Phase II Study of Combination Rucaparib With Nivolumab in Platinum-Sensitive Small Cell Lung Carcinoma Patients as Maintenance After Induction Therapy With Platinum Doublet
Phase: PHASE2
Conditions: Small Cell Lung Cancer
Sponsor: Zhonglin Hao

Document Coversheet
Study Title: Phase II Study of Combination Rucaparib With Nivolumab in Platinum-Sensitive 
Small Cell Lung Carcinoma Patients as Maintenance After Induction Therapy With Platinum 
Doublet 
Institution/Site: 
University of Kentucky 
Document (Approval/Update) Date:
12/21/2022 
NCT Number:
NCT03958045
IRB Number
49346
Coversheet created:
10/19/2023

MCC Protocol #: MCC-18-LUN-107-CLO-PMC 
Protocol Version and Version Date:  21.December.2022 
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MCC Protocol #: MCC-18-LUN-107-CLO-PMC 
ClinicalTrials.gov Identifier: NCT03958045 
TITLE: Phase II study of combination Rucaparib with Nivolumab in platinum sensitive small cell 
               lung carcinoma patients as maintenance after induction therapy with platinum doublet. 
 
 
Principal Investigator: 
Zhonglin Hao, MD 
800 Rose St., CC448 
Lexington, KY 40536 
Office: 859-323-7507 
Fax: 859-257-7715 
zhonglin.hao@uky.edu 
Co-Investigator:                          Aman Chauhan, MD 
NOTE: Contact information will be added when available. 
 
Co-Investigator:
Susanne Arnold, MD 
Susanne.Arnold@uky.edu 
 
Statistician: 
 
Heidi Weiss, PhD 
heidi.weiss@uky.edu 
 
 
Site: Markey Cancer Center
Agents: Rucaparib, Nivolumab  
Funding Support:  Clovis and BMS
IND: MCC with sponsors
 
Protocol Version / Version Date:  Amendment 7 / 16.June.2021 
                                                          Amendment 8 / 21.December.2022 
 

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Protocol Development History –
         Original Version to Current Version, w/ major Summary of Changes noted 
1/8/2019
PRMC approval
3/19/2019
IRB approval.
5/24/2019
CRSO Medicare analysis
9/3/2019
OPEN TO ACCRUAL
Amendment 1
12/10/2019
Protocol revised, new version date 10DEC2019. 
Amendment 2 
5/5/2020
Protocol revised, new version date 05MAY2020. 
Amendment 3 
8/3/2020 
Protocol revised, new version date 03AUG2020.  
8/12/2020 PRMC approval; 8/24/2020 IRB approval. 
Amendment 4 
9/16/2020 
Protocol revised, new version date 16SEPT2020.  
For criterion 3.2.26, language clarified re: prior or concurrent malignancy to 
match NCI CTEP verbiage. 
9/22/2020 PRMC approval; 9/24/2020 IRB approval 
Amendment 5 
3/10/2021 
Protocol revised, new version date 10MARCH2020.  
Language to clarify dose modifications. 
PRMC approval, 3/25/2021; IRB approval, 3/31/2021.
Amendment 6 
5/19/2021 
Protocol revised, new version date 19MAY2021, to clarify that no 
formal interim analysis is planned.  
PRMC approval, 5/26/2021.  
Amendment 7 
6/16/2021 
Protocol revised, new version date 16JUN2021, to clarify the timing of 
Off-treatment and 100-days safety visits (Section 8, Section 11).  
Amendment 8 
12/21/2022 
Protocol revised to name Dr. Zhonglin Hao as study PI, and reassigned 
Dr. Aman Chauhan (former study PI) to now be a co-I upon his 
transition to a new institution. 
Amendment 9  
Date TBD 
Placeholder for future amendment. 
 
 

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STUDY DESIGN
This is a single center, open label, Phase II study of combination rucaparib with nivolumab as 
maintenance in platinum sensitive small cell lung cancer post frontline platinum doublet. 
Study Schema: Phase II Trial
Rucaparib + Nivolumab
Stage IV Small Cell Lung Cancer (Frontline Maintenance) 
                               
           Radiologic Assessment of Disease 
          To Determine Protocol Eligibility
Maintenance 
Rucaparib + Nivolumab 480 mg IV q4 wk
Continue this maintenance treatment until 
radiological disease progression or for up to 
24 months or unacceptable toxicity occurs  
Not 
Eligible 
YES
Enrollment to Study 
within 6 weeks of 
last chemotherapy
Pre-Screening  
at time of initial 
diagnosis / first  
medical oncology visit
Radiological CR or PR
Pre-Protocol Standard of Care Induction Therapy:   
at least 4 Cycles of (Cisplatin/Carboplatin + 
Etoposide or Cisplatin/Carboplatin + Irinotecan), 
+/- 
Prophylactic Cranial Irradiation 
NO

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TABLE OF CONTENTS
STUDY DESIGN.............................................................................................................................3
1.
OBJECTIVES ......................................................................................................................6
1.1
Primary Objective: ...................................................................................................6
1.2
Secondary Objectives: .............................................................................................6
1.3
Exploratory Correlative Studies and Biomarkers ....................................................7
2.
BACKGROUND AND RATIONALe ................................................................................7
2.1
Background ..............................................................................................................7
2.2
Rationale for the Combination of PARP and Checkpoint Inhibition ......................8
Study Agents: Rucaparib .......................................................................................14
Ovarian Cancer Treatment Indication ................................................................................15
2.3.3 Ovarian Cancer Maintenance Indication ..................................................................15
Rationale for suggested Biomarkers: .....................................................................20
2.6
Rationale for Immune Biomarkers.........................................................................20
3.
PATIENT SELECTION ....................................................................................................21
3.1
Inclusion Criteria ...................................................................................................21
3.2
Exclusion Criteria ..................................................................................................22
Inclusion of Women and Minorities ......................................................................25
4.
REGISTRATION PROCEDURES ...................................................................................25
Protocol Review and Monitoring Committee and Institutional Review Board 
Review ...................................................................................................................25
Enrollment Guidelines ...........................................................................................25
Informed Consent...................................................................................................26
Compliance with Laws and Regulations................................................................26
5.
TREATMENT PLAN ........................................................................................................27
Enrollment and Screening Process.........................................................................27
Nivolumab and Rucaparib Administration ............................................................28
Drug-drug Interactions ...........................................................................................28
Duration of Therapy ...............................................................................................30
Duration of Follow-Up ..........................................................................................30
Criteria for Removal from Study ...........................................................................30
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................31
7.
ADVERSE EVENTS .........................................................................................................35
Expected Toxicities and Supportive Care guidelines ............................................35
Rucaparib Photosensitivity: ...............................................................................................36
Adverse Event Characteristics ...............................................................................37
Expedited Adverse Event Reporting ......................................................................38
Expedited Reporting to External Agencies ............................................................41
Routine Adverse Event Reporting .........................................................................42
Second Malignancy ................................................................................................42
8.
STUDY CALENDAR .......................................................................................................43
9.
MEASUREMENT OF EFFECT........................................................................................45
Antitumor Effect – Solid Tumors ..........................................................................45
10.
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................49
Data Reporting .......................................................................................................49

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11.
STATISTICAL CONSIDERATIONS AND DATA MANAGEMENT ...........................49
Study Design and Sample Size ..............................................................................49
Data Analysis .........................................................................................................49
Analysis of Primary and Secondary Endpoints .................................................................49
Data Management ..................................................................................................50
12.
Correlative Studies .............................................................................................................50
Immune studies: .....................................................................................................50
13.
REFERENCES: .................................................................................................................55
APPENDIX A. ECOG PERFORMANCE STATUS CRITERIA .................................................59
APPENDIX B. Adverse Events list for Rucaparib ........................................................................60
APPENDIX C. Adverse Events list for Nivolumab ......................................................................62
APPENDIX D. Patient-Reported Outcomes: Quality of Life measures........................................65

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1. OBJECTIVES
1.1
Primary Objective:
To evaluate progression free survival of the combination rucaparib and nivolumab as maintenance 
therapy in platinum sensitive (as defined by CR/PR via RECIST V1.1) extensive stage SCLC after 
response to initial platinum-based therapy. 
 
1.2
Secondary Objectives:  
1.2.1
To evaluate the disease control rate after 8 weeks, 16 weeks and 24 weeks of treatment. 
Disease control rate is defined as the percentage of subjects who had a partial response post initial 
chemotherapy and who have a confirmed reduction in tumor size compared to post induction 
chemotherapy baseline (complete response, CR; partial response, PR) or fulfilling the criteria for 
stable disease (SD) according to Response Evaluation Criteria in Solid Tumors (RECIST V1.1). 
Patients with CR will be considered to have disease control if they continue to remain in CR since 
they do not have measurable disease at baseline.  
1.2.2 To evaluate 1-year and 2-year overall survival. Overall survival is defined as the time from 
first dose of trial medication to date of death due to any cause. 
1.2.3 To evaluate potential biomarkers for durability of response, especially tumor mutation 
burden (refer to Biomarker Section). 
1.2.4 To assess the toxicity profile of experimental drug combination.  
1.2.5 To evaluate objective response rate at 8 weeks, 16 weeks and 24 weeks. Objective response 
rate is the proportion of patients with complete response or partial response according to RECIST 
V1.1. Patients with CR at baseline will be excluded from objective response rate (ORR) analysis. 
1.2.6 To evaluate quality of life (QOL). Quality of life is assessed by the validated, standardized 
EORTC questionnaires (specifically the QLQ-C30 and the LC-13) on screening/pre-study (for pre-
treatment baseline), once during treatment, and at the end of treatment. These EORTC QOL 
measures are located in Appendix D.  
1.2.7 To explore in a preliminary manner the response of genomic subsets to treatment focusing 
on tumor mutation burden, cMEK and TP53 mutation analysis of tumor tissue and evaluation of 
response, using the Oncology Research Information Exchange Network (ORIEN) consortium 
whole exome sequencing platform to evaluate tumor mutation burden, somatic and germline 
mutations.  
 
 

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1.3
Exploratory Correlative Studies and Biomarkers 
To evaluate, in a preliminary manner, immune-related response markers as follows:
1.3.1.1
Percentage of CD4 T cells and CD8 T cells expressing PD-1 and Ki-67.
1.3.1.2
Percentage of polyfunctional effector CD4 T cells and CD8 T cells (CD101+ and 
1.3.1.3
Percentage of effector CD4 T cells and CD8 T cells expressing CD38, HLA-DR, 
CD28, ICOS, CD27, and low Bcl2 levels.
To correlate, when available, tumor mutation burden and specific gene mutations with 
treatment using results of sequencing of tissue collected and germline mutation testing from the 
Markey Cancer Center Total Cancer Care (ORIEN) protocol.  
2. BACKGROUND AND RATIONALE
2.1
Background 
Small cell lung cancer (SCLC) is one of the most aggressive malignancies with a 5-year survival rate
less than 7%. SCLC is characterized by rapid doubling time, high growth fraction and early 
development of widespread metastases. SCLC accounts for roughly 93% of all high-grade
neuroendocrine carcinomas [1]. The prognosis for SCLC is extremely poor with median survival less 
than a year for extensive-stage disease. Therapeutic options have not advanced significantly in over 
two decades, with frontline treatment consisting of platinum doublet therapy for 3-6 cycles. While 
most patients show an initial favorable response to Carboplatin/cisplatin + etoposide or 
Cisplatin/Carboplatin +Irinotecan, this response is usually short-lived. Most patients relapse with 
relatively resistant disease between 3 to 6 months after completion of initial chemotherapy. Topotecan, 
one of the FDA-approved second line agent for SCLC, is poorly tolerated and has dismal response 
rates. 
SCLC is a critical area of unmet medical need. The Recalcitrant Cancer Research Act of 2012 (H.R. 
733) requires the National Cancer Institute (NCI) to develop a scientific framework that assists in 
making progress against recalcitrant or deadly cancers, specifically cancers with 5-year relative 
survival rates below 50%. Small cell lung cancer  clearly qualifies as a recalcitrant cancer via its less 
than 7% 5-year survival rate [2]. Kentucky unfortunately has highest lung cancer incidence and 
mortality in the U.S., with approximately 20% of lung cancer cases being SCLC [3].  

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2.2
Rationale for the Combination of PARP and Checkpoint Inhibition
PARP Inhibitors 
Platinum-based compounds, the backbone of SCLC treatment, cause harmful DNA cross-links, 
which interfere with DNA repair mechanisms and induce DNA damage. Similar to other solid 
tumors, SCLC is characterized by genomic instability, and dysfunctional DNA repair mechanisms 
can contribute to this feature. Targeting DNA repair itself can also represent a novel therapeutic 
strategy for SCLC to increase cytotoxicity of anticancer agents, reverse chemotherapy resistance 
and improve therapeutic efficacy [4]. Poly (ADP-ribose) polymerase (PARP1) is a key enzyme of 
the base excision repair (BER) system, specifically involved in DNA single-strand break (SSB) 
repair, and an E2F1 co-activator. PARP1 was found to be expressed at the highest relative levels 
among the DNA repair proteins in SCLC [5]. Because PARP1 plays an independent role as an 
E2F1 co-activator [6, 7], it is hypothesized that its inhibition may have a dual role, with direct
effects on DNA repair and on other E2F1-regulated DNA repair proteins. Antitumor activity of 
PARP1 inhibition was confirmed in SCLC cell lines [5]. 
Summary of Non-clinical Experience with rucaparib
The results from nonclinical studies are consistent with the anticipated mechanism of action and 
pharmacological effects of PARP inhibition. Pharmacological assessment demonstrated that 
rucaparib is a potent and selective inhibitor of PARP-1, PARP-2, and PARP-3 and has robust and 
durable in vitro and in vivo activity in multiple BRCA1/2-mutant cell lines and xenograft models. 

