Clinical trial NCT03448718
Conditions: Metastatic Urothelial Cancer
Sponsor: Matthew Galsky
Start date: 2018-04-17; Completion date: 2021-10-15
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single arm open label multi-institutional phase II trial of olaparib monotherapy in subjects with metastatic urothelial cancer harboring somatic DNA damage response (DDR) alterations. The primary objective of the study is to estimate the objective response rate (per RECIST 1.1) to treatment with olaparib.

Detailed description:

Arms: arm 1: The starting dose of olaparib tablets will be dependent on the subject's calculated creatinine clearance (CrCl). Subjects with a CrCl of ≥ 40 mL/min will start at a dose of olaparib tablets of 300 mg twice a day. Subjects with a CrCl of \> 30 to \< 40 mL/min will start at a dose of olaparib tablets 200 mg twice a day.
Interventions: intervention 1: Olaparib
Intervention descriptions: intervention 1: 1 cycle = 28 days. Subject's with calculated creatinine clearance (CrCl) of ≥ 40 mL/min will start at a dose of olaparib tablets of 300 mg twice a day. Subjects with a CrCl of \> 30 to \< 40 mL/min will start at a dose of olaparib tablets 200 mg twice a day.

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
HCRN GU15-262 
 
Phase 2 Trial of Olaparib in Patients with Metastatic Urothelial Cancer Harboring DNA 
Damage Response Gene Alterations 
 
 
Sponsor Investigator 
 
Matthew D. Galsky, MD 
Icahn School of Medicine at Mount Sinai 
Tisch Cancer Institute 
 
Co-Principal Investigator 
 
Matthew Milowsky, MD 
UNC Lineberger Comprehensive Cancer Center 
UNC-Chapel Hill School of Medicine 
 
Statistician 
 
Menggang Yu, PhD, MS 
 
 
Trial Management Provided by  
Hoosier Cancer Research Network, Inc. 
500 N. Meridian, Suite 100 
Indianapolis, IN 46204 
 
 
Trial Supported by  
Astra-Zeneca ESR-16-12351 
 
 
Investigational New Drug (IND) #: Exempt per FDA 10/27/17 
 
 
 
 
Initial Protocol Version Date: 13NOV2017 
Protocol Amendment Version Date:  
24MAY2018 
15MAY2019 
 
 
 


Clinical Study Protocol 
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PROTOCOL SIGNATURE PAGE 
 
Phase 2 Trial of Olaparib in Patients with Metastatic Urothelial Cancer Harboring DNA 
Damage Response Gene Alterations 
 
 
 
VERSION DATE: 15MAY2019 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable institutional review board(s). 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Site Investigator 
 
 
  
 Date 
 
 
____________________________________ 
 Site Investigator Name (printed) 
 
 
____________________________________ 
 Site Investigator Title 
 
 
____________________________________ 
 Name of Facility 
 
 
____________________________________ 
 Location of Facility (City and State) 
 
 
 
 PLEASE COMPLETE AND EMAIL A COPY TO HCRN 
 
 
 


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SYNOPSIS 
TITLE 
Phase 2 Trial of Olaparib in Patients with Metastatic 
Urothelial Cancer Harboring DNA Damage Response Gene 
Alterations
SHORT TITLE 
Phase 2 Trial of Olaparib in Metastatic UC Patients 
PHASE  
2 
OBJECTIVES 
Primary Objective 
• Estimate the objective response rate (per RECIST 1.1 
in patients with measurable disease and MD Anderson 
criteria in patients with bone-only metastases) to 
treatment with olaparib in subjects with metastatic 
urothelial cancer harboring somatic DDR alterations.   
 
Secondary Objectives 
• Describe the safety of olaparib in subjects with DDR 
mutant metastatic urothelial cancer. 
• Describe the progression-free survival of subjects with 
DDR mutant metastatic urothelial cancer treated with 
olaparib. 
• Describe the overall survival of subjects with DDR 
mutant metastatic urothelial cancer treated with 
olaparib. 
 
Exploratory Objectives 
• Explore the relationship between specific genomic 
alterations with response to olaparib. 
• Explore the relationship between prior platinum-based 
chemotherapy treatment (response, duration of 
treatment, and time since treatment) with response to 
olaparib. 
• Explore the relationship between tumor mutational 
profile, circulating DNA mutational profile, and 
response to olaparib. 
• Determine the feasibility of establishing patient-
derived xenografts from circulating tumor cells 
collected from enrolled subjects at baseline and 
progression to better explore mechanisms of response 
and resistance. 
 
 
 


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STUDY DESIGN 
This is a single arm open label multi-institutional phase II trial 
of olaparib monotherapy in subjects with metastatic urothelial 
cancer harboring DDR alterations. The primary objective of 
the study is to estimate the objective response rate (per 
RECIST 1.1) to treatment with olaparib. 
ELIGIBILITY 
CRITERIA (See 
Section 3 for full 
eligibility criteria) 
Inclusion Criteria 
 
1. Written informed consent and HIPAA authorization for 
release of personal health information prior to registration. 
NOTE:  HIPAA authorization may be included in the 
informed consent or obtained separately. 
 
2. Age ≥ 18 years at the time of consent. 
 
3. ECOG Performance Status of ≤ 1 within 14 days prior to 
registration. Cisplatin-ineligible chemotherapy-naïve 
subjects (see inclusion criteria #9) may have an ECOG 
Performance Status of ≤ 2. 
 
4. Histological or cytological evidence/confirmation of 
urothelial cancer.   
 
5. Metastatic and/or unresectable (cT4b) urothelial cancer.  
 
6. Metastatic disease evaluable on imaging studies. Subjects 
may have measurable disease according to RECIST 1.1 or 
bone-only disease within 30 days prior to registration.  
NOTE: Bone-only subjects are eligible if their disease can 
be documented/ evaluated by bone scans, CT or MRI. 
Their disease will be assessed using MD Anderson 
criteria.34 NOTE: Previously irradiated lesions are eligible 
as a target lesion only if there is documented progression 
of the lesion after irradiation. 
 
7. Somatic alteration considered pathogenic/likely 
pathogenic in one of the following DDR genes as 
determined by genomic sequencing performed in a 
Clinical Laboratory Improvement Amendments (CLIA) 
laboratory. Somatic alterations will include nonsense, 
frameshift, splice-site or missense mutations or 
homozygous deletions. Subjects with alterations in DDR 
genes not included in the list below will be considered on 
a case by case basis after discussion with the sponsor-
investigator. Subjects with germline alterations in DDR 
genes will be considered on a case by case basis and will 
be reviewed by the sponsor-investigator. At least 6 


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subjects will have BRCA or ATM alterations. 
Nucleotide 
Excision 
Repair 
Homologous 
Recombination 
Base 
Excision 
Repair 
Other 
ERCC2
BRCA1
RAD52
XRCC2 
MUTYH
ERCC3
BRCA2
RAD54L
XRCC3 
RECQL4
ERCC4
RAD50
NBN
XRCC4 
POLQ 
ERCC5
RAD51
MRE11A
XRCC5 
POLE 
ERCC6 
RAD51B 
RAD51D 
XRCC6 
WRN 
 
RAD51C
CTIP
 
 
 
DNA Sensor 
Fanconi Anemia 
Pathway
 
 
ATM 
PALB2 
FANCE
 
ATR 
BRIP1
FANCF
 
MDC1 
FANCA
FANCG
 
ATRX 
FANCB
BLM
 
CHEK1
FANCC
 
CHEK2
FANCD2
 
 
8. A subject with prior brain metastasis may be considered if 
they have completed their treatment for brain metastasis at 
least 4 weeks prior to study registration, have been off of 
corticosteroids for ≥ 2 weeks, and are asymptomatic. 
 
9. Subjects must have progressed despite at least 1 prior line 
of treatment for metastatic and/or unresectable urothelial 
cancer. However, cisplatin-ineligible (defined by a 
calculated creatinine clearance of > 30 but < 60 mL/min 
OR CTCAE v4 Grade ≥ 2 audiometric hearing loss OR 
CTCAE v4 Grade ≥ 2 peripheral neuropathy OR ECOG 
PS = 2), chemotherapy-naïve subjects are also eligible.  
 
10. Prior cancer treatment (systemic therapy or radiation 
therapy) must be completed at least 3 weeks prior to 
registration and the subject must have recovered from all 
reversible acute toxic effects of the regimen (other than 
alopecia) to Grade ≤ 1 or baseline. 
 
11. Demonstrate adequate organ function. All screening labs 
to be obtained within 28 days prior to registration. 
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L 
• Hemoglobin (Hgb) ≥ 9 g/dL 
• Platelets ≥ 100 x 109/L 
• Calculated creatinine clearance1 > 30 mL/min 
• Bilirubin ≤ 1.5 × upper limit of normal (ULN) 
• Aspartate aminotransferase (AST) and Alanine 
aminotransferase (ALT) ≤ 2.5 × ULN (or ≤ 5 × ULN 
if liver metastases)


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12. Female subjects must be postmenopausal or there must be 
evidence of non-childbearing status for women of 
childbearing potential: negative urine or serum pregnancy 
test within 28 days of study treatment and confirmed prior 
to treatment on day 1. Postmenopausal is defined as: 
• Amenorrheic for 1 year or more following cessation of 
exogenous hormonal treatments 
• Luteinizing hormone (LH) and Follicle stimulating 
hormone (FSH) levels in the post-menopausal range 
for women under 50 
• radiation-induced oophorectomy with last menses >1 
year ago 
• chemotherapy-induced menopause with >1 year 
interval since last menses 
• surgical sterilization (bilateral oophorectomy or 
hysterectomy) 
 
13. Females of childbearing potential must be willing to 
abstain from heterosexual activity or to use 2 forms of 
effective methods of contraception from the time of 
informed consent until 90 days after treatment 
discontinuation. The two contraception methods can be 
comprised of two barrier methods, or a barrier method 
plus a hormonal method. Males must be willing to abstain 
from heterosexual activity or to use 2 forms of effective 
contraception from the time of informed consent until 90 
days after treatment discontinuation. 
 
14. As determined by the enrolling physician or protocol 
designee, ability of the subject to understand and comply 
with study procedures for the entire length of the study 
 
15. All subjects must have adequate archival tissue available 
prior to registration (i.e., at least 15 unstained slides or 
paraffin block). Archival tissue should represent invasive 
or metastatic urothelial cancer with a preference for 
metastatic tissue if available. Archival tissue should be 
identified at screening and shipped by C1D1. Subjects 
without adequate tissue may be considered on a case by 
case basis after discussion with the sponsor-investigator.  
 
Exclusion Criteria 
 
1. Active infection requiring systemic therapy. 
 
2. Pregnant or breastfeeding 


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3. Known additional malignancy that is active and/or 
progressive requiring treatment; subjects with other 
malignancies that have been definitively treated and who 
have been rendered disease free will be eligible. 
 
4. Prior treatment with a PARP inhibitor, including olaparib. 
 
5. Treatment with any investigational drug within 30 days 
prior to registration.  
 
6. Involvement in the planning and/or conduct of the study 
(applies to both AstraZeneca staff and/or staff at the study 
site). 
 
7. Resting ECG with QTc > 470 msec on 2 or more time 
points within a 24 hour period or family history of long 
QT syndrome. 
 
8. Concomitant use of known strong CYP3A inhibitors (eg. 
itraconazole, telithromycin, clarithromycin, protease 
inhibitors boosted with ritonavir or cobicistat, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate 
CYP3A inhibitors (eg. ciprofloxacin, erythromycin, 
diltiazem, fluconazole, verapamil). The required washout 
period prior to starting olaparib is 2 weeks. 
 
9. Concomitant use of known strong (eg. phenobarbital, 
enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, 
carbamazepine, nevirapine and St John’s Wort) or 
moderate CYP3A inducers (eg. bosentan, efavirenz, 
modafinil). The required washout period prior to starting 
olaparib is 5 weeks for enzalutamide or phenobarbital and 
3 weeks for other agents. 
 
10. Subjects with myelodysplastic syndrome/acute myeloid 
leukemia or with features suggestive of MDS/AML. 
 
11. Major surgery within 2 weeks of starting study treatment 
and subjects must have recovered from any effects of any 
major surgery. 
 
12. Subjects considered a poor medical risk due to a serious, 
uncontrolled medical disorder, non-malignant systemic 
disease or active, uncontrolled infection.  Examples 
include, but are not limited to, uncontrolled ventricular 


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arrhythmia, recent (within 3 months) myocardial 
infarction, uncontrolled major seizure disorder, unstable 
spinal cord compression, superior vena cava syndrome, 
extensive interstitial bilateral lung disease on High 
Resolution Computed Tomography (HRCT) scan, history 
of pneumonitis, or any psychiatric disorder that prohibits 
obtaining informed consent. 
 
13. Subjects unable to swallow orally administered 
medication and subjects with gastrointestinal disorders 
likely to interfere with absorption of the study medication. 
 
14. Immunocompromised subjects, e.g., subjects who are 
known to be serologically positive for human 
immunodeficiency virus (HIV). 
 
15. Subjects with a known hypersensitivity to olaparib or any 
of the excipients of the product. 
 
16. Subjects with known active hepatitis (i.e. Hepatitis B or 
C) due to risk of transmitting the infection through blood 
or other body fluids. 
 
17. Previous allogeneic bone marrow transplant or double 
umbilical cord blood transplantation (dUCBT). 
 
TOTAL  
NUMBER OF 
SUBJECTS/ SITES 
N = 30  
Utilizing sites within Hoosier Cancer Research Network 
ESTIMATED 
ENROLLMENT 
PERIOD 
Estimated 36 months 
ESTIMATED 
STUDY DURATION  
Estimated 48 months 
 
 


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TABLE OF CONTENTS 
 
Schema ............................................................................................................................. 10 
1. 
Background and Rationale ................................................................................... 11 
2. 
Study Objectives and Endpoints........................................................................... 24 
3. 
Eligibility Criteria .................................................................................................. 25 
4. 
Subject Registration............................................................................................... 29 
5. 
Treatment Plan....................................................................................................... 29 
6. 
Toxicities and Dose Delays/Dose Modifications .................................................. 32 
7. 
Study Calendar & Evaluations ............................................................................. 38 
8. 
Biospecimen Studies and Procedures ................................................................... 41 
9. 
Criteria for Disease Evaluation ............................................................................ 42 
10 
Drug Information ................................................................................................... 47 
11 
Adverse Events ....................................................................................................... 48 
12 
Statistical Methods ................................................................................................. 53 
13 
Trial Management ................................................................................................. 54 
14. Data Handling and Record Keeping .................................................................... 56 
15 
Ethics ....................................................................................................................... 57 
16 
References ............................................................................................................... 58 
 
 
 
 
 


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SCHEMA 
 
 
 
 
*The starting dose of olaparib will be 300 mg PO BID. Subjects with a calculated creatinine 
clearance of > 30 to < 40 mL/min will start at a dose of olaparib tablets 200 mg twice a day. 
 
