 weeks prior to 
starting cediranib/olaparib and will be performed after every 8 weeks (+/- 1 week) of 
treatment.  If a partial or complete response is noted, a confirmatory CT scan or MRI should 
be performed.  The next planned restaging CT scan or MRI may be used as the confirmatory 
scan.   
m:  For patients in the Phase 1 portion of the trial who have been on trial for greater than 1 year 
without evidence of disease progression, the treating investigator may choose to decrease the 
frequency of re-staging CT scans to once every 4 cycles. 
o:   For patients in the Phase 1 portion of the trial who have been on trial for greater than 3 years 
without evidence of disease progression, the treating investigator may choose to decrease the 
frequency of visits to once every 2 cycles.  These patients should have CBC with differential, 
serum chemistry, and urine protein assessment (UPC or urinalysis) performed and con-meds, 
adverse events, and blood pressure diary should be reviewed in-person or by telephone with 
the study team, but all other assessments may be omitted. 
p:  Reference section 8.14 of the protocol for further information on exact timing requirements of 
samples.  
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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9.2. 
Study Calendar:  Phase II 
 
 
Pre-Studya 
Prior to 
Each 
Cyclea,r 
Cycles 
1&2 
Weekl
yb 
Cycles 1&2 
Day 15 
(+/- 3 days) 
Every 
2 
Cycles 
Every 
4 
Cycles 
Off 
Treatmentp 
 
Informed Consenta 
Xa 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Concomitant Medicationsc 
Xc 
Xc 
Xc 
 
 
 
Xc 
Adverse Event Assessment 
 
X 
Xb 
 
 
 
X 
Vital Signsd 
Xd 
Xd 
 
 
 
 
Xd 
BP Measurement at Homee 
(See Appendix C) 
 
Twice a day while on study 
 
Physical Exam 
X 
X 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
X 
Weight 
X 
X 
 
 
 
 
 
ECOG Performance Statusf 
Xf 
Xf 
 
 
 
 
Xf 
CBC with Differential 
X 
X 
 
X 
 
 
X 
Serum Chemistryg 
Xg 
Xg 
 
Xg 
 
 
Xg 
INR and PTT 
X 
 
 
 
 
 
 
Troponin T or I 
TSH and Free T4h 
Xh 
Xh 
 
 
 
 
X 
Urinalysisi 
Xi 
Xi 
 
Xi 
 
 
Xi 
Electrocardiogram 
Xj 
Xj 
 
 
 
 
 
MUGA or Echocardiogramk 
X 
 
 
 
 
X 
 
Pregnancy Testl 
Xl 
 
 
 
 
 
 
CA-125 Measurements 
X 
X 
 
 
 
 
X 
Tumor Measurementsm,q 
Xm 
 
 
 
Xl,q 
 
 
Family Risk Assessment 
Xn 
 
 
 
 
 
 
Translational Studies 
Xo 
 
 
 
 
 
 
a:   Informed consent will be obtained prior to any study-related screening tests and within 4 
weeks of starting study drug.  For Cycle 1 Day 1, physical examination, laboratory 
evaluations, and EKG do not have to be repeated if they have been performed at screening 
within 7 days of Cycle 1 Day 1. 
b:   Participants should be contacted at least once weekly over the phone or be assessed in person 
for the first two cycles on study to assess for adverse events and concomitant medications.  
Pre-cycle and off-study AE assessments must be done at a scheduled clinic visit. 
c:   Because of a potential for interaction of cediranib and olaparib with other drugs through the 
cytochrome P450 system, special attention should be paid to other medications known to 
affect P450 isoenzymes, in particular CYP3A4.  Please see Appendix D for a list of these 
medications. 
d:   Temperature, pulse, blood pressure 
e:   Home blood pressure monitoring is only required for patients receiving cediranib 
f:   See Appendix A for ECOG performance status 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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g:   Sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, albumin, calcium, 
phosphorus, AST (SGOT), ALT (SGPT), alkaline phosphatase, total bilirubin. 
h:   Pre-study, prior to the first 2 cycles, and at off-study visit for all participants.  Otherwise, 
should be checked prior to each cycle if clinically indicated. 
i:   A urine protein:creatinine ratio may be used instead.  See Section 6.3.3 Management of 
Proteinuria if dipstick at least 1+ on study. 
j:   ECG done prior to Cycle 1 and 2, and then prior to every cycle if clinically indicated.  The 
pre-study ECG may be used as the Cycle 1 ECG if performed within 7 days of Cycle 1 Day 
1. 
k:   MUGA or echocardiogram should be done at baseline and every 4 cycles for those patients at 
increased risk for compromised LVEF.  Increased risk patients have had one or more of the 
following:  (1) prior treatment with anthracyclines, (2) prior treatment with trastuzumab, (3) 
NY Heart Association classification of II, (4) prior central thoracic RT, (5) history of 
myocardial infarction within the 12 months prior. 
l:   beta-HCG for women of childbearing potential. 
m:  Tumor measurements by CT scans or MRI will be performed within the 4 weeks prior to 
starting cediranib/olaparib and will be performed after every 8 weeks (+/- 1 week) of 
treatment.  If a partial or complete response is noted, a confirmatory CT scan or MRI should 
be performed.  The next planned restaging CT scan or MRI may be used as the confirmatory 
scan. For patients in the Phase 2 portion of the trial, the frequency of restaging studies will 
decrease to once every 12 weeks (+/- 1 week) after the 20th cycle of treatment.   
n:   The Family Risk Assessment questionnaire (Appendix I) should be completed by the patient 
and returned to the study staff by Cycle 2. 
o:   For patients opting to participate in translational studies at the NCI.  Study schedules will be 
as per Section 5.1.4. 
p:   Off-treatment assessments should be performed within 30 days of stopping study treatment. 
q:  For patients in the Phase 2 portion of the trial who have been on trial for greater than 4 years 
without evidence of disease progression, the treating investigator may choose to decrease the 
frequency of re-staging CT scans to once every 4 cycles. 
r:   For patients in the Phase 2 portion of the trial who have been on trial for greater than 4 years 
without evidence of disease progression, the treating investigator may choose to decrease the 
frequency of visits to once every 2 cycles. These patients should have CBC with differential, 
serum chemistry, and urine protein assessment (UPC or urinalysis) performed and con-meds, 
adverse events, and blood pressure diary should be reviewed in-person or by telephone with 
the study team, but all other assessments may be omitted. 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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10. 
MEASUREMENT OF EFFECT  
 
Response is not the primary endpoint of the phase I component of this trial.  However, 
participants with measurable disease will be assessed by RECIST and those who do not have 
measurable cancer via clinical response benefit (modified GCIG CA-125 response or stable 
disease for at least 16 weeks).  For the purposes of this study, participants should be reevaluated 
for disease response based upon how their disease is being assessed.  If RECIST criteria apply, 
patients should undergo a repeat radiographic assessment every 8 weeks (+/- 1 week) with CT or 
MRI scans.  For patients with only elevated CA125 values, modified GCIG CA125 response will 
be measured every 4 weeks (+/- 1 week).  In addition to a baseline scan, confirmatory scans 
should also be obtained at least 4 weeks following initial documentation of objective response.  
The next planned restaging CT Scan or MRI may be used as the confirmatory scan. 
 
10.1. Measurable Disease Response Definition 
 
When measurable lesions are present, 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 only 
the largest diameter (unidimensional measurement) of the tumor lesions are used in the 
RECIST criteria. 
 
10.1.1. Definitions 
 
Evaluable for toxicity. All participants who receive at least one dose of study treatment will be 
evaluable for toxicity from the time of their first treatment with cediranib and olaparib. 
 
Evaluable for objective response. Only those participants 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 participants will have their response classified 
according to the definitions stated below. (Note: Participants who exhibit objective disease 
progression or die prior to the end of cycle 1 will also be considered evaluable.) 
 
10.1.2. Disease Parameters 
 
Measurable disease. Measurable disease are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10mm with calipers by clinical exam. Measurable lesions must be at least 2 
times the slice thickness in mm. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm when assessed by CT scan (CT scan slice thickness recommended to be 
no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured and 
followed. 
  

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Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with >10 to <15mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not 
followed by CT or MRI), and cystic lesions are all considered 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 tht, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the nxt 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 the lymph nodes are to 
be included in the sum, then only the short axis is added into the sum.  The baseline sum 
parameters 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 or absence 
of each should be noted at each follow-up. 
 
10.1.3. Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler, calipers, or 
digital measurement tool. All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
anti-tumor effect of a treatment. 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and > 10mm diameter as assessed using calipers 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
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Protocol Version Date: January 03, 2019 
 
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(e.g., skin nodules). For 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 5mm or less.  If CT scans have slice thickness 
greater than 5mm, 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). 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.   If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathologic 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 will not be used to assess response for the phase II 
portion of this study. If markers are initially above the upper normal limit, they must normalize 
for a subject 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 Integroup 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].  CA-125 response criteria and 
progression criteria are detailed further in Section 10.2. 
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. 
 
 

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10.1.4. Response Criteria 
 
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. 
 
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 5mm.  (Note: the appearance of one or more new lesions  (new 
lesions must be > slice thickness). 
 
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. 
 
Unknown (UN): Assessment of target lesions cannot be made due to insufficient or unevaluable 
data. In this case, a concise explanation must be given. 
 
Note: If tumor response data is missing, an overall assessment cannot be done. However, if there 
is missing or unevaluable data for non-target lesions, but data is available for all target lesions, 
the overall response for that time point will be assigned based on the sum diameters of all target 
lesions. Additionally, the assessment of CR cannot be made if there is missing or unevaluable 
data for non-target lesions. In this case, the overall assessment would be PR. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  
 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
subject to be considered in complete clinical response 
 
Non-CR/Non-PD: Persistence of one or more non-target lesions and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions (new lesions must be > 
slice thickness) and/or unequivocal progression of existing non-target lesions. 
 
Unknown (UN): Assessment of target lesions cannot be made due to insufficient or unevaluable 
data. In this case, a concise explanation must be given. 
 

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Note: 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 review of the Principal Investigator (or Protocol Chair). 
Additionally, the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment is mandatory to differentiate between stable or progressive disease 
status. 
 
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 participant's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
Category Also Requires: 
CR 
CR 
No 
CR 
> 4 wks confirmation 
CR 
NonCR/Non-PD 
No 
PR 
> 4 wks confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/not evaluated 
No 
PR 
SD 
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 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
**   Only for non-randomized trials with response as primary endpoint 
 
Note:    Participants 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. 
 
10.2. CA-125 Response Definition 
 
For patients enrolled in this study with no measurable cancer but elevated CA125 levels, these 
subjects enrolled will have CA-125 levels at least twice the upper limit of normal (see Section 
3.1.2).  The GCIG CA-125 response criteria (Rustin, 2003), which are a better prognostic tool 
than RECIST in second-line cytotoxic therapy of ovarian cancer (Gronlund et al., 2004), will be 

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modified to assess CA-125 response to combination therapy with cediranib and olaparib.  The 
original criteria were developed for the use of cytotoxic agents, which generally produce a rapid 
decline in CA-125 elevels in patients with chemosensitive disease.  However, combination 
therapy with an anti-angiogenic and a PARP-inhibitor may produce either disease stability, due 
to its cytostatic nature, or disease response of a more gradual tempo, based on mechanism of 
action.  Thus, it may take more time for CA-125 responses (and tumor measurement responses) 
to be seen with cediranib/olaparib combination therapy.  Towards that end, we have modified the 
timing of response determination set out by the GCIG. 
 
10.2.1. Baseline CA-125 Level for Response Assessment 
 
Two pretreatment CA-125 samples must be at least twice the upper limit of normal (at least 1 
day but not more than 3 months apart; at least one of the samples should be within 1 week of 
starting treatment).  A CA-125 level drawn just prior to (within 1 week of) Cycle 1 Day 1 will 
be used as the BASELINE CA-125. 
 
10.2.2. Definition of CA-125 Response 
 
CA-125 levels will be drawn at the start of each cycle.  A CA-125 response occurs if, after two 
elevated levels before therapy, a subsequent sample (taken at least 4 weeks +/- 1 week after 
initiating cediranib/olaparib) shows at least a 50% decrease that is confirmed by a sequential 
confirmatory sample (taken 4 weeks +/- 1 week after the prior sample).  The confirmatory 
sample must be less than or equal to 110% of the prior sample showing a response. 
 
10.2.3. Definition of CA-125 progression: 
 
No validated definitions of CA-125 progression have been published to date.  Given the potential 
cytostatic nature of angiogenesis inhibitors such as cediranib, in this trial the criterion for 
progression based on CA-125 level is: doubling of the CA-125 level from BASELINE (pre-
treatment). 
 
As long as interval CA-125 measurements are less than double the value from baseline, subjects 
may continue on study, provided that tumor measurements are stable as well, without the 
development of new lesions. 
 
10.3. Response Criteria 
 
Clinical response benefit is defined as: 
a)   For patients with only an elevated CA125 (no measurable cancer via radiographic 
test):  Modified GCIG CA-125 response (see Section 10.2) without progressive 
disease on CT scan for at least 16 weeks 
OR 
b)   For patients with measurable disease:  Tumor response by RECIST criteria or 
stable disease for at least 16 weeks. 
 

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10.4. Confirmatory Measurement/Duration of Response 
 
10.4.1. Confirmation 
 
To be assigned a status of clinical response benefit, the modified GCIG CA-125 response criteria 
incorporate the need for a sequential confirmatory CA-125 level as described in Section 10.2. 
 
For patients being followed with measurable disease, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed at least 4 weeks after the criteria for 
response are met.  The next scheduled CT or MRI may be used as the confirmatory scan.  In the 
case of SD, follow-up measurements must have met the SD criteria for at least 16 weeks, with 
scans every 8 weeks (+/- 1 week). 
 
10.4.2. Duration of Overall Response 
 
The duration of modified GCIG CA-125 response or RECIST assessment is measured from the 
time measurement criteria are met (see Section 10.1) until the first date that recurrent or 
progressive disease is objective documented by CA-125 level (taking as reference for 
progression of CA-125 the baseline measurement of CA-125 recorded pretreatment) or by 
progressive disease noted on CT scan by RECIST criteria. 
 
10.4.3. 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 start, with stable 
disease of at least 16 weeks meeting the primary objective of the Phase II component. 
 
10.4.4. 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 
recurrence or PD is objectively documented, taking as reference for PD the smallest 
measurements recorded since the treatment started. 
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that recurrent 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. 
 
10.4.5. Progression-Free Survival 
 

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Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to time 
of objective disease progression.  
 
