Clinical trial NCT03432897
Conditions: Prostate Cancer Adenocarcinoma of the Prostate
Keywords: High risk Defects prostate
Sponsor: Brown University
Start date: 2018-05-25; Completion date: 2021-12-07
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate approximately 3 months of treatment with the drug olaparib in patients with prostate cancer. A capsule formulation of olaparib (tradename Lynparza™) is approved by the United States Food and Drug Administration (FDA) for the treatment of women with advanced BRCA-mutated ovarian cancer. Olaparib is an investigational drug in prostate cancer. A tablet formulation of olaparib is being tested in this study. It is a new formulation which is more convenient for patients than the approved capsule formulation because fewer tablets of olaparib need to be taken daily than with capsules.

The purpose of the study is to evaluate whether olaparib can reduce prostate cancer with defects in DNA repair genes when olaparib is given for approximately 3 months before surgery.

Detailed description:
1.1 Primary Objective 1.1.1. To evaluate the Prostate Specific Antigen (PSA) response rate of olaparib prior to radical prostatectomy for patients with locally advanced prostate cancer and defects in DNA repair genes.

1.2 Secondary Objectives 1.2.1 To evaluate the PSA progression-free survival of olaparib and radical prostatectomy for patients with locally advanced prostate cancer and defects in DNA repair genes.

1.2.2 To evaluate the safety of olaparib prior to radical prostatectomy for patients with locally advanced prostate cancer

1.2.3 To evaluate the rate of defects in DNA repair genes in patients with newly diagnosed locally advanced prostate cancer.

Arms: arm 1: Olaparib 300 mg BID q 4 weeks for up to 3 cycles. The 3rd cycle will not be given if patient is found to progress post cycle 2.

Between 22-42 days post Olaparib, patients will undergo a prostatectomy.
Interventions: intervention 1: Olaparib Pill intervention 2: Prostatectomy
Intervention descriptions: intervention 1: 300 mg BID intervention 2: 22-42 days post Olaparib patients will undergo surgery

Protocol documents:
Prot_SAP_ICF_000.pdf: 
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exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
1
BrUOG 337 
 
 
 
 
 
 
 
 
IND Exempt 137649 
ESR-16-12357 
 
BrUOG 337: Olaparib Prior to Radical Prostatectomy For Patients with Locally Advanced 
Prostate Cancer and Defects in DNA Repair Genes 
 
Principal Investigator: 
Anthony Mega, MD 
 
Thomas Dipetrillo, MD, 
Dragan Golijanin, MD, 
Nimesh Patel, MD, 
Ali Amin, MD, 
Benedito Carneiro, MD 
Boris Gershman, MD 
 
Howard Safran, MD 
Medical Director, Brown University Oncology Research Group 
 
 
 
Coordinating Center 
Brown University Oncology Research Group 
233 Richmond Street Box G-R001 
Providence, Rhode Island 02903 
Phone: (401) 863-3000 
Fax: (401) 863-3820 
Email: BrUOG@brown.edu 
 
 
 
Supported in part by the Goldner Family 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the 
extent necessary to obtain informed consent, may not be disclosed to another party unless law 
or regulations require such disclosure.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them. 
Initial protocol 4/6/2017 
Amendment # 1 4/20/18 with IB edition 15 
Amendment # 2 12/8/18 
Amendment # 3 2/8/19 
 


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TABLE OF CONTENTS 
Section  
 
 
 
 
 
 
 
 
Page 
1.0 
OBJECTIVES  
 
 
 
 
 
 
3 
2.0 
BACKGROUND 
 
 
 
 
 
 
3 
3.0 
PATIENT ELIGIBILITY 
 
 
 
 
 
9 
 
 
4.0 
TREATMENT 
 
 
 
 
 
 
12 
 
5.0 
TOXICITIES, ASSESSMENT, AND DOSE MODIFICATIONS 
14 
                                                     
6.0 
SCHEDULE OF EVALUATIONS / STUDY CALENDAR 
 
20 
                          
7.0      RESPONSE ASSESSMENT  
 
 
 
 
22 
 
 
8.0 
PATIENT REGISTRATION  
 
 
 
 
22 
9.0 
PHARMACEUTICAL INFORMATION                                           
23 
10.0 
AGENT ACCOUNTABILITY     
 
 
 
 
24 
 
11.0 
ADVERSE DRUG REACTION REPORTING 
 
 
25 
 
12.0 
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
33 
13.0 
FOLLOW UP    
 
 
 
 
 
 
33 
   
14.0 
REGULATORY CONSIDERATIONS   
 
                          34 
15.0 
DATA MONITORING/QUALITY ASSURANCE/ 
 
 
35 
RECORD RETENTION 
 
 
 
 
 
 
 
16.0 
DATA SAFETY AND MONITORING BOARDS 
 
 
36 
 
17.0 
STATISTICAL CONSIDERATIONS  
 
 
    
37 
18.0 
REFERENCES                                                                        
38 
 
APPENDIX SECTION: 
 
 
 
 
 
APPENDIX A INFORMED CONSENT 
 
 
 
 
 
APPENDIX B ELIGIBILITY CHECKLIST  
 
 
 
APPENDIX C COMMON TOXICITY CRITERIA  
 
 
APPENDIX D ECOG PERFORMANCE STATUS   
 
 
APPENDIX E CASE REPORT FORMS 
 
APPENDIX F HY’S LAW 
 
 
 
 


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1.0  OBJECTIVE 
1.1 Primary  Objective 
1.1.1. To evaluate the Prostate Specific Antigen (PSA) response rate of olaparib prior to radical 
prostatectomy for patients with locally advanced prostate cancer and defects in DNA repair genes. 
 
1.2 Secondary  Objectives 
1.2.1 To evaluate the PSA progression-free survival of olaparib and radical prostatectomy for patients 
with locally advanced prostate cancer and defects in DNA repair genes. 
 
1.2.2 To evaluate the safety of olaparib prior to radical prostatectomy for patients with locally 
advanced prostate cancer  
 
1.2.3 To evaluate the rate of defects in DNA repair genes in patients with newly diagnosed locally 
advanced prostate cancer.  
 
 
2.0  
BACKGROUND 
BACKGROUND 
High Risk Prostate Cancer: Patients with prostate cancer and high risk features are at substantial risk for 
relapse following radical prostatectomy.1-3 In a study of 369 patients with positive lymph nodes identified 
after radical prostatectomy and extended lymph node dissection the 10 year freedom from recurrence was 
only 28%. Patients with seemingly localized prostate confined disease, such as those with T2c disease but 
with high risk features such as a PSA >20 or Gleason grade 8-10, have a 40% recurrence rate.4 Emerging 
data suggest that aggressive use of radical prostatectomy for patients with extra-prostatic extension, and 
extended pelvic lymph node dissection in patients with lymph node involvement, may be beneficial.6-11 
However, effective systemic adjuvant therapies are desperately needed to improve outcomes in 
combination with these aggressive surgical approaches. 
 
Adjuvant Androgen Deprivation Therapy (ADT) and Chemotherapy After Radical Prostatectomy:  
The role of adjuvant hormone therapy in patients who undergo radical prostatectomy is modest. An 
improvement in biochemical failure-free survival without an improvement in overall survival was noted 
in RTOG 85-31,12 while a modest survival benefit was noted by Messing et al.13  
 
It was hoped that combination next generation hormone therapy would be beneficial in the perioperative 
setting but this promise has not been fulfilled. Efstathiou et al performed a neoadjuvant study of 24 weeks 
of abiraterone+ enzalutamide +LHRH antagonist  versus  abiraterone +LHRH antagonist (randomized 
2:1) in pts with LHRPC (clinical stage T1c/T2 with biopsy Gleason ≥ 8, or ≥ T2b with Gleason ≥ 7 and 
PSA > 10 ng/mL).14 The primary outcome was the effect on pathologic stage. Pathologic downstaging ( ≤ 
pT2N0) occurred in 13/44 (30%) abiraterone + enzalutamide+ LHRH antagonist patients (no pathologic 
complete responses)  versus 11/21 (52 %) abiraterone +LHRH antagonist (p = 0.07) including 2 
pathologic complete responses.14 These findings do not favor adding enzalutamide to augment abiraterone 
+LHRH antagonist efficacy in localized high risk prostate cancer and there was a trend for inferior 
outcome. 
 
Similarly adjuvant docetaxel was not helpful. In the phase III trial SPCG2 459 patients were randomized 
to receive either 6 cycles of adjuvant docetaxel (Arm A) or surveillance (Arm B). Primary end-point was 
a rising PSA >0.5ng/ml. High-risk prostate cancer was defined as pT2 with a positive margin if Gleason 


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score (GS) 4+3 or higher, pT3b >GS 3+4 or any lymph node positive disease with >GS 3+4.  Patients 
were followed for 5 years with PSA every 3 months. The biochemical relapse rate was 47.9% in the 
docetaxel group and 38.9% in the observation group.15  
 
PARP Inhibition: Targeting DNA repair defects in Prostate Cancer: 
DNA damage occurs continuously in all living cells as a result of oxidative damage or DNA replicative 
stress.16 Poly ADP ribose polymerase 1(PARP1) PARP1 plays a critical role in restoration of genomic 
integrity by facilitating efficient repair of DNA breaks.17 Inherited defects in DNA repair pathways result 
in increased susceptibility to the development of malignancy.18 For example inactivating mutations in 
BRCA1 and BRCA2, which are required for efficient DNA double stranded repair, significantly increase 
the risk of breast,  ovarian and prostate cancer.19 Approximately 23% of metastatic prostate cancer have 
aberrations of BRCA 1 and BRACA 2.20  PARP inhibitors specifically target oncogenic cells with DNA 
repair deficiency and ultimately lead to their cell death from over accumulation of double stranded DNA 
breaks in the nuclei.16-19 PARP inhibitors can prevent the disassembly of PARP protein from DNA 
complexes; this has been shown to be highly toxic to a cancer cell with a DNA repair abnormality. 19  
There is substantial data indicate that PARP inhibitors possess antitumor activity within patient 
populations with DNA repair deficiency. For example phase I/II studies have demonstrated activity of 
olaparib in patients with breast, ovarian and prostate cancer with BRCA1 and BRCA2.21,22 Olaparib has 
been FDA approved for women with a BRCA mutation and metastatic ovarian cancer.  
Olaparib:  
Investigators should be familiar with the current olaparib (AZD2281) Investigator Brochure (IB). 
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly (ADP ribose)] 
polymerisation (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. 
PARP inhibition is a novel approach to targeting tumours with deficiencies in DNA repair mechanisms.  
PARP enzymes are essential for repairing DNA single strand breaks (SSBs).  Inhibiting PARPs leads to 
the persistence of SSBs, which are then converted to the more serious DNA double strand breaks (DSBs) 
during the process of DNA replication.  During the process of cell division, DSBs can be efficiently 
repaired in normal cells by homologous recombination repair (HR).  Tumours 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 tumour types, olaparib may offer a 
potentially efficacious and less toxic cancer treatment compared with currently available chemotherapy 
regimens.  
BRCA1 and BRCA2 defective tumours are intrinsically sensitive to PARP inhibitors, both in tumour 
models in vivo, 23,24  and in the clinic.25  The mechanism of action for olaparib results from the trapping of 
inactive PARP onto the single-strand breaks preventing their repair. 26,27 Persistence of SSBs during DNA 
replication results in their conversion into the more serious DNA DSBs that would normally be repaired 
by HR repair.  Olaparib has been shown to inhibit selected tumour 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. 


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Pre-clinical experience 
The pre-clinical experience is fully described in the current version of the olaparib Investigator’s 
Brochure (IB).    
Toxicology and safety pharmacology summary 
The toxicology and safety pharmacology is fully described in the current version of the olaparib 
Investigator’s Brochure (IB).    
Clinical experience - Emerging Safety Profile and Reference Safety Information. (This section lists those 
ADRs that are currently regarded as expected for regulatory reporting purposes.) 
A description of the emerging safety profile for olaparib, with guidance for investigators, is provided in 
Section 6 of the IB. Olaparib monotherapy has been associated with laboratory findings and/or clinical 
diagnoses, generally of mild or moderate severity (CTCAE Grade 1 or 2) and generally not requiring 
treatment discontinuation. The safety profile is based on pooled data from 1248 patients treated with 
olaparib monotherapy in clinical trials in the therapeutic indication at the recommended dose. The 
following adverse reactions have been identified in completed clinical trials with patients receiving 
olaparib monotherapy where patient exposure is known.  
 
Adverse Drug Reactions are organized by Medical Dictionary for Regulatory Activities (MedDRA) SOC 
and then by MedDRA preferred term in Table 41. Within each SOC, preferred terms are arranged by 
decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of 
adverse reactions are defined as: very common (≥1/10); common (≥1/100 to <1/10); 
uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); and very rare (<1/10,000) including 
isolated reports. 
 


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Description of selected adverse reactions Hematological toxicity Anemia and other hematological 
toxicities are generally low grade (CTCAE Grade 1 or 2), however, there are reports of CTCAE Grade 3 
and higher events. Anemia was the most common CTCAE Grade ≥3 adverse reaction reported in clinical 
studies with first onset generally reported in the first 3 months of treatment. An exposure-response 
relationship between olaparib and decreases in hemolobin has been demonstrated. In clinical studies with 
olaparib, the incidence of CTCAE Grade ≥2 shifts (decreases) from baseline in hemoglobin was 20%, 
absolute neutrophils 15%, platelets 5%, lymphocytes 30% and leucocytes 20% (all % approximate). The 
incidence of elevations in MCV from low to normal at baseline to above the upper limit of normal was 
approximately 55%. Levels appeared to return to normal after treatment discontinuation and did not 
appear to have any clinical consequences. Baseline testing, followed by monthly monitoring of complete 
blood counts is recommended for the first 12 months of treatment with olaparib, and periodically after 
this time to monitor for clinically significant changes in any parameter during treatment which may 
require dose interruption or reduction and/or further treatment.  
 


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Other laboratory findings in clinical studies with olaparib the incidence of CTCAE Grade ≥2 shifts 
(elevations) from baseline in blood creatinine was approximately 15%. Data from a double-blind placebo-
controlled study showed median increase up to 23% from baseline remaining consistent over time and 
returning to baseline after treatment discontinuation, with no apparent clinical sequelae; 90% of patients 
had creatinine values of CTCAE Grade 0 at baseline and 10% were CTCAE Grade 1 at baseline. Nausea 
and vomiting Nausea was generally reported very early, with first onset within the first month of olaparib 
treatment in the majority of patients. Vomiting was reported early, with first onset within the first two 
months of olaparib treatment in the majority of patients. Both nausea and vomiting were reported to be 
intermittent for the majority of patients. Combination studies Safety data from studies in which olaparib 
has been administered in combination with other agents are discussed in Section 5.2.4 of the IB.  The 
degree of bone marrow suppression observed in some patients in the combination studies has however 
been greater than would be expected with the chemotherapy agent alone, as per label information. 
Myelotoxicity has been observed in studies evaluating olaparib with the following combination therapies: 
DTIC; carboplatin; paclitaxel; carboplatin + paclitaxel; gemcitabine; topotecan; cisplatin; doxorubicin, 
cisplatin + gemcitabine; or irinotecan. 
 
Adverse events of special interest 
Myelodysplastic syndrome/acute myeloid leukemia: The incidence of MDS/AML in patients treated in 
clinical trials with olaparib monotherapy, including long-term survival follow-up, was <1.5% and the 
majority of events had a fatal outcome. All patients had potential contributing factors for the development 
of MDS/AML, having received previous chemotherapy with platinum agents. Many had also received 
other DNA damaging treatments. The majority of reports were in germline BRCA mutation carriers and 
some of the patients had a history of previous cancer or of bone marrow dysplasia. If MDS and/or AML 
are confirmed while on treatment with olaparib, it is recommended that olaparib should be discontinued 
and the patient be treated appropriately. 
 
New Primary Malignancies other than MDS/AML: New primary malignancies have been reported in <1% 
of patients. There were other contributing factors/potential alternative explanations for the development 
of the new primary malignancy in all cases, including documented BRCA mutation, treatment with 
radiotherapy and extensive previous chemotherapy including carboplatin, taxanes, anthracyclines and 
other alkylating and DNA damaging agents. 
 
