Conditions: Prostate Cancer
Keywords: radical prostatectomy Olaparib Durvalumab Castration Sensitive Biochemically Recurrent Non-Metastatic Prostate Cancer 18-480 Memorial Sloan Kettering Cancer Center
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if the combination of olaparib and durvalumab are better than the standard of care for treating prostate cancer.

Detailed description:

Arms:
arm 1: Castration Sensitive Biochemically Recurrent Non-Metastatic Prostate Cancer

Interventions: intervention 1: Olaparib intervention 2: Durvalumab
Intervention descriptions: intervention 1: Olaparib 300mg twice daily (600mg total daily dose) intervention 2: Durvalumab 1500mg IV monthly

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 18-480 A(9) 
Approval date: 19-Apr-2023 
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A Phase II Study of Olaparib and Durvalumab in Men with Castration Sensitive Biochemically Recurrent 
Non-Metastatic Prostate Cancer Harboring Mutations in DNA Damage Repair 
Prostate Cancer Clinical Trials Consortium, LLC (PCCTC) 
 
PCCTC #: c17-192 
Memorial Sloan Kettering Cancer Center 
 
Sponsor Principal Investigator 
Karen Autio, MD, MSc 
1275 York Ave 
New York, NY 10065 
email: autiok@mskcc.org 
Protocol Management 
Prostate Cancer Clinical Trials Consortium 
55 Fifth Avenue, 13th Floor 
New York, NY 10003 
email: pcctc@mskcc.org 
 
 
 
 
 
 
Protocol Date: 08-OCT-2018 
Amended Version Date (v2): 15-OCT-2019 
Amended Version Date (v3): 11-JAN-2021 
Amended Version Date (v4): 12-AUG-2021 
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document is provided to you as an investigator, potential investigator, 
consultant, or contractor, for review by you, your staff, and the appropriate Institutional Review 
Board or Ethics Committee. By accepting this document, you agree that the information contained 
herein will not be disclosed to others without written authorization from the lead site/sponsor, 
except to the extent necessary to initiate the study or conduct study-related activities. 


Memorial Sloan Kettering Cancer Center 
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Approval date: 19-Apr-2023 
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APPROVAL OF PROTOCOL 
 
 
Title: A Phase II Study of Olaparib and Durvalumab in Men with Castration Sensitive  Biochemically 
Recurrent Non-Metastatic Prostate Cancer Harboring Mutations in DNA Damage Repair 
 
 
Sponsor Principal Investigator Signature:   
 
 
Print:   
 
 
Date: 
  
 
 
 
 
 
PCCTC Signature:    
 
 
Print:   
 
 
Date: 
  
 


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Approval date: 19-Apr-2023 
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PROTOCOL AGREEMENT 
 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties include ensuring 
the safety of the study subjects enrolled under my supervision and providing Memorial Sloan Kettering 
Cancer Center (MSKCC) with complete and timely information, as outlined in the protocol. It is 
understood that all information pertaining to the study will be held strictly confidential and that this 
confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of the study staff 
and myself, I agree to maintain the procedures required to carry out the study in accordance with 
accepted Good Clinical Practice (GCP) principles, as adopted by applicable laws and regulations, and to 
abide by the terms of this protocol. 
 
 
 
 
 
 
 
 
 
Principal Investigator Signature:     
 
 
Principal Investigator Print: 
  
 
 
Date: 


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TABLE OF CONTENTS 
1. 
INTRODUCTION .............................................................................................................................................................. 6 
1.1 
Disease Background .................................................................................................................................................................. 6 
1.2 
Background ................................................................................................................................................................................... 6 
1.3 
Rationale ....................................................................................................................................................................................... 13 
2. 
OBJECTIVES ................................................................................................................................................................... 15 
2.1 
Primary Objective .................................................................................................................................................................... 15 
2.2 
Secondary Objectives ............................................................................................................................................................. 15 
2.3 
Exploratory Objectives .......................................................................................................................................................... 15 
3. 
SUBJECT SELECTION .............................................................................................................................................. 15 
3.1 
Inclusion Criteria ...................................................................................................................................................................... 15 
3.2 
Exclusion Criteria ................................................................................................................................................................ 17 
4. 
ENROLLMENT PLAN ............................................................................................................................................... 19 
4.1 
Enrollment Plan ................................................................................................................................................................... 19 
4.2 
Eligibility Confirmation .................................................................................................................................................... 19 
5. 
TREATMENT/INTERVENTION PLAN ................................................................................................................. 20 
5.1 
Study Procedures ................................................................................................................................................................ 20 
5.2 
Correlative/Special Studies ............................................................................................................................................ 23 
5.3 
Follow-up (Every 12 weeks) .............................................................................................................................................. 23 
5.4 
Dose Modifications .................................................................................................................................................................. 23 
5.5 
Concomitant Medications and Supportive Care ........................................................................................................ 24 
5.6 
Other Concomitant Treatment .......................................................................................................................................... 24 
5.7 
Removing Subjects from the Protocol ............................................................................................................................ 25 
6. 
THERAPEUTIC AGENTS ............................................................................................................................................. 25 
6.1 
Durvalumab (MEDI4736) ................................................................................................................................................ 25 
6.2 
Olaparib (AZD2281, KU-0059436) (NSC#: 747856) .......................................................................................... 28 
6.3 
Androgen Deprivation Therapy (ADT) ..................................................................................................................... 31 
6.4 
Potential for drug-drug interactions .............................................................................................................................. 31 
6.5 
Treatment Delay ....................................................................................................................................................................... 31 
7. 
SAFETY EVALUATION ............................................................................................................................................ 31 
7.1 
Definitions ................................................................................................................................................................................... 31 
7.2 
Recording and Grading of Adverse Events .................................................................................................................. 35 
7.3 
Reporting Serious Adverse Events .................................................................................................................................. 35 
7.4 
Safety Reports ............................................................................................................................................................................ 39 
8. 
CRITERIA FOR OUTCOME ASSESSMENT/THERAPEUTIC RESPONSE ........................................................ 39 
8.1 
Therapeutic Response ........................................................................................................................................................... 39 
9. 
DATA REPORTING AND REGULATORY REQUIREMENTS ............................................................................ 39 
9.1 
Data Collection and Management ................................................................................................................................ 39 
9.2 
Study Monitoring and Quality Assurance ..................................................................................................................... 40 
10. 
STATISTICAL CONSIDERATIONS ........................................................................................................................ 41 
10.1 Study Endpoints ........................................................................................................................................................................ 41 
10.2 Sample Size Determination ................................................................................................................................................. 42 
10.3 Analysis Populations .............................................................................................................................................................. 42 
10.4 Safety Analysis ..................................................................................................................................................................... 43 
10.5 Statistical Procedures and Analysis ............................................................................................................................ 43 
11. 
REGULATORY AND PROTECTION OF HUMAN SUBJECTS .............................................................................. 43 
11.1 Ethical Considerations ........................................................................................................................................................... 43 
11.2 Protocol Amendments ...................................................................................................................................................... 44 
11.3 Written Informed Consent .............................................................................................................................................. 44 
11.4 Protection of Privacy ......................................................................................................................................................... 44 


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11.5 Terminating or Modifying the Study .............................................................................................................................. 44 
12. 
REFERENCES ................................................................................................................................................................. 46 
APPENDIX A: PERFORMANCE STATUS CRITERIA ........................................................................................................ 50 
APPENDIX B: STUDY CALENDAR ................................................................................................................................... 51 
APPENDIX C. ACTIONS REQUIRED IN CASES OF COMBINED INCREASE OF AMINOTRANSFERASE AND 
TOTAL BILIRUBIN – HY’S LAW .................................................................................................................................... 55 
APPENDIX D: MEDICATIONS WITH THE POTENTIAL FOR DRUG-DRUG INTERACTIONS .............................. 58 
APPENDIX E: GLOSSARY OF ABBREVIATIONS AND ACRONYMS .......................................................................... 61 
APPENDIX F. SELECT PRO - CTCAE ................................................................................................................................... 64 
APPENDIX G. DOSE MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR DURVALUMAB... 65 
APPENDIX H. DOSE MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR OLAPARIB ........... 87 


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1. 
INTRODUCTION 
1.1 
Disease Background 
Prostate cancer is the second leading cause of cancer deaths in men. According to American 
Cancer Society estimates in 2018, as many as 164,690 American men will be diagnosed with 
prostate cancer, and nearly 29,430 will die of the disease.1 While many patients may be cured of 
prostate cancer that is localized to the prostate, others will recur either biochemically (prostate- 
specific antigen (PSA) progression) consistent with micrometastatic disease, or recur with overt 
metastatic disease visible on imaging. 
The course of prostate cancer from diagnosis to death is best categorized as a series of clinical 
states (Figure 1). These clinical states involve the complex interplay of a network of signaling 
molecules that collectively promote net cell proliferation relative to cell death. Based on the 
extent of disease, hormonal status, and absence or presence of detectable metastases on an 
imaging study, the states are defined as: localized disease, rising levels of PSA after radiation 
therapy or surgery with no detectable metastases, and clinical metastases in the non-castrate or 
castrate state. Non-castrate prostate cancer refers to a state in which prostate cancer responds 
to standard hormonal therapy with gonadotropin-releasing hormone (GnRH) analogs (castration 
sensitive) whereas a castrate state is synonymous with castration resistant disease, wherein 
cancer progresses despite standard hormonal therapy with GnRH analogs. 
Figure 1. Clinical states of prostate cancer2 
 
1.2 
Background 
 
1.2.1 
General background on DNA repair defects 
Cancer arises amongst a myriad of genetic alterations resulting in incremental changes in 
pro-survival or anti-apoptotic pathways. These can arise via germline inheritance or (more 
commonly) via random somatic genetic events. The DNA repair machinery to counter this 
implores proteins in direct enzymatic repair, surveillance, regulation of the cell cycle and 
tertiary organizers of these complex processes.3 This includes direct DNA repair pathways 
(Fanconi Anemia pathway, homologous recombination, non-homologous end-joining, 
base excision repair, direct repair, mismatch repair, nucleotide excision repair, translesion 
synthesis) and also associated pathways such as cell-cycle checkpoints, ubiquitin 
response, and chromosomal/chromatin regulation.4  Loss of these DNA repair pathways 
results in genomic instability, increased rate of error-prone repair  mechanisms and 
accumulation of non-fatal genomic mutations-the very hallmark of cancer. Disruption of 
DNA damage repair pathways is observed in many cancers.5-7 The DNA damage response 
is broad and requires complex temporal interactions between many proteins. Functional 


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or expressional loss in these direct and  indirect interactions encompasses the DNA 
damage repair defects. 
 
1.2.2 
DNA damage repair mutations are not rare events in prostate cancer 
A highlight of what we have learned from the genomic landscape in prostate cancer is the 
presence of DNA damage repair (DDR) gene mutations and deletions. The Cancer Genome 
Atlas (TCGA) data in localized prostate cancer found that 19% (62/333) of tumors had a 
germline or somatic DNA damage repair pathway mutation (BRCA2, BRCA1, CDK12, ATM, 
FANCD2, and RAD51).8 Twenty-nine of these cases involved nonsense germline variants 
and heterozygous deletions without the biallelic inactivation; hence the prevalence may 
be somewhat lower. In advanced metastatic castration resistant disease using metastatic 
biopsies, investigators from the Stand Up 2 Cancer – Prostate Cancer Foundation (SU2C- 
PCF) initiative identified 23% of cases had DNA repair gene alterations.9 12.7% of total 
cases had loss of BRCA2 and 5.6% had mutations in ATM or BRCA1. Thus almost 20% of 
all mCRPC contain DNA repair defects even when limited to just these three genes. Events 
were also found with FANCA, PALB2, RAD51B, and RAD51C although at low levels. Hence 
there is a higher prevalence of DNA Damage Repair (DDR) mutations in more advanced 
disease; however, a significant number of cases with DDR mutations still exist in earlier 
clinical states, and are enriched in those with a higher risk of cancer recurrence. 
 
1.2.3 
Olaparib (Lynparza) and PARP inhibition 
The importance of identifying DDR mutations relates to exploitation of synthetic lethality 
when PARP inhibitors are used in patients with homologous recombinant repair (HRR) 
mutations.10 Poly (ADP ribose) polymerases (PARP) help in the repair of DNA single strand 
breaks. When PARP 1/2 is inhibited, single strand breaks are not repaired and progress to 
double strand breaks which are lethal to the cell. Olaparib, a PARP inhibitor, has been 
shown to inhibit selected tumor cell lines in vitro and in xenograft and primary explant 
models as well as in genetic BRCA knock-out models, either as a stand-alone treatment 
or in combination with established chemotherapies.11-13 Cells deficient in homologous 
recombination DNA repair factors, notably BRCA1/2, are particularly sensitive to olaparib 
treatment. 
 
Encouraging preclinical data led to study PARP inhibition in BRCA1/2 mutation carriers in 
clinical trials. The efficacy of olaparib was investigated in a 137-subject subset of a single- 
arm study with germline BRCA-mutated advanced ovarian cancer and three or more prior 
lines of chemotherapy. The objective response rate was 34% and the median duration of 
response was 7.9 months.14 
Olaparib was ultimately approved in 2014 in advanced ovarian cancer patients who have 
been treated with three or more lines of chemotherapy. 
 
1.2.4 
Clinical experience with Olaparib in prostate cancer 
A phase II basket trial which enrolled on the basis of mutation rather than tumor type 
included men with metastatic castration-resistant prostate cancer (mCRPC).15  Although 
it was a small sample, tumor response was seen in half of subjects with prostate cancer, 
and another 25% with stable disease. Ultimately dedicated trials in prostate cancer were 
undertaken. PARP inhibition in patients with HRR mutations has led to high response rates 


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and improved progression-free survival (PFS) in men with CRPC. The responses in a phase 
II trial with subjects who had refractory CRPC were impressive, with 88% (14/16) clinically 
benefiting among those harboring a homologous deletion or deleterious mutation in DNA 
repair genes.16 Response was a composite endpoint defined as response according to 
RECIST 1.1, PSA decline > 50%, or conversion in circulating tumor cells (CTCs) from > 5 
cells/7.5ml to <5 cells/7.5ml. The maximum PSA declines in those subjects who were 
considered responders by the composite definition ranged from no PSA decline to 95% 
decline. 11/16 responders had a PSA decline of > 50%. 
 
The success seen with PARP inhibition in select populations with DNA damage repair 
mutations in prostate cancer has led to fast track approval with the US FDA for olaparib. 
The PROFOUND trial, a phase III trial of olaparib compared to oncologist treatment choice 
in DDR mutated subjects (NCT02987543) has resulted and led to the FDA approval for 
metastatic castration resistant prostate cancer.17 The trial enrolled men with mutations 
in DNA repair genes and divided them into two cohorts. Cohort A included men with 
alterations in the BRCA1, BRCA2, or ATM genes, each of which plays an important role in 
DNA repair. Cohort B included men who had alterations in a group of 12 other genes that 
have some involvement in repairing DNA. Based on improvements in overall survival of 
approximately 4 months, Olaparib was FDA approved for men with DDRs alterations. 
 
From the mature ovarian and breast cancer trial experience in subjects harboring a BRCA 
mutation, it is recognized that resistance develops and hence combination trials and 
methods of re-sensitizing or enhancing durability are essential.18,19 Additionally, 
maintenance therapy with olaparib adds benefit as seen in the ovarian population.20 
1.2.5 
Toxicity experience 
A full description of the emerging safety profile for olaparib, with guidance for 
investigators, is provided in the IB. 
 
This section lists those adverse events (AEs) and laboratory abnormalities experienced in 
≥20% subjects that are currently regarded as expected for regulatory reporting purposes. 
 
• 
Hematological toxicity, generally low grade (CTCAE Grade 1 or 2): 
o Anemia 
 
• 
Non-hematological toxicity, generally mild or moderate (CTCAE Grade 1 or 2), 
intermittent and manageable on continued treatment: 
o Nausea 
o Fatigue 
o Vomiting 
o Diarrhea 
o Decreased appetite 
CTCAE = NCI Common Terminology Criteria for Adverse Events 
 
 
1.2.6 
PD(L) 1 as a target to treat cancer 


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It is known that cancers can be recognized by the immune system, and, under some 
circumstances, the immune system may control or even eliminate tumors.21 PD-L1 is a 
member of the B7 family of ligands that inhibit T-cell activity through binding to the PD-1 
receptor22 and to CD80.23 PD-L1 expression is an adaptive response that helps tumors 
evade detection and elimination by the immune system. Expression of PD-L1 protein is 
induced by inflammatory signals that are typically associated with an adaptive immune 
response (e.g., IFNγ) and can be found on both tumor cells and tumor-infiltrating immune 
cells. The binding of PD-L1 to PD-1 on activated T cells delivers an inhibitory signal to the 
T cells, preventing them from killing target tumor cells and protecting the tumor from 
immune elimination.24 PD-L1 may also inhibit T cells through binding to CD80, although 
the exact mechanism is still not fully elucidated.23,25 
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a 
way of evading immune detection and elimination. The binding of an anti–PD-L1 agent to 
the PD-L1 receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors 
expressed on immune cells. This activity overcomes PD-L1–mediated inhibition of 
antitumor immunity. While functional blockade of PD-L1 results in T-cell reactivation, this 
mechanism of action is different from direct agonism of a stimulatory receptor such as 
CD28. 
 
PD-L1 is expressed in a broad range of cancers. Based on these findings, anti–PD-L1 
antibodies have been used therapeutically to enhance antitumor immune responses in 
patients with cancer. Results of non-clinical and clinical studies of monoclonal antibodies 
(mAbs) targeting the PD-L1/PD-1 pathway have shown evidence of clinical activity and a 
manageable safety profile, supporting the hypothesis that an anti–PD-L1 antibody could 
be used to therapeutically enhance antitumor immune response in cancer patients.26-31 
This has led to FDA approval of anti PD(L)1 antibodies in multiple malignancies including 
melanoma, NSCLC, squamous head and neck cancer, kidney cancer, urothelial cancer, and 
mismatch repair protein deficient patients irrespective of tumor origin.32,33 
1.2.7 
Durvalumab 
Durvalumab is a mAb of the immunoglobulin G (IgG) 1 kappa subclass that inhibits binding 
of PD-L1 and is being developed by AstraZeneca/MedImmune for use in the treatment of 
cancer 
(MedImmune 
is 
a 
wholly 
owned 
 
subsidiary 
of 
AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document). 
The proposed mechanism of action (MOA) for durvalumab is interference in the 
interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 
interactions releases the inhibition of immune responses, including those that may result 
in tumor elimination. In vitro studies demonstrate that durvalumab antagonizes the 
inhibitory effect of PD-L1 on primary human T cells resulting in the restored proliferation 
of IFN-γ.34 In vivo studies have shown that durvalumab inhibits tumor growth in xenograft 
models via a T-cell-dependent mechanism.34 Based on these data, durvalumab is 
expected to stimulate the patient’s antitumor immune response by binding to PD-L1 and 
shifting the balance toward an antitumor response. Durvalumab has been engineered to 
reduce 
antibody-dependent 
cellular 
cytotoxicity 
and 
complement-dependent 
cytotoxicity. 


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To date durvalumab has been given to more than 9000 patients as part of ongoing studies 
either as monotherapy or in combination with other anti-cancer agents, and is FDA 
approved for the treatment of patients with locally advanced or metastatic urothelial 
carcinoma who either have disease progression during or following platinum-containing 
chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant 
treatment with platinum- containing chemotherapy. Approval was based on one single- 
arm trial of 182 subjects with locally advanced or metastatic urothelial carcinoma whose 
disease progressed after prior platinum-containing chemotherapy (NCT01693562).35,36 
Durvalumab, 10 mg/kg intravenously, was administered every 2 weeks. Confirmed 
objective response rate (ORR) as assessed by blinded independent central review per 
RECIST 1.1, was 17.0% (95% CI: 11.9, 23.3). At the data cutoff for the ORR analysis, median 
response duration was not reached (range: 0.9+ to 19.9+ months). ORR was also analyzed 
by PD-L1 expression status as measured by VENTANA PD-L1 (SP263) Assay. In the 182 
subjects, the confirmed ORR was 26% (26% CI: 17.8, 36.4) in 95 subjects with a high PD- 
L1 score and 4% (4% CI: 0.9, 11.5) in 73 subjects with a low or negative PD-L1 score.36 
Toxicity from Treatment with Durvalumab 
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents 
are thought to be due to the effects of inflammatory cells on specific tissues. These risks 
are generally events with a potential inflammatory or immune mediated mechanism and 
which may require more frequent monitoring and/or unique interventions such as 
immunosuppressants and/or endocrine therapy. These immune mediated effects can 
occur in nearly any organ system, and are most commonly seen as gastrointestinal AEs 
such as colitis and diarrhea, pneumonitis/interstitial lung disease (ILD), hepatic AEs such 
as hepatitis and liver enzyme elevations, skin events such as rash and dermatitis and 
endocrinopathies including hypo- and hyper-thyroidism. 
 