10.4.6. Response Review 
 
Radiology assessments for DF/HCC sites will be provided by the DF/HCC tumormetrics core.  
Assessment for other participating sites should be performed per local protocols.  All complete 
or partial responses in patients with measurable disease should be confirmed by the DF/HCC 
tumormetrics core.  Please see Appendix H for procedures for submission of materials for 
DF/HCC tumormetrics review from non-DF/HCC participating institutions. 
 
10.5. Other Response Parameters 
 
Criteria for CA-125 response can be found in Section 10.2. 

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11. 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
11.1. General  
 
Adverse event collection and reporting is a routine part of every clinical trial. This study will use 
the descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized until March 31, 2018 for AE reporting. 
CTCAE version 5.0 will be utilized for AE reporting beginning April 1, 2018. All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE 
version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Information on all adverse events, whether reported by the participant, directly observed, or 
detected by physical examination, laboratory test or other means, will be collected, recorded, 
followed and reported as described in the following sections.  
 
Adverse events experienced by participants will be collected and reported from initiation of 
study medication, throughout the study, and within 30 days of the last dose of study medication. 
Participants who experience an ongoing adverse event or related to a study procedures and/or 
study medication beyond 30 days will continue to be contacted by a member of the study team 
until the event is resolved, stabilized, or determined to be irreversible by the participating 
investigator.  
 
Participants should be instructed to report any serious post-study event(s) that might reasonably 
be related to participation in this study. The investigator should notify the IRB and any other 
applicable regulatory agency of any unanticipated death or adverse event occurring after a 
participant has discontinued or terminated study participation that may reasonably be related to 
the study.  
 
11.2. Definitions  
 
11.2.1. Adverse Event (AE) 
 
 
An adverse event is any undesirable sign, symptom or medical condition or experience that 
develops or worsens in severity after starting the first dose of study treatment or any procedure 
specified in the protocol, even if the event is not considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests.  
 
11.2.2. Serious Adverse Event (SAE) 
 
A serious adverse event is an undesirable sign, symptom, or medical condition which: 
• is fatal or life-threatening; 
• requires or prolongs inpatient hospitalization; 

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• results in persistent or significant disability/incapacity; 
• constitutes a congenital anomaly or birth defect; or 
• jeopardizes the participant and requires medical or surgical intervention to prevent 
one of the outcomes listed above.  
 
Events not considered to be serious adverse events are hospitalizations for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures; 
• elective or pre-planned treatment for a pre-existing condition that did not worsen; 
• emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission; 
• respite care. 
 
11.2.3. Expectedness  
 
Adverse events can be 'Expected' or 'Unexpected.'  
 
Expected Adverse Event 
 
 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, the 
package insert or is included in the informed consent document as a potential risk.   
 
Refer to Section 6.1 for a listing of expected adverse events associated with the study agent(s).   
 
Unexpected Adverse Event 
 
 
For the purposes of this study, an adverse event is considered unexpected when it varies in 
nature, intensity or frequency from information provided in the current adverse event list, the 
Investigator’s Brochure, the package insert or when it is not included in the informed consent 
document as a potential risk.   
 
11.2.4. Attribution  
 
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows: 
 
• 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. 
 
 

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11.3. Recording Adverse Events 
 
Adverse event information will be obtained at each contact with the participant. All adverse 
events will be recorded on the appropriate study-specific case report forms (CRFs).  
 
11.4. Reporting Adverse Events  
 
Each adverse event will be assessed to determine if it meets the criteria for serious adverse event. 
If a serious adverse event occurs, expedited reporting will follow local policies, and federal 
guidelines and regulations as appropriate.  
 
It is the responsibility of the participating investigator to notify the Principal Investigator (or 
Protocol Chair), IRB, and others of all serious adverse events as required in the protocol.  
 
The Principal Investigator (or Protocol Chair) will provide information with respect to adverse 
events and safe use of the study treatment (e.g., safety reports, Action Letters) to all participating 
investigators as soon as the information becomes available.  
 
11.5. Sponsor Notification by Investigator  
 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP home page (http://ctep.cancer.gov).  The reporting procedures to 
be followed are presented in the “CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements” which can be downloaded from the CTEP home page (http://ctep.cancer.gov).  
These requirements are briefly outlined in the tables below (Section 11.5.3). 
 
In the rare event when Internet connectivity is disrupted a 24-hour notifications is to be made to 
NCI by telephone at: 301-897-7497, or 301-897-7402 for CIP studies.  An electronic report 
MUST be submitted immediately upon re-establishment of internet connection.  Please note that 
all paper CTEP-AERS forms have been removed from the CTEP website and will NO LONGER 
be accepted. 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Study Coordinator of the Lead Organization, Principal Investigator, and the local 
treating physician.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
11.5.1. Expedited Reporting Guidelines 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur Within 30 Days1 of the 
Last Dose of the Investigational Agent on Phase 1 Trials 

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Phase 1 Trials 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Unexpected 
and 
Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unexpected  
and 
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after 
the last dose of treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 4 unexpected events  
• 
Grade 5 expected events and unexpected events 
 
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, 
a full report is required as outlined in the table. 
December 15, 2004 
 
Phase 2 and 3 Trials 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and 
Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unex- 
pected  
Expected 
with  
Hospitali-
zation 
Without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
10 
Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last 
dose of treatment with an agent under a CTEP IND require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 unexpected events  
 
CTEP-AERS 10 calendar day report: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events 
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report 
is required as outlined in the table. 
December 15, 2004 
 
Note:   All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause must be provided. 
 
• Expedited AE reporting timelines defined: 
➢ “24 hours; 5 calendar days” – The investigator must initially report the AE via 
CTEP-AERS within 24 hours of learning of the event followed by a complete 
CTEP-AERS report within 5 calendar days of the initial 24-hour report. 

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➢ “10 calendar days” - A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the event.  
 
• Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse event 
reporting exclusions.   
 
• Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via CTEP-AERS if the event occurs 
following treatment with an agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID assigned during 
trial registration on all reports. 
 
11.5.2. Non-Serious Adverse Event Reporting Requirements 
 
Non-serious adverse events will be reported to the Principal Investigator (or Protocol Chair) on 
the toxicity Case Report Forms.   
 
 
11.6. Institutional Review Board (IRB) Notification by Investigator 
 
The participating investigator will report all adverse events and serious adverse events to the 
Principal Investigator (or Protocol Chair) and to the IRB according to the local IRB’s policies 
and procedures in reporting adverse events.  
 
In the event of a multi-center study, the Principal Investigator (or Protocol Chair) will report 
adverse events and serious adverse events from all participating sites to the DFCI IRB according 
to the IRB’s policies and procedures in reporting adverse events.  
 
11.7. Hospital Risk Management Notification by Investigator 
 
The participating investigator will report to the Principal Investigator (or Protocol Chair) and to 
local Risk Management any subject safety reports or sentinel events that require reporting 
according to institutional policy. 
 

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12. 
DATA AND SAFETY MONITORING 
 
12.1. Data Reporting  
 
12.1.1. Method  
The QACT will collect, manage, and monitor data for this study.  
Additionally, this study will be monitored by the Clinical Data Update System (CDUS) version 
3.0. Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. Reports 
are due January 31, April 30, July 31 and October 31. Instructions for submitting data using the 
CDUS can be found on the CTEP web site (http://ctep.cancer.gov/. 
 
Note: All adverse events that have occurred on the study, including those reported through 
CTEP-AERS, must be reported via CTMS or CDUS. 
 
12.1.2. Data Submission  
The schedule for completion and submission of case report forms (paper or electronic) to the 
QACT is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the 
cycle required for response evaluation 
Off Treatment/Off Study Form 
Within 14 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined 
follow up visit date or call 
 
Participating sites are responsible for submitting CDUS data and/or data forms quarterly by 
January 15, April 15, July 15, and October 15 to allow time for Coordinating Center compilation,  
 

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Principal Investigator review, and timely submission to CTEP (see Section 12.1.1.). For trials 
monitored by CTMS, the monthly data submission to CTEP from Theradex should be copied to 
the Coordinating Center. 
 
The DF/HCC sites participating in this study are responsible for compiling and submitting 
CDUS data to CTEP for all participants and for providing the data to the Principal Investigator 
for review.  Data for non-DF/HCC institutions will be entered in CDUS by the lead institution. 
 
12.2. Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Board (DSMB) will review and monitor toxicity and 
accrual data from this trial. The committee is composed of clinical specialists with experience in 
oncology and who have no direct relationship with the study. Information that raises any 
questions about participant safety will be addressed with the Principal Investigator and study 
team. 
 
The DSMB will meet every 6 months and/or more often if required to review toxicity and 
accrual data.  Information to be provided to the committee may include:  up-to-date participant 
accrual; current dose level information; DLT information; all grade 2 or higher unexpected 
adverse events that have been reported; summary of all deaths occurring within 30 days for 
Phase I or II protocols; for gene transfer protocols, summary of all deaths while being treated 
and during active follow-up; any response information; audit results, and a summary provided 
by the study team. Other information (e.g. scans, laboratory values) will be provided upon 
request. 
  
12.3. Monitoring 
 
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the Principal 
Investigator (or Protocol Chair) or DF/HCC. The purpose of these audits or inspections is to 
examine study-related activities and documents to determine whether these activities were 
conducted and data were recorded, analyzed, and accurately reported in accordance with the 
protocol, institutional policy, Good Clinical Practice (GCP), and any applicable regulatory 
requirements.  
 
All data will be monitored for timeliness of submission, completeness, and adherence to protocol 
requirements. Monitoring will begin at the time of participant registration and will continue 
during protocol performance and completion.  
 

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13. 
REGULATORY CONSIDERATIONS 
 
13.1. Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g., advertisements used to recruit participants) and any other necessary documents 
must be submitted, reviewed and approved by a properly constituted IRB governing each study 
location.  
Any changes made to the protocol must be submitted as amendments and must be approved by 
the IRB prior to implementation. Any changes in study conduct must be reported to the IRB. The 
Principal Investigator (or Protocol Chair) will disseminate protocol amendment information to 
all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in writing. 
 
13.2. Informed Consent 
 
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. 
The formal consent of a participant, using the IRB approved consent form, must be obtained 
before the participant is involved in any study-related procedure. The consent form must be 
signed and dated by the participant or the participant’s legally authorized representative, and by 
the person obtaining the consent. The participant must be given a copy of the signed and dated 
consent document. The original signed copy of the consent document must be retained in the 
medical record or research file.  
 
13.3. Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which represent good 
and sound research practice: 
• ICH Consolidated Good Clinical Practice: Guidelines (E6) 
www.fda.gov/cder/guidance/iche6.htm  
• US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki 
▪ Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
▪ Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
▪ Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  

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▪ Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
▪ Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• State laws 
• Institutional research policies and procedures www.dfhcc.harvard.edu/clinical-
research-support/clinical-research-operations-cro/policies-and-procedures 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. In such case, the deviation must be 
reported to the IRB according to the local reporting policy.  
 
13.4. Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified. 
 
Original source documents supporting entries in the case report forms include but are not limited 
to hospital records, clinical charts, laboratory and pharmacy records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic media, 
and/or x-rays.  
 
13.5. Records Retention 
 
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies.  
 
13.6. Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) 
 
CRADA INFORMATION 
 
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/default.htm#guidelines_for_collaborations) 
contained within the terms of award, apply to the use of the Agent(s) in this study: 
 

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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 investigational 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 investigational 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 NIH, 
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 investigational Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own investigational Agent. 
 
3.  Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, 
as appropriate and unless additional disclosure is required by law or court order.. 
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. 

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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: 
 
E-mail:  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. 
 
 
14. 
STATISTICAL CONSIDERATIONS  
 
This is a Phase I/II trial to investigate the combination of cediranib and olaparib in recurrent 
high-grade papillary-serous or endometrioid ovarian, fallopian tube, or peritoneal cancer and in 
metastatic triple-negative breast cancer. 
 
14.1. Study Design/Endpoints 
 
14.1.1. Primary Objectives 
 
1. Phase 1 Component:  Determine the dose limiting toxicity (DLT) and maximum 
tolerated dose (MTD) of cediranib in combination with olaparib in the treatment of 
recurrent ovarian, fallopian tube, and peritoneal cancer or metastatic triple-negative 
breast cancer. 
 
2. Phase 2 Component:  Investigate the efficacy of cediranib in combination with 
olaparib (as determined by progression-free survival (PFS) ) at the MTD / 
recommended phase 2 dose (RP2D) compared to that of olaparib alone in patients 
with recurrent platinum-sensitive grade 2 or 3 papillary-serous or endometrioid 
ovarian, fallopian tube, or peritoneal cancer. 
 
3. Phase 1-T (tablet) Component:  Determine the dose limiting toxicity (DLT) and 
maximum tolerated dose (MTD) of cediranib in combination with olaparib (tablet 

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formulation) in the treatment of recurrent ovarian, fallopian tube, and peritoneal 
cancer. 
 
14.1.2. Secondary Objectives 
 
1. Phase 1 Component:  Assess the toxicities of the combination of cediranib and 
olaparib in the treatment of recurrent ovarian, fallopian tube, and peritoneal cancer 
or metastatic triple-negative breast cancer 
 
2. Phase 2 Component:  Investigate tumor response rate, clinical benefit rate 
(response or stable disease x 16 weeks, as determined by RECIST 1.1 criteria, and 
overall survival for patients with recurrent platinum-sensitive grade 2 or 3 
papillary-serous or endometrioid ovarian, fallopian tube, or peritoneal cancer 
treated with cediranib and olaparib at the RP2D compared to cediranib alone. 
 
3. Phase 1-T (tablet) Component:  Assess the toxicities of the combination of 
cediranib and olaparib in the treatment of recurrent ovarian, fallopian tube, and 
peritoneal cancer. 
 
14.1.3. Study Design 
 
Phase 1 and Phase 1-T 
 
The Phase 1 and Phase 1-T components of this trial will employ a 3+3 design, escalating on 0/3 
or 1/6 DLT, and de-escalating if 2 DLTs are encountered.  Please refer to Section 5.3 for more 
trial-specific escalation details. 
 
Probabilities of dose escalation (based on a binomial distribution) are tabulated below for a series 
of assumed true toxicity rates: 
 
True 
Toxicity 
Rate 
0.1 
0.2 
0.3 
0.4 
0.5 
0.6 
0.65 
0.7 
0.8 
0.9 
Probability 
of 
Escalation 
0.91 
0.71 
0.49 
0.31 
0.17 
0.08 
0.053 
0.032 
0.009 
0.001 
 
At least 6 patients will be treated at MTD, and no more than 1 patient should experience a DLT 
at the MTD level.  Based on the exact binomial distribution, we would be unlikely to escalate the 
dose if the true toxicity was 65% or greater (p = 0.053). 
 
When the MTD has been determined and confirmed in at least 6 patients, up to an additional 8 
patients may be enrolled at the MTD dose to gain experience at the MTD dose level. 
 