Pneumonitis: Pneumonitis has been reported in <1.0% patients treated with olaparib monotherapy in 
clinical studies. Reports of pneumonitis had no consistent clinical pattern and were confounded by a 
number of pre-disposing factors (cancer and/or metastases in lungs, underlying pulmonary 
disease, smoking history, and/or previous chemotherapy and radiotherapy). When olaparib 
was used in clinical studies in combination with other therapies there have been events with a 
fatal outcome. If patients present with new or worsening respiratory symptoms such as 
dyspnoea, cough and fever, or anabnormal chest radiologic finding is observed, olaparib 
treatment should be interrupted and prompt investigation initiated. If pneumonitis is 
confirmed, olaparib treatment should be discontinued and the patient treated appropriately. 
Clinical experience with olaparib is fully described in the current version of the olaparib Investigator’s 
Brochure. 
Olaparib in Patients with Prostate Cancer and Defects in DNA Repair Genes:  
The Trial of PARP Inhibition in Prostate Cancer (TOPARP-A) evaluated olaparib in patients with 
prostate cancer and DNA repair deficiency.28 The primary endpoint was response rate (either objective 
radiographic response, 50% reduction in PSA level, or reduction in circulating tumor cells. All patients 
were hormone refractory and had received docetaxel and most had been treated with abiraterone or 


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enzalutamide (98%). Fifty patients were entered. Overall 16 of 49 (33%) evaluable patients were 
biomarker positive indicative of alterations in one of the following DNA repair genes -BRCA1/2, ATM, 
Fanconi anemia genes, or CHEK2. Of the 16 patients with deleterious changes in DNA repair genes, 14 
(88%) responded to olaparib. The median survival was 13.8 months for biomarker positive patients as 
compared to 7.5 months for biomarker negative patients.28 Toxicity including grade 3 or  4 anemia 
(10/50), fatigue 6/50), thrombocytopenia (2/50) and neutropenia (2/50). 
 
PSA For Determining Response/Progression in Prostate Cancer:  
A 25% increase in Serum PSA from baseline and a 50% fall in serum PSA has become a standard 
criteria for assessing progression/response in prostate cancer, 29 since radiographic measurement 
by RECIST criteria are very difficult in prostate cancer. The criteria were used in the phase III 
TAX327 prostate cancer trial and other phase III trials. 30,31 The TOPARP-A trial with olaparib 
also utilized PSA as the primary determinant of response. 28 
 
Summary of Proposal:  
This protocol will evaluate the use of olaparib prior to radical prostatectomy for patients with locally 
advanced prostate cancer and defects in DNA repair genes. Tumor tissue and peripheral blood (peripheral 
blood is not required, just highly recommended) will be sent to Foundation Medicine, Cambridge 
Massachusetts, for genomic analysis. Patients found to have DNA defects (as assessed in tumor tissue via 
the FoundationOne assay or cell-free DNA via the FoundationACT assay if insufficient tumor is available 
for the FoundationOne assay) as outlined in the eligibility will be formally screened. Patients will receive 
2 cycles of olaparib, as described on the TOPARP-A trial.28 Patients will then be screened for progression 
by serum PSA. Progression will be defined as an increase of > 25% in PSA from baseline. Patients 
without evidence of progression will receive a third cycle of treatment then undergo radical 
prostatectomy. 
 
To assess response both PSA and Circulating tumor cells will be used. The primary assessment for 
response will be a reduction of at least 50% in the prostate-specific antigen level as utilized in the 
TOPARP-A trial. A secondary response assessment will be a reduction in the circulating tumor-cell count 
from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml as also utilized in the TOPARP-A 
trial. Circulating tumor-cell counts will be performed by CellSearch (Quest Diagnostics). Secondary 
efficacy assessments will also be based on pathologic assessments as described by Efstathiou et al and 
will include pathologic CR and pathologic stage of T2N0 versus > T2N0.14 Since localized prostate cancer 
can be difficult to measure radiographically RECIST criteria will not be part of response assessment.  
 
While high PSA responses (>90%) have been reported in studies of androgen deprivation therapies, these 
responses have not been associated a high degree of major pathologic response. For example in the study 
by Efstathiou et al, pathologic downstaging was reported in 32% and 50% of patients receiving LHRH + 
abiraterone + enzalutamide as compared to LHRH + abiraterone, respectively. The pathologic complete 
response rate was 0% and 2% respectively.  Thus the primary response endpoint will be PSA response 
since this is objective, established and straightforward to measure. However, secondary assessments will 
also be important and based on pathologic criteria and reduction in circulating tumor cells. PSA 
progression-free survival will be an important assessment on the systemic effect of olaparib.  
The primary objective of this proposal is to evaluate the response rate of neoadjuvant olaparib in patients 
who will be undergoing radical prostatectomy but are at very high risk for recurrence. Patients with 
germline or somatic alterations in DNA repair genes will be eligible. The goal of this trial is to establish 
the activity of olaparib in the high-risk perioperative setting since recent phase III trials of perioperative 


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docetaxel and combination hormone therapies were negative leaving an open space for an active targeted 
agent such as olaparib.  
 
3.0 PATIENT ELIGIBILITY: Source documentation certifying each inclusion and exclusion is 
required to be sent to BrUOG to certify eligibility.  
3.1 Conditions for Patient Eligibility 
3.1.1 Biopsy confirmed adenocarcinoma of the prostate. 
3.1.2 High risk for recurrence after prostatectomy including any of the following 
• 
Lymph node involvement by radiographic criteria 
• 
T3 or T4 disease by radiographic criteria 
• 
T2 disease and either PSA > 20 or Gleason 8,9 or 10 
3.1.3 Mutations in any of the following DNA repair genes: BRCA1, BRCA 2, ATM, CHEK1, CHEK2, 
FANCONIS ANEMIA (FANCL), HDAC2, PALB2, BARD1, BRIP1, CDK12, PPP2R2A, RAD51B, 
RAD51C, RAD51D, or RAD54L, as detected by next generation sequencing performed on tumor 
specimen or circulating tumor DNA (ctDNA). Next generation sequencing must be confirmed by 
Foundation Medicine. 
If prior testing has been completed, additional testing is not needed.  
3.1.4  No prior chemotherapy or radiation for prostate cancer or PARP inhibitor. Prior and current 
hormone therapy (< 6 months from start date on study) for prostate cancer is allowed. Patients are 
allowed to remain on hormone therapy on study.  
3.1.5 ECOG performance status 0-1. 
3.1.6  Age>18. 
3.1.7  Required entry laboratory parameters within 14 days of study registration 
• 
ANC≥ 1,500 cells/mm3; 
• 
Hemoglobin > 10.0g/dL with no blood transfusion in the last 28 days 
• 
Platelet count ≥100 x 109/L,  
• 
White blood cell > 3x109/L 
• 
Total bilirubin ≤  1.5 x ULN,  
• 
AST and ALT ≤  2.5 x ULN 
• 
Patients must have creatinine clearance estimated using the Cockcroft-Gault equation of 
≥51 mL/min: 
Estimated creatinine clearance = (140-age [years]) x weight (kg)    (x F)a 
 
 
 
 
 
serum creatinine (mg/dL) x 72 
a where F=1 for males. 
3.1.8   Life expectancy of at least 1 year as documented by treating physician.  
3.1.9  All Men must be willing to consent to using a form of highly effective contraception while on 
treatment and for at least 4 months after last treatment on study 
3.1.10 Signed study-specific consent form prior to study entry. 
3.1.11 Patient is willing and able to comply with the protocol for the duration of the study including 
undergoing treatment and scheduled visits and examinations- to be documented and submitted to 
BrUOG. 
3.1.12 Patient agreed to not receiving any live virus and live bacterial vaccines while receiving study 
medication and during the 30 day follow up period.   
3.1.13Patient agreed to not consume grapefruit juice while on study treatment.  
 
3.2 Exclusion Criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled  


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7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
10 
3.2.1 
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or 
staff at the study site or BrUOG) 
3.2.2 
Participation in another clinical study with an investigational anticancer product during the last 2 
months (from day 1 of treatment on this trial).  
3.2.3 
Any previous treatment with PARP inhibitor for this or another cancer, including olaparib. 
3.2.4 
Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer or 
other solid tumors including lymphomas (without bone marrow involvement) which was 
curatively treated with no evidence of disease for ≥5 years from time of study registration. 
Diagnosis date and treatment confirmation required to be sent to BrUOG. Certification from 
treating physician that patient is disease free is required. 
3.2.5 
Resting ECG with QTc > 470 msec on 2 time-points within a 24 hour period or known family 
history of long QT syndrome 
3.2.6 
Patients receiving any systemic chemotherapy or radiotherapy within 3 weeks prior to study 
treatment. The last dose on antiandrogen hormone therapy must be > 72 hours prior to the first 
dose of olaparib. 
3.2.7 
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.  
3.2.8 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. See section 
4.3.1.3 
3.2.9 
Concomitant use of the substrates of CYP3A4, CYP1A2, 2B6, 2C9, 2C19 and P-gp should be 
cautioned while on study. Documentation that this was explained to patient or document not 
applicable. See section 4.3.1.5. 
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 
3.2.10 Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2) 
deemed related to previous cancer therapy, excluding alopecia. 
3.2.11 Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of 
MDS/AML. To be certified by treating physician. 
3.2.12 Patients with brain metastases. To be confirmed by treating physician. A scan to confirm the 
absence of brain metastases is not required unless the patient shows signs or symptoms deemed 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
11 
concerning to the treating physician. The patient can receive a stable dose of corticosteroids 
before and during the study as long as these were started at least 4 weeks prior to treatment. 
Patients with spinal cord compression unless considered to have received definitive treatment for 
this and evidence of clinically stable disease for 28 days. 
3.2.13 Major surgery within 2 weeks of starting study treatment and patients must have recovered from 
any effects of any prior major surgery. 
3.2.14 Patients 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 CT scan or any psychiatric disorder that 
prohibits obtaining informed consent. This is to be confirmed by treating physician. 
3.2.15 Patients unable to swallow oral medications.  Patients with gastrointestinal disorders likely to 
interfere with absorption of the study medication.  
3.2.16 Immunocompromised patients that according to treating investigator would increase their risk to 
protocol treatment, or Patients who are known to be HIV positive. 
3.2.17 Patients with a known hypersensitivity to olaparib or any of the excipients of the product. 
3.2.18 Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting the infection 
through blood or other body fluids 
3.2.19 Previous allogenic bone marrow transplant or double umbilical cord blood transplantation 
(dUCBT) 
3.2.20 Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells 
and platelet transfusions are acceptable as long as not within 28 days from study registration). If 
not applicable, document no prior transfusions.  
3.2.21 Major medical or psychiatric illness which, in the investigator’s opinion, would prevent 
completion of treatment and would interfere with follow-up. 
3.2.22 History and/or confirmed pneumonitis. To be confirmed in writing. 
3.2.23  No distant visceral metastases. 
 
3.3 Re-Screening: 
Re-screening is defined in this protocol as screening a patient for this trial, once they have been found to 
not meet study eligibility criteria, outside of the 28-day screening window. While in the 28-day screening 
window, the patient may be screened multiple times (i.e. labs may be drawn and re-drawn), however, if a 
patient signs consent and then screen fails (does not meet the eligibility criteria) and the treating MD 
requests that the patient be re-screened outside of the 28 day screening window, sites are to contact 
BrUOG who will assess patients on a case by case basis. Depending on many diverse factors including 
the conditions that are being evaluated, the reasons why patient initially screen failed, and the nature of 
the initial results, re-screening may or may not be medically/scientifically appropriate. BrUOG should be 
made aware of such a situation with at least 72 hours and provided with information on screen-failure.  
 
 
 
 
 
 
 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
12 
4.0 TREATMENT 
4.1 Schema 
 
Patients will be followed for PSA progression free survival 
4.2 Olaparib: 
1 cycle = 4 weeks 
Dose: Olaparib 300 mg BID q 4 weeks +/- 3 days 
All patients will receive 2 cycles of Olaparib. Post 2 cycles, patients will be assessed for progression by 
PSA. (Progression is defined as an increase of > 25% in PSA from baseline). 
If patients are found to progress they will be removed from study treatment and managed according to 
standard practice. If they have not been found to progress, a 3rd cycle of treatment will be 
administered prior to the patient going on to surgery.  
There must be at least 21 days between the final dose of Olaparib and surgery (count the day after the last 
dose to the surgery date). Surgery is recommended > 21 days and less than 42 days from the last dose of 
olaparib.  
 
Patients should be instructed on the following each cycle: 
 
Olaparib tablets should be taken at the same time each day, approximately 12 hours apart with one glass 
of water.   
The olaparib tablets should be swallowed whole and not chewed, crushed, dissolved or divided.  
Olaparib tablets can be taken with or without food. 
Newly Diagnosed Prostate 
Cancer:
T3 or T4 or Node + Prostate 
Cancer  
OR T2 disease and either 
PSA> 20 or Gleason 8,9 or 10
Baseline MRI, PSA and 
circulating tumor cells
Somatic or Germline 
Alteration of 
mutations in 3.1.3
Olaparib 300 mg 
BID for 2 cycles 
then assessment 
of potential 
progression. No 
PD= receive 3rd 
cycle of 
Olaparib 300mg 
BID. Then to 
surgery
PD=No cycle 3, 
go directly to 
surgery
Radical 
Prostatectomy
Assess for path 
CR and stage 
T2N0 vs >T2N0
Assess response:. 
Primary Assessment 
Reduction of at least 50% in 
the prostate-specific antigen 
level
Secondary Assessment: 
Reduction in the circulating 
tumor-cell count from 5 or 
more cells per 7.5 mL of 
blood to less than 5 cells per 
7.5 mL. 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
13 
If vomiting occurs shortly after the olaparib is swallowed, the dose should only be replaced if all of the 
intact tablets can be seen and counted.   
Should any patient enrolled on the study miss a scheduled dose for whatever reason (e.g., as a result of 
forgetting to take the tablets or vomiting), the patient will be allowed to take the scheduled dose up to a 
maximum of 2 hours after that scheduled dose time.  If greater than 2 hours after the scheduled dose time, 
the missed dose is not to be taken and the patient should take their allotted dose at the next scheduled 
time. 
4.3 Prohibited and Restricted Therapies While Receiving Olaparib: 
4.3.1 Medications that may NOT be administered unless otherwise noted 
4.3.1.1 Other anti-cancer therapy: 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. (Patients may 
have received up to 6 months of anti-androgen hormone therapy prior to entering the study.) The last dose 
on anti-androgen hormone therapy must be > 72 hours prior to the first dose of olaparib. Anti-androgen 
therapy must not be administered while receiving olaparib.) 
4.3.1.2 Live Virus and live bacterial vaccines: Live virus and live bacterial vaccines should not be 
administered whilst the patient is receiving study medication and during the 30 day follow up period. An 
increased risk of infection by the administration of live virus and bacterial vaccines has been observed 
with conventional chemotherapy drugs and the effects with olaparib are unknown. 
4.3.1.3 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. 
Patients requiring these medicines should be removed from study treatment.  
4.3.1.4 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. 
4.3.1.5: 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.  
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 


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7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
14 
• 
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 
4.3.1.5 Grapefruit juice 
It is not recommended to consume grapefruit juice while on olaparib therapy. 
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). 
4.3.1.6 Anticoagulant Therapy 
Patients who are taking warfarin may participate in this trial; however, it is recommended that 
international normalised ratio (INR) be monitored carefully as per institutional practice then monthly if 
the INR is stable. Subcutaneous heparin and low molecular weight heparin are permitted. 
Anti-emetics/Anti-diarrheals 
If a patient develops nausea, vomiting and /or diarrhea, then these symptoms should be reported as AEs 
and appropriate treatment of the event given on the concomitant drug log 
Contraception 
Male patients with partners of child bearing potential, who are sexually active, must agree to the use of a 
form of highly effective contraception. This should be started from the signing of the informed consent 
and continue throughout period of taking study treatment and for 4 months after last dose of study drug. 
5.0 TOXICITIES, DOSE MODIFICATIONS, AND MANAGEMENT 
Toxicities will be recorded as adverse events on the Adverse Event case report form and must be graded 
using The National Cancer Institute’s Common Toxicity Criteria (CTCAE) version 4.03 (Appendix C). 
Dose Reductions for Toxicity deemed possibly related or related to olaparib 
 
 
 


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7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
15 
In order to begin a new cycle of treatment (day 1) the following criteria must be met: 
• 
ANC≥ 1,500 cells/mm3; 
• 
Platelet count ≥100 x 109/L,  
• 
All treatment related non-heme toxicities must be < grade 2 (including electrolyte imbalances) 
• 
WBC >2,000mm3 
• 
HGB > 8 g/dl (if < 8 must improve to > 10g/dl and then dose reduce) 
• 
Estimated CrCl > 51ml/min. If < 51 ml/min: retest promptly and see “renal” section below 
 
5.1 Dose Reductions for related Toxicity Requiring Dose Reductions (I and II): 
I. Patients developing the following treatment related toxicities at any time point during 
treatment (drug) are required to have olaparib held and not restarted until the toxicity resolves 
to grade 2 or less.  
• 
ANC <1000/mm3 with fever or infection 
• 
Grade 3 or 4 treatment related non-hematologic toxicities excluding alopecia. Grade 3 or 4 
electrolyte abnormalities do not require a dose modification if the electrolyte disorder can be 
corrected to grade 2 or less within 72 hours. This must be documented and submitted to 
BrUOG. 
• 
Delay of treatment for > 2 weeks due to toxicity. 
• 
Estimated CrCl < 51 ml/min: retest promptly and see “renal” section below. If not taking 
patient off study then dose must be reduced.  
 