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Rucaparib was also active in a BRCA wild-type model, consistent with in vitro data suggesting 
that rucaparib is active in cells with other defects in homologous recombination repair (HRR) 
through synthetic lethality. In vitro screens suggested that rucaparib has a limited potential for off-
target effects. Safety pharmacology studies suggest that when given orally, rucaparib poses a 
minimal risk for causing neurobehavioral and cardiac effects in patients.
In pharmacokinetic (PK) studies, rucaparib demonstrated species-dependent oral bioavailability, 
moderate plasma protein binding, and large volumes of distribution in nonclinical species. As a P-
glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, rucaparib demonstrated 
minimal penetration of rucaparib-derived radioactivity through the blood-brain barrier in rats. In 
vitro data suggested slow metabolism by cytochrome P450 (CYP) enzymes, with CYP2D6 and to 
a lesser extent CYP1A2 and CYP3A4 contributing to the metabolism of rucaparib. Rucaparib was 
mainly excreted in feces in rats and dogs after oral dosing.
In vitro, rucaparib reversibly inhibited CYP1A2, CYP2C9, CYP2C19, and CYP3A, and to a lesser 
extent CYP2C8, CYP2D6, and uridine diphosphate (UDP)-glucuronosyltransferase (UGT) 1A1 
(UGT1A1). Rucaparib induced CYP1A2, and down-regulated CYP2B6 and CYP3A4 in human 
hepatocytes at clinically relevant exposures. Rucaparib is a potent inhibitor of multidrug and toxin 
extrusion 1 (MATE1) and MATE2-K, a moderate inhibitor of organic cationic transporter 1 
(OCT1), and may inhibit P-gp and BCRP in the gut. 
Oral dosing of rucaparib in single- and repeat-dose toxicity studies in rats and dogs resulted in 
toxicity to the hematopoietic, lymphopoietic, and gastrointestinal systems. These toxicities were 
generally both reversible upon recovery and predictive of toxicities observed in patients. Rucaparib 
was shown to be clastogenic in an in vitro chromosomal aberration assay suggesting potential 
genotoxicity in humans.  
Reproductive and development toxicity studies in rat showed that rucaparib caused maternal 
toxicity and was embryotoxic. Although no rucaparib-related effects on sperm total count, density, 
motility, or morphology were identified, based on published studies, PARP inhibitors have the 
potential to impair spermatogenesis and reduce fertility [8-11]. 
Summary of Clinical Experience with rucaparib
Rucaparib is being evaluated in Phase 1, 2, and 3 clinical studies in patients with advanced cancer 
who have evidence of homologous recombination deficiency (HRD). There are 4 clinical studies 
in patients with relapsed, high-grade epithelial ovarian, fallopian tube, or primary peritoneal 
cancer: a Phase 2 study in patients whose cancer is associated with a germline BRCA (gBRCA) 
mutation (Study CO-338-010 [Study 10]); a Phase 2 biomarker study (Study CO-338-017 
[ARIEL2]) designed to refine the molecular signature based on HRD associated with a response 
to rucaparib; a randomized, placebo-controlled Phase 3 study (Study CO-338-014 [ARIEL3]) 
evaluating rucaparib as switch maintenance treatment; and Phase 3 Study CO-338-043 (ARIEL4), 
which is evaluating rucaparib versus chemotherapy in BRCA1/2-mutant ovarian cancer patients 
with relapsed disease.
Phase 2 Study CO-338-052 (TRITON2) and Phase 3 Study CO-338-063 (TRITON3) are 
evaluating rucaparib as treatment for patients with metastatic castration-resistant prostate cancer 

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(mCRPC) associated with HRD. An additional Phase 2 study in mCRPC patients is evaluating 
rucaparib in combination with nivolumab. Additional studies of rucaparib as monotherapy and in 
combination with other anti-cancer therapies in ovarian and prostate cancer, as well as other tumor 
types, are planned. The rucaparib clinical studies and results are described in more detail in the 
rucaparib investigator brochure (IB). 
PARP1 inhibition has shown clinical activity in SCLC as single agent and in combination with 
cytotoxic chemotherapy [12, 13]. Because of the abovementioned preclinical and clinical data, 
PARP1 inhibitors are considered among the target of choice for high-grade neuroendocrine 
carcinoma. 
Fig 1: SCLC and LCNEC are sensitive to PARP1 inhibition in vitro. (Byers et al. Cancer 
Discovery)
Immune Checkpoint Inhibitors
Immunotherapy has revolutionized the field of oncology due to relatively low toxicity of these agents 
and potential for durable response. High tumor mutation burden and expression of PD-1 and PD-L1 
are often predictive of response to immune-checkpoint inhibitors. This may also hold true for SCLC 
[14]. Up to 18% of SCLC patients have PD-L1 expression in tumor infiltrating macrophages and 48% 
SCLC cases showed PD-1 positive lymphocytes [15]. Another study reported PD-L1 expression in 
10.4% of LCNEC and 5.8% of SCLC tumors [16]. Based on strong preclinical rationale, immune 
checkpoint inhibitors are being evaluated as single agent or in combination with chemotherapy for 
SCLC. 
Immune checkpoint inhibitors have also made it to NCCN guidelines for the management of 
progressive metastatic SCLC as well as front line treatment in combination with chemotherapy. IM 

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Power 133 Phase III clinical trial reported efficacy of atezolizumab in SCLC. 201 patients were 
randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median 
follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 
10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 
0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively 
(hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02) (50). Because of 
the above-mentioned positive study, Atezolizumab is now a one of the category 1 recommended option 
for frontline treatment of metastatic extensive stage SCLC in combination with platinum-based 
chemotherapy.
The investigators of current protocol believe that optimal time to start immune checkpoint inhibitor is 
during maintenance phase, since the benefit during first 3-4 month is mostly from platinum-based 
chemotherapy. A detailed look at IM Power 133 Kaplan Meier curves will highlight that benefit of 
adding atezolizumab was not evident until 2-4 months into the maintenance phase (Fig 2). Moreover, 
since the cycle 1 of chemotherapy is commonly given in the hospital immediately post-diagnosis, atezolizumab 
will likely not be given until cycle 2 as outpatient due to financial reasons. Lastly, the OS benefit in IM Power 
133 was a modest 2 months. Considering SCLC is an aggressive cancer with dismal outcomes, we 
ought to strive for better responses and therapies. We believe that by selecting a platinum sensitive 
SCLC patient population and by adding a potent anti-tumor agent (PARP inhibitor) to immune 
checkpoint inhibitor, we will hopefully see a sharp improvement in outcomes. 
Since Atezolizumab is now considered standard of care (SOC) frontline treatment option for SCLC, 
we will offer newly diagnosed SCLC patient Atezolizumab + Platinum doublet chemotherapy per 
SOC. However, we will also make patients aware of our clinical trial and if they are interested then 
we will prescreen them for the trial. If patient meets any of the exclusion criteria, they will be offered 
SOC therapy instead.

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Fig 2: OS and PFS KM Curves of IM Power 133.  
Combination of Rucaparib (PARP inhibitor) with Nivolumab (Immune checkpoint 
inhibitor) 
There is preclinical evidence suggesting that DNA damage promotes neo- antigen expression, and 
DNA-damaging agents result in systemic antitumor responses [17]. Increased DNA damage by a 
PARP inhibitor (PARPi) could potentially yield a greater mutational burden and expand neo-antigens 
[18]. Therefore, addition of PARPi to immune checkpoint blockade could complement the clinical 
benefit of immune checkpoint inhibition. Recently Jiao et al. demonstrated that PARPi upregulated 
PD-L1 expression in breast cancer cell lines and animal models. This is thought to be regulated by 

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-mediated PD-L1 upregulation. 
PARPi attenuated anticancer immunity via upregulation of PD-L1, and blockade of PD-L1 
resensitized PARPi-treated cancer cells to T-cell killing [19]. PARPi blocks DNA repair, resulting in 
DNA breaks [20]. Fragments of these DNA breaks can enter the cytoplasm and bind to cyclic GMP-
AMP synthase (cGAS) leading to an upregulation of the cGAS-STING pathway within the tumor 
microenvironment, a potent activator of a type I interferons and other immunomodulatory molecules 
[21]. This may explain why olaparib and talazoparib up-regulate PD-L1 expression in preclinical 
models [19]. This could potentiate an anti-tumor immune response.  
Cancers with defects in DNA repair generate excessive tumor neo-antigens, making them sensitive to 
both PARP inhibition and immune activation with immune checkpoint inhibitors. Therefore, we 
anticipate the combination of rucaparib and nivolumab to be synergistic. The lack of therapeutic 
options in high grade neuroendocrine carcinomas like SCLC, dismal survival statistics, non-
overlapping toxicity profile of PARP inhibitors and immune checkpoint inhibitors, and robust 
preclinical data supporting potential activity of PARP inhibitors and immune checkpoint inhibitors in 
high grade neuroendocrine carcinoma make this combination suitable for maintenance post induction 
chemotherapy. Phase I/II clinical trials of PARP inhibitors in combination with immune checkpoint 
inhibitors are currently being explored in a variety of solid tumors. (niraparib in combination with 
pembrolizumab and olaparib in combination with durvalumab) [22]. 
Based on preclinical data supporting the role of immune checkpoint inhibitors and PARP inhibitors in 
small cell lung cancer, we feel that combining these two agents has the potential to prolong progression 
free survival and overall survival. These two classes of drugs have non-overlapping toxicities. This 
novel combination has not been tried in a front-line maintenance setting for SCLC.  
 
A single arm Phase II trial will be performed using FDA approved single agent dosage for both 
nivolumab and rucaparib. Median progression-free survival (PFS) will be compared to historical PFS 
for stage IV SCLC. Based on a phase III randomized clinical trial conducted by Eastern Oncology 
Cooperative Group (ECOG), the historical median PFS for Stage IV SCLC post platinum doublet in 
platinum sensitive patients is 2.3 months in the observation arm vs 3.6 month on maintenance 
topotecan arm, a 56 % improvement [23]. We expect our experimental combination will outperform 
topotecan. Assuming a median PFS of 3.6 months from the topotecan arm as historical data, we will 
hypothesize a 75% improvement with the combination of rucaparib and nivolumab (median PFS = 6.3 
months). This is justified by the recently presented data on single agent nivolumab (unpublished) 
which exhibited exceptional durable responses in second and third line SCLC. Of 59 treated patients 
with nivolumab 3 mg/kg investigator-assessed objective response rates were 12% (95% CI, 5% to 23%). 
Responses were observed regardless of tumor-programmed death-ligand 1 status. With a median follow-
up of 28 months, 12-month progression-free survival rates were 8%, 12-month OS rates were 39% 
respectively [49] 
Thus, it is reasonable to hypothesize that the proposed combination of nivolumab and rucaparib as 
maintenance after front line chemotherapy will show even better responses.    

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Study Agents: Rucaparib
Rucaparib is a small molecule inhibitor of PARP-1, PARP-2, and PARP-3 that has demonstrated 
preclinical and clinical activity in cancers associated with a deleterious mutation in BRCA1/2 or 
other HRR gene and/or high level of genomic loss of heterozygosity (LOH). Rucaparib was 
approved by the US FDA in December 2016 for the treatment of patients with deleterious BRCA 
mutations (germline and/or somatic) associated advanced ovarian cancer who had been treated 
with 2 or more chemotherapies [24] More recently, rucaparib demonstrated improved PFS in the 
maintenance treatment of patients with recurrent platinum-sensitive ovarian cancer. Although 
HRD was predictive of response to rucaparib, activity was also observed in HRD-negative patients, 
suggesting an incomplete understanding of biomarkers responsible for PARP inhibitor sensitivity 
[25]. 
Prior Experience with rucaparib
OVERVIEW OF CLINICAL PHARMACOLOGY
Assessment of rucaparib PK in cancer patients showed an approximate dose-proportional exposure 
after once daily (QD) or twice daily (BID) dosing, rapid absorption with maximum plasma 
concentration (Cmax) achieved within 1.5 to 6 hours. The oral bioavailability was 36% and terminal 
half-life (T1/2) was approximately 24 hours. Rucaparib was moderately bound to human plasma 
proteins in vitro (70%). 
At a dose of 600 mg rucaparib BID, steady-state was achieved after approximately 1 week with 
approximately 4-fold accumulation. At the target clinical dose of 600 mg, a high-fat meal increased 
the Cmax and area under the 0 to 24 hour plasma concentration-time curve (AUC0-24h) of rucaparib 
by 20% and 38%, respectively, and delayed the median time to occurrence of Cmax (Tmax) by 
approximately 2.5 hours as compared with these parameters under fasted conditions. The effect of 
food on rucaparib PK is not considered to be clinically significant, thus rucaparib can be taken 
with or without food.  
In cancer patients, M324, a carboxylic acid, was a major inactive metabolite of rucaparib. Drug 
interactions with rucaparib as a substrate were assessed in a population PK analysis. CYP2D6 
phenotypes (poor metabolizers, intermediate metabolizers, normal metabolizers, and ultra-rapid 
metabolizers) and CYP1A2 phenotypes (normal metabolizers and hyperinducers) did not 
significantly impact the steady-state exposure of rucaparib at 600 mg BID. Current smokers had 
overlapping rucaparib exposures as compared to nonsmokers and former smokers. Collectively, 
the results suggest that CYP1A2 and CYP2D6 play a limited role in rucaparib metabolism in vivo. 
Although in vitro rucaparib metabolism mediated by CYP3A4 was slow, a significant contribution 
of CYP3A4 in vivo cannot be excluded. No rucaparib dose adjustment is needed when 
concomitantly administered with CYP inhibitors or inducers. 
Concomitant treatment with proton pump inhibitors (PPIs) showed no clinically significant effect 
on rucaparib PK. No dose modification of rucaparib is required for patients who are receiving 
concomitant treatment with a PPI. Results from Study CO-338-044 evaluating potential drug-drug 
interactions (DDI) with rucaparib, indicated that rucaparib, at 600 mg BID, moderately inhibited 
CYP1A2, weakly inhibited CYP2C9, CYP2C19, and CYP3A, and showed no clinically significant 