Phase 2 

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To assess the clinical efficacy of the combination of cediranib and olaparib, a randomized two-
arm study will be conducted with cediranib and olaparib combined at the RP2D compared to 
olaparib alone.  Patients will be randomized after stratification for prior receipt of anti-
angiogenic therapy and BRCA status.  
 
Phase 1-T pharmacokinetic (PK) Expansion 
When the MTD has been determined and confirmed in at least 6 patients, two cohorts of 6 
patients evaluable for PK purposes will be enrolled at the MTD in order to assess PK for the 
study drugs.   
 
14.1.4. Primary Study Endpoints 
 
Phase I:   The primary study endpoint for the Phase I portion of this trial will be 
establishment of the maximum tolerated dose (MTD) and the dose-limiting 
toxicity (DLT).  The MTD will then be considered the recommended Phase 2 
dose (RP2D). 
 
Phase II:  The primary study endpoint for the Phase II portion of this trial will be 
progression-free survival. 
 
Phase I-T: The primary study endpoint for the Phase I-T portion of this trial will be 
establishment of the maximum tolerated dose (MTD) and the dose-limiting 
toxicity (DLT) with cediranib and the tablet formulation of olaparib. 
 
14.1.5. Secondary Study Endpoints 
 
Phase I:  Secondary endpoints will include assessing the toxicities of cediranib in 
combination with olaparib in patients with recurrent ovarian, fallopian tube, 
and peritoneal cancer or metastatic triple-negative breast cancer. 
  
Phase II:   Secondary endpoints will include assessing response rate (as defined by 
RECIST criteria) and clinical benefit rate (response + stable disease  16 
weeks); and assessing overall survival. 
 
Phase I-T:Secondary endpoints will include assessing the toxicities of cediranib in 
combination with olaparib (tablet formulation) in patients with recurrent 
ovarian, fallopian tube, and peritoneal cancer. 
 
14.2. Sample Size and Data Analysis  
 
The planned sample size will vary depending upon the number of patients accrued in the Phase I 
and Phase I-T components of the study.  The Phase II component will randomize 90 patients 
(i.e., 45 patients in each arm).  The Phase 1 component will be accrued at the DF/HCC and 
University of Chicago sites, with an anticipated accrual rate of 2 to 3 patients per month.  The 

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Phase 1-T component will be accrued at the DF/HCC and NCI sites, with an anticipated accrual 
of 2 to 3 patients per month.  We will plan on a multi-center accrual for the Phase 2 component 
of the study, with accrual planned to complete over an 18 month period. 
 
The expected PFS to a platinum-based regimen in this setting is approximately 6 months 
(Markman et al., 1991).  The PFS observed with cediranib alone in this patient population was 
5.2 months (Matulonis et al., 2009).  In the Phase II study of olaparib in BRCA mutation 
carriers, the estimated PFS ranged from approximately 2.5 months to 5.5 months between the 
100mg BID and 400mg BID cohorts (Audeh  et al., 2010).  In BRCA wild-type patients, the 
estimated response rate was 23.9% (Gelmon et al., 2010), which is comparable to the 20% 
response rate observed with single-agent cediranib (Matulonis et al., 2008).  Given this similar 
activity and the observed data in the Audeh et al. Phase II trial, we therefore project a PFS in a 
control arm of olaparib alone to be similar to that of platinum-based regimens at 6 months. An 
increase in progression-free survival to 10.5 months (from the projected 6 months) would be 
considered of clinical interest.  In the Phase II portion of the study, for a power of 86% to reject 
Ho: Median PFS in both arms = 6 months in favor of H1: Median PFS of the group with olaparib 
combination > 10.5 months with an alpha of 0.10, 71 events (i.e., disease progressions) out of a 
total of 82 evaluable patients will be required to detect a hazard ratio of 0.5716 (experimental 
over control).  We will therefore perform the final PFS analysis when the 71st evaluable patient 
experiences cancer progression.  It is anticipated that 10% of subjects will not be evaluable, and 
thus the total number of subjects with platinum-sensitive disease to be enrolled in the Phase II 
portion of the study is 90.  Progression-free survival will be evaluated by Kaplan-Meier analysis 
and Log-Rank test for between group comparison, and median survival times reported.  To 
minimize the likelihood of exposing study patients to an inactive regimen, an interim assessment 
of the hazard ratio for disease progression (experimental over control) will be performed when 
the 36th patient experiences cancer progression.  If the estimated hazard ratio at that time is 1 or 
greater, accrual to the study will be halted for futility. 
 
Response rates with olaparib in patients with recurrent ovarian cancer have been reported at 
approximately 20% (Gelmon et al., 2010).  Second-line platinum results in a response rate of 
~30% in patients who have had a treatment-free interval between 6 and 24 months. With an 
enrollment of 41 patients in each arm, there will be an 80% power to detect a difference in tumor 
response and clinical benefit rates as small as 29.5% with an alpha of 0.05.  H0:  single-agent 
olaparib response rate = cediranib and olaparib response rate = 20%.  H1: cediranib and olaparib 
> 49.5%.  The response rates will be compared by an exact test and 95% confidence intervals 
will also be reported. 
 
The secondary endpoint of overall survival will also be evaluated by Kaplan-Meier analysis and 
Log-Rank test for between-group comparison, and median survival time will be reported.   
 
14.3. Reporting and Exclusions 
 
14.3.1. Evaluation of Toxicity 
 

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All patients will be evaluable for toxicity from the time of their first treatment with cediranib and 
olaparib. 
 
14.3.2. Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data). By arbitrary 
convention, category 9 usually designates the "unknown" status of any type of data in a clinical 
database. 
              
All of the participants who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate. 
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. Precise definitions for categories 4-9, and 
sometimes category 3, will be protocol specific. 
 
All conclusions should be based on all eligible participants. 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 may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding participants from the 
analysis should be clearly reported. The 95% confidence intervals should also be provided.  
 
 
15. 
PUBLICATION PLAN 
 
Publication guidelines exist within the DF/HCC Gynecologic Oncology Program.  The study 
principal investigator will be responsible for collection of data, interpretation of data, monitoring 
of toxicities, and publication of abstracts and final manuscripts.  The principal investigator 
chooses the different authorship slots per the DF/HCC gynecologic oncology program 
guidelines.  
 
The results will be made public within 24 months of the end of data collection. If a report is 
planned to be published in a peer-reviewed journal, then that initial release may be an abstract 
that meets the requirements of the International Committee of Medical Journal Editors. A full 
report of the outcomes will be made public no later than three (3) years after the end of data 
collection.  
 

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16. 
REFERENCES  
 
Audeh, M.W., J. Carmichael, R.T. Penson, et al.  (2010)  Oral poly(ADP-ribose) polymerase 
inhibitor olaparib in patients iwth BRCA1 or BRCA2 mutations and recurrent ovarian cancer : a 
proof-of-concept trial.  Lancet 376(9737) : 245-251. 
 
Bradley, D.P., J.T. Tessier, D.R. Checkley, et al.  (2004)  The VEGF signaling inhibitors 
ZD6474 and AZD2171 compromise hemodynamic parameters in an SW620 human colon tumor 
model: An analysis using perfusion-permeability dynamic contrast-enhanced magnetic resonance 
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Bryant, H.E., N. Schultz, H.D. Thomas, et al.  (2005)  Specific killing of BRCA2-deficient 
tumours with inhibitors of poly(ADP-ribose) polymerase.  Nature 434(7035): 913-917. 
 
Burger, R.A., M.V. Sill, B.J. Monk, et al.  (2007)  Phase II trial of bevacizumab in persistent or 
recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group 
Study.  J Clin Onc 25(33): 5165-5171. 
 
Cannistra, S., U.A. Matulonis, R.T. Penson, et al.  (2007)  Phase II study of bevacizumab in 
patients with platinum-resistant ovarian cancer or peritoneal serous cancer.  J Clin Onc 25(33): 
5180-5186. 
 
Drevs, J., J. Esser, S.R. Wedge, et al.  (2004)  Effect of AZD2171, a highly potent VEGF 
receptor tyrosine kinase inhibitor, on primary tumor growth, metastasis and vessel density in 
murine renal cell carcinoma.  Proc Am Assoc Cancer Res: A4554. 
 
Farmer, H., N. McCabe, C.J. Lord, et al.  (2005)  Targeting the DNA repair defect in BRCA 
mutant cells as a therapeutic strategy.  Nature 434(7035): 917-921. 
 
Fong, P.C., D.S. Boss, C.P. Carden, et al.  (2008)  AZD2281 (KU-0059436), a PARP (poly 
ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA 
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Gelmon, K.A., H.W. Hirte, A. Robidoux, et al.  (2010)  Can we define tumors that will respond 
to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer 
and triple-negative breast cancer.  ASCO Proceedings 28: 2010, Abstract 3002. 
 
Gronlund, B., C. Hogdall, J. Hilden, et al.  (2004).  Should CA-125 response criteria be preferred 
to response evaluation criteria in solid tumors (RECIST) for prognostication during second-line 
chemotherapy of ovarian carcinoma?  J Clin Onc 22(20): 4051-4058. 
 
Hennequin, L.F., A.P. Thomas, C. Johnstone, et al. (1999)  Design and structure-activity 
relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors.  J Med Chem.  
42:5369-5389. 
 

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Hirte, H.W., L. Vidal, G.F. Fleming, et al. (2008)  A phase II study of cediranib (AZD2171) in 
recurrent or persistent ovarian, peritoneal or fallopian tube cancer.  ASCO Proceedings 26:2008, 
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Hughes-Davies, L., D. Huntsman, M. Ruas et al.  (2003)  EMSY links the BRCA2 pathway to 
sporadic breast and ovarian cancer.  Cell 115(5): 523-535. 
 
Jemal, A., R. Siegel, E. Ward, et al.  (2008)  Cancer statistics, 2008.  CA Cancer J Clin 58(2): 
71-96. 
 
Klinowska, T.C., J.A. Jackson, P.M. Farrington, et al. (2004)  AZD2171, a highly potent 
inhibitor of VEGF receptor tyrosine kinase activity, inhibits the growth of spontaneous 
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Lakhani, S.R., M.J. Van De Vijver, J. Jacquemier, et al. (2002)  The pathology of familial breast 
cancer predictive value of immunohistochemical markers estrogen receptor, progesterone 
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Laurie, S.A., I. Gauthier, A. Arnold, et al. (2008) Phase I and pharmacokinetic study of daily 
oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in 
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Ledermann, J.A., P. Harter, C. Gourley, et al. (2011)  Phase II randomized placebo-controlled 
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Markman, M., R. Rothman, T. Hakes, et al.  (1991)  Second-line platinum therapy in patients 
with ovarian cancer previously treated with cisplatin.  J Clin Onc 9(3): 389-393. 
 
Matulonis, U.A., S.T. Berlin, C.N. Krasner, et al.  (2008)  Cediranib (AZD2171) is an active 
agent in recurrent epithelial ovarian cancer.  ASCO Proceedings 26:2008, Abstract 5501. 
 
Matulonis, U.A., S.T. Berlin, S.P. Ivy, et al.  (2009)  Cediranib, an oral inhibitor of vascular 
endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, 
fallopian tube, and peritoneal cancer.  J Clin Onc, in press. 
 
McGuire, W.P., W.J. Hoskins, M.F. Brady, et al.  (1996)  Cyclophosphamide and cisplatin 
compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer.  
New Engl J Med 334:1-6. 
 
Nguewa, P.A., M.A. Fuertes, B. Valladares, et al.  (2005).  Poly(ADP-ribose) polymerases: 
homology, structural domains and functions.  Novel therapeutic applications.  Progr Biophys 
Mol Bio 88:143-172. 

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Ogilvie, D.J., J. Kendrew, S.T. Barry, et al. (2004)  AZD2171, a high potent inhibitor of VEGF 
receptor signaling in primary human endothelial cells, exhibits broad-spectrum activity in tumor 
xenograft models.  Proc Am Assoc Cancer Res: A4553. 
 
Press, J.Z., A. DeLuca, N. Boyd, et al.  (2008)  Ovarian carcinomas with genetic and epigenetic 
BRCA1 loss have distinct molecular abnormalities.  BMC Cancer 22(8): 17-24. 
 
Pyrioichou, A., G. Olah, E.A. Deitch, et al.  (2008)  Inhibition of angiogenesis by the poly(ADP-
ribose) polymerase inhibitor PJ-34.  Int J Mol Med 22(1): 113-118. 
 
Rustin, G.  (2003)  Use of CA125 to assess response to new agents in ovarian cancer trials.  J 
Clin Onc 21(suppl 10): 187s-193s. 
 
Sandhu, S.K., R.M. Wenham, G. Wilding, et al. (2010)  First-in-human trial of a poly(ADP-
ribose) polymerase (PARP) inhibitor MK-4827 in advanced cancer patients (pts) with antitumor 
activity in BRCA-deficient and sporadic ovarian cancers.  ASCO Proceedings 28: 2010, Abstract 
3001. 
 
Shields, A.F., E. Heath, P. DeLuca, et al.  (2007)  AZD2171 in combination with various 
anticancer regimens: Follow-up results of a phase I multi-cohort study.  ASCO Proceedings 25: 
2007, Abstract 3544. 
 
Sorlie, T., R. Tibshirani, J. Parker, et al.  (2003)  Repeated observation of breast tumor subtypes 
in independent gene expression data sets.  Proc Nat Acad Sci 100(14): 8418-8423. 
 
Taniguchi, T., M. Tischkowitz, N. Ameziane, et al.  (2003)  Disruption of the Fanconi anemia-
BRCA pathway in cisplatin-sensitive ovarian tumors.  Nat Med 9(5): 568-574. 
 
Tentori, L., P.M. Lacal, A. Muzi, et al.  (2007)  Poly(ADP-ribose) polymerase (PARP) inhibition 
or PARP-1 gene deletion reduces angiogenesis.  Eur J Cancer 43(14): 2124-2133. 
 
Virag, L., and C. Szabo.  (2002)  The therapeutic potential of poly(ADP-ribose) polymerase 
inhibitors.  Pharmacol Rev: 54(3):375-429. 
 
Wedge, S.R., D.J. Ogilvie, M. Dukes, et al.  (2000)  ZD1490:  An orally active inhibitor of 
vascular endothelial growth factor signaling with broad-spectrum antitumor efficacy.  Cancer 
Res 60:970-975. 
 
Wedge, S.R., D.J. Ogilvie, M. Dukes, et al.  (2002)  ZD6474 inhibits vascular endothelial growth 
factor signaling, angiogenesis and tumor growth following oral administration.  Cancer Res 
62:4645-4655. 
 