Patients experiencing any of the above toxicities will be required to have a 1 dose level reduction of 
olaparib.  Each patient can be dose reduced a total of 2 times. All dose reductions are permanent. 
 
Patients requiring > 4 week dose delay for treatment related toxicities should be removed from protocol 
treatment.  
 
 
II. Patients experiencing the following toxicities, regardless of relationship, at any time point 
during treatment (drug), are required to have olaparib held and not re-started until resolution to 
grade 1 or less: 
• 
Grade 4 neutropenia (ANC < 500/mm3) 
• 
Grade 3 neutropenia (ANC< 1000/mm3) 
• 
Grade 3 thrombocytopenia (Platelets <50,000/mm3-25,000) 
• 
Grade 4 thrombocytopenia (Platelets <25,000/mm3) 
• 
Grade 3 leukopenia (WBC<2,000mm3-1,000) 
• 
Grade 4 leukopenia (WBC <1,000mm3) 
• 
Grade 3 anemia (HGB < 8 g/dl) (must improve to > 10g/dl) 
 
Patients experiencing any of the above toxicities will be required to have a 1 dose level reduction of 
olaparib.  Each patient can be dose reduced a total of 2 times. All dose reductions are permanent. 
 
Study treatment should be discontinued if HGB, WBC, or PLT counts do not recover to CTCAE gr 1 
or better within 4 weeks of dose interruption.  
 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
16 
 
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder should be reported 
as an SAE to BrUOG and full reports must be provided by the investigator to BrUOG, who will then 
report all information to AstraZeneca Patient Safety. Olaparib treatment should be discontinued if 
patient’s diagnosis of MDS and/or AML is confirmed. 
Renal: 
If a patient’s estimated calculated clearance falls below the threshold for study inclusion (≥51 ml/min), 
retesting should be performed promptly. A one level dose reduction is recommended for patients who 
develop moderate renal impairment (calculated creatinine clearance by Cockcroft-Gault equation of 
between 31 and 50 ml/min). 
In instances where the CrCl falls to between 31 and 50 mL/min, the investigator should use his or her 
discretion in determining whether a dose change or discontinuation of therapy is warranted. 
 
Olaparib has not been studied in patients with severe renal impairment (creatinine clearance ≤ 30 ml/min) 
or end-stage renal disease; if patients develop severe impairment or end stage disease is it recommended 
that olaparib be discontinued. 
 
Patients requiring > 4 week dose delay for treatment related toxicities should be removed from protocol 
treatment.  
 
Patients entered on the study who subsequently require strong or moderate CYP3A inhibitors should be 
removed from study treatments.  
 
5.2 Modifications for Toxicity, Additional Considerations.  
Any toxicity observed during the course of the study could be managed by interruption of the dose of 
study treatment or dose reductions at the discretion of the treating physician and as per institutional 
standard practice.  
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion. BrUOG 
must be informed of all treatment interruptions with reason. If the reduced dose of 200 mg twice daily is 
not tolerable, no further dose reduction is allowed and study treatment should be discontinued.  
Once dose is reduced, escalation is not permitted. 


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7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
17 
5.2.1 Management of hematological toxicity 
Management of anemia 
Table 4 
Management of anemia 
Hemoglobin 
Action to be taken 
Hgb < 10 but ≥ 8 g/dl 
(CTCAE Grade 2) 
Give appropriate supportive treatment per institutional practice and 
investigate causality.  
Investigator judgement to continue olaparib with supportive treatment (eg 
transfusion) or interrupt dose for a maximum of 4 weeks.  
If dose is interrupted:  
If repeat Hb< 10 but ≥ 8 g/dl, dose interrupt (for max of 4 weeks) until 
Hgb ≥ 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. 
Hgb < 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 Hgb ≥ 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 Hgb 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 patients 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 5.2.1.1 for the management of this.  
 
5.2.1.1 Management of neutropenia, leukopenia and thrombocytopenia 
 
Management of neutropenia, leukopenia and thrombocytopenia 
 
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 CTCAE grade 3 or worse neutropenia, 
leukopenia or thrombocytopenia occurs. 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
18 
Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is not recommended, however, 
if a patient develops febrile neutropenia, study treatment should be stopped and appropriate management 
including G-CSF should be given according to local hospital guidelines. Please note that G-CSF should 
not be used within at least 24 h (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. 
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 CTCAE grade 3 or worse anaemia and/or 
development of blood transfusion dependence 
• 
≥2 week interruption/delay in study treatment due to CTCAE grade 3 or worse neutropenia 
(ANC < 1 x 109/L) 
• 
≥2 week interruption/delay in study treatment due to CTCAE 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 CTCAE gr 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 to BrUOG and full reports must be provided by the investigator to BrUOG, who will then 
report all information to AstraZeneca Patient Safety. Olaparib treatment should be discontinued if 
patient’s diagnosis of MDS and/or AML is confirmed. 
Management of non-hematological toxicity 
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion. 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 
investigator considers to be related to administration of study treatment. (see section 5.1) 
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. 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
19 
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 investigator. If significant pulmonary 
abnormalities are identified, these need to be discussed with the Study Physician. 
Management of nausea and vomiting 
Nausea was generally reported very early, with first onset within the first month of olaparib 
treatment in the majority of patients. Vomiting was reported early, with first onset within the 
first two months of olaparib treatment in the majority of patients. Both nausea and vomiting 
were reported to be intermittent for the majority of patients and can be managed by dose 
interruption, dose reduction and/or antiemetic therapy. Antiemetic prophylaxis is not 
required. 
No routine prophylactic anti-emetic treatment is required at the start of study treatment, however, 
patients should receive appropriate anti-emetic treatment at the first onset of nausea or vomiting 
and as required thereafter, in accordance with local treatment practice guidelines.  Alternatively, 
olaparib tablets can be taken with a light meal/snack (ie 2 pieces of toast or a couple of biscuits). 
As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), generally a single 
agent antiemetic should be considered eg dopamine receptor antagonist, antihistamines or 
dexamethasone. 
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 BrUOG.  
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the CRF.  
If the patient requires a non-study related surgery or if they had a planned surgery- which would have had 
to be reported prior to enrollment, then 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. 
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, patients should be 
advised to use caution while driving or using machinery if these symptoms occur.  
Overdose – See reference in section 11  
 
 
 
 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
20 
6.0 SCHEDULE OF EVALUATIONS / STUDY CALENDAR *The day an assessment (PE, 
labs, scan etc) is completed is day 0 for counting for example labs drawn on Friday can be used for 
Monday dosing as this is within 3 days* 
 
Parameter 
Pre-study, 
results and 
information to 
be sent prior to 
registration 
Prior to each 
cycle dosing (-3 
days of 
treatment) and 
approximately 
Every 2 weeks 
(mid-cycle) (+/- 
3 days) while on 
olaparib E 
2 weeks after 
Olaparib 
completed 
(+7 day 
window) 
30 days 
post drug 
(+7 days) 
& 30 days 
post 
surgery 
completion 
(+ 7 day 
window) 
Surgery 
3-8 weeks 
post end of 
olaparib 
FUJ 
Informed Consent 
(within 30 days of 
day 1) *pts are to be 
re-consented if ICF 
will be outside 30 day 
window 
X 
 
 
 
 
 
History 
X 
 
 
 
 
 
Physical 
examination 
X 
X 
XG 
 
 
 
Weight 
X 
X 
X 
 
 
 
Vital signs 
X 
X 
X 
 
 
 
Toxicity Assessment 
X 
X 
XF 
XF 
XF 
 
Concomitant 
medications 
X 
X 
X  
 
 
 
Performance 
Status 
X 
X 
X 
 
 
 
Biopsy or peripheral 
blood for assessment 
of abnormalities in 
DNA repair genes to 
Foundation 
MedicineH 
Biopsy and/or 
peripheral 
blood to be 
taken from 
anytime pre 
study. Results 
required for 
registration 
 
 
 
 
 
Assessment of 
Circulating tumor 
cells H 
28 days prior to 
the start of 
treatment 
(results not 
required to 
register) 
 
X 
 
 
 
Operative report and 
pathology report 
from prostate 
surgery 
 
 
 
 
XC 
 
CBC, diff, platelet 
countE 
X (within 14 
days) 
X 
X 
 
 
 
Na, K, BUN, Cr DE 
X (within 14 
days) 
X 
X 
 
 
 
Hepatitis B and 
Hepatitis C panel k 
X (within 14 
days of drug) 
 
 
 
 
 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
21 
AST, ALT, Bili,E 
X (within 14 
days) 
X 
X 
 
 
 
INR 
X (within 14 
days) 
As clinically 
indicated 
 
 
 
 
PSAE 
X (within 14 
days of drug) 
Week 8 (post- 
cycle 2 labs/pre-
cycle 3) 
X 
 
 
X 
UA 
X (within 14 
days of drug) 
 
 
 
 
 
MRI or CT pelvisA 
X (within 56 
days ) 
As clinically 
indicated 
 
 
 
As 
clinically 
indicated 
Bone scanA 
X (within 56 
days) 
As clinically 
indicated 
 
 
 
As 
clinically 
indicated 
Chest-xray A 
X (within 56 
days) 
 
 
 
 
 
2 EKGB 
X within 56 
days 
 
 
 
 
 
Progression Free and 
overall Survival 
Disease status  
 
 
 
 
 
X 
 
A- Pelvic CT Scan or MRI, chest x-ray (chest CT may substitute) and bone scan for disease assessment to be performed within 56 
days of study entry/registration. Report sent to BrUOG.. It is required that imaging that defined progression be sent to BrUOG as 
date of progression will be captured.  
B- EKG within 56 days of study entry. Report to be sent to BrUOG at registration. Patient must have 2 EKGs within a 24 hour 
time period to certify patient does not meet exclusion 3.2.5 
C- The operative note and pathology note will be sent to BrUOG. Documentation of post op complications to be submitted to 
BrUOG as well on AE log (if none, document “none” on AE log). 
D CrCl to be calculated as well for required dose modification 
E It is appropriate to use labs from screening for day 1, if labs are within 14 days. It is appropriate to use physical, weight, vitals, 
toxicity assessment, concomitant medication, performance status from screening for day 1 if within 14 days. All subsequent labs 
can be drawn within (-)3 days prior to day 1 of treatment of each week and +/- 3 days every 2 weeks while on study. One 
additional day is provided for a holiday. For PSA drawn week 8, this value is used to determine if a patient can continue on study 
for cycle 3 or if they must come off study drug treatment and go onto surgery.  
F Adverse event evaluation will be done 2 weeks post treatment (drug) + 7 days and again with 30 days post last dose of study 
drug. A one week window is provided (+7 days). AE evaluation will be done again 30 days (+ 7 days) post surgery and this time 
point will capture surgical complications and delayed toxicities from the drug. This appointment is to occur with the treating 
physician or sub-investigator on the trial. SAEs and AESI will be captured through 30 days (+ 7 days) from the end of treatment 
(drug or surgery, whichever is last). SAEs and AESI occurring outside this 30 day window must be reported if the event is 
considered to be possibly related to the drug. BrUOG must be made aware of new treatment with start date.  
G Physical exam to be done in coordination with 2 week AE assessment only (+ 7 day window), No physical exams are required 
post 2 week visit, but if one if completed at 30 days please submit to BrUOG. 
H Biopsy for histologic confirmation of prostate cancer and assessment of DNA repair gene abnormality by Foundation Medicine 
can be performed anytime pre-study (diagnostic biopsy). Foundation Medicine final report to be sent to BrUOG in order to 
register patient. Peripheral blood analysis for circulating tumor cells should be performed with the use of CellSearch assay 
(Quest Diagnostics) and ordered as per institutional practice. The CTCs will be ordered even if at baseline the 
analysis is negative. 
J BrUOG will be notified every 6 months (+/- 2 months) for 2 years the disease-free and overall survival status. Once patient is 
found to progress PSA is no longer required. If patient begins another treatment, the type of adjuvant treatment will be submitted 
to BrUOG. 
k. HBsAg, AntiHBS, HepBcore, HCV antibody, HCV RNA 
 
 
 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
22 
7.0 RESPONSE ASSESSMENT: 
Primary Response Criteria  
• 
Reduction of at least 50% in the prostate-specific antigen level from baseline will be considered a 
response. 
• 
A 25% increase in PSA from baseline (registration) will be classified as disease progression.  
Secondary Assessment of Response  
• 
Reduction in the circulating tumor-cell count from 5 or more cells per 7.5 mL of blood to less 
than 5 cells per 7.5 mL. (CTCs will be determined by CellSearch assay through Quest 
Diagnostics) 
• 
Pathologic complete response 
• 
Pathologic stage of T2N0 versus > T2N0 
• 
PSA progression-free survival. 
 
Criteria for Disease Progression:  
  
• 
First evidence of any lesion found on a scan suggesting metastatic disease (scans are to be done 
as clinically indicated)  
• 
PSA progression: a 25% increase in the PSA level from baseline 
 
8.0 
PATIENT REGISTRATION  
All patients will be registered through the Brown University Oncology Research Group Central Office. 
Eligibility Checklist with supporting documentation, On Study Form and the signed Patient Consent 
Form must be faxed to the BrUOG Central Office, Fax: (401) 863-3820 or emailed to 
BrUOG@brown.edu, at the time of registration and prior to patient treatment. 
Details of patient’s study participation should be documented in clinic/file notes. The Brown University 
Oncology Research Group will provide case report forms, included in the appendix, for the recording and 
collection of data. In the event of corrections, each correction will be initialed and dated by the person 
making the correction. The investigator will sign the case reports to indicate that, to his/her knowledge, 
they are complete and accurate. Case report forms, flow sheets, off-study forms and follow-up forms 
should be mailed / faxed to:  
Brown University Oncology Research Group, 
Brown University 
Box G-R 001 
Providence, RI 02912 
Fax: 401-863-3820 
Phone: 401-863-3000 
BrUOG@brown.edu 
All support data must be sent in with the corresponding BrUOG forms. It is the treating physician’s 
responsibility to review all data submitted to the BrUOG Central Office for accuracy and completeness 
and he/she must sign the off study form.  Sites must confirm each element of inclusion and exclusion 
criteria and also provide support for all “pre-study” assessments on the schedule of evaluations table. 
It is the treating physician’s responsibility to review all data submitted to the BrUOG Central Office for 
accuracy and completeness. 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
23 
9.0  
PHARMACEUTICAL INFORMATION 
The AstraZeneca Pharmaceutical Development R&D Supply Chain will supply olaparib to the 
investigator as oval tablets 
Investigational product: Olaparib will be supplied as 100mg tablets, 150 mg tablets. 
For all centers, 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 patients on Day 1 and every 4 weeks (+/- 3 days) thereafter until 
the patient completes the study, withdraws from the study or closure of the study.   
Study treatment is available as a tablet containing 100 or 150 mg of olaparib in 32 count bottles. 
Patients will be administered olaparib orally twice daily.  
Dose Reductions  
For guidance on dose reductions for management of AEs refer to section 5.0 
Patients requiring strong or moderate CYP3A inhibitors are not eligible for the study ( 2 week wash-out is 
required). Patients entered on the study who subsequently require strong or moderate CYP3A inhibitors 
should be removed from study treatments.  
Renal Impairment    
If subsequent to study entry and while still on study therapy, a patient’s estimated calculated clearance.  
falls below the threshold for study inclusion (≥51 ml/min), retesting should be performed promptly.  
A one level dose reduction is recommended for patients who develop moderate renal impairment 
(calculated creatinine clearance by Cockcroft-Gault equation of between 31 and 50 ml/min) for any 
reason during the course of the study: the dose of olaparib should be reduced to 200mg BD. 
 