 
 
Informed Consent
Eligibility
Registration
Olaparib 300 mg tablet PO BID*
Cycle = 28 days
Imaging
Tumor imaging ~ every 8 weeks for the first 12 months following cycle 1 day 1. After 12 
months, tumor assessments will be performed ~ every 12 weeks.
Correlative Studies
Archival tumor tissue at registration
Tissue at progression if subject undergoing standard of care biopsy
Peripheral blood pre-dose C1D1, C3D1, C5D1, and at progression and/or end of treatment
Continue olaparib until disease progression, 
toxicity, or patient or site investigator choice


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1. 
BACKGROUND AND RATIONALE 
 
1.1 
Disease Background 
Each year in the United States, an estimated 77,000 adults are diagnosed with urothelial cancer 
of the bladder and approximately 16,400 patients succumb to the disease.1 Urothelial cancer of 
the bladder is the fourth most common cancer diagnosed in men in the United States. While the 
majority of patients with urothelial cancer of the bladder present with clinically localized disease, 
approximately 30% of patients present with muscle-invasive disease which has a high propensity 
for metastatic spread despite local therapy with curative intent. Furthermore, approximately 5% 
of patients harbor metastatic disease at the time of diagnosis.  
 
1.2 
Current Standard of Care 
While metastatic urothelial cancer is a relatively chemotherapy sensitive neoplasm with response 
rates to first-line platinum-based chemotherapy of approximately 40-60%, responses are 
generally short-lived and the median progression free survival is only 8-9 months.2 In 2016, the 
PD-L1 inhibitor atezolizumab became the first treatment approved by the United States Food and 
Drug Administration for patients with platinum-resistant metastatic urothelial cancer.3 However, 
durable responses to single-agent PD-1/PD-L1 blockade are only achieved in a small minority of 
patients with metastatic urothelial cancer (approximately 15-20% of patients) highlighting the 
critical need for the development of additional novel therapeutic strategies.3–6 
 
1.3 
DNA Damage Response Gene Alterations in Urothelial Cancer 
High throughput comprehensive genomic analyses of solid tumors, including urothelial cancer, 
have uncovered recurrent somatic alterations providing clues to disease pathogenesis and 
identifying potential therapeutic targets. Indeed, analysis of data from 389 urothelial cancer 
specimens from The Cancer Genome Atlas7 reveals deleterious (nonsense, frameshift, splice site, 
or hotspot point mutations) alterations in DNA damage response genes (DDR) in ~28% of 
specimens (Figure 1). At  least four studies have now demonstrated the potential clinical 
relevance of DDR alterations in urothelial cancer.8–11 In an analysis of a cohort of 50 patients 
with muscle-invasive bladder cancer (25 patients achieving a pathologic complete response and 
25 patients not achieving a pathologic complete response with neoadjuvant cisplatin-based 
chemotherapy), Van Allen and colleagues performed whole exome sequencing on the initial 
transurethral resection of bladder tumor (TURBT) specimens and demonstrated that the presence 
of mutations in ERCC2 were found exclusively in the patients achieving a pathologic complete 
response.9 ERCC2 encodes a nucleotide excision repair protein which is critical for repair of 
DNA damage resulting from platinum-based chemotherapy. The correlation between ERCC2 
mutations and pathologic complete response to platinum-based chemotherapy was subsequently 
validated in an independent cohort.10 Plimack et al performed targeted exome sequencing on a 
cohort of patients with muscle-invasive bladder cancer treated with dose-dense MVAC 
(methotrexate, vinblastine, doxorubicin, cisplatin) chemotherapy.11 These investigators 
demonstrated that alterations in one or more of three DDR genes (ATM, RB1, and FANCC) 
predicted pathologic complete response (p<0.001, 87% sensitivity, 100% specificity) and better 
overall survival (p=0.007). Iyer and colleagues performed targeted exome sequencing on a 
cohort of patients with muscle-invasive bladder cancer treated on a phase 2 trial of neoadjuvant 
dose-dense gemcitabine plus cisplatin.8 Mutations in a set of 29 DDR genes were correlated with 
a higher probability of achieving pathologic complete response.  Deleterious DDR gene 


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mutations were associated with achieving a pathologic complete response with 92% specificity 
and a positive predictive value of 88%. Such mutations were present in 26% of patients and 
included mutations in ERCC2, ERCC5, BRCA2, RAD51C, ATR, CHEK2, and RECQL4. 
Together, these data indicate that (a) deleterious DDR alterations are common in urothelial 
cancer and (b) DDR alterations may be relevant to selection of therapies in the clinic. Additional 
approaches to exploit these vulnerabilities in a “targeted” fashion are needed.  
 
 
 
Figure 1. Deleterious DNA Damage Response Gene Alterations in TCGA Urothelial Cancer Dataset 
 
 
 


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1.4 
Targeting Poly ADP Ribose Polymerase (PARP) in DDR mutant Tumors 
 
 
 
Figure 2. DNA repair by PARP1 and the effects of PARP inhibitors (from Pommier et al, Science 
Translational Medicine, 2016) 
 
PARP1 plays multiple key roles in the repair of DNA damage including single strand breaks 
(SSB), double strand breaks (DSB), and replication fork damage.12 The role for PARP inhibition 
as monotherapy is based on the concept of synthetic lethality where neither PARP inhibition 
alone nor DDR mutations alone are lethal but the combination results in lethal cellular damage. 
This concept was initially based on the hypothesis that unrepaired SSBs resulting from PARP 
inhibition would be converted into more genotoxic single-ended DSBs (DSEs) in replicating 
cells. These DSEs could theoretically be repaired effectively in normal cells with functional 
homologous recombination repair. However, cells with DDR mutations, such as homologous 
recombination repair deficiencies, would only have low-fidelity repair pathways intact leading to 
increase in genomic instability and tumor-specific cell death.  
 
Emerging evidence suggests that the mechanistic basis for synthetic lethality with PARP 
inhibition is likely more complex and PARP trapping may play a critical role.13 The concept of 
PARP trapping was invoked to explain why the cytotoxicity of PARP inhibition was greater than 
that of genetic loss of PARP1 in model systems and why the cytotoxic activity of PARP 
inhibitors was abrogated by genetically removing PARP1. PARP trapping was demonstrating by 
detecting PARP-DNA complexes in cells treated with PARP inhibitors. PARP1 and PARP2 are 
effectively trapped on DNA until the inhibitor dissociates from the active site. PARP trapping is 
markedly more deleterious than persistent SSBs. While the basis for the cytotoxicity of PARP 
inhibition is not fully elucidated, one possibility is that ongoing replication forks collide with 


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trapped PARP-DNA complexes leading to stalled replication forks which generate DSEs also 
known as “replication fork collapse”.  
 
1.5 
Olaparib  
Olaparib (AZD2281, KU-0059436) is a potent PARP inhibitor (PARP-1, -2 and -3) that is being 
developed as an oral therapy, both as a monotherapy (including maintenance) and for 
combination with chemotherapy and other anti-cancer agents. 
 
Tumors with HR deficiencies (HRD), such as ovarian cancers in patients with BRCA1/2 
mutations, cannot accurately repair the DNA damage, which may become lethal to cells as it 
accumulates.  In such tumor types, olaparib may offer a potentially efficacious and less toxic 
cancer treatment compared with currently available chemotherapy regimens. Indeed, BRCA1 
and BRCA2 defective tumors are intrinsically sensitive to PARP inhibitors, both in tumor 
models in vivo and in the clinic.14–16 The mechanism of action for olaparib results from the 
trapping of inactive PARP onto the single-strand breaks preventing their repair as described in 
Section 1.4.13,17 Olaparib has been shown to inhibit selected tumor cell lines in vitro and in 
xenograft and primary explant models as well as in genetic BRCA knock-out models, either as a 
stand-alone treatment or in combination with established chemotherapies. 
 
The capsule formulation of olaparib was approved in December 2014 by the European 
Commission (EC) and United States (US) Food and Drug Administration (FDA), as follows:  
 
EU indication: Lynparza is indicated as monotherapy for the maintenance treatment of adult 
patients with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic) high grade 
serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response 
(complete response or partial response) to platinum-based chemotherapy.  
 
US indication: Lynparza is indicated as monotherapy in patients with deleterious or suspected 
deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian 
cancer who have been treated with three or more prior lines of chemotherapy.  
 
1.5.1 Pre-clinical experience 
The pre-clinical experience is fully described in the current version of the olaparib Investigator’s 
Brochure (IB).    
 
1.5.2 Toxicology and safety pharmacology summary 
The toxicology and safety pharmacology is fully described in the current version of the olaparib 
Investigator’s Brochure (IB).    
 
1.5.3 Clinical experience 
The olaparib capsule formulation was registered for use in the EU and US in December 2014. 
The recommended olaparib monotherapy capsule dose is 400 mg bid. As of 15 June 2016, >5670 
patients with ovarian, breast, pancreatic, gastric and a variety of other solid tumors are estimated 
to have received treatment with olaparib in clinical studies as either monotherapy or in 
combination with other chemotherapy/anti-cancer agents. The Phase III registration studies and 


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most new clinical studies are investigating the tablet formulation which delivers the therapeutic 
dose of olaparib in fewer dose units than the capsule.  
 
The clinical experience with olaparib is fully described in the current version of the olaparib 
Investigator’s Brochure. A large number of clinical studies with olaparib to date have explored 
the efficacy of olaparib in patients with germline mutations in BRCA. Particularly relevant to the 
current study is the experience with olaparib in patients with prostate cancer harboring germline 
and/or somatic DDR alterations. The TOPARP study enrolled 50 patients with castration-
resistant metastatic prostate cancer.18 Targeted next-generation sequencing, exome and 
transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples 
from mandated tumor biopsies. Sixteen of 49 patients who could be evaluated achieved a 
response (33%; 95% CI 20-48). Next-generation sequencing identified homozygous deletions, 
deleterious mutations, or both, in DDR genes (including BRCA1/2, ATM, Fanconi’s anemia 
genes, and CHEK2) in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 
(88%) achieved a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic 
somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations.  
 
1.5.4 Safety  
This section lists those adverse events and laboratory abnormalities that are currently regarded as 
expected. A full description of the emerging safety profile for olaparib, with guidance for 
investigators, is provided in Section 6.  
 
Administration of olaparib monotherapy has been associated with reports of the following 
laboratory findings and/or clinical diagnoses, generally of mild or moderate severity (CTCAE 
Grade 1 or 2) and generally not requiring treatment discontinuation.  
 
Adverse Drug Reactions reported in Clinical Trials 
 
MedDRA SOC 
MedDRA Term 
CIOMS descriptor/ 
Overall Frequency  
(All CTCAE 
grades) 
Frequency of 
CTCAE 
Grade 3 and 
above 
Blood and 
Anemiaa 
Very common 
Very common 
lymphatic system 
disorders 
Neutropeniaa 
Common 
Common 
 
Thrombocytopeniaa 
Common 
Common 
 
Leukopeniaa 
Common 
Common 
 
Lymphopeniaa 
Uncommon 
Uncommon 
Immune system 
Rasha 
Common 
- 
disorders 
Hypersensitivitya 
Uncommon 
- 
 
Dermatitisa 
Uncommon 
- 
Metabolism and 
nutrition disorders 
Decreased appetite 
Very common 
Uncommon 


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Nervous system 
Dizziness 
Very common 
Uncommon 
disorders 
Headache 
Very common 
Uncommon 
 
Dysgeusia 
Very common 
- 
Gastrointestinal 
Vomiting 
Very common 
Common 
disorders 
Diarrhea 
Very common 
Common 
 
Nausea 
Very common 
Common 
 
Dyspepsia 
Very common 
- 
 
Stomatitis 
Common 
Uncommon 
 
Upper abdominal pain 
Common 
Uncommon 
General disorders 
Fatigue (including 
asthenia) 
Very common 
Common 
Investigations 
Increase in creatinine 
Common 
Uncommon 
 
Mean corpuscular volume 
elevation 
Uncommon 
- 
a Anemia includes PTs of anemia, hemoglobin decreased, red blood cell count decreased, and 
hematocrit decreased; Neutropenia includes PTs of neutropenia, granulocytopenia, granulocyte 
count decreased and neutrophil count decreased, febrile neutropenia and neutropenic sepsis; 
Thrombocytopenia includes PTs of thrombocytopenia, platelet count decreased and plateletcrit 
decreased; Leukopenia includes PTs of leukopenia and white blood cell count decreased; Rash 
includes PTs of rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, 
rash papular, rash pruritic, exfoliative rash and generalized erythema; Hypersensitivity includes 
PTs of hypersensitivity and drug hypersensitivity; Dermatitis includes PTs of dermatitis, 
dermatitis allergic and dermatitis 
 
CIOMS Council for International Organizations of Medical Sciences; CTCAE Common 
Terminology Criteria for Adverse Events v.3.0; MedDRA Medical Dictionary for Regulatory 
Activities; SOC System organ class. 
 
The safety profile of olaparib is further highlighted by the SOLO-2 trial which randomized 
patients with platinum-sensitive ovarian cancer received olaparib 300 mg tablets BID versus 
placebo.  
 