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effect on the PK of oral digoxin (a P-gp substrate). Caution should be exercised in the concomitant 
use of drugs that are sensitive clinical substrates of the above CYP enzymes. 
2.3.2 OVERVIEW OF EFFICACY
Ovarian Cancer Treatment Indication 
On 19 December 2016, the FDA granted accelerated approval for the marketing of rucaparib 
(Rubraca®) for monotherapy treatment of patients with deleterious BRCA mutation (germline and/or 
[26]. 
The recommended dose of rucaparib is 600 mg BID. The basis for the approval of rucaparib as 
monotherapy for the treatment of ovarian cancer are the data sets and analyses of patients with 
advanced ovarian cancer covering the primary efficacy analysis population. The primary efficacy 
analysis population included 106 patients pooled from the open-label, single-arm Phase 2 studies, 
Study CO-338-010 Part 2A and Study CO-338-017 Parts 1 and 2, with BRCA-mutant ovarian cancer, 
-based, and who had 
at least 1 dose of 600 mg rucaparib. The primary endpoint on which approval was based is investigator-
assessed ORR by RECIST Version 1.1 (v1.1), with ORR determined by central independent 
radiological review (IRR) conducted as a supportive analysis. ORR by investigators was 53.8%, while 
ORR by IRR was 41.5%, which confirms the investigator' assessment for this endpoint [27]. 
Responses were durable, indicated by a duration of response (DOR) by investigator assessment of 
approximately 9.2 months [24]. 
2.3.3 Ovarian Cancer Maintenance Indication 
The efficacy of rucaparib monotherapy for patients with advanced ovarian cancer in the maintenance 
setting was demonstrated from Study CO-338-014 showing significant benefit of rucaparib compared 
to placebo across primary, secondary, and exploratory endpoints [25]. In this study, investigator-
assessed PFS was the primary efficacy endpoint, with PFS by blinded central IRR conducted as a key, 
stand-alone, secondary endpoint. Rucaparib maintenance treatment significantly improved PFS 
compared with placebo in all primary analysis groups of patients with recurrent ovarian cancer after a 
complete or partial response to platinum-based therapy (Table 1). Overall, rucaparib as maintenance 
treatment reduced the risk of progression by 63.5% (hazard ratio 0.365 [95% CI, 0.295 0.451]; p < 
0.0001) in the ITT population, demonstrating a strong treatment effect over placebo. Analysis of non-
nested, non-overlapping patient subpopulations indicated that the significant improvement in PFS 
observed in the ITT population was not driven only by the HRD or tBRCA (deleterious tumor 
alteration in BRCA) subpopulations (Table 1). Nearly half (44.6%) of the patients in the rucaparib 
group showed benefit at 1 year compared to 8.8% in the placebo group [25]. At 18 and 24 months, 
32.0% and 26.0%, respectively, of patients who received rucaparib were still progression-free 
compared to 5.8% and 2.6% in the placebo group [25]. These investigator-assessed results were 
confirmed by results of central IRR assessment [25]. 
 
 
 

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Table 1. Summary of Primary Efficacy Analyses and Selected Exploratory Endpoints for 
ARIEL3 [25]  
ARIEL3
Analysis 
Population
PFS by Investigator Review 
(Primary Endpoint) 
PFS by Blinded Independent 
Central Review 
(Key Secondary Endpoint)
Primary Analyses
Hazard 
Ratio 
Median PFS
Rucaparib vs. 
Placebo
(months)
Hazard 
Ratio 
Median PFS 
Rucaparib vs. 
Placebo 
(months) 
 
tBRCA mut 
(n=196) 
0.23; 
 
16.6 vs. 5.4 
0.20; 
 
26.8 vs. 5.4 
HRD-positive 
(n=354) 
0.32; 
 
13.6 vs. 5.4 
0.34; 
 
22.9 vs. 5.5 
Intent-to-Treat 
(n=564) 
0.36; 
 
10.8 vs. 5.4 
0.35; 
 
13.7 vs. 5.4 
Exploratory Analyses
BRCAwt/HRD-
positive 
(n=158) 
0.44; 
 
9.7 vs. 5.4 
0.55; 
p=0.0135 
11.1 vs. 5.6 
BRCAwt/HRD-
negative 
(n=161) 
0.58; 
p=0.0049 
6.7 vs. 5.4 
0.47; 
p=0.0003 
8.2 vs. 5.3 
 

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2.3.4 OVERVIEW OF SAFETY - RUCAPARIB
The US prescribing information (USPI) for rucaparib in the treatment setting is based on 377 patients 
with advanced ovarian cancer. The most common treatment-emergent adverse events (TEAEs) were 
nausea, asthenia/fatigue, vomiting, anemia/hemoglobin decrease, increased alanine aminotransferase 
(ALT)/aspartate aminotransferase (AST), constipation, decreased appetite, and dysgeusia [26]. 
Commonly experienced Grade 3 or higher TEAEs included anemia/hemoglobin decreased, 
asthenia/fatigue, and increased ALT/AST. Results of a more recent integrated safety analysis in over 
900 patients with ovarian cancer who received 600 mg rucaparib BID in the treatment or maintenance 
setting showed that the most common TEAEs reported were primarily mild to moderate (Grade 1-2) 
in severity and included gastrointestinal disorders (nausea, vomiting, diarrhea, constipation, and 
abdominal pain), asthenia/fatigue, anemia/decreased hemoglobin, increased ALT/AST, decreased 
appetite, and dysgeusia. The most common TEAEs 
increased ALT/AST, neutropenia/decreased absolute neutrophil count (ANC), and asthenia/fatigue. 
Laboratory abnormalities were consistent with the TEAEs; the most commonly occurring were 
decreased hemoglobin (and associated increases in mean corpuscular volume [MCV] and mean 
corpuscular hemoglobin [MCH]), increased ALT, increased AST, and increased serum creatinine. 
Decreased platelets, neutrophils, leukocytes, lymphocytes, and increased cholesterol were observed to 
a lesser extent. The transient elevations in ALT/AST with rucaparib, in either the treatment or 
maintenance settings were not associated with abnormal increases in bilirubin or other criteria for 
drug-induced hepatotoxicity, and generally resolved over time. Furthermore, no cases met Hy’s law 
criteria for drug-induced liver injury (DILI) and few patients discontinued rucaparib due to ALT/AST 
elevations [24, 25]. Similarly, elevations in creatinine were self-limiting and stabilized over time. 
Elevated serum creatinine levels resolved upon interruption or discontinuation of rucaparib, were not 
accompanied by changes in blood urea nitrogen (BUN) and did not lead to discontinuation of rucaparib 
treatment [24, 25]. Increased creatinine with rucaparib treatment is likely due to the potent inhibition 
by rucaparib of MATE1 and MATE2-K renal transporters.
Effects on cardiac channel activity in vitro and a comprehensive assessment of the effects of rucaparib 
on electrocardiogram (ECG) parameters in cancer patients demonstrated a low risk of cardiac effects 
by rucaparib.
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are considered adverse events 
of special interest (AESIs), as these events have been observed in patients exposed to cytotoxic 
chemotherapy (e.g., platinum and anthracyclines) used for treatment of ovarian cancer as well as with 
PARP inhibitors, including rucaparib. Patients in rucaparib clinical studies diagnosed with MDS or 
AML had significant confounding risk factors including prior cytotoxic chemotherapy, as well as 
deleterious BRCA mutations [28, 29]. Based on these confounding factors, there is insufficient 
scientific evidence to conclude that MDS and AML are causally related to rucaparib. Clovis has added 
these potential risks to all Informed Consent Forms (ICFs) / Patient Information Sheets (PISs). AESI’s 
(both serious and non-serious) will be reported to Clovis within 48 hours of detection and will continue 
to be reported to Clovis under serious adverse event (SAE) reporting requirements. 
More information on AESIs for rucaparib is provided in the rucaparib IB. This information is also 
found in Appendix B.  
 
 

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2.4 Nivolumab 
For details regarding study agent please refer to IB provided by the sponsors and attached with this 
protocol. CA209032 is an ongoing Phase 1/2, open-label study of nivolumab monotherapy or 
nivolumab combined with ipilimumab at different dose levels in subjects with several types of 
advanced or metastatic solid tumors, including SCLC. 
Subjects with SCLC were included if they had advanced or metastatic SCLC with progressive 
-containing regimens. Key efficacy data for nivolumab monotherapy 
(3 mg/kg Q2W IV) and nivolumab + ipilimumab combination therapy (nivo 1 mg/kg+ ipi 3 mg/kg 
Q3W IV) in subjects with SCLC based on a 30-Mar06-Nov-2017 database lock date are provided in 
Table 2.3.3. Responses were observed regardless of platinum sensitivity, line of therapy, or PD-L1 
status. 
2.4.1 Recommended Storage and Use Conditions 
Vials of nivolumab injection must be stored at 2 C to 8 C (36 F to 46 F) and protected from 
light and freezing. The unopened vials can be stored at room temperature (up to 25 C, 77 F) and 
room light for up to 48 hours. Undiluted Nivolumab Injection and Diluted Nivolumab Injection in 
the IV Container 
The administration of nivolumab infusion must be completed within 24 hours of preparation. If not 
used immediately, the infusion solution may be stored under refrigeration conditions (2°C to 
8°C, 36°F to 46°F) for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at 
room temperature (up to 25 C, 77 F) and room light. The maximum of 8 hours under room 
temperature and room light conditions includes the product administration period. 
2.4.2 Adverse Event List(s) for nivolumab (For a complete list please refer to IB; also noted in 
Appendix C) 
 
Fatigue/lack of energy 
 
Musculoskeletal pain (back pain, neck pain, pain in extremities) 
 
Diarrhea 
 
Nausea 
Hypertension 
 
Autoimmune side effects 
Infusion-related reactions (chills, fever, back pain, hypersensitivity reactions and low 
blood pressure) 
 
Rash and skin redness 
 
Decreased appetite 
 
Swelling of the extremities 
 
Joint pain 
 
Constipation 
 
Abdominal pain 
 
Vomiting 
 
Itching 
 
Weight loss 
 
Cough 
 
Shortness of breath 
 
Dizziness 
 
Headache 

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Table 2.4: Nivolumab Monotherapy or in Combination with Ipilimumab in Subjects with SCLC-
CA209032 

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Rationale for suggested Biomarkers: 
Tumor mutation burden (TMB): Immune checkpoint inhibitor responders tend to have high tumor 
mutation burden (e.g., melanoma, NSCLC, bladder cancer, and microsatellite unstable colorectal 
cancers) [35-38]. Recent data presented at World Lung Meeting suggested a superior response to 
nivolumab in SCLC patients with high TMB [39].  
Smoking status: Smoking has been associated with higher tumor mutational burden and might 
portend a favorable response to immune checkpoint inhibition [40]. We will evaluate whether smoking 
is associated with distinctive mutations, which might predict a favorable response to therapy among 
SCLC patients. 
Micro Satellite Instability (MSI) Status: MSI occurs in a small portion of cancers and represents a 
potential subgroup of patients who might benefit from checkpoint inhibitor therapy. [35, 37] 
Germline BRCA1/2 Mutation: PARP inhibitors work by synthetic lethality in patients with 
mutated BRCA1 or BRCA 2. PARPi selectively targets BRCA-mutant cells by increasing DNA 
single-stranded breaks that result in irreparable DNA double-strand breaks during replication, 
culminating in cell death. We will check for presence of germline BRCA1/2 mutations and evaluate 
as a correlation to response.  
2.6
Rationale for Immune Biomarkers
The Society for Immunotherapy of Cancer (SITC) has provided the roadmap and regular updates on 
immune biomarker development. [41-43].Immunological changes in peripheral blood and the tumor 
could potentially reflect tumor response in patients and serve as immune biomarkers.  
For all study participants: we will be collecting peripheral blood (two 8ml CPT Vacutainer tubes 
with sodium citrate) for flow cytometry at two timepoints, pre-study baseline and during treatment 
(Cycle 3 Day 1) by Dr. Cohen’s lab. A total of 16 mL of blood will be collected at each timepoint, 
for cumulative total of 32 mL.  
For all study participants, we will be collecting an additional 10 ml of whole blood (Streck tube) at 
pre-study baseline, and approximately every 2 months (e.g., at 2-months, at 4-months) and at the 
time of progression (for up to a total of 4 blood sample collections) based on SITC recommendations 
to evaluate TP53 levels (Dr. Kolesar’s lab). It is possible that a total of 40 mL of blood will be 
collected (one 10mL tube drawn at 4 different timepoints).  
For any study participant co-enrolled in Total Cancer Care, peripheral blood is collected at baseline
per the ORIEN protocol for germline mutation testing.  Additionally, for these co-enrolled 
participants, tumor tissue (if available) for whole exome sequencing is also collected at baseline per
the ORIEN protocol. These blood/tissue collections are not part of this study protocol, however the 
results re: tumor mutations will be used in ancillary analyses of correlatives studies in this protocol. 

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3. PATIENT SELECTION
3.1
Inclusion Criteria 
Patients with histologically or cytologically confirmed stage IV, extensive stage, small 
cell lung cancer who achieved either PR or CR per RECIST 1.1 post frontline  
 
chemotherapy with platinum doublet (Cisplatin/Carboplatin-etoposide or 
             Carboplatin/Cisplatin-Irinotecan).
 
- No later than 6W after the last dose of platinum-based chemotherapy in cycle 4 (or later
cycles) .  
 
- Subjects may have measurable (PR status) or non-measurable (CR) disease  
ECOG
 (Appendix A) 
Adequate Bone Marrow Function is required as defined by the following:  
Absolute neutrophil count (ANC) 
1.5 × 109/L
Platelets  100 × 109/L
Hemoglobin 
9g/dL
Adequate Hepatic Function is required as defined by the following: 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
3 × upper 
limit of normal (ULN); if liver metastases, then 
5 × ULN
Bilirubin 
1.5 × ULN; < 2 × ULN if hyperbilirubinemia is due to Gilbert’s syndrome 
Adequate Renal Function is required as defined by: 
0 mL/min.  
For calculated CrCL, the Cockcroft Gault formula or institutional standard formula can
be used. 
Written informed consent: Signed and dated informed consent of the subject must be 
available before start of any specific trial procedures. The subject must be able to
understand the nature, importance and individual consequences of the clinical trial.