Because the CrCl determination is only an estimate of renal function, in instances where the CrCl falls to 
between 31 and 50 mL/min, the investigator should use his or her discretion in determining whether a 
dose change or discontinuation of therapy is warranted. 
 
Olaparib has not been studied in patients with severe renal impairment (creatinine clearance ≤ 30 ml/min) 
or end-stage renal disease; if patients develop severe impairment or end stage disease is it recommended 
that olaparib be discontinued. 
 
Labeling 
Olaparib supply will be shipped unlabeled. Drug will be shipped through Fisher Clinical Services Depot. 
A label will be found on the box that will contain the bottles inside. The bottles of drug will not be 
labeled themselves. The label on the box will outline part #, receiving #, Lot #, description (such as drug 
name) and quantity. Fisher Clinical uses the part # and receiving # as product identifiers.  
It is required that upon receipt of drug shipment the pharmacy label both the boxes and bottles of Olaparib 
to include at the very least, a label noting:  
• 
BrUOG 337 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
24 
• 
For investigational use only 
• 
Expiration date 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The investigational 
product label on the bottle and the Investigator Brochure specifies the appropriate storage. 
Ordering 
Initial: 
• 
Following submission and approval of the required regulatory documents, BrUOG will share all 
approval documented with AstraZeneca and once confirmed by AstraZeneca and BrUOG, BrUOG will 
activate the participating hospital, which will allow for initial drug request.    
 
All drug orders: 
• 
There is no drug order form for this trial, the drug request must be sent to the following email addresses, 
requesting the number of initial bottles needed.  
• 
It is required that the pharmacist confirm receipt of the requested drug shipment to the email addresses 
as well.  
• 
The drug request email must be printed and saved in the BrUOG 337 pharmacy study binder, along 
with the shipment/packaging slip and confirmation of receipt email. 
• 
All drug orders must be emailed to: 
o Gayle.Ewing@astrazeneca.com  
o  cc to BrUOG@brown.edu 
 
10.0 
AGENT ACCOUNTABILITY 
Investigational Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all olaparib using a Drug 
Accountability Record Form.  Sites may utilize the NCI drug accountability form. Sites must track lot 
numbers, expiration dates, dosing dates and doses per patients and overall inventory. Sites must submit to 
BrUOG accountability logs during the study, at the end of the study and prior to destruction. To be able to 
destroy drug, sites must contact BrUOG who will obtain approval from Astra Zeneca prior to destruction. 
See section 15.5 as well 
 
10.1 Treatment Compliance 
 
Records of olaparib used, dosages administered, and intervals between visits will be recorded during the 
study.  
Research staff are required to perform drug accountability prior to each new cycle of treatment to assess 
accountability and compliance for the prior cycle. Source documentation on the accountability is required 
to be kept as documentation in the patient’s shadow chart in the research office at the treating hospital. 
 
All drugs will be administered to eligible patients under the supervision of the investigator or identified 
sub-investigator(s). The pharmacist will maintain records of drug receipt drug preparation, and dispensing, 
including the applicable lot numbers. Any discrepancy between the calculated dose and dose administered 
and the reason for the discrepancy must be recorded in the source documents. 
 
 
 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
25 
11.0 ADVERSE DRUG REACTION (ADR) REPORTING 
BrUOG considers the AE and SAE reporting period to begin when the subject signs the study specific 
informed consent. 
 
This study will utilize the descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03 for grading all adverse events. All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.03. A copy of the CTCAE version 
4.03 can be downloaded from the CTEP web site (http://ctep.cancer.gov).  
 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and that does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use of 
olaparib whether or not considered related to olaparib. This includes any newly occurring event or 
previous condition that has increased in severity or frequency since the administration of drug. 
 
During clinical trials, adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should 
not be questioned regarding the specific occurrence of one or more adverse events.) 
 
Adverse events (AEs) will be recorded in the case report form for the duration of the trial, regardless of 
whether or not the event(s) are considered related to trial medication.  
 
11.1 Definitions 
An adverse event is any new, undesirable medical experience or change of an existing condition that 
occurs during or after treatment, whether or not considered product-related. 
Serious adverse event (SAE) 
Serious adverse event (SAE) is defined as one of the following: 
• 
Is fatal or life-threatening 
• 
Results in persistent or significant disability/incapacity 
• 
Constitutes a congenital anomaly/birth defect 
• 
Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
o Elective or pre-planned treatment for a pre-existing condition that is unrelated 
to the indication under study and has not worsened since signing the informed 
consent **This must be documented and submitted to BrUOG** 
o Treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission 
o Social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
 
The definition of serious adverse event (experience) also includes important medical event. Medical and 
scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other 
situations, such as important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above.  These should also usually be considered serious.  Examples 
of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
26 
dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency or drug 
abuse. A new diagnosis of cancer during the course of treatment should be considered an important 
medical event. 
 
The definition of “related” being that there is a reasonable possibility that the drug caused the adverse 
experience. 
 
Note that treatment on an emergency outpatient basis that does not result in hospital admission 
and involves an event not fulfilling any of the definitions of a SAE given above is not a serious 
adverse event.  
 
Adverse event of special interest= AESI 
AESI = must be reported as a SAE even if not serious, using the important medical event 
choice 
  
Unexpected adverse event 
An adverse event that is not mentioned in the Investigator's Brochure or package insert or the specificity 
or severity of which is not consistent with the investigator's brochure or package insert. 
 
Life-threatening 
Any adverse drug experience that places the patient or subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred.  It does not include a reaction that, had it 
occurred in a more severe form, might have caused death. 
 
11.2 Monitoring of Adverse Events and Period of Observation 
Adverse events, both serious and non-serious, and deaths that occur during the patient’s study 
participation will be recorded in the source documents.  All SAEs should be monitored until they are 
resolved or are clearly determined to be due to a patient’s stable or chronic condition or intercurrent 
illness(es). 
 
11.3 BRUOG ADVERSE EVENT REPORTING REQUIREMENTS  
Investigators are required by Federal Regulation to report adverse drug reactions. Questions regarding 
drugs as used in this study should be directed to the Brown University Oncology Research Group 
(BrUOG) Central Office, Phone: (401) 863-3000 Fax (401) 863-3820, which will in turn notify the 
Principal Investigator. 
 
Intensity for each adverse event will be scored using CTCAE Version 4.03.  A copy of the CTCAE 
Version 4.03 can be downloaded from the CTEP homepage (http://ctep.info.nih.gov).  All appropriate 
treatment areas have access to a copy of the CTCAE Version 4.03.  All adverse clinical experiences, 
whether observed by the investigator or reported by the patient, must be recorded, with details about the 
duration and intensity of each episode, the action taken with respect to the test drug, and the patient’s 
outcome.  The investigator must evaluate each adverse experience for its relationship to the test drug and 
for its seriousness. 
 
11.3.1 Reporting 
To ensure patient safety, every SAE and AE of special interest (AESI), regardless of suspected 
causality, occurring after the patient has provided informed consent and until 30 days after the patient 
has stopped study treatment (+7 days) (olaparib or surgery whichever occurs last), or until the subject 
withdraws consent from study participation (declines participation) or at the time patient becomes a 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
27 
screen failure, whichever occurs first, must be reported by the site (within 5 business days of being 
made aware of the event) to BrUOG who will in turn report the SAE to AstraZeneca within 2 business 
days and up to 5 business days of being receipt of signed Medwatch 3500A from the site. Non-serious 
AEs are to be captured from time of consent until 30 days after the patient has stopped study treatment 
(+7 days) (olaparib or surgery whichever occurs last), or until the subject withdraws consent from 
study participation (declines participation) or at the time patient becomes a screen failure, whichever 
occurs first. 
Any SAEs or AESIs experienced after this 30 day period (+7 days) should only be reported to BrUOG 
if the investigator suspects there may be a causal relationship to the study treatment (the study drug 
or surgery).  
 
Information about all SAEs and AESIs are to be collected and recorded by the site (submitted to 
BrUOG) on the MedWatch 3500A and all applicable sections of the form will be completed in order 
to provide a clinically thorough report. The investigator must assess and record the relationship of 
each SAE to each specific study treatment (if there is more than one study treatment), complete 
MedWatch 3500A, within 5 business days of being made aware of the event and BrUOG will then 
send the completed 3500A form to AstraZeneca within 2 business days and up to 5 business days 
(from the time of BrUOG being in receipt of the signed site submitted Medwatch 3500A. 
The original copy of the MedWatch 3500A and the email confirmation sheet must be kept with the 
case 
report 
form 
documentation 
at 
BrUOG. 
The 
email 
is: 
AEMailboxClinicalTrialTCS@astrazeneca.com 
 
Follow-up information: The Medwatch 3500A must state that it is a follow-up to the previously 
reported SAE or AESI. Each re-occurrence, complication, or progression of the original event should 
be reported as a follow-up to that event. The follow-up information should describe whether the event 
has resolved or continues and whether the patient continued or withdrew from study participation. It 
is required that sites submit a follow-up SAE to report discharge from the hospital. 
 
For Pharmacovigilance purposes and characterisation, any case of MDS/AML or new primary 
malignancy occurring after the 30 day toxicity follow up period (+7 days) should be reported to  
BrUOG via a SAE report (Medwatch 3500A) and BrUOG will report the event to AstraZeneca 
Patient Safety, whether it is considered a non-serious AE [eg non-melanoma skin cancer] or serious, 
and regardless of investigator’s assessment of causality or knowledge of the treatment 
arm.  Investigators will be asked during the regular follow up for overall survival if the patient has 
developed MDS/AML or a new primary malignancy and prompted to report any such cases. Any 
case of MDS/AML or any new primary meets AstraZeneca criteria to be reported as a SAE on this 
trial, even if this occurs more than 30 days post the last treatment (+7 days) (olaparib or surgery, 
whatever is the last date). 
11.3.2. Pregnancy 
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 4 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.  


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exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
28 
The outcome of any conception occurring from the date of the first dose until 4 months after the last dose 
should be followed up and documented. 
11.3.3 Expedited Reporting to AstraZeneca: 
Serious adverse events (SAE) are defined above.  All SAE or AESI events must be reported, by FAX or 
email, to the Brown University Oncology Research Group who must inform AstraZeneca in writing using 
a Medwatch 3500A form (provided in a completed signed manner by the site), within 2 business days and 
up to 5 business days of receipt of completed final signed 3500A form.  The initial report must be as 
complete as possible, including an assessment of the causal relationship between the event and the 
investigational product(s), if available.  Information not available at the time of the initial report (e.g., an 
end date for the adverse event or laboratory values received after the report) must be documented on a 
follow-up report.  A final report to document resolution of the SAE or AESI (such as discharge from 
hospital) is required. A copy of the fax transmission or email confirmation of the SAE report to 
AstraZeneca should be attached to the SAE or AESI and retained with the study records at BrUOG.  
 
This includes serious, related, labeled (expected) and serious, related, unlabeled (unexpected) adverse 
experiences. All deaths during treatment or within 30 days following completion of active protocol 
therapy(+7 days)  (olaparib or surgery, whatever is the last date), must be reported to BrUOG 
within 5 business days of the site being made aware of the event, or as soon as the investigator is 
made aware of the event. If the death is thought to be related to the study treatment (drug or 
surgery), deaths must be reported to BrUOG within 24 hours of the investigator being made aware 
of the event. 
 
Any serious adverse event or AESI occurring after the patient has provided informed consent and until 4 
weeks (30 days (+7 days)) after the patient has stopped study participation/treatment (olaparib or surgery, 
whatever is the last date of treatment), or until the subject withdraws consent from study participation 
(declines participation) or at the time the patient becomes a screen failure, whichever occurs first, must be 
reported to BrUOG within 5 business days of the investigator being made aware of the event. This 
includes the period in which the study protocol interferes with the standard medical treatment given to a 
patient (e.g. treatment withdrawal during washout period, change in treatment to a fixed dose of 
concomitant medication). 
 
Serious adverse events and AESIs occurring more than 4 weeks (30 days (+7 days)) after study 
discontinuation (olaparib or surgery, whatever is the last date of treatment) need only be reported if a 
relationship to the study treatment (drug or surgery) 
 
11.4 Reporting requirements and procedures depend upon: 
1. Whether investigational agents are suspected of causing toxicity; 
2. Whether the possibility of such a toxicity was reported in the protocol, consent form, or 
manufacturer’s literature (Expected toxicity); and  
3. The severity of grade of the toxicity.   
 
11.5 Assessing Causality: 
Investigators are required to assess whether there is a reasonable possibility that treatment caused or 
contributed to an adverse event.  The following general guidance may be used: 
 
Yes: if the temporal relationship of the clinical event to treatment administration makes a  
causal relationship possible, and other drugs, therapeutic interventions or underlying conditions do not 
provide a sufficient explanation for the observed event. 
 


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exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
29 
No: if the temporal relationship of the clinical event to treatment administration makes a  
causal relationship unlikely, or other drugs, therapeutic interventions or underlying conditions provide a 
sufficient explanation for the observed event. 
 
11.6 Types of Report: For sites: 
Telephone report:  For SAE’s and AESIs notification contact BrUOG Central Office (401) 863-3000 (or 
via email), immediately upon learning of the event (within 24 hours) and provide 24 hours before 
submitting the SAE for BrUOG planning (not applicable for SAEs and AESIs that require formal 
reporting within 24 hours of Investigator being made aware of event). For follow-up SAEs and AESIs 
please inform BrUOG within 24 hours and before sending in follow-up SAE reports. 
 
Written report: Send the copy of the Medwatch 3500A form, within 5 business days of being made 
aware of the event to the BrUOG Central Office by email, scan or Fax: 
 
Brown University Oncology Research Group 
Phone: (401) 863-3000, Fax: (401) 863-3820 
Emails: BrUOG@brown.edu 
 
All deaths during treatment or within 30 days (+7 days) following completion of active protocol therapy 
(olaparib or surgery, whatever is the last date of treatment) must be reported within 5 business days of 
being made aware of the event or as soon as the investigator is made aware of the event. If the death is 
thought to be related to the study treatment (olaparib or surgery), deaths must be reported to BrUOG 
within 24 hours of the investigator being made aware of the event. 
 
For Pharmacovigilance purposes and characterisation, any case of MDS/AML or new primary 
malignancy occurring after the 30 day (+7 days) toxicity follow up period should be reported to  
BrUOG via a SAE report (Medwatch 3500A) and BrUOG will report the event to AstraZeneca Patient 
Safety, whether it is considered a non-serious AE [eg non-melanoma skin cancer] or serious, and 
regardless of investigator’s assessment of causality or knowledge of the treatment arm.  Investigators 
will be asked during the regular follow up for overall survival if the patient has developed MDS/AML 
or a new primary malignancy and prompted to report any such cases. Any case of MDS/AML or any 
new primary meets AstraZeneca criteria to be reported as a SAE on this trial, even if this occurs more 
than 30 days (+7 days) post the last treatment (olaparib or surgery, whatever is the last date). 
11.6.1 Definition of Hy’s Law (HL): See appendix F for complete information 
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the study drug, 
can be found to explain the combination of increases, eg, elevated ALP indicating cholestasis, viral 
hepatitis, another drug.   
For potential HL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the elevations in 
transaminases and TBL must occur. 
Please refer to Appendix F on processes and procedures on how to manage and report such cases. For HL 
cases which are deemed SAEs, the same time frame for reporting is required (within 5 business days of 
being made aware of the event). 


