A Phase I/II Multi-site Study of Rucaparib and Pembrolizumab Maintenance Therapy in Stage IV Non-Squamous Non-Small Cell Lung Cancer After Initial Therapy With Carboplatin, Pemetrexed, and Pembrolizumab
Phase: PHASE1
Conditions: Stage IV Non-small Cell Lung Cancer
Sponsor: University of Michigan Rogel Cancer Center

ID: UMCC 
2018.033 
     
 
 
 
 
Rucaparib and Pembrolizumab for Maintenance 
Therapy in Stage IV Non-Squamous Non-Small Cell 
Lung Cancer 
    NCT03559049 
 

Protocol UMCC 2018.033 
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TITLE: A Phase I/II Multi-site Study of Rucaparib and Pembrolizumab Maintenance 
Therapy in Stage IV Non-Squamous Non-Small Cell Lung Cancer after Initial Therapy with 
Carboplatin, Pemetrexed, and Pembrolizumab 
 
SPONSOR-INVESTIGATOR: 
Angel Qin, MD 
Department of Internal Medicine, University of Michigan 
C353 Med Inn 
1500 E. Medical Center Drive, SPC 5848 
Ann Arbor, MI 48109 
Phone: 734-647-8921 
Fax: 734-615-2109 
Email: qina@med.umich.edu 
 
Coordinating Center: 
University of Michigan 
 
Biostatistician: 
John Rice, PhD 
Department of Biostatistics, University of Michigan 
Phone: 734-763-2451 
Email: jdrice@umich.edu 
 
 
Initial version: 
Mar 28, 2018 
Amendment 1: 
Jun 29, 2020 
Amendment 2: 
Mar 9, 2022 
Amendment 3: 
Aug 16, 2022 
Amendment 4:  
Aug 19, 2024 
Industry Support: (Investigational agent and pert funding for trial) 
CLOVIS [338-IIT-082] 
MERCK [MK3475-832] 

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TABLE OF CONTENTS 
 
 
 
ABBREVIATIONS ..................................................................................................................7 
1.0 
TRIAL SUMMARY .....................................................................................................9 
2.0 
TRIAL DESIGN .........................................................................................................10 
2.1 
Trial Design.............................................................................................................10 
2.2 
Trial Diagram .........................................................................................................11 
3.0 
OBJECTIVES .............................................................................................................11 
3.1 
Primary Objective & Hypothesis ..........................................................................11 
3.2 
Secondary Objectives & Hypotheses ....................................................................11 
3.3 
Exploratory Objectives ..........................................................................................12 
4.0 
BACKGROUND & RATIONALE ...........................................................................12 
4.1 
Background .............................................................................................................12 
4.1.1 Immune surveillance of malignancy and the PD-1/PD-L1 pathway ....................13 
4.1.2 Homologous recombinant repair and PARP inhibitors ........................................14 
4.1.3 Preclinical and Clinical Trial Data .......................................................................14 
4.2 
Rationale .................................................................................................................14 
4.2.1 Rationale for the Trial and Selected Subject Population ......................................14 
4.2.2 Rationale for Dose Selection/Regimen/Modification ...........................................15 
4.2.3 Rationale for Endpoints ........................................................................................17 
5.0 
PATIENT ELIGIBILITY .......................................................................................... 17 
5.1 
Inclusion Criteria ...................................................................................................17 
5.2 
Exclusion Criteria ..................................................................................................19 
6.0 
TREATMENT PLAN ................................................................................................20 

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6.1 
Drug Administration ..............................................................................................20 
6.1.1 Induction Phase ....................................................................................................20 
6.1.2 Maintenance Phase ...............................................................................................21 
6.2 
Dose Modification ...................................................................................................22 
6.2.1 Pembrolizumab Dose Modification ......................................................................22 
6.2.2 Rucaparib Dose Modification ...............................................................................24 
6.2.3 Overlapping Expected or Potential Hepatotoxicity ..............................................25 
6.2.4 Carboplatin and Pemetrexed Dose Modification ..................................................27 
6.3 
Diet/Activity/Other Considerations ......................................................................27 
6.3.1 Diet .......................................................................................................................27 
6.3.2 Photosensitivity ....................................................................................................27 
6.3.3 Contraception and Pregnancy ...............................................................................27 
6.3.4 Use in Nursing Women ........................................................................................29 
6.4 
Subject Withdrawal/Discontinuation Criteria ....................................................29 
6.4.1 Discontinuation of Study Therapy after Complete Response (CR) .....................30 
6.5 
Subject Replacement Strategy ..............................................................................30 
6.6 
Clinical Criteria for Early Trial Termination .....................................................30 
7.0 
TRIAL PROCEDURES .............................................................................................31 
7.1 
Trial Procedures .....................................................................................................31 
7.1.1 Informed Consent .................................................................................................31 
7.2 
Treatment Calendar ...............................................................................................33 
7.3 
Management of Adverse Events............................................................................36 
7.4 
Prohibited Concomitant Medications ...................................................................38 
7.4.1 CYP450 Isoenzyme Inhibitors, Inducers, and Substrates ....................................39 
7.5 
Withdrawal/Discontinuation .................................................................................40 

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7.5.1 End of Treatment Follow-up Visits ......................................................................40 
7.5.2 Survival Follow-up ...............................................................................................40 
8.0 
IMAGING AND MEASUREMENT OF DISEASE ................................................40 
8.1 
Disease Parameters ................................................................................................41 
8.2 
Guidelines for Evaluation of Measurable Disease ...............................................42 
8.3 
Response Criteria ...................................................................................................43 
9.0 
ADVERSE AND OTHER REPORTABLE EVENTS ............................................45 
9.1 
Definitions ...............................................................................................................46 
9.1.1 Adverse Event ......................................................................................................46 
9.1.2 Serious Adverse Event..........................................................................................47 
9.1.3 Expected Adverse Events .....................................................................................47 
9.1.4 Unexpected Adverse Events .................................................................................48 
9.1.5 Events Not Qualifying as SAEs ...........................................................................48 
9.2 
Evaluating Adverse Events ....................................................................................48 
9.3 
Reporting of Adverse Events .................................................................................48 
9.3.1 Reporting procedures for multi-site trials ............................................................48 
9.3.2 Reporting procedures to Merck Global Safety .....................................................49 
9.3.3 Reporting procedures to Clovis ............................................................................49 
9.3.4 Events of Clinical Interest ....................................................................................50 
9.3.5 Protocol-Specific Exceptions to Serious Adverse Event Reporting .....................50 
9.4 
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor and to Merck and Clovis ..................................................................51 
9.5 
Reporting of Pregnancy and Lactation to Merck and Clovis ............................51 
9.6 
Routine Reporting ..................................................................................................52 
9.7 
Reporting of Unanticipated Problems ..................................................................52 

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10.0 
CORRELATIVE STUDIES ..................................................................................... 52 
10.1 
PD-L1 expression ................................................................................................... 52 
10.2 
Tissue Requirements for Next Generation Sequencing ..................................... 52 
10.3 
Tumor Mutational Burden ................................................................................... 53 
10.4 
Homologous Repair Deficiency (HRD)................................................................ 53 
10.5 
Loss of Heterozygosity (LOH) .............................................................................. 53 
10.6 
Circulating tumor DNA (ct-DNA) ....................................................................... 53 
10.7 
Specimen Banking ................................................................................................. 53 
11.0 
STATISTICAL ANALYSIS PLAN ......................................................................... 54 
11.1 
Statistical Design ................................................................................................... 54 
11.2 
Sample Size Justification ...................................................................................... 54 
11.3 
Population for Analysis ......................................................................................... 56 
11.4 
Analysis of Primary Objective ............................................................................. 56 
11.5 
Analysis of Secondary Objectives ........................................................................ 56 
11.6 
Analysis of Exploratory Objectives ..................................................................... 56 
12.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES .................................................................................................................. 56 
12.1 
Investigational Drugs ............................................................................................ 56 
12.2 
Packaging and Labeling Information .................................................................. 57 
12.3 
Clinical Supplies Disclosure ................................................................................. 57 
12.4 
Storage and Handling Requirements ................................................................... 58 
12.5 
Returns and Reconciliation .................................................................................. 58 
13.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 58 
13.1 
Compliance with Trial Registration and Results Posting Requirements ......... 58 
13.2 
Quality Management System ............................................................................... 58 

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13.3 
Multi-Site Data Management ................................................................................59 
13.4 
Data and Safety Monitoring Procedures ..............................................................59 
13.5 
Clinical Monitoring Procedures ............................................................................60 
14.0 
REFERENCES ...........................................................................................................61 
15.0 
APPENDICES ............................................................................................................65 
I. ECOG Performance Status ............................................................................................65 
II. Common Terminology Criteria for Adverse Events V4.03 (CTCAE) .....................65 
 
 
 
 
LIST OF FIGURES 
 
Figure 1: Trial Design 
11 
 
 
 
LIST OF TABLES 
 
Table 1: 
Adequate organ function laboratory values 
17 
Table 2: 
Induction phase drugs 
20 
Table 3: 
Maintenance phase drugs 
21 
Table 4: 
Pembrolizumab infusion reaction dose modification and treatment 
guidelines 
23 
Table 5: 
Dose modification for rucaparib 
25 
Table 6: 
Management Guidelines for Rucaparib-Pembrolizumab 
Combination Treatment-Emergent AST/ALT Elevations 
26 
Table 7: 
Dose modification and toxicity management guidelines for immune- 
related AEs associated with pembrolizumab 
36 
Table 8: 
Trial operating characteristics based on simulation studies 
55 
Table 9: 
PFS11 estimates across 5000 simulated trials under different 
decisions 
55 

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ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
ALK 
Anaplastic Lymphoma Kinase 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CPP 
Carboplatin/Pemetrexed/Pembrolizumab 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-Lymphocyte-Associated Protein 4 
CTSU 
Clinical Trials Support Unit 
DLT 
Dose Limiting Toxicity 
DSB 
Double-Stranded Breaks 
DSMC 
Data and Safety Monitoring Committee 
ECI 
Events of Clinical Interest 
EGFR 
Epidermal Growth Factor Receptor 
ERC 
Ethics Review Committee 
GCP 
Good Clinical Practice 
H&P 
History & Physical Exam 
HRD 
Homologous Recombination Deficiency/deficient 
HRR 
Homologous Recombinant Repair 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
irRECIST 
Immune Response RECIST 
ITIM 
Immunoreceptor Tyrosine-Based Inhibition motif 
ITSM 
Immunoreceptor Tyrosine-Based Switch Motif 
IV (or iv) 
Intravenously 
MSD 
Merck Sharpe & Dohme 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PARP 
Poly (ADP-Ribose) Polymerase 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death Protein 1 

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PD-L1 
Programmed Death-Ligand 1 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PO 
per os/by mouth/orally 
PR 
Partial Response 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SSB 
Single Stranded Breaks 
TCGA 
The Cancer Genome Atlas 
TEAE 
Treatment-emergent Adverse Event 
TMB 
Tumor Mutational Burden 
TSH 
Thyroid Stimulating Hormone 
WBC 
White Blood Cells 

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1.0 
TRIAL SUMMARY 
 
Abbreviated Title 
Rucaparib and Pembrolizumab Maintenance Therapy in Stage IV Non- 
squamous NSCLC 
Trial Phase 
I/II 
Trial Type 
Interventional 
Study Centers 
Multi-Center: 3 sites total including the lead site: University of Michigan 
Objectives 
Primary: 
- 
To determine the progression free survival (PFS) of patients with 
stage IV non-squamous NSCLC on maintenance therapy with 
rucaparib and pembrolizumab after initial induction therapy with 
carboplatin/pemetrexed/pembrolizumab (CPP) 
Secondary: 
- 
To determine overall survival 
- 
To evaluate safety and tolerability of the combination of 
rucaparib and pembrolizumab as maintenance therapy 
- 
To evaluate response based on immune-related RECIST (ir- 
RECIST) criteria and compare to response rate as evaluated by 
RECIST v1.1. 
Exploratory: 
- 
To evaluate for genomic correlates that predict improved PFS to 
the combination of rucaparib and pembrolizumab maintenance 
therapy; these include tumor mutational burden, homologous 
repair deficiency, loss of heterozygosity, and PD-L1 expression 
- 
To evaluate the correlation between somatic mutations in the 
homologous repair pathway and association with improved PFS 
to the combination of rucaparib and pembrolizumab. 
Type of control 
Historical controls of patients treated with pembrolizumab +/- pemetrexed 
maintenance 
following 
induction 
therapy 
with 
carboplatin/pemetrexed/pembrolizumab 
Study drugs: dose and 
administration 
Rucaparib, PO, 600mg BID days 1-21 of a 21-day cycle 
Pembrolizumab, IV, 200mg day 1 of a 21-day cycle 
Duration of administration 
Until disease progression or intolerable toxicity, or after completing 2 
years of therapy 
Inclusion Criteria 
• 
Stage IV NSCLC whose tumors do not have a mutation in 
epidermal sensitizing growth factor (EGFR) or BRAF or 
rearrangements in ALK (anaplastic lymphoma kinase) or ROS-1 
• 
Non-squamous histology 
• 
Presence of measurable disease according to RECIST v1.1 
• 
ECOG performance status 0-1 
• 
Adequate organ function defined as AST and ALT ≤ 2.5 × ULN, 
bilirubin ≤ 1.5 × ULN, and creatinine clearance ≥ 50 ml/min 
• 
Adequate hematologic parameters 
• 
Sufficient tissue sample of adequate quality for correlative 
studies 
Exclusion Criteria 
• 
Presence of significant comorbidities precluding participation in 
a clinical study as determined by investigator 
 
