Open Label, Phase II Pilot Study of Immune Checkpoint Inhibition With Pembrolizumab in Combination With PARP Inhibition With Olaparib in Advanced BRCA-mutated or HDR-defect Breast Cancers
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Yuan Yuan

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IIT2015-18-MITA-MK3475  
 
Open Label, Phase II Pilot Study of Immune 
Checkpoint Inhibition with Pembrolizumab in 
Combination with PARP Inhibition with Olaparib in 
Advanced BRCA-mutated or HDR-defect Breast 
Cancers 
 
 
Principal Investigator: 
Monica Mita, MD 
 
 
 
 
Cedars-Sinai Medical Center 
 
 
 
 
8700 Beverly Blvd 
 
 
 
 
Los Angeles, CA 90048 
 
 
 
 
T:  310-423-1188 
 
 
 
 
F:  310-423-4759  
 
 
 
 
E:  Monica.Mita@cshs.org 
  
Co-Investigators 
Department/Division 
Philomena McAndrew, MD 
Hematology / Medical Oncology 
Dorothy Park, MD 
Hematology / Medical Oncology 
Alain Mita, MD 
Hematology / Medical Oncology 
Maryliza El-Masry, MD 
Hematology / Medical Oncology 
 
Collaborating Investigators 
Department/Division 
Stephen Shiao, MD  
Radiation Oncology/Tumor Immunology 
 
 
 
 
 
 
 
Biostatistician: 
 
Marie Lauzon, MS 
 
IND Number: 
 
130046 
 
IND Holder Name:  
Monica Mita, MD 
 
Funding Source:  
Merck 
 
Current version: 
 
Protocol Version 9 dated 05DEC2023 
 
Previous versions: 
Protocol Version 8 dated 11MAR2022 
 
 
 
Protocol Version 7 dated 03AUG2021 

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Protocol Version 6 dated 16JUL2021 
 
 
 
 
Protocol Version 5 dated 19APR2021 
 
 
 
 
Protocol Version 4.1 dated 15SEP2020 
 
 
 
 
Protocol Version #4 dated 12MAR2020 
 
 
 
 
 
 
 
Protocol Version #3 dated 21DEC2017 
 
 
 
 
Protocol Version #2 dated 07NOV2017 
 
 
 
 
Protocol Version #1 dated 06JAN2017 
 
 
 

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Signature Page 
Protocol Version #9 dated 05DEC2023 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including all 
statements regarding confidentiality, and according to local legal and regulatory requirements and applicable U.S. 
federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
Signature: _____________________________  Date: ____________________ 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS............................................................................................................. 1 
STUDY SCHEMA ............................................................................................................................ 2 
STUDY SUMMARY ......................................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE .................................................................................... 4 
2.0 
STUDY OBJECTIVES ......................................................................................................... 7 
3.0 
PATIENT ELIGIBILITY ........................................................................................................ 8 
4.0 
TREATMENT PLAN .......................................................................................................... 13 
5.0 
STUDY PROCEDURES ..................................................................................................... 29 
6.0 
ADVERSE EVENTS .......................................................................................................... 34 
7.0 
DRUG INFORMATION ...................................................................................................... 27 
8.0 
CORRELATIVES/SPECIAL STUDIES .............................................................................. 28 
9.0 
STATISTICAL CONSIDERATIONS .................................................................................. 28 
10.0 
STUDY MANAGEMENT .................................................................................................... 44 
11.0 
REFERENCES ................................................................................................................... 49 
12.0 
SUMMARY OF CHANGES……………………………………………………………………...41 

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1 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMC 
Data and Safety Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
HDR 
Homology-directed repair 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IV (or iv) 
Intravenously 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
 
 
 
 
 
 
: 

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STUDY SCHEMA   
 
 
 
 
 
 
 
Subjects with Metastatic 
Breast Cancer with 
known BRCA mutation or 
HDR-defect progressing 
on or after prior therapy 
for metastatic disease or 
locally advanced disease 
Pembrolizumab 200mg 
IV every 21 days for up 
to 2 years  
 
+ 
 
Olaparib 300 mg PO BID 
Disease Assessment every 9 
weeks while on drug during 
Year 1, then every 12 weeks 
during Year 2 or after drug 
discontinuation for any 
reason other than progression 

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STUDY SUMMARY 
 
Abbreviated Title 
Pembrolizumab plus olaparib in advanced BRCA-mutated or 
HDR-defect breast cancer 
Trial Phase 
II 
Clinical Indication 
Therapy for metastatic disease after progression on at least 
one line of prior therapy 
Trial Type 
Pilot Study - Open label phase II 
Type of control 
N/A 
Route of 
administration 
Intravenous infusion (pembrolizumab), oral (olaparib)  
Trial Blinding 
N/A 
Treatment Groups  
Advanced breast cancer with BRCA germline or somatic 
mutation or HDR-defect 
Number of trial 
subjects 
20 (pilot study) 
Estimated Enrollment 
Period 
36 months 
Estimated duration of 
trial 
42 months 
Duration of 
Participation 
2-24 months 
Main Eligibility 
Criterion  
Female and Male patients with advanced BRCA-mutated or 
HDR-defect breast cancer progressing on or after prior 
therapy for metastatic disease or locally advanced disease; 
Prior therapy is defined as follows: for triple negative breast 
cancer – progressing after at least 1 line of any prior 
chemotherapy; for HER2 positive disease must have 
progressed after at least two HER2 directed therapies in the 
metastatic setting including ado-trastuzumab emtansine (T-
DM1); for hormone receptor positive disease (ER, PR, or 
both) must have progressed after a CDK4/CDK6 inhibitor 
plus hormonal therapy. Patients with progression within 12 
months from previous neoadjuvant or adjuvant treatment 
could be enrolled in the study as 1st line therapy in 
metastatic setting. 
 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Breast cancer due to germline BRCA 1 or BRCA2 mutation represents approximately 5-10% of 
the breast cancer population. BRCA 1 and 2 germline mutations are readily determined through 
commercially available testing of blood and buccal cell DNA. While all breast cancer molecular 
subtypes may occur in BRCA mutation carriers, it is recognized that approximately 70% of breast 
cancers developing in BRCA 1 carriers are likely to be triple negative, while over 50% of breast 
cancer developing in BRCA 2 carriers are estrogen receptor positive. HER2 positive breast 
cancers may also occur with either BRCA 1 or BRCA2 mutations at a frequency of 10-13% [1]. 
Historically, breast cancer in BRCA mutation carriers has not been treated differently than breast 
cancer occurring “sporadically”, according to standard of care guidelines [2, 3]. An inhibitor of the 
poly (ADP) ribose polymerase (PARP) 1 enzyme, olaparib[4], has been FDA-approved for use in 
BRCA-mutated ovarian cancer, and clinical trials were recently conducted with these compounds 
in breast cancer [5]. In 2018, the FDA approved olaparib for germline BRCA-mutated metastatic 
breast cancer [21]. Response rates with PARP inhibitors in BRCA-mutated breast cancer have 
ranged from 0 to 41%, with a median progression free survival of 6 months [6, 7]. There remains 
a significant unmet need for therapy with specific benefit in BRCA-mutated breast cancer. 
Immunotherapy may offer a targeted therapy with less toxicity than chemotherapy, and potentially 
greater efficacy for this population with an unmet need for targeted therapy approaches. Positive 
results in this cohort would be of major clinical research interest and benefit to this population. 
 
The histopathology of BRCA-associated breast cancer suggests a role for the immune system in 
BRCA biology, based on several observations. Lymphocytic infiltrates are pathognomonic of 
medullary carcinoma of the breast, a subtype highly associated with BRCA 1 mutation, and 
lymphocytic infiltrates are commonly noted in BRCA-mutated cancers [8]. More recently the role 
of the immune system, tumor infiltrating lymphocytes (TILs), and the PD-1/PDL-1 pathway has 
been studied in breast cancer in general [9]. Of 116 breast cancers, 45% expressed PDL-1, with 
variation by molecular profile: 59% of triple negative, 33% of estrogen positive and 20% of HER2 
positive breast cancers expressed PDL-1. TILs expressing PD-1 were also observed, with the 
highest proportion having concurrent expression of PD-1 TILs and PDL-1 tumor cells (45%) seen 
in triple negative breast cancer (TNBC). The only reported analysis of PDL-1 expression in BRCA 
mutated breast cancer to date indicated in a small subset of triple negative breast cancers, a 
significant correlation of PD-L1 and BRCA germline mutation, with 7 of 7 BRCA1 mutated breast 
cancers overexpressing PD-L1[10].  
 
Additional data regarding the expression of PDL-1 in BRCA-mutated cancers have been obtained 
through a study in collaboration with Merck and Cedars-Sinai Medical Center, for which Dr. 
Audeh was the PI [11]. A cohort of 30 primary breast cancer tumor samples obtained prior to 
treatment from germline BRCA mutation carriers (identified previously by genetic testing) were 
identified within the Cedars-Sinai Pathology Department and were analyzed for relevant immune 
biomarkers through collaboration with Merck. The laboratory project, funded by Merck, assessed 
the expression of immune biomarkers PDL-1 and PD-1 using Merck-developed antibodies.  
 
The results of the study were as follows:  Twenty (20) tumors were from BRCA 1 mutations 
carriers, and 10 were BRCA2. Sixteen (16) were basal type breast cancer (13 BRCA1, 3 
BRCA2), 14 were estrogen receptor positive(ER+)(7 BRCA1, 7BRCA2), with 7 Luminal A and 7 
Luminal B. There were no HER2 amplified tumors in the cohort. PD1 expression was observed in 
11/30 (37%) of the cohort, and PDL1 expression was detected in 21/30 (70%) of the cohort.  
PDL1 expression was seen in 15/20 (75%) of tumors from BRCA1 mutation carriers, and 6/10 
(60%) of tumors from BRCA2 carriers. PDL1 expression was present in 13/16 (81%) basal 
tumors and 8/14 (57%) ER+ tumors. Within the cohort of PDL1 expressing cancers, 7/21 (33%) 
were scored as “high” or “very high”, 5 basal breast cancers and 2 ER+ cancers. The study 
therefore  identified a high rate of PDL1 expression in untreated primary breast cancers with 
germline BRCA1 and BRCA2 mutations, regardless of intrinsic subtype. PDL-1 expression, in 
association with other relevant biomarkers, in BRCA-mutated cancers may predict a dependence 

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on immune suppression for tumor survival, and may predict responsiveness to immune 
checkpoint inhibition with pembrolizumab. 
 
Evaluation of targeted therapy specific to the biology of BRCA-mutated cancers has been limited 
to the use of PARP inhibition, which acts through the mechanism of “synthetic lethality”, inducing 
additional DNA damage and cytotoxicity in cells with homologous repair defects (HRD), and 
which produces a variety of dose-limiting toxicities, primarily hematologic. 
 
Immunotherapy may offer a targeted therapy with less toxicity, and potentially greater efficacy for 
this population with an unmet need for targeted therapy approaches. Positive results in this cohort 
would be of major clinical research interest and benefit to this population. 
 
Combining PARP inhibitors and immunotherapy is a current treatment tested in several studies 
and tumor types. Rationale derives from the observation that PARP inhibitors enhanced cancer’s 
ability to produce PD-L1 which enhances the efficacy of immunotherapy (Pd-1 and PDL1 
inhibitors). In clinical studies tolerability of the combination is very good with no overlapping 
toxicities [25-28]. Due to evidence of combinatorial efficacy with the combination, patients 
previously exposed to PARP inhibitors will remain eligible as the patients PARP inhibitors naïve.  
 
Patients with ER+ disease benefit from continuous hormonal inhibition. Studies show that 
combination therapy with PARP inhibition and anti-estrogens is safe and there are no interactions 
[29-30]. Therefore, this study will allow continuation of anti-estrogen therapy for patients with ER+ 
disease. While there is pre-clinical data on the combination of PARP inhibition and trastuzumab 
antitumor activity in HER2+ disease [31], due to a lack of safety data, subjects with HER2+ 
disease will be required to discontinue trastuzumab therapy. 
1.2 
Study Agent(s) Background and Associated Known Toxicities 
1.2.1 
Pembrolizumab 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [32].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / 
FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term survival in 
many solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating lymphocytes can be 
expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such as 
melanoma [33-34]. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD L2) [35-36].   
 
The structure of murine PD-1 has been resolved [37].  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for 
ligand binding and a cytoplasmic tail which is responsible for the binding of signaling molecules.  
The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  
Following T-cell stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the 
ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such 
as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade [36; 38-40].  
The mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct from 
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consequence, the PD 1/PD-L1 pathway is an attractive target for therapeutic intervention in 
breast cancer.  
 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD 1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications because of its mechanism of action to bind the PD-1 receptor on the T cell.  For more 
details on specific indications refer to the Investigator brochure. 
 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
1.2.2 
Olaparib 
Investigators should be familiar with the current olaparib package insert. 
 
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly (ADP 
ribose)] polymerisation (PARP) inhibitor (PARP-1, -2 and -3) that is being developed as an oral 
therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy 
and other anti-cancer agents. 
 
PARP inhibition is a novel approach to targeting tumours with deficiencies in DNA repair 
mechanisms.  PARP enzymes are essential for repairing DNA single strand breaks (SSBs).  
Inhibiting PARPs leads to the persistence of SSBs, which are then converted to the more serious 
DNA double strand breaks (DSBs) during the process of DNA replication.  During the process of 
cell division, DSBs can be efficiently repaired in normal cells by homologous recombination repair 
(HR).  Tumours with HR deficiencies (HRD), such as ovarian cancers in patients with BRCA1/2 
mutations, cannot accurately repair the DNA damage, which may become lethal to cells as it 
accumulates.  In such tumour types, olaparib may offer a potentially efficacious and less toxic 
cancer treatment compared with currently available chemotherapy regimens.  
 