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3.2
Exclusion Criteria 
Prior therapy with any antibody/drug targeting T-cell co-regulatory proteins (immune 
checkpoints).  
Also excluded is major surgery within 4 weeks of initiation of study medication.  
Current use of immunosuppressants is prohibited EXCEPT for the following:  
intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection);
Systemic corticosteroids
equivalent; 
Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
Prior organ transplantation, including allogeneic stem cell transplantation. 
Active infection requiring systemic therapy. 
HIV/AIDS: known history of testing positive for human immunodeficiency virus or 
known acquired immunodeficiency syndrome. 
Autoimmune 
disease: 
Active 
autoimmune 
disease 
including 
autoimmune 
paraneoplastic syndromes that might deteriorate when receiving an immunostimulatory 
agent. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease 
not requiring immunosuppressive treatment are eligible.
Persisting toxicity related to prior therapy (NCI Common Terminology Criteria for 
Adverse Events (CTCAE) v. 5 Grade > 1); however, alopecia, sensory neuropathy 
judgment are acceptable   
Pregnancy and contraception: Pregnancy is an exclusionary criterion.    
Male patients are considered as having reproductive potential unless permanently 
sterile by bilateral orchiectomy or vasectomy.
Pregnancy and contraception: Pregnancy is an exclusionary criterion.   
Female patients or partners of male patients are considered to be of childbearing 
potential unless one of the following applies: 
Considered permanently sterile. Permanent sterilization includes hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy 
Postmenopausal, defined as no menses for at least 12 months without an 
alternative medical cause. A high follicle-stimulating hormone (FSH) level 
consistently in the postmenopausal range (30 mIU/mL or higher) may be used 
to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy; however, in the absence of 12 months of 

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amenorrhea, a single FSH measurement is insufficient to confirm a 
postmenopausal state. 
To be eligible for enrollment, female patients of childbearing potential must have a 
negative serum or urine pregnancy test result within two weeks prior to administration 
of study treatment. Once on-study, pregnancy status of female patients will be 
evaluated per standard of care.  
Women of childbearing potential must not consider getting pregnant, and must avoid 
pregnancy during the study and for at least 6 months after the last dose of rucaparib or 
Nivolumab, or longer if requested by local authorities.  
Male patients of reproductive potential with female partners of childbearing potential 
must not consider getting pregnant, and must avoid pregnancy during the study and for 
at least 6 months after the last dose of rucaparib or Nivolumab, or longer if requested 
by local authorities. 
Male patients are required to use a condom during sex with a partner to avoid the 
possibility of exposing the partner to Rucaparib or Nivolumab, regardless of whether 
the partner is a woman of childbearing potential or not. Male patients must not make 
semen donations during treatment and for 6 months following the last dose of rucaparib
or Nivolumab. Males who are sexually active with women of childbearing potential 
must agree to follow instructions for method(s) of contraception for the duration of 
treatment and 6 months after last dose of nivolumab or rucaparib.  
Female and male patients of reproductive potential must practice highly effective 
methods (failure rate < 1% per year) of contraception with their partners during
treatment, and for 6 months following the last dose of rucaparib or Nivolumab, or 
longer if requested by local authorities. Highly effective contraception includes: 
Ongoing use of progesterone-only injectable or implantable contraceptives;
Placement of an intrauterine device (IUD) or intrauterine system (IUS);
Bilateral tubal occlusion;
Sexual abstinence as defined as complete or true abstinence, acceptable only 
when it is the usual and preferred lifestyle of the patient; periodic abstinence 
(e.g., calendar, post-ovulation methods) is not acceptable;  
Male sterilization, with appropriate post-vasectomy documentation of absence 
of sperm in ejaculate.
Patients should be instructed to notify the investigator if pregnancy is discovered either 
during or within 6 months of completing treatment with rucaparib or Nivolumab. 

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Other severe acute or chronic medical conditions [including immune colitis, 
inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric 
conditions including recent (within the past year) or active suicidal ideation or 
behavior] or laboratory abnormalities that may increase the risk associated with study 
participation, study treatment administration and/or may interfere with the 
interpretation of study results and/or in the judgment of the investigator, would make 
the patient inappropriate for entry into this study. 
Vaccination: Vaccination within 4 weeks of the first dose of nivolumab and while on 
trial is prohibited EXCEPT for administration of inactivated vaccines 
Hypersensitivity to the study drugs: Known prior severe hypersensitivity to nivolumab 
or rucaparib or any components in their formulations, including known severe 
hypersensitivity reactions to monoclonal antibodies and PARP inhibitors (NCI CTCAE 
v5 
Cardiovascular disease: Clinically significant (i.e., active) cardiovascular disease: 
cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial 
New York Heart Association Classification Class II), or serious cardiac arrhythmia 
requiring medication.
Participation in other clinical trials involving an investigational drug during the present 
clinical trial or within the last 30 days, or five terminal phase half-lives of the drug
whichever is longer, prior to baseline assessment (this also includes investigational 
formulation of market products).whichever is longer, prior to baseline assessment (this 
also includes investigational formulation of market products).  
Subjects who received platinum in the adjuvant or neoadjuvant setting are eligible; 
however, subjects may not have relapsed within 6 months of the last dose of prior 
platinum therapy
Untreated CNS metastases or leptomeningeal carcinomatosis  

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Patients with a prior or concurrent malignancy whose natural history or treatment has 
the potential to interfere with the safety or efficacy assessment of this trial’s 
investigational regimen should be excluded.  
Patients with active pneumonitis will be excluded from the study.  
Current use of Warfarin, Coumadin, Tizanidine and/or Aripiprazole is excluded.  Use 
of other agents/medications that affect CYP will be reviewed for eligibility at the 
discretion of the treating physician.     
Subjects
with active autoimmune disease and subjects requiring systemic 
corticosteroids (>10 mg daily prednisone equivalent) within 24 hours of study 
registration. Subjects taking systemic corticosteroids for PCI treatment are eligible. 
Inclusion of Women and Minorities
Women and members of minority groups and their subpopulations will be included.  
4. REGISTRATION PROCEDURES
Protocol Review and Monitoring Committee and Institutional Review Board Review 
Before implementing this study, the protocol must be reviewed by the Markey Cancer Center’s (MCC) 
Protocol Review and Monitoring Committee (PRMC) and the protocol, the proposed informed consent 
form and other information to subjects, must be reviewed by the University of Kentucky (UK)
Institutional Review Board (IRB). A signed and dated UK IRB initial review approval memo must be 
maintained in the MCC Clinical Research Office (CRO) regulatory binder. Any amendments to the 
protocol, other than administrative ones, must be reviewed and approved by the PRMC, study sponsor 
and the UK IRB.  
Enrollment Guidelines
Eligible patients will be identified by the principal investigator (PI) and co-investigators of this study. 
Potentially eligible patients will be screened in the UK MCC clinics by the investigators, study 
personnel, and the PI. Upon obtaining informed consent, patients will be enrolled into the study.  

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Informed Consent
The goal of the informed consent process is to provide sufficient information so that potential 
participants can make informed choices about whether to begin or continue participation in clinical 
research. The process involves a dynamic and continuing exchange of information between the 
research team and the participant throughout the research experience. It includes discussion of the 
study’s purpose, research procedures, risks and potential benefits, and the voluntary nature of 
participation.
The informed consent document provides a summary of the clinical study and the individual’s rights 
as a research participant. The document acts as a starting point for the necessary exchange of 
information between the investigator and potential research participant. Also, research participants 
and their families may use the consent document as an information resource and reference throughout 
participation in the trial. The informed consent document is often considered the foundation of the 
informed consent process; it does not, however, represent the entirety of the process. Nor is the 
informed consent document a risk-management tool for the investigator and/or institution.
The investigator must explain to each subject (or legally authorized representative) the nature of the 
study, its purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved, and any discomfort it may entail. Each subject must be informed that participation in the 
study is voluntary and that he/she may withdraw from the study at any time and that withdrawal of 
consent will not affect his/her subsequent medical treatment or relationship with the treating physician.
This informed consent shall be provided as a standard written statement, written in non-technical 
language. The subject should read and consider the statement before signing and dating it and should 
be given a copy of the signed document. No patient can enter the study before his/her informed consent 
has been obtained. The informed consent form is considered part of the protocol and must be submitted 
by the investigator with the protocol at the time of IRB review.
Compliance with Laws and Regulations 
The study will be conducted in accordance with U.S. Food and Drug Administration and International 
Conference on Harmonization Guidelines for Good Clinical Practice, the Declaration of Helsinki, any 
applicable local health authority, and IRB requirements. The PI or designee will be responsible for 
obtaining continuing and not less than annual IRB re-approval throughout the duration of the study. 
Copies of the investigator’s annual report to the IRB and copies of the IRB continuance of approval 
must be maintained by the MCC CRO. The PI or designee is also responsible for notifying the Data 
and Safety Monitoring Committee (DSMC) of the MCC and the UK IRB of any significant adverse 
events that are serious and/or unexpected, as per standard operating procedure (SOP)’s of those 
entities. MCC DSMC will review all adverse events of this investigator-initiated trial (IIT) as per its 
SOP.

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5. TREATMENT PLAN
Enrollment and Screening Process 
Prior to any study-required tests, patients must first provide written informed consent to participate in 
this study.  
All radiographic studies should be completed within 6 weeks prior to starting investigational agents.  
Pre-study screening shall include: 
complete medical history and evaluation of ECOG Performance Status; 
EKG; 
pathological (biopsy) or cytologically proven SCLC; 
CT with contrast of chest and upper abdomen to include the liver and adrenals; 
All lab tests should be completed within 2 weeks prior to study registration:  
CBC with differential; 
Serum chemistries to include: alkaline phosphatase, glucose, creatinine, electrolytes, TSH, AST 
(SGOT), ALT (SGPT), and total bilirubin (see Study Calendar for complete list).  
Serum or urine pregnancy test for women of childbearing potential. 

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Nivolumab and Rucaparib Administration
The recommended starting dose of rucaparib as a continuously administered oral monotherapy is 600 
mg BID. Patients may take rucaparib with or without food. Each dose should be taken with 
approximately 8 oz. (240 mL) of room temperature water. Tablets should be swallowed whole without 
crushing or chewing. Patients should take rucaparib doses as close as possible to 12 hours apart, 
preferably at the same time 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 by taking the next scheduled 
rucaparib dose. Missed or vomited doses should not be made up.  
Modification of rucaparib dose may be a necessary component of AE management, and study-specific 
protocol guidelines for dose modifications should be followed. See Section 6.   
Nivolumab will be administered as intravenous infusion once every 4 weeks at fixed dose of 480 mg. 
The FDA has approved a supplemental biologics license application adding a 4-week dosing schedule 
for nivolumab (Opdivo) across several of the PD-1 inhibitor’s indications (non-small cell lung cancer, 
renal cell carcinoma, metastatic urothelial carcinoma, Hodgkin lymphoma, metastatic squamous cell
carcinoma and hepatocellular carcinoma). Adding a q 4 weekly regimen will be convenient for patients 
and will be more cost effective as it will reduce number of visits to infusion center. We have had no 
problem with using q4 week dosing in SCLC at our center. No dose modification will be allowed
(other than hold or discontinue). Please refer to Section 6 for guidance regarding Nivolumab schedule 
in response to toxicity.
Drug-drug Interactions
Cytochrome P450 Isoenzyme Inhibitors, Inducers, and Substrates
Based on the results from the in vivo CYP interaction study (CO-338-044), rucaparib is a moderate 
inhibitor of CYP1A2, and a weak inhibitor of CYP2C9, CYP2C19, and CYP3A. Caution should be 
used with concomitant medications that are sensitive clinical substrates of CYP1A2, CYP2C9, 
CYP2C19, and/or CYP3A (see IB for rucaparib). Although in vitro rucaparib metabolism mediated 
by CYP3A4 was slow, a significant contribution of CYP3A4 in vivo cannot be excluded. Caution 
should be used for concomitant use of strong CYP3A4 inhibitors or inducers such as voriconazole, 
clarithromycin etc. (see the FDA website for a list of examples of sensitive clinical substrates and 
strong perpetrators of the above--mentioned enzymes). Selection of an alternative concomitant 
medication is recommended, and concomitant medication use among study participants will be 
monitored by study staff and the study PI.  
Effects of Rucaparib on Other Medicinal Products or Concomitant Drugs 
At the steady-state following treatment with 600 mg rucaparib BID, rucaparib is a moderate inhibitor 
of CYP1A2, and a weak inhibitor of CYP2C9, CYP2C19, and CYP3A. Rucaparib also marginally 
inhibits P-gp in the gut, but this is unlikely to be clinically significant.  
CYP1A2 Substrates When co-administering medicinal products metabolized by CYP1A2, 
particularly medicines that have a narrow therapeutic index (e.g., tizanidine, theophylline), dose 
adjustments may be considered based on appropriate clinical monitoring.  
CYP2C19 Substrates No dose adjustment is considered necessary for co-administered medicinal 
products that are CYP2C19 substrates. CYP3A Substrates Caution is advised when co-administering 

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medicinal products that are CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, 
astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, terfenadine). Dose adjustments may be considered, if clinically indicated 
based on observed AEs.  
P-gp Substrates No dose adjustment is recommended for co-administered medicinal products that 
are P-gp substrates. 
Other Enzymes and Transporters Interaction of rucaparib with other enzymes and transporters 
was evaluated in vitro. Rucaparib is a weak inhibitor of CYP2C8, CYP2D6, and UGT1A1. 
Rucaparib down regulated CYP2B6 in human hepatocytes at clinically relevant exposures. 
In vitro, rucaparib is a potent inhibitor of MATE1 and MATE2-K, a moderate inhibitor of OCT1, 
and a weak inhibitor of OCT2. As inhibition of these transporters could increase metformin renal 
elimination and decrease liver uptake of metformin, caution is advised when metformin is co-
administered with rucaparib.  
In addition, rucaparib is an inhibitor of the BCRP with an IC50 value suggesting potential BCRP 
inhibition and increased exposures of medicinal products that are BCRP substrates (e.g., 
rosuvastatin). 
Effect of Food on Rucaparib Exposures:  A high-fat meal increased Cmax by 20% and increased 
AUC0-24 by 38%. The effect is not considered clinically significant. In clinical studies, rucaparib was 
administered with or without food. 
There were no meaningful changes in cytokines known to have indirect effects on CYP enzymes 
across all dose levels of nivolumab (0.3, 2 and 10 mg/kg) during the course of treatment. This lack 
of cytokine modulation suggests that nivolumab has no or low potential for modulating CYP 
enzymes, thereby indicating a low risk of therapeutic protein-drug interaction. 
Anticoagulants 
Rucaparib is a weak inhibitor of CYP2C9 in vivo. Warfarin, Coumadin, Tizanidine and Aripiprazole 
are exclusion criteria for study eligibility. Use of similar medications inhibiting CYP2C9 will be 
reviewed by the treating investigator to determine eligibility and additional monitoring for AEs if 
patient is enrolled on-study.  
Other Concomitant Medications 
Therapies considered necessary for the patient’s well-being may be given at the discretion of the 
investigator and should be documented on the eCRF. Other concomitant medications should be 
avoided, except for analgesics, chronic treatments for concomitant medical conditions, or agents 
required for life-threatening medical problems.  
Herbal and complementary therapies should be discouraged because of potential for 
unknown side effects and adverse drug interactions, but any that are taken by the patient 
should be documented appropriately on the eCRF.  