 

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• 
Has active autoimmune disease that has required systemic 
treatment in the past 2 years 
• 
Daily oral corticosteroid use >10mg of prednisone (or its 
equivalent) 
• 
ECOG performance status 2-4 
• 
Prior systemic treatment for stage IIIB/IV NSCLC 
• 
Pregnancy or lactation 
Number of trial subjects 
38 (stage I), 17 (stage II), 55 total, with a 6-12 patient safety lead-in for 
stage 1 
Statistical design 
Bayesian two-stage design with phase I safety run-in 
Estimated duration of trial 
46 months (maximum) 
Estimated average length of 
treatment per patient 
12 months 
 
 
2.0 
TRIAL DESIGN 
 
2.1 
Trial Design 
 
This study is a multicenter, Phase I/II, single arm trial to assess the safety and efficacy of the 
combination of oral rucaparib plus intravenous pembrolizumab as maintenance therapy in 
patients with stage IV non-squamous non-small cell lung cancer (NSCLC) without progressive 
disease 
(PD), 
as 
confirmed 
on 
CT 
scans, 
after 
induction 
therapy 
with 
carboplatin/pemetrexed/pembrolizumab (CPP) triplet therapy. Approximately 55 patients 
whose tumors who do not have an epidermal sensitizing growth factor (EGFR) mutation or 
rearrangements in ALK (anaplastic lymphoma kinase) or ROS-1 will be enrolled. 
 
A small safety-run in will be conducted to assess the safety of the combination of rucaparib 
and pembrolizumab at the proposed dose of rucaparib 600mg PO BID d1-21 and 
pembrolizumab 200mg IV on day 1 every 21 days. While there have not been any studies 
specifically with the combination of rucaparib and pembrolizumab, the phase I study of 
durvalumab (a PD-L1 inhibitor) and olaparib (a PARP inhibitor) did not have any DLTs. The 
only grade 3 adverse events observed were lymphopenia and anemia and all other toxicities 
were ≤Grade 2.1 However, if ≥2 DLTs occur within the DLT timeframe (Cycle 1) after 
enrolling the first 6 patients, then there will be a dose reduction of rucaparib. Specific details 
are available in section 11.1. 
 
The patients will be assessed using cross-sectional imaging obtained every 6 weeks (42 +/- 7 
days) for the first 18 weeks, every 9 weeks through the first 12 months, and every 12 weeks 
thereafter. All imaging obtained will be submitted to an independent radiology review 
committee at the University of Michigan and will be assessed according to Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). To minimize the number of 
patients to be treated, this study will use a Bayesian two-stage design with planned analysis to 
compare to historical controls of patients treated with pembrolizumab +/- pemetrexed 
maintenance after receiving four cycles of CPP. Adverse event (AE) monitoring will occur 
prior to each cycle (21 days) and events will be graded according to the NCI Common 

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Terminology Criteria for Adverse Events (CTCAE) version 4.03. Patients will continue on trial 
until confirmed progression as defined by RECIST v1.1, develops unacceptable toxicity or 
intercurrent illness that prevents further administration of treatment, withdrawal from study, 
removal by the investigator, becomes pregnant, demonstrates noncompliance with trial 
requirements, or has received 24 months of treatment with rucaparib and pembrolizumab. 
Patients may continue on treatment despite RECIST v1.1-defined progression if the subject is 
felt to be continuing to derive clinical benefit as determined by the investigator. Additional 
information including the irRC2 (immune-related response criteria) may be used by the 
investigator in deciding continuing treatment beyond RECIST v1.1-defined progression. 
 
At the end of treatment, all patients will continue to be followed for a minimum of 30 days for 
AE monitoring. Subjects will have post-treatment follow-up for disease status for 5 years, 
including initiation of non-study cancer therapy until death, withdrawal of consent, or 
becoming lost to follow-up. 
 
2.2 
Trial Diagram 
 
The trial design is depicted below in Figure 1. 
Figure 1: 
Trial Design 
 
 
 
 
 
 
 
3.0 
OBJECTIVES 
 
3.1 
Primary Objective & Hypothesis 
 
(1) Objective: To determine the progression free survival (PFS) of the combination of 
rucaparib and pembrolizumab maintenance therapy in patients with stage IV non- 
squamous NSCLC with CR, PR, or SD after completing induction therapy with four 
cycles of CPP. Response will be measured by RECIST v1.1. 
 
Hypothesis: The combination of pembrolizumab and rucaparib maintenance therapy is 
superior to historical controls in NSCLC patients who received maintenance therapy with 
pembrolizumab +/- pemetrexed. 
 
3.2 
Secondary Objectives & Hypotheses 
 
(1) Objective: To evaluate the safety and tolerability profile of pembrolizumab and rucaparib. 
 
(2) Objective: To evaluate the OS in patients treated with maintenance pembrolizumab and 
rucaparib following induction therapy with CPP. 

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(3) Objective: Evaluate response based on immune response RECIST (irRECIST) as 
proposed by Wolchok et al2 and compare with response as calculated by RECIST v1.1. 
3.3 
Exploratory Objectives 
 
(1) 
Objective: To evaluate genomic correlates of response to combination maintenance 
therapy with rucaparib and pembrolizumab. Markers will include PD-L1 expression, 
tumor mutational burden (TMB), homologous repair deficiency (HRD), and loss of 
heterozygosity (LOH). We will also evaluate serial circulating tumor DNA (ct-DNA) as 
a genomic correlate of response, while on therapy to determine if there is a correlation 
with response to therapy. 
 
(2) 
Objective: To evaluate the correlation between germline and somatic mutations in genes 
in the homologous repair pathway and association with improved PFS to the combination 
of rucaparib and pembrolizumab. 
 
 
4.0 
BACKGROUND & RATIONALE 
 
4.1 
Background 
 
Disease Under Treatment 
 
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated mortality 
worldwide. The prognosis for stage IV NSCLC remains dismal, with a 5-year survival rate of 
1-2%. In addition to standard first-line platinum-based chemotherapy, other therapeutic options 
include tyrosine kinase inhibitors for patients with eligible mutations in the EGFR, ALK, or 
ROS-1 genes, and immune checkpoint inhibitors. Currently, both PD-1 (programmed cell death 
protein 1) and PD-L1 inhibitors are approved for the treatment of advanced NSCLC, 
irrespective of histology. Multiple phase II/III trials have demonstrated their superiority in 
terms of response rate and overall survival compared to docetaxel chemotherapy.3–5 
Study Drugs 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2. It is approved in the United States for the treatment of stage IV NSCLC 
with PD-L1 ≥50% in the front-line setting or for metastatic disease with PD-L1 ≥1% after 
progression on platinum-based chemotherapy. It also recently received accelerated approval 
by the FDA to be used in conjunction with carboplatin and pemetrexed as upfront therapy 
followed pembrolizumab +/- pemetrexed maintenance irrespective of PD-L1 expression in 
non-squamous etiologies.6 
Rucaparib is a small molecule inhibitor of the poly (ADP-ribose) polymerase (PARP) enzymes 
PARP-1, PARP-2, and PARP-3. It is FDA-approved for the treatment of BRCA mutant 
(germline/somatic) advanced ovarian cancer who have been treated with two or more previous 
chemotherapy regimens. It is also being explored in other solid tumors associated with 

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homologous recombination deficiency (HRD). Recently published results of a phase III 
randomized, placebo-controlled study showed that rucaparib maintenance therapy significantly 
improved progression free survival in women with platinum-sensitive high-grade ovarian, 
fallopian tube, and primary peritoneal cancer in all patients (including those that were BRCA 
wt and HRD-negative).7 The benefit was greater for patients whose tumors carried the BRCA 
mutation or were found to possess HRD. 
 
Refer to the Investigator’s Brochures (IB)/approved labeling for detailed background 
information on pembrolizumab and rucaparib. 
 
4.1.1 Immune surveillance of malignancy and the PD-1/PD-L1 pathway 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies. In particular, the presence of CD8+ T-cells8 and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells9 seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T- 
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2). PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) 
domain responsible for ligand binding and a cytoplasmic tail which is responsible for the 
binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based 
signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an 
immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic 
tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signaling cascade. The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer 
cells. Expression has also been shown during thymic development on CD4-CD8- (double 
negative) T-cells as well as subsets of macrophages and dendritic cells. The ligands for PD-1 
(PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including non-hematopoietic tissues as well as in various tumors. Binding of either PD-1 ligand 
to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular endothelium, 
whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in 
lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control immune 
T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 
function in peripheral tissues. Although healthy organs express little (if any) PD-L1, a variety 
of cancers were demonstrated to express abundant levels of this T-cell inhibitor, including 

Protocol UMCC 2018.033 
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NSCLC. This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention. 
 
4.1.2 Homologous recombinant repair and PARP inhibitors 
 
The homologous recombinant repair (HRR) pathway is critical for error-free repair of DNA 
double-stranded breaks (DSBs). Key genes in this pathway include BRCA1 and BRCA2, 
which when mutated are involved in the pathogenesis of hereditary breast and ovarian cancers, 
among others. Poly (ADP-ribose) polymerases (PARP) are a group of proteins that are crucial 
to the repair of single-stranded breaks (SSB). Upon formation of SSB, PARP binds at the end 
of broken DNA strands, a process which activates its enzymatic activity. Activated PARP 
catalyzes addition of long polymers of ADP-ribose on several proteins associated with 
chromatin, including histones and various DNA repair proteins. Therefore, PARP plays a key 
role in sensing DNA damage and converting it into intracellular signals that activate the base- 
excision-repair (BER) and SSB repair pathways. 
 
Inhibition of PARP allows the propagation of SSBs which are converted to DSBs as the cell 
progresses through the S phase; the DSBs would normally then be repaired by the HRR 
pathway. The concept of synthetic lethality is demonstrated by the use of PARP inhibitors in 
homologous repair deficient (HRD) cells which are unable to repair DSBs, ultimately resulting 
in cell death. PARP inhibitors have been approved in the United States for treatment of 
refractory germline BRCA-mutated ovarian cancer. 
 
There is increasing data to support that some sporadic tumors also harbor somatic mutations in 
other genes involved in the HRR pathway (i.e. ATM, RAD51, etc.), which result in a similar 
phenotype as germline BRCA mutant cells. These cells are considered to possess “BRCAness” 
which are also thought to render sensitivity to PARP inhibition.10 Examination of cancer 
genomic data sets through The Cancer Genome Atlas (TCGA) reveal that 11% of all NSCLC 
sequenced possessed mutations in BRCA1 or BRCA2 with up to 38% of cases having 
mutations in genes involved in DNA damage response.11 
4.1.3 Preclinical and Clinical Trial Data 
 
Refer to the Investigator’s Brochure for both pembrolizumab and rucaparib for Preclinical and 
Clinical data. 
 
4.2 
Rationale 
 
4.2.1 Rationale for the Trial and Selected Subject Population 
A new standard of care for patients with stage IIIB/IV non-squamous NSCLC without driver 
mutations is upfront carboplatin, pemetrexed, and pembrolizumab followed by pembrolizumab 
with or without pemetrexed maintenance therapy, irrespective of tumoral PD-L1 expression. 
In the KEYNOTE-021 cohort G, pemetrexed maintenance was not required, and 85% of 
patients in the pembrolizumab group received both drugs as maintenance therapy.6 Previous 
trials with the combination of platinum-pemetrexed doublet chemotherapy followed by 
pemetrexed maintenance lead to a PFS of 4-6 months.7,12 The median PFS of 13.0 months with 

Protocol UMCC 2018.033 
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pembrolizumab +/- pemetrexed seen on the KEYNOTE-021 trial is therefore a significant 
improvement compared to pemetrexed maintenance alone. However, there is data that suggests 
that the combination of a PARP inhibitor and pembrolizumab may lead to further 
improvements in PFS. 
 