BRCA1 and BRCA2 defective tumours are intrinsically sensitive to PARP inhibitors, both in 
tumour models in vivo [43-44] and in the clinic [45]. The mechanism of action for olaparib results 
from the trapping of inactive PARP onto the single-strand breaks preventing their repair [46-47].  
Persistence of SSBs during DNA replication results in their conversion into the more serious DNA 
DSBs that would normally be repaired by HR repair.  Olaparib has been shown to inhibit selected 
tumour cell lines in vitro and in xenograft and primary explant models as well as in genetic BRCA 
knock-out models, either as a stand-alone treatment or in combination with established 
chemotherapies. 
 
Tumors with HDR-defect (homology-related repair) have the same propensity to be sensitive to 
PARP inhibitors as the BRCA mutated tumors. This has been demonstrated in several studies 
and mechanistically explained [22-24]. Two clinical studies, reported recently have confirmed 
antitumor activity with PARP inhibitors in tumors with HRD defect (but not necessary BRCA 
mutated). First study (TBCRC 048) published in JCO 2020  by N Tung presented responses to 
different somatic and germline mutations with PARP inhibitors treatment. Similar responses were 
seen in the somatic vs germline cohort in BRCA and other HRD defects tumors. A second study 
SWOG 1416 presented at ASCO 2020 revealed that addition of a PARP inhibitor, in this case 
Veliparib to chemotherapy in BRCA like triple negative metastatic breast cancer patients has 
similar efficacy compared to BRCA population. 
 

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1.3 
Tempus HRD 
The Tempus HRD detection approach is a model used in conjunction with data from the 
Tempus|xT Solid Tumor + Normal test, a 648- gene NGS panel spanning 3.6 Mb of DNA. 
Therefore, if a physician orders xT to identify actionable mutations in their patient’s tumor, no 
additional tissue is required to process an HRD status. The laboratory developed test is 
performed using Tempus DNA sequencing data to determine deleterious BRCA1/2 mutations, 
BRCA1/2-specific LOH, and somatic GW LOH, culminating in an HRD score that indicates each 
patient’s likelihood for PARPi response. Additionally, the Tempus HRD report includes results 
from a variant assessment of 16 other HR-related genes (18 total) conducted as part of the xT 
testing. 
 
1.4 
Rationale 
 
The proposed trial will evaluate the use of immunotherapy in a population with incurable 
advanced breast cancer associated with a germline or somatic BRCA mutation or HDR-defect, in 
combination with targeted therapy with olaparib. The genomic instability of BRCA-mutated breast 
cancer suggests probable increased neoantigen production and antigenicity, and predicts a 
dependence on immune suppression for carcinogenesis and tumor growth.  
 
Blockade of the inhibitory immune checkpoint controlled by programmed cell death protein 1 (PD-
1) and its ligand (PDL-1) has produced clinical responses in a number of malignancies, most 
significantly  melanoma, non-small cell carcinoma, renal cell carcinoma[12] [13]and ovarian 
cancer [14]. In breast cancer, preliminary data from a phase Ib trial of 32 women with TNBC 
treated with pembrolizumab at 10mg/kg every 2 weeks yielded a response rate of 18.5%[15]. 
Biomarkers for response to PD-1 directed therapy may be PDL-1 overexpression[16] [17],as well 
as possibly other histologic and genomic features. Genomically, the tumors in which responses 
were seen (melanoma, NSCLC, RCC and TNBC) are also known to have a high degree of 
genomic instability and mutational load relative to other malignancies [18]. A high mutation rate is 
likely to produce neoantigens, to which an immune response would be generated, and would be 
expected to produce evolutionary selection pressure favoring tumors which are able to block the 
resulting immune response. Therefore, it is hypothesized that genomically unstable tumors may 
be more likely to utilize inhibition of the immune response through upregulation of PDL-1. 
 
Tumors characterized by intrinsic genomic instability and high mutational load include those with 
mismatch repair (MMR) defects and those with homologous recombination defects due to BRCA 
1 or 2 gene germline mutations. The present study proposes a proof of concept trial in BRCA-
mutated breast cancers. 
 
Similar to the previously observed pembrolizumab-responsive tumors, BRCA-mutated cancers 
are known to be highly genomically unstable[19] [20] and are also characterized histologically by 
robust lymphocytic infiltrates. It is hypothesized that the genomic instability and high mutation rate 
in BRCA-mutated cancers results in neoantigens, eliciting a host immune response and selecting 
for mechanisms for immune escape, such as PDL-1 overexpression. 
 
Little is known regarding the role of the immune system checkpoints in BRCA-mutated cancers, 
however, data presented at ASCO 2014 by Pockaj et al [10]suggested a high degree of 
correlation of PD-L1 with lack of BRCA expression, with 7 of 7 BRCA 1 mutated breast cancers 
overexpressing PD-L1. Data from the Merck/Cedars-Sinai BRCA collaboration in which 30 
BRCA-mutated cancers were analyzed indicated a high frequency of PDL-1 expression in BRCA 
mutated breast cancer. 
 
Based on the observation that genomically unstable malignancies have shown responses to 
pembrolizumab, the association of PDL-1 expression with likelihood of response, and the 
preliminary data suggesting a high rate of PDL-1 expression in BRCA-mutated breast cancer, the 

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trial will evaluate the use of pembrolizumab in addition to olaparib in a population with incurable, 
advanced breast cancer associated with a germline or somatic BRCA mutation. The genomic 
instability of BRCA-mutated breast cancer suggests probable increased neoantigen production 
and antigenicity, and predicts a dependence on immune suppression for carcinogenesis and 
tumor growth. 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
 
Overall Response Rate (ORR) of pembrolizumab therapy in addition to olaparib therapy in 
advanced BRCA-mutated or HDR-defect breast cancer, as measured by RECIST 1.1, in patients 
progressing after prior therapy. 
2.2 
Secondary Objectives  
 
2.2.1 
Progression Free Survival (PFS), as measured by RECIST 1.1, in patients 
progressing after prior therapy from baseline to the date of the first evidence of 
progression for up to two years. 
2.2.2 
Overall survival (OS), from baseline until death for up to two years. 
2.2.3 
Clinical Benefit Rate (CR+PR+SD), as measured by RECIST 1.1, in patients 
progressing after prior therapy from baseline for up to two years. 
2.2.4 
Duration of Response (DOR) for CR and PR, as measured by RECIST 1.1, in 
patients progressing after prior therapy from baseline for up to two years. 
 
2.3 
Exploratory and Correlative Objectives 
2.3.1 
Correlative Studies  
The main objective of the translational research component of the IIT is to obtain 
biomarker measurements of PD-1 and PD-L1 expressions. Archival tumor 
samples will be sent to Qualtek Molecular Laboratories for analysis. See Sample 
Handling Manual. 
2.4 
Endpoints 
 
Therapy administered until documented progression by RECIST 1.1 criteria or 
unacceptable toxicity. 
 
This trial is a pilot study to assess the objective response rate with immunotherapy. There 
are no preliminary statistical assumptions. Stopping rules described in Section 9. 
 
First response assessments at 9 weeks; time interval for trial assessment is typical for 
time interval for assessment of response to standard of care therapy. Investigational 
therapy will not preclude subsequent standard of care therapy or subsequent 
investigational therapy. 
 
 

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3.0 
PATIENT ELIGIBILITY  
3.1 
Inclusion Criteria  
3.1.1 
Be willing and able to provide written informed consent/assent for the trial 
3.1.2 
Be ≥18 years of age on day of signing informed consent 
3.1.3 
Advanced BRCA-mutated and/or HDR-defect breast cancer progressing on or after 
prior therapy for metastatic disease or locally advanced disease; Prior therapy is 
defined as follows: for triple negative breast cancer – progressing after at least 1 line 
of any prior chemotherapy; for HER2 positive disease must have progressed after at 
least two HER2 directed therapies in the metastatic setting including ado-trastuzumab 
emtansine (T-DM1); for hormone receptor positive disease (ER, PR, or both) must 
have progressed after a CDK4/CDK6 inhibitor plus hormonal therapy. Patients with 
progression within 12 months from previous neoadjuvant or adjuvant treatment could 
be enrolled in the study as 1st line therapy in metastatic setting. 
3.1.4 
Measurable disease by RECIST 1.1, with at least one lesion, not previously irradiated, 
that can be accurately measured at baseline as ≥ 10 mm in the longest diameter 
(except lymph nodes which must have short axis ≥ 15 mm) with computed 
tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for 
accurate repeated measurements. Patients with non-measurable bone metastases in 
addition to measurable disease are eligible; however patients with non-measurable 
bone disease as the only site(s) of disease are not eligible. 
3.1.5 
ECOG 0 or 1 
3.1.6 
Documented BRCA deleterious germline or somatic mutation AND/OR HDR-defect. 
3.1.7 
FFPE tumor tissue available for analysis 
3.1.8 
Adequate organ function as defined in Table 1 
 
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥10.0 g/dL or ≥5.6 mmol/La, with no blood 
transfusion in the past 28 days 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 × ULN OR 
≥51 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN 

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3.1.9 
Female subjects: Postmenopausal or evidence of non-childbearing status for women 
of childbearing potential: negative urine or serum pregnancy test within 28 days of 
study treatment and confirmed prior to treatment on day 1. 
Postmenopausal is defined as: 
- 
Amenorrheic for 1 year or more following cessation of exogenous hormonal 
treatments Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) 
levels in the post menopausal range for women under 50 
- 
radiation-induced oophorectomy with last menses >1 year ago 
- 
chemotherapy-induced menopause with >1 year interval since last menses 
- 
surgical sterilisation (bilateral oophorectomy or hysterectomy) 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases) 
Coagulation 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.  
b Creatinine clearance (CrCl) should be calculated using Cockcroft-Gault equation or based on 24-hour urine. 
Estimated creatinine clearance = 
(140-age [years]) x weight (kg)    (x F)a 
 
 
 
 
serum creatinine (mg/dL) x 72 
a where F=0.85 for females and F=1 for males. 
 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies. 

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3.1.10 Women of childbearing potential and their partners, who are sexually active, must 
agree to the use of TWO highly effective forms of contraception in combination (as 
described in Appendix).  This should be started from the signing of the informed 
consent and continue throughout the period of taking study treatment and for at least 1 
month after last dose of study drug(s), or they must totally/truly abstain from any form 
of sexual intercourse (as described in Appendix). 
3.1.11 Male patients must use a condom during treatment and for 3 months after the last 
dose of olaparib when having sexual intercourse with a pregnant woman or with a 
woman of childbearing potential.  Female partners of male patients should also use a 
highly effective form of contraception ([see appendix for acceptable methods]) if they 
are of childbearing potential. 
3.1.12 Patients must have a life expectancy ≥ 16 weeks 
3.2 
Exclusion Criteria 
3.2.1 
Is currently participating or has participated in a study of investigational agent or using 
an investigational device with 30 days of the first dose of pembrolizumab. 
3.2.2 
 a. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 3 weeks prior to study Day 1  
b. Subjects must have recovered (i.e., ≤ Grade 1 or at baseline) from any adverse 
events due to a previously administered agent. Subjects with ≤ Grade 2 neuropathy 
are an exception to this criterion and may qualify for the study. 
c. If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy. 
3.2.3 
Is receiving systemic steroid therapy within three days prior to the first dose of 
pembrolizumab or receiving any other form of immunosuppressive medication 
3.2.4 
Is expected to require any other form of systemic or localized antineoplastic therapy 
while on trial. 
o 
Subjects with ER+/PR+ disease may be given endocrine therapy.     
o 
Subjects with HER2+ disease will be required to discontinue trastuzumab 
(Herceptin). 
 
3.2.5 
Has participated in another MK03475 trial. 
3.2.5.1 Note: Patients with or without prior PARP-inhibitor exposure may be 
included. 
3.2.6 
Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, 
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. 
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout 
period prior to starting olaparib is 2 weeks. 
3.2.7 
Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or 
moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout 
period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 
weeks for other agents. 

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3.2.8 
Major surgery within 2 weeks of starting study treatment and patients must have 
recovered from any effects of any major surgery. 
3.2.9 
Has known hypersensitivity to pembrolizumab or any of its excipients 
3.2.10 Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy. 
3.2.11 Has known history of prior malignancy except if the patient has undergone potentially 
curative therapy with no evidence of that disease recurrence for 5 years since initiation 
of that therapy. 
3.2.12 Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by MRI for at least four weeks prior to 
the first dose of pembrolizumab and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are using no 
steroids for at least three days prior to study medication. 
3.2.13 Has evidence of interstitial lung disease or active, non-infectious pneumonitis 
3.2.14 Has active tuberculosis 
3.2.15 Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as 
judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic 
arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte 
disturbances, etc.), or patients with congenital long QT syndrome. 
3.2.16 Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) 
grade 2) caused by previous cancer therapy, excluding alopecia. 
3.2.17 Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features 
suggestive of MDS/AML. 
3.2.18 Patients unable to swallow orally administered medication and patients with 
gastrointestinal disorders likely to interfere with absorption of the study medication.  
3.2.19 Patients with a known hypersensitivity to olaparib or any of the excipients of the 
product. 
3.2.20 Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first 
dose of pembrolizumab. Administration of killed vaccines is allowed.  
3.2.21 Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
3.2.22 Has an active autoimmune disease that has required systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Subjects with vitiligo or resolved childhood asthma/atopy 
would be exception to this rule. Subjects that require inhaled steroid or local steroid 
injections will not be excluded from the study. Subjects with hypothyroidism not from 
autoimmune disease and stable on hormone replacement will not be excluded from 
the study. Note: Replacement therapy (eg., thyroxine, insulin, or physiologic 

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corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment. 
3.2.23 Has had an allogenic tissue / solid organ transplant. 
3.2.24 Previous allogenic bone marrow transplant or double umbilical cord blood 
transplantation (dUCBT). 
3.2.25 Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating Investigator. 
3.2.26 Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
3.2.27 Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit (Visit 1) through 120 
days after the last dose of study treatment. 
 
4.0 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
This is an open-label, single-arm pilot study in 20 subjects with advanced BRCA mutation or 
HDR-defect associated breast cancer having progressed through standard first line therapy.  
 
The study participation is up to 35 administrations of pembrolizumab (approximately two years). 
 
Pembrolizumab and olaparib will be supplied by Merck.  
 