Adverse Reactions in SOLO-2 trial (≥20% of Patients who received Olaparib) 
Adverse Reactions 
Olaparib tablets (n=195)
Placebo (n=99)
Grade 1-4 
%
Grade 3-4 
%
Grades 1-4 
% 
Grades 2-4 
%
Blood and lymphatic disorders 
Anemia 
44
20
9
2
Gastrointestinal disorders 
Nausea 
76
3
33 
0
Vomiting 
37
3
19 
1
Diarrhea 
33
2
22 
0


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Stomatitis 
20
1
16 
0
Infections and Infestations 
Nasopharyngitis/URI/sinusitis/ 
rhinitis/influenza 
36 
0 
29 
0 
General disorders and 
administration site conditions 
 
 
 
 
Fatigue including asthenia 
66
4
39 
2
Metabolism and nutrition 
disorders 
22 
0 
11 
0 
Musculoskeletal and connective 
tissue disorder 
30 
0 
28 
0 
Nervous system disorders 
Dysgeusia 
27
0
7
0
Headache 
26
1
14 
0
 
Laboratory abnormalities in SOLO-2 trial (≥25% of Patients who received Olaparib) 
Adverse Reactions 
Olaparib tablets (n=195)
Placebo (n=99)
Grade 1-4 
%
Grade 3-4 
%
Grades 1-4 
% 
Grades 2-4 
%
Increase in mean corpuscular 
volume 
89 
- 
52 
- 
Decrease in hemoglobin 
83
17
69 
0
Decrease in leukocytes 
69
5
48 
1
Decrease in lymphocytes 
67
11
37 
1
Decrease in absolute neutrophil 
count 
51 
7 
34 
1 
Increase in serum creatinine 
44
0
29 
0
Decrease in platelets 
42
2
22 
1
 
1.5.5 Summary of Risks 
As of 15 June 2016, approximately 5670 patients with ovarian, breast, pancreatic, gastric and a 
variety of other solid tumors are estimated to have received treatment with olaparib in 
AstraZeneca-sponsored, investigator-sponsored, collaborative group studies and a Managed 
Access Program. Olaparib has been given as either monotherapy (an estimated 3624 patients) or 
in combination with other chemotherapy/anti-cancer agents (an estimated 2046 patients). An 
estimated 2343 patients to date have received the capsule formulation of olaparib. Since 
2012/2013, most new clinical studies have utilized the tablet formulation which was designed to 
deliver the therapeutic dose of olaparib in fewer dose units than the capsule. An estimated 3300 
patients to date have received the tablet formulation and 27 patients have received both 
formulations of olaparib. Approximately 1500 patients have received comparator or placebo 
across the olaparib development program. 
 
From the available data to date, there is no evidence of any unexpected toxicity following long-
term olaparib (capsule) monotherapy exposure. An analysis of data from 12 AstraZeneca-
sponsored capsule monotherapy studies (D0810C00001, D0810C00002, D0810C00007, 
D0810C00008, D0810C00009, D0810C00012, D0810C00019, D0810C00020, D0810C00024 
[capsule data], D0810C00042, D9010C0008 and D081AC00001) in 766 patients with ovarian 
cancer (398/766 [52%]) and other non-ovarian solid tumors ( 368/766 [48%]) who received 


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olaparib capsule at a range of doses, estimated that 18.3% (140/766) of patients had been 
exposed to olaparib (capsule) for >12 months, 9.4% (72/766) for >18 months, 5.4% for >24 
months, 3.3% for >36 months and 2.6% for >48 months (as of 08 August 2016). Eighteen 
patients (2.3%) had received ≥60 months of olaparib exposure. 
 
An estimated 360 patients (all on tablet) have also received olaparib from 11 investigator-
sponsored monotherapy studies/collaborative group studies. 
 
1.5.6 Serious adverse events 
A review of the AstraZeneca Patient Safety database (which includes AstraZeneca-sponsored, 
investigator-sponsored/collaborative group monotherapy studies and Managed Access Program 
reports) as of 15 June 2016 identified a total of 1413 SAEs (1093 unblinded, 320 blinded) 
received from 752 patients in olaparib monotherapy studies. SAE reports of ≥1% (≥36 patients 
treated with olaparib/placebo monotherapy) were anemia (n=143), abdominal pain (n=40), 
vomiting (n=47), nausea (n=42) and dyspnea (n=41). The most commonly reported SAEs from 
these monotherapy studies were similar for the tablet and capsule formulation. 
 
1.5.7 Other adverse events of interest 
Myelodysplastic syndrome/acute myeloid leukemia events 
As of 15 June 2016, 23 reports of MDS and/or AML have been received out of a total of 5670 
patients estimated to have received olaparib in the clinical study program, giving an estimated 
cumulative incidence of 0.41% for MDS/AML. Six additional reports of MDS/AML from 6 
patients have been received from 2 blinded studies (D0816C00002 and D0818C00001) in which 
the treatment of the 6 patients (olaparib or placebo) is unknown. If these patients are considered 
to have been on olaparib treatment, the estimated incidence would be 0.51%. 
 
MDS was also reported for 2 patients who were known to have received placebo or comparator 
in the olaparib trial program (1 patient received placebo in Study D0810C00019 and 1 patient 
received liposomal doxorubicin in Study D0810C00012). Of the 23 olaparib-treated patients and 
6 patients on blinded treatment, the MDS/AML events have been reported in patients receiving a 
range of doses from both monotherapy and combination studies and for a variety of tumor types; 
ovarian, peritoneal or fallopian tube cancer (n= 26), breast cancer (n=1) and pancreatic cancer 
(n=2). Twenty-one of the 29 patients died: in 12 of these patients, MDS/AML or myelodysplasia 
was recorded as either a primary or secondary cause of death. The other 9 deaths were reported 
as follows: 1 due to cerebral hemorrhage and disseminated intravascular coagulation, 1 due to 
complication of bone marrow transplant, 1 due to hemothorax and 6 due to disease progression 
(4 ovarian cancer, 1 breast cancer [patient had a prior history of ovarian cancer treated with 
platinum-based chemotherapy] and 1 pancreatic cancer). In 16 patients, the event of MDS/AML 
is reported as not recovered (including patients that died of other causes). In 1 patient, the 
outcome was unknown. 
 
Of the 23 olaparib-treated and 6 blinded treatment patients subsequently diagnosed with 
MDS/AML, the diagnosis occurred while receiving study treatment or within 60 days after study 
treatment discontinuation in 12 patients, more than 60 days and <120 days after study treatment 
discontinuation in 2 patients, more than 120 days and <240 days after study treatment 
discontinuation in 2 patients, and more than 240 days after study treatment discontinuation in 4 


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patients. Time to onset of MDS/AML was not reported in 9 patients. The duration of therapy 
with olaparib/blinded treatment in patients with MDS/AML reported was <6 months in 16 
patients, 6 to 12 months in 4 patients, 12 to 18 months in 1 patient, 18 to 24 months in 1 patient, 
and >2 years in 5 patients. Duration of therapy with olaparib/blinded treatment was not reported 
in 2 patients. All patients had other potential features that may be contributing factors for the 
development of MDS/AML. All patients had received previous chemotherapy with DNA 
damaging agents including platinum, with many patients having extensive previous 
chemotherapy with multiple treatment regimens over multiple years including carboplatin, 
taxanes, anthracyclines, other alkylating and DNA damaging agents and radiotherapy. Twenty-
four patients had a documented gBRCA mutation of whom 2 patients were known to be gBRCA 
wild type. In 5 patients, the BRCA mutation status was unknown. While information from bone 
marrow examination is not available for all reports, in 12 cases cytogenetic abnormalities typical 
of therapy–related MDS (abnormalities of chromosomes 5 and 7 and complex karyotypes) were 
reported. 
 
Therapy-related AML (t-AML) is a rare and fatal complication of cytotoxic chemotherapy, 
which is often preceded by the development of secondary MDS. MDS is poorly captured in 
cancer registration, as it is not always considered to be a cancer so it is difficult to quantify 
background incidence rates from large, population based registries, including Surveillance, 
Epidemiology, and End Results (SEER).19–22 Furthermore, changing International Classification 
of Diseases coding conventions and definitions of primary and secondary MDS, under-diagnosis 
and under reporting to registries are likely an underestimation of the true incidence as incidence 
rates based on cancer registries may be 2 to 3 times lower than the actual incidence rate.21 
 
A recent study investigated the incidence and risk of developing t-AML in 426,068 adults 
initially treated with chemotherapy for a first primary malignancy between 1975 and 2008. The 
study identified 801 tAML cases; this was 4.70-times more than expected in the general 
population (p<0.001).23 In an earlier study, using the US SEER database, 109 AML cases were 
identified among 63,359 epithelial ovarian cancer cases, with an overall incidence of 0.17%.24 
The median time to onset of t-AML from ovarian cancer diagnosis is reported as approximately 
5.5 years.24 The overall standardized incidence ratio (8.68 overall) varies over time - 12.07 
within 1 to 5 years, 10.81 within 5 to 10 years and 2.30 after 10 years.23 
 
There is some evidence that the risk of MDS/AML may be increased in patients with BRCA 
mutation25,26, but published data are not available to quantify this risk in BRCA mutated ovarian 
cancer due to the rarity of the event coupled with the small population of interest, and lack of 
routine BRCA mutation screening. The development of t-AML in recurrent ovarian cancer has 
been linked with the use of DNA-damaging therapies, specifically pelvic radiation, alkylating 
agents and platinum chemotherapies. 23,27–29 The risk of developing t-AML (and secondary 
MDS) is associated with the cumulative dose and duration of treatment. Travis et al reported an 
increasing relative risk after platinum therapy rising from 1.9 to 7.6 with doses <500 g to >1000 
mg, and from 1.2 to 7.0 with treatment duration rising from <6 months to >12 months.29 Morton 
et al reported a reduction of risk in the period 1975 to 1983, due to a shift in treatment from 
pelvic irradiation and melphalan to platinums, while in the period 1983 to 2008, over which time 
treatments shifted from cisplatin to carboplatin and taxanes were introduced, the excess risk has 
remained approximately stable.23 In order to minimize the potential risk for MDS/AML, 


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additional safety measures have been incorporated into the Phase III program: specified 
hematological values are required before inclusion into the studies and regular monitoring is 
continued while on treatment to detect hematological abnormalities early. In case of prolonged 
cytopenias, patients are to be referred to a hematologist and bone marrow analysis should be 
considered. If a diagnosis of MDS/AML is confirmed, study treatment must be discontinued and 
the event, treatment, course and outcome must be reported as an SAE.  
 
Evidence from across the development program for olaparib does not support a conclusion that 
there is a causal relationship between olaparib and MDS/AML. All patients had other potential 
features that may be contributing factors for the development of MDS/AML. This important 
potential risk for olaparib is being kept under close surveillance. 
 
New primary malignancies 
As of 15 June 2016, 23 patients (reporting 25 events) out of a total of 5670 patients estimated to 
have received olaparib in the clinical program have reported a new primary malignancy (other 
than MDS/AML), giving a cumulative incidence of 0.41% for new primary malignancies. Eleven 
additional reports of New Primary Malignancies (NPM) have been received from 4 blinded 
studies in which the treatment of the patient (olaparib or placebo) is unknown. If these patients 
were considered to have been on olaparib treatment, the estimated incidence would be 0.60%. 
 
One event (bladder cancer) has been reported in the placebo arm of the double-blind Study 
D0810C00019 (1/128 [0.78%]). 
 
The new primary malignancies were reported in patients receiving a range of doses from both 
monotherapy and combination studies and for a variety of tumor types, ovarian (n=24), breast 
(n=3), and one each of the following: pancreas, chronic lymphocytic leukemia, biliary tract, 
colorectal cancer, gastric cancer, lung cancer and prostate cancer. 
 
The types of new primary malignancies reported in these 34 patients (36 events) were breast 
cancer (11), basal cell carcinoma (6), squamous cell carcinoma (2), skin cancers (2), gastric 
cancer (2), lung cancer (2) and one each of: colon cancer, plasma cell myeloma, malignant 
melanoma, malignant muscle neoplasm, precursor T lymphoblastic lymphoma/leukemia, tongue 
cancer, papillary thyroid carcinoma, rectal cancer, ovarian cancer, chronic myelomonocyctic 
leukemia and bladder transitional cell carcinoma. 
 
Four spontaneous events of new primary malignancy have been received from 3 patients in the 
post marketing setting. The patients concerned were reported to have developed: peritoneal 
neoplasm in 1 patient, pancreatic cancer in 1 patient and 1 patient with gastric and renal cancers.  
 
Eleven of the 25 events of new primary malignancies reported by 10 olaparib-treated patients 
were skin cancers (2 SAEs, 9 AEs). Ten of these were the most common forms of non-melanoma 
skin cancer; basal cell carcinoma (n=6), squamous cell carcinoma (n=2), skin cancer (n=1) and 
skin neoplasm (n=1). One event of malignant melanoma was reported for a patient treated for 
chronic lymphocytic leukemia in an investigator-sponsored study. This patient had previously 
presented with a pigmented skin lesion 12 months prior to starting olaparib treatment. The lesion 
increased in size while on study treatment but the investigator did not consider it causally related 


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to olaparib treatment. Following surgery, the melanoma was removed and the event was reported 
as recovered by the investigator. The skin cancers recovered in the majority of patients. 
 
Of the 34 patients (23 on olaparib, 11 on blinded treatment) subsequently diagnosed with a new 
primary malignancy, the majority of events were reported whilst on olaparib treatment. In 4 
patients, the new primary malignancy was reported after the follow-up period of the study (>1 
year, 68 days, 49 days and 34 days and respectively from stopping olaparib treatment). The time 
from start of olaparib treatment to the onset of the 36 events was <6 months for 7 patients, 6 to 
12 months for 12 patients, 12 to 18 months for 2 patients, 18 to 24 months for 6 patients and >2 
years for 9 patients. 
 
There were other contributing factors/potential alternative explanations for the development of 
the new primary malignancy in all of the 23 olaparib-treated patients and the 11 on blinded 
treatment. All patients had already previously received various chemotherapy agents including 
multiple cycles of DNA damaging platinum containing chemotherapies, taxanes, anthracyclines 
and other alkylating and DNA damaging agents. Four patients were reported to have had prior 
radiotherapy. Twenty-five patients had a documented breast cancer gene mutation (BRCA 1 or 
2). Seven patients had previous medical histories of cancer (ovarian, cervix, breast, peritoneal) 
prior to the cancer under investigation in the olaparib studies, and 3 patients with skin cancers 
had either had previous basal cell carcinoma reported or had skin lesions evident prior to study 
treatment. 
 