Risks with durvalumab include, but are not limited to, diarrhea/colitis and intestinal 
perforation, pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I 
diabetes mellitus, hypophysitis and adrenal insufficiency) hepatitis/increases in 
transaminases, nephritis/increases in creatinine, pancreatitis/increases in amylase and 
lipase, 
rash/pruritus/dermatitis, 
myocarditis, 
myositis/polymyositis, 
pemphigoid, 
immune thrombocytopenia, other rare or less frequent inflammatory events including 
neuromuscular toxicities (e.g, Guillain-Barré syndrome, myasthenia gravis), infusion- 
related reactions, hypersensitivity reactions and infections/serious infections. 
 
In monotherapy clinical studies AEs (all grades) reported very commonly (≥ 10% of 
subjects) are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, 
vomiting, back pain, pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, 
rash, and pruritus. Approximately 9% of subjects experienced an AE that resulted in 
permanent discontinuation of durvalumab and approximately 6% of subjects experienced 
an SAE that was considered to be related to durvalumab by the study investigator. 
 
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of 
established treatment guidelines for immune-mediated toxicity 


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Refer to the current durvalumab Investigator’s Brochure for a complete summary of non- 
clinical and clinical information including safety, efficacy and pharmacokinetics. The non- 
clinical and clinical experience is fully described in the most current version of the 
durvalumab Investigator’s Brochure. 
 
Rationale for fixed dosing 
A population PK model was developed for durvalumab using monotherapy data from a 
Phase I study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid 
tumors). Population PK analysis indicated only minor impact of body weight (WT) on the 
PK of durvalumab (coefficient of ≤0.5). The impact of body WT-based (10 mg/kg Q2W) 
and fixed dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted 
steady state PK concentrations (5th, median and 95th percentiles) using the population 
PK model. A fixed dose of 750 mg was selected to approximate 10 mg/kg (based on 
median body WT of ~75 kg). A total of 1000 subjects were simulated using body WT 
distribution of 40–120 kg. Simulation results demonstrate that body WT-based and fixed 
dosing regimens yield similar median steady state PK concentrations with slightly less 
overall between-patient variability with fixed dosing regimen. 
Similar findings have been reported by others.37-40 Wang and colleagues investigated 12 
monoclonal antibodies and found that fixed and body size-based dosing perform similarly, 
with fixed dosing being better for 7 of 12 antibodies.38 In addition, they investigated 18 
therapeutic proteins and peptides and showed that fixed dosing performed better for 12 
of 18 in terms of reducing the between-patient variability in pharmacokinetic/ 
pharmacodynamics parameters.39 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given expectation of similar pharmacokinetic exposure and 
variability, AstraZeneca considered it feasible to switch to fixed dosing regimens. Based 
on average body WT of 75 kg, a fixed dose of 1500 mg Q4W durvalumab (equivalent to 
20 mg/kg Q4W) is included in the current study. 
 
1.2.8 
PD(L)1 therapy in prostate cancer 
Emerging data with pembrolizumab (anti-PD1 antibody) in mCRPC has also shown recent 
promise to a field previously lagging behind other genitourinary malignancies with 
approved anti-PD(L)1 options such as bladder and renal cell carcinoma; checkpoint 
blockade with ipilimumab produced disappointing results in the pre- and post- 
chemotherapy CRPC setting, and there was little therapeutic study of the PD1 pathway 
in prostate cancer after a phase I trial published in 2012 of nivolumab did not identify any 
complete or partial responses in 17 subjects with advanced CRPC.30,41,42 More recently, 
however, Graff et al (2016) evaluated the benefit of adding pembrolizumab to 
enzalutamide (an androgen receptor (AR) antagonist approved in mCRPC) in subjects who 
were progressing (after initial response) on enzalutamide; 5/27 subjects have responded 
as measured by dramatic PSA declines and reductions in tumor burden on computerized 
tomography (CT) scan.43 Of the published data which reported the first 10 subjects (with 
3 responders), the 3 PSA nadirs in those subjects benefiting from treatment were 0.08, 
0.02, <0.01. One of these subjects had mismatch repair protein deficiency, which is known 
from the colorectal experience and other published trials to be associated with a much 


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higher likelihood of responding to PD1 blockade, suspected as a result of higher 
mutational loads and subsequent neoantigen presentation.44,45 The FDA has approved 
pembrolizumab across all refractory metastatic solid tumors who harbor deficiency in 
mismatch repair, though very few subjects with prostate cancer were part of this analysis. 
Mismatch repair protein deficiency occurs in approximately 2-5% of metastatic prostate 
cancer.46 
1.2.9 
Combination PARP inhibition and anti-PD(L)1 therapy 
Using PARP inhibition to treat tumors deficient in homologous recombinant repair can 
reduce tumor burden and incite apoptosis with demonstrable clinical benefit. 
Preclinically, PARP inhibition is associated with triggering the cyclic GMP-AMP synthase 
(cGAS)-Stimulator of Interferon Genes (STING) pathway, and upregulation of PD-L1.47 
However, this has not been evaluated in any prospective clinical trials. Additionally, 
BRCA2 loss leads to greater genomic instability, which is associated with neo-epitope 
formation and potential increased sensitivity to checkpoint blockade. A natural extension 
of these findings is to combine PARP inhibition with an anti-PD-L1 antibody. 
 
The combination of PARP inhibition and anti PD(L)1 antibodies is being explored in several 
malignancies including NSCLC (NCT03308942), triple negative breast cancer and ovarian 
cancer (NCT02657889; NCT02484404). It is also being investigated in mCRPC 
(NCT02657889). A trial being conducted at the NCI evaluating durvalumab with olaparib 
(NCT02484404) with a cohort of subjects with metastatic CRPC in an unselected 
population (did not require the presence of DDR) suggests a manageable safety profile 
and early but promising results. As presented at ASCO 2017, seven (of 16) subjects (44%) 
on-study >2 months have had PSA declines > 50%.48 
1.2.10 Options for patients with biochemical recurrence 
For men with biochemically recurrent, non-metastatic prostate cancer, options for 
management include observation, initiation of androgen deprivation therapy (ADT), 
salvage radiation therapy, or participation in clinical trials. The decision to initiate therapy 
is dependent upon multiple factors including PSA, PSA doubling time (as a reflection of 
risk of development of metastatic disease), patient comorbidities and preferences, as well 
as clinician preferences. 
 
Most of the ADT therapies approved for prostate cancer have been on the basis of an 
equivalent effect on serum testosterone levels, or an improved safety profile relative to 
other available agents.49-51 None have shown superiority in a cancer specific outcome 
such as an improvement in disease related symptoms, time to progression or overall 
survival. A Canadian study comparing intermittent versus continuous ADT in non- 
metastatic biochemically recurrent prostate cancer showed no difference in cancer 
specific outcomes, but an improvement in prostate cancer and therapy related adverse 
events for men treated on the intermittent approach.52 With an intermittent approach, 
men receive ADT for a fixed period of time in which PSA declines, then ADT is intentionally 
held and not restarted until the PSA again begins to rise. Many have explored the 
approach with “on cycles” of varied duration, but in most studies, the maximal response 
is observed by 8 months of ADT, and 6-9 months is standard.53 Castrate levels of 
testosterone can be achieved within 48-72 hours with the administration of a GnRH 


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antagonist, degarelix. ADT has been shown to induce apoptosis of prostate cancer cells;54 
potentially leading to the release of tumor antigens. 
 
Although ADT serves as the primary basis of treatment in recurrent non-castrate 
(castration sensitive) biochemically recurrent prostate cancer that is at risk of metastatic 
recurrence, lowering testosterone to castrate levels comes with significant quality of life 
disturbance to men; this includes decreased libido, erectile dysfunction, fatigue, muscle 
loss, weight gain, hot flashes, bone density loss, and potentially increased risk of 
cardiovascular events, cognitive impairment, and diabetes.55-57 As a consequence, many 
patients at risk for developing lethal forms of the disease are appropriately interested in 
alternatives to ADT, in hopes of avoiding ADT toxicities and preventing or delaying CRPC. 
 
1.3 
Rationale 
Therapy for recurrent prostate cancer has a long history of hormonal manipulation which led to 
advances with second generation AR-directed agents such as enzalutamide in CRPC; however, 
molecular profiling and immuno-oncology is revolutionizing the field and bringing new pathways 
to the forefront with potential to transform the management and natural history of this disease 
yet again. In this proposed trial for men with castration sensitive disease, we will exploit synthetic 
lethality using PARP inhibition (olaparib) in those subjects with somatic and germline DNA damage 
repair (DDR) mutations, and couple this with anti-PDL1 immunotherapy (durvalumab) for 
enhanced and durable effect. We will first explore the combination without ADT, as a regimen 
that can avoid the quality of life detriment associated with ADT, which would be a milestone for 
the field if successful. For those who do not fully respond with olaparib and durvalumab alone, 
ADT will be added for a fixed course to potentially salvage with triplet therapy. 
 
1.3.1 
Rationale for trial endpoint and population 
The primary endpoint of this trial offers a clear signal of efficacy as an undetectable PSA 
with non-castrate levels of testosterone at 24 months suggests no malignant tumor cells 
are producing PSA and hence are not active. This has been used in other clinical trials 
(NCT02020070; NCT01751451) and offers an advantage over other interim endpoints 
such as PSA progression, radiographic PFS (e.g., time to metastatic disease), development 
of CRPC, or OS which can require a very lengthy follow up period in castration sensitive 
disease. An undetectable PSA in a subject who is post prostatectomy is a clear sign of the 
absence of cancer activity. Durability of an undetectable PSA in an environment rich with 
testosterone is synonymous with cure, and analogous to a complete response in solid 
tumors. Secondary endpoints, more synonymous with progression free survival (PFS) 
used in other immunotherapy trials, will also be collected and informative of the efficacy 
of this regimen. 
 
This trial will include men who have had a radical prostatectomy and/or primary definitive 
radiation therapy to the prostate and have developed biochemical non-metastatic 
recurrence with a PSA doubling time placing them at high risk for metastases. This trial 
will allow those subjects who are ADT naïve, as well as those who have received 
intermittent ADT and currently are on an ‘off cycle’ of ADT. Allowance of subjects who 
have received a prior cycle of ADT and failed allows them to serve as their own control. 
In the biochemically recurrent “non-metastatic” population, the inability to identify gross 
metastatic disease is more a function of the limitations of conventional imaging (CT and 


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technicium bone scan) than it is a reflection of not having micro-metastatic recurrence. 
As novel tracers such as Prostate Specific Membrane Antigen (PSMA) PET imaging 
identifies disease earlier, and with greater sensitivity, a lead time bias is anticipated across 
trials. With more sensitive imaging, subjects with earlier metastatic disease may be 
enrolled in metastatic trials in the future. This trial will use conventional imaging with 
CT/MRI and bone scan to define non-metastatic disease. It will not exclude those subjects 
with disease only detectable using investigational PET imaging. 
 
Moving into earlier disease states in the prostate cancer continuum is appealing as the 
immune system may be more receptive with fewer immunosuppressive cells and with 
less tumor burden to overcome. In clinical trials with prostate cancer, there have been 
hints that lower disease burden may be a more optimal setting for immunotherapy. Post 
hoc analysis of the IMPACT trial which evaluated the sipuleucel-T vaccine in mCRPC 
demonstrated that the subset of subjects with PSA values in the lowest quartile were 
more likely to benefit than those with PSA (as a very loose reflection of burden) in the 
highest quartile.58 More recent data in melanoma using anti-PD1 antibodies suggests the 
ratio of reinvigorated exhausted T cells relative to tumor burden can be predictive of 
response to anti-PD1 therapy. The authors postulated that if the tumor burden is high, 
even a robust reinvigoration of T cells may not be enough.59 
Outside of the hypotheses generated for the timing of immunotherapy, there is growing 
evidence that utilization of chemotherapy, and more potent anti-androgens such as 
abiraterone previously only used in the castration resistant setting can have a more 
profound impact when used in castration sensitive disease relative to ADT alone. The use 
of ADT with docetaxel for 6 cycles in metastatic castration sensitive prostate cancer as 
compared to ADT alone as well as abiraterone with prednisone with ADT relative to ADT 
alone in the castration sensitive (non-castrate) metastatic disease setting are now 
supported by several large phase III trials 60 The CHAARTED trial found the greatest benefit 
in those deemed to have a higher ‘burden’ of metastatic disease and the LATITUDE trial 
required at least 3 bone metastases.60-62 Where subjects with minimal metastatic disease 
(e.g., 1-2 bone metastases, or low volume unresectable nodal disease) are best served is 
not altogether clear. 
 
1.3.2 
Hypothesis 
PARP inhibition in subjects with prostate cancer harboring HRR mutations will reduce 
tumor burden and cause apoptosis of the cell, leading to neoantigen release, activation 
of the cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway, 
which in combination with PDL1 blockade may lead to durable responses. This 
combination may be effective in treating recurrent prostate cancer without the use of 
ADT, a maneuver which is associated with only temporary response, an inability to cure, 
and significant quality of life detriment. For those who do not achieve an undetectable 
PSA with normal testosterone at 4 months, ADT for a fixed course will be added starting 
the following cycle to determine if they can be “salvaged” with triplet therapy, as ADT has 
been demonstrated to increase cytotoxic T cell proliferation and  will reduce tumor 
burden. 


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2. 
OBJECTIVES 
2.1 
Primary Objective 
To assess the therapeutic efficacy as defined by an undetectable PSA (<0.05 or PSA <0.10 for 
institutions where this is the lower limit of detection) with non-castrate levels of testosterone 
using the combination olaparib (PARP inhibition) with durvalumab (PDL1 inhibition) at 24 months 
(cycle 24) in biochemically recurrent prostate cancer. 
 
2.2 
Secondary Objectives 
• 
To determine if a non-castrating regimen can provide disease control as measured by an 
undetectable PSA (without ADT) at 5 months (cycle 5). 
• 
To evaluate the safety of the combination of olaparib and durvalumab 
2.3 
Exploratory Objectives 
To determine: 
• Undetectable PSA at 11 months (cycle 11) (irrespective of testosterone level) 
• Time to PSA progression defined as the time to PSA increase that is ≥ 25% and ≥ 2ng/mL above 
the nadir, and which is confirmed by a second value > 3 weeks later 
• Change in PSA doubling time at 24 months relative to PSA doubling time from the first dose of 
study drug (using the last 3 values from each time point) 
• Comparison of Patient Reported Outcome  (PRO) assessments of toxicity  (PRO-CTCAE) to 
clinician reported toxicity assessments (CTCAE v.5.0) 
• Changes in immune biomarkers with treatment. Peripheral blood mononuclear cells (PBMCs) 
will be collected that can later be analyzed for the immunomodulatory effects of the regimen 
by measuring for example, discrete T-cell populations. Archival tissue will also be analyzed for 
immune-related genes that may associate with response. 
 
3. 
SUBJECT SELECTION 
3.1 
Inclusion Criteria 
To be included in this study, subjects should complete all screening procedures and meet all of 
the following criteria: 
3.1.1 
Willing and able to provide written informed consent and HIPAA authorization for the 
release of personal health information. A signed informed consent must be obtained 
before screening procedures are performed. 
NOTE: HIPAA authorization may be either included in the informed consent or obtained 
separately. 
3.1.2 
Males 18 years of age and above 
3.1.3 
Body weight > 30kg 
3.1.4 
History of radical prostatectomy and/or primary radiation therapy to the prostate 
3.1.5 
Histologically confirmed prostate cancer with progressive disease defined as: 


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• 
Rising PSA (50% or more increase to a level of 0.50 ng/mL or more, based on at least 
3 PSA determinations obtained at least 1 week apart). The 50% rise in PSA is across 
the 3 determinations, and these determinations do not need to be sequential. 
• 
PSA doubling time of ≤ 9months as calculated according to the Memorial Sloan 
Kettering Cancer Center nomogram 
(http://www.mskcc.org/mskcc/html/10088.cfm) 
3.1.6 
No evidence of metastatic disease on conventional imaging (CT/MRI and bone scan). 
However, subjects with pelvic and/or retroperitoneal nodes < 2cm in the short axis will 
be permitted on study, as they are considered not to have definitive metastases. (Note: 
Metastatic disease on investigational  imaging, Prostate Specific Membrane Antigen- 
targeted (PSMA) PET, PET-choline, or other novel PET tracers who do not have evidence of 
metastatic disease using conventional imaging (CT/MRI, bone scan) are allowed.) 
3.1.7 
Molecular evidence of DDR deleterious mutations (somatic or germline), including BRCA1, 
BRCA2, ATM, CHEK1, CHEK2, FANCA, RAD51B, RAD51C, RAD51D, RAD54L, PALB2, BRIP1, 
BARD1, or CDK12. Mutations may be truncating, splice site mutations, missense or 
homozygous deletions. Mutation status is determined by a local laboratory with the result 
documented in the subject’s medical record, previously obtained genomic testing from a 
CLIA-certified lab, or via archival or fresh tissue. 
3.1.8 
ECOG status of ≤ 1 (Appendix A: Performance Status Criteria) 
3.1.9 
Normal organ function with acceptable initial laboratory values within 14 days of 
treatment start: 
 
WBC 
³ 2000/µl 
ANC 
³ 1500/µL 
Hemoglobin 
³ 10g/dL 
Platelet count 
³ 100,000/µl 
Creatinine 
Clearance 
≥51 mL/min estimated using the Cockcroft-Gault equation 
Estimated creatinine = 
(140-age [years]) x weight (kg) 
Clearance 
serum creatinine (mg/dL) x 72 
Bilirubin 
≤ 1.5 ULN (unless documented Gilbert's disease) 
SGOT (AST) 
£ 2.5 x ULN (unless liver metastases are present, in which case AST 
must be £ 5 x ULN) 
SGPT (ALT) 
£ 2.5 x ULN (unless liver metastases are present, in which case ALT 
must be £ 5 x ULN)  
3.1.10 Non-castrate level of testosterone defined as a value ³ 150 ng/dL 
3.1.10 Life expectancy of ≥ 52 weeks. 
3.1.11 Agree to use two medically acceptable, highly effective forms of birth control (e.g., 
spermicide in conjunction with a barrier such as a condom) or sexual abstinence for the 
duration of the study, including 180 days after the last dose of study drug. Sperm 
donation is prohibited during the study and for 3 months after the last dose of study drug. 


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Female partners of childbearing potential should use hormonal or barrier contraception 
unless postmenopausal or abstinent. 
 
3.2 
Exclusion Criteria 
3.2.1 
No other malignancy from which the subject has been disease-free for less than 3 years, 
with the exception of adequately treated and cured non-invasive malignancies such as 
basal or squamous cell skin cancer or superficial bladder cancer. 
3.2.2 
Less than one month prior  to treatment  start from last  prior  regimen  or  radiation 
exposure. Prior radiotherapy to the prostate (adjuvant or salvage radiotherapy) is 
allowed. 
3.2.3 
No prior investigational use with an anti-PD(1) including durvalumab or anti-CTLA4 
antibody. 
3.2.4 
No prior treatment with a PARP inhibitor, including olaparib. 
3.2.5 
No concomitant or prior therapy with any of the following: IL-2, interferon, or other non- 
study immunotherapy regimens; immunosuppressive agents; or chronic use of systemic 
corticosteroids within 6 weeks of treatment start. Exceptions include: intranasal, inhaled, 
topical steroids, or local steroid injections (e.g., intra articular injection); Systemic 
corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its 
equivalent; Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication) 
3.2.6 
No receipt of live attenuated vaccine within 30 days prior to treatment start Note: 
enrolled subjects should not receive live vaccine while receiving IP and up to 30 days after 
the last dose of study therapy 
3.2.7 
Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate  CYP3A inhibitors (e.g. 
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout 
period prior to treatment start is 2 weeks. 
3.2.8 
Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or 
moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout 
period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks 
for other agents. 
3.2.9 
More than 2 cycles of intermittent hormones for the treatment of biochemical 
recurrence, with a cycle defined as a period of consistent ADT (generally 3-12 months) 
followed by intentional cessation of ADT without re-initiation of ADT until the PSA rises. 
Prior ADT in the treatment of localized prostate cancer or with salvage radiation therapy 
is allowed. Prior use of abiraterone acetate with prednisone, enzalutamide, apalutamide, 
or other androgen receptor/androgen biosynthesis inhibitors are allowed if used in the 
localized or biochemically recurrent disease state provided that there was no evidence of 
disease progression while on these therapies. 