Yang, H.J., V.W. Liu, Y. Wang, et al.  (2006)  Differential DNA methylation profiles in 
gynecological cancers and correlation with clinico-pathological data.  BMC Cancer 23(6): 212-
220. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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17. 
APPENDICES  

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
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Protocol Version Date: January 03, 2019 
 
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APPENDIX A:  Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Description 
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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Protocol Version Date: January 03, 2019 
 
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 DFCI IRB 09-293 APPENDIX B: PATIENT’S PILL DIARY: CEDIRANIB 
Today’s Date ________________________________ 
Patient Name_______________________________  Patient Study ID ___________________ 
Cycle #__________ 
(initials acceptable for patient’s name) 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle (28 days). 
2. 
You will take ___ (number) ____ mg (dosage) tablet(s) each morning. 
  You may take the tablet(s) one hour before or two hours after eating, as you prefer. 
3. 
Record the date, the number of pills you took, and when you took them.   
4. 
Please bring your pill bottle (including empty bottles) and this form to your physician when you go for your next appointment. 
 
Date 
 
Day 
# pills  and when 
taken:  cediranib 
 15mg       20mg       Time 
 
Comments 
 
Date 
 
Day 
# pills and when 
taken:  cediranib 
   15mg        20mg        Time 
 
Comments 
 
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: 
1. Date patient started protocol treatment________________   Date patient was removed from 
study _____________________ 
2. Patient’s planned daily dose________________________    Total number of pills taken this 
month ____________________ 
Physician/Nurse/Data Manager’s Signature 
____________________________________________________________________ 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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DFCI IRB 09-293 APPENDIX B: PATIENT’S PILL DIARY: OLAPARIB (CAPSULE) 
Today’s Date ________________________________ 
Patient Name_______________________________  Patient Study ID ____________________ 
Cycle #__________ 
(initials acceptable for patient’s name) 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle (28 days). 
2. 
You will take ___ capsules each day twice a day 12 hours apart. 
  You must take the capsules on an empty stomach either 1 hour before or 2 hours after meals. 
3. 
Record the date, the number of capsules you took, and when you took them.   
4. 
Please bring your pill bottle (including empty bottles) and this form to your physician when you go for your next appointment. 
 
Date 
 
Day 
# capsules and when 
taken:  olaparib 
#     AM     #      PM 
 
Comments 
 
Date 
 
Day 
# capsules and when 
taken:  olaparib 
#     AM     #     PM 
 
Comments 
 
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: 
1. Date patient started protocol treatment________________   Date patient was removed from 
study _____________________ 
2. Patient’s planned daily dose________________________    Total number of pills taken this 
month ____________________ 
Physician/Nurse/Data Manager’s Signature 
___________________________________________________Date _________________ 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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DFCI IRB 09-293 APPENDIX B: PATIENT’S PILL DIARY: OLAPARIB (TABLET) 
Today’s Date ________________________________ 
Patient Name_______________________________  Patient Study ID ____________________ 
Cycle #__________ 
(initials acceptable for patient’s name) 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle (28 days). 
2. 
You will take __ (number) __mg (dosage) and ___ (number) ___mg (dosage) tablet(s) each day twice a day 12 hours apart. 
  You must take the tablets on an empty stomach either 1 hour before or 2 hours after meals. 
3. 
Record the date, the number of tablets you took, and when you took them.   
4. 
Please bring your pill bottle (including empty bottles) and this form to your physician when you go for your next appointment. 
 
Date 
 
day 
# tablets and when taken:  olaparib 
 
 
Comments 
 
Date 
 
day 
# tablets and when taken:  olaparib 
 
 
Comments 
 
mg 
25   100   150 
AM 
Time 
mg 
25   100  150 
PM 
Time 
mg 
25   100   150 
AM 
Time 
mg 
25   100   150 
PM 
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: 
1. Date patient started protocol treatment________________   Date patient was removed from 
study _____________________ 
2. Patient’s planned daily dose________________________    Total number of tablets taken this 
month ____________________ 
Physician/Nurse/Data Manager’s Signature 
___________________________________________________Date _________________ 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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DFCI IRB 09-293 APPENDIX B: PATIENT’S PILL DIARY: PK EXPANSION COHORT 
Today’s Date ______________________________ Cycle # ______ 
Patient Name ______________________________ Patient Study ID _________________ 
1.  
2. Complete one form for each cycle (28 days). 
3. Record the date, the number of tablets you took, and when you took them. 
4. Bring your pill bottles (including empty bottles) and this form to every appointment. 
5. Do not chew, dissolve, or crush medications. DO NOT make up vomited doses. 
6. 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. 
7. 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 
25mg 
100mg 
150mg 
AM 
PM 
1 
1/1/15 
2 
0 
7:00 
1 
1/1/15 
2 
0 
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 
 
 
 
 
 
 
 
Patient’s Signature: ___________________________________        Date: ___________________ 
Physician/Nurse/Data Manager’s Signature _________________________  Date______________ 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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APPENDIX C:  PATIENT’S BLOOD PRESSURE DIARY 
Today’s Date ________________________________ 
Patient Name________________________________   Patient Study ID ___________________ 
INSTRUCTIONS TO THE PATIENT: 
1. 
Your blood pressure readings have two numbers.  The first number is the pressure in your blood vessels during a 
heart beat (systolic), and the second number is the pressure in the vessels when the heart rests in between beats 
(diastolic).  These numbers are usually written with a slash in between them (for example, normal blood pressure is 
120/80). 
2. 
Record the date, then record your blood pressure twice each day using a home blood pressure monitor: 
• 
each morning while you are resting or reading (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 of the day, please record the numbers and time under “Other readings.” 
4. 
If your systolic pressure is greater than 140 or your diastolic blood pressure is greater than 90 twice in a row 
measured several hours apart, please contact your doctor’s office at _______________________________ for 
instructions. 
5. 
Please bring this form to every clinic visit or appointment. 
Date 
AM 
readings 
PM 
readings 
Other readings 
(include time of 
day) 
Date 
AM 
readings 
PM 
readings 
Other readings 
(include time of 
day) 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
 
/ 
/ 
 
Patient’s Signature: _____________________________________________  Date: ____________ 
Physician’s Office will complete this section:  
Date of this clinic visit: 
Physician/Nurse/Data Manager’s Signature:                                                      Date: 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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APPENDIX D:   List of Drugs that May Have Potential CYP3A4 Interactions 
 
CYP3A4 Inducers (prohibited) 
Armodafenil1 
Barbiturates2 
Bosentan1 
Carbamazepine  
Dexamethasone1  
Efavirenz   
Fosphenytoin1 
Glucocorticoids2 (see note) 
Modafinil2  
Nafcillin1  
Nevirapine  
Oxcarbazepine 
Pentobarbital1 
Phenobarbital 
Phenytoin 
Pioglitazone2 
Primidone1 
Rifabutin 
Rifampin 
Rifapentine1 
St. John’s wort2 
Troglitazone3 
Note:  Topical steroids are permitted.  Please contact overall PI if systemic steroids are clinically 
indicated while on trial. 
1 Cited in Cytochrome P450 Enzymes:  Substrates, Inhibitors, and Inducers.  In:  Lacy CF, Armstrong LL, Goldman MP, Lance 
LL, eds.  Drug Information Handbook 20th ed.  Hudson, OH; LexiComp Inc. 2011-2012: 1810-1818 
2 Cited in Flockhart DA.  Drug Interactions:  Cytochrome P450 Drug Interaction Table.  Indiana University School of Medicine 
(2007).  http://medicine.iupui.edu/clinpharm/ddis/table.asp.  Accessed Nov 2011. 
3 Weak inhibitor per Lacy et al.  May be used with caution. 
 Note:  Drugs without a superscript are cited in both the Lacy and Flockhart references. 
 
CYP3A4 Inhibitors 
Strong Inhibitors 
(prohibited) 
Moderate Inhibitors 
(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. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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CYP3A4 Substrates (allowed – take note of possible interactions) 
Alfentanil 
Alfuzosin 
Alprazolam 
Ambrisentan 
Amiodarone 
Amlodipine 
Aprepitant 
Aripiprazole 
Armodafinil 
Astemizole2 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Budesonide 
Buprenorphine 
Buspirone 
Busulfan 
Cafergot2 
Caffeine2 
Carbamazepine 
Cerivastatin2 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Ciclesonide 
Cilostazol 
Cisapride 
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Codeine2 
Colchicine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Darifenacin 
Darunavir 
Dasatinib 
Delavirdine 
Dexamethasone 
Dexlansoprazole 
Dextromethorphan2 
Diazepam 
Dihydroergotamine 
Diltiazem 
Disopyramide 
Docetaxel 
Domperidone2 
Doxorubicin 
Eletriptan 
Efavirenz 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erlotinib 
Erythromycin 
Escitalopram 
Esomeprazole 
Estradiol 
Estrogens, conjugated 
synthetic 
Estrogens, conjugated 
equine 
Estrogens, esterified 
Estropipate 
Eszopiclone 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestane 
Felbamate 
Felodipine 
Fentanyl 
Finasteride2 
Flunisolide 
Flurazepam 
Flutamide 
Fluticasone 
Fosamprenavir 
Fosaprepitant 
Gefitinib 
Haloperidol 
Hydrocortisone2 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide dinitrate 
Isosorbide mononitrate 
Isradipine 
Itraconazole 
Ixabepilone 
Ketamine 
Ketoconazole 
Lansoprazole 
Lapatinib 
Lercanidipine2 
Levonorgestrel 
Lidocaine 
Lovastatin2 
Lopinavir 
Maraviroc 
Medroxyprogesterone 
Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methyloprednisolone 
Miconazole 
Midazolam 
Mirtazapine 
Modafenil 
Montelukast 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nilotinib 
Nimodipine 
Nitrendipine2 
Nisoldipine 
Norethindrone 
Norgestrel 
Omeprazole 
Ondansetron 
Paclitaxel 
Paricalcitol 
Pazopanib 
Pimozide 
Primaquine 
Propranolol2 
Progesterone 
Quazepam 
Quetiapine 
Quinidine 
Quinine 
Rabeprazole 
Ranolazine 
Refabutin 
Repaglinide 
Risperidone2 
Ritonavir 
Salmeterol 
Saquinavir 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Solifenacin 
Spiramycin 
Sufentanil 
Sunitinib 
Tacrolimus 
Tadalafil 
Tamoxifen 
Tamsulosin 
Temsirolimus 
Telithromycin 
Teniposide 
Terfenadine2 
Testosterone2 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tinidazole 
Tipranavir 
Tolterodine 
Toremifene 
Tramadol 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zaleplon2 
Ziprasidone2 
Zolpidem 
Zonisamide 
Zopiclone 
* Note:  CYP3A4 Substrate Table adapted from 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 
** Substrates with 2 superscript denote substrates 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 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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APPENDIX E: New York Heart Association Classifications 
 
Clinical Evaluation of Functional Capacity of Patients With Heart Disease in Relation to Ordinary Physical Activity 
 
Class 
Cardiac 
Symptoms 
Limitations 
Need for 
Additional Rest* 
Physical Ability 
to Work** 
 
 
 
 
 
I 
None 
None 
None 
Full Time 
 
 
 
 
 
II 
Only moderate 
Slight 
Usually only 
slight or 
occasional 
Usually full time 
 
 
 
 
 
III 
Defined, with 
less than 
ordinary activity 
Marked 
Usually 
moderate 
Usually part 
time 
 
 
 
 
 
IV 
May be present 
even at rest, and 
any activity 
increases 
discomfort 
Extreme 
Marked 
Unable to work 
 
*  To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician 
**  At accustomed occupation or usual tasks 
 
 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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APPENDIX F:  Medications that May Cause QTc Prolongation 
 
This table lists drugs that may prolong the QTc interval.  Cediranib may be administered after a 5 
half-life washout period elapses following discontinuation of prohibited drugs.  Drugs labeled 
“Use discretion” may be co-administered in the absence of other risk factors and with 
appropriate monitoring.  Drugs with a weak association may be administered at usual doses with 
appropriate monitoring. 
 
 
Compound 
 
Compound Half Life 
QTc 
Prolongation 
Association/ 
Concurrent 
Administration 
Possible 
Washout 
Period – 
Hours 
Possible 
Washout 
Period - 
Days 
Alfuzocin 
~10 hours 
Some/Use 
Discretion 
 
7 
Amantadine 
17 +/- 4 hours (10-25) 
Some/Use 
Discretion 
 
4 
Amiodarone 
(cordarone) 
58 days (15-142) 
36 days (active 
metabolite) 
Strong/Prohibited 
 
180 
Amitriptyline* 
> 24 hours, wide 
interpatient variability 
Weak/At usual 
doses 
 
 
Amoxapine 
~ 8 hours 
Weak/At usual 
doses 
40 hours 
2 days 
Ampicillin 
1 to 1.5 hours 
Weak/At usual 
doses 
 
 
Arsenic trioxide 
Not characterized; may 
be weeks 
Strong/Prohibited 
 
 
Azithromycin 
40 hours 
Some/Use 
Discretion 
 
 
Bepridil 
42 hr (26-64) 
Strong/Prohibited 
 
10 
Chloral hydrate 
Readily converted to 
Trichloroethanol (active 
metabolite T1/2=7-10 
hour) 
Some/Use 
Discretion 
48 
 
Chloroquine 
6 to 60 days; mean 20 
days 
Strong/Prohibited 
 
 
Chlorpromazine 
30 +/- 7 hours 
Strong/Prohibited 
 
7 
Ciprofloxacin 
3.5 to 4.5 hours 
Weak/At usual 
doses 
 
 
Cisapride 
6 – 12 hour, up to 20 
hour 
Strong/Prohibited 
60 
 
Citalopram 
 
Weak/At usual 
doses 
 
 
Clarithromycin 
Non linear PK3-4 hr 
Strong/Prohibited 
36 
3 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
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Protocol Version Date: January 03, 2019 
 
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(250mg Q12) 
5-7 hr (500mg Q12) 
Clomipramine 
~ 21 hours 
Weak/At usual 
doses 
 
 
Clozapine 
12 hours at steady state 
Some/Use 
Discretion 
 
 
Desipramine* 
> 24 hours, wide 
interpatient variability 
Weak/At usual 
doses 
 
 
Disopyramide 
6.7 hr (4-10) 
Strong/Prohibited 
36 
 
Dofetilide 
10 hr 
Strong/Prohibited 
48 
 
Dolesetron 
8.1 hr 
Some/Use 
Discretion 
 
 
Domperidone 
7-8 hr 
Strong/Prohibited 
48 
 
Doxepin* 
> 24 hours, wide 
interpatient variability 
Weak/At usual 
doses 
 
 
Droperidol 
2.2 hours 
Strong/Prohibited 
10 
 
Erythromycin 
* Each salt form has 
different Half life* 
Strong/Prohibited 
 
 
Felbamate 
20-23 hr 
Some/Use 
Discretion 
 
5 
Flecainide 
20 hr (12-27) 
Some/Use 
Discretion 
 
5 
Fluconazole 
~ 30  hours 
Weak/At usual 
doses 
 
 
Foscarnet  
87.5+/-41.8 hours 
*distribution and release 
from bone* 
Some/Use 
Discretion 
 