Pembrolizumab will be administered at a dose of 200mg as a 30 minute IV infusion Q3W. Effort 
should be made to target infusion timing to be as close to 30 minutes as possible. However, given 
the variability of infusion pumps, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min). 
 
Olaparib 300mg will be self-administered orally twice daily. The dose of olaparib used in this 
study is 300 mg twice daily which is the currently approved dose. Subjects will complete a 
compliance diary throughout the study treatment period. Olaparib tablets should be taken at the 
same time each day, approximately 12 hours apart with one glass of water. The tablets should be 
swallowed whole and not chewed, crushed, dissolved or divided. Olaparib tablets can be taken 
with or without food. Each container will be labelled in accordance with Good Manufacturing 
Practice (GMP) Annex 13 and per country regulatory requirement. If vomiting occurs shortly after 
the olaparib tablets are swallowed, the dose should only be replaced if all of the intact tablets can 
be seen and counted. Should any patient enrolled on the study miss a scheduled dose for 
whatever reason (e.g., as a result of forgetting to take the tablets or vomiting), the patient will be 
allowed to take the scheduled dose up to a maximum of 2 hours after that scheduled dose time. If 
greater than 2 hours after the scheduled dose time, the missed dose is not to be taken and the 
patient should take their allotted dose at the next scheduled time. 
 
The Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration. 
 
Table 2. Trial Intervention 
Drug 
Dose/Potency 
Dose/ 
Route of 
Regimen/ Treatment 

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Frequency 
Administration 
Period 
Pembrolizumab 
200 mg 
Q3W 
IV  infusion 
Day 1 of each cycle 
Olaparib 
300mg 
BID 
PO 
Continuous; dispensed 
each cycle day 1 (each 
cycle=3 weeks) 
4.1.1 
Meals and dietary restrictions 
It is prohibited to consume grapefruit juice while on olaparib therapy. 
4.2 
Toxicities, Dosing Delays, and Dose Modifications 
4.2.1 
Pembrolizumab  
If a dose of pembrolizumab is withheld for toxicity, then subjects may resume dosing with 
pembrolizumab if that is appropriate at their next scheduled appointment or when toxicity 
has improved as described below. 
 
Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, 
nonhematological toxicity ≥ Grade 3 including laboratory abnormalities, and severe or 
life-threatening adverse events. 
 
AEs associated with pembrolizumab exposure, including coadministration with additional 
compounds, may represent an immunologic aetiology. These immune-related AEs 
(irAEs) may occur shortly after the first dose or several months after the last dose of 
pembrolizumab/combination treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical study data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab/combination treatment, 
administration of corticosteroids and/or other supportive care. For suspected irAEs, 
ensure adequate evaluation to confirm etiology or exclude other causes. Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as 
part of the evaluation. Dose modification and toxicity management guidelines for irAEs 
associated with pembrolizumab/combination treatment are provided in Table 3. 
 
Attribution of Toxicity: 
When study interventions are administered in combination, attribution of an adverse 
event to a single component is likely to be difficult.  Therefore, while the investigator may 
attribute a toxicity event to the combination, to olaparib alone, or to pembrolizumab alone, 
for adverse events listed in Table 3, both interventions must be held according to the 
criteria in Table 3 Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events Associated with Pembrolizumab. 
 
Holding Study Interventions: 
When study interventions are administered in combination, if the AE is considered 
immune-related, both interventions should be held according to recommended dose 
modifications. 
 
Restarting Study Interventions: 
Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 3. 
If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study interventions. 
If the toxicities do resolve and conditions are aligned with what is defined in Table 3, the 
combination of olaparib and pembrolizumab may be restarted at the discretion of the 
investigator. In these cases where the toxicity is attributed to the combination or to 

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olaparib alone, re-initiation of pembrolizumab as a monotherapy may be considered at 
the principal investigator’s discretion. 
 
Dosing Interruptions: 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, 
patient vacation, and/or holidays). Subjects should be placed back on study therapy 
within 3 weeks of the scheduled interruption, unless otherwise discussed with the 
Sponsor. The reason for interruption should be documented in the patient's study record. 

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Table 3: Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with 
Pembrolizumab monotherapy and IO combinations 
 
 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of 
the last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
 
irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Pneumonitis  
Grade 2 
Withhold  
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
•  Add prophylactic antibiotics for 
opportunistic infections 
•  Monitor participants for signs and symptoms of 
pneumonitis 
•  Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea/Colitis  
Grade 2 or 3 
Withhold 
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
•  Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Recurrent 
Grade 
3 
or 
Grade 4 
Permanently 
discontinue 
 
and ileus) 
•  Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis 
•  Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion 
AST or ALT 
Elevation 
or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
•  Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or equivalent) 
followed by taper 
•  Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
T1DM 
or 
Hyperglycemia 
New 
onset 
T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence 
of 
-cell failure 
Withhold d 
•  Initiate insulin replacement therapy for 
participants with T1DM 
•  Administer antihyperglycemic in 
participants with hyperglycemia 
 
•  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Hypophysitis 
Grade 2 
Withhold 
•  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated 
•  Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Continue 
•  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate 
•  Monitor for signs and symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
•  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care 
•  Monitor for signs and symptoms of thyroid 
disorders 
Nephritis: 
grading 
according 
to 
increased 
creatinine 
or 
acute 
kidney 
injury 
Grade 2 
Withhold 
•  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper 
•  Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
 
Grade 2, 3 or 4 
Permanently 
discontinue 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, 
or 
DRESS 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Confirmed SJS, 
TEN, 
or 
DRESS 
Permanently 
discontinue 
All Other irAEs 
Persistent Grade 2 Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Grade 3 
Withhold 
or 
discontinue based 
on the event e  
Recurrent 
Grade 3 
or 
Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
 
 
 
 

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Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated infusion reaction are provided in Table 4. 
 
 
Table 4  Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds promptly 
to symptomatic treatment (e.g., 
antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate (e.g. from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further study drug treatment 
Participant may be premedicated 1.5h (± 30 minutes) 
prior to infusion with: 
Diphenhydramine 50 mg po (or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg po (or equivalent dose 
of analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov 

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4.2.2 Olaparib Dose Reductions 
 In case a dose reduction is necessary, olaparib will be administered as follows:  
 
Table 5 
Dose reductions for study treatment to manage adverse events 
Initial Dose 
Following re-challenge post 
interruption: Dose reduction 1 
Dose reduction 2 
300 mg twice daily 
250 mg twice daily 
200 mg twice daily 
 
 
Table 6 
Dose reduction for olaparib if patient develops moderate renal impairment  
Initial Dose 
Moderate renal impairment (calculated creatinine clearance by 
Cockcroft -Gault equation or based on a 24 hour urine test 
between 31 and 50 ml/min): Dose reduction  
 
300 mg twice daily 
200 mg twice daily 
 
Table 7 
Dose reductions for study treatment if patient has to start taking a strong or 
moderate CYP3A inhibitor 
Initial Dose 
Strong CYP3A inhibitor 
Moderate CYP3A inhibitor 
300 mg twice daily 
100 mg twice daily 
150 mg twice daily 
 
Any toxicity observed during the course of the study could be managed by interruption of the 
dose of study treatment or dose reductions. Repeat dose interruptions are allowed as required, 
for a maximum of 4 weeks on each occasion. If the interruption is any longer, the study team 
must be informed. Olaparib can be dose reduced to 250 mg twice daily as a first step and to 200 
mg twice daily as a second step. If the reduced dose of 200 mg twice daily is not tolerable, no 
further dose reduction is allowed and Olaparib should be discontinued.  
Once Olaparib dose is reduced, escalation is not permitted (except following concomitant 
treatment with CYP3A4 inhibitors). 
 
When Olaparib dose reduction is necessary patients will take one 150 mg tablet and one 100 mg 
tablet twice daily or two x 100 mg tablet twice daily, or one 150 mg tablet twice daily or one 100 
mg tablet twice daily. 
 
4.2.3 Olaparib Management of Adverse Events 
4.2.3.1 
Management of haematological toxicity 
Management of anaemia 

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Table 8 
Management of anaemia 
Haemoglobin 
Action to be taken 
Hb < 10 but ≥ 8 g/dl 
(CTCAE Grade 2) 
First occurrence: 
Give appropriate supportive treatment and investigate causality.  
Investigator judgement to continue olaparib with supportive treatment (eg 
transfusion) or interrupt dose for a maximum of 4 weeks. Olaparib can be 
restarted if Hb has recovered to > 9g/dl. 
Subsequent occurrences: 
If  Hb< 10 but ≥ 9 g/dl investigator judgement to continue olaparib with 
supportive treatment (eg transfusion) or dose interrupt (for max of 4 
weeks) and upon recovery dose reduction may be considered (to 250 mg 
twice daily as a first step and to 200 mg twice daily as a second step). 
If  Hb< 9 but ≥ 8 g/dl, dose interrupt (for max of 4 weeks) until Hb ≥ 9 g/dl 
and upon recovery dose reduction may be considered (to 250 mg twice 
daily as a first step and to 200 mg twice daily as a second step).  
Hb < 8 g/dl 
(CTCAE Grade 3) 
Give appropriate supportive treatment (e.g. transfusion) and investigate 
causality.  
Interrupt Olaparib for a maximum of 4 weeks until improved to Hb ≥ 9 g/dl. 
Upon recovery dose reduce to 250 mg twice daily as a first step and to 
200 mg twice daily as a second step in the case of repeat Hb decrease. 
 
Common treatable causes of anaemia (e.g., iron, vitamin B12 or folate deficiencies and hypothyroidism) 
should be investigated and appropriately managed. In some cases management of anaemia may require 
blood transfusions. For cases where patients develop prolonged haematological toxicity (≥2 week 
interruption/delay in olaparib due to CTC grade 3 or worse anaemia and/or development of blood 
transfusion dependence), refer to guidance later in this section for the management of this.  
 
Management of neutropenia, leukopenia and thrombocytopenia 
Table 9 
Management of neutropenia, leukopenia and thrombocytopenia 
Toxicity 
Study treatment dose adjustment 
CTCAE Grade 1-2 
Investigator judgement to continue treatment or if dose interruption, this 
should be for a maximum of 4 weeks; appropriate supportive treatment 
and causality investigation 
CTCAE Grade 3-4 
Dose interruption until recovered to CTCAE gr 1 or better for a maximum 
of 4 weeks. If repeat CTCAE grade 3-4 occurrence, dose reduce olaparib 
to 250 mg twice daily as a first step and 200 mg twice daily as a second 
step 
Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by the 
investigator with close follow up and interruption of study drug if CTC grade 3 or worse 
neutropenia occurs. 
Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is not recommended, 
however, if a patient develops febrile neutropenia, olaparib should be stopped and appropriate 
management including G-CSF should be given according to local hospital guidelines. Please note 
that G-CSF should not be used within at least 24 h (7 days for pegylated G-CSF) of the last dose 
of study treatment unless absolutely necessary. 
Platelet transfusions, if indicated, should be done according to local hospital guidelines. 

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For cases where patients develop prolonged haematological toxicity (≥2 week interruption/delay 
in olaparib due to CTC grade 3 or worse), refer to guidance later in this section for the 
management of this.  
 
Management of prolonged haematological toxicities while on study treatment 
If a patient develops prolonged haematological toxicity such as: 
 
≥2 week interruption/delay in olaparib due to CTC grade 3 or worse anaemia and/or development 
of blood transfusion dependence 
 
≥2 week interruption/delay in olaparib due to CTC grade 3 or worse neutropenia (ANC < 1 x 
109/L) 
 
≥2 week interruption/delay in olaparib due to CTC grade 3 or worse thrombocytopenia and/or 
development of platelet transfusion dependence (Platelets < 50 x 109/L) 
Check weekly differential blood counts including reticulocytes and peripheral blood smear. If any 
blood parameters remain clinically abnormal after 4 weeks of dose interruption, the patient should 
be referred to haematologist for further investigations. Bone marrow analysis and/or blood 
cytogenetic analysis should be considered at this stage according to standard haematological 
practice. Olaparib should be discontinued if blood counts do not recover to CTC gr 1 or better 
within 4 weeks of dose interruption. 
Development of a confirmed myelodysplastic syndrome or other clonal blood disorder should be 
reported as an SAE and full reports must be provided by the investigator to Merck.  Olaparib 
treatment should be discontinued if patient’s diagnosis of MDS and/or AML is confirmed. 
 
4.2.3.2 
Management of non-haematological toxicity 
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion. 
If the interruption is any longer than this the study monitor must be informed.  Where toxicity 
reoccurs following re-challenge with olaparib, and where further dose interruptions are considered 
inadequate for management of toxicity, then the patient should be considered for dose reduction 
or must permanently discontinue olaparib. 
Olaparib can be dose reduced to 250 mg twice daily as a first step and to 200 mg twice daily as a 
second step. Treatment must be interrupted if any NCI-CTCAE grade 3 or 4 adverse event 
occurs which the investigator considers to be related to administration of study treatment. 
 
Management of new or worsening pulmonary symptom 
If new or worsening pulmonary symptoms (e.g., dyspnoea) or radiological abnormalities occur in 
the absence of a clear diagnosis, an interruption in study treatment dosing is recommended and 
further diagnostic workup (including a high resolution CT scan) should be performed to exclude 
pneumonitis. 
Following investigation, if no evidence of abnormality is observed on CT imaging and symptoms 
resolve, then study treatment can be restarted, if deemed appropriate by the investigator. If 
significant pulmonary abnormalities are identified, these need to be discussed with the Study 
Physician. 
 
Management of nausea and vomiting 
Events of nausea and vomiting are known to be associated with olaparib treatment. These events 
are generally mild to moderate (CTCAE grade 1 or 2) severity, intermittent and manageable on 
continued treatment. The first onset generally occurs in the first month of treatment for nausea 
and within the first 6 months of treatment for vomiting. For nausea, the incidence generally 
plateaus at around 9 months, and for vomiting at around 6 to 7 months. 