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exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
30 
11.6.2 New cancers  
The development of a new primary cancer (including skin cancer) should be regarded as an AE (see 
Olaparib Adverse Events of Special Interest) and are to be reported as a SAE (important medical event).  
New primary malignancies are those that are not the primary reason for the administration of the study 
treatment and have developed after the inclusion of the patient into the study.  They do not include 
metastases of the original cancer.  Symptoms of metastasis or the metastasis itself should not be reported 
as an AE/SAE, as they are considered to be disease progression. 
11.6.3 Olaparib adverse events of special interest 
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 investigators to AstraZeneca (communication will be Investigator to BrUOG and BrUOG to 
AstraZeneca). 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. AESIs will be reported to BrUOG in the same manner a SAE is and via a MedWatch 
3500A, noting the event is an important medical event. 
ANY event of MDS/AML, new primary malignancy, or pneumonitis should be reported by the site 
as a SAE (important medical event) to AstraZeneca Patient Safety by BrUOG whether it is 
considered a non-serious AE [eg non-melanoma skin cancer] or Serious, and regardless of investigator’s 
assessment of causality or knowledge of the treatment.    
11.6.4 Other significant adverse events (OAE) 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review the list of 
AEs that were not reported as SAEs.  Based on the expert’s judgment, significant adverse events of 
particular clinical importance may, after consultation with the Global Patient Safety Physician, be 
considered OAEs and reported as such.  A similar review of laboratory/vital signs/ECG data will be 
performed for identification of OAEs. 
Examples of these are marked hematological and other laboratory abnormalities, and certain events that 
lead to intervention (other than those already classified as serious), dose reduction or significant 
additional treatment. 
There are currently no identified OAEs for olaparib 
11.6.5 OVERDOSE-To be reported by BrUOG to AstraZeneca regardless of the overdose meets 
SAE definition using the AstraZeneca Overdose form within 1 business day of being made aware of 
the event or obtaining confirmation of the overdose (there may be a situation when BrUOG is 
obtaining confirmation from the site to confirm an overdose has indeed occurred and BrUOG will 
wait to obtain confirmation prior to reporting the overdose). Sites are required to review all cases 
of overdose and the treating physician is required to determine if the overdose also meets any 
SAE definition. If so, the overdose must be reported as a SAE via SAE reporting requirements and 
time frames outlined in this protocol. 


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exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
31 
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 should be reported as an 
overdose. The Maximum Tolerated Dose is 300 mg bid (tablet). If a patient takes 2 tablets at one time, 
or exceeds total daily dose of 600mg this will be considered an overdose and also a major deviation. 
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 on the CRF  
• 
An overdose without associated symptoms is only reported on the Overdose AstraZenenca 
form (completed by BrUOG). 
The designated AstraZeneca representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca 
11.6.6 MedWatch 3500A Reporting Guidelines: 
In addition to completing appropriate patient demographic and suspect medication information, the report 
should include the following information within the Event Description (section 5) of the MedWatch 
3500A form: 
• 
Patient number, initials, age, sex, weight 
• 
Treatment regimen (dosing frequency, combination therapy) 
• 
Protocol description (and number, if assigned) 
• 
Lot number 
• 
Description of event, severity, treatment, and outcome, if known.  
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the adverse event to investigational product and 
surgery and any other suspect medication and if the SAE is related to disease progression, as 
determined by the principal investigator.   
• 
It is required that if non-serious events are included on the MedWatch, such as symptoms, 
that these be labeled as being non-serious, while the serious events be clearly labeled as 
being serious 
• 
SAEs and AESIs must be typed 
• 
*It is required that the following are written on the Medwatch 3500A for tracking: BrUOG 337 & 
ESR-16-12357 
• 
Must document current status of the patient (i.e. off study treatment, delayed cycle, coming off 
trial secondary to event etc) 
 
A final report to document SAE (such as discharge from hospital) is required. 
 
Follow-up information:   
Additional Info maybe added to a previously submitted report by any of the following methods. 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500A form  


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exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
32 
• 
At the time of follow-up submission site must submit laboratory information (admission, 
maximal, discharge), assessments/testing with results and AE log at a minimum.  
 
Summarize new information and fax it with a cover letter including subject identifiers (i.e. D.O.B. initial, 
subject number), protocol description and number, if assigned, suspect drug, brief adverse event 
description, and notation that additional or follow-up information is being submitted.  (The subject 
identifiers are important so that the new information is added to the correct initial report). 
The principal Investigator is required to notify his/her Institutional Review Board (IRB) of a serious 
adverse event according to institutional policy.   
 
11.7 BrUOG Responsibility Regarding Reporting:  
The BrUOG Central Office will notify by email and/or fax all SAEs, regardless of relationship, to the 
FDA, the Principal Investigator, and the participating sites (who will in turn notify their local IRBs) as 
soon as possible but no later than within 2 business days and up to 5 business days of receipt of 
completed final signed 3500A form (sent to BrUOG by the site). BrUOG will alert AstraZeneca to an 
SAE within 2 business days and up to 5 business days, of being made aware of the event via receipt of 
final signed Medwatch 3500A from the site. If the study has an IND, SAEs will be reported as an 
amendment to the IND and it will be sent to the division fax, within 5 calendar days of sponsor 
notification.  If the study is IND exempt, the SAE will be sent within the same time frame, to the 
Medwatch fax line. A copy of the form will be kept by the BrUOG Central Office.   
 
 
 
Fax: 1-800-FDA-0178 (1-800-332-0178) For IND exempt study or for IND study the SAE will be 
sent to Center Drug Evaluation Division fax line that has responsibility for review of IND) 
 
Mail: For IND studies BrUOG will send the SAE as an amendment to the IND as well 
 
All SAEs will be faxed or emailed to: AstraZeneca 
 
AZ SAE reporting: email is: AEMailboxClinicalTrialTCS@astrazeneca.com or by fax to AstraZeneca’s 
designated fax line:1-302-886-4114 
11.8 Safety Reporting for IND Holders 
In accordance with 21 CFR 212.32, Sponsor-Investigator of the study conducted under an IND must 
comply with following safety-reporting requirements:  
 
a. Expedited IND Safety Reports: 
BrUOG will fax reports to the FDA for IND Safety Reports: 1 (800) FDA – 0178, unless per the 
IND status BrUOG is to submit the SAEs to the Division Fax instead. 
 
b. IND Annual Reports, for IND study only 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an annual report is 
provided to the FDA within 60-days of the IND anniversary date.  21 CRF 312.33 provides the data 
elements that are to be submitted in the report.  The Annual Report should be filed in the study's 
Regulatory Binder, and a copy provided to olaparib   as a supporter of this study. 
 
11.9 Adverse event updates/IND safety reports External 
AstraZeneca shall notify the Brown University Oncology Research Group (BrUOG) via an IND Safety 
Report of the following information: 
• 
Any AE associated with the use of study drug in this study or in other studies that is both serious 
and unexpected. 


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exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
33 
• 
Any finding from tests in laboratory animals that suggests a significant risk for human subjects 
including reports of mutagenicity, teratogenicity, or carcinogenicity. 
BrUOG will then notify the sites who shall notify their IRB/EC promptly of these new serious and 
unexpected AE(s) or significant risks to subjects as per their local policies. 
 
12.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY 
Extraordinary medical circumstances or withdrawal of consent by the patient: If, at any time, the constraints 
of this protocol are detrimental to the patient's health, and/or the patient no longer wishes to continue protocol 
therapy, the patient shall be withdrawn from protocol therapy.  Patients will also be withdrawn from study for 
the following reasons: 
1. Disease Progression: Any patient with disease progression should be removed from study.  
Details and tumor measurements should be documented on flow sheets. 
2. Patient is unable to tolerate the toxicity resulting from the study treatment, even with optimal 
supportive care, in the opinion of the Treating Physician. Adverse event(s) that, in the judgment of the 
investigator, may cause severe or permanent harm or which rule out continuation of study drug.  
3. The physician feels it is in the best interest of the patient to stop the treatment. 
4. Inter current illness that would, in the judgment of the Investigator, affect assessment of clinical 
status to a significant degree or require discontinuation of study treatment 
5. Non protocol chemotherapy or immunotherapy is administered during the study 
6. Noncompliance with protocol or treatment—major violation 
7. Patient is lost to follow-up 
8. Patient refuses to continue treatment (patient will continue to be followed for disease-free 
survival and overall survival) 
9. Death 
10. Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute myeloid 
leukaemia (AML) 
 
In this event notify: 
Brown University Oncology Research Group (BrUOG) Central Office, 
Phone:  (401) 863-3000 
Fax:  (401) 860-3820 
 
The BrUOG Central Office will in turn notify the Principal Investigator. 
*Document the reason(s) for withdrawal on flow sheets.  Follow the patient for survival with follow-
up forms as dictated by the protocol 
13.0 FOLLOW-UP  
All Subjects that discontinue treatment early for any reason (not including screen fails or patient with 
withdraw consent/decline study participation) as well as patients who complete therapy will be followed 
for survival (up to 2 years). At treatment discontinuation, subjects will undergo adverse event evaluation 
and again approximately 30 days (+7 days) post the last treatment with olaparib. In addition off study 
evaluations will be done when treatment is discontinued -Section 6.0.   


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exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
34 
14.0 REGULATORY CONSIDERATIONS 
This research study is sponsored by the Principal Investigator, Dr. Anthony Mega, in collaboration with 
Brown University Oncology Research Group (BrUOG), which will serve as the central coordinating 
office for the study. This study is financially supported by Astra Zeneca (the makers of olaparib). 
14.1 Protection of Human Subjects 
The Investigator must ensure that patients or their legally acceptable representatives are clearly and fully 
informed about the purpose, potential risks and other critical issues regarding clinical trials in which they 
volunteer to participate.  Preparation of the consent form is the responsibility of the Investigator and must 
include all elements required by CFR 21 Part 50.25 and the local IRB. 
14.2 Compliance with the Protocol and Protocol Revisions: 
The study must be conducted as described in this approved protocol.   
All revisions to the protocol must be created by the Brown University Oncology Research Group, and 
approved by AstraZeneca.  The Investigator should not implement any deviation or change to the protocol 
without BrUOG’s approval/favorable opinion by way of an approved exception. Any deviation to the trial 
which is not prior approved will be reviewed per the BrUOG SOP. 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be sent to 
Brown University Oncology Research Group..  If the revision is an Administrative Letter, Investigators 
must inform their IRB(s)/IEC(s).  
The Investigator must ensure that patients or their legally acceptable representatives are clearly and fully 
informed about the purpose, potential risks and other critical issues regarding clinical trials in which they 
volunteer to participate.  Preparation of the consent form is the responsibility of the Investigator and must 
include all elements required by CFR 21 Part 50.25 and the local IRB. 
After the study has been fully explained, written informed consent will be obtained from either the patient 
or his/her guardian or legal representative prior to study participation.  The method of obtaining and 
documenting the informed consent and the contents of the consent will comply with ICH-GCP and all 
applicable regulatory requirement(s). 
 
14.3 Protocol amendments or changes in study conduct:  
Any change or addition (excluding administrative) to this protocol requires a written protocol amendment 
that must be reviewed and approved and created by Brown University Oncology Research Group, who 
will obtain approval by Astra Zeneca and the investigator before implementation. Amendments 
significantly affecting the safety of subjects, the scope of the investigation or the scientific quality of the 
study require additional approval by the IRB at each study center.  A copy of the written approval of the 
IRB must be provided to Brown University Oncology Research Group, and Astra Zeneca. 
These requirements for approval should in no way prevent any immediate action from being taken by the 
investigator or by Brown University Oncology Research Group and Astra Zeneca in the interests of 
preserving the safety of all patients included in the trial.  If an immediate change to the protocol is felt to 
be necessary by the investigator and is implemented for safety reasons Brown University Oncology 


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35 
Research Group and Astra Zeneca must be notified and the IRB at the center must be informed 
immediately.  
15.0 DATA MONITORING / QUALITY ASSURANCE/ RECORD RETENTION 
15.1 Good Clinical Practice: The study will be conducted in accordance with the International 
Conference on Harmonisation (ICH) for Good Clinical Practice (GCP) and in the US Code of Federal 
Regulations.  The investigator will be thoroughly familiar with the appropriate use of the drug as 
described in the protocol and Investigator’s Brochure.  Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected.  Master files should be 
established at the beginning of the study, maintained for the duration of the study and retained according 
to the appropriate regulations.   
15.2 Patient Confidentiality: In order to maintain patient privacy, all data capture records, drug 
accountability records, study reports and communications will identify the patient by initials and the 
assigned patient number.  The investigator will grant monitor(s) and auditor(s) from Astra Zeneca or its 
designees and regulatory authority (ies) access to the patient’s original medical records for verification of 
data gathered on the data capture records and to audit the data collection process.  The patient’s 
confidentiality will be maintained and will not be made publicly available to the extent permitted by the 
applicable laws and regulations. 
15.3 Protocol Compliance: The investigator will conduct the study in compliance with the protocol 
given approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority(ies).  Changes 
to the protocol will require approval from Astra Zeneca and written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
patients.  The IRB/IEC may provide, if applicable regulatory authority (ies) permit, expedited review and 
approval/favorable opinion for minor change(s) in ongoing studies that have the approval /favorable 
opinion of the IRB/IEC.  The investigator will submit all protocol modifications to Astra Zeneca and the 
regulatory authority (ies) in accordance with the governing regulations.  
Any departures from the protocol must be fully documented in the source documents.   
15.4 On-site Audits: Regulatory authorities, the IEC/IRB and/or Astra Zeneca clinical quality assurance 
group may request access to all source documents, data capture records, and other study documentation 
for on-site audit or inspection.  Direct access to these documents must be guaranteed by the investigator, 
who must provide support at all times for these activities. 
15.5 Drug Accountability: Accountability for the drug at all study sites is the responsibility of the 
principal investigator.  The investigator will ensure that the drug is used only in accordance with this 
protocol.  Drug accountability records indicating the drug’s delivery date to the site, inventory at the site, 
use by each patient (patient initials, patient number and date of dosing), and disposal of the drug (if 
applicable and if approved through BrUOG by Astra Zeneca) will be maintained by the clinical site.  
Accountability records will include dates, quantities, lot numbers, expiration dates, and patient numbers.  
The NCI DARF may be used for accountability. 
All material containing olaparib will be treated and disposed of as hazardous waste in accordance with 
governing regulations and site’s institutional practice. 