Rizvi et al. have demonstrated through whole exome sequencing of patients with NSCLC 
treated with pembrolizumab that possess higher nonsynonymous tumor mutational burden 
(TMB) was associated with improved objective response, durable clinical benefit (DCB), and 
PFS.13 Furthermore, in this study, 50% of patients who experienced DCB had a mutation or 
mutations in genes involved in DNA repair including BRCA2 and RAD51, suggesting a 
possible association between increased TMB, “BRCAness”, and improved response to 
checkpoint inhibitors.14 In cell models, deficiencies in proteins of other members involved in 
the HR pathway such as RAD51, ATM, and FANCA did convey sensitivity to PARP 
inhibitors.10 This is also seen in BRCA wild-type (wt) but HR-deficient high grade serous 
ovarian carcinoma cells which have a higher neoantigen load compared to those that are 
BRCA-wt/HR-proficient.15 There is also data to suggest that increased TMB correlates with 
loss of heterozygosity (LOH), which is another surrogate marker for HRD; this was seen 
through exploration of the TCGA data for lung adenocarcinoma. The recently published 
ARIEL2 trial showed that treatment with rucaparib lead to an improved progression free 
survival and a higher response rate in BRCA-wt/LOH high ovarian carcinomas compared to 
BRCAwt/LOH low tumors.16 
Elevated tumoral PD-L1 expression appears to predict response to pembrolizumab. Compared 
to a response rate of 45% in patients with tumoral PD-L1 ≥50%, the response rate for tumoral 
PD-L1 1-49% is 16.5% and 10.7% with PD-L1 <1%.17 Treatment with a PARP inhibitor was 
seen to lead upregulate PD-L1 expression in cancer cell lines and animal models.18 This is 
supported by sequencing data from Dr. Arul Chinnaiyan’s lab at the University of Michigan 
shows that there is increased PD-L1 expression in HR deficient lung tumors. 
 
Given the association between presence of HRD, increased PD-L1 expression, and increased 
TMB, the addition of a PARP inhibitor may enhance response to a PD-1 inhibitor. 
Furthermore, sensitivity to platinum chemotherapy is associated with sensitivity to PARP 
inhibitors.19 We therefore propose to study the combination of rucaparib and pembrolizumab 
maintenance therapy in patients who have SD or PR after induction therapy with CPP. 
 
 
4.2.2 Rationale for Dose Selection/Regimen/Modification 
 
Pembrolizumab 
An open-label Phase I trial (KEYNOTE-001) has been conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab (MK-3475). The dose escalation portion of this 
trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W) in subjects with advanced solid tumors. All three dose levels were well tolerated and 
no dose-limiting toxicities were observed. This first in human study of pembrolizumab showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose levels 
(1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD has been identified to date. Recent data 

Protocol UMCC 2018.033 
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from other clinical studies within the pembrolizumab program has shown that a lower dose of 
pembrolizumab and a less frequent schedule may be sufficient for target engagement and 
clinical activity. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic 
data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days). 
This early PK and pharmacodynamic data provided the scientific rationale for testing a Q2W 
and Q3W dosing schedule. 
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight is within the range observed for other antibodies and would 
support both body weight normalized dosing or a fixed dose across all body weights. The 
differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body 
weight based regimen are anticipated to remain well within the established exposure margins 
of 0.5 – 5.0 for pembrolizumab as shown in the melanoma indication. The population PK 
evaluation revealed that there was no significant impact of tumor burden on exposure. In 
addition, exposure was similar between the NSCLC and melanoma indications. Therefore, 
there are no anticipated changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established in 
melanoma that are well tolerated and safe. 
 
Rucaparib 
A three-part, open-label, Phase 1/2 study of oral rucaparib monotherapy administered daily in 
continuous 21-day cycles is ongoing. Part 1 (Phase 1) evaluated PK and safety of escalating 
doses of rucaparib in patients with solid tumors dose (N = 56; enrollment complete) and 
identified 600 mg BID as the recommended starting for Phase 2 based on safety, PK, and the 
clinical activity profile. 
 
There has been no phase I data that has specifically evaluated the combination of rucaparib 
and pembrolizumab. There are not any serious adverse events that appear to overlap between 

Protocol UMCC 2018.033 
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the two agents based on review of published phase I/II/III and data. However, we will plan for 
a small phase I run-in for safety analysis. Details are described in Section 11.0. 
 
4.2.3 Rationale for Endpoints 
 
4.2.3.1 Efficacy Endpoints 
 
The primary endpoint of this study is progression free survival. We chose PFS as the primary 
endpoint as we are studying the impact of a novel therapy combination in the maintenance 
setting. Response rate in this setting would not be an appropriate endpoint as all patients must 
respond or have SD to initial induction with CPP prior to starting maintenance therapy. We 
will assess OS as a secondary endpoint. In addition, we will evaluate safety and tolerability as 
the combination of rucaparib and pembrolizumab has not been exclusively studied in the past. 
 
4.2.3.2 Biomarker Research 
 
We anticipate that there will be a subset of patients who will remain without progressive 
disease on rucaparib and pembrolizumab maintenance therapy after induction CPP for >13 
months (the median PFS seen in KEYNOTE-021). To interrogate genomic predictors of 
response, we will evaluate archived tissue samples for TMB, HRD, and LOH. Tumoral PD-L1 
expression will also be assessed, which is currently considered standard of care in metastatic 
NSCLC. Finally, we will also measure serial ct-DNA for longitudinal monitoring of ctDNA as 
a measure of response to therapy and correlate with radiographic progression. 
 
5.0 
PATIENT ELIGIBILITY 
 
5.1 
Inclusion Criteria 
 
In order to be eligible for participation in this trial, the subject must: 
 
1. Be willing and able to provide written informed consent/assent for the trial. 
 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Have a life expectancy of at least 3 months. 
 
4. Have a diagnosis of stage IV non-squamous NSCLC whose tumors do not have an 
epidermal sensitizing growth factor (EGFR) mutation or BRAF mutation or 
rearrangements in ALK (anaplastic lymphoma kinase) or ROS-1 and haveat least one 
measurable lesion based on RECIST v1.1. 
 
5. Have a performance status of 0 or 1 on the ECOG Performance Scale (Appendix 15.1). 
 
6. Demonstrate adequate organ function as defined in Table 1; all screening labs should 
be performed within 28 days of enrollment. 
 
Table 1:    Adequate organ function laboratory values 

Protocol UMCC 2018.033 
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System 
Laboratory Value 
Hematologic 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL without transfusion or EPO dependency (within 7 days 
of assessment) 
Renal 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
≥2.5 g/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
 
7. Female subject of childbearing potential should have a serum pregnancy test within -28 
daysof enrollment and 72 hours prior to receiving the first dose of study medications. 
 
8. Female subjects of childbearing potential must be willing to use a highly effective 
method of contraception as outlined in Section 6.3.3 for the course of the study through 
180 days after the last dose of study medications. 
 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject. 
 
9. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 6.3.3, starting with the first dose of study therapy 
through 180 days after the last dose of study therapy. 
 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject. 
 
10. If the patient has archival tissue, this should be collected for correlative studies. If 
archival tissue does not exist, a new biopsy is not required 

Protocol UMCC 2018.033 
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5.2 
Exclusion Criteria 
 
The first dose of trial treatment is considered to be first dose of carboplatin, pemetrexed, and 
pembrolizumab. The subject must be excluded from participating in the trial if the subject: 
 
1. Received previous systemic therapy for stage IV NSCLC. 
 
2. Received radiation to the lungs >30Gy ≤6 months of enrollment. 
 
3. Received palliative radiation within 7 days of enrollment. 
 
4. Had prior treatment with any other anti-PD-1, PD-L1, or PD-L2 agent or an antibody 
targeting other immune-regulatory receptors or mechanisms. 
5. Received prior treatment with a PARP inhibitor. 
6. Has a known history of prior malignancy except if the patient has undergone potentially 
curative therapy with no evidence of that disease recurrence for 5 years since initiation 
of that therapy. Note: the time requirement for no evidence of disease for 5 years does 
not apply to the NSCLC tumor for which a subject is enrolled in the study. The time 
requirement also does not apply to subjects who underwent successful definitive 
resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell 
carcinoma of the skin, in situ cervical cancer, or other in situ cancers. 
7. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks 
prior to enrollment and any neurologic symptoms have returned to baseline), have no 
evidence of new or enlarging brain metastases, and are not using steroids for at least 7 
days prior enrollment. This exception does not include carcinomatous meningitis which 
is excluded regardless of clinical stability. 
 
8. Has active autoimmune disease that has required systemic treatment within the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). 
 
Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment. 
 
9. Subjects requiring daily corticosteroids >10mg of prednisone (or its equivalent) would 
be excluded from the study. 
 
Note: Subjects with asthma that require intermittent use of bronchodilators, inhaled 
steroids, or local steroid injections would NOT be excluded from the study. 

Protocol UMCC 2018.033 
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10. Has evidence of interstitial lung disease or a history of non-infectious pneumonitis that 
required oral or intravenous glucocorticoids to assist with management. 
 
Note: Lymphangitic spread of the NSCLC is not exclusionary. 
 
11. Has an active infection requiring systemic therapy. 
 
12. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 
13. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with informed consent through 180 days after 
the last dose of trial treatment. 
 
14. Has a diagnosis of immunodeficiency (including Human Immunodeficiency Virus 
(HIV) or acquired immunodeficiency (AIDS-related illness) or is receiving systemic 
steroid therapy or any other form of immunosuppressive therapy within 7 days prior to 
enrollment. 
 
15. Has a known history of active TB (Bacillus Tuberculosis). 
 
16. Has known active Hepatitis B or Hepatitis C. 
17. Has received a live vaccine within 30 days of enrollment. 
 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
 
18. A medical condition that requires daily systemic corticosteroids, greater than the 
equivalent of 10mg of prednisone. 
Note: Corticosteroids administered as part of pre-medications or supportive 
medications (as in the case of dexamethasone as an anti-emetic administered with 
pemetrexed) are allowed. 
 
6.0 
TREATMENT PLAN 
 
6.1 
Drug Administration 
 
6.1.1 Induction Phase 
The drugs to be used in the Induction Phase are outlined in Table 2 below. The first dose of 
trial treatment is considered to be first dose of carboplatin, pemetrexed, and pembrolizumab. 
Trial treatment should begin within 14 days of enrollment. 
 
Table 2:    Induction phase drugs 

Protocol UMCC 2018.033 
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Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 21-day 
cycle; given first and 
at least 30 minutes 
prior to chemotherapy 
Pemetrexed 
500 mg/m2 
Q3W 
IV infusion 
Day 1 of each 21-day 
cycle; given after 
pembrolizumab and 
before carboplatin 
Carboplatin 
AUC 5 
Q3W 
IV infusion 
Day 1 of each 21-day 
cycle; after 
pemetrexed 
 
 
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). Similarly, infusion 
times may be extended as needed for safety (e.g., infusion reaction occurs). These instances 
must be documented in the patient medical records. It must be administered first and at least 
30 minutes prior to infusion of subsequent pemetrexed and carboplatin in the Induction Phase. 
 
Pemetrexed 500mg/m2 will be administered as an IV infusion over 10 minutes (+/- 5 minutes) 
Q3W during the Induction Phase. All subjects should receive appropriate supplementation of 
vitamin B12 and folic acid according to the approved product label and/or standard practice. 
In addition, all patients should receive the appropriate corticosteroid prophylaxis as per the 
local approved label. Additional prophylaxis should be administered as per standard practice. 
 
Carboplatin AUC5 will be administered as an IV infusion over 15-60 minutes +/- 5 minutes 
Q3W during the Induction Phase immediately after pemetrexed. Additional pre-medications 
should be administered as per standard protocol. 
 
6.1.2 Maintenance Phase 
 
The drugs to be used in the Maintenance Phase are outlined in Table 3 below. 
 
Patients must have complete response (CR), partial response (PR), or stable disease (SD) after 
initial therapy with the 4 cycles of induction phase therapy to be permitted to proceed with the 
maintenance phase. 
 
Table 3:    Maintenance phase drugs 
 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Pembrolizumab 200 mg 
Q3W 
IV infusion 
Day 1 of each 21-day 
cycle 

Protocol UMCC 2018.033 
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Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Rucaparib 
600 mg 
BID 
PO 
Day 1-21 of each 21 
day cycle 
All trial treatments will be administered on an outpatient basis. 
 