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No routine prophylactic anti-emetic treatment is required at the start of study treatment, however, 
patients should receive appropriate anti-emetic treatment at the first onset of nausea or vomiting 
and as required thereafter, in accordance with local treatment practice guidelines.  Alternatively, 
olaparib tablets can be taken with a light meal/snack (ie 2 pieces of toast or a couple of biscuits). 
As per international guidance on anti-emetic use in cancer patients (ESMO, NCCN), generally a 
single agent antiemetic should be considered eg dopamine receptor antagonist, antihistamines or 
dexamethasone. 
 
Interruptions for intercurrent non-toxicity related events 
Olaparib dose interruption for conditions other than toxicity resolution should be kept as short as 
possible.  
 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF.  
 
Olaparib should be stopped at least 3 days prior to planned surgery. After surgery study 
treatment can be restarted when the wound has healed. No stoppage of study treatment is 
required for any needle biopsy procedure. 
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes 
radiation treatment. Study treatment should be restarted within 4 weeks as long as any bone 
marrow toxicity has recovered. 
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, patients should 
be advised to use caution while driving or using machinery if these symptoms occur.  
 
Table 10 
Dose reductions for study treatment 
Initial Dose 
Following re-challenge post 
interruption: Dose reduction 1 
Dose reduction 2 
300 mg twice daily 
250 mg twice daily 
200 mg twice daily 
 
4.2.3.3 
Renal impairment 
If subsequent to study entry and while still on study therapy, a patient’s estimated CrCl falls below 
the threshold for study inclusion (≥51 ml/min), retesting should be performed promptly.  
A dose reduction is recommended for patients who develop moderate renal impairment 
(calculated creatinine clearance by Cockcroft-Gault equation or based on a 24 hour urine test of 
between 31 and 50 ml/min) for any reason during the course of the study: the dose of olaparib 
should be reduced to 200 mg twice daily. 
 
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 Olaparib therapy is warranted. 
 
Olaparib has not been studied in patients with severe renal impairment (creatinine clearance 
≤ 30 ml/min) or end-stage renal disease; if patients develop severe impairment or end stage 
disease is it recommended that olaparib be discontinued. 
4.3 
Concomitant Medications/Treatments 
4.3.1 
Acceptable Concomitant Medications 
 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. The use of any natural/herbal products or other traditional remedies should be 
discouraged, but use of these products, as well as any medication or vaccine including over-the-

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counter or prescription medicines, vitamins, and/or herbal supplements that the patient is 
receiving at the time of enrolment or receives during the study must be recorded along with 
reason for use, dates of administration including start and end dates, dosage information 
including dose and frequency. If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date will also be included on the CRF. 
 
Anti-emetics/Anti-diarrhoeals 
Should a patient develop nausea, vomiting and / or diarrhoea, then these symptoms should be 
reported as AEs (see section 8.3) and appropriate treatment of the event given. 
 
Subjects with ER+/PR+ disease may be given endocrine therapy. 
 
Specifically, subjects using bisphosphonates or anti-RANKL mAb who were receiving this 
medication prior to study start, may continue receiving the medication during the study. However, 
a need to initiate this therapy during the conduct of this trial will be the equivalent of clinical 
disease progression and the subject must discontinue study treatment. 
 
All concomitant medications received within 30 days before the first dose of pembrolizumab 
through the Safety Follow-up Visit should be recorded. After the Safety Follow-up Visit record all 
medications taken for SAEs and ECIs as defined in Section 6.3.2. 
 
4.3.2 
Prohibited Concomitant Medications 
 
Subjects are prohibited from receiving the following therapies during the Screening, 
Treatment and Second Course Phases of this trial (unless otherwise noted below): 
 
• 
Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol. 
• 
Immunotherapy not specified in this protocol 
o 
Subjects with HER2+ disease will be required to discontinue trastuzumab 
(Herceptin). 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than pembrolizumab 
• 
Non-palliative radiation therapy (radiation that’s considered palliative in nature as determined 
by treating investigator is allowed).   
• 
Live vaccines or live-attenuated vaccines within 30 days prior to the first dose of 
pembrolizumab and while participating in the trial. Administration of killed vaccines is allowed. 
• 
Initiation of bisphosphonate or anti-RANKL mAb (Treatment and Second Course Phases). 
 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial. Subjects may receive other 
medications that the investigator deems to be medically necessary. 
 
 
Restricted concomitant medications 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed ): 
 
 

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Restricted concomitant medications 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed ): 
Strong CYP3A inhibitors: 
itraconazole, telithromycin, 
clarithromycin, boosted protease 
inhibitors, indinavir, saquinavir, 
nelfinavir, boceprevir, telaprevir 
 
Moderate CYP3A inhibitors: 
ciprofloxacin, erythromycin, diltiazem, 
fluconazole, verapamil  
 
Strong or moderate CYP3A inhibitors should 
not be taken with olaparib.  If there is no 
suitable alternative concomitant medication 
then the dose of olaparib should be reduced 
for the period of concomitant administration. 
The dose reduction of olaparib should be 
recorded in the CRF with the reason 
documented as concomitant CYP3A inhibitor 
use.  
• 
Strong CYP3A inhibitors – reduce the dose of 
olaparib to 100 mg twice daily for the duration 
of concomitant therapy with the strong 
inhibitor and for 5 half lives afterwards. 
• 
Moderate CYP3A inhibitors - reduce the dose 
of olaparib to 150 mg twice daily 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 inducers: 
phenobarbital, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, 
nevirapine, enzalutamide and St 
John’s Wort 
 
Moderate CYP3A inducers: 
 bosentan, efavirenz and modafinil 
Strong or moderate CYP3A inducers should 
not be taken with olaparib. 
If the use of any strong or moderate CYP3A 
inducers are considered necessary for the 
patient’s safety and welfare this could 
diminish the clinical efficacy of olaparib. 
If a patient requires use of a strong or 
moderate CYP3A inducer then they must be 
monitored carefully for any change in efficacy 
of olaparib. 

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Restricted concomitant medications 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed ): 
 
CYP3A4 substrates: hormonal 
contraceptive, simvastatin, cisapride, 
cyclosporine, ergot alkaloids, fentanyl, 
pimozide, sirolimus, tacrolimus and 
quetiapine 
 
CYP2B6 substrates: 
bupropion, efavirenz 
 
OATP1B1substrates: 
bosentan, glibenclamide, repaglinide, 
statins and valsartan 
 
OCT1, MATE1 and MATE2K 
substrates:  metformin 
 
OCT2 substrates: serum 
creatinine 
 
OAT3 substrates: furosemide, 
methotrexate 
Effect of olaparib on other drugs 
Based on limited in vitro data, olaparib may 
increase the exposure to substrates of 
CYP3A4, OATP1B1, OCT1, OCT2, OAT3, 
MATE1 and MATE2K. 
 Based on limited in vitro data, olaparib may 
reduce the exposure to substrates of 2B6. 
Caution should be observed if substrates of 
these isoenzymes or transporter proteins are 
co-administered. 
 
Anticoagulant therapy 
Patients who are taking warfarin may 
participate in this trial; however, it is 
recommended that international normalised 
ratio (INR) be monitored carefully at least 
once per week for the first month, then 
monthly if the INR is stable. Subcutaneous 
heparin and low molecular weight heparin are 
permitted. 
Palliative radiotherapy 
Palliative radiotherapy may be used for the 
treatment of pain at the site of bony 
metastases that were present at baseline, 
provided the investigator does not feel that 
these are indicative of clinical disease 
progression during the study period.  Study 
treatment should be discontinued for a 
minimum of 3 days before a patient 
undergoes therapeutic palliative radiation 
treatment.  Study treatment should be 
restarted within 4 weeks as long as any bone 
marrow toxicity has recovered.   
Administration of other anti-cancer agents 
 
Patients must not receive any other 
concurrent anti-cancer therapy, including 
investigational agents, while on study 
treatment. Patients may continue the use of 
bisphosphonates or denosumab for bone 
disease and corticosteroids for the 
symptomatic control of brain metastases 
provided the dose is stable before and during 
the study and they were started at least 4 
weeks prior to beginning study treatment.  
 
 

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4.4 
Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the ECI 
guidance document. Where appropriate, these guidelines include the use of oral or intravenous 
treatment with corticosteroids as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids. Note that several courses of steroid tapering may 
be necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are intended to 
be applied when the investigator determines the events to be related to Pembrolizumab.  
 
Note: if after the evaluation the event is determined not to be related, the investigator is instructed 
to follow the ECI reporting guidance but does not need to follow the treatment guidance (as 
outlined in the ECI guidance document). Refer to Section 4.2.1 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
4.5 
Duration of Therapy 
Patients will continue with pembrolizumab until disease progression or unacceptable 
toxicity, or until completion of 35 treatments of pembrolizumab (approximately 2 years), as 
long as in the Investigator’s opinion they are benefiting from treatment and they do not 
meet any other discontinuation criteria. Once patients have been discontinued from study 
treatment, other treatment options (including compassionate use) will be at the discretion 
of the investigator. Subjects will receive olaparib according to the FDA approved package 
insert until disease progression or unacceptable toxicity.  
 
In patients with initial disease progression substantiated by radiographic imaging per 
RECIST 1.1, study treatment may continue until repeat imaging is conducted, at least 4 
weeks and no later than 8 weeks later, under the following conditions: 
- 
No worsening of ECOG Performance Status 
- 
No clinically relevant increases in disease-related symptoms thought to be 
associated with disease progression 
- 
No requirement for intensified management of disease-related symptoms exists, 
including increased analgesia, radiotherapy, or other palliative care. 
 
Disease progression can also be confirmed histologically, cytologically, or surgically, or by 
physical examination or other clinical signs, per PI discretion. 
 
4.6  
Duration of Follow Up 
Primary and secondary response objectives will be met with approximately 1 month end of 
study follow-up for subjects discontinuing therapy due to progression. Subjects who 
discontinue trial treatment for a reason other than disease progression will move into the 
Follow-Up Phase and should be assessed every 12 weeks (56 ± 7 days) by radiologic 
imaging to monitor disease status, per standard of care for up to two years of total study 
participation. Every effort should be made to collect information regarding disease status 
until the start of new anti-neoplastic therapy, disease progression, death, or at end of the 
study.  

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4.7 
Removal of Patients from Protocol  
Patients will be removed from the study when any of the criteria listed in Section 5.15 
apply. Notify the Principal Investigator, and document the reason for study removal and 
the date the patient was removed in the Case Report Form. The patient should be 
followed-up per protocol.  
4.8 
Subject Evaluability and Replacement Guidelines 
• 
Subjects who withdraw from the study treatment prior to starting study intervention 
will be replaced.  
• 
Subjects who receive at least one dose of study treatment (pembrolizumab and 
olaparib) will be included in the safety analysis.  
• 
Subjects who do not complete at least 6 weeks (2 cycles) of study treatment 
(pembrolizumab and olaparib) will not be evaluable for efficacy and will be 
replaced.   
 
 
5.0 
STUDY PROCEDURES 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. 
 
All screening procedures must be performed within six weeks prior to C1D1 unless otherwise 
stated.  
Note: It is estimated that up to 100-200 patients may be screened on this protocol to determine 
eligibility based on HDR status.  
5.1 
Informed Consent 
 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion. 
 
A copy of the signed and dated consent form should be given to the subject before participation in 
the trial.  
 
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the subject must receive the IRB/ERC’s approval/favorable opinion 
in advance of use. The subject or his/her legally acceptable representative should be informed in 
a timely manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial. The communication of this information will be 
provided and documented via a revised consent form or addendum to the original consent form 
that captures the subject’s dated signature or by the subject’s legally acceptable representative’s 
dated signature. 
5.2 
Tempus HRD 
Tempus HRD will be used to determine HDR status, for patients who do not otherwise qualify for 
the study based on BRCA status; Tempus HRD testing will not be performed on patients who 
qualify for the study based on BRCA status. 
 
Archival tumor tissue samples (FFPE blocks or slides), as well as a normal sample type [blood 
(preferred), FFPE adjacent normal tissue, or saliva] will be sent to Tempus for testing. Refer to 
the Lab Manual and Tempus Specimen Guidelines. 

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In addition, de-identified clinical data elements will be shared with Tempus, as specified in the 
master agreement.  
5.3 
Pregnancy Test 
 
Female subjects of childbearing potential should have a negative urine or serum pregnancy prior 
to study registration and re-tested within 72 hours prior to receiving the first dose of 
pembrolizumab. If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. 
5.4 
Medical History 
 
A medical history will be obtained by the investigator or qualified designee. Medical history will 
include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator. Demographic information will be 
collected at screening and will include ethnicity, age, and gender. 
5.5 
Physical Exam  
 
The investigator or qualified designee will perform a full or directed physical exam as clinically 
indicated. Clinically significant abnormal findings should be recorded as medical history.  The 
time points for physical exam are outlined in Section 5.14. After the first dose of pembrolizumab, 
new clinically significant abnormal findings should be recorded as AEs.  
5.6 
Vital signs 
 
The investigator or qualified designee will take vital signs at screening, prior to the administration 
of each dose of trial treatment and as specified in the Trial Flow Chart. Vital signs include 
temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at 
screening only. 
5.7 
ECOG Performance Status 
 
The investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of trial treatment and during the Follow-up as specified in the Trial 
Flow Chart. 
5.8 
Laboratory Safety Evaluations 
 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided in the table below. 
 
Laboratory tests for screening should be performed within 10 days prior to the first dose of 
pembrolizumab. After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours 
prior to dosing. Results must be reviewed by the investigator or qualified designee and found to 
be acceptable prior to each dose of trial treatment. 
 
Hematology 
Chemistry 
Other 
Hemoglobin 
Albumin 
Triiodothyronine 
(T3) 
Platelets 
Alkaline phosphatase 
Free thyroxine (FT4) 
WBC (total and differential) 
Alanine aminotransferase 
Thyroid stimulating hormone 

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(ALT) 
(TSH) 
Absolute Neutrophil Count 
Aspartate aminotransferase 
(AST) 
Coagulation: PT, INR, aPTT 
Absolute Lymphocyte Count 
Creatinine or calculated 
creatinine clearance (CrCl) 
 
 
Calcium 
 
 
Glucose 
 
 
Potassium 
 
 
Sodium 
 
 
Total Bilirubin 
 
 
Blood Urea Nitrogen                     
5.9 
EKG 
5.10 
Blood Tumor Markers 
Serum tumor markers such as CA 27-29, CEA and CA-125 may be measured at the discretion of 
the investigator as a supplement to clinical parameters for monitoring of response. 
 