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36 
15.6 Premature Closure of the Study: This study may be prematurely terminated, if in the opinion of 
the investigator or Astra Zeneca, there is sufficient reasonable cause.  Written notification documenting 
the reason for study termination will be provided to the investigator or Astra Zeneca by the terminating 
party.   
Circumstances that may warrant termination include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to patients 
• 
Failure to enter patients at an acceptable rate 
• 
Insufficient adherence to protocol requirements 
• 
Insufficient complete and/or evaluable data 
• 
Plans to modify, suspend or discontinue the development of the drug 
• 
Should the study be closed prematurely, all study materials must be returned to AstraZeneca. 
15.7 Record Retention:  
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s).   
The Brown University Oncology Research Group, as coordinator of this study, is responsible for ensuring 
proper conduct of the study with regard to protocol adherence and the validity of the data recorded on the 
case report forms. The Principle Investigator (Anthony Mega, M.D.) and Brown University Oncology 
Research Group will monitor this study. The case report forms will be monitored against the submitted 
documents for accuracy, completeness, adherence to the protocol and regulatory compliance.  
U.S. FDA regulations (21CFR312.62[c] require all records and documents pertaining to the conduct of 
this study and the distribution of investigational drug, including CRFs, consents forms, laboratory test 
results and medication inventory records, must be retained by the Principal Investigator for 2 years after 
marketing application approval. If no application is filed, these records must be kept 2 years after the 
investigation is discontinued and the FDA and the applicable local health authorities are notified. Astra 
Zeneca will notify the Principle Investigator if an application is filed.  
16.0 DATA SAFETY AND MONITORING BOARDS 
All trials initiated by the Brown University Oncology Research Group (BrUOG) are subject to oversight 
by the Data Safety Monitoring Board (DSMB).  This board meets two times per year with any additional 
meetings scheduled when needed.  The responsibilities are as follows: 
• 
Familiarize themselves with the research protocol (s)  
• 
The DSMB reviews trial performance information such as accrual information.   
• 
Review interim analyses of outcome data and cumulative toxicity data summaries to determine 
whether the trial should continue as originally designed, should be changed, or should be 
terminated based on these data.   
• 
The DSMB also determines whether and to whom outcome results should be released prior to the 
reporting of study results. 
• 
All adverse events are reviewed by the committee, with assurances that these have been in fact 
sent for review to all pertinent IRBs. 
• 
Review of reports of related studies to determine whether the monitored study needs to be 
changed or terminated. 


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37 
• 
Review major proposed modifications to the study prior to their implementation (e.g., 
termination, dropping an arm based on toxicity results or other reported trial outcomes, increasing 
target sample size). 
• 
Following each DSMB meeting, provide the study leadership with written information 
concerning findings for the trial as a whole related to cumulative toxicities observed and any 
relevant recommendations related to continuing, changing, or terminating the trial.  
 
The study leadership will provide information on cumulative toxicities and relevant recommendations to 
the local principal investigators to be shared with their IRB’s. 
 
17.0 STATISTICS 
The primary objective of this study is to estimate the response rate of neoadjuvant olaparib in patients 
with high risk prostate cancer. The primary assessment will be defined as a reduction of at least 50% in 
the prostate-specific antigen level prior to radical prostatectomy.  We will differentiate between a 10% 
level of activity and a 40% level of activity.  A response rate of 40% or higher would be clinically 
meaningful while a response rate of < 10% would not be worthy of further study.  
Specifically, the hypothesis which will be tested is: 
                  H1:   p< 0.1versus H1: p> 0.4 
Sample Size Calculation: 
Thirteen patients will be accrued to this study and evaluated for response as determined by the primary 
measure of 50% reduction in the PSA antigen level.  A Simon two-stage design (Minimax) will be used in 
this study. The first 8 evaluable patients treated at the MTD will be assessed for response. The trial will 
be terminated early if 0 or 1 responses are observed in these patients. If at least 2 responses are observed, 
accrual will continue until a total of 13 evaluable patients are enrolled to the study. If 3 or fewer patients 
of 13 have a response, the null hypothesis will be accepted and it will be concluded that there is not 
sufficient activity to merit further investigation of the regimen.  Otherwise, it will be concluded that the 
treatment regimen has sufficient activity to warrant further investigation. This design yields a type I error 
rate of 0.05 and power of 80% when the true response rate is 40%. 
This study will provide the necessary preliminary data for consideration of a larger study in this 
population. The Brown University Oncology Research group has chosen to differentiate a 10% level of 
activity versus a 40% level of activity since a 30% difference of activity in this patient population with 
localized high risk prostate cancer would be clinically meaningful.  
Methods: 
Quantitative and qualitative variables will be expressed as medians (with range) and frequencies. 
Objective response rates will be calculated as relative rates with their 95% confidence interval (95% CI) 
limits. The median and two-sided 95% CIs for PFS will be estimated using the Kaplan-Meier method. 
Analysis will be performed using SPSS v.22.0 (IBM Corp., Armonk, NY, USA). 
Secondary Efficacy Analysis: 
Secondary end points include PSA progression-free survival (PFS), pathological complete remission 
(pCR) rate, pathologic stage of T2<0 versus > T2N0, and reduction in circulating tumor cells.  


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38 
Progression will be defined as the following: time to radiographic progression, and/or time to PSA 
progression (a 25% increase in the PSA level). 
PSA progression-free survival will be defined as alive without PSA progression.  
Feasibility: The Brown University Oncology Research Group performed   approximately 125 radical 
prostatectomies in 2015.  
18.0 REFERENCES: 
1. NCCN guidelines on prostate cancer, version 1.201. National Comprehensive Cancer Network Web 
site. http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. 
2. A. Heidenreich, J. Bellmunt, M. Bolla et al. EAU guidelines on prostate cancer. Part 1: screening, 
diagnosis, and treatment of clinically localised disease. Eur Urol, 59 (2011), pp. 61–71. 
3. Joniau S1, Tosco L, Briganti A et al. Results of surgery for high-risk prostate cancer. 
Curr Opin Urol. 2013 Jul;23(4):342-8. 
4. A.V. D’Amico, R. Whittington, S.B. Malkowicz et al. Biochemical outcome after radical 
prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized 
prostate cancer. JAMA, 280 (1998), pp. 969–974. 
5. Rider JR, Sandin F, Andrén O, et al. Long-term outcomes among noncuratively treated men according 
to prostate cancer risk category in a nationwide, population-based study. Eur Urol 2013; 63:88–96. 
6. Briganti A1, Joniau S, Gontero P et al. Identifying the best candidate for radical prostatectomy among 
patients with high-risk prostate cancer. Eur Urol. 2012 Mar;61(3):584-92. 
7. Abdollah F, Karnes RJ Suardi N, et al. Predicting survival of patients with node-positive cancer 
following multimodality treatment Eur Urol 2014 Mar;65(3):554-62  
8. Steuber T1, Budäus L, Walz J et al. Radical prostatectomy improves progression-free and cancer-
specific survival in men with lymph node positive prostate cancer in the prostate-specific antigen era: a 
confirmatory study. BJU Int. 2011 Jun;107(11):1755-61. 
9. Da Pozzo LF, Cozzarini C, Briganti A et al. Long-term follow-up of patients with prostate cancer and 
nodal metastases treated by pelvic lymphadenectomy and radical prostatectomy: the positive impact of 
adjuvant radiotherapy. Eur Urol 2009; 55: 261–70. 
10. Bader P, Burkhard FC, Markwalder R et al. Disease progression and survival of patients with positive 
lymph nodes after radical prostatectomy. Is there a chance of cure? J Urol 2003; 169: 849–54. 
11. Suardi N, Gandaglia G, Gallina A, et al. Long-term outcomes of salvage lymph node dissection for 
clinically ruecurrent prostate cancer: Results of a single-institution series with a minimum follow-up of 5 
years. Eur Urol 2014, S0302-2838 (14) 00130-4.  
12. Corn BW, Winter K, Pilepich MV. Does androgen suppression enhance the efficacy of postoperative 
irradiation? A secondary analysis of RTOG 85–31. Radiation Therapy Oncology Group. Urology 
1999;54(3):495 
13. Messing EM, Manola J, Yao Je et al. Immediate versus deferred androgen deprivation treatment in 
patients with node-positive prostate cancer after radical prostatectomy  and pelvic lymphadenectomy. 
Lancet Oncol 2006; 7:472.  
14. Efstathiou E, Davis JW, Titus MA, et al. Neoadjuvant enzalutamide (ENZA) and abiraterone acetate 
(AA) plus leuprolide acetate (LHRHa) versus AA+ LHRHa in localized high-risk prostate cancer 
(LHRPC). J Clin Oncol 34, 2016 (suppl; abstr 5002) 
15. Ahlgren G, Flodgren P, Tammela TLJ, et al. A randomized phase III trial between adjuvant docetaxel 
and surveillance after radical prostatectomy for high risk prostate cancer: Results of SPCG12. J Clin 
Oncol 34, 2016 (suppl; abstr 5001) 
16. Fong, P.C., et al., Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation 
carriers. N Engl J Med, 2009. 361(2): p. 123-34. 


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exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
39 
17. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA 
mutant cells as a therapeutic strategy. Nature 2005; 434: 917-21. 
18. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient 
tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005; 434: 913-7. 
19. Fong PCP, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from 
BRCA mutation carriers. N Engl J Med 2009; 361: 123-34. 
20. Grasso CS, Wu Y-M, Robinson DR, et al. The mutational landscape of lethal castration-resistant 
prostate cancer. Nature 2012; 487: 239-43. 
21. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy 
in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33: 244-50. 
22. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum sensitive relapsed 
ovarian cancer. N Engl J Med 2012; 366: 1382-92. 
23. Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, et al. High 
sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in 
combination with platinum drugs. Proc Natl Acad Sci 2008;105(44):17079-84. 
24. Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, et al. Poly(ADP-ribose) 
polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary 
tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 
2009;69(9):3850-5. 
25. Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, et al. Poly(ADP)- 
ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer 
correlating with platinum-free interval. J Clin Oncol. 2010;28(15):2512-9. 
26. Helleday, T. The underlying mechanism for the PARP and BRCA synthetic lethality: 
Clearing up the misunderstandings. Molecular Oncology 2011;5:387-393. 
27. Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1 
and PARP2 by clinical PARP inhibitors. Cancer Res 2012;72:5588-99. 
28. Mateo, J., et al., DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med, 
2015. 373(18): p. 1697-708. 
29. Fatima H. Karzai, MD; Ravi A. Madan, MD; William D. Figg, Beyond PSA: Managing Modern 
Therapeutic Options in Metastatic Castration-resistant Prostate Cancer South Med J. 2015;108(4):224-
228. 
30.Roessner M, de Wit R, Tannock IF, et al. Prostate-specific antigen (PSA) response as a surrogate 
endpoint for overall survival (OS): analysis of TAX327 study comparing docetaxel plus prednisone with 
mitoxantrone plus prednisone in advanced prostate cancer. 2005 ASCO Annual Meeting Proceedings. J 
Clin Oncol 2005;23(Suppl 4554). 
31. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for 
advanced prostate cancer. N Engl J Med 2004;351:1502–1512. 
31. FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM1740
90.pdf 
 
 
 
 


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40 
APPENDIX A  
Agreement to Participate in a Research Study 
And Authorization for Use and Disclosure of Information 
 
BrUOG 337: Olaparib Prior to Radical Prostatectomy For Patients with Locally Advanced 
Prostate Cancer and Defects in DNA Repair Genes 
 
 
You are being asked to take part in a research study.  All research studies at <INSERT HOSPITAL 
NAME> hospitals follow the rules of the state of <INSERT STATE>, the United States government and 
<INSERT HOSPITAL NAME>.  Before you decide whether to be in the study, you and the researcher 
will engage in the “informed consent” process.   During this process, the researcher will explain the 
purpose of the study, how it will be carried out, and what you will be expected to do if you participate.  
The researcher will also explain the possible risks and benefits of being in the study, and will provide 
other information.  You should feel free to ask any questions you might have.  The purpose of these 
discussions is for you to decide whether participating in the study is the best decision for you. 
If you decide to be in the study, you will be asked to sign and date this form in front of the person who 
explained the study to you.  This form summarizes the information you discussed.  You will be given a 
copy of this form to keep.   
Nature and Purpose of the Study      
Your doctors are participating in this research study sponsored by the Principal Investigator, Dr. Anthony 
Mega, in collaboration with Brown University Oncology Research Group (BrUOG), which will serve as 
the central coordinating office for the study.  The study is financially supported by Astra Zeneca 
Pharmaceuticals, the makers of the drug olaparib 
You are being asked to take part in this study because you have prostate cancer. Your cancer has not 
spread to other organs in your body and may be removable by surgery (radical prostatectomy). However 
the chance your prostate cancer will grow back in 5-10 years is approximately 40-75%. (Forty to 75 
patients out of 100 with prostate cancer similar to yours will have a recurrence of their cancer.) Your 
doctor will discuss your cancer with you and review the risk of your cancer recurring based on the 
features of your cancer.   
This study will evaluate approximately 3 months of treatment with the drug olaparib in patients with 
prostate cancer. A capsule formulation of olaparib (tradename Lynparza™) is approved by the United 
States Food and Drug Administration (FDA) for the treatment of women with certain types of ovarian 
cancer and breast cancer. Olaparib is an investigational drug in prostate cancer, which means it is not 
approved by the FDA for treatment of prostate cancer. A tablet formulation of olaparib is being tested in 
this study.  It is a new formulation which is more convenient for patients than the approved capsule 
formulation because fewer tablets of olaparib need to be taken daily than with capsules.  
Olaparib is called a PARP inhibitor. PARP inhibitors may be helpful in cancers that have “defects in 
DNA repair genes”.  This means that the function of the DNA is not working the way it should because 
the repair gene is defected, which can lead to an increased risk in cancer. Approximately 1 in 5 patients 
with prostate cancer (20%) have cancers that have defects in DNA repair genes. In a previous study of 
patients with advanced prostate cancer with defects in DNA repair genes whose cancer had spread to 
other organs (a more progressed cancer then you have), olaparib caused cancer reduction in 14 of 16 
(88%) patients. Some of the mutations found are going to be germline (inherited) and some will be 


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exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
41 
somatic (found only in the cancer cells). If it is found that the detected mutation is more likely germline 
(inherited), you have the option of also being referred for genetics consultation and additional testing. 
Please speak with your doctor about this. 
 
The purpose of the study is to evaluate whether olaparib can reduce prostate cancer with defects in DNA 
repair genes when olaparib is given for approximately 3 months before surgery.  
We expect to enroll approximately 13 patients into this study.  
Explanation of Procedures   
Determination if your cancer has a defect in a DNA repair gene. 
Your tumor tissue will be assessed by Foundation Medicine, a laboratory in Cambridge MA, to determine 
if your cancer has a defect in a DNA repair gene. If your cancer does not have a defect in a DNA repair 
gene, then you will not be able to receive treatment on this clinical study and your doctor will discuss 
with you what options are best for you. If your tumor tissue has not already been examined by Foundation 
Medicine then your doctor will send it out as part of your standard cancer assessment. 
 
What will happen if I take part in this research study?  
If you take part in this study, and your tumor tissue is found to have a defect in a DNA repair gene, and 
you choose to take part, you will have the exams, tests and procedures to show that you can be in the 
study and while on study. They are part of regular cancer care.  
Baseline tests prior to starting treatment: 
• 
Medical history  
• 
Physical examination, including weight, vitals, performance status, toxicity assessment, 
demographics, concomitant medications (to document what other medications, if any you take) 
• 
Blood tests - approximately 3 tablespoons of blood. These blood tests will evaluate your blood 
counts, kidney and liver function and whether you previously or have hepatitis. A prostate specific 
antigen (PSA) test will also be run. 
• 
About 3 tablespoons of blood will be sent to a commercial laboratory (Quest Diagnostics) to try to 
count the number of prostate cancer cells that can be detected in your bloodstream  
• 
MRI or CT scan of the pelvis 
• 
Bone scan (to be sure your cancer hasn’t spread to your bones) 
• 
Chest imaging 
• 
EKG. 
 
Tests while you receive study treatment with olaparib: 
• 
Physical examination, including weight, vitals, performance status, toxicity assessment, review of 
other medications you may be taking, approximately every 2 weeks. 
• 
Blood tests, approximately 3 tablespoons of blood, every 2 weeks. 
• 
Your PSA will be repeated after 2 months of olaparib to try to determine if the olaparib is helpful in 
treating your cancer.  
 