Rucaparib 600mg (2 X 300mg rucaparib tablets) PO will be taken twice daily starting on day 
1 of cycle 1 of the Maintenance Phase. Rucaparib should be taken with water, on an empty 
stomach or with food. Treatment is continuous and each cycle will comprise 21 days. Patients 
should take rucaparib doses as close to 12 hours apart as possible, preferably at the same times 
every day. If a patient misses a dose (i.e., does not take it within 4 hours of the scheduled time), 
the patient should skip the missed dose and resume taking rucaparib at the next scheduled dose. 
Vomited doses should not be replaced. 
 
Subjects will be given a pill diary and instructed to complete for each day of administration of 
rucaparib. Missed and/or vomited doses should be recorded on the diary as such. Subjects will 
be asked to bring their pill diary to each study visit along with all used and unused study drug 
containers. 
 
6.2 
Dose Modification 
 
In the event that one drug is discontinued for any reason, then the other drug will also be 
discontinued and the patient will come off study treatment. If one or both drugs are held for ≥6 
consecutive weeks from intended cycle start, the patient must come off study treatment. The 
primary objective of this trial is to look at the efficacy of rucaparib and pembrolizumab in the 
maintenance setting and therefore patients on maintenance therapy with a single agent should 
not be evaluated for the primary endpoint; however, they will still be evaluable for toxicity. 
 
6.2.1 Pembrolizumab Dose Modification 
 
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4. 

Protocol UMCC 2018.033 
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Table 4: 
Pembrolizumab infusion reaction dose modification and treatment 
guidelines 
 
 
NCI CTCAE Grade 
Treatment 
Premedication and Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
subject 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 
subject 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 subject should be premedicated for the 
next scheduled dose. 
Subjects who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug treatment 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 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 
subject is deemed medically stable in the opinion of the 
investigator. 
-Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used 
immediately. 
Subject is permanently discontinued from further study drug 
treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0.3 (CTCAE) at http://ctep.cancer.gov 

Protocol UMCC 2018.033 
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For dose modification/management of immune-related adverse events, please see section 7.3 
Table 7. 
 
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. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor-Investigator. The reason for interruption should be documented in 
the patient's study record. 
 
6.2.2 Rucaparib Dose Modification 
 
Phase I Safety-Run In - Dose Limiting Toxicity (DLT) 
 
The DLT for the phase I safety run in will be defined as in the phase I/II study of rucaparib in 
patients with germline BRCA 1/2 mutated solid tumors.20 A DLT was defined as any of the 
following events that occurred in Cycle 1 and were assessed by investigators as related to 
rucaparib: 
 
1) Absolute neutrophil count less than 0.5 x 109/L lasting for more than 5 days or febrile 
neutropenia (which is defined as a temperature >38.3ºC and an ANC < 1.0 x 109/L). 
2) Platelets less than 25 x 109 or less than 50 x 109/L with bleeding requiring a platelet 
transfusion 
 
3) Grade 4 anemia 
 
4) Any non-hematologic adverse event ≥ CTCAE Grade 3 (except nausea, vomiting, and 
diarrhea, if well controlled by systemic medication, and alopecia) 
 
Maintenance Phase Rucaparib Dose Modification 
 
Treatment with rucaparib should be held if any of the following are observed and a dose 
reduction should be considered or implemented. 
 
• Grade 3 or 4 hematologic toxicity 
• Grade 3 or 4 non-hematologic toxicity (except for alopecia, nausea, vomiting, or 
diarrhea adequately controlled with systemic antiemetic/antidiarrheal medication 
administered in standard doses according to the study center routines) 
 
In addition, and at the discretion of the investigator, the dose of rucaparib may be held and/or 
reduced for Grade 2 toxicity not adequately controlled by concomitant medications and/or 
supportive care. 
 
Treatment with rucaparib should be held until the toxicity improves to ≤ CTCAE Grade 2. BID 
dosing may then be resumed at either the same dose or a lower dose, per investigator discretion. 

Protocol UMCC 2018.033 
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If treatment is resumed at the same dose, and the patient experiences the same toxicity, the 
dose should be reduced following improvement of the event to ≤ CTCAE Grade 2. 
 
At the discretion of the treating investigator, treatment may be discontinued: 
 
• If a subject continues to experience toxicity despite dose reduction [as allowed per the 
phase I safety run-in] or, 
 
• If upon rechallenge, dosing with rucaparib is interrupted for >14 consecutive days due 
to toxicity 
 
Dose reduction steps are presented in Table 5. 
 
Dose re-escalation upon resolution of toxicity to ≤ CTCAE Grade 1 is permitted, upon the 
investigator’s discretion. 
 
Table 5: 
Dose modification for rucaparib 
 
Rucaparib (CO-338) 
Tablets 
300/250/200 mg 
Starting Dose 
600 mg BID 
Dose Level -1 
500 mg BID 
 
Criteria for Rucaparib Re-treatment 
 
A new cycle of treatment may begin if: 
 
• ANC ≥ 1.0 x 109/L 
• Platelet count ≥ 75 x 109/L 
• Non-hematologic toxicities have returned to baseline or ≤ CTCAE Grade 1 severity (or, 
at the investigator’s discretion, ≤ CTCAE Grade 2 severity if not considered a safety 
risk for the patient). Grade 3 or Grade 4 ALT/AST elevations should be managed as 
described in Table 6. 
 
6.2.3 Overlapping Expected or Potential Hepatotoxicity 
 
Elevated ALT/AST is among the most frequently reported treatment-related adverse events 
reported for rucaparib monotherapy. Immune-mediated hepatitis has been associated with the 
administration of pembrolizumab. Eligible patients must have adequate liver function, as 
manifested by measurements of total bilirubin and hepatic transaminase, and liver function will 
be monitored throughout study treatment. While on this study, patients presenting with right 

Protocol UMCC 2018.033 
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upper-quadrant abdominal pain and/or unexplained nausea or vomiting should have LFTs 
performed immediately and reviewed before administration of the next dose of study drug. If 
LFTs increase, neoplastic, concurrent medications, viral hepatitis, and toxic etiologies should 
be considered and addressed, as appropriate. Imaging of the liver, gall bladder and biliary tree 
should be performed to rule out neoplastic or other causes for increased LFTs. Anti-nuclear 
antibody, perinuclear anti-neutrophil cytoplasmic antibody, anti-liver kidney microsomal 
antibodies, and anti-smooth muscle antibody tests should be performed if an autoimmune 
etiology is considered. Recommended guidelines for managing LFT abnormalities are outlined 
in Table 6. 
 
Table 6: 
Management Guidelines for Rucaparib-Pembrolizumab Combination 
Treatment-Emergent AST/ALT Elevations 
 
Description 
Management 
AST/ALT > ULN to 3 x ULN 
• 
Continue rucaparib and pembrolizumab 
with the standard monitoring plan 
AST/ALT > 3 x ULN to 5 x ULN with total 
bilirubin ≤ULN 
• 
Continue rucaparib and pembrolizumab 
• 
Monitor LFTs at least weekly 
AST/ALT > 5 x ULN to 10 x ULN with total 
bilirubin ≤ ULN 
OR 
AST/ALT > 3 x ULN to 5 x ULN with bilirubin 
> ULN 
• 
Hold rucaparib and pembrolizumab 
• 
Monitor LFTs every 48-72 hours; if 
incremental increases observed after 72 
hours of initial > 5 x ULN observation, 
follow the guidelines below for 
AST/ALT>10 x ULN (even if it is ≤10 
x ULN) 
• 
Consider GI consult and liver biopsy to 
establish etiology of hepatic injury if 
necessary 
• 
If resolves to ≤5 x ULN in ≤7 days, 
restart rucaparib and pembrolizumab 
• 
If persists > 7 days, follow guidelines 
for AST/ALT > 10 x ULN 
AST/ALT > 10 x ULN 
• 
Permanently discontinue rucaparib and 
pembrolizumab 
• 
Consider GI consult and liver biopsy to 
establish etiology of hepatic injury if 
necessary 
• 
Start 60mg prednisone or equivalent per 
day 
• 
Monitor LFTs every 48 hours 
• 
If LFT results do not decrease within 48 
hours after initiation of systemic 
steroids, addition of an alternative 
immunosuppressive agent (e.g. 
mycophenolate or TNFα antagonist) 
may be considered 

Protocol UMCC 2018.033 
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• 
Continue monitoring LFTs every 48-72 
hours until decreasing and then follow 
weekly until resolution to ≤ 5 X ULN 
• 
Taper steroids over >1 month 
GI = gastrointestinal; LFT = liver function test; TNFα = tumor necrosis factor alpha; ULN = upper limit of normal. 
 
6.2.4 Carboplatin and Pemetrexed Dose Modification 
 
Dose reduction in carboplatin and pemetrexed will be done on an as needed basis as determined 
appropriate by the investigator. 
 
6.3 
Diet/Activity/Other Considerations 
 
6.3.1 Diet 
 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 
6.3.2 Photosensitivity 
 
Photosensitivity has been observed in patients treated with rucaparib. Patients should avoid 
spending time in direct sunlight because they burn more easily during treatment with rucaparib. 
When outdoors, patients should use typical precautions such as applying sunscreen (sun 
protection factor 50 or greater) and/or covering exposed skin with clothing and wearing a hat 
and sunglasses. 
 
6.3.3 Contraception and Pregnancy 
 
Pembrolizumab and rucaparib may have adverse effects on a fetus in utero. Furthermore, it is 
not known if pembrolizumab and rucaparib have transient adverse effects on the composition 
of sperm. 
 
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition). 
 
Female subjects will be considered of non-reproductive potential if they are either: 
 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.); 
 
OR 
 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening; 

Protocol UMCC 2018.033 
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OR 
 
(3) has a congenital or acquired condition that prevents childbearing. 
 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 180 days after the last 
dose of study drug by complying with one of the following: 
 
(1) practice abstinence† from heterosexual activity; 
OR 
(2) use (or have their partner use) highly effective contraception during heterosexual activity. 
Highly effective methods of contraception are‡: 
Single method (one of the following is acceptable): 
 
• 
intrauterine device (IUD) 
• 
intrauterine hormone-releasing system (IUS) 
• 
bilateral tubal occlusion 
• 
vasectomy of a female subject’s male partner 
• 
contraceptive rod implanted into the skin 
 
Combination method (requires use of two of the following): 
 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only) 
• 
contraceptive sponge (nulliparous women only) 
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin- 
only pill) associated with inhibition of ovulation, contraceptive skin patch, vaginal 
contraceptive ring, or subcutaneous contraceptive injection 
 
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception. 
 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region. 
 
Patients should be informed that taking the study medications may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 

Protocol UMCC 2018.033 
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(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 180 days after 
the last dose of trial therapy. If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
 
If a patient inadvertently becomes pregnant while on study, the subject will immediately be 
removed from the study and the site should notify the Coordinating Center within 24 hours of 
knowledge. The site will contact the subject at least monthly and document the subject’s status 
until the pregnancy has been completed or terminated. The outcome of the pregnancy will be 
reported to the Coordinating Center within 24 hours. The Coordinating Center will be 
responsible for notifying Merck and Clovis regarding pregnancies as described in Section 9.3. 
 
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. If a male subject impregnates 
his female partner the study personnel at the site must be informed immediately and the 
pregnancy reported to the Coordinating Center within 24 hours of knowledge. The 
Coordinating Center will be responsible for notifying Merck and Clovis as described in Section 
9.3. 
 
6.3.4 Use in Nursing Women 
 
It is unknown whether pembrolizumab or rucaparib 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, subjects who are breast-feeding are not eligible for enrollment. In addition, 
subjects should not breastfeed for 180 days after the last dose of study medication. 
 
6.4 
Subject Withdrawal/Discontinuation Criteria 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn if enrollment into the trial is inappropriate, the trial plan is violated, or for 
administrative and/or other safety reasons. Specific details regarding discontinuation or 
withdrawal are provided in Section 7.5. 
 
A subject must be discontinued from study treatment for any of the following reasons: 
 
• The subject withdraws consent. 
• Confirmed radiographic disease progression 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved at the 
discretion of the investigators. 
 
• Unacceptable adverse experiences as described in Section 6.2 and 7.3 
• Intercurrent illness that prevents further administration of treatment 

Protocol UMCC 2018.033 
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• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of uninterrupted treatment with pembrolizumab and rucaparib 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 7. 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 as described in Section 
9.0). End of treatment and survival follow-up procedures are listed in section 7.2. 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 every 6 months through the medical record (up to 5 years) for overall survival until 
death, withdrawal of consent, or the end of the study, whichever occurs first. 
 