20 
Fosphenytoin 
12-29 hr 
Some/Use 
Discretion 
 
6 
Galantamine 
 
Weak/At usual 
doses 
 
 
Gatifloxacin 
7-14 hr 
Some/Use 
Discretion 
48 
 
Gemifloxacin 
7 hours 
Some/Use 
Discretion 
48 
 
Granisetron 
3 to 4 hours 
Some/Use 
Discretion 
 
 
Grepafloxacin 
16 hr 
Some/Use 
Discretion 
 
3 
Halofantrine 
6-10 days ( variable 
among individual) 
Strong/Prohibited 
 
45 
Haloperidol 
18 +/-5 hr 
Strong/Prohibited 
 
5 
Ibutilide 
6 hours (2-12) * variable 
among subject* 
Strong/Prohibited 
36 
3 
Imipramine* 
> 24 hours, wide 
Weak/At usual 
 
 

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interpatient variability 
doses 
Indapamide 
14 hours (biphasic 
elimination) 
Some/Use 
Discretion 
 
3 
Isradipine 
8 hours ( multiple 
metabolites) 
Some/Use 
Discretion 
48 
 
Itraconazole 
20 hours, increasing to 
40 hours 
Weak/At usual 
doses 
 
 
Ketoconazole 
2 hours, increasing to 8 
hours 
Weak/At usual 
doses 
 
 
Levofloxacin 
6-8 hours 
Some/Use 
Discretion 
48 
 
Levomethadyl 
Multiple compartment 
PK with active 
metabolite 
2.6 day for LAAM, 2 day 
for nor-LAAM, 4 day for 
dinor-LAAM 
Strong/Prohibited 
 
20 
Lithium 
24 hour (10-50) 
Some/Use 
Discretion 
 
7 
Mefloquine 
13 to 24 days 
Weak/At usual 
doses 
 
 
Mesoridazine 
24-48 hours ( animal 
study) 
Strong/Prohibited 
 
10 
Methadone 
15-30 hours 
Strong/Prohibited 
 
7 
Mexiletine 
>10 hours 
Weak/At usual 
doses 
 
 
Moexipril/HCTZ 
2-9 hour (include active 
metabolite) for 
moexipril; 5.6-14.8 
hours for HCTZ  
Some/Use 
Discretion 
48 
 
Moxifloxacin 
12 +/-1.3 hours 
Some/Use Discretion 
72 
 
Naratriptan 
6 hours 
 
36 
 
Nicardipine 
~ 2 hour post IV 
infusion 
Some/Use 
Discretion 
12 
 
Nortriptyline* 
> 24 hours, wide 
interpatient variability 
Weak/At usual 
doses 
 
 
Octreotide 
1.7 hours 
Some/Use 
Discretion 
12 
 
Ofloxacin 
5 to 7.5 hours 
Some/Use 
Discretion 
 
2 
Ondansetron 
4 hours (IV/IM); 3 
hours (PO) 
Some/Use 
Discretion 
 
1 to 3 
Paroxetine 
 
Weak/At usual 
doses 
 
 
Pentamidine 
6.4+/-1.3 hours 
Strong/Prohibited 
36 
 
Pimozide 
55 hours 
Strong/Prohibited 
 
10 

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Procainamide 
3-4 hour for PA and 
NAPA (active 
metabolite) 
Strong/Prohibited 
24 
3 
Protiptyline* 
> 24 hours, wide 
interpatient variability 
Weak/At usual 
doses 
 
 
Quetiapine 
6 hours 
Some/Use 
Discretion 
36 
 
Quinidine 
6-8 hours in adult; 3-4 
hours in children 
Strong/Prohibited 
36 
 
Quinine 
4-5 hours 
Weak/At usual 
doses 
 
 
Risperidone 
3-20 hours (extensive to 
poor metabolizer) 
9-hydroxyrisperidone 
(active metabolite) T ½ 
=21-30 hours (extensive 
to poor metabolizer) 
Some/Use 
Discretion 
 
4 
Roxithromycin 
 
Some/Use 
Discretion 
 
 
Salmeterol 
5.5 hours ( only one 
datum) 
Some/Use 
Discretion 
36 
 
Sertraline 
~ 26 hours 
Weak/At usual 
doses 
 
 
Solifenacin 
40 to 68 hours 
Weak/At usual 
doses 
 
 
Sotalol 
12 hours 
Strong/Prohibited 
72 
 
Sparfloxacin 
20 hours (16-30) 
Strong/Prohibited 
 
4 
Sumatriptan 
2.5 hours 
 
12 
 
Tacrolimus 
~34 hours in healthy; 
~19 hours in Kidney 
transplant 
Some/Use 
Discretion 
 
7 
Tamoxifen 
5-7 days (biphasic) 
Some/Use 
Discretion 
 
30 
Telithromycin 
2-3 hr 
Some/Use 
Discretion 
24 
 
Thioridazine 
20-40 hours 
(Phenothiazines) 
Strong/Prohibited 
 
7 
Tizanidine 
2.5 hours 
Some/Use 
Discretion 
12 
 
Trimethoprim/sulfa 6 to 17 hours 
Weak/At usual 
doses 
 
 
Trimipramine 
~ 23 hours 
Weak/At usual 
doses 
 
 
Vardenifil 
4 to 5 hours 
Some/Use 
Discretion 
 
 

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Venlaflaxine 
5 +/-2 hours for parent 
comp. 
11+-2 hours for OVD 
(active metabolite) 
Some/Use 
Discretion 
60 
 
Voriconizole 
6 hours; dose dependent 
Some/Use 
Discretion 
 
 
Ziprasidone 
7 hr 
Some/Use 
Discretion 
36 
 
Zolmitriptan 
2.8-3.7 hours (higher in 
female) 
Weak/At usual 
doses 
18 
 
 
* These agents are tricyclic antidepressants; traditionally, they have only been associated 
with QTc interval prolongation at serum levels approaching or into the range of toxicity. 
Special caution is advised is the elderly and children/adolescents. 
 
References: 
1. Physician’s Desk Reference 2002 
2. Facts and Comparisons ( update to June 2005) 
3. The Pharmacological Basis of Therapeutics 9th Edition, 1996 
4. ArizonaCERT Center for Education and Research on Therapeutics, 
https://www.crediblemeds.org/index.php 
 
Disclaimer:  This chart was updated on August 23, 2005.  It may not include all drugs associated with 
QTc prolongation.  Prescribers are advised to do further research if they have additional questions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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DFCI IRB Protocol # 09-293 
 
 
 
 
 
APPENDIX G: 
 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
 
1. 
Introduction   
 
1.1 Purpose 
1.2 Data and Safety Monitoring Plan Components  
2. 
General Roles and Responsibilities  
2.1 Protocol Chair  
 
2.2 Coordinating Center  
 
2.3 Participating Institution  
 
3. 
DF/HCC Quality Assurance Office for Clinical Trials  
3.1 Organizational Structure  
 
 
4. 
Protocol Development  
4.1 Activation of a Protocol 
4.2 Coordinating Center Support Function  
5. 
Protocol Management  
5.1 Protocol Distribution  
 
5.2 Protocol Revisions and Closures  
5.3 Informed Consent Requirements 
5.4 IRB Documentation 
 
 
5.5 IRB Re – Approvals  
 
5.6 Participant Confidentiality and Authorization  
5.7 Participant Registration  
 
5.8 DF/HCC Multi-center Protocol Case Number  

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5.9 DF/HCC Multi-center Protocol Registration Policy  
5.10 Schedule of Data Submission  
 
5.11 Data Form Review  
 
5.12 Missing and Deficient Memorandum  
6. 
Requisitioning Investigational Drug   
6.1 CTEP Trial Routine Drug Requisitions  
 
6.2 Medical Emergency Drug Ordering  
7. 
Safety Assessments and Toxicity Monitoring        
7.1 Serious Adverse Events  
 
7.2 Guidelines for Reporting Serious Adverse Events  
7.3 Guidelines for Processing IND Safety Reports 
8. 
Protocol Violations and Deviations           
8.1 Definitions    
 
8.2 Reporting Procedures  
 
9. 
Quality Assurance   
 
9.1 Ongoing Monitoring of Protocol Compliance  
9.2 Evaluation of Participating Institution Performance  
9.3 On-Site Auditing  
 
9.4 Substandard Performance 
 
 
 
 
 
 
 
 
 

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1. 
INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for a DF/HCC Multi-Center research protocol.  
 
1.1 
Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center (DF/HCC) 
Multi-center protocol will comply with Federal regulations (21 CFR Part 11); Good Clinical 
Practice (GCP) Guidelines; and  Health Insurance Portability and Accountability Act (HIPAA) 
requirements in accordance with the CTEP Multi-center Guidelines.        
 
1.2 
Multi-Center Data and Safety Monitoring Plan Components 
 
The Multi-Center Data and Safety Monitoring Plan includes the following components: 
 
DF/HCC Multi-center Protocol:  One or more outside institutions collaborating with Dana-
Farber/Harvard Cancer Center on a research  protocol where DF/HCC is the Lead Institution. 
Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial Affiliates are not viewed as 
outside sites in this definition. 
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center sites (DFCI, MGH, BIDMC, 
CH, BWH) will be the Lead Institution and will be responsible for the coordination, 
development, submission, and approval of a protocol as well as its subsequent amendments per 
the DFCI IRB and applicable regulatory guidelines (CTEP, FDA, OBA etc.).  
 
DF/HCC Contract Principal Investigator:  Investigator located at the Lead Institution who 
will be charged with the responsibility of the administration of the DF/HCC Project. This most 
often will be the Protocol Chair, but occasionally this may be the overall grant or contract holder, 
as applicable. 
 
Protocol Chair:  The Protocol Chair is the Principal Investigator for the DF/HCC protocol 
submitted as the Lead Institution.  For applicable protocols, the Protocol Chair will be the single 
liaison with any regulatory agencies (i.e. CTEP Protocol and Information Office (PIO), FDA, 
OBA etc.).  
 
Participating Institution:  A participating institution is an institution that desires to collaborate 
with DF/HCC and commits to accruing participants to a DF/HCC protocol.  The participating 
institution acknowledges the Protocol Chair as having the ultimate authority and responsibility 
for the overall conduct of the study.    
 
Coordinating Center: The Lead Institution is the Coordinating Center for the DF/HCC Multi-
center Protocol. The Coordinating Center will provide the administrative support to the Protocol 
Chair in order that he/she may fulfill the responsibilities outlined in the DSMP and as specified 
in applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines).  In addition to the Lead 
Institution, the Quality Assurance Office for Clinical Trials (QACT) provides support services to 

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assist the Protocol Chair.  
 
 
2. 
GENERAL ROLES AND RESPONSIBILITIES 
 
In accordance with the CTEP Multi-center Guidelines, the Protocol Chair (DF/HCC Principal 
Investigator), Coordinating Center (Lead Institution or designee), and the Participating 
Institutions will all agree to the general responsibilities as follows (specific procedures for these 
general responsibilities are detailed in the DSMP): 
 
2.1 
Protocol Chair (DF/HCC Principal Investigator) 
 
The Protocol Chair, Joyce Liu, will accept responsibility for all aspects of the Multi-Center Data 
and Safety Monitoring Plan to: 
• Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments.    
• Submit the Multi-Center Data and Safety Monitoring Plan as an inclusion to the 
protocol. 
• Assure all participating institutions are using the correct version of the protocol. 
• Monitor progress and overall conduct of the study at all participating institutions.  
• Ensure all DFCI IRB, DF/HCC and other applicable (i.e. CTEP) reporting 
requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
• Act as the single liaison with CTEP/PIO Office (CTEP trials). 
• Identify participating institutions and obtain accrual commitments.   The title page 
must include the names and contact information for all participating institutions that 
perform the function of recruiting, enrolling, and treating participants for the protocol. 
The Coordinating Center (Lead Institution or designee) must be designated on the 
title page.  
 
2.2 
Coordinating Center (Lead Institution) 
 
The Coordinating Center is the DF/HCC Lead Institution’s study team or designee (i.e Medical 
Monitor, Clinical Research Organization). The DF/HCC Lead Institution Dana-Farber Cancer 
Institute will ensure that all participating sites within the Multi-Center Protocol demonstrate 
their intent and capability of complying with Federal Regulations, GCPs and Health Insurance 
Portability and Accountability Act (HIPAA) requirements.   To assist the Protocol Chair in 
meeting his/her responsibilities as required by the DSMP, the DF/HCC Lead Institution’s study 
team or designee will assume the following general responsibilities: 
• Assist in protocol review. 
• Maintain copies of Institutional Review Board (IRB) approvals from all participating 
institutions. 
• Maintain CTEP correspondence. 
• Maintain updated roster of participants.  
• Verify eligibility. 

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• Verify response. 
• Collect data on protocol specific CRFs. 
• Prepare all submitted data for review by the Protocol Chair. 
• Maintain documentation of Serious Adverse Event (SAE) reports submitted by 
Participating Institutions and submit to Protocol Chair for timely review.   
• Distribute external Serious Adverse Event safety reports.  
• Monitor and audit Participating Institutions either by on-site inspection of selected 
participant records and/or with source documents and research records submitted to 
the Lead Institution.  
    
In addition to the Lead Institution, the DF/HCC Quality Assurance Office for Clinical Trials 
provides the following support services to assist the Protocol Chair: 
• Develop protocol specific case report forms (CRF/eCRFS). 
• QA/QC data of protocol specific CRFs.  
• Provide Central Participant Registration. 
• Confirm eligibility and consent.  
• Provide auditing services (funding and QACT approval required). 
 
2.3 
Participating Institutions 
 
The Participating Institutions will be identified on the title page for each protocol.   In addition, 
each participating institution will provide to the Lead Institution or designee a list of the key 
personnel assigned to the role for oversight of data management at their site. All sites must have 
office space, office equipment, and internet access that meet HIPAA standards. 
 