5.11 
Archival Tumor Tissue Collection 
Archival tumor tissue will be collected for Exploratory Studies (see Section 8). This tissue from a 
prior biopsy or surgery will also be collected for routine analysis if confirmation of diagnosis or 
histologic subtype is uncertain from available data. 
 
5.12 
Tumor Assessments  
Tumor assessments will be conducted according to protocol timeline at 9 week intervals, with 
CT, MRI or other appropriate imaging, as well as physical exam and clinical measurements as 
appropriate while on study drug during Year 1. Tumor imaging will be obtained every 12 
weeks after drug discontinuation, per standard of care, or during Year 2 of study treatment. 
RECIST version 1.1 will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
 
Bone  scans  will  be  performed  at  screening  for  any subject  with  known  bone  
metastases and/or new bone pain and musculoskeletal complaints. During the study, bone 
scans will be performed as needed for evaluation of worsening and/or new bone pain and 
musculoskeletal complaints or if the site believes they have attained a Complete Response. If 
a subject has no known metastatic disease in the bone or active symptoms, a bone scan at 
baseline is not needed. A bone scan can be obtained at follow up if there are new symptoms 
of bone pain. 
5.13 
Adverse Event Assessment 
Adverse event assessment will be undertaken at every clinical visit. See 5.14. 
 
An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 

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5.14 
Concomitant Medications 
Concomitant Medications will be assessed at every clinical visit. See 5.14. 
 
5.15 Time and Events Table 
 
Procedure 
Screening 
(Within 6 
weeks of 
Day 1) 
Treatment Phase (+/- 3 days)3 
End of 
Treatment4 
SOC 
Follow-
up5 
C1 
D1 
C1 
D8 
C1 
D15 
C2 
D1 
 
C2 
D8 
C3 
D1 
C4 
D1 
 
C5 
D1 
 
C6 
D1 
Even 
Cycles 
Odd 
Cycles 
30-days after 
drug 
discontinuation, 
+/- 7 days 
Every 
12 
Weeks 
Informed 
Consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tempus 
HRD11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Exam 
(includes 
Medical 
history) 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vitals2 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
Performance 
Status 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor 
markers 
(CA2729, 
CEA, CA-
125) 
as per standard of care, at the investigator’s discretion 
T3 Free, T4 
Free, TSH8 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
X 
 
Coagulation 
(PT, INR, 
aPTT) 
X8 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine or 
serum 
pregnancy 
test 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival 
Tumor 
Tissue 
Collection 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT Scan 
(Chest, 
Abdomen, 
Pelvis) 
and/or MRI 
X 
 
As clinically indicated (or every 9 weeks for Response assessment) 
X 
Whole body 
Bone Scan 
X 
 
As clinically indicated 

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Procedure 
Screening 
(Within 6 
weeks of 
Day 1) 
Treatment Phase (+/- 3 days)3 
End of 
Treatment4 
SOC 
Follow-
up5 
C1 
D1 
C1 
D8 
C1 
D15 
C2 
D1 
 
C2 
D8 
C3 
D1 
C4 
D1 
 
C5 
D1 
 
C6 
D1 
Even 
Cycles 
Odd 
Cycles 
30-days after 
drug 
discontinuation, 
+/- 7 days 
Every 
12 
Weeks 
Adverse 
Event 
Assessment 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X6 
X6 
Concomitant 
Medications 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
Pembrolizu
mab 
Administrati
on 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Olaparib 
Administrati
on and 
Olaparib 
Compliance 
Diary 
 
Daily7 
 
 
1Informed consent may be obtained within 6 weeks of Cycle 1, Day 1 
 
2Vital signs to include temperature, pulse, respiratory rate, weight, and blood pressure. Height will be 
measured at Screening only. 
 
3Study treatment is up to 35 administrations of pembrolizumab (approximately two years).  
 
4If subject discontinues drug due to progression, the End of Treatment visit (30 days after study treatment 
discontinuation, +/- 7 days) will end their participation in the study and will not be followed thereafter. 
 
5Subjects who discontinue trial treatment for a reason other than disease progression will move into the 
Follow-Up Phase and should be assessed every 12 weeks (56 ± 7 days) by radiologic imaging to monitor 
disease status, per standard of care for up to two years of total study participation. 
 
 
6SAEs and ECIs should be reported for 90 days after last pembrolizumab dose or until new anticancer 
treatment is initiated, but for a minimum of 30 days, whichever occurs first. 
 
7Olaparib will be dispensed each cycle day 1 (each cycle=3 weeks). Subjects will be given an olaparib 
dosing diary at Cycle 1 Day 1, and at Day 1 of each subsequent cycle while taking olaparib. The 
completed diary will be collected at the next cycle Day 1. Olaparib dosing must begin within 3 days of 
pembrolizumab C1D1. 
 
8Laboratory tests for screening should be performed within 10 days prior to the first dose of 
pembrolizumab. After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to 
dosing. Results must be reviewed by the investigator or qualified designee and found to be acceptable 
prior to each dose of trial treatment. 
 
9 Female subjects of childbearing potential should have a negative urine or serum pregnancy prior to 
study registration and re-tested within 72 hours prior to receiving the first dose of pembrolizumab. If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
 
10The pre-treatment archival tumor tissue sample for correlative studies may be sent to QualTek any time 
after eligibility verification. 
 

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11 Tempus testing will be performed only on patients who do not otherwise qualify based on BRCA status. 
Archival tumor tissue plus a normal matching sample (blood preferred) will be collected and shipped to 
Tempus. De-identified clinical data elements will be shared with Tempus as specified in the master 
agreement (may be sent after screening).  
 
 
 
5.16 
Removal of Subjects from Study 
Patients can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.16.1 Patient voluntarily withdraws from treatment (follow-up permitted);  
5.16.2 Patient withdraws consent (termination of treatment and follow-up); 
5.16.3 Patient is unable to comply with protocol requirements; 
5.16.4 Patient experiences toxicity that makes continuation in the protocol unsafe; 
5.16.5 Treating physician judges continuation on the study would not be in the patient’s best 
interest; 
5.16.6 Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event). 
 
6.0 
ADVERSE EVENTS 
6.1 
Definitions 
6.1.1 
Definition of Adverse Event 
 
Adverse Event (AE or Adverse Experience): Any untoward medical 
occurrence associated with the use of a drug in humans, whether or not 
considered drug related. Therefore, an AE can be ANY unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product 
(attribution of unrelated, unlikely, possible, probable, or definite).  AE’s will be 
collected once the consent is signed and treatment is initiated. 
6.1.2 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of 
Clinical Interest (ECI) and must be recorded as such on the Adverse Event case 
report forms/worksheets and reported within 2 working days from time of PI 
acknowledgment to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 
215 661-6229) 
 
Events of clinical interest for this trial include: 
 

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1. an overdose of pembrolizumab that is not associated with clinical symptoms 
or abnormal laboratory results. For purposes of this study, an overdose of 
pembrolizumab will be defined as any dose of 1,000 mg or greater (≥5 times 
the indicated dose). No specific information is available on the treatment of 
overdose of pembrolizumab. In the event of overdose, the participant should 
be observed closely for signs of toxicity.  Appropriate supportive treatment 
should be provided if clinically indicated.  If an adverse event(s) is associated 
with (“results from”) the overdose of a Merck product, the adverse event(s) is 
reported as a serious adverse event, even if no other seriousness criteria are 
met. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the 
upper limit of normal and an elevated total bilirubin lab value that is greater 
than or equal to 2X the upper limit of normal and, at the same time, an 
alkaline phosphatase lab value that is less than 2X the upper limit of normal, 
as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.* 
 
*Note:  These criteria are based upon available regulatory guidance documents. 
The purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require an additional evaluation for an underlying etiology.   
 
ECIs (both non-serious and serious adverse events) identified in this guidance 
document from the date of first dose through 90 days following cessation of 
treatment, or 30 days after the initiation of a new anticancer therapy, whichever is 
earlier, need to be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 661-
6229), regardless of attribution to study treatment, consistent with standard SAE 
reporting guidelines. 
 
Subjects should be assessed for possible ECIs prior to each dose.  Lab results 
should be evaluated and subjects should be asked for signs and symptoms 
suggestive of an immune-related event.  Subjects who develop an ECI thought to 
be immune-related should have additional testing to rule out other etiologic 
causes.  If lab results or symptoms indicate a possible immune-related ECI, then 
additional testing should be performed to rule out other etiologic causes.  If no 
other cause is found, then it is assumed to be immune-related. 
6.1.2.1 Olaparib Overdose 
There is currently no specific treatment in the event of overdose with olaparib and 
possible symptoms of overdose are not established.  
Olaparib must only be used in accordance with the dosing recommendations in this 
protocol. Any dose or frequency of dosing that exceeds the dosing regimen specified in 
this protocol should be reported as an overdose. The maximum tolerated dose is 300mg 
twice daily (tablet). 
Adverse reactions associated with overdose should be treated symptomatically and 
should be managed appropriately.  
For overdoses associated with a SAE, the standard reporting timelines apply, see 
Section 6.4. For other overdoses, reporting must occur within 30 days. 
6.1.3 
Severity of Adverse Events 
 

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All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The 
CTCAE v4 is available at http://ctep.cancer.gov/reporting/ctc.html 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
• 
Mild (grade 1): the event causes discomfort without disruption of normal 
daily activities. 
• 
Moderate (grade 2): the event causes discomfort that affects normal 
daily activities. 
• 
Severe (grade 3): the event makes the patient unable to perform normal 
daily activities or significantly affects his/her clinical status. 
• 
Life-threatening (grade 4): the patient was at risk of death at the time of 
the event. 
• 
Fatal (grade 5): the event caused death. 
6.1.4 
Serious Adverse Events 
 
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that: 
• 
Results in death. 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
• 
Is life-threatening. 
(the patient was at risk of death at the time of the event; it does not refer to 
an event that hypothetically might have caused death if it were more severe). 
• 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
• 
Results in persistent or significant disability or incapacity. 
 
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event 
 
Any event that does not meet the above criteria, but that in the judgment of the 
investigator jeopardizes the patient, may be considered for reporting as a serious 
adverse event. The event may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition of “Serious Adverse Event”.  
 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in hospitalization; 
development of drug abuse or drug dependency. 
 
 
Pregnancy: If a female subject or male subject’s female partner inadvertently 
becomes pregnant while on treatment with pembrolizumab, the subject will 
immediately be removed from the study.  The site will contact the subject at least 
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completed or terminated.  The outcome of the pregnancy will be reported to the 
IRB and to Merck within 10 days of the PI becoming aware of the outcome.   If 
the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or 
newborn), the PI upon learning of the event, will report to Merck.  
 
The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the 
IRB. 
 
6.2 Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE v4).  
 
Step 2:  Grade the adverse event using the NCI CTCAE v4. 
 
Step 3:  Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and is 
attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. SAEs and ECIs should be reported for 90 days after last pembrolizumab dose 
or until new anticancer treatment is initiated, but for a minimum of 30 days, whichever 
occurs first. 
 
Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in the current known adverse events listed in: 
 
• 
the current known adverse events listed this protocol; 
• 
the drug package insert; and/or 
• 
the current Investigator’s Brochure 
 
6.3 Data Collection Procedures for Adverse Events 
 
The principal investigator is responsible for evaluating all adverse events, obtaining 
supporting documents, and determining that documentation of the event is adequate. 
He/she is responsible for determining the seriousness, severity, and relationship of the 
adverse event to the investigational drug. The principal investigator may delegate these 
duties to sub-investigators and must assure that these sub-investigators are qualified to 
perform these duties under the supervision of the principal investigator. All adverse events 
will be documented in the subject’s source and recorded on Case Report Form(s).  
 
The term of the adverse event should reflect the diagnosis rather than its symptoms, when 
available.  In the event of death, the cause of death should be recorded as the adverse 

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event. The detailed description of the event will include appropriately graded severity of the 
adverse event and its relationship to the study drug. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from 
lack of efficacy will be reported if they fulfill the definition of an AE or SAE.  
 
Events that do not meet the definition of an AE include: 
 
Any clinically significant abnormal laboratory finding or other abnormal safety assessments 
that is associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the subject’s condition. 
Abnormal laboratory findings deemed by the investigator as not clinically significant. 
The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to 
the procedure is an AE 
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital) 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen 
All patients experiencing an adverse event will be monitored until:  
• The adverse event resolves or the symptoms or signs that constitute the adverse event 
return to baseline;  
• Any abnormal laboratory values have returned to baseline1;  
• There is a satisfactory explanation other than the study drug for the changes observed; or 
• Death. 
 
Serious adverse events, occurring after the informed consent is signed but prior to the initial 
dose of the investigational product will be collected as part of the subject’s medical 
history/baseline symptoms but will only be reportable if they are considered by the 
Investigator to be causally related to required research procedures.   
 
SAEs and ECIs should be reported for 90 days after last pembrolizumab dose or until new 
anticancer treatment is initiated, but for a minimum of 30 days, whichever occurs first. 
 
 
1 An abnormal laboratory value is considered to be an AE if the abnormality: 1) results in discontinuation 
from the study; 2) requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or 3) is judged to be of significant clinical importance. Regardless of severity grade, only 
laboratory abnormalities that fulfill a seriousness criterion need to be documented as a serious adverse 
event. 
 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis or 
syndrome should be recorded on the AE page/screen of the eCRF.  If the abnormality was not a part of a 
diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. 
 
 
 

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Non-serious adverse events (AEs) will be collected throughout the treatment period through 
the End of Treatment assessment 30 days after removal from treatment. Patients removed 
from treatment for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  Events occurring during this period must be followed until 
resolution or death unless in the Investigator’s opinion, the condition is unlikely to resolve due 
to the patient’s underlying disease.  After the End of Treatment assessment, any adverse 
event documented in the subject’s medical record as being at least possibly related to study 
intervention will also be recorded in the Case Report Form.  
 
