Clinical trial NCT04483544
Conditions: Cervical Cancer Cervical Carcinoma
Sponsor: Baptist Health South Florida
Start date: 2020-12-03; Completion date: 2024-12-12
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study is a non-randomized, open-label phase II clinical trial to test the investigational combination of the drug pembrolizumab with the drug olaparib in patients diagnosed with advanced or recurrent cervical carcinoma after standard chemotherapy.

Detailed description:

Arms: arm 1: PD-1 inhibitor pembrolizumab, in combination with the PARP inhibitor olaparib
Interventions: intervention 1: pembrolizumab intervention 2: olaparib
Intervention descriptions: intervention 1: PD-1 inhibitor pembrolizumab, 200mg intravenously (IV) every 3 weeks intervention 2: PARP inhibitor olaparib 300 mg orally, twice daily (BID)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Immunotherapy in combination with PARP inhibition in advanced cervical 
cancer patients functionally competent or deficient for the Fanconi Anemia 
repair pathway 
 
 
Protocol Number: 2019-JEK-DIA-001 
Protocol Version: Version 1.0 
Protocol Version Date: 10 Feb 2020 
 
 
Principal Investigator: 
 
John P. Diaz, MD 
Miami Cancer Institute, Baptist Health South Florida 
8900 N. Kendall Drive, Miami, FL 33176 
 786-596-2000 
Email: JohnPD@baptisthealth.net  
 
 
Sponsor: 
  
Miami Cancer Institute, Baptist Health South Florida 
8900 N. Kendall Drive, Miami, FL 33176 
 
 
IND Number: 151495 
 
 
Study Funding Provided By: 
 
Florida Department of Health  
James & Esther King Biomedical Research Program 
Grant # 9JK03 
 
 
Study Drug Support Provided By: 
 
Merck & Co, Inc. 
Merck Investigator Studies Program # 59481 
NCT Number: NCT04483544


Protocol # 2019-JEK-DIA-001 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab and Olaparib in Cervical Cancer Patients 
Trial Phase 
II 
Clinical Indication 
Cervical Cancer 
Trial Type 
Therapeutic 
Type of control 
None 
Route of administration 
Intravenous and Oral 
Trial Blinding 
None 
Treatment Groups  
One 
Number of trial participants 
48 
Estimated enrollment period 
2-3 years 
Estimated duration of trial 
3-4 years 
Duration of Participation 
Until lack of clinical benefit is demonstrated. 
Estimated average length of 
treatment per patient 
6 months 
 
 
 
 
2.0 TRIAL DESIGN 
The study is a non-randomized, open-label phase II clinical trial of the PD-1 inhibitor pembrolizumab, 
in combination with the PARP inhibitor olaparib, in patients with stage IV, unresectable or recurrent 
cervical cancer after failure of first-line therapy.  
Patients will be treated with standard doses of pembrolizumab, 200 mg intravenously (IV) every 3 weeks 
[Chung et al., 2019], which is approved for metastatic cervical cancer patients with PDL-1 expression 
(CPS ≥1) and disease progression on or after chemotherapy. They will also receive olaparib 300mg 
orally (PO) twice daily (BID), which is the FDA approved dose for treatment of BRCA positive ovarian 
and breast cancers [Barber et al., 2013; Swisher, 2008; Bouwman et al., 2010; Robson et al., 2017]. One 
cycle is defined as 3 weeks or 21 days, and both drugs will be started on day 1 of cycle 1. Treatment 
will be continued until progressive disease or unacceptable toxicity. Evaluation for response with 
imaging (CT or MRI) will be performed every 9 weeks (3 cycles) using Immune Response Evaluation 
Criteria (iRECIST) [Seymour et al., 2017].  By this set of criteria, progression will need confirmation 
with a repeat scan at least four weeks later to rule out the rare but occasionally seen pseudo-progression.  
New lesions are added to the total burden of disease and only by themselves do not represent 
progression.   
Treatment beyond initial investigator-assessed iRECIST-defined progression will be permitted in a case-
by-case basis if the treating physician can document that the patient is experiencing clinical benefit and 
is tolerating study therapy.  
Overlapping toxicities to the combination are not expected.  However, the first six patients on the study 
will be evaluated for any grade 4 hematologic or grade 3 or higher non-hematologic toxicity during the 
first two cycles of treatment.  Adjustment of the doses of olaparib to 300 mg PO daily will be made in 
subsequent patients if grade 4 hematologic toxicities lasting longer than 7 days, neutropenic fevers or 
grade 3 non-hematologic toxicities lasting longer than 7 days are observed in at least three of the initial 


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six patients. If intolerable toxicities arise after three or more cycles in patients otherwise experiencing 
clinical benefit, patients will have the option of continue pembrolizumab as monotherapy. Special 
attention will be placed on persistent grade 3 or higher anemia, as myelodysplastic syndromes have been 
described in around 1.5% of patients receiving olaparib in previous trials[Pujade-Lauraine et al., 2017; 
Robson et al., 2017; Ledermann et al., 2012; Moore et al., 2014].  Hematologic consultation (with bone 
marrow aspiration as needed) will be requested for patients developing persistent anemia. 
Patients will be followed for three (3) years or until time of death. ORR, PFS, and OS will be determined. 
Correlative studies will determine the functional status of the Fanconi Anemia pathway promoting 
homologous recombination repair as well as the microbiome composition in responsive and non-
responsive patients. In addition, tumor mutation burden, MSI, and PD-L1 expression will be correlated 
with Fanconi Anemia pathway status and response to therapy. 
2.1 Trial Design 
The study is a non-randomized, open-label, multi-center, phase II clinical trial of the PD-1 inhibitor 
pembrolizumab, in combination with the PARP inhibitor olaparib, in patients with stage IV, unresectable 
or recurrent cervical cancer after failure of first-line therapy. 
2.2 Trial Schema 
 
2.3 Schedule of Activities 
Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatm
ent 
Post-Treatment 
Treatment Cycle/Title: 
Screening 
1 
2  
3 
4 
To be repeated 
beyond 8 cycles 
Discon 
Safety 
Follow
-up 
Follow 
Up 
Visitsb 
Survival 
Follow-Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-28 to -1 
 
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 
At time 
of 
Discon 
±7 
30 
days 
post 
discon 
±7 
Every 8 
weeks 
post 
discon 
± 7 
Every 12 
weeks ±7 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 


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Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatm
ent 
Post-Treatment 
Treatment Cycle/Title: 
Screening 
1 
2  
3 
4 
To be repeated 
beyond 8 cycles 
Discon 
Safety 
Follow
-up 
Follow 
Up 
Visitsb 
Survival 
Follow-Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-28 to -1 
 
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3 
At time 
of 
Discon 
±7 
30 
days 
post 
discon 
±7 
Every 8 
weeks 
post 
discon 
± 7 
Every 12 
weeks ±7 
Prior and Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X  
X 
X 
 
 
 
 
Trial Treatment Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
X  
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum β-
HCG 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
Xa  
Xb 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Comprehensive Serum Chemistry 
Panel 
Xa 
Xb 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Urinalysis 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
Xa 
 
 
X 
 
 
Xf 
 
 
 
 
 
 
Efficacy Measurements 
Tumor Imaging 
X 
 
 
 
X 
 
 
 
Xd 
X 
 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collection 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Stool Collection 
Xe 
 
 
 
Xe 
 
 
 
 
Xe 
 
 
 
a Must be performed within 10 days of the first treatment visit (Cycle 1 Day 1). 
b Hematology (CBC with differential) and Creatinine results must be available and reviewed by the 
Investigator prior to infusion. A spot creatinine result may be used to proceed with treatment, as 
Chemistry results may not be available.  
c Must be performed within 72 hours of the first treatment visit (Cycle 1 Day 1).   
d Tumor imaging to be done every 9 weeks (within 1 week before every 4th cycle) and will only be 
required every 12 weeks for patients that have been on treatment for more than 1 year. 
e See Protocol Laboratory Manual. 
f Begining with Cycle 9, T3, FT4 and TSH will be performed every 3 cycles/9 weeks. 


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3.0 OBJECTIVE(S), HYPOTHESIS(ES), AND ENDPOINT(S) 
3.1 
Primary Objective(s), Hypothesis(es), and Endpoint(s) 
(1) Objective: To determine the ORR through the Immune Response Evaluation Criteria in Solid 
Tumors (iRECIST) [Seymour et al., 2017]. 
Hypothesis: The combination of PD-1 and PARP inhibition will result in an immune overall 
response for patients with recurrent cervical carcinoma. 
Primary Endpoint: Immune overall response rate (iORR)  
3.2 
Secondary Objective(s), Hypothesis(es), and Endpoint(s) 
(1) Objective: To determine PFS and OS, defined as time from treatment initiation to disease 
progression or death.     
Hypothesis: The combination of PD-1 and PARP inhibition will result in a progression-free 
survival advantage for patients with recurrent cervical carcinoma. 
Secondary Endpoint: Progression-free survival (PFS) 
(2) Objective: To evaluate safety and tolerability per the Common Terminology Criteria for 
Adverse Events (CTCAEv5.0) [Common Terminology Criteria for Adverse Events 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_8.5x11.pdf. Accessed September 30, 2018]. 
Hypothesis: Combination of PD-1 and PARP inhibitors is tolerable in patients with recurrent 
cervical cancer. 
Secondary Endpoint: Toxicities associated with the regimen 
(3) Objective: To evaluate if baseline tumor deficiencies in the Fanconi Anemia pathway are 
associated with antitumor responses to the combination as assessed by the FATSI assay, 
performed on archived paraffin embedded tumor tissues. 
Hypothesis: Deficiencies in homologous recombination (HR) repair based on the Fanconi 
Anemia Triple Stain Immunofluorescence (FATSI) assay will predict a higher iORR to the 
combination of pembrolizumab and olaparib in patients with cervical cancer. 
Secondary Endpoint: Immune overall response rate (iORR) 
(4) Objective: To determine duration of response (DoR). 
Hypothesis: The combination of PD-1 and PARP inhibition will result in a duration of response 
(DoR), defined as time from documentation of tumor response to disease progression, in this 
cohort. 
Secondary Endpoint: Duration of response (DoR) 


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3.3 
Exploratory Objective(s) 
(1) Objective: To determine whether increased baseline TMB, other deficiencies in DNA damage 
repair mechanisms and PD-L1 expression correlate with FATSI negativity, and if these findings 
are independently associated with response to therapy. 
4.0 BACKGROUND & RATIONALE 
Excitement has been generated following the identification of mutations on the BRCA genes as potential 
predictors of response to PARP inhibitors and recent clinical trials demonstrating antitumor activity with 
PARP inhibitors in cancer patients with germline BRCA deficiency [Bryant et al., 2005; Farmer et al., 
2005; Tutt et al., 2009;  Fong et al.,2009; W Audeh et al., 2010]. The rationale behind these observations 
is that the BRCA genes are involved in homologous recombination (HR), an example of double-strand 
break repair, and patients with inherited BRCA germline heterozygocity who developed cancer had 
acquired BRCA homozygous deficiency in their tumors. The resulting genetic instability becomes an 
advantage for the tumor to perpetuate. Targeting an additional repair pathway, such as base excision 
repair through PARP inhibition would induce inability for the tumor to survive, an example of a concept 
commonly called synthetic lethality. The main role of PARP is to detect and initiate an immediate 
cellular response to metabolic, chemical, or radiation-induced single-strand breaks by signaling the 
enzymatic machinery in single-strand breaks.   
The BRCA genes collaborate with 
several others in the Fanconi Anemia 
(FA) HR pathway [Bagby, 2003; 
D'Andrea et al., 2003; Reid et al., 2007; 
Xia et al., 2007; Smogorzewska et al., 
2007; Kim et al., 2011; Vaz et al., 2010; 
Machida et al., 2006; Meetei et al., 2004; 
Garcia-Higuera et al., 2000]. Seventeen 
complementation 
groups/genes 
plus 
other interactive proteins have been 
described. 
Monoubiquitination 
of 
FancD2 and FancI by an FA core 
complex followed by nuclear co-
localization with other DNA damage 
response proteins result in the formation of nuclear repair foci, thus foci formation is the focal functional 
output of this pathway (Fig 1). Based on this, we developed the FATSI Assay, an immunofluorescence 
based method that detects FancD2/DAPI/Ki67 and permits the observation of FancD2 foci formation 
(or lack thereof) in the nucleus of proliferating cells in paraffin embedded tumor tissues [Duan et al., 
2013].  We also developed a targeted FA sequencing panel to evaluate potential genetic defects resulting 
in Fanconi Anemia functional deficiency and confirmed the ability of the FATSI test to enrich for 
patients exhibiting these alterations at the genomic level. 
Supported by an NCI R01 and The NCI Cancer Therapy and Evaluation Center Phase II contract we 
screened >600 patients in a clinical trial for foci formation deficiency [Villalona-Calero et al.,2016]. 
Functional deficiency was found in 29% of solid tumor patients. We also showed that it is safe to 
administer the PARP inhibitor veliparib at doses up to 300 mg per day to patients with FA deficient 


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tumors, and that veliparib can be safely combined with the DNA damaging agent mitomycin C. Activity 
was seen for the combination in heavily pretreated patients [Villalona-Calero et al., 2016]. Veliparib as 
a single agent, showed clinical activity in BRCA/RAD51 germline mutated breast cancer, initially 
identified through FATSI.  However, PARP trapping, rather than PARP inhibition, appears to be a better 
measure of the activity of PARP inhibitors and veliparib has been demonstrated to be a weaker PARP 
trapping agent compared to agents such as olaparib and niraparib [Murai et al., 2012; Murai et al., 2014]. 
4.1 
Background 
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.  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. 
Investigators should be familiar with the current olaparib (AZD2281) Investigator Brochure (IB). 
Olaparib (AZD2281, KU-0059436) is a potent Polyadenosine 5’diphosphoribose [poly (ADP ribose)] 
polymerisation (PARP) inhibitor (PARP-1, -2 and -3) that is being developed as an oral therapy, both 
as a monotherapy (including maintenance) and for combination with chemotherapy and other anti-
cancer agents. 
PARP inhibition is a novel approach to targeting tumors 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).  Tumors with HR deficiencies 
(HRD), such as ovarian cancers in patients with BRCA1/2 mutations, cannot accurately repair the DNA 
damage, which may become lethal to cells as it accumulates.  In such tumor types, olaparib may offer a 
potentially efficacious and less toxic cancer treatment compared with currently available chemotherapy 
regimens.  
BRCA1 and BRCA2 defective tumors are intrinsically sensitive to PARP inhibitors, both in tumor 
models in vivo [Rottenberg et al., 2008; Hay et al., 2009] and in the clinic [Fong et al., 2009]. The 
mechanism of action for olaparib results from the trapping of inactive PARP onto the single-strand 
breaks preventing their repair [Helleday, 2011; Murai et al 2012].  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 tumor cell lines in vitro and in xenograft and 
primary explant models as well as in genetic BRCA knock-out models, either as a stand-alone treatment 
or in combination with established chemotherapies. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of olaparib is provided in 
the Investigator’s Brochure. 