Treatment- Olaparib: 
All patients will receive 2 cycles of treatment. A cycle is considered 4 weeks. You will take two doses of 
olaparib at approximately the same time each day, morning and evening, approximately 12 hours apart, 
for 2 months. After 2 cycles of treatment you will have a blood test, approximately 3 tablespoons and 


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exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
42 
your doctors will assess if the olaparib is helping to treat your prostate cancer by checking the PSA blood 
test. As long as the PSA is not increasing you will receive 1 additional cycle of olaparib to complete 3 
cycles (months) of treatment.  
• 
Olaparib tablets should be swallowed with one glass of water, with or without food.   
• 
The tablets should be swallowed whole and not chewed, crushed, dissolved or divided.  
• 
If vomiting occurs shortly after the study drug tablets are swallowed, the dose should only be 
replaced if you are able to clearly see all of the intact tablets and you can count all tablets   
• 
Should you miss a scheduled dose for whatever reason (e.g., as a result of forgetting to take the 
tablets or vomiting), you will be allowed to take the scheduled dose up to a maximum of 2 hours 
after that scheduled dose time.  If greater than 2 hours after the scheduled dose time, the missed 
dose is NOT to be taken and you should take your next dose at the next scheduled time. 
• 
You should also not drink grapefruit juice as this can affect the way the study medication works. 
It is possible that your olaparib could affect your other medication. There are certain medications that you 
will not be allowed to take with the study medication during the study including other anti-cancer therapies 
and certain vaccines. Your study doctor will discuss a list of medications that you must avoid while you are 
taking your study medication so it is important to consult them before taking anything new.  
Once you complete the study treatment with olaparib, you will have a study visit. During this visit the 
following will occur: 
• 
Physical examination, including weight, vitals, performance status, toxicity assessment, concomitant 
medications (to document what other medications, if any you take) 
• 
Blood tests, approximately 3 tablespoons of blood 
• 
After you have completed treatment, about 3 tablespoons of your blood will be sent to Quest 
Diagnostics to try to count the number of prostate cancer cells that can be detected in your 
bloodstream to compare this to the number of prostate cancer cells detected in your blood before 
starting olaparib.  
• 
You will also undergo a toxicity assessment, physical, performance status assessment approximately 
30 days after your last treatment with olaparib 
 
Surgery: 
3-8 weeks after completion of olaparib you will have surgery to remove your prostate cancer.  
By enrolling in this trial, you understand that you are delaying surgery for your high-risk localized 
disease. 
 
Follow-up: 
 
After surgery, you will see your study doctor approximately every 4 months for 2 years. During that time 
the following will occur: 
• 
Blood PSA (about a tablespoon of blood) until you are found to progress. 
• 
Survival and disease status  
 
 
 
 
How long will I be in the study?  


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43 
You will receive olaparib for approximately 3 months. Then you will have surgery 3-8 weeks after 
completing olaparib. Afterwards you will be followed for cancer recurrence every 4 months for 
approximately 2 years. Total study involvement is about 2.5 years. 
Can I stop being in the study?  
Yes. You can decide to stop at any time.  Tell your doctor if you are thinking about stopping or decide to 
stop.  He or she will tell you how to stop safely.   
It is important to tell your doctor if you are thinking about stopping so any risks from the discontinuation 
of treatment can be evaluated. Another reason to tell your doctor that you are thinking about stopping is to 
discuss what follow-up care and testing could be most helpful for you.  
Your doctor may stop you from taking part in this study at any time if he/she believes it is in your best 
interest; if you do not follow the study rules; or if the study is stopped.  
Costs for participating in this study  
Some of the services you will receive are being performed only because you are participating in this 
research study.  Examples of these ‘research only’ services include the following: 
• 
You will receive the drug olaparib at no charge as it is being provided at no cost by AstraZeneca, 
the maker of the drug. 
• 
The analysis to determine if your cancer has a defect in the DNA repair genes 
• 
Evaluation of your blood for circulating tumor cells before receiving olaparib and after you have 
completed olaparib. 
Other services you will receive during this research study are considered "routine clinical services" that 
you would have received even if you were not in the research study. Examples are; all study doctor visits, 
blood tests, PSA test, drugs used to reduce side effects from olaparib, MRIs, EKG, chest x-ray and CT 
scans and bone scans. These services will be billed to your health insurance company, but you will be 
responsible for paying any deductibles, co-payments, or co-insurance that are a normal part of your health 
insurance plan.  If you do not have health insurance, you will be responsible for those costs.  
 Contact Information: If you have any questions regarding this study, you may contact your site 
Principal Investigator, Anthony Mega, 401-444-3234. 
Discomforts and Risks 
You may have side effects while on this study.  We will monitor everyone in the study for any side 
effects. Contact your study doctor if you experience a side effect or have any questions about possible 
side effects. 
 
OLAPARIB  
Side effects may be mild or serious.  We may give you medicines to help lessen side effects.  Some side 
effects will go away as soon as you stop taking the drug.  In some cases, side effects can be serious, long-
lasting, or may never go away. Taking part in this study may lead to time away from work. 


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7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
44 
 
Tell your doctor straight away if you notice any of the following side effects – you may need urgent 
treatment: 
Very common side effects > 10% : 
• 
Feeling sick (nausea) 
• 
Being sick (vomiting)  
• 
Tiredness/weakness 
• 
Indigestion/heartburn (dyspepsia) 
• 
Loss of appetite 
• 
Headache 
• 
Change in taste of foods (dysgeusia) 
• 
Dizziness 
• 
Diarrhea. Your doctor may prescribe a medicine to treat this.  If it gets severe, tell your doctor 
straight away. 
• 
Decrease in the number of red blood cells (anemia) which can be associated with symptoms of 
shortness of breath, fatigue, pale skin or fast heart beat 
• 
Decrease in the number of white blood cells that support the immune system (lymphopenia) 
which can be associated with increased susceptibility to infection 
• 
Increase in blood creatinine seen from a laboratory test showing how your kidneys are working. 
• 
Cough 
• 
Constipation 
• 
Abdominal and back pain 
• 
Fever 
• 
Anorexia/decreased appetite 
• 
Dyspnea (shortness of breath) 
• 
Reduced number of neutrophils in the blood (a type of white blood cell), leading to increased 
chance of infection 
• 
Decrease in the number of platelets in blood (thrombocytopenia) which can be associated with 
symptoms of bruising or bleeding for longer if injured 
• 
Decrease in the total number of white blood cells (leukopenia) and in certain white blood cells 
(neutropenia) that protect from infection, which can be associated with symptoms of fever 
• 
Joint pain 
• 
Pain in the stomach area under the ribs (upper abdominal pain) 
 
Common side effects: 1-10% 
• 
Sore mouth (stomatitis) 
• 
Rash 
• Reduced platelets which can cause bleeding 
 
 
 


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7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
45 
Uncommon side effects that may occur are: <1% 
• 
Allergic reactions 
• 
Itchy rash on swollen, reddened skin (dermatitis) 
• 
Mean cell volume elevation (an increase in size of red blood cells): This will be monitored by the 
laboratory safety tests that will be done in this study because this doesn’t normally have any 
symptoms.  
Driving and using machines: The study drug may affect your ability to drive or use machines. If you 
feel dizzy, weak, or tired while taking your study treatment, take special care when driving or using tools 
or machines. 
Other potential risks: 
Other side effects have been seen in previous studies, but it is not yet known if these were related to 
olaparib, or if they were unrelated events possibly due to the patient’s cancer or other cause.  Assessing 
the full range of side effects of olaparib is an important part of this study. 
Pneumonitis (lung inflammation) has been reported in a small number of patients treated with olaparib in 
previous studies, and some reports have been fatal.  It is not known if olaparib caused the pneumonitis in 
these patients as they had other possible causes such as lung cancer and/or metastases in the lungs, pre-
existing lung disease, were smokers, or had been treated previously with chemotherapy or radiotherapy.   
If you experience any new or worsening symptoms of shortness of breath, cough and fever, you should 
contact your Study Doctor as soon as you can. 
Myelodysplastic syndrome and acute myeloid leukemia: These side effects have been reported in a 
small number of patients treated with olaparib in previous studies and the majority of cases have been 
fatal.  It is not known if olaparib caused myelodysplastic syndrome and/or acute myeloid leukemia in 
these patients as they had other possible causes, in particular they had received extensive previous 
chemotherapy.  Your Study Doctor will monitor your blood cell levels during the study and may decide 
you need to have further tests, which may include a bone marrow sample or a blood sample. 
• 
Myelodysplastic syndrome is a pre-cancerous condition where the bone marrow isn’t as good at 
producing blood cells as it was before (red blood cells and/or white blood cells and/or platelets). 
This condition has the potential to transform into acute myeloid leukaemia 
• 
Acute myeloid leukaemia is a cancer of the bone marrow where many abnormal and immature 
white blood cells (blast cells) are made while normal functioning blood cells are not made. 
The Study Doctor may decide to interrupt and/or reduce your olaparib dose if you experience certain side 
effects.  If your dose is reduced you will be given a new bottle of tablets. 
Male patients 
The study drug may harm the unborn child. Tell your study doctor immediately if your partner becomes 
pregnant while taking study treatment or within 4 months after your last dose of study treatment. 


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7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
46 
While taking the study drug, and for 4 months after stopping treatment, you must use a condom when 
having sexual intercourse with a female partner, even if they are pregnant.  Your female partner must also 
use a suitable method of contraception.  You must not donate sperm while taking study treatment and for 4 
months after the last dose of study treatment. 
By signing this document you are acknowledging that you understand and agree to the information 
presented in this reproductive risk section. 
Surgery: 
Surgery to remove your prostate (prostatectomy) is a standard operation for prostate cancer. You will be 
given a separate consent form to review and sign prior to that surgery. That consent form will review the 
standard risks associated with the surgery.  
By participating in this study, you agree to delay your surgery by up to 3 months to receive the drug. 
Your doctors are studying olaparib before surgery to learn if olaparib can reduce the risk that your cancer 
may recur after surgery. However, if olaparib is not effective, this may leave you at a higher risk of 
metastasis (cancer spreading to other places in the body), death, and disability. 
Antiemetics (anti-nausea medications): Various medications used to prevent nausea and vomiting may 
cause drowsiness, dry mouth, diarrhea, constipation, headache, restlessness, agitation, anxiety, dizziness, 
involuntary tremors, skin rash, and possible allergic reaction. 
You will receive pre-medication to reduce the risk of infusion/injection reactions on your treatment days. 
Overall, the pre-medications you will be given are well tolerated. 
 
Venipuncture (inserting a needle into a vein to obtain blood or give medication): May cause 
inflammation, pain, bruising, bleeding, or infection. 
In order to monitor the side effects, your physician will examine you frequently and obtain laboratory 
tests to determine the effects of your treatment and alter the drug dosages if necessary. 
Risk of MRI imaging:  
Rarely MRI has been associated with kidney damage. 
Your doctors will be carefully monitoring your condition to minimize any possible risks to you. If your 
doctors feel that the side effects are too severe in your particular case, they will lower the dose of the 
medications or even stop them. 
There may be other side effects that have not been reported. If you have any unusual symptoms, you 
should report them immediately to your doctor or nurse. 
 
Benefits 
The goal of this study is to determine if olaparib can reduce the size of prostate cancers that have defects 
in DNA repair genes when administered for 3 months prior to radical prostatectomy. The treatment may 
not be effective and may not help in treating your cancer.  
We do know that the information from this study will help doctors learn more about this drug as a 
treatment for cancer. This information could help future cancer patients. 


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7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
47 
Alternative Therapies 
What other choices do I have if I do not take part in this study?  
• 
Having surgery for prostate cancer 
• 
Having hormone therapy for prostate cancer 
• 
Having radiation therapy for prostate cancer 
• 
Having no treatment and just being observed.  
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
Refusal/Withdrawal 
It is up to you whether you want to be in the study.  You are not required to enroll or participate.  If you 
decide to participate, you can always change your mind and quit at any time.  If you decide not to be in 
the study, or if you quit later, you will still be able to get the health care services you normally get.  If you 
join, but later on the researcher or your doctor feels being in the study is no longer good for you, they may 
choose to take you out of the study before it is over.  If new information becomes available that might 
change your mind about whether you want to stay in the study the researcher will share this information 
with you as soon as possible. 
 
If you decide to withdraw from this study (stop taking study medication) for any reason, you will be 
asked to sign a form indicating whether you give your permission for your doctor and the research staff to 
continue to collect and submit follow-up information on your health status from your physicians and 
medical record. After signing the form, you still have the right to change your mind, at any time, 
regarding follow-up after withdrawal. 
 
Medical Treatment/Payment in Case of Injury 
A research injury is any physical or mental injury or illness caused by being in the study. If you are 
injured by a medical treatment or procedure you would have received even if you were not in the study 
that is not a research injury.  To help avoid research injury and added medical expenses, it is very 
important to follow all study directions carefully.  If you do experience a research injury, <INSERT 
HOSPITAL NAME> or the study doctor can arrange medical treatment for you. Such treatment will be 
paid for as described below. 
 
If you have insurance and have a research injury that is not covered by the study, it is possible that some 
or all of the cost of treating you could be billed to your insurer.  If your health insurance will not cover 
such costs, it is possible you would have to pay out of pocket.  In some cases, <INSERT HOSPITAL 
NAME> might be able to help you pay if you qualify for free care under <INSERT HOSPITAL NAME> 
policy.  However, <INSERT HOSPITAL NAME> has no policy to cover payment for such things as lost 
wages, expenses other than medical care, or pain and suffering.   
 
Neither Dr. Anthony Mega, the sponsor of the study, nor BrUOG, the coordinating center, have money 
set aside to reimburse you for medical bills from treatment of a research related injury or otherwise 
compensate you in the event of a study-related injury.  


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7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
48 
Rights and Complaints 
Signing this form does not take away any of your lawful rights.  If you have any complaints about this 
study, or would like more facts about the rules for research studies, or the rights of people who take part 
in research studies you may contact<INSERT NAME> in the <INSERT HOSPITAL NAME> Office of 
Research Administration, at <INSERT CONTACT> 
Confidentiality 
Your research records will be treated as private health care records and will be protected according to 
<INSERT HOSPITAL NAME> privacy practices and policies that are based on state and federal law.   In 
particular, federal law requires us to get your permission to use or disclose (release your information to 
someone outside of <INSERT HOSPITAL NAME>) your health information for research purposes. If 
you sign this form you agree to be in this research study and you permit the use and disclosure of your 
health information for the purpose of conducting the research, providing treatment, collecting payment 
and running the business of the hospital.  This permission has no expiration date.  You may withdraw 
from the study at any time.  However, if you do not want the researchers to use or disclose any further 
information in this study you must cancel permission in writing and may do so at any time. If you cancel 
your permission, you will stop taking part in the study and no new information will be collected about 
you.  However, if you cancel your permission, it will not apply to actions already taken or information 
already collected about you by the hospital or the researchers before you canceled your permission. 
Generally, the entire research record and any medical records held by the hospital may be used and 
released for research purposes.  The following people or businesses/companies/ might use, release, or 
receive such information: 
• 
The researcher and their support staff; 
• 
The study sponsor Dr. Anthony Mega, BrUOG, the group coordinating the study and their 
affiliates, and Astra Zeneca, the supplier of olaparib, and financial supporter of this trial and their 
authorized agents 
• 
Doctors, nurses, laboratories and others who provide services to you or the sponsor in connection 
with this study;   
• 
The company or section of the U.S. government that is paying for the study and others they hire 
to oversee, administer, or conduct the research;  
• 
The United States Food and Drug Administration, the Department of Health and Human Services, 
the Office of Inspector General, and the Office of Civil Rights; Governmental agencies in other 
countries where the study drug may be considered for approval 
• 
People who volunteer to be patient advocates or research volunteer protectors;   
• 
Members of the hospital's administrative staff responsible for reviewing, approving and 
administering clinical trials and other healthcare or research activities. 
• 
Accrediting Organizations  
 
The results of this research study and any correlative studies, in which you agree to participate, will 
probably be shared with other people and may be published in scientific reports, but your name and the 
fact that you were in this study will be kept confidential. Efforts will be made to keep your personal 
information confidential. We cannot guarantee absolute confidentiality. 


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7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
49 
There are times when the law might require or permit <INSERT HOSPITAL NAME> to release your 
health information without your permission.  For example, <INSERT STATE> law requires researchers 
and health care workers to report abuse or neglect of children to the Department of Children, Youth and 
Families (DCYF) and to report abuse or neglect of people age 60 and older to the Department of Elderly 
Affairs. 
 
All researchers and health care providers are required to protect the privacy of your health care 
information.  Other people and businesses/organizations that are not health care providers are not required 
by law to do that so it is possible they might re-release your information.   
 