The general responsibilities for each participating institution are as follows: 
 
• Commit to accrual to the Lead Institution’s (DF/HCC) protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Update Coordinating Center (Lead Institution or designee) with research staff 
changes on a timely basis. 
• Register participants through the QACT.  
• Submit source documents, research records, and CRFs per protocol specific                            
submission guidelines to the Coordinating Center (Lead Institution or designee).  
• Submit Serious Adverse Event reports to local IRB and directly to the Coordinating  
 
Center (Lead Institution or designee). For CTEP trials, submit SAE reports directly to 
CTEP and provide copies to the Coordinating Center (Lead Institution or designee).  
• Submit deviations and violations to local IRB and the Coordinating Center (Lead 
Institution or designee). 
• For protocols using investigational agents, the participating institution will order their 
own investigational agents regardless of the supplier (i.e. NCI, pharmaceutical 
company). 
 
 

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3. 
DF/HCC QUALITY ASSURANCE OFFICE FOR CLINICAL TRIALS 
 
The DF/HCC QACT is a unit that has been developed to computerize, manage, and monitor data 
for DF/HCC trials.  The DF/HCC QACT is located administratively in the office of the Senior 
Vice President for Clinical Research, at Dana-Farber Cancer Institute.  The QACT uses DF/HCC 
computerized institutional databases for participant registrations and for the management of trial 
data as well as a set of quality assurance programs designed to monitor DF/HCC trials.   
 
3.1 
Organizational Structure 
 
The DF/HCC Quality Assurance Office for Clinical Trials administrative structure consists of: 
 
DF/HCC Quality Assurance Officer for Clinical Trials: Oversees the functions of the DF/HCC 
QACT. 
 
QACT Assistant Director for Data: Provides direct oversight to the QACT Data Analysts 
assigned to CRF design, data collection and computerization for DF/HCC trials.  
 
The DF/HCC QACT Data Analysts will be assigned on a protocol by protocol basis. Each 
protocol’s data analyst is responsible for database management, data entry, data quality 
assurance, and protocol specific correspondence related to the collection and quality assurance of 
data. 
 
QACT Assistant Director for Monitoring: Provides direct oversight to the QACT Protocol 
Registrars and Clinical Research Auditors. 
 
The DF/HCC Protocol Registrars are responsible for the confirmation of each participant’s 
eligibility and consent prior to protocol registration.  
 
If funded and QACT approved, the DF/HCC Clinical Research Auditors may assist the Lead 
Institution in their auditing responsibilities for multi-center trials. The QACT auditor is 
responsible for systematically evaluating participant safety, protocol compliance, institutional 
SOPs, ICH GCP and Federal regulation compliance, data accuracy and investigational drug 
handling to assure a high standard of quality for DF/HCC trials. 
 
 
4. 
PROTOCOL DEVELOPMENT 
 
4.1 
Activation of a Protocol 
 
The Protocol Chair is responsible for the coordination, development, and approval of the 
protocol as well as its subsequent amendments, and reporting SAEs, violations and deviations 
per DFCI IRB guidelines and CTEP Multi-center Guidelines.  Further, the Protocol Chair will be 
the single liaison with the CTEP/PIO. 
 

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To meet these requirements, the Protocol Chair will be responsible for the following minimum 
standards: 
 
• Inclusion of the DF/HCC Multi-Center Data and Safety Monitoring Plan in the 
protocol as an appendix. 
• Identify participating institutions and obtain accrual commitments. The title page 
must include the names and contact information for all participating institutions that 
perform the function of recruiting, enrolling, and treating participants for the protocol. 
The Coordinating Center (Lead Institution or designee) must be designated on the 
title page.  
• Commit to the provision that the protocol will not be rewritten or modified by anyone 
other than the Protocol Chair. 
• Ensure that there is only one version of the Protocol and that all Participating 
Institutions use the correct version.  
• Oversee the development of data collection forms (case report forms) that are of 
common format for use at all the Participating Institutions.  
 
4.2 
Coordinating Center Support Function 
 
The DF/HCC Lead Institution’s study staff or designee will provide administrative and clerical 
support to the Protocol Chair for the development and distribution of the protocol.  
 
The tasks to be performed by the DF/HCC Lead Institution’s study staff or designee include: 
 
• Review of the protocol and consent to check for logistics, spelling, and consistency.  
Provide the Protocol Chair a list of queries related to any inconsistencies. 
• Provide necessary administrative sections, including paragraphs related to registration 
logistics, data management schedules, and multi-center guidelines.  
• Maintenance of contact list of all participating institutions in the DF/HCC Multi-
center Protocol and the distribution of updates to the sites as needed.  
• Derivation of the study calendar, if applicable. 
• Assistance in preparation and maintenance of case report forms.  Conduct regular 
communications with all participating sites (conference call, emails, etc).  Maintain 
documentation of all communications.  
 
 
5. 
PROTOCOL MANAGEMENT 
 
The Coordinating Center (Lead Institution of designee) is responsible for assuring that each 
Participating Institution in the DF/HCC Multi-center Protocol has the appropriate assurance on 
file with the Office of Human Research Protection (OHRP).   Additionally, the Lead Institution 
or designee must maintain copies of all IRB approvals, for each participating institution.  
 
 
 

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5.1 
Protocol Distribution 
 
The Coordinating Center (Lead Institution or designee) will distribute the final approved 
protocol and any subsequent amended protocols to all Participating Institutions.    
 
5.2 
Protocol Revisions and Closures 
 
The participating institutions will receive phone, fax, mail or e-mail notification of protocol 
revisions from the Lead Institution or designee.  It is the individual participating institution’s 
responsibility to notify its IRB of these revisions. 
 
Non life-threatening revisions: Participating institutions will receive written notification of 
protocol revisions regarding non life-threatening events from the Lead Institution or designee. 
Non-life-threatening protocol revisions should be IRB approved and implemented within 90 days 
from receipt of the notification. 
 
Revisions for life-threatening Causes: Participating institutions will receive telephone 
notification from the Lead Institution or designee concerning protocol revisions required to 
protect lives with follow-up by fax, mail or e-mail.  Life-threatening protocol revisions will be 
implemented immediately followed by IRB request for approval 
 
Protocol Closures and Temporary Holds: Participating institutions will receive fax, e-mail, or 
phone notification of protocol closures and temporary holds, with follow-up by mail from the 
Lead Institution or designee. Closures and holds will be effective immediately.  In addition, the 
Lead Institution or designee will update the Participating institutions on an ongoing basis about 
protocol accrual data so that they will be aware of imminent protocol closures. 
 
5.3 
Informed Consent Requirements 
 
 
 
The Principal Investigator (PI) at each participating site will identify the physician members of 
the study team who will be obtaining consent and signing the consent form for therapeutic 
protocols. It is DF/HCC policy that Nurses and Fellows cannot obtain consent to greater than 
minimal risk trials.   
 
5.4 
IRB Documentation 
 
The following must be on file with the DF/HCC Lead Institution or designee prior to participant 
registration: 
• Approval Letter of the institution's IRB (An Expedited IRB first approval is NOT 
acceptable) 
• IRB approval for all amendments 
 
It is the individual institution's responsibility to notify its IRB of protocol revisions.  
Participating institutions will have 90 days from receipt to provide the DF/HCC Lead Institution 
or designee their IRB approval for Major Amendments to a protocol.    

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DF/HCC defines a Major Amendment as: A substantive change in the study which may increase 
or decrease the risk to study participants.  Major revisions require full IRB approval.  The 
following criteria are examples of revisions to a protocol that are considered to be major 
amendments:  
 
 
 
• Change of eligibility (inclusion/exclusion) criteria 
• Change in design of protocol 
• Change in statistical section 
• Change in sample size/accrual (e.g., doubling the sample size) 
• Change in informed consent 
• Change of estimated dropout rate 
• Change of treatment or intervention 
• Change of device 
• Change in primary objective evaluation process 
 
 
5.5 
IRB Re-Approval 
          
Annual IRB re-approval from the Participating institution is required in order to register 
participants onto a protocol.  There is no grace period for annual re-approvals. 
 
Protocol registrations will not be completed if a re-approval letter is not received by the DF/HCC 
Lead Institution or designee from the Participating Institutions on or before the anniversary of 
the previous approval date.   
 
5.6 
Participant Confidentiality and Authorization Statement 
 
The Health Insurance Portability and Accountability Act of 1996 contains, as one of its six major 
components, the requirement to create privacy standards for health care information that is used 
or disclosed in the course of treatment, payment or health care operations.  The original Privacy 
Rule, as it has come to be known, was published in December 2000.  The Final Rule was 
published on August 14, 2002, which has modified the privacy rule in significant ways vis-à-vis 
research. 
 
In order for covered entities to use or disclose protected health information during the course of a 
DF/HCC Multi-Center Protocol the study participant must sign an Authorization.  This 
Authorization may or may not be separate from the Informed Consent.  The DF/HCC Multi-
Center Protocol, with the approval from the DFCI IRB and NCI/CTEP, will provide an Informed 
Consent template, which covered entities (DF/HCC Multi-Center Protocol participating 
institutions) must use.  
 
The DF/HCC Multi-Center Protocol will use all efforts to limit its use of protected health 
information in its trials.  However, because of the nature of these trials, certain protected health 
information must be collected per National Cancer Institute requirements. These are the primary 
reasons why DF/HCC has chosen to use Authorizations, signed by the participant in the trial, 
rather than limited data sets with data use agreements.   

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5.7 
Participant Registration and Randomization  
To register a participant, the following documents should be completed by the DF/HCC Multi-
Center Protocol participating site and faxed to or e-mailed to the Lead Institution or designee 
(Contact Information: Emily Eisenberg; email: emily_eisenberg@dfci.harvard.edu; phone: (617) 
632-6930; fax: (617) 632-3550): 
• Copy of required laboratory tests: 
o CBC with differential 
o Serum chemistries (Sodium, potassium, chloride, bicarbonate, BUN, creatinine, 
glucose, albumin, calcium, phosphorus, AST (SGOT), ALT (SGPT), alkaline 
phosphatase, total bilirubin, LDH) 
o Troponin T or I, TSH and Free T4 
o Urinalysis or urine protein:creatinine ratio 
o CA-125 
• Signed informed consent form 
• HIPAA authorization form (if separate from the informed consent  
 
document) 
• Completed and Signed QACT Eligibility Screening Worksheets 
• CT Scan 
• Pathology report 
• Most recent clinic visit note 
 
The research DF/HCC Multi-center Protocol participating site will then call or e-mail the Lead 
Institution or designee to verify eligibility. To complete the registration process, the Lead 
Institution or designee will: 
 
• Register the participant on the study with the DF/HCC Quality Assurance  Office  
for Clinical Trials (QACT) 
• Fax or e-mail the participant case number, and if applicable the dose treatment level, 
to the participating site 
• Call the research nurse or data manager at the participating site and verbally confirm 
registration 
 
Randomization can only be done between normal QACT business hours, 8:30am-5:00pm. 
 
5.8 
DF/HCC Multi-center Protocol Case Number 
 
Once eligibility has been established and the participant successfully registered, the participant is 
assigned a five digit protocol case number.  This number is unique to the participant on this trial 
and must be used for QACT CRF/eCRF completion and written on all data and QACT 
correspondence for the participant. 
 
5.9 
DF/HCC Multi-center Protocol Registration Policy 
 
5.9.1 Initiation of Therapy: Participants must be registered with the DF/HCC QACT before 
receiving treatment.  Treatment may not be initiated until the site receives a faxed or e-

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mailed copy of the participant’s Registration Confirmation memo from the DF/HCC 
QACT. Therapy must be initiated per protocol guidelines.  The Protocol Chair and DFCI 
IRB must be notified of any exceptions to this policy.  
 
5.9.2 Eligibility Exceptions: The DF/HCC QACT will make no exceptions to the eligibility 
requirements for a protocol without DFCI IRB approval.  In addition, the Cancer Therapy 
Evaluation Program (CTEP) specifically prohibits registration of a participant on any 
NCI Sponsored protocol that does not fully and completely meet all eligibility 
requirements. The DF/HCC QACT requires each institution to fully comply with this 
requirement. 
 
5.9.3 Verification of Registration, Dose Levels, and Arm Designation: A registration 
confirmation memo for participants registered to DF/HCC Multi-Center Protocol will be 
faxed or emailed to the registering institution within one working day of the registration. 
Treatment may not be initiated until the site receives a faxed or e-mailed copy of the 
registration confirmation memo.  
 
5.9.4 Confidentiality: All documents, investigative reports, or information relating to the 
participant are strictly confidential. Any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Lead Institution or 
designee must have the participant’s full name & social security number “blacked out” 
and the assigned DF/HCC QACT case number and protocol number written in (with the 
exception of the signed informed consent document). Participant initials may only be 
included or retained for cross verification of identification. 
  
 
5.10 
Schedule of Data Submission 
 
The DF/HCC QACT develops a set of either paper or electronic case report forms, (CRF/eCRFs) 
for use with the DF/HCC Multi-Center Protocol.  QACT provides a web based training for eCRF 
users.  These forms are designed to collect data for each study. The schedule for submission of 
case report forms to the DF/HCC QACT is generally specified in each protocol. When not 
specified in the protocol, the DF/HCC QACT will require the forms to be submitted as follows: 
 
Note: It is necessary to send only ONE copy of all paper Case Report Forms, if applicable.  
   
5.10.1 Eligibility Checklist 
 
Purpose - Outlines protocol-specific eligibility criteria and includes the following: 
              
Participant Demographics (address, zip code, sex, race, ethnicity, initials, date of birth) 
1) Parameters for eligibility 
2) Parameters for exclusion 
3) Parameters for stratifications 
 
If a time frame is not specified in the protocol, tests must be completed as follows: 

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• Lab tests required for eligibility must be completed within 14 days prior to study 
enrollment by the QACT. 
• For protocols requiring measurable disease, lab baseline measurements must be 
completed within 14 days prior to study enrollment by the QACT.  A baseline CA-
125 must be drawn within 7 days of starting treatment. 
• Tumor measurements by MRI or CT must be completed within 28 days of initiating 
treatment.  Other non-lab tests required for eligibility must be performed within 30 
days prior to study entry. 
 
Schedule for Submission - Completed prior to participant registration. The Informed 
Consent/ Participant Authorization for the Release of Personal Health Information should 
be submitted with the Eligibility Checklist at the time of registration. 
 
5.10.2 On-study Form 
 
Purpose - documents the following items: 
• Demographic data 
• Prior therapy 
• Past medical and surgical history 
• Description of participant’s physical status at protocol registration 
• Disease site specific data 
 
 
Schedule for Submission - Submitted to DF/HCC QACT within 14 days after 
registration. 
 
5.10.3 Baseline Assessment Form 
 
 
Purpose – Documents objective and subjective disease status as defined by the protocol. 
Records all pertinent radiographic and laboratory measurements of disease utilized in 
determining response evaluations.  
 
 
Schedule of Submission – Submitted within 14 days after registration. 
 