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3.2.10 No medical conditions such as uncontrolled hypertension, uncontrolled diabetes mellitus, 
cardiac disease that would, in the opinion of the investigator, make this protocol 
unreasonably hazardous. 
3.2.11 Subjects considered a poor medical risk due to a serious, uncontrolled medical disorder 
or non-malignant systemic disease. Examples include, but are not limited to, uncontrolled 
ventricular arrhythmia, myocardial infarction within 3 months of treatment start, 
uncontrolled major seizure disorder, unstable spinal cord compression, superior vena 
cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed 
Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed 
consent. 
3.2.12 No active infection including tuberculosis (TB) (clinical evaluation that includes clinical 
history, physical examination and radiographic findings, and TB testing in line with local 
practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or 
active infection with human immunodeficiency virus (positive HIV 1/2 antibodies). 
Subjects with a past or resolved HBV infection (defined as presence of hepatitis B core 
antibody [anti-HBc] and absence of HBsAg) are eligible. Subjects positive for hepatitis C 
(HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA 
3.2.13 No autoimmune disease: subjects with a history of inflammatory bowel disease, including 
ulcerative colitis and Crohn’s Disease, are excluded from this study, as are subjects with 
a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive 
sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., 
Sarcoidosis syndrome or Wegener’s granulomatosis with polyangiitis]); motor 
neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and 
myasthenia gravis); Graves’ disease. Exceptions include history of eczema, vitiligo, 
alopecia, hypothyroidism (e.g., following Hashimoto syndrome), and any chronic skin 
condition that does not require systemic therapy; subjects without active disease in the 
last 5 years prior to treatment start may be included but only after consultation with the 
treating physician. Exceptions may be made on a case by case basis upon discussion with 
the Sponsor Principal Investigator. 
3.2.14 No history of active primary immunodeficiency 
3.2.15 No major surgery within 4 weeks of treatment start. Subjects must have recovered from 
any significant effects of any major surgery but investigators may discuss with the Sponsor 
Principal Investigator in the case of any exceptions. 
3.2.16 No blood transfusion within 28 days of treatment start. 
3.2.17 Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or 
family history of long QT syndrome 
3.2.18 Enrollment in another clinical trial with a therapeutic agent. Subjects may co-enroll on 
investigational imaging studies (e.g., PSMA PET) or correlative trials. 
3.2.19 No previous allogeneic bone marrow transplant or double umbilical cord blood 
transplant. 
3.2.20 No history of leptomeningeal carcinomatosis 


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3.2.21 No unresolved toxicity (Common Terminology Criteria for Adverse Event (CTCAE) Grade ≥ 
2) caused by previous anticancer therapy, excluding alopecia, vitiligo, and the laboratory 
values described in the inclusion criteria. Subjects with Grade ≥ 2 neuropathy will be 
evaluated on a case-by-case basis after consultation with the Sponsor Principal 
Investigator. Subjects with irreversible toxicity not reasonably expected to be 
exacerbated by treatment with study drugs may be included only after consultation with 
the Sponsor Principal Investigator. 
3.2.22 No subjects who are HIV-positive on combination antiretroviral therapy because of the 
potential for pharmacokinetic interactions with olaparib. In addition, these subjects are 
at increased risk of lethal infections when treated with marrow suppressive therapy. 
3.2.23 No subjects with baseline moderate to severe hepatic impairment (Child-Pugh Class B and 
C). 
3.2.24 No subjects with myelodysplastic syndrome/acute myeloid leukemia or with features 
suggestive of MDS/AML. 
3.2.25 No known allergy to any of the compounds under investigation or excipients of the 
product. 
3.2.26 Subjects   unable   to   swallow   orally   administered   medication   and   subjects   with 
gastrointestinal disorders likely to interfere with absorption of the study medication. 
3.2.27 No other condition which, in the opinion of the investigator, would preclude participation 
in this trial. 
 
4. 
ENROLLMENT PLAN 
4.1 
Enrollment Plan 
 
4.1.1 
Anticipated Enrollment 
This study is anticipated to enroll 32 subjects. 
 
4.1.2 
Recruitment 
Potential research subjects will be identified by a member of the subject’s treatment 
team, the protocol investigator, or research team at participating centers from Medical 
Oncology, Radiation Oncology and Urology offices. Investigators will screen the subject’s 
medical records for suitable research study subjects and discuss the study and their 
potential for enrolling in the research study. 
 
4.2 
Eligibility Confirmation 
Confirmation of eligibility will be completed centrally by the PCCTC prior to treatment start. A 
record of subjects who fail to meet eligibility criteria (i.e., screen failures) will be maintained. A 
complete, signed informed consent and HIPAA authorization are required as part of eligibility 
confirmation. All subjects must sign an IRB-approved informed consent prior to starting any 
protocol-specific procedures; however, evaluations performed as part of routine care prior to 
informed consent can be used for screening and eligibility confirmation. 


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5. 
TREATMENT/INTERVENTION PLAN 
This is a phase II, single arm, multi-center trial that will evaluate the combination of olaparib 
300mg twice daily (600mg total daily dose) with durvalumab 1500mg IV monthly in biochemically 
recurrent castration sensitive  prostate cancer. The trial will be conducted at sites who are 
members of the PCCTC Network. 
 
As seen in the trial design (Figure 2), subjects will be treated concurrently with olaparib + 
durvalumab continuously for 24 months. After the first 4 months, if a subject fails to achieve an 
undetectable PSA with the combination of olaparib and durvalumab, ADT will be added for 6 
months (starting at Cycle 5) while continuing treatment with olaparib and durvalumab. For 
subjects who have an undetectable PSA [PSA of <0.05 or PSA <0.10) for institutions where this is 
the lower limit of detection] after the first 4 months of treatment, they will continue on the 
combination of olaparib + durvalumab continuously for 24 months (without ADT). As long as it is 
believed that subjects are clinically benefiting, they will remain on treatment for up to 24 months 
with olaparib and durvalumab. For example, a subject with a PSA reduction that does not achieve 
an undetectable PSA would be allowed to remain on study for the duration of the trial. Subjects 
who meet progression criteria while on active therapy would come off of trial. If subjects respond 
and later progress in the one-year follow-up period (beyond 24 months), they will be allowed to 
be re-induced with the combination. 
 
Figure 2. Study schema for olaparib and durvalumab in subjects with castration-sensitive 
prostate cancer (biochemical recurrence) harboring DNA damage repair mutations 
 
DDR deleterious mutations (somatic or germline) will include BRCA1 (breast cancer susceptibility 
gene), BRCA2, ATM (ataxia telangiectasia mutated serine/threonine kinase), CHEK2, FANCA, 
RAD51C, RAD51D, PALB2, BRIP1, BARD1, and CDK12. Mutations may be truncating, splice site 
mutations, missense or homozygous deletions. Subjects will be allowed on trial using local testing, 
previously obtained genomic testing from a validated lab (e.g., expedited germline testing from 
Color), or via archival or fresh tissue. 
 
The following assessments and procedures will occur during the study. A schedule of assessments 
is provided in Appendix B. 
 
5.1 
Study Procedures 
 
5.1.1 
Informed consent and research/HIPAA authorization 


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Before initiating any protocol-specific screening activities, the scope of the study should 
be explained to each subject. Subjects should be consented in accordance with Section 
11.3 Written Informed Consent, including completion of a research/HIPAA authorization. 
5.1.2 
Inclusion/exclusion criteria 
During the screening period, subject eligibility will be determined according to the 
inclusion and exclusion criteria (Sections 3.1 Inclusion Criteria & 3.2 Exclusion 
Criteria). 
 
5.1.3 
Demographics and medical history 
Demographics and medical history collected will include: 
o Date of birth (or age if date of birth is not allowed to be collected by local 
regulations) 
o Significant past and ongoing conditions 
o Dates of the primary prostatectomy and pathologic state 
o Dates of prior radiation therapy 
o Dates of prior hormonal therapies 
5.1.4 
Concomitant medications 
Concomitant medications are permitted while on study if the medication is not expected 
to interfere with the evaluation of safety or efficacy, and is not otherwise restricted or 
prohibited (see Appendix C for a listing of medications with  the potential  for drug 
interactions). 
 
5.1.5 
Vital signs, height, and weight 
Vitals will include temperature, blood pressure, and pulse. Height and weight will also be 
collected as described in Appendix B. 
 
5.1.6 
Performance Status 
Performance status will be assessed using ECOG or Karnofsky scales (Appendix A). 
 
5.1.7 
Physical examination 
A complete physical examination will be performed at screening. A symptom-directed 
physical exam may be performed at subsequent visits. 
 
5.1.8 
Histologic and radiologic (per PCWG3 and RECIST 1.1 criteria) confirmation of disease 
Pathologic   confirmation   of   prostate   cancer   and   no   evidence   of   metastasis   on 
conventional CT or Bone Scan. 
 
5.1.9 
Laboratory tests 
Laboratory tests will be performed by local labs and will include: 
 
• 
CBC with differential: white blood cells count (WBC), red blood cell count (RBC), 
hemoglobin (HGB), hematocrit (HCT), platelet count (UNVPLT), neutrophils (NEUTP), 
lymphocytes (LYMP), monocytes (MONP), eosinophils (EOSP), basophils (BASOP)). If 
absolute differentials not available please provide % differentials. 


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• 
PSA 
• 
Serum testosterone (TEST) 
• 
Comprehensive Metabolic Panel (CMP): glucose (GLU), calcium (CA), albumin (ALB), 
total protein (TP), sodium (NA), potassium (K), bicarbonate (CO2), chloride (CL), blood 
urea nitrogen (BUN), creatinine (CREAT), alkaline phosphatase (ALK), alanine 
transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBILI) 
• 
Thyroid function tests: TSH, free T4 and free T3 
• 
Urinalysis: pH, specific gravity, hemoglobin, glucose, ketones, and protein by dipstick, 
with microscopic exam if any of the dipstick analytes are 2+ or higher. 
• 
Coagulation Tests: Coagulation [activated partial thromboblastin time (APTT) and 
international normalized ratio (INR)] will be performed at baseline and if clinically 
indicated unless the subject is receiving warfarin. Subjects taking warfarin  may 
participate in this study; however, it is recommended that prothrombin time (INR and 
APTT) be monitored carefully at least once per week for the first month, then monthly 
if the INR is stable. The reason(s) for the use, doses and dates of treatment should be 
recorded in the subject’s medical records and appropriate section of the EDC. 
 
• 
If clinically indicated, the investigator may order amylase and lipase 
 
• 
Bone marrow or blood cytogenetic samples may be collected for subjects with 
prolonged hematological toxicities 
 
 
These tests will be performed by the hospital’s local laboratory. Additional analyses may 
be performed if clinically indicated. 
 
Any clinically significant abnormal laboratory values should be repeated as clinically 
indicated and recorded on the CRF. 
 
In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer to 
Appendix C: ‘Actions required in cases of combined increase of aminotransferase and 
Total Bilirubin – Hy’s Law’, for further instructions 
 
5.1.10 ECG 
All ECGs should be 12-lead ECGs performed in a supine position. ECGs should be 
performed prior to drawing blood when possible. An ECG is required prior to starting 
study treatment and when clinically indicated. 
 
Twelve-lead ECGs will be obtained after the subject has been rested in a supine position 
for at least 5 minutes in each case. ECGs will be recorded at 25 mm/sec. All ECGs should 
be assessed by the investigator as to whether they are clinically significantly abnormal / 
not clinically significantly abnormal. If there is a clinically significant abnormal finding, the 
site will record it as an AE on the eCRF. The original ECG traces must be stored in the 
subject medical record as source data. 


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5.1.11 Computerized tomography (CT) or magnetic resonance imaging (MRI) 
Radiographic evaluations will include CT of the chest, abdomen, and pelvis with contrast 
or MRI with contrast of the abdomen and pelvis, and CT chest without contrast. The 
method of assessment and techniques while on study should be the same as used at 
baseline. 
 
5.1.12 Radionuclide bone scan 
Radionuclide bone scanning (whole body) should be performed using 99mTc-methylene. 
 
5.1.13 Select PRO – CTCAE 
Designed to assess potential drug toxicity from the patient perspective (Appendix F) 
 
5.2 
Correlative/Special Studies 
5.2.1 
Blood Biomarkers: PBMCs and serum will be collected while on trial for future 
investigation of immune correlatives. This may include evaluation of T-cell subsets and 
immunophenotyping, functional status of T effector cells, multiplex cytokine analysis, 
tumor associated antigens; cfDNA will also be collected for potential future use. 
 
5.2.3 
PDL-1 Expression: PDL-1 expression may be performed in the future using archival 
prostatectomy or prostate biopsy tissue. 
5.2.4 
Next generation sequencing and analysis of mutational load, immune driver genes, 
activation of the cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) 
pathway, and immune microenvironment characterization may be performed using 
archived prostatectomy or prostate biopsy tissue. 
5.2.5 
As part of eligibility to determine if a subject has a DNA Damage Repair alteration, a 
matched normal control sample (e.g., blood or saliva) may be required dependent upon 
the assay being utilized. MSK-IMPACT requires a normal control blood sample while 
Tempus uses a saliva sample. 
 
5.3 
Follow-up (Every 12 weeks) 
Subjects will be followed per the schedule in Appendix B. Subjects withdrawn from the study 
because of AEs will be followed until the adverse event has either resolved or stabilized. Reasons 
for premature withdrawal should be determined and noted. 
 
5.4 
Dose Modifications 
If subject requires that the study drug be discontinued because of an adverse event (as described 
below) or have a treatment interruption of greater than 8 weeks for olaparib or 8 weeks for 
durvalumab, at the investigator’s discretion, they may continue on the other agent alone until 
progression. Refer to Appendix G and Appendix H for management of toxicities. 
 
5.4.1 
Durvalumab Dose Modification 
Dose reductions for durvalumab are not permitted. For dose modification and toxicity 
management guidelines for durvalumab, refer to Appendix G. 


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5.4.2 
Olaparib dose levels 
 
Dose Level 
Olaparib 
Level 0 
300 mg BID 
Level -1 
250 mg BID 
Level -2 
200 mg BID 
Level -3 
Discontinue 
 
Subjects requiring more than two dose reductions will have to discontinue olaparib. 100 
mg and 150 mg tablets will be supplied for olaparib. 
 
5.4.3 
Toxicities that require discontinuation from study treatment 
Protocol therapy should be discontinued if a subject experiences: 
• 
Any CTCAE Grade 4 toxicity with the exception of: 
o 
CTCAE Grade 4 neutropenia of 5 days or fewer duration 
o 
CTCAE Grade 4 nausea/vomiting or diarrhea that resolves to Grade 3 or less 
within 72 hours 
o 
CTCAE Grade 4 laboratory abnormalities that can be readily corrected with 72 
hours and do not result in hospitalization. 
• 
CTCAE Grade 3 thrombocytopenia with hemorrhage 
• 
CTCAE Grade 3 febrile neutropenia 
• 
Hy’s Law (AST or ALT >3x ULN with concomitant serum bilirubin >2x ULN and no 
alternate etiology) 
• 
Bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute 
myeloid leukemia (AML) 
 
5.5 
Concomitant Medications and Supportive Care 
Because of the potential for drug-drug interaction, the concurrent use of all other drugs, over- 
the-counter medications, and alternative therapies must be documented on the eCRF. 
 
Subjects should not donate blood while participating in this study or for at least 90 days following 
the last infusion of durvalumab or olaparib. 
 
Refer to Appendix D for more information on concomitant medications and supportive care 
guidance. 
 
5.6 
Other Concomitant Treatment 
Any medications, with the exceptions noted in Appendix D, which are considered necessary for 
the subject's welfare, and which it is believed will not interfere with the study medication, may 
be given at the discretion of the Investigator, providing the medications, the doses, dates and 
reasons for administration are recorded in the EDC. 
 
In addition, any diagnostic, therapeutic or surgical procedure performed during the study period 
must be recorded in the EDC. 


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All medications (prescriptions or over-the-counter medications) continued at the start of the trial 
(from the time of informed consent) or started during the study or until 30 days from the end of 
the last protocol treatment and different from the study medication must be documented. 
 
5.7 
Removing Subjects from the Protocol 
In the absence of treatment delays because of adverse events, treatment will continue for 24 
cycles or until one of the following criteria applies: 
• 
Withdrawal by subject: subject decides to withdraw from the study 
• 
Progressive disease. PSA progression during the treatment period is defined as a 
rising PSA confirmed on repeat measurement at least two weeks later and at a least 
25% rise and 2 ng/mL above nadir or baseline, whichever is lower. The assessment 
for PSA progression that may lead to discontinuation while on treatment will not 
begin prior to Cycle 6 as ADT would not start until Cycle 5. PSA progression during 
the follow up period defined as PSA > 0.2 ng/mL confirmed by repeat measurement 
at least 2 weeks later. 
• 
symptomatic disease progression at any time 
• 
objective clinical disease progression 
• 
Intercurrent illness that prevents further administration of treatment, including 
bone marrow findings consistent with myelodysplastic syndrome (MDS)/acute 
myeloid leukemia (AML) 
• 
Adverse event: unacceptable adverse event(s) that may or may not be directly related 
to treatment but that, in the judgment of the treating physician, makes it dangerous 
for the subject to be retreated 
• 
Physician decision: general or specific changes in the subject’s condition that render 
the subject unacceptable for further treatment, in the judgment of the investigator 
 
Because an excessive rate of withdrawals can render the study uninterpretable, unnecessary 
withdrawal of subjects should be avoided. When a subject discontinues treatment early, the 
investigator should make every effort to contact the subject and to perform a final evaluation. 
The reason(s) for withdrawal should be recorded. 
 
6. 
THERAPEUTIC AGENTS 
6.1 
Durvalumab (MEDI4736) 
Description 
Durvalumab is a human mAb of the IgG 1 kappa subclass that inhibits binding of PD-L1 and is being 
developed by AstraZeneca/MedImmune for use in the treatment of cancer (MedImmune is a 
wholly owned subsidiary of AstraZeneca). 
Pharmacokinetics 
Refer to the current durvalumab Investigator’s Brochure for a complete summary of non-clinical 
and clinical information including safety, efficacy and pharmacokinetics. 
 
Dosage Selected, Preparation, and Schedule of Administration 


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Subjects will receive 1500mg durvalumab (MEDI4736) on Day 1 of each cycle via IV infusion every 
4 weeks. The dose of durvalumab for administration must be prepared by the Investigator’s or 
site’s designated IP manager using aseptic technique. Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed: 
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
 
If in-use storage time exceeds these limits, a new dose must be prepared from new vials. Infusion 
solutions must be allowed to  equilibrate to  room temperature prior to  commencement of 
administration. 
 
A dose of 1500 mg (for subjects >30 kg in weight) will be administered using an IV bag containing 
0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) concentration 
ranging from 1 to 15 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22- 
μm in-line filter. Add 30.0 mL of durvalumab (MEDI4736) (i.e., 1500mg of durvalumab 
[MEDI4736]) to the IV bag. The IV bag size should be selected such that the final concentration is 
within 1 to 15 mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the 
bag. 
 
Weight-based dosing (for subjects ≤30 kg) will be administered using an IV bag containing 0.9% 
(w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) concentration ranging 
from 1 to 15 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm in-line 
filter. 
 
Do not co-administer other drugs through the same infusion line. 
 
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the infusion 
set used after the contents of the IV bag are fully administered, or complete the infusion according 
to institutional policy to ensure the full dose is administered and document if the line was not 
flushed. 
 
In the event that there are interruptions during infusion, the total allowed time should not exceed 
8 hours at room temperature. 
 
Durvalumab will be administered at room temperature (approximately 20-25°C) by controlled 
infusion into a peripheral or central vein.  Following preparation  of  durvalumab, the entire 
contents of the IV bag should be administered as an IV infusion over approximately 60 minutes 
(±5 minutes). Less than 55 minutes is considered a deviation, the total allowed time should not 
exceed 8 hours at room temperature. 
 
If either preparation time or infusion time exceeds the time limits a new dose must be prepared 
from new vials. Durvalumab does not contain preservatives, and any unused portion must be 
discarded. 
 
Monitoring of dose administration 
Subjects are monitored (pulse rate, blood pressure) every 30 minutes during the infusion period 
(including times where infusion rate is slowed or temporarily stopped). Subjects will be monitored 
before, during and after the infusion with assessment of vital signs at the following times. Subjects 


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are monitored (pulse rate, blood pressure) every 30 minutes during the infusion period (including 
times where infusion rate is slowed or temporarily stopped). First infusion: On the first infusion 
day, subjects will be monitored and vital signs collected/recorded in eCRF prior to, during and 
after infusion of IP. BP and pulse will be collected from subjects before, during, and after each 
infusion at the following times (based on a 60-minute infusion): Prior to the beginning of the 
infusion (measured once from approximately 30 minutes before up to 0 minutes [i.e., the 
beginning of the infusion]) Approximately 30 minutes during the infusion (halfway through 
infusion). At the end of the infusion (approximately 60 minutes ±5 minutes). If the infusion takes 
longer than 60 minutes, then BP and pulse measurements should follow the principles as 
described above or be taken more frequently if clinically indicated. A 1-hour observation period 
is recommended after the first infusion. Subsequent infusions: BP, pulse and other vital signs 
should be measured, collected/recorded in eCRF prior to the start of the infusion. Subjects should 
be carefully monitored and BP and other vital signs should be measured during and post infusion 
as per institution standard and as clinically indicated. 
 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 
50% of the initial rate until completion of the infusion. For subjects with a ≤ Grade 2 infusion-
related reaction, subsequent infusions may be administered at 50% of the initial rate. 
Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent medications per 
institutional standard may be administered at the discretion of the investigator. If the 
infusion-related reaction is Grade 3 or higher in severity, study drug will be discontinued. The 
standard infusion time is one hour; however if there are interruptions during infusion, the total 
allowed time from infusion start to completion of infusion should not exceed 8 hours at room 
temperature, with maximum total time at room temperature not exceeding 8 hours (otherwise 
requires new infusion preparation). For management of subjects who experience an infusion 
reaction, please refer to the toxicity and management guidelines in Appendix G. 
 