There is insufficient evidence for an association between olaparib treatment and the development 
of new primary malignancies in the clinical study program to date. The types of new primary 
cancers reported were generally in line with secondary cancers observed in ovarian and breast 
cancer populations reported in the literature or were cancers such as, skin cancers known to be 
the most common cancer in the general population and associated with high cure rates.30,31 
Patients with gBRCA mutations are at risk of developing other primary cancers notably breast 
cancer. Ginsburg et al 2010 reported higher rates of skin cancers in patients with BRCA1 (1.6%) 
and BRCA2 (3.0%) mutations.32 All patients had other contributory factors that offer alternative 
explanations for the development of the secondary primary tumor including documented BRCA 
mutation, treatment with radiotherapy and extensive previous chemotherapy including 
carboplatin, taxanes, anthracyclines and other alkylating and DNA damaging agents. This safety 
topic is an important potential risk for olaparib and is being kept under close surveillance. The 
ongoing placebo-controlled Phase III studies will be important in providing additional 
information. 
 
Pneumonitis events 
As of 15 June 2016, pneumonitis has been reported in 22 olaparib-treated patients out of a total 
of 5670 patients estimated to have received olaparib in the clinical study program, giving an 
estimated cumulative incidence of 0.39%. Eleven additional reports of pneumonitis have been 
received from 4 blinded studies, where the treatment of the patients is unknown (7 either olaparib 
or placebo [D0816C00002 or D0818C00001]; 2 either olaparib + paclitaxel or placebo + 
paclitaxel [D081BC00004] and 2 olaparib + abiraterone or placebo + abiraterone 
[D081DC00008]). If these patients were considered to have been on olaparib treatment, the 
estimated cumulative incidence would be 0.58% (33/5670). 


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Pneumonitis has also been reported for 1/128 (0.78%) patient randomized to placebo in Study 
D0180C00019, 1/62 (1.61%) patient randomized to placebo + paclitaxel in a double-blind study 
in recurrent or metastatic gastric cancer (Study D0810C00039) and 1/262 (0.38%) patient 
randomized to placebo + paclitaxel in a double-blind, phase III study in advanced gastric cancer 
(Study D081BC00004). 
 
The reports of pneumonitis were from patients receiving olaparib at a range of doses, given 
either as monotherapy or in combination with the other chemotherapy treatments. The diagnosis 
of pneumonitis was made while on treatment or within a 60-day follow-up period for all patients. 
The patients were treated with olaparib for ovarian cancer (n=14), breast cancer (n=4), NSCLC 
or small cell lung cancer (SCLC; n=7), pancreatic cancer (n=1), gastric cancer (n=4), prostate 
cancer (n=2) and thymic cancer (n=1). 
 
Four of the 33 patients died due to pneumonitis (2 of these patients who were receiving olaparib 
in combination with liposomal doxorubicin [Study D0810L00001] and the cause of death also 
included pulmonary insufficiency); in 1 patient receiving olaparib and radiotherapy, the cause of 
death included bronchopulmonary hemorrhage. An additional 7 patients subsequently died. In 5 
patients, the pneumonitis was ongoing at the time of death due to disease progression (n=4) and 
at the time of euthanasia (n=1). Two patients had recovered from the pneumonitis but then 
subsequently died due to disease progression (1 patient with gastric cancer and 1 patient with 
ovarian cancer). 
 
The reports of pneumonitis presented with no consistent clinical pattern and were heavily 
confounded by a number of pre-disposing factors (including disease under investigation, 
underlying pulmonary disease, pre-existing medical conditions, smoking history and/or previous 
chemotherapy and radiotherapy). The majority of patients had received prior radiotherapy and/or 
chemotherapy and had other risk factors within the medical histories including pneumonitis, 
interstitial lung fibrosis, dyspnea, hemoptysis, chest infection, allergic asthma, pleural effusion, 
pleural metastases, or smoking. Seven patients had current SCLC or NSCLC. An independent 
review of available chest computed tomography (CT) scans and radiographs associated with the 
reports of pneumonitis concluded that there appeared to be no clear consistent clinical pattern. 
 
The mechanisms of drug-induced pneumonitis are not well understood. Pre-clinical data do not 
show any evidence of lung induced toxicity due to a direct effect of olaparib on lung tissues. 
Patients with lung disorders including cancer (lung and breast), lung metastases, medical history 
of medications/chemotherapy (including alkylating agents), radiation treatment, occupational and 
environmental factors are associated with a high risk of development of interstitial lung disease. 
 
Summary of other adverse events of interest 
MDS/AML, new primary malignancies and pneumonitis have been identified as important 
potential risks for olaparib. The cumulative incidences are consistent with that expected for the 
patient population under study according to the available literature. These events are being 
closely monitored in ongoing studies. 
 
 
 


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1.6 
Rationale 
 
1.6.1 Rationale for studying olaparib in metastatic urothelial cancer 
There are few standard therapies available for patients with metastatic urothelial cancer. While 
PD-1/PD-L1 blockade represents the first new treatment approved for metastatic urothelial 
cancer in over 30 years, only ~20% of patients with metastatic urothelial cancer respond such 
treatment. Novel approaches to treatment are urgently needed.  
 
1.6.2 Rationale for patient selection based on the presence of somatic DDR alterations 
Germline and somatic alterations in DDR genes have been associated with response to PARP 
inhibition across several malignancies establishing proof-of-concept for synthetic lethality. 
While there are likely a number of mechanisms whereby tumors acquire faulty DDR machinery 
which may be captured by means other than targeted or whole exome sequencing (e.g., gene 
expression profiling for evidence of “BRCAness” or assays for “genomic scars”), selection of 
patients with DDR mutations based on somatic exome sequencing is included in the current 
study due to (a) the increasing use of exome sequencing in CLIA laboratories as part of routine 
clinical care, (b) the correlation between DDR mutations and response to PARP inhibition in 
other solid tumors, and (c) the goal of enriching the population with those most likely to respond 
in this initial proof-of-concept study (i.e., if sufficient antitumor activity is observed, future 
studies may enroll patients without DDR mutations in hopes of expanding the biomarker profile 
associated with response).   
 
1.6.3 Potential limitations of study design and approach to address limitations 
There are several potential explanations in the event that anticancer activity is not observed with 
PARP inhibition in this study. These potential explanations, and our plans to address these 
limitations, are outlined below: 
 
Specific DDR alterations, as a result of their functional consequences, may not result in synthetic 
lethality with PARP inhibition. While urothelial cancers harbor a large number of diverse 
somatic alterations in DDR genes (Figure 1), we will enrich the population with patients 
harboring somatic alterations in BRCA1, BRCA2, and ATM as alterations in these genes have 
been associated with sensitivity to PARP inhibition in other studies such as prostate cancer. 
 
There is overlap with mechanisms of sensitivity and resistance to platinum-based chemotherapy 
such that patients progressing despite prior platinum-based chemotherapy may be uniformly 
resistant to PARP inhibition. Importantly, in studies in patients with ovarian cancer treated with 
PARP inhibition, responses have indeed correlated with platinum-sensitivity.16 However, while 
patients with platinum-sensitive ovarian cancer achieve the highest response rates with PARP 
inhibition, response rates in platinum-resistant and platinum-refractory disease are 45% and 23% 
respectively. Furthermore, cisplatin-ineligible patients will be eligible for the current study.  
 
DDR alterations present in archival primary tumor specimens are not present in metastatic sites 
relevant to a patient’s current disease state. Metastatic lesions may not harbor tumor cells with 
DDR alterations present in a patient’s archival primary tumor specimen due to an elimination of 
the DDR mutant clones with prior therapy or due to genomic evolution of the disease.33 While 


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we will not mandate metastatic biopsies prior to enrollment, we will collect peripheral blood 
specimens to facilitate retrospective assessment of circulating tumor DNA.  
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
Objectives 
 
2.1.1 Primary Objective 
• Estimate the objective response rate (per RECIST 1.1 or MD Anderson criteria for bone 
only metastases) to treatment with olaparib in subjects with metastatic urothelial cancer 
harboring somatic DDR alterations 
 
2.1.2 Secondary Objectives 
• Describe the safety of olaparib in subjects with DDR mutant metastatic urothelial cancer 
• Describe the progression-free survival of subjects with DDR mutant metastatic urothelial 
cancer treated with olaparib 
• Describe the overall survival of subjects with DDR mutant metastatic urothelial cancer 
treated with olaparib 
 
2.1.3 Correlative/Exploratory Objectives 
• Explore the relationship between specific genomic alterations with response to olaparib 
• Explore the relationship between prior platinum-based chemotherapy treatment 
(response, duration of treatment, and time since treatment) with response to olaparib 
• Explore the relationship between tumor mutational profile, circulating DNA mutational 
profile, and response to olaparib 
• Determine the feasibility of establishing patient-derived xenografts from circulating 
tumor cells collected from enrolled subjects at baseline and progression to better explore 
mechanisms of response and resistance 
 
2.2 
Endpoints 
 
2.2.1 Primary Endpoint 
• Objective response rate will include confirmed complete response (CR) + confirmed 
partial response (PR) and will be determined as per RECIST 1.1 or MD Anderson 
Criteria (for bone-only metastatic disease) 
 
2.2.2 Secondary Endpoints 
• Adverse events are defined by the NCI Common Terminology Criteria for Adverse 
Events (NCI CTCAE) v4 
• Progression-free survival is defined as the time from Day 1 of treatment until the criteria 
for disease progression is met as defined by RECIST 1.1 or death as a result of any cause.  
• Overall survival is defined as the time from Day 1 of treatment until death as a result of 
any cause 
 
 
 


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3. 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
Subject must meet all of the following applicable inclusion criteria to participate in this study: 
 
1. Written informed consent and HIPAA authorization for release of personal health 
information prior to registration. NOTE:  HIPAA authorization may be included in the 
informed consent or obtained separately. 
 
2. Age ≥ 18 years at the time of consent. 
 
3. ECOG Performance Status of ≤ 1 within 14 days prior to registration. Cisplatin-ineligible 
chemotherapy-naïve subjects (see inclusion criteria #9) may have an ECOG Performance 
Status of ≤ 2. 
 
4. Histological or cytological evidence/confirmation of urothelial cancer.   
 
5. Metastatic and/or unresectable (cT4b) urothelial cancer.  
 
6. Metastatic disease evaluable on imaging studies. Subjects may have measurable disease 
according to RECIST 1.1 or bone-only disease within 30 days prior to registration.  
 
NOTE: Bone-only subjects are eligible if their disease can be documented/evaluated by bone 
scans, CT or MRI. Their disease will be assessed using MD Anderson criteria.34  
 
NOTE: Previously irradiated lesions are eligible as a target lesion only if there is 
documented progression of the lesion after irradiation. 
 
7. Somatic alteration considered pathogenic/likely pathogenic in one of the following DDR 
genes as determined by genomic sequencing performed in a Clinical Laboratory 
Improvement Amendments (CLIA) laboratory. Somatic alterations will include nonsense, 
frameshift, splice-site or missense mutations or homozygous deletions. Subjects with 
alterations in DDR genes not included in the list below will be considered on a case by case 
basis after discussion with the sponsor-investigator(s). Subjects with germline alterations in 
DDR genes will be considered on a case by case basis and will be reviewed by the sponsor-
investigator(s). At least 6 subjects will have BRCA or ATM alterations. 
 
Nucleotide 
Excision 
Repair 
Homologous 
Recombination 
DNA 
Sensor 
Fanconi Anemia 
Pathway 
Base 
Excision 
Repair 
Other 
ERCC2 
BRCA1 
RAD52
ATM
PALB2
FANCE
XRCC2 
MUTYH
ERCC3 
BRCA2 
RAD54L
ATR
BRIP1
FANCF
XRCC3 
RECQL4
ERCC4 
RAD50 
NBN
MDC1
FANCA
FANCG
XRCC4 
POLQ
ERCC5 
RAD51 
MRE11A
ATRX
FANCB
BLM
XRCC5 
POLE
ERCC6 
RAD51B 
RAD51D 
CHEK1 
FANCC 
 
XRCC6 
WRN 
 
RAD51C 
CTIP
CHEK2
FANCD2
 
 


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8. A subject with prior brain metastasis may be considered if they have completed their 
treatment for brain metastasis at least 4 weeks prior to study registration, have been off 
corticosteroids for ≥ 2 weeks, and are asymptomatic 
 
9. Subjects must have progressed despite at least 1 prior line of treatment for metastatic and/or 
unresectable urothelial cancer. However, cisplatin-ineligible (defined by a calculated 
creatinine clearance of >30 but < 60 mL/min OR CTCAE v4 Grade ≥ 2 audiometric hearing 
loss OR CTCAE v4 Grade ≥ 2 peripheral neuropathy OR ECOG PS = 2) and chemotherapy-
naïve subjects are also eligible.  
 
10. Prior cancer treatment (systemic therapy or radiation therapy) must be completed at least 3 
weeks prior to registration and the subject must have recovered from all reversible acute 
toxic effects of the regimen (other than alopecia) to Grade ≤ 1 or baseline. 
 
11. Demonstrate adequate organ function as defined in the table below. All screening labs to be 
obtained within 28 days prior to registration. 
 