5.10.4 Treatment Form 
 
Purpose - Records the following information related to the time the participant receives 
protocol treatment: 
• Participant, Protocol, Affiliate information 
• Protocol treatment and supportive therapy per treatment cycle 
• Protocol specific laboratory values per treatment cycle 
• All medications other than protocol chemotherapy agents used to treat concomitant    
diagnoses, if applicable 
 
Schedule for Submission – Submitted within 10 days after the last day of the cycle.   
 

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5.10.5 Adverse Event Report Form  
 
Purpose – Documents adverse events that occur while the participant is receiving 
treatment and for up to 30 days after the last dose of treatment.  All adverse events are to 
be graded by number using the toxicity grading scale required by the protocol. This form 
is not for IRB submission, but for recording the AE in the research database. 
 
Schedule for Submission – Submitted within 10 days after the last day of the cycle. 
 
5.10.6 Response Assessment Form 
 
Purpose – Documents objective and subjective response as defined by the protocol. 
Records all pertinent radiographic and laboratory measurements of disease utilized in 
determining response evaluations.  
 
Schedule of Submission – Submitted within 10 days after the completion of  
the cycle required for response evaluation.  
 
5.10.7 Off Treatment/Off Study Form 
 
Purpose - The Off Treatment/Off Study Form is submitted when the participant is 
removed from the study or has completed all protocol treatment.  Note: If the participant 
dies while on protocol, the Off Study Form is the last form submitted. 
 
Schedule of Submission – Submitted within 14 days after completing treatment or taken 
off study for any reason. 
 
5.10.8 Follow up / Survival Form 
 
Purpose - Summarizes participant status at a given point in time after being removed 
from treatment.  
 
Schedule of Submission – Submitted within 14 days after the protocol defined follow up 
visit date or call.    
 
5.11 
Data Form Review 
 
When data forms arrive at the DF/HCC QACT, they are reviewed for: 
  
Timelines:  
Did the form arrive on time as specified in the protocol? 
  
 
 
Completeness:  
Is all the information provided as required per protocol? 
 
Participant Eligibility:  

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Does the participant meet the eligibility requirements for the study based on the 
demographic data, lab values and measurements provided? 
 
Stratification:  
Are the stratification parameters consistent with what was given at the time of 
registration? 
 
Protocol Treatment Compliance:  
Are the body surface area (BSA) and drug dosage calculations correct?  The dose must 
be within 10% of the calculated protocol dose. 
  
Adverse Events (Toxicities):  
Did the participant experience adverse events (toxicities or side effects) associated with 
the treatment? Was the treatment delayed due to the adverse event? What was the most 
severe degree of toxicity experienced by the participant? 
 
Notations concerning adverse events will address relationship to protocol treatment for 
each adverse event grade.  All adverse events encountered during the study will be 
evaluated according to the NCI Common Toxicity Criteria assigned to the protocol and 
all adverse events must be noted on the participant's Adverse Event (Toxicity) Forms. 
 
Response:  
Did the participant achieve a response?  What level of response did they achieve?  On 
what date did the participant achieve the response and how was the response 
determined? 
 
Response criteria are defined in the protocol.  A tumor assessment must be performed 
prior to the start of treatment and while the participant is on treatment as specified by 
the protocol.   
 
Objective responses must have documentation such as physical measurements, x-rays, 
scans, or laboratory tests.   
 
A subjective response is one that is perceived by the participant, such as reduction in 
pain, or improved appetite. 
 
5.12 
Missing and Deficient Memorandum 
 
Data submissions are monitored for timeliness and completeness of submission. Participating 
institutions are notified of their data submission delinquencies in accordance with the following 
policies and procedures: 
 
Incomplete or Questionable Data 
 
If study forms are received with missing or questionable data, the submitting institution will 
receive a written query from the DF/HCC QACT Data Analyst.  Responses to the query should 

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be completed and returned within 14 days.  Responses may be returned on the written query or 
on an amended case report form. In both instances the query must be attached to the specific data 
being re-submitted in response.   
 
Missing Forms 
 
If study forms are not submitted on schedule, the participating institution will receive a Missing 
Form Report from the DF/HCC QACT noting the missing forms.  These reports are compiled by 
the DF/HCC QACT and distributed a minimum of three times a year. 
  
 
6. 
REQUISITIONING INVESTIGATIONAL DRUG 
       
The ordering of investigational agent is specified in the protocol.  
 
Participating sites should order their own agent.  
 
The agents in the study are investigational, and the pharmacy must be able to receive and store 
the agent. The local IRB should be kept informed of who will supply the agent (i.e., NCI or a 
pharmaceutical company) so that any regulatory responsibilities can be met in a timely fashion.  
 
6.1 
CTEP Trial Routine Drug Requisitions  
 
Investigational drugs for use in Cancer Therapy Evaluation Program’s (CTEP) approved 
protocols are obtained through the Pharmaceutical Management Branch at CTEP in accordance 
with the guidelines provided in the NCI’s Investigator Handbook. The DF/HCC Multi-center 
Protocol institutions may order drugs directly from Division of Cancer Treatment and Diagnosis 
(DCTD) through the PMB Online Agent Order Processing (OAOP) application < https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx>. 
 
 
6.1.1 Guidelines for Clinical Drug Request Submission: 
 
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 < https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx >.  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account < https://eapps-
ctep.nci.nih.gov/iam/ > and the maintenance of an “active” account status and a “current” password.   For 
questions about drug orders, transfers, returns, or accountability, call (240) 276-6575 Monday through 
Friday between 8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime.   
 
Orders will only be shipped to the investigator's designated shipping address. All changes to the 
investigator’s shipping address must be in writing and signed by the investigator/designee. 
 
1) Orders must use the NCI protocol numbers only.  
2) Limit drug requests to an eight week supply. 

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DF/HCC Protocol: 09-293 
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3) When a number of investigators are participating on a clinical study at the same 
institution, one investigator should be considered or designated the principal 
investigator under whom all investigational agents for that protocol should be 
ordered. 
 
Normal PMB processing time will be two (2) working days. Orders will be shipped within two 
working days based on drug availability and provided there are no shipping restrictions, (e.g. 
thermo-labile agents, holiday restrictions). 
 
Requests for next day delivery must be received at PMB by 2:30 PM, Eastern Time. Next day 
delivery must be stated on the order and an express courier account number must be provided.  
If there are any comments or suggestions, direct them to the PMB by phone (240) 276-6575 or 
PMBafterhours@mail.nih.gov. 
 
6.2 
Medical Emergency Drug Ordering 
 
Clinical drug requests are submitted through the PMB Online Agent Order Processing (OAOP) 
application < https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx. The need-by date should be specified 
accordingly and an overnight courier number provided if the shipment is needed urgently.  
All orders sent via overnight courier are filled the same day if the order arrives before 2:30 PM, 
EST. 
 
 
7. 
SAFETY ASSESSMENTS AND TOXICITY MONITORING 
 
All participants receiving investigational agents will be evaluated for safety.   The safety 
parameters include all laboratory tests and hematological abnormalities, physical examination 
findings, and spontaneous reports of adverse events reported to the investigator by participants.  
All toxicities encountered during the study will be evaluated according to the NCI criteria 
assigned to the protocol and recorded prior to each course of therapy. This study will use the 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized until March 31, 2018 for AE reporting. 
CTCAE version 5.0 will be utilized for AE reporting beginning April 1, 2018. All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE 
version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Life-threatening 
toxicities should be reported immediately to the Protocol Chair and Institutional Review Board 
(IRB).  Protocols using CTEP supplied agents should also report these toxicities via the CTEP-
AERS system. 
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
7.1 
Serious Adverse Events 
 

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A serious adverse event (SAE) is any adverse drug experience at any dose that results in any of 
the following outcomes: death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect.  Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition.  
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions in a participant who has never 
had seizure activity in the past that do not result in inpatient hospitalization, or the development 
of drug dependency or abuse. 
 
Unless otherwise specified in the protocol, the study will utilize the Cancer Therapy Evaluation 
Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 for Toxicity 
and Adverse Event reporting until March 31, 2018. CTCAE version 5.0 will be utilized for AE 
reporting beginning April 1, 2018. All appropriate treatment areas should have access to a copy 
of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
7.2 
Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Serious Adverse Events (SAEs) will be followed as is delineated in the 
protocol Section 11.  
 
 
 
 
 
Participating Institutions must report serious adverse events for CTEP trials online using 
CTEP-AERS.  This applies to any medical event equivalent to an unexpected grade 2 with a 
possible, probable or definite attribution, most grade 3 and all grade 4 and grade 5 (death) 
toxicities regardless of study phase or attribution.  
 
In addition, the Participating Institutions must report the serious adverse events to the Protocol 
Chair and the Coordinating Center (Lead Institution) following the DFCI IRB SAE Reporting 
Requirements.  
 
The Lead Institution will maintain documentation of all Adverse Event Reporting and be 
responsible for communicating all SAEs that are related to study drug(s) to all Participating sites. 
 
7.3 
Guidelines for Processing IND Safety Reports  
 
The U.S. Food and Drug Administration (FDA) regulations require sponsors of clinical studies to 
notify the FDA and all participating investigators of any serious and unexpected adverse 
experiences that are possibly related to the investigational agent. In compliance with these FDA 
regulations, the Protocol Chair is responsible for reviewing all IND Safety Reports and 
forwarding the IND Safety Reports to the Participating Institutions.  The investigator’s are to file 
a copy with their protocol file and send a copy to their IRB according to their local IRB’s 
policies and procedures. 
 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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CTEP will notify the Participating sites via the DF/HCC Lead Institution by the following 
methods:  Investigators will be sent a copy of expedited adverse events which CTEP has sent to 
the FDA. CTEP will notify the Protocol Chair at the Lead Institution. Within 7 business days of 
receipt of the notification, the Lead Institution or designee will forward the letters to the 
Participating sites with protocol specific instructions for IRB submissions, participant 
notifications, etc. For routine IND Safety Reports, CTEP does not generally require an 
immediate revision to the protocol and/or model informed consent documents. The investigators 
are to file a copy with their protocol file and send a copy to their IRB according to their local 
IRB’s policies and procedures. 
 
 
8. 
PROTOCOL VIOLATIONS AND DEVIATIONS 
 
Neither the FDA nor the ICH GCP guidelines define the terms “protocol violation” or “protocol 
deviation.”  All DF/HCC Protocol Chairs must adhere to those policies set by the DFCI IRB, the 
definitions for protocol violation and deviation as described by the DFCI IRB will be applied for 
reporting purposes for all institutions participating in the DF/HCC Multi-center Protocol.  
   
8.1 
Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-approved 
protocol. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g., 
enrollment of a subject who does not meet all inclusion/exclusion criteria. 
 
 
 
Protocol Violation: Any protocol deviation that was not prospectively approved by the IRB 
prior to its initiation or implementation.   
 
8.2 
Reporting Procedures 
 
The Protocol Chair: is responsible for ensuring that clear documentation is available in the 
medical record to describe all protocol exceptions, deviations and violations.  
The Protocol Chair will also be responsible for ensuring that all protocol violations/deviations 
are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from DFCI IRB. 
The Participating institution must submit the deviation request to the Protocol Chair or designee, 
who will submit the deviation request to the DFCI IRB. Upon DFCI IRB approval the deviation 
should be submitted to the participating site’s own IRB, per its institutional policy. 
 
A copy of the participating institution’s IRB report and determination will be forwarded to the 
DF/HCC Lead Institution or designee by mail, facsimile, or via e-mail within 10 business days 
after the original submission.  
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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All protocol violations must be sent to the DF/HCC Lead Institution Protocol Chair or designee 
in a timely manner.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the participating 
institution, the DF/HCC Lead Institution or designee will submit the report to the Protocol Chair 
for review. Subsequently, the participating institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will forward 
all violation reports to CTEP via an internal DF/HCC process, as applicable. 
 
 
9. 
QUALITY ASSURANCE 
 
The quality assurance process for a clinical trial research study requires verification of protocol 
compliance and data accuracy. As the Coordinating Center, the DF/HCC Lead Institution or 
designee with the aid of the QACT provides quality assurance oversight for the DF/HCC Multi-
center Protocol. 
 
9.1 
Ongoing Monitoring of Protocol Compliance 
  
All data submitted to the DF/HCC QACT will be monitored for timeliness of submission, 
completeness, and adherence to protocol requirements.  Monitoring will begin at the time of 
participant registration and will continue during protocol performance and completion.  The 
Lead Institution or designee and if applicable QACT Data Analysts assigned to the Protocol will 
perform the ongoing protocol compliance monitoring with the support of the participating 
institution’s Coordinators, the Principal Investigators, and the Protocol Chair.  
 
Participating institutions will be required to submit source documents for monitoring to the 
Coordinating Center, Clinical Research Specialist, and/or QACT as requested for ongoing virtual 
monitoring.  On-site and/or virtual monitoring will be conducted by the Clinical Research 
Specialist at all participating institutions.  Monitoring activities will include, but are not limited 
to, review of the following:  source documentation supporting data submitted, eligibility 
requirements of all participants, informed consent documents, adverse events and all associated 
documentation, records of study drug storage/administration/treatment, regulatory records and 
site Trial Master File, protocol deviations/violations, and response assessments. The Lead 
Institute will conduct an on-site monitoring visit after three patients have been accrued at a site, 
or at a minimum once a year for sites with active patients.  Additional on-site monitoring visits 
will be scheduled if there are significant findings or discrepancies to be resolved.  An on-site SIV 
will be conducted at each site prior to study activation, and a study manual outlining specific 
study instructions will be given to each site.  Additionally, QACT and/or the Clinical Research 
Specialist will periodically review data for completion and quality of information submitted, and 
the sites’ overall adherence to protocol requirements, regulatory compliance, good clinical 
practice, and accrual goals.  
 
The Coordinating Center will provide regular communication to participating sites via email and 
biweekly teleconference updates, SAE reporting, amendment submissions, and other regulatory 
activities.  The Coordinating Center will be available to all sites’ study team members for 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
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resolving questions, concerns and facilitating compliance. It is the primary responsibility of the 
Principal Investigator and Clinical Research Specialist to ensure that sites maintain accurate and 
completed documentation and CRF submission to DF/HCC 
 
9.2 
Evaluation of Participating Institution Performance 
 
9.2.1 Eligibility Checklist: Eligibility criteria are checked on a protocol-specific eligibility 
checklist and faxed to the DF/HCC QACT prior to registration on protocol.  The 
checklist and informed consent document are reviewed by a DF/HCC QACT Protocol 
Registrar before the participant can be registered on a protocol.  The DF/HCC QACT 
cannot make exceptions to the eligibility requirements. 
 
9.2.2 Accrual of Eligible Participants: Annual accrual rates for eligible participants enrolled 
onto therapeutic clinical trials is calculated for each institution. Institutions are expected 
to maintain the minimum annual average accrual as defined by the protocol grant or 
contract.  
 