6.4.1 Discontinuation of Study Therapy after Complete Response (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 the combination of pembrolizumab and 
rucaparib and had at least two treatments with the two drugs beyond the date when the initial 
CR was declared. 
 
Discontinuation of therapy should occur if the patients have received 2 years of treatment with 
pembrolizumab (counting from C1 of induction phase). 
 
6.5 
Subject Replacement Strategy 
 
Any subject that does not receive at least one dose of rucaparib and one dose of pembrolizumab 
will be replaced. 
 
6.6 
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 subjects 
 
4. Plans to modify or discontinue the development of the study drug 

Protocol UMCC 2018.033 
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In the event of Merck and Clovis decision to no longer supply study drug, ample notification 
will be provided so that appropriate adjustments to subject treatment can be made. 
 
7.0 
TRIAL PROCEDURES 
 
7.1 
Trial Procedures 
 
Patient registration for this trial will be centrally managed by the Coordinating Center of The 
University of Michigan Rogel Cancer Center as described below: 
 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on the Screening and 
Enrollment Log provided by the Coordinating Center. 
 
It is the responsibility of the local site investigator to determine patient eligibility prior to 
submitting patient registration request to the Coordinating Center. After patient eligibility has 
been determined, a copy of the completed Eligibility Worksheet together with all the pertinent 
de-identified source documents will be submitted by the requesting site to the Coordinating 
Center, by email to CTSU-Oncology-Multisite@med.umich.edu. 
 
The Multi-Site Coordinator, who acts as the registrar, will review the submitted documents and 
process the registration. Sites should inform the Multi-Site Coordinator of a potential 
registration by 5 p.m. on the day prior to registration. Same day registrations cannot be 
guaranteed. 
 
An email will be sent by the registrar to the requesting site registrar to confirm patient 
registration and to provide the study identification number that has been assigned to the patient. 
In addition, a copy of the completed Eligibility Worksheet signed and dated by the registrar, 
will be sent back to the requesting site registrar. 
 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in the Screening and Enrollment Log. These patients will not 
have study identification number assigned to them, and will not receive study treatment. 
 
The Treatment Calendar - Section 7.2 summarizes the trial procedures to be performed at each 
visit. It may be necessary to perform these procedures at unscheduled time points if deemed 
clinically necessary by the investigator. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the investigators 
and/or Merck/Clovis for reasons related to subject safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus 
local regulations may require that additional informed consent be obtained from the subject. In 
these cases, such evaluations/testing will be performed in accordance with those regulations. 
 
7.1.1 Informed Consent 
 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 

Protocol UMCC 2018.033 
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Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
 
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB’s approval/favorable 
opinion in advance of use. The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial. The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature. 
 
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. 

Protocol UMCC 2018.033 
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7.2 
Treatment Calendar 
 
 
Screening 
Visit 1 
Induction Phase 
Maintenance Phase 
End of 
Treat- 
ment2 
Progress- 
ion Free 
Follow- 
up 9 
Survival 
Follow- 
up 10 
A ± 3-day window will be allowed for all treatment visits and assessments, unless otherwise specified. However, every effort must be made to follow the schedule 
outlined in the table below. 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 and 
beyond 
Day -28 to - 
1 
Informed Consent 
X 
History, physical 
exam and 
medication 
review3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
monitoring11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete blood 
count with 
differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive 
metabolic panel4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipid panel5 
X 
PT/INR and 
aPTT 
X 
X 
Urinalysis 
X 
X 
TSH 
X 
X 
X 
X 
X 
X 
Pregnancy test – 
serum β-HCG6 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
CT of chest and 
other relevant 
sites of disease7 
X 
X 
(within 
7 days 
prior to 
C3) 
X 
(within 
7 days 
prior to 
C1 of 
Mainte 
nance) 
X 
(within 
7 days 
prior to 
C3) 
X 
(within 
7 days 
prior to 
C6) 
X 
(within 7 
days prior 
to C9, C12, 
C15)7a 
X 
X (q12 
weeks)7b 

Protocol UMCC 2018.033 
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Screening 
Visit 1 
Induction Phase 
Maintenance Phase 
End of 
Treat- 
ment2 
Progress- 
ion Free 
Follow- 
up 9 
Survival 
Follow- 
up 10 
A ± 3-day window will be allowed for all treatment visits and assessments, unless otherwise specified. However, every effort must be made to follow the schedule 
outlined in the table below. 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 and 
beyond 
Day -28 to - 
1 
Infusion of 
pembrolizumab 
200mg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infusion of 
pemetrexed 
500mg/m2 
X 
X 
X 
X 
Infusion of 
carboplatin AUC 
5 
X 
X 
X 
X 
Rucaparib 600mg 
PO BID 
X 
X 
X 
X 
X 
X 
Tissue sent and 
archived for 
correlative 
studies 
X 
Whole blood 
sample collection 
to assess for 
ctDNA8 
X 
X 
X 
X 
Survival status 
X 
 
1. 
Assessment for eligibility, including blood tests and cross sectional imaging, must occur within 28 days of starting therapy. If complete blood count with differential 
and comprehensive metabolic panel was obtained within 7 days prior to initiation of therapy, it does not need to be repeated. 
2. 
The end of treatment visit will occur 30days (+/-10 days) after the last dose of rucaparib [or last induction dose, for those who don’t initiate maintenance therapy] or before 
the start of subsequent antineoplastic therapy if that occurs sooner. 
3. 
Includes vital signs as well as evaluation of performance status 
4. 
Comprehensive metabolic panel includes serum sodium, potassium, chloride, bicarbonate, BUN, creatinine, calcium, protein, albumin, AST, ALT, alkaline phosphatase, 
and total bilirubin. 
5. 
Lipid panel includes total cholesterol, triglycerides, HDL, and LDL. 
6. 
Serum pregnancy testing will be performed every 6 weeks (i.e. every other cycle) throughout the duration of the study. 

Protocol UMCC 2018.033 
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7. 
CT scan to assess response to be obtained every 6 weeks for the first 18 weeks (starting from Screening visit), every 9 weeks for the first 12 months (starting from Cycle 
3 of Maintenance phase), and every 12 weeks (from last CT during treatment intervention) thereafter. There will be a scheduling leeway of 7 days prior to the next cycle. 
If treatment is held greater than 30 days after most recent scans, new scans should be obtained prior to restarting treatment, i.e., if scans were within 30 days, no new scan 
is needed. 
7a. Until after 52 weeks since starting induction. 
7b. Starting from last CT during treatment intervention. 
8. 
Whole blood samples to assess for ctDNA will be obtained at start of induction phase, start of maintenance phase, and every 4 cycles (i.e. 12 weeks) on maintenance 
therapy until progression. 
9. 
Progression Free follow-up: subjects who discontinue for reasons other than progressive disease will have follow-up for disease status every 12 weeks (+/- 2 weeks) until 
disease progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost to follow-up (limited to subjects who have received at least one dose 
of  Rucaparib). 
10. Survival follow-up (every 6 months =+/- 2 weeks) limited to subjects who have received at least one dose of rucaparib. After documented disease progression each 
subject will be followed every 6 months through the medical record for overall survival up to 5 years until death, withdrawal of consent, or the end of study, whichever 
occurs first. 
11. Serious adverse events will be collected for 90 days after the last dose as described in Section 9. 

Protocol UMCC 2018.033 
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7.3 
Management of Adverse Events 
 
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 one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical trial 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. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided in 
Table 7. 
 
Table 7: 
Dose modification and toxicity management guidelines for immune-related 
AEs associated with pembrolizumab 
 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks. 
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-related 
AEs 
Toxicity 
grade or 
conditions 
(CTCAEv4. 
0) 
Action 
taken to 
pembrolizu 
mab 
irAE 
management with 
corticosteroid 
and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
1-2mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
• 
Monitor subjects for signs and 
symptoms of pneumonitis 
• 
Evaluate subjects with suspected 
pneumonitis with radiographic 
imaging and initiate 
corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 
4, or 
recurrent 
grade 2 
Permanently 
discontinue 

Protocol UMCC 2018.033 
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Diarrhea / colitis 
Grade 2 or 3 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
1-2mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
• 
Monitor subjects for signs and 
symptoms of enterocolitis (i.e. 
diarrhea, abdominal pain, blood 
or mucus in stool with or without 
fever) and of bowel perforation 
(i.e. peritoneal signs and ileus). 
• 
Subjects with ≥ Grade 2 diarrhea 
suspecting colitis should consider 
GI consultation and performing 
endoscopy to rule out colitis. 
• 
Subjects 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 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
Bilirubin 
Please see section 6.2.3 regarding the management of overlapping hepatotoxicity with 
rucaparib and pembrolizumab. 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglyce 
mia 
associated 
with 
evidence of 
β-cell failure 
Withhold 
• Initiate insulin 
replacement 
therapy for 
subjects with 
T1DM 
• Administer 
anti- 
hyperglycemic 
in subjects with 
hyperglycemia 
• 
Monitor subjects 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 
discontinue1 
Hyperthyroidism 
Grade 2 
Continue 
• Treat with non- 
selective beta- 
blockers (e.g. 
propranolol) or 
thionamides as 
appropriate 
• 
Monitor for signs and symptoms 
of thyroid disorders. 
Grade 3 or 4 
Withhold or 
Permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue 
• Initiate thyroid 
replacement 
hormones (e.g. 
levothyroxine 
or 
liothyroinine) 
• 
Monitor for signs and symptoms 
of thyroid disorders. 

Protocol UMCC 2018.033 
Page 38 of 65 
 
 
 
per standard of 
care 
Nephritis and 
renal dysfunction 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(prednisone 1- 
2mg/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 
Grade 3, or 
intolerable/ 
persistent 
Grade 2 
Withhold 
• Based on 
severity of AE 
administer 
corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology or exclude 
other causes 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 
NOTES: 
1. 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. 
2. For subjects with Grade 3 or 4 immune-related endocrinopathy where withholding 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) 
 
7.4 
Prohibited Concomitant Medications 
 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
 
1. Antineoplastic systemic chemotherapy or biological therapy 
2. Immunotherapy not specified in this protocol 
3. Chemotherapy not specified in this protocol 
4. Investigational agents 
5. Radiation therapy 
- 
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion. 
6. Live vaccines within 30 days prior to enrollment and while participating in the trial. 
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 
 
7. Daily systemic glucocorticoids with dose >10mg of prednisone (or its equivalent) for 
any purpose other than to modulate symptoms from an event of clinical interest of 
suspected immunologic etiology. Note that corticosteroids administered as part of pre- 

Protocol UMCC 2018.033 
Page 39 of 65 
 
 
medications or supportive medications (as in the case of dexamethasone as an anti- 
emetic administered with pemetrexed) is allowed. 
8. Pegfilgrastim (Neulasta, Udenyca, etc. via any delivery method), unless used during 
Induction phase (with carboplatin/pemetrexed/pembrolizumab). 
 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. Subjects 
may receive other medications that the investigator deems to be medically necessary. 
 
7.4.1 CYP450 Isoenzyme Inhibitors, Inducers, and Substrates 
Based on results of in vitro CYP interaction studies, caution should be used for concomitant 
medications with narrow therapeutic windows that are substrates of CYP2C19, CYP2C9, 
and/or CYP3A. Selection of an alternative concomitant medication is recommended. 
 
Examples of CYP Substrates with Narrow Therapeutic Range 
 
CYP Enzyme 
Substrates with Narrow Therapeutic Range a 
CYP2C9 
Warfarin, phenytoin 
CYP2C19 
S-mephenytoin 
CYP3A 
Alfentanil, astemizole, cisapride, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, terfenadine 
 
The table is based on the Draft FDA Guidance on Drug Interaction Studies — Study Design, 
Data Analysis, Implications for Dosing, and Labeling Recommendations, 2012. 
a CYP substrates with narrow therapeutic range refers to drugs whose exposure-response 
relationship indicates that small increases in their exposure levels by the concomitant use of 
CYP inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes). 
Anticoagulants 
 
Caution should be exercised in patients receiving rucaparib and concomitant warfarin 
(Coumadin) as rucaparib showed a mixed inhibition of CYP2C9 in vitro. If appropriate, low 
molecular weight heparin should be considered as an alternative treatment. Patients taking 
warfarin should have international normalized ratio (INR) monitored regularly per standard 
clinical practice. 
 