You have the right to refuse to sign this form and not participate in the research.  Your refusal would have 
no affect on your treatment, charges billed to you, or benefits at any <INSERT HOSPITAL NAME> health 
care site.  If you do not sign, you will not be able to enroll in the research study and will not receive treatment 
as a study participant.   
 
If you decide to quit the study after signing this form (as described in Section 6) no new information will 
be collected about you unless you gave us permission to do so.  However, the hospital or the researchers 
may continue to use information that was collected before you quit the study to complete analysis and 
reports of this research.  
Additionally, a description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
For more detail about your privacy rights see the <INSERT HOSPITAL NAME> Joint Privacy Notice 
which has or will be given to you.   
 
GINA STATEMENT  
This study involves ‘genetic testing’ as defined by the Genetic Information Nondiscrimination Act of 
2008 (GINA). GINA generally makes it illegal for health insurance companies, group health plans, and 
most employers to discriminate against you based on your genetic information.  There are some 
limitations to GINA’s protections (it does not apply to all insurers or employers, nor does it apply to all 
genetic information, such as information related to a genetic disease that you already have).  In addition to 
GINA’s protections regarding the ultimate use to which your genetic information is put, Lifespan’s 
privacy policies generally protect the privacy of such information and restrict its release outside of 
Lifespan, unless you specifically authorize its disclosure or unless disclosure without your authorization 
is permitted under applicable privacy laws.  
SIGNATURE 
 
I have read this informed consent and authorization form.  ALL OF MY QUESTIONS HAVE BEEN 
ANSWERED, AND I WANT TO TAKE PART IN THIS RESEARCH STUDY. 
 
By signing below, I give my permission to participate in this research study and for the described uses and 
releases of information.  I also confirm that I have been now or previously given a copy of the <INSERT 
HOSPITAL NAME> Privacy Notice 
 
 
 
 
This informed consent document expires on _________________.   


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7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
50 
The Researcher is required to provide a copy of this consent to you.  
 
_________________________________________ 
________          ____________ 
Signature of study volunteer/authorized representative* Date         and    Time when signed 
 
 
 
I was present during the consent PROCESS AND signing of this agreement by the study volunteer or 
authorized representative 
 
__________________________________________ 
 
______________ 
Signature of witness (required if consent  
 
 
 
Date 
is presented orally or at the request of the IRB)  
 
 
 
 
 
 
 
 
__________________________________________ 
 
______________ 
Signature of Translator  
 
 
 
 
Date 
 
___________________________________________ 
________          __________ 
Signature of researcher or designate 
 
 
 
Date         and    Time when signed 
 
* If signed by agent other than study volunteer, please explain below. 
________________________________________________________________________________ 
 
________________________________________________________________________________ 
 
 


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7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
51 
APPENDIX B: Checklist 
BrUOG 337: Olaparib Prior to Radical Prostatectomy For Patients with Locally Advanced 
Prostate Cancer and Defects in DNA Repair Genes 
 
Inclusion Criteria 
________(y/n) Histologically confirmed adenocarcinoma of the prostate  
________(y/n) No prior chemotherapy for advanced prostate cancer or PARP inhibitor. Prior and current 
hormone therapy (< 6 months) for prostate cancer is allowed. 
_________(y/n) High risk for recurrence after prostatectomy including any of the following 
• 
Lymph node involvement by radiographic criteria 
• 
T3 or T4 disease by radiographic criteria 
• 
T2 disease and either PSA > 20 or Gleason 8,9 or 10 
 
________(y/n) Defects in any of the genes noted in section 3.1.3, document on “on study” form and submit 
results 
________(y/n) No distant visceral metastases.  
________(y/n) Voluntary, signed written informed consent, Date signed_____________ 
________(y/n) Age >18  
___________(y/n) Must be willing to consent to use effective contraception while on treatment and for at 
least 4 months afterwards  
___________(y/n) Bone scan, MRI or CT of the pelvis, and chest X-ray completed per section 6  
___________(y/n) EKG per section 6 at study entry and resting ECG with QTc > 470 ms. 
 
___________(y/n) Life expectancy at least 1 year as noted by treating investigator 
__________(y/n) Absolute neutrophil count ≥ 1,500/ul, Date_________  
___________(y/n) Platelet ≥ 100,000/uL,  Date_________ 
 
___________(y/n) Total bilirubin <1. 5 x ULN, Date_________ 
___________(y/n) AST≤  2.5x ULN and ALT < 2.5x ULN Institution  
___________(y/n) Creatinine clearance > 51 mL/min 
__________(y/n) HGB > 10.0g/dL with no blood transfusión in last 28 days 
___________(y/n) WBC > 3x 109/L 
___________(y/n) ECOG PS 0-1 
___________(y/n) Patient is willing and able to comply with the protocol for the duration of the study 
including undergoing treatment and scheduled visits and examinations 
 


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7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
52 
___________(y/n) Patient agreed to not consume grapefruit juice while on study treatment. Submit 
documentation patient was instructed and agreed. 
 
_________(y/n) Patient agreed to not receive any live virus and live bacterial vaccines while receiving 
study medication and during the 30 day follow up period. Patient should be made aware of this  
Exclusion Criteria: 
_________(y/n) Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site or BrUOG) 
_________(y/n) Participation in another clinical study with an investigational anticancer product during 
the last 2 months (from day 1 of treatment on this trial).  
 
_________(y/n) Any previous treatment with PARP inhibitor for this or another cancer, including 
olaparib. 
_________(y/n) Other malignancy in the last 5 years except adequately treated non-melanoma skin 
cancer or other solid tumors including lymphomas (without bone marrow involvement) which was 
curatively treated with no evidence of disease for ≥5 years from registration.  
 
_________(y/n) Resting ECG with QTc > 470 msec see section 3.2.5 
 
_________(y/n)  Known family history of long QT syndrome 
 
_________(y/n) Patients receiving any systemic chemotherapy or radiotherapy within 3 weeks prior to 
study treatment  
 
_________(y/n) The last dose on antiandrogen hormone therapy must be > 72 hours prior to the first 
dose of olaparib. 
 
_________(y/n) Receiving strong or moderate CYP3A inhibitors 
 
_________(y/n) Receiving strong or moderate CYP3A inducers 
 
_________(y/n) Concomitant use of the substrates of CYP3A4, CYP1A2, 2B6, 2C9, 2C19 and P-
gp should be cautioned while on study.  
 
_________(y/n) Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) 
grade 2) deemed related to previous cancer therapy, excluding alopecia. 
 
_________(y/n) Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features 
suggestive of MDS/AML. 
_________(y/n) Patients with brain metastases. 
 
_________(y/n) Major surgery within 2 weeks of starting study treatment and patients must have 
recovered from any effects of any prior major surgery. 
 


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7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
53 
_________(y/n) Patients 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 CT  scan or any psychiatric 
disorder that prohibits obtaining informed consent. 
 
_________(y/n) Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication.  
_________(y/n) Patients who are known to be HIV positive or who are immunocompromised- see section 
3.2.16 
_________(y/n) Patients with a known hypersensitivity to olaparib or any of the excipients of the product. 
_________(y/n) Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk of transmitting the 
infection through blood or other body fluids 
_________(y/n) Previous allogeneic bone marrow transplant or double umbilical cord blood 
transplantation (dUCBT) 
_________(y/n) Whole blood transfusions in the last 120 days prior to entry to the study (packed red 
blood cells and platelet transfusions are acceptable as long as not within 28 days from study 
registration) 
_________(y/n) Major medical or psychiatric illness which, in the investigator’s opinion, would prevent 
completion of treatment and would interfere with follow-up. 
_________(y/n) History and/or confirmed pneumonitis 
________(y/n) Visceral metastases 
 
The support documentation, per the requirements under the study parameters section of this study, as well 
as the consent form and this checklist, must be faxed to the BrUOG Central Office at the time of 
registration.  Please check if “Enclosed”, state reason when “Not Enclosed,” or check if "Not Applicable."  
1) Eligibility Form  
 
Enclosed __Not Enclosed   
___ Not Applicable  __ 
2) Heme/Onc initial note 
Enclosed __Not Enclosed   
___ Not Applicable  __ 
3) Pathology Report(s)         
Enclosed __Not Enclosed   
___ Not Applicable  __ 
4) MRI/CT Report(s)   
Enclosed __Not Enclosed   
___ Not Applicable  __ 
5) Lab Source Document         Enclosed __Not Enclosed   
___ Not Applicable  __ 
6) ICF signature page 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
54 
7) Other documents, please list________________________ 
 
IRB approval date of protocol:   
  
Hospital where patient will be treated with Oncologist:    
 
 
 
 
 
Date patient will begin treatment:  
 
  Primary Physician: 
  
 
 
 
 
Your signature:  
 
 
 
 
 
 
 
 
 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
55 
 APPENDIX C 
NCI CTC Version 4 
 
Toxicity will be scored using NCI CTC Version 4 for toxicity and adverse event reporting.  A copy of the 
NCI CTC Version 4can be downloaded from the CTEP homepage: (http://ctep.info.nih.gov).  All 
appropriate treatment areas have access to a copy of the CTC Version 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
56 
APPENDIX D 
 ECOG PATIENT PERFORMANCE STATUS 
STATUS 
KARNOFSKY 
ZUBROD-ECOG-
WHO 
Description 
No complaints 
100 
0 
Normal activity 
 
Able to carry on 
normal activities 
90 
1 
Symptoms, but fully 
ambulatory 
 
Normal activity with 
effort 
 
80 
 
 
 
Cares for self.  Unable 
to carry on normal 
activity or to do active 
work 
 
70 
2 
Symptomatic, but in 
bed <50% of the day 
Requires occasional 
assistance, but able to 
care for most of his 
needs 
 
60 
 
 
Requires considerable 
assistance and 
frequent medical care 
 
50 
3 
Needs to be in bed 
>50% of the day, but 
not bedridden 
Disabled, requires 
special care and 
assistance 
 
40 
 
 
Severely disabled.  
Hospitalization 
30 
4 
Unable to get out of 
bed 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
57 
indicated though 
death non imminent 
 
Very sick.  
Hospitalization  
Necessary.  Active 
support treatment 
necessary 
 
20 
 
 
Moribund 
 
10 
 
 
Dead 
0 
 
 
From: Minna J.D., Higgins G.A and Glapstein E.J.  Cancer of the lung:  In: DeVita V, Hellman S., 
Rosenberg S., (Eds.).  Cancer: Principles and Practice of Oncology, Lippincott, Philadelphia, 1984, p. 536


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
58 
APPENDIX E 
CASE REPORT FORMS 
Attached separately are the BrUOG Case Report Forms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
59 
APPENDIX F:  
HY’S LAW Actions Required in Cases of Increases in Liver Biochemistry and Evaluation of Hy’s 
Law 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately report cases of 
Hy’s Law.  It is not intended to be a comprehensive guide to the management of elevated liver 
biochemistries.   
During the course of the study the Investigator will remain vigilant for increases in liver biochemistry.  
The investigator is responsible for determining whether a patient meets potential Hy’s Law (PHL) criteria 
at any point during the study. 
The Investigator participates, in review and assessment of cases meeting PHL criteria to agree whether 
Hy’s Law (HL) criteria are met.  HL criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than Drug Induced Liver Injury (DILI) caused by the 
Investigational Medicinal Product (IMP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting Adverse 
Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review and assessment 
in line with standard safety reporting processes. 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of Normal 
(ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study following the start of 
study medication irrespective of an increase in Alkaline Phosphatase (ALP).  
Hy’s Law (HL) 
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the IMP, can be 
found to explain the combination of increases, eg, elevated ALP indicating cholestasis, viral hepatitis, 
another drug.   
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the same day) 
the elevation in TBL, but there is no specified timeframe within which the elevations in transaminases 
and TBL must occur. 
Identification of Potential Hy’s Law Cases 
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory data for 
any patient who meets any of the following identification criteria in isolation or in combination: 
• 
ALT ≥ 3xULN 
• 
AST ≥ 3xULN 
• 
TBL ≥ 2xULN 
 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
60 
For Studies using local laboratories: 
The Investigator will without delay review each new laboratory report and if the identification criteria are 
met will: 
• 
Determine whether the patient meets PHL criteria (see Definitions within this Appendix for 
definition) by reviewing laboratory reports from all previous visits 
• 
Promptly enter the laboratory data into the laboratory CRF 
Follow-up 
Potential Hy’s Law Criteria not met 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in the 
Clinical Study Protocol. 
Potential Hy’s Law Criteria met 
If the patient does meet PHL criteria the Investigator will: 
• 
Determine whether PHL criteria were met at any study visit prior to starting study treatment (See 
Error! Reference source not found. 
• 
Notify the AstraZeneca representative  (contact BrUOG who will contact the company) 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an approach for the 
study patients’ follow-up and the continuous review of data.   
Subsequent to this contact the Investigator will: 
• 
Monitor the patient until liver biochemistry parameters and appropriate clinical symptoms and 
signs return to normal or baseline levels, or as long as medically indicated  
• 
Investigate the etiology of the event and perform diagnostic investigations as discussed with the 
Study Physician.  
• 
Complete CRF  
• 
If at any time (in consultation with the Study Physician) the PHL case meets serious criteria, 
report it as an SAE using standard reporting procedures 
Review and Assessment of Potential Hy’s Law Cases 
The instructions in this Section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study Physician 
contacts the Investigator in order to review available data and agree on whether there is an alternative 
explanation for meeting PHL criteria other than DILI caused by the IMP.  The AstraZeneca Medical 
Science Director and Global Safety Physician will also be involved in this review together with other 
subject matter experts as appropriate.  (this communication will be organized by BrUOG) 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
61 
According to the outcome of the review and assessment, the Investigator will follow the instructions 
below. 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a determination of 
whether the alternative explanation is an AE will be made and subsequently whether the AE meets the 
criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the appropriate 
CRF 
• 
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF and report the SAE 
according to section 11 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL elevations other 
than the IMP: 
• 
Report an SAE (report term ‘Hy’s Law’) according to SAE processes in section 11 
− 
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply 
− 
As there is no alternative explanation for the HL case, a causality assessment of ‘related’ 
should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made: 
• 
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and causality 
assessment as per above 
• 
Continue follow-up and review according to agreed plan.  Once the necessary supplementary 
information is obtained, repeat the review and assessment to determine whether HL criteria are 
met.  Update the SAE report according to the outcome of the review 
 
 
 
 
 
 


4/6/17, 4/14/17, 4/19/17, 4/21/17, 4/27/17, 4/28/17, 5/21/17, 5/22/17, 5/25/17, AZ 7/6/17, 7/7/17, 7/13/17, 7/14/17, 7/18/17, 7/24/17, 
7/31/17, 8/7/17, 8/8/17, 8/15/17, 8/18/17, 8/22/17, 8/28/17, AZ approval 8/31/17, 9/7/17, 9/11/17, 9/14/17, 9/15/17, 9/21/17, 9/22/17, FDA 
exemption, 12/5/17, Amendment # 1 4/20/18, Amendment # 2 12/8/18, Amendment # 3 2/8/19 
62 
Actions Required for Repeat Episodes of Potential Hy’s Law 
This section is applicable when a patient meets PHL criteria on study treatment and has already met PHL 
criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL is based 
on the nature of the alternative cause identified for the previous occurrence.   
The investigator should determine the cause for the previous occurrence of PHL criteria being met and 
answer the following question: 
• 
Was the alternative cause for the previous occurrence of PHL criteria being met found to be the 
disease under study e.g. chronic or progressing malignant disease, severe infection or liver disease 
If No: follow the process described in Potential Hy’s Law Criteria met of this Appendix 
If Yes: Determine if there has been a significant change in the patient’s condition# compared with when 
PHL criteria were previously met 
• 
If there is no significant change no action is required 
• 
If there is a significant change follow the process described in Section 4.2 of this Appendix 
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of the 
individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in combination, or a 
clinically relevant change in associated symptoms.  The determination of whether there has been a 
significant change will be at the discretion of the Investigator; this may be in consultation with the Study 
Physician if there is any uncertainty. 
References 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM1740
90.pdf