9.2.3 Quality Improvement Report:  For CTEP trials, the DF/HCC Lead Institution is bound 
by institutional and federal regulations in the conduct of cancer research trials; protocol 
performance is reported to the NCI annually.  
 
Yearly quality improvement reports will summarize proficiency from January 1 – 
December 31 and will be sent to the NCI in January. 
 
The DF/HCC Lead Institution will distribute Quality Improvement Reports (QI) to each 
institution on a semi-annual basis to help the affiliate monitor data management and 
detect changes over time. This data can be used to detect trends in protocol adherence and 
present opportunities for improvement. The semi-annual reporting period will be: 
 
January 1 - June 31 
July 1 - December 31 
 
9.3 
On-Site Auditing 
 
Auditing is a method of Quality Assurance. The main focus in auditing is to measure if the 
standards and procedures set are being followed. Auditing is the systematic and independent 
examination of all trial related activities and documents.  Audits determine if evaluated activities 
were appropriately conducted and the data were generated, recorded and analyzed, and 
accurately reported per the protocol, Standard Operating Procedures (SOPs), Good Clinical 
Practice (GCP) and the Code of Federal Regulations. 
 
9.3.1 DF/HCC Sponsored Trials 
 
Auditing visits will occur as needed and at least once for all enrolling sites. Auditing will be 
performed by the DF/HCC QACT. Auditing visits entail source verification and review of the 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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following: study drug administration/treatment, informed consent procedures, pharmacy records, 
study drug, eligibility criteria, adverse events, response assessments, procedures and tests, data 
management, regulatory records, and good clinical practice. Because of limited auditing visits, 
participating sites will be required to submit (either electronically or via paper) requested source 
documents to the Coordinator Center for source verification, at the Coordinator Center’s request. 
In addition, appropriate regulatory documents should be sent electronically to the Coordinating 
Center in lieu of being collected at the time of the auditing visit. 
 
9.3.2 Participating Institution 
 
It is the participating institution’s responsibility to notify the DF/HCC Lead Institution or 
designee of all scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which 
involve the DF/HCC Multi-Center Protocol. All institutions will forward a copy of final audit 
and/or re-audit reports and corrective action plans (if applicable) to the DF/HCC Lead Institution 
or designee within 12 weeks after the audit date.  
 
9.3.3 Coordinating Center (Lead Institution or Designee)  
 
The Protocol Chair will review all DF/HCC Multi-Center Protocol Final Audit reports and 
corrective action plans if applicable. The Lead Institution or designee must forward these reports 
to the DF/HCC QACT per DF/HCC policy for review by the DF/HCC Audit Committee. Based 
upon the audit assessments the DF/HCC Audit Committee could accept or conditionally accept 
the audit rating and final report. Conditional approval could require the Protocol Chair to 
implement recommendations or require further follow-up.  For unacceptable audits, the Audit 
Committee would forward the final audit report and corrective action plan to the DFCI IRB as 
applicable. 
 
9.4 
Sub-Standard Performance 
 
The Protocol Chair, DFCI IRB and the NCI for CTEP trials, is charged with considering the 
totality of an institution’s performance in considering institutional participation in the DF/HCC 
Multi-Center Protocol. 
 
 
9.4.1 Corrective Actions: Institutions that fail to meet the performance goals of accrual, 
submission of timely accurate data, and adherence to protocol requirements will be 
recommended for a six-month probation period. Such institutions must respond with a 
corrective action plan and must demonstrate during the probation period that deficiencies 
have been corrected, as evidenced by the improved performance measures. Institutions 
that fail to demonstrate significant improvement will be considered by the Protocol Chair 
for revocation of participation. 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
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APPENDIX H:  DF/HCC Tumor Metrics Submission Procedures for non-DF/HCC Sites 
 
All participants with measurable disease with partial or complete responses on trial should have 
their responses confirmed by the DF/HCC Tumor Imaging Metrics Core (TIMC).  For patients 
with responses, the following materials should be submitted to the Dana-Farber Cancer Institute: 
 
• Baseline CT/MRI study on CD 
• CT/MRI documenting response on CD 
• CT/MRI confirming response on CD 
• Radiology reports from baseline CT/MRI and CT/MRIs in which response was 
documented and confirmed. 
 
All materials should be sent to the Study Coordinator at the following address: 
450 Brookline Ave, DA129 
Dana-Farber Cancer Institute 
Boston, MA 02215

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer  
Protocol Version Date: January 03, 2019 
 
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APPENDIX I: 
Family History Questionnaire 
 
Instructions:  
1.  When completing this questionnaire, please be sure to complete all sections.  
2.  If there is not enough space to list all relatives, please include that information on a separate sheet of paper 
 
 
Name: ____________________________________________________ 
                       (Last)                            (First)                        (Maiden) 
Date of Birth: _________________________________ 
                                         (MM/DD/YYYY) 
Phone No: Home: __________________  Work: __________________ 
When is the best time to contact you? ❑ Morning (❑Home ❑ Work)    
                                                                      ❑ Afternoon (❑Home ❑ Work)   
                                                                      ❑ Evening (❑Home ❑ Work)    
What best describes your family’s ethnic heritage? (ex. Irish, Jewish) 
     Mother’s Family______________________________ 
     Father’s Family______________________________ 
 
Are you adopted?    ❑ Y  ❑ N  ❑  Unknown 
Are you a twin?       ❑ Y  ❑ N   If Yes:  ❑ Identical 
                                                                   ❑ Same sex, unknown if identical 
                                                                   ❑ Unknown 
 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
144 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Please complete the following table for your parents and children even if they have not had cancer.  If they have not had cancer, please write in 
“NONE” in the Cancer Type column.  If they have had more than one type of cancer, please list all types and age at diagnosis of each cancer.   
 
YOUR PARENTS AND CHILDREN 
Relative and Name 
Date of Birth 
Cancer Type(s) 
Age(s) @ 
Diagnosis 
Date of Death 
Father   
 
 
 
 
 
Mother  
 
 
 
 
 
Child #1  
Sex   M   F 
 
 
 
 
Child #2   
Sex   M   F 
 
 
 
 
Child #3  
Sex   M   F 
 
 
 
 
Child #4  
Sex   M   F 
 
 
 
 
Child #5  
Sex   M   F 
 
 
 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
145 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Please complete the following table for your brothers and sisters even if they have not had cancer.  If they have not had cancer, please write in 
“NONE” in the Cancer Type column.   If they have had more than one type of cancer, please list all types and age at diagnosis of each cancer.    
 
YOUR BROTHERS AND SISTERS 
Relative and Name 
Date of Birth 
Cancer Type(s) 
Age(s) @ 
Diagnosis 
Date of Death 
Brother #1   
 __Full   __Half (same mother) 
               __Half (same father) 
 
 
 
 
Brother #2  
 __Full   __Half (same mother) 
              __Half (same father) 
 
 
 
 
Brother #3 
 __Full   __Half (same mother) 
             __Half (same father) 
 
 
 
 
Brother #4  
  __Full  __Half (same mother) 
              __Half (same father) 
 
 
 
 
Sister #1  
 __Full     __Half (same mother) 
                 __Half (same father) 
 
 
 
 
Sister #2   
  __Full     __Half (same mother) 
                 __Half (same father) 
 
 
 
 
Sister #3   
 __Full     __Half (same mother) 
                __Half (same father) 
 
 
 
 
Sister #4  
__Full     __Half (same mother) 
                 __Half (same father) 
 
 
 
 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
146 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Please complete the following table for your nieces and nephews (children of your brothers and sisters) even if they have not had cancer.  If they have 
not had cancer, please write in “NONE” in the Cancer Type column.   If they have had more than one type of cancer, please list all types and age at 
diagnosis of each cancer.    
 
NIECES AND NEPHEWS 
Relative and Name of Parent 
Date of Birth 
Cancer Type(s) 
Age(s) @ 
Diagnosis 
Date of Death 
Niece/Nephew #1 
Name of Parent 
 
 
 
 
Niece/Nephew #2 
Name of Parent 
 
 
 
 
Niece/Nephew #3 
Name of Parent 
 
 
 
 
Niece/Nephew #4 
Name of Parent 
 
 
 
 
Niece/Nephew #5 
Name of Parent 
 
 
 
 
Niece/Nephew #6 
Name of Parent 
 
 
 
 
Niece/Nephew #7 
Name of Parent 
 
 
 
 
Niece/Nephew #8 
Name of Parent 
 
 
 
 
Niece/Nephew #9 
Name of Parent 
 
 
 
 
Niece/Nephew #10 
Name of Parent 
 
 
 
 
Niece/Nephew #11 
Name of Parent 
 
 
 
 
Niece/Nephew #12 
Name of Parent 
 
 
 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
147 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Please complete the following table for your grandparents, aunts, and uncles on your FATHER’s side even if they have not had cancer.  If they have 
not had cancer, please write in “NONE” in the Cancer Type column.   If they have had more than one type of cancer, please list all types and age at 
diagnosis of each cancer.    
 
GRANDPARENTS, AUNTS, and UNCLES ON YOUR FATHER’S SIDE 
Your Father's Side 
Relative 
Date of Birth 
Cancer Type(s) 
Age(s) @ 
Diagnosis 
Date of Death 
Grandfather 
 
 
 
 
 
Grandmother 
 
 
 
 
 
Uncle #1  
 
 
 
 
 
Uncle #2  
 
 
 
 
 
Uncle #3  
 
 
 
 
 
Uncle #4 
 
 
 
 
 
Uncle #5 
 
 
 
 
 
Aunt #1  
 
 
 
 
 
Aunt #2  
 
 
 
 
 
Aunt #3  
 
 
 
 
 
Aunt #4 
 
 
 
 
 
Aunt #5 
 
 
 
 
 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
148 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Please complete the following table for your grandparents, aunts, and uncles on your MOTHER’s side even if they have not had cancer.  If they have 
not had cancer, please write in “NONE” in the Cancer Type column.   If they have had more than one type of cancer, please list all types and age at 
diagnosis of each cancer. 
    
GRANDPARENTS, AUNTS, and UNCLES ON YOUR MOTHER’S SIDE 
Your Mother’s Side 
Relative 
Date of Birth 
Cancer Type(s) 
Age(s) @ 
Diagnosis 
Age @ Death 
Grandfather 
 
 
 
 
 
Grandmother 
 
 
 
 
 
Uncle #1  
 
 
 
 
 
Uncle #2  
 
 
 
 
 
Uncle #3  
 
 
 
 
 
Uncle #4 
 
 
 
 
 
Uncle #5 
 
 
 
 
 
Aunt #1  
 
 
 
 
 
Aunt #2  
 
 
 
 
 
Aunt #3  
 
 
 
 
 
Aunt #4 
 
 
 
 
 
Aunt #5 
 
 
 
 
 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
149 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Please complete the following table for your cousins (children of your aunts and uncles) on your FATHER’S side even if they have not had cancer.  If 
they have not had cancer, please write in “NONE” in the Cancer Type column.   If they have had more than one type of cancer, please list all types and 
age at diagnosis of each cancer.    
 
COUSINS ON YOUR FATHER’S SIDE 
Relative and Name of Parent 
Date of Birth 
Cancer Type (s) 
Age(s) @ 
Diagnosis 
Date of Death 
Cousin #1 
Sex   M   F  
Name of Parent 
 
 
 
 
Cousin #2 
Sex   M   F  
Name of Parent 
 
 
 
 
Cousin #3 
Sex   M   F  
Name of Parent 
 
 
 
 
Cousin #4 
Sex   M   F  
Name of Parent 
 
 
 
 
Cousin #5 
Sex   M   F  
Name of Parent 
 
 
 
 
Cousin #6 
Sex   M   F  
Name of Parent 
 
 
 
 
Cousin #7 
Sex   M   F  
Name of Parent 
 
 
 
 
Cousin #8 
Sex   M   F  
Name of Parent 
 
 
 
 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
150 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Please complete the following table for your cousins (children of your aunts and uncles) on your MOTHER’S side even if they have not had cancer.  
If they have not had cancer, please write in “NONE” in the Cancer Type column.   If they have had more than one type of cancer, please list all types 
and age at diagnosis of each cancer. 
    
COUSINS ON YOUR MOTHER’S SIDE 
Relative and Name of Parent 
Date of Birth 
Cancer Type(s) 
Age(s) @ 
Diagnosis 
Date of Death 
Cousin #1 
Sex   M   F  
Name of Parent 
 
 
 
 
Cousin #2 
Sex   M   F  
Name of Parent 
 
 
 
 
Cousin #3 
Sex   M   F  
Name of Parent 
 
 
 
 
Cousin #4 
Sex   M   F  
Name of Parent 
 
 
 
 
Cousin #5 
Sex   M   F  
Name of Parent 
 
 
 
 
Cousin #6 
Sex   M   F  
Name of Parent 
 
 
 
 
Cousin #7 
Sex   M   F  
Name of Parent 
 
 
 
 
Cousin #8 
Sex   M   F  
Name of Parent 
 
 
 
 
 

NCI Protocol: 8348 
DF/HCC Protocol: 09-293 
Phase I/II Cediranib/Olaparib in Recurrent Ovarian or Triple-Negative Breast Cancer 
 
Protocol Version Date: January 03, 2019 
 
151 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Please complete the following table for other relatives we have not asked about on your FATHER’s side even if they have not had cancer.  If they 
have not had cancer, please write in “NONE” in the Cancer Type column.   If they have had more than one type of cancer, please list all types and age 
at diagnosis of each cancer.    
OTHER RELATIVES ON YOUR FATHER’S SIDE 
Your Father's Side 
Relative 
Date of Birth 
Cancer Type(s) 
Age(s) @ 
Diagnosis 
Date of Death 
Other Relative #1 
Sex   M   F  
 
 
 
 
Other Relative #2 
Sex   M   F  
 
 
 
 
Other Relative #3 
Sex   M   F  
 
 
 
 
Other Relative #4 
Sex   M   F  
 
 
 
 
 
Please complete the following table for other relatives we have not asked about on your MOTHER’s side even if they have not had cancer.  If they 
have not had cancer, please write in “NONE” in the Cancer Type column.   If they have had more than one type of cancer, please list all types and age 
at diagnosis of each cancer.    
OTHER RELATIVES ON YOUR MOTHER’S SIDE 
Your Mother's Side 
Relative 
Date of Birth 
Cancer Type(s) 
Age(s) @ 
Diagnosis 
Date of Death 
Other Relative #1 
Sex   M   F  
 
 
 
 
Other Relative #2 
Sex   M   F  
 
 
 
 
Other Relative #3 
Sex   M   F  
 
 
 
 
Other Relative #4 
Sex   M   F