System 
Laboratory Value 
Hematological 
Absolute Neutrophil Count (ANC)
≥ 1.5 x 109/L 
Hemoglobin (Hgb) 
≥ 9 g/dL  
Platelets 
≥ 100 x 109/L
Renal 
Calculated creatinine clearance1
> 30 mL/min 
Hepatic 
Bilirubin 
≤1.5 × upper limit of normal (ULN) 
Aspartate aminotransferase (AST) 
≤2.5 × ULN (or ≤5 × ULN if liver metastases) 
Alanine aminotransferase (ALT) 
≤2.5 × ULN (or ≤5 × ULN if liver metastases) 
1 
Cockcroft-Gault formula will be used to calculate creatinine clearance (See SPM) 
 
12. Female subjects must be postmenopausal or there must be evidence of non-childbearing 
status for women of childbearing potential: negative urine or serum pregnancy test within 28 
days of study treatment and confirmed prior to treatment on Day 1. Postmenopausal is 
defined as: 
• Amenorrheic for 1 year or more following cessation of exogenous hormonal 
treatments 
• Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post-
menopausal range for women under 50 
• radiation-induced oophorectomy with last menses >1 year ago 
• chemotherapy-induced menopause with >1 year interval since last menses 
• surgical sterilization (bilateral oophorectomy or hysterectomy) 
 
13. Females of childbearing potential must be willing to abstain from heterosexual activity or to 
use 2 forms of highly effective methods of contraception from the time of informed consent 
until 90 days after treatment discontinuation. The two contraception methods can be 
comprised of two barrier methods, or a barrier method plus a hormonal method. Males must 
be willing to abstain from heterosexual activity or to use 2 forms of highly effective methods 


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of contraception from the time of informed consent until 90 days after treatment 
discontinuation. 
 
Acceptable non-hormonal birth control methods: 
• Total sexual abstinence ie, refrain from any form of sexual intercourse in line with 
the patients’ usual and/or preferred lifestyle. Periodic abstinence (eg, calendar ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
• Vasectomised sexual partner PLUS male condom. With participant assurance that 
partner received post-vasectomy confirmation of azoospermia. 
• Tubal occlusion PLUS male condom 
• Intrauterine Device PLUS male condom. Provided coils are copper-banded. 
 
Acceptable hormonal methods: 
• Etonogestrel implants (eg, Implanon®, Norplant®) PLUS male condom 
• Normal and low dose combined oral pills PLUS male condom 
• Hormonal shot or injection (eg, Depo-Provera) PLUS male condom 
• Intrauterine system device (eg, levonorgestrel-releasing intrauterine system - 
Mirena®) PLUS male condom 
 
14. As determined by the enrolling physician or protocol designee, ability of the subject to 
understand and comply with study procedures for the entire length of the study 
 
15. All subjects must have adequate archival tissue available prior to registration (i.e., at least 15 
unstained slides or paraffin block). Archival tissue should represent invasive or metastatic 
urothelial cancer with a preference for metastatic tissue if available. Archival tissue should be 
identified at screening and shipped by C1D1. Subjects without adequate tissue may be 
considered on a case by case basis after discussion with the sponsor-investigator.   
 
3.2 
Exclusion Criteria 
Subjects meeting any of the criteria below may not participate in the study: 
 
1. Active infection requiring systemic therapy. 
 
2. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the 
mother is being treated on study). 
 
3. Known additional malignancy that is active and/or progressive requiring treatment; subjects 
with other malignancies that have been definitively treated and who have been rendered 
disease free will be eligible. 
 
4. Prior treatment with a PARP inhibitor, including olaparib. 
 
5. Treatment with any investigational drug within 30 days prior to registration.  
 


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6. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site). 
 
7. Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or 
family history of long QT syndrome. 
 
8. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, 
nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, 
erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to 
starting olaparib is 2 weeks. 
 
9. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A 
inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting 
olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. 
 
10. Subjects with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive 
of MDS/AML. 
 
11. Major surgery within 2 weeks of starting study treatment and subjects must have recovered 
from any effects of any major surgery. 
 
12. Subjects considered a poor medical risk due to a serious, uncontrolled medical disorder, non-
malignant systemic disease or active, uncontrolled infection.  Examples include, but are not 
limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial 
infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior 
vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution 
Computed Tomography (HRCT) scan, history of pneumonitis, or any psychiatric disorder 
that prohibits obtaining informed consent. 
 
13. Subjects unable to swallow orally administered medication and subjects with gastrointestinal 
disorders likely to interfere with absorption of the study medication.  
 
14. Immunocompromised subjects, e.g., subjects who are known to be serologically positive for 
human immunodeficiency virus (HIV). 
 
15. Subjects with a known hypersensitivity to olaparib or any of the excipients of the product. 
 
16. Subjects with known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting the 
infection through blood or other body fluids. 
 
17. Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation 
(dUCBT). 
 
 


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4. 
SUBJECT REGISTRATION 
All subjects must be registered through HCRN’s electronic data capture (EDC) system. Subjects 
will be considered registered when an “on study” date is entered into the EDC system.  
 
Subjects must be registered prior to starting protocol therapy and begin study treatment within 7 
business days of registration.  
 
5. 
TREATMENT PLAN 
This is a single-arm open label phase II trial of olaparib in subjects with DDR mutant metastatic 
urothelial cancer. Subjects will receive olaparib, in the absence of prohibitive adverse events, 
until the time of disease progression.  
 
5.1 
Olaparib 
Olaparib tablets will be packed in high-density polyethylene (HDPE) bottles with child-resistant 
closures. Each dosing container will contain sufficient medication for at least 28 days plus 
overage. Olaparib will be dispensed to subjects on Day 1 of each cycle thereafter until the patient 
completes the study, withdraws from the study or closure of the study.   
 
Study treatment is available as a film-coated tablet containing 150 mg or 100 mg of olaparib. 
Subjects will be administered olaparib orally twice daily. Olaparib tablets should be taken at the 
same time each day, approximately 12 hours apart. The starting dose of olaparib tablets will be 
dependent on the subject’s calculated creatinine clearance (CrCl). Subjects with a CrCl of ≥ 40 
mL/min will start at a dose of olaparib tablets of 300 mg twice a day (total 600 mg per day). 
Subjects with a CrCl of > 30 to < 40 mL/min will start at a dose of olaparib tablets 200 mg twice 
a day (total 400 mg per day). 
 
Olaparib should be taken with one glass of water. The tablets should be swallowed whole and 
not chewed, crushed, dissolved, or divided. Olaparib tablets can be taken with or without food. It 
is not recommended to consume grapefruit juice or consume Seville oranges while on olaparib 
therapy. 
 
5.2 
Concomitant Medications 
 
5.2.1 Allowed Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care unless as otherwise indicated below. 
 
5.2.1.1 
Anticoagulant Therapy 
Subjects who are taking warfarin may participate in this trial; however, it is recommended that 
international normalized ratio (INR) be monitored carefully at least once per week for the first 
month, then monthly if the INR is stable. Subcutaneous heparin and low molecular weight 
heparin are permitted. 
 
5.2.1.2 
Anti-emetics/Anti-Diarrheals 
If a patient develops nausea, vomiting and/or diarrhea, these symptoms should be reported as 
AEs and should be treated per institutional guidelines. 


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5.2.1.3 
Palliative radiotherapy  
Palliative radiotherapy may be used for the treatment of pain at the site of bony metastases that 
were present at baseline, provided the site investigator does not feel that these are indicative of 
clinical disease progression during the study period.  Study treatment should be discontinued for 
a minimum of 3 days before a patient undergoes therapeutic palliative radiation treatment.  Study 
treatment should be restarted within 4 weeks as long as any bone marrow toxicity has recovered. 
 
5.2.1.4 
Contraception 
 
Olaparib is regarded as a compound with medium/high fetal risk. 
Women of childbearing potential and their partners, who are sexually active, must agree to 
the use of TWO highly effective forms of contraception in combination [as listed below], 
throughout the period of taking study treatment and for at least 90 days after last dose of 
study drug(s), or they must totally/truly abstain from any form of sexual intercourse (see 
below). 
Male subjects and their partners, who are sexually active and of childbearing potential, must 
agree to the use of TWO highly effective forms of contraception in combination [as listed 
below], throughout the period of taking study treatment and for 90 days after last dose of 
study drug(s) due to the unknown effects of the study drug on the sperm, or they must 
totally/truly abstain from any form of sexual intercourse (see below). Male subjects 
should not donate sperm throughout the period of taking study treatment and for 90 days 
following the last dose of study drug(s).  
 
Acceptable non-hormonal birth control methods: 
• Total sexual abstinence ie, refrain from any form of sexual intercourse in line with 
the patients’ usual and/or preferred lifestyle. Periodic abstinence (eg, calendar ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
• Vasectomised sexual partner PLUS male condom. With participant assurance that partner 
received post-vasectomy confirmation of azoospermia. 
• Tubal occlusion PLUS male condom 
• Intrauterine Device PLUS male condom. Provided coils are copper-banded. 
 
Acceptable hormonal methods: 
• Etonogestrel implants (eg, Implanon®, Norplant®) PLUS male condom 
• Normal and low dose combined oral pills PLUS male condom 
• Hormonal shot or injection (eg, Depo-Provera) PLUS male condom 
• Intrauterine system device (eg, levonorgestrel-releasing intrauterine system - 
Mirena®) PLUS male condom 
 
5.2.2 Prohibited Concomitant Medications 
The use of any natural/herbal products or other traditional remedies should be discouraged, but 
use of these products, as well as use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the case report form (CRF). 
 
 


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5.2.2.1 
Medications that may NOT be administered 
No other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy (Hormone 
replacement therapy (HRT) is acceptable), radiotherapy, biological therapy or other novel agent) 
is to be permitted while the patient is receiving study medication. 
 
Live virus and live bacterial vaccines should not be administered while the patient is receiving 
study medication and during the 30 day follow up period. An increased risk of infection by the 
administration of live virus and bacterial vaccines has been observed with conventional 
chemotherapy drugs and the effects with olaparib are unknown. 
 
5.2.2.2 
Restricted concomitant medications 
Subjects must not be taking strong or moderate CYP3A inhibitors or strong or moderate 
CYP3A inducers at the time of study enrollment. Subjects for whom these medications are 
being considered after subjects have already been enrolled on study should follow the 
guidance below:  
 
Strong or Moderate CYP3A inhibitors  
Known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, boosted 
protease inhibitors, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A 
inhibitors (ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) should not be taken 
with olaparib. 
 
If there is no suitable alternative concomitant medication then the dose of olaparib should be 
reduced for the period of concomitant administration. The dose reduction of olaparib should be 
recorded in the eCRF with the reason documented as concomitant CYP3A inhibitor use.  
• Strong CYP3A inhibitors – reduce the dose of olaparib to 100 mg bid for the duration of 
concomitant therapy with the strong inhibitor and for 5 half-lives afterwards. 
• Moderate CYP3A inhibitors - reduce the dose of olaparib to 150 mg bid for the duration 
of concomitant therapy with the moderate inhibitor and for 3 half-lives afterwards. 
• After the washout of the inhibitor is complete, the olaparib dose can be re-escalated. 
 
Strong or Moderate CYP3A inducers 
Strong (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide and St John’s Wort) and moderate CYP3A inducers (eg. bosentan, 
efavirenz, modafinil) of CYP3A should not be taken with olaparib. 
 
If the use of any strong or moderate CYP3A inducers are considered necessary for the patient’s 
safety and welfare this could diminish the clinical efficacy of olaparib. 
 
If a patient requires use of a strong or moderate CYP3A inducer or inhibitor then they must be 
monitored carefully for any change in efficacy of olaparib. 
 
P-gp inhibitors 
It is possible that co-administration of P-gp inhibitors (eg amiodarone, azithromycin) may 
increase exposure to olaparib. Caution should therefore be observed. 
 


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Effect of olaparib on other drugs 
Based on limited in vitro data, olaparib may increase the exposure to substrates of CYP3A4, P-
gp, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K.  Based on limited in vitro data, 
olaparib may reduce the exposure to substrates of CYP3A4, CYP1A2, 2B6, 2C9, 2C19 and P-gp.  
 
The efficacy of hormonal contraceptives may be reduced if co administered with olaparib.  
Caution should therefore be observed if substrates of these isoenzymes or transporter proteins are 
co-administered. 
 
Examples of substrates include: 
• CYP3A4 – hormonal contraceptive, simvastatin, cisapride, cyclosporine, ergot alkaloids, 
fentanyl, pimozide, sirolimus, tacrolimus and quetiapine 
• CYP1A2 – duloxetine, melatonin 
• CYP2B6 – bupropion, efavirenz 
• CYP2C9 – warfarin  
• CYP2C19 - lansoprazole, omeprazole, S-mephenytoin 
• P-gp - simvastatin, pravastatin, digoxin, dabigatran, colchicine 
• OATP1B1 - bosentan, glibenclamide, repaglinide, statins and valsartan 
• OCT1, MATE1, MATE2K – metformin 
• OCT2 - serum creatinine 
• OAT3 -furosemide, methotrexate 
 
5.2.2.3 
Administration of other anti-cancer agents 
Subjects must not receive any other concurrent anti-cancer therapy, including investigational 
agents, while on study treatment. Subjects may continue the use of bisphosphonates or 
denosumab for bone disease.  
 
6. 
TOXICITIES AND DOSE DELAYS/DOSE MODIFICATIONS 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.03 will be used to 
grade adverse events.  
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in Study 
Calendar & Evaluations. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse 
events requiring study drug interruption or discontinuation as specified in Study Calendar & 
Evaluations.   
 
6.1 
Dose Delays/Dose Modifications 
For guidance on dose reductions when concomitant strong or moderate CYP3A inhibitors or 
inducers cannot be avoided see section 5.2.2. 
 
Any toxicity observed during the course of the study could be managed by interruption of the 
dose of study treatment or dose reductions. Repeat dose interruptions are allowed as required, for 
a maximum of 4 weeks on each occasion. If the interruption is > 4 weeks, the sponsor-


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investigator should be informed. Study treatment can be dose reduced to 250 mg twice daily as a 
first step and to 200 mg twice daily as a second step. If the reduced dose of 200 mg twice daily is 
not tolerable, no further dose reduction is allowed and study treatment should be discontinued. 
There will be no dose reductions for subjects (with moderate renal insufficiency) starting at a 
dose of 200 mg twice daily.  
 
6.1.1 Dose Levels for Dose Reductions 
 
Table 1 Dose reductions for olaparib* 
Initial Dose 
Following re-challenge post 
interruption: Dose reduction 1 
Dose reduction 2 
300mg twice daily 
250mg twice daily
200mg twice daily 
*see section 6.1 for more specific guidance 
 
Once dose is reduced, escalation is not permitted except as indicated in section 5.2.2. for 
temporary dose reductions association with concomitant use of CYP3A inhibitors or inducers. 
 