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4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (Disis, 2010).  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes 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 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  (Dudley 
et al., 2005; Hunder et al., 2008). 
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 immunoglobulin (Ig) superfamily member related 
to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) 
that has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands 
(PD-L1 and/or PD-L2) [Greenwald et al., 2005; Okazaki et al., 2001]. 
The structure of murine PD-1 has been resolved (Zhang et al., 2004).  PD-1 and its family members 
are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible 
for ligand binding and a cytoplasmic tail 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, and an immunoreceptor tyrosine-based switch motif.  Following T-cell 
stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor 
tyrosine-based switch motif within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated protein 
kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade  [Okazaki et al., 2001; 
Chemnitz et al., 2004; Sheppard et al., 2004; and Riley, 2009].  The mechanism by which PD-1 down-
modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because both molecules 
regulate an overlapping set of signaling proteins [Parry et al., 2005; Francisco, 2010].  As a 
consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic intervention in cervical 
cancer.  
On June 12, 2018, the FDA approved pembrolizumab for patients with recurrent or metastatic cervical 
cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as 
determined by an FDA-approved test. The accelerated approval was based on the results of 
KEYNOTE 158 (NCT02628067). Pembrolizumab was investigated in 98 patients with recurrent or 
metastatic cervical cancer enrolled in a single cohort of a multicenter, non-randomized, open-label, 
multi-cohort trial. Patients were treated with pembrolizumab intravenously at a dose of 200 mg every 
3 weeks until unacceptable toxicity or documented disease progression [Chung, 2019].  
Among the 98 patients, 82 (83.7%) patients had tumors that expressed PD-L1 with a CPS ≥1 PD-L1 
status was determined using the PD-L1 IHC 22C3 pharmDx Kit. The major efficacy outcomes were 
objective response rate (ORR) according to RECIST 1.1 as assessed by blinded independent central 
review, and response duration. With a median follow-up time of 10.2 months, the ORR was 12.2% 


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(95% CI: 6.5 to 20.4%), including three complete responses and nine partial responses. All 12 
responses were in patients with PDL-1 positive tumors, for an overall response rate of 14.6% (95% 
CI, 7.8 to 24.2%). The estimated median response duration was not reached (range ≥3.7 to ≥ 18.6+ 
months).  Treatment related grade 3 to 4 adverse events (diarrhea, asthenia, pyrexia, arthralgias and 
increase in AST) occurred in 12.2% of patients.    
PARP inhibition has been evaluated in several randomized controlled trials.  Olaparib was evaluated in 
two randomized, placebo-controlled double-blind, multi-center studies in patients with recurrent ovarian 
cancers who were in response to platinum-based therapy.  SOLO-2 evaluated patients with a gBRCAm, 
who had a response to platinum based therapy.  These patients were then randomized to maintenance 
therapy with olaparib.  The patient who received olaparib had a PFS 19.1 months compared to 5.5 
months in the control arm [Pujade-Lauraine et al., 2017].  STUDY 19 also evaluated olaparib as 
maintenance therapy for recurrent ovarian cancer, regardless of BRCA status and also demonstrated a 
PFS advantage to those women receiving olaparib maintenance [Ledermann et al., 2012].  The POLO 
trial evaluated olaparib for gBRCAm metastatic pancreatic cancer [Golan et al, 2019].  Maintenance 
olaparib demonstrated a longer PFS for this cohort of pancreatic cancer patients.     
 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.1.3  The Interplay between DNA repair deficiency and Immune Checkpoint inhibition 
Le et al. reported a Phase II study evaluating the clinical activity of pembrolizumab, in 41 patients with 
progressive metastatic carcinoma with or without mismatch-repair deficiency [Le et al., 2015]. The 
immune-related objective response rate and immune-related progression-free survival rate were 40% 
(4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal 
cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal 
cancers. The median progression-free survival and overall survival were not reached in the cohort with 
mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort 
with mismatch repair-proficient colorectal cancer.  
Interestingly, patients with mismatch repair-deficient non-colorectal cancer had responses similar to 
those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response 
rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). 
Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-
deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high 
somatic mutation loads were associated with prolonged progression-free survival (P=0.02). Since 
somatic mutations have the potential to encode "non-self" immunogenic antigens the authors 
hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may 
be susceptible to immune checkpoint blockade. 
Vergote et al. is evaluating the combination of pembrolizumab to traditional carboplatin and paclitaxel 
followed by olaparib maintanence therapy, KEYLYNK-001, as first line treatment in BRCA-
nonmutated patients with advanced epithelial ovarian cancer [Vergote et al., 2019].  Similarly, 
KEYLYNK-009 is evaluating efficacy of olaparib plus pembrolizumab with chemotherapy plus 


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pembrolizumab after induction with first-line chemotherapy plus pembrolizumab in triple negative 
breast cancer (TNBC). The primary hypotheses are that olaparib plus pembrolizumab prolongs 
progression-free survival (PFS) compared with chemotherapy plus pembrolizumab. 
4.2 Rationale 
4.2.1 Rationale for the Trial and Selected Population 
The overarching hypothesis for this trial is that the combination of pembrolizumab and olaparib in 
patients with advanced cervical cancer will increase the efficacy of pembrolizumab in this population, 
and that the increase in efficacy will be more marked in those patients harboring recombination repair 
deficiencies in their tumors. We also hypothesize that the combination will be safe and tolerable without 
overlapping toxicities. The mechanism for enhanced response to immunotherapy would be primarily 
through persistence of DNA damage, leading to a greater mutational load and consequently greater 
neoantigen presentation, recognition by the immune system and improved effector T-cell function 
leading to tumor cell death. The FATSI assay will identify those patients in which an innate (both 
somatic or germline) FA pathway repair deficiency exists. 
Forty-eight evaluable patients will be enrolled into this study. Patients must have histologically 
confirmed cervical cancer that is metastatic, unresectable or recurrent and exhibit ECOG performance 
status (PS) of less than or equal to 2. Patients will be eligible after failure of standard of care first line 
therapy. Prior therapy with an immune checkpoint inhibitor (PD-1, PDL-1 or PDL-2) is not allowed. 
PD-L1 positivity is not required for enrollment or treatment, but all patients will have PDL-1 expression 
assessed by the FDA approved PD-L1 IHC 22C3 pharmDx Kit (Agilent technologies, Carpinteria, CA; 
standard at our institution). No prior therapy with a PARP inhibitor is allowed. 
4.2.2 Justification for Dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab for adults across all indications and regardless of tumor type.  As outlined below, 
this dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• Clinical data showing meaningful improvement in benefit-risk including overall survival at 200 
mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred from 
pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK [PBPK] 
analysis) at 200 mg Q3W 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and non-small cell lung cancer (NSCLC), covering different disease settings (treatment 
naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment settings 
(monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg Q3W versus 
10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006).  


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All of these studies demonstrated flat dose- and exposure-response relationships across the doses 
studied representing an approximate 5- to 7.5-fold difference in exposure.  The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied.  Subsequently, flat dose-
exposure-response relationships were also observed in other tumor types including head and neck 
cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg Q3W as 
the appropriate dose independent of the tumor type.  These findings are consistent with the mechanism 
of action of pembrolizumab, which acts by interaction with immune cells, and not via direct binding 
to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated saturation of 
PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a PBPK analysis was 
conducted to predict tumor PD-1 saturation over a wide range of tumor penetration and PD-1 
expression.  This evaluation concluded that pembrolizumab at 200 mg Q3W achieves full PD-1 
saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body weight 
and other participant covariates on exposure, has shown that the fixed-dosing provides similar control 
of PK variability as weight based dosing, with considerable overlap in the distribution of exposures 
from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported by these PK characteristics, 
and given that fixed-dose has advantages of reduced dosing complexity and reduced potential of 
dosing errors, the 200 mg Q3W fixed-dose was selected for evaluation across all pembrolizumab 
protocols. 
The FDA approved dose for treatment of BRCA positive ovarian and breast cancers [Pujade-Lauraine 
et al., 2017; Ledermann et al., 2012] of olaparib 300mg orally (PO) twice daily (BID) will be utilized.  
The dose of olaparib used in this study is 300 mg twice daily which is the currently approved dose. 
One cycle is defined as 3 weeks or 21 days, and both drugs (pembrolizumab and olaparib) will be 
started on day 1 of cycle 1.  Overlapping toxicities to the combination are not expected.  However, the 
first six patients on the study will be evaluated for any grade 4 hematologic or grade 3 or higher non-
hematologic toxicity during the first two cycles of treatment.  Adjustment of the doses of olaparib to 
300 mg PO daily will be made in subsequent patients if grade 4 hematologic toxicities lasting longer 
than 7 days, neutropenic fevers or grade 3 non-hematologic toxicities lasting longer than 7 days are 
observed in at least three of the initial six patients. If intolerable toxicities arise after three or more 
cycles in patients otherwise experiencing clinical benefit, patients will have the option to continue 
pembrolizumab as monotherapy. Special attention will be placed on persistent grade 3 or higher 
anemia, as myelodysplastic syndromes have been described in around 1.5% of patients receiving 
olaparib in previous trials [Pujade-Lauraine, et al., 2017; Ledermann et al., 2012; Moore et al., 2014].   
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
The primary clinical endpoint is overall Objective Response Rate by iRECIST criteria (iORR).  


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Secondary clinical endpoints will include Progression Free Survival (PFS) and Overall Survival (OS) 
and safety and tolerability per the Common Terminology Criteria for Adverse Events (CTCAEv5.0) 
(Common 
Terminology 
Criteria 
for 
Adverse 
Events 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Referen
ce_8.5x11.pdf. Accessed September 30, 2018). 
Although cervical cancer is curable in early stages, once it has recurred or metastasized less than 20% 
of patients survive 5 years (Howlader et al., 2017). Pembrolizumab was recently approved for treatment 
of PD-L1 positive cervical cancer patients in the second line metastatic setting, with an ORR of only 
12.2% in the general population on study (Chung et al., 2019). A proposed model to increase 
pembrolizumab activity is through increasing tumor mutational load and formation of neoantigens 
expressed on cancer cells, thereby leading to greater recognition of those tumor cells by the immune 
system (Rizvi et al., 2015; Snyder et al., 2014; Van Allen et al., 2015). This strategy could be achieved 
through either enriching treated populations with cancer patients harboring innate (germline or somatic) 
DNA repair deficiencies, by combining immune checkpoint inhibitors with compounds causing DNA 
damage, such as platinum and other alkylating agents, or using compounds that directly inhibit DNA 
repair, such as (PARP) inhibitors.   
Olaparib is an oral inhibitor of PARP, causing synthetic lethality in BRCA1/2 deficient tumors and is 
FDA approved for the treatment of metastatic breast and ovarian cancers harboring germline mutations 
in the BRCA genes or as maintenance in ovarian cancer patients with tumors experiencing prior 
sensitivity to platinum agents [Pujade-Lauraine et al., 2017: Robson et al., 2017; Ledermann, et al., 
2012]. 
We expect that the combination of pembrolizumab and olaparib in patients with advanced cervical 
cancer after failure of chemotherapy will lead to increased efficacy compared to single agents in this 
population, and that the increase in efficacy will be substantial in those patients harboring homologous 
recombination repair and other deficiencies in DNA damage repair. We also expect that the combination 
will be safe and tolerable without significant overlapping toxicities. 
4.2.3.2 Planned Exploratory Biomarker Research 
One of the barriers to the generalized applicability of immunotherapy is the identification of patients 
who will derive the most benefit from this type of therapy, and better predictive biomarkers are urgently 
needed. 
Correlative endpoints in this study will include determining the functional status of the Fanconi Anemia 
pathway in promoting homologous recombination repair as well as describing the microbiome 
composition in responsive and non-responsive patients. 
Fanconi Anemia pathway analysis 
 
The principal correlative endpoint is to evaluate if baseline tumor deficiencies in the FA pathway are 
associated with antitumor responses to the combination of pembrolizumab and olaparib, as assessed by 
the FATSI assay performed on archived paraffin embedded tumor tissues. 
 


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Since somatic mutations have the potential to encode "non-self" immunogenic antigens, tumors with a 
large number of somatic mutations due to mismatch-repair defects are predicted to be susceptible to 
immune checkpoint blockade.  Following this logic, tumors with other types of repair deficiency, such 
as homologous recombination repair would plausibly have a large number of somatic mutations and 
would likely be susceptible to immune checkpoint blockade.   
 
The FATSI assay has the ability to differentiate between functionally deficient and functionally 
competent Fanconi Anemia pathway tumors and therefore, could be used to identify additional patients 
susceptible to pembrolizumab.  We hypothesize that the efficacy of immune checkpoint inhibitors could 
be increased by combining them with compounds causing DNA damage, or compounds causing 
inhibition of DNA repair such as (PARP) inhibitors. Thus targeting both HR repair and immune 
checkpoints will result in a synergistic anti-tumor effect.  We expect that patients with pre-existing 
homologous recombination repair as assessed by FATSI would benefit the most from this combination 
approach. 
 
The FATSI assay will be performed to assess functional deficiency of the FA pathway, as previously 
described [Duan et al.,. 2013; Villalona-Calero et al., 2016] using archived paraffin embedded tumors. 
We hypothesize that a FATSI negative result, correlated with a higher mutational burden, will be 
associated with a better response rate.  FA deficiency in tumors is not required for enrollment on the 
trial, thus patients with both FA functionally deficient tumors and patients with FA functionally 
competent tumors will be receiving treatment. Based on prior screening data in solid tumors [Villalona-
Calero et al., 2016], we anticipate that approximatively 30% of patients in this trial will be FA 
functionally deficient. 
 