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Rucaparib marginally increased digoxin area under the plasma concentration-time curve 
(AUC) by 20%. Caution should be exercised for patients receiving rucaparib and requiring 
concomitant medication with digoxin. Patients taking digoxin should have their digoxin 
levels monitored after starting rucaparib and then regularly per standard clinical practice. 
In vitro, rucaparib is a potent inhibitor of MATE1 and MATE2-K, a moderate inhibitor of 
OCT1, and a weak inhibitor of OCT2. As inhibition of these transporters could increase 
metformin renal elimination and decrease liver uptake of metformin, caution is advised 
when metformin is co-administered with rucaparib.  
In addition, rucaparib is an inhibitor of the BCRP with 50% inhibitory concentration (IC50) 
value suggesting potential BCRP inhibition and increased exposures of medicinal products 
that are BCRP substrate (e.g., rosuvastatin).
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue for 24 months or 
until one of the following criteria applies:  
Disease progression, 
Intercurrent illness that prevents further administration of treatment, 
Unacceptable adverse event(s), 
Patient decides to withdraw from the study, or 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator
The date and the reason for removal from study treatment must be documented in the Case 
Report Form. 
Duration of Follow-Up
Patients will be followed until death or 3 years after registration for survival, whichever occurs first.
Patients removed from study therapy due to unacceptable adverse event(s) will be followed per 
protocol, until resolution or stabilization of the adverse event.  
Criteria for Removal from Study 
Patients will be removed from study therapy when any of the criteria listed in Section 5.4 applies and 
followed per section 5.5. The reason for study therapy removal and the date the patient was removed 
must be documented in the Case Report Form.

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6. DOSING DELAYS/DOSE MODIFICATIONS
Doses of oral study drug (rucaparib), and/or IV study drug (nivolumab), may be interrupted or delayed for 
toxicity and other protocol-specified criteria. Dose reductions are permitted for Rucaparib, but not for 
Nivolumab. The assessment for delay or discontinuation should be made separately for the oral study drug 
(rucaparib) and the IV study drug (nivolumab) where class-specific safety profiles do not overlap; however, 
if toxicity is considered related to all study drugs or if the investigator is unable to determine which study 
drug is the cause of the AE, then all study drugs in the combination should be delayed and/or discontinued.
For management of AEs which can be clearly attributed to rucaparib OR nivolumab, independent 
dose modification for either agent is allowed. If the relationship to an AE that is common to both drugs 
can be clearly distinguished, then a recommendation from the ET CCART for continuation of the non-
offending drug can be requested by the investigator.  Treatment may be prematurely discontinued due to 
withdrawal of consent, unacceptable toxicity, disease progression, completion of treatment cycles, or 
termination of the study, whichever occurs first.  
Dose modification and re-treatment of oral and/or IV study drug are to be based on criteria presented in 
Table 4.  

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RECOMMENDED DOSE ADJUSTMENTS FOR RUCAPARIB
Dose
Total mg per day
Starting Dose
600 mg twice daily (each dose is two 300-mg tablets)
1200 mg per day 
First Dose Reduction
500 mg twice daily 
(each dose is one 300-mg tablet and one 200-mg tablet)
1000 mg per day
Second Dose Reduction 400 mg twice daily (each dose is two 200-mg tablets)
800 mg per day 
Third Dose Reduction
300 mg twice daily (each dose is one 300-mg tablet)
600 mg per day
7. ADVERSE EVENTS 
The following list of adverse events (Section 7.1, Appendices B and C) and the characteristics of the 
observed AEs (Section 7.2) will determine whether the event requires expedited reporting via the 
MedWatch Forms in addition to routine reporting.  
Expected Toxicities and Supportive Care guidelines
Adverse Event List for rucaparib; nausea, fatigue (including asthenia), vomiting, anemia, 
dysgeusia, AST/ALT elevation, constipation, decreased appetite, diarrhea, thrombocytopenia, 
neutropenia, stomatitis, nasopharyngitis/URI, rash, abdominal pain/distention, and dyspnea. 
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) and Embryo-Fetal Toxicity. See 
also Appendix B. 
Adverse Event List for nivolumab: Fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, 
asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory 
tract infection, pyrexia, headache, abdominal pain, and vomiting. Immune-mediated pneumonitis, 
Immune-mediated colitis, Immune-mediated hepatitis, Immune-mediated endocrinopathies, 
Immune-mediated nephritis and renal dysfunction, Immune-mediated skin adverse reactions, 
Immune-mediated encephalitis, Infusion reactions. See also Appendix C.  
Supportive care guideline for rucaparib and nivolumab toxicity
Opportunistic Infections: It is rare for a patient receiving immunosuppression for nivolumab-related AEs 
to develop an opportunistic infection. Subjects with inflammatory events of any organ category expected to 
require more than 4 weeks of corticosteroid or other immunosuppressive agents to manage the AE should be 
considered for antimicrobial/antifungal prophylaxis, per institutional guidelines, to prevent opportunistic 
infections such as P. jiroveci (formerly P carinii) and fungal infections. 
Immune-Mediated Pneumonitis: Nivolumab can cause immune-mediated pneumonitis, defined as 
requiring use of corticosteroids and no clear alternate etiology. Fatal cases have been reported. 
Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer 
corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for moderate (Grade 2) or more severe 
(Grade 3-4) pneumonitis, followed by corticosteroid taper. Please refer to section 6 for dose modification 
guidance.  
Immune-Mediated Colitis: Nivolumab can cause immune-mediated colitis, defined as requiring use of 
corticosteroids with no clear alternate etiology. Monitor patients for signs and symptoms of colitis. 
Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid 

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taper for severe (Grade 3) or life- threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 
mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more 
than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase 
dose to 1 to 2 mg/kg/day prednisone equivalents. Refer to section 6 for dose modification guidance. 
Immune-Mediated Hepatitis: Nivolumab can cause immune-mediated hepatitis, defined as requiring use 
of corticosteroids and no clear alternate etiology. Monitor patients for abnormal liver tests prior to and 
periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents 
followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) transaminase elevations, 
with or without concomitant elevation in total bilirubin. Administer corticosteroids at a dose of 0.5 to 1 
mg/kg/day prednisone equivalents for moderate (Grade 2) transaminase elevations. Refer to section 6 for dose 
modification guidance.  
Immune-Mediated Endocrinopathies: Nivolumab can cause immune-mediated hypophysitis. Monitor 
patients for signs and symptoms of hypophysitis. Administer hormone replacement as clinically indicated and 
corticosteroids at a dose of 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate 
(Grade 2) or greater hypophysitis. Refer to section 6 for dose modification guidance. 
Adrenal Insufficiency: Nivolumab can cause immune-mediated adrenal insufficiency. Monitor patients for 
signs and symptoms of adrenal insufficiency. Administer corticosteroids at a dose of 1 to 2 mg/kg/day 
prednisone equivalents followed by a corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) 
adrenal insufficiency. Please refer to section 6 for dose modification guidance.
Immune-Mediated Nephritis and Renal Dysfunction: Nivolumab can cause immune-mediated 
nephritis, defined as renal dysfunction or Grade 2 increased creatinine, requirement for corticosteroids, and no 
clear alternate etiology. Monitor patients for elevated serum creatinine prior to and periodically during 
treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by 
corticosteroid taper for life-threatening (Grade 4) increased serum creatinine. Administer corticosteroids at a 
dose of 0.5 to 1 mg/kg/day prednisone equivalents for moderate (Grade 2) or severe (Grade 3) increased 
serum creatinine, if worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day 
prednisone equivalents. Please refer to section 6.
Immune-Mediated Encephalitis: Nivolumab can cause immune-mediated encephalitis with no clear 
alternate etiology. Evaluation of patients with neurologic symptoms may include, but not be limited to, 
consultation with a neurologist, brain MRI, and lumbar puncture.  
Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate 
to rule out infectious or other causes of moderate to severe neurologic deterioration. If other etiologies are 
ruled out, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for patients with 
immune-mediated encephalitis, followed by corticosteroid taper. Permanently discontinue OPDIVO for 
immune-mediated encephalitis 
Infusion Reactions: Nivolumab can cause severe infusion reactions, which have been reported in less than 
1.0% of patients in clinical trials. Discontinue OPDIVO in patients with severe or life-threatening infusion 
reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions 
Rucaparib 
Rucaparib 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.
Anticoagulants: Rucaparib is a weak inhibitor of CYP2C9 in vivo. Use of Warfarin, Coumadin, 

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Tizanidine, and Aripiprazole is now an exclusion criterion for study eligibility. 
Other Concomitant Medications
Therapies considered necessary for the patient’s well-being may be given at the discretion of the investigator 
and should be documented on the eCRF. Other concomitant medications, except for analgesics, chronic 
treatments for concomitant medical conditions, or agents required for life-threatening medical problems, 
should be avoided. Herbal and complementary therapies should not be encouraged because of unknown side 
effects and potential drug interactions, but any taken by the patient should be documented appropriately on 
the eCRF. Rucaparib marginally increased digoxin area under the plasma concentration-time curve (AUC) by 
20%. Caution should be exercised for patients receiving rucaparib and requiring concomitant medication with 
digoxin. Patients taking digoxin should have their digoxin levels monitored after starting rucaparib and 
then regularly per standard clinical practice. In vitro, rucaparib is a potent inhibitor of MATE1 and MATE2-
K, a moderate inhibitor of OCT1, and a weak inhibitor of OCT2. As inhibition of these transporters could 
increase metformin renal elimination and decrease liver uptake of metformin, caution is advised when 
metformin is co-administered with rucaparib. In addition, rucaparib is an inhibitor of the BCRP with 50% 
inhibitory concentration (IC50) value suggesting potential BCRP inhibition and increased exposures of 
medicinal products that are BCRP substrate (e.g., rosuvastatin). 
Adverse Event Characteristics
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI CTCAE version 5.0 will be utilized for AE reporting. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 
can be downloaded from the CTEP web site: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf 
For expedited reporting purposes only: 
o
AEs for the agent(s) that are listed above (and in the Investigational Brochures for both 
nivolumab and rucaparib in the appendices) should be reported only if the adverse event varies 
from expected toxicities (differs in nature, and/or exceeds anticipated intensity or frequency as 
noted in the provided expected toxicity information). 
o
Other AEs for the protocol that do not require expedited reporting are outlined in Section 7.3.3 
(Expedited Adverse Event Reporting under the sub-heading of Protocol-Specific Expedited 
Adverse Event Reporting Exclusions). 
Attribution of the AE:
o
Related – The AE is clearly related to the study treatment.
o
Unrelated – The AE is clearly NOT related to the study treatment.

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Expedited Adverse Event Reporting  
BMS-specific SAE reporting guidelines:   
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through 100 days of discontinuation of dosing must be reported to BMS 
Worldwide Safety, whether related or not related to study drug. If applicable, SAEs must be 
collected that relate to any later protocol-specified procedure (e.g., a follow-up skin biopsy). 
An SAE report should be completed for any event where doubt exists regarding its seriousness;  
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy or a complication of a 
study procedure), the relationship should be specified in the narrative section of the SAE 
Report Form. 
An appropriate SAE form (e.g., USA = Medwatch form) should be used to report SAEs to BMS.  If 
you prefer to use your own Institutional form, it must be reviewed by BMS prior to study initiation.  
Note:  Please include the BMS Protocol number on the SAE form or on the cover sheet with the 
SAE form transmission.   
o
The CIOMS form is available at: http://www.cioms.ch/index.php/cioms-form-i  
o
The MedWatch form is available at: MedWatch 3500 Form
For studies with long-term follow-up periods in which safety data are being reported, include 
the timing of SAE collection.  
The Sponsor will reconcile the clinical database SAE cases (case level only) transmitted to BMS 
Global Pharmacovigilance (Worldwide.Safety@bms.com). Frequency of reconciliation should be 
every 3 months and prior to the database lock or final data summary. BMS GPV&E will email, 
upon request from the Investigator, the GPV&E reconciliation report. Requests for reconciliation 
should be sent to aepbusinessprocess@bms.com. The data elements listed on the GPV&E 
reconciliation report will be used for case identification purposes. If the Investigator determines a 
case was not transmitted to BMS GPV&E, the case should be sent immediately to BMS. 
BMS will notify investigators of all reported SAEs that are suspected (related to the investigational 
product) and unexpected (i.e., not previously described in the IB). An event meeting these criteria 
is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). Investigator notification 
of these events will be in the form of a SUSAR Report.  
o
Other important findings which may be reported by BMS as an Expedited Safety Report (ESR) 
include: increased frequency of a clinically significant expected SAE, an SAE considered 
associated with study procedures that could modify the conduct of the study, lack of efficacy that 
poses significant hazard to study subjects, clinically significant safety finding from a nonclinical 
(e.g., animal) study, important safety recommendations from a study data monitoring committee, 
or sponsor decision to end or temporarily halt a clinical study for safety reasons. 
o
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the IB. 
Where required by local regulations or when there is a central IRB/IEC for the study, the sponsor 
will submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will determine if 
the informed consent requires revision. The investigator should also comply with the IRB/IEC 
procedures for reporting any other safety information.  