SAEs must be reported to oversight agencies as described below. 
6.4 Reporting Requirements for Adverse Events 
6.4.1 
Expedited Reporting to PI 
The Principal Investigator must be notified within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study or 
within 30 days of the last administration of the study drug. SAEs and ECIs 
should be reported for 90 days after last pembrolizumab dose or until new 
anticancer treatment is initiated, but for a minimum of 30 days, whichever 
occurs first. 
 
Phone Number for Expedited Reporting: 
310-248-6733 
 
Alternate Phone Number for Expedited Reporting: 
310-423-1188 
 
6.4.2 
Reporting to DSMC 
Serious Adverse Event deemed to be related to the protocol and on-study 
deaths, including death of a research subject unless the death is expected 
(e.g. due to disease progression) to be reported to the DSMC within 24 
hours for medical monitor ad hoc review between meetings to determine if 
immediate action is required. Reports may be emailed to the DSMC Admin 
at GroupSOCCICCTODSMCAdmin@cshs.org. 
6.4.3 
Reporting to the Institutional Review Board (IRB) 
The CSMC IRB requires that investigators report all adverse events that may 
represent an unanticipated problem involving risks to subjects or others as 
defined below. 
 
All adverse events (those involving subjects who were enrolled at CSMC) which 
are both unexpected and probably related to the research must be reported to 
the IRB. 
 
All reportable events should be submitted in CS-IRB to the Office of Research 
Compliance and Quality Improvement as soon as possible, but no more than 
10 days from the investigator’s awareness of the event. 
 
The report must contain at least: 
 
• 
Identification of the PI, study coordinator (if applicable), contact information, 
study title, and IRB number. 

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• 
A detailed summary of the problem, including all relevant details and the PI’s 
assessment of the events leading up to the problem, to assist the IRB in its 
evaluation. 
• 
A description of any action taken to address or remedy the problem, 
including a description of the resolution, if any, or current status. 
• 
An assessment as to whether any changes are required in the conduct of the 
research to resolve the problem or prevent further problems. 
 
6.4.4 
Reporting to the Food and Drug Administration (FDA) 
The investigator or his designee must submit documentation of adverse reactions 
according to the following reporting criteria: 
 
• 
Reporting any unexpected fatal or life-threatening suspected adverse 
reactions no later than 7 calendar days after initial receipt of the information 
 
• 
Reporting any (1) serious, unexpected suspected adverse reactions, (2) 
findings from other clinical, animal, or in-vitro studies that suggest significant 
human risk, and (3) a clinically important increase in the rate of a serious 
suspected adverse reaction no later than 15 calendar days after determining 
that the information qualifies for reporting.  
 
6.4.5 
Expedited Reporting to Merck 
 
 
All Adverse events will be documented according to GCP and graded according to 
CTCAE. SAE reports and any other relevant safety information are to be forwarded to 
the Merck Global Safety facsimile number:  +1-215-661-6229. 
 
Alternatively, reports may be called into the Merck National Service Center at 1-800-444-
2080, or sent via secure email to Whitney.Sarchiapone@merck.com.  
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by 
FDA, European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or 
other local regulators. Investigators will cross reference this submission according to local 
regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the time 
of submission.  Additionally, investigators will submit a copy of these reports to Merck & 
Co., Inc. (Attn: Worldwide Product Safety; FAX 215 661-6229) at the time of submission 
to FDA. 
 
All subjects with serious adverse events must be followed up for outcome. 
 
7.0 
DRUG INFORMATION 
7.1 Pembrolizumab 
See current version of the Investigator’s Brochure. 
Study drug will be provided by Merck. 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck as summarized below: 
Product Descriptions 

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Product Name & Potency 
Dosage Form 
pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
7.1.1 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
7.1.2 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
7.1.3 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
7.1.4 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper 
disposal have been established according to applicable federal, state, local and institutional 
guidelines and procedures, and provided that appropriate records of disposal are kept. 
 
7.2 
Olaparib 
See current version of the package insert. Olaparib supply will be provided by Merck. Commercial 
supply will be used.  
 
Olaparib will be provided as marketed packs of Lynparza (100 mg and 150 mg tablets in bottles 
of 120 tablets). Approved dosage is 300 mg (two 150 mg tablets) twice daily for a total daily dose 
of 600 mg daily. To manage adverse reactions, dose reduce to 250 mg (one 150 mg tablet and 
one 100 mg tablet) twice daily for a total daily dose of 500 mg.  If further dose reduction is 
required, dose reduce to 200 mg (two 100 mg tablets) twice daily for a total daily dose of 400 mg.   
 
8.0 
CORRELATIVES/RESEARCH STUDIES  
The main objective of the translational research component of the IIT is to obtain biomarker 
measurements of PD-1 and PD-L1 expressions. Archival tumor samples will be sent to Qualtek 
Molecular Laboratories for analysis. See Sample Handling Manual. 
9.0 
STATISTICAL CONSIDERATIONS 
Therapy administered until documented/confirmed progression by RECIST 1.1 criteria. This trial 
is a pilot study to assess the objective response rate with immunotherapy and PARP inhibition. 

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There are no preliminary statistical assumptions. First response assessments at 9 weeks; time 
interval for trial assessment is typical for time interval for assessment of response to standard of 
care therapy. Investigational therapy will not preclude subsequent standard of care therapy or 
subsequent investigational therapy. 
9.1 Study Design/Study Endpoints 
This study is a pilot study intended to determine ORR to single agent pembrolizumab in addition 
to standard of care olaparib treatment in study population.  
9.2 Sample Size and Early Stopping 
Clinical benefit is defined as complete response, partial response, or stable disease (if stable 
disease, lasting for at least four months). A proportion of patients with clinical benefit less than 
15% will be of no interest. The new treatment would be of interest if the proportion of patients with 
clinical benefit is at least 41%. Simon's two-stage design (Simon, 1989) will be used. The null 
hypothesis: p<= 0.15 is against the alternative hypothesis p>= 0.41. In the first stage, 10 patients 
will be accrued. If there are 2 or fewer subjects with clinical benefit among these 10 patients, the 
study will be terminated. The probability of early stopping under the null is 0.82, and under the 
alternative is 0.16.  Otherwise, 10 additional patients will be accrued for a total of 20. The null 
hypothesis will be rejected if 6 or more responses are observed in 20 patients. This design yields 
a 1-sided type I error rate of 5% and power of 80%.  
 
The early stopping rule is based on responses in the first 10 patients, rather than dose limiting 
toxicity, as the study drug is FDA-approved at the current dose used in this trial, has a known and 
predictable rate of toxicity at the present dose, has been used in prior cohorts of breast cancer 
patients at the current dose, and there is no biological basis on which to expect excessive or 
unusual toxicity in the study cohort.  
9.3 Data Analysis Plans 
Data will be analyzed after enrollment and tumor assessments of the first 10 subjects to 
determine whether early stopping point has been met.  

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 Analysis of Endpoints 
9.3.1 
Exploratory Data Analysis:  Exploratory analyses will be performed to elucidate 
the relationships among variables. Graphical data analysis will be applied to examine the 
distribution of the data and to reveal the association among covariates and outcome 
variables.  Statistical graphics provide effective data summaries and can be very useful 
for error checking and outlier identification.  Standard distribution plots such as 
histograms and box-plots will be applied.  A scatter plot matrix will be used to explore the 
association among multiple variables.  The main purpose of the exploratory data analysis 
is to “let the data speak”.  These analyses not only provide an assumption free, graphical, 
presentation of the data, but can also be used to help select appropriate statistical 
models to use during data analysis. 
9.3.2 
Analysis of Survival Data:  We will estimate the survival distributions for time-to-
event outcomes using the method of Kaplan and Meier and compare these distributions 
among groups using the logrank test.  Multivariable proportional hazards regression 
models will be used to assess which biomarkers are predictive of patient outcomes in the 
presence of covariates.  The proportional hazards assumption will be evaluated 
graphically and analytically, and regression diagnostics (e.g., martingale and Shoenfeld 
residuals) will be examined to ensure that the models are appropriate. Violations of the 
proportional hazards assumption will be addressed by use of time-dependent covariates 
or extended Cox models.  The possibility of collinearity will be reduced through the 
careful initial assessment of correlations among all study covariates.  
9.3.3 
Analysis of Categorical Response Variables:  We will test for differences among 
groups using Pearson’s chi-square statistic, or Fisher’s exact test.  In those situations 
where we must stratify on a characteristic of the population under study, we may employ 
the Cochran-Mantel-Haenszel test.  In those situations in which we are interested in 
modeling the relationship between a binary response variable and single or multiple 
covariates, we will use logistic regression.    Logistic regression diagnostics will be 
employed to ensure that the logistic model is appropriate.  Similarly, the possibility of 
collinearity will be reduced through the careful initial assessment of correlations among 
all study covariates. 
9.3.4 
Analysis of Continuous Response Variables:  For the analysis of continuous 
response variables, we will use analysis of variance (ANOVA), analysis of covariance 
(ANCOVA), and mixed models.  We will test the data to ensure that the underlying 
assumptions (i.e., normality, homoscedasticity) of the ANOVA model are met.  If these 
assumptions are not met, then we will attempt to transform the data such that the 
transformed data meet these assumptions.  Standard transformations of the response 
variable such as the log, square root and Box-Cox transformations will be examined.  If 
data transformation is inadequate to meet the analysis assumptions, then rank 
transformation of the data will be performed and one-way ANOVA on the rank 
transformed response variables will be analyzed and reported.  In those situations where 
covariates could potentially have an effect on the response variable in an ANOVA 
context, we will use ANCOVA to adjust treatment effects.  The underlying assumptions of 
the ANCOVA model will be tested (such as homogeneity of slopes across groups).  
Standard regression criteria will be used to assess appropriateness of including particular 
covariates.  In situations where more than one covariate is being included in the model, 
the possibility of collinearity will be reduced through the careful initial assessment of 
correlations among all study covariates. 
9.3.5 
Analysis of Biomarker Data:   Associations between biomarkers will be assessed 
using Cohen’s Kappa with appropriate 95 percent confidence intervals reported.  Kappas 
of .75 or greater are considered excellent, whereas Kappas between .4 and .75 denote 
good agreement.  

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10.0 
STUDY MANAGEMENT 
10.1 
Conflict of Interest 
Any reportable conflict of interest will be disclosed to the local IRB and will be outlined in 
the Informed Consent Form. 
10.2 
Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations.  
 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB.  The IRB’s written approval of the study protocol and the 
informed consent form will be in the possession of the Investigator before the study is 
initiated and prior to the shipment of study supplies to participating sites, if applicable.  
This approval must refer to the study by exact protocol title and number and should 
identify the documents reviewed and the date of review. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion. 
10.3 Registration Procedures 
 
All patients will be tracked following written informed consent. Those patients who are 
consented to participate in the clinical trial but do not meet one or more criteria required 
for participation during the screening phase will be listed as screen failures on the master 
list of consented subjects. Eligible subjects, as determined by screening procedures and 
verified by a treating investigator, will be registered on study at Cedars Sinai Medical 
Center by the Study Coordinator.   
 
Issues that would cause treatment delays after registration should be discussed with the 
Principal Investigator (PI). If a patient does not receive protocol therapy following 
registration, the patient’s registration on the study may be canceled.  The Study 
Coordinator should be notified of cancellations as soon as possible. 
 
Assignment of Subject ID: The study team will track all subjects who sign consent using 
OnCore. Subjects found to be ineligible will be recorded as screen failures. Subjects 

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found to be eligible will be registered using a three-digit numeric ID that follows the 
standard SOCCI format (001, 002, etc.). 
 
A) 
Eligibility Verification 
 
Prior to registration, all subjects must undergo eligibility verification by the SOCCI Cancer 
Clinical Trials Office (CCTO) Quality Management Core (QMC). The following documents 
will be organized into an eligibility packet, scanned as a pdf, and emailed to 
GroupSOCCICROQMC@cshs.org for review: 
 
• 
QMC approved Eligibility Checklist signed by investigator and 2 members of the 
study team (or equivalent) 
• 
Source documents substantiating eligibility that cannot be located in the subject’s 
CS Link medical record  
• 
Signed consent form with Subject’s Bill of Rights, HIPAA authorization form, 
consent progress note, and any optional consent forms, as applicable, if not 
available in CS Link 
 
B) 
Registration 
 
After eligibility is verified, each site will assign the subject a study number and site staff 
will then register the patient in OnCore®.   
 
 
Registration is completed as follows: 
 
• 
Assign a patient study number 
• 
Enter the patient in OnCore 
• 
Notify the investigational pharmacy and treating physicians that a subject has 
gone on study and anticipated treatment start date 
 
Oversight by the principal investigator is required throughout the entire 
registration process 
 
10.4 Data Management and Quality Control and Reporting 
REDCap is the Cedars-Sinai Cancer institutional choice for the electronic data capture of 
case report forms for SOCCI Investigator Initiated Trials. REDCap, a HIPAA-compliant 
database, will be used for electronic case report forms in accordance with institutional 
requirements, as appropriate for the project. The Study Staff will be responsible for data 
processing, in accordance with procedural documentation. Database lock will occur once 
quality assurance procedures have been completed. See also Section 10.5.2, Monitoring. 
 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
 
10.5 Data and Safety Monitoring 
 
10.5.1 Safety Oversight 
Adherence to the protocol, Good Clinical Practices (GCP), and institutional policy will be 
monitored by the PI during the course of the study through routine Disease Research 
Group (DRG) meetings (or equivalent). The PI will maintain continuous safety monitoring 
for the duration of the study by reviewing subject/study data. It is the responsibility of the 

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principal investigator to adhere to the Data Safety Monitoring Plan throughout the life of 
the study. 
 
In addition, safety oversight and efficacy data will be reviewed by the SOCC Data and 
Safety Monitoring Committee (DSMC). The DSMC will review this trial commensurate 
with the assigned risk class as categorized by the PRMC. The DSMC membership and 
responsibilities are governed by the committee charter. The DSMC findings and 
recommendations will be reported in writing to the Principal Investigator as a summary 
letter which will be forwarded by the Principal Investigator or designee to the CS-IRB. 
The DSMC outcome letters will be furnished to the FDA, as applicable. Refer to the 
DSMC Charter for details of the DSMC review.  
 