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit subjects to an intensive care unit if necessary. 
 
Supply and packaging 
Durvalumab (MEDI4736) will be supplied in glass vials containing 500 mg of liquid solution at a 
concentration of 50 mg/mL for intravenous (IV) administration. 
 
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for infusion 
after dilution. The solution contains 50  mg/mL durvalumab (MEDI4736),  26  mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% (weight/volume) 
polysorbate 80; it has a pH of 6.0. The nominal fill volume is 10 mL. 
 
Storage requirements 
All study drugs should be kept in a secure place under appropriate storage conditions. Drug 
product should be kept in original secondary packaging until use to prevent prolonged exposure 


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to light. The investigational product label on the bottle and the Investigator Brochure specifies 
the appropriate storage. 
 
Durvalumab vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Durvalumab must 
be used within the individually assigned expiry date on the label. 
 
For more information refer to the current version of the durvalumab IB. 
 
6.2 
Olaparib (AZD2281, KU-0059436) (NSC#: 747856) 
Description 
Olaparib is a potent PARP inhibitor (PARP-1, -2 and -3) that is being developed as an oral therapy, 
both as a monotherapy (including maintenance) and for combination with chemotherapy and 
other anti-cancer agents. 
 
Molecular Formula 
C24H23FN4O3 
 
Molecular Weight 
434 Daltons 
 
Supply and Packaging 
The Astra-Zeneca Pharmaceutical Development R&D Supply Chain will supply olaparib to the site. 
Olaparib tablets will be packed in high-density polyethylene (HDPE) bottles with child-resistant 
closures. Each dosing container will contain 32 tablets and desiccant. Multiple bottles of study 
treatment may be required for dispensing in order to make up the desired dose. Bottles will be 
labeled per local regulations. 
 
Drug product Administration 
Two 150mg tablets orally twice daily with or without food (600 mg total daily dose). The tablets 
are to be swallowed whole with water. Tablets cannot be broken, opened, or chewed. 
 
Olaparib will be dispensed to subjects on Day 1 and every 28 days thereafter until the subject 
completes the study, withdraws from the study or closure of the study. 
 
The olaparib tablets should be swallowed whole and not chewed, crushed, dissolved or divided. 
 
If vomiting occurs shortly after the olaparib tablets are swallowed, the dose should only be 
replaced if all of the intact tablets can be seen and counted. Should any subject 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 subject 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 subject should take their allotted dose at the next scheduled time. 
 
There are no special dosing instructions for olaparib on days when durvalumab is administered. 


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Labeling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfill GMP Annex 13 requirements for labeling. Label text 
will be translated into local language. 
 
Each bottle of olaparib will have an investigational product label permanently affixed to the 
outside stating that the material is for clinical trial/investigational use only and should be kept out 
of reach of children. The label will include the dosing instructions. 
 
The label will include the following information: 
 
• 
blank lines for quantity of tablets to be taken 
• 
date of dispensing 
• 
Instructions stating that the olaparib tablets should be taken at approximately the same 
time each morning and evening 
 
Storage Requirements 
All study drugs should be kept in a secure place under appropriate storage conditions. The 
investigational product label on the bottle and the IB specifies the appropriate storage. 
 
Subjects will continue treatment until disease progression, unacceptable toxicity or other reason 
for discontinuation of protocol treatment (Section 5.6). 
 
Intake Calendar: Olaparib compliance will be recorded on an Intake Calendar/Pill Diary. 
Institutional staff will review and ascertain subject adherence with protocol treatment. If a dose 
is missed, subjects are to take the normal dose on the following day. If more than one daily dose 
is missed, the study doctor or study team must be informed. 
 
Pharmacokinetics 
 
Absorption 
Following oral administration of olaparib via the capsule formulation, absorption is rapid with 
peak plasma concentrations typically achieved between 1 to 3 hours after dosing. On multiple 
dosing there is no marked accumulation (accumulation ratio of 1.4 – 1.5 for twice daily dosing), 
with steady state exposures achieved within 3 to 4 days. 
 
Limited data suggest that the systemic exposure (AUC) of olaparib increases less than 
proportionally with dose over the dose range of 100 to 400 mg, but the PK data were variable 
across trials. 
 
Co-administration with a high fat meal slowed the rate (Tmax delayed by 2 hours) of absorption, 
but did not significantly alter the extent of olaparib absorption (mean AUC increased by 
approximately 20%). 


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Distribution 
Olaparib had a mean (± standard deviation) apparent volume of distribution at steady state of 
167 ± 196 L after a single 400 mg dose of olaparib. The in vitro protein binding of olaparib at 
plasma concentrations achieved following dosing at 400 mg twice daily is approximately 82%. 
 
Metabolism 
In vitro, CYP3A4 was shown to be the enzyme primarily responsible for the metabolism of 
olaparib. Following oral dosing of 14C-olaparib to female patients, unchanged olaparib accounted 
for the majority of the circulating radioactivity in plasma (70%). It was extensively metabolized 
with unchanged drug accounting for 15% and 6% of radioactivity in urine and feces, respectively. 
The majority of the metabolism is attributable to oxidation reactions with a number of the 
components produced undergoing subsequent glucuronide or sulfate conjugation. 
 
Excretion 
A mean (± standard deviation) terminal plasma half-life of 11.9 ± 4.8 hours and apparent plasma 
clearance of 8.6 ± 7.1L/h were observed after a single 400 mg dose of olaparib. 
Following a single dose of 14C-olaparib, 86% of the dosed radioactivity was recovered within a 7- 
day collection period, 44% via the urine and 42% via the feces. The majority of the material was 
excreted as metabolites. 
 
Based on preliminary data from a dedicated renal impairment trial, the mean AUC and Cmax of 
olaparib increased by 1.5and 1.2-fold, respectively, when olaparib was dosed in patients with mild 
renal impairment (CLcr = 50-80 mL/min; N=14) compared to those with normal renal function 
(CLcr >80 mL/min; N=8). There are no data in patients with CLcr < 50 mL/min or in patients on 
dialysis. 
 
Drug Interactions 
In vitro, olaparib was an inhibitor of CYP3A4 and an inducer of CYP2B6 at higher concentrations 
than are clinically achieved. Olaparib produced little/no inhibition of other CYP isozymes. In vitro 
studies have shown that olaparib is a substrate of CYP3A4. 
 
Based on the data from a drug-interaction trial (N=57), the AUC and Cmax of olaparib increased by 
2.7- and 1.4-fold, respectively, when olaparib was administered in combination with itraconazole, 
a strong CYP3A inhibitor. Simulations using physiologically-based pharmacokinetic (PBPK) models 
suggested that a moderate CYP3A inhibitor (fluconazole) may increase the AUC and Cmax of 
olaparib by 2- and 1.1-fold, respectively. 
 
Based on the data from a drug-interaction trial (N=22), the AUC and Cmax of olaparib decreased by 
87% and 71%, respectively, when olaparib was administered in combination with rifampicin, a 
strong CYP3A inducer. Simulations using PBPK models suggested that a moderate CYP3A inducer 
(efavirenz) may decrease the AUC and Cmax of olaparib by 50 - 60% and 20 - 30%, respectively. In 
vitro studies have shown that olaparib is a substrate of P-gp and an inhibitor of BCRP, OATP1B1, 
OCT1, OCT2, OAT3, MATE1 and MATE2K. The clinical relevance of these findings is unknown. 
 
For more information refer to the current version of the olaparib IB. 


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6.3 
Androgen Deprivation Therapy (ADT) 
Physician’s choice of GnRH agonist/antagonist. A one month or three month formulation is 
acceptable. Casodex to prevent testosterone flare is allowed if a GnRH agonist is used. 
 
6.4 
Potential for drug-drug interactions 
Medications with the potential for drug-drug interactions are listed in Appendix C. 
 
6.5 
Treatment Delay 
Subjects receiving durvalumab or olaparib who require therapy delay of more than 8 weeks due 
to toxicity will be removed from treatment but will be followed according to the schedule of 
assessments. If toxicity is attributed to a single agent, upon discussion with the Sponsor Principal 
Investigator, subjects may continue the other drug. 
 
7. 
SAFETY EVALUATION 
7.1 
Definitions 
7.1.1 
Adverse Event (AE) 
Any untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment (ICH E2A). 
 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not related to the medicinal product. 
 
An adverse event will be recorded and followed from informed consent to 30 days post 
treatment or resolution. 
 
7.1.2 
Expected Adverse Events 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. An adverse event can be considered expected when it 
appears in the current adverse event list, the Investigator’s Brochure, the package insert 
or is included in the informed consent document as an identified risk. 
 
7.1.3 
Unexpected Adverse Events 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator's Brochure for an unapproved investigational 
medicinal product) (ICH E2A). 
 
Contact the Sponsor Principal Investigator to confirm unexpected adverse events when 
necessary. 
 
7.1.4 
Serious Adverse Event (SAE) 
An SAE as defined in the Code of Federal Regulations (21CFR312.32) is any event that: 
• 
results in death 
• 
is life-threatening 
• 
results in inpatient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability or incapacity 


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• 
results in congenital anomaly or birth defect 
• 
is medically significant in the opinion of the investigator 
 
Hospitalizations that are not considered SAEs include: 
• 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
• 
elective or pre-planned treatment for a pre-existing condition that did not worsen 
• 
emergency  outpatient  treatment  for  an  event  not  fulfilling  the  serious  criteria 
outlined above and not resulting in inpatient admission 
• 
respite care 
7.1.5 
Progression of malignancy 
Progression of a subject’s malignancy should not be considered an AE, unless in the 
investigator’s opinion, study treatment resulted in an exacerbation  of the subject’s 
condition. If disease progression results in death or hospitalization while on study or 
within 30 days of the last dose, progressive disease will be considered an SAE. 
 
7.1.6 
Life-threatening 
An adverse event or suspected adverse reaction is considered “life-threatening “if, in the 
view of either investigator or sponsor, its occurrence places the subject at immediate risk 
of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death (FDA 21 CFR 312.32). 
 
7.1.7 
Hospitalization (or prolongation of hospitalization) 
Hospitalization encompasses any inpatient admission (even for less than 24 hours) 
resulting from a precipitating, treatment-emergent adverse event. For chronic or long- 
term patients, inpatient admission also includes transfer within the hospital to an acute 
or intensive care inpatient unit. Hospitalizations for administrative reasons or a non- 
worsening preexisting condition should not be considered AEs (e.g., admission for workup 
of a persistent pretreatment laboratory abnormality, yearly physical exam, protocol- 
specified admission, elective surgery). Preplanned treatments or surgical procedures 
should be noted in the baseline documentation. Hospitalization because of an unplanned 
event will be deemed an SAE. 
 
Prolongation of hospitalization is any extension of an inpatient hospitalization beyond the 
stay anticipated or required for the original reason for admission. 
 
7.1.8 
Persistent or Significant disability/incapacity 
Any AE that results in persistent or significant incapacity or substantial disruption of the 
subject’s ability to conduct normal life functions. 
 
7.1.9 
Congenital anomaly 
If the female partner of a male patient becomes pregnant during the course of the study, 
the treating physician should be notified immediately. All confirmed pregnancies must be 
immediately reported to the PCCTC. 
 
7.1.10 AEs of Special Interests (AESIs) 


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An adverse event of special interest (AESI) is one of scientific and medical interest specific 
to understanding of the Investigational Product and may require close monitoring and 
rapid communication by the investigator to the sponsor. An AESI may be serious or non- 
serious. The rapid reporting of AESIs allows ongoing surveillance of these events in order 
to characterize and understand them in association with the use of this investigational 
product. 
 
AESIs for durvalumab include but are not limited to events with a potential inflammatory 
or immune-mediated mechanism and which may require more frequent monitoring 
and/or interventions such as steroids, immunosuppressants and/or hormone 
replacement therapy. These AESIs are being closely monitored in clinical studies with 
durvalumab monotherapy and combination therapy. An immune-mediated adverse 
event (imAE) is defined as an AESI that is associated with drug exposure and is consistent 
with an immune-mediated mechanism of action and where there is no clear alternate 
etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be 
used to support an imAE diagnosis. Appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. 
 
If the Investigator has any questions in regards to an event being an imAE, the Investigator 
should promptly contact the Sponsor Principal Investigator. 
 
AESIs observed with durvalumab include: 
• 
Rash / Dermatitis 
• 
Diarrhea / Colitis 
• 
Endocrinopathies (adrenal insufficiency, hyper- and hypothyroidism, 
hypophysitis/hypopituitarism, thyroiditis, and Type I diabetes mellitus) 
• 
Hepatitis / transaminase increases 
• 
Intestinal perforation 
• 
Myocarditis 
• 
Myositis / Polymyositis 
• 
Nephritis / Blood creatinine increases 
• 
Pancreatitis / serum lipase and amylase increases 
• 
Pneumonitis / ILD 
• 
Other rare/less frequent events (including, but not limited to, haematological 
events, neuromuscular toxicities [such as Guillain-Barre syndrome and myasthenia 
gravis], non-infectious encephalitis, non-infectious meningitis, pericarditis, 
rheumatological events, sarcoidosis, skin events, uveitis [and other events involving 
the eye], and vasculitis). It is possible that events with an inflammatory or immune- 
mediated mechanism could occur in nearly all organs. In addition, infusion-related 
reactions and hypersensitivity/anaphylactic reactions with a different underlying 
pharmacological aetiology are also considered AESIs. 
 
Further information on these risks (e.g. presenting symptoms) can be found in the current 
version of the durvalumab IB. More specific guidelines for their evaluation and treatment 
are described in detail in Appendix G. These guidelines have been prepared by the 
Sponsor to assist the Investigator in the exercise of his/her clinical judgment in treating 


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these types of toxicities. These guidelines apply to AEs considered causally related to the 
study drug/study regimen by the reporting investigator. 
 
AESIs observed with olaparib include: 
 
Adverse Events of Special Interest for olaparib are the Important Potential Risks of 
MDS/AML, new primary malignancy (other than MDS/AML) and pneumonitis. 
 
Any event of MDS/AML, new primary malignancy, or pneumonitis should be reported to 
AstraZeneca Patient Safety whether it is considered a non-serious AE (e.g., non- 
melanoma skin cancer) or SAE, and regardless of investigator’s assessment of causality or 
knowledge of the treatment arm. 
 
A questionnaire will be sent to any investigator reporting an AESI, as an aid to provide 
further detailed information on the event. During the study there may be other events 
identified as AESIs that require the use of a questionnaire to help characterize the event 
and gain a better understanding regarding the relationship between the event and study 
treatment. 
 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological abnormality 
suggestive of pneumonitis/interstitial lung disease is observed, toxicity management as 
described in detail in the Dosing Modification and Toxicity Management Guidelines (see 
Appendix H) will be applied. The results of the full diagnostic workup (including high- 
resolution computed tomography (HRCT), blood and sputum culture, hematological 
parameters etc) will be captured in the eCRF. It is strongly recommended to perform a 
full diagnostic workup, to exclude alternative causes such as lymphangitic carcinomatosis, 
infection, allergy, cardiogenic edema, or pulmonary hemorrhage. In the presence of 
confirmatory HRCT scans where other causes of respiratory symptoms have been 
excluded, a diagnosis of pneumonitis (ILD) should be considered and the Dosing 
Modification and Toxicity Management Guidelines should be followed. 
 
Pneumonitis (ILD) investigation 
The following assessments, and additional assessments if required, will be performed to 
enhance the investigation and diagnosis of potential cases of pneumonitis. The results of 
the assessment will be collected. 
• Physical examination: Signs and symptoms (cough, shortness of breath and pyrexia, 
etc.) including auscultation for lung field will be assessed. 
• Saturation of peripheral oxygen (SpO2) 
7.1.11 Hy’s Law 
Cases where a subject shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN 
may need to be reported as SAEs. Please refer to Appendix C for further instruction on 
cases of increases in liver biochemistry and evaluation of Hy’s law. 


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7.2 
Recording and Grading of Adverse Events 
 
7.2.1 
Recording 
All observed or volunteered adverse events, regardless of treatment group, severity, 
suspected causal relationship, expectedness, or seriousness will be recorded. 
A clinically significant change in a physical examination finding or an abnormal test result 
should be recorded as an AE, if it: 
• 
is associated with accompanying symptoms 
• 
requires additional diagnostic testing or medical or surgical intervention 
• 
leads to a change in study dosing or discontinuation from the study 
• 
requires additional concomitant drug treatment or other therapy, or 
• 
is considered clinically significant by the investigator or sponsor 
An abnormal test result that is subsequently determined to be in error does not require 
recording as an adverse event, even if it originally met one or more of the above criteria. 
 
7.2.2 
Grading severity 
All adverse events will be graded based on the NCI CTCAE version 5.0. A copy of the 
CTCAE Version 5.0 can be downloaded from the CTEP home page 
(http://ctep.cancer.gov). All appropriate treatment areas should have access to a copy 
of the CTCAE Version 5.0. 
 
7.2.3 
Attributing causality 
After assigning a grade to an adverse event, the investigator must evaluate all AEs for 
possible causal relationship to the investigational agent(s). Causality attribution will be 
decided using the criteria outlined in Table 1. 
 
Table 1. Relationship of Adverse Event to Study Drug 
Relationship 
Description 
Unrelated 
AE is clearly not related 
Unlikely 
AE is doubtfully related 
Possible 
AE may be related 
Probable 
AE is likely related 
Definite 
AE is clearly related 
 
 
7.3 
Reporting Serious Adverse Events 
7.3.1 
Reporting serious adverse events 
All SAEs, events determined to be medically significant by the treating Investigator, and 
unknown reactions or unexpected events should be reported to the PCCTC within 24 
hours of knowledge of the event using the contact information below. The initial report 
should include the following information at a minimum: 
• protocol # and title 


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• subject identification number, sex, age at event 
• date the event occurred 
• description of the SAE 
• causal relationship to the study treatment(s) 
The SAE Report Form will be used for reporting each SAE and should be submitted to the 
PCCTC Project Coordinator within 24 hours. The PCCTC will facilitate all SAE report form 
submissions to lead site/sponsor. 
 
Grade, relationship, action taken, concomitant medications, outcome, etc. should be 
reported to the PCCTC as soon as possible. 
 
Follow-up of adverse events should continue until the event and any sequela resolve or 
stabilize at a level acceptable to the investigator. 
SAE contact information for the PCCTC is listed below. 
PCCTC: 
Prostate Cancer Clinical Trials Consortium 
Email: pcctc@mskcc.org 
 
The PCCTC will be responsible for reporting to AstraZeneca by facsimile any Serious 
Adverse Event that occurs during the SAE reporting period. The PCCTC will report the SAE 
within 24 hours of PCCTC first awareness of the event (immediately if the event is fatal or 
life-threatening). 
 
The PCCTC will disseminate information regarding SAEs to the participating sites provided 
by AstraZeneca within five (5) days of review of the information by the Sponsor Principal 
Investigator (or her designee in the event of extended absence) only in the case that the 
event(s) is believed to be related (i.e., possibly, probably, or definitely) to the study 
medication. 
 
The PCCTC will be responsible for reporting of events to the FDA and supporters, as 
appropriate (outlined below). 
 
 
7.3.1 
Serious Adverse Event Reporting to the FDA and AstraZeneca 
It is the responsibility of MSKCC to submit an investigational new drug application (IND) 
or receive an IND exemption from the FDA for clinical trials conducted with investigational 
agents and to ensure that FDA and all participating investigators are promptly informed 
of significant new AEs or risks with respect to the investigational agent. 
 
Serious, unexpected AEs believed to be definitely, probably, or possibly related to the 
study treatment will be reported to the FDA by MSKCC in accordance with IND 
regulations. AEs that must be reported to the FDA will also be concurrently submitted to 
AstraZeneca by the PCCTC. *A cover page should accompany the SAE form indicating the 
following: 
 
• 
Investigator Sponsored Study (ISS) 


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• 
The investigator IND number assigned by the FDA, if applicable 
• 
The investigator’s name and address 
• 
The trial name/title and AstraZeneca ISS reference number 
 
* Investigative site must also indicate, either in the SAE report or the cover page, the 
causality of events in relation to all study medications and if the SAE is related to disease 
progression, as determined by the principal investigator. 
 
* Send SAE report and accompanying cover page 
by way of email to 
AEMailboxClinicalTrialTCS@astrazeneca.com 
 
If a non-serious AE believed to be definitely, probably or possibly related to olaparib or 
durvalumab becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca and the FDA if applicable. 
 