FFPE tumor tissue will be cut at 4 microns, placed on positively charged slides and stained with 
hematoxylin and eosin.  Additional sections for immunofluorescence staining will be placed in a 60oC 
oven for 1 h, cooled, deparaffinized and rehydrated through xylenes and graded ethanol solutions to 
water in standard fashion.  Antigen retrieval will be performed by placing slides in Dako’s TRS (pH 
6.1) antigen retrieval solution (Dako, Carpenteria, CA) in a calibrated vegetable steamer (Black & 
Decker).  Slides will then be placed on a Dako Autostainer for automated staining. Subsequently, tissue 
sections will be incubated for 1 hour at room temperature with a primary antibody cocktail of rabbit 
polyclonal FANC-D2 antibody at a dilution of 1:1000 and a monoclonal anti-Ki67 mouse antibody at a 
dilution of 1:150.  Sections will then be co-incubated for 1 hour at room temperature with a secondary 
antibody (FITC conjugated to anti-rabbit IgG and Alexafluor 594 donkey anti-mouse) at 1:1000.  All 
rinses will be performed on the autostainer with TBST. The sections will be mounted on glass slides 
using a 4’ 6-diamidino-2-phenylindole (DAPI)–containing embedding medium (Vysis Dapi 1, Abbott 
Laboratories, Downers Grove, IL).  FANCD2 foci positive and negative cell lines (MCF-7 and PD20 
cells) will be used as controls. Slides will be analyzed under a Nikon E-400 fluorescence microscope. 
Ki-67 nuclear positivity of greater than 10% (Ki-67/DAPI) is required to consider a sample evaluable. 
Evaluation of a total of 300 cells (300 DAPI stained nuclei) with less than one foci positive nucleus per 
100 cells is the benchmark to define FA pathway deficiency through FATSI. 
 
Exploratory Correlative Endpoints include determining if increased baseline tumor mutation burden 
(TMB), MSI, and PD-L1 expression correlate with FATSI negativity, and if these findings are 
independently associated with response to therapy. 
 


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5.0 METHODOLOGY 
5.1 Study Population 
Diagnosis/Condition for Entry into the Trial  
Patients with metastatic or recurrent histologically confirmed cervical carcinoma who have progressed 
on or after first line standard of care treatment.   
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this study in 
order to be assigned to the study intervention.  Under no circumstances, can there be exceptions to this 
rule. Patients who do not meet the entry requirements are screen failures. 
5.1.1 Participant Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
 
1. Female participants who are at least 18 years of age on the day of signing informed consent with 
histologically confirmed diagnosis of cervical carcinoma will be enrolled in this study. 
 
2. Cervical cancer is a disease of the female genital tract. No male patients will be enrolled. 
 
3. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not 
breastfeeding, and at least one of the following conditions applies:  
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3  
OR  
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the 
treatment period and for at least 120 days after the last dose of study treatment. 
 
4. Participant must have recurrent cervical cancer and have a low potential for cure with radiation 
therapy or surgery alone and: 
a. May have received up to 2 prior chemotherapy regimens.  Platinum sensitizing agents 
for radiation therapy are considered a chemotherapy regimen. 
 
5. The participant (or legally acceptable representative if applicable) provides written informed 
consent for the trial, which includes compliance with the requirements and restrictions listed in 
the informed consent form (ICF) and this protocol.   
 
6. Have measurable disease based on RECIST 1.1.  Lesions situated in a previously irradiated area 
are considered measurable if progression has been demonstrated in such lesions. 
 
7. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a 
tumor lesion not previously irradiated.  Formalin-fixed, paraffin embedded (FFPE) tissue blocks 
are preferred to slides.  Newly obtained biopsies are preferred to archived tissue. 
 


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8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation 
of ECOG is to be performed prior to the first dose of treatment. 
 
9. Patient’s life expectancy ≥ 16 weeks. 
 
10. Have adequate organ function as defined in the following table (Table 1).  Specimens must be 
collected within 10 days prior to the start of study treatment. Before patients can be enrolled, 
they must have normal laboratory values as outlined in Table 1. Labs must also fall within normal 
limits prior to infusion.  
Table 1  Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 × ULN OR 
≥30 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 
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 per institutional standard. 
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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5.1.2 Participant Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to the first dose of 
treatment (see Appendix 3).  If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. 
2. Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first 
dose of study treatment, another pregnancy test (urine or serum) must be performed and must be 
negative in order for subject to start receiving study medication.  
 
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent 
directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).  
 
4. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks 
prior to the first dose of treatment.  
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or 
baseline. Participants with ≤Grade 2 neuropathy may be eligible. 
 
Note: If participant received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting study treatment. 
 
Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) 
within 3 weeks prior to study treatment 
 
5. Has received prior radiotherapy within 2 weeks of start of study intervention.  Participants must 
have recovered from all radiation-related toxicities, not require corticosteroids, and not have had 
radiation pneumonitis.  A 1-week washout is permitted for palliative radiation (≤2 weeks of 
radiotherapy) to non-CNS disease. 
 
6. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples of live 
vaccines include, but are not limited to, the following:  measles, mumps, rubella, varicella/zoster 
(chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine.  
Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; 
however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not 
allowed. 
 
7. Is currently participating in or has participated in a study of an investigational agent or has used 
an investigational device within 4 weeks prior to the first dose of study intervention. 
 
Note:  Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous investigational agent. 


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8. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, 
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, 
nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, 
erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting 
olaparib is 2 weeks. 
9. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A 
inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting 
olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. 
10. Major surgery within 2 weeks of starting study treatment and patients must have recovered 
from any effects of any major surgery. 
11. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing 
exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive 
therapy within 7 days prior to the first dose of study drug.  
12. Has a history of a second malignancy, unless potentially curative treatment has been completed 
with no evidence of malignancy for ≥5 years except: adequately treated non-melanoma skin 
cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, 
grade 1 endometrial carcinoma.    
 
Note: The time requirement does not apply to participants who underwent successful definitive 
resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial 
bladder cancer, in situ cervical cancer, or other in-situ cancers 
 
13. Has known active CNS metastases and/or carcinomatous meningitis.  Participants with 
previously treated brain metastases may participate provided they are radiologically stable, i.e. 
without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat 
imaging should be performed during study screening),  clinically stable and without requirement 
of steroid treatment for at least 14 days prior to first dose of study intervention. 
Patients with symptomatic uncontrolled brain metastases.  A scan to confirm the absence of brain 
metastases is not required. The patient can receive a stable dose of corticosteroids before and 
during the study as long as these were started at least 4 weeks prior to treatment.  Patients with 
spinal cord compression unless considered to have received definitive treatment for this and 
evidence of clinically stable disease for 28 days. 
14. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients, or patients 
with a known hypersensitivity to olaparib or any of the excipients of the product. 
 
15. Has 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). Replacement 
therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.  


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16. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. 
17. Has an active infection requiring systemic therapy. 
18. Has a known history of Human Immunodeficiency Virus (HIV) infection.   
Note: No HIV testing is required unless mandated by local health authority. 
Immunocompromised patients, e.g., patients who are known to be serologically positive for 
human immunodeficiency virus (HIV), solid organ, and hematopoietic transplant patients. 
19. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) 
or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.  
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health 
authority.  
Patients with known active hepatitis (i.e. Hepatitis B or C). 
− 
 Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen 
(HBsAg) result.  Patients with a past or resolved HBV infection (defined as the 
presence of hepatitis B core antibody and absence of HBsAg) are eligible. 
− 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction is negative for HCV RNA. 
20. Has a known history of active TB (Bacillus Tuberculosis).   
21. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the subject’s participation for the full duration 
of the study, or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator.   
Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-
malignant systemic disease or active, uncontrolled infection.  Examples include, but are not 
limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, 
uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava 
syndrome, extensive interstitial bilateral lung disease on High Resolution Computed 
Tomography (HRCT) scan or any psychiatric disorder that interferes with the requirements of 
the trial or prohibits obtaining informed consent. 
22. Has known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial. 
23. Is pregnant or breastfeeding or expecting to conceive children within the projected duration of 
the study, starting with the screening visit through 120 days after the last dose of trial treatment. 


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24. Has had an allogenic tissue/solid organ/bone marrow transplant or double umbilical cord blood 
transplantation (dUCBT). 
25. Resting ECG and EKG 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. 
26. Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) V. 5.0 grade 
2) caused by previous cancer therapy, excluding alopecia. 
27. Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of 
MDS/AML. 
28. Patients unable to swallow orally administered medication and patients with gastrointestinal 
disorders likely to interfere with absorption of the study medication. 
29. Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells 
and platelet transfusions are acceptable). 
 
5.1.3 Lifestyle Considerations 
5.1.3.1 Meals and Dietary Restrictions 
Participants are prohibited to consume grapefruit juice while on olaparib therapy. 
Participants should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
5.1.3.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Refer to Appendix 3 for approved 
methods of contraception. 
5.1.4 Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab and/or 
olaparib, the participant will be immediately discontinued from study intervention(s).  The site will 
contact the participant at least monthly and document the participant’s status until the pregnancy has 
been completed or terminated.  The outcome of the pregnancy will be reported to Merck within 2 
working days 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 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 Merck.   


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5.1.5 Use in Nursing Women 
It is unknown whether pembrolizumab or olaparib is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the nursing infant, 
participants who are breast-feeding are not eligible for enrollment. 
5.2 Trial Intervention(s) 
The intervention(s) to be used in this trial is outlined below in Table 2 
Table 2  Trial Intervention(s) 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 3-
week cycle 
Experimental 
Olaparib tablet 
300 mg 
Twice 
Daily 
Oral 
Daily 
Experimental 
 
Trial intervention(s) should begin as close as possible to the date on which intervention is assigned. 
 
5.2.1 Timing of Dose Administration  
Trial interventions should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial interventions may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
All trial interventions will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion every 3 weeks.  Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  However, given 
the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted 
(i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
Pembrolizumab treatment may continue until 24 months of treatment or 35 doses of pembrolizumab, 
or disease progression, whichever occurs first. 
Olaparib will be initiated on cycle 1 day 1 immediately following the completion of the first dose of 
pembrolizumab. Cycle 1 day 1 infusion should occur in the morning (AM) in order to receive 2 doses 
on day 1.   
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. If vomiting occurs shortly after the olaparib tablets 


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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. 
Patients should be given clear instructions on how and when to take their study treatment.  Patients 
will self-administer olaparib.    
Any change from the dosing schedule, dose interruptions, dose reductions, dose discontinuations 
should be recorded in eCRF. 
5.2.2 Dose Modification and toxicity management for immune-related AEs associated with 
Olaparib and/or Pembrolizumab 
Olaparib Dose Modification  
Olaparib Dose Reductions  
In case a dose reduction is necessary, olaparib will be administered as follows:  
Table 3a 
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 3b 
Dose reduction for study treatment 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 3c 
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 
 
For guidance on dose reductions for management of AEs (including renal impairment), refer to section 
6.2. 


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For guidance on dose reductions when concomitant strong or moderate CYP3A inhibitors cannot be 
avoided see section 6.5. 
When 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 (see Section 8.4.6), or one 150 mg tablet twice daily or one 100 mg 
tablet twice daily (see Section 6.5). 
Pembrolizumab Dose Modification 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These immune-
related AEs (irAEs) may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than on 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, 
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 are provided in Table 4. 


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Table 4 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab  
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. Pembrolizumab 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 
pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizum
ab 
Corticosteroid 
and/or other 
therapies  
Monitoring and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer 
corticosteroids 
(initial dose of 1 - 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 
 
Grade 3 or 4, 
or recurrent 
Grade 2  
 
Permanently 
discontinue 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
• Administer 
corticosteroids 
(initial dose of 1 - 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 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 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 


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AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
0.5 - 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 - 2 
mg/kg prednisone 
or equivalent) 
followed by taper 
Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglycemia 
New onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
β-cell failure 
Withhold d 
• Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 
• Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
 
• Monitor participants for hyperglycemia or other signs and 
symptoms of diabetes 
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 
Hyperthyroidis
m  
Grade 2 
Continue 
• Treat with non-
selective 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 


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Hypothyroidis
m 
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 and 
renal 
dysfunction: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(prednisone 
1 – 2 mg/kg or 
equivalent) 
followed by taper 
• Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 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 
All Other 
immune-
related AEs 
Intolerable/per
sistent 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.  
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 
a AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x ULN if 
baseline normal; >3.0 - 10.0 x baseline if baseline abnormal 


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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. For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or 
achieved metabolic control (in case of T1DM) 
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, Stevens-Johnson 
Syndrome and toxic epidermal necrolysis. 
 
 
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 5. 
 
 
 
 
 
 
 
 
Table 5  Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 


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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 intervention 
Participant may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
_____ 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 
intervention. 
No subsequent dosing 


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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 v5.0 (CTCAE) at http://ctep.cancer.gov 
 


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Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as medical / surgical 
events or logistical reasons not related to study therapy. Participants 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. 
 
5.2.3 Second Course * 
All participants who stop study treatment with SD or better may be eligible for up to an additional 17 cycles 
(approximately 1 year) of pembrolizumab treatment if they progress after stopping study treatment from the 
initial treatment phase.  This retreatment is termed the Second Course Phase of this study and is only 
available if the study remains open and the participant meets the following conditions: 
Either 
• Stopped initial treatment with study treatment after attaining an investigator-determined confirmed 
CR based on RECIST 1.1, and 
o Was treated with at least 8 cycles of study treatment before discontinuing treatment, and 
o Received at least 2 treatments with pembrolizumab beyond the date when the initial CR was 
declared 
OR 
• Had SD, PR, or CR and stopped study treatment after completion of 35 administrations 
(approximately 2 years) of study treatment for reasons other than disease progression or intolerability 
AND 
• Experienced an investigator-determined radiographic disease progression by iRECIST 1.1 after 
stopping initial treatment, and 
o At the time of centrally verified disease progression were found to have received pembrolizumab, 
and 
o No new anticancer treatment was administered after the last dose of study treatment, and 
o The participant meets all of the safety parameters listed in the inclusion criteria and none of the 
safety parameters listed in the exclusion criteria, and 
o The study is ongoing 
An objective response or disease progression that occurs during the Second Course Phase for a participant 
will not be counted as an event for the primary analysis of either endpoint in this study. 
*Note: patients must have measurable disease at the start of protocol treatment to be eligible for this 
provision. 