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o
In addition to the Sponsor Investigator’s responsibility to report events to their local HA, 
suspected serious adverse reactions (whether expected or unexpected) shall be reported by BMS to 
the relevant competent health authorities in all concerned countries according to local regulations 
(either as expedited and/or in aggregate reports). 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS within 24 
hours \ 1 Business Day of becoming aware of the event. SAEs must be recorded on either CIOMS, 
MedWatch, or approved site SAE form.   
Pregnancies must be reported and submitted to BMS on any of the following form(s): 
1. MedWatch or, CIOMS or 
2. BMS Pregnancy Surveillance Form or,  
3. Approved site SAE form  
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  +1 609-818-3804 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.)  
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours \ 1 Business Day to BMS using the 
same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization.

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Markey Cancer Center (MCC) IITs Reporting Guidelines 
MCC IIT investigators must report to the PI any SAE that occurs after the initial dose of study 
treatment, during treatment, or within 100 days of the last dose of treatment (Nivolumab or 
Rucaparib) on the local institutional SAE form.  
SAEs for rucaparib must be reported to PI regardless of causality even after reporting 
period.   
This applies to the following categories:
Grade 3 (severe) Medical Events – Events that are related or unrelated with the 
Intervention. 
ALL Grade 4 (life-threatening or disabling) Medical Events –  
ALL Grade 5 (fatal) Events
Note: If subject is in long-term follow-up, death is reported at continuing review.  
The following table outlines the required forms and reporting structure for clinical trials.
Study type
Expedited 
reporting to 
MCC
Expedited 
reporting to 
External 
Agency
Non-
expedited AE
Form
IRB
Industry-sponsored 
studies 
Yes, if it 
meets the 
sponsor-
required  
SAE 
reporting
Yes, if it meets 
the sponsor-
required  
SAE 
reporting
Sponsor 
required 
process
MedWatch
3500 or 3500a 
per industry 
sponsor 
OnCore for all 
SAEs 
Yes

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MCC Expedited Reporting Guidelines for MCC IITs
Investigators within MCC will report SAEs directly to the MCC DSMC per the MCC DSMC SOP 
and 
UK
IRB 
reporting 
policy. 
IRB 
reporting 
is 
as 
outlined 
in 
IRB 
SOP: 
http://www.research.uky.edu/ori/SOPs_Policies/C2-0350 
Unanticipated_Problems_Adverse_Events_SOP.pdf
Attribution
MCC Reportable SAEs
Grade 2 AE
Expected
Grade 2 AE 
Unexpected
ALL Grade 3 and 
Grade 4 AEs
ALL Grade 4 
AE
ALL 
Grade 5 AE 
Unrelated
Unlikely 
Not required
Not required
Within 5 calendar 
days
Within 5 
calendar days
Within 24 
hours*
Possible
Probable 
Definite
Not required 
Within 5 
calendar days
Within 5 calendar 
days
Within 5 
calendar days
Within 24 
hours*
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be 
reported.
* The SAE should be reporting within 24 business hours of learning of the event for participants 
enrolled and actively participating in the study or for SAEs occurring within 100 days of the last 
intervention of Nivolumab and also Rucaparib. 
Exclusions to Protocol-Specific Expedited Adverse Event Reporting
The adverse events listed below do not require expedited reporting however, they still must be 
reported through the routine reporting mechanism (i.e., case report form).. 
CTCAE 
SOC
Adverse Event
Grade
Hospitalization/ 
Prolongation of 
Hospitalization
Attribution
Comments
Nausea or vomiting occurring for less 
than 3 days
1 & 2
All
Alopecia
All
All
Expedited Reporting to External Agencies
Overall PI will comply with the policies of all external funding agencies and the University of 
Kentucky IRB regarding expedited reporting, as per the IRB’s SOP on safety reporting: 
http://www.research.uky.edu/ori/SOPs_Policies/C4-0150-
Mandated_Reporting_to_External_Agencies_SOP.pdf. 
Grade 5 SAEs will be also reported to BMS and Clovis Oncology within 24 hours of the learning of 
the event, up to the point of 100-days after the last dose of Nivolumab and Rucaparib.  

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Expedited Reporting to the FDA
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.  
Expedited Reporting to Hospital Risk Management 
Participating investigators will report to the UK Office of Risk Management any participant safety 
reports or sentinel events that require reporting according to the institutional policy. 
Routine Adverse Event Reporting
All AEs must be reported in routine study data submissions to the Overall PI on the OnCore case
report forms  per timeline guidance mentioned in section 7.3.3 AEs reported through expedited 
processes (e.g., reported to the IRB, FDA, etc.) must also be reported in routine study data 
submissions.
Second Malignancy
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis 
from the initial malignancy). Second malignancies require ONLY routine AE reporting unless 
otherwise specified. 

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8. STUDY CALENDAR  
Baseline (pre-study) evaluations will be conducted within 2 weeks prior to start of protocol therapy. Scans and 
x-rays must be done 46 weeks prior to the start of therapy. If the patient’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy.  
Pre- 
Study
Treatment Period
( continues until 
radiologic progression or 
unacceptable toxicities 
or 24 months, 
whichever comes first )
Cycle 1 
Day  
15 
Off 
Treatment 
Visit 
(within 30 
days) 
 100-days
Safety 
Visit 
 
(+/- 14-days) 
Follow- 
Up
Every 6 mos 
up to max 
of  3 years  
from 
on-study
Informed Consent
R
Demographics
R
 
 
HCG 1  
S
Concomitant Medications
---------- R ------------
 
R 
R
 
Adverse Event evaluation 11
Q 4 weeks  *,***
R  
R 12
 
Daily  *,*** 
 
 
Q4 weeks   *,*** 
  
 
Pill Diary (Ruca)
R 
R 
 
Medical History
S
 
 
Physical Exam
S
Per S 
 
S 
 
Vital Signs 
S
Per S 
 
S 
 
Height 
S
 
 
Weight  
S
Per S 
 
 
ECOG Performance Status 
S
   Q 4 weeks *,***
R 
S 
 
CBC w/diff 2 
S
 Q 4 weeks *,**
S 
S 
 
Serum chemistry 3, ** 
S
 Q 4 weeks *,**
R 3,4
S 
S 
 
EKG 5
R
As clinically indicated
 
 
Smoking Status
R
 
 
Imaging 
 
CT Chest w. contrast 
CT Abdomen w. contrast 
Bone scan 
S/R
Q 8 weeks  *,***
S,  
as clinically 
indicated 
 
S/R
Q 8 weeks  *,***
 
As clinically indicated
 
Patient-Reported Outcomes 
(Quality of Life) 6
R
R 6
 
 
PBMCs collection for Flow 
Cytometry studies (BPTP 
SRF, Cohen lab) 7
R
At Cycle 3, Day 1
 
 
TP53 assay - blood collection: 
One 10mL streck tube  
(Kolesar lab) 8 
R
Also collected at 2-months, at 4-months;  
and, if applicable, at the time of disease progression. 
 

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Check status of enrollment to 
ORIEN Protocol for Tumor 
Whole Exome Sequencing 
and Germline Mutation 
Testing 9
R 9
Survival Status 10
 
R 10
S = standard of care  /   R = research-related activity   / QOL = quality of life 
*: A scheduling window of ± 7 days exists to accommodate adverse weather, holidays, or other issues. 
** These tests are not required on the Cycle 1 Day 1 visit IF evaluated during the participant’s pre-study 
visit.
*** : dose delays could move the visit windows out of the 7-day allowance – this will be noted in the  
                  eCRF and dates adjusted as needed.
1 : to ascertain eligibility of sexually active female patients who are pre-menopausal/of child-bearing potential (serum  
     or urine pregnancy test).  
2: CBC with diff as per Standard of Care. Only recording results for the following labs in the eCRF: ANC,  
                  Absolute lymphocytes, WBC, Platelets, and Hemoglobin.  
3: CMP Panel includes SGOT [AST], SGPT [ALT], total bilirubin, creatinine, Albumin, alkaline phosphatase,  
 
bicarbonate, BUN, calcium, chloride, TSH, glucose, potassium, total protein, sodium.  
4 : Cycle 1 Day 15,  CMP in order to assess liver function. Only AST/ALT will be recorded in the eCRF.  
5 : EKG at baseline, and as clinically indicated during active treatment.  
6:  Patient-Reported Outcomes assessing quality of life comprise two complementary, validated, standardized    
            questionnaires, the EORTC QLQ-C30 and LC13. These two questionnaires will be administered at  
baseline (pre-treatment), at 4-months (with a +3 week window to allow this to be collected in the course 
             of a regularly scheduled clinic visit), and at the time of disease progression (if greater than 4-months).  
7: PBMCs for Flow Cytometry; collected for Biospecimen SRF. Each sample consists of two 8 mL BD Vacutainer  
    CPTs with Sodium Citrate, so 16 mL is collected at pre-study, and again at Cycle 3, Day 1 (+/- 7-day study visit  
    windows per *).  
8:  One 10 mL whole blood draw in streck tube up to a total of at 4 timepoints (i.e., 4 total samples collected).  
     The timepoints for collection comprise: Pre-study; twice during active treatment (approximately every 2 months,  
     e.g., Cycle 3 Day 1, and Cycle 5 Day1), and at time of disease progression.  
     Samples will be processed by Dr. Kolesar’s lab.  
9: Checking status of enrollment on ORIEN protocol, 17-MTB-01 (Yes/No status for each patient on-study).  
10: Survival Status – patients are in follow-up up to 3 years post-registration. Survival will be checked every 6- 
      months (once patient is off-treatment) up to a total of 3 years post-registration. Survival Status can be ascertained  
      via clinic visit or phone calls.  
11: Additionally, S/AEs will be reported per protocol, 100-days after the last dose of study drug.  
12: Nivolumab and Rucaparib 100-days Safety Visit reporting window:  Adverse Events for Nivolumab 
      and Rucaparib will be monitored and reported for a 100-day period after Off-Treatment (i.e., the last dose 
      of Nivolumab and Rucaparib per protocol). The 100-day safety visit allows a study visit window of  
     +/- two-weeks to capture late sequelae of Nivolumab and Rucaparib, as well as any other ongoing  
      treatment-related S/AEs).  
 

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9. MEASUREMENT OF EFFECT 
Antitumor Effect – Solid Tumors
For the purposes of this study, patients should be re-evaluated for response every 8 weeks per standard 
of care.  
Response and progression will be evaluated in this study using the new international criteria proposed 
by the revised RECIST (version 1.1) [45]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are 
used in the RECIST V1.1 criteria.
Definitions
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of first dose of 
study medication. 
Evaluable for objective response. Only those patients who have measurable disease present at 
baseline, and have received at least 75% of the intended doses of cycle 1 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.)
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
Disease Parameters
Measurable disease. Measurable lesions are defined as those that can be accurately measured in at 
with CT scan or MRI. 
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 
in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm [0.5 cm]). At baseline and in follow-up, only the short 
axis will be measured and followed. 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm [<1 cm]
 short 
axis), are considered non-measurable disease. In addition, bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable disease. 
Note: Simple cysts, defined as cystic lesions that meet the criteria for radiographically defined 
simple cysts, should not be considered malignant lesions (neither measurable nor non-measurable).

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Conversely, ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, the preferred category is as target lesions.
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 will be recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, AND additionally should be lesions that lend themselves to 
reproducibly repeated measurements. For instance, if the largest lesion does not lend itself to 
reproducible measurement, then the next largest lesion which can be measured reproducibly should 
be selected as a target lesion.  
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 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. 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Additional measurement of these non-target lesions is not required, but the 
presence, absence, or in rare cases unequivocal progression of each non-target lesion should be 
noted throughout follow-up.  
Methods for Evaluation of Measurable Disease
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT scans have slice thickness 
greater than 5 mm (0.5 cm), 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).  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible. 
Response Criteria
9.1.4.1
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 

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(whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm (0.5 cm). (Note: the appearance of one or more new 
lesions is also considered progression).  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
9.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Non-CR/Non-PD: 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. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a single 
lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should 
be confirmed at a later time by the review panel (or PI). 
9.1.4.3 
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. 
 

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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR
CR
No
CR
>4 wks. Confirmation**
CR
Non-CR/Non-
PD
No
PR
>4 wks. Confirmation** 
CR
Not evaluated
No 
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
SD
Non-CR/Non-
PD/not 
evaluated
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 
*See RECIST V1.1 manuscript for further details on what is evidence of a new lesion. 
**Only for non-randomized trials with response as primary endpoint. 
***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. 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions 
New Lesions
Overall Response
CR
No
CR 
Non-CR/non-PD 
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
*‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised

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10. DATA REPORTING / REGULATORY REQUIREMENTS
Data Reporting 
Method 
This study will require data submission and reporting via the OnCore Database, which is the 
official database of the MCC CRO. Instructions for submitting data is listed in Study-Specific Data 
Management Plans (DMP) created by the CRO staff.  
Responsibility for Data Submission 
Study staff are responsible for submitting study data and/or data forms to OnCore as per the MCC 
CRO’s SOPs. This trial will be monitored by the MCC DSMC on a schedule determined by PRMC
at its initial review. The CRO staff are responsible for compiling and submitting data for all 
participants and for providing the data to the PI for review.  
11. STATISTICAL CONSIDERATIONS AND DATA MANAGEMENT
Study Design and Sample Size
A single arm Phase II trial will be performed using FDA approved single agent dosage for both 
nivolumab and rucaparib.  We will estimate the proportion of patients who exhibit PFS at 6 months.  
Based on a phase III randomized clinical trial conducted by ECOG, the historical median PFS for 
Stage IV SCLC, post platinum doublet in platinum sensitive patients, is 2.3 months in the observation 
arm vs 3.6 month on maintenance topotecan arm [23].   Assuming that the proportion who exhibit PFS 
at 6 months is 50%, a sample of 36 patients produces a one-sided 90% confidence interval with a lower 
limit equal to 38%, providing some evidence of efficacy.   
Data Analysis 
Analysis of Primary and Secondary Endpoints 
Progression-free survival will be estimated using the Kaplan-Meier curve and the proportion who do 
not exhibit PFS at 6 months and at other specific timepoints will be calculated along with confidence 
intervals.  The median PFS and confidence interval will also be calculated. Other time to event 
endpoints including OS will be estimated using the same methods. The disease control rate, objective 
response rate and best overall response rate will be estimated, along with exact 95% binomial 
confidence intervals.  
Immune markers including percentage of CD4 T cells and CD8 T cells expressing PD-1 and Ki-67, 
expression of CD101 and CD38 will be summarized descriptively at baseline and at each time point 
of evaluation. The change from baseline will also be calculated and compared using paired test 
statistics. QOL measures will also be summarized using descriptive statistics.  
Analysis of baseline whole exome sequencing data (where available) will be performed in the 
Biostatistics and Bioinformatics Shared Resource at MCC. Customized data processing and data 