Other Medications 
 
In vitro data showed that rucaparib is an inhibitor of P-gp and thus patients taking digoxin, a 
P-gp substrate, should have their digoxin levels monitored regularly via standard clinical 
practice. Caution should also be exercised for concomitant use of certain statin drugs (e.g., 
rosuvastatin and fluvastatin) due to potential increase in exposure from inhibition of BCRP and 
CYP2C9 

Protocol UMCC 2018.033 
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7.5 
Withdrawal/Discontinuation 
 
When a subject discontinues/withdraws 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/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 9.0. 
 
7.5.1 End of Treatment Follow-up Visits 
 
The mandatory Safety Follow-Up Visit should be conducted within 30 +/- 10 days after the 
last dose of rucaparib. Subjects with an AE of Grade >1 will be further followed until the 
resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, whichever 
occurs first. Procedures should be conducted according to the Treatment Calendar in Section 
7.2. SAEs that occur within 90 days of the end of treatment or before initiation of a new anti- 
cancer treatment should be followed and recorded. 
 
7.5.2 Survival Follow-up 
 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject will be followed through his/her medical record and assessed for survival status 
until death or 5 years. Data will be collected every 6 months. 
 
8.0 
IMAGING AND MEASUREMENT OF DISEASE 
 
Response and progression will be evaluated in this study using the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 
1.1.21 
Immunotherapy drugs can initially cause inflammation in the early stages of treatment. 
Immune-related RECIST (irRECIST) utilizes RECISTv1.1 but considers an inflammatory 
response (or “pseudo-progression”) as normal. The main difference between RECISTv1.1 and 
irRECIST is that patients can stay on trial after the first progressive disease (PD) assessment 
(as per RECISTv1.1) if using immune-related RECIST criteria. This PD per RECISTv1.1 is 
then re-labeled as immune related stable disease (irSD) per irRECIST and requires addition of 
unidimensional measurements of all new lesions (that meet the definition of target lesion) to 
be added to the sum of longest diameters (SLD) calculation for response assessment. 
Importantly, immune-related progression (irPD) must be confirmed by a follow-up scan at least 
4 weeks (within 4-8 weeks) following the initial PD/irSD assessment in order to take thepatient 
off the trial. 
 
Subjects that are deemed to have clinical progression and unstable should not be continued on 
therapy after PD (per RECISTv1.1) and are therefore not required to have repeat tumor 
imaging for confirmation as per irPD definition. It is at the discretion of the site investigator 
whether to continue a subject on study treatment until repeat imaging is obtained. This clinical 
judgment decision by the site investigator should be based on the subject’s overall clinical 
condition, including performance status, clinical symptoms, and laboratory data. 

Protocol UMCC 2018.033 
Page 41 of 65 
 
 
Definitions 
 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least 2 cycle(s) of therapy, and have had their disease re-evaluated 
will be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
8.1 
Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter in the plane of measurement is to be recorded) with 
a minimum size of: 
 
• 10 mm by CT scan (or MRI) for studies with a slice thickness of ≤5mm, or twice 
the slice thickness 
• 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
• 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
 
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Note: Tumor lesions that are situated in a previously irradiated area will only be considered 
measurable, if they have had subsequent progression by at least 5 mm. 
 
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using CT scan), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not 
followed by CT or MRI), and cystic lesions are all non-measurable. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), 
representative of all involved organs, and those that lend themselves to reproducible repeated 
measurements. If a non-nodal lesion is either not present or is initially measured with longest 
diameter <10mm as a non-target then grows to >10mm after baseline, this lesion then becomes 
a new target lesion as per irRECIST criteria. The non-nodal longest diameter is then added to 
the sum of diameters, and patient response is calculated with the new lesion. 
 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 

Protocol UMCC 2018.033 
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measurable and may be identified as target lesions must meet the criterion of a short axis of ≥ 
15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the 
plane of acquisition may be axial, sagittal or coronal). The smaller of these measures is the 
short axis. For example, an abdominal node which is reported as being 20 mm x 30 mm has a 
short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm 
should be recorded as the node measurement. All other pathological nodes (those with short 
axis ≥ 10 mm but <15 mm) should be considered non-target lesions. Nodes that have a short 
axis <10 mm are considered nonpathological and should not be recorded or followed. 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression 
in the measurable dimension of the disease. If a non-target lymph node grows to >15mm after 
baseline, this node then becomes a new target lesion as per irRECIST. The nodal short axis is 
then added to the sum of diameters, and patient response is calculated with the new lesion. 
 
Non-target lesions: All other lesions (or sites of disease) including pathological lymph nodes 
should be identified as non-target lesions and should also be recorded at baseline. 
Measurements are not required and these lesions should be followed as ‘present’, ‘absent’, or 
in rare cases ‘unequivocal progression’ (more details to follow). In addition, it is possible to 
record multiple non-target lesions involving the same organ as a single item on the case record 
form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’) 
 
8.2 
Guidelines for Evaluation of Measurable Disease 
 
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before enrollment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and > 10 mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the lesion 
is suggested. As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
 
CT and MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 

Protocol UMCC 2018.033 
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scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
8.3 
Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions, determined by two separate 
observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of 
target lesions, taking as reference the baseline sum LD. There can be no appearance of new 
lesions. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment started, or the appearance of one 
or more new lesions. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment started. 
 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. 
 
Incomplete Response/Stable Disease (SD): Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 

Protocol UMCC 2018.033 
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Target Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Response for this 
Category 
Also 
Requires: 
CR 
CR 
No 
CR 
≥4 wks. confirmation 
CR 
Non-CR/SD 
No 
PR 
≥4 wks. confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
Documented at least 
once ≥4 wks. from 
baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration”. Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
 
Treatment Beyond Progression 
 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD. 
 
Subjects will be permitted to continue study treatment beyond initial RECISTv1.1 defined PD, 
assessed by the investigator, as long as they meet the following criteria: 
 
• Investigator determined clinical benefit 
• Tolerance of study drug 
• Stable performance status 
• Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (e.g., CNS metastases) 
• Tumor markers are stable/improving, if expressed 
 
A radiographic assessment/ scan should be performed within 4-8 weeks of initial investigator- 
assessed progression to determine whether there has been a decrease in the tumor size or 
continued PD (termed irPD). The assessment of clinical benefit should be balanced by clinical 
judgment as to whether the subject is clinically deteriorating and unlikely to receive any benefit 
from continued treatment. 

Protocol UMCC 2018.033 
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If the investigator feels that the subject continues to achieve clinical benefit by continuing 
treatment, the subject should remain on the trial and continue to receive monitoring according 
to the Study Calendar (see Table 7.2). 
 
For the subjects who continue study therapy beyond progression, further progression is defined 
as an additional 20% increase in tumor burden with a minimum 5 mm absolute increase from 
time of initial PD. This includes an increase in the sum of diameters of all target lesions and/ 
or the diameters of new measurable lesions compared to the time of initial PD. Study treatment 
should be discontinued permanently upon documentation of further progression (i.e. irPD). 
 
Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that recurrent disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started. 
 
Progression-Free Survival 
 
Progression-free survival is defined as the duration of time from start of treatment to time of 
progression. 
 
9.0 
ADVERSE AND OTHER REPORTABLE EVENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is done 
to ensure the safety of subjects enrolled in the studies as well as those who will enroll in future 
studies using similar agents. Data on adverse events will be collected from the time of the 
initial dose of pembrolizumab and rucaparib through 30 days after the last dose of rucaparib or 
pembrolizumab (whichever is later). Serious adverse events will be collected from the timeof 
the initial dose of pembrolizumab and rucaparib through 90 days after the last dose of rucaparib 
or pembrolizumab (whichever is later). Any serious adverse event that occurs morethan 90 
days after the last dose of study treatment and is considered related to the study must also be 
reported. Serious Adverse Events (SAEs) will continue to be followed until: 
 
• Resolution or the symptoms or signs that constitute the serious adverse event return to 
baseline; 
 
• There is satisfactory explanation other than the study drugs for the changes observed; 
• The patient is lost to follow-up or withdraws consent; or 

Protocol UMCC 2018.033 
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• Death. 
The investigator is responsible for the detection, documentation, grading and assignment of 
attribution of events meeting the criteria and definition of an AE or SAE. The definitions of 
AEs and SAEs are given below. It is the responsibility of the principal investigator to ensure 
that all staff involved in the trial is familiar with the content of this section. 
 
Any medical condition or laboratory abnormality with an onset date before enrollment onto 
study is considered to be pre-existing in nature. Any known pre-existing conditions that are 
ongoing at time of study entry should be considered medical history. 
 
All events meeting the criteria and definition of an AE or SAE, as defined in Section 9.1, 
occurring from the initial dose of pembrolizumab and rucaparib through 30 days following the 
last dose of rucaparib or pembrolizumab (whichever is later) must be recorded as an adverse 
event in the patient’s source documents and on the CRF regardless of frequency, severity 
(grade) or assessed relationship to the study drugs. 
 
In addition to new events, any increase in the frequency or severity (i.e., toxicity grade) of a 
pre-existing condition that occurs after the patient begins study is also considered an adverse 
event. 
 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol- 
specified procedure or intervention. If the subject requires a blood draw, fresh tumor biopsy 
etc., the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting. 
Investigators are not obligated to actively seek AE or SAE 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 treatment or study participation, the investigator 
must promptly notify the Coordinating Center. 
 
9.1 
Definitions 
 
9.1.1 Adverse Event 
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding or vital sign which 
requires protocol treatment to be modified, for example), symptom, or disease temporally 
associated with the use of a medicinal product or protocol-specified procedure, whether or not 
considered related to the medicinal product or protocol-specified procedure. Any worsening 
(i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting 
condition that is temporally associated with the use of the study drugs, is also an adverse event. 

Protocol UMCC 2018.033 
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Progression of the cancer under study and/or symptoms related to progression of the 
underlying cancer are not considered an adverse event unless it resulted in death. 
 
9.1.2 Serious Adverse Event 
 
An adverse event is considered “serious” if, in the view of either the investigator or Sponsor it 
results in any of the following outcomes: 
 
• Death 
If death results from (progression of) the disease, the disease should be reported as 
event (SAE) itself. 
 
• A life-threatening adverse event 
An adverse event is considered ‘life-threatening’ if, in the view of either the 
investigator or sponsors, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event that, had it occurred in a more severe 
form, might have caused death. 
 
• Inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours. 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
• A congenital anomaly/birth defect 
• Important medical event: Any event that may not result in death, be life-threatening, 
or require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition of 
“Serious Adverse Event”. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; 
convulsions that do not result in inpatient hospitalization or the development of 
drug dependency or drug abuse. 
 
9.1.3 Expected Adverse Events 
 
An adverse event (AE) is considered “expected” if: 
 
• For approved and marketed drugs or devices, those adverse events are described in 
the approved Package Insert. 
 
• For investigational new drugs or devices, those adverse events are described in the 
Reference Safety Information section of the Investigator’s Brochure. 

Protocol UMCC 2018.033 
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9.1.4 Unexpected Adverse Events 
 
An adverse event (AE) is considered “unexpected” if it is not described in the Package Insert, 
Investigator’s Brochure, in published medical literature, in the protocol, or in the informed 
consent document. 
 
9.1.5 Events Not Qualifying as SAEs 
 
Previously planned (prior to signing the informed consent form) surgeries should not be 
reported as SAEs unless the underlying medical condition has worsened during the course of 
the study. Preplanned hospitalizations or procedures for preexisting conditions that are already 
recorded in the patient’s medical history at the time of study enrollment should not be 
considered SAEs. Hospitalization or prolongation of hospitalization without a precipitating 
clinical AE (for example, for the administration of study therapy or other protocol-required 
procedure) should not be considered SAEs. However, if the preexisting condition worsened 
during the course of the study, it should be reported as an SAE. Progression of the cancer 
under study and/or symptoms related to progression of the underlying cancer are not 
considered a serious adverse event unless it resulted in death. 
 
9.2 
Evaluating Adverse Events 
 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0.3 All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.03. A copy of the 
CTCAE 
version 
4.03 
can 
be 
down 
loaded 
from 
the 
CTEP 
web 
site 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06- 
14_QuickReference_8.5x11.pdf). Any adverse event which changes CTCAE grade over the 
course of a given episode will have each change of grade recorded. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 
Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment/intervention 
 
9.3 
Reporting of Adverse Events 
 
9.3.1 Reporting procedures for multi-site trials 
All serious adverse events (SAEs) and unanticipated problems (UPs), regardless of causality 
to study drug, will be reported to the Principal Investigator and also to the Coordinating Center. 
All SAEs and UPs must be reported to the Coordinating Center within 24 hours of first 

Protocol UMCC 2018.033 
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awareness of the event. Events should be reported using the Coordinating Center’s SAE form 
as available in the study database. A copy of the SAE form as available in the study database 
should be sent to the Coordinating Center via fax at 734-232-0744 or via email to CTSU- 
Oncology-Multisite@med.umich.edu within 24 hours of the site’s knowledge of the event. 
 