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5.3 Randomization or Treatment Allocation 
This is a non-randomized trial. 
5.4 Stratification 
5.5 Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the ongoing 
trial.  If there is a clinical indication for one of these or other medications or vaccinations specifically prohibited 
during the trial, discontinuation from trial therapy or vaccination may be required.  The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the participant's primary physician. 
However, the decision to continue the participant on study intervention requires the mutual agreement of the 
investigator, the Sponsor, and the participant. 
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be administered at 
the discretion of the investigator in keeping with the community standards of medical care.  All concomitant 
medication will be recorded on the case report form (CRF) including all prescription, over-the-counter 
(OTC), herbal supplements, and IV medications and fluids.  If changes occur during the trial period, 
documentation of drug dosage, frequency, route, and date may also be included on the CRF. 
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-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 
Anti-emetics/Anti-diarrheals 
From screening Part 2 onwards, should a patient develop nausea, vomiting and / or diarrhea, then these 
symptoms should be reported as AEs (see section 8.3) and appropriate treatment of the event given. 
All concomitant medications received within 28 days prior to the first dose of trial intervention and up to 30 
days after the last dose of trial intervention should be recorded.  Concomitant medications administered after 
30 days after the last dose of trial intervention should be recorded for SAEs and Events of Clinical Interest 
(ECIs) as defined in Section 7.2. 
5.5.2 Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the Screening and Treatment Phase 
(including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  


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• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab and olaparib 
• Radiation therapy  
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed at the investigator’s 
discretion.   
• Live vaccines within 30 days prior to the first dose of study treatment and while participating in the 
study.  Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines 
(eg, FluMist®) are live attenuated vaccines and are not allowed.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of clinical 
interest of suspected immunologic etiology.  The use of physiologic doses of corticosteroids may be 
approved after consultation with the Sponsor. 
Participants who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study.  All treatments that the Investigator 
considers necessary for a participant’s welfare may be administered at the discretion of the Investigator in 
keeping with the community standards of medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study.  If there is a clinical indication for any medication or vaccination specifically prohibited 
during the study, discontinuation from study therapy or vaccination may be required.  The final decision on 
any supportive therapy or vaccination rests with the investigator and/or the participant's primary physician.  
However, the decision to continue the participant on study treatment requires the mutual agreement of the 
investigator, the Sponsor and the participant. However, the decision to continue the participant on study 
intervention requires the mutual agreement of the investigator, the Sponsor, and the participant. 
Medications that may NOT be administered 


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Table 6 
Prohibited medications 
Prohibited medication/class of drug: 
 
Anticancer therapy: 
Chemotherapy 
Immunotherapy 
Hormonal therapy* 
Radiotherapy (except palliative) 
Biological therapy 
Other novel agents 
Not permitted while the patient is receiving study 
medication 
Live virus vaccines 
Live bacterial vaccines 
Not permitted while the patient is receiving study 
medication and during the 30 day follow up period.  
An increased risk of infection by the administration 
of live virus and bacterial vaccines has been observed 
with conventional chemotherapy drugs and the effects 
with olaparib are unknown. 
*Hormone Replacement Therapy (HRT) is acceptable 
 
Restricted concomitant medications 
 
Table 7 
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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Table 7 
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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Table 7 
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 normalized ratio (INR) be monitored 
carefully at least once per week for the first month, 
then monthly if the INR is stable. Subcutaneous 
heparin and low molecular weight heparin are 
permitted. 
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.   


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Table 7 
Restricted concomitant medications 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed ): 
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.  
 
 
 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.5.3 Rescue Medications & Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined along with the dose modification guidelines in Section 5.2.2 (Table 5).  Where 
appropriate, these guidelines include the use of oral or IV 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 and/or 
olaparib.  
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, the Investigator 
does not need to follow the treatment guidance.  Refer to (Table 5) in Section 5.2.2 for guidelines regarding 
dose modification and supportive care.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
5.6 Participant Discontinuation Criteria 
Discontinuation of study intervention does not represent withdrawal from the study. 
Participants may discontinue study treatment at any time for any reason or be dropped from the study 
treatment at the discretion of the investigator should any untoward effect occur.  In addition, a participant 
may be discontinued from study treatment by the investigator or the Sponsor if study treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding procedures to be performed at study treatment discontinuation are provided in Section 7.1.4 – Other 
Procedures. 


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A participant must be discontinued from study treatment but continue to be monitored in the study for any 
of the following reasons: 
• The participant or participant’s legally acceptable representative requests to discontinue study 
treatment 
• Confirmed radiographic disease progression outlined in Section 7.1.2.6 
• Any progression or recurrence of any malignancy, or any occurrence of another malignancy that 
requires active treatment 
• Unacceptable adverse experiences as described in Section 5.2.2. 
• The participant has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or sponsor, placed the participant at unnecessary risk from continued administration 
of study treatment. 
• The participant has a confirmed positive serum pregnancy test 
• Noncompliance with study treatment or procedure requirements 
• Recurrent Grade 2 pneumonitis 
• Discontinuation of treatment may be considered for participants who have attained a confirmed 
complete response (CR) and have been treated for at least 8 cycles (at least 24 weeks), receiving 2 
cycles of the combination including 2 doses of pembrolizumab and at least 80% of the planned 
doses of olaparib beyond the date when the initial CR was declared. These participants may be eligible 
for second course treatment described in Section 5.2.3. 
• The participant is lost to follow-up 
• Completion of 35 treatments (approximately 2 years) with pembrolizumab 
Note: The number of treatments is calculated starting with the first dose.  Participants who stop the 
combination or pembrolizumab after receiving 35 doses may be eligible for retreatment if they progress 
after stopping study treatment provided they meet the requirements detailed in Section 5.2.3. 
Participants may be retreated in the Second Course Phase (Retreatment) for up to an additional 17 
cycles (approximately 1 year). 
• Administrative reasons 
• The End of Treatment and Follow-up visit procedures are listed in Section 8 (Protocol Flow Chart) and 
Section 10.0.1 (Visit Requirements).  After the end of treatment, each subject will be followed for 30 
days for adverse event monitoring (serious adverse events will be collected for 90 days after the end of 
treatment).  Subjects who discontinue for reasons other than progressive disease will have post-
treatment follow-up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease progression each 
subject will be followed by telephone for overall survival until death, withdrawal of consent, or the end 
of the study, whichever occurs first. 


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5.7 Participant withdrawal From Study 
A participant must be withdrawn from the study if the participant or the participant’s legally acceptable 
representative withdraws consent from the study. 
If a participant withdraws from the study, they will no longer receive study intervention or be followed 
at scheduled protocol visits. 
Specified details regarding procedures to be performed at the time of withdrawal from the study as well 
as specific details regarding withdrawal from future biomedical research are outlined in Sections 7.1.4.1 
and 7.1.4.2. 
Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR that 
have been treated for at least 24 weeks with pembrolizumab or the combination and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared.   
5.8 
Participant Replacement Strategy 
We anticipate enrollment of 48 patients for which tumor and toxicity assessments following 
pembrolizumab/olaparib administration can be made. We will replace patients enrolled for which 
clinical trial discontinuation was performed prior to any administration of pembrolizumab or those for 
which pembrolizumab is discontinued due to acute hypersensitivity reactions during the first 
administration of pembrolizumab.  An attempt will be made to assess tumor response in all enrolled 
patients as specified in the protocol.  Patients experiencing clinical deterioration after two doses of 
pembrolizumab, will be considered treatment failures, will count as tumor progression, and will not be 
replaced. 
5.9 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health hazard 
to participants 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply either study drug, adequate notification will be 
provided so that appropriate adjustments to participant treatment can be made. 
6.0 TRIAL ASSESSMENTS AND PROCEDURES 
6.1 Trial Procedures 
• Study procedures and their timing are summarized in The Trial Flow Chart - Section 6.0.   


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• Adherence to the study design requirements, including those specified in the Trial Flow Chart, is 
essential and required for study conduct. 
• The investigator is responsible for ensuring that procedures are conducted by appropriately qualified 
(by education, training, and experience) staff. 
• All screening evaluations must be completed and reviewed to confirm that potential participants meet 
all eligibility criteria. 
• Additional evaluations/testing may be deemed necessary by the investigator, the Sponsor and/or Merck 
for reasons related to participant safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations may require that additional 
informed consent be obtained from the participant. In these cases, such evaluations/testing will be 
performed in accordance with those regulations. 
6.1.1 Administrative and General Procedures 
6.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential participant or each participant’s 
legally acceptable representative prior to participating in a clinical trial. If there are changes to a 
participant’s status during the study (e.g. health requirements) the investigator must ensure appropriate 
consent is in place. 
6.1.1.2 General Informed Consent 
Consent must be documented by the participant’s dated signature or by the participant’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 participant before participation in the 
trial. 
The initial informed consent form, any subsequent revised written informed consent form and any written 
information provided to the participant must receive the IRB/ERC’s approval/favorable opinion in advance 
of use.  The participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’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 participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the protocol 
level.   
The informed consent will adhere to IRB requirements, applicable laws and regulations and Sponsor 
requirements. 


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6.1.1.3 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure 
that the participant qualifies for the trial.  
6.1.1.4 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 clinically 
significant by the Investigator.  Details regarding the disease for which the participant has enrolled in this 
study will be recorded separately and not listed as medical history.   
6.1.1.5 Prior and Concomitant Medications Review 
6.1.1.5.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-specified 
washout requirement, and record prior medication taken by the participant within 28 days before starting 
the trial.  Treatment for the disease for which the participant has enrolled in this study will be recorded 
separately and not listed as a prior medication.  
6.1.1.5.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the participant during the 
trial.  In addition, new medication started during the Second Course should be recorded. All medications 
related to reportable SAEs and ECIs should be recorded as defined in Section 7.2. 
6.1.1.6 
Disease Details and Treatments 
6.1.1.6.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status.  
6.1.1.6.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic treatments, 
radiation and surgeries. 
6.1.1.6.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after the last 
dose of trial treatment.  If a participant initiates a new anti-cancer therapy within 30 days after the last 
dose of trial treatment, the 30-day Safety Follow-up visit must occur before the first dose of the new 
therapy.  Once new anti-cancer therapy has been initiated, the participant will move into survival follow-
up.  


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6.1.1.7 
Assignment of Screening Number 
6.1.1.8 
Assignment of Randomization Number 
Not applicable. 
6.1.1.9 Trial Compliance (Medication/Diet/Activity/Other) 
6.1.2 Clinical Procedures/Assessments 
6.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  Adverse 
experiences will be graded and recorded throughout the study and during the follow-up period according 
to NCI CTCAE Version 5.0 (see Appendix 2).  Toxicities will be characterized in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of AEs.   
6.1.2.2 
Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the screening period.  
Clinically significant abnormal findings should be recorded as medical history.  A full physical exam 
should be performed during screening,  
6.1.2.3 
Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or qualified 
designee will perform a directed physical exam as clinically indicated prior to trial treatment 
administration.   
6.1.2.4 
Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration of each 
dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart (Section 6.0).  
Vital signs should include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be 
measured at screening only. 
6.1.2.5 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix 1) at screening, prior to the 
administration of each dose of trial treatment and discontinuation of trial treatment as specified in the 
Trial Flow Chart.   
 
6.1.2.6 
Tumor Imaging and Assessment of Disease 
Tumor assessments will be performed by computer tomography (CT), PET/CT or Magnetic Resonance 
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Tumor imaging is strongly preferred to be acquired by computed tomography (CT).  For the abdomen and 
pelvis, contrast-enhanced magnetic resonance imaging (MRI) may be used when CT with iodinated 
contrast is contraindicated, or when local practice mandates it.  MRI is the strongly preferred modality for 
imaging the brain.  The same imaging technique regarding modality, ideally the same scanner, and the use 
of contrast should be used in a participant throughout the study to optimize the reproducibility of the 
assessment of existing and new tumor burden and improve the accuracy of the assessment of response or 
progression based on imaging. 
Scans obtained prior to consenting will be allowed, as long as performed within 21 days of study initiation.  
CT Scans or MRI’s will be repeated every 3 cycles (3 weeks cycles); that is before every fourth dose of 
pembrolizumab in order to assess response to therapy.  Tumor imaging will only be required every 12 
weeks for patients that have been on treatment for more than 1 year. Immune Response Evaluation Criteria 
(iRECIST) [36] will be utilized for assessment of response to therapy. 
Expedited confirmation of measurable disease based on RECIST 1.1 at Screening should be used to 
determine participant eligibility.  Confirmation that the participant’s imaging shows at least 1 lesion that 
is appropriate for selection as a target lesion per RECIST 1.1 is highly recommended prior to 
participation allocation.   
Participant eligibility will be determined using local assessment (Investigator assessment) based on 
RECIST 1.1.  In addition, images (including via other modalities) that are obtained at an unscheduled 
time point to determine disease progression, as well as imaging obtained for other reasons, but which 
demonstrate radiologic progression, should also be used to determine progression. 
When the Investigator identifies radiographic progression per RECIST 1.1, efforts should be made to 
verify radiologic PD. Treatment should continue until PD has been verified.  Regardless of whether PD is 
verified, if the Investigator considers the participant has progressed, but elects to implement iRECIST, 
the Investigator will assess for confirmation of progression by iRECIST at subsequent time points.   
6.1.2.6.1   Initial Tumor Imaging 
Initial tumor imaging at Screening must be performed within 21 days prior to the date of allocation.  The 
site study team must review screening images to confirm the participant has measurable disease per 
RECIST 1.1.  
The screening images must be submitted to the central imaging vendor for confirmation of measurable 
disease per RECIST 1.1 for eligibility prior to allocation. 
Brain imaging, if performed to document the stability of existing metastases, should be by MRI if possible.  
If MRI is medically contraindicated, CT with contrast is an acceptable alternative. 
6.1.2.6.2   Tumor Imaging During the Study 
The first on-study imaging assessment should be performed at 9 weeks ( ±7 days]) from the date of first 
dose.  Subsequent tumor imaging should be performed every 9 weeks ([±7 days) or more frequently if 
clinically indicated.  After 52 weeks (±7 days), participants who remain on treatment will have imaging 
performed every 12weeks (±7 days).  Imaging timing should follow calendar days and should not be 