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analysis pipelines will be applied and exploratory comparisons of mutation data with response and 
clinical outcomes will be performed using Fisher’s exact test with control for false discovery rate 
(FDR).  
Data Management 
The study statistician and staff from the MCC Biostatistics and Bioinformatics Shared Resource 
Facility will work closely with the study team, the Clinical Research Office, and the Cancer Research 
Informatics Shared Resource Facility to implement several aspects of data management for this trial. 
This will include development of eCRFs in the Oncore system, trial-specific processes for data entry, 
generation of reports, data management and statistical analysis. Specifically, the statistician will attend 
several meetings including the eCRF development meeting, the data management process meeting and 
the protocol initiation meeting. Appropriate and accurate collection of primary and secondary study 
endpoints and inclusion of valid values and range checks for data fields will be designed for the eCRFs. 
The OnCore clinical trial management system, managed by MCC CRO and Cancer Research 
Informatics Shared Resource Facility, will be the primary database repository of clinical data from all 
patients enrolled into this trial. Data will be accessed by the study statistician on a regularly scheduled 
basis to perform statistical programming for conduct of data quality control, data management, 
generation of interim reports and statistical analysis. In collaboration with the study team, procedures 
will be developed for data quality control timelines, resolution of data queries, interim reporting and 
final data analysis.
A protocol-specific DMP will be authored by a senior data manager in collaboration with the 
biostatistician and the CRO, each team will be expected to review and sign off on the DMP prior to 
finalization. In order to maintain best clinical practices in data management, the DMP may include, 
but is not limited to, CRF/eCRF design, database build and design, database training, edit 
check/validation specifications, study database testing/release, data and paper workflow, report, 
metrics, query/discrepancy management, management of external (including lab) data, medical 
coding, SAE handling/reconciliation, data transfers and database lock. The protocol specific DMP will 
additionally define the schedule at which data will be accessed by study statisticians to perform 
statistical programming for conduct of data quality, data control, data management, generation of 
interim reports and statistical analysis. Cross-team members will collaborate to establish procedures 
and timelines for quality control, audits, query resolution, interim and final data analysis.
12. CORRELATIVE STUDIES
Immune studies:
Two 8.0 ml BD Vacutainer® CPT™ Mononuclear Cell Preparation Tubes - Sodium Citrate will be 
drawn prior to treatment (on the day of treatment) and 2 weeks after treatment (per study calendar). 
This should yield up to 16 million PBMCs for each blood draw that will be analyzed by flow 
cytometry. We will evaluate three different sets of immune cell markers to identify clinical benefit. 
Percentage of CD4 T cells and CD8 T cells expressing PD-1 and Ki-67. 
Increased circulating blood levels of Ki-67, PD-1 expressing T cells is a predictor of clinical 
benefit while on anti-PD-1 therapy. A positive signal will be an increased in cells expressing 
Ki-67, PD-1 on CD4 and CD8 T cells while on treatment compared to the pre-treatment sample

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[47].  
Percentage of polyfunctional effector CD4 T cells and CD8 T cells (CD101+ and CD38+) 
Polyfunctional T cells expressing multiple cytokines have been shown to have enhanced anti-
tumor activity and CTLA-4 blockade increased the number of polyfunctional T cells in patients 
with metastatic melanoma. [48] 
Percentage of effector CD4 T cells and CD8 T cells expressing CD38, HLA-DR, CD28, 
ICOS, CD27, and low Bcl2 levels.
Patients responding to anti-PD-1 therapy have an increase in proliferating effector T cells 
defined by expression of CD38, HLA-DR, CD28, CD27, ICOS, and low Bcl2 levels.  
The part of the study is based on peripheral blood to assess immune activation. The following steps 
for processing and cryopreservation of blood samples listed below are to be performed in Flow 
Cytometry and Cell Sorting Shared Resource Facility (FCCS SRF). FCCS provides flow cytometric 
analysis and cell sorting as well as human immune monitoring services. These services include blood 
processing and cryopreservation of PBMC. All samples cryopreserved by the FCCS are then banked 
and managed by the Biospecimen Procurement and Translational Pathology Shared Resource Facility 
(BPTP SRF) until all samples for a subject have been collected. Once all samples are collected, all 
stored samples for a subject will be thawed and analyzed simultaneously by the FCCS to obtain 
correlative endpoints as described above. Data analysis will be performed by Dr. Cohen with members 
of his laboratory along with review and discussion of data with Drs. Jerry Woodward (Co-director 
FCCS) and Aman Chauhan. 
Isolation of Mononuclear Cells from Peripheral Blood  
15 ml of blood will be collected from patients at the indicated times (Whole Blood tube w/ 
Anticoagulant, BD Vacutainer™ CPT™ Tube with Sodium Citrate). Blood collection will be
performed in clinic and handed to FCCS staff. 
The FCIM group will perform the following steps to process the samples for cryopreservation. 
Centrifuge at 400 x g for 30 minutes at room temperature 
Aspirate buffy coat at interface, resuspend cells in sterile saline and wash by centrifugation. 
Repeat wash procedure twice.
Resuspend pellet containing PBMCs in ice cold 100% fetal calf serum (FCS) 
Determine cell concentration and viability
Perform flow cytometry analysis on one fresh aliquot and store remainder on ice for 
cryopreservation by FCCS. 
NOTE: PBMCs from all blood collections from each patient will be cryopreserved by the FCCS and
banked by the BPTP SRF until all blood collections are completed. Flow cytometric analysis by the 
FCCS SRF will be performed on fresh samples as they are collected and in bulk on all cryopreserved 
samples per patient.
Following determination of cell number and viability, PBMCs in FCS will be adjusted to a 

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concentration of 2 x 106 viable cells/ml.
 2 x 106 viable cells will be added to cryopreservation vials containing DMSO to obtain a final 
concentration of 10% DMSO. 
 Vials will be transferred to cryopreservation containers for slow freezing in a -80°C freezer.
Following overnight freezing, vials will be transferred to liquid nitrogen freezers maintained by the 
BPTP SRF for banking until all patient blood samples are collected. 
 
 
Activation of Peripheral Bloo
detection (performed by FCCS SRF). 
 Culture 2 x 106 freshly thawed PBMC will be incubated for 5 hours in 37oC incubator in 
complete RPMI medium containing PMA (50ng/ml) and Ionomycin (1ug/mL), plus 
Brefeldin A to activate cells 
 Cells will then be washed by centrifugation and then stained as follows for flow cytometry 
analysis:  
 Suspend cells in FACS buffer (PBS, 1% BSA, sodium azide [0.01%]) at a concentration 
of 107 cells per ml 
Add Fc Block to all tubes and incubate for 10 minutes on ice 
Add all of the indicated fluorochome-labelled antibodies for surface membrane staining as 
indicated in antibody panels below (Table) 
o Anti- human CD3, CD4, CD8 (T cell subset markers) 
o Anti-human CD38, CD101 (effector T cell markers) 
o Anti-human CD27, CD28, Bcl2, HLA-DR, ICOS (activation markers) 
o Anti-human CD279 (PD-1) 
 Incubate on ice in the dark for 30 minutes 
 Wash cells twice with PBS+Azide to remove excess antibody
 Fix and permeabilize cells (paraformaldehyde/saponin)  
-labeled anti-
-67 
Wash cells by centrifugation and resuspend in FACS buffer for flow cytometry analysis 

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Flow cytometric analysis (performed by FCCS SRF). 
Set the flow cytometer on the following gates
o
Live cell gate
o
Lymphocyte gate
Set the following fluorescent gates on the live lymphocyte population 
o
CD3+, CD4+ to identify helper T-cells 
o CD3+, CD8+ to identify cytotoxic T-cells
Analyze both the helper T-cell and cytotoxic T-cell subpopulations for expression of the 
following 
o
Surface expression levels of CD27, CD28, Bcl2, HLA-DR, ICOS, CD38, CD101, and 
PD-1 
o 
Analysis and storage of flow cytometric data (performed by FCCS SRF). 
 
Flow cytometric data will be analyzed using FlowJo analytical software to determine the 
percentage of T cell subsets (CD4+ and CD8+) which express surface and intracellular biomarkers as
indicated above. 
 
Calculated results for each patient and blood collection will be recorded in an Excel 
spreadsheet. Note: patients will be identified only with the unique code assigned for each patient.  
Flow Cytometry Antibody Panels for PD-1/PARP 
Panel #1 
(Fresh blood) 
Panel #2 
(Cryopreserved blood)
CD3
CD3
CD4
CD4
CD8
CD8
PD-1 
CD38
Ki-67
CD101
CD27
PD-1
CD28
IFN gamma 
CD38
TNF alpha
Bcl-2
Viability dye
HLA-DR
ICOS
Viability dye 

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Spreadsheet containing all results will be stored in a private folder on Dr. Cohen’s UK server site, 
which UK backs up daily. 
Raw flow cytometry data and spreadsheet containing calculated results will also be 
submitted to the OnCore Database, the official database of the MCC CRO, as required.
Only the following individuals will have access to the results in the private folder of Dr. Cohen:  
Dr. Chauhan, Dr. Weiss, and the biostatistician assigned to the study.
Analytical procedures 
Patient PBMCs will be analyzed by the FCCS SRF for the percentage of cells expressing each 
marker and for the mean fluorescence intensity for each marker. PBMC samples will be analyzed 
on a Beckman-Coulter CytoFLEX LX cell analyzer with 19 color detection capacity. Flow 
cytometric data sets will be interpreted by the MCC Biostatistics and Bioinformatics Shared 
Resource Facility by computational flow cytometry using SPADE algorithm to automatically 
identify populations.   
Assessment of baseline tumor mutational burden and correlation with radiological 
response. 
All patients enrolled in the study will be assessed as to whether they have also enrolled on the 
Markey Cancer Center Total Cancer Care (ORIEN protocol; Yes/No status will be documented in 
the eCRF).  
- Patients enrolled on ORIEN protocol undergo whole exome sequencing of tumor tissue (at 
baseline, and progression, when available) and germline mutation testing via peripheral blood 
or buccal swab. Genomic profiling will be done under Markey Cancer Center Total Cancer 
Care (ORIEN) protocol, wherein all consenting patients treated at MCC are sequenced. 
Genomic testing is funded by the ORIEN protocol.  
For our on-study patients who are also co-enrolled in ORIEN (participant status is “Yes”),  we will 
study patterns of tumor mutation burden and correlate genomic data to durability of treatment 
response and treatment resistance patterns using bioinformatics pipelines developed by the 
Biostatistics and Bioinformatics Shared Resource Facility at Markey. 
The ORIEN Total Cancer Care is a very large clinical research protocol and data are stored
within the Moffitt Data Warehouse (DW). For further details, please visit www.oriencancer.org.   

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cancer (KEYNOTE-162). Journal of Clinical Oncology 34:TPS5599-TPS5599, 2016.  
23. 
Schiller JH, Adak S, Cella D, III RFD, Johnson DH. Topotecan Versus Observation After 
Cisplatin Plus Etoposide in Extensive-Stage Small-Cell Lung Cancer: E7593—A Phase III Trial of 
the Eastern Cooperative Oncology Group. Journal of Clinical Oncology 19:2114-2122, 2001.  
24. 
Oza AM, Tinker AV, Oaknin A, Shapira-Frommer R, et al. Antitumor activity and safety 
of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or 
somatic BRCA1 or BRCA2 mutation: Integrated analysis of data from Study 10 and ARIEL2. 
Gynecol Oncol 147:267-275, 2017.  
25. 
Coleman RL, Oza AM, Lorusso D, Aghajanian C, et al. Rucaparib maintenance treatment 
for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-
blind, placebo-controlled, phase 3 trial. Lancet 390:1949-1961, 2017. PMCID: PMC5901715 

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26. 
Rubraca® Package Insert. 2016. Available at http://clovisoncology.com/media
/1094/rubraca-prescribing-info.pdf. 
27. 
Bryant HE, Schultz N, Thomas HD, Parker KM,  et al. Specific killing of BRCA2-
deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913-917, 2005.  
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Fulcher N, Shenolikar RA, Durden E, Moore KN. Incidence of secondary 
myelodysplastic syndrome and acute myeloid leukemia in patients with ovarian and breast cancer in 
real-world setting in the U.S. Journal of Clinical Oncology 35:5574-5574, 2017.  
29. 
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and ovarian cancers. BMC Cancer 7:152, 2007. PMCID: PMC1959234 
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Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, et al. Pembrolizumab versus 
Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 375:1823-1833, 
2016.  
31. 
Robert C, Long GV, Brady B, Dutriaux C, et al. Nivolumab in previously untreated 
melanoma without BRAF mutation. N Engl J Med 372:320-330, 2015.  
32. 
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, et al. Combined Nivolumab and 
Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 373:23-34, 2015. PMCID: 
PMC5698905 
33. 
Weber JS, D'Angelo SP, Minor D, Hodi FS, et al. Nivolumab versus chemotherapy in 
patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a 
randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375-384, 2015.  
34. 
Weber JS, Kudchadkar RR, Yu B, Gallenstein D, et al. Safety, efficacy, and biomarkers 
of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol 31:4311-
4318, 2013. PMCID: PMC3837092 
35. 
Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, et al. Cancer immunology. Mutational 
landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124-
128, 2015. PMCID: PMC4993154 
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Lawrence MS, Stojanov P, Polak P, Kryukov GV, Mutational heterogeneity in cancer and 
the search for new cancer-associated genes. Nature 499:214-218, 2013. PMCID: PMC3919509 
37. 
Snyder A, Makarov V, Merghoub T, Yuan J, et al. Genetic basis for clinical response to 
CTLA-4 blockade in melanoma. N Engl J Med 371:2189-2199, 2014. PMCID: PMC4315319 
38. 
Van Allen EM, Miao D, Schilling B, Shukla SA, et al.  Genomic correlates of response to 
CTLA-4 blockade in metastatic melanoma. Science 350:207-211, 2015. PMCID: PMC5054517 
39. 
Janjigian YY, Bendell J, Calvo E, Kim JW, et al. CheckMate-032 Study: Efficacy and 
Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric 
Cancer. Journal of Clinical Oncology 2018 36:28, 2836-2844  