Follow-up information must also be reported within 24 hours of receipt of the information by 
the investigator. 
 
All SAEs and UPs will be reported to the IRB per current institutional standards. 
 
The Coordinating Center will disseminate information regarding SAEs and UPs to the 
participating sites within 5 days of review of the information by the Coordinating Center’s 
Principal Investigator (or designee in the event of extended absence) only in the case that the 
event(s) is believed to be related (i.e., possibly, probably, or definitely) to the study drug. The 
Coordinating Center will be responsible for reporting of events to Clovis and Merck, as 
appropriate (outlined below). 
 
9.3.2 Reporting procedures to Merck Global Safety 
 
All Serious Adverse Events (SAEs) occurring from the initial study treatment administration 
through 90 days following the last dose of the study treatment will be reported by the 
Coordinating Center to Merck Global Safety. Any SAEs occurring after 90 days following the 
last dose of the study treatment that are believed to be related to study drug will also be reported 
to Merck Global Safety. 
 
The Coordinating Center will send the initial completed SAE Form and any other relevant 
safety information within 24 hours of receipt to the Merck Global safety facsimile number 1- 
215-993-1220. 
 
If only limited information is initially available or an ongoing SAE changes in its intensity or 
relationship to the study drug, or if new information becomes available, a follow-up report will 
be generated and sent to Merck Global Safety within 24 hours of receipt. 
 
9.3.3 Reporting procedures to Clovis 
 
All Serious Adverse Events (SAEs) occurring from the initial study treatment administration 
through 90 days following the last dose of the study treatment will be reported by the 
Coordinating Center to Clovis. Any SAEs occurring after 90 days following the last dose of 
the study treatment that are believed to be related to study drug will also be reported to Clovis. 
 
The Coordinating Center will send the initial completed SAE Form within 24 hours of receipt 
via email to Clovis (drugsafety@clovisoncology.com) or facsimile (1-303-261-8319). 
 
If only limited information is initially available or an ongoing SAE changes in its intensity or 
relationship to the study drug, or if new information becomes available, a follow-up report will 
be generated and sent to Clovis within 24 hours of receipt. 

Protocol UMCC 2018.033 
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9.3.4 Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) which are defined as AEs of scientific and medical concern specific to the drug product 
or program, for which ongoing monitoring and rapid communication by the investigator can 
be appropriate. Such an event might warrant further investigation in order to characterize and 
understand it. 
 
All ECIs must be reported as SAEs as outlined above. 
Events of clinical interest for this trial include: 
1. An overdose of drugs (further detail can be found in Section 9.4). 
 
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 testingor 
unscheduled laboratory testing.* This is in absence of any other explanation for the 
elevation in liver enzymes. 
 
*Note: These criteria are based upon available regulatory guidance documents. Thepurpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. 
 
3. Any AE of pneumonitis, or any of the following AEs, irrespective of causality assessment: 
 
• pneumonitis 
• interstitial lung disease 
• pulmonary fibrosis 
• acute interstitial pneumonitis 
• alveolitis necrotizing 
• alveolitis 
• hypersensitivity pneumonitis 
• organizing pneumonia 
9.3.5 Protocol-Specific Exceptions to Serious Adverse Event Reporting 
 
Efficacy endpoints as outlined in this section will not be reported to Merck and Clovis as 
described in Section 9.3, unless there is evidence suggesting a causal relationship between the 
drugs and the event. should be. 

Protocol UMCC 2018.033 
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Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be considered an SAE and reported as outlined 
above. 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered a 
SAE. 
 
9.4 
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck and Clovis 
For purposes of this trial, 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. Appropriate supportive treatment should be provided 
if clinically indicated. In the event of overdose, the subject 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. 
 
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non- 
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event will be considered an SAE and 
reported as outlined above There is currently no specific dosage of rucaparib that is considered 
an overdose. An overdose of rucaparib is NOT considered an SAE unless it is associated with 
a serious adverse event. If so, it will be reported as an SAE as outlined above. 
 
9.5 
Reporting of Pregnancy and Lactation to Merck and Clovis 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur from the time of study drug through 180 days following 
cessation of Sponsor’s product, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, must be reported by the investigator to 
the Coordinating Center. 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. 

Protocol UMCC 2018.033 
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Such events will be reported within the same timelines as an SAE. 
 
9.6 
Routine Reporting 
 
All other adverse events are to be reported per current IRB guidelines. 
 
9.7 
Reporting of Unanticipated Problems 
 
There are types of incidents, experiences and outcomes that occur during the conduct of human 
subjects research that represent unanticipated problems but are not considered adverse events. 
For example, some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, unanticipated 
problems place subjects or others at increased risk of harm, but no harm occurs. 
 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse event) 
that may represent an unanticipated problem, the investigator should assess whether the 
incident, experience, or outcome represents an unanticipated problem. The incident, 
experience or outcomes is considered unanticipated if it meets all of the following criteria: 
 
1. Unexpected (in terms of nature, severity, or frequency); 
 
2. Related or possibly related to participation in the research; and 
 
3. Suggests that the research places subjects or others at a greater risk of harm than was 
previously known or recognized. 
 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the IRB within 14 calendar days of 
the study team becoming aware of the problem. 
 
10.0 
CORRELATIVE STUDIES 
 
10.1 PD-L1 expression 
 
A specific cut-off for tumoral PD-L1 expression is not a pre-requisite for enrollment onto this 
protocol. Tumoral PD-L1 expression will be determined by immunohistochemistry (IHC) 
methods per institutional standards as testing is currently considered standard of care in all 
patients with metastatic NSCLC. PD-L1 expression will be divided as low (PD-L1<1%), 
intermediate (1-49%), and high (≥50%). 
 
10.2 Tissue Requirements for Next Generation Sequencing. 
Tumor mutational burden, homologous repair deficiency, and loss of heterozygosity will be 
determined through NGS (next generation sequencing). FFPE (formalin-fixed paraffin 
embedded) tissue samples will be sent to Foundation Medicine as outlined in the Laboratory 
Manual. Tissue requirements for this assay are 1) tissue block + 1 H&E (haematoxylin and 
eosin) slide, OR 2) 10 unstained slides (4-5µm in thickness) + 1 H&E slide. In order for the 

Protocol UMCC 2018.033 
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tissue sample to be used, there must be histological evidence of at least 30% viable tumor 
content. 
 
10.3 Tumor Mutational Burden 
 
The methods for determining TMB have been previously described in detail.22 TMB will be 
reported as mutations/megabase (mb) and will be divided into three groups: low (1-5 
mutations/mb), intermediate (6-19/mb), and high (≥20 mutations/mb). TMB has been shown 
to be an independent predictor of favorable response to checkpoint inhibitors across different 
cancer types.22 
10.4 Homologous Repair Deficiency (HRD) 
 
The method for calculating HRD has already been previously described.16 The sequence data 
will be processed using a customized analysis pipeline to detect protein truncating mutations, 
splice site mutations, homozygous base substitutions, short insertions/deletions, large protein 
truncating rearrangements, and deleterious missense mutations in BRCA 1/2 and other 
homologous recombination genes. All genes and their corresponding mutations will be 
reported. Tumors with protein-truncating mutations (with the exception of amino acids 3’ of 
codon K3226 in BRCA2) and splice-site mutations (±2 bp of exon starts/ends) in known or 
putative tumor suppressor genes will be classified as potentially deleterious. Homozygous 
deletions (deletions in both gene alleles of ≥1 exon in size) and large protein truncating 
rearrangements will be considered deleterious. Based on the Breast Cancer Information Core 
database23, BRCA 1/2 missense mutations known to be deleterious will also be classified. 
10.5 Loss of Heterozygosity (LOH) 
 
To compute the percent genomic LOH for each tumor, LOH segments will be inferred across 
the 22 autosomal chromosomes using the genome-wide aneuploidy/copy number profile and 
minor allele frequencies of the more than 3,500 polymorphic small nucleotide polymorphisms 
(SNPs) sequenced through Foundation Medicine’s NGS assay. This method and calculation 
has also been described elsewhere.16 
10.6 Circulating tumor DNA (ct-DNA) 
 
The details of this assay have been described elsewhere.24 In brief, blood samples will be 
collected at the start of the induction phase, start of the maintenance phase, and every 4 cycles 
(i.e. 12 weeks) while on the maintenance phase to evaluate for ct-DNA to determine if there is 
a correlation between levels of ct-DNA and radiographic progression of disease. See the 
Laboratory Manual for collection, handling and shipping of correlative samples. 
 
10.7 Specimen Banking 
Patient samples collected for this study will be retained at University of Michigan. Specimens 
will be stored indefinitely or until they are used up. If future use is denied or withdrawn by the 
patient, best efforts will be made to stop any additional studies and to destroy the specimens. 

Protocol UMCC 2018.033 
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11.0 
STATISTICAL ANALYSIS PLAN 
 
11.1 
Statistical Design 
 
Small phase I run-in for safety: we will first treat a cohort of 6 patients at the approved dose of 
rucaparib of 600mg BID in combination with pembrolizumab, if < 2 dose limiting toxicity 
(DLT) are observed during cycle 1, we will consider the dose safe and continue to the Phase II 
portion using this dose, otherwise we de-escalate to dose-1 of rucaparib at 500mg BID and 
treat another 6 patients. If ≥2 DLT are seen with dose-1 of rucaparib, then a meeting will be 
held with the investigators, Merck, and Clovis to discuss whether the trial needs to be stopped 
or if the rucaparib dose can be further de-escalated. The pembrolizumab dose will remain fixed 
at 200mg IV every 21 days. 
 
Bayesian two-stage design: based on data from KEYNOTE-021 and KEYNOTE-189, the 
median PFS on CPP followed by pembrolizumab +/- pemetrexed maintenance is estimated to 
be 11 months. In this study, we want to demonstrate that maintenance therapy with rucaparib 
and pembrolizumab after induction therapy with CPP is better than pembrolizumab +/- 
pemetrexed maintenance. Thus, the null hypothesis is PFS median ≤ 11 months, while the 
alternative hypothesis is PFS median > 11 months. The hypothesized 11 months therefore 
corresponds to a 50% PFS rate at 11 months (PFS11) and we expect that the rucaparib and 
pembrolizumab will increase PFS11 to 64% (corresponding to a median of 17 monthsassuming 
an 
exponential 
model 
with 
a 
constant 
progression 
rate 
over 
time; 
i.e., 
log(0.5)/(log(0.64)/11)=17 months). 
 
We will use a Bayesian decision-theoretic two-stage design.25 In this design, costs (c2 and c3) 
are associated with making erroneous claims about the efficacy and the expenses of enrolling 
patients in the second stage. The risk is defined as the expected cost. The first stage will enroll 
38, and then we will pause patient recruitment until 75% of the 38 patients (≈ 29 patients) have 
progressed or have completed 17 months’ follow-up. Based on the data collected at this time 
point, we will first decide whether to stop or continue the trial to the second stage by comparing 
the risks of stopping and continuation. If the risk of stopping is smaller, we will stop the trial 
and make a rejection or acceptance decision by comparing the risks of rejection and acceptance 
of the null hypothesis. We will choose the decision with the smaller risk. If the risk of 
continuation is smaller, we will enroll an additional 17 patients and follow the last patient for 
an additional 18 months to make the final decision. The final decision of rejecting and 
accepting the null hypothesis is again based on the risks of the two decisions. This design 
makes use of all patients’ follow-up data and allows early stopping for both superiority and 
inferiority. The total number of patients enrolled will be approximately 55. 
 