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adjusted for delays in cycle starts.  Imaging should continue to be performed until disease progression is 
identified by the Investigator.  
Objective response should be confirmed by a repeat imaging assessment.  Tumor imaging to confirm PR 
or CR should be performed at least 4 weeks after the first indication of a response is observed.  Participants 
will then return to regular scheduled imaging every 9 weeks, starting with the next scheduled imaging 
time point.  Participants who receive additional imaging for confirmation do not need to undergo the next 
scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may resume at the subsequent 
scheduled imaging time point.   
Per iRECIST (Section 7.1.2.6.6), disease progression should be confirmed by the site 4 to 8 weeks after 
first radiologic evidence of PD in clinically stable participants.  Participants who have unconfirmed 
disease progression may continue on treatment at the discretion of the investigator until progression is 
confirmed by the site provided they have met the conditions detailed in Section 7.1.2.6.6.  Participants 
who receive confirmatory imaging do not need to undergo the next scheduled tumor imaging if it is less 
than 4 weeks later; tumor imaging may resume at the 1.2.6.6.subsequent scheduled imaging time point, if 
clinically stable.  Participants who have confirmed disease progression by iRECIST, as assessed by the 
site, will discontinue study treatment.  Exceptions are detailed in Section 7. 
6.1.2.6.3   End of Treatment and Follow-up Tumor Imaging 
In participants who discontinue study treatment, tumor imaging should be performed at the time of 
treatment discontinuation (±4 week window).  If previous imaging was obtained within 4 weeks prior to 
the date of discontinuation, then imaging at treatment discontinuation is not mandatory.  In participants 
who discontinue study treatment due to documented disease progression and the investigator elects not to 
implement iRECIST, this is the final required tumor imaging. 
For participants who discontinue study treatment without documented disease progression, every effort 
should be made to continue monitoring their disease status by tumor imaging using the same imaging 
schedule used while on treatment (every 9 weeks in Year 1 or every 12 weeks after Year 1) to monitor 
disease status until the start of a new anticancer treatment, disease progression, pregnancy, death, 
withdrawal of consent, or the end of the study, whichever occurs first. 
6.1.2.6.4   Second Course (Retreatment) Tumor Imaging 
Tumor imaging must be performed within 21 days prior to restarting treatment with pembrolizumab.  
Local reading (Investigator assessment with site radiology reading) will be used to determine eligibility. 
The first on-study imaging assessment should be performed at 9 weeks (±7 days) after the restart of 
treatment.  Subsequent tumor imaging should be performed every 9 weeks (±7 days) or more frequently, 
if clinically indicated. 
Per RECIST 1.1 (Section 7.1.2.6.5), if tumor imaging shows initial PD, tumor assessment should be 
repeated 4 to 8 weeks later in order to confirm PD with the option of continuing treatment while awaiting 
radiologic confirmation of progression with the option of continuing treatment while awaiting radiological 
confirmation of progression in clinically stable patients.  Participants who obtain confirmatory imaging 
do not need to undergo scheduled tumor imaging if it is less than 4 weeks later and may wait until the 
next scheduled imaging time point, if clinically stable. 


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Imaging should continue to be performed until disease progression, the start of a new anticancer treatment, 
withdrawal of consent, death, or notification by the Sponsor, whichever occurs first.  Disease progression 
may be confirmed 4 to 8 weeks after the first tumor imaging indicating PD, by the investigator using 
iRECIST, in clinically stable participants. 
In participants who discontinue study treatment, tumor imaging should be performed at the time of 
treatment discontinuation (±4 week window).  If previous imaging was obtained within 4 weeks prior to 
the date of discontinuation, then imaging at treatment discontinuation is not mandatory.  For participants 
who discontinue study treatment due to documented disease progression, this is the final required tumor 
imaging. 
For participants who discontinue study treatment without documented disease progression, every effort 
should be made to continue monitoring their disease status by radiologic imaging every 12 weeks (±7 
days) until either the start of a new anticancer treatment, disease progression, pregnancy, death, or the end 
of the study, whichever occurs first. 
6.1.2.6.5   RECIST 1.1 Assessment of Disease 
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of disease 
progression, and as a basis for all protocol guidelines related to disease status (eg, discontinuation of study 
treatment).  Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, the 
Sponsor allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant to enable a 
broader sampling of tumor burden.  
6.1.2.6.6    iRECIST Assessment of Disease 
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen with 
immunotherapeutic drugs.  When clinically stable, participants should not be discontinued until 
progression is confirmed by the Investigator, working with local radiology, according to the rules below.  
This allowance to continue treatment despite initial radiologic PD takes into account the observation that 
some participants can have a transient tumor flare in the first few months after the start of immunotherapy, 
and then experience subsequent disease response. 
A description of the adaptations and iRECIST process is provided in Appendix 4, with additional detail 
in the iRECIST publication [Seymour et al., 2017].  iRECIST will be used by the Investigator to assess 
tumor response and progression, and make treatment decisions.   
 
 


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Table 8 Imaging and Treatment after First Radiologic Evidence of Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic evidence of 
PD by RECIST 1.1  
Repeat imaging at 4 to 
8 weeks to confirm PD 
May continue study treatment at 
the Investigator’s discretion while 
awaiting confirmatory tumor 
imaging by site by iRECIST 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion only 
Discontinue treatment 
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per Investigator 
assessment 
No additional imaging 
required 
Discontinue treatment (exception is 
possible upon consultation with 
Sponsor) 
No additional imaging 
required. 
Not applicable 
Repeat tumor imaging shows 
iUPD by iRECIST per 
Investigator assessment 
Repeat imaging at 4 to 
8 weeks to confirm PD.  May 
occur at next regularly 
scheduled imaging visit 
Continue study treatment at the 
Investigator’s discretion 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion only 
Discontinue treatment 
Repeat tumor imaging shows 
iSD, iPR, or iCR by iRECIST 
per Investigator assessment. 
Continue regularly scheduled 
imaging assessments 
Continue study treatment at the 
Investigator’s discretion 
Continue regularly scheduled 
imaging assessments. 
May restart study treatment if 
condition has improved and/or 
clinically stable per Investigator’s 
discretion.  Next tumor imaging 
should occur according to the regular 
imaging schedule. 
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumors 1.1.. 


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Figure 1: Imaging and Treatment for Clinically Stable Participants after First Radiologic Evidence of PD 
Assessed by the Investigator 
 
 
 


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6.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Formalin fixed paraffin embedded (FFPE) tissue will be obtained from patients participating in the trial.  
The presence of archival tumor material is part of the criteria for eligibility for this trial.  
Stools will be collected prior to the beginning of treatment (within 7 days), after two treatment cycles 
(prior to the third dose of pembrolizumab) and at the end of treatment.  
6.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are provided 
below.  
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 9.   


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Table 9 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
PK 
 
Calcium 
 
 
 
Chloride 
 
Stools for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 
 


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Table 10 Laboratory safety variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
B-Hemoglobin (Hb) 
S/P-Creatinine 
B-Leukocyte count 
S/P-Bilirubin, total 
B-Absolute neutrophil count 
S/P-Alkaline phosphatise (ALP) 
B-Absolute lymphocyte count 
S/P-Aspartate transaminase (AST) 
B-Platelet count 
S/P-Alanine transaminase (ALT) 
B-Mean cell volume (MCV) 
S/P-Albumin 
S/P-Potassium 
S/P-Calcium, total 
 
S/P-Sodium 
Urinalysis (dipstick) 
S/P-Urea or Blood Urea Nitrogen (BUN) 
U-Hb/Erythrocytes/Blood  
S/P-Total Protein 
U-Protein/Albumin  
 
U-Glucose  
 
NB. In case a patient shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN please refer to Appendix E ‘Actions required 
in cases of increases in liver biochemistry and evaluation of Hy’s Law’, for further instructions. 
6.1.3.1 
Coagulation 
· 
activated partial thromboblastin time {APTT}will be performed at screening and if clinically indicated   
· 
international normalised ratio {INR} will be performed at screening and if clinically indicated. Patients taking warfarin may 
participate in this study; however, it is recommended that INR be monitored carefully at least once per week for the first month, then 
monthly if the INR is stable. 
Each coagulation test result will be recorded in CRF. 
 


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6.1.3.2 
Bone marrow or blood cytogenetic samples 
Bone marrow or blood cytogenetic samples may be collected for patients with prolonged hematological toxicities as defined in Section 
8.4.7 per routine medical oncology at Miami Cancer Institute. 
Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic analysis and flow cytometry, and a core biopsy 
for bone marrow cellularity. If it is not possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then 
attempts should be made to carry out the tests on a blood sample. Full reports must be provided by the investigator for documentation 
on the Patient Safety database. These data are not required to be entered into CRF. 


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Laboratory tests for screening or entry into the Second Course Phase should be performed within 10 
days prior to the first dose of treatment.  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.  
 
6.1.4 Other Procedures 
6.1.4.1 Discontinuation and withdrawal 
When a participant discontinues prior to trial completion, all applicable activities scheduled for the final 
trial visit should be performed at the time of discontinuation.  Any adverse events which are present at 
the time of discontinuation should be followed in accordance with the safety requirements outlined in 
Section 7.2. - Assessing and Recording Adverse Events.  Participants who a) attain a CR or b) complete 
24 months of treatment with pembrolizumab may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 5.2.3.  After discontinuing treatment following 
assessment of CR, these participants should return to the site for a Safety Follow-up Visit (described in 
Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study (described in Section 7.1.5.3.2). 
Participants who withdraw prior to completion of the trial should be encouraged to complete all 
applicable activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety requirements 
outlined in Section 7.2. 
6.1.4.2 Withdrawal from Future Biomedical Research  
Participants may withdraw their consent for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator. The investigator will inform the Sponsor. It is the 
responsibility of the investigator to subsequently inform the participant of completion of withdrawal. 
Any analyses in progress at the time of request for withdrawal or already performed prior to the request 
for withdrawal being received will continue to be used as part of the overall research study data and 
results. No new analyses should be generated after the request is received. 
In the event that the specimens have been completely anonymized, there will be no link between the 
participant’s personal information and their specimens. In this situation, the request for specimen 
withdrawal cannot be processed. 
6.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related details are 
provided above in Section 7.1 - Trial Procedures. 


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6.1.5.1 
Screening 
6.1.5.1.1 Screening Period 
6.1.5.2 
Treatment Period 
6.1.5.3 
Post-Treatment Visits 
6.1.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of study treatment or before the initiation of a new anti-cancer treatment, whichever comes 
first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Participants with 
an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anti-cancer therapy, whichever occurs first.  SAEs that occur within 90 days 
of the end of treatment or before initiation of a new anti-cancer treatment should also be followed 
and recorded.  Participants who are eligible for retreatment/crossover with pembrolizumab (as 
described in Section 5.2.3) may have up to two safety follow-up visits, one after the Initial 
Treatment Period and one after the Second Course Treatment. 
6.1.5.3.2 Follow-up Visits 
Participants who discontinue study treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed every 6 weeks (42 ± 7 days) by radiologic 
imaging to monitor disease status.  After 1 year, the imaging time point will occur every 9 weeks 
(± 7 days). Every effort should be made to collect information regarding disease status until the 
start of new anti-cancer therapy, disease progression, death, end of the study or if the participant 
begins retreatment with pembrolizumab as detailed in Section 5.2.3.  Information regarding post-
study anti-cancer treatment will be collected if new treatment is initiated. 
Participants who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 5.2.3 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.   
6.1.5.3.3 Survival Follow-up 
Participants who experience confirmed disease progression or start a new anticancer therapy, will 
move into the Survival Follow-Up Phase and should be contacted by telephone every 12 weeks to 
assess for survival status until death, withdrawal of consent, or the end of the trial, whichever 
occurs first.  
 
6.2 Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable Safety Events 
The definitions of an AE or SAE, as well as the method of recording, evaluating, and assessing causality 
of AE and SAE and the procedures for completing and transmitting AE, SAE, and other reportable safety 
event reports can be found in Appendix 5.   


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Adverse events, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting events that 
meet the definition of an AE or SAE as well as other reportable safety events. Investigators remain 
responsible for following up AEs, SAEs, and other reportable safety events for outcome. 
The investigator, who is a qualified physician, will assess events that meet the definition of an AE or 
SAE as well as other reportable safety events with respect to seriousness, intensity/toxicity and causality. 
Olaparib 
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. Study 
treatment can be dose reduced to 250 mg twice daily as a first step and to 200 mg twice daily as a second 
step. If the reduced dose of 200 mg twice daily is not tolerable, no further dose reduction is allowed and 
study treatment should be discontinued.  
Once dose is reduced, escalation is not permitted (except following concomitant treatment with CYP3A4 
inhibitors – see Section 6.5 
6.2.1 Time Period and Frequency for Collecting AE, SAE, and Other Reportable Safety Event 
Information 
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed but before 
intervention allocation/randomization must be reported by the investigator if the participant is receiving 
placebo run-in or other run-in treatment, if the event cause the participant to be excluded from the study, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, or a procedure. 
• All AEs from the time of intervention allocation/randomization through 30 days following 
cessation of study intervention must be reported by the investigator. 
• All AEs meeting serious criteria, from the time of intervention allocation/randomization through 
90 days following cessation of study intervention or 30 days following cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator. 
• All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation/randomization through 120 days following cessation of study intervention, or 30 days 
following cessation of study intervention if the participant initiates new anticancer therapy must 
be reported by the investigator. 
• Additionally, any SAE brought to the attention of an investigator at any time outside of the time 
period specified above must be reported immediately to Merck if the event is considered drug-
related. 
 


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Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events in 
former study participants. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly 
notify Merck. 
 
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and reported 
to Merck within the time frames as indicated in Table 11. 
 