SAEs that do not require expedited reporting to the FDA need to be reported to 
AstraZeneca preferably using the MedDRA coding language for SAEs. This information 
should be reported on a monthly basis and under no circumstance less frequently than 
quarterly. 
 
All SAEs have to be reported to AstraZeneca by the PCCTC, whether or not considered 
causally related to the investigational product. All SAEs will be documented. The 
investigator is responsible for informing the IRB and/or the Regulatory Authority of the 
SAE as per local requirements. 
 
An SAE which occurs after consent and before a subject starts study treatment does not 
need to be reported if it is unrelated to screening procedures. All SAEs that occur once a 
subject has started study treatment will be reported irrespective of causality. Non-serious 
AEs will be collected from the time consent is given, throughout the treatment period and 
up to and including the 30 days after the last dose of study drug, unless the toxicity is 
considered related to study drug. If related to study drug, non-serious AEs and SAEs will 
be collected from the time the consent is given, throughout the treatment period and up 
to and including the 90 days after the last dose of study drug. After withdrawal from 
treatment, subjects must be followed-up for all existing and new AEs for 90 calendar days 
after the last dose of trial drug and/or until event resolution. All new AEs occurring during 
that period must be recorded  (if SAEs, then  they  must be reported  to the FDA, if 
applicable, and AstraZeneca). All study-related toxicities/SAEs must be followed until 
resolution, unless in the Investigator’s opinion, the condition is unlikely to resolve due to 
the subject’s underlying disease. 
 
7.3.2 
Reporting of paternal exposure 
Male subjects should refrain from fathering a child or donating sperm during the study 
and for 180 days after the last dose of durvalumab or olaparib therapy. 
 
Pregnancy of the subject’s partner is not considered to be an AE. However, if allow able 
per local procedures, the outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from 


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the date of the first dose until 180 days after the last dose of durvalumab or olaparib if 
possible, will be followed up and documented. 
7.3.3 
Other events that require reporting 
Overdose 
An overdose is defined as a patient receiving a dose of durvalumab or olaparib in excess 
of that specified in the IB, unless otherwise specified in this protocol. 
 
Any overdose of a study subject with durvalumab or olaparib, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to PCCTC. 
PCCTC will report to the sponsor and AstraZeneca/MedImmune Patient Safety or 
designee. If the overdose results in an AE, the AE must also be recorded as an AE (see 
Section 7.2). Overdose does not automatically make an AE serious, but if the 
consequences of the overdose are serious, for example death or hospitalization, the event 
is serious and must be recorded and reported as an SAE. There is currently no specific 
treatment in the event of an overdose of durvalumab or olaparib. 
 
The investigator will use clinical judgment to treat any overdose. 
 
New Cancer 
The development of a new cancer should be regarded as an SAE. New primary cancers 
are those that are not the primary reason for the administration of the IP and have been 
identified after the patient’s inclusion in this study. 
 
Hepatic function abnormality 
Hepatic function abnormality that fulfills the biochemical criteria of a potential Hy’s Law 
case in a study subject, with or without associated clinical manifestations, is required to 
be reported as “hepatic function abnormal” within 24 hours of knowledge of the event to 
the PCCTC, unless a definitive underlying diagnosis for the abnormality (e.g., cholelithiasis 
or bile duct obstruction) that is unrelated to investigational product has been confirmed. 
The criteria for a potential Hy’s Law case is 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). 
 
• If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study 
subject will be based on the clinical judgment of the investigator. 
 
• If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study subject must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
 
Each reported event of hepatic function abnormality (meeting criteria for Hy’s Law as per 
above) will be followed by the investigator and evaluated by the sponsor and 
AstraZeneca/MedImmune. 


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7.3.3 
Reporting of deaths 
All deaths that occur during the study, or within the protocol-defined 90-day post-last 
dose of study drug must be reported to the PCCTC as follows: 
• 
Death that is clearly the result of disease progression should be documented but 
should not be reported as an SAE. 
• 
Where death is not due (or not clearly due) to progression of the disease under 
study, the AE causing the death must be reported to AstraZeneca as a SAE within 
24 hours. The report should contain a comment regarding the co-involvement of 
progression of disease, if appropriate, and should assign main and contributory 
causes of death. 
• 
Deaths with an unknown cause should always be reported as a SAE. 
 
Deaths that occur following the protocol-defined 90-day post-last-dose of durvalumab 
safety follow-up period will be documented, but will not be reported as an SAE. 
 
The PCCTC will be responsible for reporting deaths to AstraZeneca. 
 
7.4 
Safety Reports 
• 
PCCTC will distribute outside safety reports to the participating sites. 
• 
Participating sites must submit safety reports to their institution’s IRB/PBs per participating 
site guidelines. 
 
8. 
CRITERIA FOR OUTCOME ASSESSMENT/THERAPEUTIC RESPONSE 
8.1 
Therapeutic Response 
 
8.1.1 
PSA 
This trial will measure PSA monthly for the first 24 months. The primary endpoint is an 
undetectable PSA at 24 months with non-castrate levels of testosterone (>150 ng/dL). 
 
9. 
DATA REPORTING AND REGULATORY REQUIREMENTS 
9.1 
Data Collection and Management 
Data collected during this study will be entered into a secure database. 
 
9.1.1 
Electronic Case Report Forms (eCRFs) 
Standardized eCRFs and CRF Completion Guidelines will be created by the PCCTC for the 
collection of study data. Access and training for PCCTC Medidata Rave EDC will be made 
available to participating sites upon local regulatory approval.  The participating site 
investigator is responsible for ensuring eCRFs are completed accurately and in a timely 
manner. 


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9.1.2 
Source documents 
Source documentation refers to original records of observations, clinical findings and 
evaluations that are subsequently recorded as data. Source documentation will be made 
available to support the subject’s research record. 
 
9.1.3 
Record retention 
The investigator will maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. After 
study closure, the investigator will maintain all source documents and study-related 
documents. Records are to be retained and securely stored until the later of: (a) two (2) 
years following the date a New Drug Application is approved for the Study Drug that is 
the subject of the Clinical Trial; or (b) two (2) years after the Investigational New Drug 
Application for such Study Drug is terminated or withdrawn, or such longer period of time 
as may be required by Participant policies, applicable laws, rules or regulations. 
 
9.2 
Study Monitoring and Quality Assurance 
 
9.2.1 
Data and Safety Monitoring 
The Data and Safety Monitoring Plans (DSMP) at MSKCC were approved by the National 
Cancer Institute in September 2001. The plans address the new policies set forth by the 
NCI in the document entitled Policy of the National Cancer Institute for Data and Safety 
Monitoring of Clinical Trials. The DSMPs at MSKCC were established and are monitored 
by the Office of Clinical Research. 
 
There are several different mechanisms by which clinical trials are monitored for data, 
safety, and quality. There are institutional processes in place for quality assurance (e.g., 
protocol monitoring, compliance and data verification audits, therapeutic response, and 
staff education on clinical research quality assurance) and departmental procedures for 
quality control, plus there are two institutional committees that are responsible for 
monitoring the activities of our clinical trials programs. There are several committees: 
Data and Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, and the 
Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, report to the MSKCC 
Research Council and Institutional Review Board. As a moderate risk trial, this study will 
be monitored by DSMC twice per year. 
 
9.2.2 
Data Monitoring, Auditing, and Quality Assurance 
In addition to review by DSMC, PCCTC will conduct regularly scheduled monitoring visits. 
Reports will be generated by the PCCTC to monitor subject accruals and the completeness 
of data. Routine data quality reports will  be generated to assess missing data and 
inconsistencies. Accrual rates and the extent and accuracy of evaluations and follow-up 
will be monitored periodically throughout the study period, and potential problems will 
be brought to the attention of the Sponsor Principal Investigator for discussion and action. 
The monitoring visit will include a review of source documentation to evaluate: 
 
• 
Regulatory/IRB compliance (review of current protocol and amendments, Informed 
consent documents and procedures, annual continuing review reports, AEs/SAEs) 
• 
Protocol defined treatment compliance 


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• 
Subject records 
• 
A signed and dated informed consent form for each subject 
• 
Adherence to eligibility criteria 
• 
Source Data Verification for identified subjects 
Monitoring findings will be reviewed and disseminated to the site investigators and staff. 
The PCCTC may also perform site audits. If a site is notified of an external audit relating 
to this study, the site should notify the PCCTC immediately. The PCCTC and/or Monitors 
assigned to this study will provide site support during audits (quality control and/or 
regulatory agency) including review and assisting sites with responses to audit findings. 
 
9.2.3 
Data Review and Queries 
The PCCTC will review data and source documentation. Data will be monitored and source 
data verified as defined in the Monitoring and Data Management plans and discrepancies 
will be issued as queries in the EDC. In addition, the PCCTC will review data for logic, 
consistency, and obvious anomalies. 
 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
 
10.1.1 Primary endpoint 
Undetectable PSA with recovered testosterone (non-castrate defined as testosterone > 
150ng/dL) at 24 months. Undetectable is defined as PSA < 0.05 ng/ml. For institutions 
where the lower limit of detectable is 0.10 ng/ml, then undetectable will be defined as 
PSA <0.10 ng/ml. 
 
10.1.3 Secondary endpoints 
• 
Undetectable PSA at 5 months (with the combination of durvalumab and olaparib, no 
ADT) 
• 
Safety of the combination of durvalumab and olaparib will be determined by the 
summary of AEs 
 
10.1.4 Exploratory endpoints/correlative studies 
• 
Measurement of patient reported toxicities using PRO-CTCAE at screening, cycle 5, 
cycle 11, and EOT. Changes over time and comparison to clinician reported toxicities 
(CTCAE v5.0) 
• 
Blood biomarkers at cycle 1, cycle 2, cycle 5, cycle 11, and end of treatment: PBMCs 
collected to assess immunomodulation, for example, changes in T -cell populations 
over time, multiplex cytokine analysis, tumor associated antigens; cfDNA will also be 
collected at cycle 1, cycle 5 and end of treatment for potential future use. 
• 
Archival tissue for analysis of immune activating genes and PDL1 expression 
• 
Undetectable PSA at 11 months (irrespective of testosterone level) 
• 
PSA PFS 
• 
Change in PSA doubling time relative to trial entry 


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10.2 
Sample Size Determination 
The primary objective of the study is to determine the efficacy of the combination of olaparib with 
durvalumab in subjects with biochemically recurrent castration sensitive disease. The primary 
endpoint of the study is maintaining an undetectable PSA with recovered testosterone at 24 
months and this event is defined as a success. Subjects that withdraw prior to the 24 month follow 
up time are deemed as failures for the primary endpoint. A single stage design that differentiates 
between population success rates of 0.15 and 0.35 will be used to assess treatment activity.63 
Thirty-two subjects will be accrued to this trial. If eight or more successes are observed, it is 
concluded that the therapy is sufficiently active to warrant further study. This design has power 
greater than 0.90 for a population success proportion of 0.35 using a one-sided test with size 0.10 
for the population success rate 0.15. 
 
In addition to the evaluation of the primary endpoint, the study will be monitored for 
unacceptable toxicity, which is defined as Grade 3 or greater immune related toxicity requiring 
steroids or ≥ Grade 3 non-immune toxicity requiring trial discontinuation. The stopping rule for 
excessive toxicity and the corresponding power calculation is provided in the table below. 
 
Toxicity 
# of toxicities needed to 
stop the study 
Toxicity rate in 
the population 
Probability boundary 
is crossed 
≥ Grade 3 immune 
related toxicity 
requiring steroids or ≥ 
Grade 3 non-immune 
toxicity requiring trial 
discontinuation 
4 in the first 8 subjects 
5 in the first 16 subjects 
7 in the first 24 subjects 
9 within 32 subjects 
0.15 
0.11 
0.35 
0.89 
 
 
10.3 
Analysis Populations 
 
10.3.1 Intent-to-treat/Response-to-treatment/Evaluable population 
All subjects who meet eligibility criteria and receive at least one dose of study drugs will 
be included in the main analysis of efficacy, even if there are major protocol deviations 
(e.g., incorrect treatment schedule or drug administration). 
 
Conclusions are to be based on the population of all eligible subjects. Subanalyses may be 
performed on various subsets of subjects, such as those with no major protocol deviations 
or those who continued in  the study for the entire treatment  period  (i.e., did  not 
withdraw prematurely). Subanalyses will not serve as the basis for drawing conclusions 
concerning treatment efficacy. 
 
10.3.2 Safety population 
All subjects enrolled in the study who receive at least one dose of study drugs will be 
included in the safety analysis population and considered evaluable for toxicity and safety 
from the time of their first dose. 


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10.4 
Safety Analysis 
 
10.4.1 Evaluation of adverse events 
Treatment-emergent adverse events will be summarized (number and percentage of 
subjects) for all subjects who receive at least one dose of both investigational therapies. 
Adverse event summaries will be organized by body system, frequency of occurrence, 
intensity (i.e., severity grade), and causality or attribution. Subjects who experience an 
adverse event more than once will be counted only once. The occurrence with the 
maximum severity will be used to calculate intensity. 
 
10.4.2 Evaluation of serious adverse events and premature withdrawals 
Adverse events deemed serious and those resulting in treatment withdrawal or death will 
be summarized separately. 
 
10.4.3 Evaluation of laboratory parameters and assays 
Selected clinical laboratory parameters will be summarized and clinically significant 
changes from baseline will be discussed. 
 
10.4.4 Extent of exposure 
Treatment exposure will be summarized for all subjects, including dose administration, 
number of cycles, dose modifications or delays, and duration of therapy. 
 
10.5 
Statistical Procedures and Analysis 
Summary statistics include the number of observations, mean, standard  deviation, median, 
minimum, and maximum values. 
 
Statistical methods for the analyses 
An exact binomial test will be used to evaluate the efficacy of the 24 months undetectable PSA 
endpoint. In addition, the proportion of subjects that attain an undetectable PSA at (1) 5 months, 
(2) 11 months, and (3) 24 months will be computed along with their attendant 95% confidence 
intervals. The probability of PSA progression over time will be estimated using the cumulative 
incidence function. 
 
A paired t-test will be used to compare the PSA doubling time at 24 months to the PSA doubling 
time at study entry. 
 
Kendall’s tau with longitudinal  data will be used  to compare patient recorded  toxicities to 
physician recorded toxicities over time. 
The immunologic profile of patients over time will be described using nonparametric kernel 
smoothing. 
 
11. 
REGULATORY AND PROTECTION OF HUMAN SUBJECTS 
11.1 
Ethical Considerations 
This study will be conducted in compliance with the protocol, GCP guidelines established by the 
International Conference on Harmonisation, as adopted by applicable laws and regulations, and 
the 
ethical 
standards 
set 
forth 
in 
the 
Declaration 
of 
Helsinki 
(available 
at: 
www.laakariliitto.fi/e/ethics/helsinki.html). 


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11.2 
Protocol Amendments 
Before starting the study, the protocol must be approved by each institution’s IRB or Independent 
Ethics Committee (IEC). Amendments to the protocol may be made only with consent of the lead 
site/sponsor and PCCTC and are subject to IRB approval before instituting. 
 
11.3 
Written Informed Consent 
Before obtaining consent, members of the study team will review the rationale for the treatment 
program with the subject. The discussion will review the alternatives available (including 
hormonal therapy, chemotherapy, or supportive care as appropriate), the potential benefits of 
this program, the risks and the probability of their occurrence, and the procedures to minimize 
these risks. Should an adverse event occur, the provisions available to ensure medical 
intervention will also be reviewed. Why the risks are reasonable in relation to the anticipated 
benefits, incentives, or costs that will or may be incurred as a result of participating in the study, 
as well as the efforts to maintain confidentiality, will also be discussed with the subject. 
 
Subjects will be required to sign and date an informed consent form that meets the requirements 
of the Code of Federal Regulations and the IRB. The medical record will include a statement that 
written informed consent was obtained (and document the date that it was obtained) before the 
subject is enrolled in the study. 
 
The consent form will include the following: 
• 
the nature and objectives, potential toxicities, and benefits of the intended study 
• 
the length of therapy and likely follow-up required 
• 
alternatives to the proposed therapy (including available standard and 
investigational therapies) 
• 
the name of the investigator(s) responsible for the protocol 
• 
the right of the subject to accept or refuse treatment and to withdraw from 
participation in this study 
• 
Text regarding the consortium and the coordinating center should be added to all 
institutional informed consent documents and sections in the research 
authorization/HIPAA forms (e.g., “Prostate Cancer Clinical Trial Consortium”) 
 
11.4 
Protection of Privacy 
Subjects will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. After this discussion, they will be asked to 
sign a Notice of Privacy Practice research authorization/HIPAA form. The original signed 
documents will become part of the subject’s medical records, and each subject will receive a copy 
of the signed documents. The use and disclosure of protected health information will be limited 
to the individuals described in the research authorization form. The research authorization form 
must be completed by the investigator and approved by the IRB. 
 
11.5 
Terminating or Modifying the Study 
Adverse event and laboratory data from this trial will be assessed by the Sponsor Principal 
Investigator on an ongoing basis. SAEs will be reviewed as they are reported to the sponsor and 
PCCTC, and the Sponsor Principal Investigator will make an assessment regarding the safety of 


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continuing or modifying the study. This assessment will be shared with the investigators either in 
writing or as part of a teleconference. Should the assessment of either the lead site/sponsor or 
the principal investigator be that the study should be terminated, the study will be closed to 
further accrual. Subjects who are receiving an investigational agent(s) will be assessed individually 
by the investigator to see if it is in the subjects’ best interest to continue, which might be the case 
for a subject that is responding to the intervention. Follow-up safety assessments will be 
performed for all subjects who are terminated from the study prematurely. 


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12. 
REFERENCES 
1. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018. 
2. 
Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant 
Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working 
Group 3. J Clin Oncol 2016. 
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Drug Administration Center for Drug Evaluation and Research; December 24, 2008. 
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associated with anti-PD-1 response. Nature 2017;545:60-5. 


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Sensitive Prostate Cancer. The New England journal of medicine 2015;373:737-46. 
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Oncol 2018;36:abstr 5016. 


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APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
% 
Description 
0 
Normal activity. Fully active, able to 
continue all predisease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease 
1 
Symptoms, but ambulatory. Restricted in 
physically strenuous activity but 
ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort, some signs or 
symptoms of disease 
70 
Cares for self, unable to carry on normal 
activity or to do active work 
2 
In bed < 50% of the time. Ambulatory and 
capable of all self-care but unable to carry 
out any work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance but is able 
to care for most needs 
50 
Requires considerable assistance and 
frequent medical care 
3 
In bed > 50% of the time. Capable of only 
limited self-care, confined to bed or chair 
> 50% of waking hours. 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization indicated. 
Death not imminent. 
4 
100% bedridden. Completely disabled, 
cannot carry on any self-care, totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly 
5 
Dead 
0 
Dead 


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APPENDIX B: STUDY CALENDAR 
(A cycle = 28 days; a month = 28 days) 
 
Screening 
Treatment/Intervention Period 
End of 
Treatment 
(EOT) 
within 30 
days of last 
dose 
Follow 
Up s 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7- 
Cycle 24 
Day -42 
to Day - 
1 
Day - 
14 to 
Day - 
1 
Day 
1 
(±3 
d) 
Day 15, 
(±3 d) 
Day 1 
(±3 d) 
Day 15 
(±3 d) 
Day 1 
(±3 d) 
Day 1 
(±3 d) 
Day 1 
(±3 d) 
Day 1 
(±3 d) 
Day 1 
(±3 d) 
(±7 d) 
Informed 
consent and 
research 
authorization/ 
HIPAA form a 
X 
Demographics, 
medical 
history, 
histologic 
confirmation 
X 
Physical 
examination, 
Vitals (Blood 
Pressure, Pulse 
Temperature), 
weight b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
12-lead EKG 
X 


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Screening 
Treatment/Intervention Period 
End of 
Treatment 
(EOT) 
within 30 
days of last 
dose 
Follow 
Up s 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7- 
Cycle 24 
Day -42 
to Day - 
1 
Day - 
14 to 
Day - 
1 
Day 
1 
(±3 
d) 
Day 15, 
(±3 d) 
Day 1 
(±3 d) 
Day 15 
(±3 d) 
Day 1 
(±3 d) 
Day 1 
(±3 d) 
Day 1 
(±3 d) 
Day 1 
(±3 d) 
Day 1 
(±3 d) 
(±7 d) 
Performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Radiologic 
evaluations and 
measurements 
c 
X 
For non-metastatic, rising PSA subjects, radiologic tests are performed at Cycle 5 (+/- 2 week), Cycle 24 
(+/- 2 week) or at EOT (+/- 2 week) if discontinued sooner. 
X d 
CBC w/ diff plts 
e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive 
Metabolic 
Panel f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
Tests g 
X 
PSA h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TFTs i 
X 
X 
X 
X 
X 
X 
Testosterone j 
X 
X 
X 
Hepatitis Panel 
X 
HIV 
X 
Urinalysis k 
X 


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Screening 
Treatment/Intervention Period 
End of 
Treatment 
(EOT) 
within 30 
days of last 
dose 
Follow 
Up s 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7- 
Cycle 24 
Day -42 
to Day - 
1 
Day - 
14 to 
Day - 
1 
Day 
1 
(±3 
d) 
Day 15, 
(±3 d) 
Day 1 
(±3 d) 
Day 15 
(±3 d) 
Day 1 
(±3 d) 
Day 1 
(±3 d) 
Day 1 
(±3 d) 
Day 1 
(±3 d) 
Day 1 
(±3 d) 
(±7 d) 
PBMC l 
X 
X 
X 
X 
X 
PRO-CTCAE m 
X 
X 
X 
X 
cfDNA n 
X 
X 
X 
PDL-1 
Expression 
(archived 
tissue) o 
X 
Tissue 
Sequencing p 
X 
Normal Sample 
q 
X 
Olaparib 
Administration 
r 
X 
Durvalumab 
Administration 
r 
X 
ADT 
Administration 
r 
X 
a. Informed consent and radiologic assessments should be obtained within 42 days. 
b. Refer to section 6.1 for monitoring of vital signs and observation period. 