11.2 
Sample Size Justification 
 
Patients who are treated at the target dose in the safety run-in phase will be included in the 
phase II trial. The published survival data6,26 has approximately an exponential distribution. 
We fix the design parameters c2=3.5 and c3=0.08 and assume that 3 patients will be enrolled 
per month. These values of c2 and c3 were determined by simulation to obtain approximately 
80% power and 10% type I error in the overall study and probability of stopping at stage I 
>50%. Table 8 shows the trial operating characteristics based on 5000 Monte Carlo 

Protocol UMCC 2018.033 
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simulations. If the PFS11 is truly 0.64 (an efficacious therapy), we will have approximately 
53% probability of stopping at the first stage to declare that our proposed maintenance therapy 
is promising. The expected sample size is 44 and trial duration is 29 months on average. If the 
PFS11 is truly 0.50 (an inferior therapy), we will have approximately 68% probability of 
stopping at the first stage to show that the new maintenance therapy is inferior. The expected 
sample size is 42 and trial duration is 25 months on average. The trial has an overall type I 
error of 10% and power of 82% (see first column of Table 8) with a type I error at the end of 
the first stage of 8% (see third column of Table 8). The trial will pause patient enrollment for 
about 7-8.4 months before stage II. Table 9 lists the PFS11 (posterior) estimates (mean and 
std) over 5000 simulated trial under different decisions. As shown in this table, stronger 
evidence is needed in order to show superiority and inferiority an earlier time point (stronger 
evidence means larger estimates of PFS11 for the superiority decision and smaller estimates of 
PFS11 for the inferiority decision). For example, the PFS11 estimate is 0.69 on average under 
the superiority decision, which is larger than PFS11 estimate of 0.64 at the end of the study; 
the PFS11 estimate is 0.47 on average under the inferiority decision, which is much smaller 
than PFS11 estimate of 0.53 at the end of the study. When the decision is to continue to stage 
II, PFS11 estimates are around 0.59 (± 0.02), which suggests no strong evidence in either 
decision. 
 
Table 8:    Trial operating characteristics based on simulation studies 
 
True PFS11 
Reject 
NULL 
% 
Stop 
at 
Stage 
I for 
futility 
% Stop at 
Stage I 
for 
efficacy 
Expected 
Sample 
Size 
Expected 
Trial 
Duration 
Average 
Enrollment 
Pause 
Months 
at Stage I 
0.50 
(drug is inferior) 
0.10 
0.68 
0.08 
42 
25.10 
6.99 
0.64 
(drug is superior) 
0.82 
0.11 
0.53 
44 
29.15 
8.35 
 
 
Table 9:    PFS11 estimates across 5000 simulated trials under different decisions 
 
PFS11 
Continue 
at Stage I 
At stage I stop 
for futility 
At stage I stop 
for efficacy 
At stage II 
show futility 
At stage II show 
efficacy 
Mean 
0.59 
0.47 
0.69 
0.53 
0.64 
Std 
0.02 
0.06 
0.04 
0.03 
0.03 

Protocol UMCC 2018.033 
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11.3 Population for Analysis 
 
Intent-to-Treat Population: All patients consented and enrolled in the trial. 
 
Evaluable Population: Only those patients who have received at least one cycle of maintenance 
therapy with rucaparib and pembrolizumab at the safe dose will be considered evaluable; this 
will include the patients in the safety run-in phase that received the safe dose. 
 
Safety Evaluable Population: Patients who receive any treatment on protocol will be 
considered evaluable for safety. 
 
11.4 Analysis of Primary Objective: 
 
The proposed Bayesian decision theoretic approach will be used to make decisions at both 
stages. Since the real data may not follow an exponential distribution, we will also consider a 
Weibull distribution in the Bayesian decision theoretic approach.25 At the end of the study, the 
Product-limit (Kaplan-Meier) method will be used to estimate PFS11 and median PFS, along 
with 95% confidence intervals. 
 
11.5 Analysis of Secondary Objectives 
 
1. To evaluate the safety and tolerability profile of pembrolizumab and rucaparib. The toxicity 
profile will be described, both overall and by grade. Toxicity rates will be tabulated by type 
and category. 
 
2. To evaluate the OS in patients treated with pembrolizumab and rucaparib following 
induction therapy with CPP. Kaplan-Meier method will be used to estimate OS. Median 
survival will be calculated, along with 95% confidence intervals. 
 
3. To evaluate response based in immune response RECIST (irRECIST). The response rate will 
be calculated with a 95% confidence interval. 
 
11.6 Analysis of Exploratory Objectives 
 
Log-rank tests or Cox proportional hazard regression models will be used to associate the 
genomic features, including PD-L1 expression, TMB, HRD, LOH and presence of somatic HR 
mutations to PFS. 
 
12. 0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
 
12.1 Investigational Drugs 
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. 

Protocol UMCC 2018.033 
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Pembrolizumab is available as below. It will be administered intravenously every 21 days. It 
will be supplied by Merck and Co. 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
Rucaparib camsylate (formerly known as PF-01367338 and AG-014447) is an oral formulation 
with a molecular weight of 555.67 Daltons. Rucaparib tablets for oral administration will be 
supplied by Clovis Oncology. 
 
Drug Name: 
Rucaparib 
INN: 
Rucaparib 
Formulation: 
Tablet; film coated; 200 mg, 250 mg, 300 mg 
How Supplied: 
200, 250, and/or 300 mg strength (based on free base) in high- 
density polyethylene bottles or equivalent with child-resistant 
caps. Patients may receive 1 or more strengths. Each bottle 
contains 60 tablets 
Storage Conditions: 
15–30 °C (59 and 86° F) 
 
12.2 Packaging and Labeling Information 
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
Rucaparib tablets are provided in high-density polyethylene (HDPE) bottles with child- 
resistant caps and should be stored in the provided containers between 15° and 30° C (59 and 
86° F). Patients will be dispensed one or more strengths depending on their current dose of 
rucaparib. The number of bottles of each strength dispensed will be sufficient to supply 21 days 
treatment per cycle, including a small overage. 
 
Study drug containers containing rucaparib tablets will be labeled according to national 
regulations for investigational products. 
 
12.3 Clinical Supplies Disclosure 
 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 

Protocol UMCC 2018.033 
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12.4 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. 
 
12.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck and Clovis, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 
13. 0 ADMINISTRATIVE AND REGULATORY DETAILS 
 
13.1 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. 
 
13.2 Quality Management System 
 
The Data and Safety Monitoring Committee can request a ‘for cause’ quality assurance audit 
of the trial if the committee identifies a need for a more rigorous evaluation of study-related 
issues. 
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during 
its conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the Coordinating Center that such a 
request has been made. 

Protocol UMCC 2018.033 
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13.3 Multi-Site Data Management 
 
All information will be recorded locally and entered into Case Report Forms (CRFs) on the 
web-based electronic data capture (EDC) system of the University of Michigan. Online access 
will be provided to each site by the Coordinating Center. 
 
CRFs will be reviewed and source verified by the MSC during annual monitoring visits and 
prior to and between visits. Discrepant, unusual and incomplete data will be queried by the 
MSC. The investigator or study coordinator will be responsible for providing resolutions to the 
data queries, as appropriate. The investigator must ensure that all data queries are dealt with 
promptly. 
 
The data submission schedule is as follows: 
• At the time of registration 
o Subject entry into EDC 
 Subject Status 
 Demographics 
• During study participation 
o All data should be entered online within 10 business days of data acquisition. 
Information on Serious Adverse Events must be entered within the reporting 
timeframe specified in Section 9.3 of the protocol. 
All study information should be recorded in an appropriate source document (e.g. clinic chart). 
 
13.4 Data and Safety Monitoring Procedures 
 
This study will be monitored in accordance with the NCI approved University of Michigan 
Rogel Cancer Center Data and Safety Monitoring Plan, with oversight by the Rogel Cancer 
Center Data and Safety Monitoring Committee (DSMC). 
 
The Sponsor-Investigator (S-I)/Study Principal Investigator will provide ongoing monitoring 
of data and patient safety in this trial and conduct regular data review with participating sites. 
 
The 
Sponsor-Investigator 
(S-I)/Study 
Principal 
Investigator 
and/or 
the 
Project 
Manager/Delegate will review data and patient safety issues with participating sites monthly 
(during phase I) and quarterly (during phase II). Depending on the protocol activity, the 
meeting cadence may be more frequent. This data review meeting may be achieved via a 
teleconference or another similar mechanism to discuss matters related to: 
 
• Enrollment rate relative to expectations, characteristics of participants 
• Safety of study participants (SAE reporting, unanticipated problems) 
• Adherence to protocol (protocol deviations) 
• Completeness, validity and integrity of study data 
• Retention of study participants 
 
Participating sites are required to ensure all pertinent data for the review period are available 
in the database at the time of the discussion. 

Protocol UMCC 2018.033 
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Participating sites unable to participate in the data review meeting are required to provide 
written confirmation that their site has reviewed the relevant data and patient safety issues for 
the review period and their site’s data are in alignment with the data reported in the database. 
Written confirmation is to be provided to the Project Manager/Delegate within the timeline 
requested to retain compliance with monitoring timelines. 
 
Documentation of the teleconference or alternate mechanism utilized to review items above is 
to be retained in the Trial Master File. 
 
The Project Manager/Delegate is responsible for collating the data from all participating sites 
and completing the Protocol Specific Data and Safety Monitoring Report (DSMR) form to 
document the data review meeting discussion. 
 
The DSMR will be signed by the Sponsor-Investigator (S-I)/Study Principal Investigator or 
designated Co-Investigator and submitted to the DSMC on a monthly (during phase I) and 
quarterly (during phase II) basis for independent review. 
 
13.5 Clinical Monitoring Procedures 
Clinical studies coordinated by The University of Michigan Rogel Cancer Center must be 
conducted in accordance with the ethical principles that are consistent with Good Clinical 
Practices (GCP) and in compliance with other applicable regulatory requirements. 
 
This study will be monitored by a representative of the Coordinating Center of Rogel Cancer 
Center. Monitoring visits will be made during the conduct of the study and at study close-out. 
 
Prior to subject recruitment, a participating site will undergo a site initiation meeting to be 
conducted by the Coordinating Center. This will be done as an actual site visit; teleconference, 
videoconference, or web-based meeting after the site has been given access to the study 
database and assembled a study reference binder. The site’s principal investigator and his/her 
study staff should make every effort in attending the site initiation meeting. Study–related 
questions or issues identified during the site initiation meeting will be followed-up by the 
appropriate Rogel Cancer Center personnel until they have been answered and resolved. 
 
Monitoring of this study will include both ‘Centralized Monitoring’, the review of source 
documents at the Coordinating Center and ‘On-site Monitoring’, an actual site visit. The first 
‘Centralized’ visit should occur after the first subject enrolled completes [first treatment 
cycle/course]. The study site will send the de-identified source documents to the Coordinating 
Center for monitoring. ‘Centralized’ monitoring may be requested by the Coordinating Center 
if an amendment requires changes to the protocol procedures. The site will send in pertinent 
de-identified source documents, as defined by the Coordinating Center for monitoring. 
 
The first annual ‘On-site’ monitoring visit should occur after the first five study participants 
are enrolled or twelve months after a study opens, whichever occurs first. The annual visit may 
be conducted as a ‘Centralized’ visit if less than three subjects have enrolled at the study site. 
The type of visit is at the discretion of the Coordinating Center. At a minimum, a routine 

Protocol UMCC 2018.033 
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monitoring visit will be done at least once a year, or once during the course of the study if the 
study duration is less than 12 months. The purpose of these visits is to verify: 
• Adherence to the protocol 
• Completeness and accuracy of study data and samples collected 
• Proper storage, dispensing and inventory of study medication 
• Compliance with regulations 
During a monitoring visit to a site, access to relevant hospital and clinical records must be 
given by the site investigator to the Coordinating Center representative conducting the 
monitoring visit to verify consistency of data collected on the CRFs with the original source 
data. While most patient cases will be selected from patients accrued since the previous 
monitoring visit, any patient case has the potential for review. At least one or more 
unannounced cases will be reviewed, if the total accruals warrant selection of unannounced 
cases. 
 
The Coordinating Center expects the relevant investigational staff to be available to facilitate 
the conduct of the visit, that source documents are available at the time of the visit, and that a 
suitable environment will be provided for review of study-related documents. Any issues 
identified during these visits will be communicated to the site and are expected to be resolved 
by the site in a timely manner. For review of study-related documents at the Coordinating 
Center, the site will be required to ship or fax documents to be reviewed. 
 
Participating site will also undergo a site close-out upon completion, termination or 
cancellation of a study to ensure fulfillment of study obligations during the conduct of the 
study, and that the site Investigator is aware of his/her ongoing responsibilities. In general, a 
site close-out is conducted during a site visit; however, site close-out can occur without a site 
visit. 
 
14.0 
REFERENCES 
 
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NDED=nsclc_tcga_broad_2016_mutations&genetic_profile_ids_PROFILE_COPY_NU 
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15.0 
APPENDICES 
 
I. 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. 
 
II. Common Terminology Criteria for Adverse Events V4.03 (CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 will be utilized for adverse event reporting. 
(https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06- 
14_QuickReference_8.5x11.pdf)