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40. 
Garon EB, Rizvi NA, Hui R, Leighl N, et al. Pembrolizumab for the treatment of non-
small-cell lung cancer. N Engl J Med 372:2018-2028, 2015.  
41. 
Butterfield LH, Disis ML, Khleif SN, Balwit JM, Marincola FM. Immuno-oncology 
biomarkers 2010 and beyond: perspectives from the iSBTc/SITC biomarker task force. J Transl Med 
8:130, 2010. PMCID: PMC3014892 
42. 
Bedognetti D, Balwit JM, Wang E, Disis ML, et al. SITC/iSBTc Cancer Immunotherapy 
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biomarker discovery. J Transl Med 9:155, 2011. PMCID: PMC3189883 
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biomarkers for personalized cancer immunotherapy. J Immunother Cancer 4:3, 2016. PMCID: 
PMC4717548 
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2009. 2009. Available at https://www.fda.gov/downloads/Drugs/Guidance/UCM174090.pdf. 
45. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, et al. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247, 2009.  
46. 
Wu J. Sample size calculation for the one-sample log-rank test. Pharm Stat 14:26-33, 
2015.  
47. 
Kamphorst AO, Pillai RN, Yang S, Nasti TH, et al. Proliferation of PD-1+ CD8 T cells in 
peripheral blood after PD-1-targeted therapy in lung cancer patients. Proc Natl Acad Sci U S A 
114:4993-4998, 2017. PMCID: PMC5441721 
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Donia M, Kjeldsen JW, Andersen R, Westergaard MCW, et al. PD-1(+) Polyfunctional T 
Cells Dominate the Periphery after Tumor-Infiltrating Lymphocyte Therapy for Cancer. Clin Cancer 
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49. 
 Antonia SJ, López-Martin JA, Bendell J, Ott PA, et al. Nivolumab alone and nivolumab 
plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, 
phase 1/2 trial. The Lancet Oncology 17:883-895, 2016. 
 
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Horn L, Mansfield AS, 
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Firstline atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N engl j 
med. 2018 DEC 6;379(23):2220-2229 
 

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APPENDIX A. ECOG PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale
Grade 
Descriptions 
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 out any self-care. Totally confined to bed or 
chair. 
5 
Dead. 
 

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APPENDIX B. ADVERSE EVENTS LIST FOR RUCAPARIB  
Rucaparib Side Effects  
The following is a list of reported side effects as well as other notable side effects considered to be 
possibly due to rucaparib, as reported by physicians about their patients who are taking rucaparib 
alone:  
Very common (Occurring in 10% or more of patients)  
• Nausea 
• Feeling tired 
• Low Blood Counts (red blood cells, white blood cells, and platelets). Sometimes fever occurs with 
the low blood counts. These low blood count effects may be more likely to occur after multiple 
cycles of treatment.  
  A low red blood cell count may make you feel tired or dizzy. If you feel dizzy while taking 
rucaparib, you should avoid potentially hazardous tasks such as driving or operating 
machinery. 
 A low white blood cell count puts you at higher risk for bacterial or viral infection. Having a 
high temperature or fever while your white blood cell count is low is a medical emergency 
and you must proceed to the nearest emergency room as soon as possible  
 A low platelet count affects the ability of your blood to clot and could lead to bleeding 
events. Symptoms include but are not limited to easy bruising, prolonged bleeding from cuts, 
blood in stools or urine, or nose bleeding. It is possible that rucaparib may make your skin 
and eyes more sensitive to sunlight. You should take all of the usual sun protection 
precautions when going outside. It is advised that you avoid excessive sun exposure, wear 
protective clothing (including wearing a hat and sunglasses), and use sunscreen regularly 
(sun protection factor 50 or greater).  
• A low phosphate level in your blood. Usually there are no symptoms but if the levels are critically 
low, you may notice trouble breathing, confusion, muscle weakness, or irritability.  
• Increase in cholesterol. If your cholesterol increases significantly, your doctor may prescribe a 
medicine to lower your cholesterol level.  
• Changes in kidney and liver function blood tests. These changes will be evaluated by your study 
doctor along with any other side effects that you are experiencing as well as other test results. 
• Changes in your sense of taste.  
• Stomach-related effects such as constipation, vomiting, diarrhea, decreased appetite, stomach pain 
(epigastric pain), and indigestion.  
• Difficulty breathing 
• Dizziness 
• Photosensitivity reaction
• Fever sometimes can occur independent of a low blood count. If you experience elevation of your 
temperature, please refer to your study doctor for fever management.  
• Difficulty sleeping 
 

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Common Side Effects of Rucaparib (Occurring in 1% to less than 10% of patients)  
• Rash, which will appear as changes in your skin color (e.g. redness) and texture (e.g. bumps, 
blisters, peeling). Some rashes may be itchy, painful, or cause no symptoms at all. This can vary in 
severity from mild to severe. 
• Upper airway infection (like the common cold). You may experience infections involving the nose, 
pharynx, larynx, and sinuses. Symptoms include a blocked (congested nose, a runny nose, and 
sneezing. You may also have clear discharge (mucus) from the nose. You may feel generally unwell 
and may also be associated with fever. Treatment is usually supportive but if symptoms persist 
please inform you doctor.  
• Hand-Foot Syndrome (Palmar-plantar erythrodysaesthesia syndrome) When a small amount of 
drug leaks out of the blood vessels, it damages the surrounding tissues. Symptoms would include 
tingling, burning, redness, flaking, swelling, blistering, and sores of the hands and feet due to the 
increased friction and heat your extremities are exposed to. If you experience these symptoms, apply 
ice packs and elevate hands and feet, then contact your study doctor immediately for treatment.  
Uncommon Side Effects of Rucaparib (Occurring in 0.1% to less than 1% of patients)
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)a have been reported in a very 
small number of patients treated with rucaparib during the safety period (while on treatment with 
rucaparib and 28 days after last dose). MDS is a pre-cancerous condition where the bone marrow is 
not as good at producing blood cells (red and/or white blood cells and/or platelets). People with 
MDS may need transfusions (red blood cells and/or platelets) and/or other treatments. In some cases,
MDS can progress to AML, which is a cancer of the bone marrow where more abnormal and 
immature white blood cells (also called blasts) are made than normal white blood cells. People with 
AML need treatment with chemotherapy and/or a bone marrow transplant. Patients may develop 
AML without first being diagnosed with MDS.  
Events of MDS and AML have also been reported with PARP inhibitors similar to rucaparib. At this 
time,  it is not known whether rucaparib or other PARP inhibitors cause MDS or AML, or if these 
developed as a result of previous chemotherapy these patients received. Your study doctor will 
closely monitor your blood cell levels during treatment. If he/she has any concerns about your blood 
counts you may be asked to have a biopsy of your bone marrow.  
a These risks have not yet been determined by Clovis as related to rucaparib. Some of these risks 
have been reported in a high frequency of patients in clinical trials involving rucaparib (e.g. itchy 
skin, rash), others have been reported in a small number of patients but pose significant risk (e.g. 
MDS/AML) or are generally known to be caused by other anti-cancer treatments (e.g.,  palmar-
plantar erythrodysaesthesia). 
 

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APPENDIX C. ADVERSE EVENTS LIST FOR NIVOLUMAB  
Nivolumab Side Effects 
Very common: (Occurring in 10% or more of patients) 
• Diarrhea
• Fatigue 
• Itching 
• Rash 
Common: (Occurring in 1% to fewer than 10% of patients)  
• Abdominal pain  
• Alkaline phosphatase increased: lab test result associated with liver or bone abnormalities
• Allergic reaction/hypersensitivity 
• ALT Increased: lab teste result associated with abnormal liver function 
• Amylase increase: lab test associated with pancreas inflammation_
• AST Increased: lab teste result associated with abnormal liver function 
• Bilirubin (liver function blood test) increased  
• Chills
• Constipation 
• Cough 
• Creatinine increased: lab test associated with abnormal kidney function _ 
• Decreased appetite
• Dizziness or vertigo (feeling off balance, which can lead to dizziness)  
• Dry skin 
• Fever 
• Headache 
• High Blood Pressure 
• Increased Blood Sugar
• Inflammation of the colon 
• Inflammation of the mouth 
• Infusion related reactions 
• Joint pain or stiffness 
• Lipase increased: lab test result associated with pancreatic inflammation 
• Loss of color (pigment) from areas of skin  
• Lung inflammation (pneumonitis—see details below)  
• Musculoskeletal pain 
• Nausea 

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• Redness (of the skin)  
• Shortness of breath 
• Sodium levels in the blood low 
• Swelling including face, arms, legs 
• Thyroid gland function decreased/thyroid stimulating hormone increased (lab test associated with 
              abnormal thyroid function)  
• Thyroid gland function increased 
• Tingling, numbness, burning or weakness 
• Upper respiratory tract infections 
• Vomiting 
Uncommon Side Effects of Nivolumab: (Occurring in 0.1% to less than 1% of patients)  
• Adrenal gland function decreased 
• Bronchitis 
• Cranial nerve disorder 
• Diabetes 
• Dry eyes and/or blurred vision 
• Hair loss 
• Heart rate increased 
• Hear rhythm abnormal 
• High blood pressure 
• Hives 
• Inflammation of the eyes 
• Inflammation of the kidney  
• Inflammation of the pancreas 
• Inflammation of the pituitary gland 
• Inflammation of the stomach, intestines, colon 
• Inflammation of the thyroid gland 
• Liver inflammation 
• Low Blood pressure 
• Lung infiltrate associated with infection or inflammation 
• Pituitary gland function decreased  
• Psoriasis, a skin condition characterized by scaly patches of skin. 
• Kidney failure or kidney injury 
• Respiratory failure 
Rare: [Occurring in 0.01% to less than 0.1% of patients]  
• Anaphylactic reaction (severe allergic reaction) 

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• Damage to the protective covering of the brain, nerves and spinal cord.  
• Diabetes complication resulting in increased blood acid and diabetic coma 
• Guillain-Barre syndrome, an autoimmune disorder associated with progressive muscle weakness or  
paralysis 
• Inflammation of blood vessel 
• Inflammation of the brain, potential life threatening or fatal 
• Inflammation of the heart 
• Muscle inflammation
• Myasthenic syndrome (neurologic syndrome characterized by muscle weakness) including  
myasthenia gravis, a nerve disease that may cause weakness of eye, face, breathing, and 
swallowing muscles. 
• Pemphigoid: blistering of the skin or mouth caused by the immune system attacking healthy tissue. 
• Rhabdomyolysis: muscle fiber released into the blood stream, which could damage your kidneys  
• Rosacea: acne-like skin condition resulting in redness of face  
• Sarcoidosis, a disease involving abnormal collections of inflammatory cells (granulomas) in organs 
         such as lungs, skin, and lymph nodes  
• Stevens Johnson syndrome: inflammatory disorder of skin and mucous membranes, resulting in  
        blistering and shedding of skin  
• Toxic epidermal necrolysis: a potentially fatal disease characterized by blistering and peeling of the  
       top layer of skin resembling a severe burn  
• Histiocytic necrotizing lymphadenitis or Kikuchi lymphadenitis: disorder of the lymph nodes,  
which causes the lymph nodes to become enlarged, inflamed and painful, commonly affecting 
lymph nodes of the neck and possibly associated with fever or muscle and joint pains.  
• Vogt Koyanagi Harada syndrome; a disease that affects the pigmented tissue; this may affect the
 eye, leading to swelling, pain and/or blurred vision; the ear, leading to hearing loss, ringing in the 
ears; and /or the skin, leading to loss of skin color  
 
Lung Inflammation (pneumonitis): It is possible that nivolumab may cause inflammation of the 
tissues of the lung. This adverse effect has been reported in those treated with nivolumab. While 
many patients with x-ray or CT abnormalities have not developed any symptoms, some patients have 
developed mild to severe symptoms and in rare cases, death has occurred as a result of their lung 
inflammation. Signs and symptoms of lung inflammation may include difficulty breathing, pain or 
discomfort while breathing, chest pain, cough, shortness of breath, increased rate of breathing, fever, 
low blood oxygen levels, or fatigue. Your study doctor and nurse will watch you closely for changes 
in your ability to breathe and for other signs or symptoms that might show you are developing this 
type of lung inflammation.  
 

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APPENDIX D. PATIENT-REPORTED OUTCOMES: QUALITY OF LIFE MEASURES
 

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EORTC QLQ - LC13 
Patients sometimes report that they have the following symptoms or problems. Please indicate the 
extent to which you have experienced these symptoms or problems during the past week. Please 
answer by circling the number that best applies to you.
During the past week : Not at
A
Quite
Very
All
Little
a Bit
Much
31. How much did you cough? 
1
 
2
3
4
32. Did you cough up blood?
1
 
2
3
4
33. Were you short of breath when you rested? 
1
 
2
3
4
34. Were you short of breath when you walked?
1
 
2
3
4
35. Were you short of breath when you climbed stairs? 
1
 
2
3
4
36. Have you had a sore mouth or tongue?
1
 
2
3
4
37. Have you had trouble swallowing?
1
 
2
3
4
38. Have you had tingling hands or feet?
1
 
2
3
4
39. Have you had hair loss? 
1
 
2
3
4
40. Have you had pain in your chest? 
1
 
2
3
4
41. Have you had pain in your arm or shoulder? 
1
 
2
3
4
42. Have you had pain in other parts of your body?
1
 
2
3
4
If yes, where 
 
 
43. Did you take any medicine for pain? 
 
 
1 No                                                  2
Yes  
 
If yes, how much did it help?
1
2
3
4