6.2 
Management of Hematological Toxicity 
 
6.2.1 
Management of Anemia 
 
Table 2 Management of anemia 
Hemoglobin 
Action to be taken 
Hb < 10 but ≥ 8 g/dl 
(CTCAE Grade 2) 
Give appropriate supportive treatment and investigate causality.  
Site investigator judgement to continue olaparib with supportive treatment 
(e.g. transfusion) or interrupt dose for a maximum of 4 weeks.  
If repeat Hb < 10 but ≥ 8 g/dl, dose interrupt (for max of 4 weeks) until 
Hb ≥ 10 g/dl and upon recovery dose reduction to 250 mg twice daily as a 
first step and to 200 mg twice daily as a second step may be considered.
Hb < 8 g/dl 
(CTCAE Grade 3) 
Give appropriate supportive treatment (e.g. transfusion) and investigate 
causality. Interrupt olaparib for a maximum of 4 weeks. until improved to 
Hb ≥ 10 g/dl. Upon recovery dose reduce to 250 mg twice daily as a first 
step and to 200 mg twice daily as a second step in the case of repeat Hb 
decrease. 
 
Common treatable causes of anemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed. In some cases, management 
of anemia may require blood transfusions. For cases where subjects develop prolonged 
hematological toxicity (≥ 2 week interruption/delay in study treatment due to CTC Grade 3 or 
worse anemia and/or development of blood transfusion dependence), refer to Section 6.2.3 for 
the management of this.  
 
 
 


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6.2.2 
Management of Neutropenia, Leukopenia and Thrombocytopenia 
 
Table 3 Management of neutropenia, leukopenia and thrombocytopenia 
Toxicity 
Study treatment dose adjustment 
CTCAE Grade 1-2 
Investigator judgement to continue treatment or if dose interruption, this 
should be for a maximum of 4 weeks; appropriate supportive treatment 
and causality investigation
CTCAE Grade 3-4 
Dose interruption until recovered to CTCAE gr 1 or better for a maximum 
of 4 weeks. If repeat CTCAE grade 3-4 occurrence, dose reduce olaparib 
to 250 mg twice daily as a first step and 200 mg twice daily as a second 
step 
Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by the 
investigator with close follow up and interruption of study drug if CTC Grade 3 or worse 
neutropenia occurs. 
 
Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is not recommended, 
however, if a patient develops febrile neutropenia, study treatment should be stopped and 
appropriate management including G-CSF should be given according to local hospital 
guidelines. Please note that G-CSF should not be used within at least 24 hours (7 days for 
pegylated G-CSF) of the last dose of study treatment unless absolutely necessary. Platelet 
transfusions, if indicated, should be done according to local hospital guidelines. 
 
For cases where subjects develop prolonged hematological toxicity (≥ 2 week interruption/delay 
in study treatment due to CTC grade 3 or worse), refer to Section 6.2.3. 
 
6.2.3 
Management of Prolonged Hematological Toxicities While on Study Treatment 
If a patient develops prolonged hematological toxicity such as: 
≥ 2 week interruption/delay in study treatment due to CTC Grade 3 or worse anaemia and/or 
development of blood transfusion dependence 
≥ 2 week interruption/delay in study treatment due to CTC Grade 3 or worse neutropenia 
(ANC < 1 x 109/L) 
≥ 2 week interruption/delay in study treatment due to CTC Grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (Platelets < 50 
x 109/L) 
 
Check weekly differential blood counts including reticulocytes and peripheral blood smear. If 
any blood parameters remain clinically abnormal after 4 weeks of dose interruption, the patient 
should be referred to hematologist for further investigations. Bone marrow analysis and/or blood 
cytogenetic analysis should be considered at this stage according to standard hematological 
practice. Study treatment should be discontinued if blood counts do not recover to CTC Grade 1 
or better within 4 weeks of dose interruption. 
 
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder should be 
reported as an SAE and full reports must be provided by the site investigator to HCRN who will 
then report to AstraZeneca Patient Safety (See Section 11). Olaparib treatment should be 
discontinued if patient’s diagnosis of MDS and/or AML is confirmed. 
 


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6.3 
Management of Non-Hematological Toxicity 
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion. 
If the interruption is any longer than this the sponsor-investigator must be informed.  Where 
toxicity reoccurs following re-challenge with study treatment, and where further dose 
interruptions are considered inadequate for management of toxicity, then the patient should be 
considered for dose reduction or must permanently discontinue study treatment. 
 
Study treatment can be dose reduced to 250 mg bid as a first step and to 200 mg bid as a second 
step. Treatment must be interrupted if any NCI-CTCAE Grade 3 or 4 adverse event occurs which 
the site investigator considers to be related to administration of study treatment. 
 
6.3.1 
Management of New or Worsening Pulmonary Symptoms  
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormalities occur in 
the absence of a clear diagnosis, an interruption in study treatment dosing is recommended and 
further diagnostic workup (including a high resolution CT scan) should be performed to exclude 
pneumonitis. 
 
Following investigation, if no evidence of abnormality is observed on CT imaging and symptoms 
resolve, then study treatment can be restarted, if deemed appropriate by the site investigator. If 
significant pulmonary abnormalities are identified, these need to be discussed with the sponsor-
investigator. If pneumonitis is confirmed, discontinue olaparib.  
 
6.3.2 
Management of Nausea and Vomiting 
Events of nausea and vomiting are known to be associated with olaparib treatment. In study 
D0810C00019 nausea was reported in 71% of the olaparib treated subjects and 36% in the 
placebo treated subjects and vomiting was reported in 34% of the olaparib treated subjects and 
14% in the placebo treated patients. These events are generally mild to moderate (CTCAE grade 
1 or 2) severity, intermittent and manageable on continued treatment. The first onset generally 
occurs in the first month of treatment for nausea and within the first 6 months of treatment for 
vomiting. For nausea, the incidence generally plateaus at around 9 months, and for vomiting at 
around 6 to 7 months. 
 
No routine prophylactic anti-emetic treatment is required at the start of study treatment; however, 
subjects should receive appropriate anti-emetic treatment at the first onset of nausea or vomiting 
and as required thereafter, in accordance with local treatment practice guidelines.  Alternatively, 
olaparib tablets can be taken with a light meal/snack (i.e. 2 pieces of toast). 
 
As per international guidance on anti-emetic use in cancer subjects (ESMO, NCCN), generally a 
single agent antiemetic should be considered eg dopamine receptor antagonist, antihistamines or 
dexamethasone. 
 
6.3.3 Renal Impairment 
If subsequent to study entry and while still on study therapy, a patient’s estimated CrCl falls 
below the threshold for study inclusion, retesting should be performed promptly.  
 


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A dose reduction is recommended for subjects who develop a decline in renal function as defined 
by a calculated creatinine clearance by Cockcroft-Gault equation of between 31 and 39 ml/min 
for any reason during the course of the study: the dose of olaparib should be reduced to 200mg 
BID. 
 
Olaparib should be discontinued if the calculated creatinine clearance declines to ≤ 30 ml/min. 
 
6.4 
Interruptions for Intercurrent Non-Toxicity Related Events 
Study treatment dose interruption for conditions other than toxicity resolution should be kept as 
short as possible. If a patient cannot restart study treatment within 4 weeks for resolution of 
intercurrent conditions not related to disease progression or toxicity, the case should be discussed 
with sponsor-investigator. 
 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF.  
 
Study treatment should be stopped at least 3 days prior to planned surgery. After surgery study 
treatment can be restarted when the wound has healed. No stoppage of study treatment is 
required for any needle biopsy procedure. 
 
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
radiation treatment. Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered. 
 
6.5 
Protocol Therapy Discontinuation 
In addition to discontinuation from therapy related to toxicities as outlined above, a subject will 
also be discontinued from protocol therapy and followed per protocol under the following 
circumstances outlined below.  The reason for discontinuation of protocol therapy will be 
documented on the electronic case report form (eCRF)   
• Documented disease progression  
• 
Site investigator determines a change of therapy would be in the best interest of the 
subject 
• 
Subject requests to discontinue protocol therapy, whether due to unacceptable toxicity or 
for other reasons 
o In a subject decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the subject should be asked if he or she may still be contacted for further 
scheduled study assessments. The outcome of that discussion should be documented 
in both the medical records and in the eCRF. 
• 
Female subject becomes pregnant  
• 
Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute myeloid 
leukemia (AML) 
• 
Pneumonitis 
• 
Protocol therapy is interrupted for > 4 weeks.  
 
 


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6.6 
Protocol Discontinuation  
If a subject decides to discontinue from the protocol (and not just from protocol therapy) all 
efforts should be made to complete and report study assessments as thoroughly as possible. A 
complete final evaluation at the time of the subject’s protocol withdrawal should be made with 
an explanation of why the subject is withdrawing from the protocol. If the reason for removal of 
a subject from the study is an adverse event, it will be recorded on the eCRF. 
 


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7. 
STUDY CALENDAR & EVALUATIONS 
 
Study Evaluation  
Cycle = 28 days 
Screening 
Treatment 
Tumor 
Assessments8 
± 7 days 
Safety Follow Up 
Visit13 
Survival  
Follow Up14
-28 days 
Cycle 1 + 
Day 1 
± 2 days
30 Days 
Post Treatment 
(±7 days)
Every 3 Months 
(±7 days) 
REQUIRED ASSESSMENTS 
Informed Consent 
X
 
Medical History1  
X
 
Physical Exam 
X
X
 
X
Vital signs and ECOG Performance Status2 
X
X
 
X
Documentation of DDR alteration in CLIA lab assay3
X
 
ECG4 
X4 
 
 
AEs & Concomitant Medications 
X
X
 
X
LABORATORY ASSESSMENTS 
 
Complete Blood Cell Count with diff (CBC)5 
X
X
 
X
Comprehensive Metabolic Profile (CMP)5 
X
X
 
X
PT/INR and aPTT6 
X
 
Pregnancy test (serum or urine) (WOCBP)7 
X
X7 
 
Urinalysis 
X
 
DISEASE ASSESSMENT 
CT of chest8 
X
X8 
CT or MRI of abdomen and pelvis8 
X
X8 
Bone Scan8 
X
X8 
TREATMENT EXPOSURE 
Olaparib 
X
 
CORRELATIVE SAMPLES  
Archival Tumor Tissue9 
X
 
Collection of tumor tissue obtained as standard of care10 
 
 
X10
Blood Samples for correlative research11 
 
X11 
 
X11 
BANKING SAMPLES  
 
Whole Blood12 
X12 
 
X12 
FOLLOW-UP 
Survival Status, Subsequent Therapy 
X


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Key to Footnotes  
 
1: Medical History should include the following information: (1) Diagnosis and staging to include Tumor Node Metastasis (TNM) staging (2) 
smoking history, (3) trial awareness question (4) prior cancer treatment history and (5) genetic sequencing information. 
 
2: Vital signs to include blood pressure, weight, and height (screening only) and ECOG performance status. 
 
3: The laboratory report indicating the presence of a DDR alteration (see eligibility) from a CLIA laboratory is required for registration. 
 
4: ECG is required within 7 days prior to starting study treatment.   
 
5: If screening (baseline) CBC and CMP were performed within 7 days of Day 1 of treatment, these do not need to be repeated.  CMP to include 
sodium, potassium, chloride, creatinine, blood urea nitrogen; liver function tests (LFTs) to include AST, ALT, total bilirubin, alkaline phosphatase 
 
6: Subjects taking warfarin may participate in this study; however, it is recommended that prothrombin time (INR and APTT) be monitored 
carefully at least once per week for the first month, then monthly if the INR is stable. 
 
7: For women of childbearing potential (WOCBP): urine or serum βhCG will be checked at screening and prior to study drug on Cycle 1 Day 1 
(only if clinically appropriate). If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
 
8: Tumor imaging to continue near the end of every 2nd cycle (~every 8 weeks) for the first 12 months following Cycle 1 Day 1.  After 12 months, 
tumor assessments will be performed near the end of every 3rd cycle (~every 12 weeks). Imaging selected for each subject should remain the same 
throughout the study. Bone scan will be obtained at screening if there is any clinical or laboratory suspicion of metastatic bone involvement. If 
bone scan is positive at baseline for metastases, it will be included with tumor response assessments as noted above.  
 
9: All subjects must have adequate archival tissue available; identified at screening and shipped by C1D1 (i.e., at least 15 unstained slides or 
paraffin block). Archival tissue should represent invasive or metastatic urothelial cancer with a preference for metastatic tissue if available. If 
acceptable archival tissue is not available, this should be discussed with the sponsor-investigator. Subjects will be consented to optional banking of 
any remaining tumor samples after protocol-specified studies are complete. Banked samples will be reserved for future unspecified cancer-related 
research. See Correlative Laboratory Manual (CLM) for additional details.  
 
 
 


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10: If a subject has a biopsy at progression or for other clinical reasons as per standard of care, they will be asked permission to store some of this 
tissue for research directed at mechanisms of resistance. Subjects will also be consented to optional banking of any remaining tumor samples after 
protocol-specified studies are complete. Banked samples will be reserved for future unspecified cancer-related research. See Correlative 
Laboratory Manual (CLM) for additional details.  
 
11:  Serial blood samples will be collected to support biomarker research; There are 4 time points for blood samples to be obtained: (1) pre-dose 
C1D1, (2) pre-dose C3D1, (3) pre-dose C5D1 and at (4) Progression. If a subject comes off study due to progression, samples may be obtained at 
the Safety Follow Up visit. See CLM for additional details. 
 
12: Serial blood samples will be collected for banking; See CLM for additional details. There are 4 time points for blood samples to be obtained: 
(1) pre-dose C1D1, (2) pre-dose C3D1, (3) pre-dose C5D1 and at (4) Progression. If a subject comes off study due to progression, samples may be 
obtained at the Safety Follow Up visit. 
 
13: Safety Follow-Up Visit should only occur when subjects permanently stop study treatment for whatever reasons (toxicity, progression, or at 
discretion of site investigator) and should be performed 30 days (±7 days) after the last dose of treatment. Subjects who have an ongoing Grade ≥ 
2 or serious AE (SAE) at this visit will continue to be followed until the AE resolves to Grade ≤ 1 or baseline, deemed clinically insignificant, 
and/or until a new anti-cancer treatment starts, whichever is earlier.  
 