Table 11 Reporting Time Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events 
Type of Event 
Reporting Time 
Period: 
Consent to 
Randomization/ 
Allocation 
Reporting Time 
Period: 
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period 
Reporting Time Period: 
After the Protocol-
specified Follow-up 
Period 
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Merck: 
 
 
 
 
 
Serious Adverse Event 
(SAE) including Cancer 
and Overdose 
Report if: 
- due to protocol-
specified 
intervention 
- causes exclusion 
- participant is 
receiving placebo 
run-in or other run-
in treatment 
Report all 
Report if: 
- drug/vaccine related. 
(Follow ongoing to 
outcome) 
Within 2 
business days 
but no longer 
than 3 
calendar days 
of learning of 
event 
Pregnancy/Lactation 
Exposure 
Report if: 
- due to 
intervention 
- causes exclusion 
Report all 
Previously reported – 
Follow to 
completion/termination; 
report outcome 
Within 2 
business days 
but no longer 
than 3 
calendar days 
of learning of 
event 
Event of Clinical 
Interest (require 
regulatory reporting) 
Report if: 
- due to 
intervention 
- causes exclusion 
Report 
- potential drug-
induced liver 
injury (DILI) 
- require regulatory 
reporting 
Not required 
Within 2 
business days 
but no longer 
than 3 
calendar days 
of learning of 
event 
 
 
 
 
 
 


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6.2.1.1 
Management of hematological toxicity 
Management of anemia 
Table 12 
Management of anemia 
Hemoglobin 
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. Study treatment 
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 anemia (e.g., iron, vitamin B12 or folate deficiencies and hypothyroidism) 
should be investigated and appropriately managed. In some cases, management of anemia may require 
blood transfusions. For cases where patients develop prolonged hematological toxicity (≥2 week 
interruption/delay in study treatment due to CTC grade 3 or worse anemia and/or development of blood 
transfusion dependence), refer to guidance later in this section for the management of this.  
 
Management of neutropenia, leukopenia and thrombocytopenia 
Table 13 
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 


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Adverse event of neutropenia and leukopenia should be managed as deemed appropriate by the 
investigator with close follow up and interruption of study drug if CTC grade 3 or worse neutropenia 
occurs. 
Primary prophylaxis with Granulocyte colony-stimulating factor (G-CSF) is not recommended, however, 
if a patient develops febrile neutropenia, study treatment should be stopped and appropriate management 
including G-CSF should be given according to local hospital guidelines. Please note that G-CSF should 
not be used within at least 24 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. 
For cases where patients develop prolonged hematological toxicity (≥2 week interruption/delay in study 
treatment due to CTC grade 3 or worse), refer to guidance later in this section for the management of 
this.  
 
Management of prolonged hematological toxicities while on study treatment 
If a patient develops prolonged hematological toxicity such as: 
• 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse anaemia and/or 
development of blood transfusion dependence 
• 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse neutropenia (ANC 
< 1 x 109/L) 
• 
≥2 week interruption/delay in study treatment due to CTC grade 3 or worse thrombocytopenia 
and/or development of platelet transfusion dependence (Platelets < 50 x 109/L) 
Check weekly differential blood counts including reticulocytes and peripheral blood smear. If any blood 
parameters remain clinically abnormal after 4 weeks of dose interruption, the patient should be referred 
to hematologist for further investigations. Bone marrow analysis and/or blood cytogenetic analysis should 
be considered at this stage according to standard hematological practice. Study treatment should be 
discontinued if blood counts do not recover to CTC 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 AstraZeneca Patient Safety. Olaparib 
treatment should be discontinued if patient’s diagnosis of MDS and/or AML is confirmed. 
6.2.1.2 
Management of non-hematological toxicity 
Repeat dose interruptions are allowed as required, for a maximum of 4 weeks on each occasion. If the 
interruption is any longer than this the study monitor must be informed.  Where toxicity reoccurs following 
re-challenge with study treatment, and where further dose interruptions are considered inadequate for 
management of toxicity, then the patient should be considered for dose reduction or must permanently 
discontinue study treatment. 


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Study treatment can be dose reduced to 250 mg twice daily as a first step and to 200 mg twice daily as a 
second step. 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., dyspnea) or radiological abnormalities occur in the 
absence of a clear diagnosis, an interruption in study treatment dosing is recommended and further 
diagnostic workup (including a high resolution CT scan) should be performed to exclude pneumonitis. 
Following investigation, if no evidence of abnormality is observed on CT imaging and symptoms resolve, 
then study treatment can be restarted, if deemed appropriate by the 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. 
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 (i.e. 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 e.g., dopamine receptor antagonist, antihistamines or 
dexamethasone. 
Interruptions for intercurrent non-toxicity related events 
Study treatment dose interruption for conditions other than toxicity resolution should be kept as short as 
possible. If a patient cannot restart study treatment within 4 weeks for resolution of intercurrent conditions 
not related to disease progression or toxicity, the case should be discussed with AZ study physician. 
All dose reductions and interruptions (including any missed doses), and the reasons for the 
reductions/interruptions are to be recorded in the eCRF.  
Study treatment should be stopped at least 3 days prior to planned surgery. After surgery study treatment 
can be restarted when the wound has healed. No stoppage of study treatment is required for any needle 
biopsy procedure. 
Study treatment should be discontinued for a minimum of 3 days before a patient undergoes radiation 
treatment. Study treatment should be restarted within 4 weeks as long as any bone marrow toxicity has 
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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 14 
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 
 
6.2.1.3 
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 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. 
6.2.2 Method of Detecting AEs, SAEs, and Other Reportable Safety Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other reportable safety 
events. Open-ended and nonleading verbal questioning of the participant is the preferred method to 
inquire about AE occurrence. 
6.2.3 Follow-up of AE, SAE, and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All AEs, SAEs, and other reportable safety events including pregnancy and 
exposure during breastfeeding, ECIs, cancer, and overdose will be followed until resolution, stabilization, 
until the event is otherwise explained, or the participant is lost to follow-up. In addition, the investigator 
will make every attempt to follow all non-serious AEs that occur in randomized participants for outcome. 
Further information on follow-up procedures is given in Appendix 5. 
6.2.4 Sponsor Responsibility for Reporting Adverse Events  
All AEs will be reported to regulatory authorities, IRB/IECs and investigators in accordance with all 
applicable country specific regulatory requirements, global laws and regulations.  


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6.2.5 Pregnancy and Exposure During Breastfeeding 
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any pregnancy or 
infant exposure during breastfeeding in a participant (spontaneously reported to the investigator or their 
designee) that occurs during the study are reportable to Merck. 
All reported pregnancies must be followed to the completion/termination of the pregnancy. Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage, and stillbirth must be reported as serious events (Important Medical 
Events). If the pregnancy continues to term, the outcome (health of infant) must also be reported. 
6.2.6 Events of Clinical Interest (ECIs) 
Selected non-serious and SAEs are also known as ECIs and must be reported to Merck.  
Events of clinical interest for this study include:  
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.  
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.  
Adverse reactions associated with overdose should be treated symptomatically and should be managed 
appropriately. 


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7.0 STATISTICAL ANALYSIS PLAN 
7.1 Statistical Analysis Plan Summary 
7.2 Statistical Analysis Plan 
Sample size calculation: Single-Stage design will be used for this study [A'Hern, 2001; Fleming, 1982]. 
The study will require 48 subjects to decide whether the proportion responding (P), is less than or equal 
to 0.130 or greater than or equal to 0.280. If the number of responses is 10 or more, the hypothesis that P 
≤ 0.130 is rejected with a target error rate of 0.100 and an actual error rate of 0.087. If the number of 
responses is nine or less, the hypothesis that P ≥ 0.280 is rejected with a target error rate of 0.100 and an 
actual error rate of 0.099.  
Efficacy analyses: The iORR will be defined as the proportion of patients with an “immune” complete 
response (iCR) or “immune” partial response (iPR). For the primary iORR analysis in all the treated 
population, patients with an iCR or iPR will be counted as successes and all other patients (including those 
with missing response information) will be counted as failures. The percentage of iORR with its 95% 
confidence interval (CI) will be presented.  
Progression free survival (PFS) will be defined among all treated patients as the time from first dose of 
study drug until the first date of either disease progression or death due to any cause. The date of disease 
progression will be defined as the earliest date of disease progression based on central review. For patients 
whose disease has not progressed at the time of the analysis, censoring will be performed using the date 
of the last valid disease assessment. The data will be analyzed by the Kaplan-Meier method. The median 
PFS time and 95% CI will be recorded.  
Overall survival (OS): Median OS will be defined as the time from the beginning of study drug treatment 
until death due to any cause. For patients who have not died at the time of the analysis, censoring will be 
performed using the date the patient was last known to be alive. The data will be analyzed by the Kaplan-
Meier method. The median OS and 95% CI will be recorded.  
Safety analyses: Safety analyses will be presented descriptively. The focus of adverse event (AE) 
summarization will be on treatment-emergent adverse event (TEAEs). A TEAE is defined as an AE that 
occurs or worsens in the period extending from the first dose of study drug to 30 days after the last dose 
of study drug in this study. TEAEs will be summarized and summary tables will be created to show the 
number of patients reporting TEAEs by severity grade and corresponding percentages. A patient who 
reports multiple TEAEs within the same Preferred Term (or System Organ Class) is counted only once 
for that Preferred Term (or System Organ Class) using the worst severity grade. Separate summaries will 
be prepared for TEAEs classified as severe or life threatening (Grade 3 or higher); study drug-related AEs; 
AEs leading to treatment interruption, modification, or discontinuation; serious AEs; and death. Dose 
interruptions, reductions, and relative dose intensity will also be summarized.  
All results including efficacy, PFS, OS and safety analysis will also be reported based on race/ethnicity 
stratification. 
FATSI analysis will be conducted in batches.  We expect that similar to mismatch repair deficient patients, 
the immune-related objective response will be at or above 40% in patients with functional FA deficiency 
(FATSI negative), and less than 10% in patients without either homologous recombination repair 


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deficiency or mismatch repair deficiency. Based on our prior screening data, we anticipate that close to 
30% of patients will be FA functionally deficient.  
Total enrollment of 48 patients is planned. We will report the 90% confidence interval estimates of iORR 
both overall and by FATSI status using the exact method (Clopper Pearson). However, the planned study 
is small for a well powered comparison given that we expect only 15 FATSI-negative patients. Instead, 
variation in iORR by FATSI status will be assessed by considering the one-sided 95% lower confidence 
limit (95%LCL) for the difference. As an example, an observed increase in iORR for FATSI- patients of 
30.9%, based on 6 out of 15 FATSI- responders compared with 3 out of 33 FATSI+ responders, provides 
95% confidence that the true increase for patients with FA deficient tumors is at least 7.1%, suggesting 
that further study of pembrolizumab/olaparib in FA deficient cervical cancer patients is warranted.  
Kaplan-Meier curves will be used to estimate the distributions of overall survival and immune-related 
progression-free survival (iPFS). Point estimates and 2-sided 95% confidence intervals will be reported 
for selected times using Greenwood’s variance and the log-log transform method. This will include the 
20-week iPFS for purposes of comparison. Based on the panel sequencing results, somatic alterations will 
be summarized and reported as proportions for genes in FA competent and FA functionally deficient 
tumors. Confidence intervals will be calculated using the exact method. Additional analyses will be done 
to establish relationships between treatment and certain baseline characteristics, including deficiencies in 
the FA pathway, PD-L1 expression, TMB, other deficiencies in DNA damage repair mechanisms. These 
relationships will be explored primarily through logistic regression or cox proportional hazards regression, 
depending on the outcome of interest.  
For known or predicted deleterious mutations of suspected inheritance trait detected during the trial, the 
process would be aided by making sure that patients carrying these mutations get referred for genetic 
counseling and CLIA certified germline analysis.  The Miami Cancer Institute has these services readily 
available. 
Stool Microbiome Data Analyses: Centered log-ratio (CLR) transformations will be applied to 
microbiome data. Log-ratios make the data symmetric and linearly related, and places the data in a log-
ratio coordinate space. Thus, we can obtain information about the log-ratio abundances of features relative 
to other features in the compositional dataset. Zero counts of operational taxonomic units (OTU) will be 
converted to a probability vector prior to centered log-ratio transformation. Aitchison distance, which is 
simply the Euclidian distance between samples after CLR transformation, and the distances between 
samples same as the phylogenetic isometric log-ratio (ILR), will be calculated and used for clustering and 
ordination. Compositional principal component analysis (PCA) will be applied and biplots will be used to 
display the relationships between OTUs and the distances between samples.  
Differential relative abundance will be based on the CLR values from a modelled probability distribution 
of the dataset, and the expected values of parametric and non-parametric statistical tests along with effect-
size estimates will be reported. This approach reduces the false-positive identification problem to near 0 
in real and modelled microbiome datasets with little effect of sensitivity to the negative correlation bias 
and is observed to be relatively insensitive to change when the data are subset. 
Considering possible correlations among metabolites, penalized logistic model will be applied for 
selecting compositional components, which can predict the status of response to treatment and of treatment 


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related toxicity. The penalization coefficient λ is selected through leaving-one-out cross-validation.  λ, 
which gives the smallest conditional likelihood deviance, will be used in final prediction.  
Penalized survival models will be applied to investigate potential compositional components, which are 
associated with PFS. Similar to penalized logistic models, penalization hyperparameters will be selected 
through leaving-one-out cross-validation. 
8.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
8.1 Investigational Product  
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. 
Pembrolizumab and olaparib will be provided by Merck as summarized in Table 15. 
Table 15 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
Olaparib 100 and 150 mg tablets 
Oral 
 
8.2 Packaging and Labeling Information 
Supplies will be labeled in accordance with regulatory requirements. 
8.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, 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. 
8.4 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. 


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8.5 Returns and Reconciliation 
The Miami Cancer Institute has a dedicated Investigational Drug Service (IDS), including a dedicated 
IDS Supervisor who leads the coordination of investigational drugs services for clinical research at Miami 
Cancer Institute (including inventory and receipt as detailed below).   
Investigational Drug Services (IDS) Supervisor: 
 
Nicholas Chow, Pharm D, BCOP 
8900 N. Kendall Drive 
Miami, FL 33176 
Office: (786) 527-7615 
Email: nicholascho@baptisthealth.net  
  
The IDS team provides required pharmacy services for investigational drug studies including oversight 
of drug storage, handling, preparation, deposition, medication dosing, staff education, and other related 
activities. All pharmacists involved in the compounding of investigational products are trained on each 
individual protocol in regards to receipt, preparation, storage, dispensing and administration, product 
reconciliation and source documentation. Additionally, all pharmacists involved in the compounding 
aspect are CITI trained and listed on the delegation of authority.    
• 
Disposition and/or destruction of IPs following drug accountability are performed according to 
specific instructions provided by the sponsor and/or protocol. Disposal and/or destruction of 
investigational products on-site are performed in accordance with BHM BCH administrative 
policy  
• 
All products will be disposed of according to regulatory requirements according to institutional 
policy and in accordance with the Environmental Protection Agency and the State of Florida 
Department of Transportation (DOT) regulations for hazardous and non-hazardous pharmaceutical 
waste.  
• 
Disposition of the investigational product must be witnessed by two members of the research team 
and documented per institutional policy 
• 
Documentation of IDS accountability will be performed from the time of initial product receipt 
through the destruction or return of the product to the supplier 
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 participants 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. 