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c. 
Radiographic evaluations will include CT CAP with contrast or MRI with contrast of the abdomen and pelvis, and CT chest without contrast. 
Radionuclide bone scan will be performed. All disease sites must be assessed using the same methodology as performed at baseline. At the 
discretion of the investigator, additional radiological evaluations may be performed at an unscheduled time point. 
d. If radiographic evaluations were completed within 30 days of EOT, they do not need to be repeated. 
e. CBC w/diff, platelets will be monitored biweekly during Cycle 1 and 2, and monthly from Cycle 3-Cycle 24 (see section 5.1.9 for additional 
information regarding laboratory tests) 
f. 
CMP will be monitored biweekly during Cycle 1 and 2, and monthly from Cycle 3-Cycle 24 (see section 5.1.9 for additional information regarding 
laboratory tests) 
g. APTT and INR. See section 5.1.9 for more information on coagulation tests. 
h. PSA will be collected monthly during each cycle. 
i. 
Thyroid function tests (TFTs), including TSH, free T4, and free T3 will be monitored every other cycle (beginning with Cycle 2, Cycle 4, Cycle 6, 
etc.) 
j. 
Testosterone will be monitored at Screening, Cycle 6, Cycle 11 and every other month from Cycle 12-Cycle 24 
k. Urinalysis: to be collected at screening. If clinically indicated, urinalysis should be performed while on treatment. See section 5.1.9 for additional 
information. 
l. 
Peripheral Blood Mononuclear Cells (PBMCs) will be drawn C1D1 before treatment, Cycle 2, Cycle 5, Cycle 11, and EOT. 
m. QoL Assessment (PRO-CTCAE) compared from screening, Cycle 5, Cycle 11, and EOT. 
n. Non-immune blood biomarkers: cfDNA from C1D1 before treatment, Cycle 5, and EOT. 
o. Tissue biomarkers: PDL1 expression at screening. 
p. Tissue sequencing does not need to be repeated if performed prior to consent and subject has a confirmed DDR mutation. If DDR mutation status 
is unknown or sequencing was not previously performed, archival tissue as well as a matched normal sample must be sent for Next Generation 
Sequencing. If available, additional archival tissue from all subjects should be sent and banked for future analysis of immune markers. 
q. A blood or saliva sample will be collected during screening as matched normal for sequencing for patients completing prospective Next 
Generation Sequencing using assays that require a matched normal sample. 
r. 
Subjects will be treated concurrently with olaparib + durvalumab continuously for 24 months. Durvalumab will be administered on Day 1 of each 
cycle (±3). After the first 4 months, if a subject fails to achieve an undetectable PSA [PSA of <0.05 (or PSA <0.10 for institutions where this is the 
lower limit of detection] with the combination of olaparib and durvalumab, ADT will be added for 6 months (starting at Cycle 5) while continuing 
treatment with olaparib and durvalumab (see section 6.3 for additional details regarding ADT). For subjects who have an undetectable PSA after 
the first 4 months of treatment, they will continue on the combination of olaparib + durvalumab continuously for 24 months (without ADT). As 
long as it is believed that subjects are clinically benefiting, they will remain on treatment for up to 24 months with olaparib and durvalumab. For 
example, a subject with a PSA reduction that does not achieve an undetectable PSA would be allowed to remain on study for the duration of the 
trial. Subjects who meet progression criteria while on active therapy would come off of trial. 
s. 
Subjects who have an undetectable PSA after completion of protocol therapy will be followed every 12 weeks. PSA, CMP, CBC, and TFTs should be 
performed. A physical exam will be performed. Subjects who respond and later progress in the first year following the 24 month treatment phase 
will be allowed to re-induce with the combination and will restart their calendar with C1D1 if they continue to meet all clinical eligibility criteria 
are met. PCCTC must review the confirmation of eligibility prior to re-inducing treatment. 


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APPENDIX C. ACTIONS REQUIRED IN CASES OF COMBINED INCREASE OF AMINOTRANSFERASE AND 
TOTAL BILIRUBIN – 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.  Specific guidance on the managing liver abnormalities can be found in Appendix H and 
Appendix I of the protocol. 
 
During the course of the study the Investigator will remain vigilant for increases in liver biochemistry. 
The investigator is responsible for determining whether a subject 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, e.g., 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 subject who meets any of the following identification criteria in isolation or in combination: 
 
• 
ALT ≥ 3xULN 
 
• 
AST ≥ 3xULN 


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• 
TBL ≥ 2xULN 
 
The Investigator should without delay review each new laboratory report and if the identification 
criteria are met will: 
 
• 
Notify the PCCTC. The PCCTC will notify AstraZeneca when appropriate. 
 
• 
Determine whether the subject 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 
protocol. 
 
Potential Hy’s Law Criteria met 
• 
Notify the PCCTC. The PCCTC will notify AstraZeneca when appropriate. 
 
The Sponsor Principal Investigator contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up and the continuous review of data. Subsequent to this 
contact the Investigator will: 
 
• 
Monitor the subject 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 
Sponsor Principal Investigator. 
 
• 
Enter data into the CRFs as information becomes available 
 
• 
If at any time (in consultation with the Sponsor Principal Investigator) 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 Sponsor Principal 
Investigator 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 Lead Principal 
Investigator, PCCTC and AstraZeneca may also be involved in this review together with other subject 
matter experts as appropriate. 


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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 accordingly 
 
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’). 
 
− 
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 
 
References 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical evaluation’:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf 


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APPENDIX D: MEDICATIONS WITH THE POTENTIAL FOR DRUG-DRUG INTERACTIONS 
Olaparib is an investigational drug for which no data on in vivo interactions are currently available. Based 
on in vitro data and clinical exposure data, olaparib is considered unlikely to cause clinically       
significant drug interactions through inhibition or induction of cytochrome P450 enzyme activity. In vitro 
data have, however, also shown that the principal enzyme responsible for the formation of the 3 main 
metabolites of olaparib is CYP3A4 and consequently, to ensure subject safety, the following potent 
inhibitors of CYP3A4 must not be used during this study for any subject receiving olaparib. 
 
While this is not an exhaustive list, it covers the known potent inhibitors, which have most often 
previously been reported to be associated with clinically significant drug interactions. 
 
Prohibited Concomitant Medications while subjects are taking Olaparib: 
 
Agent 
Agent 
ketoconazole 
rifapentine 
itraconazole 
rifabutin 
ritonavir 
carbamazepine 
indinavir 
phenobarbitone 
saquinavir 
nevirapine 
telithromycin 
modafinil 
clarithromycin 
St John’s Wort (Hypericum perforatum) 
nelfinavir 
phenytoin 
rifampicin 
 
After enrollment if the use of any potent inducers or inhibitors of CYP3A4 are considered necessary for 
the subject’s safety and welfare, the Sponsor Principal Investigator must contact the AstraZeneca Study 
Physician. A decision to allow the subject to continue in the study will be made on a case-by-case basis. 
 
If there is no suitable alternative concomitant medication then the dose of olaparib should be reduced 
for the period of concomitant administration. The dose reduction of olaparib should be recorded in the 
CRF with the reason documented as concomitant CYP3A inhibitor use. 
 
• 
Strong CYP3A inhibitors – reduce the dose of olaparib to 100mg BID for the duration of concomitant 
therapy with the strong inhibitor and for 5 half-lives afterwards. 
 
• 
Moderate CYP3A inhibitors - reduce the dose of olaparib to 150mg BID for the duration of 
concomitant therapy with the moderate inhibitor and for 3 half-lives afterwards. 
 
• 
After the washout of the inhibitor is complete, the olaparib dose can be re-escalated. 
 
Strong or Moderate CYP3A inducers 
 
Strong (e.g., phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine, 
enzalutamide and St John’s Wort) and moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil) of 
CYP3A should not be taken with olaparib. 


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If the use of any strong or moderate CYP3A inducers are considered necessary for the subject’s safety 
and welfare this could diminish the clinical efficacy of olaparib. 
 
If a subject requires use of a strong or moderate CYP3A inducer or inhibitor then they must be 
monitored carefully for any change in efficacy of olaparib. 
 
P-gp inhibitors 
 
It is possible that co-administration of P-gp inhibitors (e.g. amiodarone, azithromycin) may increase 
exposure to olaparib. Caution should therefore be observed. 
 
Effect of olaparib on other drugs 
 
Based on limited in vitro data, olaparib may increase the exposure to substrates of CYP3A4, P-gp, 
OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. 
 
Based on limited in vitro data, olaparib may reduce the exposure to substrates of CYP3A4, CYP1A2, 2B6, 
2C9, 2C19 and P-gp. 
 
The efficacy of hormonal contraceptives may be reduced if co administered with olaparib. 
 
Caution should therefore be observed if substrates of these isoenzymes or transporter proteins are co- 
administered. 
 
Examples of substrates include: 
 
• 
CYP3A4 – hormonal contraceptive, simvastatin, cisapride, cyclosporine, ergot alkaloids, fentanyl, 
pimozide, sirolimus, tacrolimus and quetiapine 
• 
CYP1A2 – duloxetine, melatonin 
• 
CYP2B6 – bupropion, efavirenz 
• 
CYP2C9 – warfarin 
• 
CYP2C19 - lansoprazole, omeprazole, S-mephenytoin 
• 
P-gp - simvastatin, pravastatin, digoxin, dabigatran, colchicine 
• 
OATP1B1 - bosentan, glibenclamide, repaglinide, statins and valsartan 
• 
OCT1, MATE1, MATE2K – metformin 
• 
OCT2 - serum creatinine 
• 
OAT3 -furosemide, methotrexate 
 
Natural/Herbal Products 
 
The use of any natural/herbal products or other traditional remedies should be discouraged, but use of 
these products, as well as use of all vitamins, nutritional supplements, and all other concomitant 
medications must be recorded in the case report form (CRF). 
 
It is not recommended to consume grapefruit juice while on olaparib therapy. 


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Vaccines 
 
Live virus and live bacterial vaccines, with the exception of shingles vaccine (live), should not be 
administered while the subject is receiving study medication until 30 days after the last dose of study 
therapy. 
 
Anticoagulant Therapy 
 
Subjects who are taking warfarin may participate in this trial; however, it is recommended that 
international normalized ratio (INR) be monitored carefully at least once per week for the first month, 
then monthly if the INR is stable. Subcutaneous heparin and low molecular weight heparin are 
permitted. 
 
Anti-emetics/Anti-diarrheal 
 
If a subject develops nausea, vomiting and / or diarrhea, then these symptoms should be reported as 
AEs and appropriate treatment of the event given. 
 
Administration of other anti-cancer agents 
 
Subjects must not receive any other concurrent anti-cancer therapy, including investigational agents, 
while on study treatment. No other chemotherapy, immunotherapy, hormonal therapy or other novel 
agent is to be permitted while the subject is receiving study medication. 


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APPENDIX E: GLOSSARY OF ABBREVIATIONS AND ACRONYMS 
 
 
ADR 
adverse drug reaction 
ADT 
androgen-deprivation therapy 
AE 
adverse event 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AR 
androgen receptor 
ASAEL 
Agent Specific Adverse Event List 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BMI 
body mass index 
CAEPR 
Comprehensive Adverse Event and Potential Risks 
CBC 
complete blood count 
CDE 
common data element 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
Cmin 
trough observed concentration 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CRPC 
castration resistant prostate cancer 
CT 
computerized tomography 
CTC 
circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHEA 
dehydroepiandrosterone 
DHT 
dihydrotestosterone 
DLT 
dose-limiting toxicity 
DSMB 
data and safety monitoring board 
DSMC 
data and safety monitoring committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EORTC 
European Organisation for Research and Treatment of Cancer 
FDA 
Food and Drug Administration 
FDG-PET 
2-[18F]fluoro-2-deoxyglucose positron emitting tomography 


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FDHT 
18-fluoro-dehydrotestosterone 
FISH 
fluorescence in situ hybridization 
GCP 
good clinical practice 
GnRH 
gonadotropin-releasing hormone 
HDAC 
histone deacetylase 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRQOL 
health-related quality of life 
HRPC 
hormone-refractory prostate cancer 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IHC 
immunochemical 
IIT 
investigator-initiated trial 
imAE 
immune-mediated adverse event 
IND 
investigational new drug 
IO 
Immuno-oncology 
IRB 
Institutional Review Board 
ITT 
intent-to-treat population 
IV 
intravenous 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LOI 
letter of intent 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MSKCC 
Memorial Sloan Kettering Cancer Center 
MTD 
maximum tolerated dose 
N 
number of subjects or observations 
N/A 
not available 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NOAEL 
no observed adverse effect level 
NOS 
not otherwise specified 
NSAID 
nonsteroidal anti-inflammatory drug 
PBMCs 
peripheral blood mononuclear cells 
PCCTC 
Prostate Cancer Clinical Trials Consortium 
PCRP 
Department of Defense Prostate Cancer Research Program 
PCWG2, PCWG3 
Prostate Cancer Working Group 


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PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PI 
principal investigator 
PK 
pharmacokinetics 
PMB 
Pharmaceutical Management Branch 
PO 
per os (by mouth) 
PR 
partial response 
PSA 
prostate-specific antigen 
PSADT 
prostate-specific antigen doubling time 
PSMA 
prostate specific membrane antigen 
QC 
quality control 
qd 
quaque die (every day) 
qRT-PCR 
quantitative reverse transcription-polymerase chain reaction 
QOL 
quality of life 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP 
radical prostatectomy 
RPC 
eResearch Program Coordinator 
RSA 
Research Study Assistant 
SAE 
serious adverse event 
SD 
standard deviation 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOP 
Standard Operating Procedures 
SPORE 
Specialized Programs of Research Excellence 
SUV 
standardized uptake value 
t1/2 
terminal half-life 
TDP 
time to disease progression 
Tmax 
time of maximum observed concentration 
TMPRSS2 
transmembrane protease, serine 2 
TNM 
tissue, lymph node, metastases 
ULN 
upper limit of normal 
Vss 
volume of distribution at steady-state 
WBC 
white blood cell 
WHO 
World Health Organization 


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APPENDIX F. SELECT PRO - CTCAE 


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APPENDIX G. DOSE MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR 
DURVALUMAB 
 
The below table represents recommended management of imAE. These represent guidelines, not 
mandates of the study protocol. 
 
 
General Considerations Regarding Immune-Mediated Reactions 
 
These guidelines are provided as a recommendation to support investigators in the management of potential immune- 
mediated adverse events (imAEs). 
 
Immune-mediated events can occur in nearly any organ or tissue; therefore, these guidelines may not include all the 
possible immune-mediated reactions. Investigators are advised to take into consideration the appropriate practice 
guidelines and other society guidelines (e.g., NCCN, ESMO) in the management of these events. Refer to the section of the 
table titled “Other -Immune-Mediated Reactions” for general guidance on imAEs not noted in the “Specific Immune- 
Mediated Reactions” section. 
Early identification and management of immune-mediated adverse events (imAEs) are essential to ensure safe use of the 
study drug. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune- 
mediated adverse events. Patients with suspected imAEs should be thoroughly evaluated to rule out any alternative 
etiologies (e.g., disease progression, concomitant medications, infections). In the absence of a clear alternative etiology, all 
such events should be managed as if they were immune-mediated. Institute medical management promptly, including 
specialty consultation as appropriate. In general, withhold study drug/study regimen for severe (Grade 3) imAEs. 
Permanently discontinue study drug/study regimen for life-threatening (Grade 4) imAEs, recurrent severe (Grade 3) imAEs 
that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks of initiating corticosteroids. 
 
Based on the severity of the imAE, durvalumab should be withheld and corticosteroids administered. Upon improvement to 
Grade ≤ 1, corticosteroid should be tapered over ≥ 28 days. More potent immunosuppressive agents such as TNF inhibitors 
(e.g., infliximab) should be considered for events not responding to systemic steroids. Alternative immunosuppressive 
agents not listed in this guideline may be considered at the discretion of the investigator based on clinical practice and 
relevant guidelines. With long-term steroid and other immunosuppressive use, consider need for Pneumocystis jirovecii 
pneumonia (PJP, formerly known as Pneumocystis carinii pneumonia) prophylaxis, gastrointestinal protection, and glucose 
monitoring. 
 
Dose modifications of study drug/study regimen should be based on severity of treatment-emergent toxicities graded per 
NCI CTCAE version in the applicable study protocol. 
 
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune- 
mediated adverse event; NCI National Cancer Institute; NCCN National Comprehensive Cancer Network; ESMO European 
Society for Medical Oncology 


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Specific Immune-Mediated Reactions 
Adverse Event 
Severity Grade of 
the Event (NCI 
CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
Pneumonitis/ 
Interstitial Lung 
Disease (ILD) 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for 
defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Monitor subjects for signs and symptoms of 
pneumonitis or ILD (new onset or worsening 
shortness of breath or cough). Subjects should 
be evaluated with imaging and pulmonary 
function tests, including other diagnostic 
procedures as described below. 
− 
Suspected pneumonitis should be confirmed 
with radiographic imaging and other infectious 
and disease-related aetiologies excluded and 
managed as described below. 
− 
Initial work-up may include clinical evaluation, 
monitoring of oxygenation via pulse oximetry 
(resting and exertion), laboratory work-up, and 
high- resolution CT scan. 
− 
Consider Pulmonary and Infectious Disease 
Consults. 
Grade 1 
No dose modifications 
required. However, 
consider holding study 
drug/study regimen 
dose as clinically 
appropriate and during 
diagnostic work-up for 
other etiologies. 
For Grade 1 
− 
Monitor and closely follow up in 2 to 4 days for 
clinical symptoms, pulse oximetry (resting and 
exertion), and laboratory work-up and then as 
clinically indicated. 
Grade 2 
Hold study drug/study 
regimen dose until 
Grade 2 resolution to 
Grade ≤1. 
If toxicity worsens, then 
treat as Grade 3 or 
Grade 4. 
If toxicity improves to 
Grade ≤1, then the 
decision to reinitiate 
study drug/study 
regimen will be based 
upon treating 
physician’s clinical 
judgment and after 
completion of steroid 
taper. 
For Grade 2 
− 
Monitor symptoms daily and consider 
hospitalization. 
− Promptly start systemic steroids (e.g., 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent). 
− 
Reimage as clinically indicated, consider Chest 
CT with contrast and repeat in 3-4 weeks 
− 
If no improvement within 2 to 3 days, 
additional workup should be considered and 
prompt treatment with IV methylprednisolone 
2 to 4 mg/kg/day started 
− 
If no improvement within 2 to 3 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, 
promptly start immunosuppressive therapy 
such as TNF inhibitors (e.g., infliximab at 
5 mg/kg IV once,  may be repeated at 2 and 6 
weeks after initial dose at the discretion of the 
treating provider). Caution: It is important to 
rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 


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− 
Consider, as necessary, discussing with Sponsor 
Principal Investigator. 
Grade 3 or 4 
Permanently 
discontinue study 
drug/study regimen. 
− 
For Grade 3 or 4 Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day or 
equivalent. 
− Obtain Pulmonary and Infectious Diseases 
Consults, consider discussing with Sponsor 
Principal Investigator as needed. 
− 
Hospitalize the subject. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 2 to 3 days, 
additional workup should be considered and 
prompt treatment with additional 
immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg IV, may 
be repeated at 2 and 6 weeks after initial dose 
at the discretion of the treating provider). 
Caution: rule out sepsis and refer to infliximab 
label for general guidance before using 
infliximab. 
Diarrhea/Colitis 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, 
cramping, or changes in bowel habits such as 
increased frequency over baseline or blood in 
stool) or related to bowel perforation (such as 
sepsis, peritoneal signs, and ileus). 
− 
WHEN SYMPTOMS OR EVALUATION INDICATE 
AN INTESTINAL PERFORATION IS SUSPECTED, 
CONSULT A SURGEON EXPERIENCED IN 
ABDOMINAL SURGERY IMMEDIATELY 
WITHOUT ANY DELAY. 
− 
PERMANENTLY DISCONTINUE STUDY DRUG 
FOR ANY GRADE OF INTESTINAL 
PERFORATION. 
− 
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., disease 
progression, other medications, or infections), 
including testing for Clostridium difficile toxin, 
etc. 
− 
Steroids should be considered in the absence 
of clear alternative etiology, even for low- 
grade events, to prevent potential progression 
to higher grade event including intestinal 
perforation. 
− 
Use analgesics carefully; they can mask 
symptoms of perforation and peritonitis. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening symptoms. 
− 
Consider symptomatic treatment, including 
hydration, electrolyte replacement, dietary 
changes (e.g., American Dietetic Association  