14: Survival Follow Up will occur in all subjects until documented disease progression. Subjects who discontinue treatment for any reason without 
documented disease progression will be followed for disease progression every 3 months for 2 years from safety follow up visit. Once disease 
progression is documented, subjects will enter a survival follow up period every 3 months for 2 years from the time of documented progression. 
Follow up may be accomplished via clinic visit, phone call, or other avenues as appropriate. During this follow up, any radiology imaging results 
performed should be entered into the EDC system. 
 
 
 
 
 
 


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8. 
BIOSPECIMEN STUDIES AND PROCEDURES 
See Correlative Laboratory Manual for collection, processing and shipping instructions for all 
tissue and blood specimens. 
 
8.1 
Correlative Analyses 
Tissue based and peripheral-blood based correlative analyses will focus on the identification of 
biomarkers of response and resistance to treatment with olaparib and will include, but not be 
limited to, DNA, RNA, and protein-based assays. Because all patients enrolled on this study will 
have been previously identified as having a DDR mutation, we will obtain prior genetic 
sequencing reports for exploratory analyses of co-alterations and response/resistance to treatment 
and time-to-event outcomes. Furthermore, whole exome sequencing may be pursued on select 
archival specimens, or all specimens, to better define the genomic landscape. Circulating DNA 
will be utilized to correlate genomic alterations in the peripheral blood with alterations present in 
tumor tissue.  
 
In addition to the analyses described above, we may generate circulating tumor cell-based 
patient-derived xenograft models and/or organoids using an approach that we have previously 
described.35,36 The feasibility of establishing these models will be assessed and if successful, we 
will evaluate sensitivity and resistance to olaparib in these model systems.   
 
8.2 
Archival Tissue 
All subjects must have adequate archival tissue available; identified at screening and shipped by 
C1D1 (i.e., at least 15 unstained slides or paraffin block). Archival tissue should represent 
invasive or metastatic urothelial cancer with a preference for metastatic tissue if available. If 
archival tissue is not available, enrollment must be discussed with the sponsor-investigator on a 
case by case basis.  
 
8.3 
Peripheral Blood  
All samples to be drawn prior to study drug administration (if applicable). Serial blood samples 
will be collected to support biomarker research; There are 4 time points for blood samples to be 
obtained: (1) pre-dose C1D1, (2) pre-dose C3D1, (3) pre-dose C5D1 and at (4) Progression. If a 
subject comes off study due to progression, samples may be obtained at the Safety Follow Up 
visit. 
 
8.4 
Tumor Specimens Obtained at the Time of Disease Progression or for Other 
Clinical Purposes  
Subjects may have tumor tissue obtained during the course of the study or at the time of disease 
progression for clinical purposes (e.g., confirmation of disease progression, management of 
complication of disease progression, etc.). Specimens obtained in these settings may be accessed 
by the research team to facilitate an understanding of the pharmacodynamic effects of treatment 
at the level of the tumor and microenvironment including mechanisms of treatment resistance. 
 
8.5 
Samples for Future Unspecified Cancer Related Research 
Subject consent will be obtained for additional samples collected for future unspecified cancer 
related research. Hoosier Cancer Research Network will manage the banked samples. Samples 
will be banked indefinitely in the Hoosier Cancer Research Network Biorepository.  


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• Whole Blood will be collected prior to treatment on Cycle 1 Day 1, C3D1, C5D1 and at 
progression/D30 Safety Follow-up visit.  
 
8.6 
Storage of Excess Biospecimens 
Excess biospecimens not completely utilized in these experiments will be stored indefinitely at 
HCRN for future use in research focused on GU malignant diseases that are yet to be 
determined. All specimens collected will maintain the assigned unique study number of the 
corresponding patient. Deidentified samples may be shared with other research institutions. We 
believe that allowing for storage and usage of the remaining samples for future research is 
ethically justified and a preferred option to discarding these materials given the potential impact 
on improving clinical outcomes for subjects with bladder cancer. Subjects will be given the 
option to store excess specimens during the informed consent process. 
 
8.7 
Confidentiality of Biospecimens 
Samples that are collected will be identified by a subject’s sequence ID number assigned at the 
time of registration to the trial. Any material issued to collaborating researchers will be 
anonymized and only identified by the subject’s sequence number. 
 
9. 
CRITERIA FOR DISEASE EVALUATION 
 
9.1 
Measurable Disease 
Measurable disease is defined as the presence of at least one measurable lesion. Measurable 
lesions 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 >10 mm with 
calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
9.1.1 Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in 
short axis 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. 
 
9.2 
Non-measurable Lesions 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered as non-measurable. 
 
NOTE:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
 


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9.3 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then only the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. 
 
9.4 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up. 
 
9.5 
Evaluation of Target Lesions 
NOTE: In addition to the information below, also see the international criteria proposed by the 
Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 1.1 (Eur J Cancer 
45;2009:228-247) for special notes on the assessment 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 5 mm. (Note:  the appearance of one or more new 
lesions is also considered progressions).
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters 
while on study
 
 
 


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9.6 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size 
(<10 mm short axis) 
 
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 lesion(s) and/or maintenance 
of tumor marker level above the normal limits
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be 
representative of overall disease status change, not a single lesion 
increase.
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the site 
investigator should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the sponsor investigator. 
 
9.7 
Evaluation of Best Overall Response 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No
CR 
CR 
Non-CR/ Non-PD
No
PR 
CR 
Not evaluated
No
PR 
PR 
Non-PD/ or not all evaluated
No
PR 
SD 
Non-PD or not all evaluated
No
SD 
Not all evaluated 
Non-PD 
No
Non-evaluable 
PD 
Any 
Yes or No
PD 
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.
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration.” Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 
 
 


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9.8 
Definitions for Response Evaluation – RECIST 1.1 
 
9.8.1 First Documentation of Response 
The time between initiation of therapy and first documentation of PR or CR. 
 
9.8.2 Confirmation of Response 
To be assigned a status of complete or partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than four weeks after the criteria for response 
are first met. 
 
9.8.3 Duration of Response 
Duration of overall response—the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since treatment started). 
 
9.8.4 Duration of Overall Complete Response 
The period measured from the time that measurement criteria are met for complete response until 
the first date that recurrent disease is objectively documented. 
 
9.8.5 Objective Response Rate  
The objective response rate is the proportion of all subjects with confirmed PR or CR according 
to RECIST 1.1, from the start of treatment until disease progression/recurrence (taking as 
reference for progressive disease the smallest measurements recorded since the start of 
treatment). 
 
9.8.6 Disease Control Rate 
The disease control rate is the proportion of all subjects with stable disease (SD) for 8 weeks, or 
partial response (PR), or complete response (CR) according to RECIST 1.1, from the start of 
treatment until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the start of treatment). 
 
9.8.7 Time to Progression: 
A measurement from the date of initiation of therapy until the criteria for disease progression is 
met as defined by RECIST 1.1. Subjects who have not progressed or have died due to any cause 
will be right-censored at the date of the last disease evaluation or date of death. 
 
9.8.8 Progression Free Survival 
A measurement from the date of initiation of therapy until the criteria for disease progression is 
met as defined by RECIST 1.1 or death occurs. Subjects who have not progressed will be right-
censored at the date of the last disease evaluation. 
 
9.8.9 Overall Survival 
Overall survival is defined by the date of enrollment to date of death from any cause. 
 


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9.9 
Definitions for Response Criteria for patients with bone-only metastases; MD 
Anderson (MDA) criteria34 
 
Complete Response (CR) 
• Complete sclerotic fill-in of lytic lesions on XR or CT 
• Normalization of bone density on XR or CT 
• Normalization of signal intensity on MRI 
•
Normalization of tracer uptake on SS 
Partial Response (PR) 
• Development of a sclerotic rim or partial sclerotic fill-in 
of lytic lesions on XR or CT 
• Osteoblastic flare - Interval visualization of lesions with 
sclerotic rims or new sclerotic lesions in the setting of 
other signs of PR and absence of progressive bony 
disease 
• ≥ 50% decrease in measurable lesions on XR, CT, or 
MRI 
• ≥ 50% subjective decrease in the size of ill-defined 
lesions on XR, CT, or MRI 
•
≥ 50% subjective decrease in tracer uptake on SS
Progressive Disease (PD) 
• > 25% increase in size of measurable lesions on XR, 
CT, or MRI 
• > 25% subjective increase in the size of ill-defined 
lesions on XR, CT, or MRI 
• > 25% subjective increase in tracer uptake on SS 
•
New bone metastases
Stable Disease (SD) 
• No change 
• < 25% increase or < 50% decrease in size of measurable 
lesions 
• < 25% subjective increase or < 50% subjective decrease 
in size of ill-defined lesions 
•
No new bone metastases
Abbreviations: XR: radiography; CT: computed tomography; SS: skeletal scintigraphy; 
MRI: magnetic resonance imaging.
 
Measurements are based on the sum of a perpendicular, bi-dimensional measurement of the 
greatest diameters of each individual lesion. 
 
 
 
 


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10 
DRUG INFORMATION 
Please refer to the current version of the Investigator’s Brochure (IB) for additional information 
regarding this drug. 
 
10.1 
Olaparib 
Olaparib (AZD2281, KU-0059436) is a potent PARP inhibitor (PARP-1, -2 and -3).  
 
10.1.1 Supplier/How Supplied 
Astra Zeneca will supply olaparib at no charge to subjects participating in this clinical trial.  
 
The site investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
 
The AstraZeneca Pharmaceutical Development R&D Supply Chain will supply olaparib to the 
investigator as round or oval film coated tablets. NOTE: The capsule and tablet forms of 
olaparib should not be substituted as they have different bioavailability and dosing instructions.  
 
Investigational product 
Dosage form and strength 
Olaparib 
100 mg tablet 
Olaparib 
150 mg tablet 
a 
Descriptive information for olaparib can be found in the Investigator’s Brochure 
 
10.1.2 Preparation  
When possible, refer to the prescribing information and/or investigator’s brochure for details on 
the preparation of the drug. Dosing and administration should be addressed in the Treatment Plan 
section. 
 
10.1.3 Storage and Stability 
All study drugs should be kept in a secure place under appropriate storage conditions. Olaparib 
tablets should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C 
(59°F to 86°F). Protect from moisture. 
 
10.1.4 Handling and Disposal 
Investigational drug should be disposed as per institutional policy.  
 
10.1.5 Dispensing 
Olaparib must be dispensed only from official study sites and to eligible subjects under the 
supervision of the site investigator. Olaparib should be stored in a secure area according to local 
regulations. It is the responsibility of the site investigator to ensure that study drug is only 
dispensed to subjects.   
 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfill GMP Annex 13 requirements for labelling. Label 
text will be translated into local language.  


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Each bottle of olaparib will have an investigational product label permanently affixed to the 
outside stating that the material is for clinical trial/investigational use only and should be kept 
out of reach of children. The label will include the dosing instructions and a space for the 
enrolment code (E-code) to be completed at the time of dispensing. 
 
The label will include the following information: 
blank lines for quantity of tablets to be taken 
enrolment code (E-code) 
date of dispensing 
Instructions stating that the olaparib tablets should be taken at approximately the same time 
each morning and evening 
 
10.1.6 Potential Adverse Events 
See the most current IB or package insert for a comprehensive list of adverse events. 
 
11 
ADVERSE EVENTS 
The descriptions and grading scales found in the NCI CTCAE v4 will be utilized for AE 
assessment. A copy of the CTCAE v4 can be downloaded from the CTEP website at 
http://ctep.cancer.gov. All forms for AE/SAE recording and reporting can be found in the Study 
Procedure Manual or in the EDC system (Documents and Information Tab). 
 
11.1 
Definitions 
 
11.1.1 
Adverse Event (AE) 
An AE is any untoward medical occurrence whether or not considered related to the study drug 
that appears to change in intensity during the course of the study. The following are examples of 
AEs:  
• Unintended or unfavorable sign or symptom 
• A disease temporally associated with participation in the protocol 
• An intercurrent illness or injury that impairs the well-being of the subject 
 
Abnormal laboratory values or diagnostic test results constitute AEs only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests   
 
Hospitalization for elective surgery or routine clinical procedures that are not the result of an AE 
(e.g., surgical insertion of central line) should not be recorded as an AE.  
 
Disease progression should not be recorded as an AE, unless it is attributable to the study 
regimen by the site investigator. 
 
 
 


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11.1.2 Serious Adverse Event (SAE) 
A SAE is an adverse event that: 
• Results in death. NOTE: Death due to disease progression should not be reported as a 
SAE, unless it is attributable by the site investigator to the study drug(s) 
• Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• Requires inpatient hospitalization for >24 hours or prolongation of existing 
hospitalization. NOTE: Hospitalization for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered serious 
adverse events. 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed in the definition 
above). Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
not resulting in hospitalization; or the development of drug dependency or drug abuse. 
 
11.1.3 Olaparib Adverse Events of Special Interest (AESI) 
Adverse events of special interest [AESI] are events of scientific and medical interest specific to 
the further understanding of olaparib’s safety profile and require close monitoring and rapid 
communication by the local investigator to the sponsor-investigator via HCRN. An AESI may be 
serious or non-serious. Adverse Events of Special Interest for olaparib are the Important 
Potential Risks of MDS/AML, new primary malignancy (other than MDS/AML) and 
pneumonitis.  
  
ANY event of MDS/AML, new primary malignancy, or pneumonitis should be reported to 
AstraZeneca Patient Safety whether it is considered a non-serious AE [eg non-melanoma skin 
cancer] or SAE, and regardless of site investigator’s assessment of causality.  
 
A questionnaire will be sent to any investigator reporting an AESI, as an aid to provide further 
detailed information on the event.  During the study there may be other events identified as 
AESIs that require the use of a questionnaire to help characterize the event and gain a better 
understanding regarding the relationship between the event and study treatment. 
 
11.1.4 Overdose of Olaparib 
There is currently no specific treatment in the event of overdose with olaparib and possible 
symptoms of overdose are not established.  
 