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9.0 ADMINISTRATIVE AND REGULATORY DETAILS 
9.0.1 Confidentiality of Data 
Both the investigator and the Sponsor affirm that information regarding this trial will be maintained in 
confidence, and such information will be divulged to the institutional review board, ethics review 
committee (IRB) or similar or expert committee; affiliated institution and employees, only under an 
appropriate understanding of confidentiality with such board or committee, affiliated institution and 
employees. Data generated by this trial will be considered confidential by the Sponsor and the investigator. 
 
 9.0.2 Confidentiality of Subject Records 
The investigator agrees that the IRB or regulatory authority representatives may consult and/or copy trial 
documents in order to verify worksheet/case report form data. By signing the consent form, the subject 
agrees to this process. If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor. 
 
The investigator and Sponsor agree to treat all subject data used and disclosed in connection with this 
trial in accordance with all applicable privacy laws, rules and regulations. 
 
9.0.3 Confidentiality of Investigator Information 
The investigator recognizes that certain personal identifying information with respect to the investigator, 
and all sub-investigators and trial site personnel, may be used and disclosed for trial management 
purposes, as part of a regulatory submission, and as required by law. This information may include: 
 
1. Name, address, telephone number and e-mail address; 
2. Hospital or clinic address and telephone number; 
3. Curriculum vitae or other summary of qualifications and credentials; and 
4. Other professional documentation. 
 
Consistent with the purposes described above, this information may be transmitted to the Sponsor, and 
subsidiaries, affiliates and agents of the Sponsor, in your country and other countries, including countries 
that do not have laws protecting such information. Additionally, the investigator’s name and business 
contact information may be included when reporting certain serious adverse events to regulatory 
authorities or to other investigators. By signing this protocol, the investigator expressly consents to these 
uses and disclosures. 
 
9.0.4 Confidentiality of IRB Information 
The Sponsor is required to record the name and address of each IRB that reviews and approves this trial. 
The Sponsor is also required to document that each IRB meets regulatory and ICH GCP requirements by 
requesting and maintaining records of the names and qualifications of the IRB members and to make these 
records available for regulatory agency review upon request by those agencies. 


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10.1 Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug Administration Regulations, 
Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the Sponsor's responsibility to 
determine, based on these regulations, whether a request for Financial Disclosure information is required. 
It is the investigator's/subinvestigator's responsibility to comply with any such request. 
 
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 CFR Part 54, 
to provide his/her financial interests in and/or arrangements with the Sponsor to allow for the submission 
of complete and accurate certification and disclosure statements. The investigator/subinvestigator(s) 
further agree to provide this information on a Certification/Disclosure Form, commonly known as a 
financial disclosure form, provided by the Sponsor. The investigator/subinvestigator(s) also consent to the 
transmission of this information to the Sponsor in the United States for these purposes. This may involve 
the transmission of information to countries that do not have laws protecting personal data. 
 
10.2 Compliance with Law, Audit and Debarment 
The investigator agrees to conduct the trial in an efficient and diligent manner and in conformance with 
this protocol; generally accepted standards of Good Clinical Practice (e.g., International Conference on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Good 
Clinical Practice: Consolidated Guideline and other generally accepted standards of good clinical 
practice); and all applicable federal, state and local laws, rules and regulations relating to the conduct of 
the clinical trial. 
 
The investigator also agrees to allow monitoring, audits, IRB review and regulatory authority inspection 
of trial-related documents and procedures and provide for direct access to all trial-related source data and 
documents. 
 
The investigator agrees not to seek reimbursement from subjects, their insurance providers or from 
government programs for procedures included as part of the trial reimbursed to the investigator by the 
Sponsor. 
 
The investigator shall prepare and maintain complete and accurate trial documentation in compliance with 
Good Clinical Practice standards and applicable federal, state and local laws, rules and regulations; and, 
for each subject participating in the trial, provide all data, and, upon completion or termination of the 
clinical trial, submit any other reports to the Sponsor as required by this protocol or as otherwise required 
pursuant to any agreement with the Sponsor. 
 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator upon request 
and also shall be made available at the trial site upon request for inspection, copying, review and audit at 
reasonable times by representatives of the Sponsor or any regulatory authorities. The investigator agrees 
to promptly take any reasonable steps that are requested by the Sponsor as a result of an audit to cure 
deficiencies in the trial documentation and worksheets/case report forms. 
 
The investigator must maintain copies of all documentation and records relating to the conduct of the trial 
in compliance with all applicable legal and regulatory requirements. This documentation includes, but is 
not limited to, the protocol, worksheets/case report forms, advertising for subject participation, adverse 


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event reports, subject source data, correspondence with regulatory authorities and IRBs/ERCs, consent 
forms, investigator’s curricula vitae, monitor visit logs, laboratory reference ranges, laboratory 
certification or quality control procedures and laboratory director curriculum vitae. The investigator agrees 
that documentation shall be retained until at least 2 years after the last approval of a marketing application 
in an ICH region or until there are no pending or contemplated marketing applications in an ICH region 
or until at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  
 
Because the clinical development and marketing application process is variable, it is anticipated that the 
retention period can be up to 15 years or longer after protocol database lock. The Sponsor will determine 
the minimum retention period and notify the investigator when documents may be destroyed. The Sponsor 
will determine the minimum retention period and upon request, will provide guidance to the investigator 
when documents no longer need to be retained. The sponsor also recognizes that documents may need to 
be retained for a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult with and obtain 
written approval by the Sponsor prior to destroying trial and/or subject files. 
 
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s primary 
physician about the subject’s participation in the trial if the subject has a primary physician and if the 
subject agrees to the primary physician being informed. 
 
The investigator will promptly inform the Sponsor of any regulatory authority inspection conducted for 
this trial. 
 
Persons debarred from conducting or working on clinical trials by any court or regulatory authority will 
not be allowed to conduct or work on this Sponsor’s trials. The investigator will immediately disclose in 
writing to the Sponsor if any person who is involved in conducting the trial is debarred or if any proceeding 
for debarment is pending or, to the best of the investigator’s knowledge, threatened. 
 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will promptly notify 
that trial site’s IRB. 
 
11.0 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and 
Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely responsible for 
determining whether the trial and its results are subject to the requirements for submission to the Clinical 
Trials Data Bank, http://www.clinicaltrials.gov.  Information posted will allow subjects to identify 
potentially appropriate trials for their disease conditions and pursue participation by calling a central 
contact number for further information on appropriate trial locations and trial site contact information.     
The Sponsor agrees to be responsible for implementing and maintaining a quality management system 
with written development procedures and functional area standard operating procedures (SOPs) to ensure 
that trials are conducted and data are generated, documented, and reported in compliance with the protocol, 
accepted standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial. 


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The Quality Assurance (QA) division in the Miami Cancer Institute Office of Clinical Research (MCI 
OCR) is responsible for ensuring that industry standards of quality are met and exceeded on an on-going 
basis.  The division is responsible for the identification, management, and prevention of quality issues, 
reviewing subject research charts, and mapping out current processes. They develop and implement 
quality and verification checks, including necessary assessment tools and checklists used during the QC 
process. Moreover, they facilitate and advice on corrections and corrective and preventive actions related 
to quality issues, provide guidance on interpretation and application of regulations, manage FDA and 
sponsor site visits, and work with site manager to create, implement, and evaluate action plans. 
12.0 DATA MANAGEMENT 
The Miami Cancer Institute Office of Clinical Research (MCI OCR) oversees record keeping and handling 
of data is to record, store, transfer and, where necessary, convert efficiently and accurately, the information 
gathered on each trial subject into data. 
All steps involved in data management should be documented in order to allow step-by-step retrospective 
assessment of quality of the data and the performance of the clinical trial (the “audit paper trail” concept). 
Documentation is facilitated by methods such as the use of checklists and forms giving details of action 
taken, dates, the individuals responsible, etc. 
In the event of electronic data handling, confidentiality of the database must be secured by safety 
procedures such as passwords and written assurances from all staff involved. Provision must be made for 
the satisfactory maintenance of the database and for back-up procedures. 
12.1 Responsibilities of the investigator 
a)  The investigator has overall responsibility for ensuring the accuracy and completeness of data entry. 
The investigator must ensure that the observations and findings are recorded correctly and completely in 
the case-report forms (CRFs) and signed by the responsible person designated in the protocol. When 
conducting a study and using CRFs to report clinical trial data to the sponsor, the investigator must also 
ensure that the routine requirements for recording of data in the source documents (e.g. hospital and 
laboratory records, consultation files) are met, particularly those relating to the treatment given to the 
subject and adverse events. 
b)  If trial data are entered directly into a computer, there must always be an adequate safeguard to ensure 
validation, including a signed and dated print-out and back-up records. Computerized systems should be 
validated and a detailed description for their use be produced and kept up-to-date. 
c)  All corrections to CRFs and to raw data must be made in a way which does not obscure the original 
entry. The correct data must be inserted with the reason for the correction (if not obvious), the date, and 
the initials of the investigator or authorized person. For electronic data processing, only authorized persons 
should be permitted to enter or modify data in the computer and there should be a record of changes and 
deletions. If data are altered during processing, the alteration must be documented. 
d)  Laboratory values with normal reference ranges, preferably together with the specificity and sensitivity 
of the methods used, should always be recorded on the CRF or be attached to it. Values outside a clinically 
accepted reference range or values that differ significantly from previous values must be evaluated and 
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e)  Data other than those required by the protocol may appear on the CRF, provided they are clearly 
marked as additional or optional findings, with an explanation of their significance. 
f)  Units of measurement must always be stated, and conversion of units must always be indicated and 
documented. 
g)  The final report of the trial should be drawn up as defined in the protocol. The report should be signed 
by the sponsor, monitor and investigator(s) as well as the responsible statistician, in accordance with the 
applicable regulations. 
h)  For a period of time defined by national regulations, the investigator should maintain a confidential 
record to allow the translation of the unambiguous code used to conceal the identity of the individual 
subjects in the trial (subject identification code). The investigator may submit the subject identification 
code list to the drug regulatory authority after the trial, together with the final report, according to national 
regulations. 
i)  The investigator should ensure that the subject’s participation in the clinical trial is clearly marked in 
his or her medical records. 
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8. Ledermann J, Pujade-Lauraine E. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian 
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9. Moore KN, DiSilvestro P, Lowe ES, Garnett S, Pujade-Lauraine E SOLO1 and SOLO2: Randomized 
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ASCO. 2014. Chicago, IL.  
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Terminology 
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Adverse 
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repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434(7035):917-21. 
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PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. J Clin Oncol 27:18s, 2009 (suppl; 
abstr CRA501). 
14. Fong P, Boss D, 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. 
15. Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, 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):245-51.  
16. Bagby GC Jr.  Genetic basis of Fanconi anemia.  Curr Opin Hematol 2003;10(1):68-76.  
17. D'Andrea AD, Grompe M. The Fanconi anaemia/BRCA pathway. Nat Rev Cancer 2003;3:23-34.  
18. Reid S, Schindler D, Hanenberg H, Barker K, Hanks S, Kalb R, et al. Biallelic mutations in PALB2 
cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 2007;39(2):162-4.  
19. Xia B, Dorsman JC, Ameziane N, de Vries Y, Rooimans MA, Sheng Q, et al.  Fanconi anemia is 
associated with a defect in the BRCA2 partner PALB2.  Nat Genet 2007;39(2):159-61.  
20. Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER 3rd, Hurov KE, Luo J, et al.  
Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell 
2007;129(2):289-301.  
21. Kim Y, Lach FP, Desetty R, Hanenberg H, Auerbach AD, Smogorzewska A. Mutations of the SLX4 
gene in Fanconi anemia. Nat Genet 2011; 43:138-141.  
22.Vaz F, Hanenberg H, Schuster B, Barker K, Wiek C, Erven V, et al. Mutation of the RAD51C gene in 
a Fanconi anemia-like disorder. Nat Genet 2010;42:406-409.  
23. Machida YJ, Machida Y, Chen Y, Gurtan AM, Kupfer GM, D'Andrea AD, et al. UBE2T is the E2 in 
the Fanconi anemia pathway and undergoes negative autoregulation. Mol Cel 2006;23(4):589-96. 


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24. Meetei AR, Yan Z, Wang W.  FANCL replaces BRCA1 as the likely ubiquitin ligase responsible for 
FANCD2 monoubiquitination.  Cell Cycle 2004;3(2):179-81.  
25. Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, et al.  Interaction of the 
Fanconi anemia proteins and BRCA1 in a common pathway.  Mol Cell 2000;7(2):249-62.  
26. Duan W, Gao L, Zhao W, Leon M, Sadee W, Webb A, et al. Assesment of FANCD2 nuclear foci 
formation in paraffin embedded tumors: a potential patient enrichment strategy for treatment with DNA 
interstrand crosslink agents.  Transl Res 2013; 161(3):156-64. 
27. Villalona-Calero MA, Duan W, Zhao W, Shilo K, Schaaf LJ, Thurmond J, et al. Veliparib Alone or 
in Combination with Mitomycin C in Patients with Solid Tumors With Functional Deficiency in 
Homologous Recombination Repair. J Natl Cancer Inst 2016;4;108(7).  
28. Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1 and 
PARP2 by Clinical PARP Inhibitors. Cancer Res 2012; 72(21):5588-5599.  
29. Murai J, Huang SY, Renaud A, Zhang Y, Ji J, Takeda S, et al. Stereospecific PARP trapping by BMN 
673 and comparison with olaparib and rucaparib. Mol Cancer Ther 2014; 13(2):433-443.  
30. 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.  
31. 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.  
32. 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.  
33. Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the 
misunderstandings. Mol Oncol 2011; 5: 387-393.   
34. Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.  
35. 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.  
36. 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.  
37. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 2005;23:515-
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38. 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.  
39. 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.  
40. 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.  
41. 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. 
42. Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229:114-25.  
43. 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.  
44. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 
2010;236:219-42.  
45. Golan T, Hammel P, Reni M, Van Cutsem E, Macarulla T. Olaparib as maintenance treatment 
following first-line platinum-based chemotherapy in patients with a germline BRCA mutation and 
metastatic pancreatic cancer: phase III POLO trial. Ann Oncol, 2019;20:152.  
 