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colitis diet), loperamide other supportive care 
measures. 
− 
If symptoms persist, consider checking 
lactoferrin; if positive treat as Grade 2 below. 
If negative and no infection, continue Grade 1 
management. 
Grade 2 
Hold study drug/study 
regimen until 
resolution to Grade ≤1 
If toxicity worsens, then 
treat as Grade 3 or 
Grade 4. 
If toxicity improves to 
Grade ≤1, then study 
drug/study regimen can 
be resumed after 
completion of steroid 
taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including 
hydration, electrolyte replacement, dietary 
changes (e.g., American Dietetic Association 
colitis diet), and loperamide and/or 
budesonide. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO 
or IV equivalent. 
− 
If event is not responsive within 2 to 3 days or 
worsens despite prednisone at 1 to 2 
mg/kg/day PO or IV equivalent, consult a GI 
specialist for consideration of further workup, 
such as imaging and/or colonoscopy, to 
confirm colitis and rule out perforation 
− 
If still no improvement within 2 to 3 days 
despite 1 to 2 mg/kg IV methylprednisolone, 
promptly start immunosuppressives such as 
infliximab at 5 mg/kg IV, may be repeated at 2 
and 6 weeks after initial dose at the discretion 
of the treating provider.a  Caution: it is 
important to rule out bowel perforation and 
refer to infliximab label for general guidance 
before using infliximab. 
− 
Consider, as necessary, discussing with Sponsor 
Principal Investigator if no resolution to Grade 
≤1 in 3 to 4 days. 
Grade 3 or 4 
Grade 3 
For patients treated 
with PD-1 or PDL-1 
inhibitors, hold study 
drug/study regimen 
until resolution to 
Grade ≤1; study 
drug/study regimen can 
be resumed after 
completion of steroid 
taper. Permanently 
discontinue study 
drug/study regimen for 
Grade 3 if toxicity does 
not improve to Grade 
≤1 within 14 days. 
Permanently 
discontinue study drug  
For Grade 3 or 4: 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent. 
− 
Monitor stool frequency and volume and 
maintain hydration. 
− 
Urgent GI consult and imaging and/or 
colonoscopy as appropriate. 
− 
If still no improvement within 2 days continue 
steroids and promptly add further 
immunosuppressives agents (e.g., infliximab at 
5 mg/kg IV, may be repeated at 2 and 6 weeks 
after initial dose at the discretion of the 
treating provider) 
− 
Caution: Ensure GI consult to rule out bowel 
perforation and refer to infliximab label for 
general guidance before using infliximab. 


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for 1) Grade 3 colitis in 
patients treated with 
CTLA-4 inhibitors or 2) 
Any grade large 
intestine 
perforation/Intestinal 
perforation in any 
patient treated with ICI. 
Grade 4 
Permanently 
discontinue 
study drug/study 
regimen. 
− 
If perforation is suspected, consult a surgeon 
experienced in abdominal surgery 
immediately without any delay. 
Hepatitis 
(elevated LFTs) 
Infliximab should 
not be used for 
management of 
immune-related 
hepatitis. 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for 
defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Monitor and evaluate liver function test: AST, 
ALT, ALP, and TB. 
− Evaluate for alternative etiologies (e.g., viral 
hepatitis, disease progression, concomitant 
medications) 
Grade 1 
No dose modifications. 
If it worsens, then treat 
as Grade 2. 
For Grade 1: 
− 
Continue LFT monitoring per protocol. 
Grade 2 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
If toxicity worsens, then 
treat as Grade 3 or 
Grade 4. 
If toxicity improves to 
Grade ≤1 or baseline, 
resume study 
drug/study regimen 
after completion of 
steroid taper. 
Permanently 
discontinue study 
drug/study regimen for 
any case meeting Hy’s 
law criteria (AST and/or 
ALT >3 × ULN + bilirubin 
>2 × ULN without initial 
findings of cholestasis 
(i.e., elevated alkaline 
P04) and in the absence 
of any alternative 
cause.b 
For Grade 2: 
− 
Regular and frequent checking of LFTs (e.g., 
every 1 to 2 days) until LFT elevations improve 
or resolve. 
− 
If no resolution to Grade ≤1 in 1 to 2 days, 
consider discussing with the Sponsor Principal 
Investigator as needed. 
− 
If event is persistent (>2 to 3 days) or worsens, 
promptly start prednisone 1 to 2 mg/kg/day PO 
or IV equivalent. 
Grade 3 or 4 
For Grade 3: 
For Grade 3 or 4: 


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For elevations in 
transaminases 
≤8 × ULN, or elevations 
in total bilirubin 
≤5 × ULN: 
 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1 
or baseline 
 
Resume study 
drug/study regimen if 
elevations downgrade 
to Grade ≤1 or baseline 
within 14 days and 
after completion of 
steroid taper. 
 
Permanently 
discontinue study 
drug/study regimen if 
the elevations do not 
downgrade to Grade ≤1 
or baseline within 
14 days 
 
For elevations in 
transaminases >8 × ULN 
or elevations in 
bilirubin >5 × ULN, 
discontinue study 
drug/study regimen. 
 
For Grade 4: 
Permanently 
discontinue study 
drug/study regimen. 
− 
Promptly initiate empiric IV 
methylprednisolone at 1 to 2 mg/kg/day or 
equivalent. 
− 
If still no improvement within 2 to 3 days 
despite 1 to 2 mg/kg/day methylprednisolone 
IV or equivalent, promptly start treatment with 
an immunosuppressant therapy 
(mycophenolate mofetil 0.5- 1g every 12 hours 
then taper in consultation with hepatology 
consult). Discuss with Sponsor Principal 
Investigator if mycophenolate is not available. 
Infliximab should NOT be used. 
− 
Perform Hepatology Consult, abdominal 
workup, and imaging as appropriate. 
 
 
 
 
 
 
 
 
 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for 
defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Consult a nephrologist. 
− 
Monitor for signs and symptoms that may be 
related to changes in renal function (e.g., 
routine urinalysis, elevated serum BUN and 
creatinine, decreased creatinine clearance, 
 
 


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electrolyte imbalance, decrease in urine 
output, or proteinuria). 
− 
Subjects should be thoroughly evaluated to 
rule out any alternative etiology (e.g., disease 
progression, infections, recent IV contrast, 
medications, fluid status). 
− Consider using steroids in the absence of clear 
alternative etiology even for low-grade events 
(Grade 2), to prevent potential progression to 
higher grade event. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Monitor serum creatinine weekly and any 
accompanying symptoms. 
• 
If creatinine returns to baseline, 
resume its regular monitoring per 
study protocol. 
• 
If creatinine worsens, depending on 
the severity, treat as Grade 2, 3, or 4. 
− 
Consider symptomatic treatment, including 
hydration, electrolyte replacement, and 
diuretics. 
− 
If baseline serum creatinine is elevated above 
normal, and there is a rise to >1 to 1.5 x 
baseline, consider following recommendations 
in this row. 
Grade 2 
Hold study drug/study 
regimen until 
resolution to Grade ≤1 
or baseline. 
If toxicity worsens, then 
treat as Grade 3 or 4. 
If toxicity improves to 
Grade ≤1 or baseline, 
then resume study 
drug/study regimen 
after completion of 
steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including 
hydration, electrolyte replacement, and 
diuretics. 
− 
Carefully monitor serum creatinine every 2 to 3 
days and as clinically warranted. 
− 
Consult nephrologist and consider renal biopsy 
if clinically indicated. 
− 
If event is persistent beyond >3 to 5 days or 
worsens, promptly start prednisone 1 to 2 
mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 5 days or 
worsens despite prednisone at 1 to 2 
mg/kg/day PO or IV equivalent, consider 
additional workup. 
− 
When event returns to baseline, resume study 
drug/study regimen and routine serum 
creatinine monitoring per study protocol. 
Grade 3 or 4 
Permanently 
discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Carefully monitor serum creatinine. 
− 
Consult nephrologist and consider renal biopsy 
if clinically indicated. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO 
or IV equivalent. 


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− 
If event is not responsive within 3 to 5 days or 
worsens despite prednisone at 1 to 2 
mg/kg/day PO or IV equivalent, additional 
workup and prompt treatment with an 
immunosuppressive in consultation with a 
nephrologist. 
Rash or 
Dermatitis 
(Including 
Pemphigoid) 
Any Grade 
(refer to NCI 
CTCAE v 5.0 for 
definition of 
severity/grade 
depending on 
type of skin rash) 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of dermatitis 
(rash and pruritus). 
− 
Hold study drug if Stevens-Johnson Syndrome 
(SJS), Toxic Epidermal Necrolysis (TEN), or 
other severe cutaneous adverse reaction 
(SCAR) is suspected. 
− 
Permanently discontinue study drugs if SJS, 
TEN or SCAR is confirmed. 
Grade 1 
No dose modifications. 
For Grade 1: 
− Consider symptomatic treatment, including 
oral antipruritics (e.g., diphenhydramine or 
hydroxyzine) and topical therapy 
(e.g., e.g., emolient, lotion, or institutional 
standard). 
Grade 2 
For persistent (>1 
week) Grade 2 events, 
hold scheduled study 
drug/study regimen 
until resolution to 
Grade ≤1 or baseline. 
If toxicity worsens, then 
treat as Grade 3. 
If toxicity improves to 
Grade ≤1 or baseline, 
then resume 
drug/study regimen 
after completion of 
steroid taper. 
For Grade 2: 
− 
Obtain dermatology consult. 
− Consider symptomatic treatment, including 
oral antipruritics (e.g., diphenhydramine or 
hydroxyzine) and topical therapy. 
− 
Consider moderate-strength topical steroid. 
− 
If no improvement of rash/skin lesions occurs 
within 3 days or is worsening despite 
symptomatic treatment and/or use of 
moderate strength topical steroid, consider 
discussing with Sponsor Principal Investigator 
and promptly start systemic steroids such as 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. If > 30% body surface area is 
involved, consider initiation of systemic 
steroids promptly. 
− 
Consider skin biopsy if the event persists for >1 
week or recurs. 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen until 
resolution to Grade ≤1 
or baseline. 
If toxicity improves to 
Grade ≤1 or baseline, 
then resume  
For Grade 3 or 4: 
− 
Consult dermatology. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 


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drug/study regimen 
after completion of 
steroid taper. 
If toxicity worsens, then 
treat as Grade 4. 
For Grade 4: 
Permanently 
discontinue study 
drug/study regimen. 
− 
Consider skin biopsy (preferably more than 1) 
as clinically feasible. 
− 
Consider, as necessary, discussing with Sponsor 
Principal Investigator. 
Amylase/Lipase 
increased 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for 
defining the CTC 
grade/severity) 
 
For Grade 1: 
For grade 2, 3, or 
4: 
General Guidance 
  
 
No dose modifications 
For Grade 2, 3, or 4 
In consultation with 
relevant pancreatic 
specialist consider 
continuing study 
drug/study regimen if 
no clinical/radiologic 
evidence of pancreatitis 
± improvement in 
amylase/lipase. 
For Any Grade: 
− 
For modest asymptomatic elevations in serum 
amylase and lipase, corticosteroid treatment is 
not indicated if there are no other signs or 
symptoms of pancreatic inflammation. 
− 
Assess for signs/symptoms of pancreatitis 
− 
Consider appropriate diagnostic testing (e.g, 
abdominal CT with contrast, MRCP if clinical 
suspicion of pancreatitis and no radiologic 
evidence on CT) 
− 
If isolated elevation of enzymes without 
evidence of pancreatitis, continue 
immunotherapy. Consider other causes of 
elevated amylase/lipase 
− 
If evidence of pancreatitis, manage according 
to pancreatitis recommendations 
Acute 
Pancreatitis 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for 
defining the CTC 
grade/severity) 
Grade 1 
Grade 2, 3, or 4 
General Guidance 
For Grade 1: 
No dose modifications 
For Grade 2: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
For Any Grade: 
− 
Consider gastroenterology referral 
For Grade 1: 
− 
IV hydration 
− 
Manage per amylase/lipase increased 
(asymptomatic) 
For Grade 2, 3, or 4: 
- 
Promptly start systemic steroids prednisone 1 
to 2 mg/kg/day PO or IV equivalent 
- 
IV hydration 


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For Grade 3 or 4: 
Permanently 
discontinue study 
drug/study regimen 
Endocrinopathy 
(e.g., hyperthyroi 
dism, 
hypothyroidism, 
type 1 diabetes 
mellitus, 
hypophysitis, 
hypopituitarism, 
and adrenal 
insufficiency) 
Any Grade 
(depending on 
the type of 
endocrinopathy, 
refer to NCI 
CTCAE v5.0 for 
defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Consider consulting an endocrinologist for 
endocrine events. 
− 
Consider discussing with Sponsor Principal 
Investigator. 
− 
Monitor subjects for signs and symptoms of 
endocrinopathies. Non-specific symptoms 
include headache, fatigue, behavior changes, 
mental status changes, photophobia, visual 
field cuts, vertigo, abdominal pain, unusual 
bowel habits, polydipsia, polyuria, 
hypotension, and weakness. 
− 
Subjects should be thoroughly evaluated to 
rule out any alternative etiology (e.g., disease 
progression including brain metastases, or 
infections). 
− 
Depending on the suspected endocrinopathy, 
monitor and evaluate thyroid function tests: 
TSH, free T3 and free T4 and other relevant 
endocrine and related labs (e.g., blood glucose 
and ketone levels, HgA1c). 
− 
Investigators should ask subjects with 
endocrinopathies who may require prolonged 
or continued hormonal replacement, to 
consult their primary care physicians or 
endocrinologists about further monitoring and 
treatment after completion of the study. 
− 
If a subject experiences an AE that is thought 
to be possibly of autoimmune nature (e.g., 
thyroiditis, pancreatitis, hypophysitis, or 
diabetes insipidus), the investigator should 
send a blood sample for appropriate 
autoimmune antibody testing. 
Grade 1 
No dose modifications. 
For Grade 1 
− 
Monitor subject with appropriate endocrine 
function tests. 
− 
For suspected hypophysitis/hypopituitarism, 
consider consulting an endocrinologist to guide 
assessment of early-morning ACTH, cortisol, 
TSH and free T4; also consider gonadotropins, 
sex hormones, and prolactin levels, as well as 
cosyntropin stimulation test (though it may not 
be useful in diagnosing early secondary adrenal 
insufficiency). 
− 
TSH < 0.5 × LLN, or TSH >2 × ULN, or 
consistently out of range in 2 subsequent  


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measurements, include free T4 at subsequent 
cycles as clinically indicated and consider 
consultation of an endocrinologist. 
Grade 2,3, or 4 
For Grade 2-4 
endocrinopathies other 
than hypothyroidism 
and type 1 diabetes 
mellitus, consider 
holding study 
drug/study regimen 
dose until acute 
symptoms resolve. 
Study drug/study 
regimen can be 
resumed once subject 
stabilizes and after 
completion of steroid 
taper. 
Subjects with 
endocrinopathies who 
may require prolonged 
or continued steroid 
replacement (e.g., 
adrenal insufficiency) 
can be retreated with 
study drug/study 
regimen if the patient is 
clinically stable as per 
investigator or treating 
physician’s clinical 
judgement. 
If toxicity worsens, then 
treat based on severity. 
For Grade 2,3, or 4 
− 
Consult endocrinologist to guide evaluation of 
endocrine function and, as indicated by 
suspected endocrinopathy and as clinically 
indicated, consider pituitary scan. 
− 
For all subjects with abnormal endocrine work 
up, except for those with isolated 
hypothyroidism or type 1 DM, and as guided 
by an endocrinologist, consider short-term 
corticosteroids (e.g., 1 to 2 mg/kg/day 
methylprednisolone or IV equivalent) and 
prompt initiation of treatment with relevant 
hormone replacement (e.g., hydrocortisone, 
or sex hormones). 
− 
Isolated hypothyroidism may be treated with 
replacement therapy, without study 
drug/study regimen interruption, and without 
corticosteroids. 
− 
Isolated type 1 diabetes mellitus (DM) may be 
treated with appropriate diabetic therapy, and 
without corticosteroids.  Only hold study 
drug/study regimen in setting of hyperglycemia 
when diagnostic workup is positive for diabetic 
ketoacidosis. 
− 
For subjects with normal endocrine workup 
(laboratory assessment or MRI scans), repeat 
laboratory assessments/MRI as clinically 
indicated. 
Neurotoxicity 
(to include but 
not limited to 
non-infectious 
meningitis, non- 
infectious 
encephalitis, and 
autonomic 
neuropathy, 
excluding 
Myasthenia 
Gravis and 
Guillain-Barre) 
Any Grade 
(Depending on 
the type of 
neurotoxicity, 
refer to NCI 
CTCAE applicable 
version in study 
protocol for 
defining the CTC 
grade/severity) 
For Any Grade: 
For Any Grade: 
− 
Subjects should be evaluated to rule out any 
alternative etiology (e.g., disease progression, 
infections, metabolic syndromes, or 
medications). 
− 
Monitor subject for general symptoms 
(headache, nausea, vertigo, behavior change, 
or weakness). 
− 
Consider appropriate diagnostic testing 
(e.g., electromyogram and nerve conduction 
investigations). 
− 
Perform symptomatic treatment with 
neurological consult as appropriate. 
− 
FOR TRANSVERSE MYELITIS, PERMANENTLY 
DISCONTINUE FOR ANY GRADE. 


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Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” recommendations above. 
− 
Treat mild signs/symptoms as Grade 1 (e.g. 
loss of deep tendon reflexes or paresthesia) 
Grade 2 
For acute motor 
neuropathies or 
neurotoxicity, hold 
study drug/study 
regimen dose until 
resolution to Grade ≤1. 
For sensory 
neuropathy/neuropathi 
c pain, consider holding 
study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently 
discontinue study 
drug/study regimen if 
Grade 2 imAE does not 
resolve to Grade ≤1 
within 30 days. 
If toxicity worsens, then 
treat as Grade 3 or 4. 
For Grade 2: 
− 
Consider, as necessary, discussing with the 
Sponsor Principal Investigator. 
− 
Obtain neurology consult. 
− 
Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications (e.g., 
gabapentin or duloxetine). 
− 
Promptly start systemic steroids prednisone 1 
to 2 mg/kg/day PO or IV equivalent. 
− 
If no improvement within 2 to 3 days despite 1 
to 2 mg/kg/day prednisone PO or IV 
equivalent, consider additional workup and 
promptly treat with additional 
immunosuppressive therapy (e.g., IV IG or 
other immunosuppressive depending on the 
specific imAE). 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently 
discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Consider, as necessary, discussing with the 
Sponsor Principal Investigator. 
− 
Obtain neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent. 
− 
If no improvement within 2 to 3 days despite IV 
corticosteroids, consider additional workup and 
promptly treat with an additional 
immunosuppressants (e.g., IV IG or other 
immunosuppressant depending on the specific 
imAE). 
− 
Once stable, gradually taper steroids over ≥28 
days. 
Peripheral 
neuromotor 
syndromes 
(such as Guillain- 
Barre and 
myasthenia 
gravis) 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for 
General Guidance 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated 
peripheral neuromotor syndromes is 
important, since certain subjects may 
unpredictably experience acute 
decompensations that can result in substantial 
morbidity or in the worst case, death. Special  


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defining the CTC 
grade/severity) 
care should be taken for certain sentinel 
symptoms that may predict a more severe 
outcome, such as prominent dysphagia, rapidly 
progressive weakness, and signs of respiratory 
insufficiency or autonomic instability. 
− 
Subjects should be evaluated to rule out any 
alternative etiology (e.g., disease progression, 
infections, metabolic syndromes or 
medications). It should be noted that the 
diagnosis of immune-mediated peripheral 
neuromotor syndromes can be particularly 
challenging in subjects with underlying cancer, 
due to the multiple potential confounding 
effects of cancer (and its treatments) 
throughout the neuraxis. Given the importance 
of prompt and accurate diagnosis, it is essential 
to have a low threshold to obtain a 
neurological consult. 
− 
Neurophysiologic diagnostic testing 
(e.g., electromyogram and nerve conduction 
investigations, and “repetitive stimulation” if 
myasthenia is suspected) are routinely 
indicated upon suspicion of such conditions 
and may be best facilitated by means of a 
neurology consultation. 
− 
It is important to consider that the use of 
steroids as the primary treatment of Guillain- 
Barre is not typically considered effective. 
Subjects requiring treatment should be started 
with IV IG and followed by plasmapheresis if 
not responsive to IV IG. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider discussing with the Sponsor Principal 
Investigator. 
− 
Care should be taken to monitor subjects for 
sentinel symptoms of a potential 
decompensation as described above. 
− 
Consult a Neurologist. 
Grade 2 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently 
discontinue study 
drug/study regimen if it 
does not resolve to 
Grade ≤1 within 30 
days or if there are 
signs of respiratory 
insufficiency or 
autonomic instability. 
For Grade 2: 
− 
Consider discussing with the Sponsor Principal 
Investigator. 
− 
Care should be taken to monitor subjects for 
sentinel symptoms of a potential 
decompensation as described above. 
− 
Obtain a neurology consult 
− 
Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications (e.g., 
gabapentin or duloxetine). 
MYASTHENIA GRAVIS: 
o Steroids may be successfully used to treat 
myasthenia gravis. It is important to consider  


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that steroid therapy (especially with high 
doses) may result in transient worsening of 
myasthenia and should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
o 
Subjects unable to tolerate steroids may be 
candidates for treatment with plasmapheresis 
or IV IG. Such decisions are best made in 
consultation with a neurologist, taking into 
account the unique needs of each subject. 
o 
If myasthenia gravis-like neurotoxicity is 
present, consider starting AChE inhibitor 
therapy in addition to steroids. Such therapy, if 
successful, can also serve to reinforce the 
diagnosis. 
o 
Avoid medications that can worsen myasthenia 
gravis 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of 
steroids as the primary treatment of Guillain- 
Barre is not typically considered effective. 
o 
Subjects requiring treatment should be started 
with IV IG and followed by plasmapheresis if 
not responsive to IV IG. 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently 
discontinue study 
drug/study regimen if 
Grade 3 imAE does not 
resolve to Grade ≤1 
within 30 days or if 
there are signs of 
respiratory insufficiency 
or autonomic 
instability. 
For Grade 4: 
Permanently 
discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Consider discussing with the Sponsor Principal 
Investigator. Recommend hospitalization. 
− 
Recommend hospitalization 
− 
Monitor symptoms and obtain neurological 
consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat 
myasthenia gravis. They should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis 
or IV IG. 
o 
If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in 
addition to steroids. Such therapy, if successful, 
can also serve to reinforce the diagnosis. 
o 
Avoid medications that can worsen myasthenia 
gravis 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of 
steroids as the primary treatment of Guillain- 
Barre is not typically considered effective. 