Olaparib must only be used in accordance with the dosing recommendations in this protocol. 
Any dose or frequency of dosing that exceeds the dosing regimen specified in this protocol 


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should be reported as an overdose. Adverse reactions associated with overdose should be treated 
symptomatically and should be managed appropriately. 
 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant AE 
modules in the eCRF and on the Overdose CRF module. An overdose without associated 
symptoms is only reported on the Overdose CRF module. 
 
If an overdose on an AstraZeneca study drug occurs in the course of the study, site investigators 
or other site personnel inform appropriate Hoosier Cancer Research Network (HCRN) within 
one business day and HCRN will report to AstraZeneca within one business day.  
 
11.1.5 Reproductive Reporting Information 
 
11.1.5.1 
Pregnancy 
All outcomes of pregnancy should be reported to HCRN who will then report to AstraZeneca. 
 
11.1.5.2 
Maternal Exposure 
If a patient becomes pregnant during the course of the study, olaparib should be discontinued 
immediately.  The outcome of any conception occurring from the date of the first dose until 1 
month after the last dose should be followed up and documented.  Pregnancy itself is not 
regarded as an adverse event unless there is a suspicion that the investigational product under 
study may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital abnormality) should be followed up and documented even if the patient was 
withdrawn from the study.  
 
If any pregnancy occurs in the course of the study, site investigators or other site personnel must 
inform HCRN within one business day and HCRN will report to AstraZeneca within one 
business day. 
 
11.1.5.3 
Paternal Exposure 
Male subjects should refrain from fathering a child or donating sperm during the study and for 3 
months following the last dose.  Pregnancy of the patient’s partners is not considered to be an 
adverse event. However, the outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth or congenital abnormality) should if possible be 
followed up and documented.  The outcome of any conception occurring from the date of the 
first dose until 3 months after the last dose should be followed up and documented. 
 
11.1.6 Unexpected Adverse Event 
For this study, an AE is considered unexpected when it varies in nature, intensity or frequency 
from information provided in the current IB, prescribing information or when it is not included in 
the informed consent document as a potential risk. Unexpected also refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or are anticipated from the 


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pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.   
 
11.1.7 Relatedness 
AEs will be categorized according to the likelihood that they are related to the study drug(s). 
Specifically, they will be categorized using the following terms:  
 
Unrelated 
Adverse Event is not related to the study drug(s)  
Unlikely 
Adverse Event is doubtfully related to the study drug(s)  
Possible 
Adverse Event may be related to the study drug(s)  
Probable 
Adverse Event is likely related to the study drug(s)  
Definite 
Adverse Event is clearly related to the study drug(s)  
 
11.2 
Reporting 
 
11.2.1 Adverse Events  
• AEs will be recorded from time of signed informed consent until 30 days after 
discontinuation of study drug(s) or until a new anti-cancer treatment starts, whichever 
occurs first.  
• AEs will be recorded regardless of whether or not they are considered related to the study 
drug(s).   
• All AEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system. 
• AEs considered related to study drug(s) will be followed until resolution to  
Grade ≤ 1 or baseline, deemed clinically insignificant, and/or until a new anti-cancer 
treatment starts, whichever occurs first. 
• Transient asymptomatic laboratory abnormalities that do not require treatment will not be 
collected as adverse events. 
 
11.2.2 Serious Adverse Events (SAEs) 
 
11.2.2.1 
Site Requirements for Reporting SAEs to HCRN 
• SAEs will be reported from time of signed informed consent until 30 days after 
discontinuation of study drug(s).  
• SAEs will be reported on the SAE Submission Form within 1 business day of discovery 
of the event.   
• SAEs include events related and unrelated to the study drug(s).  
• All SAEs will be recorded in the subject’s medical record and on the appropriate study 
specific eCRF form within the EDC system.   
• All SAEs regardless of relation to study drug will be followed until resolution to ≤ Grade 
1 or baseline and/or deemed clinically insignificant and/or until a new anti-cancer 
treatment starts, whichever occurs first. 
 


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The site will submit the completed SAE Submission Form to HCRN within 1 business day of 
discovery of the event. The form may be submitted to HCRN electronically to 
safety@hoosiercancer.org. The site investigator is responsible for informing the IRB and/or other 
local regulatory bodies as per local requirements.   
 
The original copy of the SAE Submission Form and the email correspondence must be kept 
within the study file at the study site. 
 
Once the SAE has resolved (see resolution guidelines listed in 11.2.2.1), sites must submit a 
follow-up SAE Submission Form within a reasonable timeframe to HCRN electronically to 
safety@hoosiercancer.org.   
 
11.2.2.2 
HCRN Requirements for Reporting Events to AstraZeneca 
HCRN will report all SAEs, AESIs, and other reportable events to AstraZeneca within 1 
business day of knowledge of the event.  Follow-up information will be provided to 
AstraZeneca as reasonably requested. 
 
Serious adverse events that do not require expedited reporting to the FDA still need to be 
reported to AstraZeneca, preferably using the MedDRA coding language for serious adverse 
events. This information should be reported on a monthly basis and under no circumstance less 
frequently than quarterly. 
 
Send SAE report and accompanying cover page by way of email to AstraZeneca’s 
designated mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com. 
 
11.2.2.3 
Sponsor-Investigator Responsibilities  
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness.   
 
11.2.2.4 
HCRN Responsibilities to FDA 
This protocol was deemed exempt by the FDA 10/27/17. For protocols exempt from the 
requirements of an IND, the above stated requirements are not applicable. HCRN will continue 
to facilitate compliance of applicable requirements for the sponsor-investigator in relation to this 
study. This includes but is not limited to 21 CFR 50.20 informed consent, 21 CFR Part 56 IRB, 
and pertinent sections of the Public Health Service Act and FDAAA. 
 
11.2.2.5 
IND Safety Reports Unrelated to this Trial 
AstraZeneca will provide to HCRN IND safety reports from external studies that involve the 
study drug(s) per their guidelines. HCRN will forward safety reports to the sponsor-investigator 
who will review these reports and determine if revisions are needed to the protocol or consent. 
HCRN will forward these reports to participating sites within 1 business day of receiving the 
sponsor-investigator’s review. Based on the sponsor-investigator’s review, applicable changes 
will be made to the protocol and informed consent document (if required). All IND safety reports 
will also be made available to sites via the EDC system.    
 


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Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies. 
 
12 
STATISTICAL METHODS 
 
12.1 
Study Design 
This is a single arm open label multi-institutional phase II trial of olaparib monotherapy in 
subjects with metastatic urothelial cancer harboring somatic DDR alterations. The primary 
objective of the study is to estimate the objective response rate (per RECIST 1.1 or MD 
Anderson criteria for bone-only metastases) to treatment with olaparib. 
 
12.2 
Endpoints 
 
12.2.1 Definition of Primary Endpoint 
The primary endpoint is objective response rate as determined by RECIST 1.1 (or MD Anderson 
criteria for bone-only metastases). Objective response rate will include confirmed complete 
response (CR) + confirmed partial response (PR) and will be determined as outlined in section 9. 
 
12.2.2 Definition of Secondary Endpoints 
• Safety of olaparib, defined as rates of Grade 1-5 toxicity according to CTCAE v4.03. 
• PFS, which is defined as the time from initiation of treatment to death or progression, 
depending on which occurs first (as defined by RECIST 1.1). 
• Overall survival (OS), which is defined as the time from initiation of treatment to death. 
 
12.3 
Sample Size and Accrual 
Assume the null hypothesis (P0) of 10% as the response rate (the response rate with standard 
cytotoxic chemotherapy in this setting37), a sample size of 27 achieves 81% power to detect a 
difference (P1-P0) of 18% (that is, P1=28%) using a one-sided exact test with a target 
significance level of 0.05. The actual significance level achieved by this test is 0.0471. The 
sample size may be inflated to 30 if replacement of subjects is needed due to early withdrawals 
or unevaluable subjects.  
 
12.4 
Data Analysis Plans 
 
12.4.1 Analysis Plans for Primary Objective 
Any subjects who receive at least one dose of treatment on this protocol will be included in the 
analysis of the objective response rate. Patients who discontinue treatment prior to the first 
response assessment will be defined as “non-evaluable” but will be included in the denominator. 
The objective response rate and its associated 95% confidence interval will be constructed based 
on the exact binomial test due to the small sample size.  
 
12.4.2 Analysis Plans for Secondary Objectives 
Any subject who receives at least one dose of treatment on this protocol is evaluable for toxicity, 
progression free survival and overall survival. Toxicity rates will be summarized using frequency 
tables. Progression free survival and overall survival curves will be based on the Kaplan-Meier 
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12.4.3 Analysis Plans for Exploratory Objectives 
To explore the relationship between specific genomic alterations with response to olaparib, 
Fisher's exact test will be used. To explore the relationship between prior platinum-based 
chemotherapy treatment (exposure, response, duration of treatment, and time since treatment) 
with response to olaparib, Fisher's exact test (for chemo response) and T-test (for duration of 
treatment and time since treatment) will be used. To explore the relationship between tumor 
mutational profile, circulating DNA mutational profile, and response to olaparib, both Fisher's 
exact test and T-test will be used.  
 
12.5 
Stopping Study for Excessive Toxicities 
A stopping rule will be employed after 10 and 20 subjects finish at least one cycle of treatment. 
This safety stopping rule will be performed with respect to a) SAEs that are treatment related and 
b) events of specific interest (that is, MDS/AML, new primary malignancies and pneumonitis). 
Two-sided 95% exact binomial confidence intervals (CIs) of these event rates will be constructed 
at 10 and 20 subjects. If their lower bounds exceed pre-defined levels, the study drug will be 
considered unacceptably toxic for this patient population and the study will be terminated.  
Therefore, we have the following 2 stopping rules:  
1. In a prospective trial of olaparib in subjects with advanced solid tumors and germline 
BRCA 1 and 2 mutations, among the ovarian, breast, pancreatic, and prostate cancer 
groups, 10.4%, 9.7%, 17.4%, and 12.5% of subjects, respectively, experienced serious 
AEs considered causally related to olaparib.38 We will use 15% as our cutoff and if the 
lower bounds of the CIs exceed 15%, the study will be halted. This corresponds to ≥ 5+ 
(5 or more) out of 10 and ≥ 7+ out of 20 subjects. 
2. The rate of other events of interest (that is, MDS/AML, new primary malignancies and 
pneumonitis) varies around 1% (see Section 1.5.6). If the lower bounds of the CIs exceed 
1%, the study will be halted. This corresponds to ≥ 2+ (2 or more) out of 10 and ≥ 2+ out 
of 20 subjects. 
 
Enrollment will not be halted while these safety assessments take place.  
 
There will be no planned interim efficacy assessment.  
 
13 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan (DSMP) 
The study will be conducted in accordance with the Icahn School of Medicine/Tisch Cancer 
Institute’s DSMP.  
 
HCRN oversight activities include: 
• Review all adverse events requiring expedited reporting as defined in the protocol 
• Provide trial accrual progress, safety information and data summary reports to the 
sponsor-investigator  
• Submit data summary reports to the lead institution Data Safety Monitoring Committee 
according to Icahn School of Medicine/Tisch Cancer Institute’s DSMP. 
 
 
 


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13.2 
Icahn School of Medicine/Tisch Cancer Institute Data Safety Monitoring Committee 
HCRN will provide the following for the Icahn School of Medicine/Tisch Cancer Institute’s 
DSMC to review: 
• Adverse event summary report 
• Audit results if applicable 
• Data related to stopping/decision rules described in study design 
• Study accrual patterns  
• Protocol deviations 
 
The Icahn School of Medicine/Tisch Cancer Institute’s DSMC will review study data every 
quarter.  Documentation of DSMC reviews will be provided to sponsor-investigator and HCRN.  
Issues of immediate concern by the DSMC will be brought to the attention of the sponsor-
investigator and other regulatory bodies as appropriate.  The sponsor-investigator will work with 
HCRN to address the DSMC’s concerns.   
 
13.3 
Data Quality Oversight Activities 
Remote validation of the EDC system data will be completed on a continual basis throughout the 
life cycle of the study. Automated edit check listings will be used to generate queries in the EDC 
system and transmitted to the site to address in a timely fashion. Corrections will be made by the 
study site personnel.  
 
Participating sites may also be subject to quality assurance audits by BMS or its designee as well 
as inspection by appropriate regulatory agencies. 
 
13.3.1 Onsite Monitoring 
Monitoring visits to the trial sites may be made periodically during the trial to ensure key aspects 
of the protocol are followed. Selected source documents will be reviewed for verification of 
agreement with data entered into the EDC system. It is important for the site investigator and 
their relevant personnel to be available for a sufficient amount of time during the monitoring 
visits or audit, if applicable. The site investigator and institution guarantee access to source 
documents by HCRN or its designee. The trial site may also be subject to quality assurance audit 
by AstraZeneca-MedImmune or its designee as well as inspection by appropriate regulatory 
agencies. 
 
13.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and study 
site contact information.   
 


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14. 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform, a system compliant with Good Clinical Practices 
and Federal Rules and Regulations.  HCRN personnel will coordinate and manage data for 
quality control assurance and integrity. All data will be collected and entered into the EDC 
system by study site personnel from participating institutions.   
 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in the EDC system and correlative results 
will be captured in the EDC system or other secure database(s). If procedures on the study 
calendar are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in the EDC system, according to 
study-specific objectives.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without permission from the sponsor-investigator and HCRN. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition. All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with the site contract with HCRN.  No records 
will be destroyed until HCRN confirms destruction is permitted. 
 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.  
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, AstraZeneca, IRB, or government agencies, like the 
FDA, may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
 
 


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15 
ETHICS 
 
15.1 
Institutional Review Board (IRB) Approval 
The final study protocol and the final version of the informed consent form must be approved in 
writing by an IRB. The site investigator must submit written approval by the IRB to HCRN 
before he or she can enroll subjects into the study.   
 
The site investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB, as local regulations 
require.  
 
Progress reports and notifications of serious and unexpected adverse events will be provided to 
the IRB according to local regulations and guidelines. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki.  Conduct of the study will be in compliance with ICH Good Clinical 
Practice, and with all applicable federal (including 21 CFR parts 56 & 50), state, or local laws. 
 
15.3 
Informed Consent Process 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject.  
 
 


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