10.5.2 Monitoring 
The SOCC Cancer Clinical Trials Office (CCTO) Quality Management Core (QMC) will 
conduct internal monitoring visits and audits to ensure that the rights and well-being of 
trial participants are protected, that the reported trial data are accurate, complete, and 
verifiable, and that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and with applicable regulatory requirement(s). 
 
Refer to the DSMP for details pertaining to the type, frequency, and extent of monitoring 
that will be performed.   
10.6 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, monitoring/auditing logs/letters, records of study drug receipt, 
dispensation, destruction and regulatory documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent forms). Source documents include 
all recordings of observations or notations of clinical activities and all reports and records 
necessary for the evaluation and reconstruction of the clinical research study. 
Government agency regulations and directives require that the study investigator must 
retain all study documentation pertaining to the conduct of a clinical trial. Study 
documents should be kept on file in accordance with all applicable federal guidelines and 
local guidelines. 
Investigators must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB, and Regulatory Agency (e.g., FDA) 
inspectors upon request. 
10.7 
Adherence to the Protocol 
It is the responsibility of the Investigator-sponsor to ensure that patient recruitment and 
enrollment, treatment, follow-up for toxicities and response, and documentation and 
reporting at SOCCI are all performed as specified in the protocol. For multi-site studies, 
the site Principal Investigator at each participating site will assume the responsibilities for 
the day-to-day monitoring of the trial, including but not limited to review of eligibility of 
new subjects, proper documentation informed consent, administration of treatment per 
protocol, thorough documentation and capturing of research notes in the subject’s charts, 
and timely completion of required case report forms.  Except for an emergency situation 
in which proper care for the protection, safety, and well-being of the study patient 
requires alternative treatment, or a protocol exception request approved by the SOCCI 
Medical Director and IRB of record, the study shall be conducted exactly as described in 
the approved protocol.  

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10.7.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, the IRB must be notified as 
soon as possible, but no more than 72 hours from the investigator’s awareness 
of the event. 
10.7.2 Protocol Exceptions and Eligibility Waivers  
 
A protocol exception is an anticipated or planned deviation from the IRB-
approved research protocol, as described in the IRB Policy, Reporting Possible 
Unanticipated Problems Involving Risks to Subject or Others (UPIRSO) Policy: 
Institutional Review Board/Research Compliance and Quality Improvement. A 
protocol exception most often involves a single subject and is not a permanent 
revision to the research protocol. Protocol exceptions that extend beyond a 
single subject should result in a protocol amendment to avoid serial violations.  
 
Planned exceptions to the protocol that are more than logistical in nature and/or 
affect timing of study drug administration, or the investigator assesses the event 
may impact subject safety and/or study integrity, may not be implemented 
without prior approval from the SOCCI CCTO Medical Director and the IRB. The 
PI or her/his designee is responsible for submitting a protocol exception and its 
supporting documents to the SOCCI CCTO Medical Director for review and 
further instructions on IRB reporting.   
 
Study team should refer to the IRB Reporting Possible Unanticipated Problems 
Involving Risks to Subject or Others (UPIRSO) Policy: Institutional Review 
Board/Research Compliance and Quality Improvement guidelines to determine 
which deviations and exception requests meet reporting guidelines. Once 
approved by the medical director, the deviation or exception request must be 
submitted to the IRB for review and approval prior to implementation.  
 
Special considerations for Eligibility Waivers (EW)  
Subjects who do not meet the eligibility requirements should not be enrolled. 
Eligibility waivers are not permitted.  
 
Exception Request Submission Process  
The PI and/or treating physician should provide a written request for a protocol 
exception including case history and justification for prospective deviation from 
the study design to the SOCCI CCTO Medical Director. The “IIT Exception 
Requests (ER) Form” must be completed then submitted, along with any 
applicable supporting documents, must be emailed to QMC 
(GroupSOCCICROQMC@cshs.org) to request a protocol exception from the 
CCTO Medical Director. This is only a requirement for studies with a DSM 
classification of moderate or high. An assessment from the CCTO Medical 
Director or designee must be done prior to submission to the IRB for review.   
10.7.3 Other Protocol Deviations/Violations 
Logistical deviations from the protocol (e.g., minor changes to the study schedule 
for an individual subject) do not require prior IRB approval unless the deviation 
has the potential to affect the subject’s safety or study integrity. Such planned 
deviations that do meet this definition and do not affect the subject’s safety or 
study integrity should be noted in the subject’s research record or deviation log 

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as described in the SOCCI CCTO’s Standard Operating Procedure 12: Deviation 
and Noncompliance Reporting.  
 
Unintentional deviations from the protocol that might affect subject safety or 
study integrity should be reported to the IRB within 10 days from when the 
investigator becomes aware that such a deviation has occurred, as outlined in 
the SOCCI CCTO’s Standard Operating Procedure 12:  Deviation and 
Noncompliance Reporting. In this case, a Protocol Deviation report must be 
submitted in CS-IRB, per CSMC IRB policy, Reporting Possible Unanticipated 
Problems Involving Risks to Subject or Others (UPIRSO) Policy: Institutional 
Review Board/Research Compliance and Quality Improvement.  
All submissions should include a description of the plan to avoid similar 
deviations or exceptions in the future. 
10.8 
Amendments to the Protocol 
 
  Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an 
amendment to the protocol substantially alters the study design or the potential risk to the 
patient, a revised consent form might be required.  
 
 
 The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation. Repeat exceptions or deviations to the protocol 
may suggest a protocol amendment is needed. 
10.9 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator will be responsible for assuring that all the required data will be 
collected and entered onto the Case Report Forms and/or into a HIPAA-compliant study 
database. Periodically, monitoring visits will be conducted and the Principal Investigator 
will provide access to his/her original records to permit verification of proper entry of data. 
At the completion of the study, all case report forms will be reviewed by the Principal 
Investigator and will require his/her final signature to verify the accuracy of the data. 
10.10 
Publications 
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among 
the sponsor-investigator and participating institutions.  The publication or presentation of 
any study results shall comply with all applicable privacy laws, including, but not limited 
to, the Health Insurance Portability and Accountability Act of 1996.  
 
 
 
 
 
 
 
 

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11.0 
REFERENCES 
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Mavaddat, N., et al., Pathology of breast and ovarian cancers among BRCA1 and BRCA2 
mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). 
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2. 
NCCN. Genetic/Familial High Risk Assessment: Breast and Ovarian. 2014  [cited v1. 2014; 
Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#detection. 
3. 
Bayraktar, S. and S. Glück, Systemic therapy options in BRCA mutation-associated breast 
cancer. Breast Cancer Res Treat, 2012. 135(2): p. 355-66. 
4. 
Audeh, M.W., et al., Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 
or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet, 2010. 
376(9737): p. 245-51. 
5. 
Curtin, N.J. and C. Szabo, Therapeutic applications of PARP inhibitors: anticancer therapy and 
beyond. Mol Aspects Med, 2013. 34(6): p. 1217-56. 
6. 
Gelmon, K.A., et al., Can we define tumors that will respond to PARP inhibitors? A phase II 
correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer. 
ASCO Meeting Abstracts, 2010. 28(15_suppl): p. 3002. 
7. 
Tutt, A., et al., Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or 
BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet, 2010. 376(9737): 
p. 235-44. 
8. 
Coronella, J.A., et al., Evidence for an antigen-driven humoral immune response in medullary 
ductal breast cancer. Cancer Res, 2001. 61(21): p. 7889-99. 
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Gatalica, Z., et al., Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers 
and their correlation with molecular cancer type. Cancer Epidemiol Biomarkers Prev, 2014. 
23(12): p. 2965-70. 
10. 
Pockaj et al (J Clin Oncol 32:5s, s.a., J Clin Oncol  2014. 32:5s, . 
11. 
Audeh, M.W., Dadmanesh, F, Yearly, J., PDL1 
            expression in primary breast cancers with germline mutations in BRCA 1 and 2. San Antonio 
Breast Cancer Symposium, 2015. Abstract P4-04-01. 
12. 
Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N 
Engl J Med, 2012. 366(26): p. 2443-54. 
13. 
Hamid, O., et al., Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N 
Engl J Med, 2013. 369(2): p. 134-44. 
14. 
Brahmer, J.R., et al., Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. 
N Engl J Med, 2012. 366(26): p. 2455-65. 
15. 
Nanda, R.C., L; Dees, E; Berger, R; et al, A Phase Ib study of pembrolizumab in patients with 
advanced triple-negative breast cancer. San Antonio Breast Cancer Symposium, 2014. 
16. 
Ribas, A., Tumor immunotherapy directed at PD-1. N Engl J Med, 2012. 366(26): p. 2517-9. 
17. 
Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer, 
2012. 12(4): p. 252-64. 
18. 
Vogelstein, B., et al., Cancer genome landscapes. Science, 2013. 339(6127): p. 1546-58. 
19. 
Vollebergh, M.A., J. Jonkers, and S.C. Linn, Genomic instability in breast and ovarian cancers: 
translation into clinical predictive biomarkers. Cell Mol Life Sci, 2012. 69(2): p. 223-45. 
20. 
Jasin, M., Homologous repair of DNA damage and tumorigenesis: the BRCA connection. 
Oncogene, 2002. 21(58): p. 8981-93. 
21. 
U.S. Food & Drug Administration. FDA approves olaparib for germline BRCA-mutated metastatic 
breast cancer. Retrieved May 7, 2019 from https://www.fda.gov/drugs/resources-information-
approved-drugs/fda-approves-olaparib-germline-brca-mutated-metastatic-breast-cancer 
22. 
Chen, C., et al., ATM loss leads to synthetic lethality in BRCA1 BCRT mutant mice associated 
with exacerbated defects in homology-directed repair. PNAS, 2017. 114(29): p. 7665-7670. 
23. 
Chen, C., et al., Homology-directed repair and the role of BRCA1, BRCA2, and related proteins in 
genome integrity and cancer. Annu Rev Cancer Biology, 2018. Vol 2: p. 313-336. 
24. 
Frey, M.K. and Pothuri, B., Homologous recombination deficiency (HRD) testing in ovarian cancer 
clinical practice: a review of the literature. Gynecol Oncol Res Pract, 2017. (4):4. Review. 

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25. 
Chabanon, R.M., et. al., PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-
deficient non-small cell lung cancer. J Clin Invest, 2019. 129(3): p. 1211-1228. 
26.  
Konstantinopoulos, P., et. al., Single-arm phases 1 and 2 trial of niraparib in combination with 
pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncology, 
2019. 5(8): p. 1141-1149. 
27.  
Zimmer, A.S., et. al., A phase 1 study of the PD-L1 inhibitor, durvalumab, in combination with a 
PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women’s cancers with 
biomarker analyses. Journal for ImmunoTherapy of Cancer, 2019. 7(197). 
28.  
Friedlander, M., et. al., Pamiparib in combination with tislelizumab in patients with advanced solid 
tumours: Results from the dose-escalation stage of a multicentre, open-label, phase 1a/b trial. 
The Lancet Oncology, 2019. 20(9): p. 1306-1315.  
29. 
Feiersinger G.E., et. al., Olaparib is effective in combination with, and as maintenance therapy 
after, first-line endocrine therapy in prostate cancer cells. Mol Oncol. 2018 Apr;12(4):561-576. 
30. 
Plummer, R, et. al., Pharmacokinetic Effects and Safety of Olaparib Administered with Endocrine 
Therapy: A Phase I Study in Patients with Advanced Solid Tumours. Adv Ther. 2018 
Nov;35(11):1945-1964. 
31.  
García-Parra, J, et. al., Poly (ADP-ribose) polymerase inhibition enhances trastuzumab 
antitumour activity in HER2 overexpressing breast cancer. Eur J Cancer. 2014 Oct;50(15):2725-
34. 
32. 
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8 
33. 
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive cell 
transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment 
of patients with refractory metastatic melanoma. J Clin Oncol 2005;23(10):2346-57. 
34. 
Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703. 
35.  
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 
2005;23:515-48. 
36. 
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell 
receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 2001;98(24):13866-71. 
37.  
Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and functional 
analysis of the costimulatory receptor programmed death-1. Immunity 2004;20:337-47. 
38. 
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with 
immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell 
stimulation, but only receptor ligation prevents T cell activation. J Immunol 2004;173:945-54. 
39. 
Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 inhibits T-cell 
receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling 
to PKCtheta. FEBS Lett. 2004;574:37-41. 
40. 
Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229:114-25. 
41. 
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. CTLA-4 
and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 
2005;25(21):9543-53. 
42. 
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol 
Rev 2010;236:219-42. 
43.  
Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, et al. High 
sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in 
combination with platinum drugs. Proc Natl Acad Sci. 2008;105(44):17079-84. 
44.  
Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, et al. Poly(ADP-ribose) 
polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in 
vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 2009;69(9):3850-5.  
45.  
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-
ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123-34. 
46.  
Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up 
the misunderstandings. Molecular Oncology 2011; 5: 387-393. 

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47.  
Murai J, Huang SN, Das BB, Renaud A, Zhnag, Y, Doroshow, JH, et al. Trapping of PARP1 and 
PARP2 by Clinical PARP Inhibitors. AACR; 72(21); 5588–99. 
 
12.0 
Appendix: Acceptable Birth Control Methods 
 
Olaparib is regarded as a compound with medium/high foetal risk. 
Women of childbearing potential and their partners, who are sexually active, must agree to the use of 
TWO highly effective forms of contraception in combination [as listed below].  This should be started from 
the signing of the informed consent and continue throughout the period of taking study treatment and for 
at least 1 month after last dose of study drug(s), or they must totally/truly abstain from any form of sexual 
intercourse (see below). 
Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when 
having sexual intercourse with a pregnant woman or with a woman of childbearing potential.  Female 
partners of male patients should also use a highly effective form of contraception if they are of 
childbearing potential (as listed below).  Male patients should not donate sperm throughout the period of 
taking olaparib and for 3 months following the last dose of olaparib. 
Acceptable Non-hormonal birth control methods include: 
 
Total/True abstinence: When the patient refrains from any form of sexual intercourse and 
this is in line with their usual and/or preferred lifestyle; this must continue for the total duration of 
the trial and for at least 1 month after the last dose of study drug <<for 3 months after last dose 
for male patients>>. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods, or declaration of abstinence solely for the duration of a trial) and withdrawal 
are not acceptable methods of contraception]  
 
Vasectomised sexual partner PLUS male condom.  With participant assurance that partner 
received post-vasectomy confirmation of azoospermia. 
 