46 . Le DT, Uram J, Wang H, Bartlett BC, Kemberling H, Eyring AD,  et al. PD-1 Blockade in Tumors 
with Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20.  
 
47. Vergote I, Sehouli J, Salutari V, Zola P, Madry R, Wenham RM, et al. ENGOT-OV43/KEYLYNK-
001: A phase III, randomized, double-blind, active- and placebo-controlled study of pembrolizumab plus 
chemotherapy with olaparib maintenance for first-line treatment of BRCA-nonmutated advanced 
epithelial ovarian cancer. J Clin Oncol 2019 37:15 suppl), TPS5603-TPS5603.  
48. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, et al. (eds). SEER Cancer Statistics 
Review, 1975-2014, National Cancer Institute, Bethesda, MD, http://seer.cancer.gov/ csr/1975_2014/, 
based on November 2016 SEER data submission, posted to the SEER website April 2017.  
49. Rizvi, NA, Hellman MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. 
Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 2015. 
348(6230): 124-8.  
50. Snyder, A. Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A,  et al., Genetic basis for 
clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014 371(23): p. 2189-2199.  
51. Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, et al., Genomic correlates of 
response to CTLA-4 blockade in metastatic melanoma. Science 2015;350(6257):207-211.  


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52. A'Hern, R. P. A. 2001. 'Sample size tables for exact single-stage phase II designs.' Statistics in 
Medicine, Volume 20, pages 859-866.  
53. Fleming, T. R. 1982. 'One-sample multiple testing procedure for Phase II clinical trials.'Biometrics, 
Volume 38, pages 143-151.  
 


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14.0 APPENDICES 
Appendix 1: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2: Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events 
(CTCAE) 
version 
5.0 
will 
be 
utilized 
for 
adverse 
event 
reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
For each episode of an adverse event, all changes to the CTCAE grade attained as well as the highest 
attained CTC grade should be reported. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 3: Contraceptive Guidance and Pregnancy Testing 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s medical records, 
medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause.  
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with two FSH measurements in the postmenopausal range is required.  
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) 
 
○ Females on HRT and whose menopausal status is in doubt will be required to use one of the non-
hormonal highly effective contraception methods if they wish to continue their HRT during the 
study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status 
before study enrollment. 
Contraception Requirements 
Female Participants: 


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Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception that has a low user dependency consistently and correctly as described 
in Table 9 during the protocol-defined time frame.  


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Acceptable Birth Control Methods 
Olaparib is regarded as a compound with medium/high fetal risk. 
Women of childbearing potential and their partners, who are sexually active, must agree to the use of 
TWO highly effective forms of contraception in combination [as listed below].  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). 
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. [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  
 
Table 16  Highly-Effective Contraceptive Methods That Have Low User Dependency 
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant a, b 
● Intrauterine hormone-releasing system (IUS) b 
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 


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● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.  
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies. 
 
a) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive implants are limited to those which inhibit ovulation. 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for 
at least [X days, corresponding to time needed to eliminate study treatment plus 30 days for study 
treatments with genotoxic potential] after the last dose of study treatment.   
 
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test. 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or when pregnancy 
is otherwise suspected. 
 


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Appendix 4:  Description of the iRECIST Process for Assessment of Disease Progression 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment. 
Assessment and Decision at RECIST 1.1 Progression 
In participants who show evidence of radiological PD by RECIST 1.1 the Investigator will decide whether 
to continue a participant on study treatment until repeat imaging is obtained (using iRECIST for 
participant management (see Table 5 and Figures 1 and 3).  This decision by the Investigator should be 
based on the participant’s overall clinical condition. 
Clinical stability is defined as the following:  
• Absence of symptoms and signs indicating clinically significant progression of disease 
• No decline in ECOG performance status  
• No requirements for intensified management, including increased analgesia, radiation, or other 
palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at site-assessed 
first radiologic evidence of PD and is not required to have repeat tumor imaging for confirmation of PD 
by iRECIST. 
If the Investigator decides to continue treatment, the participant may continue to receive study treatment 
and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by iRECIST, per 
Investigator assessment.  I 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and ≥ 5 mm 
from nadir 
o Please note: the iRECIST publication uses the terminology “sum of measurements”, but “sum 
of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) and iCPD 
(confirmed progressive disease).  For purposes of iRECIST assessment, the first visit showing progression 
according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, regardless of which factors 
caused the progression. 
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed as usual. 


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New lesions will be classified as measurable or non-measurable, using the same size thresholds and rules 
as for baseline lesion assessment in RECIST 1.1.  From measurable new lesions, up to 5 lesions total (up 
to 2 per organ), may be selected as New Lesions – Target.  The sum of diameters of these lesions will be 
calculated and kept distinct from the sum of diameters for target lesions at baseline.  All other new lesions 
will be followed qualitatively as New Lesions – Non-target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed (with an overall 
response of iCPD), or as showing persistent unconfirmed progression (with an overall response of iUPD), 
or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the following 
occurs: 
• Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of ≥ 5 mm, compared 
to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, compared to a 
prior iUPD time point; this does not have to meet the “unequivocal” standard of RECIST 1.1 
o For new lesions, worsening is any of these: 
 An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD time point  
 Visible growth of new non-target lesions  
 The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• None of the progression-confirming factors identified above occurs AND 
• The target lesion sum of diameters (initial target lesions) remains above the initial PD threshold 
(by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on which iUPD is 
seen.  This may correspond to the next visit in the original visit schedule.  The assessment of the 
subsequent confirmation scan proceeds in an identical manner, with possible outcomes of iCPD, iUPD, 
and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 


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• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) is not above the initial PD threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), or iCR 
if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion for 
progression is “reset”.  This means that the next visit that shows radiographic progression, whenever it 
occurs, is again classified as iUPD by iRECIST, and the confirmation process is repeated before a response 
of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the participant 
continues to be clinically stable, study treatment may continue and follow the regular imaging schedule.  
If PD is confirmed, participants will be discontinued from study treatment. 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but the 
participant is achieving a clinically meaningful benefit, an exception to continue study treatment may be 
considered.  In this case, if study treatment is continued, tumor imaging should continue to be performed 
following the intervals as outlined in Section 6. 
Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated by any of the 
following events: 
• Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from nadir) either for 
the first time, or after resolution of previous pseudo-progression.  The nadir is always the 
smallest sum of diameters seen during the entire trial, either before or after an instance of 
pseudo-progression. 
• Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so for the first 
time results in iUPD. 
o If non-target lesions had shown previous unequivocal progression, and this progression has not 
resolved, iUPD results from any significant further growth of non-target lesions, taken as a 
whole. 
• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new lesion sum of 
diameters, from the nadir value of that sum 


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o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD evaluation 
process (see Assessment at the Confirmatory Imaging above) is repeated.  Progression must be confirmed 
before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, except in one respect. 
If new lesions occurred at a prior instance of iUPD, and at the confirmatory scan the burden of new lesions 
has increased from its smallest value (for new target lesions, their sum of diameters is ≥5 mm increased 
from its nadir), then iUPD cannot resolve to iSD or iPR. It will remain iUPD until either a decrease in the 
new lesion burden allows resolution to iSD or iPR, or until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication [Seymour et al., 2017]. 
 


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Appendix 5: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting 
14.1.1 Definition of AE 
AE definition 
• An AE is any untoward medical occurrence in a clinical study participant, temporally associated 
with the use of study intervention, whether or not considered related to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of a study intervention. 
• NOTE: For purposes of AE definition, study intervention (also referred to as Merck product) 
includes any pharmaceutical product, biological product, vaccine, diagnostic agent, or protocol 
specified procedure whether investigational or marketed (including placebo, active comparator 
product, or run-in intervention), manufactured by, licensed by, provided by, or distributed by 
Merck for human use in this study. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgment of the 
investigator. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. 
• For all reports of overdose (whether accidental or intentional) with an associated AE, the AE term 
should reflect the clinical symptoms or abnormal test result. An overdose without any associated 
clinical symptoms or abnormal laboratory results is reported using the terminology “accidental or 
intentional overdose without adverse effect.” 
      


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Events NOT meeting the AE definition 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• Situations in which 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. 
• Surgery planned prior to informed consent to treat a pre-existing condition that has not worsened. 
 
14.1.2 Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are 
met. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
• The term “life-threatening” in the definition of “serious” refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an 
elective procedure to treat a pre-existing condition that has not worsened is not an SAE. A pre-
existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and 
is documented in the participant’s medical history. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, 
sprained ankle) that may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. Is a congenital anomaly/birth defect 


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• In offspring of participant taking the product regardless of time to diagnosis. 
f. Other important medical events 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the participant or may require 
medical or surgical intervention to prevent 1 of the other outcomes listed in the above definition. 
These events should usually be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 
14.1.3 Additional Events Reported in the Same Manner as SAE 
Additional events that require reporting in the same manner as SAE 
In addition to the above criteria, AEs meeting either of the below criteria, although not serious per ICH 
definition, are reportable to Merck in the same time frame as SAEs to meet certain local requirements. 
Therefore, these events are considered serious by Merck for collection purposes. 
• Is a new cancer (that is not a condition of the study) 
• Is associated with an overdose of pembrolizumab 
14.1.4 Recording AE and SAE 
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (eg, 
hospital progress notes, laboratory, and diagnostics reports) related to the event. 
• The investigator will record all relevant AE/SAE information on the AE CRFs/worksheets at each 
examination. 
• There may be instances when copies of medical records for certain cases are requested by the Merck. 
In this case, all participant identifiers, with the exception of the participant number, will be blinded 
on the copies of the medical records before submission to the Merck. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. In such cases, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 
Assessment of intensity/toxicity 
• An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, not when it is rated as severe. 


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1. 
The investigator will make an assessment of intensity for each AE and SAE (and other reportable 
safety event) according to the NCI Common Terminology for Adverse Events (CTCAE), version 
5. Any AE that changes CTCAE grade over the course of a given episode will have each change 
of grade recorded on the AE CRFs/worksheets. 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL). 
• Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
• Grade 4: Life threatening consequences; urgent intervention indicated. 
• Grade 5: Death related to AE. 
Assessment of causality 
1. 
Did Merck product cause the AE? 
2. 
The determination of the likelihood that Merck product caused the AE will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source 
document or worksheet that supports the causality noted on the AE form, ensures that a medically 
qualified assessment of causality was done. This initialed document must be retained for the 
required regulatory time frame. The criteria below are intended as reference guidelines to assist 
the investigator in assessing the likelihood of a relationship between the test product and the AE 
based upon the available information. 
3. 
The following components are to be used to assess the relationship between Merck’s product 
and the AE; the greater the correlation with the components and their respective elements (in 
number and/or intensity), the more likely Merck product caused the AE: 
• Exposure: Is there evidence that the participant was actually exposed to Merck product such 
as: reliable history, acceptable compliance assessment (pill count, diary, etc.), expected 
pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
• Time Course: Did the AE follow in a reasonable temporal sequence from administration of 
Merck product? Is the time of onset of the AE compatible with a drug-induced effect (applies 
to studies with investigational medicinal product)? 
• Likely Cause: Is the AE not reasonably explained by another etiology such as underlying 
disease, other drug(s)/vaccine(s), or other host or environmental factors. 
• Dechallenge: Was Merck product discontinued or dose/exposure/frequency reduced? 
• If yes, did the AE resolve or improve? 
• If yes, this is a positive dechallenge. 


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• If no, this is a negative dechallenge. 
• (Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; 
(2) the AE resolved/improved despite continuation of the Merck product; (3) the study is a 
single-dose drug study; or (4) Merck product(s) is/are only used 1 time.) 
• Rechallenge: Was the participant re-exposed to Merck product in this study? 
• If yes, did the AE recur or worsen? 
• If yes, this is a positive rechallenge. 
• If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, 
or (2) the study is a single-dose drug study; or (3) Merck product(s) is/are used only 1 time.) 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND MAY HAVE 
BEEN CAUSED BY MERCK PRODUCT, OR IF RE-EXPOSURE TO MERCK’S PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN THE 
RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE INIRB/IEC. 
4. 
Consistency with study intervention profile: Is the clinical/pathological presentation of the 
AE consistent with previous knowledge regarding Merck product or drug class pharmacology or 
toxicology? 
5. 
The assessment of relationship will be reported on the case report forms/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
6. 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative 
of Merck product relationship). 
• Yes, there is a reasonable possibility of Merck product relationship: 
• There is evidence of exposure to the Merck product. The temporal sequence of the AE onset 
relative to the administration of Merck product is reasonable. The AE is more likely explained 
by Merck product than by another cause. 
• No, there is not a reasonable possibility of Merck product relationship: 
• Participant did not receive the Merck product OR temporal sequence of the AE onset relative 
to administration of the Merck product is not reasonable OR the AE is more likely explained 
by another cause than the Merck product. (Also entered for a participant with overdose without 
an associated AE.) 


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7. 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
8. 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Merck. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Merck. 
9. 
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
10. 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
11. 
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each AE causality to the combination regimen or to a single agent of 
the combination. In general, causality attribution should be assigned to the combination regimen 
(ie, to all agents in the regimen). However, causality attribution may be assigned to a single agent 
if, in the investigator’s opinion, there is sufficient data to support full attribution of the AE to the 
single agent. 
Follow-up of AE and SAE 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or causality 
of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals.  
• New or updated information will be recorded in the CRF.  
• The investigator will submit any updated SAE data to Merck within 2 business days but no longer 
than 3 calendar days of receipt of the information. 
14.1.5 Reporting of AEs, SAEs, and Other Reportable Safety Events to the Merck 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-661-6229 
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.