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o 
Subjects requiring treatment should be started 
with IV IG and followed by plasmapheresis if 
not responsive to IV IG. 
Myocarditis 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for 
defining the CTC 
grade/severity) 
General Guidance 
Discontinue drug 
permanently if biopsy- 
proven immune- 
mediated myocarditis. 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated 
myocarditis is important, particularly in 
subjects with baseline cardiopulmonary 
disease and reduced cardiac function. 
− 
Consider discussing with the Sponsor Principal 
Investigator. 
− 
Monitor subjects for signs and symptoms of 
myocarditis (new onset or worsening chest 
pain, arrhythmia, shortness of breath, 
peripheral edema). As some symptoms can 
overlap with lung toxicities, simultaneously 
evaluate for and rule out pulmonary toxicity as 
well as other causes (e.g., pulmonary 
embolism, congestive heart failure, malignant 
pericardial effusion). A Cardiology consultation 
should be obtained early, with prompt 
assessment of whether and when to complete 
a cardiac biopsy, including any other diagnostic 
procedures. 
− 
Initial work-up should include clinical 
evaluation, BNP, cardiac enzymes, ECG, 
echocardiogram (ECHO), monitoring of 
oxygenation via pulse oximetry (resting and 
exertion), and additional laboratory work-up as 
indicated. Spiral CT or cardiac MRI can 
complement ECHO to assess wall motion 
abnormalities when needed. 
− 
Subjects should be thoroughly evaluated to 
rule out any alternative etiology (e.g., disease 
progression, other medications, or infections) 
Grade 1 
No dose modifications 
required unless clinical 
suspicion is high, in 
which case hold study 
drug/study regimen 
dose during diagnostic 
work-up for other 
etiologies. If study 
drug/study regimen is 
held, resume after 
complete resolution to 
Grade 0. 
For Grade 1 
− 
Monitor and closely follow up in 2 to 4 days for 
clinical symptoms, BNP, cardiac enzymes, ECG, 
ECHO, pulse oximetry (resting and exertion), 
and laboratory work-up as clinically indicated. 
− 
Consider using steroids if clinical suspicion is 
high. 
Grade 2, 3 or 4 
Grade 2: 
Hold study 
drug/study regimen 
dose until resolution 
to Grade 0. If toxicity 
rapidly improves to 
Grade 0, then the 
For Grade 2-4: 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IV methylprednisolone 2 to 
4 mg/kg/day or equivalent after Cardiology 
consultation has determined whether and 


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decision to reinitiate 
study drug/study 
regimen will be 
based upon treating 
physician’s clinical 
judgment and after 
completion of 
steroid taper. If 
toxicity does not 
rapidly improve, 
permanently. 
discontinue study 
drug/study regimen. 
Grade 3: 
Permanently 
discontinue study 
drug/study regimen. 
when to complete diagnostic procedures 
including a cardiac biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 2 to 3 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, 
promptly start immunosuppressive therapy 
such as TNF inhibitors (e.g., infliximab at 
5 mg/kg every kg IV, may be repeated at 2 and 
6 weeks after initial dose at the discretion of 
the treating provider). Caution: It is important 
to rule out sepsis and refer to infliximab label 
for general guidance before using infliximab. 
Infliximab is contraindicated for patients who 
have heart failure. 
Myositis/Polymy 
ositis 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for 
defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Monitor subjects for signs and symptoms of 
poly/myositis. Typically, muscle weakness/pain 
occurs in proximal muscles including upper 
arms, thighs, shoulders, hips, neck and back, 
but rarely affects the extremities including 
hands and fingers; also difficulty breathing 
and/or trouble swallowing can occur and 
progress rapidly. Increased general feelings of 
tiredness and fatigue may occur, and there can 
be new-onset falling, difficulty getting up from 
a fall, and trouble climbing stairs, standing up 
from a seated position, and/or reaching up. 
− 
If poly/myositis is suspected, a Neurology 
consultation should be obtained early, with 
prompt guidance on diagnostic procedures. 
Myocarditis may co-occur with poly/myositis; 
refer to guidance under Myocarditis. Given 
breathing complications, refer to guidance 
under Pneumonitis/ILD. 
Given possibility of an existent (but previously 
unknown) autoimmune disorder, consider 
Rheumatology consultation. 
− 
Consider, as necessary, discussing with the 
Sponsor Principal Investigator. 
− 
Initial work-up should include clinical 
evaluation, creatine kinase, aldolase, LDH, 
BUN/creatinine, erythrocyte sedimentation 
rate or C-reactive protein level, urine 
myoglobin, and additional laboratory work-up 
as indicated, including a number of possible 
rheumatological/antibody tests (i.e., consider 
whether a rheumatologist consultation is 
indicated and could guide need for rheumatoid 
factor, antinuclear antibody, anti-smooth 
muscle, antisynthetase [such as anti-Jo-1], 
and/or signal-recognition particle antibodies). 


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Grade 1 
No dose modifications. 
Grade 2 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently 
discontinue study 
drug/study regimen if it 
does not resolve to 
Grade ≤1 within 30 
days or if there are 
signs of respiratory 
insufficiency. 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
Permanently 
discontinue study 


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drug/study regimen if 
Grade 3 imAE does not 
resolve to Grade ≤1 
within 30 days or if 
there are signs of 
respiratory 
insufficiency. 
 
For Grade 4: 
Permanently 
discontinue study 
drug/study regimen. 
− 
Promptly start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along with 
receiving input from Neurology consultant. 
− 
If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 2 
to 3 days, consider start of immunosuppressive 
therapy such as TNF inhibitors (e.g., infliximab 
at 5 mg/kg IV, may be repeated at 2 and 6 
weeks after initial dose at the discretion of the 
treating provider ). Caution: It is important to 
rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Consider whether subject may require IV IG, 
plasmapheresis. 
 
 
 
 
aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
cNCCN Clinical Practice Guidelines in Oncology “Management of Immunotherapy-Related Toxicities” Version 1.2020 – 
December 2019 
 
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine 
aminotransferase; AST Aspartate aminotransferase; BUN Blood urea nitrogen; CT Computed tomography; CTCAE 
Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated adverse event; IG 
Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI Magnetic 
resonance imaging; NCI National Cancer Institute; NCCN National Comprehensive Cancer Network; PJP Pneumocystis 
jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); PO  ; PO By mouth; T3 Triiodothyronine; T4 
Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal. 


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Other–Immune-Mediated Reactions 
Severity Grade of the 
Event (Refer to NCI CTCAE 
applicable version in study 
protocol for defining the 
CTC grade/severity) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: It is possible that events with an 
inflammatory or immune mediated 
mechanism could occur in nearly all 
organs, some of them are not noted 
specifically in these guidelines (e.g. 
immune thrombocytopenia, haemolytic 
anaemia, uveitis, vasculitis). 
− 
The study physician may be contacted 
for immune-mediated reactions not 
listed in the “specific immune- 
mediated reactions” section 
− 
Thorough evaluation to rule out any 
alternative etiology (e.g., disease 
progression, concomitant medications, 
and infections) 
− 
Consultation with relevant specialist 
− 
Treat accordingly, as per institutional 
standard. 
Grade 1 
No dose modifications. 
Monitor as clinically indicated 
Grade 2 
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
If toxicity worsens, then treat as Grade 3 
or Grade 4. 
Study drug/study regimen can be 
resumed once event stabilizes to Grade 
≤1 after completion of steroid taper. 
Consider whether study drug/study 
regimen should be permanently 
discontinued in Grade 2 events with high 
likelihood for morbidity and/or mortality 
when they do not rapidly improve to 
Grade <1 upon treatment with systemic 
steroids and following full taper 
For Grade 2, 3, or 4 
Treat accordingly, as per institutional 
standard, appropriate clinical practice 
guidelines, and other society guidelines 
(e.g., NCCN, ESMO) 
Grade 3 
Hold study drug/study regimen 
Grade 4 
Permanently discontinue study 
drug/study regimen 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, 
please discuss with Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute. 


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Infusion-Related Reactions 
Severity Grade of 
the Event (Refer to 
NCI CTCAE 
applicable version in 
study protocol for 
defining the CTC 
grade/severity) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the 
discretion of investigator. 
− 
Monitor subjects for signs and symptoms of 
infusion-related reactions (e.g., fever and/or 
shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, 
dyspnea or chest discomfort, or skin rashes) 
and anaphylaxis (e.g., generalized urticaria, 
angioedema, wheezing, hypotension, or 
tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study 
regimen may be decreased by 50% or 
temporarily interrupted until resolution of 
the event. 
For Grade 2: 
The infusion rate of study drug/study 
regimen may be decreased 50% or 
temporarily interrupted until resolution of 
the event. 
Subsequent infusions may be given at 
50% of the initial infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may 
be administered per institutional standard at 
the discretion of the investigator. 
− 
Consider premedication per institutional 
standard prior to subsequent doses. 
− 
Steroids should not be used for routine 
premedication of Grade ≤2 infusion 
reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions per 
institutional standards (e.g., IM epinephrine, 
followed by IV diphenhydramine and 
famotidine, and IV glucocorticoid). 
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute. 


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Non–Immune-Mediated Reactions 
Severity Grade of the 
Event (Refer to NCI 
CTCAE applicable version 
in study protocol for 
defining the CTC 
grade/severity) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for 
AEs not deemed to be related to study 
treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not 
deemed to be clinically significant. 
Treat accordingly, as per institutional 
standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional 
standard. 
Grade 2 
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
Treat accordingly, as per institutional 
standard. 
Grade 3 
Hold study drug/study regimen until 
resolution to ≤Grade 1 or baseline. 
For AEs that downgrade to ≤Grade 2 within 7 
days or resolve to ≤Grade 1 or baseline within 
14 days, resume study drug/study regimen 
administration. Otherwise, discontinue study 
drug/study regimen. 
Treat accordingly, as per institutional 
standard. 
Grade 4 
Discontinue study drug/study regimen (Note: 
For Grade 4 labs, decision to discontinue 
should be based on accompanying clinical 
signs/symptoms, the Investigator’s clinical 
judgment, and consultation with the 
Sponsor.). 
Treat accordingly, as per institutional 
standard. 


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APPENDIX H. DOSE MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR OLAPARIB 
 
Olaparib dose reductions based on hematologic nadir 
 
Granulocytes and Platelets 
Olaparib Dose Adjustment 
ANC < LLN* but ≥1000/mm3 and/or PLT<LLN but 
≥50,000/mm3 
(CTCAE Grade 1-2) 
Investigator judgment to continue study treatment in full 
dose or if dose interruption, this should be for a 
maximum of 4 weeks; appropriate supportive treatment 
and causality investigation 
ANC<1000/mm3 and/or PLT<50,000/mm3 
(CTCAE Grade 3 - 4) 
Hold olaparib. Once toxicity resolves to Grade 1, olaparib 
may be continued -1 dose level. 
*LLN = lower limit of normal 
 
• 
If the ANC nadir is under 1000/mm3 (CTCAE Grade 3 - 4) and/or the platelet nadir is under 
50,000/mm3 (CTCAE Grade 3 - 4) after a 1 dose level reduction of olaparib, then the next 
cycle will be started at -2 dose level once toxicity resolved to CTCAE Grade 1 or better 
• 
Subjects requiring more than two dose reductions will discontinue olaparib 
 
Management of toxicity related to olaparib 
Any toxicity observed during the course of the study could be managed by interruption and/ or 
dose reduction of the dose if deemed appropriate by the Investigator. Olaparib must be 
interrupted until the subject recovers completely or the toxicity reverts to the NCI-CTCAE Grade 1 
or less. If olaparib is delayed more than 8 weeks for any reason, or if a dose reduction below 200 
mg daily is required, subjects will discontinue treatment with olaparib. 
• 
Where toxicity reoccurs following re-challenge with olaparib, and where further dose 
interruptions are considered inadequate for management of toxicity, then the subject 
should be considered for dose reduction or must permanently discontinue treatment with 
olaparib. 
• 
Treatment must be interrupted if any NCI-CTCAE Grade 3 or Grade 4 AE occurs which the 
Investigator considers to be related to administration of olaparib. 
 
Action to Take 
Adverse Event with Possible Relationship to 
Olaparib 
Non-hematologic 
toxicities including 
nausea, vomiting, and 
diarrhea 
Grade 1 and Grade 2 
If subjects develop intolerable Grade 1 or Grade 2 toxicities 
(per subject) then they can undergo a dose reduction. For 
Grade 4 toxicities despite optimal medical therapy, hold 
olaparib until equal or under Grade 1. Resume at one dose 
level reduction. 
Events of nausea and vomiting are known to be associated 
with olaparib treatment. In study, they are generally mild 
to moderate (CTCAE Grade 1 or Grade 2) severity, 
intermittent and manageable on continued treatment. The 
first onset generally occurs in the first month of treatment 
with the incidence of nausea and vomiting not showing an 
increase over the treatment cycles. 


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No routine prophylactic anti-emetic treatment is required 
at the start of study treatment; however, subjects should 
receive appropriate anti-emetic treatment at the first 
onset of nausea or vomiting and as required thereafter, in 
accordance with local treatment practice guidelines 
General non- 
hematologic toxicities 
excluding nausea, 
vomiting, and diarrhea 
Grade 3 or higher 
toxicities 
Delay until recovery to Grade 1 or lower and reduce one 
dose level to 250mg BID). A maximum of 2 dose reductions 
can be made for repeat toxicity. 
Anemia 
CTCAE Grade 1 or Grade 
2 (Hemoglobin (Hb) > 8 
g/dl) 
Investigate and manage as deemed appropriate by the 
investigator with or without interruption of study drug or 
change in dose, taking into account previous history of 
anemia. Common treatable causes of anemia (e.g., iron, 
vitamin B12 or folate deficiencies and hypothyroidism) 
should be excluded. In some cases, management of anemia 
may require blood transfusions. 
CTCAE Grade 3 (Hb < 
8g/dl) or worse 
Study treatment should be interrupted for up to maximum 
of 4 weeks to allow for bone marrow recovery and the 
subject should be managed appropriately. Study 
treatment can be restarted at the reduced dose if Hb has 
recovered to > 10 g/dl. Any subsequently required anemia 
related interruptions, considered likely to be dose related, 
or coexistent with newly developed neutropenia, and or 
thrombocytopenia, will require a further study treatment 
dose reduction to 200 mg BID. 
If a subject has been treated for anemia with multiple 
blood transfusions without study treatment interruptions 
and becomes blood transfusion dependant as judged by 
investigator, study treatment should be permanently 
discontinued. 
Neutropenia and 
leukopenia 
CTC Grade 3 or worse 
neutropenia occurs 
Manage as deemed appropriate by the investigator with 
close follow up and interruption of study drug. Primary 
prophylaxis with Granulocyte colony-stimulating factor (G- 
CSF) is not recommended, however, if a subject 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 of the 
last dose of study treatment. 
Study treatment can be restarted at the same dose if an AE 
of neutropenia or leukopenia have been recovered up to 
CTC AE Grade less than or equal to Grade 1 (ANC > 1.5 x 
109/L). Growth factor support should be stopped at least 
24h before restarting study drug (7 days for pegylated G- 
CSF). 
Any subsequent interruptions will require study treatment 
dose reductions to 250 mg BID as a first step and to 200 mg 


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BID as a second step for a 300 mg monotherapy starting 
dose 
Thrombocytopenia 
CTCAE Grade 3 or worse 
Study treatment should be interrupted for a maximum of 4 
weeks. In some cases, management of thrombocytopenia 
may require platelet transfusions. Platelet transfusions 
should be done according to local hospital guidelines. 
Any subsequent interruptions will require study treatment 
dose reductions to 250 mg BID as a first step and to 200 mg 
BID as a second step for a 300 mg monotherapy starting 
dose 
Prolonged 
hematological 
toxicities while on 
study treatment 
≥2 week 
interruption/delay in 
study treatment due to 
CTC Grade 3 or worse 
anemia and/or 
development of blood 
transfusion dependence 
≥2 week 
interruption/delay in 
study treatment due to 
CTC Grade 3 or worse 
neutropenia (ANC < 1 x 
109/L) 
≥2 week 
interruption/delay in 
study treatment due to 
CTC Grade 3 or worse 
thrombocytopenia 
(Platelets < 50 x 109/L) 
Weekly differential blood counts including reticulocytes 
(calculate reticulocyte index (RI), RI = reticulocyte count x 
hematocrit (Hct)/normal Hct; a value of 45 is usually used 
for normal Hct) (1, 2) and peripheral blood smear should 
be performed. If any blood parameters remain clinically 
abnormal after 4 weeks of dose interruption, the subject 
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 haematological practice. 
Bone marrow or blood cytogenetic analysis may be 
performed according to standard hematological practice 
for subjects with prolonged hematological toxicities. Bone 
marrow analysis should include an aspirate for cellular 
morphology, cytogenetic analysis and flow cytometry, and 
a core biopsy for bone marrow cellularity. If it is not 
possible to conduct cytogenetic analysis or flow cytometry 
on the bone marrow aspirate, then attempts should be 
made to carry out the tests on a blood sample. If findings 
are consistent with MDS/AML, study drug should be 
discontinued, and a full description of findings should be 
submitted with an SAE report (see Section 7.3 – Reporting 
of SAEs for reference) to the PCCTC.   Presence or absence 
of blood cytogenetic abnormalities and flow cytometry will 
be documented on the clinical database. 
Pneumonitis 
Suspected or any grade 
If subjects present with new or worsening respiratory 
symptoms such as dyspnea, cough and fever, or a 
radiological abnormality occurs in the absence of a clear 
diagnosis, olaparib treatment should be interrupted and 
prompt investigation initiated. If pneumonitis is confirmed, 
olaparib treatment should be discontinued and the subject 
treated appropriately. 
Renal Impairment 
Creatinine clearance 
below threshold for 
study inclusion 
(51ml/min) 
If subsequent to study entry and while still on study 
therapy, a subject’s estimated CrCl falls below the 
threshold for study inclusion (≥51 ml/min), retesting should 
be performed promptly. 
A dose reduction is recommended for subjects who 
develop moderate renal impairment (calculated creatinine 
clearance by Cockcroft-Gault equation of between 31 and 


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50 ml/min) for any reason during the course of the study: 
the dose of olaparib should be reduced to 200 mg BID. 
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 subjects with severe renal 
impairment (creatinine clearance ≤ 30 ml/min) or end- 
stage renal disease; if subjects develop severe impairment 
or end stage disease is it recommended that olaparib be 
discontinued.