Tubal occlusion PLUS male condom  
 
IUD PLUS male condom.  Provided coils are copper-banded 
Acceptable hormonal methods: 
 
Normal and low dose combined oral pills PLUS male condom  
 
Cerazette (desogestrel) PLUS male condom.  Cerazette is currently the only highly efficacious 
progesterone based pill. 
 
Hormonal shot or injection (eg., Depo-Provera) PLUS male condom 
 
Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom  
 
Norelgestromin / EE transdermal system PLUS male condom  
 
Intrauterine system [IUS] device (eg., levonorgestrel releasing IUS -Mirena®) PLUS male condom  
 
Intravaginal device (e.g., EE and etonogestrel) PLUS male condom  
13.0 
Summary of Changes 

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Protocol Amendment 1 (Protocol Version 2 dated 07 NOV 2017) 
 
• 
Updates to Section 5.13: Time and Events Table 
o 
Addition of Thyroid lab panel (Free T3, Free T4, TSH) time points at C2D1 and C6D1. 
o 
Removal of Pembro Administration timepoint at C1D8. 
o 
Addition of +/- 3 day window to treatment phase procedures.  
o 
Addition of Hematology and Chemistry time points at C1D1, C1D8, C1D15.  
 
Protocol Amendment 2 (Protocol Version 3 dated 21 DEC 2017) 
 
• 
Addition of Co-Investigators: Alain Mita, MD; Reva Basho MD; Bobbie Rimel; MD 
 
• 
Section 4.1: Addition of Table 3: Dose Modification and Toxicity Management Guidelines for 
Immune-related AEs Associated with Pembrolizumab 
 
• 
Section 4.3: Clarification to allow for palliative radiation  
 
• 
Section 5.12: Modification to Time and Events Table 
 
o 
Clarification that Pembro administration will occur Q3W D1 of each cycle. Addition of 
check box at C2D1. 
 
Protocol Amendment 3 (Protocol Version 4 dated 12 MAR 2020) 
 
• 
Cover page:  
o 
Updated study title. 
o 
Removal of co-investigator Dr. Julie Dunhill. 
• 
Study Schema: Updated to add treatment with olaparib. 
• 
Study Summary: 
o 
Updated to add treatment with olaparib. 
o 
Increased accrual duration to 36 months. 
o 
Increased duration of trial to 42 months. 
• 
Section 1.0 Background and Rationale: Updated to reflect treatment with olaparib, 
inclusion of subjects with or without prior PARP-inhibitor exposure, and rationale for 
allowing subjects with ER+/PR+ disease to continue endocrine therapy. Updated with 
most current pembrolizumab data.  
• 
Section 2.1 Primary Objective: Revised to reflect treatment with olaparib. 
• 
Section 2.2 Secondary Objectives: Revised for consistency with protocol inclusion 
criteria. 
• 
Section 3.1 Inclusion Criteria: 
o 
3.1.8 Revised table of adequate organ fucntion per updated Merck template. 
• 
Section 3.2 Exclusion Criteria: 
o 
3.2.4 Clarification to allow inclusion of ER+/PR+ subjects receiving endocrine 
therapy; subjects with HER2+ disease will be required to discontinue Herceptin 
(trastuzumab). 
o 
3.2.5.1 Clarification to allow inclusion of patients with or without prior PARP-
inhibitor exposure. 
o 
3.2.12. Added examples of live vaccines per Merck template. 
• 
Section 4.1 Treatment Dosage and Administration and Section 4.2.2 Toxicities and 
Dosing Delays: Addition of olaparib treatment per standard of care and subject 
completion of compliance diary. 
• 
Section 4.2.1. Pembrolizumab: Updated toxicity management guidelines per Merck 
template. 
• 
Section 4.2.2. Olaparib: New section referring to olaparib package insert. 

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• 
Section 4.3 Concomitant Medications: Clarification that subjects with ER+/PR+ disease 
may continue endocrine therapy; subjects with HER2+ disease will be required to 
discontinue Herceptin (trastuzumab). 
• 
Section 4.4. Supportive Care Guidelines: Edited to follow updated Merck template. 
• 
Section 4.5 Duration of Therapy: Addition of olaparib 
• 
Section 4.6 Duration of Follow-up: Removal of re-treatment with pembrolizumab. 
• 
Section 5.0 Study Procedures: Addition of EKG at baseline. 
• 
Section 5.7 Laboratory Safety Evaluations: Addition of coagulation parameters 
• 
Section 5.14 Time and Events Table:  
o 
Addition of EKG at baseline 
o 
Addition of CBC and CMP at C2 D8. 
o 
Addition of coagulation parameters 
o 
Addition of olaparib daily dosing and compliance diary completion. 
o 
Addition of footnotes 7-9 for consistency with Merck safety language and addition 
of olaparib. 
o 
Minor clarification to footnote 5; addition of footnote 10 for clarification. 
• 
Section 6.1.2 Adverse Events: Addition of AE collection for events determined to be 
unexpected and at least possibly related to olaparib. 
• 
Section 6.4 Data Collection Procedures for Adverse Events: Clarification that abnormal 
laboratory findings of no clinical significance are not considered reportable AEs. 
• 
Section 6.5.2 Expedited Reporting: Addition of boilerplate language for reporting to 
DSMC. 
• 
Section 6.5.3 Reporting to the Institutional Review Board: Updated to reflect revised IRB 
reporting policy. 
• 
Section 7.0 Drug Information: Addition of olaparib; revisions to follow updated Merck 
template. 
• 
Section 10 Study Management: Updated institutional boilerplate language. 
• 
Addition of Olaparib Dosing Diary (separate document). 
 
Protocol Amendment 4 (Protocol Version 4.1 dated 15 SEP 2020) 
• 
Cover page: Removal of co-investigator Dr. Sarna. 
• 
Section 5.14 Time and Events Table, footnote 8: Clarification that Olaparib dosing must 
begin within 3 days of pembrolizumab C1D1. 
• 
Section 6.4 Steps to Determine if an Adverse Event Requires Expedited Reporting, 
Section 6.6.1 Expedited Reporting to PI: Clarification that SAEs and ECIs should be 
reported for 90 days after last pembrolizumab dose or until new anticancer treatment is 
initiated, but for a minimum of 30 days, whichever occurs first. 
• 
Section 6.4 Steps to Determine if an Adverse Event Requires Expedited Reporting: 
Clarification of sources of current known adverse events.  
• 
Section 6.5 Data Collection Procedures for Adverse Events: Clarification of adverse 
event reporting timeframe. 
 
Protocol Version 5 dated 19APR2021  
• 
Inclusion criterion 3.1.6: Inclusion of BRCA somatic mutations. 
• 
Exclusion criterion 3.2.2: Minor formatting change for clarification. 
• 
Exclusion criterion 3.2.12 and Section 4.3.2 Prohibited Concomitant Medications have been 
revised regarding vaccine administration per Merck’s revised pembrolizumab protocol template. 
• 
Section 4.2.1 Pembrolizumab and Table 3 have been updated per Merck’s revised 
pembrolizumab protocol template.  
• 
Section 4.5 Duration of Therapy: The maximum duration of study treatment will be 35 
administrations of pembrolizumab (approximately 2 years).  
• 
Addition of Section 4.8 Subject Replacement and Evaluability Guidelines 
• 
Section 5.15 Time and Events table:  

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o 
Timing of tumor marker measurements will be as per standard of care, at the 
investigator's discretion 
o 
Footnote 3: The maximum duration of study treatment will be 35 administrations of 
pembrolizumab (approximately 2 years).  
o 
Addition of footnote 11: The archival tumor tissue for correlative studies may be sent to 
QualTek any time after eligibility verification.  
• 
Section 6.1.2 Events of Clinical Interest: Incorporation of pembrolizumab template language for 
overdose.  
• 
Section 6.4.5 Expedited Reporting to Merck: Addition of phone and email reporting options.  
• 
Section 9.2 Sample Size and Early Stopping: Clarification of the definition of favorable 
response/clinical benefit relevant to the early stopping rule. 
• 
Section 9.3 Data Analysis Plans: Deletion of inconsistent definition of early stopping rule.  
 
 Protocol Version 6 dated 16JUL2021  
• 
Cover page: Removal of co-investigator Rimel; addition of co-investigator El-Masry 
• 
Throughout protocol: 
o 
Addition of HDR-defect cohort 
o 
Addition of Tempus HRD testing at screening for subjects who do not qualify based on 
BRCA status 
o 
Change in olaparib from standard of care drug to research drug, due to addition of HDR-
defect cohort. Incorporation of olaparib protocol template language in the following 
sections: 
▪ 
Sections 3.1-3.2: Inclusion/exclusion criteria 
▪ 
Section 4.1.1: Meals and dietary restrictions 
▪ 
Section 4.3 Concomitant Medications/Treatments 
▪ 
Section 4.2.2 Olaparib Dose Reductions 
▪ 
Section 4.2.3 Olaparib Management of Adverse Events 
▪ 
Section 6.1.2.1 Olaparib Overdose 
▪ 
Section 12: Appendix: Acceptable Birth Control Methods  
• 
Study Schema, Study Summary, and Section 1.4 Rationale: Correction to include subjects with 
somatic BRCA mutations. 
• 
Section 4.5 Duration of Therapy: Addition of parameters for subjects to remain on treatment 
following initial disease progression by RECIST 1.1. until confirmation of progression 4-8 weeks 
later.  
• 
Section 5 Study Procedures: Screening window extended from four weeks to six weeks prior to 
C1D1. 
• 
Section 5.15 Time and Events table:  
o 
Screening window extended from four weeks to six weeks prior to C1D1. 
o 
Addition of Tempus HRD testing and footnote 12  
o 
Addition of +/- 7 day window for end-of-treatment visit.  
• 
Addition of Section 7.2: Olaparib drug information. 
 
Protocol version 7 dated 03AUG2021 
 
• 
Removed Dr. McArthur as an Investigator 
 
• 
Exploratory Objectives, Section 2.3.1: Removed exploratory objective related to (ir) RECIST 
 
2.3.1     Exploratory: ORR, PFS, CBR and DOR based on immune-related (ir)RECIST as 
assessed by local investigator/local radiology. 
 
• 
Correlative Objectives, Section 2.3.1: Renumbered Correlative Study section 
 
2.3.12   Correlative Studies 
 

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• 
Study Summary, page 3 & Inclusion Criteria, Section 3.1.3: Revised prior line therapy 
inclusion criteria to allow 1st line therapy for patients who have progressed within 12 months 
following neoadjuvant or adjuvant treatment. 
 
3.1.3     Advanced BRCA-mutated and/or HDR-defect breast cancer progressing on or after prior 
therapy for metastatic disease or locally advanced disease; Prior therapy is defined as follows: for 
triple negative breast cancer – progressing after at least 1 line of any prior chemotherapy; for 
HER2 positive disease must have progressed after at least two HER2 directed therapies in the 
metastatic setting including ado-trastuzumab emtansine (T-DM1); for hormone receptor positive 
disease (ER, PR, or both) must have progressed after palbociclib plus hormonal therapy . 
Patients with progression within 12 months from previous neoadjuvant or adjuvant treatment 
could be enrolled in the study as 1st line therapy in metastatic setting. 
 
• 
Exclusion Criteria, Section 3.2.5: Revised exclusion criteria to allow for patients who were on 
previous immunotherapy treatment. 
 
3.2.5     Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any 
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).  Has 
participated in another MK03475 trial. 
 
• 
Events of Clinical Interest, Section 6.1.2 & Expedited Reporting to Merck, Section, 5.4.5: 
Update the fax number for reporting adverse events to Merck, per the recent contract 
amendment. 
 
  FAX 215 993661-12206229 
 
Protocol v8 dated 11MAR2022 
• 
Study Summary and Section 3.1, Inclusion Criteria: 
o 
Expand recruitment to allow patients who have progressed on any CDK4/CDK6 inhibitor. 
3.1.3 
Advanced BRCA-mutated and/or HDR-defect breast cancer progressing on or 
after prior therapy for metastatic disease or locally advanced disease; Prior therapy is 
defined as follows: for triple negative breast cancer – progressing after at least 1 line of 
any prior chemotherapy; for HER2 positive disease must have progressed after at least 
two HER2 directed therapies in the metastatic setting including ado-trastuzumab 
emtansine (T-DM1); for hormone receptor positive disease (ER, PR, or both) must have 
progressed after palbociclib a CDK4/CDK6 inhibitor plus hormonal therapy. 
• 
Section 4.5, Duration of Therapy: 
o 
Clarify the methods for confirming disease progression. 
In patients with initial disease progression substantiated by radiographic imaging per 
RECIST 1.1, study treatment may continue until repeat imaging is conducted, at least 4 
weeks and no later than 8 weeks later, under the following conditions: 
- 
No worsening of ECOG Performance Status 
- 
No clinically relevant increases in disease-related symptoms thought to be 
associated with disease progression 
- 
No requirement for intensified management of disease-related symptoms exists, 
including increased analgesia, radiotherapy, or other palliative care. 

IIT2015-18-MITA-MK3475 
________________________________________________________________________ 
Protocol Version 9 dated 05DEC2023 
 
56 
 
Disease progression can also be confirmed histologically, cytologically, or 
surgically, or by physical examination or other clinical signs, per PI discretion. 
 
Protocol v9 dated 05DEC2023 
• 
Removed Dr. Basho as Co-I. 
• 
Biostatistician updated to Marie Lauzon, MS 
• 
Section 5.15 Time and Events Table: Removal of erroneous footnote 6. 
• 
Section 10: Updated throughout to current boilerplate template language.